Eixo hipotlamo-hipfise-adrenal

Resumindo:

O eixo Hipotlamo Hipfise Adrenal (HHA) atua na regulao de respostas a

circunstncias adversas, modulando o metabolismo de carboidratos, protenas, e
lipdios, proporcionando excitabilidade do crtex cerebral, alm de produzir efeitos anti-
inflamatrios e supresso da resposta imune. (Guyton & Hall, 2006; Costanzo, 2011,
Oakley & Cidlowski, 2011).

As diversas atividades mediadas pelo eixo HHA ocorrem em resposta aos hormnios
esterides, estes secretados pela glndula adrenal (Conceio 2012). O Eixo HHA
ativado por estmulos estressantes, como o jejum, o que leva a liberao de
corticotrofina (CRH) pelo hipotlamo (o controlador de todas as secrees hipofisrias),
estimulando assim, a sntese e secreo de adrenocorticotrofina (ACTH) pela adeno
hipfise. (Conceio 2012). Ao cair na corrente sangunea, o ACTH passa a atuar no
crtex adrenal, proporcionando a sntese e liberao de hormnios esterides, como os
glicocorticoides (GC), sintetizado na zona fasciculada (Charmandari, 2005; Plotsky,
1989).

O hipotlamo e glndula hipfise formam uma unidade que exerce controle sobre a
funo de vrias glndulas endcrinas perifricas, incluindo as adrenais. No hipotlamo,
alm dos elementos neurais caractersticos, encontramos neurnios peptidrgicos,
especializados em secretar hormnios. Esses neurnios apresentam as mesmas
propriedades eltricas das outras clulas nervosas, inclusive a deflagrao de potenciais
quando estimulados: o potencial de ao gerado no corpo celular trafega at a
terminao do axnio onde, por determinar influxo de Ca++, desencadeia a secreo de
hormnios armazenados em vesculas.
Os neurnios hipotalmicos que se relacionam com a adeno-hipfise constituem o
sistema parvicelular ou tbero-infundibular. Entre eles, esto os neurnios secretores de
CRH (hormnios liberados de corticotrofina), cujos corpos celulares encontram-se no
ncleo paraventricular do hipotlamo (NPV). Desta regio, partem axnios que
convergem para a eminncia mediana, onde o CRH secretado. Devido existncia de
um sistema vascular altamente especializado, que conecta a eminncia mediana
adeno-hipfise (sistema porta hipotlamo-hipofisrio), o CRH atinge a adeno- hipfise
em altas concentraes. Em humanos, cerca de 80 a 90% do suprimento sanguneo da
adeno-hipfise dado pelos vasos porta-hipofisrios longos. Por meio dessa via, altas
concentraes dos hormnios neuro-hipofisrios atingem a adeno-hipfise, modulando
localmente a liberao de hormnios, incluindo o ACTH.

O CRH regula a produo e secreo de hormnios derivados da POMC (pr-

piomelanocortina) POMC. A POMC um precursor de pr hormonios produzidos
pelos corticotrofos da adeno-hipfise.

A protena resultante ento processada, gerando ACTH (hormnio

adrenocorticotrfico) e outros produtos (as melanocortinas). Alguns outros peptdeos,
como a ocitocina e a vasopressina, tambm so estimuladores de secreo de ACTH;
eles no so to potentes agindo isoladamente, embora apresentem efeitos marcantes
quando associados ao CRH (especialmente a vasopressina). O CRH circula no sangue
ligado a protenas transportadoras, no estado livre, o CRH se liga a receptores
especficos localizados na membrana celular das clulas corticotrficas, o que
provocava aumento da gerao intracelular de AMPc e consequente sntese e
processamento da POMC, com liberao de ACTH.
O receptor de CRH tambm se encontra expresso em outras regies do SNC, como
crtex, sistema lmbico, bulbo e medula espinhal, o que explica certos efeitos centrais
do CRH como estimulao da atividade simptica e inibio do comportamento de
ingesto alimentar e sexual, caractersticas do estresse. A secreo de ambos as
hormnios (CRH e ACTH) controlada pelo produto final do eixo HHA,
glicocorticoides, que exercem o mecanismo de retroalimentao negativa tanto sobre a
hipfise quanto sobre o hipotlamo.

Vale ressaltar que o bed nucleus da estria terminal (BST) a nica regio do sistema
lmbico que apresenta projees diretas sobre os neurnios CRH-rgicos do hipotlamo.
O BST, por sua vez, recebe projees da amgdala, hipocampo e ncleo septal,
sugerindo que ele seja um centro integrativo da fundamental importncia para a
transmisso de informaes lmbicas ao NPV. Assim, todas essas aferncias sinalizam
impulsos gerados por estresse, hipovolemia, hipxia, hiperosmolaridade e dor.
Alm disso, como em outros sistemas fisiolgicos, o eixo HPA apresenta ritmicidade
circadiana, dada por padres internos gerados no ncleo supraquiasmtico, com o
auxlio de pistas externas (quantidade de luz na retina). Atualmente j se sabe que o
padro alimentar um forte temporizador do eixo HPA, de modo que se o horrio de
alimentao for invertido para o perodo de inatividade, tambm se inverter o padro
de secreo de cortisol/corticosterona normalmente observado.
Como j mencionado, a hipfise uma glndula endcrina localizada em intima relao
anatmica com o hipotlamo, mantendo-se conectada a este atravs da haste hipofisria
ou pednculo hipofisrio. Em humanos, a hipfise composta basicamente por 2
pores, como j dito: 1) a hipfise anterior ou adeno-hipfise e a 2) hipfise posterior
ou neuro-hipfise. Na maioria dos vertebrados, porm, a pars intermdia apresenta
importante papel na secreo do hormnio melanotrfico ( ((MSH), que se origina
tambm a partir de clivagem da POMC, assim como o ACTH. A adeno e a neuro-
hipfise so constitudas por clulas de distintas origem embriolgicas. A adeno-
hipfise deriva de uma invaginao de teto da cavidade oral, a bolsa de Rathke,
apresentando, portanto, caractersticas morfolgicas de clulas epiteliais. A neuro-
hipfise, por outro lado deriva de uma projeo do assoalho do 3 ventrculo, possuindo
uma populao de de clulas gliais (pitucitos) e axnios, cujos corpos celulares
encontram-se agrupados em ncleos especficos do hipotlamo.
Como j mencionado, o ACTH formado a partir da clivagem da POMC e exerce seus
efeitos nas clulas-alvo atravs da interao com receptores especficos localizados na
membrana plasmtica. A ocupao destes receptores resulta na ativao do sistema da
adenilil ciclase e da via do fosfatidil-inositol; segue-se a fosforilao de protenas
especficas e a consequente manifestao de seus efeitos biolgicos, que se resumem na
estimulao da secreo de glicocorticoides, mineralocorticoides e esteroides
andrognicos pelo crtex da adrenal.

As glndulas adrenais, por sua vez, esto localizadas acima dos rins e so compostas
nos adultos por 3 regies corticais: a zona glomerulosa, mais externa; a zona fasciculada
(intermediria) e a zona reticular (mais interna). A medula adrenal, localizada
internamente ao crtex, responsvel pela secreo de catecolaminas, especialmente
adrenalina e noradrenalina. Esta regio composta pelas clulas cromafins que, na
verdade, so homlogas aos neurnios ps-ganglionares simpticos. Assim, a medula
adrenal considerada uma gnglio simptico modificado. As trs zonas do crtex
adrenal, por outro lado, secretam diferentes hormnios esteroidais e esto sob diferente
regulao.
A medula adrenal corresponde poro central da glndula, constituda por clulas
chamadas de cromafins, responsveis por sintetizar e secretar catecolaminas, como
adrenalina, epinefrina, e outros neurormnios, que atingem a circulao sistmica e
atuam em diferentes tecidos-alvo. J o crtex apresenta clulas secretoras de hormnios
esterides, as quais no armazenam os seus produtos de secreo em grnulos, pois a
maior parte de seus hormnios sintetizada aps o estmulo e posteriormente secretada
(Fonseca, E. A. I. et al. 2009, Aires, M. 2012). Ademais, a regio cortical est
subdividida em trs partes, a zona glomerulosa, fasciculada e a reticulada.
A zona glomerulosa est localizada baixo da cpsula de tecido conjuntivo, sendo,
portanto, a camada

mais externa do crtex. Corresponde a 15% do volume cortical, apresenta uma

quantidade moderada de gotculas lipdicas no citoplasma e composta de clulas
piramidais e colunares, que se agregam numa disposio semelhante de um glomrulo
(Aires, M. 2012). Recebe estmulo da angiotensina II, sendo responsvel pela secreo
dos mineralocorticoides, principalmente a aldosterona, que contribui para manter o
equilbrio adequado de eletrlitos e de gua no organismo, alm de manter os nveis de
presso arterial (Junqueira, L.& Carneiro, J., 2008). A zona reticulada, a camada mais
interna do crtex, corresponde a 7% da regio cortical, intensamente eosinoflica,
constituda por clulas arranjadas de maneira pouco organizada, dispostas em cordes
irregulares que formam uma rede anastomosada, e tem por funo, a sntese de
esteroides C19, chamados andrgenos adrenais (Junqueira, L.& Carneiro, J., 2008;
Loriaux, DL., 2009, Kierszenbaum, A.L., 2012).

A camada intermediria chamada de zona fasciculada, representa cerca de 65% do

volume do crtex adrenal, suas clulas so polidricas, dispostas de maneira linear
(Junqueira, L.& Carneiro, J., 2008; Kierszenbaum, A.L., 2012). A regio fasciculada,
estimulada pelo hormnio ACTH (adrenocorticotrofina), responsvel pela secreo
dos glicocorticides, cortisona e cortisol, ou em alguns animais, corticosterona, que
regulam o metabolismo de carboidratos, protenas e lipdios (Kierszenbaum, A.L., 2012;
Aires,M. 2012). Seu citoplasma comporta um grande nmero de gotculas de lipdios
contendo colesterol e seus metablitos, alm de apresentar trs componentes que
caracterizam sua funo esteroidognica: 1) abundantes gotculas de lipdios contendo
colesterol, o precursor dos hormnios esterides; 2) mitocndrias; e 3) um retculo
endoplasmtico agranular (ou liso), contendo enzimas envolvidas na sntese de
hormnios esterides (Kierszenbaum, A.L., 2012).

O precursor para todos os hormnios adrenocorticais o colesterol, que pode ser

sintetizado a partir da acetilcoenzima A; porm, a maior fonte de colesterol para a
esteroidognese o colesterol transportado pelo plasma pelas lipoproteinas de baixa
densidade (LDL), que so captados pelas clulas adrenocorticais por meio de receptores
especficos presentes na membrana.
Os glicocorticoides so sintetizados por ao do ACTH na zona fasciculada. Uma vez
sintetizado, o cortisol, principal glicocorticoide em humanos, se difunde para fora das
clulas e cai na circulao, onde transportado em sua maior parte ligado a uma
protena carreadora (globulina ligadora de corticosterides). Cerca de 10 a 15% do
cortisol est ligado a albumina e perto de 5% circula na forma livre, sendo esta a
responsvel pelas aes fisiolgicas deste hormnio. A metabolizao de cortisol
envolve a sua converso em cortisona, um metablito inativo pela enzima 11( HSD-2.
Este um mecanismo importante a nvel local para controlar as aes do cortisol, pois
como veremos adiante, este hormnio liga-se no somente ao receptor de
glicocorticoides (GR), bem como aos receptores de mineralocorticoides (MR), ambos
pertencentes superfamlia de receptores nucleares. Alm de GR e MR, esta
superfamlia inclui os receptores para o hormnio tireoidiano e para os andrgenos,
entre outros. A ligao do glicocorticoide ao GR induz mudanas conformacionais no
receptor, seguidas de sua hiperfosforilao, o que facilita a translocao de complexo
hormnio-receptor para o ncleo.
Dentro do ncleo, o receptor ativado pelo hormnio pode agir por 2 diferentes
mecanismos: 1) interao com os elementos responsivos aos glicocorticoides (GREs) no
DNA, estimulando a transcrio gnica (em dmeros); 2) ligao de GR aos elementos
responsivos negativos aos glicocorticoides (nGREs), localizados na regio promotora de
genes especficos, onde causariam inibio da transcrio gnica.
Atualmente, admite-se a existncia de receptores de membrana para glicocorticoides;
estes receptores, j identificados em algumas espcies, pertenceriam classe de
receptores acoplados protena G e seriam responsveis pela mediao de respostas
rpidas, independente da sntese proteica, incluindo o mecanismo de feedback negativo
a nvel hipotalmico e hipofisrio, observado em questes de minutos.

Os glicocorticoides regulam o metabolismo de carboidratos agindo como

contrarreguladores da ao de insulina, protegendo o organismo contra a hipoglicemia.
Desta maneira, os glicocorticoides estimulam a neoglicognese heptica e aumentam a
mobilizao de substratos neoglicognicos de tecidos perifricos. A neoglicognese
heptica estimulada pelos glicocorticoides mediante o aumento da atividade de
enzimas chave como o fosfoenolpiruvato carboxiquinase (PEPCK) e glicose-6 fosfatase.
O aumento de neoglicognese decorrente do aumento de substratos para o fgado,
como aminocidos de tecido muscular e glicerol do tecido adiposo. Os glicocorticoides
diminuem ainda a utilizao perifrica de glicose, atuando sobre o receptor de insulina e
diminuindo os transportadores de glicose.
A sntese de glicognio no fgado estimulada pelo glicocorticoide como fonte de
estoque de glicose que pode rapidamente liberada quando necessrio, pela glicogenlise
induzida pelo glucagon e epinefrina. Em condies de excesso de glicocorticoides,
contudo, ocorre deposio de gordura preferencialmente na regio abdominal. Alm das
aes sobre o metabolismo energtico, os glicocorticoides apresentam importante
funo imunossupressora, sobre o sistema cardiovascular (efeito hipertensor em longo
prazo) e sobre os ossos (causando osteopenia ou osteoporose). O quadro clnico
decorrendo de excesso de glicocorticoides (causado pela ingesto excessiva ou
problemas endgenos, como tumores hipofisrios produtores de ACTH ou tumores
adrenais produtores de cortisol) conhecido como sndrome de Cushing e tem como
principais manifestaes clinicas a presena de face em forma de lua, obesidade
visceral, fraqueza muscular, osteoporose, estrias largas violceas, equimoses e perda da
ritmicidade do eixo. Em indivduos normais, o pico de secreo do cortisol ocorre no
incio da manh, imediatamente antes do perodo de atividade. Em animais de habito
noturno como os roedores, esse pico ocorre por volta das 17 s 18 horas, imediatamente
antes do perodo escuro.

Os glicocorticoides suprarrenais so muitas vezes chamados de hormnios do estresse,

devido ao seu papel como mediadores de estresse em longo prazo. Por outro lado, as
catecolaminas, notadamente a adrenalina, secretadas pela medula adrenal, so
responsveis pelas respostas metablicas rpidas necessrias s chamadas reaes de
luta ou fuga. Nesse sentido, sabe-se que a manuteno de constncia do meio interno
(ou homeostase) crtica para a sobrevivncia dos organismos. Dessa maneira, h
necessidade de adaptaes contnuas a estmulos internos e externos (estressores) que
envolvem alteraes comportamentais, viscerais e endcrinas para garantir a
preservao da homeostase. O principal mecanismo endcrino que participa destes
ajustes envolve o eixo hipotlamo-hipfise-adrenal, que ativado nestas circunstncias,
onde uma grande liberao de CRH corre em funo da ativao de vias de
adrenrgicas. Segue-se um rpido aumento na secreo de ACTH, com subsequente
elevao de nveis circulantes de glicocorticoides, os quais desempenham importante
papel na mobilizao de substratos energticos e na modulao das respostas cognitivas,
imunitrias e cardiovasculares, o que critico para o sucesso da resposta ao estresse.

Referncias bibliogrficas:

- Aires, MM. Fisiologia, 3 ed. RJ: Guanabara Koogan, 2008.

Chapter 7. Adrenal Fatigue the Ignored Epidemic of

Modern Civilization
Section Three: Chapter
7.

Adrenal Fatigue the

Ignored Epidemic of

Modern Civilization
Ignored by mainstream medicine,
adrenal fatigue is a common
problem seen routinely every day
at any busy medical office. The
paramount symptom is fatigue
unrelieved by sleep. Other symptoms include craving for salty foods, hypoglycemic
episodes, decreased libido, stress intolerance, light headed upon standing, depression,
loss of memory and cognitive decline, allergies, sinus problems, and prolonged recovery
from flu-like illnesses. The basic underlying cause is low cortisol output by the adrenal
glands.

Left Image: Adrenal Glands Drawing, courtesy of Pearson Scott Foresman, and the Wikimedia
Foundation

A Self-Help Book for Chronic Burn-Out called Adrenal Fatigue

Sergent
(sr-zhon[h]'),
Emile, French physician, 1867-1943. See: Sergent white line, Bernard-Sergent syndrome.
THE WHITE ADRENAL LINE: ITS PRODUCTION
AND DIAGNOSTIC SIGNIFICANCE Emile Sergent,
M.D.
Endocrinology (1917) 1 (1): 18-
23.DOI:https://doi.org/10.1210/endo-1-1-18
Published:01 January 1917

The definitive book on this topic is entitled, Adrenal Fatigue, by James L Wilson,
PhD, a self-help guide for all of us chronically stressed out members of the "rat race"
suffering from this new 21st century epidemic. (1) In his book, Wilson outlines how to
diagnose and treat adrenal fatigue, a syndrome not yet recognized by mainstream
medicine and it should be. I found Chapter 10 on physical signs of adrenal fatigue the
most useful. This chapter describes the findings on physical examination such as the
unstable pupil, blood pressure reduction upon standing, and Sergent's white line test.

Cortisol Testing

Chapter eleven of Wilson's book covers the different cortisol testing methods available
for cortisol in saliva, blood, and urine, as well as the ACTH stimulation test. Wilson
favors the four sample salivary cortisol test as the easiest and most convenient method;
with the added advantage that salivary testing can be done at home without a doctor's
prescription.

Another chapter in the book covers treatment and recovery from adrenal fatigue with
modification of diet and lifestyle, and diet, avoiding food allergies, and the use of
hormone supplements and dietary supplements. He also weighs the use of Cortef
(cortisol) vs. adrenal cortical extracts.

Results from Years of Chronic Stress

Adrenal fatigue is the net result of years of continuous high cortisol output by the
adrenals caused by chronic stress from job, family, illness, injury, and poor diet and
lifestyle associated with high-tech modern living. After years of chronic stress, the two
small triangular supra-renal glands poop out, and we become another casualty of
adrenal fatigue, the 21st century epidemic. Since mainstream doctors can't seem to help,
either ignoring the syndrome, or prescribing SSRI anti-depressants for it, this self-help
book may be a life-saver.

Definition of Adrenal Fatigue:

"Adrenal Fatigue is a collection of signs and symptoms that results from low
function of the adrenal glands. The paramount symptom is fatigue that is not
relieved by sleep. The syndrome may be caused by intense or prolonged stress, or
after acute or chronic infections, especially respiratory infections such as influenza,
bronchitis or pneumonia....People suffering from Adrenal Fatigue often have to use
coffee, colas and other stimulants to get going in the morning and to prop
themselves up during the day. Quoted from James L. Wilson, Adrenal Fatigue.(1)

Symptoms and Conditions Associated with Adrenal Fatigue

Anxiety
Asthenia - lack of, or loss of strength, generalized weakness
Asthma
Autoimmune problems
Bronchitis - recurrent, chronic or slow recovery from
Burnout
Chemical Sensitivity
Chronic fatigue syndrome (CFS)
Chronic infections,
Chronically run down - with early morning fatigue and low blood pressure
Chronic mental and/or physical exhaustion
Cravings for carbohydrates, sweets or salt
Depression
Fatigue - severe, disabling early morning fatigue
Feeling tired despite sufficient hours of sleep
Fibromyalgia
Hair loss
Hypoglycemia
Immune System dysfunction - frequent illnesses
Insomnia - or non-restful sleep
Low Blood Pressure
Nervous breakdown (nervous exhaustion)
Pneumonia
Respiratory infections - recurrent, chronic or slow recovery from
Rheumatoid arthritis
Reliance on stimulants like caffeine
Slow recovery following acute infectious diseases, especially influenza, pneumonia,
or other respiratory Infections
Weight gain
Why is Cortisol Important?

Cortisol is the stress hormone, and is produced in response to stress. Cortisol is

important for blood sugar regulation. Cortisol mobilizes glycogen in the liver to
maintain blood glucose levels. Symptoms of hypoglycemia are common in low cortisol
adrenal fatigue. Also low blood pressure or inability to maintain blood pressure upon
standing is also a common symptom. Another physical exam finding is an unstable
pupil response to light. The pupil at first contracts and then after a few seconds opens
and closes.

The Adrenal Glands Make the Cortisol

The two small triangular adrenal glands are located just above the kidneys and secrete
the hormone cortisol in response to stress, physical, emotional, or traumatic stress. The
adrenal glands make the hormone cortisol.

What is Cortisol? It's the Stress Hormone

Cortisol is a steroid hormone, and like all the others it is made from cholesterol.
Cholesterol, in turn, is made from Vitamin B5 and Acetyl CoA. The manufacture of
steroidal hormones can be best understood by referring to a steroidal pathway chart.

Salivary Cortisol Test:

Although cortisol can be measured in a blood sample, the best way to measure cortisol
levels is with 4 saliva samples taken throughout the day. There are literally hundreds of
medical research studies validating the usefulness of salivary cortisol measurements. A
recent study showed that low early morning salivary cortisol is associated with chronic
fatigue syndrome in women.(8) We use a 4 sample salivary kit that has a cotton
cylinder that is placed under the tongue to collect the sample. Collecting a sample with
this kit is much easier than the older method of spitting into the tube.

Nutritional Supplement Program for Adrenal Fatigue and Recovery

The keystone of the treatment program is a nutritional supplement program to restore

adrenal function that includes vitamin C, B5, magnesium, biotin and adaptogenic herbs.
Recovery takes about 6 weeks.

Cortef for Severe Cases of Adrenal Fatigue

In very severe cases of adrenal failure, Cortef tablets are available and produce a
dramatic improvement in clinical condition. For more information, see the classic book,
Safe Use of Cortisol by William Mck Jefferies. (41) Cortef is the name for bio-
identical cortisol which is widely available at the local drug store. Synthetic forms of
cortisol such as prednisone and dexamethasone are not recommended as they can be
associated with adverse side effects.

Other Useful Interventions For Adrenal Fatigue:

Avoid excess caffeine, refined carbohydrates, alcohol and sugar.
Get plenty of sleep.
Take steps to reduce stress with gentle exercise, meditation, and yoga.
Bioidentical hormones as determined by lab profile.

Warning:
Paradoxically, thyroid medication may worsen symptoms when given to a
patient with adrenal fatigue. Salivary cortisol testing and treatment of
adrenal fatigue is mandatory prior to beginning thyroid medication to
avoid this pitfall.

Cortisol's Relation to Thyroid Function - Avoiding A Common Pitfall

Low cortisol level adrenal fatigue will induce a protective state in which the bodys
metabolic rate is reduced in order to cope with low cortisol levels. The body
compensates by reducing thyroid function by shunting thyroid hormone production into
the reverse T3 pathway, the inactive form of thyroid hormone. This creates a functional
low thyroid state which will show up on thyroid labs. Treating the patient with thyroid
hormone under this scenario is a common error and a pitfall to be avoided. Giving
thyroid hormone to a patient with low cortisol adrenal fatigue will only make the patient
feel worse. The low adrenal function must be addressed first before attempting to raise
thyroid levels. This is done with a salivary cortisol test and a nutritional supplement
program over 6 weeks as described above. In the event the patient is already taking
thyroid hormone medication which doesn't seem to be working or is not tolerated, this is
a red flag that most likely cause is low cortisol adrenal fatigue. Once this is addressed,
the patient will do well with thyroid medication.

For More Reading:

Another excellent book on adrenal fatigue is, From Fatigued to Fantastic, by Jacob
Teitelbaum MD.(43) Also recommended is the article, Diagnosis and Treatment of
Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysfunction in Patients with Chronic
Fatigue Syndrome (CFS) and Fibromyalgia by Kent Holtorf M.D. (44)

For references and links, see my web site: www.bioidenticalhormones101.com

References for Chapter 7. Adrenal Fatigue

(1) http://www.adrenalfatigue.org/ Adrenal Fatigue by James Wilson, Smart Publications; January

25, 2002.

(2) http://coastherbal.com/web_standard/adrenal_stress.html THE STANDARD Adrenal Stress:

Measuring and Treating Thomas G. Guilliams Ph.D.

(3) http://www.spinelife.com/pdf/AdrenalStress.pdf THE STANDARD Adrenal Stress: Measuring

and Treating Thomas G. Guilliams Ph.D.
(4) http://www.medaus.com/p/200,516.html Saliva Reference Summary ZRT Laboratory (3-12-01)
METHOD VALIDATION.

(5) http://advan.physiology.org/cgi/content/full/31/1/110
ADV PHYSIOL EDUC 31:110-115, 2007 TEACHING IN THE LABORATORY A laboratory
exercise to illustrate increased salivary cortisol in response to three stressful conditions using
competitive ELISA
Mark F. Haussmann, Carol M. Vleck and Eugenia S. Farrar

(6) http://www.biovit.hr/ibl/saliva/cortisol_e.pdf Cortisol Physiology / Effects of Cortisol

(7) http://www.jacemedical.com/store/low_cortisol.html
The Medical Evidence for Low Cortisol in Chronic Fatigue Syndrome!

(8) http://www.cdc.gov/cfs/publications/clinical_10.htm
Attenuated morning salivary cortisol concentrations in a population-based sample of cases with
chronic fatigue syndrome and well controls. Nater UM, Maloney E, Boneva RS, Jones JF, Reeves
WC, Heim C.
Journal of Clinical Endocrinology & Metabolism 26 December 2007

(9) http://ajp.psychiatryonline.org/cgi/content/full/162/4/807
Am J Psychiatry 162:807-809, April 2005 Brief Report Enhanced Early Morning Salivary Cortisol in
Neuroticism . Maria J. Portella et al

(10) http://archpsyc.ama-assn.org/cgi/content/full/57/1/38
Low Salivary Cortisol and Persistent Aggression in Boys Referred for Disruptive Behavior Keith
McBurnett, PhD; Benjamin B. Lahey, PhD; Paul J. Rathouz, PhD; Rolf Loeber, PhD Arch Gen
Psychiatry. 2000;57:38-43.

(11) http://www.sav.sk/journals/endo/full/er0298f.pdf
Iatrogenic Adrenal Cortex Failure in Patients woth Steroid Dependent Asthma in Relation to
Different Methods of Glucocorticoid Treatment, B. KOS-KUDLA, Endocrine Regulations, Vol. 32,
99.106, 1998

(12) http://bbh.hhdev.psu.edu/labs/bbhsl/PDF%20files/klein%20et%20al.%20cortisol%20and
%20naltrexone.pdf Sex Differences in Salivary Cortisol Levels Following Naltrexone
Administration LAURA COUSINO LARRY D. JAMNER, JANEL ALBERTS, MATTHEW

(13) http://bjp.rcpsych.org/cgi/content/full/184/2/136
Salivary cortisol response to awakening in chronic fatigue syndrome Amanda D. L. Roberts, PhD .
The British Journal of Psychiatry (2004) 184: 136-141

(14) http://www.virginiahopkinstestkits.com/cortisolzava.html Cortisol Levels, Thyroid Function

and Aging HOW CORTISOL LEVELS AFFECT THYROID FUNCTION AND AGING Interview
with David Zava, Ph.D. Originally published in the John R. Lee, M.D. Medical Letter

(15) http://www.drmyhill.co.uk/article.cfm?id=266 Common Hormonal Problems in CFS - Adrenal

Underactive adrenal gland (DHEA and cortisol) If the pituitary gland is underfunctioning then the
adrenal gland will also underfunction. However the gland itself may fail as a result of chronic stress.

(16) http://www.adrenalfatigue.org/qa.php James Wilson Questionnaires on Adrenal Fatigue.

(17) http://www.jacemedical.com/store/low_cortisol.html The Medical Evidence for Low Cortisol in

Chronic Fatigue Syndrome! Jace Medical
(18) http://www.cdc.gov/cfs/publications/clinical_10.htm Attenuated morning salivary cortisol
concentrations in a population-based sample of cases with chronic fatigue syndrome and well
controls.
Nater UM, Maloney E, Boneva RS, Jones JF, Reeves WC, Heim C. Journal of Clinical
Endocrinology & Metabolism 26 December 2007

(19) http://ajp.psychiatryonline.org/cgi/content/full/162/4/807
Am J Psychiatry 162:807-809, April 2005. Brief Report Enhanced Early Morning Salivary Cortisol
in Neuroticism. Maria J. Portella et al.

(20) http://www.intlhormonesociety.org/ref_cons/Ref_cons_3_mild_glucocorticoid_deficiency.pdf
International Hormone Society . Uses of Cortisol references.

(21) http://archpsyc.ama-assn.org/cgi/content/full/57/1/38
Low Salivary Cortisol and Persistent Aggression in Boys Referred for Disruptive Behavior Keith
McBurnett, PhD; Benjamin B. Lahey, PhD; Paul J. Rathouz, PhD; Rolf Loeber, PhD Arch Gen
Psychiatry. 2000;57:38-43.

(22) http://www.drmyhill.co.uk/article.cfm?id=266 Common Hormonal Problems in CFS

(23) http://www.drpressman.com/library/view.html?id=78
The Use Of Adrenal Cortical Extracts In Adrenal Fatigue by James L. Wilson DC, ND, PhDWhat Is
Hypoadrenia and Adrenal Fatigue?Wilson, James L. ND, DC, PhD. Adrenal Fatigue: The 21st
Century Stress Syndrome Smart Publications, Petaluma CA, 2001

(24) http://www.ncbi.nlm.nih.gov/pubmed/12377295 Tsigos C, Chrousos GP.Hypothalamic-

pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002 Oct;53(4):865-71.

(25) http://ajp.psychiatryonline.org/cgi/content/full/160/9/1554
Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid
signaling in the pathophysiology of stress-related disorders. Am J Psychiatry. 2003 Sep;160(9):1554-
65.

(26) http://www.biodia.com/TechnicalCharts/ChronicStresschart.pdf
Chronic Stress Response Chart

(27) http://www.biodia.com/TechnicalCharts/SteroidalHormonechart.pdf
Steroidal Hormone Principle Pathways. (Understanding Pregnenolone Steal, the Preferential
Pathway Under Chronic Stress)

(28) http://www.drlam.com/A3R_brief_in_doc_format/adrenal_fatigue.cfm
Cortisol (The Hormone of Death) , Dr. Lam.

(29) http://meeting.chestjournal.org/cgi/content/abstract/132/4/555 Chest 2007, Critical Care Sepsis:

Markers. Wednesday, October 24, 2007 . SALIVARY CORTISOL IN CRITICAL CARE PATIENTS.
Eduardo F. Sad et al.

(30) http://www.ncbi.nlm.nih.gov/pubmed/6316831
Salivary cortisol: a better measure of adrenal cortical function than serum cortisol.Vining RF,
McGinley RA, Maksvytis JJ, Ho KY. Ann Clin Biochem. 1983 Nov;20 (Pt 6):329-35.

(31) http://www.ncbi.nlm.nih.gov/pubmed/2828410
Salivary cortisol measurement: a practical approach to assess pituitary-adrenal function. J Clin
Endocrinol Metab. 1988 Feb;66(2):343-8. Laudat MH, Cerdas S, Fournier C, Guiban D, Guilhaume
B, Luton JP.
(32)) http://www.ncbi.nlm.nih.gov/pubmed/11164057 Salivary cortisol patterns in vital exhaustion.
Nicolson NA, van Diest R. J Psychosom Res. 2000 Nov;49(5):335-42.

(33) http://bjp.rcpsych.org/cgi/content/full/184/2/136 Salivary cortisol response to awakening in

chronic fatigue syndrome.Roberts AD, Wessely S, Chalder T, Papadopoulos A, Cleare AJ. Br J
Psychiatry. 2004 Feb;184:136-41. (FULL TEXT)

(34)) http://jcem.endojournals.org/cgi/content/full/86/8/3545
Hypothalamo-Pituitary-Adrenal Axis Dysfunction in Chronic Fatigue Syndrome, and the Effects of
Low-Dose Hydrocortisone Therapy. The Journal of Clinical Endocrinology & Metabolism Vol. 86,
No. 8 3545-3554 A. J. Cleare et al.

(35) http://www.annalsnyas.org/cgi/content/abstract/1057/1/466
Stress-Induced Hypocortisolemia Diagnosed as Psychiatric Disorders Responsive to Hydrocortisone
Replacement, SUZIE E. SCHUDER Ann. N.Y. Acad. Sci. 1057: 466478 (2005).

(36) http://edrv.endojournals.org/cgi/content/full/24/2/236
The Neuroendocrinology of Chronic Fatigue Syndrome. Anthony J. Cleare. Endocrine Reviews 24
(2): 236-252, 2003, Full Text.

(37) http://crobm.iadrjournals.org/cgi/content/full/13/2/197 THE DIAGNOSTIC APPLICATIONS

OF SALIVA A REVIEW, The Monitoring of Hormone Levels, Eliaz Kaufman,Ira B. Lamster. Crit
Rev Oral Biol Med 13(2):197-212 (2002)

(38) http://www.biodia.com/TechnicalCharts/SALIVARY_REFERENCES.pdf
Listing of about one hundred medical references on salivary hormone testing with hyperlinks.

(39) http://coastherbal.com/web_standard/adrenal_stress.html
Adrenal Stress: Measuring and Treating, by Thomas G. Guilliams Ph.D. The Standard, Volume 3,
No. 1. Excellent review article on diagnosis, treatment of adrenal fatigue with salivary cortisol
testing.

(40) http://www.amazon.com/review/R1QNDLO1R9EX3U/ref=cm_cr_rdp_perm
Adrenal Fatigue by James L Wilson D.C., N.D., Ph.D. The 21st Century Syndrome reviewed by
Jeffrey Dach MD.

(41) http://www.amazon.com/review/R2IPB7XGMO20NE/ref=cm_cr_rdp_perm
Safe Uses of Cortisol (Cortisone, Hydrocortisone) by William McK., M.D. Jefferies (Author)
reviewed by Jeffrey Dach MD.

(42) http://jcem.endojournals.org/cgi/content/abstract/93/3/703
The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 3 703-709. Attenuated Morning
Salivary Cortisol Concentrations in a Population-Based Study of Persons with Chronic Fatigue
Syndrome and Well Controls Urs M. Nater, Elizabeth Maloney, Roumiana S. Boneva, B

(43) From Fatigued to Fantastic by Jacob Teitelbaum MD, Avery Trade; 3rd edition (October 4,
2007).

(44) http://jeffreydach.com/files/80618-70584/JOURNAL_CFSF_6_(2).pdf Diagnosis and

Treatment of Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysfunction in Patients with Chronic
Fatigue Syndrome (CFS) and Fibromyalgia (FM) Kent Holtorf M.D. J of Chronic Fatigue
Syndrome, V 14:3. (pub) 2008.

Author: Jeffrey Dach MD

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