Physiology of the normal menstrual cycle Author Corrine K Welt, MD Section Editors William F Crowley, Jr, MD Amy B Middleman,

MD, MPH, MS Ed Deputy Editor Kathryn A Martin, MD Disclosures All topics are pdated as new e!idence "ecomes a!aila"le and o r peer re!iew process is complete# Literature review current through: $o! %&'%# ( This topic last updated: Apr '), %&'%# INT !D"#TI!N * +he normal menstr al cycle is a ti,htly coordinated cycle o- stim latory and inhi"itory e--ects that res lts in the release o- a single mature oocyte -rom a pool o- h ndreds otho sands o- primordial oocytes# A !ariety o- -actors contri" te to the re, lation o- this process incl din, hormones and paracrine and a tocrine -actors that are still "ein, identi-ied# +he cyclic chan,es in the ma.or pit itary and ,onadal hormones are ill strated in the -i, re /-i, re ' and -i, re %0# +he physiolo,y o- the normal menstr al cycle will "e disc ssed here# Detection o- o! lation and ltraso nd e!al ation o- the menstr al cycle are re!iewed separately# /See 12ltraso nd e!al ation o- the normal menstr al cycle1 and 1E!al ation o- the menstr al cycle and timin, o- o! lation1#0 P$ASES AND D" ATI!N !% T$E &ENST "AL #'#LE * By con!ention, the -irst day o- menses represents the -irst day o- the cycle /day '0# +he cycle is then di!ided into two phases3 -ollic lar and l teal#

+he -ollic lar phase "e,ins with the onset o- menses and ends on the day o- the l teini4in, hormone /5H0 s r,e# +he l teal phase "e,ins on the day o- the 5H s r,e and ends at the onset o- the ne6t menses#

+he a!era,e ad lt menstr al cycle lasts %7 to )8 days, with appro6imately '9 to %' days in the -ollic lar phase and '9 days in the l teal phase : ',%;# +here is relati!ely little cycle !aria"ility amon, women "etween the a,es o- %& and 9& years# <n comparison, there is si,ni-icantly more cycle !aria"ility -or the -irst -i!e to se!en years a-ter menarche and -or the last '& years "e-ore cessation omenses /-i, re )0 :';# <n ,eneral, menstr al=cycle len,th pea>s at a"o t a,e %8 to )& years and then ,rad ally declines so that women in their -orties ha!e sli,htly shorter cycles# Chan,es in intermenstr al inter!al are primarily d e to chan,es in the -ollic lar phase? in comparison, the l teal phase remains relati!ely constant :);# +he remainder o- this topic will re!iew the hormonal, o!arian, and endometrial chan,es that occ r d rin, the di--erent phases o- the menstr al cycle# EA L' %!LLI#"LA P$ASE * +he early -ollic lar phase in h mans is the time when the o!ary is the least hormonally acti!e, res ltin, in low ser m estradiol and pro,esterone concentrations /-i, re '0# @elease -rom the ne,ati!e -eed"ac> e--ects o- estradiol, pro,esterone, and pro"a"ly l teal phase inhi"in A res lts in a late l tealAearly -ollic lar phase increase in ,onadotropin=releasin, hormone /Bn@H0 p lse -reC ency and a s "seC ent increase in ser m -ollicle=stim latin, hormone /FSH0 concentrations o- appro6imately )& percent : 9;# +his small increase in FSH secretion appears to "e reC ired -or the recr itment o- the ne6t cohort o- de!elopin, -ollicles, one o- which will "ecome the dominant and ltimately o! latory -ollicle d rin, that cycle : 8=D;# Ser m inhi"in B concentrations, secreted "y the recr ita"le pool o- small -ollicles, are ma6imal at this time and may play a role in s ppressin, the FSH rise at this time in the cycle / -i, re 90 :7;# +here is also a rapid increase in 5H p lse -reC ency at this time, -rom one p lse e!ery -o r ho rs in the late l teal phase to one p lse e!ery E& min tes in the early -ollic lar phase : E;# +he early -ollic lar phase is also associated with a niC e ne roendocrine phenomenon3 slowin, or cessation o- 5H p lses d rin, sleep that does not occ r at other times o- the menstr al cycle /-i, re 80# How this occ rs in not >nown# !varies and endometrium * F!arian ltrasono,raphy has demonstrated that the o!ary is C iescent in the early -ollic lar phase e6cept -or the occasionally !isi"le resol!in, corp s l te m -rom the pre!io s cycle# +he endometri m is relati!ely indistinct d rin, menses and then "ecomes a thin line once menses is complete# <t is normal to see small -ollicles o- ) to 7 mm in diameter at this time# /See 12ltraso nd e!al ation o- the normal menstr al cycle1#0 &ID(%!LLI#"LA P$ASE * +he modest increase in FSH secretion in the early -ollic lar phase ,rad ally stim lates -ollic lo,enesis and estradiol prod ction, leadin, to pro,ressi!e ,rowth othe cohort o- -ollicles selected that cycle# As se!eral -ollicles initially ,row to the antral sta,e, their ,ran losa cells hypertrophy and di!ide, prod cin, increasin, ser m concentrations o- -irst estradiol !ia FSH stim lation o- aromatase and then inhi"in A -rom the ,ran losa cells in the o!aries# +he increase in estradiol prod ction -eeds "ac> ne,ati!ely on the hypothalam s and pit itary, res ltin, in s ppression o- mean ser m FSH and 5H concentrations as well as the 5H p lse amplit de# <n comparison, the Bn@H p lse ,enerator speeds p sli,htly to a mean 5H p lse -reC ency o- a"o t one per ho r /!ers s one per E& min tes in the early -ollic lar phase0# Bn@H stim lation is pres ma"ly d e to release o- ne,ati!e -eed"ac> e--ects o- pro,esterone -rom the pre!io s l teal phase# /See 1Physiolo,y o- ,onadotropin=releasin, hormone1#0 !varian and endometrial changes * Within a"o t se!en days -rom the onset o- menses, se!eral E to '& mm antral -ollicles are !isi"le on o!arian ltrasono,raphy# +he risin, ser m estradiol concentrations res lt in proli-eration o- the terine endometri m, which "ecomes thic>er, with an increase in the n m"er o- ,lands and the de!elopment o- a 1triple stripe1 pattern on ltraso nd /-i, re %0 :'&;# /See 12ltraso nd e!al ation o- the normal menstr al cycle1#0 LATE %!LLI#"LA P$ASE * +he ser m concentrations o- estradiol and inhi"in A increase daily d rin, the wee> "e-ore o! lation d e to release -rom the ,rowin, -ollicle# Ser m FSH and 5H concentrations are -allin, at this time d e to ne,ati!e -eed"ac> e--ects o- estradiol and perhaps other hormones released -rom the o!ary / -i, re '0# As the dominant -ollicle is selected, FSH ind ces 5H receptors in the o!ary and increases o!arian secretion o- intra terine ,rowth -actors s ch as ins lin=li>e ,rowth -actor=< /<BF=<0# !varian) endometrial) and cervical mucus changes * By the late -ollic lar phase, a sin,le dominant -ollicle has "een selected, while the rest o- the ,rowin, cohort o- -ollicles ,rad ally stop de!elopin, and nder,o atresia# +he dominant -ollicle increases in si4e "y a"o t % mm per day ntil a mat re si4e o- %& to %G mm is reached# /See 12ltraso nd e!al ation o- the normal menstr al cycle1#0 @isin, ser m estradiol concentrations res lt in ,rad al thic>enin, o- the terine endometri m and an increase in the amo nt and 1strin,iness1 /Spinn"ar>eit0 o- the cer!ical m c s# Many women are a"le to detect this chan,e in m c s character# St dies o- cer!ical m c s samples d rin, the menstr al cycle demonstrate a late -ollic lar=phase pea> in the m cin protein M2C8B that may "e important -or sperm transit to the ter s :'';# L"TEAL P$ASE: &ID(#'#LE S" *E AND !+"LATI!N * Ser m estradiol concentrations contin e to rise ntil they reach a pea> appro6imately one day "e-ore o! lation# +hen, a niC e ne roendocrine phenomenon occ rs3 the mid=cycle s r,e :'%;# +he s r,e represents a switch -rom ne,ati!e -eed"ac> control o- 5H secretion "y o!arian hormones /s ch as estradiol and pro,esterone0 to a s dden positi!e -eed"ac> e--ect, res ltin, in a '&=-old increase in ser m 5H concentrations and a smaller rise in ser m FSH concentrations /-i, re '0# <n addition to estro,en and pro,esterone, other o!arian -actors contri" te to the 5H s r,e, "eca se it cannot "e recreated simply "y administerin, estro,en and a pro,estin to women in the early to mid=-ollic lar phase to achie!e ser m concentrations similar to those at the mid=cycle :');# At this time the -reC ency o- 5H p lses contin es to "e appro6imately one per ho r, " t the amplit de o- the 5H p lses increases dramatically# +he switch -rom ne,ati!e to positi!e -eed"ac> o- 5H release is poorly nderstood# An increase in the n m"er o- pit itary Bn@H receptors may contri" te " t there is pro"a"ly no chan,e in Bn@H inp t to the pit itary :'9;# !varian changes * +he 5H s r,e initiates s "stantial chan,es in the o!ary# +he oocyte in the dominant -ollicle completes its -irst meiotic di!ision# <n addition, the local secretion o- plasmino,en acti!ator and other cyto>ines reC ired -or the process o- o! lation is increased :'8,'G;# +he oocyte is released -rom the -ollicle at the s r-ace o- the o!ary appro6imately )G ho rs a-ter the 5H s r,e# <t then tra!els down the -allopian t "e to the terine ca!ity# +here is a close relation o- -ollic lar r pt re and oocyte release to the 5H s r,e? as a res lt, meas rements o- ser m or rine 5H can "e sed to estimate the time o- o! lation in in-ertile women# /See 1E!al ation o- the menstr al cycle and timin, o- o! lation1#0 E!en "e-ore the oocyte is released, the ,ran losa cells s rro ndin, it "e,in to l teini4e and prod ce pro,esterone# Pro,esterone acts rapidly to slow the p lse ,enerator so that 5H p lses "ecome less -reC ent "y the termination o- the s r,e# Endometrium * +he ,rad ally increasin, ser m pro,esterone concentrations ha!e a pro-o nd impact on the endometrial linin,, leadin, to cessation o- mitoses and 1or,ani4ation1 o- the ,lands :'D;# +his chan,e can "e detected on ltrasono,raphy relati!ely soon a-ter o! lation3 the 1triple stripe1 ima,e is lost and the endometri m "ecomes more ni-ormly "ri,ht / -i, re %0 :'&;# /See 12ltraso nd e!al ation o- the normal menstr al cycle1#0 &IDDLE T! LATE L"TEAL P$ASE * Pro,esterone secretion -rom the corp s l te m :'7; res lts in ,rad ally risin, pro,esterone concentrations in the middle to late l teal phase# +his leads to pro,ressi!e slowin, o- 5H p lses down to one p lse e!ery -o r ho rs# P lses o- pro,esterone occ r soon a-ter these slow 5H p lses# As a res lt, there can "e si,ni-icant e6c rsions in ser m pro,esterone concentrations d rin, the l teal phase /-i, re G0 :'E;# <nhi"in A is also prod ced "y the corp s l te m, and ser m concentrations o- inhi"in A pea> in the mid=l teal phase# <nhi"in B secretion is !irt ally a"sent d rin, the l teal phase /-i, re 90# Ser m leptin concentrations are hi,hest in the l teal phase :%&;# /See 1Physiolo,y o- leptin1#0 <n the late l teal phase, a ,rad al decrease in 5H secretion res lts in a ,rad al -all in pro,esterone and estradiol prod ction "y the corp s l te m in the a"sence o- a -ertili4ed oocyte# <-, howe!er, the oocyte "ecomes -ertili4ed, it implants in the endometri m se!eral days a-ter o! lation# +he early em"ryo "e,ins to ma>e chorionic ,onadotropin, which maintains the corp s l te m and pro,esterone prod ction# Endometrial changes * +he decline in estradiol and pro,esterone release -rom the resol!in, corp s l te m res lts seC entially in the loss o- endometrial "lood s pply, endometrial slo ,hin,, and the onset o- menses appro6imately '9 days a-ter the 5H s r,e# Menses is a relati!ely imprecise mar>er o- hormonal e!ents in the menstr al cycle, since there is considera"le inter=indi!id al !aria"ility in the relationship "etween the onset o- endometrial slo ,hin, and the -all in ser m hormone concentrations d rin, the l teal phase /-i, re %0 :9;#

<n response to -allin, corp s l te m steroid prod ction, the hypothalamic=pit itary a6is is released -rom ne,ati!e -eed"ac> and FSH le!els rise, there"y "e,innin, the ne6t cycle# S"&&A ' * By con!ention, the -irst day o- menses represents the -irst day o- the cycle /day '0# +he cycle is then di!ided into two phases3 -ollic lar and l teal#

+he -ollic lar phase "e,ins with the onset o- menses and ends on the day o- the l teini4in, hormone /5H0 s r,e# +he l teal phase "e,ins on the day o- the 5H s r,e and ends at the onset o- the ne6t menses#

+he a!era,e ad lt menstr al cycle lasts %7 to )8 days, with appro6imately '9 to %' days in the -ollic lar phase and '9 days in the l teal phase# +here is relati!ely little cycle !aria"ility amon, women "etween the a,es o- %& and 9& years# <n comparison, there is si,ni-icantly more cycle !aria"ility -or the -irst -i!e to se!en years a-ter menarche and -or the last '& years "e-ore cessation omenses /-i, re )0# <n ,eneral, menstr al=cycle len,th pea>s at a"o t a,e %8 to )& years and then ,rad ally declines so that women in their -orties ha!e sli,htly shorter cycles# Chan,es in intermenstr al inter!al are primarily d e to chan,es in the -ollic lar phase? in comparison, the l teal phase remains relati!ely constant