Evaluation of Hirsutism

David M. Slovik

Hirsutism is the development in women of excessive androgendependent terminal body hair in a male pattern. It is present in 5% to 10% of women of reproductive age and results from increased androgenic activity. Excessive growth occurs of hormone-dependent pubic, axillary, abdominal, chest, back, and facial hair. Women commonly present for evaluation when such hair growth is viewed as exceeding that of others in their societal, geographic, or racial environment. For those living in a society preoccupied with stereotypical perceptions of beauty, hirsutism may be extremely upsetting and connote loss of femininity and sexuality. For the primary physician, hirsutism raises the question of an underlying endocrinopathy, ranging in severity from minor changes in androgen metabolism to the development of a hormonally active neoplasm.

When confronted with a complaint of excessive hair growth, the primary care physician must distinguish between need for endocrine evaluation and simple reassurance +/- symptomatic measures.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16)

Pathophysiology

Hirsutism is a manifestation of excessive androgenic effect, either from increased androgen levels or increased end-organ sensitivity. Virilization develops with extremely high levels of circulating androgens. The hormonal stimulus for hair growth is 5-a-dihydrotestosterone, a potent testosterone metabolite derived from the peripheral conversion at the hair follicle of testosterone by 5-α-reductase. δ-4-Androstenedione and dehydroepiandrosterone (DHEA), produced by the ovaries and adrenal glands, are the precursors for 50% to 70% of circulating testosterone in women; the remainder of the testosterone is secreted directly by the ovaries or occasionally by the adrenals.

Hirsute women generally have increased production rates of DHEA and Ô-4-androstenedione, which are relatively weak androgens, or of testosterone, a more potent androgen. Serum measurements of the total concentrations of androgens reflect the binding of sex steroid hormones to sex hormone-binding globulin; however, only the free fraction, which in the case of testosterone is 1% of total testosterone, is biologically active. The source of enhanced androgen production may be the ovary, the adrenal gland, or both. Testosterone excess is usually of ovarian origin, dehydroepiandrosterone sulfate (DHEA-S) excess is of adrenal origin, and androstenedione excess can be of either adrenal or ovarian origin. Hyperinsulinism resulting from insulin resistance has been noted to trigger excess ovarian androgen production, providing a possible link between obesity and hirsutism, a common association. In addition, obesity leads to a reduction in the concentration of sex hormone-binding globulin.

Clinical Presentation

Hair follicles are located over the entire body except for the palms and soles. Hair growth is of two types: (a) lanugo (neonatal) or vellus, which is androgen-independent, soft, unpigmented, and rarely more than 2 cm long; and (b) terminal, which is coarse, stiff, and pigmented and grows in excess of 2 cm. A survey of college women revealed that one fourth had easily noticeable facial hair, one third reported hair extending along the linea alba from the pubic area (male escutcheon), and 17% had periareolar hair. Three fourths of women older than age 60 years have a measurable growth of facial hair.

Hirsutism presents as excessive growth of hormone-dependent pubic, axillary, abdominal, chest, back, and facial hair and follows familial, ethnic, and racial patterns. Eastern European women are more hirsute than are Scandinavian women; white women are more hirsute than are black women, who have more body hair than Asian women.

Virilization presents as temporal and vertical hair recession, acne, deepening voice, increased muscle mass, and clitoromegaly.

Ovarian Sources

Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the most common cause of androgen excess in women (65% to 85%). It is characterized by menstrual irregularity (oligomenorrhea or amenorrhea) and hyperandrogenism (either clinical or with elevated androgen levels). Androgen excess is usually evident at the time of puberty or shortly thereafter, and the symptoms gradually worsen with age. Gonadotropin dynamics are abnormal, with a loss of pulsatile secretion of luteinizing hormone (LH), an increased ratio of LH to follicle-stimulating hormone (FSH), and elevated levels of LH. Concurrent obesity and insulin resistance are noted in many patients, which contribute to androgen excess. Both LH and insulin stimulate excessive secretion of ovarian testosterone and androstenedione. As a consequence of insulin resistance, hyperglycemia and dyslipidemia can develop. Acanthosis nigricans, precocious puberty, and metabolic syndrome may occur. Large numbers of small ovarian follicles form, but follicular growth is abnormal, and no preovulatory follicles develop. Menstrual abnormalities and infertility are the consequence (see Chapter 112). The ovaries may be of normal size or enlarged, and they characteristically contain multiple follicular cysts.

Ovarian Hyperthecosis.

Ovarian hyperthecosis is a nonmalignant condition, characterized by increased testosterone production by luteinized theca cells in the stroma. It may be part of the spectrum of PCOS.

Ovarian Tumors.

Ovarian tumors, including arrhenoblastomas and hilar cell tumors, are capable of causing virilization through an excess production of testosterone. The virilized patient often has testosterone levels exceeding 150 to 200 ng/dL. Hirsutism caused by these tumors is most likely to occur later in life with more rapid progression of symptoms compared with PCOS. Such androgen-secreting tumors are present in about 0.2% of hyperandrogenic women; over half are malignant.

Adrenal Sources

Late-onset congenital adrenal hyperplasia (nonclassical congenital adrenal hyperplasia) designates a heterogeneous group of mild disorders of cortisol biosynthesis that are increasingly recognized as an important cause of adult-onset hirsutism. Prevalence is less than 5% of hyperandrogenic women in the general population. They are most commonly due to a deficiency in the activity of 21-hydroxylase, which leads to increased production of both 17-hydroxyprogesterone (substrate for 21-hydroxylase) and androstenedione with resultant hyperandrogenicity. These patients are not cortisol deficient due to an increase in adrenocorticotropic hormone (ACTH) secretion. Their condition is inherited as an autosomal recessive trait closely linked to the human leukocyte antigen (HLA) gene.

Adrenal Tumors.

Adrenal neoplasms may cause androgen excess. Cushing syndrome, especially if the underlying cause is an adrenocortical carcinoma, may produce virilization. Other causes of Cushing syndrome are more likely to produce excess hair growth and typical cushingoid features without true virilization.

Other Causes

Hyperprolactinemia.

Androgen excess may accompany hyperprolactinemia because prolactin stimulates androgen production, particularly DHEA. Characteristic features are amenorrhea and galactorrhea (see Chapter 112). Many of these women have PCOS and the hyperandrogenism related to it, especially because DHEA-S is such a weak androgen.

Idiopathic Hirsutism.

This group of women has hirsutism with normal serum androgen levels, no menstrual irregularities, and no other identifiable cause. This etiology appears to involve enhanced peripheral conversion of testosterone to dihydrotestosterone by increased 5-α-reductase activity in hair follicles and skin.

Idiopathic Hyperandrogenism.

Idiopathic hyperandrogenism is characterized by clinical hyperandrogenism, increased serum androgen levels, normal ovulatory cycles, and normal ovaries on ultrasound.

Drugs.

Drugs are another important cause of hirsutism. Most potent are the anabolic steroids (methyltestosterone, oxandrolone), used surreptitiously by some women engaged in competitive body building or athletics. The sex steroid precursor androstenedione is available without prescription and is very popular among adolescents; it is estimated that 2.5% of all adolescent girls take the drug regularly, especially those engaged in competitive athletics. When used in doses of 300 mg/d by young men, it results in increased levels of testosterone and estradiol. Similar increases in sex hormones are likely in young women, although they are not yet documented.

Danazol, used to treat endometriosis, may also bring on hirsutism. In an occasional patient, oral contraceptives containing androgenic progestogens may stimulate hair growth (see Chapter 119), although this is not a frequent side effect. Phenytoin, glucocorticoids, cyclosporine, diazoxide, and minoxidil stimulate hair growth by poorly understood, nonandrogenic mechanisms. Taking growth hormone can also result in hirsutism.

TABLE 98-1 Differential Diagnosis of Hirsutism

Cause		Mechanism
Hirsutism without Virilization
	Idiopathic	Increased peripheral conversion of androgens
	Late-onset congenital adrenal hyperplasia	Adrenal androgen overproduction
	Cushing syndrome (ACTH induced)	Adrenal androgen overproduction
	Polycystic ovary disease	Ovarian androgen overproduction
	Insulin resistance/obesity	Ovarian androgen overproduction
	Drugs: anabolic steroids, danazol, minoxidil, phenytoin, diazoxide, glucocorticoids	Varies, ranging from direct androgenic activity to nonandrogenic effects
Hirsutism with Virilization
	Ovarian hyperthecosis	Autonomous ovarian androgen production
	Ovarian neoplasms	Autonomous ovarian androgen production
	Adrenal neoplasms, especially adrenal carcinoma	Autonomous adrenal androgen production
ACTH, adrenocorticotropic hormone.

DIFFERENTIAL DIAGNOSIS (1,9,13)

The causes of hirsutism can be divided into those that do and those that do not cause virilization and categorized according to adrenal and ovarian sources of androgen excess (Table 98-1). Among 950 hirsute patients presenting to an endocrine clinic with evidence of androgen excess, PCOS accounted for 72.1% (classic anovulatory 56.6%, mild ovulatory 15.5%); idiopathic hyperandrogenism for 15.8%; idiopathic hirsutism for 7.6%; 21-hydroxylase-deficient, nonclassic adrenal hyperplasia for 4.3%; and androgen-secreting tumor for 0.2%.

Some patients with anorexia nervosa report an increase in body hair (see Chapter 234), and excessive tweezing may traumatize the hair follicle and cause coarse hair to grow at the site of repeated injury.

WORKUP (1, 2, 3 and 4,9,10,12, 13, 14, 15 and 16)

The paramount objective in the evaluation of hirsutism is to identify the women who are likely to have important underlying endocrine disease.

History

The history should include information about menstrual history, time course of symptoms, other clinical features of androgen excess, medication history, and family history. Features suggestive of serious endocrine disease include virilization (voice change, temporal hair recession, increased muscle mass, acne); rapid progression, particularly a sudden increase in hair growth after age 25 years or progression in spite of therapy; amenorrhea or menstrual changes; and galactorrhea. The new onset of hypertension in the setting of hirsutism should also raise suspicion. A peripubertal onset of hirsutism is generally reassuring. A detailed drug history (anabolic steroids, androgens, oral contraceptives, danazol, phenytoin, valproic acid, corticosteroids, minoxidil, cyclosporine, diazoxide) is essential. Inquiry into any daily or regular use of nonprescription sex hormone precursors, such as androstenedione, is essential because the substance is popular among adolescent
competitive athletes, who take it to enhance their performance (as noted earlier, the estimated prevalence of regular use among adolescent women is 2.5%). Southern European or Mediterranean ancestry in conjunction with hirsutism of a similar degree in a mother, grandmothers, aunts, and sisters reduces the probability of serious disease. However, a positive family history may also be found in some patients with polycystic ovary disease and partial congenital adrenal hyperplasia.

Physical Examination

Terminal hair on the face, about the areolae, and on the lower abdomen is normal, but new growth, especially on the lip, chin, upper abdomen, sternum, upper back, and shoulders, suggests androgen excess and hirsutism. Virilization, indicative of marked androgenic stimulation, is heralded by temporal and vertical hair loss, deepening voice, increasing muscle mass, and cliteromegaly.

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