Published: August 2010
Hirsutism is defined as a male pattern of hair distribution in a female, with the hair being transformed from fine villous hair to visible, coarse, terminally medullated hair under the influence of androgens.1 Hirsutism must be distinguished from hypertrichosis and lanugo. Hypertrichosis is the growth of villous hair that is not androgen dependent and that is prominent in sexual and nonsexual areas. Lanugo is very soft, villous, nonpigmented hair that covers the body.
Overall, the prevalence of hirsutism is unknown but may be as high as 50%. It is said that “even a single hair casts a shadow,” so that in cultures in which a lack of hair is a feature of female beauty, minimal hirsutism is considered a disorder, whereas in other cultures, in which some excess hair growth is acceptable, a significant change in the pattern and texture of the hair needs to be present before it is deemed a problem. In a classic British study of 430 normal women, there was no hair seen on the upper back or abdomen, indicating that the presence of hair in these areas is abnormal. In this study, 10% had hair on the chest, 22% had chin hair, and 49% had hair on the upper lip. The distribution of hair was very scanty in all these areas. Hence, the ethnic background, as well as distribution and density of hair growth, determine the degree of hirsutism. The practicing physician must place the patient in the spectrum of individuals in the locality in which he or she practices to be able to assess the severity of hirsutism objectively. In addition, the age at onset, rate of growth and progression, and associated symptoms and signs can determine the severity of the problem.
Androgens are a prerequisite for sexual hair development. Hirsutism can arise from increased androgen production or from increased sensitivity of the hair follicles to circulating androgens.
Testosterone is the most important circulating androgen because of its relatively high plasma concentration and greater potency at the target organ level. Circulating testosterone is the sum of the secretion from the ovaries (35%-40%) and adrenals (40%) in response to the tropic hormones—luteinizing hormone (LH) and adrenocorticotropic hormone (ACTH)—respectively. The remaining circulating testosterone is derived from the conversion of androgenic precursors, mainly androstenedione (derived from the ovaries and adrenals) and dehydroepiandrosterone (DHEA; derived almost exclusively from the adrenals).1-3 Peripheral conversion of androgenic prohormones to testosterone occurs in the liver, skin, and adipose tissue.1-3 Testosterone is present in the circulation as the free or conjugated form. Almost 98% to 99% of plasma testosterone is bound to steroid hormone-binding globulin (SHBG), to cortisol-binding globulin, or nonspecifically to albumin and other proteins and is biologically inactive. The free portion of testosterone is biologically active. In the hair follicles, testosterone is converted to its biologically active form, dihydrotestosterone, by the enzyme 5α-reductase.1-3
Sex hormones work independently in the liver to control SHBG production. Estrogens increase and androgens decrease the production of SHBG. Thus, in hyperandrogenic states, the SHBG level is decreased, thereby allowing even higher free androgen levels. The other major modulator of SHBG is insulin. Insulin decreases the production of SHBG so that in conditions of insulin resistance and compensatory hyperinsulinemia, the SHBG level is decreased.
The pilosebaceous unit (PSU) consists of a pilary component and sebaceous component. Each PSU has the capacity to form either a terminal hair (a dark, pigmented, large medullated hair) as its prominent structure or a sebaceous follicle in which the hair remains villous and the sebaceous gland is more prominent. Androgens play a key role in the development of the PSU. Before the onset of puberty, in androgen-sensitive areas, the hair is villous and sebaceous glands are small. When androgen levels increase during puberty or hyperandrogenic states, PSUs form terminal hairs in sexual areas and increase the size of sebaceous glands in sebaceous areas. Formation of terminal hairs, when excessive, leads to hirsutism; excess secretion from sebaceous glands predisposes to acne.8
The hair follicle is one of the androgen-sensitive appendages in the skin and is a major site for the formation of testosterone from its precursors. Also, the 5α-reductase enzyme present in the outer root sheath cells converts testosterone to its active metabolite, dihydrotestosterone. The dermal papilla cells are believed to be the target cells releasing the growth factors that act on other cells of the hair follicles.
Development of hirsutism is determined by androgen levels and the sensitivity of the PSU to androgens. Thus, the level of androgens does not always correlate to the degree of hirsutism. Increase in sensitivity is believed to be caused by exaggerated peripheral 5α-reductase activity, androgen receptor polymorphism, or altered androgen metabolism.2
Polycystic ovary syndrome (PCOS) and idiopathic causes account for 90% of cases of hirsutism.2-3 The androgen source is a mixture of contributions from the ovaries and adrenal glands. Other conditions can be classified according to the source of excess androgens. Ovarian causes are mainly ovarian tumors and hyperthecosis. Adrenal causes include Cushing’s syndrome, androgen-producing tumors, and congenital adrenal hyperplasia (CAH), most commonly resulting from 21-hydroxylase deficiency. Other causes of CAH are 11β-hydroxylase deficiency and 3β-hydroxysteroid dehydrogenase deficiency. Hyperprolactinemia can stimulate adrenal DHEA sulfate (DHEAS) production, thus predisposing to hirsutism.
In patients predisposed to hirsutism, exogenous androgens can cause hirsutism and should not be used. Androgen preparations, mainly estrogen-testosterone combinations, have been approved for treating postmenopausal symptoms, and need to be stopped. Tibolone, a steroid with estrogenic, progestogenic, and androgenic effects, should also be discontinued.4
Valproic acid, a commonly used antiepileptic agent, has been associated with PCOS. History of the use of this medication should be specifically determined in the evaluation of women with hirsutism.5 Although insulin resistance is a feature of PCOS, severe insulin resistance syndromes such as maturity-onset diabetes of the young and lipodystrophies are rarer causes of hirsutism.
Hirsutism can occur in older women, beginning a few years before menopause, and can continue for a few years after menopause. Ovarian estrogen secretion declines rapidly, whereas ovarian androgen production continues for a few years after menopause. Androgen production after menopause is gonadotropin dependent and, when excessive, can lead to hirsutism.6,7
History should include age at onset, rate of progression, virilization, family history, and current medications. Idiopathic hirsutism typically begins at the peripubertal age. Rate of progression is important because hirsutism caused by malignant lesions progresses rapidly. The presence of virilizing signs such as change in voice, male-pattern baldness, clitoromegaly, change in muscle distribution, and increase in libido make the presence of a serious underlying disorder likely. Family history, race, and ethnicity are important determinants of hirsutism; patients of Mediterranean, Middle Eastern, or South Asian descent are more likely to be hirsute without necessarily having significantly elevated androgen levels. Finally, current medications should be evaluated to screen for the use of androgenic steroids.
The amount and distribution of hair are an index of androgen effect. As noted, before puberty, most of the body is covered by fine, nonpigmented, nonmedullated hair called villous hair. In the presence of androgens, these hairs are converted to coarse, pigmented, medullated terminal hairs. Terminal hair on the face, around the areola, and on the abdomen below the level of the umbilicus is present in 10% of “normal” women. Terminal hairs of the upper back, shoulders, sternum, and upper abdomen suggest a more marked androgen effect.
Grading of hirsutism is done using the Ferriman-Gallway scale, which semiquantitatively measures the amount of hair growth; however, it is subject to large observer variability. Examination should include a search for signs of virilization such as male-pattern baldness, decreased voice pitch, increases muscle bulk, and clitoromegaly (length >10 mm or clitoral index [length > width] >35 mm2). Signs of insulin resistance (e.g., acanthosis nigricans, abdominal obesity), Cushing’s syndrome, and ovarian enlargement should be sought during the examination.
The goals of biochemical assessment are to evaluate the source of hyperandrogenism and to rule out the presence of a malignancy. Some physicians recommend no further evaluation in patients with mild hirsutism and regular ovulatory menses because these women do not have a serious underlying disorder.1 The major biochemical parameters tested are discussed next.
Testosterone, total and free, should be measured. In most patients with hirsutism, especially that associated with abnormal periods, the testosterone levels are high-normal or just above the upper limit of normal. The free testosterone level is also similarly affected. Values of total testosterone higher than 200 ng/mL suggest an androgen-producing tumor. Because testosterone has a diurnal rhythm and varies with the menstrual cycle, most norms are standardized to early morning blood samples drawn between days 4 and 10 of the cycle. In the absence of cycles, a random early-morning sample usually suffices.
DHEAS should be measured, but marginal elevations of the DHEAS level are common. Elevated values suggest an adrenal source of androgens. Levels higher than 700 μg/dL suggest an androgen-producing adrenal tumor. These patients should undergo further evaluation with computed tomography or magnetic resonance imaging to check for a tumor.
17-Hydroxyprogesterone, a precursor of cortisol, should be measured. To screen for adult-onset CAH, it should be measured between 7 am and 9 am in the early follicular phase of the menstrual cycle. Levels lower than 200 ng/dL exclude the disease. Mildly increased levels, from 300 to 1000 ng/dL, require an ACTH stimulation test. Cosyntropin (synthetic ACTH), 250 μg, is administered intravenously, and levels of 17-hydroxyprogesterone are measured before and 1 hour after the injection. Poststimulation values that exceed 1000 ng/dL indicate a positive test result.
Free cortisol in a 24-hour urine sample should be measured in women with signs and symptoms of Cushing’s syndrome.
Prolactin levels should be measured because an occasional woman with hirsutism and irregular menses could have hyperprolactinemia caused by hypothalamic disease or a pituitary tumor. Levels are also mildly elevated in up to 20% of patients with PCOS.
Serum follicle-stimulating hormone (FSH) level should be measured if ovarian failure is a consideration, but otherwise it is of minimal help.
Serum LH level should be measured because women with PCOS tend to have higher serum LH levels and a ratio of LH to FSH levels higher than 3. This is believed to be significant by some, but most authorities do not consider this a requirement for the diagnosis of PCOS. Ratios less than 3 do not exclude the diagnosis. Routine measurements of FSH and LH are therefore not needed.
Fasting plasma glucose and lipid profiles are not necessary for the diagnosis of PCOS. However, in patients suspected to have PCOS, insulin resistance, or both, these profiles are helpful to define the presence of metabolic risk, which over the long term can significantly affect a patient’s morbidity and mortality.
Ultrasound evaluation of the ovaries, adrenals, or both, may be useful for screening if the symptoms or biochemical levels suggest the presence of a neoplasm. Pelvic sonography findings have been included in the criteria for the diagnosis of PCOS.
The underlying cause should be treated. These guidelines refer to the treatment of hirsutism caused by PCOS and idiopathic hirsutism. Hirsutism is a cosmetic and psychological problem, not a life- threatening illness. Therefore, the risks and benefits of treatment have to be weighed.
Before beginning treatment, women should be warned that they might not see improvement in hair growth for 3 to 9 months. Drug treatment affects the growth of new hair follicles, but the half-life of established follicles is up to 6 months, so it takes that much time to see its effect.
Because of the significant association of insulin resistance and obesity with PCOS, therapy to reduce insulin resistance is appropriate. Diet, exercise, and weight loss should be prescribed for all women with PCOS. Diet therapy, consisting of decreased total caloric intake and an appropriately mixed high-fiber diet, in addition to a daily exercise program to induce weight loss, have been shown to reduce androgen production. A modest weight loss of 7 to 15 pounds with an appropriate exercise program are all that is needed to relieve menstrual and biochemical abnormalities.8
Mechanical hair removal can be achieved by shaving, waxing, or plucking or the use of depilatory creams. These treatments do not compound the problem. Bleaching can mask hair growth. Electrosurgical methods include electrosurgical epilation and laser treatment. Electrosurgical epilation was formerly the only commercially available method of long-term hair removal until the availability of laser treatment, but it is time-consuming, causes discomfort, and requires many treatments. There is a small but definite risk of punctate scarring and postinflammatory skin color changes. Laser treatment was introduced to remove hairs over larger areas effectively, with few complications. There are several different methods, and further studies are needed to determine the ideal treatment.
The antiandrogens are effective in the treatment of hirsutism. Their main effect is to inhibit the binding of testosterone and dihydrotestosterone to the androgen receptor.9 They all share the potential risk of teratogenicity to the developing fetus and should always be used with adequate contraception in women of childbearing age.
Spironolactone is a potent antiandrogen. In addition to binding testosterone and dihydrotestosterone to the androgen receptor, it can inhibit ovarian testosterone synthesis.9 The starting dose is 50 mg twice daily, which may be increased to a total daily dose of 200 mg/day. It takes at least 6 months for it to be fully effective. Numerous studies have shown its efficacy in the treatment of hirsutism, reducing clinical hirsutism scores by 15% to 40%. Side effects include nausea, fatigue, headaches, mastodynia, and irregular menses. There is a theoretical risk of an increase in serum potassium levels; renal insufficiency can predispose patients to this adverse effect. This drug can interfere with the appropriate sexual maturation of the fetus, especially a male fetus, and we strongly recommend the use of oral contraceptives along with spironolactone. In addition to protecting against pregnancy, and therefore against potential teratogenic effects, the oral contraceptives overcome irregular menses, a side effect of spironolactone. However, spironolactone use as an antiandrogen is not licensed in the United States.
Cyproterone acetate is a potent progestin and moderately potent antiandrogen. Like spironolactone, it inhibits the binding of dihydrotestosterone to the androgen receptor and suppresses gonadotropins. Side effects include nausea, breakthrough bleeding, decreased libido, and depression. It is generally used in combination with ethinyl estradiol. Cyproterone can cause fatal hepatitis and has not been licensed for use in the United States.
Flutamide is another androgen receptor blocker; it is used more commonly for the hormonal treatment of prostate cancer. Flutamide has been shown to be as effective as spironolactone, although some studies have suggested that it is more potent. Dosages of 125 to 500 mg/day are effective for hirsutism. Flutamide is not licensed in the United States for the treatment of hirsutism and, because of the significant risk of hepatoxicity, off-label use for hirsutism is discouraged by the U.S. Food and Drug Administration (FDA).
Cimetidine is a weak antiandrogen and is rarely used in the treatment of hirsutism.
Finasteride is an agent that inhibits 5α-reductase. Its efficacy is similar to that of cyproterone, spironolactone, or flutamide, but it can cause fatal hepatitis and is associated with a significant risk of teratogenicity; hence, it is rarely used. There are reports of a significant synergistic effect when combined with spironolactone.
Eflornithine cream (Vaniqa) is a topical agent that is believed to inhibit hair growth by inhibiting ornithine decarboxylase; this enzyme is modulated by androgens and regulates matrix cell proliferation in the hair follicle and thereby hair growth. The cream is applied to the face twice daily. Gradual improvement is seen in 4 to 6 weeks. Patients should be advised to use mechanical hair removal methods along with this treatment. However, 8 weeks after stopping this agent, hair growth reappears, without change from the pretreatment appearance.9
Estrogen-progesterone combinations act by reducing gonadotropin secretion and thereby reducing ovarian androgen production. They also increase levels of SHBG, resulting in lower levels of free testosterone, and they inhibit adrenal androgen production.9 Oral contraceptive pills (OCPs) containing progestins that are low in androgenic activity should be used. OCPs that contain norgestrel and levonorgestrel are more androgenic than others and must be avoided. The newer progestins, such as norgestimate, norethindrone, and desogestrel, have a lower androgenic potential and are preferable. We recommend starting with 35 μg of ethinylestradiol and one of the progestins mentioned earlier. If there is no response in biochemical parameters such as testosterone after two or three cycles of treatment, the pill can be changed to one with 50 μg ethinylestradiol. These agents are also effective in controlling hirsutism in the older woman at about the time of menopause.7
Yasmin is a newer contraceptive pill that contains 30 μg of estradiol and 3 mg of drospirenone as the progestin and has been shown to have the antiandrogenic action of spironolactone. Yaz is a similar preparation containing a lower dose (20 μg) of estradiol with the same amount of drospirenone. The antiandrogen effect of 3 mg of drospirenone is equivalent to that of 25 mg of spironolactone.
Long-acting gonadotropin-releasing hormone (GnRH) analogues (GnRH agonists) decrease gonadotropin secretion, reducing ovarian stimulation and hence testosterone. Estrogen production is also reduced, so this treatment is usually combined with an OCP containing estrogen and progestin. This therapy is parenteral and expensive, however, and is reserved for women with severe hirsutism who do not respond to a combination of an OCP and antiandrogen. Because GnRH agonist therapy causes a medical menopause, there is a significant risk for premature bone loss; therefore, bone mineral density must be tested and therapies to prevent bone loss may need to be simultaneously started.
Oral glucocorticoids cause a decrease in androgen levels in most women. We suggest prednisone 2.5 mg or dexamethasone 0.25 mg at bedtime. Side effects at these doses are small. Higher doses are associated with significant side effects, including a cushingoid habitus; weight gain; osteoporosis; glucose, lipid, and blood pressure abnormalities; and possible vascular disease. These drugs have a definite role in the treatment of hirsutism secondary to CAH. In other forms of hirsutism, they are best if combined with antiandrogens and should be reserved for severe cases, where the risk-to-benefit ratio is appropriate.
PCOS is strongly and significantly related to the presence of insulin resistance and its consequent hyperinsulinemia; thus, the use of insulin sensitizers for PCOS has gained wide acceptance. They improve ovulatory function and pregnancy rates in women with PCOS. Thus, metformin is used as a first-line therapy for infertile women with PCOS. Glitazones, because of their direct effect on nuclear receptors and ability to activate numerous gene products, are not often used to induce ovulation because of undetermined potential effects on embryo development. The effect of insulin sensitizers on hirsutism is debated and possibly marginal.10
Ovarian wedge resection was a frequently used option in the past. Currently, however, it has little to no usefulness. Laser drilling has been attempted and can restore ovulation but rarely improves hirsutism. All operative procedures carry a significant risk of postoperative adhesions and therefore mechanical infertility. Oophorectomy for perimenopausal or menopausal women with increasing severe hyperandrogenism is sometimes necessary.
Hirsutism is a distressing condition for most women. Although it is sometimes the harbinger of a more serious metabolic disorder, it often is not associated with significant underlying pathology. The principles of treatment include patience to wait and see the efficacy of treatment and a combination of nonpharmacologic and pharmacologic measures. Combining pharmacologic measures such as OCPs and antiandrogenic therapy yields the best results, making the problem more acceptable to the patient so that over time, she usually can balance the need for treatment with its cosmetic benefits.