MER DOMAIN TABLE OF CONTENTS

Hypothalamus & Pituitary Physiology/Anatomy..............................................................................2 Hypothalamus............................................................................................................................ 2 Pituitary...................................................................................................................................... 6 Hypothalamus & Pituitary Pathology............................................................................................. 15 Hypothalamus.......................................................................................................................... 16 Pituitary.................................................................................................................................... 16 Thyroid Physiology/Anatomy......................................................................................................... 20 Thyroid Pathology......................................................................................................................... 28 Parathyroid Physiology/Anatomy.................................................................................................. 41 Parathyroid Pathology................................................................................................................... 46 Adrenal Physiology/Anatomy........................................................................................................ 52 Adrenal Pathology......................................................................................................................... 5 !ale "eprodu#ti$e Physiology/Physiology....................................................................................%2 !ale &e' (rgan Pathology........................................................................................................... %5 )emale "eprodu#ti$e Physiology.................................................................................................. 82 *ormal +reast Anatomy & Physiology.....................................................................................82 ($arian Hormone Physiology.................................................................................................. 84 !enstraul ,y#le....................................................................................................................... 8% Physiology o- Pregnan#y.......................................................................................................... 8 Pla#ental Anatomy & Physiology............................................................................................. 1 )emale Pathology......................................................................................................................... 2 !enstraul ,y#le .isorders & /yne#ologi# Pathology.............................................................. 2 /yne#ologi# Pathology &enagore 0e#ture............................................................................... % Poly#ysti# ($arian &yndrome Arti#le.....................................................................................101 ($arian Pathology................................................................................................................. 106 Pla#ental Pathology............................................................................................................... 110 1ndo#rine Pan#reas Physiology/Anatomy..................................................................................112 1ndo#rine Pan#reas Pathology................................................................................................... 115 .ia3etes !ellitus................................................................................................................... 115 Pan#reati# *eoplasms........................................................................................................... 122 Adipose Tissue & (3esity........................................................................................................... 125 *utrition....................................................................................................................................... 142 +io#hemistry !eta3olism............................................................................................................ 154 /eneti#s...................................................................................................................................... 161

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HYPOTHALAMUS & PITUITARY PHYSIOLOGY Jeffs Sect !" H#$!t%&'&()s P%#s !'!*# 4 1. /eneral me#hanisms o- hormone a#tion 50ippin#ott6s 4th ed. p. 2407 +"& Phys 4th ed. p. 22682409: a. &teroid hormones di--use a#ross the plasma mem3rane o- target #ell 3inds #ytosoli# or nu#lear re#eptorre#eptor8ligand #omple' 3inds regulatory .*A se;uen#es 5hormone response element< H"19 $ia =in#8-inger moti- in nu#leus promoter a#ti$ation and trans#ription o- genes (" inhi3ition o- trans#ription and promoter ina#ti$ation. 3. Alternately< other hormones may 3ind #ell sur-a#e re#eptorsa#ti$ate /s or /i proteins 5/TP83inding proteins9 propagate signal $ia 2 potential 2nd messenger me#hanisms: i. Adenylyl #y#lase 5A,9 a#ti$ation#A!P produ#tionProtein >inase A 5P>A9 a#ti$ationphosphorylation o- spe#i-i# proteinsphysiologi# a#tion 1. #A!P is degraded 3y phosphodiesterase7 P.1 inhi3itors there-ore augment the a#tion o- #A!P. ii. (pening ,a?2 mem3rane re#eptors A*. #ausing release o- ,a?2 -rom 1",a?28#almodulin a#ti$ationphysiologi# a#tion iii. A#ti$ation o- phospholipase ,#lea$age o- mem3rane lipidsdia#ylgly#erol 5.A/9 and 1<4<58triphosphate 5@P29,a?2 release -rom 1"< a#ti$ation o- Protein >inase , 5P>,9protein phosphorylationphysiologi#al a#tion #. *(T1: / protein has A< B< C su3units. A su3unit determines i- inhi3itory or stimulatory7 / protein is ina#ti$e Dhen /.P is 3ound. cAMP (ec%&" s( IP3 (ec%&" s( Ste+! , H!+(!"e Ot%e+ (ec%&" s(s (ec%&" s( A,TH /n"H /lu#o#orti#oids A#ti$ation o- tyrosine Einase 0H and )&H T"H 1strogen @nsulin T&H /H"H Testosterone @/)81 A.H 5F2 re#eptor9 Angiotensin @@ Progesterone /H H,/ A.H 5F1 re#eptor9 Aldosterone #/!P !&H ('yto#in Fitamin . A*P ,"H A1 re#eptors Thyroid hormone 1.") B1 and B2 re#eptor *itri# o'ide ,al#itonin PTH /lu#agon 2. !eta3olism o- steroid hormones 50ippin#ott6s 4th ed. p. 2409: a. &teroid hormones are generally #on$erted into ina#ti$e meta3olites in the li$er: i. "edu#tion o- unsaturated 3onds< addition o- hydro'yl groups< #onGugation D/ glu#uroni# a#id or sul-ate 3. 20820H o- these meta3olites are se#reted in the 3ile/-e#es7 %0880H are released into the 3lood and -iltered in the Eidneys and e'#reted in the urine. 2. Anatomy 5"oades & +ell p.5 685 7 Pathophys. o- .isease< #hp. 1 9: a. The hypothalamus is lo#ated in the -loor and lateral Dalls o- the third $entri#le< 3eloD the hypothalami# sul#us and #omprises a3out 1H o- the mass o- the 3rain. 3. Hypothalami# nu#lei are #lusters o- neurons Dhose #ell 3odies lie in dis#rete regions. #. Hypothalami# neurons send proGe#tions 5either dire#tly or $ia neuronal relay9 to other parts o- the #entral and peripheral ner$ous systems and se#rete hormones< produ#ing hierar#hi#al #ontrol o- $arious physiologi# pro#esses.

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d. Hypothalami# "eleasing Hormones: H("!(*1 A,T@(*& 5on anterior pituitary9 ,orti#otropin8 ,"H is produ#ed 3y par$i#ellular neurons in the para$entri#ular nu#lei o- the releasing hormone hypothalamus: 5,"H9 o The a'ons o- par$i#ellular neurons terminate on #apillaries leading to "&+ p. 6018602 hypophyseal portal $essels 5ant. pituitary9< se#reting pre8-ormed +"& p. 2508251 ,"H granules D/ the appropriate neural stimulation. ,"H stimulates A,TH se#retion 3y #orti#otrophs: o ,"H 3inds re#eptors on #orti#otrophs/ protein stimulationadenylyl #y#lase a#ti$ated#A!P produ#tiona#ti$ates protein Einase A 5P>A9protein phosphorylationA,TH se#retion. ,"H stimulates e'pression o- P(!, gene in #orti#otrophs: o P(!, is A,TH prohormone7 replenishes supply o- se#reted A,TH7 o##urs due to in#reased #A!P. /lu#o#orti#oids pro$ide -eed3a#E inhi3ition on 3oth A,TH synthesis and se#retion. This #ontrol loop is #alled the hypothalami#8pituitary8adrenal a'is. o @nhi3its ,"H se#retion 5I le$el o- hypothalamus9 o @nhi3its A,TH se#retion 3y #orti#otrophs 5I ant. pituitary9

&tress in#reases A,TH se#retion $ia ,"H

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Thyrotropin8 releasing hormone 5T"H9 "&+ p. 6048605 +"& p. 246

&tress-ul stimulistimulation o- para$entri#ular nu#leiin#r. ,"H in#r. A,TH T"H is produ#ed in the hypothalamus< se#reted into #apillaries leading to hypophyseal portal $essels7 se#reted at a ,(*&TA*T rate. T"H stimulates T&H sec+et !" 3y thyrotrophs in ant. pituitary: o T"H re#eptor/ protein a#ti$.P0, #lea$es P@P2@P2?.A/ releasedin#r. ,a?2 and in#r. P>, a#ti$ityT&H se#retion &timulates e.$+ess !" o- genes -or alpha and 3eta su3units o- T&H in thyrotrophs 5to replenish supply9: o *ote: the alpha su3unit is the same -or T&H< )&H< and 0H7 the 3eta su3unit is di--erent< gi$ing them spe#ial physiologi# -'n. Thyroid hormone 5primarily T29 e'hi3its "e*&t /e fee,0&c1 on 3oth the hypothalamus6 release o- T"H and on the thyrotroph release o- T&H in the pituitary. o Thyroid hormone also #auses the release o- somatostatin 5&"@)9< Dhi#h inhi3its the release o- T&H -rom thyrotrophs. o

/roDth hormone8 releasing hormone 5/H"H9 "&+ p. 6068608

T"H also stimulates P"0 s#"t%es s 3y la#totrophs /H"H is s#"t%es 2e, in the #ell 3odies o- the Ar#uate nu#lei and Fentromedial nu#lei o- the hypothalamus: o 2 di--erent -orms e'ist< depending on hoD the prohormone Das #lea$ed. o The a'ons o- these neurons proGe#t to #apillaries tra$eling to the portal $essels 5ant. pituitary9< i.e. into hypophyseal portal system. /H"H stimulates /H se#retion 3y somatotrophs: o /H"H re#eptor/s proteinadenylyl #y#lasein#r. #A!Pin#r. protein Einase A 5P>A9proteins phosphorylated /H sec+et !" and /H *e"e e.$+ess !" o Also< /H"H re#eptorin#r. ,a?2in#r. /H se#retion o *(T1: somatostatin also 3inds /H"H re#eptors< 3ut uses a /i protein 5inhi3itory9< Dhi#h de#reases adenylyl #y#lase a#ti$ity< and loDers intra#ellular ,a?2 #on#entrationde#r. /H se#retion7 somatostatin has a .(!@*A*T e--e#t o$er /H"H.

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/onadotrophin8 releasing hormone 5/n"H9 "&+ p. 6%0 "&+ p. 688 +"& p. 265826%

*eurons that produ#e /n"H are lo#ated throughout the hypothalamus< Dith highest #on#entration in the medial 3asal hypothalamus 5regions o- ar#uate nu#leus and in-undi3ulum9. /n"H is se#reted into the hypothalami#8pituitary portal system ant. pituitary)&H and 0H s#"t%es s and +e'e&se 3y gonadotrophs. o /n"H #auses )&H and 0H se#retion through a phosphoinositide8 Protein >inase ,8mediated pathDay.

&omatostatin 5aEa somatotropin release inhi3iting -a#tor< &"@)9 .opamine

/n"H is se#reted in a $)'s&t 'e manner7 #ontinuous e'posure ogonadotrophs to /n"H results in desensiti=ation o- /n"H re#eptors. o The /n"H Jpulse generatorK may 3e intrinsi# to /n"H neurons. o The pulse generator is under negati$e -eed3a#E #ontrol 3y gonadal steroids 53oth testosterone and estradiol9 at the le$el o- the hypothalamus and pituitary. Pu3erty 5male and -emale9: o Pu3erty is initiated 3y the onset o- pulsatile /n"H release -rom the hypothalamus)&H and 0H are se#reted in pulsatile -ashion. o /n"H up8regulates its oDn re#eptor in the anterior pituitary. @nhi3its /H se#retion 3y somatotrophs7 @nhi3its T&H se#retion 3y thyrotrophs @*H@+@T& P"0 synthesis A*. se#retion 3y la#totrophs7 @*H@+@T& /n"H

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&erotonin 1pinephrine *orepinephrine

se#retion 3y gonadotrophs. @*H@+@T& se#retion o- /n"H &timulates se#retion o- /n"H &timulates se#retion o- /n"H

i. "eleasing hormones are se#reted in response to neural inputs -rom other areas o- the ,*& 5e.g. internal/e'ternal stimuli97 these pathDays are not Dell understood.

ii. P t) t&+# *'&", 8 1. Anatomy: 5"&+ p. 5 685

a. Pituitary gland A>A JHypophysisK< is #onne#ted to the hypothalamus 3y a stalE. 3. Pituitary gland is lo#ated at the 3ase o- the 3rain7 sits in a depression o- the sphenoid 3one o- the sEull< #alled the &ella Tur#i#a. #. ,omposed o- 2 morphologi#ally and -un#tionally distin#t glands 5Adenohypophysis $s. *eurohypophysis9: i. Adenohypophysis: 1. ,onsists o- Pars Tu3eralis 5outer #o$ering o- the pituitary stalE9 and Pars .istalis 5anterior lo3e9. 2. 1m3ryologi#ally< -ormed -rom e$agination o- oral e#toderm #alled the "athEe Pou#h. 2. Anterior pituitary hormones are synthesi=ed and se#reted in response to Hypothalami# "eleasing Hormones< Dhi#h are #arried to the anterior pituitary in high #on#entration $ia the Hypophyseal Portal ,ir#ulation: a. Thus< Anterior pituitary 5AP9 #ells are *(T inner$ated7 Hypothalami# "eleasing Hormones 5aEa Hypophysiotropi# hormones9 are synthesi=ed 3y neural #ell 3odies in the hypothalamusse#reted into #apillary netDorE in !edian 1minen#ein-undi3ular stem AP regulate se#retory a#ti$ity o- AP. 3. Anterior lo3e is made up o- #lusters o- histologi#ally distin#t #lusters o- CELLS< ea#h produ#ing a distin#t Anterior Pituitary Hormone. #. These #ells se#rete their hormones into 3lood sinusoids< Dhi#h drain into the $enous #ir#ulation: d. ,orti#otrophs Adreno#orti#otropi# Hormone 5A,TH< aEa #orti#otropin9

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e. Thyrotrophs Thyroid8&timulating Hormone 5T&H9 -. &omatotrophs /roDth Hormone 5/H9 g. 0a#totrophs Prola#tin 5P"09 h. /onadotrophs )olli#le8&timulating Hormone 5)&H9 i. /onadotrophs 0uteini=ing Hormone 50H9 ii. *eurohypophysis: 1. ,onsists o- !edian 1minen#e 5o- the hypothalamus9< the @n-undi3ular &tem 5inner part o- the stalE9 and @n-undi3ular Pro#ess 5posterior lo3e9. 2. 1m3ryologi#ally< -ormed -rom e'tension o- the de$eloping hypothalamus< and is there-ore #omposed o- neural tissue 5i.e. is a -un#tional part o- the hypothalamus< deri$ed -rom neural e#toderm9. 2. Hypothalami# neurons Dhose a'ons terminate in the Posterior lo3e synthesi=e Posterior Pituitary Hormones: a. The @n-undi3ular &tem #ontains 3undles o- *(*!L10@*AT1. NER6E FIBERS< Dhi#h terminate on the #apillary 3ed in the posterior lo3e. i. )i3ers originate in the supraopti# and para$entri#ular nu#lei o- the hypothalamus. ii. Are $ery large neurons< so are #alled !agno#ellular neurons. iii. Arginine $asopressin 5AFP< aEa A.H9 and o'yto#in are synthesi=ed as P"1,M"&("& 5prohormones9pa#Eaged in granules & en=ymati#ally pro#essed to AFP & o'yto#ingranules transported doDn a'ons to a'on terminals in posterior lo3ereleased into #apillary #ir#ulation 5D/ appropriate ,*& signal9systemi# #ir#ulation. i$. @ndi$idual neurons maEe 1@TH1" AFP or o'yto#in< 3ut *(T +(TH. $. The prohormones 5in addition to AFP or o'yto#in9 also en#ode -or *europhysins< Dhi#h are important in pro#essing and se#retion 5are #arrier proteins D/in neuron9. d. +lood &upply: i. &uperior Hypophyseal arteries#apillary netDorE in median eminen#e0ong Hypophyseal Portal $ein tra$eling doDn pituitary stalEanterior lo3e 5empty into 3lood sinusoids9. ii. @n-erior Hypophyseal arteriesposterior lo3e. iii. @n-erior Hypophyseal arteries&hort Hypophyseal Portal Fesselsanterior lo3e 5empty into 3lood sinusoids9. i$. *(T1: "eleasing hormones are se#reted in su#h small ;uantity that they are undete#ta3le in systemi# 3lood7 only enough to stimulate anterior pituitary se#retion.

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2. Physiology:

a. Hormones o- the Anterior/Posterior pituitary 5"&+ p. 5 86119: i. A"te+ !+ Pituitary: GH7 PRL7 TSH7 LH7 FSH7 ACTH ii. P!ste+ !+ Pituitary: A6P 8&1& ADH97 !.#t!c " H("!(*1 PHL&@(0(/@,A0 A,T@(* Arginine Fasopressin (riginates primarily in the supraopti# nu#lei o- the hypothalamus. 5AFP< aEa antidiureti# @n#reases rea3sorption o- Dater 3y the Eidneys 5prin#iple #ells o- #olle#ting hormone A.H9 du#ts9< Dhi#h is signaled 3y: o "ise in 3lood !s(!'&' t# "&+ p. 602 o .e#rease in 3lood /!')(e "&+ p. 411 o ,ate#holamines< angiotensin @@< atrial natriureti# peptide 5A*P9 +"& p. 244 "esults in de#reased Dater e'#retion< -ormation o- osmoti#ally #on#entrated urine 5dys-un#tiondia3etes insipidus9 F2 re#eptor/s proteinadenylyl #y#lase#A!PProtein Einase A a;uaporin82 insertion and synthesis. F1 re#eptor@P2/,a?2 pathDay a#ti$ation$aso#onstri#tion $as#ular &!. &light o'yto#in agonist. AFP #an stimulate #orti#otrophs to se#rete A,TH: o "e#eptor/ proteinphospholipase ,P@P2@P2 ? .A/in#r. ,a?2 in #ell< and a#ti$ation protein Einase , A,TH se#retion. )a#tors that increase A.H se#retion: in#r. serum osmolarity< $olume #ontra#tion< pain< nausea< hypogly#emia< ni#otine< opiates< antineoplasti# drugs. )a#tors that decrease A.H se#retion: de#r. serum osmolarity< ethanol< A8 agonists< A*P.

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('yto#in "&+ p. %208%21 +"& p. 2448245

(riginates primarily in the para$entri#ular nu#lei o- the hypothalamus. &timulates the #ontra#tion o- smooth mus#le in the mammary glands and uterus< Dhi#h is signaled 3y: o B+e&st fee, "*me#hani#al stimulation o- a--erent sensory ner$es in the nippleo'yto#in release myoepithelium #ontra#tion around milE8laden al$eolimilE eGe#tion. Ce+/ c&' , '&t !" D/ onset o- la3orstimulates #er$i#al stret#h

re#eptors in #er$i'a--erent signalo'yto#in release#ontra#tion osmooth mus#le in uterus 5aiding deli$ery9. &light AFP 5i.e. A.H9 agonist 5and $i#e8$ersa9. &u#Eling "e-le': ner$e stimulation in nipplea--erent ar#in#r. release oP"0< o'yto#in and A,TH< Dhile inhi3iting se#retion o- gonadotropins 5de#r. /n"Hano$ulation9. o *(T1: The sight/sound o- the in-ant #an stimulate o'yto#in release< e$en in the a3sen#e o- su#Eling. (rgasm #an also #ause this. A,TH is synthesi=ed as a prohormone #alled Proopiomelano#ortin 5P(!,97 it is en=ymati#ally #lea$ed in the anterior pituitary< @*&@.1 the se#retory granule. A,TH stimulates produ#tion o- glu#o#orti#oids 5c!+t s!' and c!+t c!ste+!"e ;mostly in =ona -as#i#ulata9 and androgens 5,e%#,+!e$ &",+!ste+!"e; mostly in =ona reti#ularis9 3y adrenal #orte': o *ote: aldosterone is se#reted 3y =ona glomerulosa. @t is under toni# #ontrol 3y A,TH< 3ut is separately regulated 3y renin8angiotensin system and >?. o A,TH promotes e'pression o- genes -or en=ymes in$ol$ed in steroidogenesisregulates synthesis o- steroid hormones. A,TH 3inds melano#ortin82 re#eptor/s protein#A!PProtein >inase A phosphorylated proteins. o e.g. steroidogeni# a#ute regulatory protein 5&tA"9 phosphorylation #holesterol trans-er into mito#hondriasteroidogenesis. o A,TH in#reases the N o- 0.0 re#eptors and the a#ti$ity o- H!/8,oA redu#tase in these #ells< in#reasing #holesterol -or steroidogenesis. A,TH "c+e&ses steroid hormone synthesis in all =ones o- the adrenal #orte'< 3y stimulating #holesterol desmolase and in#reasing the #on$ersion o#holesterol to pregnenolone. A,TH maintains the si=e o- =ona -as#i#ulata and =ona reti#ularis o- #orte'. A,TH is a Jtropi#K/Ktrophi#K hormone. *(T1: upon #lea$age o- P(!,< a small amount o- a8melano#yte8stimulating hormone is released. This hormone #auses the dispersion o- melanin granules in pigment #ells. This is the reason Dhy people D/ high 3lood le$els o- A,TH 5e.g. Addison6s d=9 are hyperpigmented. Arginine $asopressin 5AFP9 #an stimulate A,TH se#retion o AFP re#eptor a#ti$ationphospholipase ,inositol triphosphate 5@P29 ? dia#ylgly#erol 5.A/9in#r. ,a?2 and protein Einase , a#ti$ationA,TH se#retion A,TH up8regulates its oDn re#eptor so that the sensiti$ity o- the adrenal

Adreno#orti#otropin hormone 5A,TH< #orti#otropin9 "&+ p. 6008604 "&+ p. 6228624 +"& p. 2488255

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#orte' to A,TH is in#reased. ,ortisol "% 0 ts the se#retion o- ,"H -rom hypothalamus and A,TH -rom anterior pituitary 5negati$e -eed3a#E9. .e'amethasone suppression test88A3ility o- syntheti# glu#o#orti#oid to inhi3it/suppress A,TH se#retion: o *ormal person: loD8dose de'amethasones)$$+ess !". A,TH8se#reting tumor: loD8doseno response7 high8dose s)$$+ess !". o Adrenal #orti#al tumor: N! +es$!"se D/ either loD or high dose. A,TH se#retion e'hi3its diurnal $ariation 5pulsatile9< D/ se$eral pulses o$er a 24 hr period 5loDOe$ening< highO early morning97 -olloD #ir#adian rhythm< so may #hange Dith #hange in sleep pattern. T&H is a gly#oprotein synthesi=ed -rom 2 stru#turally di--erent su3units 5alpha and 3eta9. 5The alpha su3unit is identi#al to that o- 0H and )&H7 only the 3eta su3unit is uni;ue9. T&H stimulates produ#tion o- thyroid hormones 5thyro'ine T4 and triiodothyronine T29< 3y thyroid -olli#ular #ells: o E/e+# ste$ in synthesis o- thyroid hormones is stimulated 3y T&H. o T&H promotes nu#lei# a#id and protein synthesis D/in thyroid -olli#les< maintaining #ell s 2e< f)"ct !"7 and st+)ct)+e. o *(T1: T2 also -eed3a#E8inhi3its T&H se#retion $ia gene alterations< and de#reases thyrotroph sensiti$ity to T"H. T&H is a Jtropi#K/Ktrophi#K hormone. o T&H re#eptor/s proteinadenylyl #y#lase#A!PProtein >inase A o o stimulates synthesis o- *@& and uptaEe o- iodide 3y -olli#ular #ells stimulates pino#ytosis o- #olloid 3y api#al mem3ranes and in#reases endo#ytosis and hydrolysis o- thyroglo3ulinin#r. T2< T4 released into the 3lood. in#reases energy meta3olism in thyroid -olli#ular #ells.

Thyroid8stimulating hormone 5T&H< thyrotropin9 "&+ p. 6048605 "&+ p. 61%8618 +"& p. 2458248

/roDth hormone 5/H9 "&+ p. 6058608 +"& 2418242

T&H se#retion e'hi3its , )+"&' /&+ &t !"= o PeaEs in early morning< loD in e$ening. T&H se#retion is in#reased Dith e'posure to c!',= o Thyroid hormones are important in regulating 3ody heat produ#tion. o This o##urs in neD3orns< 3ut *(T adults. Produ#ed 3y &omatotrophs o- the ant. pituitary: o Produ#ed as a prohormone< 3ut is pro#essed to /H +1)("1 3eing pa#Eed into granules. P+!,)ct !" o- /H is regulated 3y +(TH /H"H and thyroid hormone. o There-ore< a thyroid hormone de-i#ient person is also /H de-i#ient. Sec+et !" o- /H is regulated 3y +(TH /H"H and &omatostatin 5hypothalami# #ontrol9: o /H"HOstimulatory< &omatostatinOinhi3itory 5inhi3its /H"H at Ant. pituitary97 result depends on Dhi#h hormone predominates. Sec+et !" o- /H is also regulated 3y +(TH /H and @/)8@ 5-eed3a#E inh9: o /H -eed3a#E8 "% 0 ts /H"H se#retion< Dhi#h results in less /H se#retion

Page 1> o- 173

@/)8@ 5aEa &omatomedin9 -eed3a#E8 "% 0 ts /H"H se#retion< st ()'&tes somatostatin release< and also "% 0 ts /H release dire#tly at Ant. pit. 1motional/physi#al st+ess< $igorous physi#al e.e+c se also stimulate /H se#retion 3y in#reasing /H"H release. O0es t# de#reases /H release. H#$!*'#ce( & Pe.g. star$ationQ stimulates /H release< %#$e+*'#ce( & inhi3its /H release. /H stimulates trigly#eride lipolysis mo3ili=ation o- trigly#erides -rom -at depots o- the 3ody o !o3ili=es Hormone8sensiti$e lipasehydrolysis o- trigly#erides o -atty a#ids ? gly#erol. /H @nhi3its insulin a#tion on mus#le< adipose< li$er: o @nhi3its glu#ose use 3y mus#le/adipose7 in#reases glu#ose produ#tion 3y li$er. o !aEes mus#le/-at #ells +es st&"t t! "s)' ". o !ay lead to hypergly#emia 5/lu#. o$erprodu#tion/underuse9 OKdia3etogeni# a#tionK o *(T1: /H has t+&"s t!+# "s)' "?' 1e effect on /H8de-i#ient people 5in#r. /lu use 3y mus#le/adipose< de#r. li$er synth.9 /H e'hi3its a $)'s&t 'e se#retory pattern: o Periodi# 3ursts< short8li$ed< o##urring +(TH at night and during day 5'&+*e+ 3ursts at " *%t Pe.g. sleepQ9. o Thought to 3e due to #hanges in somatostatin le$els. /H stimulates $!st"&t&' 3ody *+!@t% and (et&0!' s(< i.e. #hildhood/adoles#en#e 5*(T -etal groDth97 /H remains important e$en a-ter groDth has stopped< 3ut le$els de#line Dith age. o /H stimulates produ#tion o- insulin8liEe groDth -a#tor @ 5@/)8@9 in the li$er< Dhi#h is a potent ( t!*e". o /H 3inding to re#eptorsa#ti$ates tyrosine Einase 5RA>29 o phosphorylation o- proteinstrans#ription o- genes 5e.g. @/)8@9. /H has dire#t groDth8promoting a#tions on stem #ells 5e.g. pre#hondro#ytes in 3one< or satellite #ells in sEeletal mus#le9 di--erentiate into #ells produ#ing @/)8@para#rine or auto#rine se#retion @/)8@lo#al tissue groDth 5#ell repli#at.9. Also< /Hin#r. protein synth in organsin#r. organ si=e 5e.g. in#r.

)olli#le8stimulating hormone 5)&H9 "&+ p. 6108611 "&+ p. 6%086%2 "&+ p. 68886 4 +"& p. 265

protein in mus#lein#r. lean mus#le mass9 o .e-e#ti$e /H se#retion/re#eptorOdDar-ism7 e'#essi$e /HOgigantism 5#hildhood9 or a#romegaly 5adulthood9. *(T a tropi#/trophi# hormone 53/# target organ is *(T other endo#rine gland9 !A01 )&H regulates spermatogenesis in testes< 3inding &ertoli #ells o- testes. o &ertoli #ells are lo#ated D/in the semini-erous tu3ules. o / protein#A!PProtein >inase Aa#ti$ation o- trans#ription -a#tors 5e.g. steroidogeni# -a#tor81 P&)81Q or #A!P response element 3inding protein P,"1+Q9 steroidogeni# en=yme produ#tion estradiol produ#tion

Page 11 o- 173

Testosterone -rom 0eydig #ells 50H me#hanism9 a#t in a para#rine -ashion to promote spermatogenesis in &ertoli #ells. )&H is a Jtropi#K/Ktrophi#K hormone. ,omposed o- 2 di--erent su3units: alpha and 3eta. o The su3units must 3e #om3ined in a 1:1 ratio -or a#ti$ity. o The )&H and 0H &'$%& su3unit is ,e"t c&'7 0et& su3unit is , ffe+e"t< and is the rate8limiting step in hormone synth. o )&H and 0H may 3e produ#ed in the same or distin#t gonadotrophs. )&H< M*0@>1 /n"H and 0H< is "!t &'@&#s e'#reted in a $)'s&t 'e -ashion7 )&H pulses are also smaller< 3/# )&H has a longer hal- li-e than 0H in #ir#ulation. )&H release in males is regulated 3y Testosterone< estradiol< inhi3in< a#ti$in< and -ollistatin. o Testosterone< estradiol< inhi3in and -ollistatin "% 0 t )&H se#retion< Dhile A#ti$in st ()'&tes )&H se#retion. o @nhi3in a#ts dire#tly on the anterior pituitary to inhi3it )&H se#retion o 53ut not 0H9. &ertoli #ells se#rete inhi3innegati$e -eed3a#E. A#ti$in is produ#ed 3y &ertoli #ells & stimulates )&H se#retion7 )ollistatin is produ#ed 3y &ertoli #ells and 3inds and dea#ti$ates a#ti$in de#r. )&H se#retion.

)1!A01& )&H stimulates de$elopment/groDth o- o$arian -olli#les. Along Dith 0H< )&H regulates -olli#ular steroidogenesis and androgen and estradiol se#retion. )&H a#ts on granulosa #ells to in#rease mitosis and #ell proli-eration< stimulate progesterone synthesis< a#ti$ate aromatase< in#rease inhi3in synthesis< and as the -olli#le matures stimulate -ormation o- 0H re#eptors on granulosa #ells. )&H is inhi3ited 3y o$arian steroids< e'#ept Gust prior to o$ulation< Dhen a surge in estradiol #auses a positi$e -eed3a#E loop to in#rease le$els o- /n"H< )&H and 0H. o )&H is also inhi3ited 3y o$ary se#retion o- inhi3in< and -ollistatin< and in#reased 3y a#ti$in 5an inhi3in83inding protein9.

Page 1- o- 173

TDo8#ell< tDo8gonadotropin hypothesis: )&H is restri#ted to granulosa #ells 3/# all other o$arian #ell types la#E )&H re#eptors. 0H a#tions are e'erted on the#a< granulosa< stromal 5interstitial9 #ells and the #orpus luteum. o Aromatase is e'pressed only in granulosa #ells< and )&H regulates its a#ti$ation and indu#tion.

0uteini=ing hormone 50H9 "&+ p. 6108611 "&+ p. 6%086%2< 6%8 "&+ p. 68886 4

!A01& &timulates testosterone produ#tion 3y 0eydig #ells o- testes. o 0eydig #ells reside in interstitium o- testes< 3etDeen semini-erous tu3ules. o 0H re#eptor/ protein#A!PProtein >inase Aa#ti$ation otrans#ription -a#tors 5e.g. steroidogeni# -a#tor81 P&)81Q or #A!P response element 3inding protein P,"1+Q9 steroidogeni# en=yme produ#tion testosterone $+!,)ct !" o .uring the pro#ess< #holesterol esterase is phosphorylated< Dhi#h releases #holesterol -rom its intra#ellular stores7 also< ,LP11A1 is a#ti$ated7 +(TH play a maGor role in stimulating steroidogenesis. o Phosphodiesterase ina#ti$ates #A!PA!P7 it is stimulated 3y gonadotropinsde#r. response to 0H. 0H< liEe /n"H< is released in a $)'s&t 'e -ashion 5$s. )&H9. 0H is a Jtropi#K/Ktrophi#K hormone. ,omposed o- 2 di--erent su3units: alpha and 3eta. o The su3units must 3e #om3ined in a 1:1 ratio -or a#ti$ity. o The )&H and 0H alpha su3unit is identi#al7 3eta su3unit is di--erent< and is the rate8limiting step in hormone synth. o )&H and 0H may 3e produ#ed in the same or distin#t gonadotrophs. 0H release in males is regulated 3y Testosterone< estradiol. o Testosterone< estradiol< redu#e 0H se#retion Testosteronede#reases /n"H se#retion and redu#es gonadotroph sensiti$ity to /n"H 5redu#es 0H re#eptors9. o 1stradiolde#reases /n"H se#retion. *(T1: 0eydig #ells also ha$e re#eptors -or P"0. This may inter-ere Dith 5pathologi#al #onditions9 or a#t synergisti#ally 5normal #onditions9 Dith 0H to stimulate testosterone produ#tion 3y in#reasing the num3er o- 0H re#eptors. )1!A01& 0H #auses o$ulation and -ormation o- #orpus luteum 5o- o$ulated /raa-ian -olli#le9 in o$aries. o

Page 13 o- 173

Along Dith )&H< 0H regulates -olli#ular steroidogenesis and androgen and estradiol se#retion7 LH is s$ec f c f!+ progesterone 5P9 synthesis. *(T1: 1strogen 519 up8regulates 0H re#eptors 5also 1 and P re#eptors9. *egati$e and Positi$e -eed3a#E #ontrol 5on 0H/)&H9 o- the !enstrual #y#le: P%&se !f (e"st+)&' H!+(!"e T#$e !f fee,0&c1As te c#c'e )olli#ular 1strogen *egati$e7 A pituitary !id#y#le 1strogen Positi$e7 A pituitary 0uteal 1strogen *egati$e7 A pituitary Progesterone *egati$e7 Hypothalamus

Prola#tin 5P"09 "&+ p. 611 "&+ p. %208%21 +"& 2428244< 2%1

+(TH @n c% ',%!!,< hormone le$els are loDest and )&HS0H. At $)0e+t# and during the +e$+!,)ct /e #e&+s< hormone le$els in#rease and 0HS)&H. @n se"esce"ce< hormone 'e/e's are % *%est and )&HS0H. P"0 is se#reted 3y la#totrophs in the anterior pituitary. 1strogens and T"H increase e.$+ess !" o- P"0 gene and stimulate s#"t%es s and sec+et !" o- P"0. .opamine toni#ally inhibits the s#"t%es s o- P"0. o P"0 inhi3its its oDn release 5-eed3a#E inhi3ition9 3y stimulating .opamine se#retion in the hypothalamus. .uring pregnan#y< ele$ated progesterone &"t&*!" 2es the a#tions o- P"0 and $+e/e"ts -ull '&ct&t !". P"0 is essential -or ( '1 $+!,)ct !" 3y la#tating mammary glands. o P"0 promotes la#togenesis< mammary #ell , / s !" & , ffe+e"t &t !" 5i.e. 3reast de$elopment9< and in#reased s#"t%es s omilE #onstituents 5e.g. #asein< la#tal3umin9. P"0 is *(T a tropi#/trophi# hormone 53/# target organ is *(T other endo#rine glands9. ($ulation is suppressed as long as la#tation #ontinues 3/# P"0 has the -olloDing e--e#ts: o @nhi3its hypothalami# /n"H se#retions. o @nhi3its the a#tion o- /n"H on the anterior pituitary 5thus inhi3iting 0H/)&H se#tion9. o Antagoni=es the a#tion o- 0H and )&H on the o$aries. P"0 has #onsidera3le s ( '&+ t# to /H< and to human Pla#ental 0a#togen

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5hP09 Dhi#h is produ#ed 3y the pla#enta. o /H has signi-i#ant la#togeni# 5P"08liEe9 a#ti$ity7 hoDe$er< P"0 and hP0 ha$e little /H8liEe a#ti$ity. &u#Eling "e-le': ner$e stimulation in nipplea--erent ar#in#r. release oP"0< o'yto#in and A,TH< Dhile inhi3iting se#retion o- gonadotropins 5de#r. /n"H se#retionano$ulation9. o *(T1: P"0 #an also "% 0 t s$e+(&t!*e"es s in males 3y de#r. /n"H. )a#tors that "c+e&se prola#tin se#retion: 1strogen 5pregnan#y9< 3reast8 -eeding< sleep< stress< T"H< .opamine antagonists. )a#tors that ,ec+e&se prola#tin se#retion: .opamine< somatostatin< prola#tin 5neg. -eed3a#E9.

HYPOTHALAMUS & PITUITARY PATHOLOGY D&"s Sect !" Pathology o- the HPA A'is (Note: see the adrenal portion of Dans section below) " O "o33ins %th 1d.7 ! O !#Phee Pathophys. te't3ooE 5note< @ printed these #hapters -rom !#Phee -rom o-- the #omputer< so @ don6t ha$e JrealK page num3ers to re-eren#e to7 @ re-eren#e the #hapter N instead7 sorry9 #p O #oursepa#E 5*ote7 (!st c$ "f! s 0!',e,9 Ge"e+&' P+ "c $'es !f t%e HPA A. s 8c$3359 1. ,lini#al testing o- the HPA A'is: *ote< some o- these #on#epts Dill 3e re$isited in this re$ieD 5see adrenal path 3eloD9 a. .e'amethasone Test: Msed to determine Dhether the HPA a'is is inta#t7 potent #ortisol analogue

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i. *ormally< de'amethasone Dill #ause a de#rease in ,"H and A,TH de#reased #ortisol ii. @- #ortisol doesn6t drop< then a pro3lem e'ists someDhere in the HPA a'is 3. A,TH &timulation Test: /i$e A,TH ,ortisol should in#rease i. *o in#rease in #ortisol O Adrenal #orte' dys-un#tion/destru#tion #. @nsulin8@ndu#ed Hypogly#emia: &hould stimulate #ortisol i. @nsulin8indu#ed hypogly#emia sensed 3y hypothalamus as stress ,"H released ii. ,"H release A,TH release ,ortisol release iii. @- no #ortisol release< then a pro3lem e'ists someDhere in HPA a'is d. !etyrapone: *ormally inhi3its 118hydro'ylation< last step in #ortisol 3iosynthesis i. *ormal: Administer metyrapone a#ute #ortisol de-i#ien#y ,"H and A,TH release 5$ia negati$e -eed3a#E9 118deo'y#ortisol a##umulates 5sin#e #an6t #on$ert to #ortisol9 ii. @- high le$els o- 118deo'y#ortisol< then HPA a'is inta#t iii. @- no in#rease o- 118deo'y#ortisol< then pro3lem someDhere in HPA a'is H#$!t%&'&( c P&t%!'!*# 8M c%B 1<9= 1. (3esity 5! 129: 0eptin or leptin re#eptors mutations #an #ontri3ute to hypothalami# role in o3esity a. 0eptin resistan#e seems more #ommon than leptin resistan#e 3. 0eptin a#ts on hypothalami# re#eptors to help person -eel -ull 5helps person eat less9 and in#reases &*& 5to help 3urn more #alories9 #. &ee separate Adipose tissue and (3esity se#tion -or more detail 2. H#$!t%&'&( c S)$+&se''&+ T)(!+s 8R11537 c$3719= a. C&" c&)se %#$e+? !+ %#$!f)"ct !" !f $ t) t&+#7 D &0etes I"s $ ,)s7 $!!+ *+!@t%7 (&ss effect 3. !ost #ommon tumors are gliomas and #raniopharyngiomas #. ,raniopharyngiomas: O+ * "&te f+!( R&t%1es $!)c%C !fte" c#st c7 sD)&(!)s7 2 $ariants i. Adamantinomatous: &hoDs c&'c f c&t !"sC same tissue type as teeth 1. &hoD JDet Eeratin:K #ompa#t lamellar Eeratin 2. .ystrophi# #al#i-i#ation #ommon 2. ,ysts -illed D/ E(&c% "e+# ! 'F< a thi#E 3roDn8yelloD #holesterol -luid ii. Papillary: "arely en#ountered7 la#E #ysts< Eeratin< and #al#i-i#ation d. /lioma: (riginate -rom !$t c c% &s( e. S#($t!(s: -. 1pidemiology: Typi#ally 3etDeen 5 4 15 years and S 50 years g. 1'#ellent prognosis< 3ut tumors #an re#ur i- S 5 #m P t) t&+# P&t%!'!*# 8M c%B 1<7 c$3539 2. Ge"e+&' P t) t&+# A"&t!(# I"f! 8c$35-9= a. Anterior 0o3e: "athEe6s pou#h origin7 80H o- gland7 portal $ein system i. A#idophili#: L&ct!t+!$%s &", s!(&t!t+!$%s JmilE helps you groDK7 #ells stain red ii. +asophili#: T%#+!t+!$%s7 c!+t c!t+!$%s7 *!"&,!t+!$%s7 #ells stain purple iii. ,hromopho3es: .on6t stain a #olor 3. Posterior 0o3e: *eurohypophysis7 doDngroDth o- hypothalamus7 arterial/$enous supply i. M!, f e, *' &' ce''s &", &.!"&' $+!cesses o- hypothalamus ii. Hormones: A.H and ('yto#in 4. /eneral Pituitary Pathology @n-o 5#p4649: a. Anterior Hyperpituitarism: Typi#ally #aused 3y: i. F)"ct !" "* &,e"!(& ii. H#$e+$'&s & iii. N!"?$ t) t&+# t)(!+s

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i$. H#$!t%&'&( c , s!+,e+s 3. Anterior Hypopituitarism: Typi#ally #aused 3y: i. Dest+)ct !" 8(!st c!((!" c&)se9= S)+* c&'7 t+&)(&t c7 !+ +&, &t !" ii. I"f'&((&t !" !+ %e(!++%&*e iii. N!"?f)"ct !" "* t)(!+ #. Posterior Pathology= M&" feste, 0# c%&"*es " ADH sec+et !" d. 0o#al !ass 1--e#ts o- Pituitary .isorders= i. R&, !*+&$% c se''& t)+c c& c%&"*es= 1. &ellar e'pansion 2. +one erosion 2. .iaphragma sella disruption ii. 6 s)&' F e', Defects 1. (pti# ner$e/#hiasm #ompression 2. +itemporal hemianopsia iii. I"c+e&se, ICP= Heada#he< nausea< $omiting i$. Ac)te He(!++%&*e: Pituitary apople'y 5. Pituitary Adenoma 5! 12< "1158< #p4659: +enign tumor o- epithelial #ell origin 7 t#$ c&''# &"te+ !+ '!0e a. /eneral @n-o: i. &in#e pituitary in en#losed spa#e< these tumors #an #ause mass e--e#ts ii. C&" c&)se %!+(!"e %#$e+sec+et !" !+ %#$!sec+et !" 1. F)"ct !"&' T)(!+= H!+(!"e sec+et "* 2. N!"?f)"ct !"&' t)(!+= N!"?sec+et "*C ,&(&*e / & (&ss effects 2. C&"t ,ete+( "e f)"ct !"&' st&t)s / & % st!'!*#C ()st c%ec1 se+)( 'e/e's f!+ %!+(!"e effects iii. +asophili# Adenoma: N! +et c)' " "et@!+1 3. /ross and !i#ros#opi# !orphology 5#p4669: i. !i#ro 5T1 #m9 $s !a#ro 5S1 #m9 ii. &o-t< #ir#ums#ri3ed tumors iii. J@n$asi$eK adenomas are not en#apsulated< and ,! "!t (est&st&s 2e 1. Mest&st&s s G $ t) t&+# c&+c "!(& i$. U" f!+(7 $!'#*!"&' ce''s @ t% NO +et c)' " "et@!+1 &", +&+e ( t!ses $. #. Pathophys/1tiology: Adenomas #an arise -or any spe#i-# pituitary #ell type. i. &pe#i-i# #ell8type tumors #ause di--erent pathophysiologi# e--e#ts. ii. !ost pituitary adenomas are mono#lonal iii. /8protein mutations are the 3est8#hara#teri=ed mole#ular a3normalities in these tumors 1. M)t&t !" !cc)+s " t%e GNAS1 *e"e 2. Primarily in$ol$es s!(&t!t+!$%s &", c!+t c!t+!$%s 2. !utation in alpha8su3unit #onstituti$ely a#ti$ates the g8protein persistent #A!P generation )"c%ec1e, ce'')'&+ $+!' fe+&t !" i$. (ther /eneti# #ontri3utions 5#p4659: 1. !1*@*< ,.>*13< P">A"@A< A@P< and /*A&1 gene mutations in#rease risE o- tumor 2. !1*@*: Tumor suppressor that #ontri3utes to !ultiple 1ndo#rine *eoplasia Type 1 syndrome 5!1*8197 o##urs on #hromosome 11 2. !ultiple 1ndo#rine *eoplasia #ommon D/ these tumors 4. Ce'' c#c'e c%ec1$! "t ()t&t !"s: "esult in $ery aggressi$e tumors a. p52< ,y#lin .1 on#ogene< retino3lastoma< H"A& on#ogene $. Tumors de$elop in a similar multi8step pro#ess as #olon #an#ers d. ,lini#al: i. +itemporal Hemianopia: ,ommon mass e--e#t7 tumor en#roa#hes on opti# #hiasm ii. (ther mass e--e#ts: Heada#he< hydro#ephalus< #ranial ner$e palsy< #ere3rospinal -luid rhinorrhea< temporal lo3e epilepsy

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iii. @n-ar#tion or hemorrhage into e'panind mass: ,an destroy normal pituitary gland 6. Hyperprola#tinemia 5! #h 1 < "1160< #p46%9: M!st c!((!" &"te+ !+ $ t) t&+# , s!+,e+7 many #auses. a. Prola#tinoma: !ost #ommon pituitary adenoma 520H97 adenoma o- la#totrope #ells i. P+!'&ct "!(&s )",e+*! ,#st+!$% c c&'c f c&t !" 3. (ther #auses: i. P+e*"&"c#: Prola#tin in#reases throughout pregnan#y< peaEing at deli$ery ii. St&'1 Effect: !ass in suprasellar #ompartment distur3s normal inhi3ition ohypothalamus on prola#tin se#retion. iii. Hyperthyroidism or dopamine8re#eptor 3lo#Eing drugs i$. .opamine is negati$e -eed3a#E on prola#tin7 no dopamine O e'#essi$e prola#tin #. 1--e#ts o- prola#tinemia: A(e"!++%e& 5prola#tin inhi3its /n"H release9< *&'&ct!++%e&< loss o- li3ido< and in-ertility. d. Treatment: B+!(!c+ $t "e 5dopamine agonist9 or surgery %. /H Adenoma 5! #h 1 < "11619: 2nd most #ommon pituitary adenoma7 #auses gigantism or a#romegaly a. 1'#essi$e /H st ()'&tes (!+e IGF?1 5insulin8liEe groDth -a#tor97 @/)81 has insulin8liEe e--e#ts that #auses tissue to store -uel and -a#ilitates groDth 3. 3>H %&/e G?$+!te " ()t&t !" #. /igantism: Occ)+s 0ef!+e e$ $%#ses c'!se d. A#romegaly: Occ)+s &fte+ e$ $%#ses c'!se e. Tumors may de$elop -or years 3e-ore #lini#ally apparent -. (ther symptoms: DM< CHF< mus#le DeaEness< higher risE o- /@ #an#er< gonadal dys-un#tion g. .iagnosis= F& ')+e t! s)$$+ess GH " +es$!"se t! !+&' *')c!se '!&, h. Treatment: "emo$e tumor surgi#ally< use radiation< or drug therapy 8. A,TH Pituitary Adenoma 4 C)s% "*s Disease 5! #h 1 < "1162< #p4689: ,ause o- ,ushing6s syndrome a. 8' more liEely in men than Domen 3. H#$e+sec+et !" !f ACTH 0# $ t) t&+# t)(!+C t)(!+s te", t! 0e s(&'' #. !ust distinguish these tumors -rom e--e#ts #aused 3y other sour#es o- high A,TH or ,"H i. .istinguish -rom high ,"H release -rom hypothalamus ii. .istinguish -rom A,TH releasing tumors o- adrenal gland d. &ymptoms #om3ination o- tumor mass e--e#t A*. e--e#ts o- o$erprodu#tion o- #ortisol 3y adrenals i. Hyperpigmentation o##urs due to e'#essi$e A,TH 5Dhi#h a#ts on melano#ytes9 e. *elson6s &yndrome: "apid progression o- A,TH8se#reting pituitary adenoma< o-ten -olloDing 3ilateral adrenale#tomy to #ontrol hyper#ortisolism. . (ther Pituitary Adenomas 5"11629 a. /onadotroph adenomas: !ost #ommon in middle8aged men and Domen< Dhen they 3e#ome large enough to #ause neurologi# symptoms i. ,an #ause de#reased energy and li3ido in men< and amenorrhea in Domen ii. P&+&,!. c&''# c&)se *!"&,&' %#$!f)"ct !" 3. Thyrotroph Adenomas 5"11629: "are< less than 1H o- pituitary adenomas i. S#($t!(s !f %#$e+t%#+! , s( 0)t @ t% & "!+(&' t%#+! , #. *on-un#tioning adenomas 5"11629: Typi#ally present D/ mass e--e#t7 #an a#tually #ause hypopituitarism 3y destroying healthy pituitary d. Pituitary ,ar#inomas 5"11629: Fery rare7 re;uires diagnosis o- metastasis to other organs. 10. Hypopituitarism 5! #h 1 < "1162< "46 9: 0oss o- one or more pituitary hormones a. Panhypopituitarism: 0oss o- all pituitary hormones 3. 1tiology/,auses o- hypo8pit.: 74H !f $&+e"c%#(& ()st 0e '!st 0ef!+e %#$!f)"ct !" !cc)+s

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i. EH#$!$ t) t&+ s( &cc!($&" e, 0# e/ ,e"ce !f $!ste+ !+ $ t) t&+# ,#sf)"ct !" 8 BeB , &0etes "s $ ,)s9 s &'(!st &'@&#s !f %#$!t%&'&( c !+ * "BF ii. Tumors: Any sella tumor #an damage pituitary 3y #ompression iii. Pituitary surgery or radiation7 3oth #an destroy pituitary i$. S)0&+&c%"! , %e(!++%&*e $. P t) t&+# A$!$'e.#: S),,e" %e(!++%&*e "t! $ t) t&+# 1. Uill #ause sudden heada#he< diplopia 2. ,an #ause death true neurosurgi#al emergen#yV $i. Traumati# head inGury & disruption o- pituitary stalE : 0oss o- hypothalami# stimulation 1. Fasopressin de-i#ien#y Dill also o##ur 2. &ymptoms may impro$e through time as stalE #onne#tions to hypothalamus are re3uilt 2. Prola#tin se#retion is *(T 0(&T7 sin#e prola#tin is inhi3ited 3y hypothalami# release o- dopamine< the negati$e regulation is lost7 $+!'&ct " (&# "c+e&seI $ii. &heehan6s &yndrome: P!st$&+t)( "ec+!s s o- anterior pituitary 1. pituitary enlarges during pregnan#y< 3ut $as#ulature to pituitary doesn6t in#rease7 is#hemia then results 2. Posterior pituitary is typi#ally spared< sin#e has 3etter 3lood supply $iii. E($t# Se''& S#",+!(e= 1nlarged< empty sella tur#i#a not -illed D/ pituitary tissue 1. Primary: .e-e#ti$e diaphragma sella< alloDing ,&) to herniated into sella 2. &e#ondary: A mass taEes up sellar spa#e< 3ut is then remo$ed< lea$ing a spa#e #. Pathophys: ,hara#teri=ed 3y loD le$els o- pituitary hormones D/ loD le$els o- end8organ produ#ts o- the HPA a'is. i. This helps di--erentiate -rom end8organ -ailure in HPA a'is ii. ,onsider that one Dould normally e'pe#t loD pituitary hormones D/ H@/H end8 organ produ#ts o- the HPA a'is 1. &imilarly< end8organ -ailure normally results in #ompensatory high le$els o- the rele$ant pituitary hormones. d. ,lini#al ,onsideration: &igns and symptoms $ary on e'tent o- disease< type o- hormone loss i. 0oss o- hormones o##urs in a stepDise -ashion: 1. GH J FSH J LH J TSH J ACTH ii. A#ute panhypopituitarism 5as in stalE transe#tion< or hemorrhage9: 2 -atal #onditions #an o##ur: 1. Pt #an6t mount stress reponse to e$en small stress-ul stimuli 5sin#e no glu#o#orti#oid se#retion97 stress e$ents #an pro$e lethal 2. .ia3etes @nsipidus: @- patient #an6t #ompensate -or resulting dia3etes insipidus 5sin#e loss o- $asopressin o##urs9 3y more Dater intaEe< pt Dill ;ui#Ely 3e#ome #omatose as a result o- Dater loss< hyperosmolarity< and dehydration. iii. &ymptoms may de$elop sloDly: amenorrhea and ere#tile dys-un#tion 5loD )&H/0H se#retion7 lethargy 5due to loD T&H 11. Posterior Pituitary Pathology 88 .ia3etes @nsipidus 5! #h 1 < "1162< #p4%09 : a. .ia3etes @nsipidues 5.@9: Poor $asopressin/A.H a#tion< #ausing $!'#)+ & and %e&/ '# , ')te urine 3. ,entral .@: *o synthesis o- A.H 3y posterior pituitary i. ,ommonly #aused 3y head trauma 5stalE transe#tion9< intra#ranial tumor 5#raniopharyngioma9< and post8surgi#al state #. *ephrogeni# .@: >idney doesn6t respond to #ir#ulating A.H i. ,an 3e -amilial or a#;uired

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1. )amilial nephrogeni# .@ #aused 3y de-e#ts in either 19 F2 #lass o$asopressin re#eptors< or 29 a;uaporin82 #hannels. 2. A#;uired d= typi#ally #aused 3y drugs 5lithium< -luoride< or other salts9 2. !ay a#tually o##ur during pregnan#y ii. !ust distinguish -rom osmoti# diuresis: (smoti# diuresis Dill ha$e hyper8 or isotoni# urine< rather than hypotoni# 5su#h is the #ase in .@9 d. ,lini#al ,onsiderations: i. !ust di--erentiate -rom other #auses o- polyuria and hypernatremia 1. H&''(&+1 !f DI s , ')te )+ "e7 e/e" " t%e f&ce !f %#$e+"&+e( & 2. Primary polydipsia Dill ha$e hyponatremia7 .@ should ha$e normal or ele$ated serum sodium. a. Primary polydipsia: un#ontrolled Dater intaEe dri$es polyuria 3. @n .@< polyuria and resulting hypertoni#ity dri$es the thirst ii. Polydipsia: T% +st c!($e"s&tes f!+ @&te+ '!ss !"'# " &0'e $&t e"ts 12. &@A.H 5! #h 1 < #p4%19: Hyperse#retion o- A.H 3eyond normal #ompensatory le$els -or hypertoni#ity or hypo$olemia D/ resulting hyponatremia. a. 1tiology and pathophys: i. (nly 1/2 o- #ases are o- hypothalami#8pituitary origin : 1. Tumors 53ron#hial espe#ially9< ,*& disorders< pulmonary disorders< and drugs 5$asopressin< #ar3ama=epine9 #an all #ause &@A.H. ii. Pulmonary disorders may #ause &@A.H 3y inter-ering Dith 3arore#eptor input iii. ,*& disorders may #ause &@A.H 3y interrupting A.H inhi3iting neural pathDays i$. Hyponatremia results< sin#e 3ody is retaining Dater in e'#ess 1. Hyponatremia partially limited 3y se#retion o- atrial natriureti# peptide 3. ,lini#al ,onsiderations: Ce+e0+&' e,e(&7 %#$!"&t+e( &7 NO $e+ $%e+&' e,e(& i. ,on-usion< lethargy< DeaEness< myo#lonus< asteri'is< sei=ures< #oma #an all result 1. (##ur due to osmoti# -luid shi-ts #ausing 3rain edema< high @,P< herniation 2. !ore rapid #auses o- &@A.H Dill #ause ;ui#Eer 3rain edema and ele$ated @,P7 permanent 3rain damage is more liEely ii. *eed to di--erentiate -rom pseudohyponatremia: 1. Pseudohyponatremia o##urs Dhen 19 in-usion o- hyperosmolar solutions pulls solution out o- #ells 5there3y diluting sodium7 3e#ome hyponatremi# 3ut not hypo8osmoli#9 or 29 *ona;ueous portion o- plasma is larger than normal. iii. Therapy: 0imit Dater intaEe and/or treat underlying disease 5tumor< pulmonary or ,*& disorder< halt $asopressin drug use THYROID PHYSIOLOGY Ke t%s Sect !" ANATOMY= gland is inner$ated 3y adrenergi# -i3ers -rom #er$i#al ganglia and #holinergi# -i3ers -rom $agus ner$e f!'' c)'&+ ce''s o #olumnar in stimulated gland o s;uamous in ina#ti$e gland ha$e c!''! , -ound in lumen that #ontains t%#+!*'!0)' " 8TG9 o in the stroma< ha$e ' *%tAC ce''s maEe c&'c t!" "

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THYROID HORMONES= T%#+!. "e 8T39 o 0H o- thyroid hormones se#reted -rom gland o pre#ursor o- T2 5more potent9 T+ !,t%#+!" "e 8T39 o H o- hormones se#reted Re/e+se T3 o 1H o- se#retions o *(T a#ti$e MIT &", DIT -ormed 3ut not a#ti$e SYNTHESIS OF THYROID HORMONES I!, ,e T+&"s$!+t o @odine taEen up as inorgani# ioide $ia a#ti$e transport !, ,e t+&$ o T%#+! ,ASe+)( +&t ! 8TAS9 measured $ia radioa#ti$e iodide 20' in -olli#ular #ell as in serum regulated 3y TSH (a.pituitary) T&H $ia hypophyse#tomy T/& drops T&H $ia hyperthyroidism T/& rises o R&, !&ct /e I!, ,e U$t&1e 8RAIU9 Assess a3ility o- thyroid to taEe up serum iodine An a#ti$ely -un#tioning thyroid Dill ha$e -aster uptaEe than poor one TG S#"t%es s

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Pre#ursor -or all thyroid hormones Tyrosine residues iodinated and #oupled to -orm a#ti$e thyroid hormones &ynthesi=ed in "1"< gly#osylated in /olgi< pa#Eaged in e'o#ytoti# $esi#les< e'truded into lumen o- -olli#le O. ,&t !" !f I!, ,e o @odide is o'idi=ed into a#ti$e intermediate $ia t%#+! , $e+!. ,&se 8TPO9 O+*&" f c&t !" 8I!, "&t !"9 o ,ataly=ed 3y TP( o Produ#es !@T 5monoiodotyrosine9 and .@T 5diiodotyrosine9 residues in T/ C!)$' "* o TDo .@T O T4 o (ne !@T ? one .@T O T2 o thyroid pero'idase also #ataly=es this o 10' more T4 than T2 in T/ St!+&*e o Thyroid hormones stored as part o- T/ mole#ule in lumen o- -olli#le o "e-ereed to as c!''! , o o o

THYROID HORMONE SECRETION T&H stimulates endo#ytosis o- #olloid droplets into -olli#ular #ells Pseudopodia engul- the droplet and then -used D/ lysosome to -orm $%&*!s!(e o 1n=ymes in phagosome 5$+!te&ses9 hydroly=e T/ to T4<T2<rT2< .@T< !@T )olli#ular #ells #ontain t%#+! , ,e !, "&se o "elease iodine -rom iodotyrosines so that it #an 3e reused in the iodination o- neD T/ o E.t+&t%#+! ,&' P!!' o 1/2 o- 3ody6s T4 stored in li$er and Eidney o T4 pool is 20' larger than T2 and sloDer in turno$er o &er$es as a 3u--er a#ute #hanges in hormone se#retion rate o T4 may 3e admit orally on#e a day and serum hormone le$els Dill not #hange appre#ia3ly o$er the 24 hour period L!'ff?C%& 1!ff Effect o 1'#ess iodine gi$en inhi3its organi-i#ation and hormone synthesis o +lo#Eage temporary and es#ape generally Dithin days COMPOUNDS ALTERING THYROID HORMONE SYNTHESIS

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G! t+!*e"s o +lo#E thyroid hormone produ#tion and thus produ#e goiters o T% !)+e&s 8' 1e $+!$'#t% !)+&c '9 @nhi3it TP( and 3lo#E o'idation o- iodide and organi-i#ation @nhi3it 58monodeiodinase 5#on$erts T4 to T2 peripherally9 o Met% (&2!'e @nhi3its organi-i#ation (*0L o Per#hlorate and thio#yanate @nhi3itors o- iodide uptaEe )ound in #a33age and #assa$a

THYROID HORMONE TRANSPORT P+!te " B ", "* o T%#+!. "e?0 ", "* *'!0)' " 8TBG9 %%H o- T4 3ind to T+/ o other 3inding at: t+&"st%#+et " 5thyro'ine83inding preal3umin9 T4 a--inity less than that o- T+) *ot e--e#ti$ely 3ind T2 A'0)( " 3inds small portion o- #ir#ulating hormones o &erum 3ound le$els $s. -ree: T3 5 . 6H $s. 0.049 T3 5 .6H $s. 0.49 o I"c+e&se, TBG c!"ce"t+&t !" / &= High estrogen le$els 3/# pregnant or oral #ontra#epti$es o Dec+e&se, TBG c!"ce"t+&t !" / &= Androgens and glu#o#orti#oids !alnutrition o D+)*s Dec+e&s "* B ", "*= Phenytoin 5dilantin9 &ali#ylates METABOLISM OF THYROID HORMONES T4 is the maGor se#retory produ#t in the thyroid T4 deiodinated $ia 4?(!"!,e !, "&se and i- the: o (uter ring T3 o @nner ring +T3 T4 #an 3e made into T2< T1< T0 too no a#ti$ity 80H o- #ir#ulating T2 made -rom peripherial deiodination o- T4 o also most o- rT2 made this Day during star$ation and de3ilitating illness: o a#ti$ity o- 58monodeiodinase o de#reased T2 produ#tion o le$els o- rT2 o ser$es to de#rease 3asal meta3oli# rate CONTROL OF THYROID FUNCTION TSH -rom anterior pituitary o &timulate groDth and $as#ularity o- thyroid gland o &timulate synthesis and se#retion o- thyroid hormones

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@n#reases iodide uptaEe @n#reases o'idation o- iodide< organi-i#ation and #oupling T&H le$els -olli#ular #ell 3e#omes #olumnar endo#ytosis o- #olloid T/ proteolysis C!"t+!' Mec%&" s(s o T&H se#retion inhi3ited 3y high serum T4 le$els 5and less also 3y T29 o 80H o- pituitary intra#ellular T2 3e#omes -rom in situ deiodination o- T2 o 20H #omes -rom serum T2 o TRH T"H in#reases le$el o- set point -rom the regulatory -eed3a#E loop &timulates T&H se#retion and synthesis &ensiti$ity o- pituitary to T"H depends on intrapituitary T2 le$els High T2 in pituitary T"H 0oD serum T4 intra#ellular T2 T"H re#eptors o @- person has %#$!t%#+! ,= +asal serum T&H le$els higher and rise in serum T&H in response to T"H Dould 3e greater: o i- ha$e G+&/es , se&se 5high T49: sensiti$ity to pituitary to T"H #an 3e so loD that little/no T"H se#retion in response to T"H o i- tertiary 5hypothalami#9 hypothyroid: pituitary resonse to T"H Pe+t)0&t !"s !f C!"t+!' S#ste( o G! te+ 1nlargement o- the thyroid gland &ei=e depends on T&H stimulation ,an o##ur in %#$!t%#+! ,7 e)t%#+! ,7 %#$e+t%#+! , o @- dietary iodine de-i#ien#y: &ynthesis o- hormones de#reases pituitary T&H synthesis/se#retion stimulate groDth and $as#ularity o- thyroid gland enlarges T&H stimulates uptaEe o- remaining iodide and synthesis/se#retion o- hormone @- de-i#ien#y is not too great< gland Dill #ompensate and return serum T4 to normal le$els @t tooE a hypertrophied gland to produ#e #ompensation Thus pt D/ euthyroid has a goiter o @- there is su--i#ient iodide< intense T&H stimulation hypothyroid ? goiter o i- ha$e /ra$e6s disease stimulated 3y t%#+! ,?st ()'&t "* *'!0)' "s 8TSI9 gland hypertrophies 3/# T&@ 3inds to T&H8" mimi#s a#tions o- T&H stimulate se#retion/synthesis o- T2 hypertrophied and goiter serum T&H le$els are loD/nonmeasura3le o o o

MECHANISM OF HORMONE ACTION T%#+! , H!+(!"e Rece$t!+s o 1nter #ell $ia #arrier8mediated transport systems and 3ind to nu#lear re#eptors and to the t%#+! , +es$!"s /e e'e(e"t o A--inity o- re#eptor o- T2 is 10' that -or T4 o Thyroid hormones #an also a#t on mito#hondria to in#rease si=e and num3er TSH?R

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o o o o

Present on sur-a#e o- thyroid -olli#ular #ell A#t 3y stimulating #A!P produ#tion T&H does stimulate adipo#yte lipolysis @n /ra$es6 disease< pro3lems seen D/ -i3ro3last in eye E.!$%t%&'(!s Also in the sEin o- the preti3ial region 5$+et 0 &' (#.e,e(&9 These are all mediated 3y nonthyroidal T&H re#eptors

ACTIONS OF THYROID HORMONES M&t)+&t !"&' &", D ffe+e"t &t !"&' Effects o +one maturation delayed in hypothyroid Eids o "ole in perinatal thyroid maturation and admit in utero -or sur-a#tant -ormation Ne)+!'!* c Effects o *e#essary -or normal -etal and neonatal 3rain de$elopment o *euronal proli-eration and di--erentiation o !yelinogenesis o *euronal outgroDth o &ynapse -ormation o At age 2 during Dhi#h a thyroid hormone de-i#ien#y results in stru#tural and physiologi#al impairment o ,ongenital hypothyroidism #an result in se$er and irre$ersi3le 3rain damage S$!+&, c c!"*e"t &' %#$!t%#+! , s( o !ental retardation #ould result D/o T' is se$ere enough to Darrant #ost o- routine s#reening o Hypothyroid adults tend to 3e dull and lethargi# and ha$e prolonged re-le' times Thought and spee#h pro#esses are sloDed &leep e'#essi$ely Psy#hologi#al distur3an#es 5(#.e,e(& (&,"ess9 o Hyperthyroid patients are e'#ita3le< restless< distra#ta3le @nsomnia and de#reased re-le' time Effects !" G+!@t% o *e#essary -or normal groDth o .e-i#ien#y leads to stunted groDth 0oD thyroid le$els stimulate /H and @/) se#retion Dhi#h in#reases groDth stunting Met&0!' c Act !"s o ,ontrol 0&s&' (et&0!' c +&te 8BMR9 o ,alorigeni# and in#rease (2 #onsumption and heat produ#tion o +!" de#rease in hypothyroid7 +!" in#rease in hyperthyroid o Hormone in#rease mem3rane *a/> ATPase #on#entration and a#iti$ity @n#reases mem3rane *a and > permea3ility @n#reases energy e'penditure in resting #ells o Thyroid hormone admit de#reases ration o- intra#ellular *a to > in li$er< sEeletal mus#le and heart o @n#rease energy e'penditure 3y in#reasing -utile #y#ling 3/# stimulate 3oth ana3oli# and #ata3oli# en=ymes o- the same pathDays o &timulate protein synthesis and degradation @n hypothyroid H o- 3ody Dt that is protein @n hyperthyroid may ne 3e ade;uate su3strate a$aila3le to maintain protein le$els o &timulate lipogenesis and lipolysis $ia in#reasing hormone8sensiti$e lipase a#ti$ity -or the latter

Page -4 o- 173

.egradation !("1 a--e#ted than synthesis Hypothyroid synthesis and degradation Hyperthyroid 3oth 3ut total lipids de#rease o Thyroid hormones #an loDer #holesterol in euthyroid< 3ut e--e#ts are transient o ,an in#rease #holesterol synthesis< in#rease a$aila3ility o- 0.0 re#eptors &o more #holesterol #leared -rom serum &erum #holesterol rise in hypothyroid o +lood glu#ose normal in hypo and hyper o A-ter ingestion o- glu#ose load< glu#ose tends to rise more rapidly than normal in hyper o @n#rease /@ tra#t rate o- a3sorption o- glu#ose High hormone le$els promote insulin resistan#e and insulin degradation o @n hypo: gly#ogen le$els in#rease o Hyper: gly#ogen synthesis and degradation in#rease gly#ogen #on# de#rease Act !"s t%&t M ( c SNS Act / t# o 1'#ess hormone leads to in#reased H"< tremor< e'#ess sDeating o ,an 3e relie$ed 3y propanolol Act !"s !" S1e'et&' M)sc'e o @n#rease #ontent o- plasmalemma ele#trogeni# *a/> pump and in#rease resting mem3rane potential o @n#rease rate and amount o- ,a?2 uptaEe in &" @n#rease ,a?2 a$aila3ility on stimulation o @n#rease myosin ATPase a#ti$ity o @n hypo: mus#le sti--ness and dis#om-ort .elayed mus#le #ontra#tion and rela'ation sloDed mo$ement !us#le mass may in#rease o @n hyper: mus#le DeaEness< Dasting< -atiga3ility Pro'imal lim3 mus#les lead to di--i#ulty #lim3ing stairs .eplete proteins @nhi3it phospho#reatine Einase Act !"s !" C6 o @n#rease H"< #ontra#tility and ,( o @n#rease a#tin/myosin #ontra#tion< mem3rane *a/> ATPase #ontent and myosin ATPase a#ti$ity o @n hyper: myo#ardial hypertrophy o Thyroid hormones in#rease $elo#ity o- rela'ation 3y e'pression o- #ardia#8spe#i-i# sloD &" ,a?2 ATPase o @n hype: &F< H"< mean systoli# eGe#tion $elo#ity D/ de#reased peripheral resistan#e o Thyroid hormones a#t on $as#ular mus#le to #ause $asodilation o @n#reased heat and meta3olite leads to #utaneous $asodilation D/ hyper Darm< moist sEin ,( in#reases< peripheral resistan#e < pulse pressure o H" and &F de#rease in hypo and peripheral resistan#e 0oss o- #utaneous $asodilation 0oss o- dire#t a#tion o- thyroid hormones on $as#ular smooth mm ,utaneous $aso#onstri#tion -or #old sEin in pts D/ my'edema

PHYSIOLOGIC ACTION OF THYROID HORMONES

!eta3oli# rat Proteins H#$!t%#+! , +!" synthesis< degradation< turno$er E)t%#+! , Protein ana3oli# H#$e+t%#+! , +!" synthesis< degradation< turno$er

Page -5 o- 173

0ipids

glu#ose

synthesis/degradation and turno$er< serum #holesterol *ormal

3eta o'idation< lipolysis< lipogenesis *ormal

/ly#ogen

synthesis/degradation and turno$er< gly#ogen a##umulates

A#tion D/ &*&

.ire#t ,F a#tions

amplitude o- 1,/ Da$es

H"< ,(< #ontra#tility< pulse pressure< a#tin/myosin

synthesis/degradation and turno$er< serum glu#ose *ormal serum glu#ose A3normal glu#ose toleran#e test synthesis/degradation and turno$er< gly#ogen is depleted 1'#ess mimi# -' o- 38 adrenergi# stimulation< #an no. o- +8re#eptors and adenylyl #y#lase sensiti$ity amplitude o- 1,/ Da$es

CALCITONIN ,al#itonin is a 228amino a#id linear polypeptide hormone o Produ#ed 3y the para-olli#ular #ells 5also EnoDn as ,8#ells9 o- the thyroid Msed medi#ally to de#rease 3one turno$er in high8turno$er diseases liEe Paget6s disease ina#ti$ated in the Eidneys 5le$els ele$ated in Eidney -ailure9 a#tions in#lude: o loDers serum #al#ium and phosphate le$els 3y inhi3iting 3one resorption o in#reases renal #learan#e o- #al#ium and phosphate #ontrol o- se#retion #al#ium #al#itonin se#retion [Think: Calcitonin, TONES down bld Ca !" also #ontrolled 3y: gastrin< gli#entin se#retion< #hole#ystoEinin8pan#reo=ymin t W O 10 minutes ## See $ore in%o in the &T' section below due to its association w( bld Ca ! ho$eostasis.

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THYROID PATHOLOGY Rustin6s &e#tion THYROID GLAND a) synthesizes the hormones thyroxine (T4) and triiodothyronine (T3), iodine-containing amino acids that regulate the body's metabolic rate b) Adequate levels of thyroid hormone are necessary in infants for normal development of the CN , in children for normal s!eletal gro"th and maturation, and in adults for normal function of multiple organ systems# c) smooth gland consisting of t"o lateral lobes and a connecting central isthmus d) A pyramidal lobe of variable size may e$tend up"ard from the isthmus# e) %he normal "eight of the thyroid is from &'()' g# f) ecretion of thyroid hormones (%& and %)) is controlled by trophic factors secreted by both the hypothalamus and the anterior pituitary g) %& and %) are synthesized in the colloid by iodination and condensation of tyrosine molecules bound together in thyroglobulin h) *ecreased levels of %& and %) stimulate the release of thyrotropin-releasing hormone (%+,) from the hypothalamus and thyroid-stimulating hormone (% ,) from the anterior pituitary, causing %& and %) levels to rise# -levated %& and %) levels, in turn, feed bac! to suppress the secretion of both %+, and % ,# i) .n response to hypothalamic factors, % , (thyrotropin) is released in the anterior pituitary into the circulation# %he binding of % , to its receptor on the thyroid epithelium /0activation of the receptor, allo"ing it to associate "ith a 1s protein/0 increase in intracellular cA23 levels/0 thyroid gro"th, and hormone synthesis and release via cA23-dependent protein !inases# 4) %hyroid follicular epithelial cells convert thyroglobulin into thyro$ine (%)) and lesser amounts of triiodothyronine (%&)# %) and %& are released into the systemic circulation, E9 5or normal %, synthesis, an adult requires a minimum daily inta!e of 67' g of iodine l) %he function of the thyroid gland can be inhibited by goitrogens, 8ecause they suppress %& and %) synthesis, the level of % , increases, and subsequent hyperplastic enlargement of the gland (goiter) follo"s# m) propylthiouracil inhibits the peripheral deiodination of circulating %) into %&, ameliorating symptoms of thyroid hormone e$cess n) %he thyroid gland follicles contain parafollicular cells, or C cells, "hich synthesize and secrete calcitonin /0promotes the absorption of calcium by the s!eletal system and inhibits the resorption of bone by osteoclasts#

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1. Lab tests a# % , is belo" normal in hyperthyroidism and above normal in hypothyroidism b# 2ost clinical laboratories are no" able to accurately measure free thyro$ine (5% )) directly, often reflects the functional state of the thyroid hormone(binding proteins c# thyroid autoantibodies tests i# thyroidal peroxidase antibody (T O Ab ) ii# thyro!lob"lin antibody (T! Ab# iii# T$H re%eptor antibody& sti'"latin!(T$H)R 9sti': Ab ) or blo%*in! (T$H)R 9blo%*: Ab )# iv# %hyroglobulin and thyroidal pero$idase antibodies are commonly found in hypothyroidism resulting from ,ashimoto's thyroiditis and occasionally in hyperthyroidism from 1raves' disease v# % ,-+ 9stim: Ab is present in individuals "ith hyperthyroidism caused by 1raves' disease vi# *etection of % ,-+ 9bloc!: Ab in maternal serum is predictive of congenital hypothyroidism in ne"borns of mothers "ith autoimmune thyroid disease

+ondition

+on%entrations o, Total .ree las'a +lini%al -indin! roteins las'a las'a T$H $tate T4& T3& RT T4& T3& RT Normal Normal ,igh ,igh ;o" ,igh ,igh ;o" Normal ;o" ,igh Normal ,yperthyroid ,ypothyroid -uthyroid

3rimary hyperthyroidism 3rimary hypothyroidism *rugs (estrogens, methadone, heroin, perphenazine, clofibrate), pregnancy, acute and chronic hepatitis, acute intermittent porphyria, estrogen-producing tumors, idiopathic, hereditary

*rugs (glucocorticoids, androgens, ;o" ;o" Normal Normal -uthyroid danazol, asparaginase), acromegaly, nephrotic syndrome, hypoproteinemia, chronic liver disease (cirrhosis), testosteroneproducing tumors, hereditary <# Hyperthyroidis')a hypermetabolic state caused by elevated circulating levels of free % & and %)# 6# causes an overactivity of the sympathetic nervous system (an increase in the N =tone>)# <# ?hatever the cause of hyperthyroidism, %& and %) serum thyroid hormones are elevated# &# .n 7(6'@ of patients, %) secretion is normal "hile %& levels are high ( T& toxi%osis# )# -$cessive levels of thyroid hormone result in an increase in the basal metabolic rate# 7# !inA soft, "arm, and flushed because of inc# 85 and peripheral vasodilation a# ,eat intolerance is common# b# "eating is increased because of higher levels of calorigenesis# c# .ncreased basal metabolic rate also results in "eight loss despite increased appetite# B# Cardiac probs are the earliest and most consistent features of hyperthyroidism# a# increase in cardiac output, due to both increased cardiac contractility and increased peripheral o$ygen requirements# b# %achycardia, palpitations, and cardiomegaly are common# c# Arrhythmias, particularly atrial fibrillation d# ome individuals "ith thyroto$icosis develop reversible left ventricular dysfunction and =lo"-output> heart failure, so-called thyroto$ic or hyperthyroid cardiomyopathy# C# NeuromuscularA tremor, hyperactivity, emotional lability, an$iety, inability to concentrate, and insomnia# 3ro$imal muscle "ea!ness and decreased muscle mass are common

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D# EcularA A "ide, staring gaze and lid lag are present because of sympathetic overstimulation of the levator palpebrae superioris ,o"ever, true thyroid ophthalmopathy associated "ith proptosis is seen only in 1raves disease F# 1.A N hyperstimulation of the gut results in hypermotility, malabsorption, and diarrhea# 6'# s!eletal systemA %hyroid hormone stimulates bone resorption, increasing porosity of cortical bone and reducing the volume of trabecular bone# %he net effect is osteoporosis and an increased ris! of fractures in patients "ith chronic hyperthyroidism# 66# 2ost common causes of ,yperthyroidismA a# 1raves disease (D7@) b# ,yperfunctional 2ultinodular 1oiter c# ,yperfunctional adenoma of the thyroid Hyperthyroidis'/ +a"ses and atho!eneti% 0e%hanis's. 1tiolo!i% +lassi,i%ation Thyroid hor'one o2erprod"%tion 1raves' disease %o$ic multinodular goiter 5ollicular adenoma 3ituitary adenoma 3ituitary insensitivity ,ypothalamic disease 1erm cell tumorsA choriocarcinoma, hydatidiform mole truma ovarii (ovarian teratoma) 2etastatic follicular thyroid carcinoma Thyroid !land destr"%tion ;ymphocytic thyroiditis 1ranulomatous (subacute) thyroiditis ,ashimoto's thyroiditis Dr"! e,,e%t %hyroto$icosis medicamentosa, thyroto$icosis factitia Amiodarone .nterferon alpha .ngestion of e$cessive e$ogenous thyroid hormone -$cess iodine andGor thyroiditis %hyroiditis +elease of stored hormone +elease of stored hormone %ransient release of stored hormone %hyroid-stimulating hormone receptor-stimulating antibody (% ,-+ 9stim: Ab) Autonomous hyperfunction Autonomous hyperfunction % , hypersecretion (rare) +esistance to thyroid hormone (rare) -$cess %+, production ,uman chorionic gonadotropin stimulation 5unctioning thyroid elements 5unctioning metastases atho!eneti% 0e%hanis'

6<# %hyroid stormA is used to designate the abrupt onset of severe hyperthyroidism a# most commonly in patients "ith underlying 1raves disease b# probably results from an acute elevation in catecholamine levels, as might be encountered during infection, surgery, cessation of antithyroid medication, or stress# c# medical emergency- death by cardiac arrhythmias# 6&# Apathetic hyperthyroidismA occurring in the elderly, in "hom advanced age and various comorbidities may blunt the typical features of thyroid hormone e$cess seen in younger patients# a# diagnosis is often made during laboratory "or!-up for une$plained "eight loss or "orsening cardiovascular disease# 6)# *iagnosisA a# measurement of serum % , concentration using sensitive % , assays- most useful

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67#

13. i# ii# iii#

iv# v# vi# vii#

viii# i$#

b# confirmed "ith measurement of free %), "hich is e$pectedly increased (rarely high %&) c# %he radioactive iodine (+A.) upta!e of the thyroid gland at ), B, or <) hours i# diffusely increased upta!e in the "hole gland /01raves' disease ii# increased upta!e in a solitary nodule /0to$ic adenoma iii# decreased upta!e/0thyroiditis, "hen hormone is produced else"here, and "hen e$cessive e$ogenous thyroid hormone is being ingested (eg, factitious hyperthyroidism)# d. %he %+, test is sometimes helpful in diagnosis "hen patients have confusing results of thyroid function tests# .n normal individuals, administration of %+, (7'' g intravenously) produces an increase in serum % , of at least B mHG; "ithin 67(&' minutes# .n primary hyperthyroidism, % , levels are lo" and %+, administration induces little or no rise in the % , level# A normal rise in % , after administration of %+, e$cludes secondary hyperthyroidism %reatment optionsA a# I-bloc!er to control symptoms induced by increased adrenergic tone b# thionamide to bloc! ne" hormone synthesis c# iodine solution to bloc! the release of thyroid hormone d# agents that inhibit peripheral conversion of %) to %& e# +adioiodine /0 ablation of thyroid function over a period of B to 6D "ee! Gra2es Disease characterized by =violent and long continued palpitations > assoc# "ith enlargement thyroid the most common cause of endogenous hyperthyroidism# .t is characterized by a triad of clinical findingsA a# Hyperthyroidis' due to diffuse, hyperfunctional enlargement of the thyroid b# .nfiltrative ophthal'opathy "ith resultant e$ophthalmos c# ;ocalized, infiltrative der'opathy, sometimes called pretibial my$edema pea! incidence bet"een <' and )' years of age# ?omen are affected as much as 6' times more than men, present in 6#7@ to <#'@ of "omen in the Hnited tates susceptibility has been lin!ed to polymorphisms in immune-function genes li!e C%;A) and 3%3N<< and the ,;A-*+& allele# %he serum of more than F'@ of patients contains % ,-+ 9stim: Ab, an antibody directed against the % , receptor site in the thyroid follicular epithelial membrane characterized by a brea!do"n in self-tolerance to thyroid auto-antigens, most importantly the % , receptor/0production of multiple autoantibodies, includingA a# Thyroid)sti'"latin! i''"no!lob"linA binds to the % , receptor and mimics the action of % ,, stimulating adenyl cyclase and increasing the release of thyroid hormones# Almost all individuals "ith 1raves disease have detectable levels of this autoantibody# %hyroid-stimulating immunoglobulin is relatively specific for 1raves disease, in contrast to thyroglobulin and thyroid pero$idase antibodies b# Thyroid !ro4th)sti'"latin! i''"no!lob"linsA Also directed against the % , receptor, implicated in the proliferation of thyroid follicular epithelium# c# T$H)bindin! inhibitor i''"no!lob"linsA prevent % , from binding normally to its receptor on thyroid, some forms mimic the action of % , /0 stimulation of thyroid epithelial cell activity, "hereas other forms may actually inhibit thyroid cell function# i# the coe$istence of stimulating and inhibiting immunoglobulins in the serum of the same patient is rare but it could e$plain "hy some patients "ith 1raves disease have episodes of hypothyroidism# Autoimmunity also plays a role in the development of the infiltrative ophthalmopathy the volume of the retro-orbital connective tissues and e$traocular muscles is increased for several reasons a# infiltration of the retro-orbital space by mononuclear cells, predominantly % cells b# inflammatory edema and s"elling of e$traocular muscles c# accumulation of e$tracellular matri$ components, specifically hydrophilic glycosaminoglycans such as hyaluronic acid and chondroitin sulfate d# increased numbers of adipocytes (fatty infiltration)

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$#

$i#

$ii#

$iii# $iv#

$v#

e# %hese changes displace the eyeball for"ard and can interfere "ith the function of the e$traocular muscles# %he orbital preadipocyte fibroblasts e$press the % , receptor and thus become targets of an autoimmune attac!, % cells reactive against these fibroblasts secrete cyto!ines/0 stimulate fibroblast proliferation and synthesis of e$tracellular matri$ proteins (glycosaminoglycans) and increase surface % , receptor e$pression, perpetuating cycle 2orphology- gland is symmetrically enlarged because of diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells a# .ncreases in "eight to over D' gm are not uncommon b# ;ymphoid infiltrates, consisting predominantly of % cells, "ith fe"er 8 cells and mature plasma cells, are present throughout the interstitiumJ germinal centers c# administration of iodine causes involution of the epithelium and the accumulation of colloid by bloc!ing thyroglobulin secretion d# %reatment "ith the antithyroid drug propylthiouracil e$aggerates the epithelial hypertrophy and hyperplasia by stimulating % , secretion e# e$tra-thyroidal changesA generalized lymphoid hyperplasia, heart may be hypertrophied, and ischemic f# .n patients "ith ophthalmopathy, the tissues of the orbit are edematous because of the presence of hydrophilic mucopolysaccharides and an infiltration by lymphocytes and fibrosis# g# *ermopathyA thic!ening of the dermis due to deposition of glycosaminoglycans and lymphocyte infiltration# h# 2icroscopically, the follicular epithelial cells are columnar in appearance and increased in number and size, %he follicles are small and closely pac!ed together# %he colloid is scantyJ the edges are scalloped in appearance secondary to the rapid proteolysis of thyroglobulin, %he gland's interstitium is diffusely infiltrated "ith lymphocytes and may contain lymphoid follicles "ith germinal centers# Clinical Course- *iffuse enlargement of the thyroid is present in all cases a# 2ay have increased bf through the hyperactive gland, often producing a bruit# b# ympathetic overactivity produces a characteristic "ide, staring gaze and lid lag# c# %he ophthalmopathy results in abnormal protrusion of the eyeball (e$ophthalmos)# d# %he e$traocular muscles are often "ea! e# %he idermopathy, or pretibial my$edema, is most common in the s!in overlying the shins, has scaly thic!ening and induration# f# Causes a slight rise in body temperature and activate heat-dissipating mechanisms includingA cutaneous vasodilation, decrease in 3K+ and increased s"eating# g# .n the elderlyA "eight loss "ith poor appetite# h# .n younger patients, food inta!e increases, some have seemingly insatiable appetites# i# %remor is common and deep tendon refle$es are bris!, "ith a rapid rela$ation phase# 2uscle "ea!ness and atrophy (thyrotoxi% 'yopathy) commonly develop 4# %he s!in is "arm, s"eaty, and velvety in te$ture# !# ,yperpigmentation on the lo"er e$tremities, most stri!ingly on the shins, the bac!s of the feet, and the nail beds# %he hyperpigmentation is due to basal melanosis and heavy deposition of hemosiderin around dermal capillaries and s"eat glands# 3atients are at increased ris! for other autoimmune diseases, such as systemic lupus erythematosus, pernicious anemia, type 6 diabetes, and Addison disease, hypoparathyroiedism, lupus, cirrhosis, etc (you get the picture) treated "ith I-bloc!ers, "hich address symptoms related to the increased I-adrenergic tone (e#g#, tachycardia, palpitations, tremulousness, and an$iety), and by measures aimed at decreasing thyroid hormone synthesis, such as the administration of thionamides (e#g#, propylthiouracil), radioiodine ablation, and surgical intervention# 3atients "ith 1raves' disease often develop hypothyroidism fromA (6) thyroid ablation by surgery or 6&6. radiation treatmentJ (<) autoimmune thyroiditis, leading to thyroid destructionJ and (&) development of antibodies that bloc! % , stimulation (% ,-+ 9bloc!: Ab)#

Page 3- o- 173

.t may lead to increased hepatic gluconeogenesis, enhanced carbohydrate absorption, and increased insulin degradation# .n nondiabetic patients, after ingestion of carbohydrate, the blood glucose rises rapidly, sometimes causing glycosuria, and then falls rapidly# $vii# *iabetic patients have an increased insulin requirement in the hyperthyroid state# $viii# may lead to oligomenorrhea and decreased fertility-.n the follicular phase of the menstrual cycle, there is an increased basal plasma ;, and an increased ;, and 5 , response to 1n+, and there is an increase levels of total estradiol $i$# .n men, hyperthyroidism may cause decreased fertility and impotence from altered steroid hormone metabolism- erum levels of total testosterone, total estradiol, se$ hormone( binding globulin, ;,, and 5 , and gonadotropin response to 1n+, are significantly inc# $$# Hntreated hyperthyroidism may decompensate into a state called thyroid stor'. 3atients so affected have tachycardia, fever, agitation, nausea, vomiting, diarrhea, and restlessness or psychosis# 15. GOIT1R i# *iffuse thyroid enlargement most commonly results from prolonged stimulation by % , ii# stimulation may be the result of one of the causes of hypothyroidism (eg, % , in ,ashimoto's thyroiditis) or of hyperthyroidism (eg, % ,-+ 9stim: Ab in 1raves' disease, hC1 in germ cell tumors, or % , in pituitary adenoma)# iii# Alternatively, goiter may occur in a clinically euthyroid patient# Table 6785 Goiter/ +a"ses and atho!eneti% 0e%hanis's. +a"ses I. Goiter asso%iated 4ith hypothyroidis' or e"thyroidis' .odine deficiency .odine e$cess 1oitrogen in diet or drin!ing "ater 1oitrogenic medication %hioamidesA propylthiouracil, methimazole, carbimazole %hiocyanatesA nitroprusside Aniline derivativesA sulfonylureas, sulfonamides, aminosalicylic acid, phenylbutazone, aminoglutethimide ;ithium Congenital disorders *efective transport of iodide *efective organification of iodide due to absence or reduction of pero$idase or production of an abnormal pero$idase ynthesis of an abnormal thyroglobulin Abnormal interrelationships of iodotyrosine .mpaired proteolysis of thyroglobulin *efective deiodination of iodotyrosine 3ituitary and peripheral resistance to thyroid hormone II. Goiter asso%iated 4ith hyperthyroidis' 1raves' disease % ,-+ 9stim: Ab stimulation of gland L +eceptor defects 8loc!s secretion of hormone Karious defects in hormone biosynthesis .nterferes "ith hormone biosynthesis 8loc!s secretion of hormone .nterferes "ith hormone biosynthesis .nterferes "ith hormone biosynthesis atho!eneti% 0e%hanis'

$vi#

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+a"ses %o$ic multinodular goiter 1erm cell tumor 3ituitary adenoma %hyroiditis

atho!eneti% 0e%hanis' Autonomous hyperfunction hC1 stimulation of gland % , overproduction -nlargement due to Min4ury,M infiltration, and edema

.odine deficiency is the most common cause of goiter in developing nations# *eits "ith less than 6' gGd of iodine dec#synthesis of thyroid hormone, resulting in an elevated % , level and thyroid hypertrophy# .odination of salt has eliminated this problem in much of the developed "orld# v# may also develop from ingestion of !oitro!ens(factors that bloc! thyroid hormone synthesis) vi# goitrogens are in veggies of the 8rassicaceae family rutabagas, cabbage, turnips, cassava)# vii# 2edications that act as goitrogens include thioamides and thiocyanates (eg, propylthiouracil, methimazole, and nitroprusside), sulfonylureas, and lithium# ;ithium inhibits thyroid hormone release and perhaps also iodide organification viii# A congenital goiter associated "ith hypothyroidism (sporadi% %retinis') may occur as a result of a defect in any of the steps of thyroid hormone synthesis i$# 1oiter "ith hyperthyroidism is usually due to 1raves' disease- the gland is diffusely enlarged because of stimulation by % ,-+ 9stim: Ab and other antibodies rather than by % ,# $# .n goiter resulting from impaired thyroid hormone synthesis, there is a progressive fall in serum %) and a progressive rise in serum % ,# As the % , increases, iodine turnover by the gland is accelerated and the ratio of %& secretion relative to %) secretion is increased# Consequently, the serum %& may be normal or increased, and the patient may remain clinically euthyroid $i# .f there is more mar!ed impairment of hormone synthesis, goiter formation is associated "ith a lo" %), lo" %&, and elevated % ,, and the patient becomes clinically hypothyroid $ii# severe iodine deficiency or inherited metabolic defects, a nonto$ic goiter develops because impaired hormone secretion leads to an increase in % , secretion# %he elevation in serum % , level results in diffuse thyroid hyperplasia -As % , stimulation continues, multiple nodules may develop in some areas and atrophy and fibrosis in others, producing a multinodular goiter $iii# .f % , stimulation is prolonged, the diffuse hyperplasia is follo"ed by focal hyperplasia "ith necrosis, hemorrhage, and formation of nodules# %hese nodules often vary from MhotM nodules that can trap iodine and synthesize thyroglobulin to McoldM ones that cannot $iv# .n early goiters, the hyperplasia is % , dependent, but in later stages the nodules become % ,independent a"tono'o"s nod"les $v# over a period of time there may be a transition from a nonto$ic, % ,-dependent, diffuse hyperplasia to a to$ic or nonto$ic, % ,-independent, multinodular goiter $vi# %he enlarged gland may "eigh 6(7 !g and may produce respiratory difficulties secondary to obstruction of the trachea or dysphagia secondary to obstruction of the esophagus# $vii# l"''er syndro'e- an autonomous nodule may develop "ithin a long-standing goiter and produce hyperthyroidism (to$ic multinodular goiter)# a# not accompanied by the infiltrative ophthalmopathy and dermopathy of 1raves disease b# clinically apparent autonomous nodules can develop in appro$imately 6'@ of multinodular goiters over a 6'-year follo"-up c# %he incidence of malignancy in long-standing multinodular goiters is lo" (N7@) concern for malignancy arises in goiters that demonstrate sudden changes in size or symptoms (e#g#, hoarseness)# $viii# *ominant nodules in a multinodular goiter can mimic! a thyroid neoplasm 3. Hypothyroidis' a) structural or functional derangement that interferes "ith the production of adequate levels of thyroid hormone- abnormally lo" serum %) and %& levels# b) prevalence of overt hypothyroidism is '#&@, "hile subclinical hypothyroidism can be found in greater than )@, increases "ith age, nearly ten fold more common in "omen than in men# c) .t can result from a defect any"here in the hypothalamic-pituitary-thyroid a$is d) can be accompanied by an enlargement in the size of the thyroid gland -goiter#

i$.

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e) 3rimary hypothyroidism accounts for the vast ma4ority of cases of hypothyroidism i# can be congenital, acquired, or autoimmune# ii# congenital hypothyroidism is most often due to endemic iodine deficiency in the diet# iii# a highly preventable cause of mental retardation, occurs in appro$imately 6 in )''' birthsJ girls are affected about t"ice as often as boys# iv# 2ost cases (D7@) are sporadic in distribution, but 67@ are hereditary v# %he most common cause of sporadic congenital hypothyroidism is thyroid dysgenesis, in "hich hypofunctioning ectopic thyroid tissue is more common than thyroid hypoplasia or aplasia# f) Ether less common forms of congenital hypothyroidism include a# inborn errors of thyroid metabolism (dyshormonogenetic goiter), "herein any one of the multiple steps leading to thyroid hormone synthesis may be deficient, such as i# iodide transport into thyrocytes, ii# iodide =organification> (binding of iodide to the storage protein, thyroglobulin iii# iodotyrosine coupling to form hormonally active %& and %)# b# 2utations in thyroid pero$idase (%3E) gene are the most common cause of dyshormonogenetic goiter# c# endred syndro'e, characterized by hypothyroidism and sensorineural deafness, is caused by mutations in the ;C<BA) gene, "hose product, pendrin, is an anion transporter e$pressed on the apical surface of thyrocytes and in the inner ear d# .n rare instances there may be complete absence of thyroid parenchyma (thyroid agenesis), or the gland may be greatly reduced in size (thyroid hypoplasia)# e# 1ermline mutations in transcription factors that are e$pressed in the developing thyroid and regulate follicular differentiation, such as thyroid transcription factor-< (%%5-<), also !no"n as 5EO-6, and paired bo$-D (3AO-D), have been reported in individuals "ith thyroid agenesis# %hese patients typically present "ith a constellation of e$trathyroidal malformations# f# .nactivating germline mutations of the % , receptor (% ,+) is a rare genetic cause of isolated hypothyroidism (note that activating somatic mutations of % ,+ are found in autonomous thyroid nodules, see belo")# g# %hyroid hormone resistance syndrome is a rare autosomal-dominant disorder caused by inherited mutations in the thyroid hormone receptor, "hich abolish the ability of the receptor to bind thyroid hormones# 3atients demonstrate a generalized resistance to thyroid hormone, despite high circulating levels of %& and %)# ince the pituitary is also resistant to feedbac! from thyroid hormones, % , levels tend to be high as "ell# Hypothyroidis'/ +a"ses and atho!eneti% 0e%hanis's. 1tiolo!i% +lassi,i%ation +on!enital A%9"ired ,ashimoto's thyroiditis evere iodine deficiency ;ymphocytic thyroiditis %hyroid ablation %hyroid surgery
6&6

atho!eneti% 0e%hanis' Aplasia or hypoplasia of thyroid gland *efects in hormone biosynthesis or action Autoimmune destruction *iminished hormone synthesis, release *iminished hormone synthesis, release *iminished hormone synthesis, release

. radiation treatment of hyperthyroidism

-$ternal beam radiation therapy of head and nec! cancer *rugs *iminished hormone synthesis, release

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1tiolo!i% +lassi,i%ation .odine, inorganic .odine, organic (amiodarone) %hioamides (propylthiouracil,6 methimazole) 3otassium perchlorate %hiocyanate ;ithium Amiodarone unitinib ,ypopituitarism ,ypothalamic disease

atho!eneti% 0e%hanis'

*eficient % , secretion *eficient %+, secretion

g) Acquired hypothyroidism can be caused by surgical or radiation-induced ablation of thyroid parenchyma# a# .t is often caused secondary to treatment of hyperthyroidism by surgery or radiation b# *rugs given it to intentional decrease thyroid secretion (e#g#, methimazole and propylthiouracil) can cause acquired hypothyroidism, as can agents used to treat nonthyroid conditions (e#g#, lithium, p-aminosalicylic acid)# h) Autoimmune hypothyroidism is the most common cause of hypothyroidism in iodine-sufficient areas of the "orld# a# 2ost are due to ,ashimoto thyroiditis# Circulating autoantibodies, including antimicrosomal, anti-thyroid pero$idase, and anti-thyroglobulin antibodies, are present and thyroid is typically enlarged (goitrous)# b# Autoimmune hypothyroidism can occur in isolation or in con4unction "ith autoimmune polyendocrine syndrome (A3 ), types 6 and < (see discussion in =Adrenal 1lands>)# i) econdary (or central) hypothyroidism is caused by deficiency of % , or %+, (uncommon)# 4) Any of the causes of hypopituitarism or of hypothalamic damage from tumors, trauma, radiation therapy, or infiltrative diseases can cause central hypothyroidism# !) Classic clinical manifestations a# C+-%.N. 2-hypothyroidism that develops in infancy or early childhood i# commonly in areas of the "orld "here dietary iodine deficiency is endemic ii# much less frequent in recent years, as a result of the "idespread supplementation of foods "ith iodine iii# may also result from inborn errors in metabolism that interfere "ith the biosynthesis of normal levels of thyroid hormone- dyshormonogenetic goiter iv# Clinical featuresA impaired development of the s!eletal system and central nervous system/0 severe mental retardation, short stature, coarse facial features, a protruding tongue, and umbilical hernia v# Normally, maternal %& and %), cross the placenta, are critical to brain development# vi# thyroid deficiency before the development of the fetal thyroid gland/0severe mental retardation vii# reduction in maternal thyroid hormones later in pregnancy, after the fetal thyroid has developed, allo"s normaler brain development# b# 2PO-*-2A (1ull disease)- hypothyroidism developing in the older child or adult i# initial symptoms include generalized fatigue, apathy, and mental sluggishness, "hich may mimic depression ii# %hen speech and intellectual functions become slo"ed iii# -ventually they become listless, cold intolerant, and frequently over"eight, decreased sympathetic activity results in constipation and decreased s"eating,

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iv# %he s!in of these patients is cool and pale because of decreased blood flo"# v# +educed cardiac output probably contributes to shortness of breath and decreased e$ercise capacity vi# an increase in total cholesterol and lo"-density lipoprotein (;*;) levels vii# ,istologically, there is an accumulation of matri$ substances, such as glycosaminoglycans and hyaluronic acid, in s!in, subcutaneous tissue, and a number of visceral sites /0non)pittin! ede'a, a broadening and coarsening of facial features, enlargement of the tongue, and deepening of the voice# viii# 3atients "ith une$plained increase in body "eight or hypercholesterolemia should be assessed for potential hypothyroidism# i$# 2easurement of the serum % , level is the most sensitive screening test# $# %he % , level is not increased in persons "ith hypothyroidism due to primary hypothalamic or pituitary disease# $i# %) levels are decreased in individuals "ith hypothyroidism of any origin# $ii# $y'pto's A lo" thin!ing, ;ethargy, decreased vigor, *ry s!inJ thic!ened hairJ hair lossJ bro!en nails, *iminished food inta!eJ "eight gain, Constipation, 2enorrhagiaJ diminished libido, Cold intolerance $iii# $i!ns A +ound puffy faceJ slo" speechJ hoarseness, ,ypo!inesiaJ generalized muscle "ea!nessJ delayed rela$ation of deep tendon refle$es, Cold, dry, thic!, scaling s!inJ dry, coarse, brittle hairJ dry, longitudinally ridged nails, 3eriorbital edema, Normal or faint cardiac impulseJ indistinct heart soundsJ cardiac enlargementJ bradycardia, AscitesJ pericardial effusionJ an!le edema, 2ental clouding, depression $iv# Laboratory ,indin!s A .ncreased serum % , level, *ecreased serum free thyro$ine, decreased serum total %) and %&J decreased resin %& or %) upta!eJ decreased free thyro$ine inde$, *ecreased radioiodine upta!e by thyroid gland, *iminished basal metabolic rate, 2acrocytic anemia, -levated serum cholesterol level, -levated serum CQ level, ,yponatremia (from e$cess secretion of antidiuretic hormone), *ecreased circulation timeJ lo" voltage of R+ comple$ on -C1 c# %hyroiditis- inflammation of the thyroid gland i# .nfectious thyroiditis may be either acute or chronic ii# infections can reach the thyroid by hematogenous spread or through direct seeding of the gland, such as through the piriform sinus ad4acent to the laryn$ iii# mycobacterial, fungal, and 3neumocystis infections, are more chronic and frequently occur in immunocompromised patients iv# sudden onset of nec! pain and tenderness in the area of the gland and is accompanied by fever, chills, and other signs of infection d# ,A ,.2E%E %,P+E.*.%. i# most common cause of hypothyroidism in iodine sufficient areas of the "orld ii# gradual thyroid failure because of autoimmune destruction of the thyroid gland# iii# most prevalent bet"een )7 and B7 years of age and is more common in "omen than in men, "ith a female predominance of 6' A 6 to <' A 6# iv# .s a ma4or cause of nonendemic goiter in the pediatric population (rare) v# has a strong genetic component-.ncreased susceptibility is associated "ith cytoto$ic % lymphocyte(associated antigen-) (C%;A)) polymorphisms# vi# C%;A) is a negative regulator of %-cell responses, thus polymorphisms of the C%;A) gene that result in reduced protein level or function are associated "ith a predisposition to autoimmune disease# vii# .t is also assoc "ith protein tyrosine phosphatase-<< (3%3N<<)gene "hich is also thought to inhibit %-cell function# viii# usceptibility to other autoimmune diseases, such as type 6 diabetes has been associated "ith polymorphisms in both C%;A) and 3%3N<< i$# caused by a brea!do"n in self-tolerance to thyroid auto-antigens- e$emplified by the presence of circulating autoantibodies against thyroglobulin and thyroid

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pero$idase-etiology is un!no"n but it may be due to abnormalities of regulatory % cells (%regs) $# 2orphology-%he thyroid is often diffusely enlarged 6# %he cut surface is pale, yello"Gtan, firm, and some"hat nodular <# e$tensive infiltration of the parenchyma by a mononuclear inflammatory infiltrate containing small lymphocytes, plasma cells, and "ell-developed germinal centers &# %he thyroid follicles are atrophic and are lined in many areas by epithelial cells distinguished by the presence of abundant eosinophilic, granular cytoplasm, termed ,Srthle cells )# .n fine-needle aspiration biopsy samples, the presence of ,Srthle cells in con4unction "ith a heterogeneous population of lymphocytes is characteristic of ,ashimoto thyroiditis# 7# =classic> ,ashimoto thyroiditis, interstitial connective tissue is increased and may be abundant B# Hnli!e +eidel thyroiditis the fibrosis does not e$tend beyond the capsule of the gland# $i# Clinical Course-painless enlargement of the thyroid in a middle-aged "oman 6# %he enlargement of the gland is usually symmetric and diffuse <# hypothyroidism develops gradually &# .ndividuals are at increased ris! for developing other autoimmune diseases, both endocrine (type 6 diabetes, autoimmune adrenalitis) and nonendocrine (systemic lupus erythematosus, myasthenia gravis, and 4Tgren syndrome e# H8ACH%- (1+ANH;E2A%EH ) %,P+E.*.%. AQA granulomatous thyroiditis or *e Ruervain thyroiditis i# most common bet"een the ages of )' and 7' and, li!e other forms of thyroiditis, affects "omen considerably more often than men () A 6)# ii# is believed to be triggered by a viral infection iii# ma4ority of patients have an upper respiratory infection 4ust before the onset iv# has a seasonal incidence, "ith occurrences pea!ing in the summer, and clusters of cases have been reported in association "ith co$sac!ievirus, mumps, measles, adenovirus, and other viral illnesses v# .t may results from a viral infection that leads to e$posure to a viral or thyroid antigen, "hich is released secondary to virus-induced host tissue damage# vi# %his antigen stimulates cytoto$ic % lymphocytes, "hich then damage thyroid follicular cells# .n contrast to autoimmune thyroid disease, the immune response is virus-initiated and not self-perpetuating, so the process is limited# vii# %he gland may be un-biilaterally enlarged and firm, "ith an intact capsule viii# -arly in the active inflammatory phase, scattered follicles may be entirely disrupted and replaced by neutrophils forming microabscesses i$# ;ater, it appear in the form of aggregates of lymphocytes, activated macrophages, and plasma cells about collapsed and damaged thyroid follicles $# 2ultinucleate giant cells enclose na!ed pools or fragments of colloid $i# *ifferent histologic stages are sometimes found in the same gland, suggesting "aves of destruction over a period of time $ii# most common cause of thyroid pain $iii# thyroid inflammation and hyperthyroidism are transient, diminishing in <-B "ee!s $iv# Nearly all patients have high serum %) and %& levels and lo" serum % , levels during this phase# ,o"ever, unli!e in hyperthyroid states such as 1raves disease, radioactive iodine upta!e is diminished $v# After recovery, generally in B to D "ee!s, normal thyroid function returns# f# H8ACH%- ;P23,ECP%.C (3A.N;) %,P+E.*.%.

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i# also referred to as painless thyroiditis, usually comes to clinical attention because of mild hyperthyroidism, goitrous enlargement of the gland, or both# ii# it is most often seen in middle-aged adults and is more common in "omen iii# A variant of ,ashimoto thyroiditis, since the ma4ority of patients have circulating anti-thyroid pero$idase antibodies or a family history of other autoimmune stuff iv# As many as a third of cases can evolve into overt hypothyroidism over the ne$t 6'yrs, and the thyroid histology is also reminiscent of ,ashimoto thyroiditis v# lymphocytic infiltration "ith hyperplastic germinal centers "ithin the thyroid parenchyma and patchy disruption and collapse of thyroid follicles# vi# Hnli!e ,ashimoto thyroiditis fibrosis and ,Srthle cell metaplasia are not prominent features# vii# present "ith a painless goiter, transient overt hyperthyroidism, or both g# +iedel thyroiditis, i# a rare disorder of un!no"n etiology ii# characterized by fibrosis involving the thyroid and contiguous nec! structures# iii# a hard and fi$ed thyroid mass clinically simulates a thyroid carcinoma# iv# .t may be associated "ith idiopathic fibrosis in other sites in the body, such as the retroperitoneum# v# %he presence of circulating anti-thyroid antibodies in most patients suggests an autoimmune etiology# 4. Neoplas's o, the Thyroid a# %umors of the thyroid usually present as a solitary mass in the nec!# b# incidence of solitary palpable nodules in tadults in the is Hnited tates bet"een 6@ and 6'@ c# ingle nodules are )$ more common in "omen than in men, increasing throughout life# d# ma4ority of solitary nodules of the thyroid prove to be localized, non-neoplastic conditions (e#g#, a dominant nodule in multinodular goiter, simple cysts, or foci of thyroiditis) or benign neoplasms such as follicular adenomas- benign tumors outnumber thyroid tumors 6' A 6 e# ?hile under 6@ of solitary thyroid nodules are malignant, this still represents about 67,''' ne" cases of thyroid carcinoma per year in the Hnited tates# 5ortunately, most of these cancers are indolent, permitting a F'@ survival at <' years f# Clinical cues i# olitary nodules are more li!ely to be neoplastic than are multiple nodules ii# Nodules in younger patients are more li!ely to be neoplastic than in older patients iii# Nodules in males are more li!ely to be neoplastic than are those in females iv# radiation treatment to the head and nec! is assoc# "ith an incr# thyroid malignancy v# 5unctional nodules that ta!e up radioactive iodine in imaging studies (hot nodules) are significantly more li!ely to be benign than malignant g# ,olli%"lar adeno'a account for &'@ of all solitary thyroid nodules i# .t is a solitary, firm, gray or red nodule, up to 7 cm in diameter, completely surrounded by a fibrous capsule, derived from follicular epithelium ii# %he surrounding normal thyroid tissue is compressed by the adenoma# iii# 2icroscopically, the adenoma consists of normal-appearing follicles of varying size, associated "ith hemorrhage, fibrosis, calcification, and cystic degeneration iv# follicular adenomas are not forerunners to carcinomas v# Although the vast ma4ority of adenomas are nonfunctional, a small proportion produces thyroid hormones and causes clinically apparent thyroto$icosi vi# ,ormone production in functional adenomas (=to$ic adenomas>) is independent of % , stimulation and represents another e$ample of thyroid autonomy vii# Nonfunctioning adenomas ta!e up less radioactive iodine than normal parenchyma viii# En radionuclide scanning nonfunctioning adenomas usually appear as cold nodules relative to the ad4acent thyroid tissue i$# As many as 6'@ of cold nodules eventually prove to be malignant on histologic analysis, but malignancy is rare in hot nodules h# Thyroid %an%ers are not common#

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i# %he ma4or ris! factor predisposing to epithelial thyroid carcinoma is e$posure to radiation, but genetic factors have also been recognized# ii# 2ost papillary and follicular cancers have prolonged clinical course (67(<' years)# iii# apillary %ar%ino'a (:;<# typically metastasizes to lymph nodes in the nec! 6# most often bet"een the ages of <7 and 7', <# strongest assoc# "ith ionizing radiation# &# single nodule, moves freely during s"allo"ing, )# ,oarseness, dysphagia, cough, or dyspnea suggests advanced disease# 7# hematogenous metastases are most commonly to the lung# B# e$cellent prognosis, 6'-year survival rate in e$cess of F7@# C# 8et"een 7@ and <'@ of patients have recurrences D# 6'@ to 67@ have distant metastases# iv# ,olli%"lar %an%er(7-6'@)tends to spread via the bloodstream to distant sites such as bone or lung# 6# common in "omen (& A 6) and present at an older age than do papillary carcinomas, "ith a pea! incidence bet"een )' and B' years of age <# more frequent in areas "ith dietary iodine deficiency &# have little propensity for invading lymphaticsJ therefore, regional lymph nodes are rarely involved, but vascular (hematogenous) dissemination is common, "ith metastases to bone, lungs, liver, and else"here )# as many as half the patients succumb to their disease "ithin 6' years 7# treated "ith total thyroidectomy follo"ed by the administration of radioactive iodine, the rationale being that metastases are li!ely to ta!e up the radioactive element, "hich can be used to identify and ablate such lesions# v# 0ed"llary %ar%ino'a (7@)is an uncommon neoplasm of the C cells (parafollicular cells) of the thyroid that produce calcitonin# 6# &'@ of medullary thyroid carcinomas are a manifestation of multiple endocrine neoplasia type < (2-N-<), inherited as autosomal dominant <# composed of polygonal to spindle-shaped cells, "hich may form nests, trabeculae, and even follicles# &# %he tumor spreads hematogenously, typically to lymph nodes, bone, lung# )# Everall survival is estimated to be D'@ at 7 years and B'@ at 6' years 7# about equal frequency in males and females and is typically found in patients older than 7' years# B# .n 2-N-<a or 2-N-<b, the tumor occurs at a much younger age, often in childhood# .n fact, medullary carcinoma in a patient younger than )' years should suggest familial medullary carcinoma or 2-N-<a or 2-N-<b C# 8ecause C cells are neuroendocrine cells, these tumors have the capacity to release calcitonin and other hormones such as prostaglandins, serotonin, adrenocorticotropin, somatostatin, and calcitonin D# radionuclide thyroid scan may demonstrate one or more cold nodules F# Circulating calcitonin levels are typically elevated in most patients, and serum levels correlate "ith tumor burden

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urgery is the mainstay of therapy "ith radioactive iodine ablation of any residual thyroid tissue, vi# Anaplasti% (=ndi,,erentiated# +ar%ino'as (7@)-highly aggressive and lethal tumors can arise de novo, or more commonly, by =dedifferentiation> of a "elldifferentiated papillary or follicular carcinoma 6# inactivation of p7& or activating mutations of I-catenin, are essentially restricted to anaplastic carcinomas <# mortality rate approaching 6''@ &# older than those "ith other types of thyroid cancer, "ith a mean age of B7 )# a quarter of patients "ith anaplastic thyroid carcinomas have a past history of a "ell-differentiated thyroid carcinoma, and another quarter harbor a concurrent "ell-differentiated tumor in the resected specimen 7# large, pleomorphic giant cells, including occasional osteoclast-li!e multinucleate giant cells B# spindle cells "ith a sarcomatous appearance C# present as a rapidly enlarging bul!y nec! mass D# %here are no effective therapies, and the disease is almost uniformly fatal F# most cases death occurs in less than 6 year as a result of aggressive gro"th and compromise of vital structures in the nec! vii# %he ma4or ris! factor predisposing to thyroid cancer is e$posure to ionizing radiation, particularly during the first < decades of life viii# *eficiency of dietary iodine (and by e$tension, an association "ith goiter) is lin!ed "ith a higher frequency of follicular carcinomas# ;. +on!enital Ano'alies a# Thyro!lossal d"%t or %yst -is the most common clinically significant congenital anomaly of the thyroid i# A persistent sinus tract remains as a remnant of the tubular development of the thyroid, parts of this tube may be obliterated, leaving small segments to form cysts ii# %hese occur at any age and might not become evident until adult life iii# 2ucinous, clear secretions may collect "ithin these cysts to form either spherical masses or fusiform s"ellings, rarely over < to & cm in diameter

6'#

PARATHYROID PHYSIOLOGY Ke t%s Sect !" Parathyroid glands 4 Parathyroid hormone ANATOMY= Parathyroid glands 5small endo#rine glands9 in the ne#E that produ#e parathyroid hormone 5PTH9 Humans ha$e -our parathyroid glands lo#ated 3ehind the thyroid gland< and< in rare #ases< Dithin the thyroid gland or #hest. The parathyroid glands are named -or their pro'imity to the thyroid 3ut ser$e a #ompletely di--erent role than the thyroid gland. They are densely pa#Eed #ells< in #ontrast Dith the -olli#le stru#ture o- the thyroid. o .uring surgery< they are harder to di--erentiate -rom the thyroid or -at 4 o-ten mistaEenly remo$ed 5see 3eloD -or #onse;uen#es9. ,ontain tDo types o- #ells: o parathyroid #hie- #ells 4 5darEer/numerous/dense #ells9 manu-a#ture PTH o o'yphil #ells 4 5lighter/-eD/less dense9 -un#tion unEnoDn CONTROL OF CALCIUM HOMEOSTASIS R!'e !f C&M- " 0!,# Ne)+!()sc)'&+ e.c t&0 ' t# o ,a?2 permea3ility neuromus#ular e'#ita3ility o i- too loD possi3ly tetany results

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 ,a?2 essential -or sec+et !" o- hormones and *Ts +lood #lotting 1'#itation8#ontra#tion #oupling &e#ond messenger Se+)( C&M- 'e/e's 1,) S @,) 50H serum ,a?2 -ree< 40H 3ound to protein< 10H #omple'ed as #itrate pH ,a?2 3ind to proteins -ree ,a?2 le$els alEalosis o tingling in e'tremities or tetany or hyper$entilation Se+)( C&M 0&'&"ce 3ased on o /@ a3sorption o 3one deminerali=ation o renal ,a?2 #learan#e o 3one mineral -ormation input to serum calcium o c&'c t+!' 51<25 dihyro'y#hole#al#i-erol9 /@ ,a?2 a3sorption o -a#tors that de#rease ,a?2 solu3ility: high dietary phosphate< -at< o'ylate le$els #orti#osteroids inhi3it #al#ium a3sorption o most a3sor3ed in $+!. (&' SI o less than 50H o- dietary #a?2 is a3sor3ed o #al#ium #ontinually e'#hange 3tD serum and 3one output from serum calcium o i- le$els lea$e serum and enter 3one o loD le$els -lu' out o- 3one o hormone regulators: PTH ,al#itonin ,al#itriol o 8H o- -iltered 3one normally rea3sor3ed D/ $ast maGority in pro'imal tu3ule CONTROL OF PHOSPHATE HOMEOSTASIS R!'e !f $%!s$%&te " 0!,# o ,onstituent o- gly#olyti# intermediates o 0arge amounts present in sEeleton o !aGor intra#ellular ion o @,) S 1,) le$els Se+)( P%!s$%&te Le/e's o 85H o- serum le$els are in -ree -orm o le$els $ary Didely during the day Se+)( P%!s$%&te B&'&"ce o 1nters serum $ia: /@ a3sorption +one &o-t tissue o 0ea$es $ia: "enal e'#retion 1ntry into 3one 1ntry into so-t tissue o Input to Serum Phosphate 0oD /@ phosphate le$els 808 0H a3sor3ed

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.e#reased /@ a3sorption not a typi#al #ause o- hypophosphatemia

Output from Serum Phosphate 0H rea3sor3ed in the Eidney that is -iltered urinary e'#retion regulated 3y #hanging Tm 5tu3ular ma'9 or -iltered load PTH de#reases Tm phosphate e'#retion in urine @n so-t tissue damage: -iltered load phosphate e'#retion C!"seD)e"ce !f Se/e+e H#$!$%!s$%&te( & o *er$e #ondu#tan#e de#reases o +one minerali=ation is de-e#ti$e o Hemolyti# anemia 5loD ATP9

BONE Ge"e+&' o ,ollagen is predominant #omponent o- organi# matri' o Highly $as#ular tissue o +alan#e 3tD 3one -ormation 5&cc+et !"9 $s. 3reaEdoDn 5+es!+$t !"9 o "esorption -rom= 3one matri' degradation dissolution o- 3one minerals o 3one -ormation -rom: synthesis o- organi# matri' su3se;uent deposits in this matri' o 3e-ore 20: -ormation S resorption o at 20: resorption S -ormation o 3one loss a##elerates a-ter menopause o 3one plays a maGor role in regulation o- homeostasis o-: #al#ium magnesium phosphate lar)e *uantities are stored in bone o !ste!0'&sts 3one -orming #ells deri$ed -rom !ste!$+!*e" t!+ ce''s ha$e PTH and #al#itriol re#eptors #an synthesi=e matri' 5#ollagen and osteo#al#in9 Dhen synthesi=ed #al#i-ied produ#es &'1&' "e $%!s$%&t&se 5 phosphate le$els9 marEers o- osteo3last a#ti$ity: alEaline phosphatase osteo#al#in o 3one mineral made o- %#,+!.#&$&t te &", (&*"es )( minerals in 3one #ontinually e'#hanged Dith 1,) minerals PTH< $it .< #al#itonin in-luen#e this -lu' o Oste!c#tes Uhen osteo3lasts entrapped in 3one matri' )ound in la#unae and #anali#uli Ha$e gap Gun#tions o Oste!c'&sts 1'ternal to 3one8lining layer o- sur-a#e osteo3#lasts Play role in 3one resorption H!@s% $s '&c)"&e

Page 33 o- 173

"u--led 3order Dhere 3one resor3ed Has a#id en$ironment pH hydro'yapatite solu3ility promote 3one dissolution no PTH and #al#itriol re#eptors HAF1 #al#itonin re#eptors

B!"e f') , o )ound in la#unae and #anali#uli o Plays role in determining le$el o- #al#ium -lu' 3tD 3one -luid and 1,) o ,a?2 in 3one -luid is 1/2 that o- 1,) o 0arge aggregate sur-a#e area o- la#unae and #anali#uli pro$ides si=a3le sur-a#e -or mineral e'#hange 5in-luen#ed 3y osteo#ytes9 o A#id produ#tion 3y osteo#yte pH o- 3one -luid 3one salt solu3ility promote dissolution o- 3one mineral o PTH stimulation ,a?2 in-lu' loDer 3one -luid #al#ium #on#.

MAJOR GROLTH FACTORS IN BONE F 0+!0'&st GF o &timulate 3one8#ell proli-eration and #ollagen synthesis I"s)' "?' 1e GF o &timulate 3one and #artilage groDth o @n#rease osteo3last proli-eration< #ollagen deposition< 3one minerali=ation o "egulated 3y /H< insulin< estrogen< PTH T+&"sf!+( "* GF o &timulate 3one resorption C#t!1 "es o Ha$e e--e#ts on 3one remodeling PARATHYROID HORMONE St+)ct)+e o &e#reted 3y #hie- #ells o- parathyroid gland o 0H degraded in li$er and Eidney C!"t+!' !f Sec+et !" o serum #al#ium stimulate PTH se#retion o se#retion *(T a3olished 3y high #al#ium le$els sigmoidal relationship 3tD serum #al#ium and serum PTH o phosphate indire#tly stimulate PTH se#retion 3y #al#ium magnesium same a#tion on PTH 3ut hal- as potent Act !"s !" B!"e o 3one resorption A*. #al#ium mo3ili=ation -rom 3one o no and a#ti$ity o- osteo#lasts and osteo#lasti# 3one dissolution o 3one resorption 3one -ormation o stimulate release o- #ytoEines -rom osteo3lasts that a#t to osteo#last a#ti$ity o PTH #al#ium permea3ility #al#ium in-lu' &timulates a#ti$e #al#ium transport out o- osteo3last sur-a#e and into 1,) This de#reases 3one -luid #al#ium and in#reases 1,) #al#ium o )a$ors 3one deminerali=ation o This pro#ess is !ste!c#t c !ste!'#s s Act !"s !" K ,"e# o #al#ium rea3sorption in thi#E as#ending loop o- henle o PTH serum #al#ium -iltered load -or #al#ium o "enal a#tion mediated 3y #A!P 5thus see urinary #A!P9

Page 33 o- 173

Re"&' Act !"s !" P%!s$%&te Re&0s!+$t !" o 0oDers Tm -or phosphate rea3sorption renal phosphate e'#retion Re"&' Act !"s !" B c&+0 Re&0s!+$t !" o renal 3i#ar3 rea3sor3 5leads to #hloride #on#entrations9 GI &0s!+$t !" o &timulates renal 1a8hydro'ylase Fit .2 a#ti$ation to #al#itriol o ,al#itriol /@ #al#ium and phosphate a3sorption

6ITAMIN D St+)ct)+e7 S#"t%es s &", C!"t+!' !f Sec+et !" o (3tained in sEin and sunlight o .2 24 hydro'y#hole#al#i-erol 5in li$er9 1<258dihydro'y#al#i-erol or c&'c t+!' 5in Eidney9 ,al#itriol is the A,T@F1 )("! o PTH and serum phosphate regulate 1&?%#,+!.#'&se &ct / t# o PTH stimulates en=yme synthesis Dhile phosphate stimulates a#ti$ation #a in#reases PTH se#retion en=yme o #al#itriol 3ound to plasma protein t+&"sc&'c fe+ " Act !"s o #al#ium and phosphate le$els -a$ora3le -or 3one minerali=ation o in#rease /@ a3sorption o- the tDo o Fit . re#eptors in gut< 3one< Eidneys o ,al#itriol inhi3its #ellular proli-eration in some tumors and psoriasis o ,al#itriol le$els are in#reased in pregnan#y o Actions in GI system @n#reases synthesis o- c&'0 ", "< transporter o- #al#ium< !g< P(428 o Actions in Bone &ynergi=es D/ PTH on 3one and in#rease oste#lasti# a#ti$ity and 3one turno$er Mltimately pro$ides high 3one -luid #al#ium and phosphate #on#entrations -or 3one minerali=ation .e-i#ien#y: ri#Eets and osteomala#ia o Actions in Kidney &timulates #al3indin synthesis -or renal #al#ium rea3sorption

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ACTIONS OF OTHER HORMONES ON BONE Est+!*e" o &timulatory e--e#ts on osteo3lasti# -un#tion o A-ter menopause< de#rease rate o- 3one loss o Androgens ha$e same e--e#t as estrogen on 3one G')c!c!+t c! ,s o .e#rease a#ti$e #omponent o- /@ #al#ium a3sorption o @n#reases urinary #al#ium e'#retion o Produ#es mild se#ondary hyperparathyroidism T%#+! , H!+(!"es o 1'#essi$e le$els #an produ#e osteoporosis PARATHYROID PATHOLOGY J)st "s Sect !" ARATHYROID GLAND$ Anato'y i# Normal parathyroid glands each "eigh &'()' mg -ach individual typically has four glands, so that the average total parathyroid tissue mass in the adult is 6<'(6B' mg# ii# %he superior pair of parathyroid glands arise from the fourth branchial pouches in the embryo iii# %he superior parathyroid glands may be attached to the thyroid capsule posteriorly or, rarely, embedded in the thyroid gland itself iv# %he inferior parathyroid glands develop from the third branchial pouch, as does the thymus gland v# %here location is variable, typically near the lo"er pole of the thyroid gland lateral to the trachea vi# ectopic glands are typically found in the anterior mediastinum# vii# About 6'@ of people have additional (supernumerary) parathyroid glands# Histolo!y i# composed of three different cell typesA chief cells, clear cells, and o$yphil cells# ii. +hie, %ells are small in diameter ()(D m) "ith central nuclei and are thought to be responsible for the synthesis and secretion of parathyroid hormone (3%,)# iii# +lear %ells are probably chief cells "ith an increased glycogen content# i$. Oxyphil %ells appear in the parathyroid glands after puberty# %hey are larger than chief cells (B( 6' m), and their number increases "ith age# .t is not clear "hether these cells secrete 3%, and

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"hether they are derived from chief cells# hysiolo!y i# Circulating levels of 3%, can change "ithin seconds after an alteration in serum calcium# ii# %here is an inverse sigmoidal relationship bet"een 3%, and blood calcium- ;o" ionized calcium concentrations ma$imally stimulate secretion, "hereas increases in calcium suppress the production and release of 3%,# iii# 3%, secretion is e$quisitely sensitive to very small changes in the calcium concentration, "hich have substantial effects on the rate of hormone synthesis and release# iv# %he e$tracellular calcium-sensing receptor (Ca +), e$pressed by parathyroid cells, detects changes in the e$tracellular calcium concentration, is activated by increases in the calcium concentration and couples to intracellular path"ays that produce inhibition of hormone secretion and parathyroid cell proliferation v# Chronic hypocalcemia is also a stimulus to the proliferation of parathyroid cells, "hich eventually results in glandular hyperplasia# Causes of ,ypercalcemia +aised 93%,: ,yperparathyroidism 3rimary (adenoma 0 hyperplasia)9U: econdary9V: %ertiary9V: *ecreased 93%,: ,ypercalcemia of malignancy9U: Kitamin * to$icity .mmobilization %hiazide diuretics

5amilial hypocalciuric hypercalcemia 1ranulomatous disease (sarcoidosis) HY 1R ARATHYROIDI$0 6# ri'ary hyperparathyroidis'-due to e$cessive production and release of 3%, a# %he prevalence of hyperparathyroidism is appro$imately 6A6''' in the Hnited tates, and the incidence of the disease increases "ith age# b# %he patient group most frequently affected is postmenopausal "omen# c# may be caused by adenoma, hyperplasia, or carcinoma d# +hie, %ell adeno'as are D7@ of all cases# e# primary hyperparathyroidism is a more common cause of asymptomatic elevated blood calcium (incidental hypercalcemia) f# calcium affects the functioning of nearly every organ system,so the symptoms and signs can vary, very "idely, miss diagnosis are often psychiatric disorders, a malignancy, or, less commonly, a granulomatous disease such as tuberculosis or sarcoidosis g# stones containing calcium phosphate or calcium o$alate occur in 6'(67@ of patients Table 1583 $y'pto's and $i!ns o, ri'ary Hyperparathyroidis'. $yste'i% ?ea!ness -asy fatigue ?eight loss Anemia Anore$ia 3ruritus -ctopic calcifications Ne"ropsy%hiatri% and Ne"ro'"s%"lar O%"lar 8and !eratopathy +ardia% ,ypertension Renal tones 3olyuria, polydipsia 2etabolic acidosis $*eletal and Rhe"'atolo!i% Esteopenia 3athologic fractures 8one pain 1out 3seudogout Chondrocalcinosis Esteitis fibrosa cystica

hortened R% interval 8ro"n tumors of bone

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*epression 3oor concentration 2emory deficits 3eripheral sensory neuropathy 2otor neuropathy 3ro$imal and generalized muscle "ea!ness

Concentrating defects GI Nephrocalcinosis 3eptic ulcer disease 3ancreatitis Constipation Nausea Komiting

h# 3atients may e$perience increased bone turnover and progressive loss of bone mineral, especially in postmenopausal "omen i# %he diagnosis of primary hyperparathyroidism is confirmed by at least t"o simultaneous measurements of calcium and intact 3%, +a"ses o, ri'ary Hyperparathyroidis'. olitary adenomas ,yperplasia 2ultiple adenomas Carcinoma D'(D7@ 6'@ W<@ W<(7@

4#

!#

l#

arathyroid hyperplasia) an enlargement or abnormality of all four glands# i# Eft part of an autosomal dominant '"ltiple endo%rine neoplasia (01N) syndromes ii# 2-N-6, caused by mutations in the MEN1 gene, "hich encodes the protein 'enin, have high penetrance of hyperparathyroidism, affecting as many as F7@ of patients# iii# Abnormalities are found in all four glands# iv# +ecurrent hyperparathyroidism, even after successful surgery, is common v# ,yperparathyroidism also occurs in 2-N-<, although at a much lo"er frequency in 2-N-<a (about <'@) and rarely in 2-N-<b# vi# 5amilial hyperparathyroidism, "ithout other features of 2-N syndromes, characteristically involves all four glands# vii# 8oth the hyperparathyroidism-4a" tumor syndrome and familial isolated hyperparathyroidism are causes for autosomal dominant hyperparathyroidism, caused by inactivating germline mutations in the HRPT2 gene that encodes the protein para,ibro'in# 01N)1 - 0"ltiple 1ndo%rine Neoplasia $yndro'es)1 i# 8enign parathyroid tumors (very common) ii# 3ancreatic tumors (benign or malignant) iii# 1astrinoma, .nsulinoma, 1lucagonoma, K.3oma (both rare) iv# 3ituitary tumorsA 1ro"th hormone-secreting, 3rolactin-secreting, AC%,-secreting 01N)6a ( 0"ltiple 1ndo%rine Neoplasia $yndro'es)6a

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i# 2edullary carcinoma of the thyroid ii# 3heochromocytoma (benign or malignant) iii# ,yperparathyroidism (uncommon) m# 01N)6b ( 0"ltiple 1ndo%rine Neoplasia $yndro'es)6b i# 2edullary carcinoma of the thyroid ii# 3heochromocytoma iii# 2ucosal neuromas, ganglioneuromas iv# 2arfanoid habitus v# ,yperparathyroidism (very rare) n# arathyroid %ar%ino'a is a rare malignancy, but the diagnosis should be considered in a patient "ith severe hypercalcemia and a palpable cervical mass# i# Kascular or capsular invasion by tumor cells is a good indicator of malignancy, but these features are not al"ays present# ii# .n many cases, local recurrences or distant metastases to liver, lung, or bone are the clinical findings that support this diagnosis# iii# Appro$imately <'@ of patients "ith the hyperparathyroidism-4a" tumor syndrome and germline mutations in the HRPT2 gene develop parathyroid cancer# iv# mutations in HRPT2 have also been found in familial isolated hyperparathyroidism and in sporadic parathyroid cancers# <# $e%ondary hyperparathyroidis'-glandular hyperplasia from a defect outside the parathyroids# i# may be observed in patients "ith severe calcium and vitamin * deficiency states ii# .n patients "ith chronic renal failure, there are many causative factors that contribute to the often dramatic enlargement of the parathyroid glands# %hese includeA 6# decreased 6,<7-(E,)<* production, <# reduced intestinal calcium absorption, &# s!eletal resistance to 3%,, )# +enal phosphate retention 3. .A0ILIAL (-1NIGN# HY O+AL+I=RI+ HY 1R+AL+10IA a# Assoc# "ith asymptomatic hypercalcemia b# elevated serum calcium and magnesium, normal or mildly elevated 3%, levels, hypocalciuria c# inheritance is autosomal dominant, due to point mutations in one allele of the Ca + gene d# the ability to detect serum calcium is faulty in both the !idney and parathyroid e# 3arathyroid chief cells missense the serum calcium as Mlo",M and 3%, secretion occurs "hen it should be suppressed, produces inappropriately normal or slightly high 3%, levels f# .n the !idney, calcium is detected (inappropriately) as lo", and calcium is retained g# they are not thought to suffer the consequences of end-organ dysfunction characteristic of long-standing hyperparathyroidism and hypercalcemia# %hese individuals are generally spared the nephrolithiasis, lo" bone mass, and renal dysfunction that can occur in patients "ith primary hyperparathyroidism# . h# %heir hypercalcemia does not remit "ith surgery unless a total parathyroidectomy is performed# urgery is not recommended because the condition is benign# i# can cause rare neonatal se2ere pri'ary hyperparathyroidis') usually the result of consanguinity i# have mar!ed hypercalcemia, dramatic elevations in serum 3%,, bone demineralization at birth, hypotonia, and profound failure to thrive ii# require total parathyroidectomy in the ne"born period for survival#

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4. HY 1R+AL+10IA O. 0ALIGNAN+Y a# occurs in appro$imately 6'@ of all malignancies b# .t is commonly seen in solid tumors, particularly squamous cell carcinomas (eg, lung, esophagus), renal carcinoma, and breast carcinoma c# occurs in more than one third of patients "ith multiple myeloma, unusual in lymphomas and leu!emias# d# %his is humoral hypercalcemia, "hich mimics primary hyperparathyroidism and results from a diffuse increase in bone resorption induced by high circulating levels of 3%,r3 e# typically occurs in advanced malignancyXthe average survival of hypercalcemic patients is usually several "ee!s to months f# often severe and symptomatic, "ith nausea, vomiting, dehydration, confusion, or coma ;. Di,,erential Dia!nosis o, Hyper%al%e'ia a# 3rimary hyperparathyroidismA Adenoma, Carcinoma, ,yperplasia b# 5amilial (benign) hypocalciuric hypercalcemiaA .nheritedA Ca + mutations, AcquiredA autoantibodies inhibiting the Ca + c# 2alignancy-associated hypercalcemiaA olid tumors (ma4ority "ith e$cess 3%,r3 production), 2ultiple myeloma, Adult %-cell leu!emia and lymphoma d# %hyroto$icosis e# *rugsA %hiazides, ;ithium, Kitamin * or A into$ication f# 1ranulomatous diseasesA arcoidosis, %uberculosis, ,istoplasmosis etc# g# 2il!-al!ali syndrome, Adrenal insufficiency HY O ARATHYROIDI$0 > $1=DOHY O ARATHYROIDI$0 6# A common cause of lo" serum total calcium is hypoalbuminemia# <# ,ypocalcemia- from reduced 3%, secretion caused by hypoparathyroidis' or hypomagnesemia# &# .t can also be due to decreased end-organ responsiveness to 3%, despite adequate or even e$cessive levels of the hormoneJ this is termed pse"dohypoparathyroidis'. )# 2ost cases are the result of inadvertent trauma to, removal of, or devascularization of the parathyroid glands during thyroid or parathyroid surgery- postoperative hypoparathyroidism (rangeA '#<(&'@) depends on the e$tent of the antecedent surgery and the surgeon's s!ill in identifying normal parathyroid tissue and preserving its blood supply ;. +a"ses o, Hypoparathyroidis' a# Complication of thyroid, parathyroid or laryngeal surgery b# Autoimmune destruction, Autoimmune polyendocrine failure syndrome type 6 ( A $)1) c# econdary to magnesium depletion i# may occur from chronic alcoholism, diarrhea, and drugs such as loop diuretics, aminoglycoside antibiotics, amphotericin 8, and cisplatin ii# 2agnesium is required to maintain normal 3%, secretory responses# Ence body magnesium stores are replete, 3%, levels rise appropriately in response to the hypocalcemia, and the mineral imbalance is corrected# iii# Classic featuresA vitiligo, mucocutaneous candidiasis, adrenal insufficiency d# 3ost-6&6. therapy for 1raves' disease or thyroid cancer e# econdary to accumulation of iron (thalassemia, hemochromatosis) or copper (?ilson's) f# 1enetic forms of hypoparathyroidismA *i1eorge or <<q deletion syndrome, Autosomal recessive or autosomal dominant mutations in pre-pro3%, gene, O-lin!ed hypoparathyroidism, 2utations in transcription factors involved in parathyroid development (eg, 1C28, 1A%A&), 2itochondrial *NA mutations g# Activating mutations of the Ca + i# present "ith autosomal dominant hypocalcemia and hypercalciuria# 8oth defects are due to overly sensitive Ca +s, "hich turn off 3%, secretion and renal calcium reabsorption at subnormal serum calcium levels# h# %umor invasion (very rare) B# %he mineral disturbance occurs because the amount of 3%, released is inadequate to maintain normal serum calcium concentrations, mainly due to the loss of the renal calcium-conserving effects of 3%, and the inability to generate 6,<7-(E,) <*#

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C# ,ypocalcemia results, and hyperphosphatemia is also observed because the pro$imal tubular effect of 3%, to promote phosphate e$cretion is lost# D# 8ecause 3%, is required to stimulate the renal production of 6,<7-(E,) <*, levels of 6,<7-(E,)<* are lo" /0 lead to reduced intestinal calcium absorption# F# 8ecause 3%, is deficient, urinary calcium e$cretion is often high, despite the hypocalcemia# 6'# .n pse"dohypoparathyroidis', 3%, levels are usually elevated, but the ability of target tissues (particularly !idney) to respond to the hormone is subnormal# i# type 6, reduced ability of 3%, to generate an increase in the cA23 ii# assoc# "G features collectively !no"n as Albri!ht?s hereditary osteodystrophy/ short stature, obesity, mental retardation, round facies, shortened fourth and fifth metacarpal and metatarsal bones, and subcutaneous ossifications b# type <, urinary cA23 is normal but the phosphaturic response to infused 3%, is reduced 66# $A symptoms and signs of hypocalcemia are similar, regardless of the underlying cause a# ystemicA Confusion, ?ea!ness, 2ental retardation, 8ehavioral changes b# NeuromuscularA 3aresthesias, 3sychosis, eizures, Carpopedal spasms, Chvoste!'s and %rousseau's signs, *epression, 2uscle cramping, 3ar!insonism, .rritability c# CardiacA 3rolonged R% interval, %-% "ave changes, Congestive heart failure d# Cataracts, -namel hypoplasia of teeth, ;aryngospasm, tridor

Laboratory .indin!s in Hypo%al%e'ia. $er"' +a6@ ,ypoparathyroidism 3seudohypoparathyroidism 2agnesium depletion econdary hyperparathyroidism& $er"' O438 ,N ,N N N, , N6 Inta%t TH , N6 6;) =rinary %A0 (OH#D3 Response to TH In,"sion N N N N
<

N N

6<# %reatmentA a# .n some patients "ith decreased parathyroid reserve, only situations of increased stress on the glands, such as pregnancy or lactation, induce hypocalcemia# b# .n other patients, 3%, deficiency is a chronic symptomatic disorder necessitating lifelong therapy "ith calcium supplements and vitamin * analogues# c# All patients so treated should have periodic monitoring of serum calcium, urinary calcium, and renal function# d# 3atients "ith autoimmune hypoparathyroidism should also be e$amined regularly for the development of adrenal insufficiency, hypothyroidism, and diabetes mellitus as "ell as other complications of A3 -6# O$T1O ORO$I$)since "e learned it once before . "ill briefly summarize 6# Esteoporosis is defined as lo" bone mass- normal in composition but reduced in amount <# 8one mass accrues rapidly throughout childhood and very rapidly in adolescence 3ea! bone mass is accomplished at appro$imately age <7 yearsJ &# 8one mass then remains relatively stable through the adult years )# rapid loss of bone in "omen at the time of menopause 7# .n the later stages of life, both men and "omen continue to lose bone, although at a slo"er rate than that seen at the time of menopause#

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B# Achieving ma$imum pea! bone mass depends on optimal nutrition, physical activity, general health, and hormonal e$posure throughout childhood and adolescence C# After bone gro"th is completed, the bone mass is determined by the level of pea! bone mass that "as attained and the subsequent rate of loss D# +is!s of EsteoporosisA a# Aging (senile or involutional b# Connective tissue diseases c# Esteogenesis imperfect d# ,omocystinuria e# -hlers-*anlos syndrome f# 2arfan syndrome g# *rug-inducedA Corticosteroids, Alcohol, %hyroid hormone, Chronic heparin, Anticonvulsants h# 2ultiple myeloma, ystemic mastocytosis i# .mmobilization 4# -ndocrine A,ypogonadism, ,ypercortisolism, ,yperthyroidism, ,yperparathyroidism !# ubtotal gastrectomy, 2alabsorption syndromes Ebstructive 4aundice, 8iliary cirrhosis

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F# 8ecause bone remodeling involves the coupled resorption of bone by osteoclasts and the deposition of ne" bone by osteoblasts, bone loss could result from increased bone resorption, decreased bone formation, or a combination 6'# Esteoclasts have estrogen receptors and could respond directly to estrogen deficiency, but there is strong evidence that cyto!ines such as interleu!in-B are released from cells in the bone microenvironment in estrogen deficiency# %hese cyto!ines increase the e$pression of +ANQ-; and decrease the e$pression of E31 on stromal cells and osteoblasts/0 imbalance in bone remodeling that favors increased osteoclastogenesis and bone resorption# 66# %he capacity of the intestine to absorb calcium diminishes "ith age/0 age-related bone loss is a relative deficiency of dietary calcium and 6,<7-(E,)<* 6<# Can be caused by high 3%, levels "hich increases "ith age- hyperparathyroidism of aging may thus result from the combined effects of age on the !idney, intestine, and parathyroid glands# 6&# %ypical osteoporotic fractures occur in the spine, the hip, and the "rist 6)# vertebral bodies may be crushed, resulting in loss of height, or may be "edged anteriorly, resulting in height loss and !yphosis 67# %reatmentA calcium and Kitamin * supplementation, -strogen replacement reduces bone loss, relieves hot flushes after menopause, and reduces fracture ris!, bisphosphonates that directly inhibit osteoclastic bone resorption, +alo$ifene, a selective estrogen response modulator, inhibits bone resorption as estrogen does, but does not induce endometrial changes and can dec# ris! of breast cancer, %he only agent currently available that can stimulate bone formation is parathyroid hormone (3%,6-&)) (teriparatide), a single daily in4ection of 3%, stimulates bone formation and, to a lesser e$tent, bone resorption, resulting in net gains in bone density and decreased fracture ris!# O$T1O0ALA+IA since "e learned it once before . "ill briefly summarize 6# defined as a defect in the mineralization of bone <# it occurs in the young, it also affects the mineralization of cartilage in the gro"th plate, a disorder called ri%*ets. &# Kitamin * deficiency is becoming more common in the Hnited tates because of decreased sunlight e$posure, increased use of sunscreens, and limited dietary sources of vitamin *# a# .n the early stage, reduced calcium absorption produces secondary hyperparathyroidism, preventing hypocalcemia at the cost of increased renal phosphate e$cretion and hypophosphatemia b# .n later stages, hypocalcemia ensues, and hypophosphatemia progresses because of the combined effects of reduced absorption and the phosphaturic action of 3%, )# 3hosphate deficiency "ith osteomalacia is usually caused by inherited or acquired renal phosphate "asting 7# Esteomalacia and hypophosphatemia can also result from tumors that are typically mesenchymal in origin and often located in the head and nec! region B# 3atients "ith osteomalacia have bone pain, muscle "ea!ness, and a "addling gait# C# %he hallmar! of the disorder, ho"ever, is the pseudofractureA local bone resorption that has the appearance of a nondisplaced fracture, classically in the pubic rami, clavicles, or scapulas D# .n children "ith ric!ets, the leg bones are bo"ed (osteomalacia means Msoftening of bonesM), the costochondral 4unctions are enlarged (Mrachitic rosaryM), and the gro"th plates are "idened and irregular, reflecting the increase in unmineralized cartilage F# 8iochemically, the hallmar!s of vitamin *(deficient osteomalacia are hypophosphatemia, hyperparathyroidism, variable hypocalcemia, and mar!ed reductions in urinary calcium to less than 7' mgGd 6'# %reatment "ith vitamin * or aggressive phosphate replacement in patients "ith renal phosphate "asting "ill reverse osteomalacia or heal ric!ets#

ADRENAL PHYSIOLOGY Ke t%s Sect !" $. Adrenal glands GENERAL= 3ilateral and a3o$e the Eidneys adrenal medulla is neurologi# o site o- *1< 1P@< .A produ#tion adrenal #orte' is glandular o site o- mineralo#orti#oid< glu#o#orti#oid and se' hormone produ#tion

ADRENAL MEDULLA= ANATOMY= o C%+!(&ff " ce''s 8$%e!c%+!(!c#tes9 ,omponent o- &*& &timuli -or &*& also stimulate se#retion o- adrenal medullary hormones o ,ate#holamines se#reted in 3lood 5so hormones< *(T *Ts9 o @nner$ated 3y &*& preganglioni# that release A,h "elease *1 and 1P@ on postganglioni# o Primary se#retory produ#t o- the medulla is EPI o C%+!(&ff " *+&")'es !em3rane 3ound that #ontain #ate#holamines< ATP and c%+!(&*+&" " o (nly 20H o- #ir#ulating *1 #ome -rom medulla SYNTHESIS OF CATECHOLAMINES o Tyrosine .(PA $ia t#+!s "e %#,+!.#'&se 5rate8limiting step9 &*& pregang stimulate adrenal to in#rease a#ti$ity o- tyrosine hydro'ylase &ynthesis 3egins in #tytoplasm sin#e en=yme in #ytoplasm o .(PA then to granule .(PA to *1 $ia DA 0?%#,+!.#'&se o NE t! EPI $ia $%e"#'et%&"!'&( "e N?(et%#'t+&"sfe+&se 8PNMT9

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This o##urs in the #ytoplasm as *1 di--uses out o- granule 1P@ into granule and stored D/ ATP and #hromagranin

DEGRADATION OF CATECHOLAMINES o .egraded 3y (!"!&( "e !. ,&se 8MAO9 &", c&tec%!'?O?(et%#'t+&"sfe+&se 8COMT9 o Predominant -ate is methylation 3y ,(!T in nonneuronal tissue liEe li$er and Eidney o Mrinary /&" ''#(&",e' c &c , 86MA9 &", (et&"e$%+ "e Assess these le$els to assess #ate#holamine produ#tion in a patient ACTIONS OF CATECHOLAMINES o A#ti$ate and re#eptors 1P@ greater e--e#ts on 2 than *1 &imilar -' on 121 o 1 DorEs $ia a /; re#eptors that stimulate phosphatidyinositol o 2 DorEs on /i re#eptors that @*H@+@T #A!P o 12 DorE on /s re#eptors to &T@!M0AT1 #A!P 2 e--e#ts e--e#ts 1P@ SS *1 1P@ O *1 !eta3oli# !eta3oli# /ly#ogenesis /lu#oneogenesis 0ipolysis .e#rease insulin se#retin ,alorigenesis Faso#onstri#tor in most tissues liEe @n#reases insulin se#retion sEeletal Fasodilator in sEeletal mus#le @n#reases mean arterial pressure *o #hange in mean arterial .ilation o- pupil pressure &Deating +ron#hodilation &phin#gter #ontra#tion o a#ti$ate %!+(!"e se"s t /e ' $&se 8HSL9 in adipose tissue to #ataly=e hydrolysis o- Tgs to ))A and gly#erol ))A are taEen up 3y li$er and o'idi=ed 3y 3eta o'idation Too mu#h a#etyl ,oA #an lead to produ#tion o- Eetone 3odies @n#rease 3asal meta3olism 5#alorigeni# e--e#t9 *& e--e#ts ,annot #ross +++ 3ut has indire#t e--e#ts mediated through #hanges in #ardia# -un#tion @n#rease arousal< sensation D/ 1P@ admit des#ri3ed as an'iety or -eeling oimpending doom

o o

ADRENAL CORTEN ANATOMY Xona *'!(e+)'!s& o ,on$ert #orti#osterone to &',!ste+!"e Primary a#tion: regulate mineral meta3olism "enal retention o- *a Promote se#retion o- H/> Has minimal glu#o#orti#oid a#ti$ity o Also maEe deo'y#orti#osterone 5DOC9 o "egulated 3y Ang@@ @nnermost layers: o F&sc c)'&t& glu#o#orti#oid produ#tion @mportant regulators o- 3lood glu#ose !ain hormone: c!+t s!'

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Has some mineralo#orti#oid a#ti$ity Ret c)'&+ s androgen produ#tion DHEA &", &,"+!ste"e, !"e ,an 3e #on$erted to testosterone and estrogen o These =ones ha$e CYP17 817&?%#,+!.#'&seA177-> '#&se9 /lomerulosa does not 1n=yme need to maEe #ortisol and se' steroids o ,ontrolled 3y ACTH P+!*este+!"e -ound in all three layers and pre#ursors o- other 3iologi#ally a#ti$e #orti#al hormones !ineralo#orti#oids and glu#o#orti#oids #an intera#t D/ ea#h other6s re#eptors o

SYNTHESIS OF ADRENAL CORTICOSTEROIDS o C%!'este+!' is the pre#ursor -or steroid produ#tion o rate8limiting step o- steroid -ormation: s ,e c%& " c'e&/&*e 8SCC9 e"2#(e remo$es 6 #ar3ons -rom #holesterol and maEes $+e*"e"!'!"e indu#ed 3y A,TH in -as#i#ulata and reti#ularis A*. Ang@@ in glomerulosa o i- there is an en=yme 3lo#E and pre#ursors -ormed 3/4 3lo#Eage a##umulate< nature ohormones se#reted 3y endo#rine #hange remarEedly &,+e"!*e" t&' s#",+!(e a3ility o- maEe #ortisol @!PA@"1.7 leading to: o e'#essi$e androgen produ#tion and mas#ulini=ation a3normal se' hair de$elopment< male pattern 3aldness and #litoral enlargement in Domen ALDOSTERONE o Re*)'&t !" sec+et !"= Ang @@ is a potent stimulator and its a#tions are:

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Faso#onstri#tion groDth and $as#ularity o- glomerulosa &,, en=yme a#ti$ity aldosterone synthesis $as#ular $olume renin Ang @ Ang @@ t+&"s$!+t " t%e 0'!!, loD a--inity to al3umin< trans#ortin 508%0H are 3ound t W O 20 minutes &ct !"s= renal sodium retention Dater retention due to sodium retention H/> se#retion in Eidney E&',!ste+!"e esc&$eF #ontinuous adlosterone admit *a retend $olume e'pand 3ut not inde-initely $as# $olume /)" *a deli$ery to nephron renal sodium e'#retion A*. also there is stimulation o- ANP

CORTISOL AND GLUCOCORTICOIDS o Produ#ed in -as#i#ulata A*. reti#ularis *(T glomerulosa o /lomerulosa maEes DOC &", c!+t c!ste+!"e Ha$e mineralo#orti#oid A*. glu#o#orti#oid a#ti$ity o &teroidogenesis in -as#i#ulata and reti#ularis regulated 3y A,TH A,TH stimulates groDth and $as#ularity A-ter hypophyse#tomy 8S loss o- A,TH atrophy o- those =one

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o o

o o

C!+t s!' %&s "e*&t /e fee,0&c1 !" ACTH &", CRH sec+et !" Re*)'&t !" !f c!+t s!' sec+et !" &T"1&& 5 ,"H se#retion A,TH se#retion9 HLP(/0L,1!@A H1!(""HA/1 A,TH A,TH and #ortisol shoD , )+"&' /&+ &t !" PeaEs Gust 3e-ore DaEe in morning and -all during day Mec%&" s( !f &ct !" !f ACTH @n#rease #A!P in those =ones Mec%&" s( !f &ct !" !f C!+t c!ste+! ,s Adrenal steroid di--use into target #ell and intera#t D/ intra#ellular re#eptors Hormone 3inds to re#eptor8H&P #omple' and releases H&P -rom .*A Higher a--inity noD -or steroid8responsi$e element o- .*A (n#e 3ound to .*A< a#ts as a trans#ription -a#tor T+&"s$!+t &", I"&ct /&t !" !f C!+t s!' +inds to CBG 5%5H9 0i$er is site o- steroid ina#ti$ation T W O %0 mins Met&0!' c Act !"s Proteolyti# and glu#oneogeni# hormone Antagoni=es insulin on mus#le and adipose tissue glu#ose uptaEe o &paring glu#ose -or 3rain @n#reases li$er output o- glu#ose 3y in#rease glu#ose produ#tion -rom *')c!"e!*e"es s D/ && &s ,!( "&"t c&+0!" s!)+ce 0ipolyti# e--e#ts are !@*(" 1'#ess total 3ody -at in#rease o ,ortisol stimulates appetite o @n#rease 3lood glu#ose le$el in#reases insulin se#retion @nsulin is a strong lipogeni# hormone ,ortisol is U1A> lipolyti# hormone H#$e+c!+t s!' s( leads to ce"t+ f)*&' f&t , st+ 0)t !" &", & 0)ff&'! %)($ ,ortisol de-i#ien#y *(T liEely to produ#e hypogly#emia unless -ood is Dithheld or person is stressed C!+t s!' ESSENTIAL f!+ $+!$e+ (!0 ' 2&t !" !f $+!te "s f!+ *')c!se $+!,)ct !" Act !"s !" B!"e @n#rease 3one resorption .e#rease intestinal ,a?2 a3sorption and renal ,a?2 rea3sorption 0(U1"& serum ,a?2 #on#entration A#t dire#tly on osteo3lasts Dhere they inhi3it 3one -ormation and suppress #ollagen -ormation 1'#ess use hoDe$er #an lead to osteoporosis C6 &ct !"s A3sen#e o- #ortisol< peripheral resistan#e drops ,ortisol stimulate 1P( synthesis in#rease "+, produ#tion A"e( & f ,ef c e"tC $!'#c#t%e( & f e.cess /e Act !"s !" CT @nhi3it -i3ro3last proli-eration and #ollage -ormation &Ein thins and readily damaged

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,T support o- #aps impaired #ap inGury or 3ruising Act !"s !" K ,"e# @nhi3its A.H se#retion and a#tion UeaE mineralo#orti#oid stimulate *a/Dater a3sorption @n#reases /)" 3y in#reasing ,( and a#ting dire#tly on Eidney Act !"s !" M)sc'e 1'#essi$e mus#le DeaEness 1'#ess hypoEalemia mus#le DeaEness GI &ct !"s &timulates gastri# a#id se#retion *e#essary -or integrity and -un#tion o- /@ tra#t Hyper#ortisolism asso#iated D/ Deight gain A"t ? "f'&((&t!+# &", I(()"!s)$$+es /e Act !"s @nhi3it phospholipase A2 to pre$ent P/< leuEotriene< throm3o'ane synthesis &ta3ili=es lysosomal mem3ranes release o- proteolyti# en=ymes @nhi3it U+, migration and phago#yti# a#ti$ity o- P!*s )i3ro3lasti# proli-eration inhi3ited Uhen #ortisol le$els high 3ody de-ense me#hanism against in-' inhi3ited /lu#o#orti#oids #ontraindi#ated as sole med -or T' o- in-e#tions @nhi3its immune response de#rease #ir#ulating T #ell *(T A3s produ#tion 3y + #ells Ps#c%!'!* c Act !"s Alter mood and 3eha$ior 1'#ess -eeling o- Dell 3eing< 3ut #ontinued 's leads to emotional la3ility and depression ,an lead to insomnia and de#reased "1! sleep

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ADRENAL ANDROGENS o .H1A and androstenedione in the reti#ularis o ,on$erted to stronger androgens in peripheral tissues o Adrenal maGor sour#e o- androgens -or Dmen &timulate pu3i# and a'illary hair de$elopment

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ADRENAL PATHOLOGY D&"s Sect !" " O "o33ins %th 1d.7 ! O !#Phee Pathophys. te't3ooE 5note< @ printed these #hapters -rom !#Phee -rom o-- the #omputer< so @ don6t ha$e JrealK page num3ers to re-eren#e to7 @ re-eren#e the #hapter N instead7 sorry9 #p O #oursepa#E 5*ote7 (!st c$ "f! s 0!',e,9 A,+e"&' C!+te. P&t%!'!*# 8M c% -17 R1->77 c$3739= 1. /eneral Adrenal Anatomy and Phys. a. ,orti#al Xones: J/)"K: /lomerulosa )as#i#ulata "eti#ularis i. J&alt8&ugar8&e'K: !ineral#ort. /lu#o#ort. Androgens 2. ,ushing6s &yndrome 5#p25%<4%59: aEa Hyper#ortisolism or hyperadreno#orti#alism a. Any #ondition #ausing ele$ation in glu#o#orti#oids 3. Treat D/ surgery< or drugs that de#rease #ortisol synthesis 5aminoglutethimide or ortho8 para8...9 #. 3 (& " c&)ses !f C)s% "*s S#",+!(e= .etailed des#riptions o- spe#i-i# #auses -urther doDn i. Administration o- e.!*e"!)s *')c!c!+t c! ,s= M!st c!((!" c&)se ii. Primary pituitary d= Dith A,TH hyperse#retion 5most #ommon endogenous #ause9 iii. Adrenal adenoma< #ar#inoma< or hyperplasia: ,auses e'#ess #ortisol se#retion i$. 1#topi# A,TH 3y non8endo#rine neoplasm 5small #ell lung #an#er9 d. ,auses #an 3e A,TH .ependent o- @ndependent: i. A,TH .ependent 5hyper#ortisolism dire#tly related in#reased le$els o- A,TH9: ,ushing6s .= 5A,TH8se#reting pituitary adenoma9< 1#topi# A,TH &yndrome7 ii. A,TH @ndependent: )un#tioning Adreno#orti#al tumor7 hyper#ortisolism is *(T related to le$els o- A,TH iii. @atrogeni#: 1'ogenous glu#o#orti#oid administration e. Histologi# -eatures o- ,ushing6s &yndrome: i. C+!!1e H#&' "e C%&"*e= A,TH 3asophili# granules repla#ed 3y Eeratin 1. T%)s7 t%e %#&' " 2e, t ss)e s "!+(&'I -. Hypothalami# ,"H Hyperse#retion: 1'#essi$e se#retion o- hypothalami# ,"H o- e#topi# ,"H #an #ause di--use hyperplasia o- pituitary #orti#otroph #ells g. ,ushing6s .=: Pituitary adenoma that hypse#retes A,TH 5A,TH dependent9 i. !ost #ommon #ause o- non8iatrogeni# 5endogenous9 hyper#ortisolism ii. 5' more #ommon in Domen7 typi#ally o##urs in 20s 4 20s iii. !i#roadenoma: T 1 #m7 !a#roadenoma: S 1 #m7 $ery rare

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1. !i#roadenomas that don6t #ause mass e--e#t are the more #ommon i$. ,hroni# A,TH hyperse#retion 3y tumor #auses 3ilateral adrenal #orte' hyperplasia $. A,TH hyperse#retion is disorderly< episodi#< and random7 normal diurnal rhythm a3sent $i. Nee, & -3 %!)+ )+ "e f+ee c!+t s!' test t! c!"f +( % *% 'e/e's !f c!+t s!' 5sin#e A,TH se#retion is random< #an6t Jspot #he#EK -or #ortisol le$els9 $ii. !ost 5 0H9 o- pts ha$e high A,TH and #ortisol response to ,"H stimulation $iii. De.&(et%&s!"e test !"'# $&+t &''# s)$$+esses ACTH &", c!+t s!' sec+et !" i'. .espite high A,TH< adrenals and pituitary -ail to respond to stress7 #hroni# hyper#ortisolism has desensiti=ed ,"H se#retion 3y hypothalamus. '. Treatment: &urgi#al remo$al h. 1#topi# A,TH &yndrome: A,TH dependent i. &mall #ell #ar#inoma o- the lung is most #ommon ii. A,TH release is also random and episodi# iii. A,TH se#retion is *(T suppressed 3y e'ogenous glu#o#orti#oids or de'amethasone i. 1#topi# ,"H &yndrome: "are i. ,lini#ally indistinguisha3le -rom e#topi# A,TH syndrome ii. Plasma ,"H is high iii. ,"H stimulated se#retion o- A,TH is &MPP"1&&@+01 D/ de'amethasone G. )un#tioning Adreno#orti#al Tumors: A,TH @ndependent7 hyperse#rete glu#o#orti#oids i. Adenomas or #ar#inomas #an #ause autonomous #ortisol se#retion 1. Adenomas: Typi#ally 1 4 6 #m in diameter7 ine--i#ient in #ortisol synthesis a. Androgen o$erprodu#tion is rare7 symptoms limited to #ortisol e'#ess 2. ,ar#inoma: Ueigh 100 g to se$eral Eg7 o-ten palpa3le and $ery large7 highly $as#ular< D/ areas o- ne#rosis< hemorrhage< #ysti# degeneration< and #al#i-i#ation a. Fery malignant 3. Androgen o$erprodu#tion is #ommon7 symptoms in#lude $irili=ation and hirsutism. ii. *ot under hypothalami#8pituitary #ontrol iii. Hyper#ortisolism suppresses pituitary A,TH produ#tion7 atrophy o- unin$ol$ed adrenal #orte' results. i$. ,ortisol se#retion *(T suppressi3le Dith de'amethasone $. .iagnosis: E'e/&te, se+)( c!+t s!' @ t% '!@ 'e/e's !f ACTH E. Adrenal !a#ronodular Hyperplasia: A,TH @ndependent7 hyperse#rete glu#o#orti#oids i. "are #ause7 3oth glands are hyperplasti# ii. Hyper#ortisolism< 0(U plasma A,TH< loss o- diurnal A,TH rhythm all o##ur iii. ,ortisol se#retion *(T suppressi3le Dith de'amethasone l. &u3#lini#al ,ushing6s &yndrome: aEa J@n#identalomasK i. Asymptomati# patients< though some o- these tumors are -un#tional 5produ#ing hormone9 ii. )ound in#identally during radiology e'am iii. "elati$ely #ommon 5% per 100<0009 i$. !ost adrenal in#identalomas are non-un#tioning tumors 5%0H97 another 20H ha$e su3#lini#al hormonal o$erprodu#tion. $. !ay need to remo$e tumor i- it is unilateral< and symptoms or signs shoD e$iden#e o- hormone o$erse#retion or pheo#hromo#ytoma. m. ,lini#al mani-estations o- ,ushing6s &yndrome: i. G')c!se "t!'e+&"ce= ,ortisol promotes glu#ose synth in li$er< in#reases hepati# synth o- gly#ogen and Eetone 3odies< and antagoni=es e--e#ts o- insulin in periphery.

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ii. M)sc'e L&st "*: ,ortisol #auses protein #ata3olism< de#reased mus#le synth< anti8insulin e--e#ts in mus#le iii. O0es t# &", f&t +e, st+ 0)t !"= ,lassi# Jmoon -a#iesKand J3u--alo humpK 1. Primarily o##urs around -a#e< ne#E< trunE< a3domen 2. "easons -or su#h redistri3ution largely unEnoDn a. @nterestingly< leptin le$els are signi-i#antly ele$ated in ,ushing6s syndrome pts< e$en 3eyond o3ese people Dithout ,ushing6s 3. @n#reased -at deposition seems parado'i#al< sin#e #ortisol a#tually has a lipolyti# e--e#t7 may 3e e'plained 3y lipogeni# e--e#ts o- hyperinsulinemia that e'#ess #ortisol #auses. i$. &triae< thinning o- sEin< easy 3ruising< poor Dound healing: /lu#o#orti#oid e'#ess inhi3its -i3ro3lasts< leading to loss o- #ollagen and #onne#ti$e tissue. 1. St+ &e &+e $)+$'e &", +e, $. Hyperpigmentation: Typi#ally o##urs D/ high le$els o- plasma A,TH 5A,TH has some melano#yte8stimulating hormone P!&HQ e--e#ts9. 1. HoDe$er< hyperpigmentation is rare in ,ushing6s .= 2. ,ommon in e#topi# A,TH &yndrome $i. Hirsutism and a#ne: ,an o##ur -rom in#reased adrenal androgens $ii. (steoporosis: /lu#o#orti#oids inhi3it osteo3last di--erentiation< prolong osteo#last sur$i$al< de#reases ,a2? intestinal a3sorption 5#ausing se#ondary PTH in#rease9 1. These e--e#ts in#rease 3one resorption< de#rease 3one -ormation $iii. Hypogonadism: Hyper#ortisolism inhi3its hypothalami# /n"H in males & -emales. i'. High rates o- in-e#tion= /lu#o#orti#oids are EnoDn anti8in-lammatories and anti8 immune agents 1. @nhi3its proin-lammatory genes< ,.4 T lympho#yte a#ti$ity< -i3ro3last a#ti$ity 2. @ndu#e lipo#ortins< Dhi#h inhi3it a#tion o- phospholipase A in releasing ara#hidoni# a#id redu#ed leuEotrienes 5poDer-ul mediators oin-lammation9 a. Also de#reases -ormation o- throm3o'ane< prostaglandins< prosta#y#lin '. Hypertension: 1'a#t pathogenesis un#lear 'i. /onadal .ys-un#tion: .ue to in#reased se#retion o- adrenal androgens in -emales and #ortisol in males and -emales. 1. ,an inhi3it /n"H release inhi3its doDnstream 0H and )&H release 'ii. !ental &ymptoms: 1uphoria< in#reased appetite< irrita3ility< de#reased li3ido 'iii. Poor groDth in #hildren: .ire#tly inhi3its 3one -ormation and de#reases /H and T&H se#retion 'i$. 1'opthalmos: A3out 50H o- pts de$elop this. '$. &ee diagram 3eloD -or depi#tion o- ,ushing6s &yndrome n. .iagnosis: i. )irst #on-irm hyper#ortisolism< then determine Dhether A,TH dependent or independent ii. Test #ortisol le$els using a 24 hour urinary -ree #ortisol measurement. iii. Per-orm loD8dose de'amethasone suppression test7 normal indi$iduals Dill ha$e #ortisol le$els suppressed 3y de'amethasone 1. @- #ortisol le$els are normal and de'amethasone test is negati$e 5i.e.< #ortisol le$els are loDered Dith de'amethasone9< then ,ushing6s &yndrome is e'#luded. i$. To #on-irm diagnosis o- ,ushing6s syndrome< per-orm a high8dose de'amethasone test 1. This test #an di--erentiate pituitary -rom e#topi# A,TH se#retion. o. 1pidemiology: 2 84 #ases per million people7 ' more #ommon in Domen

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p. UA*T &(!1 () TH@& 1F1* +1TT1" &M!!A"@X1.Y &ee the pi#tures and -igures at the $ery end o- my se#tion. 2. Adreno#orti#al @nsu--i#ien#y 5! #h 21< "1214< #p24 <4819 a. ,aused 3y primary adrenal disease or de#reased stimulation o- adrenals due to loD A,TH 5se#ondary d=9 3. &ymptoms result -rom de-i#ien#ies o- #ortisol< aldosterone< and in Domen< androgens #. 2 860 #ases per 1 million7 1.25' more #ommon in Domen d. S 0H o- 3oth adrenals must 3e destroyed 3e-ore o$ert #lini#al symptoms appear e. Primary ,hroni# @nsu--i#ien#y 4 A,, s!"s D2 5#p 24 <4829: ,hroni# destru#tion oadrenal i. %0H o- #ases due to autoimmune destru#tion o- adrenal #orte'7 a3out 20H due to T+ ii. All #orti#al =ones in$ol$ed and are gradually destroyed iii. &mall num3er due to other granulomatous d=< adrenal hemorrhage< adrenal metastases< A@.& related i$. @nitially< only reser$e le$els o- adrenal glu#o#orti#oid le$els are lost 1. +asal se#retion is typi#ally normal at -irst< 3ut adrenals #an6t produ#e glu#o#orti#oids in response to stress< surgery< in-e#tion $. 1$entually< enough adrenal destru#tion #auses total loss o- 3asal se#retion $i. )all in plasma #ortisol #auses #ompensatory in#rease in plasma A,TH $ii. 4 most #ommon #auses: 19 A)t! (()"e &,+e"&' t s7 -9 TB7 39 AIDS7 39 Met&st&s s 1. !ore detail on these -our #auses des#ri3ed -urther 3eloD $iii. .iagnosis: 1. Xona )as#i#ulata/"eti#ularis destru#tion: *o in#rease in #ortisol -olloDing e'ogenous A,TH 2. Xone /lomerulosa destru#tion: *o aldosterone in#rease -olloDing A,TH administration i'. Treatment: /lu#o#ort. and mineral#ort. repla#ement 1. /i$e oral #ortisol and generous salt intaEe. -. Primary A#ute Adreno#orti#al @nsu--i#en#y 5#p250<4819 : i. "apid adreno#orti#al destru#tion #auses loss o- 3oth glu#o#orti#oids and mineral#orti#oids #auses a#ute adrenal #risis ii. Pre#ipitated 3y st+essf)' s t)&t !"s @%e+e ((e, &te ste+! , !)t$)t s "ee,e, " c%+!" c&''# "s)ff c e"t $ts iii. Pre#ipitated 3y st+essf)' e/e"ts " $ts @%! %&/e &,+e"&' &t+!$%# ,)e t! $+!'!"*e, e.!*e"!)s c!+t c!ste+! , t%e+&$#7 &", @%! O)st %&, +ece"t @ t%,+&@&' !f f& ')+e t! "c+e&se ,!s&*e @ t% st+ess i$. Also #aused 3y (&ss /e &,+e"&' %e(!++%&*e< Dhi#h destroys adrenal #orte' 1. ,ommon in neD3orns< those on anti#oagulants< or in Uaterhouse8 )rideri#hsen &yndrome 5hemorrhage during 3a#teremi# in-'9 $. Uaterhouse8)rideri#hsen &yndrome: Adrenal hemorrhage #hara#teri=ed 3y 19 ($erDhelming 3a#terial in-'< 29 rapid hypotension leading to sho#E< 29 .@, 1. Asso#iated Dith Ne sse+ & &", St&$% 2. .eath o##urs ;ui#Ely 2. Adrenals appear as Jsa#s o- #lotted 3lood $irtually o3s#uring all underlying detail.K $i. Treatment: 0arge doses o- intra$enous #ortisol g. &e#ondary @nsu--i#ien#y 5#p251<4829: N! $ t) t&+# ACTH !+ %#$!t%&'&( c CRH sec+et !" i. .e-i#ien#y in A,TH is the primary pro3lem ii. &ymptoms result -rom sele#ti$e #ortisol 5and androgen9 de-i#ien#y 1. A',!ste+!"e sec+et !" &ct)&''# +e(& "s "!+(&' 8Re" " s#ste( (& "t& "s t9 iii. H#$e+$ *(e"t&t !" @ '' NOT !cc)+7 s "ce ACTH 'e/e's &+e '!@ i$. Typi#ally results -rom #hroni# e'ogenous glu#o#orti#oid therapy

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$. M!st c!((!" c&)se: P+!'!"*e, e.!*e"!)s *')c!c!+t c! , t%e+&$# suppresses ,"H< A,TH< and endogenous #ortisol se#retion $i. A3rupt dis#ontinuation o- therapy #an also pre#ipitate a#ute adrenal #risis< sin#e pituitary and hypothalamus need time to return to normal -un#tion a-ter doDnregulation. $ii. "arely results -rom pituitary or hypothalami# tumors or ,"H de-i#ien#y $iii. Treatment: G')c!c!+tB +e$'&ce(e"t h. Autoimmune Adreno#orti#al @nsu--i#ien#y: Primary insu--i#en#y 5a3out 60 8 80H o- #ases9 i. Antiadrenal Anti3odies: 2 types: 19 Adrenal ,orte' A3 5A,A9< and 29 218 hydo'ylase en=yme A3 5$ery spe#i-i# -or Addison6s9 ii. Autoimmune A3 against other endo#rine organs -re;uently e'ist iii. Autoimmune polyendo#rine syndrome type @ 5AP&8@9: "are disorder Dith mutation in the autoimmune regulator 5A@"19 Dith onset in #hildhood 1. .' must ha$e 2 o- -olloDing: Adrenal insu--i#ien#y< hypoparathyroidism< mu#o#utaneous #andidiasis 2. .! and gonadal -ailure #an also o##ur 2. A3 -ormation against #yto#hrome P8450 #holesterol side8#hain #lea$age en=yme< Dhi#h #on$erts #holesterol to pregnenolone 5-irst step in #ortisol synth9 a. 1n=yme -ound in adrenals and gonads i$. Autoimmune polyendo#rine syndrome type @@ 5AP&8@@9: ,onsists o- adrenal insu--i#ien#y< Hashimoto6s thyroiditis< and Type @ .!. 1. Typi#ally o##urs in adulthood 2. A3 -ormation against 218hydro'ylase en=yme 2. (ther autoimmune #ompli#ations: $itiligo< perni#ious anemia< #elia# d=< myasthenia gra$is i. Adrenal Tu3er#ulosis: ,auses primary insu--i#. 3y total or near8total destru#tion o- 3oth glands i. .estru#tion usually o##urs gradually ii. Adrenal repla#ed Dith #aseous ne#rosis7 #al#i-i#ation o- adrenals #an also o##ur G. Adrenal !etastasis: Primary insu--i#ien#y7 metastasi=e -rom lung< 3reast< stoma#h< melanoma< Z E. A@.&8"elated: Primary or &e#ondary @nsu--i#7 adrenals #ommonly a--e#ted 3y opportunisti# in-'. i. ,!F< !y#o3a#terium a$ium< T+< pneumo#ystis Giro$e#i #an all #ause l. /eneti# .isorders: Typi#ally primary insu--i#ien#y i. ,ongenital Adrenal Hyperplasia: ii. Adrrenal Hypoplasia D/ #ytomegaly: Adrenal #orte' has odd8shaped< large adrenal #ells D/ large nu#lei iii. Adrenal Hypoplasia D/o #ytomegaly: A,TH insensiti$ity syndrome 5resistan#e to A,TH9 1. )amilial /lu#o#orti#oid .e-i#ien#y: Adren#orti#al unresponsi$eness to A,TH #auses de#reased glu#o#orti#oid and androgen se#retion< and in#reased pituitary A,TH se#retion m. ,lini#al ,onsiderations o- Adreno#orti#al @nsu--i#ien#y 5#p24 9: i. /lu#o#orti#oid insu--i#ien#y symptoms: DeaEness< -atigue< lethargy< anore'ia< nausea< hypogly#emia ii. Hyperpigmentation: Occ)+s " $+ (&+# "s)ff c e"c#7 NOT sec!",&+# "s)ff c e"c# 1. "esults -rom ele$ated le$els o- A,TH iii. High A,TH le$els o##ur in primary insu--i#ien#y i$. Hypo$olemia< prerenal a=otemia< hyponatremia< hyperEalemia< dehydration< hypotension: (##urs in primary insu--i#ien#y due to de#reased aldosterone 1. .oes *(T o##ur in se#ondary insu--i#ien#y< sin#e aldosterone is preser$ed $. Ueight loss< loss o- appetite< and /@ distur3an#e: .ue to loD #ortisol

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$i. @n Domen: 0oss o- pu3i# & a'illary hair and amenorrhea #an o##ur due to loD androgens $ii. A#ute Adrenal ,risis: Pre#ipitated 3y in-'< trauma< surgery< dehydration 1. ,an #ause -e$er< DeaEness< apathy< #on-usion< $omiting< #oma< death n. .iagnosis: i. Primary @nsu--i#: !ust pro$e ina3ility o- adrenals to respond to A,TH 1. P'&s(& ACTH s % *%C "! c!+t s!' sec+et !" +es$!"se t! ACTH st ()'&t !" ii. &e#ondary @nsu--i#: Test 3lood le$els o- A,TH 5should 3e loD9 1. P'&s(& ACTH s '!@C c!+t s!' "c+e&ses @A ACTH st ()'&t !" 2. Also looE -or other endo#rine signs o- loD A,TH 5should ha$e loD le$els o- )&H< 0H< and T&H< resulting in hypogonadism or hypothyroidism9 iii. &ee summary diagnosti# diagram at end o- this se#tion 4. Hyperaldosteronism 5! #h 21< "1210< #p264<4%%9: ,hroni# e'#essi$e produ#tion o- aldosterone a. Primary hyperaldosteronism: 1'#essi$e< unregulated se#retion 3y adrenal #orte'. i. 2 main #auses o- primary -orm: All des#ri3ed later 3eloD 1. A,+e"!c!+t c&' &,e"!(&= C!"" S#",+!(e 2. I, !$&t% c 0 '&te+&' "!,)'&+ &,+e"&' %#$e+$'&s & 2. G')c!c!+t c! ,?+e(e, &0'e %#$e+&',!ste+!" s( ii. Autonomous mineral#orti#oid produ#tion 3y a3normal =ona glomerulosa 5hyperplasia or adenoma9 iii. D &*"!se, 0# % *% 'e/e's !f &',!ste+!"e @A '!@ 'e/e's !f +e" " i$. "AA system #an help modulate e--e#ts o- primary hyperaldosteronism 1. ,hroni# aldosterone produ#tion e'pansion o- e'tra#ellular and plasma $olume stret#h re#eptors o- ma#ular densa a#ti$ated suppressed renin le$els 5#an help loDer aldosterone a little9 2. 0oD renin le$els are present in these pts 3. &e#ondary hyperaldosteronism 5#p48%9: ,aused 3y e.cess /e +e" " se#retion i. (##urs in response to 19 Re"&' sc%e( &< 29 L!@ "t+&/&sc)'&+ /!')(e 5,H)< nephroti# syndrome9< 29 *a? Dasting disorders 5#hroni# renal -ailure< renal tu3ular a#idosis9< 49 Hyperplasia o- Gu'taglomerular apparatus< or 59 "enin se#reting tumors< 69 P+e*"&"c#7 79 E,e(& ii. Adrenals may appear grossly normal< 3ut may ha$e mis#ros#opi# hyperplasia o=ona glomeruEosa #. Adrenal Adenoma: Primary hyperaldosteronism7 most #ommon #ause thereoi. .ire#tly produ#es aldosterone ii. T)(!+ 0)+ e, " *'&",C "! &t+!$%# !cc)+s iii. S$ +!"!'&ct!"e 0!, es in medi#ally treated pts i$. !ore #ommon in Domen7 o##ur in 20s in 40s $. Typi#ally unilateral solitary tumor o- adrenal #orte' 5C!"" S#",+!(e9 1. Typi#ally on le-t side $i. Tumor #an #ompress adGa#ent normal adrenal tissue $ii. Adreno#orti#al #ar#inoma: Fery rare #ause o- aldosterone8only -un#tional tumors d. +ilateral Adrenal Hyperplasia 5#p4%%9: +ehind adrenal adenoma< a##ounts -or most other #ases o- primary hyperaldosteronism i. +ilateral non8adenomatous hyperplasia o- =ona glomerulosa ii. Mnilateral hyperplasia is a rare #ause iii. Hyperplasia is di--use and -o#al i$. T': A',!ste+!"e &"t&*!" st e. /lu#o#orti#oid "emedia3le hyperaldosteronism 88 /"A: Also a primary #ause7 geneti#/-amilial i. .ominantly inherited gene de-e#t in 1183eta8hydro'ylase8aldosterone synthase gene ii. )usion o- the ,LP11+1 gene 51138hydo'ylase gene9 Dith ,LP11+2 5aldosterone synthase gene9

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iii. "esult is that A,TH stimulates aldosterone synthase a#ti$ity 3y in#reasing gene e'pression i$. @n#reases produ#tion o- aldosterone and other steroids $. ,an inhi3it the pro#ess 3y gi$ing glu#o#orti#oids 5de'amethasone suppressi3le9 -. ,lini#al ,onsiderations: N&M +ete"t !"7 KM &", HM '!ss 0# 1 ,"e# i. 1'tra#ellular -luid $olume in#reases %#$e+te"s !" c&" +es)'t ii. Esc&$e P%e"!(e"!" 8c$3559= P+e/e"ts e,e(& ,es$ te e'e/&te, f') , /!')(e 1. Atrial natriureti# peptide e$entually helps e'#rete *a?7 pre$ents edema 2. HoDe$er< >? and H? e'#retion #ontinues in e'#ess iii. HypoEalemi# nephropathy: (##urs D/ prolonged >? diuresis i$. !eta3oli# alEalosis: Uith marEed >? loss< intra#ellular >? is repla#ed 3y *a? and H? 1. @ntra#ellular mo$ement o- H? and in#reased renal H? loss #auses alEalosis $. 0e-t $entri#ular hypertrophy: .ue to $olume o$erload $i. Hypo#al#emia: >? loss #an #ause this g. .iagnosis: i. Primary Hyperaldosteronism: Use $'&s(& &',!ste+!"e?+e" " +&t ! 5sin#e aldosterone should 3e high and renin loD in this d=9 1. N!+(&' P'&s(& &',!ste+!"e?+e" " +&t != P -4 2. H *% $'&s(& &',!ste+!"e?+e" " +&t !"= J-4 2. C&" &'s! )se &',!ste+!"e s)$$+ess !" test 8s&' "e "f)s !"9 4. Mse ,T and/or !"@ to di--erentiate adenoma -rom hyperplasia ii. &e#ondary Hyperaldosteronism: ,on-irm high plasma renin7 sear#h -or underlying #ause 5. Hypoaldosteronism: .e-i#ient mineral#orti#oid produ#tion or a#tion a. ,hara#teri=ed 3y *a? loss< hyponatremia< hyperEalemia< meta3oli# a#idosis< hypo$olemia< hypotension< impaired se#retion o- >? and H? 3. Primary hypoaldosteronism: ,aused 3y destru#tion o- adreno#orti#al tissue< de-e#ts in synthesis< inade;uate stimulation o- aldosterone se#retion 5Y 88 seems liEe a se#ondary -orm to me9< or resistan#e to ion transport e--e#ts o- aldosterone i. "enin a#ti$ity is typi#ally in#reased #. &e#ondary Hypoaldosteronism: &uppressed or de-i#ient renin produ#tion d. Hypopituitarism: ,auses primary hypoaldosteronism due to atrophy o- =ona glomerulosa e. Hyporeninemi# hypoaldosteronism 5type @F renal tu3ular a#idosis9: .ue to impairment othe Gu'taglomerular apparatus asso#iated D/ underlying renal d= -. ,ongenital Adrenal Hyperplasia 4 ,AH: 1n=ymati# de-i#ien#ies in synthesis o- mineral8 and glu#o8#orti#oids i. &ee adrenal androgen pathology se#tion 3eloD -or more detail o- this disorder g. Pseudohypaldosteronism: "enal tu3ular resistan#e to mineral#orti#oids i. Aldosterone le$els are a#tually high< 3ut they don6t DorE Dell h. ,lini#al ,onsiderations: ,hara#teri=ed 3y *a? loss< hyponatremia< hypo$olemia< hypotension< impaired se#retion o- H? and >?< hyperEalemia< and meta3oli# a#idosis i. Pts Dho ha$e had 3ilateral adrenale#tomy need mineral#orti#oid repla#ement therapy 6. Adrenal Androgen Pathology 5! #h 21< "12119: a. Adrenal #orte' se#retes androstenedione< dehydroepiandrosterone 5.H1A9< and dehydroepiandrosterone sul-ate 5.H1A&9 i. &e#retion o- these adrenal se' hormones generally parallels #ortisol se#retion7 3oth regulated 3y A,TH ii. .H1A has mas#ulini=ing and ana3oli# e--e#ts< 3ut it is 1/5 as potent as androgens produ#ed 3y testes7 thus< has little e--e#t under normal #onditions iii. !ust 3e #on$erted to testosterone in peripheral tissues to ha$e their e--e#t 3. 1'#essi$e adrenal androgens has little e--e#t in 3oys< 3ut #an #ause hirsutism and $irili=ation in -emales

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1'#essi$e androgen produ#tion #an o##ur due to ,ushing6s syndrome< adreno#orti#al neoplasms< or ,ongenital Adrenal Hyperplasia 5,AH9 d. Adreno#orti#al neoplasms: Ne!$'&s(s t%&t sec+ete &",+!*e"s &+e t#$ c&''# c&+c "!(&s i. C&+c "!(& $+ese"ts @A / + ' 2 "* s#",+!(e &", %#$e+c!+t s!' s( e. C!"*e" t&' A,+e"&' H#$e+$'&s & Q CAH 8c$345737<9= 1n=ymati# de-e#ts in steroid meta3olism that #ause in#reased produ#tion o- androgens 5Dhi#h #auses the hyperplasia o- adrenal #orte'9 i. All ,AH #ases: B '&te+&''# e"'&+*e, &,+e"&'sC c!+te. s 0+!@"7 t% c1 &", "!,)'&+ ii. !ost #ommon #ause o- am3iguous genitalia iii. ,olle#tion !f &)t!s!(&' +ecess /e geneti# mutations that all c&)se ,ec+e&se, c!+t s!' &", &',!ste+!"e $+!,)ct !" c&)ses e.cess &",+!*e" $+!,)ct !" 1. Adrenal hormone synthesis< 3lo#Eed at the glu#o#orti#oid and mineral#orti#oid pathDays< is e'#essi$ely shunted o$er to the androgen produ#tion pathDay 2. Androstenedione and .H1A are parti#ularly produ#ed in high num3er i$. Res)'t "* c!+t s!' ,ef c e"c# "c+e&ses ACTH sec+et !" &,+e"&' %#$e+$'&s & $. !ost #ommon en=yme de-i#ien#y 5 0H9: -10?%#,+!.#'&se ,ef c e"c# 1. @nhi3its #on$ersion o- progesterone to 118deo'y#orti#osterone 2. 2nd most #ommon en=yme de-i#ien#y: 1138hydro'ylase 2. 2138hydro'ylase de-i#ien#y has 2 #lini#al -orms: s&'t @&st "* 8c'&ss c f!+(9 &", "!"?s&'t @&st "* a. &alt Dasting -orm has c!($'ete -1?%#,+!.#'&se ,ef c e"c#7 se$ere #ortisol & aldosterone de-i#ien#y7 salt Dasting e--e#ts Dill present in neonate at 2 DEs lethal adrenal #risisV 5due to hypotension< #ardio$as#ular #ollapse< death9 3. *on8Dasting 5simple $irili=ing9 -orm has su--i#ient #ortisol and aldosterone to a$oid adrenal #risis< 3ut $irili=ation o##urs 3etDeen 3irth and 5 years $i. ,lini#al #onsideration: Pregnant mom #an 3e gi$en de'amethasone to suppress A,TH a#tion< Dhi#h Dill de#rease androgen produ#tion< pre$ent genital am3iguity 1. Pts ha$e androgen e'#ess and de-i#ient aldosterone and glu#o#orti#oids 2. *ormal pu3erty Dill 3e suppressed< due to high androgens 2. Pt Dill not rea#h normal height< due to premature epiphysis #losure %. !ore general in-o on adreno#orti#al neoplasms 5"121%< #p4829: a. M!st &,e"!(&s &+e "!"?f)"ct !"&'= i. )un#tional adenomas more liEely asso#iated D/ high aldosterone or #ortisol 3. Firili=ing neoplasm more liEely to 3e #ar#inoma #. )un#tional $s. *on-un#tional neoplasms #an only 3e di--erentiated 3y #lini#al< *(T morphologi#/histologi# -eatures d. !ost adreno#orti#al adenomas are a#tually #lini#ally silent< typi#ally dis#o$ered in#identally or at autopsy e. Adrenal #ar#inomas more liEely to 3e -un#tional7 tenden#y to in$ade adrenal $ein< $ena #a$a< and lymphati#s7 '&+*e7 ,est+)ct /e7 &", "/&s /eC "ec+!s s &", %e(!++%&*e !cc)+C &"&$'&st c ce''s Adrenal !edulla Pathology 5! #h 12< "121 < #p268<4829: 8. +asi# Adrenal !edulla anatomy and phys 5#p4829: a. 1pinephrine: S#ste( c c +c)'&t !" 3. *orepinephrine: M!st'# '!c&' s#($&t%et c $!st?*&"*' !" c "e)+!"s #. Paraganglion &ystem: Adrenal medulla ? paraganglia7 &'' &+e $!te"t &' "e!$'&s & s tes . Pheo#hromo#ytoma 5#p2%0< 4849: !ost #ommon pathology o- adrenal medulla

#.

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a. *eoplasm o- the #hroma--in #ells o- adrenal medulla or e'tramedullary sites 5i.e. s#($&t%et c *&"*' &7 !+*&" !f R)c1e+1&",'9. 3. These tumors se#rete e'#essi$e epinephrine< norepinephrine 5or 3oth9< and rarely dopamine. i. !ost se#rete norepinephrine< Dhi#h #ause the sustained or episodi# HT* ii. 1pinephrine se#reting tumors #ause HT* less o-ten7 typi#ally produ#e episodi# hypergly#emia< glu#osuria< and other meta3oli# e--e#ts. #. 0H are 3enign< 10H malignant d. 1pidemiology: "are7 2 #ases per 1 million people7 less than 0.1H o- all patients Dith hypertension i. (##ur in 3oth genders and in all ages 5most #ommon 4th or 5th de#ade9 ii. >ids Dith pheo#hromo#ytoma more liEely to ha$e multi-o#al and e'tra8adrenal tumors e. 1tiology and Pathophys: i. &e$eral autosomal dominant syndromes are asso#iated D/ pheo#hromo#ytoma: 1. *euro-i3romatosis type 1: *)1 gene mutation 2. Fon Hippel80indau &yndrome: FH0 tumor suppressor gene mutation 2. !ultiple 1ndo#rine *eoplasia type @@: Asso#iated D/ mutation o- "1T proto8on#ogene 4. )amilial paraganglia syndrome 5. ,om3ined< represent 20 4 20H o- pheo#hromo#ytoma ii. 0H o- tumors o##ur in the a3domen< and 85H o- these are in the adrenal medulla 1. 1'tra8adrenal tumors #omprise 10H o- adult pheo#hromo#ytoma< 208 40H -or Eids iii. !ost se#rete epinephrine< Dhi#h dri$es the #hara#teristi# Jsympatheti#K symptoms i$. HTN: ,aused 3y 19 a8re#eptor mediated $aso#onstri#tion< 29 +18mediated in#rease in #ardia# output and rennin in#rease<Dhi#h ele$ates angiotensin @@ 5more $aso#onstri#tion9 1. HT* #risis #an o##ur due to drugs: tri#y#li# antidepressants< anti8 dopamines< meto#lopramide< and nalo'one 2. -A3 !f HTN c&ses &+e c!"st&"t7 t%!)*% $&+!.#s(&' e$ s!,es !cc)+ 2. D!"t * /e B?0'!c1e+s f t%e+e s 1"!@" &'$%&?(e, &te, c!"st+ ct !"I a. +28re#eptors mediate $asodilation7 3lo#E +2 re#eptors< and the a8re#eptors Dill run Dild Dith unopposed $aso#onstri#tion $. O+t%!st&t c H#$!te"s !" 8c$37-9= 1. 1'#essi$e $aso#onstri#tion #aused 3y alpha8#onstri#tion e$entually de#reases plasma $olume. 2. Also< sustained #ate#holamine e'#ess de#reases sympatheti# a#ti$ity that maintains postural 3lood pressure 2. ,om3ined< these tDo -a#tors #an #ause postural hypotension. $i. !eta3oli# 1--e#ts are #ommon: +lood glu#ose and -ree -atty a#id le$els in#rease 1. ,aused 3y in#reased gly#olysis and gly#ogenolysis< and alpha8 adrenergi# mediated inhi3ition o- insulin release. 2. 1pinephrine also stimulates glu#oneogenesis and de#reases insulin8 mediated glu#ose uptaEe 3y peripheral tissue. 2. 1pineph also raises 3lood la#tate 3y in#reasing gly#ogenolysis and gly#olysis 4. @n#reased meta3oli# rate may #ause Deight loss $ii. A#ute hemorrhagi# ne#rosis o- tumor: J)ulminant pheo#hromo#ytoma #risisK 1. @nitially presents as a#ute a3dominal pain Dith marEed hypertension 2. )olloDed 3y hypotension< sho#E< and sudden death as a #onse;uen#e osudden #ate#holamine #essation. $iii. Paraneoplasti# 1--e#ts: 1'amples in#lude: 1. Hyper#al#emia< due produ#tion o- PTH8related peptide 5PTHrP9

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2. J1#topi#K ,ushing6s &yndrome< 3y maEing e#topi# A,TH Histology: Fery $as#ular tumors< -re;uently #ysti#< ne#roti#< or hemorrhagi# i. Re''0&''e" "ests= 6&sc)'&+ $&tte+" !f t)(!+ 1. 0arge pleomorphi# #ells arranged in sheets separated 3y $as#ular stroma ii. R&"*e f+!( 1 * t! se/e+&' 1* iii. O/e+'# "* *'&", s c!($+esse, i$. +enign $s !alignant Tumor: C&""!t 0e ,ete+( "e, % st!'!* c&''#7 malignan#y only determined 3y presen#e o- metastases g. ,lini#al ,onsiderations: i. ,lassi# symptoms: Heada#he< palpitation< perspiration< pallor< orthostasis< HTN ii. &ustained< or less #ommonly episodi#< hypertension7 sDeating7 palpitations7 hypergly#emia7 gly#osuria #an all o##ur iii. Heart pro3lems: "esult -rom HT*7 also< #ate#holamines #an #ause arrhythmias< myo#ardial insta3ility< -i3rosis< -o#al ne#rosis. i$. &pe#ial 1pinephrine &ymptoms: 1pi8releasing tumors #an a#tually #ause hypotension< prominent ta#hy#ardia< Didened pulse pressure< #ardia# arrhythmias< non#ardiogeni# pulmonary edema. $. &ymptoms #an 3e paro'ysmal< Dith paro'ysms o##urring on#e e$ery -eD months to 25 times per dayV 1. Paro'ysms typi#ally indu#ed 3y a#ti$ities that #ompress the tumor and 3y emotional stress and an'iety. $i. Mntreated< the HT* #an #ause all the typi#al e--e#ts o- #hroni# HT* $ii. @mportant to diagnose< 3e#ause sudden release o- #ate#holamines in surgery or deli$ery #an 3e -atal 5in#reases maternal mor3idity and -etal demise9. $iii. E1>H R)'eF= 1a#h o- the -olloDing situations represent 10H o- patient/tumor pool 1. 1'tra8adrenal paraganglia 2. (utside the a3domen 2. !ultiple tumors 4. +ilateral 5. *ot asso#iated D/ HT* 6. @n #hildren %. !alignant 8. 20 8 20H are -amilial h. .iagnosis: .emonstrate 3y a3normally high #ate#holamines in 3lood or their meta3olites in urine or plasma i. Assay using metanephrines instead o- #ate#holamines7 more relia3le test 1. !etanephrines made -rom #ate#holamines leaEing -rom stores and meta3oli=ed 3y ,(!T ii. ,hromogranin A: )ound in #hroma--in #ells7 $! "ts t! (&' *"&"t $%e!c%+!(!c#t!(& iii. ,lonidine testing: /i$e #lonidine to determine to di--erentiate essential HT* -rom pheo#hromo#ytoma HT* 1. ,lonidine a#ts 3y stimulating alpha82 re#eptors in 3rain< Dhi#h de#rease sympatheti# out-loD 2. @n essential HT*< #lonidine Dill de#rease sympatheti# out-loD< su3stantially loDer plasma epinephrine< and loDer +P 2. +MT< in pheo#hromo#ytoma< #lonidine U@00 *(T a--e#t +P< sin#e the tumors emit #ate#holamines autonomously. i. Treatment 5#p2%29: i. DO NOT )se B?0'!c1e+sC 3lo#Eing the $asodilation e--e#t o- +2 re#eptors Dill #ause unopposed $aso#onstri#tion 3y alpha8agonist e--e#ts o- the tumor ii. @nstead< )se &'$%& 0'!c1e+s iii. &urgery #an 3e done -.

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M)'t $'e E",!c+ "e Ne!$'&s & S#",+!(es ?? MEN 8R1--17 c$3:49= 1. /roup o- geneti#ally inherited diseases c&)s "* 'es !"s " ()'t $'e e",!c+ "e !+*&"s 2. 2 geneti#ally distin#t types< !1*81 and !1*82 2. !1* tumors ha$e #hara#teristi# traits #ompared to sporadi# endo#rine #an#ers a. (##ur at #!)"*e+ &*e 3. (##ur in multiple endo#rine organs 5duh9 #. Tumors #an 3e ()'t f!c&' @ t% " &" !+*&" d. Tumors typi#ally $+ece,e, 0# &s#($t!(&t c e",!c+ "e %#$e+$'&s & e. !ore &**+ess /e &", +ec)+ more -re;uently 4. !1*81 aEa Uermer &yndrome: "are 52 per 100<0009 a. ,aused 3y germline mutation in !1*1 gene at 11;127 en#odes the !1*@* protein i. Tumor suppressor gene 3. ,hara#teri=ed 3y a3normalities o- t%e 3 Ps Q P&+&t%#+! ,7 P&"c+e&s7 P t) t&+# #. P&+&t%#+! ,: !ost #ommon mani-estation7 hyperplasia and adenomas o##ur7 hyper#al#emia d. P&"c+e&s: 1ndo#rine tumors here -re;uently #ause death in pts7 insulinoma and hypogly#emia B De"se "s)' " ,e$!s ts t%+!)*%!)t % st!'!* c sect !" e. P t) t&+#: Typi#ally shoDs a prola#tinoma -. .uodenum also -re;uently in$ol$ed 5. !1*82: 2 #lini#al su3types a. !1*82A: ,hara#teri=ed 3y pheo#hromo#ytoma< medullary thyroid #ar#inoma< $&+&t%#+! , %#$e+$'&s & i. 0inEed to germline ()t&t !" " RET $+!t!?!"c!*e"e ii. !utation #auses gain8o-8-un#tion mutation that upregulates groDth signals 3. !1*82+: Presents D/ pheo#hromo#ytoma< medullary thyroid #an#er< "e)+!(&s !+ *&"*' !(&s7 &", (&+f&"! , %&0 t)s. i. ,aused 3y a single amino8a#id de-e#t in "1T gene 5di--erent -rom !1*82A9 #. )amilial !edullary Thyroid ,an#er: Predisposition to medullary thyroid #an#er< 3ut not the other lesions o- !1*82A and !1*82+ i. Also has a RET *e"e ()t&t !" 6. P+!$%#'&ct c T%#+! ,ect!(#: "outinely re#ommended noD to people Dith germline "1T mutations to pre$ent ine$ita3le medullary thyroid #an#er.

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Pi#ture to the le-t: Typi#al ,ushing6s symptoms

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.iagram to the le-t: Testing s#heme -or ,ushing6s &yndrome

.iagram to the le-t: Testing s#heme -or adreno#orti#al insu--i#ien#y

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D &*+&( !f H#$$t%&'&( c?P t) t&+#?A,+e"&' Re'&t !"s% $s " %e&'t%# &", , se&se, c!", t !"s= Hypothalamic, pituitary, and adrenal cortical relationships. Solid arrows indicate stimulation; dashed arrows, inhibition. Normal: orticotropin!releasin" hormone ( #H) elaborated by the median eminence of the hypothalamus stimulates secretion of adrenocorticotropic hormone ($ %H) by the anterior pituitary ($&). $ %H tri""ers the synthesis and release of cortisol, the principal "lucocorticoid of the adrenal corte'. $ risin" le(el of cortisol inhibits the stimulatory action of #H on $ %H release (or cortisol may inhibit #H release), completin" a ne"ati(e feedbac) loop. Addison's disease: *n primary destructi(e disease of the adrenal corte', the le(el of plasma cortisol is (ery low, and the effect of #H on the anterior pituitary proceeds without inhibition, causin" a mar)ed increase in the secretion of $ %H. Hi"h le(els of $ %H produce characteristic s)in pi"mentary chan"es. Cushing's disease: %he primary lesion may be at the le(el of the pituitary or hypothalamus. *n either case, production of $ %H and cortisol is e'cessi(e. %he former causes bilateral adrenal hyperplasia and the latter causes clinical manifestations of hypercortisolism. ells of the anterior pituitary are relati(ely resistant to the hi"h le(els of circulatin" cortisol. Ectopic ACTH: *n this syndrome, $ %H or an $ %H!li)e peptide is elaborated by a tumor such as carcinoma of the lun". %he adrenals are stimulated, circulatin" cortisol is increased, and pituitary $ %H secretion is inhibited. Ectopic CRH: *n this rare syndrome, #H is elaborated by a tumor such as a bronchial carcinoid. %he pituitary is stimulated, and there is elaboration of e'cess $ %H. %he adrenals are stimulated, and circulatin" cortisol is increased. %he hypercortisolism causes diminished hypothalamic #H production; howe(er, the ne"ati(e feedbac) on the pituitary production of $ %H is o(ercome by the ectopic #H. Adrenal adenoma or carcinoma: $n adenoma or carcinoma of the adrenal corte' may produce cortisol autonomously. +hen the rate of production e'ceeds physiolo"ic ,uantities, ushin"-s syndrome results; the effect of #H on the anterior pituitary isHORMONE) inhibited by the hi"h le(els of circulatin" cortisol, with resultant MALE REPRODUCTIVE (AND PHYSIOLOGY diminished $ %H secretion and atrophy of normal adrenal tissue. Iatrogenic Cushing's syndrome: .'o"enous corticosteroid administration in e'cess of physiolo"ic ,uantities of cortisol leads directly to peripheral manifestations of hypercortisolism and inhibits the effect of #H on Page 73 o173 the anterior pituitary, with resultant diminished $ %H secretion, diminished cortisol production, and atrophy of normal adrenal tissue.

Jonathans Sect on Male Reproductive Anatomy and Physiology a. Development of Male Reproductive Tract i. SRY (sex-determining region on Y located on the short arm! "hich regulates the differentiation of the primitive gonad into a testis ii. #efore $ "ee%s differentiation the fetus contains undifferentiated gonads & have potential to 'ecome either ovaries or testes iii. (enetic )nfluence of *RY (+! )f SRY s !"esent, (a! -ndifferentiated #ona$ %eco&es test s an$ !" &o"$ a' #e"& ce''s %eco&e s!e"&ato#on a ('! Testes develop at $-. "%s gestation (/! )f *RY is a'sent gonads follo" female development tra0ectory iv. 1ormonal )nfluence of Inte"na' Gen ta' a De(e'o!&ent (+! Mediates phenotypic gender expression (/! 2etus originally starts "ith multipotential internal and external genitalia, (a! )nternally there are t"o )o'** an $+cts & have the potential of 'ecoming &a'e nte"na' #en ta' a ('! Also have t"o M+''e" an $+cts & have the potential of 'ecoming *e&a'e nte"na' #en ta' a (3! 4hether male or female genitalia internal genitalia develop depends on presence or a'sence of / hormones produced 'y the fetal testis, (a! Testoste"one (T) (i! Produced 'y the 5eydig cells of testis (%) M+''e" an, nh % t n# s+%stance (MIS) (i! Produced 'y the *ertoli cells of the seminiferous tu'ules (6! *ummary of )nternal (enital Development, (a! #y . "%s gestation the fetal testis is actively producing T ('! #ecause fetal pituitary isn7t secreting 51 yet testosterone production is regulated 'y h8( (c) T acts n a !a"ac" ne &anne" to st &+'ate #"o-th.$e(e'o!&ent o* )o'** an $+cts nto e! $ $/& s0 (as $e*e"ens0 se& na' (es c'es0 an$ e1ac+'ato"/ $+cts ( ) ) tho+t T2 -o'** an $+cts "e#"ess (d! *ertoli cells of fetal testis produce M)* (e) MIS st &+'ates "e#"ess on o* &+''e" an $+cts (i! ) tho+t MIS2 &+''e" an $+cts !e"s st and 'ecome the fallopian tu'es uterus cervix and upper +93 of vagina 5-9 Th s s an !s 'ate"a' e**ect:if testis is a'sent on one side then no MIS produced no regression of mullerian ducts female internal genitalia on that side (and no T so Wolffian ducts regress on that side! (g! ;ote, if high T levels present in a female fetus (due to a congenital adrenal disorder or '9c of maternal endocrine d9o!, 'oth sets of ducts ("olffian and mullerian! "ill 'e retained (<! Dihydrotestosterone (DHT! is not n(o'(e$ n $e(e'o!&ent o* nte"na' #en ta' a since <-alpha reductase is not expressed in these tissues at the time of differentiation of the 4olffian duct v. 1ormonal )nfluence on =xternal (enitalia Development (+! Differentiation of external genitalia occurs around >-+/ "%s gestation (/! In !"esence o* DHT (and other androgens! the genital tu'ercle genital fold s"elling and urogenital sinus 'ecome the !en s0 sc"ot+&0 an$ !"ostate3 (3! In a%sence o* DHT they 'ecome the 'a% a &a1o"a an$ & no"a0 c' to" s0 an$ 'o-e" 4.5 o* (a# na (a) Occ+"s * 6,a'!ha "e$+ctase s $e* c ent.a%sent (6! ;ote, in a'sence of either ovary or testis female internal and external genitalia develop

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'. Testicular Anatomy i. During 3rd trimester under the influence of androgens and M)* testes descend from retroperitoneal position high in a'dominal cavity do"n through inguinal canal into scrotum ii. Testes must descent to maintain temperature at /8 lo"er than core temp (+! 2ailure to descend results in infertility (failed spermatogenesis! and increased ris% of malignancy (/! Tight-fitting under"ear or 'athing in hot "ater9hot tu' decreases sperm motility 3 Se& n *e"o+s t+%+'es (+! Se"to' ce''s line the 'asement mem'rane and surround developing germ cells (a! T #ht 1+nct ons 'et"een cells form the %'oo$,test s %a"" e" (i! Testosterone needed for integrity of 0unction (ii! ?unction separates 'asal and adluminal compartment ('! Produce a"o&atase to convert 5eydig-derived androgens to estrogens nh % n an$"o#en % n$ n# !"ote n MIS (fetal! (c! Produce seminiferous tu'ule fluid (d! 1ave 7SH an$ an$"o#en "ece!to"s (/! Le/$ # ce''s are present in the interstitial space 'et"een seminiferous tu'ules (a! Androgen synthesis & Testoste"one ('! 1ave LH "ece!to"s (c! After fetal development testicular an$"o#enes s "e&a ns 'o- +nt ' !+%e"t/ 5d9 At !+%e"t/ LH sec"et on act (ates testes an$ an$"o#en !"o$+ct on c3 S!e"&ato#enes s i. #egins at pu'erty located in the seminiferous tu'ules 3 S!e"&ato#on a (+! (erm cells & diploid located along the 'asement mem'rane among *ertoli cells 3 S!e"&ato#enes s (+! Mitotic division to primary spermatocytes that "ill 'ecome sperm (/! Meiotic divisions to produce secondary spermatocytes then haploid spermatids (3! *permiogenesis of spermatids to spermato@oa (3 S!e"& o#enes s (+! ;ucleus si@e decreases and prominent tail is formed (/! 8hromatin material in sperm nucleus condenses and cytoplasm is lost (3! Ac"oso&e forms on head of sperm & has lysosome and hyaluronic acid needed for ovum penetration (6! S!e"& at on & Release of sperm 559 2rom spermatogonia to spermato@oa AB days ($! *perm in head of epididmyis are immature and incapa'le of directional motility or capacitation 5a9 4hen reach tail of epididymis capa'le of directional motility and capacitation v. *perm are stored in the epididymis and ampulla of vas deferens $i. *perm and tu'ular fluid travels from seminiferous tu'ules rete testis efferent ductules coalesce into the epididymis drains into vas deferens vii. *permatogenesis is LH $e!en$ent (nee$s an$"o#en sec"et on) (+! 4ithout Testosterone spermatogenesis stops at the primary spermatocyte stage viii. 7SH nee$e$ to n t ate s!e"&ato#enes s and for long-term maintenance (+! 2acilitates sperm maturation through action on *ertoli cells ix. 51 and 2*1 exert fx on spermatogenesis via actions on 5eydig and sertoli cells x. Cits A 8 = are also needed for early stages of spermatogenesis $3 Se&en i. 3-< m59e0aculation ii. *eminal fluid, (+! *eminiferous tu'ules (/! Se& na' (es c'es ($BD! (a! Prostaglandins *"+ctose (3! P"ostate (3BD!

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(a! Al%aline secretions (!hos!hate and % ca"% 'uffers! ('! #uffers the acidity of vaginal secretions and promotes sperm via'ility (c! *permine @inc acid phosphatase (6! 8o"per7s glands (a! Mucous secretions for lu'ricating urethra (<! 8ontains hormones, (a! androgens ('! =strogens (c! Progesterones (8) Ac"os n nh % to" (a! Prevents conversion of proacrosin to acrosin in sperm head (9) S!e"& ne (a! Released from deteriorating sperm and mar%er for semen (.! Prevents capacitation until in the female reproductive tract iii. )nfertility may result from, E /B million9ml sperm less than <BD motile sperm or less than $BD normally conformed sperm e3 S!e"& Ca!ac tat on 3 S!e"& n se&en nca!a%'e o* *e"t ' : n# an o(+& 3 Ca!ac tat on occ+"s n the *e&a'e "e!"o$+ct (e t"act (+! Fccurs after seminal fluid dissipates iii. Meta'olic rate mem'rane fluidity intracellular calcium and motility increase after capacitation (+! necessa"/ *o" ac"oso&a' "eact on to occur *3 Ac"oso&a' "eact on i. Occ+"s -hen ca!ac tate$ s!e"& "eaches o(+& & permits penetration of ovum ii. GP3 (Gona Pellucida! glycoprotein induces acrosomal reaction iii. 2usion of mem'ranes releases acrosomal en@ymes, (+! Acrosin & protease that hydroly@es the glycoprotein of the @ona AAellucid surrounding the ovum (/! 1yaluronidase & proteolytic en@yme that hydroly@es hyaluronic acid 'inding the cells of cumulus oophorus #3 P+%e"t/ 3 A$"ena"che (+! #efore pu'erty "hen adrenal androgens (under A8T1 influence! rise (/! Promotes early development of pu'ic and axillary hair as "ell as gro"th spurt ii. At pu'erty (nR1 pulsitile secretion 'egins (+! )ncreases 51 and 2*1 secretion "hich increases testicular androgen production iii. 8hanges associated "ith !+%e"ta' noct+"na' GnRH !+'ses 519 Gona$ot"o!e sens t ( t/ to GnRH nc"eases increase in 5192*1 secretion (/! *ensitivity to negative feed'ac% inhi'ition of testosterone on (nR1 and 51 secretion decreases (3! HResett n# the #ona$ostat; 549 =nd result is a " se n LH an$ 7SH 'e(e's testes gro"th increased testosterone and sperm production h3 Senescence i. At older ages gonadal sensitivity to 51 decrease and androgen production drops ii. 51 and 2*1 levels rise /. Testicular 1ormone Physiology a3 An$"o#ens i. T"ans!o"t < .AD 'ound to proteins (6BD to *1#( 6AD to al'umin! 3 Meta%o' s& (+! Testosterone to D1T via <a-reductase (/! Testosterone to estrogen via aromatase (3! D1T cannot 'e made into estrogens (6! =xcreted in urine as =9,>etoste"o $

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559 8on0ugated "ith glucuronate or sulfate in liver excreted in urine 3 MOA (+! Testosterone (or D1T! freely enters cell and 'inds to androgen receptor (/! #inding to AR releases heat shoc> !"ote n (HSP! from receptor (a! )ncreases availa'ility of D;A-'inding sites ('! Permit 'inding of ligand-receptor to hormone responsive element of D;A (c! 5igand 'ound receptor acts as transcription factor to regulate gene expression iv. Testes !"o$+ce a%o+t ?6@ o* testoste"one the rest is mostly adrenal v. DHT is produced in the !e" !he"/ 'y conversion of testosterone via 6a,"e$+ctase (=) DHT s 436 t &es &o"e !otent than Testoste"one vi. Testosterone can %e con(e"te$ to est"a$ o' ( a a"o&atase (+! *ource of circulating estrogen in males is usually adipose tissue aromati@ation of testicular and adrenal androgens vii. Fther less potent androgens, D1=A and androstenedione %3 Inh % n i. *ecreted fron *ertoli cells ii. *ecretion is stimulated 'y androgens and 2*1 iii. Acts to inhi'it 2*1 via negative feed'ac% to the pituitary c3 Cont"o' o* Test c+'a" Ste"o $o#enes s i. LH acts on Le/$ # ce''s to stimulate ste"o $o#enes s ii. 7SH an$ an$"o#ens stimulate an$"o#en,% n$ n# !"ote n !"o$+ct on %/ Se"to' ce''s iii. Testoste"one acts on ! t+ ta"/ an$ h/!otha'a&+s to nh % t GnRH production in hypothalamus 519 And inhi'it (nR1 action on gonadotrope inhi'it 51 production9secretion $3 Act ons Regulate differentiation of male internal and external genitalia in fetus *timulate gro"th development function of male internal and external genitalia *timulate secondary sexual traits (hair se'aceous glands! *timulate =PF synthesis 8ontrol of protein ana'olic effects *timulate 'one gro"th and closure of epiphyses )nitiate and maintain spermatogenesis *timulate androgen-'inding protein Maintain secretions of sex glands Regulate 'ehavioral effects including li'ido

MALE SEN ORGAN PATHOLOGY A"stinBs $e%tion 6# 0AL1 IN.1RTILITY -tinability of a couple to achieve pregnancy despite unprotected intercourse for a period of more than 6< months a# 67@ of couples are infertile, a male factor plays a role in about half of the cases# b# 5or conception to occur, the follo"ing conditions must be met i# %he testes must have normal spermatogenesis ii# the spermatozoa must complete their maturation iii# the ducts for sperm transport must be patent iv# prostate and seminal vesicles must supply adequate amounts of seminal fluid v# semen is deposited near the female's cervi$ vi# spermatozoa must penetrate the cervical mucus and reach the uterine tubes vii# the spermatozoa must undergo capacitation and the acrosome reaction, fuse "ith the oolemma, and be incorporated into the ooplasm c# 2ale infertility can be divided into pretesticular, testicular, and posttesticular forms

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<#

retesti%"lar +a"ses) disorders of the hypothalamic-pituitary-gonadal a$is a# AQA# %he hypogonadotropic hypogonadism "ith lo" ;, and 5 ,# b# can originate on either the hypothalamic level (gonadotropin-releasing hormone) or the pituitary level (luteinizing hormone and 5 ,)# c# most often caused by mutations in genes involved in the biosynthesis of the hormones, gro"th factors or receptors, and associated signal transduction path"ays# d# result in a loss of intratesticular testosterone production and cessation of spermatogenesis# e# %he condition is characterized either by decreased output of gonadotropin-releasing hormone (1n+,), causing circulating levels of 5 , and ;, to diminish, or by rare disorders of the pituitary ("ith normal 1n+,) that result in primary deficiencies of 5 , andGor ;,# %hese defects result in deficient androgen secretion and spermatogenesis# f# abnor'al synthesis and release o, GnRH are most often caused by mutations, small deletions, or polymorphic e$pansions "ithin genes involved in the endocrine or humoral regulation of se$ual development and function#or by hypothalamic tumors# g# 1n+, deficiencies/0firm prepubertal-sized testes and a small penis# h# Call'ann?s syndro'e is caused by a deficiency in 1n+, secretion from the hypothalamus due to mutation in the KALIG-1 gene on Op<<#&# i# %his gene codes for a protein necessary in olfactory and in 1n+, a$onal migration from the olfactory placode to the septal preoptic nuclei# ii# typically tall and anosmic, and often present "ith failure of pubertal initiation# iii# may also have congenital deafness, asymmetry of the cranium and face, cleft palate, cerebellar dysfunction, cryptorchidism, or renal abnormalities iv# ome men "ith Qallmann's syndrome suffer only from infertility due to an isolated gonadotropin deficiency and have no other phenotypic abnormalities i# 0"tations in Dax1& another O chromosome gene, cause hypogonadotropic hypogonadism in association "ith congenital adrenal hypoplasia i# Dax1 encodes an orphan nuclear hormone receptor that has a critical role in the development of the hypothalamus, pituitary, adrenal, and gonads and in the maintenance of testicular epithelial integrity and spermatogenesis# 4# GnRH re%eptor '"tations) e$ist and cause a spectrum of repo dysfunction !# rader)Dilli syndro'e is caused either by mutations or deletions of a specific locus "ithin paternal chromosome 67 or, less commonly, "hen maternal uniparental disomy (< maternal copies) of this locus occur# i# obesity, mild or moderate mental retardation, and infantile hypotonia and hypogonadotropic hypogonadism l# He'o%hro'atosis) treatable primary testicular failure# m# ina%ti2e LH or .$H- happens and cause a spectrum of repo dysfunction n# it"itary 'ass lesions) interfere "ith the release of ;, and 5 ,, either by direct compression of the portal system or by decreasing secretion of these gonadotropins# o# Hyperprola%tine'ia) elevated serum prolactin level causes hypogonadism because it interferes "ith the normal pulsatile release of 1n+, i# Adenomas of the pituitary cause hyperprolactinemia, headaches and visual field impairment because of direct compression on the optic chiasm# ii# elective serotonin reupta!e inhibitors can also cause hyperprolactinemia p# %on!enital adrenal hyperplasiaEFimpaired corticosteroid and androgenic steroid syntheses can cause failure of any one of the chemical conversions involved in the production of testosterone together "ith cortisol and aldosterone/0 abnormalities ranging from incomplete virilization to completely feminized genitalia and cryptorchid testes q# Andro!en insensiti2ity syndro'es) result from abnormalities in the androgen receptor (AR) gene# i# result in feminization of )B OP individuals ii# spectrum from simple male infertility to ambiguous genitalia and hypospadias iii# .n severe cases, since a portion of testosterone is converted to estradiol by aromatization, estradiol levels are usually elevated and feminization occurs in a similar fashion to normal OO females at the time of puberty

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iv# should be suspected in a patient "ith a family history of interse$ disorders in one or more maternal uncles r# Anaboli% steroid ab"se) results in negative feedbac! at the level of the hypothalamus and pituitary, and ;, and 5 , release is reduced i# disables endogenous testosterone production and spermatogenesis since normal spermatogenesis requires both 5 , and adequate intratesticular testosterone ii# *ecreased testicular size and gynecomastia afterlong term use iii# Normal hormonal function usually returns after these agents are discontinued &# T1$TI+=LAR +A=$1$-damage spermatogenic potential by direct effects on the testicles a# Gari%o%eles- are considered the most common cause of subfertility in men i# dilated scrotal veins ii# in 67@ of the normal males, but in )'@ of men presenting "ith infertility iii# mechanismsA anatomical configuration of the left internal spermatic vein, incompetent or absent valves, and potential for a partial left renal vein compression bet"een the aorta and the superior mesenteric artery (the Mnutcrac!erM phenomenon)# iv# acute varicocele can also be caused by retroperitoneal malignancies "ith arteriovenous shunting into the venous system# v# associated "ith impaired spermatogenesis by one of several mechanismsA increased scrotal temperatures, alterations in testicular blood flo", reduced testicular size, overproduction of adrenal steroid metabolites, increased o$idative stress, "hich may damage cell membrane integrity or cause *NA damage, and alterations in the hypothalamic-pituitary-gonadal a$is, leading to decreased serum testosterone levels# vi# decreased semen quality and increased sperm *NA damage b# About 6 in <' infertile men has a chromosomal abnormality and most of these cases involve a se$ chromosome# Hsually these men are azoospermic or severely oligospermic c# Cline,elter?s syndro'e ()C,OOP) -most common chromosomal disorder assoc#"ith it i# severely oligospermic or azoospermic ii# phenotypeA increased height, female hair distribution, gynecomastia, decreased level of intelligence, diabetes mellitus, obesity, increased incidence of leu!emia and nonseminomatous e$tragonadal germ cell tumors, small firm testes, and infertility iii# ;aboratory studies sho" inc# 5 ,, normal or increased serum estradiol, and normal or lo" serum testosterone ("ith a tendency to decrease "ith age) iv# ;eydig cell function is commonly impaired v# mosaics "ith )B,OPG)C,OOP have a less severe phenotype, including a variable presence of germ cells and sperm production d# 'ixed !onadaldys!enesis) have a mosaic !aryotype of )7,OG)B,OP i# can have male, female, or ambiguous genitalia, strea! gonads, or normal testes# e# HH 'ale syndro'e ()B,OO) is caused by translocation of the SRY se$-determination gene from the paternal P chromosome to the paternal O of the offspring, resulting in MnormalM development of testes in the OO fetus, but lac! of all spermatogenic genes normally found on the P chromosome f# HYY 'ale syndro'e ()C,OPP) is characterized by decreased intelligence, antisocial behavior, an increased incidence of leu!emia, and impairment of spermatogenesis# g# 0i%rodeletions o, the Y %hro'oso'e) %he long arm of the P chromosome contains genes that are critical for spermatogenesis, most importantly the AY5 region h# +ryptor%hidis') testicular descent does not proceed normally during development and the testis remains in the abdominal cavity or groin i# 7'(C'@ of unilaterally cryptorchid men are oligospermic or azoospermic and almost 6''@ of bilaterally cryptorchid men are azoospermic# i# +i!arette s'o*in!) associated "ith an overall reduction in semen quality, and specifically a reduction in sperm count and motility and an increase in abnormal forms i# damage to sperm *NA ii# lo"ered sperm concentration by 6&(6C@

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4.

iii# some evidence that maternal smo!ing may be related to decreased sperm counts in the offspring# iv# the ris! of developing erectile dysfunction is almost doubled for smo!ers compared to nonsmo!ers, and this can limit male fertility# 4# .ncreases in scrotal temperature reduce sperm quantity and quality !# +he'otherapy and radiation therapy -are potent !onadotoxins i# can cause permanent damage to the germinal epithelium "ith variable recovery of spermatogenesis ii# it is recommended that patients ban! their semen before such therapy is initiated l# Testi%"lar or epididy'al in,e%tions) i# mumps may result in orchitis in postpubertal males ii# Necrosis from acute s"elling and increased intratesticular pressure can cause permanent testicular atrophy and infertility m# 1pididy'itis can lead to scarring of the tubules and obstruction of sperm flo" n# Torsion o, the sper'ati% %ordEF interruption of testicular blood flo" results in acute, intense testicular pain i# absence of blood flo" after )(B hours of causes irreparable damage ii# may also induce sperm autoimmunity due to a brea!do"n of the blood testis barrier during the ischemic event o# Testi%"lar tra"'a) can lead to scrotal or testicular edema, hematoma, hematocele, hydrocele, torsion, fracture, or rupture i# ?hen operated on in C< hours the testicle can be saved in up to F'@ of patients# O$TT1$TI+=LAR +A=$1$ a# D"%tal obstr"%tion) can occur any"here along the male reproductive system i# Complete obstruction of the e4aculatory duct results in a lo"-volume, acidic, fructose-negative e4aculate ii# Ebstruction of the vasa or epididymides results in a normal-volume, al!aline, fructose-positive e4aculate# iii# 2en "ith ductal obstruction as the only cause for their infertility have normal serum testosterone and 5 , levels# iv# Congenital causes include congenital atresia or stenosis of the e4aculatory ducts and utricular, or 2Sllerian and ?olffian duct cysts v# Acquired vasal obstruction may be caused by inguinal or pelvic surgery, but is most commonly the result of a 2ase%to'y# vi# -pididymal obstruction may be caused by scrotal surgery and epididymitis# vii# -pididymitis can result from a number of genitourinary infections, including the se$ually transmitted diseases chlamydia and gonorrhea viii# eIa%"latory d"%t obstr"%tion may be due to genitourinary infections, pelvic surgery, urethral trauma, chronic prostatitis, and calcifications and cysts in the prostate or seminal vesicles# b# +on!enital bilateral absen%e o, the 2as de,erens) a cystic fibrosis complication i# 2utations of the cystic fibrosis transmembrane conductance regulator ( CFTR) ii# occurs in 6(<@ of infertile men, ma!ing it the most common congenital abnormality of the ?olffian duct system c# 1Ia%"latory d"%t obstr"%tion) i# congenital isolated e4aculatory duct obstruction may be associated "ith CFTR mutations ii# Acquired cases may be due to prostatic nodule formation or inspissated secretions in the e4aculatory ducts causing calculi or Htricular cysts iii# ymptoms from e4aculatory duct obstruction include infertility, decreased e4aculate volume, reduced e4aculatory force, hematospermia, pain "ith e4aculation, and dysuria iv# must be considered in patients "ith azoospermia, lo" e4aculate volume, absence of fructose in the e4aculate, and normal serum gonadotropin and testosterone levels d# I''"nolo!i% in,ertility) result from a breach in the blood-testis barrier, e$posing the

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mature spermatozoa to the immune system "ith the formation of antisperm antibodies i# +is! factorsA trauma to the testes, epididymitis, congenital absence of the vas deferens, or vasectomy ii# found in 7(6'@ of infertile couples but are also present in 6(<#7@ of fertile men iii# Antisperm antibodies react "ith all of the ma4or regions of sperm and can impair sperm motility, sperm penetration through the cervical mucus, acrosome reaction, and sperm-oocyte interactions and fertilization# e# re'at"re eIa%"lation) is the inability to control e4aculation for a satisfactory length of time during intercourse, reported to affect up to &6@ of men 6D to 7F years of age f# AneIa%"lation) complete absence of seminal emission into the posterior urethra i# %rue ane4aculation is al"ays connected "ith central or peripheral nervous system dysfunction or "ith drugs# ii# Ergasm (clima$) may or may not be achieved iii# $pinal %ord inI"ry is the most common neurological cause of ane4aculation even though many men "ith spinal cord in4ury do have refle$ erections and some capability for vaginal intercourse iv# men "ith diabetes mellitus are at ris! for complications such as vasculopathy and neuropathy, "hich can affect e4aculatory function v# alpha-adrenergic bloc!ers, antipsychotics, and antidepressants# Ane4aculation can also be psychogenic or idiopathic can cause ane4acuation g# Retro!rade eIa%"lation) caused by a dysfunction in bladder nec! closure that results in a total or partial absence of antegrade e4aculation# i# the e4aculate flo"s into the bladder ii# the condition can be caused by the same conditions as neurogenic ane4aculation h# -pididymitis- inflammation due most commonly to infection of epididymis arising from a se$ually transmitted disease or a urinary tract infection# i# .n men younger than &7 years, the most common se$ually transmitted pathogens are Chlamydia tra h!mati" and N#i""#ria $!%!rrh!#a## ii# .n young children and in men older than &7 years, the most common urinary tract pathogen is E !li ;. IDIO ATHI+ OLIGO$ 1R0IA a# the pathophysiology of spermatogenic failure in a ma4ority of infertile men remains un!no"n b# 'at"ration arrest) %he most common lesion, is defined as failure to complete spermatogenesis beyond a particular stage, early- or late c# hyposper'ato!enesis) all stages of spermatogenesis are present but there is a reduction in the number of germinal epithelial cells per seminiferous tubule# d# Ger' %ell aplasia- complete absence of germ cells, "ith only ertoli cells lining the seminiferous tubules ($ertoli)%ell8only syndrome 9 CE :)# 3. $e'en Analysis a# tandard instructions for semen collection include a defined period of abstinence of <(& days# ;onger periods of abstinence lead to decreased sperm motility, and shorter periods result in lo" semen volume and sperm concentration# b# emen analysis provides information on semen volume, and sperm concentration, motility, and morphology c# .n normal men, the e4aculate volume is 6#7(7 m;, and the normal semen p, is slightly al!aline (range C#<(D#')# d# %he normal sperm parameters include sperm concentration <' million spermGm;, motility 7'@ motile sperm, and normal morphology &'@# e# %he quality of motile sperm can then be observed by the degree and pattern of for"ard progression displayed by the ma4ority of motile spermatozoa

$e'en Analysis/ Nor'al Gal"es and De,initions.

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+hara%teristi% -4aculate volume p, perm concentration perm count perm motility perm morphology Ter' Normospermia Eligozoospermia Asthenozoospermia Azoospermia Aspermia f#

Re,eren%e $tandard 0 < m; C#<(C#D <' millionGm; )' millionGm; 7'@ "ith normal motility 67@6(&'@ "ith normal forms De,inition Normal e4aculate (as defined by reference standards above) perm concentration N <' millionGm; N 7'@ of spermatozoa "ith for"ard progression of N <7@ "ith rapid progression No spermatozoa in e4aculate No e4aculate

About <7@ of men "ith sperm concentrations belo" 6<#7 millionGm; can father a child through spontaneous conceptionJ conversely, 6'@ of men "ith a normal female partner cannot contribute to pregnancy despite a sperm concentration of up to <7 millionGm;# 5. 1ndo%rine 12al"ation a# permatogenesis is evaluated by serum 5 , and inhibin, b# ;eydig cell function is evaluated by serum ;,, testosterone, se$ hormone(binding globulin ( ,81), and free testosterone# c# 2en "ith azoospermia caused by none$istent sperm production produce very lo" levels of inhibin, leading to high 5 , levels# d# Normal 5 , and inhibin levels in an azoospermic man suggest normal spermatogenesis "ith obstruction e# "ith spermatogenic arrest, normal values of 5 , and inhibin can be found, especially if maturation arrest is present, since there may be enough spermatogenic progress to allo" inhibin secretion# .r"%tose is produced in the seminal vesicles, and its absence in the semen implies obstruction of the e4aculatory ducts

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:. Testi%"lar t"'ors a# 3ea! incidence is 67-&) yo b# 2ost common male tumor c# 1erm cell tumors are F7-FD@ i# Aggressive, rapid, "ide spread metastasis, curable ii# EriginA intratubular germ cell neoplasm iii# +is! factorsA testicular dysgensis, cryptochidsm, prior germ cell tumor, family h$# (%his is the reason that cryptochidism is bad- predisposes totumors) iv# All types have painless enlargement of the testes v# All spread thre" the lymphatics to the para aorta, and blood to lung, liver, brain, bone- "ill metastasis in the first < yrs vi# eminomatous tumors 6# eminoma-7'@ of all 1erm cell tumors a# Ene morphological pattern b# 67-7' yo c# 6'$ size of normal testes d# %unica usually not breached e# Clear cytoplasm, large nucleas and nucleoli, PN giant cells f# % cell infiltrate in septea <# permatocytic seminoma a# 0B7yo b# lo" gro"ing, no matastasis c# & cell types daddy cells, momma cell, and little baby cells d# Not clear cytoplasm, no lymphocytes vii# Non-seminomatous tumor (B'@ have more that one of these patterns) 6# -mbryonal carcinoma a# Aggressive tumor of primitive embryonic cless b# %unica breached-spreads into the epididymis

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F#

c# CellsA large, epithelial li!e, form sheets, glands, tubules, papilea d# Nuclei are large and anaplastic "ith mitoses and nucleoli <# %ertatoma a# *erived from & germ layers b# 3repubertal is a pure tumor-benign c# 3ostpuberal often mi$ed "ith other tumors-maliganant d# ;arge 7-6'cm, solid, cystic e# *isorganized combo of cartilage, lung, neural, 1., thyroid cells &# Pol! sac- AQA endodernal sinus tumor a# 2ost common tumor in !ids N&yo, good prognosis b# chiller-duval bodies c# 3roduce Z- fetoprotein )# Choriocarcinoma a# %umor of cytotrophoblasts and syncytiophoblasts b# Cells of the placenta, produce IhC1 c# Kery very small- may loo! li!e a scar, but spreads very "idely d# 1ro" rapidly "ith prominent hemorrhage and necrosis viii# tagingA 6# tage 6 (C'@)- local, no serum mar!ers <# tage < (<'@)- spread to retroperitoneal ;N, N7cm &# tage & (6'@)- "ide metastasis, d# Nongerm cell tumors AQA se$ cord stromal tumors i# Are benign, secrete hormones ii# ;eydig cell tumor 6# .nterstitial cell tumor <# ecretes androgens, estrogen, progesterone, corticosteroids &# Circumscribed nodules,N7cm )# 3olygonal cells, eosinophilic cytoplasm, round nucleus 7# +ein!e crystalloids iii# ertoli cell tumor 6# 2ostly nonfunctional, some estrogen and androgens <# mall firm nodule &# Cells form cords resembling immature seminiferous tubules iv# ;eydig [ sertoli 6# 8enign s"elling <# .f functional prepuberty/0precocious puberty, feminization or masclinzationJ postpuberty/0gynecomastia permatic cord tumors a# ;ipoma-fat tumor of the inguinal canal b# Adenomatoid tumor-benign tumor or the epididymis, surgery may spare testes c# +habdomyosarcoma- in distal spermatic cord in !ids d# ;iposarcoma - in distal spermatic cord in adults FEMALE REPRODUCTI6E PHYSIOLOGY

J)' es Sect !" BREAST *("!A0 A*AT(!L 6810 maGor du#tal systems originate I nipple .ou3le layered #u3oidal epithelium lines the du#ts Terminal du#t lo3ular unit: in adult Domen< 3ran#h into grapeliEe #lusters o- small a#ini to -orm lo3ule

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.u#ts 4 2 #ell types line du#ts. ,ommitted stem #ell gi$es rise to 3oth o !yoepithelial #ells o ,ontra#tile< #ontain myo-ilaments. !ilE eGe#tion< stru#tural support to lo3ules

1pithelial #ells 0uminal< produ#e milE

2 types o- 3reast stroma o @nterlo3ular stroma o .ense -i3rous ,T admi'ed Dith adipose tissue

@ntralo3ular stroma 1n$elops a#ini o- lo3ules and ha$e 3reast8spe#i-i# hormonally responsi$e -i3ro3last8liEe #ells admitted D/ s#attered lympho#ytes

Prepu3ertal +reast 4 males and -emales

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0arge du#t system ends in terminal du#ts D/ minimal lo3ule -ormation

"eprodu#ti$e Lears o o o As endometrium groDs< so does 3reast 1st hal- menstrual #y#le lo3ules ;uies#ent A-ter o$ulation : estrogen in-luen#e and P4 [ #ell proli-eration< [ N o- a#ini/lo3ule o @ntralo3ular stroma 3e#omes edematous

!enstruation : 12 & P4 regression o- lo3ules and stromal edema disappears

Pregnan#y o o o +reast #ompletely matures and -un#tional 0o3ules [ in num3er and si=e 1nd o- pregnan#y entirely lo3ules< s#ant stroma

A-ter .eli$ery o o 0uminal #ells o- lo3ules produ#e colostru$ 5high in protein9 P4< then #hanges to milE 5higher in -at and #alories9 o$er ne't 10 days

+reast !ilE o o Prote#tion against in-e#tion< allergies< some autoimmune ds !aternal A3 5@gA9< $itamins< en=ymes< other mediators 5#ytoEines< antio'idants< -i3rone#tin< lyso=yme9 ,ertain drugs< radioa#ti$e #ompounds< $iruses passed to in-ant through 3reast milE

,essation o- 0a#tation o o o o +reast epithelium and stroma 4 e'tensi$e remodeling 1pithelial #ells 4 apoptosis 0o3ules regress and atrophy )ull regression doesn6t o##ur 4 permanent in#rease in si=e and num3ers o- lo3ules

A-ter 2rd de#ade o 0o3ules and spe#iali=ed stroma start to in$olute

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o o

0o3ular atrophy almost #omplete in elderly -emales @nterlo3ular stroma #hanges 4 repla#ed 3y radiolu#ent adipose tissue

O6ARIAN PHYSIOLOGY J!"&t%&"s Sect !" 3. Fvarian 1ormone Physiology a. 2emale 1ormones 3 Est"a$ o' (+! Most potent and plentiful ovarian estrogen (/! Made in #"an+'osa an$ '+tea' ce''s ii. =striol 519 5ess potent ;FT made a lot except during pregnancy (/! Ma0or source, 5)C=R (a! Made from estrone or estradiol iii. =strone (+! 5east potent (/! Most formed in periphery from estradiol or androstenedione (3! Predominant estrogen in postmenopausal "omen (3 P"o#este"one (+! Precursor for androgens and estrogens 529 Fther progestin, +A--hydroxyprogesterone v. Androgens (+! Dehydroepiandrosterone (/! Androstenedione (3! *mall amounts of testosterone vi. Fther hormones, (=) Inh % n (a! *ecreted 'y granulose cells in response to 2*1 ('! Acts to inhi'it 2*1 secretion from pituitary (/! Activins (3! Relaxins %3 O(a" an Ste"o $o#enes s 3 Theca nte"na (+! *ite of an$"o#en s/nthes s in pre-ovulatory follicle (/! Analogous to 5eydig cells in the testes 529 1ave 51 receptors LH st &+'ates ste"o $o#enes s 3 G"an+'osa ce''s (+! Analogous to *ertoli cells (/! *urround ovum (3! 1ave 2*1 receptors (a) 7SH to st &+'ate nh % n !"o$+ct on an$ an$"o#en a"o&at :at on to est"o#en ('! Fnly type of receptors present early in follicular phase (6! Predominant s te o* est"a$ o' !"o$+ct on n !"e,o(+'ato"/ *o'' c'e 5a9 Pre-ovulatory cells do not have +A hydroxylase to ma%e androgens

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iii. 4ith follicular gro"th, (+! *erum estrogen levels rise due to action of 51 on theca and 2*1 on granulosa 5a9 this estrogen I 2*1 granulose develop 51 receptors (i! leads to increased progesterone production iv. After ovulation, 519 Theca I granulosa cells luteal cells (a! 1ave 51 receptors ('! *ecrete estrogen and progesterone in response to 51 stimulation c3 Cont"o' o* O(a" an Ste"o $o#enes s i. 51 and 2*1 action mediated 'y cAMP ii. 51, (+! Acts on theca interna cells granulosa cells in late follicular phase and luteal cells (/! *timulates cell gro"th and steroidogenesis iii. 2*1, (+! *timulates granulosa cells to aromati@e androgen to estrogen iv. =stradiol (+! 2eed'ac% to inhi'it 51 and 2*1 synthesis9secretion at hypothalamic and pituitary levels $3 T"ans!o"t i. =strogen, (+! $BD 'ound o sex-hormone-'inding glo'ulin (*1#(! (/! /BD 'ound to al'uminJ /BD are free ii. Progesterone, (+! #ound to transcortin and al'umin (/! 8irculating t K, < minutes e3 Meta%o' s& i. Degraded in liver ii. 8on0ugated "9 sulfate or glucuronide iii. =xcreted in urine iv. =strogen to estrone estriol v. Progesterone to pregnanediol *3 Mechan s& o* Act on i. =nter cell via diffusion and 'ind to nuclear receptors ii. *teroid to receptor dimeri@ation of receptor release of heat shoc% proteins (1*P! increase in affinity of D;A 'inding domain ligand-receptor associated "ith hormone response element (1R=! of D;A to act as transcription factor #3 Act ons Est"o#en P"o#este"one -stimulate gro"th of uterus 2T vagina -produce secretory endometrium

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-gro"th of mammary ducts -secrete plentiful thin cervical mucus -stimulate follicular gro"th -stimulate granulosa cell 51 receptor formation -delay 'one loss at menopause -stimulate thin se'aceous gland secretions -stimulate 'one gro"th9close epiphyses -stimulate endometrial proliferation -stimulate renal ;a91/F retention - serum cholesterol - serum 1D5 - glucose tolerance - production of clotting factors - T#( *1#( transcortin synthesis - Progesterone receptors -may increase li'ido in some "omen -8;* stimulant An$"o#ens -pu'ic9axillary hair development -increases in pu'erty -max levels at midcycle

-stimulate secretion of scant viscous cervical mucus -stimulate mammary lo'ular-alveolar gro"th -antagoni@es aldosterone action -suppress mil% synthesis - 'ody temp (B.<2! - uterine motility - ventilation - sodium retention -8;* depressant

Re'aA n -induces relaxation of pelvic ligaments -softens cervix to facilitate child'irth -inhi'its uterine motility

MENSTRUAL CYCLE J)' es Sect !"

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LH= groDth o- -olli#les & o$ulation o- 1 -olli#le E-= proli- o- endometrial stroma & epithelium< glands P3: stimulates proteolyti# e=6s in the#al #ells< migration o- 3lood $essels into endometrial Dall< Pg se#retion< sDelling/se#retion o- endometrium 5luteal phase9 1B PROLIFERATI6E PHASE E&+'# F!'' c)'&+ P%&se 5.ay 1869 8)&H & 0H 812 & P4 8primordial -olli#le8888FSH88SMnilaminar -olli#le 8-un#tionalis shed

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L&te F!'' c)'&+ P%&se 5.ay %8149 8)&H 12 )&H 5negati$e -eed3a#E9 8Mnilaminar -olli#le888E-888S!ultilaminar -olli#le 5D/ -luid8-illed $esi#les9 8-un#tionalis proli-eration 5due to 129 8non8se#retory gland elongation P+e?O/)'&t !" & O/)'&t !" 5.ay 128149 PM+1"TL +@"TH 812 0H & )&H surge 2 oo#yte 1 oo#yte 8I o$ulation< 0H & )&H !etaphase Prophase 8.ominant -olli#leantrum< !eiosis @ #omplete to -orm 2 oo#yte @@ @ e'pelled into peritoneum< uptaEe in o$idu#t 8ma'imal -un#tionalis 8non8se#retory glands -B SECRETORY PHASE E&+'# L)te&' P%&se 8/n"H pulsing0H surge 5most sensiti$e to /n"H9#orpus luteum 5le-to$er te#al & granulosa #ells9 releases 12 & P4 80H & )&H 8P4gly#ogen & mu#us se#retion in glands 8P4 & T/)8B1 inhi3it matri' metalloproteinases 5!!Ps9 that normally alloD -or dissolution & reorgani=ation o- the endometrium. 8this inhi3ition alloDs -or maintenan#e o- se#retory endometrium 3B MENSTRUAL PHASE L&te L)te&' P%&se 8#orpus luteum degeneration#orpus al3i#ans 812 & P4endometrial in$olution< spiral a. F,< -un#tionalis apoptosis & sloughing 8)&H 5disinhi3ition9 8P4 alloDs -or disinhi3ition o- !!P6s & shedding ###Endo$etrial Cycle### P+e?!/)'&t !": 12 synthesi=es a#id phosphatase D/in lysosome P!st?!/)'&t !": P4 sta3ili=es phosphatase< pre$ents release 12 synthesi=es Pg6s 5-or mus#le #ontra#tion9< P4 inhi3its these Pg6s P+e?(e"st+)&t !"= 12 & P4< 8lysosomal e= es#apes#ellular auto8digestion 8Pg6smus#le #ontra#tion< $as#ular throm3osis< is#hemia

PHYSI ! "Y

# PRE"NANCY

!ayne$s Section &hysiolo"y of &re"nancy haracteri/ed by steadily increasin" le(els of estro"en and pro"esterone which maintain the endometrium for the fetus, suppress o(arian function by inhibitin" 0SH 1 2H, and stimulatin" de(elopment of the breast. &hysiolo"ic chan"es occur in essentially e(ery maternal or"an system. %hese include o increased blood (olume (increased by more than 345 by the middle of the third trimester) o increased total body water (increased by 678 2)

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increased cardiac output because of increased stro)e (olume (increased by 945) and heart rate (increased by :;5). o stri)in" increase in minute (entilation (increased by ;45 compared with nonpre"nant state) without any chan"e in respiratory rate is obser(ed as a result of increased tidal (olume o dramatic increases in renal blood flow and "lomerular filtration rate (increased by 345) <ost of these alterations are related in comple' ways to the effects of steroid hormones produced in pre"nancy. %he roles of steroids are belie(ed to be the followin" on the mother: o &#=>.S%.#=N. promotion of implantation suppression of the maternal immune response to fetal anti"ens, thus pre(entin" re?ection of the fetus cardio(ascular compliance pro(ision of substrate for manufacture by the fetal adrenal of "lucocorticoids and mineralocorticoids maintenance of uterine ,uiescence throu"h "estation a role in parturition o .S%#=>.N (olume e'pansion cardiac remodelin" preparati(e production of clottin" factors, anticipatin" blood loss that commonly follows deli(ery o H@<$N H=#*=N* S=<$%=<$<<=%#=&*N ounterre"ulatory hormone to insulin h S is released in order to pre(ent hypo"lycemia of the fetus it ser(es to increase lipolysis, thereby raisin" maternal free fatty acids this is a diabeto"enic burden on the mother, and leads to the de(elopment of "estational diabetes in susceptible indi(iduals &rocesses in pre"nancy 0ertili/ation o *f fertili/ation occurs, the corpus luteum is rescued from re"ression by human chorionic "onadotropin (h >) which is produced by the placenta 0irst %rimester o %he corpus luteum is responsible for the production of estradiol and pro"esterone o &ea) le(els of h > occur at "estational wee) A and then decline Second trimester o &ro"esterone is produced by the placenta o .stro"ens are produces by the interplay of the fetal adrenal "land (produces DH.$!S)and the placenta (remo(es Sulfur). %he ma?or placental estro"en is .S%#*=2 o Human &lacental lacto"en is produces throu"hout pre"nancy. *ts actions are similar to those of >H and prolactin &artuition o %hrou"hout pre"nancy, pro"esterone increases the threshold for uterine contraction o Near term, .B& ratio increases, which ma)es the uterus more sensiti(e to contractile stimuli o %he initiatin" e(ent in parturition is un)now. 2actation o .stro"ens and pro"esterone stimulate the "rowth and de(elopment of the breasts throu"hout pre"nancy o &rolactin le(els increase steadily durin" pre"nancy because estro"en stimulates prolactin secreation from the anterior pituitary. o 2actation does not occur durin" pre"nancy because estro"en and pro"esterone inhibit the actions of prolactin on the breast. $fter parturition, estro"en and pro"esterone le(els decrease abruptly, causin" lactation. o 2actation is maintained by o'ytocin and suc)lin" o

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=(ulation is suppressed because prolactin does the followin": *nhibits hypothalamic >n#H secretion *nhibits the action of >n#H on the ant. &ituitary, and conse,uently inhibits 2HB0SH secretion $nta"oni/es the actions of 2HB0SH on the o(aries

P!ACENTA! ANAT %Y & PHYSI ! "Y !ayne$s Section &lacental $natomyB&hysiolo"y %he placenta forms consistin" of two functional layers, the cytotrophoblast and the syncytiotrophoblast, as well as an ad?acent maternal layer, the endometrial decidua with the underlyin" mesenchymal core %he placenta secretes a (ariety of important hormones, includin" an 2H!li)e hormone termed human chorionic "onadotropin (h >). @nli)e 2H secretion by the "onadotrophs of the anterior pituitary, placental secretion of h > is not inhibited by the hi"h le(els of estro"en and pro"esterone. %he h > maintains the corpus luteum for a period of 87:4 wee)s until the full pro"esterone!producin" capacity of the placenta has

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de(eloped. $t that point, h > le(els fall and the mature placenta produces pro"esterone from the maternal supply of cholesterol =ther factors produced by the placenta include placental "rowth hormone (>H!&), and a "rowth hormone7 li)e protein termed human chorionic somatomammotropin (h S), also )nown as placental lacto"en (h&2) Durin" most of pre"nancy, the fetus pro(ides the placenta with andro"ens, which are used to ma)e estro"ens secreted into the maternal circulation. %his reflects the action of a special /one in the fetal adrenal corte' en"a"ed in andro"en production. %oward the end of pre"nancy, the increasin" $ %H secretion by the fetal pituitary tri""ers the fetal adrenal to produce cortisol in addition to andro"en. %his switch may play a role in tri""erin" the onset of labor.

%he placenta is composed of chorionic (illi that sprout from the chorion to pro(ide a lar"e contact area between the fetal and maternal circulations. *n the mature placenta, the maternal blood enters the inter(illous space throu"h endometrial arteries (spiral arteries) and circulates around the (illi allowin" for "aseous and nutrient e'chan"e. %he deo'y"enated blood flows bac) from the inter(illous space to the decidua and enters the endometrial (eins. Deo'y"enated fetal blood enters the placenta throu"h two umbilical arteries that branch radially to form chorionic arteries. horionic arteries additionally branch as they enter the (illi. *n the chorionic (illi they form an e'tensi(e capillary system, brin"in" fetal blood in close pro'imity to maternal blood. %he "as and nutrient diffusion occurs throu"h the (illous capillary endothelial cells and thinned!out syncytiotrophoblast and cytotrophoblast. @nder normal circumstances there is no mi'in" between the fetal and maternal blood. Clood o'y"enated in the placenta returns to the fetus throu"h the sin"le umbilical (ein. FEMALE REPRODUCTI6E & REPRODUCTI6E ORGAN PATHOLOGY MENSTRAUL CYCLE DISORDERS & GYNECOLOGIC PATHOLOGY

J)' es Sect !" ANO6ULATION

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a) +e%inition i9 \& & prolonged 12 stimulation D/out progestational 5luteal9 phase that normally -olloDs o$ulation 519 endometrial glands undergo mild #hanges< su#h as #ysti# dilation 5perisitent proliendometrium9< D/ possi3le o##asional 3reaEdoDn o- stroma 5ano$ulatory menstruation9 b) Causes i9 ii9 thyroid disease adrenal disease

iii9 pituitary tumors i$9 primary o$arian lesion 5P,(& or o$arian tumor9 $9 generali=ed meta3oli# distur3an#e 5se$ere o3esity or malnutrition9

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INFERTILITYGno #on#eption a-ter at least 1 yr o- regular se'ual inter#ourse D/out #ontra#eption. 19 Et !'!*# a9 20H o- #ases due to male in-ertility 39 -emale in-ertility #auses< see 3eloD: T&0'e --Q1- C&)ses !f Fe(&'e I"fe+t ' t#B1 C&)se P&t e"ts @ t% I"fe+t ' t# 3>H

O ulatory dysfunction .iminished o$arian reser$e (ligo8o$ulation or amenorrhea P,(& Hypothalami# amenorrhea (ther Tu!al or pel ic patholo"y 1ndometriosis &#arring and adhesions 5-rom pel$i# in-lammatory disease< #hroni# in-e#tion< tu3al surgery< e#topi# pregnan#y< or ruptured appendi'9 Miscellaneous Thyroid disease Pituitary disease 5hyperprola#tinemia9 ,ne-plained

3>H

1>H

10H

-9 P&t%!'!*# & P&t%!*e"es s &9 O/)'&t!+# c&)ses i9 ii9 Hypothal/pituitary disordersinade;ute gonadotropi# stimulation o- o$ary ($arian disordersinade;uate se#retory produ#ts or o$ulation -ailure 519 ,an use arti-i#ial insemination or @F) i- ne#essary i$9 +i$inished o.arian reser.e: age related< a##elerated loss o- -olli#les near menopause 519 N -olli#les or o$arian steroidogenesis)&H due to inade;uate inhi3inshortened -olli#ular phase< in-ertility

iii9 1'ogenous gonadotropins #an stimulate o$aries to #ause -olli#ular groDth

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529 T': #lomiphene 512 antag9 to negati$e -eed3a#E & gonadotropin stimulation o- o$ary -or o$ulation $9 (ther #auses: P,(& & hypothalami# amenorrhea88alter #oordination 3/t o$ary & hypothal 519 (o#ytes don6t de$elop and mature properly -or regular o$ulation 09 T)0&' &", $e'/ c c&)ses i9 ii9 Pel$i# in-e#tions D/ adhesions or in-lamm-ailure o- sperm or egg transport< -ailure oimplantation< e#topi# pregnan#y 1ndometriosis D/ #y#li# proli- & sloughing o- e#topi# endometrial tissue 5possi3ly due to endometrial stem #ells9in-lamm< s#arring< adhesions 519 &trong liEelihood i- pt presents D/ dysmenorrheal ? in-ertility 529 T': surgi#al & medi#al t' c9 Ot%e+ c&)ses !f fe(&'e "fe+t ' t# i9 disorders a--e#ting /n"H produ#tion or its e--e#t on pituitary: thyroid disease< hyper8P"0 19 ENDOMETRIOSIS a. .e-inition i. 1ndometrial glands or stroma outside o- the uterus 4 in o$aries< uterine ligaments< re#to$aginal septum< pel$i# peritoneum< laparotomy s#ars< or rarely in the um3ili#us< $agina< $ul$a< appendi' ii. This is di--erent -rom ADENOMYOSIS O endometrial tissue in the myometrium 1. .uring menstruation< hemorrhage o- endometrial stromal nests #an #ause menorrhagia< #oli#Ey dysmenorrheal< dyspareunia & pel$i# pain 3. ,auses i. Re*)+* t&t !"A ($'&"t&t !" t%e!+#: retrograde menstruation through -allopian tu3es and into peritoneal #a$ity< esp. -olloDing surgi#al pro#edures 1. +est e'planation -or endometriosis in #er$i' or pel$i# sites ii. Met&$'&st c t%e!+#: endometrium arising dire#tly -rom #oelomi# epithelium< Dhere the mullerian du#ts and endometrium originate emy3ryoni#ally 1. +est e'planation -or endometriosis on other sites< liEe the o$aries iii. 6&sc)'&+A'#($%&t c , sse( "&t !" t%e!+#: spread through peli$ $$ & lymphati#s to present in lungs & lymph nodes i$. Also< geneti#< hormonal< & immune -a#tors may 3e in$ol$ed #. Pathology i. Aromatase ,LP450 in endometrioti# tissue 3ut not normal endometrium suggests that this a3normal tissue #an produ#e its oDn estrogens. @t may also 3e #lonal

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d. !orphology i. "espond to o$arian & intrinsi# hormonal stimulation D/ periodi# 3leeding< #auses red8 3lue to yelloD83roDn nodules ii. (rgani=ing hemorrhage #an #ause -i3rous adhesions 3/t )allopian tu3es< o$aries< pou#h o- .ouglas< et#. iii. ($aries might 3e#ome distorted D/ large #ysti# masses D/ 3roDn 3lood de3ris88 J#ho#olate #ystsK i$. ,an diagnose histoligi#ally D/ presen#e o- endometrial stroma< or mullerian epithelium D/ su3Ga#ent hemosiderin pigment e. ,lini#al ,ourse i. &e$ere dymsmenorrhea< dyspareunia< pel$i# pain 5due to intrapel$i# 3leeding & adhesions9 ii. Pain on de-e#ation 5i- re#tal in$ol$ement9 iii. .ysuria 5i- 3ladder in$ol$ement9 i$. Possi3le intestinal pro3s $. !enstrual irregularity $i. @n-ertility in 20840H o- pt6s $ii. risE o- malignan#y 4 endometrioti# lesions might 3e Jat8risEK epithelium

19 )1!A01 ("/A&!@, .@&(".1" &9 STATISTICS I9 :?1>H OF ADULT LOMEN IN THE UBSB ARE ANORGASMIC II9 1>H MAY ONLY REACH ORGASM LA FANTASY ALONE B9 DEFINITIONS I9 PRIMARY ANORGASMIA= NE6ER ENPERIENCED AN ORGASM IN ANY SITUATION7 E6EN LA PROLONGED & EFFECTI6E SENUAL STIMULATION II9 SECONDARY ANORGASMIA= HA6E HAD NORMAL ORGASMS IN THE PAST III9 ANORGASMIC LOMEN MAY LUBRICATE NORMALLY AND ENJOY INTERCOURSE BUT ARE NOT ABLE TO PROGRESS PAST THE PLATEAU PHASE OF THE SENUAL? RESPONSE CYCLE I69 MANY LOMEN ARE PHYSIOLOGICALLY ABLE TO REACH ORGASM7 BUT THERE ARE MANY CULTURAL7 RELATIONAL7 AND PERSONAL ISSUES THAT CAN INFLUENCE LOMENS ABILITY TO REACH THIS PHASE C9 THERAPY I9 GOAL= HELP INDI6IDUAL ACHIE6E ORGASM7 USUALLY LAOUT PARTNER PRESENT II) ENHANCE SENSORY STIMULATION & PTS IN6OLUNTARY INHIBITIONS III9 ENSURE THAT THE PT UNDERSTANDS THE NEED FOR SUFFICIENT CLITORAL STIMULATION7 COMMUNICATING NEEDS TO PARTNER7 AND KNOLS THAT IS NORMAL TO BE SENUAL

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I69 DISREGARD ANY OBSESSI6E THOUGHTSADISTRACTIONS7 FOCUS ON EROTIC THOUGHTS AND FANTASY V) SELF?STIMULATION TO LEARN LHAT FEELS PLEASURABLE AND SENUAL AROUSAL 6I9 LOMENS DISCUSSION GROUP TO ADDRESS FEARS7 EDUCATIONAL ISSUES7 LEARN SPECIFIC SENUAL TASKS TO DO AT HOME ALONE AND THEN FOLLOL?UP LITH DISCUSSION IN GROUP AND A FUTURE SESSION VII) TRANSFER ORGASMIC ENPERIENCE TO PARTNER SITUATION BY AROUSAL PRE?PENETRATION7 FOCUS ON PERSONAL PLEASURE AND A6OID DISTRACTING THOUGHTS7 TAKE AD6ANTAGE OF FANTASY 19 D s!+,e+s !f Se.)&' D ffe+e"t &t !" a9 .e-inition i9 A3errations in em3ryogenesis that in-luen#e #hromosomal< gonadal< or phenotypi# se'ual de$elopment

39 1'amples i9 Turner6s syndrome 545< \9 519 Phenotypi# -emales D/ primary amenorrhea< a3sent se#ondary se' #hara#teristi#s< short staure< #ongenital anomalies< 3ilateral streaE gonads 5hypoplasti# & dys-un#tional< mainly #omposed o- -i3rous tissue9 ii9 /onadal dysgenesis 519 +ilateral streaE gonads & immature -emale phenotype 3ut normal height and no other somati# de-e#ts @@@9 Pseudohermaphroditism. ,auses: 519 )emale em3ryo e'posed to \& androgen 5maternal or e'ogenous9 during se'ual di--erentiation 529 .e-e#ts in androgen synthesis or sensiti$ity in the em3ryo 5a9 e.g. #ongenital adrenal hyperplasia 4 \& produ#tion o- se' steroids

19 PRECOCIOUS PUBERTY A. .e-inition i. .e$elopment o- se#ondary se' #hara#teristi#s T8 y.o. 5guidelines may $ary 3ased on ra#e 4 A-Am -emales may de$elop earlier9 ii. Ad$an#ement o- 3one age S2 &.< Dith re#ent groDth a##eleration & se#ondary se' #hara#teristi#s iii. Premature adrenar#he may 3e asso#iated Dith o3esity< hyperinsulinemia< and su3se;uent predisposition to P,(&. 3. ,auses i. ,entrally mediated 1. 1arly a#ti$ation o- HP( a'is< D/ pulsatile 0H & 0H/)&H reponse to e'ogenous /n"H ii. Peripherally mediated

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1. gonadotropins D/ 12 #. Therapy i. )or #entrally mediated< use /n"H agonistspituitary desensiti=ation to pre$ent premature epiphyseal #losure ii. )or peripherally mediated< treat underlying disorder & limit steroid e--e#ts $ia aromatase inhi3itors< steroidogenesis inhi3itors< 128re#eptor antag

-9 DELAYED PUBERTY A. .e-inition i. A3sen#e o- se#ondary se' #hara#teristi#s 3y age 12 3. ,auses i. 25840H due to o$arian origin 5usually Turner syndrome9 ii. 25H due to -un#tional hypogonadotropi# hypogonadism< asso#iated D/ systemi# illnesses su#h as #elia# disease< #hroni# renal disease< dia3etes< hypothyroidism< a3normal energy 3alan#e 5diet< e'er#ise< eating disorders9 iii. ,ongenital hypogonadotropi# hypogonadism #an 3e #aused 3y se$eral genes<a long D/ geneti# sus#epti3ility to en$ironmental stresses liEe diet & e'er#ise i$. *euroanatomi#

SENAGORES LECTURE= GYNECOLOGIC PATH JULIES SECTION 19 1m3ryology

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a9 !ullerian du#t 5paramesonephri#9 stru#tures i9 ,oelomi# epithelium in$aginates & -uses 519 +oth inner & outer sur-a#es 5in#luding o$aries9 deri$ed -rom this same epithelium ii9 groDs #audally & medially

iii9 -uses D/ urogenital sinus 29 )emale genital tra#t in-e#tions &9 Pe'/ c "f'&((&t!+# , se&se 8PID G EP)s " De+F9 i9 ii9 Pel$i# pain< -e$er< adne'al tenderness< $aginal dis#harge< upDard spread Hydrosalpin': Dhen supurati$e material is resor3ed & Datery residual is le-t

iii9 ,hroni# salpingitis D/ #lu33ed mu#osa< not amena3le to -ertili=ation i$9 Tu3o8o$arian adhesions D/ torsion 39 !u#osal sur-a#e in-e#tion 5&T@ a--e#ting adne'a9 i9 /onorrhea< ,hlamydia tra#homatis

#9 &T@ #an 3e#ome a deep tissue in-e#tion i9 ii9 A--e#ts endometrium & myometrium &preads $ia $$ & lymphati#s

iii9 (-ten post8pro#edure 5a3ortion< parturition9< D/ aggressi$e instrumentation

i$9 Postpartum/puerperal in-e#tions: staph< strep< entero3a#teria#eae< #lostridia per-ringens 5o-ten #ontaminating mi#roorganisms -rom /@9
Characteristics @ntra#ellular< /ram 589 diplo#o##i @ntra#ellular /*" polymi#ro3ial S@n-lamm o#er$i#al mu#osa< $esti3ular or periurethral glands< urethritis )e$er< uterine tenderness< U+,< -oul odor /orpholo)y A#ute suppuration< upDard spread $ia ()c!s&' s)+f&ce Co$plications A#ute: &alpingooophoritis< tu3o8 o$arian a3s#ess/adhesions ,hroni#: in-ertility A#ute: 3a#teremia D/ endo#arditis< arthritis< meningitis

*. gonorrhoeae ,. tra#homatis Puerperal

Dee$ s$+e&, 4 endometritis&myometritis< pel$i# & 3road ligaments< peritoneum

29 *on8neoplasti# $ul$ar disorders]lympho#yti# in-iltrate O li#hen. risE ,A< 3ut not #onsidered pre#ursor lesion. &9 L c%e" sc'e+!s s i9 Thinnin) o- epithelium< hydropi# degeneration< deep s#lerosis

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09 L c%e" s ($'e. c%+!" c)s i9 ii9 &e#ondary pruritic s#rat#hing Thi#E epithelium due to s;uamous hyperplasia< hyperEeratosis/a#anthosis 5epidermal hyperplasia #ausing thi#E Dhite pat#h9

49 Ful$ar *eoplasms 4 $agina< $ul$a & #er$i' all ha$e strati-ied s;uamous epithel a9 )ield e--e#t: lesion in one area risE in other area 39 @ntraepithelial *eoplasia. ,an pre#ede/#oe'ist D/ s;uamous ,A i9 ii9 F@*: $ul$ar Fa@*: $aginal

iii9 ,@*: #er$i#al #9 +enign: 9 C!",#'!(& &c)( "&t)( HP6 519 Ferru#ous groDth D/ multiple e'ophyti# Darts D/ s;uamous proli-eration< #an regress 529 types 6 & 11 529 HPF #ytopathi# e--e#t: Eoilo#ytoti# atypia 5sur-a#e nu#lear atypia D/ perinu#lear $a#uoli=ation< nu#lear:#ytoplasm ratio9 d9 !alignant &;uamous ,ell ,A: i9 I"/&s /e B&s&'! , & L&+t# HP6 520H9 519 @ndurated< ul#erated nodules due to proli- o- immature 3asaloid #ells 529 Types 16< 18< 21 529 Pre#eded 3y #lassi# F@* 4 multi#entri# Dhite pla;ues 549 10820H asso#iated D/ a primary s;uamous neoplasm in $agina or #er$i' 559 !ore liEely to progress in older indi$iduals ii9 N!"?HP6 Ke+&t " 2 "* sD)&(!)s ce'' CA 5%0H9 519 ,hroni# in-lamm< s;uamous hyperplasia< li#hen s#lerosis 529 Pre#eded 3y di--erentiated F@* 529 Msually presents in older 5^%6 y.o.9 549 .i--erentiated malig s;uamous epithel nodules D/ #entral Eeratini=ed JpearlsK 59 Faginal *eoplasms 4 linEs D/ high on#ogeni# risE HPF6s. 5H s;uamous

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a9 !ostly upper posterior Dall I e#to#er$i' Gun#tion 39 Fa@* 5thi#E dysplasti# epithel9,A 5pla;ue8liEe< upper 1/2ilia# 0*. loDer 2/2inguinal 0*9 i9 A,e"!s s 5pre#ursor9 519 258 0H o- -emales e'posed to .1& in utero 529 /landular epithel persistes D/out repla#ement 3y s;uamous #ells 529 !i#ro: mu#us glands 549 /ross: red granules ii9 A,e"!c&+c "!(& 519 presents in 15820 y.o. -emales e'posed to .1& in utero 529 anterior Dall< upper 1/2 529 #lear #ells/gly#ogen 9 E(0+#!"&' R%&0,!(#!s&+c!(& 519 Presents T5 y.o. 529 &ar#oma 3otryoides: J3un#h o- grapesK 4 polypoid 3ulEy mass protruding -rom $agina 529 !i#ro: 5a9 small #ells< o$al nu#lei< small #ytoplasmi# protrusion on one end 4 Jtennis ra#EetK 539 rare striations in #ytoplasm 4 JstrapK #ells 5rha3domyo3lasts9 5#9 #am3ium layer: dense 3and o- small darE #ells 3eneath $aginal epithelium 5d9 deeper edematous -i3romy'omatous stroma D/ in-lamm #ells 549 T': surgery< #hemo 69 ,er$i#al *eoplasms a9 There is some #hroni# in-lamm in most all Domen i9 ii9 &;uamous metaplasia o- glandular epithel !igration o- s;uamo8#olumnar Gun#tion during pu3erty

iii9 Trans-ormation =one: area o- s;uamous metaplasia. highest risE o- HPF< pre8#an#er< ,A 09 HP6 c&+c "!*e"es s i9 ii9 HPF in-e#ts immature s;uamous< repoli#ates in maturing s;uamous 1pisomal in pre#an#ers & #ondylomas

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iii9 @ntegrated in host .*A in #ar#inomas i$9 16 & 1% early $iral proteins: #ell #y#ling & #ell longe$ity< inhi3 apoptosis 5#auses #ompensatory p16@*>4 tumor suppressor9 $9 !i#ro: Eoilo#ytoti# atypia8 perinu#lear halo & hyper#hromati# nu#leus c9 CIN & SD)&(!)s Ce'' C&+c "!(& i9 ,aused 3y HPF< esp. high risE types 516< 189 519 high grade pre#an#ers I 20 y.o.< peaE in$asi$e I 40845 y.o. 8&9 CIN IAL!@ *+&,e SIL 8sD)&(!)s "t+&e$ t%e' &' 'es !"9 5i9 >oilo#ytes D/ sur-a#e atypia 5ii9 1pisomal $irus 5iii9 3asal proli539 CIN IIAH *% *+&,e SIL 5i9 +asal atypia 5ii9 0arger nu#leus< #ytoplasm 5iii9 nu#lear dysplasia as $iral in-o en#oded into .*A 5i$9 +egin to lose hori=ontal arrangement 8c9 CIN IIIAH *% *+&,e SIL 5i9 !ost layers D/ atypia< *:, 5ii9 0ose pinE Eeratini=ation 5iii9 Ferti#al orientation< loss o- polarity 529 Uell8di--erentiated Eeratini=ing< or moderately di--erentiated non8Eeratini=ing 529 Adeno#ar#inoma #an de$elop in endo#er$i' 549 "arely< poorly or undi--erentiated small #ell s;uamous or neuroendo#rine 5a9 HPF 18 4 poor prognosis< early met6s ii9 &taging 519 >: ,@* @@@< H&@0 4 intraepithel only 529 I&1: % mm Dide< 2 mm depth stromal in$asion 5mi#roin$asi$e9 529 I&-: 285mm depth

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549 I0: S5 mm depth 559 II: gross in$asion 3eyond #er$i' 569 III: in$asion to pel$i# Dall< loDer 1/2 $agina 5areas drained 3y other 3lood $essels9 5%9 I6: 3eyond pel$is< to 3ladder or re#tum iii9 .ire#t #ontiguous spread< seeds lo#al 0*< met6s in li$er< lung< 3one marroD i$9 "isE -a#tors: 1arly se'ual de3ut< multiple partners< immunosuppression< ni#otine< (,P< geneti#s< multiparity $9 Fa##ines #ontain types 6/11 5loD risE9 & 16/18 5high risE9 %9 Mterine/1ndometrial Pathology a9 !enstrual #y#le i9 ii) dating looEs at hormonal status< do#uments o$ulation< #auses o- 3leeding/in-ertility only upper (0 o% endo$etriu$ responds to hor$ones

iii9 proli- phase 12< se#retory phase 12 & P4< menstrual phase 12 & P4 -or shedding 09 A"!/)'&t!+# C#c'e i9 ii9 prolonged 12< no P4 ,an 3e due to endo#rine< o$arian< meta3oli# disorder

iii9 &hed endometrium in proli% phase 5a3normal9 i$9 ,ompli#ation: hyperplasia c9 I"&,eD)&te L)te&' P%&se i9 P4 post8o$ulation< D/ lag in endometrial dating 5P 4 se#retory #hanges aren6t as ad$an#ed as e'pe#ted9 ,ompli#ations: in-ertility< spontaneous a3ortion< 3leeding or amenorrhea

ii9

,9 O+&' c!"t+&ce$t /es i9 ii9 12 4 ina#ti$e glands Thinner endometrium

iii9 P48 .e#idual #hange 5gly#ogen9 in stroma e9 Pe+ (e"!$&)se i9 12< no P4

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ii9 -9

Ano$ulatory #y#le#ysti# hyperplasia 5gland< stroma9e$entual #ysti#< o$arian atrophy

,hroni# e",!(et+ t s i9 ii9 Plasma #ells &': 3leeding< pain< dis#harge< in-ertility

iii9 ,ause: #hroni# P@.< retained gestational tissue or @M.< T+< possi3ly ,hlamydia g9 E",!(et+ !s sAA,e"!(#!s s (see endo$etriosis section abo.e %or $ore in%o) i9 /lands & stroma in a3n. site 5outside uterus -or endometriosis< D/in myometrium -or adenomyosis9 This tissue responds to hormones & 3leeds during menstruation

ii9

iii9 Possi3le #auses o- endometriosis: metastati#< metaplasti#< in-lamm/12 i$9 Possi3le #auses o- adenomyosis: deep endometrial doDngroDth< enlargement/#ontra#tion outerus post8pro#edure $9 1ndometriosis signs: 519 ,ho#olate #ysts 5old 3lood9 529 @n$ol$ement o- uterine ligament< re#to$aginal septum< pel$i# peritoneum< surgi#al s#ar< um3ili#us 529 "ed83lue or yelloD83roDn adhesions 549 Msually presents in younger. @n-ertility< dysmenorrhea< pain $i9 Adenomyosis signs: 519 Msually presents in older. !enorrhagia< pain< dysmenorhea< dyspareunia %9 E",!(et+ &' $!'#$s i9 ii9 sessile. ,an 3e atrophi#< hyperplasti#< or -un#tional 5#y#ling9 59 risE adeno#ar#inoma

iii9 ,an #ause 3leeding i$9 6p21 rearrangements #lonal stromal #ells $9 0inEs D/ tamo'i-en t' 9 E",!(et+ &' %#$e+$'&s & i9 Prolonged 12 stimulation< ano$ulation

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519 (3esity< menopause< P,(&< granulose #ell tumors< o$arian #orti#al hyperplasia< e'ogenous 12 ii9 PT1* tumor suppressor ina#ti$ation#ell proli-< inhi3ition o- apoptosis

iii9 !orphology: 519 &imple or #omple' hyperplasia D/ or D/out atypia 529 #ysti# 5stroma9. gland:stroma ratio 529 irregular gland shape due to persistent 12

O9

E",!(et+ &' CA i9 Type @: hyperplasia/hyperestrinism 585H9 519 0inEs D/ o3esity< .!< HT* 529 Pro3s D/ in-ertility< ano$ulatory #y#les. 529 Histo: endometrioid type 5looEs liEe endometrial glands9 549 !utation: PT1* 559 Presents in younger. +etter p' 569 /ross: polpypoid tumor D/ di--use sur-a#e 5%9 /rading: 3ased on H solid 5s;uamous elements not graded9 5a9 /rade 1: T5H 539 /rade 2: 5850H 5#9 /rade 2: S50H ii9 Type @@: atrophy 519 Histo: serous type< papillary 5a9 e'-oliation & spread due to papillary -ormation 529 &ur-a#e pre#ursor lesion 5endometrial intraepithel neoplasia9 529 !utation: p52 4 aggressi$e. 549 Presents in older. Uorse p' 559 /ross: 3ulEy< in$asi$e 569 /rading: alDays grade 2

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19 Le !(#!(& i9 ii9 +enign J-i3roidK #lonal proli- o- smooth mus#le #ells< #an 3e in di-- layers o- uterus .is#rete< round< -irm< gray8Dhite< range o- si=es< 3ulging #ut sur-a#e

iii9 ,an 3e asymptomati# or #ause 3leeding< urinary s'< pain< -ertility< pregnan#y #ompli#ations '9 Le !(#!s&+c!(& i9 ii9 @n$asi$e< polypoid mass o- malig smooth mus#le #ells .' 3y nu#lear atypia< S10 mitoses/10hp- (" atypia ? 5 mitoses/10hp-

iii9 !et6s to a3domen< lung i$9 ,hromo a3normalities 89 )allopian tu3es a9 @n-lamm< suppurati$e P@.< granulomatous T+ 39 1#topi# preg #9 1ndometriosis d9 Adenomatoid tumors 53enign mesotheliomas9 e9 "are adeno,A 4 tu3al mass D/ mu#osal in$ol$ement< linEs D/ +",A mutation

POLYCYSTIC O6ARIAN SYNDROME ARTICLE Julies Section PCOS ARTICLE 19 pre$alen#e: 1/15 Domen DorldDide< 6.588H in the M.&. a9 there seems to 3e a higher pre$alen#e among immigrants -rom the @ndian su3#ontinent to the M>< and Australian Domen o- A3original heritage 29 e'#essi$e androgen se#retion or a#ti$ity< o-ten D/ a3normal insulin a#ti$ity 29 asso#iated #ompli#ations: menstrual dys-un#tion< in-ertility< hirsutism< a#ne< o3esity< and meta3oli# syndrome< D/ risE o- .! type 2 & possi3ly ,F. 49 diagnosti# #riteria: %#$e+&",+!*e" s(7 c%+!" c &"!/)'&t !"7 &", $!'#c#st c !/&+ es identi-ied D/ ultrasound 5as long as other disorders Dith these s' are ruled out9. a9 o3esity< insulin resistan#e< and meta3oli# syndrome ha$e all 3een asso#iated D/ P,(&< 3ut are not intrinsi# distur3an#es o- the disorder 39 other similar disorders to e'#lude: hyperandro)enis$: #ongenital adrenal hyperplasia< ,ushing6s syndrome< and androgen8se#reting tumors ano.ulation: hyperprola#tinemia or 0H de-i#ien#y

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#9 there is some de3ate a3out Dhether poly#ysti# o$aries should 3e on the diagnosti# #riteria< or Dhether it is su--i#ient to e'hi3it the other -eatures Dithout hyperandrogenism. There seems to 3e a trend to re;uire hyperandrogenism as a #hara#teristi# -eature o- the syndrome. i9 "otterdam #riteria:

59 #ause is 3elie$ed to ha$e a strong geneti# #omponent< in-luen#ed 3y gestational en$ironment & li-estyle -a#tors a9 there is a polymorphism in the androgen re#eptor 5 poten#y9< Dhi#h is 3elie$ed to 3e impli#ated 69 ,lini#al -eatures & diagnosis &9 H#$e+&",+!*e" s( i9 Clinically: Hirsutism< a#ne 5younger9< -emale8pattern alope#ia 5older9 i9 1ioche$ically: measure serum total testosterone 5T9 and se' hormone 3inding protein 5&H+/9< then #al#ulate -ree or 3ioa$aila3le T Dith the -ree androgen inde' #al#ulation O 5T/&H+/_1009 519 There are radioimmunoassays that suppusodely measure -ree T dire#tly< 3ut are unrelia3le 529 There is also the )erriman8/allDey s#ore -or hirsutism ii9 !any tests do not #at#h hyperandrogenism in 20840H o- patients< so some #lini#ians still 3elie$e that a3sen#e o- #lini#ally/3io#hemi#ally dete#ted hyperandrogenism should not e'#lude P,(& 09 A"!/)'&t !" i9 (ligomenorrhea O T 8 periods/yr< or S25 days/#y#le ii9 Amenorrhea O a3sen#e o- menstruation -or S2 months 519 "egular #y#les don6t e'#lude ano$ulation until e$aluating P 4 #on#entration in serum during the luteal phase o- the menstrual #y#le that is #onsistent Dith a re#ent o$ulation. 529 @- #hroni# ano$ulation is #on-irmed< should run P"0 & 0H assays to #he#E -or hypothalami# and pituitary disorders 5hyperprola#tinemia< gonadotropin de-i#ien#y9 529 Also need to rule out -un#tional hypothalami# amenorrhea due to e'treme #alori# restri#tion or e'er#ise 5a9 12< unresponsi$e to P4 DithdraDal 5Dhi#h normally indu#es menstruation9< gonadotropin. c9 P!'#c#st c !/&+ es i9 Mltrasound 519 12? -olli#les measuring 24 mm in diameter< or in#reased o$arian $olume 5S10 m09 5a9 Trans$aginal -or adults 539 Transa3dominal -or adoles#ents< measuring only o$arian $olume ii9 &erum assays 519 &erum anti8!ullerian hormone 5A!H9< se#reted 3y granulosa #ells o- de$eloping -olli#les< helps Dith estimation o- antral -olli#le #ount

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5a9 Mse-ul i- M/& isn6t an option< 3ut only -or Domen T25 y.o. %9 Pathogenesis &9 A",+!*e" &0"!+(&' t es i9 Mn#ontrolled steroidogenesis may 3e the primary a3normality 519 60880H ha$e high T< 25H ha$e high .H1A& ii9 Thi#Eened the#al layer around o$aries< se#reting \& androgens iii9 a#ti$ity o- steroidogeni# en=ymes in the#al #ells< possi3ly due to disrupted intra#ellular signaling 09 F!'' c)'!*e"es s &0"!+(&' t es i9 286' more primary< se#ondary< & antral -olli#les< liEely due to a3n. androgen signaling 519 Positi$e #orrelation 3/t T< androstenedione< and -olli#le N 5a9 .HT admin to rhesus monEeys #auses -olli#le N & o$arian $olume 539 &imilar #orrelation D/ )T! transse'uals D/ long8term T t' 5#9 )urther supported 3y -lutamide t'< Dhi#h o$arian $olume & -olli#le N in P,(& adoles#ents 529 @t may not Gust 3e a -olli#ular trophi# e--e#t due to androgen 4 the %ollicles $i)ht be )rowin) $ore slowly 5due to de-i#ient groDth signals -rom the oo#yte or inhi3itory signals -rom e'#ess A!H9 #reating a Jsto#Epile e--e#tK 529 Antral -olli#le groDth stops Gust 3e-ore rea#hing 10mm diameter 5the stage Gust 3e-ore emergen#e o- dominant -olli#le9 5a9 )olli#ular arrest #an 3e indu#ed 3y \& insulin< 0H< or 3oth 5i9 @nsulin responsi$eness o- granulosa #ells to 0H< #an #ause premature luteini=ation 5ii9 /ranulosa #ells seem selecti.ely insulin resistant< in that there is impaired insulin8stimulated glu#ose meta3olism 5Dhi#h is 3elie$ed to #ontri3ute to ano$ulation9 3ut inta#t insulin8stimulated steroidogenesis 1. (ne therapeuti# approa#h: use insulin sensiti=ers 5e.g. met-ormin9 to indu#e o$ulation< 3ut Deight loss is the 3est approa#h c9 G!"&,!t+!$ " &0"!+(&' t es i9 Hypothalami#8pituitary de-e#t 519 A3n. gonadotropin pulsatility: \& stimulation o- 0H 3ut normal )&H stimulation a3n )&H:0H ratio 5a9 /n"H #hallenge tests e'a#er3ate this di--eren#e< #ausing 0H & 1%8 hydro'yprogesterone 529 pituitary sensiti$ity to ,")\& A,TH & #ortisol response 529 androgens desensiti=e the hypothal to negati$e -eed3a#E 3y P4< so the a3n. gonadotropin pulsatility seems to 3e se#ondary to a3n steroid release 3y o$aries & adrenals &9 I"s)' " &ct !" &0"!+(&' t es i9 @nsulin resistan#e is #ompara3le to that o- type 2 .! 525840H in glu#ose uptaEe9 519 )asting & glu#ose8#hallenged hyperinsulinemia 529 @nade;uate B8#ell #ompensation 529 ^40H o- o3ese Domen D/ P,(& ha$e impaired glu#ose toleran#e D/ glu#ose #hallenge ii9 @nsulin resistan#ehyperandrogenism< gonadotropin a3normalities 519 insulin&H+/3ioa$aila3le Tadrenal & o$arian androgen synthesis a3n gonadotropin 529 @nsulin might also a#t dire#tly on hypothalamus/pituitary to regulate gonadotropin release 529 Selecti.e insulin sensiti.ity: sEeletal mus#le appears highly resistant< Dhile adrenals & o$ary aren6t iii9 P,(& is 3eginning to 3e $ieDed more as a meta3oli# syndrome D/ reprodu#ti$e impli#ations 519 P,(& pt6s tend to ha$e dyslipidemia< in-lamm. marEers< endothelial dys-un#tion< sleep apnea

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29 ,auses & "isE )a#tors a9 % H herita3ility in tDin studies< Dith epigeneti# $ariation a9 0inEage dise;uili3rium has 3een noted in a mi#rosatellite marEer 5.1 &8849 on #hromosome 1 p12.2< lo#ated in non#onser$ed introni# se;uen#es 3etDeen e'ons 55 and 56 o- the -i3rillin 2 5)+*29 gene< Dhi#h en#odes an e'tra#ellular matri' protein impli#ated in the regulation o- spe#i-i# groDth -a#tors 39 \& Deight e'a#er3ates meta3oli# & reprodu#ti$e a3normalities 4 o3esity might promote the P,(& phenotype #9 &ome e$iden#e suggests that pregnant en$ironmental e'posure to \& androgens may predispose -emale o--spring to P,(&. &u#h en$ironmental -a#tors may #ause epigeneti# modi-i#ations that risE 29 Health @mpli#ations a9 Mp to 10H o- Domen de$elop .! in 2rd or 4th de#ade 39 ,F. risE -a#tors 4 hyperlipidemia< hyperandrogenemia< HT*< prothrom3oti# & in-lamm marEers #9 !eta3oli# syndrome]un#lear Dhether this is due to P,(& or adiposity itseli9 #entral -at< hyperinsulinemia< glu#ose intoleran#e< HT* ii9 \& androgen itsel- is su--i#ient to risE

29 !anagement &9 L fest#'e c%&"*es i9 1$en a small 5285H9 redu#tion in 3ody Deight 5esp. a3dominal -at9 #an: 519 restore o$ulation 529 insulin sensiti$ity 3y %1H 529 &H+/ & T & androgen stimulation o- sEin 549 @mpro$e menstrual -un#tion< #on#eption rate< spontaneous a3ortions 09 C!s(et c ss)es i9 ($arian suppression $ia oral #ontra#epti$es to treat hirsutism & a#ne< also regulates menstrual #y#le ii9 ,yproterone 5antiandrogen9 ? 12 is ideal -or hirsutism t' 3ut has &1 o- -atigue< li3ido< & #hanges in li$er -un#tion iii9 1le#trolysis< topi#al e-lornithine #ream to hair groDth i$9 (ral #ontra#epti$es ? #yproterone or drospirenone to treat a#ne

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$9 @nsulin8sensiti=ing agents 5met-ormin< thia=olidinediones9 may 3e e--e#ti$e t' -or hirsutism & a#ne 3/# insulin resistan#e a--e#ts 3oth $i9 285H topi#al mino'idil -or androgeni# alope#ia c9 Me"st+)&' ++e*)'&+ t# i9 &ome risE o- endometrial ,A due to endometrial hyperplasia D/ in-re;uent menstruation 519 T': indu#e menstruation D/ (,P6s or progestagens ii9 ,om3ined (,P6s androgen produ#tion< &H+/ synthesis< progestagen #ompetiti$e 3inding to androgen re#eptors 519 +MT there are some risEs o- long8term use o- (,P6s: insulin sensiti$ity< impaired glu#ose toleran#e< altered lipid pro-iles 529 &o it might 3e good to #om3o D/ insulin sensiti=ers & antiandrogens ,9 I"fe+t ' t# i9 P,(& pt6s ha$e UH( #lass 2 o$ulatory dys-un#tion 4 #hroni# ano$ulation D/ normal )&H & 12 519 )irst8line t': indu#tion o- o$ulation to stimulate groDth & o$ulation o- a single dominant -olli#le 5a9 Clo$i%ene: 128re#eptor modulator< antagoni=es negati$e -eed3a#E o- 12 on hypothal/pituitary. Helps to 0H to normal & )&H to stimulate -olli#le groDth & o$ulation 5i9 Fery e--i#a#ious< 3ut may ha$e negati$e e--e#t on endometrium that #an #ause pregnan#y -ailure despite o$ulation. &ome reasons -or -ailure: hyperandrogenemia< o3esity< o$arian $olume< and menstrual dys-un#tion. 539 2etro3ole: aromatase inhi3itor< 12 stimulation o- hypothal/pituitary 3y 12 synthesis 5i9 /ood option -or those Dho are #lomi-ene8resistant 8 &1 on endometrial thi#Eness< risE o- multiple pregnan#y 53/# less o$arian stimulation9 5ii9 Possi3le risE o- -etal a3normalities 5#9 4onadotropins: start loD8dose and gradually as needed< 3ased on hormone & M/& response 5i9 "isE]3/# o$aries are $ery sensiti$e to gonadotropin indu#tion< there is a risE oli-e8threatening o$arian hyperstimulation syndrome 5d9 O.arian drillin) D/ laser or diathermy #an alloD -or long8lasting 3ene-its D/ no risE omultiple pregnan#y< 3ut there is risE o- intrapel$i# adhesions 5e9 5nsulin sensiti3ers: thia=olidinediones & .8#hiro8inositol 8 o$ulation< hyperandrogenism 5i9 !et-ormin is most o-ten used< 3ut this is o--8la3el usage and #lomi-ene is still -ound to 3e more e--e#ti$e 529 There may 3e a rate o- early preg loss D/ o$ulation indu#tion in P,(& 5a9 Hyperinsulinemia or insulin resistan#e may play a role< Dhi#h may 3e mitigated D/ met-ormin t' 53ut one multi8#enter trial shoDed rate o- early preg loss in the met-ormin grp #ompared D/ the #lomi-ene grp9 529 567 might 3e ne#essary i- there are male -ertility pro3s or additional -emale pro3s 5a9 Hyperstimulation D/ gonadotropins pre8@F) to promote the groDth o- multiple -olli#les & surgi#al aspiration o- mature oo#ytes 539 "isE o- o$arian hyperstimulation syndrome 4 try )&H< a$oiding )&H -or se$eral days< or early #an#ellation. (r #an retrie$e immature oo#ytes & promote in $itro maturation 549 P,(& pregnan#ies more liEely to 3e #ompli#ated D/ pre8e#lampsia< gestational .!< pre8 term la3or< pregnant HT*< perinatal mortality rate e9 Pe+ $)0e+t&' ss)es i9 ,hildhood o$erDeight< loD 3irth Deight< and premature pu3ar#he all risE -or premature pu3erty & P,(& in adoles#en#e 519 Pre$entati$e t': loD8dose -lutamide 5androgen antag9 ? met-ormin ? (,P 5D/ drospirenone as progestin9 f9 He&'t% ss)es f!+ f&( '# (e(0e+s

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@nsulin resistan#e & hyperandrogenemia 5an important predi#tor o- insulin resistna#e9 are more #ommon in sisters o- P,(& pt6s ii9 )irst8degree relati$es ha$e similar meta3oli# disorders iii9 0.0 & total #holesterol in mothers o- P,(& pt6s *9 A,, t !"&' c' " c&' "/est *&t !"s i9 "e$ieD -amily history -or e$iden#e o- .!< ,F.< dyslipidemia ii9 0ooE at li-estyle issues 4 diet & e'er#ise iii9 !easure Daist #ir#um-eren#e< serum lipids< glu#ose meta3olism 5esp. 3/# more rapid #on$ersion to pathologi#al status in P,(& pt6s9 i$9 -re;uen#y o- depression< psy#hologi#al & psy#hose'ual mor3idity 5may 3e someDhat impro$ed i- o3esity & hirsutism are addressed therapeuti#ally9 O6ARIAN PATHOLOGY L&#"es Sect !" (from lectures, #obbins, >ol?an, and pathophysio te't online) =(arian &atholo"y o =(arian ysts o an be follicular or luteal cysts o =ccur so fre,uently that they are considered DnormalE or Dphysiolo"icalE ystic follicle <ost common, non!neoplastic <ost re"ress spontaneously %ermed a cystic follicle if FGcm 1 a follicular cyst if HGcm ori"inate in unruptured "raafian follicles or in follicles that ha(e ruptured and immediately sealed filled with a clear serous fluid, and are lined by a "ray, "listenin" membrane possibly cause hemorrha"e and rupture hyperthecosis: caused by the luteini/ation of the surroundin" theca o Su""esti(e of increased estro"en production and endometrial abnormalities 2uteal ysts <ost common cyst in pre"nancy; non!neoplastic <ay be confused for an amniotic sac Iellow rimmed (luteini/ed "ranulosa cells) occasionally rupture and cause a peritoneal reaction o &olycistic =(arian Disease o ;5 reproducti(e a"e females o <ultiple cystic follicles J oli"omenorrhea o 3 clinical dia"nostic criteria: obesity, infertility, amenorrhea, and hirsutism o 2in)ed to insulin resistance; increased ris) of diabetes and K e(ents o =(aries appear HG' normal si/e, and ha(e a thic) corte' o %hic) corte' associated with numerous subcortical cystic follicles and hyperplasia of the theca cells (hyperthecosis) o *nitiatin" e(ent of & =D is unclear, but mi"ht be due to increased 2H sur"e, which produces e'cessi(e andro"ens from the theca cells, and then con(erted to estrone o $nother theory 7 due to insulin resistance; when insulin dysfunction is corrected, o(arian dysfunction sometimes corrects itself o Stromal Hyperthecosis o Cilateral o(arian enlar"ement (Lcm); appears tan!white stroma o *ncreased amount of stromal cells with luteini/ed cell clusters 2uteini/ed cells produce e'cess andro"ens which may cause hirsutism or (irili/ation o =ccurs primarily in obese, postmenopausal females

i9

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=(arian %umors o %umors are most li)ely beni"n in women M3;yrs of a"e o #is) increases with a"e; median a"e of presentation N 6:yrs o $ppro' 645 present with ad(anced disease 7 tumors are asymptomatic and are not cau"ht until they are ad(anced and ha(e become metastatic o #is) factors include: nulliparity, "enetic factors (C# $:BG), 2ynch syndrome, %urner Syndrome, &eut/! Oeu"ers syndrome, postmenopausal estro"en therapy, = &s o Surface .pithelial!Stromal %umors o Deri(ed from transformed surface coelomic epithelium o $ccount for 6;!L;5 of o(arian tumors 7 "reatest number of mali"nant tumors o <ost tumors are associated with cysts; this arises from the in(a"ination of the surface epithelium into the corte' formin" a cyst o linical &resentation <ost tumors are non!functional and do not secrete hormones *f beni"n, may be asymptomatic *f mali"nant, mild symptoms until lar"e; usually spread beyond o(ary at dia"nosis, ascites, low abdominal pain, distention, symptoms of >* tract compression or in(asion, wea)ness, wei"ht loss, cache'ia, abdominal and (a"inal bleedin"; &==# &#=>N=S*S *f mali"nant, half in(ol(e contralateral o(ary, metastasi/ed to re"ional lymph node, li(er, lun"s, >* o Screenin"B&re(ention C# $ "ene mutation *ncreased le(els of $!:G; or osteopontin Decreased ris) 7 tubal li"ation, lon" term = Salpin"o!oophorectomy o S.#=@S %@<=#S: beni"n serous cystadenoma, borderline serous tumor, or mali"nant serous cystadenomcarcinoma ystic neoplasms filled with clear serous fluid 2ined by cililated tall columnar epithelium <ost common mali"nant tumor of the o(ary an be : of 9 cate"ories: beni"n, borderline, or mali"nant <ali"nancy ris) increases by Decrease parity "onadal dys"enisis <ali"nancy ris) decreases by %ubal li"ation =ral contraception use 2ow "rade serous tumor associated with P#$S and C#$0 mutation Hi"h "rade serous tumor associated with p;9 mutation (C# $ related) <ost common of the epithelial tumors, and of o(arian tumors an be *N or =N o(ary ontains a smooth cyst wall, clear fluid, ciliated cells, &sammoma bodies (round collection of calcium) an be bilateral *ncreased solid of papillary areas su""est borderlineBcarcinoma, C@% the definition of carcinoma is stromal invasion o <@ *N=@S %@<=#S: beni"n mucinous cystadenoma, borderline mucinous tumor, or mali"nant mucinous cystadenocarcinoma ystic neoplasms filled with "elatinous mucinous fluid 2ined by tall columnar epithelial cells with apical mucin ontains a lot of chambers 7 Dmulti!loculatedE *ncreased ris) with smo)in"

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2ow "rade: P#$S mutation Hi"h "rade: P#$S mutation 2ess common than serous tumors H@>., multi!loculated and slimy N=% on surface Ceni"n : cell layer with apical mucin

o o

Corderline H: cell layer with comple' papillae *ntestinal adenoma!li)e "lands J nuclear atypia <ali"nant Solid, necrosis present JJJJ Nuclear atypia Stromal in(asion difficult to dia"nose %I&. =0 <@ *N=@S 7 &S.@D=<IQ=<$ &.#*%=N.* <assi(e mucinous ascited ystic epithelial implants on peritoneal surfaces <ucinous tumors of both o(aries $dhesions which cause obstructions Dia"nose by bilateral o(arian tumors with metastatic appendi' tumor *f both o(aries in(ol(ed, thin) metastasis .ND=<.%#*=*D %@<=#S 7 beni"n endometrioidfibroadenoma, borderline endometrioid tumor, endometrioid adenocarcinoma (most common 7 G45 of o(arian cancer) <ostly solid, partly cystic neoplasms with appearance of endometrial tissue distin"uished from serous and mucinous tumors by the presence of tubular "lands bearin" a close resemblance to beni"n or mali"nant endometrium ysts contain blood &roliferatin" endometrial "lands and some beni"n stroma or fibrous tissue *ncreased ris) 7 comorbidity with endometriosis (found in :;5 of cases) 2ow "rade 7 &%.N loss, P#$S, and C!catenin mutations, microsatellite instability Hi"h "rade 7 p;9 mutations See presence of solidBcystic areas with hemorrha"e Cilateral tumor su""ests spread beyond "enital tract :;!945 also ha(e carcinoma of the endometrium >.#< .22 %@<=#S #ule for patholo"ists 0emales prepurbertal 7 mali"nant 0emale postpubertal repro a"e 7 beni"n 0emale post repro 7 increase mali"nancy <ale prepubertal 7 beni"n <ale postpubertal 7 mali"nant %.#$%=<$ 7 contains tissue from 9 "erm layers Ceni"n cystic teratoma <ost common "erm cell tumor $lso )nown as a dermoid cyst; )aryotype almost always 36QQ =ccurs in reproducti(e a"e of females >rossly: unilocular cysts with s)in, teeth, hair and cheesy sebaceous material

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S.Q

<icroscopically: s)inBadne'a bone, cartila"e, "land, thyroid, brain and other tissues :5 turn mali"nant 7 spread to s,uamous cancer <ali"nant solid teratomas ontains immature fetalBembryonic tissue Histolo"ic "rade determined by the 5 of neuroepithelium =ccurs in prepubertalByoun" (:8yrs of a"e) ontains dermoid components Hemorrha"e or necrosis present <onodermal or Speciali/ed teratoma @nilateral always Struma =(arii o omposed entirely of mature thyroid tissue o <ay cause what appears to be hyperfunction of the thyroid o @sually beni"n arcinoid o @sually mali"nant o <ay be functional as well, producin" serotonin Dys"erminoma <ali"nant ounterpart to testicular seminoma @nilateral;solid #an"e in si/e from barely (isible nodules to massi(e tumors 0lesh, homo"enous and soft 2ar"e sin"le cells in sheets ytoplasm is clear from "lyco"en #ound nucleus with JNuceloli 2ymphocytes present Iol) Sac %umor $lso )nown as an endodermal sinus tumor deri(ed from differentiation of mali"nant "erm cells alon" the e'tra!embryonic yol) sac linea"e the tumor is rich in alpha!fetoprotein and alpha!antitrypsin unilateral tymors contains Schiller!Du(al bodies: blood (essels surrounded by "erm cells in space lined by "erm cells found in youn" females (1children) presents with pain and increasin" pel(ic mass chemotherapy "i(es impro(ed pro"nosis horiocarcinoma <ost common in the placenta (synctiotrophoblast J cytotrophoblast) Differentiations from e'tra!embryonic mali"nant "erm cells Dia"nostic mar)er: hi"h le(els of beta!h > =N2I found in pre!pubertal female <ostly a component of other "erm cell tumors .'tremely a""ressi(e and fatal Not chemotherapy responsi(e <etastasi/es to lun", li(er, bone =#D %@<=#S (not common) Deri(ed from o(arian stroma that is deri(ed from the uro"enital rid"e mesenchyme

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Cecause the undifferentiated "onadal mesenchyme e(entually produces structures of specific cell type in both male (Sertoli and 2eydi") and female ("ranulosa and theca) "onads, tumors resemblin" all of these cell types can be identified in the o(ary Same uro"enital rid"e that adrenal corte' forms from apable of producin" se' hormones %H. $ .22 %@<=#S <a)es femini/in" estro"en >#$N@2=S$ .22 %@<=#S all!.'ner bodies: dia"nostic mar)ers that mimic follicles *nhibin: another dia"nostic mar)er (positi(e in the tissue and increased in the serum) an be functional *n childhood can cause increased se'ual precocity *n adulthood, endometrial hyperplasia and cancer; breast fibrocystic disease 0*C#=<$!%H. =<$ See spindled fibroblasts J plump thecal cells Solid, round, hard, "ray!white, encapsulated mass (theca cells are yellow) Symptoms: o &ain J pel(ic mass o JB! <ei"s si"n: #. hydrothora', ascites, o JB!basal cell ne(us syndrome *f mali"nant, called a fibrosarcoma S.#%=2*!2.ID*> .22 %@<=#S <asculini/ation or de!femini/ation results #esults from recapitulations of testes cells SBS o Kirili/ation: hirsutism, clitoral hypertrophy, hair and (oice chan"es o Defemini/ation: breast atrophy, amenorrhea, hair loss, sterility Solid; "ray to "old!brown Sertoli cell tubules, leydi" cells, and stroma =K$#*$N %@<=#S: <.%$S%$%* =#*>*N <ost commonly of <ullerian ori"in <eli"nancies of "enital tract or peritoneum .'tramullerian 7 breast and "astrointestinal; rare 7 pseudomy'oma peritonei of appendi' Pru)enber" tumor 7 >astric si"net rin" cell of carcinoma; metastatic bilateral o(aries .Q%#$ 0I* 0#=< S.N$>=#. lear cell adenocarcinoma 7 (ariant of endometrioid cancer ystadenofibroma 7 prominent fibrous stroma Crenner %umor 7 transitional cell of the urinary tract epithelium solid or cystic A45 unilateral <ay be seen in mucinous cystadenomas @sually beni"n

P!ACENTA! PATH ! "Y !ayne$s Section Spontaneous $bortion o Defined as loss of pre"nancy before G4 w)s (but most occur before :Gw)s) o =ccurs in about :4!:;5 of clinically reco"ni/ed pre"nancies o Celie(ed to occur in as many as GG5 of early pre"nancies that ha(e not been reco"ni/ed

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auses (can be maternal or fetal) hromosomal anomalies (aneuploidy, polyplopidy) ;45 of the time 2uteal phase defects (in mother) &oorly controlled diabetes .ndocrine disorders 2eiomyomas @terine polyps or other malformations $ntiphospholipid antibody syndrome Hi"h blood pressure oa"ulopathies %=# H infections .ctopic &re"nancy o implantation of the fetus in any site other than a normal intrauterine location. %he most common site is within the fallopian tubes (A45). o =ther sites include the o(ary, the abdominal ca(ity, and the intrauterine portion of the fallopian tube o =ccurs in : out of :;4 pre"nancies o <ost common predisposin" condition (9;!;45 of cases): &*D which results in scarrin" of the fallopian tubes o *@Ds also increase the ris) o %ubal pre"nancy responsible for hematosalpin' N blood!filled fallopian tubes #upture of the tubes due to inappropriate fertili/ation o linical course Se(ere abdominal pain 6w)s after pre(ious period Hemorrha"ic shoc) o Dia"nosis *ncreased h > @ltrasoundBlaproscopy $scendin" *nfection o <ostly bacterial, enter amniotic fluid o Neutrophils respond and result in maternal chorio!amnion!it is $ND fetal (asculitis and funisitis (cord) Hemato"enous infection o =r"anisms from the materal blood bathin" (illi o an be (iral, bacterial, proto/oal o *nflu' of fetal lymphocytes; plasma cells respond resultin" (illitis %win &re"nancies and &lacentas o %win pre"nancies (di/y"otic N G fertili/ed o(a) .ach o(a has its own placenta (G amnions, G chorions) &lacentas can be fused (one disc) or unfused (G separate discs) o <ono/y"otic (: fertili/ed o(um di(ides N G conceptuses) an ha(e 9 possible outcomes .ach has their own chorion and amnion .ach has their own amnion and share a chorion Share both amnion and chorion 2ater di(ision of the o(a leads to increased amount of sharin" %win %win %ransfusion o %his is a complication with D*$<N*=N* <=N= H=#*=N* twin placenta o Clood (essels anastamose between the fetal circulations in the shared chorion o $rtery (ein (one way blood flow) o Donor twin (anemic twin) has increased ris) of death in!utero; hypo(olemia o

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o #ecipient twin (hyperemic twin) has increased neonatal death from H0 &lacenta $ccreta o caused by partial or complete absence of the deciduas, with adherence of the placental (illous tissue directly to the myometrium and failure of placental separation o common cause of postpartum bleedin" o 645 associated with placenta pre(ia &lacenta &re(ia o condition in which the placenta implants in the lower uterine se"ment or cer(i', often with serious third!trimester bleedin" o a complete placenta pre(ia co(ers the internal cer(ical os and thus re,uires deli(ery (ia cesarean section to a(ert placental rupture and fatal maternal hemorrha"e durin" (a"inal deli(ery &re!eclampsiaB.clampsia o +idespread endothelial dysfunction o =ccurs in ;5 of pre"nancies o <ostly occurs in 9rd trimester o <ore commonly occurs in primiparas (first time pre"nancies) o &re!eclampsia: Hypertension .dema &roteinuria &lacental decidual blood (essel lesions 7 atherosis, thrombi, infarcts, hemorrha"e in disc commonly starts after 93 wee)s of "estation but be"ins earlier in women with hydatidiform mole or pree'istin" )idney disease, hypertension, or coa"ulopathies o .clampsia pre!eclampsia con(ulsions D* =r"an dama"e <aternal (ascular lesions 7 thrombi, infarcts, hemorrha"e in li(er, )idney, heart, brain, and pituatary o :45 de(elop H.22&: hemolysis, ele(ated li(er en/ymes, and low platelets o .tiolo"y for &re!eclampsia is un)nown, but belie(ed to be due to the followin": $bnormal placental (asculature abnormal trophoblastic implantation and lac) of de(elopment of physiolo"ic alterations in the maternal (essels re,uired for ade,uate perfusion of the placental bed .ndothelial dysfunction and imbalance of an"io"enic and anti!an"io"enic factors in response to hypo'ia, the ischemic placenta releases factors into the maternal circulation that cause an imbalance in circulatin" an"io"enic and anti! an"io"enic factors; this in turn leads to systemic maternal endothelial dysfunction and the clinical symptoms of the disease *n support of this, the blood le(els of two placenta!deri(ed anti!an"io"enic factors, soluble fms!li)e tyrosine )inase (s0ltl) and endo"lin, are se(eral orders of ma"nitude hi"her in women with preeclampsia than in healthy controls oa"ulation abnormalities &reeclampsia is associated with a hypercoa"uable state; thrombosis of arterioles and capillaries may occur throu"hout the body, particularly in the li(er, )idneys, brain, and pituitary >estational %rophoblastic Disease (>%D) o &roliferation of trophoblasts +*%H (illi results in hydatidiform moles an be complete, partial mole, in(asi(e mole, can persist or precede choriocarcinoma o N= K*22* N Neoplasms

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horiocarcinoma &lacental site trophoblastic tumor #espond to chemotherapy >%D: Hydatidiform mole Hydatidiform mole is characteri/ed histolo"ically by cystic swellin" of the chorionic (illi, accompanied by (ariable trophoblastic proliferation *ncreased serum beta!h > (made by trophoblast) associated with an increased ris) of persistent trophoblastic disease (in(asi(e mole) or choriocarcinoma most patients presented in the fourth or fifth month of pre"nancy with (a"inal bleedin" =<&2.%. <=2. omplete mole results from fertili/ation of an e"" that has lost its chromosomes, and the "enetic material is completely paternally deri(ed Ninety percent ha(e a 36,QQ diploid pattern, all deri(ed from duplication of the "enetic material of one sperm (a phenomenon called andro"enesis). %he remainin" :45 are from the fertili/ation of an empty e"" by two sperm (36,QQ and 36,QI) >reatest trophoblast proliferation 2oo)s li)e a Dbunch of "rapesE Ne"ati(e p;L stain; paternal imprint :45 ris) of in(asi(e mole G.;5 ris) of mali"nancy &$#%*$2 <=2. &artial moles result from fertili/ation of an e"" with two sperm. *n these moles the )aryotype is triploid (6A,QQI) or e(en occasionally tetraploid (AG,QQQI) Killi loo)s hydropic; DbubblyE G:: paternal to maternal <ildfocal trophoblast proliferation; synctiotrophoblast *ncreased beta!h > &ositi(e p;L stain :45 ris) of in(asi(e mole <inimal ris) of mali"nancy *NK$S*K. <=2. <olar (illi with synctiotrophoblast and cytotrophoblast penetrate myometrium and blood (essels %ra(el to distant sites but wBo metastatic "rowth &ersistently hi"h beta!h > le(els Ka"inal bleedin" .nlar"ed uterus *ncreased ris) of uterine rupture #esponds to chemotherapy >.S%$%*=N$2 H=#*= $# *N=<$ <ali"nant synctiotrophoblast and cytotrophoblast proliferation N= K*22*; hemorrha"ic Deri(ed from a prior pre"nancy *ncreased with abnormal "estations an metastasi/e to lun", (a"ina, and other sites .K.N <=#. *N #.$S.D serum h > than found in moles %': remo(al J chemotherapy :445 cure "estational cases Non!"estational cases are resistant

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&2$ .N%$2 S*%. %#=&H=C2$S%* %@<=# <ali"nant e'tra(illous trohphoblast cell proliferation <ore li)ely preceded by normal pre"nancy than abnormal pre"nancy ell are human placental lacto"en positi(e, wea)ly beat!h > positi(e <oderate serum increase in beta!h > &ro"nosis: poor chemo response o Cetter pro"nosis if occurs MGyr post pre"nancy o +orse if HGyrs post pre"nancy

ENDOCRINE PANCREAS PHYSIOLOGY J!"&t%&"s Sect !" 6. The =ndocrine Pancreas a. Anatomy 3 s'et o* Lan#e"hans < !" &a"/ *+nct ona' +n t o* the en$oc" ne !anc"eas ii. There is no uniform arrangement of cells "ithin the islets in humans (unli%e previously thought! '. 8ell Types, i. glucagon ii. insulin and amylin iii. somatostatin i$. PP pancreatic polypeptide $. ghrelin (stimulates hunger not covered! c3 Ins+' n an$ P"o ns+' n i. Made in and secreted 'y cells ii. Proinsulin is produced in the =R iii. Proinsulin is cleaved into mature insulin and 8 peptide (+! #oth are in secretory granules and are secreted together after physiologic stimulation (/! Modifications performed 'y P8+ P8/ and 8ar'oxypeptidase = iv. Most important stimulus, glucose levels 519 Rise in 'lood glucose glucose upta%e into cells via (5-T-/ (/! (ycolysis results in increased ATP "hich closes mem'rane LI channels (3! Mem'rane depolari@ation triggers voltage gated 8aII channels increasing intracellular 8aII activating the phospholypase 8 path"ay (relases more 8aII form =R! (6! )ncreased 8aII initiates release of secretory vesicles v. )nsulin Receptor 2unction, 519 Made up of and su'units ( has the tyrosine %inase activity! $i. Principal meta'olic function, rate of glucose transport into cells via (5-T-6 (+! *triated muscle cells (/! 2i'ro'lasts (3! Adipocytes vii. 2unctions of )nsulin, (+! Transmem'rane transport of glucose and amino acids (/! (lycogen formation in liver and s%eletal muscles (3! (lucose conversion to T(s (6! ;ucleic acid synthesis (<! Protein synthesis viii. )nsulin targets translocation of (5-Ts from (olgi apparatus to plasmalemma (+! 2acilitates cellular upta%e of glucose ix. 2Y), (5-T-/ 519 )n liver hepatocytes and cells of pancreas (/! )nsulin );D=P=;D=;T (3! 2acilitate eMuili'ration of glucose 't" extracellular N intracellular compartments (6! 8onduit for pancreatic N hepatic operation of insulin-glucose feed'ac% loop $3 G'+ca#on

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Produced 'y ce''s 4or%s "ith insulin to maintain 'lood glucose levels #inds to receptors on hepatocytes to stimulate #'/co#eno'/s s an$ #'+coneo#enes s Paracrine actions, 519 Activates and cells v. MFA (+! The glucagon receptor is a G,!"ote n co+!'e$ "ece!to" acting via adenylate cyclase action on camp "hich activates protein %inase A (/! PLA activates phosphorylase %inase "hich activates #'/co#en !hos!ho"/'ase (3! (lycogen phosphorylase releases glucose from glycogen vi. *ecretion caused 'y, (+! 5o" plasma glucose (/! )ncreased catecholamines9*;* (3! )ncreased plasma amino acids (6! Acetylcholine (<! 8holecysto%inin vii. *ecretion is inhi'ited 'y, (+! )nsulin (/! *omatostatin (3! )ncreased free fatty acids %etoacids or urea e3 So&atostat n i. Produced 'y ce''s of the pancreas also in the stomach intestine and 'rain ii. Acts to inhi'it insulin and glucagon secretion in the pancreas iii. Additional actions (+! )nhi'its gro"th hormone release (/! )nhi'its T*1 release (3! )nhi'its release of numerous () hormones (gastrin motilin 88L C)P ()P! iv. MFA (+! The somatostatin receptor is a G,!"ote n co+!'e$ "ece!to" acting via adenylate cyclase action on camp "hich activates protein %inase A v. *ecretion is caused 'y, (+! =levated (1 and somatomedins (pituitary only! vi. *ecretion is inhi'ited 'y, *3 Panc"eat c Po'/!e!t $e i. Produced 'y PP ce''s mostly in the head of the pancreas ii. Acts to regulate endocrine and exocrine functions of the pancreas iii. *ecretion is caused 'y, (+! 1ypoglycemia (/! 1igh protein inta%e (3! 2asting (6! =xercise iv. *ecretion is inhi'ited 'y, (+! *omatostatin (/! 1yperglycemia #3 A&/' n i. *ecreted 'y ce''s along "ith insulin ii. 8orrelated "ith Type-/ dia'etes 519 1igh concentrations may cause apoptosis of cells (/! 1igh concentrations may induce fi'ril formation (analogous to amyloid plaMues in Al@heimer7s! "hich is cytotoxic iii. Actions, (+! Decreases glucagon secretion (/! #one meta'olism (3! *lo"ing of gastric emptying (6! )nhi'ition of gastric secretions i. ii. iii. iv.

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ENDOCRINE PANCREAS PATHOLOGY Me' ss&s Sect !" &Ncourse pac) #N#obbins DN re,uired nutritional D ><N>eriatric <edicine: $n e(idence based approach. '( Pathology o) the Endocrine pancreas a. Note: please see physiology section for a description of the normal pancreas. b. *ia+etes %ellitus: "roup of metabolic disorders with common underlyin" feature of hyper"lycemia (#). i. Epidemiology: :. $ffects o(er G4 million children and adults (L5 of @S populations) (#). a. :.; million new cases are dia"nosed a year. b. Nearly a third of those with the disease do not )now they are hyper"lycemic. c. &re(alence is e'pected to increase due to increasin" a"e of the @S population, our sedentary lifestyle and obesity ( & G44). G. 6th leadin" cause of death in the @.S. (:AA9 statistic) ( &GG6). 9. 2eadin" cause of end!sta"e renal disease (335 of new cases), adult!onset blindness (a"esG4!L3), and non!traumatic lower e'tremity amputations (645 of cases). ( &GG6) ,aria+le Increase in RR due to dia+etes *eath 'G -lindness 'G4 End.stage renal disease 'G; Amputation '34 %yocardial In)arction 'G!; Stro/e 'G!9 64!L45 of people with diabetes ha(e mild!se(ere forms of ner(ous system dama"e ( &GGL). ;. Diabetes costs the @S :L3 billion dollars a year. a. Hospitali/ation rates in diabetics are 34!845 hi"her than in nondiabetics (increases with a"e of indi(idual) (><) ii. *iagnosis: :. .stablished by ele(ation of blood "lucose by any one of the followin" three criteria: a. $ random "lucose concentration "reater than G44 m"Bd2, with classical si"ns and symptoms (see clinical manifestations section for more information). b. $ fastin" "lucose concentration "reater than :G6 m"Bd2 on more than one occasion. i. 0astin" "lucose concentration: no caloric inta)e for at least 8 hours. c. $n abnormal oral "lucose tolerance test (=>%%), in which the "lucose concentration is "reater than G44 m"Bd2 two hours after a standard carbohydrate load. i. Standard carbohydrate load: L; " anhydrous "lucose dissol(ed in water. d. H"$:!c R 6.;5 ( &G4:) G. ommon "lucose concentration classifications: (#) %erm 0astin" "lucose test =ral "lucose tolerance test .u"lycemia M:44 m"Bd2 :34 m"Bd2 3.

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Normal ran"e L4!:G4 m"Bd2 &re!diabetic :44!:G6 m"Bd2 :34!G44 m"Bd2 Diabetic (see abo(e) H:G6 m"Bd2 HG44 m"Bd2 S&re!diabetes can also be dia"nosed based on a THb$:cU of ;.L!6.35.S a. ;!:45 of those with pre!diabetes pro"ress to full diabetes mellitus per year. iii. *isease classi)ication: :. Type 1 diabetes: absolute insulin deficiency. a. 0rom V!cell destruction by immune!mediated or idiopathic means. b. ;!:45 of all cases. c. <ost common subtype dia"nosed in patients youn"er than G4 years of a"e. i. ommon timeline: de(elops in childhood, manifests in puberty, and pro"resses throu"hout life. 2. Type 2 diabetes: combination of peripheral resistance to insulin action and inade,uate insulin secretory response V!cells ( Drelati(e insulin deficiencyE). a. A4!A;5 of all cases, the (ast ma?ority are o(erwei"ht. b. lassically considered an Dadult!onsetE diabetes, but the pre(alence in children and adolescence is increasin" alarmin"ly. 9. an occur secondary to other diseases: (#) a. >enetic defects in V!cell function: i. <aturity!onset diabetes of the youn" (<=DI). ii. Neonatal diabetes. iii. <aternally inherited diabetes and deafness (<*DD). i(. *nsulin "ene mutations. b. >enetic defects in insulin action: i. %ype $ insulin resistance. ii. 2ipoatrophic diabetes, includin" mutations in &&$#>. c. .'ocrine pancreatic defects: i. hronic pancreatitis. ii. &ancreatectomyBtrauma. iii. Neoplasia. i(. ystic fibrosis. (. Hemachromatosis. (i. 0ibrocalculous pancreatopathhy. d. .ndocrinopathies: i. $crome"aly. ii. ushin" syndrome. iii. Hyperthyroidism. i(. &heochromocytoma. (. >luca"onoma. e. *nfections: i. <K. ii. o'sac)ie C (irus. iii. on"enital rubella. f. Dru"s: i. >lucocorticoids. ii. %hyroid hormone iii. *N0!W. i(. &rotease inhibitors.

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(. X!adrener"ic a"onists. (i. %hia/ides. (ii. Nicotinic acid. (iii. &henytoin (Dilantin). i'. Kacor. ". >estational diabetes mellitus (>D<). i(. Predisposing )actors 0)or type ' and type 1 dia+etes2: :. &redisposin" factors for a specific type of diabetes is listed with patholo"y. G. >enetic syndromes associated with diabetes: a. Down syndrome. b. Pleinfelter syndrome. c. %urner syndrome. d. &rader!+illi syndrome. 9. #ace: ( &G4:) a. Nati3e Americans4 A)rican Americans and Hispanics are :.L 7 G.G times more li)ely to de(elop diabetes o(er their lifetime than non!Hispanic whites. 3. $"e: ( &G4:) a. #is) of diabetes increases with a"e: i. ould be contributed to by a"e related decrease in "lucose absorption (><). :. Non!insulin mediated "lucose upta)e is mar)edly impaired in eldery, and more impaired in those with type G diabetes (><). ii. G5: G4!9A years. iii. :45: 34!;A years. i(. G:5: 64J years. :. $dditional G4!G;5 of older patients ha(e impaired "lucose tolerance. (. $d(ancin" a"e in diabetics is associated with increasin" >* disease (hiatus hernia, ulcers, "allstones). (><) :. <ore apparent in female diabetics than male diabetics (><). ;. 0amily: a. %ype : diabetes: ( &G4;) i. Siblin"s with diabetes: ris) increases by ;!:45. :. *dentical twin with diabetes: ris) increases by 94!;45. ii. 0ather with diabetes: ris) increases by 3!65. iii. <other with diabetes: ris) increases by G!95. b. %ype G diabetes: ( &G46) i. 0irst de"ree relati(e with diabetes: lifetime ris) is 94!345. ii. =ffsprin" of one parent with diabetes: lifetime ris) is 94!345. iii. =ffsprin" of both parents with diabetes: lifetime ris) is 845. i(. Siblin" with diabetes: lifetime ris) is 94!345. :. *dentical twin with diabetes: L4!845. 6. H2$ "enes for type : diabetes: ( &G4;) a. Discussed further later. b. No shared haplotypes: ris) increases by :!G5. c. =ne shared haplotypes: ris) increases by ;!L5.

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d. %wo shared haplotypes: ris) increases by :6!:L5. e. H2$!D#9 or D#3: ris) increases by G4!G;5. (. Pathogenesis: 1. Please see the physiology section for a review of normal glucose homeostasis. G. #e"ardless of type, disease is due to an absolute or relati(e deficiency in insulin secretion (or action). a. 2eads to metabolic dysre"ulation which can result in secondary dama"e to eyes, ner(es, )idneys and blood (essels. 5( Type ' dia+etes mellitus: a. *mmune effector cells (% lymphocytes) react a"ainst endo"enous V!cell anti"ens. i. 2eads to immune!mediated destruction in islets. b. <ost indi(iduals depend on insulin for sur(i(al, but not all. c. "enetics: (#) i. Hi"her concordance rates for disease in mono/y"otic (ersus di/y"otic twins. ii. Specific "ene loci ( &G;8): :. lass ** <H molecules (displays peptides to % cells4: a. H2$ locus on chromosome 6pG: 7 up to ;45 of "enetic susceptibility. b. A4!A;5 of whites with type : diabetes ha(e H!A.*R5 or H!A.*R6 haplotype, compared to 345 of non!diseased whites. c. 34!;45 of whites ha(e both D#9 and D#3, compared to ;5 of non!diseased whites. d. 0rom siblin" studies: indi(iduals with *R57*R6 com+ined 8ith *9: ha3e the highest ris/ )or inherited type ' dia+etes. i. H2$!DY8 haplotype fre,uencies are "reatest in entral and South $merica, and in Scandina(ia ( &G;8). e. =ther altered pre(alences worth notin" ( &G43): i. H2$C8and C:;are increased. ii. H2$D#G and D#; are decreased. G. Non!<H "ene polymorphisms: a. 2ead to decreased protein stability and function. b. *nsulin: i. Kariable number of tandem repeats in promoter re"ion of the "ene is associated with diseases susceptibility. ii. <echanism un)nown. c. %2$3 and &%&NGG: i. $ssociated with autoimmune thyroiditis and increased type : diabetes. ii. Coth "enes thou"ht to inhibit %!cell responses. d. DG;: i. .ncodes the W chain of the *2!G receptor.

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ii. &olymorphism reduces acti(ity, decreases inhibition of self reactin" %! cells. d. En3ironment: ( &G;L, #) i. Kiral infections tri""er autoimmunity :. <umps, rubella co'sac)ie C, <K, etc. G. &roposed mechanisms for dama"e: a. Bystander damage: (iral infections induce islet in?ury and inflammation release of se,uestered V!cell anti"ens and acti(ation of autoreacti(e % cells. b. olecular mimicry!: Kirus produces proteins that mimic V!cell anti"ens. #esultin" immune response to (irus cross!reacts with the self tissue. c. Predisposing virus and precipitating virus!: (iral infections early in life persist in islets. 2ater re!infection with another (irus that has similar anti"enic epitopes to islets leads to an immune response a"ainst infected islet cells. i. $lso )nown as D(iral dZ? (uE (cute[) and may e'plain why there is a latent period after a (iral infection before diabetes symptoms appear. 9. &roblem\ Some epidemiolo"ic data and e'perimental models actually state that (iral infections are protecti(e (#). ii. Nutrition: cows (ersus breast mil) may play a role ( &G4;). %echanism o) ;.cell destruction: i. #undamental a+normality: failure of self!tolerance of %!cells. :. <ay result from combination of defecti(e clonal deletion of self!reacti(e % cells in the thymus as well as defects in the functions of autore"ulatory % cells, or resistance to suppression of effector % cells by re"ulatory cells. G. Cottom line: auto reacti(e %!cells sur(i(e the Dprunin"E process and can react to self!anti"ens. ii. $utoreacti(e %!cells are li)ely acti(ated in the peripancreatic lymph nodes, in response to anti"ens released from dama"ed islets. :. &ossible islet cell auto!anti"ens (* $) include: insulin "lutamic acid decarbo'ylase (>$D) and islet cell autoanti"en ;:G (* $;:G). G. $utoantibodies are found in most patients with type : diabetes as well as relati(es at ris) for the disease. a. Howe(er not clear if the autoantibodies result in initial in?ury or are produced as a conse,uence of islet in?ury. iii. $cti(ated %!cells tra(el to pancreas and cause V cell in?ury. :. %H: cells: produce cyto)ines (*N0!]) and acti(ate macropha"es (which secrete %N0!W and *2!:).

e.

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6(

%HG cells: directly cytoto'ic to V!cells as well as release cyto)ines. f. <.cell dys)unction: ( &G:9) i. *mpaired resultin" in appropriate secretion of "luca"on. ii. SSNot mentioned in #obbins.SS Type 1 dia+etes mellitus: a. <ultifactorial comple' disease. i. &rimary resistance in peripheral tissue to insulin, followed by V! cell dysfunction that manifests inade,uate insulin secretion. :. *nsulin resistance leads to compensatory V!cell hyperfunction and hyperinsulinemia in the early sta"es of type G diabetes. ii. N= e(idence supportin" autoimmunity as a cause for disease ( &G;8). :. Not associated with "enes for immune tolerance and re"ulation (e.".: H2$) (#). b. "enetics: i. 9;!645 concordance rate in mono/y"otic twins, twice the concordance in di/y"otic twins. ii. >enetics plays a greater role in type 1 dia+etes than type ' dia+etes. iii. Stron"est "enetic ris) related to polymorphisms in "enes associated with V!cell function and insulin secreton. :. .'ample: transcription factor L!li)e!G (% 0L2G) on chromosome :4,, which encodes a transcription factor in the +N% pathway. c. En3ironment: i. =besity and sedentary lifestyle. ii. =besity is present in H845 of indi(iduals with type G diabetes (#). d. Insulin resistance: failure of tar"et tissues to respond normally to insulin. (#) i. 2eads to decreased upta)e of "lucose in muscle, reduced "lycolysis and fatty acid o'idation in the li(er, and inability to suppress hepatic "luconeo"enesis. :. 2oss of insulin sensiti(ity in hepatocytes is li)ely the lar"est contributor to insulin resistance. 2. &ossible functional defects causin" resistance: reduced tyrosine phosphorylation and increased serine phosphorylation of insulin receptor and of *#S proteins attenuated si"nal transduction. a. Data from mouse studies. ii. *nsulin sensiti(ity is detected :4!G4 years before onset of type G diabetes and predicts the pro"ression to the disease ( &G;A). iii. =besity: plays the lar"est role in de(elopment of insulin resistance. :. #is) for diabetes increases as C<* increases. a. $bsolute amount of fat as well as distribution of body fat affect insulin sensiti(ity.

G.

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G.

entral obesity (abdominal fat) more li)ely to be lin)ed with peripheral ("lutealBsubcutaneous) fat. (#) auses of insulin insensiti(ity in obesity: a. Nonesterified fatty acids: i. .'cess circulatin" nonesterified fatty acids are deposited in muscle and li(er tissue. ii. Cody attempts to brea) them down usin" fatty acid o'idation pathways accumation of cytoplasmic intermediates (D$> and ceramide) acti(ation of serineBthreonine )inases serine phosphorylation of insulin receptor and *#S proteins, attenuatin" insulin si"nalin". iii. .'cess insulin allows phosphoenolpyru(ate carbo'y)inase to increase "luconeo"enesis. i$. Nonesterified fatty acids also compete with "lucose for substrate o'idation inhibition of "lycolytic en/ymes.

i.

b.

c.

d.

"dipo#ines: i. ollecti(e term for proteins secreted into systemic circulaton by adipose tissue. ii. $nti!hyper"lycemic adipo)ines (leptin, adiponectin) are decreased in obesity, contributin" to insulin resistance. (#) Note: $P2%& states that there is an increase in pro' hyperglycemic adipo#ines. (obbins does not mention this. Please see lecture for more information. )nflammation: i. &ro!inflammatory cyto)ines (%N0, *2! 6, macropha"e chemoattractant protein! :) released by adipose tissues. ii. %hese cyto)ines increase cellular DstressE, which anta"oni/es insulin action in peripheral tissues insulin resistance. Pero*isome proliferator'activated receptor +:

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i. Nuclear receptor and transcription factor in adipose tissue, plays a role in adipocyte differentiation. ii. $cti(ation of &&$# ] secretion of anti!hyper"lycemic adipo)ines shiftin" deposition of nonesterified fatty acids to adipose tissue and from the li(er and s)eletal muscles. e( ;.cell dys)unction: 0R2 i. Seems that V cells simply e'haust their capacity to adapt to lon"! term demands of peripheral insulin resistance. ii. *nitially, insulin resistance is met with hyperinsulinemia, allowin" normal plasma "lucose le(els to be maintained. iii. .(entually, V cell compensation becomes inade,uate and there is a pro"ression to hyper"lycemia. :. an be a subtle decrease in V!cell number ( &G;A). i(. $ssociated "enes: % 0L2G as pre(iously noted. (. &otential causes o(erlap with the causes that resulted in insulin resistance. (i. $myloid deposits in islets is commonly seen and could be cytoto'ic to V!cells (similar to amyloid pla,ues in $l/heimer disease). (ii. $mylin becomes deficient late in type G diabetes. ( &G:L) :. $mylin is commonly co!stored is co!secreted with insulin (molar ration :::44) ( &G;A). G. $cts to suppress postprandiol "luca"on concentration, slows "astric emptyin" and decreases food inta)e. ( &G48) (iii. %he affect of incretins are impaired. ( &G:6) :. Hormones that ori"inate in the >* tract. G. #eleased durin" nutrient absorption to modulate islet cell function. 9. %wo main incretins: ( &G:G) a. >luca"on!li)e peptide : (>2&!:). i. #eleased from 2 cells in the ileum and colon. ii. Stimulates insulin response from V cells in a "lucose!dependent manner. iii. *nnhibits "astric emptyin". i(. #educes food inta)e and body wei"ht. (. *nhibits "luca"on secretion from W cells in a "lucose!dependent manner. b. >lucose!dependent insulinotropic polypeptide (>*&). i. #eleased from P cells in the duodenum. ii. Stimulates insulin response from V cells in a "lucose!dependent manner. iii. Has minimal effect on "astric emptyin".

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c.

i(. No si"nificant affects on food inta)e or body wei"ht. (. Does not appear to inhibit "luca"on secretion from W cells. Coth >2&!: and >*& are de"raded by D&&!3 en/yme.

f.

See summary picture re"ardin" pro"ression of diabetes from #obbins below.

;.

%onogenic )orms o) dia+etes: 0R2 ("enetically defined causes of diabetes) a. "enetic de)ects in ;.cell )unction: i. #esults in a primary defect in cell function but not cell loss.

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:. $ffects either V!cell mass or insulin production. ii. $ccounts for :!G5 of diabetics. iii. haracteri/ed by: :. $utosomal dominant inheritance with hi"h penetrance. G. .arly onset (before the a"e of G;, e(en in neonatal period) as opposed to late onset (after 34) for type G diabetes. 9. $bsence of obesity. 3. $bsence of V!cell autoantibodies. i(. 2ar"est sub"roup is Dmaturity'onset diabetes of the youngE (<=DI) because of resemblance to type G diabetes and occurs in youn". :. Hemi/y"ous loss!of!function mutations in one of si' "enes (not worth your time to remember which, but they encode transcription factors controllin" insulin e'pression in V cells and V!cell mass). (. ,-.2 caused by mutations in the "luco)inase "ene, increasin" fastin" blood "lucose le(els. :. ;45 of carriers of "luco)inase mutations de(elop "estation diabetes mellitus (which is defined as any de"ree of "lucose intolerance durin" pre"nancy). (i. Permanent neonatal diabetes: :. #esults from mutations in P NO:: and $C 8 "enes, encodin" parts of the $%&!sensiti(e PJ channel. a. *nacti(ation of this channel is re,uired for physiolo"ic insulin secretion from V!cells. b. >ain of function mutations lead to constituti(e acti(ation of the channel, and hypoinsulinemic diabetes. G. &resents with se(ere hyper"lycemia and )etoacidosis. 9. =ne fifth of patients also ha(e neurolo"ic symptoms li)e epilepsy. (ii. aternally inherited diabetes and deafness: 1. #esult from mitochondrial DN$ mutations impairment of mitochondrial $%& synthesis in metabolically acti(e islet cells decrease in insulin secretion. b. "enetic de)ects in insulin action: i. #are. ii. $ffect receptor synthesis, insulin bindin" or recetpro tyrosine )inase acti(ity. iii. =ften associated with acanthosis nigricans (hyperpi"mentation of the s)in). i(. 0emales often ha(e polycystic o(aries and ele(ated andro"en le(els. (. /ipoatrophic diabetes: hyper"lycemia associated with loss of adipose tissue selecti(ely occurrin" in subcutaneous fat. :. #are "roup of "enetic disorders. (i. Clinical mani)estations o) dia+etes:

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:. G.

9.

lassic manifestations of diabetes (hyper"lycemia and )etosis) occur late in the disease course, after more than A45 of V!cells ha(e been destroyed. >reat (ariability amon" patients in the time of onset of late complications, their se(erity and the particular or"an(s) in(ol(ed. (#). a. *n elderly, polyuria or polydipsia is rarely present. =ften present with a complication of diabetes (<* or stro)e) (><). Symptoms: type ' 3ersus type 1 dia+etes mellitus 0CP1'=2: a. %ype :: i. Decrease in insulin increase in blood "lucose osmotic dieresis, polyuria, polydipsia. ii. 2oss of calories 7 "lucose uria leads to increase in brea)down of fat and proteins. b. %ype G: i. Symptoms associated with type : diabetes may be present. ii. 0re,uently asymptomatic. iii. <ay present with symptoms of complications: :. &eripheral neuropathy. G. <*. 9. *nfections ((ul(o(a"initis, ballanitis).

TA-!E 16.> from #obbins .. Type ' ,ersus Type 1 *ia+etes %ellitus %ype : Diabetes <ellitus %ype G Diabetes <ellitus 2*N* $2 =nset: usually childhood and adolescence =nset: usually adult; increasin" incidence in childhood and adolescence Normal wei"ht or wei"ht loss precedin" Kast ma?ority are obese (845) dia"nosis &ro"ressi(e decrease in insulin le(els *ncreased blood insulin (early); normal or moderate decrease in insulin (late) irculatin" islet autoantibodies (anti!insulin, No islet auto!antibodies anti!>$D, anti!* $;:G) Diabetic )etoacidosis in absence of insulin Non)etotic hyperosmolar coma more common therapy >.N.%* S <a?or lin)a"e to <H class * and ** "enes; also No H2$ lin)a"e; lin)a"e to candidate diabeto"enic and lin)ed to polymorphisms in$T/"0 and PTPN22, obesity!related "enes (T$12/2, PP"(3, 1T,, etc.) and insulin "ene KN%#s &$%H=>.N.S*S Dysfunction in re"ulatory % cells (%re"s) leadin" *nsulin resistance in peripheral tissues, failure of to brea)down in self!tolerance to islet auto! compensation by V!cells anti"ens <ultiple obesity!associated factors (circulatin" nonesterified fatty acids, inflammatory mediators, adipocyto)ines) lin)ed to patho"enesis of insulin resistance &$%H=2=>I *nsulitis (inflammatory infiltrate of % cells and No insulitis; amyloid deposition in islets macropha"es) V!cell depletion, islet atrophy <ild V!cell depletion H2$, human leu)ocyte anti"en; <H , ma?or histocompatibility comple'; KN%#s, (ariable number of tandem repeats. 3. ascade of e(ents in diabetes depicted in the followin" ima"e from #obbins:

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?(

Complications o) dia+etes: a( Acute complications: i. Diabetic )etoacidosis: :. omplication of type :diabetes that can also occur in type G thou"h not as commonly. G. <ar)ed insulin deficiency, epinephrine bloc)s any residual insulin action, stimulatin" the secretion of "luca"on. 9. &eripheral utili/ation of "lucose decreases, increase in "luconeo"enesis which e'acerbates hyper"lycemia. 4. Hyper"lycemia osmotic dieresis and dehydration. ;. Peto"enesis occurs due to alteration in insulin: "luca"on ratio. ii. Hyperosmolar non)etotic coma: :. <ore common in type G diabetes. +( Chronic complications o) dia+etes: i. &atholo"ic findin"s in the pancreas are (ariable and not necessarily dramatic (#). ii. Pathologenesis is multi)actorial4 +ut largely mediated +y persistent hyperglycemia . :. <acro(ascular disease: lesions in lar"e! and medium! si/ed muscular arteries.

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auses endothelial dysfunction which causes accelerated atherosclerosis leadin" to increased ris) of <*, stro)e and lower e'tremity "an"rene. G. <icro(ascular dama"e: capillary dysfunction in or"ans. a. Has lar"est effect in retina, )idneys, peripheral ner(es. 9. >lycemic control can help control lon"!term complications of diabetes. iii. <etabolic pathways associated with diabetic complications: :. "dvanced glycation end products: formed from nonen/ymatic reactions between intracellular "lucose! deri(ed dicarbonyl precursors with amino "roups of intracellular and e'tracellular proteins. a. &rocess is "reatly accelerated in hyper"lycemia. b. $d(anced "lycation end products bind to receptors on inflammatory cells, endothelium and (ascular smooth muscle (#$>. receptors) leadin" to: i. <acropha"es: release of pro! inflammatory cyto)ines and "rowth factors. ii. .ndothelial cells: reacti(e o'y"en species. iii. Kascular smooth muscle: enhanced proliferation and synthesis of e'tracellular matri'. i(. *ncreases coa"ulation acti(ity ( &G6:). c. $nta"onists to the receptor has helped treat diabetes. d. $d(anced "lycation end products can also:directly cross!lin) e'tracellular matri' proteins, type *K colla"en. i. .'tracellular matri' proteins: decreases the proteins elasticity, leadin" to increased shear stress and in?ury. ii. olla"en: decreases endothelial cell adhesion and increase e'tra(asion of fluid. =(erall decrease in protein remo(al and increase in protein deposition. %raps 2D2 in lar"e blood (essels and albumin in capillaries. e. "ctivation of Protein 4inase $: i. Done by aGJ ions and D$>. ii. 2eads to: &roduction of proan"io"enic (ascular endothelial "rowth

a.

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f.

".

factor (K.>0). neo(asculari/ation in diabetic retinopathy. .le(ated (asoconstrictor endothelin!: and deceased le(els of (asodilator N=, due to decreased N= synthase e'pression. &roduction of profibro"enic factors li)e %>0!V, leadin" to increased e'tracellular matri' and basement membrane. &roduction of &$*!:, causin" reduced fibrinlysis and possible (ascular occlusi(e episodes. &roduction of pro!inflammatory cyto)ines by (ascular endothelium. iii. =(erlaps with ad(anced "lycation end! products. -isturbances in polyol pathways: i. *n tissues where insulin is not re,uired for "lucose transport into tissues, "lucose is absorbed in "reater amounts. ii. .'cess "lucose is metaboli/ed to sorbitol and fructose, usin" N$D&H. iii. N$D&H is re,uired for production of reduced "lutathione, which is an antio'idant. Decrease in N$D&H leads to increased susceptibility to o'idati(e stress. i. .specially in ner(es and the retina.

i3( Pancreas: :. 2esions ha(e N= dia"nostic (alue. G. #eduction in number and si/e of islets. a. <ost often seen in type : diabetes, particularly with rapidly ad(ancin" disease. 9. 2eu)ocyte infiltrates in the islets (insulitis). a. &rincipally composed of % lymphocytes. b. <ay be present at time of clinical presentation in type : diabetics. 3. Subtle reduction of islet cell mass. a. *n type G diabetes, only demonstrated by special morphometric studies. ;. $myloid deposition. a. +ithin islets in type G diabetes. b. Ce"ins in and around capillaries and between cells.

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(.

(i.

(ii.

(iii.

*n ad(anced sta"es, islets may be (irtually obliterated. d. 0ibrosis may occur. e. $lso present in normal elderly nondiebetics as a part of a"in". 6. *ncrease in number and si/e of islets. a. haracteristic of nondiabetic newborns of diabetic mothers. b. 0etal islets li)ely under"o hyperplasia in response to maternal hyper"lycemia. %acro3ascular structure: :. 2ar"ely a result of endothelial dysfunction caused by diabetes as pre(iously described. G. $ccelerated atherosclerosis in the aorta, lar"e! and medium!si/ed arteries. a. .'cept for "reater se(erity and earlier a"e at onset, atherosclerosis in diabetics is indistin"uishable from that in nondiabetics. b. 2eads to: <* (most common cause of death in diabetics), ele(ated ris) for cardio(ascular disease, "an"rene in lower e'tremities. Hyaline arteriolosclerosis: :. $fferent and efferent (ascular lesion associated with hypertension 7 amorphous hyaline thic)enin" of the walls of the arterioles, causin" narrowin" of lumen. G. <ore pre(alent and more se(ere in diabetics than nondiabetics, but not specific for diabetes. a. *ncrease in se(erity with disease duration as well as increase in blood pressure. *ia+etic microangiopathy: :. Diffuse thic)enin" of basement membranes, most e(ident in the capillaries of the s)in, s)eletal muscle, retina, renal "lomeruli and renal medulla. G. an also been seen in renal tubules, Cowman capsules, peripheral ner(es and placenta. 9. Diabetic capillaries are lea) more proteins than normal capillaries despite thic)ened basement membrane. 3. auses nephropathy, retinopathy, and some forms of neuropathy. ;. an be seen in nondiabetics, but rarely to the e'tent seen in diabetics. *ia+etic nephropathy: :. #enal failure is the second most common cause of death in diabetics. a. G4 years after dia"nosis: 845 of type : and 94! 345 of all diabetics de(elop nephropathy. b. Nati(e $mericans, Hispanics and $frican $mericans are at "reater ris) for end sta"e renal disease than non!Hispanic whites.

c.

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%ype G diabetics account for half of those startin" dialysis each year. 9. Diabetes causes: a. >lomerular lesions (C< thic)enin" in the capillaries and Cowmans capsule, C< thic)enin" of mesan"ium diffuse and nodular layers nodular "lomerulosclerosis DPimmelstiel!+ilson lesionE). i. C< thic)enin" be"ins as early as G years after onset of type : diabetes. ii. Cy ; years usually amounts to a 945 increase in basement membrane width. iii. @sually occurs concurrently with mesan"ial widenin". b. #enal (ascular lesions (principally arteriolosclerosis). c. &yelonephritis, includin" necroti/in" papillitis. i'. *ia+etic ocular complications: :. #etinopathy, cataract formation, "laucoma. G. 64!845 of patients de(elop retinopathy :;!G4 years after dia"nosis. '. *ia+etic in)ection: :. *ncreased incidence in s)in, )idney, lun"s (%C). G. Due to decreased neutrophil concentration and decreased macropha"e function. 9. *nfections are two times more fre,uent in diabetics than nondiebetics, but there is not an a"e related increase in infections in diabetics. (><) 3. auses ;5 of deaths in diabetics. (ii. Treating *ia+etes: :. >oals: a. $lle(iate symptoms. b. #e(erse metabolic effects of hyper"lycemia ("lucose to'icity). c. &re(ent lon" term complications (macro(ascular, micro(ascular, neuropathic, as discussed abo(e). G. <ethods used: a. Nutrition. i. o(ered in nutrition section. b. .'ercise. i. Cenefits ( &GG9): :. *mpro(es insulin sensiti(ity. G. @sed as an ad?unct to diet for wei"ht reduction. 9. *ncreases physical wor)in" capacity. 3. *ncreases sense of well!bein" and ,uality of life. ii. #ecommendations: :. 94!64 minutes on most days of the wee). G. >i(e an e'ercise tolerance test to the elderly before be"innin" a pro"ram (><).

G.

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9.

Dru"s. i. @sed if diet and e'ercise are not sufficient. ii. See dru" chart for more information. Cenefits of controllin" hyper"lycemia: a. Diabetes ontrol and omplications %rial #esearch >roup: ( &GGA) i. *mpro(ed control of blood "lucose reduces the ris) of clinically meanin"ful symptoms: Symptom Relati3e Ris/ Reduction Retinopathy L65 pF 4.44G Nephropathy ;35 pF 4.43 Neuropathy 645 pF 4.44G Cardio3ascular e3ents L85 pN 4.46; b.

c.

@nited Pin"dom &rospecti(e Diabetes *nter(ention %rial: Symptom Ris/ Reduction %icro3ascular G;5 pN4.44AA Retinopathy G:5 pN4.4:; Al+uminuria 995 pN4.4444;3 %yocardial in)arction :65 pN4.4;G *ia+etes.related end points :G5 pN4.4GA 3. %ar"et numbers for treatment: a. Hb$:c!*: "lycated hemo"lobin. i. @sed primarily to identify the a(era"e plasma "lucose concentration o(er prolon"ed periods of time. ii. No e'act consensus on (alues: :. ML5: $merican Diabetes $ssociation. a. $lso state that should be less than 65 for indi(idual patients. G. M6.;5: $merican olle"e of .ndocrinolo"y. 9. *ndi(iduali/ed (ML5): $merican olle"e of &hysicians. b. &lasma "lucose le(els: i. Karyin" numbers. Target !e3el American *ia+etes American College Association o) Endocrinology %easurement #asting plasma glucose A4!:94m"Bd2 M::4 m"Bd2 Postprandial plasma glucose &ea) M:84 m"Bd2 M:34 m"Bd2 -edtime plasma glucose ::4!::; m"Bd2 No recommendation <etabolic tar"ets: i. @sed for type G diabetes. Parameter Target ,alue Total Cholesterol MG44 m"Bd2 !*!.C M:44 m"Bd2 (ML4 for (ery hi"h ris) patients) H*!.C H34 m"Bd2 (men) H;4 m"Bd2 (women) Triglycerides F :;4 m"Bd2 c. Pancreatic Endocrine Neopasms: c.

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i. %umors of the pancreatic islet cells. :. an occur anywhere alon" the len"th of the pancreas, embedded in the pancreas or the immediate peripancreatic tissue. G. .'crete pancreatic hormones or are nonfunctional. ii. Epidemiology: :. $ccounts for only G5 of all pancreatic neoplasms. G. <ost common in adults. iii. Prognosis: :. A45 of insulinomas are beni"n. a. <ost common type. G. 64!A45 of other pancreatic endocrine neoplasms (both secretin" and non!secretin") are mali"nant. 9. Hints towards mali"nancy ( &G6L): a. <etastasis to blood (essels or ad?acent or"ans. b. >ross findin"s: i. Si/e "reater than G cm. ii. Creach of the tumor capsule. iii. %umor necrosis. c. <icroscopic findin"s: i. %ype that isnt an insulinoma. ii. *ncrease in cell atypia and mitoses rate. i(. Types: :. Insulinoma (hyperinsulinism) a. X!cell tumor. i. <ost are solitary and beni"n. ii. @sually small (MG cm diameter), encapsulated, and are pale to red! brown. :. >enerally loo) li)e "iant islets as re"ular cords of cells and (asculature are preser(ed. G. Deposition of amyloid in e'tracellular tissue is a characteristic feature. iii. %he :45 that are mali"nant are dia"nosed based on local in(asion and distant metastases (li)e most mali"nancies). b. Note: hyperinsulinism can also be caused by focal or diffuse hyperplasia of islets. i. <ost often found as con"enital hyperinsulinism with hypo"lycemia in neonates and infants. :. aused by maternal diabetes, Cec)with!+iedemann syndrome, and rare mutations in V!cell PJ!channel proteins or in sulfonylurea receptors. c. Clinical )eatures: i. 845 demonstrate e'cessi(e insulin secretion. ii. Hypo"ly"emia is mild in all but G45 cases and often doesnt become symptomatic. (#) iii. Hypo"lycemic episodes that: (#) :. =ccur when blood "lucose le(els are below ;4 m"Bd2 of serum. G. onsist primarily of central ner(ous system symptoms (confusion, stupor and loss of consciousness),

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G.

5(

$re precipitated by fastin" or e'ercise and are promptly relie(ed by feedin" or administration of "lucose. i(. ritical laboratory findin"s: high circulating le3els o) insulin and high insulin.to.glucose ratio. d. Sur"ical remo(al of the tumor usually followed by prompt re(ersal of the hypo"lycemia. e. =ther conditions to eliminate: i. $bnormal insulin sensiti(ity. ii. Diffuse li(er disease. iii. *nherited "lyco"enoses. i(. .ctopic production of insulin from retroperitoneal fibromas or fibrosarcomas. (. Self!in?ection of insulin causin" hypo"lycemia. "astrinoma(^ollin"er!.llison Syndrome): a. Hypersecretion of "astrin. b. $rise in the gastrinoma triangle (duodenum, peripancreatic soft tissue, pancreas). c. 2ittle a"reement on the cell of ori"in for tumor. i. 2i)ely endocrine cells of "ut or pancreas. d. %umors are histolo"ically DblandE and rarely show mar)ed anaplasia (#). e. Clinical )eatures: i. H;45 of "astrin!producin" tumors are locally in(asi(e or ha(e already metastasi/ed at the time of dia"nosis. :. %ypically sin"le tumors. ii. G;5 arise as part of <.N!: syndrome (<ultiple .ndocrine Neoplasia!:: affects parathyroid, pancreas and pituitary "lands. aused by "ermline mutation in <.N: tumor suppressor "ene). :. *n this case, tumors are fre,uently multifocal. iii. A4!A;5 arise with ^ollin"er!.llison syndrome. :. Hypersecretion of "astric acid causin" se(ere peptic ulceration alon" with "astrinoma. G. Duodenal and "astric ulcers are often multiple and unresponsi(e to therapy. a. =therwise, loo) li)e ulcers seen in the "eneral population. b. =ften in unusual locations such as the ?e?unum. 9. %reatment includes controllin" "astric acid secretion with a hydro"en!potassium $%&ase inhibitor and e'cision of the neoplasm. a. %otal e'cision eliminates the syndrome. i(. Symptoms: :. ;45 diarrhea (for 945 this is the presentin" symptom\). f. Hepatic metastases results in shortened life e'pectancy. i. 2i(er failure in :4 years. Rare pancreatic endocrine neoplasms: a. 3lucagonomas 56'cell tumors 7: increased serum le(els of "luca"on, mind diabetes mellitus, s)in rash (necrolytic mi"ratory erythema) and anemia. i. =ccur most fre,uently in perimenopausal and postmenopausal women.

9.

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b.

c.

d.

e. f.

ii. haracteri/ed by e'tremely hi"h le(els of plasma "luca"on. 8omatostatinomas 59'cell7: associated with diabetes mellitus, cholelithiasis, steatorrhea, hypochlorhydria. i. Difficult to locali/e preoperati(ely. ii. Hi"h le(els of somatostatin re,uired for dia"nosis. :)Poma 5;-<" syndrome7: endocrine tumor with a syndrome caused by release of (asoacti(e intestinal peptide. i. Syndrome: watery diarrhea, hypo)alemai, achlorhydria. ii. Some are locally in(asi(e and metastatic. iii. linical note: perform a K*& assay on all patients with se(ere seccretory diarrhea. i(. K*& syndrome can also be caused by: neuroblastomas, "an"lioneuroblastomas, "an"lioneuromas, pheochromacytoma. Pancreatic carcinoid tumors: produce serotonin and an atypical carcinoid syndrome. i. .'ceedin"ly rare. Pancreatic polypeptide'secreting endocrine tumors: endocrinolo"ically asymptomatic, despite presence of hi"h le(els of hormones in plasma. ultihormonal tumors: e'actly how they sound. i. &roduce two or more hormones (insulin, "luca"on, "astrin, $ %H, <SH, $DH, serotonin, norepipenhrine) simultaneously or in se,uence.

PATH ! "Y 1(

# A*IP SE TISS@E

Pathology o) Adipose Tissue: a. %otal number of adipocytes is established durin" childhood and adolescence. (#) i. Hi"her in obese than lean indi(iduals. ii. *n adults, the number of adipocytes remains constant, e(en after wei"ht loss or "ain. iii. Howe(er this is a continuous turno(er of the cell population. :. :45 are renewed annually, re"ardless of body mass. b. 0at mass in an adult person increases by enlar"ement of e'istin" adipocytes. i. Difficulties in maintainin" wei"ht loss is due, in part, to the fact that adipocyte number does not chan"e. c. +esity: i. %echnically, e'cess adiposity in relation to lean body mass that is of sufficient ma"nitude to impair health (#). :. %his is D*00.#.N% from e'cess body wei"ht, althou"h body wei"ht is used as a pro'y for adiposity. ii. $entral 5visceral7 obesity: fat accumulations in the trun) and in the abdominal ca(ity. :. Hi"her ris) for diseases than e'cess accumulation of fat diffusely in subcutaneous tissue. iii( *iagnosis: :. ommonly, C<* of 94 or hi"her. a. Normal wei"ht: C<*N:8.;!G; )"BmG. b. =(erwei"ht: C<*NG;!94 )"BmG.

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#. G.

alculation for C<*N

9.

$ccumulation of body fat can also be physically measured ( &:6;). a. %riceps s)in fold thic)ness, mid!arm circumference, and the ratio between the waist and hip circumferences. i. .asy and ine'pensi(e but less accurate. b. <#*B % scan. i. Cenefit: can measure re"ional fat distribution. c. Cioelectrical impedance. i. <easure opposition of flow to electrical current and calculate body fat based on that. ii. on(enient and ine'pensi(e (my _G; bathroom scale does it\) d. Dual!ener"y '!ray absorptiometry (D.Q$). i. $ccurate and easily a(ailable, but e'pensi(e. e. @nderwater wei"hin". i. >old standard, but needs special e,uipment. riteria differs for men and women based on normal e'pected body fat: Category %ales #emales Normal :G!G45 G4!945 -orderline G:!G;5 9:!995 +ese HG;5 H995

i(. Epidemiology: :. .pidemic in the @.S. (#) a. 2ate :AL4s: 3L5 of adults o(erwei"ht or obese. :;5 of adults obese. b. 2ate :A84s: ;65 of adults o(erwei"ht or obese. G95 of adults obese. c. 2ate :AA4s: 635 of adults o(erwei"ht or obese. 9:5 of adults obese. i. &ercent of children o(erwei"ht in :AAA: :. :4.35 of G!; year olds. G. :;.95 of 6!:: year olds. 9. :;.;5 of :G!:A year olds. d. G443: 9G5 of population is obese. e. G44A: 665 of population is o(erwei"ht or obese. i. :65 of children are obese or o(erwei"ht. f. G4:;: pro?ected 3:5 of adults will be obese. G. =besity differs by state, indicatin" lifestyle factors ( &:6G).

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ost of treatin" obesity and obesity!related diseases _G98 billion. a. G45 of nations health care bill. 3( Predisposing )actors: :. See patho"enesis below. 3i( Pathogenesis: 1. Note: (ecommended that you understand neuroendocrine regulation of appetite section of this lecture before attempting the pathology of obesity. G. $t most basic le(el, obesity is a disease of caloric imbalance resultin" from an e'cess inta)e of calories abo(e their consumption by the body (#). 9. &atho"enesis is e'tremely comple' and not completely understood. 3. "enetics: ( &:L4) a. #efer to neuroendocrine re"ulation of appetite for more information. b. 2eptin: defects in the polypeptide or its receptor. c. <elanocortin 3 receptor "enes: i. :.85 of obese adults. ii. @p to 65 of early onset se(ere obesity in children. iii. 0at mass and =besity!associated "ene (0=%) (ariant: :. :65 of adults homo/y"ous for the ris) allele wei"hed 9)" more than controls. G. +ere :.6L' more li)ely to be obese. En3ironment: ( &:L:) a. *ncreased access to hi"hly palatable, calorie!dense foods. i. &ortion si/es ha(e increased o(er time ( &:L:). b. Decreased physical acti(ity. 6. Kiral infections may play a role ( &:LG). a. #apid increase in obesity since :A84 resembles an infectious ori"in. b. ; animal (iruses and 9 human (iruses ha(e been shown to cause obesity. c. So, some obesity may be due to (iruses[ 3ii( Clinical mani)estations: :. *ncreasin" obesity is associated with increased disease ris). ( &:66) ;.

9.

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Classi)ication @nder8eight Normal 3er8eight +esity +esity EEtreme o+esity

-%I 0/g7m12 M:8.; :8.;!G3.A G;.4!GA.A 94.4!93.A 9;.4!9A.A R34 G.

+esity Class

* ** ***

*isease Ris/ 0relati3e normal 8eight and 8aist circum)erence2 %en A6B in 0A'B1 cm2 %en C6B in 0C'B1 cm2 Domen A5? in 0A:: cm2 Domen C5? in 0C:: cm2 ! ! ! ! *ncreased Hi"h Hi"h Kery Hi"h Kery Hi"h Kery Hi"h .'tremely Hi"h .'tremely Hi"h

Hormonal abnormalities associated with obesity ( &:LG): a. &ancreas: i. *nsulin: insulin resistance and hyperinsulinemia, metabolic syndrome. :. See below for more information on insulin resistance. ii. >luca"on: normal or increased. b. &ituitaryB"onadal a'is: i. <ales: :. 2ow le(els of testosterone. ii. 0emales: :. <enarche at a youn"er a"e. G. Normal total testosterone. 9. Decreased se' hormone bindin" "lobulin. 3. *ncreased free testosterone. ;. an cause polycystic o(arian syndrome. c. &ituitaryBadrenal a'is: i. *ncrease cortisol secretion rate. ii. Normal circadian rhythem of cortisol. iii. Normal response to de'amethasone suppression. d. &ituitaryB"rowth hormone a'is: i. Decreased secretion of "rowth hormone. ii. Kariable *0>: le(els. e. &ituitaryBthyroid a'is: i. Normal. f. Summary of hormonal chan"es in obesity (#).

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9.

Insulin resistance: less than normal biolo"ic response to a "i(en amount of insulin. a. auses: i. Systemic inflammation. ii. .ndothelial dysfunction. iii. Disordered fibrinolysis. i(. $therosclerosis. (. %ype G diabetes. :. See patholo"y of the endocrine pancreas for more information. (i. Kisceral obesity. :. 2eads to non!alcoholic fatty li(er disease. (#) a. <ost often occurs in diabetic patients and can pro"ress to fibrosis and cirrhosis. G. holelithiasis is 6 times more common in obese than lean sub?ects. (#) a. *ncrease in total body cholesterol, increased cholesterol turno(er, and au"mented biliary e'retion of cholesterol predispose to the formation of cholesterol!rich "allstones. (ii. Hypo(entilation and hypersomnolence: (#) :. Hypo(entilation syndrome: (arious respiratory abnormalities in (ery obese indi(iduals. a. Hypersomnolence both at ni"ht and durin" the day. b. $pneic pauses durin" sleep. c. &olycythemia. d. .(entual ri"ht!sided heart failure. e. $lso called pic)wic)ian syndrome (from harles Dic)ens &ic)wic) &apers). (iii. Hypertension: :. auses hyperinsulinema, which results in increased renal NaJ re!absorption and stimulates the sympathetic ner(ous system. G. $lso causes decreased (asodilation.

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6(

;.

Decreased (asoldilation, increased NaJ re!absorption and sympathetic stimulation results in hypertension. 3. #is) of de(elopin" hypertension in pre(iously normotensi(e persons increases proportionally with wei"ht (#). i'. omple' dyslipidemia ( &:L;): :. *nsulin does not si"nal to fat cells that enou"h nutrients e'ist. G. 0ree fatty acids are relased from adipose tissue. a. %ri"lyceride, $poC and K2D2 concentration increases in the li(er. i. K2D2s are transformed to 2D2s and then to SD2D2s (usin" 2p or hepatic lipase). ii. $lso results in decrease in HD2s in the )idney. 9. Decreased HD2. 3. <ay increase the ris) of coronary artery disease in (ery obese. '. =steoarthritis (#): :. %ypically in older persons, from cumulati(e effects of obesity on wei"ht!barin" ?oints. %eta+olic syndrome: a. %hree or more of the followin": ( &:L6) i. Kisceral or intra!abdominal adiposity. :. +aist circumference H:4G cm (H34in) in men, H88 cm (H9;in) in women. ii. *nsulin #esistance (with or without "lucose intolerance). :. 0astin" plasma "lucose R::4 m"Bd2 (H:44 m"Bd2 accordin" to the $merican Diabetes $ssociation) iii. Hypertension: :. Systolic C& R :94 mmH". G. Diastolic C& R8; mmH". i(. Hypertri"lyceridemia: :. R:;4 m"Bd2. (. Decreased HD2 cholesterol: :. M34 m"Bd2 in men. G. M;4 m"Bd2 in women. b. an also ha(e prothrombic and proinflammatory mar)ers: i. *ncreased #&, fibrino"en and other coa"ulation factors. c. $ppears to lead to an increased ris) for cardio(ascular morbidity and mortality (:.;!G'). i. ontro(ersial relationship. Summary of medical complications of obesity ( &:LL): 9.

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+esity and cancer: (#) a. 35 of cancers in men and L5 of cancers in women are associated with obesity. i. *n men, C<*HG; )"BmG correlated with increased incidence of adenocarcinoma of the esopha"us, cancers of the thyroid colon and )idney. ii. *n women, C<*HG; )"BmG correlated with increased incidence of adenocarcinoma of the esopha"us, endometrial, "allbladder and )idney cancer. b. <echanism hypothesi/ed: i. Due to hyperinsulinemia and insulin resistance and resultin" affects of insulin on cell si"nalin". :. .'ample: insulin inhibits the production of *>0!bindin" proteins *>0C&!: and *>0C&!G, which causes an increase in insulin!li)e "rowth factor!:. a. *>0!: is a mito"enic and anti!apoptotic a"ent that is hi"hly e'pressed in human cancers. b. Cinds to *>0!:# receptor and acti(ates pathways acti(ated by insulin. G. $lso affect steroid hormones that re"ulate cell "rowth and differentiation in the breast, uterus and other tissues. a. *ncreases synthesis of estro"en from andro"en precursors throu"h an effect of adipose tissue aromatases. b. *nsulin increases andro"en synthesis in o(aries and adrenals and enhances estro"en a(ailability in obese persons by inhibitin" the production of se'!hormone!bindin" "lobulin in the li(er. (iii. Treatment )or o+esity: ( &:8:) :. 2ifestyle mana"ement: a. Dietary therapy. i. See nutritional principles for the mana"ement of obesity section. b. *ncreased physical therapy ( &:8A).

6.

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Treatment *iet physical acti3ity4 and +eha3ior therapy Pharmacotherapy Surgery

i. Cenefits: :. Decreases loss of fat!free mass associated with wei"ht loss. G. *mpro(es maintenance of wei"ht loss. 9. *mpro(es cardio(ascular and metabolic health independent of wei"ht loss. ii. #ecommended: 94!64 minutes 9!; timesBwee). c. Ceha(ior therapy. G. &harmacotherapy. a. See dru" chart for more information. 9. Sur"ery: ( &:AG) a. >astroplasty (stomach staplin"): i. #estricti(e technie,ue for mana"in" obesity: $ band and staples are used to create a small stomach pouch. ii. #est of stomach is treated as transport to intestines. iii. Kery serious and dan"erous procedure. b. >astric bypass procedures: i. Sur"ically di(ide stomach into two pouches 7 small upper pouch and a lar"er lower DremnantE pouch. ii. #earran"e the small intestine so that both the upper pouch and lower pouch ha(e intestines comin" from it. :. an be done in multiple ways. Sur"eons ha(e "otten creati(e to ha(e namin" ri"hts to new ways of attachin" intestines. iii. 2eads to mar)ed reduction in stomach (olume. c. Ciliopancreatic bypass: i. $ttach end of the small intestine to middle part of the stomach, so food s)ips half of the stomach, the pancreatic ducts and nearly all of the small intestine. 3. >uide to selectin" treatment for obesity ( &:8;): -%I: 1?.1F(= 1>.1=(= 5B.56(= 5?.5=(= G6B +ith comorbidities ! ! ;. +ith comorbidities +ith comorbidities ! J J ! J J +ith comorbidities J J +ith comorbidities

Cenefits of intentional wei"ht loss ( &:A6): a. <ost of physical abnormalities impro(e. b. omorbidities decrease. c. =(erall mortality decreases (###N945). d. $(era"e follow up :4.A years (see lecture for what in the world he means by follow up[li)ely continuin" wei"ht loss`) d( Su+.clinical In)lammatory State: i. $dipose tissue is an acti(e, dynamic tissue that produces cyto)ines (%N0, *2!6, *2!:, *2!8), chemo)ines and steroid hormones.

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ii. *ncreased cyto)ine and chemo)ine presence from adipose tissue in obese patients leads to a chronic sub!clinical inflammatory state. :. $symptomatic. G. Hi"h le(els of circulatin" !reacti(e protein. NUTRITION C%+ st&s Sect !" %eta+olism o) 3itamins (2N 2ippincotts Ciochemistry 3th ed. TSorry 2illy. Iou are replaced.U, #N#obbins Lth ed, #1CN#hoades 1 Cell, &Ncoursepac)) *ma"e courtesy of 0irst $id:

%odi)ied Ro++ins Ta+le =.11 .. ,itamins: %aHor #unctions and *e)iciency Syndromes (#3;4 1 0irst $id) ,itamin Acti3e #orm Fat-Soluble (ADEK) Kitamin $ !#etinal !#etinol !#etinoic $cid $ component of (isual pi"ment (retinal) <aintenance of speciali/ed epithelia (mucus!secretin" and pancreatic) <aintenance of resistance to infection $ntio'idant Kitamin D :,G;!(=H)G D9 (calcitriol) Ni"ht blindness, 'erophthalmia, blindness S,uamous metaplasia Kulnerability to infection, particularly measles =ther s': dry s)in #unctions *e)iciency Syndromes

DG 1 D9 are not acti(e; 0acilitates intestinal absorption of calcium and phosphorus and #ic)ets in children minerali/ation of bone =steomalacia in adults Spinocerebellar de"eneration, muscle wea)ness, a fra"ility erythrocytes (hemolytic anemia)

$lpha!tocopherol Kitamin . Kitamin P !<enadione <a?or antio'idant; sca(en"es free radicals

ofactor in hepatic "amma!carbo'ylation of Cleedin" diathesis

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,itamin

Acti3e #orm !<ena,uinone !&hyllo,uinone

#unctions "lutamic acid residues on procoa"ulantsb factors ** (prothrombin), K**, *Q, and Q; and protein and protein S

*e)iciency Syndromes

Water-Soluble (Bs & C) Kitamin C: (thiamine) Kitamin CG (ribofla(in) N$DJ, N$&&J Niacin (C9) %hiamine pyrophosphate (%&&) 0<N, 0$D oen/yme in decarbo'ylation reactions Dry and wet beriberi, +ernic)e syndrome, `Porsa)off syndrome; commonly seen in alcoholics

on(erted to coen/ymes fla(in $ribofla(inosis, cheilosis, mononucleotide (0<N) and fla(in adenine stomatitis, "lossitis, dermatitis, dinucleotide (0$D), cofactors in o'idation corneal (asculari/ation 1 reduction (e.". 0$DHG) *ncorporated into nicotinamide adenine dinucleotide (N$D) and N$D phosphate (N$D&), in(ol(ed in a (ariety of redo' reactions; deri(ed from tryptophan (need (it. C6 for synthesis) &ella"rabthree cD-sc: dementia, dermatitis, diarrhea (3th DNdeath)

Kitamin C6 (pyrido'ine)

&yrido'al phosphate

Deri(ati(es (e.". pyrido'al phosphate) ser(e as coen/ymes in many intermediary heilosis, "lossitis, dermatitis, reactions (e.". transamination, peripheral neuropathy, sideroblastic decarbo'ylation reactions); needed for anemia, hyperirritability synthesis of niacin from tryptophan

Kitamin C:G (cobalamin)

!<ethylcobalamin #e,uired for normal folate metabolism and ombined system disease !Deo'yadenosyl DN$ synthesis; cofactor for homocysteine (me"aloblastic pernicious anemia cobalamin methyltransferase (transfers methyl "roups and de"eneration of posterolateral as methylcobalamin); methymalonyl spinal cord tracts) o$succinyl o$ <aintenance of myelini/ation of spinal cord tracts

Kitamin (ascorbic acid)

$scorbic acid

$ntio'idant; Ser(es in many o'idation! reduction (redo') reactions and hydro'ylation of colla"en on(erted to tetrahydrofolate (%H0); .ssential for transfer and use of :!carbon units in DN$ synthesis

Scur(y <e"aloblastic anemia, neural tube defects; most common (itamin deficiency in the @.S.; most common in pregnancy and alcoholics No none'perimental syndrome reco"ni/ed (DpanE N throu"hout diet; found in many foods) No clearly defined clinical syndrome (also in many foods); deficiency can be induced by e'cessi(e in"estion of raw e""s (a(idin binds biotin)

%H0 0olate (CA)

&antothenic acid (C;)

oen/yme $

*ncorporated in coen/yme $ (cofactor for acyl transfers) and fatty acid synthase

Ciotin (CL; Kit H)

.n/yme!bound biotin ofactor in carbo'ylation reactions

=Note: The most important column to #now in this table is the active form of the vitamin> since that?s what they are metaboli@ed to! 5since this section is titled metabolism of vitamins!7

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,itamins 8ith %ost Ris/ o) ToEicity Syndromes (Kitamin .'cess; i.e. they ha(e a %olerable @pper 2e(el of *nta)e Tsee belowU) ,itamin ToEicity Symptoms (0irst $id) Kitamin C9 (Niacin) 0acial flushin" (hi"h doses for hyperlipidemia) Kitamin C6 (pyrido'ine) Neurolo"ic symptoms (29L8) Kitamin $ $rthral"ia, fati"ue, H$, s)in chan"es, alopecia, Teratogenic (cleft palate, cardiac abnormalities) thus, need pre"nancy test prior to use for se(ere acne Kitamin D Hypercalcemia, hypercalcuria, loss of appetite, stupor; seen in sarcoidosis "bsorption A 8torage B 3eneral $omments from 1irst "id 0at soluble (itamins $bsorption dependent on "ut (ileum) and pancreas (0irst $id) %o'icity more common than water!soluble (itamins because they are stored inBaccumulate in fat Deficiency seen with "ut malabsorption syndromes (steatorrhea 7 cystic fibrosis, sprue) +ater soluble (itamins $ll wash out easily from body e'cept C:G and folate, which are stored in the li(er "bsorption 8ite A 1ood 8ources of :itamins Note: *m not sure how much of this well need to )now for this domain (s. the ne't domain. <odified %ables G6.8 1 G6.A #1C;GG!G3 ,itamin Fat-Soluble (ADEK) Kitamin $ Kitamin D Kitamin . Kitamin P Water-Soluble (Bs & C) ereal, "rains Kitamin C: (thiamine) Oe?unum; 2ow concentrationacti(e, carrier! mediated process Hi"h concentrationpassi(e diffusion $cti(e transport in pro'imal small intestine Small intestine; 2ow concentrationNaJ dependent, carrier!mediated, facilitated transport Hi"h concentrationdiffusion Cutter, whole mil), cheese, beta!carotene (plant sources li)e carrots) (it. D fortified mil)Byo"urtB soy mil)Boran"e ?uice, @K li"ht >reen plants, e"" yol), mil), meat >reen (e"etables; >* flora Small intestine; passi(e Small intestine; passi(e Small intestine; passi(e 0rom diet 7 upper small intestine; acti(e 0rom >* flora ! Small intestine; passi(e #ood Sources Site and %ode o) A+sorption

Kitamin CG (ribofla(in)

Dairy products <eat

Niacin (C9)

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,itamin Kitamin C6 (pyrido'ine) Kitamin C:G (cobalamin) Kitamin 0olate (CA) &antothenic acid (C;) <any foods Ciotin (CL; Kit H)

#ood Sources <eat, whole "rain cereals, dairy products $nimal products 7 dairy, e""s, fish

Site and %ode o) A+sorption Small intestine; passi(e diffusion %erminal ileum; acti(e transport in(ol(in" bindin" to intrinsic factor $cti(e transport by the ileum Oe?unum; NaJ!dependent facilitated transport Small intestine; NaJ dependent acti(e transport; must be con(erted to its free form for absorption Small intestine; free form absorbed passi(ely. *f bound to protein in foods, proteolysis is needed for absorption

(ascorbic acid) 0ruits 1 (e" Dar) "reen leafy (e"etables, fortified cereals 1 "rains, beans <ost foods

Note: 2i(er is hi"h in pretty much all (itamins 1 minerals -asal meta+olic rate4 energy eEpenditure4 thermogenesis Christa$s Section +ei"ht is determined by *N&@% (foodBener"y) of calories (s. @TP@T 0energy eEpenditure2 & p. :8G :. +ei"ht "ain inputHoutput; wei"ht loss inputMoutput G. $ deficit of d9,;44 )cal is needed to lose : lb of body fat %o lose one pound per wee), this would be a deficit of ;44)calBday Kice (ersa for wei"ht "ain Note: *n real life, this is actually an o(er"enerali/ation 9. See more in nutrition 1 obesity section This section is a summary o) energy eEpenditure 0i(e( @TP@T2 IN D THISJJJ Energy eEpenditure 0EE2 includes a person$s 5 aspects: 1B +asal meta+olic rate 0a(/(a( resting energy eEpenditure2 FB.>?K EE -B thermal e))ect o) )ood 'BK EE 3B physical acti3ity le3el '?.5BK EE -asal meta+olic rate 0-%R2 a/a resting energy eEpenditure 0REE2 a/a resting meta+olic rate 0R%R2 0!5?=.5FB2 o %he ma?ority of ener"y e'penditure ( &:8G) o .ner"y needed to carry out normal body functions (e.". respiration, blood flow, ion transport) Thermic e))ect o) )ood 0TE#2 o *ncreased ener"y e'penditure that occurs durin" di"estion 1 absorption of food &roduction of heat may increase up to 945 abo(e restin" le(el Physical Acti3ity o o a muscle mass a .. <uscle acti(ity pro(ides the "reatest (ariation in ener"y e'penditure $ sedentary person may need 94!;45 more calories than their C<# while a hi"hly acti(e person may need :445 or more calories abo(e their C<#

Nutrition reLuirements o) healthy children7adolescents7adults 0pregnant and non.pregnant2 Christa$s Section

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$alories alories in foods ( &:89) arbohydrates 3 )calB"ram &rotein 3 )calB"ram 0at A )calB"ram $lcohol L )calB"ram .ner"y (calories) in food =N2I come from macronutrients (carbs, protein, fat)[.and alcohol, N=% (itamins and minerals (those health food stores lie\) Estimated Energy ReLuirements N estimated ener"y inta)e predicted to maintain ener"y balance (29;8) o Cased on a"e, "ender, wei"ht, hei"ht, physical acti(ity le(el o Difficult to measure due to differences in "enetics, body composition, metabolism, and indi(idual beha(ior Estimated Energy ReLuirements 0EER2 )or 0non.pregnant2 adults (%he ,uic) n dirty calculation 7 easy to use clinically) ta)es into account body wei"ht and physical acti(ity le(el Deight "oal !o8 Acti3ity !e3el %oderate Acti3ity High Acti3ity !e3el !e3el 2ose wei"ht :; )calB)" G4 )calB)" G; )calB)" <aintain wei"ht (i.e. G4 )calB)" G; )calB)" 94 )calB)" estimated nutritional needs) >ain wei"ht G; )calB)" 94 )calB)" 9; )calB)" o Note that if body wei"ht is e, caloric needs will also e due to less body mass. %hus, to )eep losin" wei"ht, a person will li)ely need to restrict calories more so than when they be"an to lose wei"ht. %his is reflected in the abo(e estimated re,uirements. @sin" ..# with obese and o(erwei"ht @sually the actual body wei"ht is substituted for :) $d?usted body wei"ht (lower than actual, but abo(e their DidealE wei"ht) or G) %heir Dideal body wei"htE for their hei"ht o 0I*: +omens ideal wei"ht is :44lbs for ; J ;lbsBinch of hei"ht o ..". ;;E N :44 J (;S;) N :G; lbs. <en 7 ideal wei"ht is :46 lbs for ; J 6lbsBinch of hei"ht

-ietary (eference )nta#es 5-()s7 B :itamins and minerals 5/C%D7 Different (itamins 1 minerals use different (D#*s). <ost nutrients ha(e an .$# and correspondin" #D$. <ost are set by a"e 1 "ender. &re"nancy 1 lactation would chan"e the estimated needs. Estimated A3erage ReLuirement 0EAR2: $(era"e daily nutrient inta)e le(el estimated to meet the re,uirement of one half of the healthy indi(iduals in a particular life sta"e 1 "ender "roup Recommended *ietary Allo8ance 0R*A2: $(era"e daily nutrient inta)e le(el that is sufficient to meet the nutrient re,uirements of nearly all (AL!A85) the indi(iduals in a life sta"e and "ender "roup. o Set up to pro(ide a mar"in of safety for most indi(iduals AdeLuate Inta/e 0AI2: 8et in the place of an (-" if sufficient scientific e(idence is not a(ailable to calculate an .$# or #D$; based on nutrient inta)e of an apparently healthy "roup of people (e.". infant M3!6months, nutrient inta)e based on breast mil) as sole nutrition)

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Tolera+le @pper Inta/e !e3el 0@!2: %he highest a(era"e daily nutrient inta)e that is li)ely to pose no ris) of ad(erse health effects to almost all indi(iduals. *f inta)e is abo(e the @2, ris) of ad(erse e(ents increases (to'icities). See the e'amples of (itamin to'icities abo(e. SEE CHAR A HE E!D "F HIS SEC I"! WI H DRIs & RDAs 5) can?t scan straightE /olE7

!ote: The following specific recommendations come from online resources due to the fact that none of our resources contain the information. y apologies for not having a better source. The info. is from websites that appeared to be reliable> and the information seemed to be accurate from my recollections during undergrad.

$hildren (from <ayo linic) Nutrient

#emales &%ales 1.5 y7o 6.: y7o alories :,444!:,344 :,G44!G,444S arbohydrates ::9!:69 " :9;!GG8 " &rotein :9!;4 " 94!:4; " alcium ;44 m" 844 m" S depends on acti(ity le(el $polo"ies for the wide ran"es.

"dolescents Hi"her caloric 1 protein needs Hi"her calcium 1 iron needs hart of macronutrient needs: Nutrient =.'5 y7o alories G,4L: arbohydrates :94 " &rotein 93 " Pregnancy

#emales '6.': y7o G,968 :94 " 36 "

'=.5B y7o G,349 :94 " 36 "

=.'5 y7o G,GLA :94 " 93 "

%ales '6.': y7o 9,:;G :94 " ;G "

'=.5B y7o 9,46L :94 " ;6 "

<inimal a in caloric needs in the :st trimester aneed of calories in Gnd 1 9rd trimester o =nly d9;4!3;4 e'tra calories per day (not really Deatin" for twoE\) o =nly d:4 "Bday more protein a needs for iron (94 m"Bday; most important nutrient in prenatal (itamins)

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a le(els of folic acid (644 mc"Bday, especially important prior to conception 1 in the first trimester) $ssure diet is ade,uate in calcium, especially in the last trimester $ssure to drin) enou"h water $(oid hi"h doses of (itamin $, which are terato"enic. &renatal (itamins ha(e lower le(els of (itamin $ to pre(ent this to'icity effect +ei"ht "ain recommendations in pre"nancy Pre. Pregnancy Deight Corresponding -%I Suggested Deight "ain Normal +ei"ht :A.8!G3.A G;!9; lbs. @nderwei"ht M:A.8 (true cutoff is :8.;) G8!34 lbs. =(erwei"ht G;!GA.A :;!G; lbs. =bese H94 d:; lbs. %wins 7 recommended wei"ht "ain of 34lbs. %riplets 7 recommended wei"ht "ain of ;4lbs. &re"nant teen 7 needs enou"h nutrients to support her own "rowth in addition to the increased needs from pre"nancy. *ron needs are increased with both "rowth and pre"nancy.

/actation a d944!;44 caloriesBday ((arious sources differ in recommendations) a need protein :4 "Bday (as in pre"nancy) a folate needs (;44 mc"Bday) a need for (itamin $ (breastmil) is hi"h in (itamin $) a need for (itamin C:G $de,uate calcium inta)e $de,uate folic acid

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Me' ss&s Sect !" &Ncourse pac) #N#obbins DN re,uired nutritional D ><N>eriatric <edicine: $n e(idence based approach. Nutritional principles )or the management o) o+esity '( Nutritional principles )or the management o) o+esity: a. .mphasis needs to be on balancin" ener"y input and output. i. %reat all le(els of obesity with diet, as seen patholo"y of adipose tissue, obesity, treatment options. b. $n indi(iduals wei"ht is determined by: i. *nput: foodBener"y ii. =utput: calculated as: ( &:8G)

c.

d.

:. Casal metabolic rate (C<#) N 64!L;5 of total ener"y output. G. %hermal effect of food (%.0) N :45 of ener"y output. 9. &hysical acti(ity (&$) N :;!945 of ener"y output. iii. +ei"ht "ain: *nputH=utput. i(. +ei"ht loss: *nput M =utput. .stimatin" an indi(iduals ener"y re,uirements: i. %o maintain hisBher current wei"ht: :. 2ow physical acti(ity N G4 PcalB)". G. <oderate physical acti(ity N G; PcalB)". 9. Hi"h physical acti(ityN 94 PcalB)". ii. %here is a ;44 PcalBday to "ain or lose : pound in : wee) (about G wee)s per : )") ( &:83). #ecommended nutrient content for a 8eight reducing diet: i. alories: ;44!:,444 PcalBday reduction. :. Kery low calorie diets ( &:8L): a. aloric content: 844 PcalBday. b. &rotein: 4.84:.; "B)" (usin" the persons ideal body wei"ht) c. <ineralsB(itamins: use recommended daily allowances. d. ompletely replace food o(er :G!:6 wee)s. e. Diet must be medically super(ised. i. See &:8L for effects of these diets on metabolic parameters. :. *n short, they wor), but do not produce "reater lon"!term wei"ht loss than low calorie diets. ii. holesterol: M944 m"Bday. iii. 0iber G4!94 "Bday. i(. %a)e in: :. R;;5 carbohydrates. a. 2ow carbohydrate diets (ersus hi"h carbohydrate diets ( &:86): i. 2ow carbohydrate diets ha(e a "reater wei"ht loss at si' months, but not at one year. ii. *n some studies, low carbohydrate diets appear to ha(e a "reater wei"ht loss for up to two years. G. :;5 protein. 9. F 945 fat: a. 8!:45 saturated fatty acids. b. F:45 polyunsaturated fatty acids. c. F:;5 monounsaturated fatty acids.

Me' ss&s Sect !"

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Nutritional principles )or management o) dia+etes 1( Nutritional principles )or management o) dia+etes: a. Dietary ad(ice is indi(iduali/ed 7 there is no $merican Diabetes $ssociation Diet ( &GG:). b. Determine each indi(iduals caloric needs based on: i. Desire to "ainBlose wei"ht. ii. &hysical acti(ity le(el. c. &roportions used in diet ( &GG:): i. ;;!645: carbohydrates. ii. :;!G45: proteins. :. Should be less than 4.8 "B)" for indi(iduals with any de"ree of )idney disease. iii. M945: fat. :. ML5: saturated fats. i(. MG44 m"Bday: cholesterol. 0or your own )nowled"e: aloric (alues of common foods ( &GG:). #ood Caloric ,alue %il/4 5K )at 016B m!2 :;4 %il/4 s/im 016B m!2 84 %eat 05B g2 L; Apple 0small2 34 -read 0' slice2 L4 ,egeta+les 0'BBg2 G4!94 -acon 0' strip2 3; Rice coo/ed 0>?g2 L4 d. $D$ diabetic e'chan"es ( &GGG): i. oncept that food can be treated as interchan"eable based on the protein, fat and carbohydrate content. (i.e. you dont ha(e to prescribe e(ery patient to eat oatmeal and stea).) ii. arbohydrate content: :. @seful for control of post prandiol blood "lucose. G. Determine what each indi(iduals insulin to carbohydrate ratio should be. a. <ay (ary from ;!:; " carbohydrateBunit insulin. 9. alculate the "rams of carbohydrate eaten and ta)e insulin accordin"ly. iii. ommon carbohydrate content in food ( &GGG): Car+ohydrate content #ood 0per ser3ing2 Starch :;" #ruits :;" ,egeta+les ;" %il/ :G" Proteins none i(. 1iber: portion of carbohydrates that are not bro)en down durin" di"estion (indi"estible H=) ( &GG9). :. Soluble carbohydrates: pectins and "um. a. .'amples: oats, bran, fruits, (e"etables, dried beans. G. *nsoluble carbohydrates: cellulose, li"nin and hemicelluloses. a. .'amples: 8heat, bran, fruits, (e"etables, dried beans. b. (Ies[bran, fruits, (e""ies, and beans are listed as both in the course pac).) 9. #ecommended fiber to calories ratio: :3" fiberB:,444 calores.

Me' ss&s Sect !"

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Neuroendocrine regulation o) appetite 5( Neuroendocrine regulation o) appetite: a. omple' humoral and neural mechanisms control appetite and satiety (#). i. Neuralhumoral mechanisms respond to "enetic, nutritional, en(ironmental and psycholo"ical si"nals and tri""er a metabolic response throu"h stimulation of centers located in the hypothalamus. b. %erms worth )nowin": i. "nore*igenic: referrin" to a dru"Bneurohumoral chemical that causes a loss of appetite. ii. ,re*igenic: referrin" to a dru"Bneurohumoral chemical that stimulates appetite. c. an be di(ided into three components: (#) i. Peripheral 5afferent7 system: "enerates si"nals from (arious sites. :. <ain components: leptin and adiponectin from fat cells, "hrelin from stomach, peptide II (&II) from the ileum and colon and insulin from the pancreas. G. !eptin: a. :6!)D hormone synthesi/ed by fat cells from the ob "ene. i. #e"ulated by multiple post!transcriptional mechanisms that affect its synthesis, secretion and turno(er. b. 2eptin receptor (=C!#) is a product of the diabetes "ene. c. <ice deficient in leptin or the leptin receptor fail to sense the ade,uacy of fat stores and o(ereat, "ainin" wei"ht. i. &recise mechanism of how leptin is released to indicate an ade,uate amount of adipose tissue e'ists is not )nown. ii. Durin" dietin", leptin release decreases, enhancin" appetite. :. %hus, wei"ht lost is often re"ained. d. 0unction: i. Stimulates &=< B $#% neurons in hypothalamus to produce anore'i"enic neuropeptides (primarily <SH). ii. *nhibits N&IB$"#& neurons that produce ore'i"enic neuropeptides. iii. *n indi(iduals with stable wei"ht, &=< B $#% and N&IB$"#& are balanced. :. 2oss of function mutations in leptin causes early!onset se(ere obesity (#). a. #are. i(. $n abundance of leptin also stimulates physical acti(ity, heat production and ener"y e'penditure. :. %hermo"enesis is controlled by hypothalamic si"nals that increase the release of norepinephrine from sympathetic ner(e endin"s in adipose tissue. (. 2eptin can act as a pro!inflammatory cyto)ine and re"ulate hematopoiesis and lymphopoiesis. 9. Adiponectin: a. &roduced by adipocytes. i. omple'es in 9, 6 or more units to bind to $dipo#: (s)eletal muscle) and $dipo#G (li(er). b. 2e(els in blood are (ery hi"h, :,444' hi"her than other polypeptide hormones. c. 2e(els are lower in obese than in lean indi(iduals. d. 0unction: i. Directs fatty acids to muscle for o'idation, causin" a decrease in fat mass. ii. Decreases the influ' of fatty acids to the li(er and the total hepatic tri"lyceride content. iii. Decreases "lucose production in the li(er, causin" an increase in insulin sensiti(ity and protection a"ainst metabolic syndrome

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(discussed in patho"enesis of adipose tissue section, under obesity). "hrelin: a. &roduced in the stomach and in the arcuate nucleus of the hypothalamus. b. Has an ore'i"enic effect. c. <echanism: i. Cinds "rown hormone secreta"o"ue receptor (in hypothalamus and pituitary). ii. 2i)ely stimulates N&B$"#& neurons to increase food inta)e. d. 2e(els rise before meals and fall between : and G hours after eatin". i. 2on"!term in?ections in mice caused wei"ht "ain by increasin" caloric inta)e and reducin" ener"y utili/ation. ii. *n obese indi(iduals, postprandial suppression (after eatin") is decreased, leadin" to maintenance of obesity. ?( Peptide YY 0PYY2 a. Secreted from endocrine cells in the ileum and colon. b. 0unction: i. Stimulate &=< B $#% neurons in the hypothalamus causin" a decrease in food inta)e. c. &lasma le(els are low durin" fastin" and increase after food inta)e. i. *K administration of &II and reduces ener"y inta)e. ii. 2e(els "enerally increase after "astric bypass sur"ery. d. &rader!+*lli syndrome: i. 2e(els of &II are decreased, may contribute to hyperpha"ia and obesity. ii. "rcuate nucleus in the hypothalamus: processes and inte"rates neurohumoral peripheral sin"als and "enerates efferent si"nals. :. ontains two subsets of first!order neurons: a. :st: subset: &=< (proopiomelanocortin) and $#% (cocaine and amphetamine!re"ulated transcripts) neurons. i. .nhance ener"y e'penditure and wei"ht loss throu"h production of anore'i"enic W!melanocyte!stimulatin" hormone (<SH) and the acti(ation of melanocortin receptors 9 and 3 (< 9B3#). :. <utations in the melanocortin receptor 3 (< 3#) and downstream pathways leads to ;5 of cases of massi(e obesity (#). a. $nore'i"enic si"nal is not "enerated, so indi(iduals beha(e as thou"h they are undernourished. b. Specific case: insufficiency of brain!deri(ed neurotropic factor (CDN0), which is an important component of the downstream < 3# pathway, is associated with obesity in patients with DA"R syndrome. i. +ilms tumor, aniria, "enitor!urinary defects, mental retardation and obesity. ii. $lso influence wei"ht "ain throu"h acti(ation of I:B; receptors in secondary neurons. b. Gnd subset: neurons containin" N&I (neuropeptide I) and $"#& (a"outi! related peptide). i. #obbins doesnt elaborate on them. G. %hese first order neurons communicate with second order neurons. iii. Ffferent system: carries si"nals "enerated in second order neurons in the hypothalamus to control food inta)e and ener"y e'penditure. :. Hypothalamic system also communicates with the forebrain and midbrain centers to control the autonomic ner(ous system. 3.

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d.

=(erall summary of neuroendocrine re"ulation of appetite (#).

e.

Summary of si"nalin" pathways in appetite. (#)

BIOCHEMISTRY K#'es Sect !" P+!te " Met&0!' s( "e$ieD -rom +lo#E @ 3io#hem ,ata3olism: 3reaEdoDn o- amino a#ids 3y the remo$al o- the amine group and the resulting #ar3on sEeletons #an 3e #ompletely degraded to ,(2 $ia the T,A #y#le or used to synthesi=e glu#ose and Eeton 3odies 1'#ess amino a#ids are *(T stored< they are degraded to pro$ide energy or syntheti# intermediates. The nitrogen #an 3e used to synthesi=e nitrogen #ontaining #ompounds. &teps in #ata3olism: 1. remo$e amino groups 5*H29 and trans-er it to alpha8Eetogluterate to -orm glutamate 5transamination r'n9

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2. Another amino group is usually added to glutamate to maEe glutamine a. /lutamine: #arries 2 amino groups -or remo$al and is the primary UAT1" solu3le< nonto'i#< nitrogen #arrying intermediate e'ported 3y most #ells to the li$er 2. !us#le tissue also e'ports amino groups using alanine 53y transamination o- pyru$ate9< Dhi#h is also a Dater solu3le< non8to'i# nitrogen #arrier 2. /lutamine and alanine are #arried $ia the 3loodstream to the li$er to e'#rete the amino groups as urea Amino group "emo$al/)i'ation. @ a$oided the details so here is the nitty8gritty 1. Amino group +e(!/&'At+&"sfe+ stage: re;uires 2 en=ymes a. Aminotrans-erases8in #ytosol and mito#hondria o- all #ells 3. /lutamate dehydrogenase8 in mito#hondria 5mostly in li$er and Eidney9 #. Amino a#id o'idases7 minor role in amino group remo$al. 2. Amino group nitrogen f .&t !"Ae.c+et !" stage: 2 en=ymes re;uired< plus the urea #y#le a. /lutamine synthetase8 in mito#hondria in most tissues 5in #ytosol in 3rain9 3. /lutaminase8 in the li$er and Eidney #. ,ar3amoyl8phosphate synthetase 5-irst en=yme o- the urea #y#le9 d. Mrea #y#le8 urea is produ#ed in the li$er 0i$er: #ataly=ed the o'idati$e .1amination o- glutamate< the en=yme is inhi3ited in high energy states and a#ti$ated in loD energy states. /lutaminase is the primary en=yme. Peripheral tissues: #ataly=es the redu#ti$e amination o- alpha8Eetoglutarate to glutamate. The purpose is to )@\ nitrogen. /lutamine synthetase is the primary en=yme. Mrea ,y#le: ,ar3amoyl phosphate synthetase @ 5,P&@9 is the #ommitted step and is regulated. @t is a mito#hondrial en=yme. ! @t #on$erts T(\@, ammonia to *(*8T(\@, urea -or e'#retion and a##ounts -or S85H o- the nitrogen e'#retion ! Mrea is Dater solu3le and nonto'i# and is transported in the 3lood to the Eidney -or e'#retion ! +M*O 3lood urea nitrogen o @- +M* is high: Eidney is not e'#reting urea properly and there is some -orm o - Eidney -ailure/mal-un#tion e$en though the urea #y#le in the li$er is operating -ine. 5heart -ailure< dehydration< high protein diet #an also lead to in#reased +M*9 o @- +M* is loD: #an result -rom li$er disease/damage< #an also o##ur normally in the se#ond or third trimester o- pregnan#y Hyperammonemia 5ammonia to'i#ity9 ! s/s: nausea< $omiting< tremors< slurred spee#h< 3lurred $ision< mental retardation< later #oma< death ! )irst theory: neurotransmitter depri$ation 5glutamate9 ! &e#ond theory: energy depri$ation in the 3rain Hereditary Hyperammonemia ! geneti# de-e#ts are EnoDn in all 5 en=ymes o- the urea #y#le Dit o$erall o##urren#e o- around 1/20<000 3irths ! Hyperammonemia @: #ar3amoyl8phosphate synthetase @ de-i#ien#y ! Hyperammonemia @@: ornithine trans#ar3amoylase de-i#ien#y. !ost #ommon urea #y#le disorder. \8linEed re#essi$e. @nter-eres Dith the 3ody6s a3ility to eliminate ammonia. (-ten e$ident in the -irst -eD days o- li-e. 1'#ess #ar3amoyl phosphate is #on$erted to oroti# a#id. )indings: e'#ess oroti# a#id in the 3lood< loD +M*< symptoms o- hyperammonemia /lu#ose8alanine #y#le: alloDs the mus#le to shunt nitrogen in a non to'i# -orm to the li$er -or e'#retion. the li$er then uses the alanine in glu#oneogenesis )ate o- #ar3on sEeletons: ! all sEeleton 3reaEdoDn pathDays #on$erge to -orm % intermediates: o'aloa#etate< alpha8 Eetogluterate< pyru$ate< -umarate< su##inly ,oA< a#etyl ,oA and a#etoa#etyl ,oA

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! !

! !

Produ#ts used -or: synthesis o- glu#ose< lipids or Eetone 3odies< or energy produ#tion 3y #omplete o'idation in the T,A #y#le 2 Einds o- amino a#ids: o >etogeni# amino a#ids: ,A**(T 3e used to maEe glu#ose. (nly leu#ine and lysine are the stri#tly Eetogeni# amino a#ids. ,an 3e used to maEe Eetone 3odies. o /lu#ogeni#: yields any o- the a-orementioned produ#ts 5o'aloa#etate< et#9 e'#ept -or a#etyl ,oA and a#etoa#etyl ,oA. Pro$ide more than Gust the 2 #ar3on a#etyl ,oA so they #an pro$ide anet yield o- glu#ose. 18 amino a#ids 5all e'#ept leu#ine and lysine9 o !i'ed: yields produ#ts that are 3ot Eetogeni# and glu#ogeni#. @soleu#ine< phenylalanine< threonine< tryptophan< tyrosine. Phenylalanine is #on$erted to tyrosine 3y phenylalanine hydro'ylase. A de-i#ien#y in this en=yme O PhenylEetonuria 5P>M9. A 3uild up o- phenylalanine #auses mental retardation. !ust a$oid phenylalanine in diet and supplement Dith tyrosine. )urther doDn the same pathDay is homogentisate< Dhi#h is #on$erted to 48 maleyla#etoa#etate 3y homogentisate o'idase. .e-i#ien#y in this en=yme #an lead to al#aptonuria J3la#E urineK. @t turns 3la#E 3e#ause homogentisate 3uilds up and is rapidly o'idi=ed Dhen e'posed to the air. Autosomal re#essi$e.

Per 1st Aid: ! Amino a#id deri$ati$es: o Tryptophan nia#in *A.?/*A.P? o &erotonin melatonin o Histidine Histamine o /ly#ine porphyrin heme o Arginine #reatinine o Mrea o *itri# ('ide o /lutamate /A+A 5glutamate de#ar3o'ylase8re;uires +69 o /lutathioine o Phenylalanine tyrosine .opa .opamine *1 1pi thyro'ine melanin ! Al3inism: o ,ongenital de-i#ien#y o- either o- the -olloDing: Tyrosinase 5ina3ility to synthesi=e melanin -rom tyrosine9 autosomal re#essi$e .e-e#ti$e tyrosine transporters 5 de#reased amounts o- tyrosine and thus melanin. ,an result -rom a la#E o- migration o- neural #rest #ells 0a#E o- melanin results in an in#reased risE o- sEin #an#er. ! Homo#ystinuria: o 2 -orms o All three -orms result in e'#ess homo#ysteine and #ystine 3e#omes essential. o )indings: large in#rease in homo#ystein in the urine< !"< osteoporosis< tall stature< Eyphosis< lens su3lu'ation 5doDnDard and inDard9 and atheros#lerosis 5stroEe and !@9 ,ystathionine synthase de-i#ien#y 5t': de#rease methionine and in#rease #ysteine and in#rease +12 and -olate9 de#reased a--inity o- #ystathionine synthase -or pyrido'al phosphate 5t': large in#rease in $itamin +6 in diet9 Homo#ysteine mythltrans-erase de-i#ien#y ! ,ystinuria: hereditary de-e#t o- renal tu3ular amino a#id transporter -or #ysteine< ornithine< lysine< and arginine in the P,T o- the Eidneys o 1'#ess #ystine in the urine #an lead to the pre#ipitation o- #ystine Eidney stones 5#ystine staghorn #al#uli9

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Autosomal re#essi$e. #ommon 51:%0009. T': a#eta=olamide to alEalini=e the urine. ,ystine is made o- 2 #ysteines #onne#ted 3y a dou3le 3ond ! !aple &yrup urine disease: o +lo#Eed degradation o- +"A*,H1. amino a#ids 5@le< 0eu< Fal9 due to a de#reased alpha8Eetoa#id dehydrogenase. ,auses in#reased alpha8Eetoa#ids int eh 3lood< espe#ially 0eu. ,auses se$ere ,*& de-e#ts< !" and death. Mrine smells liEe maple syrup. 1st Aid mnemoni#: I Lo$e 6ermont maple syrup -rom maple trees Dith 0+&"c%esB Ke t%s sect !" C&+0!%#,+&tes `` @ Dill spare you all Dith another gly#olysis le#ture .. instead @6$e in#luded some great diagrams that are -ound in the >aplan +io#hem re$ieD 3ooE -or &tep 1. o

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L&#"es sect !" !ipid %eta+olism ((ia C#S physio) Ce"innin" in the Stomach 2ipids are bro)en into droplets by the mi'in" action of the stomach. %his increases the surface area for di"estion by pancreatic en/ymes 2in"ual lipases di"est some of the tri"lycerides mono"lycerides J fatty acids. Cut most of the in"ested lipids are di"ested in the intestine by pancreatic lipases. .nterin" the Small *ntestine

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 Cile acids emulsify lipids in the small intestine, increasin" the surface area for di"estion &ancreatic lipase hydroly/es lipids to fatty acids, mono"lycerides, cholesterol, and lysolecithin. %he hydrophobic products of lipid di"estion are solubili/ed in micelles by bile acids $bsorption from the intestine <icelles brin" the products of lipid di"estin" into contact with the absorpti(e surface of the intestine. %hen the fatty acids, mono"lycerides, and cholesterol diffuse across the luminal surface. =nce across the cells, the products of di"estion are reesterified to tri"lycerides, cholesterol ester, and phospholipids, and with apoproteins, form chylomicrons hylomicrons are then transported out of the intestinal cells by e'ocytosis, and then transferred to lymph (essels and are added to the bloodstream (ia the thoracic duct. &atholo"y of lipid absorption ! malabsorption of lipids leads to steatorrhea (the presence of e'cess fat in the stool). an be due to any of the followin": &ancreatic disease (pancreatitis, ystic 0ibrosis) 7 pancreas cannot synthesi/e ade,uate amounts of en/ymes necessary for lipid di"estion Hypersecreation of "astrin *leal resection Cacterial o(er"rowth Decreased number of intestinal cells 0ailure to synthesi/e apoprotein C (abetalipoproteinemia) GENETICS Jeffs Sect !" ARTICLE: US Newborn Screening System Guidelines II: Follow-u o! C"ildren# $i%gnosis# &%n%gement# %nd E'%lu%tion ()ART I# g* +-,+* .* Newborn screening is %n essenti%l %nd roducti'e re'enti'e public health program* In +,/0# t"e b%sis !or our current o ul%tion-b%sed systems o! screening newborns !or hemoglobinopathies# endocrine disorders# metabolic diseases# %nd infectious diseases beg%n wit" t"e &%ss%c"usetts PKU Newborn Screening )rogr%m* 0* Currently# e%c" st%te# t"e $istrict o! Columbi%# )uerto Rico# %nd t"e 1irgin Isl%nds screen %ll newborns !or PKU %nd congenital hypothyroidism# %nd most include ot"er in"erited disorders* 2* T"ese N3S rogr%ms were t"e !irst o ul%tion- b%sed screening rogr%ms !or genetic disorders %nd sign%led t"e integration o! genetic 4nowledge into public health rogr%ms* 5* C"ildren wit" s eci%l "e%lt" c%re needs %re de!ined %s t"ose w"o "%'e or %re %t ris4 !or % chronic physical# developmental# behavioral# or emotional condition %nd w"o %lso require "e%lt" %nd rel%ted services o! % ty e or %mount beyond t"%t re6uired by c"ildren gener%lly* /* 7istoric%lly# ser'ices !or c"ildren wit" s eci%l "e%lt" c%re needs "%'e been di!!icult !or !%milies to %ccess %nd !or ro'iders to coordin%te* F%milies "%'e "%d to n%'ig%te % m%8e o! org%ni8%tions# ro'iders# %nd geogr% "ic %nd !in%nci%l b%rriers* 9* T"e &C73 belie'es t"%t ser'ices !or c"ildren wit" s eci%l "e%lt" c%re needs s"ould be ro'ided wit"in t"e conte:t o! % medical home. %* &eeting t"is go%l re6uires t"%t (+- we de'elo %de6u%te provider networks %nd (.- we encour%ge collaborative roles between primary %nd subspecialist ro'iders* .* T"e 7um%n Genome )ro;ect resents o ortunities !or underst%nding %nd romoting "e%lt"# lowering mort%lity %nd morbidity r%tes# %nd re'enting dise%ses* %* 3y unco'ering % genetic b%sis !or most common dise%ses# e: %nded genetic ser'ices could be integr%ted bro%dly into ublic "e%lt" rogr%ms* 3. The .i2e arts o, a Ne4born $%reenin! $yste' a. Screening Testing of newborns. i. !iseases tested vary by state. 3. "ollow#up: Rapid location, follow-up, and referral of the screen-positive infant. i* Go%l: elimin%te or reduce t"e mortality# morbidity# %nd disabilities t"%t result !rom t"e disorders included in t"e screening %nel*

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ii* R% id !ollow-u o! %ll in!%nts wit" % <not norm%l= screening test result>including <borderline#= <unsatisfactory#= or <screen positive=>is cruci%l to !ul!illing t"is mission* iii* S"ort-term !ollow-u begins w"en t"e l%bor%tory obt%ins %n initi%l result t"%t is screen ositi'e %nd ends wit" % de!initi'e di%gnosis %nd document%tion t"%t % ro ri%te treatment "%s been initi%ted regardless of the family$s ability to pay. i'* Long-term !ollow-u begins wit" tre%tment %nd continues t"roug"out li!e* $. SCREEN-NEGATIVE (NORMAL) TEST RESULTS. A l%bor%tory re ort on e'ery in!%nt s"ould be sent to t"e in!%nt?s )7C) %nd@or birt"ing !%cility within % days o! recei t o! t"e s ecimen* $i. SCREEN-POSITIVE (ABNORMAL) TEST RESULTS. &ust ensure t"%t t"e in!%nt is loc%ted %nd broug"t into t"e di%gnostic %nd m%n%gement com onents o! t"e system in time to ensure optimal outcome and to prevent irreversible damage* +* Timely !ollow-u is im ort%nt !or %ll disorders but is especially urgent !or &SU$# g%l%ctosemi%# %nd CA7 bec%use t"ese disorders c%n be r% idly !%t%l* .* Legisl%tion %nd regul%tions '%ry# but most rogr%ms re6uire t"%t t"e in!%nt?s "e%lt" c%re ro'ider be noti!ied o! t"e test result* 'ii* Some mec"%nism s"ould be in l%ce to ensure t"%t % s%tis!%ctory s ecimen is recei'ed wit"in % re%son%ble time* Addition%l %ction s"ould be t%4en until % s%tis!%ctory s ecimen is recei'ed or t"e c%se is design%ted <lost to !ollow-u *= 'iii* Routine screening o! second s ecimens "el s t"e rogr%m %scert%in t"e r%te o! !%lse-neg%ti'e results on t"e initi%l screen# including biologic false#negative results* Second screens %re %lso '%lu%ble !or disorders in w"ic" t"e indicator metabolites rise rel%ti'ely slowly# suc" %s "omocystinuri%# tyrosinemi%# %nd some !orms o! "y er "enyl%l%ninemi%* #. !iagnosis Evaluation of the infant with a positive screening test to make a definitive diagnosis or exclude the disorder. i* A ositi'e screening result re6uires %ssessment o! t"e in!%nt by % 6u%li!ied "ysici%n %nd l%bor%tory in % time !r%me % ro ri%te !or t"e disorder* ii* L%bor%tory directors %nd tec"nic%l su er'isors must meet t"e tr%ining %nd e: erience re6uirements s eci!ied by t"e Clinic%l L%bor%tory Im ro'ement Amendment o! +,AA (CLIAAA-* A ro ri%te rotocols@e6ui ment must be used* iii* )ro!iciency tests s"ould be run %s quality control# %nd %ll o! t"ese di%gnostic tests s"ould meet current CLIA %nd st%tutory st%nd%rds* i'* &ost o! t"ese disorders %re %utosom%l recessi'e* T"ere!ore# family testing m%y r%ise concerns %bout %ternity %nd s"ould be discussed initially wit" t"e mother* $. Core tests %nd rocedures %re t"ose t"%t %re essenti%l to rapidly confirm % di%gnosis %nd to initiate treatment* Supplemental tests %nd rocedures m%y be needed to refine t"e diagnosis o! some c"ildren %nd !or t"e ur ose o! genetic counseling* d. &anagement Rapid planning and implementation of long-term therap . i* )%tients identi!ied t"roug" N3S usu%lly re6uire li!elong tre%tment* T"e go%l o! tre%tment is to %c"ie'e o tim%l "e%lt"# growt"# %nd de'elo ment* e. 'valuation !alidation of testing procedures, assessment of the efficienc of follow-up and intervention, and assessment of the benefit to the patient, famil , and societ . i* Rigorous determin%tion o! sensiti'ity# s eci!icity# %nd neg%ti'e redicti'e '%lue re6uires com lete %scert%inment o! !%lse-neg%ti'e results# w"ic" is not re%listic%lly %c"ie'%ble* ii* A'%il%ble d%t% %re incom lete bec%use studies %re still in rogress* T"e o'erriding concern reg%rding %ll %rts o! t"e system is rapid completion o! each rocess phase to ensure t"%t t"e c"ild recei'es appropriate care %s soon %!ter birt" %s ossible* L%bor%tory testing %nd medic%l inter'ention s"ould be cost#effective* T"is document re resents % consensus o! ro!ession%ls in medicine# genetics# %nd ublic "e%lt" w"o %re dedic%ted to t"e rinci le t"%t c"ildren wit" r%re %nd com le: "e%lt" roblems need s eci%li8ed# interdisci lin%ry l%bor%tory %nd clinic%l ser'ices* T"ese services s"ould be 'iewed %s complementary %nd consultative to rim%ry medic%l c%re*

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D&"s Sect !" &ummary o- 2nd Part o- !. ,onsult /eneti#s Arti#le 4 *eD3orn &#reening /uidelines 5pg. 148269 1. .iagnosis o- a positi$e s#reen: a. ,on-irmation o- diagnosis is the third step in *+& guidelines 3. Positi$e s#reening patients need to 3e e$aluated 3y a #ompetent physi#ian 5duh9 #. )or a positi$e s#reen< determine Dhether #hild had any 3lood trans-usions prior to the s#reen d. .iagnosti# la3s need to meet stri#t standards go$erning personnel< e;uipment< and pro#edures e. ,ore tests: Tests used to rapidly #on-irm a diagnosis and initiate treatment -. &upplemental tests: Msed to re-ine a diagnosis or -or geneti# #ounselling 2. .iagnosti# ,riteria -or #ertain diseases: *(T1: The article details dia)nostic criteria %or a lar)e nu$ber o% diseases8 5 a$ only su$$ari3in) in%or$ation %or the diseases encountered in this do$ain8 see article i% you want to learn about all the others a. ,ongenital 5primary9 hypothyroidism: i. !ost la3s us T4 as the initial s#reening test< -olloDed 3y a T&H test i- needed ii. .= has in#iden#e o- 1/2<5000 3irths DorldDide iii. @n M.&.< most #ommon in Hispani#s and *ati$e Ameri#ans i$. ,ore tests: T4< T2 uptaEe< T&H $. TaEe T4 sample more than 24 hours a-ter 3irth< to a$oid the T4 surge right a-ter 3irth $i. &upplemental Tests: &erum T+/< anti8thyroid pero'idase< anti8thyroid anti3odies< iodine uptaEe< 3one age $ii. Premature in-ants need di--erent s#reening standards< sin#e their T4 le$els are JDha#Eed outK 3. ,ongenital Adrenal Hyperplasia: i. @nitially s#reen in-ants -or ele$ated le$els o- 1%8hydro'yprogesterone 51%8(HP9< sin#e this is the pre#ursor hormone that 3uilds up due to 218hydro'ylase de-i#ien#y ii. (ther #ore tests in#lude serum sodium< potassium< #hloride< ,(2< glu#ose< and state o- gentilia iii. &upplemental tests in#lude #ortisol< testosterone< androstenedione< renin< aldosterone< 1. ,ould also #he#E the ,LP21 gene< Dhi#h en#odes 218hydo'ylase en=yme J)st "s Sect !" Department of Community Health, Newborn Screening for Cystic Fibrosis AND Important Update on Cystic Fibrosis Screening: All stuff "e already !no" C5 6# cystic fibrosis "ill be added to the current dried blood spot screening panel of )D disorders# <# 6 in &,7'' "hite ne"born infants &# autosomal recessive )# affects the e$ocrine glands of the lungs, liver, pancreas and digestive system 7# thic!, stic!y mucous "hich clogs the lungs leading to serious lung infections and can inhibit the pancreas from the production of digestive enzymes B# %he first test is the immunoreactive trypsinogen (.+%) test - measures trypsin- an enzyme produced in the pancreas that is transiently elevated in the blood of pancreatic insufficient C5 patients at birth# C# .f the initial test is positive -*NA screening test is done to detect C5 related mutations# D# Ne"borns "ith both an elevated .+% and an identified C5 mutation are then referred to the C5 Center for a s"eat chloride test# F# Er 4ust lic! them li!e the old days# (does medicade reimburse for thatL)

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