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Hirsutism and Virilization
David A. Ehrmann
Hirsutism, defined as excessive male-pattern hair growth, affects approximately 10% of women. If often represents a variation of normal hair growth, but rarely it is a harbinger of a serious underlying condition. Hirsutism is often idiopathic but may be caused by conditions associated with androgen excess, such as polycystic ovarian syndrome (PCOS) or congenital adrenal hyperplasia (CAH) (Table 1). Cutaneous manifestations commonly associated with hirsutism include acne and male-pattern balding (androgenic alopecia). Virilization refers to the state in which androgen levels are sufficiently high to cause additional signs and symptoms such as deepening of the voice, breast atrophy, increased muscle bulk, clitoromegaly, and increased libido; virilization is an ominous sign that suggests the possibility of an ovarian or adrenal neoplasm.
TABLE 1 Causes of Hirsutism
HAIR FOLLICLE GROWTH AND DIFFERENTIATION
Hair can be categorized as either vellus (fine, soft, and not pigmented) or terminal (long, coarse, and pigmented). The number of hair follicles does not change over an individual's lifetime, but the follicle size and type of hair can change in response to numerous factors, particularly androgens. Androgens are necessary for terminal hair and sebaceous glanddevelopment and mediate differentiation of pilosebaceous units (PSUs) into either a terminal hair follicle or a sebaceous gland. In the former case, androgens transform the vellus hair into a terminal hair; in the latter, the sebaceous component proliferates and the hair remains vellus.
There are three phases in the cycle of hair growth: (1) anagen (growth phase), (2) catagen (involution phase), and (3) telogen (rest phase). Depending on the body site, hormonal regulation may play an important role in the hair growth cycle. For example, the eyebrows, eyelashes, and vellus hairs are androgen-insensitive, whereas the axillary and pubic areas are sensitive to low levels of androgens. Hair growth on the face, chest, upper abdomen, and back requires greater levels of androgens and is therefore more characteristic of the pattern typically seen in males. Androgen excess in women leads to increased hair growth in most androgen-sensitive sites except in the scalp region, where hair loss occurs because androgens cause scalp hairs to spend less time in the anagen phase.
Although androgen excess underlies most cases of hirsutism, there is only a modest correlation between androgen levels and the quantity of hair growth. This is due to the fact that hair growth from the follicle also depends on local growth factors, and there is variability in end-organ sensitivity. Genetic factors and ethnic background also influence hair growth. In general, dark-haired individuals tend to be more hirsute than blonde or fair individuals. Asians and Native Americans have relatively sparse hair in regions sensitive to high androgen levels, whereas people of Mediterranean descent are more hirsute.
Historic elements relevant to the assessment of hirsutism include the age of onset and rate of progression of hair growth and associated symptoms or signs (e.g., acne). Depending on the cause, excess hair growth is typically first noted during the second and third decades. The growth is usually slow but progressive. Sudden development and rapid progression of hirsutism suggests the possibility of an androgen-secreting neoplasm, in which case virilization may also be present.
The age of onset of menstrual cycles (menarche) and the pattern of the menstrual cycle should be ascertained; irregular cycles from the time of menarche onward are more likely to result from ovarian rather than adrenal androgen excess. Associated symptoms such as galactorrhea should prompt evaluation for hyperprolactinemia and possibly hypothyroidism. Hypertension, striae, easy bruising, centripetal weight gain, and weakness suggest hypercortisolism (Cushing's syndrome). Rarely, patients with growth hormone excess (i.e., acromegaly) will present with hirsutism. Use of medications such as phenytoin, minoxidil, or cyclosporine may be associated with androgen-independent causes of excess hair growth (i.e., hypertrichosis). A family history of infertility and/or hirsutism may indicate disorders such as nonclassic CAH.
Physical examination should include measurement of height, weight, and calculation of body mass index (BMI). A BMI >25 kg/m2 is indicative of excess weight for height, and values >30 kg/m2 are often seen in association with hirsutism. Notation should be made of blood pressure, as adrenal causes may be associated with hypertension. Cutaneous signs sometimes associated with androgen excess and insulin resistance include acanthosis nigricans and skin tags.
An objective clinical assessment of hair distribution and quantity is central to the evaluation in any woman presenting with hirsutism. This assessment permits the distinction between hirsutism and hypertrichosis and provides a baseline reference point to gauge the response to treatment. A simple and commonly used method to grade hair growth is the modified scale of Ferriman and Gallwey, where each of nine androgen-sensitive sites is graded from 0 to 4. Approximately 95% of Caucasian women have a score below 8 on this scale; thus, it is normal for most women to have some hair growth in androgen-sensitive sites. Scores above 8 suggest excess androgen-mediated hair growth, a finding that should be assessed further by hormonal evaluation (see below). In racial/ethnic groups that are less likely to manifest hirsutism (e.g., Asian women), additional cutaneous evidence of androgen excess should be sought, including pustular acne or thinning hair.
Androgens are secreted by the ovaries and adrenal glands in response to their respective tropic hormones, luteinizing hormone (LH) and adrenocorticotropic hormone (ACTH). The principal circulating steroids involved in the etiology of hirsutism are testosterone, androstenedione, dehydroepiandrosterone (DHEA) and its sulfated form (DHEAS). The ovaries and adrenal glands normally contribute about equally to testosterone production. Approximately half of the total testosterone originates from direct glandular secretion, and the remainder is derived from the peripheral conversion of androstenedione and DHEA.
Although it is the most important circulating androgen, testosterone is, in effect, the penultimate androgen in mediating hirsutism; it is converted to the more potent dihydrotestosterone (DHT) by the enzyme 5α-reductase, which is located in the PSU. DHT has a higher affinity for, and slower dissociation from, the androgen receptor. The local production of DHT allows it to serve as the primary mediator of androgen action at the level of the pilosebaceous unit. There are two isoenzymes of 5α-reductase: type 2 is found in the prostate gland and in hair follicles, whereas type 1 is found primarily in sebaceous glands.
One approach to testing for hyperandrogenemia is depicted in. In addition to measuring blood levels of testosterone and DHEAS, it is also important to measure the level of free (or unbound) testosterone. The fraction of testosterone that is not bound to its carrier protein, sex-hormone binding globulin (SHBG), is biologically available for conversion to DHT and for binding to androgen receptors. Hyperinsulinemia and/or androgen excess decrease hepatic production of SHBG, resulting in levels of total testosterone within the high-normal range, whereas the unbound hormone is more substantially elevated. Although there is a decline in ovarian testosterone production after menopause, ovarian estrogen production decreases to an even greater extent, and the concentration of SHBG is reduced. Consequently, there is an increase in the relative proportion of unbound testosterone, and it may exacerbate hirsutism after menopause.
Because adrenal androgens are readily suppressed by low doses of glucocorticoids, the dexamethasone androgen-suppression test may broadly distinguish ovarian from adrenal androgen overproduction. A blood sample is obtained before and after administering dexamethasone (0.5 mg orally every 6 h for 4 days). An adrenal source is suggested by suppression of unbound testosterone into the normal range; incomplete suppression suggests ovarian androgen excess.
A baseline plasma total testosterone level >12 nmol/L (>3.5 ng/mL) usually indicates a virilizing tumor, whereas a level >7 nmol/L (>2 ng/mL) is suggestive. A basal DHEAS level >18.5 µmol/L (>7000 µg/L) suggests an adrenal tumor. Although DHEAS has been proposed as a “marker” of predominant adrenal androgen excess, it is not unusual to find modest elevations in DHEAS among women with PCOS. Computed tomography (CT) or magnetic resonance imaging (MRI) should be used to localize an adrenal mass, and ultrasound will usually suffice to identify an ovarian mass, if clinical evaluation and hormonal levels suggest these possibilities.
PCOS is the most common cause of ovarian androgen excess. However, the increased ratio of LH to follicle-stimulating hormone that is characteristic of carefully studied patients with PCOS is not seen in up to half of these women due to the pulsatility of gonadotropins. If performed, ultrasound shows enlarged ovaries and increased stroma in many women with PCOS. However, polycystic ovaries may also be found in women without clinical or laboratory features of PCOS. Therefore, polycystic ovaries are a relatively insensitive and nonspecific finding for the diagnosis of ovarian hyperandrogenism. Gonadotropin-releasing hormone agonist testing can be used to make a specific diagnosis of ovarian hyperandrogenism. A peak 17-hydroxyprogesterone level ≥7.8 nmol/L (≥2.6 µg/L), after the administration of 100 µg nafarelin (or 10 µg/kg leuprolide) subcutaneously, is virtually diagnostic of ovarian hyperandrogenism.
Nonclassic CAH is most commonly due to 21-hydroxylase deficiency but can also be caused by autosomal recessive defects in other steroidogenic enzymes necessary for adrenal corticosteroid synthesis. Because of the enzyme defect, the adrenal gland cannot secrete glucocorticoids efficiently (especially cortisol). This results in diminished negative feedback inhibition of ACTH, leading to compensatory adrenal hyperplasia and the accumulation of steroid precursors that are subsequently converted to androgen.Deficiency of 21-hydroxylase can be reliably excluded by determining a morning 17-hydroxyprogesterone level <6 nmol/L (<2 µg/L) (drawn in the follicular phase). Alternatively, 21-hydroxylase deficiency can be diagnosed by measurement of 17-hydroxyprogesterone 1 h after administration of 250 µg of synthetic ACTH (cosyntropin) intravenously.
Treatment of hirsutism may be accomplished pharmacologically or by mechanical means of hair removal. Nonpharmacologic treatments should be considered in all patients, either as the only treatment or as an adjunct to drug therapy.
Nonpharmacologic treatments include (1) bleaching; (2) depilatory (removal from the skin surface) such as shaving and chemical treatments; or (3) epilatory (removal of the hair including the root) such as plucking, waxing, electrolysis, and laser therapy. Despite perceptions to the contrary, shaving does not increase the rate or density of hair growth. Chemical depilatory treatments may be useful for mild hirsutism that affects only limited skin areas, though they can cause skin irritation. Wax treatment removes hair temporarily but is uncomfortable. Electrolysis is effective for more permanent hair removal, particularly in the hands of a skilled electrologist. Laser phototherapy appears to be efficacious for hair removal. It delays hair regrowth and causes permanent hair removal in most patients. The long-term effects and complications associated with laser treatment are being evaluated.
Pharmacologic therapy is directed at interrupting one or more of the steps in the pathway of androgen synthesis and action: (1) suppression of adrenal and/or ovarian androgen production; (2) enhancement of androgen-binding to plasma-binding proteins, particularly SHBG; (3) impairment of the peripheral conversion of androgen precursors to active androgen; and (4) inhibition of androgen action at the target tissue level. Attenuation of hair growth is typically not evident until 4 to 6 months after initiation of medical treatment and, in most cases, leads to only a modest reduction in hair growth.
Combination estrogen-progestin therapy, in the form of an oral contraceptive, is usually the first-line endocrine treatment for hirsutism and acne, after cosmetic and dermatologic management. The estrogenic component of most oral contraceptives currently in use is either ethinyl estradiol or mestranol. The suppression of LH leads to reduced production of ovarian androgens. The reduced androgen levels also result in a dose-related increase in SHBG, thereby lowering the fraction of unbound plasma testosterone. Combination therapy has also been demonstrated to decrease DHEAS, perhaps by reducing ACTH levels. Estrogens also have a direct, dose-dependent suppressive effect on sebaceous cell function.
The choice of a specific oral contraceptive should be predicated on the progestational component, as progestins vary in their suppressive effect on SHBG levels and in their androgenic potential. Ethynodiol diacetate has relatively low androgenic potential, whereas progestins such as norgestrel and levonorgestrel are pargenic, as judged from their attenuation of the estrogen-induced increase in SHBG. Norgestimate exemplifies the newer generation of progestins that are virtually nonandrogenic. Drospirenone, an analogue of spironolactone that has both antiineralocorticoid and antiandrogenic activities, has been approved for use as a progestational agent in combination with ethinyl estradiol. Its properties suggest that it should be the preferred choice for the treatment of hirsutism.
Oral contraceptives are contraindicated in women with a history of thromboembolic disease or in women with increased risk of breast or other estrogen-dependent cancers. There is a relative contraindication to the use of oral contraceptives in smokers or in those with hypertension or a history of migraine headaches. In most trials, estrogen-progestin therapy alone improves the extent of acne by a maximum of 50 to 70%. The effect on hair growth may not be evident for 6 months, and the maximum effect may require 9 to 12 months owing to the length of the hair growth cycle. Improvements in hirsutism are typically in the range of 20%, but there may be an arrest of further progression of hair growth.
Adrenal androgens are more sensitive than cortisol to the suppressive effects of glucocorticoids. Therefore, glucocorticoids are the mainstay of treatment in patients with CAH. Although glucocorticoids have been reported to restore ovulatory function in some women with PCOS, this effect is highly variable. Because of side effects from excessive glucocorticoids, low doses should be used. Dexamethasone (0.2 to 0.5 mg) or prednisone (5 to 10 mg) should be taken at bedtime to achieve maximal suppression by inhibiting the nocturnal surge of ACTH.
Cyproterone acetate is the prototypic antiandrogen. It acts mainly by competitive inhibition of the binding of testosterone and DHT to the androgen receptor. In addition, it may act to enhance the metabolic clearance of testosterone by inducing hepatic enzymes. Although not available for use in the United States, cyproterone acetate is widely used in Canada, Mexico, and Europe. Cyproterone (50 to 100 mg) is given on days 1 to 15 and ethinyl estradiol (50 µg) is given on days 5 to 26 of the menstrual cycle. Side effects include irregular uterine bleeding, nausea, headache, fatigue, weight gain, and decreased libido.
Spironolactone, usually used as a mineralocorticoid antagonist, is also a weak antiandrogen. It is almost as effective as cyproterone acetate when used at high enough doses (100 to 200 mg daily). Patients should be monitored intermittently for hyperkalemia or hypotension, though these side effects are uncommon. Pregnancy should be avoided because of the risk of feminization of a male fetus. Spironolactone can also cause menstrual irregularity. It is often used in combination with an oral contraceptive, which suppresses ovarian androgen production and helps prevent pregnancy.
Flutamide is a potent nonsteroidal antiandrogen that is effective in treating hirsutism, but concerns about the induction of hepatocellular dysfunction have limited its use. Finasteride is a competitive inhibitor of 5α-reductase type 2. Beneficial effects on hirsutism have been reported, but the predominance of 5α-reductase type 1 in the PSU appears to account for its limited efficacy. Finasteride would also be expected to impair sexual differentiation in a male fetus, and it should not be used in women who may become pregnant.
Eflornithine cream (Vaniqa) has been approved as a novel treatment for unwanted facial hair in women, but long-term efficacy remains to be established. It can cause skin irritation under exaggerated conditions of use. Ultimately, the choice of any specific agent(s) must be tailored to the unique needs of the patient being treated. As noted previously, pharmacologic treatments for hirsutism should be used in conjunction with nonpharmacologic approaches. It is also helpful to review the pattern of female hair distribution in the normal population to dispel unrealistic expectations.