Adrenal hyperandrogenism

INTRODUCTION — The adrenal glands are a prominent source of androgen, particularly in children and women. Excess adrenal androgen secretion occurs in several different patient groups:

●It is a common and well-recognized cause of virilization in infants and children and an occasional cause of hirsutism and virilization in women. (See "Adrenal steroid biosynthesis" and "Pathophysiology and causes of hirsutism".)

●It can occur in men, in whom it has few clinical manifestations.

●It may contribute to the clinical findings in some patients with Cushing syndrome. (See "Epidemiology and clinical manifestations of Cushing syndrome".)

This topic will provide an overview of adrenal androgen synthesis and disorders associated with excess adrenal androgen secretion. More detailed discussions of individual disorders are found separately.

NORMAL ADRENAL ANDROGEN SYNTHESIS — Androgens are byproducts of the synthesis of cortisol in the adrenal glands. As a result, the major determinant of their production is corticotropin (ACTH). The primary adrenal androgens are dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) (figure 1). Less than 10 percent of DHEA and DHEAS are produced by the testes or ovaries.

DHEA and DHEAS have little, if any, intrinsic androgenic activity. However, small amounts are converted to androstenedione and then to testosterone (and to estrogen) in both the adrenal glands and peripheral tissues, including hair follicles, sebaceous glands, the prostate, external genitalia, and adipose tissue. Thus, while excess secretion of DHEA and DHEAS defines adrenal hyperandrogenism, the hirsutism and virilization are in fact caused by the more potent androgens androstenedione and testosterone. DHEA and DHEAS are metabolized primarily by reduction and conjugation to sulfates or glucuronides in the liver; the metabolites of these steroids and androstenedione are excreted as 17-ketosteroids in the urine.

DHEA and DHEAS are secreted in small amounts during infancy and early childhood. Their secretion gradually increases during late childhood, and the increase correlates with the development of small amounts of pubic and/or axillary hair in older, but still prepubertal, children, a phenomenon known as adrenarche. The cause of this increase in androgen secretion is not known; however, the increase is in parallel with the development of the zona reticularis of the adrenal cortex. ACTH and cortisol secretion do not increase, suggesting that ACTH is not responsible. Other proopiomelanocortin (POMC)-derived peptides or a postulated, but never confirmed, adrenal androgen-stimulating hormone may be involved [1,2]. Although the major factor responsible for adrenarche is not known, there are a number of hypotheses that are discussed separately. (See "Physiology and clinical manifestations of normal adrenarche", section on 'Regulation of zona reticularis/adrenarchal growth, development, and function'.)

In men, less than 5 percent of testosterone is derived from the adrenal or from adrenal precursors in peripheral tissues. In women, however, androstenedione and testosterone secreted by the adrenals and produced peripherally from DHEA, and to a lesser extent from DHEAS, contribute substantially to total androgen production. In the follicular phase of the menstrual cycle, as an example, the adrenals directly or indirectly account for approximately 65 percent of testosterone production. In the midcycle, the ovarian contribution increases, so that the adrenals contribute only approximately 40 percent. (See "Overview of androgen deficiency and therapy in females", section on 'Premenopausal females'.)

In both males and females, serum DHEA and DHEAS concentrations rise throughout puberty and for a few years thereafter, reaching a peak in the third decade of life (the concentrations of DHEAS are 100 to 1000 times higher than those of DHEA at all ages). Thereafter, they decline progressively; by age 80 years, the concentrations are only approximately 25 percent of those at age 25 years [3]. The cause or consequences, if any, of this decline, also called adrenopause, are not known. (See "Overview of androgen deficiency and therapy in females", section on 'Effect of age and menopause'.)

In contrast, some menopausal women may experience an increase in hyperandrogenism manifestations [4]. The increase in androgens during this time may be of adrenal and/or ovarian origin. (See "Evaluation and management of postmenopausal hyperandrogenism".)

CLINICAL MANIFESTATIONS — The clinical manifestations of adrenal hyperandrogenism vary with the age at onset and the sex of the patient.

Prepubertal children — In prepubertal children, androgen excess from any source increases height velocity, somatic development, and skeletal maturation. Epiphyseal fusion may occur prematurely, leading to short adult height. (See "Premature adrenarche" and "Definition, etiology, and evaluation of precocious puberty".)

Other findings vary with the sex of the child:

●In prepubertal boys, increases in androgen exposure causes virilization manifested by penile enlargement, growth of hair in androgen-dependent areas, deepening of the voice, and development of other secondary sexual characteristics (eg, isosexual precocious puberty)

●In prepubertal girls, androgen excess causes hirsutism, acne, and clitoromegaly (eg, heterosexual precocious puberty)

Pubertal children — In pubertal boys, androgen excess increases the rate of progression of puberty and skeletal maturation, which can lead to premature epiphyseal fusion, thereby decreasing adult height. However, pubertal development and growth may also be arrested in boys who have hypercortisolism (Cushing syndrome) [5] because chronic cortisol excess inhibits pituitary-gonadal function and growth hormone secretion [6]. (See "Diagnostic approach to children and adolescents with short stature" and "Definition, etiology, and evaluation of precocious puberty".)

In pubertal girls, androgen excess causes virilization, primary or secondary amenorrhea, and increased skeletal maturation. As in boys, concurrent hypercortisolism may cause gonadal suppression and stunt linear growth.

Adults — In adult men, adrenal androgen excess has little effect (ie, hair growth or muscle mass do not increase; however, acne and hirsutism in early puberty may occur). It does, however, inhibit gonadotropin secretion so that testes size, testicular testosterone secretion, and spermatogenesis may decrease [7].

In adult women, increased adrenal androgen production causes hirsutism, acne, male-pattern baldness, menstrual irregularities, oligomenorrhea or amenorrhea, infertility, and even frank virilization. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Female reproduction' and "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

PRIMARY ADRENAL CAUSES — Excessive adrenal production of androgens may occur as a result of both acquired and inherited adrenal diseases and other diseases that affect adrenal function (table 1).

Premature adrenarche — Premature adrenarche is the appearance of pubic or axillary hair before the age of eight years in girls and nine years in boys, without other signs of puberty or virilization and without a major advance in bone age [8]. It is more common in girls than in boys, usually occurs after the age of six years, and is not progressive. (See "Premature adrenarche".)

A rare genetic defect in dehydroepiandrosterone (DHEA) sulfation, caused by a mutation in the gene encoding the sulfate donor PAPSS2, has been described. This mutation results in premature pubarche (isolated premature appearance of sexual hair), hirsutism, acne, oligomenorrhea, and very low (undetectable) DHEA sulfate (DHEAS) levels. (See "Uncommon congenital adrenal hyperplasias", section on 'PAPSS2 deficiency (apparent DHEA sulfotransferase deficiency)'.)

Adrenal tumors — Both benign and malignant adrenal tumors or bilateral macronodular adrenal hyperplasia can produce mainly or only androgens, including testosterone.

Adenomas — Androgen-secreting adrenal adenomas are rare. Affected patients have high serum androgen concentrations that do not fall in response to dexamethasone; in rare cases, the tumor secretes only testosterone [9]. These patients usually do not have marked clinical or biochemical androgen excess. The tumors are typically small (diameter less than 4 cm) but are generally visible on computed tomography (CT) or magnetic resonance imaging (MRI). (See "Clinical presentation and evaluation of adrenocortical tumors", section on 'Androgen and estrogen-secreting tumors'.)

Carcinoma — Androgen-secreting adrenal carcinomas are more common than adenomas. These tumors characteristically produce androgens, many steroid intermediates, and sometimes cortisol. Some patients have a palpable abdominal mass or metastatic disease at the time of diagnosis, and many have clinical manifestations of both cortisol and androgen excess. Nearly all patients have very high serum DHEA and DHEAS concentrations and urinary 17-ketosteroid excretion, and the values do not fall in response to high-dose dexamethasone. Serum cortisol concentrations and urinary cortisol excretion are often increased. Most adrenal carcinomas are larger than 5 cm in diameter and have already invaded the capsule of the gland or neighboring tissues by the time they are discovered. (See "Clinical presentation and evaluation of adrenocortical tumors", section on 'Clinical presentation'.)

Bilateral macronodular adrenal hyperplasia — Although the majority of patients with bilateral macronodular adrenal hyperplasia present with subclinical or overt Cushing syndrome, some have cosecretion of cortisol with other steroids, including adrenal androgens. (See "Cushing's syndrome due to primary bilateral macronodular adrenal hyperplasia".)

ACTH-DEPENDENT CAUSES — There are several forms of adrenal hyperandrogenism that are mediated by corticotropin (ACTH).

Congenital adrenal hyperplasia — Congenital adrenal hyperplasia is the prototypic disorder of adrenal androgen secretion. Hyperandrogenism occurs in those disorders in which cortisol synthesis is impaired, but the androgen secretory pathway is intact. These include CYP21A2 (21-hydroxylase) and CYP11B1 (11-beta-hydroxylase) deficiencies. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Uncommon congenital adrenal hyperplasias".)

Hexose-6-phosphate-dehydrogenase deficiency (apparent cortisone reductase deficiency) — 11-beta-hydroxysteroid dehydrogenase type 1 deficiency has also been referred to as "apparent cortisone reductase deficiency" [10]. The type 1 enzyme converts the inactive cortisone to cortisol in the liver and other tissues. Deficiency of this enzyme is compensated for by ACTH hypersecretion in a mechanism similar to that described for glucocorticoid resistance. This disorder is discussed in greater detail separately. (See "Uncommon congenital adrenal hyperplasias", section on 'Hexose-6-phosphate-dehydrogenase deficiency (apparent cortisone reductase deficiency)'.)

ACTH-dependent Cushing syndrome — Corticotropin (ACTH)-dependent Cushing syndrome is the most common cause of endogenous hypercortisolism, most often caused by a corticotroph adenoma of the pituitary, occasionally by ectopic ACTH secretion, and very rarely by excess corticotropin-releasing hormone (CRH) secretion. Thus, cortisol secretion should be evaluated in any adult patient with androgen excess. (See "Establishing the diagnosis of Cushing syndrome" and "Establishing the cause of Cushing syndrome".)

Primary familial or sporadic glucocorticoid resistance syndrome — The rare syndrome of familial or sporadic glucocorticoid resistance is due to inactivating mutations in the gene for the glucocorticoid receptor and results in partial resistance to the actions of cortisol in all tissues [7]. As a result of pituitary resistance, there are increases in ACTH secretion and, therefore, in the secretion of cortisol, adrenal androgens, and the mineralocorticoid 11-deoxycorticosterone. The high serum cortisol concentrations maintain normal or near-normal glucocorticoid activity in tissues. Thus, the manifestations of glucocorticoid resistance vary from none, to chronic fatigue (perhaps reflecting glucocorticoid deficiency), to variable degrees of hyperandrogenism or mineralocorticoid excess. (See "Causes of primary adrenal insufficiency in children", section on 'End-organ unresponsiveness'.)

OTHER CAUSES

Hyperprolactinemia — Rarely, women with marked hyperprolactinemia due to a lactotroph adenoma have slight hirsutism and slightly high serum dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and androstenedione concentrations [11,12]. The cause of the hyperandrogenism is uncertain. Serum prolactin need not be measured in hirsute women, unless they have other manifestations of hyperprolactinemia such as oligomenorrhea, amenorrhea, or especially galactorrhea. (See "Clinical manifestations and evaluation of hyperprolactinemia".)

Exogenous DHEA intake — Dehydroepiandrosterone (DHEA) has been studied as a potential therapy for a number of disorders including adrenal insufficiency, depression, menopausal symptoms, fibromyalgia, and as a possible antiaging agent. However, the clinical benefits and safety of DHEA for any clinical indication is not well established. While DHEA is available by prescription only in most countries, in the United States, DHEA is widely available in stores that sell health foods and nutritional supplements. However, quality control (purity and potency) of these over-the-counter products has been shown to be quite poor. (See "Treatment of adrenal insufficiency in adults".)

Placental aromatase deficiency — Pregnant women who have placental aromatase or sulfatase deficiency are unable to produce estradiol and estriol from their precursors, DHEAS and 16-alpha-DHEAS, which come from the fetus [13,14].

Mothers with placental aromatase deficiency and their female fetuses may have some signs of androgen excess, and they have increases in serum DHEA, DHEAS, and testosterone concentrations. In comparison, women with placental sulfatase deficiency are asymptomatic but have low serum estriol concentrations. (See "Gestational hyperandrogenism".)

P450 oxidoreductase deficiency (apparent combined CYP17A1 and CYP21A2 deficiency) — In P450 oxidoreductase deficiency (ORD), affected neonates may present with severe undervirilization in boys and severe virilization in girls [10]. Maternal virilization, associated with a high excretion of androgen metabolites beginning around midgestation, is frequently but not invariably observed during pregnancies with ORD. This disorder is reviewed in detail separately. (See "Uncommon congenital adrenal hyperplasias", section on 'P450 oxidoreductase deficiency (apparent combined CYP17A1 and CYP21A2 deficiency)'.)

DIFFERENTIAL DIAGNOSIS — Hypersecretion of androgens from the adrenal glands nearly always results in high serum dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) concentrations, and one or both of these compounds (and serum testosterone) should be measured in any hirsute or virilized woman in whom the cause is not obvious. The results of measurements of serum DHEA and DHEAS must be interpreted on the basis of the patient's age.

The importance of measuring serum DHEA or DHEAS is that a high value in a hirsute or virilized patient strongly suggests that the patient has adrenal hyperandrogenism, whereas serum testosterone values are high in patients with either adrenal or ovarian hyperandrogenism. As an example, women with idiopathic hirsutism or the polycystic ovary syndrome, the most common causes of hirsutism and virilization in women, have normal or very minimally elevated serum DHEA and DHEAS concentrations. A serum DHEAS concentration above 500 mcg/dL (13.6 micromol/L) in a young woman strongly suggests the presence of an adrenal tumor [15,16]. Many clinicians use a higher DHEAS cutoff of 700 mcg/dL (19 micromol/L). (See "Evaluation of premenopausal women with hirsutism".)

Most androgen-secreting adrenal tumors can be identified by computed tomography (CT) or magnetic resonance imaging (MRI). Adrenal masses with low signal intensity on T1- and T2-weighted MRI images are usually adenomas, whereas carcinomas have low signal intensity on T1-weighted images and enhanced activity on T2-weighted images (image 1 and image 2). (See "Clinical presentation and evaluation of adrenocortical tumors", section on 'Imaging'.)

TREATMENT AND PROGNOSIS — The treatment and prognosis of patients with adrenal hyperandrogenism vary with the underlying cause.

Premature adrenarche — No treatment is needed besides reassurance. Pubertal development usually begins at the expected time. When associated with obesity or insulin resistance, appropriate advice for diet and lifestyle changes should be given [17]. (See "Premature adrenarche".)

When associated with nonclassic congenital adrenal hyperplasia, appropriate glucocorticoid replacement is given. (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Children'.)

Adrenal tumors — Surgery is the treatment of choice for all patients with hormone-secreting adrenal tumors [16,18]. Surgery is the initial treatment for patients with adrenocortical carcinoma and is technically feasible in most. (See "Treatment of adrenocortical carcinoma".)

Congenital adrenal hyperplasia — Patients with congenital adrenal hyperplasia are treated with a glucocorticoid and often a mineralocorticoid. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults" and "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Uncommon congenital adrenal hyperplasias".)

ACTH-dependent Cushing syndrome — Patients with corticotropin (ACTH)-dependent Cushing syndrome due to a corticotroph adenoma should be treated with pituitary surgery. Patients with ectopic ACTH or corticotropin-releasing hormone (CRH)-secreting tumors are more difficult to treat. (See "Overview of the treatment of Cushing syndrome" and "Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation".)

Primary glucocorticoid resistance — Patients with glucocorticoid resistance should be treated with appropriately titrated doses of a glucocorticoid that has no intrinsic mineralocorticoid activity, such as dexamethasone [7]. The goals of therapy are to reduce ACTH and therefore adrenal androgen (and mineralocorticoid) secretion, taking care not to cause iatrogenic Cushing syndrome. Women can be given spironolactone or flutamide to block the action of androgen. (See "Management of hirsutism in premenopausal women" and "Causes of primary adrenal insufficiency in children", section on 'End-organ unresponsiveness'.)

Hyperprolactinemia — The treatment of hyperprolactinemia varies with the cause. (See "Management of hyperprolactinemia".)

Placental enzyme deficiencies — Women with placental sulfatase deficiency need no therapy. Those with aromatase deficiency who have female fetuses could be treated with dexamethasone, which crosses the placenta and inhibits fetal adrenal function. However, the efficacy of this approach is not known. (See "Gestational hyperandrogenism", section on 'Placental aromatase deficiency'.)

SUMMARY

●Adrenal androgens – The adrenal glands are a prominent source of androgens. In fact, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are the most abundant products of the adrenal glands. The major determinant of their production is corticotropin (ACTH) (figure 1). Less than 10 percent of DHEA and DHEAS are produced by the testes or ovaries.

DHEA and DHEAS have little, if any, intrinsic androgenic activity. However, small amounts are converted to androstenedione and then to testosterone (and to estrogen) in both the adrenal glands and peripheral tissues, including hair follicles, sebaceous glands, the prostate, external genitalia, and adipose tissue. Thus, while excess secretion of DHEA and DHEAS defines adrenal hyperandrogenism, the hirsutism and virilization are, in fact, caused by the more potent androgens androstenedione and testosterone.

●Primary adrenal causes of adrenal hyperandrogenism

•Premature adrenarche (see "Premature adrenarche")

•Adrenal tumors – Adenomas and carcinomas, and bilateral macronodular adrenal hyperplasia (see "Clinical presentation and evaluation of adrenocortical tumors")

●ACTH-dependent causes of adrenal hyperandrogenism:

•Congenital adrenal hyperplasia (common forms such as 21-hydroxylase deficiency, as well as others) (see 'Congenital adrenal hyperplasia' above)

•ACTH-dependent Cushing syndrome (see 'ACTH-dependent Cushing syndrome' above)

•Primary glucocorticoid resistance syndrome (see 'Primary familial or sporadic glucocorticoid resistance syndrome' above)

●Other causes

•Hyperprolactinemia (see 'Hyperprolactinemia' above)

•Exogenous DHEA intake (see 'Exogenous DHEA intake' above)

•Placental aromatase deficiency (see 'Placental aromatase deficiency' above)

●Management – Management of adrenal hyperandrogenism depends upon the underlying cause. (See 'Treatment and prognosis' above.)