Hirsutism is the excessive growth of terminal hair in androgen-dependent areas: upper lip, chin, sideburns, earlobes, tip of the nose, back, chest, areolae, axillae, lower abdomen, pubic triangle, and anterior thighs. Hirsutism is frequently associated with irregular menses and acne. Hirsutism should be distinguished from hypertrichosis, which is a nonandrogen-dependent increase in vellus hair. Hirsutism affects 5% to 10% of females.

Virilization consists of hirsutism, acne, and irregular menses along with signs of masculinization: deepening of the voice, increased muscle mass, temporal balding, clitoromegaly, and increased libido. Virilization results from high circulating levels of androgens, close to or in the male range, and is usually caused by an androgen-secreting tumor.

Twenty-five percent of testosterone comes from the ovaries, 25% from the adrenal glands, and 50% from peripheral conversion of androstenedione, which is produced by both the ovaries and adrenals. Testosterone is converted into dihydrotestosterone (DHT) by the enzyme 5-alpha-reductase, which is present in hair follicles, or to estradiol by the aromatase enzyme present in adipose tissue (Fig. 48-1). DHT binds to androgen receptors and is responsible for the transformation of vellus into terminal hair. Hair follicles also contain the enzymes that convert dehydroepiandrosterone (DHEA), which is produced by the adrenals, and androstenedione into testosterone.

Hirsutism is caused by hyperandrogenism. Androgens transform the fine, downy, minimally pigmented vellus hair in androgen-sensitive areas into coarse, pigmented, terminal hair. An increase in any of the androgenic steroids may cause high levels of DHT in the hair follicle and result in hirsutism.

Low levels of sex hormone–binding globulin (SHBG), which is produced by the liver, may promote hirsutism. Eighty percent of circulating testosterone is bound to SHBG, 19% is bound to albumin, and 1% is free. Decreases in SHBG increase the free fraction of hormone available to androgen-sensitive hair.

Increased activity of 5-alpha-reductase, even with normal circulating androgen levels, also may cause hirsutism by the excessive conversion of testosterone into DHT.

 Polycystic ovary syndrome (PCOS)

 Congenital adrenal hyperplasia (CAH)

 Idiopathic or familial hirsutism

 Cushing syndrome

 Prolactinoma

 Hypothyroidism

 Acromegaly

 Medications

The exact cause of PCOS is unknown, but affected patients have been shown to have an accelerated rate of pulsatile gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus. The gonadotropin secretory profile is highly dependent on the rate of GnRH pulsatility. Rapid GnRH pulses stimulate the secretion of luteinizing hormone (LH), but not follicle-stimulating hormone (FSH), from the pituitary gland. The increased LH/FSH secretory ratio results in arrested ovarian follicle development with cyst formation and hypertrophy of theca cells (hyperthecosis), thus leading to constant estrogen and increased androgen production with chronic anovulation.

PCOS affects 5% to 10% of premenopausal women and is the most common cause of hirsutism. The hirsutism is gradually progressive, usually beginning at puberty, and most patients have irregular menses from the onset of menarche. However, in a study of hirsute patients with regular menses, 50% had polycystic ovaries. PCOS patients also frequently have insulin resistance and hyperinsulinemia. Because insulin decreases SHBG and increases the ovarian androgen response to LH stimulation, the hyperinsulinemia contributes to the elevated free androgen levels in PCOS. Thus, PCOS presents as a spectrum: some patients have minimal findings, whereas others have the entire constellation of hirsutism, acne, obesity, infertility, amenorrhea or oligomenorrhea, male pattern alopecia, acanthosis nigricans, hyperinsulinemia, and hyperlipidemia. The hyperandrogenism-insulin resistance-acanthosis nigricans (HAIR-AN) syndrome is a subtype of PCOS with marked hyperinsulinemia and androgen excess frequently associated with insulin receptor defects.

CAH results from a deficiency of one of the key enzymes in the cortisol biosynthesis pathway; it often manifests with precocious puberty and childhood hirsutism. Partial or late-onset CAH, resulting from milder deficiencies of the same enzymes, may cause postpubertal hirsutism. Ninety percent of CAH is secondary to 21-hydroxylase deficiency, which causes a defect in the conversion of 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol and of progesterone to desoxycorticosterone (DOC). The resulting low cortisol production rate leads to hypersecretion of pituitary adrenocorticotropic hormone (ACTH), which stimulates overproduction of 17-OHP and progesterone, as well as adrenal androgens, particularly androstenedione (Fig. 48-2). Hirsutism results from the androgen excess.

Deficiency of 11-beta-hydroxylase decreases the conversion of 11-deoxycortisol to cortisol and of DOC to corticosterone. This stimulates hypersecretion of ACTH, with consequent overproduction of 11-deoxycortisol, DOC, and androstenedione. Patients also frequently develop hypertension from the mineralocorticoid DOC. Deficiency of 3-beta-hydroxysteroid dehydrogenase (3β HSD) decreases the conversion of pregnenolone to progesterone and 17-hydroxypregnenolone to 17-OHP. This defect increases pregnenolone, 17-hydroxypregnenolone, and the androgens DHEA, DHEA sulfate (DHEAS), and androstenediol, which promote the development of hirsutism. Deficiency of 17-ketosteroid reductase decreases the conversion of androstenedione to testosterone, DHEA to androstenediol, and estrone to estradiol. Affected patients have elevated basal levels of androstenedione, DHEA, and estrone (see Fig. 48-2).

Idiopathic hirsutism is believed to be caused by increased cutaneous activity of 5-alpha-reductase or enhanced skin sensitivity to androgens. Familial hirsutism is an ethnic tendency to have a higher density of hair follicles per unit area of skin. Mediterraneans and Hispanics have increased hair density, whereas Asians have lower density. Patients with idiopathic or familial hirsutism usually have the onset of hirsutism shortly after puberty with a slow subsequent progression. They have normal menses and fertility, as well as a normal hormonal profile.

All causes of Cushing syndrome may result in hypertrichosis because of increased vellus hair on the face, forehead, limbs, and trunk secondary to cortisol hypersecretion. Cushing syndrome resulting from an adrenal tumor also may produce hirsutism and virilization from increased secretion of androgens with cortisol.

Hyperprolactinemia suppresses GnRH activity, which diminishes pulsatile LH secretion from the pituitary gland and results in decreased ovarian estrogen production and amenorrhea. Prolactin also increases the adrenal androgens, DHEA and DHEAS. Hypothyroidism decreases SHBG and thereby leads to an increase in free testosterone. Acromegaly is frequently associated with PCOS, and the hirsutism may result from the PCOS in conjunction with excessive insulin-like growth factor-I (IGF-I), growth hormone, and insulin resistance.