Adrenal Androgen Excess Disorders

ADRENAL ANDROGEN EXCESS DISORDERS

Adrenal disorders that cause an increase in androgen pro-duction can lead to hirsutism and virilization; the most common are congenital adrenal hyperplasia, Cushing syn-drome, and adrenal neoplasms.

Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is caused byenzyme deficiencies that result in precursor (substrate) excess, thus resulting in androgen excess. DHEA is a pre-cursor for androstenedione and testosterone.

The most common cause of increased adrenal androgen pro-duction is adrenal hyperplasia as a result of 21-hydroxylasedeficiency; 21-hydroxylase catalyzes the conversion of pro-gesterone and 17α-hydroxyprogesterone to desoxycortico-sterone and compound S.

When 21-hydroxylase is deficient, there is an accumu-lation of progesterone and 17α-hydroxyprogesterone, which are metabolized subsequently to DHEA. This dis-order affects approximately 2% of the population and is caused by an alteration in the genes for 21-hydroxylase, which are carried on chromosome 6. The genetic defect is autosomal recessive and has variable penetrance.

In the most severe form of 21-hydroxylase deficiency, the newly born female infant is simply virilized (ambiguous geni-talia) or is virilized and suffers from life-threatening salt wast-ing (Box 36.1). However, milder forms are more commonand can appear at puberty or even later in adult life. A mild deficiency of 21-hydroxylase is frequently associated with terminal body hair, acne, subtle alterations in menstrual cycles, and infertility.

Box 36.1

Manifestations of 21-Hydrolase Deficiency

Severe:

·               Newborn female infant

·               Virilized (ambiguous genitalia), or virilized and has life-threatening salt wasting

Mild:

·               Frequently associated with terminal body hair, acne, subtle alterations in menstrual cycles and infertility

·               Patients can also have sonographic evidence of polycystic-appearing ovaries.

Manifested at puberty

·               Adrenarche may precede thelarche.

·               History of pubic hair growth occurring before the onset of breast development may be a clinical clue.

These patients can also have sono-graphic evidence of polycystic-appearing ovaries. When21-hydroxylase deficiency is manifested at puberty, adrenarche may precede thelarche. The history of pubic hair growthoccurring before the onset of breast development may be a clinical clue to this disorder. The diagnosis of 21-hydroxylase deficiency is made by measuring increased 17-OH progesterone in plasma during the follicular phase (preferably measured while fasting). Patients with classic 21-hydroxylase deficiency will have significantly elevated plasma 17-OH progesterone levels, usually over 2000 ng/dL. Those with less severe 21-hydroxylase deficiency may have mildly elevated basal levels, 200 ng/dL, and an increase to usually 1000 ng/dL in response to ACTH stimulation. Dehydroepiandrosterone sulfate (DHEA-S) and androstenedione will also be elevated and contribute to the hirsutism and virilizing signs.

A less-common cause of adrenal hyperplasia is 11β-hydroxylase deficiency. The enzyme 11β-hydroxylase catalyzesthe conversion of desoxycorticosterone to cortisol. A defi-ciency in this enzyme also results in increased androgen production. The clinical features of 11β-hydroxylase defi-ciency are mild hypertension and mild hirsutism. The diagnosis of 11β-hydroxylase deficiency is made by dem-onstrating increased plasma desoxycorticosterone.

Treatment of CAH is aimed at restoring normal corti-sol levels. In CAH, cortisol production is reduced secondary to enzymatic block. This decreased cortisol production results in a compensatory increase in ACTH secretion to attempt to stimulate cortisol production. This increased ACTH production results in the oversecretion of precur-sor molecules proximal to the enzymatic block, which results in oversecretion of androgens. In patients with a high-grade enzymatic block, inadequate amounts of glu-cocorticoids and mineralocorticoids are made, resulting in salt loss, which can be life-threatening. Nonclassic CAH canbe managed easily by supplementing glucocorticoids. Usually,prednisone, 2.5 mg daily (or its equivalent), suppresses adrenal androgen production to within the normal range. When this therapy is instituted, facial acne usually clears promptly, ovulation is restored, and there is no new termi-nal hair growth.

Medical therapy for adrenal and ovarian disorders cannot resolve hirsutism. It can only suppress new hair growth. Hairthat is present must be controlled by shaving, bleaching, using depilatory agents, by electrolysis or laser hair ablation.

Cushing Syndrome

Cushing syndrome is an adrenal disease resulting in adrenalexcess. As a result of an adrenal neoplasm or an ACTH-producing tumor, the patient demonstrates signs of corti-costeroid excess that include truncal obesity, moonlike facies, glucose intolerance, skin thinning with striae, osteo-porosis, proximal muscle weakness in addition to evidence of hyperandrogenism, and menstrual irregularities.

Adrenal Neoplasms

Androgen-secreting adrenal adenomas cause a rapid in-crease in hair growth associated with severe acne, amenor-rhea, and sometimes virilization. In androgen-secreting adenomas, DHEA-S is usually elevated above 6 mg/mL. The diagnosis of this rare tumor is established by computed axial tomography (CAT) or magnetic resonance imaging (MRI) of the adrenal glands. Adrenal adenomas must be removed surgically.