Adrenal insufficiency-How to diagnose,
treat and manage
Theodore C. Friedman, M.D., Ph.D.
Professor of Medicine-UCLA
Chief, Division of Endocrinology, Molecular
Medicine and Metabolism
Charles R. Drew University
www.goodhormonehealth.com
Magic Convention
Chicago
June 13, 2010
Case (1961)
• 44 y.o male
• PMH/PSH
-Age 23-Episode of hypotension
-Age 28 -frail (150 lbs), looked tired, hollowed-eyed and
anemic, then collapsed
-Age 37- back surgery
-Age 38-diagnosed with hypothyroidism-metabolic rate of
-15 (low)- liiothyronine started
-lifelong history of GI symptoms (cramping, diarrhea,
inability to gain weight)
-age 38-43 intentional 35 lbs weight gain, including
increased muscle mass
Family hx
• Sister-Addison’s disease
• Son-Graves’ disease
Medications
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ascorbic acid, 500 mg twice daily
hydrocortisone, 10 mg daily
prednisone, 2.5 mg twice daily
methyltestosterone, 10 mg/d
liothyronine sodium, 25 mcg twice daily
fludrocortisone, 0.1 mg/d
diphenoxylate hydrochloride (opioid agonist)
atropine sulfate, 2 tablets as needed (Lomotil)
PE
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6 feet, 175 lbs
Appeared pale and anemic
Appeared bronze (before treatment)
Impaired vibration sense
• Labs-Hgb 15.5 g/dL, hematocrit 41%
• Otherwise none available
Case
• What is the diagnosis?
• Who is it?
• Why the medications?
President John F. Kennedy
• Dx: Polyglandular failure syndrome, Type 2
• (Mandel LR. Endocrine and autoimmune
aspects of the health history of John F.
Kennedy. Ann Intern Med. 2009, 151:3504)
John F. Kennedy
1944- 27 year-old JFK at reunion with fellow navy mates
John F
Mandel L R Ann Intern Med 2009;151:350-354
©2009 by American College of Physicians
President Kennedy’s
Medications
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ascorbic acid, 500 mg twice daily- Why?
hydrocortisone, 10 mg daily
prednisone, 2.5 mg twice daily Why both?
methyltestosterone, 10 mg/d Oral no longer given!,
Suggests hypogonadism secondary to steroid replacment
vs primary hypogonadism vs hypophysitis. Helped with
muscle mass and weight.
• liothyronine sodium, 25 mcg twice daily Why not
desiccated thyroid? Levothyroxine first introduced in 1962
• fludrocortisone, 0.1 mg/d Good, check renin level
• diphenoxylate hydrochloride/atropine sulfate-test for
Celiac disease instead
Polyglandular Failure Syndromes
• Type I autoimmune polyglandular syndrome (children)
– mucocutaneous candidiasis
– hypoparathyroidism
– adrenal insufficiency
• Type II autoimmune polyglandular syndrome (Schmidt
syndrome, adults)
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Addison’s disease
autoimmune thyroid disease (Graves disease or Hashimoto's thyroiditis)
insulin-dependent diabetes mellitus
Pernicious anemia
Gonadal failure
Hypophysitis
Celiac disease
Vitilgo
Adrenal Glands
• The adrenal glands lie at the superior pole
of each kidney.
• They are composed of two distinct regions:
the cortex and the medulla.
Adrenal Hormones
• Glucocorticoids-Cortisol
• Mineralocorticoids-Aldosterone
• Androgens-DHEA(S), testosterone,
androstenedione
• Estrogens
• Catecholamines-Epinephrine, Dopamine
Cortisol
• Daily secretion 10-15 mg
• Circadian cycle
• Has three forms:
– Free (5%), physiologically active
– bound to CBG/albumin
– Cortisol metabolites
Cortisol: Brain-Hypothalamic-PituitaryAdrenal Axis
Renin-AngiotensinAldosterone Axis
Site
Angiotensinogen (452 A.A.)
Liver
Kidney
Prorenin
Renin
Angiotensin I (10 A.A.)
Lung,
Plasma
Angiotensinconverting enzyme
Angiotensin II (8 A.A.)
Adrenal,
Vascular
Adrenal
Angiotensin II receptor
Aldosterone
Actions of Glucocorticoids
• Maintains metabolic homeostasis
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Regulates blood glucose levels
Raises insulin levels
Increases catabolism/decreases anabolism
Inhibits reproductive, thyroid and growth hormone axes
Mineralocorticoid activity of cortisol
• Affects connective tissue
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Causes loss of collagen
Loss of connective tissue
Inhibits fibroblasts
Inhibits bone formation/incr. resorption
Actions of Glucocorticoids (2)
• Maintains cardiovascular function
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Increases cardiac output
Increases vascular tone
Permissive effects on pressor hormones
Increases sodium retention
• Affects behavior and cognitive function
• Affects immune system
– Decrease # of circulating lymphocytes, monocytes, and
eosinophils
– decrease migration of PMNs to sites of injury
• Regulates about 25% of human genome
Renin-Angiotensin-Aldosterone Actions
• Angiotensin II
– vasopressor
– stimulates aldosterone
• Aldosterone
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Activates sodium/potassium pump
Increases plasma sodium
Decreases plasma potassium
Decreases plasma hydrogen
Daily ACTH/Cortisol Trends
Different Types of Glucocorticoid
Insufficiency
• Primary Adrenal Insufficiency
– Glucocorticoid and Mineralocorticoid Insufficiency
– Compensatory Increase in POMC (hyperpigmentation)
• Secondary (Central) Adrenal Insufficiency
– Glucocorticoid Insufficiency Only
• Glucocorticoid Withdrawal
– Glucocorticoid Insufficiency Only
Causes of Primary Adrenal Insufficiency
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Autoimmune (Addison’s Disease)
Tuberculosis
Fungal Disease
AIDS (HIV, CMV, MAI)
Metastatic Cancer
Adrenal Hemorrhage
Bilateral Adrenalectomy
Agents which inhibit cortisol biosynthesis (ketoconazole)
Sepsis
Causes of Secondary Adrenal Insufficiency
(corticotropes are the most preserved cells in the pituitary)
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Pituitary Tumors
Radiation
Surgery
Pituitary Apoplexy/Sheehan’s Syndrome
Infiltrative Diseases
After Cure of Cushing’s Syndrome
Glucocorticoid Withdrawal
Symptoms of Glucocorticoid Insufficiency
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Fatigue
Vomiting
Diarrhea
Anorexia
Malaise
Muscle and joint pain
Abdominal pain
Weight loss
Hypoglycemia
Hyponatremia (SIADH)
Symptoms of Mineralocorticoid Insufficiency
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Decreased intracellular volume
Hypotension
Dehydration
Shock
Hyponatremia
Hyperkalemia
– Arrhythmias
• Acidosis
• Salt-craving
Laboratory Findings of Primary
Adrenal Insufficiency
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Hyponatremia
Hyperkalemia
Hypoglycemia
Lymphocytosis
Eosinophilia
Mild normochromic Anemia
Symptoms of Primary Adrenal Insufficiency
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Hypotension
Dehydration
Hyponatremia
Hyperkalemia
Salt-craving
Amenorrhea
Decreased libido
Hyperpigmentation
• Fatigue
• GI- vomiting, diarrhea,
abdominal pain
• Anorexia/weight loss
• Malaise
• Muscle and joint pain
• Hypoglycemia
• Hyponatremia
• Depression
Hyperpigmentation
Symptoms of Secondary Adrenal
Insufficiency
• Amenorrhea
• Decreased libido
• Fatigue
• GI- vomiting, diarrhea,
abdominal pain
• Anorexia/weight loss
• Malaise
• Muscle and joint pain
• Hypoglycemia
• Hyponatremia
• Depression
Stages in Development of
Primary Adrenal Insufficiency
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Stage1- renin rises, aldosterone normal
Stage 2- ACTH rises, cortisol normal
Stage 3- impaired cortisol response to ACTH
Stage 4- aldosterone levels drop
Stage 5- cortisol levels drop
Stages in Development of Primary Adrenal
Insufficiency
Ten, S. et al. J Clin Endocrinol Metab 2001;86:2909-2922
Copyright ©2001 The Endocrine Society
Diagnosis of Adrenal Insufficiency
• Goals:
– Demonstrate inappropriately low cortisol and
aldosterone (if primary)
– Determine whether the cortisol deficiency is
dependent or independent of ACTH deficiency
Is the Cortisol Level Low?
A Quick Approach
• Checking an 8AM fasting cortisol level can usually make
or exclude the diagnosis in a patient levels of cortisol < 5
ug/dl or > 12 ug/dl respectively.
• Should only be done in subjects with signs/symptoms of
adrenal insufficiency or history consistent with it.
• Can be used in those patients with a moderate index of
suspicion.
• Measurement of ACTH levels can differentiate between
primary and secondary insufficiency
• Consistently high ACTH can be a sign of early adrenal
insufficiency [Roy, R., and Friedman, T.C. (2004)
Subclinical Adrenal Insufficiency-A Disease, Like
Subclinical Hypothyroidism, Whose Time Has Come.
EndoTrends 11 (3):14-15.]
Problems with Just Checking
Morning Cortisol Levels
Erturk et al. Evaluation of hypothalamic-pituitary adrenal axis by
insulin hypoglycemia test J.Clin. J.Clin Endocrinol Met.
1998;83:2350
– Found that some patients with an AM cortisol between
12-18 mg/dL had a ITT-induced cortisol < 17 and
would be classified as being adrenally-insufficient.
– I doubt these have clinically significant cortisol
defiency and need replacement
– May need coverage during surgery or major illness.
Cosyntropin Stimulation Test
• 250 ug IV bolus of cosyntropin (synth. ACTH) in
morning or afternoon
• Plasma cortisol at time 0, 30, 60 minutes
• Cortisol >18 ug/dl from baseline rules out primary adrenal
insufficiency and 90% secondary insufficiency
• if peak response is less than 10 mg/dl, glucocorticoid
replacement is required
• if peak response is between 10 and 20 mg/dl, glucocorticoid
replacement is recommended during stresses and maybe during
everyday
– Incremental increase in cortisol not recommended
– Need to have central hypocortisolism for about 1 month (some
articles say 12 days) prior to enough adrenal atrophy and failed
cosyntropin test.
1 mcg Cosyntropin Stimulation
Test
• Proposed to be more physiological
• By definition will pick up more cases of adrenal
insufficiency.
• Loraiux and Fleseiru* point our several problems with this
test
– A lower dose is on the steeper part of the dose-response curve resulting in
more variation.
– “normals” will have a lower response to 1 mcg cosyntropin, but we don’t
know the cutoff for this test.
– Calling someone abnormal based on a blunted response to 1 mcg
cosyntropin and putting them on lifelong glucocorticoids may be the
worse thing we can do to a patient
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* Loraiux and Fleseiru Cur. Opin. Endocrinol. Diabetes Obe 16:392-400, 2009.
Salivary cortisol testing
Advantages
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Avoid anticipatory stress of blood draws
Measures free cortisol
Not affected by CBG variations
Easy to collect
More pleasant
Two studies suggest it was similar to serum cortisol to
diagnose adrenal insufficiency. One looked at baseline
cortisol levels and one looked at during cosyntropin
testing.
Salivary cortisol testing
Disadvantages
• Cut-offs are not known.
• Low levels of cortisol, accuracy might be a problem
• Most cortisol in the morning is bound: Articles showed not as much
differences in salivary vs serum cortisol between adrenal insufficient
patients and normals
• Reliable at standard labs: Esoterix, Labcorp, Quest, ACL
• Less reliable at labs dealing directly to the consumer: Diagnos-tech,
Geneva, Great Smokie, Hormone Saliva Tests
• Almost always low: I have had Cushing’s patients with low levels
who received steroids.
• Big divide on this between Endos and Alternative Docs/Naturopaths
Insulin-Induced Hypoglycemia
• 0.1 units/kg insulin in morning (more if insulin-resistant)
• Check glucose at time 0,15,30,45,60,90
• Cortisol should rise above 18 ug/dL and glucose should
fall below 40 mg/dL
• Patients and docs do not like it.
• If hypopit, missing counter-regulatory hormones (cortisol
and GH)-hard to get out of hypoglycemia.
• Many hypopit patients are insulin resistant-have to give
more insulin.
• Literature suggests giving a second dose of insulin if 1st
one doesn’t achieve hypoglycemia-but that already
stimulates cortisol, so on the 2nd insulin dose, cortisol
doesn’t respond-false positives.
Urine cortisol
• Urinary free cortisol and 17-OH corticosteroids
• Not great at separating low normal from low.
• Might give you a hint.
Reminder
• ACTH is the last hormone to be affected in pituitary insufficiency
(GH, TSH, gonadotropins have to be invariably lost)
• Symptoms of glucocorticoid insufficiency are unique (weight loss,
nausea, abdominal pain)
• Primary adrenal insufficiency is relatively rare and also has a unique
symptom and lab complex.
• Once started, glucocorticoids may be hard to stop and are often very
detrimental.
• Its probably a false-positive test, unless its in the right context.
• Think twice before going on glucocorticoids.
• Glucocorticoids stimulate mood, so the fact that you feel better on
glucocorticoids does not mean you have adrenal insufficiency
Adrenal Fatigue-Fiction
• Wildly proposed by alternative and anti-aging doctors
• Lots of internet discussion on it
• Often based on salivary cortisol assays (sometimes
marketed directly to patients, which lack both precision
and accuracy.
• Theory is that “stress” leads the adrenals to work harder
and make more cortisol, then it burns out (peters out) and
makes less cortisol
• “It’s like a hormone factory and it wanes in its production,
one of the way it wanes is just by stress.”-Dr. Tori
Hudson-Naturopathic Physician.
• Alternative doctors may give herbs and supplements to
stimulate the adrenal gland but also give Isocort (ground
up sheep adrenals) or hydrocortisone.
• “Eat lean, green and clean”-one alternative doctor said is
the treatment for adrenal fatigue
Adrenal Fatigue-Fact
• The adrenals are up-regulated during stress and make
cortisol, not less cortisol.
• Mommersteeg et al. [Psychoneuroendocrinology (2006)
31, 216–225] studied 74 clinically diagnosed burnout
individuals mostly on sick-leave and compared with 35
healthy controls.
• They found similar salivary cortisol after awakening and at
different times of the day and after an overnight
dexamethasone suppression test in the 2 groups.
• Patients should not be put on cortisol unless they are
shown to be adrenally insufficient.
• Isocort contains 2.5 mg of hydrocortisone (often 6 or more
pills a day are given), plus aldosterone and DHEA/DHEAS
and is dangerous.
Adrenal Insufficiency and
Hypothyroidism
• Addison’s Disease and Hashimoto’s (autoimmune) hypothyroidism
co-exist as part of Type II autoimmune polyglandular syndrome
(Schmidt syndrome).
• In hypopituitarism, adrenal insufficiency and central hypothyroidism
often co-exist
• Patients with full-blown adrenal insufficiency and hypothyroidism do
need to have glucocorticoid replacement prior to thyroid replacement.
• That is because in hypothyroidism, cortisol metabolism is decreased
(11b-HSD1 favoring cortisone to cortisol conversion). Treatment of
hypothyroidism causes the low levels of cortisol to be broken down
and will lead to an adrenal crisis.
• Probably not true in borderline adrenal insufficiency or “adrenal
fatigue”
• Statements of needing cortisol to support thyroid replacement are
myths.
Adrenal Crisis
• Usually in Patients with Primary Adrenal
Insufficiency
• Precipitated by Stress
• Newly diagnosed vs. established patient
– stopped medicines
– illness
– vomiting
Presentation of Adrenal Crisis
(usually primary adrenal insufficiency)
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Hypotension/shock (90%)
Abdominal pain (80%)
Fever (65%)
Anorexia/nausea/vomiting (60%)
Confusion (40%)
Hyponatremia/hyperkalemia/acidosis (80%)
Hypoglycemia (20%)
Workup/Treatment for Suspected Adrenal
Crisis
• Establish IV access
• Draw blood for electrolytes, glucose,
cortisol, ACTH, aldosterone and plasma
renin activity
• Infuse up to 3 liters of normal saline
• Follow fluid status
• Give 100 mg of IV hydrocortisone
• Supportive Measures
Subacute Measures for Suspected Adrenal
Crisis
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Continue IV fluids
Search for an infectious source
Determine if primary or central adrenal insufficiency
Give fludrocortisone if primary insufficiency (not required
initially if hydrocortisone dose is more than 50 mg/day)
• Continue IV hydrocortisone
Maintenance Therapy for Adrenal
Insufficiency
Daily cortisol production rate in man
• Esteban et al. (JCEM, 72: 39, 1991) measured daily
cortisol production rates in normal volunteers with a stable
cortisol isotope method.
• 9.9 +/- 2.7 mg/day, 5.7 mg/m2 day.
• Not all of oral cortisol is absorbed, need to take 12-15
mg/day
• Most glucocorticoid replacement is supraphysiological.
• Leads to osteoporosis, glucose intolerance and increased
infections.
• True physiological replacement is likely to be benign
Glucocorticoid Replacement
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Most patients are over-treated
Earliest manifestation of excess treatment is easy bruisability
Weight gain, central obesity, etc.
Earliest manifestation of inadequate treatment is joint pain.
Reasonable to mimic circadian rhythm with most or all
cortisol given first thing in the morning
• Want to avoid nighttime administration as it could lead to
sleep disturbances,
• But, some patients need a bit of cortisol to go into deep sleep
• No studies comparing different treatment regimens
Glucocorticoid Replacement (2)
• My approach is to use hydrocortisone mainly in AM-aim for dose
between 15 and 20 mg/day in a women and slightly higher in a man.
– Hydrocortisone 10-20 mg on awakening
– Hydrocortisone 2.5-5 mg in mid-afternoon
– Occasionally a 3rd dose is needed
– More physiological than prednisone or dexamethasone
• Decrease dose slowly until some symptoms develop, then go back a
dose.
• Small changes make a big difference
• Increase dose with illness, short term its better to err on giving more,
long term its better to give less
• Cortef is brand name, hydrocortisone is generic (most of my patients
prefer generic)
Modified-Release
Hydrocortisone
• Investigational- DuoCort hydrocortisone dual-release tablet combines
both a rapid release dose and an extended release dose.
• Designed to better mimic circadian rhythm of cortisol
• Website states: Existing administration forms cannot adequately mimic
the 24 hour circadian pattern of cortisol.
• Probably best use will be in congenital adrenal hyperplasia.
• Not sure replacement is a big problem in adrenal insufficient patients
due to cortisol-cortisone shuttle
• Many patients do fine on a single dose of hydrocortisone in AM even
though blood cortisol levels are almost 0. This is due to the conversion
of cortisol to cortisone, which goes back to cortisol in the tissues.
• 30 mg of modified hydrocortisone may over-replace individuals
Modified-Release
Hydrocortisone-circadian rhythm
Debono, M. et al. J Clin Endocrinol Metab 2009;94:1548-1554
Modified-Release
Hydrocortisone-only long-lasting
Debono, M. et al. J Clin Endocrinol Metab 2009;94:1548-1554
Maintenance Therapy for Primary
Adrenal Insufficiency
• Primary adrenal insufficiency may need a bit more
glucocorticoids than secondary
• Mineralocorticoid Replacement
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Fludrocortisone 0.05 mg to 0.5 mg daily (0.05 mg twice a day)
Should be given twice a day-half-life is 3.5 hrs
Fludrocortisone is generic; brand (Florinef) is not available)
Probably will need more fludrocortisone in the summer
• Med-Alert Bracelet (can also be given in
secondary, but less crucial)
• Solucortef -100 mg in Act-O-vial
Monitoring glucocorticoid
replacement
• Signs and symptoms
• 24 hr UFC over-estimate cortisol as it reflects
amount in the urine right after dosing that exceeds
11b-HSD2 capacity.
• 17-OHS (can be corrected for creatinine excretion
in g/day) reflects cortisol metabolism and is more
integrated throughout the day.
• Day curves under-estimate cortisol as the ignore
cortisone-cortisol shuttle
• ACTH is high unless over-replaced
Monitoring glucocorticoid replacement
• LW: Sheehan’s syndrome-very athletic and health
conscious
• HC tapered from 20 mg/day to 17.5 mg/day (12.5 mg in
AM, 5 mg in PM)-less bruising, slight weight loss
• On 17.5 mg a day-UFC 191 mg/day (10-34)
• 17-OHS 4.7 mg/day (2-6)
• 17-OHS/gm Cr 3.5 mg/day (1.6-3.6)
• Went down to 15 mg/day of HC, had an adrenal crisis
when had the flu
Monitoring mineralocorticoid
replacement in primary adrenal
insufficiency
• Plasma renin activity is very accurate and probably should
be measured every 2-3 months
• If its high, more fludrocortisone is given, if its low, less
fludrocortisone is given
• Electrolytes are relatively insensitive and are not a
substitute for frequent renin monitoring
Hormonal Interactions
• Treating adrenal insufficiency may unmask
diabetes insipidus
Hormonal Interactions
• Increased GH/ IGF-I leads to lower levels of
cortisol (11-HSD1).
• Thus, treating a patient with hypopituitarism with
GH will decrease cortisol levels.
• Similarly, treating a patient with hypopituitarism
with thyroid hormone will decrease cortisol levels.
• We had one patient that was over-replaced on
glucocorticoids, under-replaced on thyroid hormone
and not treated with GH.
– We started GH, decreased her glucocorticoids
and increased her L-thyroxine-she went into
adrenal crisis.
• Make changes slowly.
• Monitor frequently
Glucocorticoids are Needed for Sleep
• García-Borreguero D. et al.
(J Clin Endocrinol Metab. 2000 85:4201-6).
• In Addison's patients, cortisol plays a positive,
permissive role in REM sleep regulation and may
help to consolidate sleep.
• Suggests a need for a low dose of hydrocortisone
(2.5 mg) at night.
Physiological Equivalents of
Glucocorticoids
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20 mg of hydrocortisone
5 mg of prednisone
4 mg of methylprednisolone
0.75 mg of dexamethasone
Treatment of Minor Illnesses
– Fever
– Vomiting
• Double glucocorticoid dose
Emergency Treatment of Severe
Illnesses
• 100 mg of IM hydrocortisone
• Go to physician immediately
Peri-operative Glucocorticoid Replacement
•Normal adults: 50 mg/24hr of cortisol during minor surgery
•75-100 mg/24 hr during major surgery
•The increase is mainly due to anesthesia
•“Common practice” to give “stress doses” of glucocorticoids
peri-operatively
•Scant evidence to support this practice
•1950’s 2 young patients on glucocorticoids died unexpectedly
during orthopedic surgery
Risks of acute excessive glucocorticoids
•reduced tissue repair rates
•increased susceptibility to infection
•glucose intolerance
Steroid coverage for illnesses or surgery
• Moderate illness
– 50 mg of hydrocortisone twice a day
• Severe illnesses
– 100 mg of IV hydrocortisone Q 8 hours
• Minor procedures without anesthesia
– No extra coverage
• Moderately stressful procedures (endoscopy or
arteriography
– Single 100 mg IV dose of hydrocortisone prior to procedure
• Major surgery
– 100 mg of IV hydrocortisone before anesthesia and Q 8 hours
References
• Mandel LR. Endocrine and autoimmune aspects of the health history
of John F. Kennedy. Ann Intern Med. 2009 Sep 1;151(5):350-4.
• Arlt W. The approach to the adult with newly diagnosed adrenal
insufficiency. J Clin Endocrinol Metab. 2009 Apr;94(4):1059-67.
• Loriaux DL, Fleseriu M. Relative adrenal insufficiency. Curr Opin
Endocrinol Diabetes Obes. 2009 Oct;16(5):392-400.
• Mommersteeg PM, Heijnen CJ, Verbraak MJ, van Doornen LJ.
Clinical burnout is not reflected in the cortisol awakening response, the
day-curve or the response to a low-dose dexamethasone suppression
test. Psychoneuroendocrinology. 2006 Feb;31(2):216-25. Epub 2005
Sep 16.
• Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill
patients. N Engl J Med. 2003 Feb 20;348(8):727-34.
• García-Borreguero D, Wehr TA, Larrosa O, Granizo JJ, Hardwick D,
Chrousos GP, Friedman TC. Glucocorticoid replacement is permissive
for rapid eye movement sleep and sleep consolidation in patients with
adrenal insufficiency. J Clin Endocrinol Metab. 2000
Nov;85(11):4201-6.
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