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

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: 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 ACTH-independent. 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

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: Reduce cortisol production before surgery. Maintain normal plasma cortisol levels while awaiting results of surgery or radiation Tx. 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: Steroidogenic Inhibitors: ( Ketoconazole, Metyrapone, Aminoglutethimide, Mitotane, Etomidate ) *Used almost exclusively to treat ACTH- dependent synd. *Most effective agents available for treating Cushing’s synd. Neuromodulators of ACTH Secretion: ( Bromocriptine, Cyproheptadine, Valproate) *Disappointing results. 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 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: 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: Ketoconazole inhibits metabolism of drugs i.e. warfarin, phenytoin, … 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: Transsphenoidal microadenomectomy: Surgery of choice for circumscribed microadenomas (cure 95%) Preserves normal anterior pituitary function. ACTH- & CRH- Secreting Tumors Resection: Curative, but most tumors are non-resectable.

c. Bilateral Total Surgical Adrenalectomy: indications: 1 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: 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: Previously normal adrenal function(in isolation): Serum Na & K w/in NL limits & NOT hyperpigmented. Superimposed on chronic adrenal insufficiency: Dehydration, hyponatremia, hyperkalemia, wt. loss, & azotemia.

Diagnosis: Establishing Adrenal Insufficiency: 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.

The GC dose is titrated to relieve clinical SxS *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.