Evaluation and Treatment of Women with MELISSA H. HUNTER, M.D., and PETER J. CAREK, M.D. Medical University of South Carolina, Charleston, South Carolina

Hirsutism is a common disorder, often resulting from conditions that are not life- threatening. It may signal more serious clinical pathology, and clinical evaluation should differentiate benign causes from tumors or other conditions such as polycystic syndrome, late-onset adrenal hyperplasia, and Cushing’s syndrome. Laboratory testing should be based on the patient’s history and physical findings, but screening for levels of serum and 17-hydroxyprogesterone is sufficient in most cases. Women with irregular menses and hirsutism should be screened for dys- function and disorders. Pharmacologic and/or nonpharmacologic treatments may be used. Advances in removal methods and topical hair growth retar- dants offer new options. The use of -sensitizing agents may be useful in women with polycystic ovary syndrome. (Am Fam 2003;67:2565-72. Copyright© 2003 American Academy of Family .)

Members of various irsutism is a common disor- growth varies widely among women, and dis- family practice depart- der affecting up to 8 percent tinguishing normal variations of hair growth ments develop articles of women.1 It often results from and true hirsutism is for “Practical Therapeu- tics.” This article is one from conditions that are not important. in a series coordinated life-threatening, such as With hirsutism, grows from by the Department of chHronic . Hirsutism is defined as -sensitive pilosebaceous units.3,4 Family Medicine at the the presence of excessive terminal hair in While 60 to 80 percent of women with hir- Medical University of androgen-dependent areas of a ’s sutism have increased levels of circulating South Carolina. Guest 2 editor of the series is body. The disorder is a sign of increased , degrees of hirsutism correlate William J. Hueston, M.D. androgen action on hair follicles, from poorly with androgen levels.5 The ovary is the increased circulating levels of androgens major source of increased levels of testos- (endogenous or exogenous) or increased sen- terone in women who have hirsutism.6 Dehy- sitivity of hair follicles to normal levels of cir- droepiandrosterone sulfate (DHEAS) is an culating androgens. androgen that arises almost exclusively from Infrequently, hirsutism may signal more the but is an uncommon cause serious pathology, and clinical evaluation of hirsutism. Nearly all circulating testos- should differentiate benign causes from terone is bound to binding glob- tumors or other conditions that require spe- ulin (SHBG) and albumin, with free testos- cific treatment. Most women who seek treat- terone being the most biologically active form. ment for hirsutism do so for cosmetic rea- When elevated insulin levels are present, sons, because excess outside of SHBG levels decrease while free testosterone cultural norms can be very distressing. Hair levels increase. Hypertrichosis is defined as a diffuse in- crease in growth and is not andro- Hirsutism is a sign of increased androgen action on hair gen dependent. Hypertrichosis may be con- genital (e.g., Hurler’s syndrome, trisomy 18 follicles, from increased circulating levels of androgens or syndrome, or fetal alcohol syndrome) or asso- increased sensitivity of hair follicles to normal levels of ciated with , , epi- circulating androgens. dermolysis bullosa, , malnu- trition, or dermatomyositis. It also may occur

JUNE 15, 2003 / VOLUME 67, NUMBER 12 AMERICAN FAMILY PHYSICIAN 2565 TABLE 1 That May Cause Hirsutism and/or Hypertrichosis

Hirsutism Hypertrichosis Anabolic Cyclosporine (Sandimmune) (Danocrine) Diazoxide (Hyperstat) after severe head injury, be present at sites of skin trauma, Metoclopramide 7 (Reglan) (Rogaine) or be drug induced (Table 1). Methyldopa Penicillamine (Cuprimine) (Aldomet) (Dilantin) Causes of Hirsutism Phenothiazines Psoralens (Oxsoralen) When evaluating hirsutism, it is important to remember Progestins Streptomycin that it is only one sign of . Other abnor- Reserpine (Serpasil) malities associated with excessive levels of androgen are Testosterone listed in Table 2.6,8 Increased androgen effect that results in hirsutism can be familial, idiopathic, or caused by excess Information from Leung AK, Robson WL. Hirsutism. Int J Derma- androgen secretion by the ovary (e.g., tumors, polycystic tol 1993;32:773-7. ovary syndrome [PCOS]), excess secretion of androgens by adrenal glands (e.g., congenital adrenal hyperplasia [CAH], Cushing’s syndrome, tumor), or exogenous phar- macologic sources of androgens. Table 38 outlines consid- TABLE 2 eration for these causes, along with laboratory findings. 9 Abnormalities Associated with Androgen Excess Idiopathic hirsutism is common and often familial. It is a diagnosis of exclusion and thought to be related to dis- Glucose intolerance/ orders in peripheral androgen activity. Onset occurs Alopecia Hirsutism shortly after with slow progression. Patients with Android idiopathic hirsutism generally have normal menses and Cardiovascular normal levels of testosterone, 17-hydroxyprogesterone Menstrual dysfunction (17-OHP), and DHEAS. PCOS affects approximately 6 percent of women of Adapted with permission from Gilchrist VJ, Hecht BR. A practical reproductive age,10 and is represented by chronic anovula- approach to hirsutism. Am Fam Physician 1995;52:1837-46, with information from Speroff L, Glass RH, Kase NG, eds. Clinical gyne- tion and hyperandrogenemia, excluding other causes such cologic and infertility. 6th ed. Baltimore: Lippincott as adult-onset CAH, hyperprolactinemia, and androgen- Williams & Wilkins, 1999:529-56. secreting tumors.11 Patients often report menstrual irregu- larities, infertility, obesity, and symptoms associated with androgen excess, and diagnosis usually is based on clinical rather than laboratory findings. Up to 70 percent of pa- tients with PCOS have signs of hyperandrogenism.12 The Authors CAH is a spectrum of inherited disorders of adrenal MELISSA H. HUNTER, M.D., is an associate professor in the Depart- steroidogenesis, with decreased production result- ment of Family Medicine, Medical University of South Carolina College ing in overproduction of androgenic steroids.13 Hirsutism, of Medicine, Charleston. She received her medical degree from the acne, menstrual disorders, and infertility may be present- Medical University of South Carolina College of Medicine, and com- pleted a residency in family medicine at McLeod Regional Medical ing symptoms during or adulthood. Center, Florence, S.C. Dr. Hunter also completed a faculty develop- Although rare, Cushing’s syndrome should be considered ment fellowship at the University of North Carolina at Chapel Hill in the . It may be caused by increased School of Medicine. production of adrenocorticotropic hormone (ACTH) by the PETER J. CAREK, M.D., is an associate professor in the Department of pituitary, adrenal carcinoma/, or secretion of Family Medicine, Medical University of South Carolina College of Med- 14 icine. He received his medical degree from the Medical University of ectopic ACTH. Profound hirsutism is seen most commonly South Carolina College of Medicine, where he also served a residency in patients with macronodular hyperplasia, and clinical in family medicine. Dr. Carek completed a sports medicine fellowship signs of Cushing’s syndrome are usually quite apparent.14 and obtained a master’s degree in exercise physiology at the University of Tennessee, Memphis, College of Medicine. Hirsutism may result from use of exogenous pharmaco- logic agents, including danazol (Danocrine), anabolic Address correspondence to Melissa H. Hunter, M.D., University Family Medicine, 9298 Medical Plaza Dr., N. Charleston, SC 29406 [e-mail: steroids, and testosterone. Oral contraceptives (OCs) con- [email protected]]. Reprints are not available from the authors. taining , norethindrone, and tend

2566 AMERICAN FAMILY PHYSICIAN VOLUME 67, NUMBER 12 / JUNE 15, 2003 TABLE 3 Causes of Hirsutism, Associated Laboratory Findings, and Recommended Additional Testing

Diagnosis Testosterone 17-OHP LH/FSH Prolactin DHEAS Cortisol Additional testing

Congenital Normal to Increased Normal/ Normal Normal Normal to ACTH stimulation may be adrenal increased normal to increased decreased necessary to make diagnosis. hyperplasia Polycystic Normal to Normal Normal to Normal to Normal to Normal Primarily a clinical diagnosis ovary increased increased increased increased Consider laboratory testing and syndrome LH and ultrasonography of to decreased rule out other disorders/tumors. to normal Consider screening , glucose. FSH Ovarian Increased Normal Normal/ Normal Normal Normal Ultrasonography or CT to image tumor normal tumors Adrenal Increased Normal Normal/ Normal Increased Normal to Ultrasonography or CT to image tumor normal increased tumors Pharmacologic Normal Normal Normal/ Normal Normal Normal Withdrawal of offending agent agents normal recommended (exogenous) Idiopathic Normal Normal Normal/ Normal Normal Normal normal Familial Normal Normal Normal/ Normal Normal Normal normal

17-OHP = 17-hydroxyprogesterone; LH = ; FSH = follicle-stimulating hormone; DHEAS = sulfate; ACTH = adrenocorticotropic hormone; CT = computed tomography. Adapted with permission from Gilchrist VJ, Hecht BR. A practical approach to hirsutism. Am Fam Physician 1995;52:1841. to have stronger androgenic effects, while those with ethyn- Androgen-secreting adrenal tumors are less common. odiol diacetate, , and are less Generally large at the time of diagnosis, these adrenal car- androgenic.9 Medications that cause hyperprolactinemia cinomas are associated with a poor prognosis.9 also may cause hirsutism (Table 1).7 Androgen-secreting tumors of the ovary or adrenal are Clinical Evaluation usually heralded by (i.e., development of male A thorough history and physical examination are essen- characteristics in women) and rapid progression of hir- tial to evaluate women with hirsutism to determine which sutism and cessation of menses. Virilization occurs in less patients need additional diagnostic testing. Family history than 1 percent of patients with hirsutism (Table 4).8 is important; 50 percent of women with hirsutism have a Arrhenoblastoma is the most common .2,9 positive family history of the disorder.4 Key elements of history and physical examination are noted in Table 5.6,8 Methods the patient has used to treat hirsutism should be TABLE 4 noted, including methods, to provide some Signs of Virilization semiquantitative measure for evaluating severity and pro- gression of hair growth. Discussion of the psychosocial Acne Infrequent or absent menses effects of hirsutism as well as the patient’s infertility con- Clitoromegaly Loss of breast tissue or normal cerns is also important. Deepening of voice female body contour Physical examination should distinguish normal Hirsutism Malodorous perspiration amounts of hair growth from hirsutism and hypertri- Temporal hair recession and balding Increased chosis. Amounts, characteristics, and distribution of hair Increased muscle mass (primarily shoulder girdle) growth should be noted. Standardized scoring systems for evaluating hirsutism are limited by subjective variability Information from Gilchrist VJ, Hecht BR. A practical approach to and felt by some to be of little clinical use.6 Diagnosis often hirsutism. Am Fam Physician 1995;52:1837-46. can be made on clinical assessment alone or by limited lab- oratory testing.Virilization should be noted (Table 4),8 and

JUNE 15, 2003 / VOLUME 67, NUMBER 12 AMERICAN FAMILY PHYSICIAN 2567 TABLE 5 History and Physical Examination in the Evaluation of Hirsutism

History Abdominal symptoms Family history Breast discharge Extent of hair growth underlying ovarian and/or adrenal tumors and adult-onset Menstrual, reproductive, and history adrenal hyperplasia.2,6 For diagnostic purposes, serum levels Skin changes (i.e., acne, striae) of testosterone and 17-OHP are usually sufficient.6 A diag- Symptoms of virilization nostic algorithm is provided in Figure 1.6,8 Use of hair removal methods For patients with irregular menses, anovulation, PCOS, Weight gain late-onset adrenal hyperplasia, and idiopathic hirsutism, Physical examination prolactin levels and thyroid function tests may be consid- Height, weight, (may suggest condition of ered to identify thyroid dysfunction and pituitary tumors. androgen excess related to adrenal deficiencies) Documentation of hair amount, distribution, and characteristics Testing of glucose, testosterone, and 17-OHP levels should Skin changes (i.e., acne, acanthosis nigricans) be considered, along with careful breast examination to Galactorrhea rule out galactorrhea. Abdominal and pelvic examination/palpation for masses Hirsutism outside of the perimenarchal period, rapid Physical features of Cushing’s syndrome (i.e., striae, acne, progression of hirsutism, or signs of Cushing’s syndrome or proximal muscle weakness, “moon” facies, central obesity) virilization should indicate the possibility of an ovarian or Signs of virilization adrenal . Diagnostic testing should examine levels of serum testosterone, 17-OHP, and DHEAS. Levels of Adapted with permission from Gilchrist VJ, Hecht BR. A practical serum testosterone greater than 200 ng per dL (6.94 nmol approach to hirsutism. Am Fam Physician 1995;52:1837-46, with per L) and/or DHEAS greater than 700 ng per dL information from Speroff L, Glass RH, Kase NG, eds. Clinical gyne- cologic endocrinology and infertility. 6th ed. Baltimore: Lippincott (24.3 nmol per L) are strongly indicative of virilizing Williams & Wilkins, 1999:529-56. tumors.16 For patients with this degree of hormonal ele- vation or those whose history suggests a neoplasm, addi- tional diagnostic imaging, including abdominal com- puted tomography to assess the adrenals, should be thorough abdominal and pelvic examinations should be performed. Selective venous catheterization may be nec- performed to exclude any masses. Acanthosis nigricans, a essary whenever imaging has not identified a tumor but marker for insulin resistance, also should be noted.15 strong clinical suspicion remains.17 Identification of serious underlying disorders is the pri- mary purpose of laboratory testing and should be individ- Treatment ualized. About 95 percent of these patients have PCOS or Treatment options for patients who have hirsutism can idiopathic hirsutism.3,4 History and physical examination be divided into those measures targeting local manifesta- can exclude most underlying disorders, and full hormonal tions of hirsutism and pharmacologic therapy aimed at the investigation is usually warranted only in those patients underlying causes. Therapy that targets local manifestations with rapid progression of hirsutism, abrupt symptom includes physical methods of hair removal ranging from onset, or virilization. to laser therapy, topical treatment, and weight loss. In patients with hirsutism of peripubertal onset and slow progression, regular menses, otherwise normal phys- LOCAL THERAPIES ical examination, and no virilization, the likelihood of an For patients with mild hirsutism, local measures such as underlying neoplasm is small. Whether laboratory investi- shaving, bleaching, depilatories, and electrolysis may suf- gation in these patients is warranted is controversial; how- fice. Shaving is the easiest and safest method, but is often ever, some experts recommend routine testing to exclude unacceptable to patients. Bleaching products are often ineffective for dark hair growth, and skin irritation may occur. Chemical depilatories produce results similar to Identification of serious underlying disorders is shaving, but skin irritation is common. Electrolysis is one of the most effective and permanent methods of hair the primary purpose of laboratory testing for removal, and may be an adjunct to hormonal treatment.18 hirsutism. However, electrolysis is costly and time consuming, and largely has been supplanted by use of laser techniques.


Evaluation of Hirsutism

Complaint of excessive hair growth

History and physical examination

Normal variant Hirsutism Hypertrichosis

Symptomatic Examine for virilization. Use local treatment measures. with local Discontinue measures offending pharmacologic agent. No virilization Virilization present

Menstrual history Full hormonal work-up (DHEAS, testosterone, 17-OHP)

Imaging studies Irregular menses Normal (anovulation)

Surgical exploration

Thyroid function tests Prolactin 17-OHP and serum testosterone Serum 17-OHP testosterone

Abnormal Normal Normal Elevated ≤200 ng per dL ≥ 200 ng per dL ≤200 ng ≥ 200 ng (6 nmol per L) (6 nmol per L) Treat Consider CAH, Consider per dL (6.94 per dL (6.94 dysfunction. PCOS, imaging nmol per L) nmol per L anovulation. of pituitary and/or Rules out ACTH stimulation test ovaries. adrenal Anovulation hyperplasia/ 21-hydroxylase Normal pelvic Palpable deficiency examination adnexal ≤ 1,000 ng ≥ 1,000 ng mass per dL (2.2 per dL (2.2 nmol per L) nmol per L) Imaging

Heterozygote Late-onset adrenal Surgical exploration carriers of 21- hydroxylase hyperplasia/ deficiency 21-hydroxylase deficiency

FIGURE 1. Algorithm showing the evaluation of hirsutism. (ACTH = adrenocorticotropic hormone; CAH = congenital adrenal hyperplasia; DHEAS = dehydroepiandrosterone sulfate; PCOS = polycystic ovary syndrome; 17-OHP = 17-hydroxy- progesterone) Information from Gilchrist VJ, Hecht BR. A practical approach to hirsutism. Am Fam Physician 1995;52:1837-46, and Speroff L, Glass RH, Kase NG, eds. Clinical gynecologic endocrinology and infertility. 6th ed. Baltimore: Lippincott Williams & Wilkins, 1999:529-56.

JUNE 15, 2003 / VOLUME 67, NUMBER 12 AMERICAN FAMILY PHYSICIAN 2569 that all preparations are comparable in .24 These methods work best on dark agents increase the level of SHBG and therefore decrease hair growth, although post-treatment hyperpig- ovarian androgen production while decreasing the risk of endometrial hyperplasia often seen in anovulatory mentation may occur. women.25,26 may be combined with OCs for the treat- ment of hirsutism. Up to 75 percent of women report clini- The need for rapid methods of hair removal has led to cal improvement with ,27 but data have the development of laser therapy for hirsutism. Several dif- shown that combined therapy is not significantly better than ferent exist, including ruby, alexandrite, pulsed single agents alone. Patients who use antiandrogens alone diode, and Q-switched yttrium-aluminum-garnet (YAG) may experience irregular uterine bleeding and .6 lasers. Pulsed diode lasers are generally less expensive and The most commonly used antiandrogens are spironolac- more reliable than other laser sources for hair removal.19 tone (Aldactone) and (Eulexin). However, no Q-switched YAG lasers work well in patients with darker antiandrogens are approved by the U.S. Food and Drug skin; however, these lasers are ineffective for long-term hair Administration for the treatment of hirsutism. Spi- removal.20 Most patients experience a two- to six-month ronolactone is most commonly used because of its safety, growth delay after a single treatment, and some have per- availability, and low cost. Flutamide has been shown to be as manent hair removal after multiple treatments. Laser ther- effective as ; however, hepatic function must apy works best on dark hair, although post-treatment be monitored.28 Finally, (Proscar), a competitive may occur. inhibitor of 5-reductase, has been shown to be effective in Weight loss should be encouraged for obese patients, treating hirsutism with relatively few side effects.29 Response because this increases SHBG levels and decreases insulin to antiandrogens is slow and may take up to 18 months. resistance and the levels of serum androgens and luteiniz- Duration of therapy is unclear, but treatment cessation gen- ing . Women who are overweight, hyperandro- erally is followed by recurrent hair growth. genic, or hyperinsulinemic should be counseled regarding Gonadotropin-releasing hormone (Gn-RH) analogs future risk of mellitus and .6 such as leuprolide (Lupron) should be reserved for use in women who do not respond to combination hormonal PHARMACOLOGIC TREATMENT therapy or those who cannot tolerate OCs. Gn-RH analogs Pharmacologic treatment for hirsutism should be aimed should be used cautiously with particular attention to pos- at blocking androgen action at hair follicles or suppression sible long-term consequences (e.g., hot flushes, bone de- of androgen production (Table 6).Response to pharmaco- mineralization, atrophic vaginitis).27 logic agents is slow, occurring over many months. When For patients whose terminal hair growth does not medical therapy is unacceptable to patients, combining decrease significantly, treatment with insulin-sensitizing local measures with medical therapy may be appropriate. agents may be useful. (Glucophage) has been (Vaniqa) topical cream has been shown to shown to improve insulin sensitivity and decrease testos- slow rates of terminal hair growth significantly in up to terone levels in patients with PCOS.30 Clinical manifesta- 32 percent of patients and can be used adjunctively with tions of hyperandrogenism have shown improvement after usual methods of hair removal.21,22 Once use of eflor- metformin therapy.31,32 A three-month therapeutic trial of nithine is discontinued, hair growth usually returns to pre- metformin to assess efficacy may be useful. treatment levels in about eight weeks.23 Increased androgen production from nonspecific hyper- For women with idiopathic hirsutism, PCOS, or late- secretion or adult-onset adrenal hyperplasia responds to onset CAH, appropriate treatment decisions depend on suppression with dexamethasone.33 Adrenal each patient’s desires and childbearing plans. Women who androgen secretion is more sensitive to dexamethasone do not wish to become pregnant should use low-dose OCs. than is cortisol secretion.33 Generally, glucocorticoid ther- OCs containing less androgenic progestins, such as norges- apy in patients with uncomplicated adrenal hyperplasia timate, (not available in the ), and results in normal menstrual cycles and improvement in hir- desogestrel, seem to be the best choice, but some maintain sutism or acne.34 Combined therapy with Gn-RH analogs,

2570 AMERICAN FAMILY PHYSICIAN VOLUME 67, NUMBER 12 / JUNE 15, 2003 TABLE 6 Medications Commonly Used in the Treatment of Hirsutism

Class of drug Drug Dosage Side effects and warnings* Comments Cost (generic)†

Oral Ethinyl with One tablet per GI distress, breast category X $31.00 per month contraceptives norgestimate, day for 21 days, tenderness, headache, No FDA labeling for treatment desogestrel, followed by intolerance to of hirsutism norethindrone, seven-day pill- contact lenses Least androgenic progestin ethynodiol free interval component preferred diacetate Ethinyl estradiol Hyperkalemia may occur. Monitor serum potassium during 29.00 per month with Contraindicated with first cycle with concurrent use hepatic dysfunction, of NSAIDs, ACE inhibitors, renal insufficiency, angiotensin-II receptor blockers, adrenal disease , potassium supplements, potassium sparing diuretics.

Antiandrogens Spironolactone 50 to 200 mg Hyperkalemia (rare), D 29.00 per month (no FDA labeling (Aldactone) per day theoretic Irregular bleeding may occur, (22.00 to 25.00) for treatment of male , monitor electrolytes. of hirsutism) Flutamide (Eulexin) 250 mg two to Monitor liver function. Combine with other method of 144.00 per three times daily contraception. month (125.00) Pregnancy category D Finasteride (Proscar) 5 mg daily Monitor liver function. Pregnancy category X 70.00 per month

Glucocorticoids Dexamethasone 0.5 mg nightly Weight gain, hypokalemia, Pregnancy category C. May be 20.00 per month (no FDA labeling decreased bone density, combined with oral (2.00 to 10.00) for treatment immune suppression contraceptives or Gn-RH of hirsutism) agonists for severe hirsutism. 5 to 10 mg daily Pregnancy category C 1.50 per month (2.00 to 3.00)

Gn-RH agonists Leuprolide (Lupron) 3.75 mg IM per Hot flushes, decreased bone Pregnancy category X. Use with 535.00 per (no FDA labeling month for up mineral density, atrophic caution for short periods month for treatment to six months vaginitis because of hypoestrogenic of hirsutism) effect. 11.25 mg IM every May need add-back HT. Use nonhormonal contraception 1,605.00 for three months during treatment. three months (depot form)

Antifungal agents 400 mg daily Scalp , dry skin, Pregnancy category C 231.00 per (no FDA labeling (Nizoral) abdominal pain, fatigue, Use as last resort. month (182.00 for treatment headache, vaginal to 190.00) of hirsutism) spotting, Monitoring of hepatic function necessary

Topical hair growth Eflornithine HCI Apply to face Skin adverse effects include Pregnancy category C 42.00 for retardant (Vaniqa) twice daily at acne, , stinging/ May cause mild elevations in 30-g tube least eight burning, dry skin. transaminase levels. hours apart. FDA approval for reduction No significant drug interaction of unwanted hair known

Insulin-sensitizing Metformin 500 mg twice daily GI distress, lactic acidosis Pregnancy category B 47.00 per month agents (not FDA (Glucophage) 1,000 mg twice (rare with mortality nearly Resumption of ovulation may (42.00) approved for daily (maximal 50 percent), numerous occur. treatment of dosage 2.0 to drug interactions No FDA labeling for treatment hirsutism) 2.5 g per day)` Monitor liver function, of PCOS 850 mg three confirm normal renal times daily function before starting, and monitor.

GI = gastrointestinal; FDA = U.S. Food and Drug Administration; NSAIDs = nonsteroidal anti-inflammatory drugs; ACE = angiotensin-converting enzyme; Gn-RH = gonadotropin-releasing hormone; IM = intramuscular; HT = ; PCOS = polycystic ovary syndrome. *—For more detailed information, consult the package insert provided by the manufacturer of each drug. †—Estimated cost to the pharmacies (rounded to the nearest dollar) based on average wholesale prices in Red book, Montvale, N.J.: Medical Economics Data, 2002. Cost to the patient will be higher, depending on prescription filling fee.


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