Adrenal Disorders
• The 3 components of the HPA axis function as integral system.
• Corticotropin-releasing hormone (CRH):
*Released from the hypothalamus in response to a
variety of stimulants (neurotrasmitters, catecholamines,….)
• Adrenocorticotropic hormone (ACTH):
*Anterior pituitary hormone released into the systematic
circulation in response to stimulation by the CRH.
*ACTH stimulates the adrenal cortex to produce cortisol.
*ACTH also binds to milanocortin-2 receptors, increasing
pigment deposition.
• As serum cortisol levels increase, the biosynthesis & secretion
of CRH & ACTH decrease in a negative feedback mechanism.
• CIRCADIAN RHYTM:
• ACTH release is controlled by:
1. CRH
2. Free cortisol plasma conc.
3. The sleep-wake cycle.
• ACTH plasma conc. peaks early A.M., then decreases, & nadirs
@ ~ midnight.
• Cortisol plasma conc. peaks @ awakening then declines &
nadirs 1 or 2 after falling asleep.
• Stress ( injury, pain, hypoglycemia, hypovolemia, exercise,
emotional trauma,…) enhances ACTH release & abolishes
ACTH circadian rhythm.
• High-dose glucocorticoid adm. supresses stress-related ACTH
release.
• Key Concepts
1. Glucocorticoid secretion from the adrenal cortex is stimulated by
adrenocorticotropic hormone (ACTH) or corticotropin that is released from
the anterior pituitary in response to the hypothalamic-mediated release of
corticotropin-releasing hormone (CRH).
2. To ensure the proper treatment of Cushing's syndrome, diagnostic
procedures should (1) establish the presence of hypercortisolism &
(2) discover the underlying etiology of the disease.
3. The rationale for treating Cushing's syndrome is to reduce the morbidity &
mortality resulting from disorders i.e., diabetes mellitus, cardiovascular
disease, & electrolyte abnormalities.
4. The treatment of choice for both ACTH-dependent and ACTH-independent
Cushing's syndrome is surgery, whereas pharmacologic agents are reserved
for adjunctive therapy, refractory cases, or inoperable disease.
5. Pharmacologic agents that may be used to manage the patient with
Cushing's syndrome include steroidogenesis inhibitors, adrenolytic agents,
neuromodulators of ACTH release,& glucocorticoid-receptor blocking agents.
6. Spironolactone, a competitive aldosterone receptor antagonist, is
the drug of choice in bilateral adrenal hyperplasia (BAH)-dependent
hyperaldosteronism.
7. Addison's disease (primary adrenal insufficiency) is a deficiency in
cortisol, aldosterone, & various androgens resulting from the loss
of function of all regions of the adrenal cortex.
8. Secondary adrenal insufficiency usually results from exogenous
steroid use, leading to hypothalamic-pituitary-adrenal (HPA)-axis
suppression followed by a decrease in ACTH release, & low levels of
androgens & cortisol.
9. Virilism results from the excessive secretion of androgens from the adrenal
gland & often manifests as hirsutism in females.
Cushing’s Syndrome
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•
Definition:
A disorder caused by persistent glucocorticoid excess.
Etiology:(see table2)
The increase of serum cortisol by:
*ACTH-dependent Disorders
Or
*ACTH-independent Disorders
• Cushing’s disease is a specific type of Cushing’s
Syndrome caused by ACTH-secreting pituitary tumors.
• Women develop Cushing’s disease 3-8X > men
• Pathophysiology:
• Cushing’s Syndrome:
• Results from a prolonged exposure to
excessive glucocorticoids.
• Cushing’s Disease:
• Pituitary micro- or macroadenomas or
hyperplasia increased ACTH secretion
(relativ. resistant to glucocorticoid negative
feedback)
• Ectopic tumors secrete ACTH or CRH 
Adrenocortical hyperplasia & hyperfunction.
• Exogenous adm. of glucocorticoids 
Increase serum cortisol  Inhibiting CRH &
ACTH secretion  Bilateral adrenocortical
atrophy.
• Diagnosis & Clinical Findings:
1. Rule out hypercortisolism by:
a. iatrogenic (prescribed glucocorticoids) causes.
b. surreptitious (nonprescribed glucocort. use
w/o intent of self-harm) causes.
or c. factitious (nonprescribed glucocort. use
w/ intent of self-harm) causes.
The definitive test is HPLC analysis of urine for
synthetic corticosteroids.
2. Establish the presence of hypercortisolism:
HPA axis tests to determine the cause of
hypercortisolism
.
• Differential Diagnosis:
• Defining the precise cause of Cushing’s syndrome: essential to
appropriate surgical management.
• Plasma ACTH:
• Elevated w/ ACTH-dependent Cushing’s & low in ACTHindependent.
• CRH-Stimulation Test:
• A subnormal response of ACTH to an IV bolus synthetic CRH
ACTH-independent Cushing’s syndrome
• An elevated ACTH to an IV bolus synthetic CRH
ACTH-dependent Cushing’s syndrome
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•
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Differential Diagnosis (cont.):
Metyrapone Test:
Sometimes used when other tests are equivocal.
It differentiates between Cushing’s disease & ectopic
ACTH-secreting tumors.
• As a response to metyrapone:
*Cushing’s disease pts. show a decrease in cortisol.
*Ectopic ACTH-secreting tumors pts. show little
or no response.
• Radiologic Imaging:
• CT scan is used to:
*Determine the location & size of tumors.
*Differentiate between adrenal adenomas
& carcinomas.
• CT in pts w/ ACTH-dependent Cushing’s Synd.
shows bilateral hyperplastic glands though the
adrenals may be normal or atrophic.
• MRI > sensitive for detecting ACTH-producing
pituitary microadenomas than CT scans.
• Therapeutic Plan:
• Tx depends on the etiology.
• Appropriate Tx  Resolves hypercortisolism SxS over weeks
to months.
• Iatrogenic Cushing’s syndrome Tx:
*Slowly tapering the steroids over several wks.
*Manage the adverse physiologic consequences of
excessive chronic glucocot. adm. (i.e. hyperglycemia,
elevated BP).
*Monitor for & treat infections
*Replace K⁺
*Give Ca supplement
*Glucocort. Dosage supplement in acute illness, injury or
surgery.
• Therapeutic Plan (cont.):
• Cushing’s dz.:
• Treated by selective surgical removal of
pituitary microadenomas (Transsphenoidal
adenectomy).
• ACTH production temporarily drops after
surgery: Pt. requires glucocort. replacement
X 3-12 months until HPA-axis recovers.
• Therapeutic Plan (cont.)
• Pituitary irradiation is indicated for those who failed
or unable to tolerate pituitary surgery.
• Ectopic ACTH-secreting tumors, adrenal adenomas,
adrenalomas are:
1. Surgically removed
Or
2. Treated w/ radiation
Or
3. Treated w/ standard chemotherapy
* Adrenocorticolytic drugs control cortisol prod. during
treatment.
• Treatment of Cushing’s Dz.:
• Pharmacotherapy indicated to:
1. Reduce cortisol production before surgery.
2. Maintain normal plasma cortisol levels while
awaiting results of surgery or radiation Tx.
3. Treat pts. w/ severe physical or psychiatric
hypercortisolism Sx.
4. Reduce cortisol effects in pts. w/ nonresectable
tumors.
3 Categories of Meds. for Cushing’s Syndrome:
1. Steroidogenic Inhibitors:
( Ketoconazole, Metyrapone, Aminoglutethimide,
Mitotane, Etomidate )
*Used almost exclusively to treat ACTH- dependent synd.
*Most effective agents available for treating Cushing’s synd.
2. Neuromodulators of ACTH Secretion:
( Bromocriptine, Cyproheptadine, Valproate)
*Disappointing results.
3. Glucocorticoid Receptor Antagonists:
( Mifepristone )
*Limited clinical experience
• Ketoconazole: Is usually the initial Tx.
• Metyrapone: May be added as a second
steroidognic inhibitor.
• Aminoglutethimide: May be added if the
combination of
ketoconazole &
metyrapone is ineffective.
• The 3 act synergistically & their S/Es reduced
@ < than max. doses of each.
• Dexamethasone (0.25-0.5 mg QD):
• Added as cortisol serum levels approach
normal w/ adjusting the dose to alleviate Sx of
hypocortisolism.
• Dexamethasone has advantage over other GCs
in: 1. Not interfering w/ serum cortisol assay.
& 2. Having a long t1/2 (QD dosing)
• Fludrocortisone: *Mineral corticoid
replacement may be
indicated depending on
specific Tx.
*Dose adjusted to alleviate
SxS of volume depletion,
& normalize electrolytes &
plasma renin.
• Coexisting ovulatory disorders make
pregnancy rare in Cushing’s synd.:
 Tx same as above with consideration
of the benefits vs. risks of each drug.
A. Steroidogenic Inhibitors:
1. Ketoconazole:
• Inhibits cortisol synthesis & ACTH secretion
• V. effective in lowering cortisol in Cushing’s.
• Initial Tx: * 200mg p.o. QD
& increase @ 4-7d intervals till UFC
decrease to upper normal limits.
* Tx usually requires 600-800mg QD
• Ketoconazole (Cont.):
• Careful clinical monitoring , including serum
drug levels when appropriate, is indicated due
to high DI profile.
• Examples:
1. Ketoconazole inhibits metabolism of drugs
i.e. warfarin, phenytoin, …
2. Ketoconazole absorption is decreased by:
antacids, H₂ antagonists, sucralfate.
3. Ketoconazole levels are decreased by:
isoniazid & rifamin.
2. Metyrapone:
* Blocks the synthesis of cortisol.
• Used to treat Cushing’s:
* when dose-limiting ketoconazole S/Es
Or * as part of combination therapy w/ other
steroidogenic inhibitors.
*Initial Dose: *250mg QD
*up to 2000 mg QD are well
tolerated.
* Induces hepatic oxidase (metabolism of
phenytoin or phenobarbital)
3. Aminoglutethimide:
* Inhibits cortisol synthesis.
• Short duration of effect.
• Duration of effects longer w/:
1. Cortisol-secreting adrenocarcinomas
Or
2. When used in combination w/ metyrapone or
pituitary irradiation.
• Initial Tx:
*250mg QID
& *increased as required to normalize UFC conc.(<1g/d)
* It induces metabolism of Dexamethasone
* Has No effect on cortisone metabolism
4. Mitotane:
• Inhibits Cortisol synthesis.
• Used mostly w/ pituitary irradiation.
• May be used in combination w/ other
steroidogenic inhibitors.
• Most pts. respond to pit. irradiation & do not
require chronic mitotane therapy.
• Initial Tx: 500 mg QD @ bedtime
Increased as required to normalize
UFC conc.
• Mitotane (cont.):
• Concomitant glucocort. replacement is
required during & after therapy ( Mitotane
accumulates in fatty tissues & persists in
plasma X several months after D/C.)
• Mitotane induces mineralocorticoid deficiency
& Fludrocortisone replacement is guided by
SxS of vol. depletion or excess .
5. Etimodate:
• A hypnotic parenteral anesthetic that inhibits
cortisol synthesis @ low & high doses BUT data about its use
in Cushing’s is limited.
B. Neuromodulators:
• All were used experimentally in Cushing’s but w/ very limited
data & were disappointing.
C. Glucocorticoid Receptor Antagonists:
• Mifepristone use in Cushing’s has limited data.
• Serum cortisol conc. is unaffected.
• Concomitant adm. of spironolactone may be required to
control hypokalemia secondary to cortisol activation of
mineralocorticoid receptors).
• Nonpharmacologic Therapy:
1. Surgery:
a. Transsphenoidal microadenomectomy:
• Surgery of choice for circumscribed
microadenomas (cure 95%)
• Preserves normal anterior pituitary function.
b. ACTH- & CRH- Secreting Tumors Resection:
• Curative, but most tumors are non-resectable.
c. Bilateral Total Surgical Adrenalectomy:
indications:
1.Bilateral micronodular or macronodular
adrenal hyperplasia & non-resectable ectopic
tumors.
2. When rapid hypercortisolism reduction is
needed.
3. When all other therapies have failed.
• Nonpharmacologic Therapy (cont.):
2. Pituitary Irradiation:
* Indicated for treating Cushing’s Dz. Not cured
by transphenoidal surgery.
• Newer forms of computer assisted radiotherapy
may be more effective but has limited
experience.
• Until remission, hypercortisolism is controlled
w/ adrenal enzyme inhibitors, i.e. ketoconazole.
Addison’s Disease
• Treatment Goals:
1. Restore HPA hormonal balance by replacing
glucocorticoids & mineralocorticoids.
2. Manage hormonal needs during intercurrent
illness.
• Definition:
• Addison’s dz. is rare.
• Also known as primary adrenal insufficiency.
• Most often caused by autoimmune-mediated
destruction of the adrenal cortex.
• SxS result from Decreased production of :
1. Glucocorticoids
2. Mineralocorticoids
3. Androgens
• Etiology:
1. Primary Addison’s:
• Caused by adrenal gland dz., assoc. w/
Glucocort., mineralocort., & androgen
deficiencies.
• > 90% are autoimmune assoc.
• Other causes, include:
*Infections
*Infiltrating dz. ( sarcoidosis,…)
*Hemorrhage or infarction
*Tumors
2. Secondary Addison’s:
• Caused by ACTH insufficiency assoc. w/ glucocortic.
deficiency; the RAA axis is intact.
• The most common cause:
*Sudden withdrawal of chronic adm. of
exogenous glucocorticoids.
* Other causes, include:
1. Hypothalamic or pituitary tumors or lesions.
2. Surgical removal of pituitary.
3. Pituitary irradiation.
4. Aneurysm of the internal carotid artery.
5. Proopiomelanocortin (POMC) gene mutation.
6. Drugs that interfere reversibly w/ steroidogenesis.
• Pathophysiology:
• All 3 zones of adrenal gland are progressively
destroyed & replaced by fibrotic tissue.
• The medulla is spared but may be atrophic.
• Adrenal dysfunction may be gradual or abrupt.
• SxS appear when ≥90% adrenal cortex is destroyed.
• Acute adrenal bleeding or infection is assoc. w/
sudden & complete adrenal loss.
• Autoantibodies directed against adrenal cortex
steroid-producing cells are characteristic of
Autoimmune Addison’s dz.
• Clinical Presentation (cont.):
• > 90% present w/ biochemical abnormalities,
including: * Hyponatremaia
* Hyperkalemia
* Mild Acidosis
* Hypoglycemia
* hypercalcemia
• All of which are opposite from Cushing’s
biochemical changes.
• Acute Adrenal Crisis:
• Usually occurs w/ undiagnosed Addison’s &
untreated stress.
• SxS mimic septic shock, including:
Anorexia, N/V, sev. dehydration, hypotension,
shock unresponsive to vasopressors &
inotropics, tachycardia, fever, hypoglycemia,
progressively deteriorating mental status, &
biochemical changes.
• Acute Addison’s Crisis (cont.):
• May occur in:
a. Previously normal adrenal function(in isolation):
Serum Na & K w/in NL limits
& NOT hyperpigmented.
b. Superimposed on chronic adrenal insufficiency:
Dehydration, hyponatremia, hyperkalemia,
wt. loss, & azotemia.
Diagnosis:
Establishing Adrenal Insufficiency:
1. Basal Serum Cortisol:
*A very low morning serum or salivary
cortisol conc. suggests adrenal dysfunction.
*A high basal cortisol serum conc. suggests
an intact HPA axis.
2. Short ACTH Stimulation Test:
• Serum Cortisol is measured before & 30-60min
after IM or IV short ACTH adm.:
Addison’s is Ruled Out if pk. Cortisol conc.
>19mcg/dL.
• It Does:
*NOT exclude mild 1⁰or 2⁰ Addison’s.
*NOT distinguish between 1⁰ & 2⁰ Addison’s.
*Not always predict the response to stress.
• Differential Diagnosis:
1. Basal Plasma ACTH:
* Normally, Plasma ACTH conc. Is highest @ 8A.M. &
lowest @ midnight.
* Very high 8 A.M. plasma ACTH establishes
1⁰ adrenal insufficiency.
* Low or low normal Basal plasma ACTH establishes
2⁰ adrenal insufficiency.
2. Two-day ACTH Stimulation Test:
• When ACTH is infused over 8 hrs. on 2
consecutive days:
* In 1⁰ Addison’s, serum cortisol & UFC are
low & do NOT ↑with time.
* In 2⁰ adrenal insufficiency, serum cortisol &
UFC are increased @ 24 & 48 hrs.
3. Insulin-Induced Hypoglycemia:
• Hypoglycemia (BS < 40mg/dL) stimulates HPA.
a. Cortisol & BS are measured @ baseline.
b. IV Regular insulin is adm. then cortisol & BS
are measured every 15 min. for 90 min.
c. Adrenal insufficiency is suggested if:
plasma cortisol <18-20 mcg/dL @ 60-90min.
4. RAA:
*Plasma renin is increased & plasma aldosterone is
decreased in 1⁰ adrenal insufficiency
BUT Normal in 2⁰ adrenal insufficiency
5. CT & MRI:
*May also be helpful
• Therapeutic Plan:
* Addison’s Dz. Tx consists of :
a. Hormone replacement therapy.
& b. Supplemental glucocorticoid therapy during
stress periods.
• Replacement Glucocort. & Mineralocort. therapy is
continued indefinitely.
• Some cases of subclinical autoimmune adrenal
insufficiency may be self-limiting.
• Androgen replacement therapy may be considered
( NOT routinely recommended ).
• Treatment:
• Pharmacotherapy:
• Chronic Replacement Therapy:
1. Dexamethasone:
* Currently the glucocorticoid of choice for:
a. Chronic replacement therapy
b. Patient-initiated rescue therapy
c. Initial Tx of an adrenal crisis before the
diagnosis is confirmed.
2. Fludrocortisone:
* The mineralocorticoid of choice for chronic
replacement therapy.
• Approx. equipotent w/aldosterone but is only
available p.o.
* Dose is titrated to:
*relieve postural hypotension symptoms
*normalize standing & sitting BP
*normalize serum K & plasma renin
• The Current Recommendation:
• Dexamethasone 0.5mg (0.25-0.75mg)
+
Fludrocortisone 0.1mg (0.05-0.2mg) QD @ HS
• Doses are individualized to clinical response.
• If caused insomnia: Take the glucocort. when arise in A.M.
• Some pts. need a small (5-10mg) mid-afternoon supplemental
Hydrocortisone dose.
* For women, whose main source of androgens are the adrenals:
Androgen replacement therapy w/ Dehydroepiandrosterone
( DHEA ) (25-50 mg QD ) may improve the mood & sense of well-being
( Not well established ), but w/ high incidence of S/Es: sweat odor,
acne, hirsutism, …
• Acute Adrenal Crisis:
• Life-threatening
• Empiric GC replacement therapy & supportive therapy
must be started before Dx is confirmed.
• Hydrocotisone: DOC for the acute Tx or for
short-term parenteral use.
• Concomitant mineralocort. replacement therapy is not
necessary when large doses of hydrocortisone are adm.
because HC has ~ 1% of aldosterone mineral activity.
Acute Adrenal Crisis (cont.) :
• The GC dose is titrated to relieve clinical SxS
& normalize the morning plasma ACTH.
*
• HC is tapered to maintenance doses over
1-3 days as the precipitating illness resolves.
• Mineralcort. deficiency is treated w/:
Saline + Fluid loading
(Aldosterone replacement therapy is NOT effective
since it takes several days for Na-retaining effect to
be seen)
• Acute Adrenal Crisis (cont.) :
• Once pt. is stable, IV fluids are continued @
lower rate X 1-2 days.
• Fludrocortisone (mineralocort.replace.therapy):
started when the pt. is stable & able to take
p.o. meds.
• Supplemental Stress-Dose Steroids:
• Physiologically stressed Addison’s dz. pts. by
acute medical illness or trauma need
supplemental steroids.
• For special situations: See table
• Nonpharmacologic Therapy:
• For normotensive pts. consists of:
a. Liberalizing dietary salt intake.
b. Avoidance of Na-wasting diuretics &
spironolactone.
* Hypertensive pts. should be maintained on
salt-restricted diets.