Hunter

Evaluation and Treatment
of Women with Hirsutism
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
ovary 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 testosterone and 17␣-hydroxyprogesterone is sufficient in most
cases. Women with irregular menses and hirsutism should be screened for thyroid dys-
function and prolactin disorders. Pharmacologic and/or nonpharmacologic treatments
may be used. Advances in laser hair removal methods and topical hair growth retar-
dants offer new options. The use of insulin-sensitizing agents may be useful in women
with polycystic ovary syndrome. (Am Fam Physician 2003;67:2565-72. Copyright 2003
American Academy of Family Physicians.)
growth varies widely among women, and dis- tinguishing normal variations of hair growth from hypertrichosis and true hirsutism is for “Practical Therapeu-tics.” This article is onein a series coordinatedby the Department of der affecting up to 8 percentof women.1 It often resultsfrom conditions that are not chronic anovulation. Hirsutism is defined as androgen-sensitive pilosebaceous units.3,4 the presence of excessive terminal hair in While 60 to 80 percent of women with hir- sutism have increased levels of circulating body.2 The disorder is a sign of increased androgens, degrees of hirsutism correlate editor of the series isWilliam J. Hueston, M.D. 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- androgen that arises almost exclusively from the adrenal gland but is an uncommon cause serious pathology, and clinical evaluation of hirsutism. Nearly all circulating testos- terone is bound to sex hormone 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 body hair outside of SHBG levels decrease while free testosterone cultural norms can be very distressing. Hair Hypertrichosis is defined as a diffuse in- crease in vellus hair growth and is not andro-gen dependent. Hypertrichosis may be con- Hirsutism is a sign of increased androgen action on hair 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 hypothyroidism, porphyrias, epi- dermolysis bullosa, anorexia nervosa, malnu-trition, or dermatomyositis. It also may occur TABLE 1
Medications That May Cause Hirsutism
and/or Hypertrichosis
Hirsutism
Hypertrichosis
after severe head injury, be present at sites of skin trauma, Causes of Hirsutism
When evaluating hirsutism, it is important to remember that it is only one sign of hyperandrogenism. Other abnor- malities associated with excessive levels of androgen are listed in Table 2.6,8 Increased androgen effect that results inhirsutism 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 ovary syndrome [PCOS]), excess secretion of androgensby adrenal glands (e.g., congenital adrenal hyperplasia[CAH], Cushing’s syndrome, tumor), or exogenous phar-macologic sources of androgens. Table 38 outlines consid-eration for these causes, along with laboratory findings.
Idiopathic hirsutism is common9 and often familial. It is Abnormalities Associated with Androgen Excess
a diagnosis of exclusion and thought to be related to dis-orders in peripheral androgen activity. Onset occurs shortly after puberty with slow progression. Patients with idiopathic hirsutism generally have normal menses and normal levels of testosterone, 17␣-hydroxyprogesterone 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 tion and hyperandrogenemia, excluding other causes such information from Speroff L, Glass RH, Kase NG, eds. Clinical gyne-cologic endocrinology 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 withandrogen excess, and diagnosis usually is based on clinicalrather than laboratory findings. Up to 70 percent of pa-tients with PCOS have signs of hyperandrogenism.12 CAH is a spectrum of inherited disorders of adrenal steroidogenesis, with decreased cortisol production result- MELISSA H. HUNTER, M.D., is an associate professor in the Depart-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- ing symptoms during adolescence or adulthood.
pleted a residency in family medicine at McLeod Regional MedicalCenter, 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 differential diagnosis. It may be caused by increased production of adrenocorticotropic hormone (ACTH) by the PETER J. CAREK, M.D., is an associate professor in the Department of pituitary, adrenal carcinoma/adenoma, or secretion of Family Medicine, Medical University of South Carolina College of Med- ectopic ACTH.14 Profound hirsutism is seen most commonly icine. He received his medical degree from the Medical University ofSouth 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 Hirsutism may result from use of exogenous pharmaco- of Tennessee, Memphis, College of Medicine.
logic agents, including danazol (Danocrine), anabolic Address correspondence to Melissa H. Hunter, M.D., University Family steroids, and testosterone. Oral contraceptives (OCs) con- Medicine, 9298 Medical Plaza Dr., N. Charleston, SC 29406 [e-mail:[email protected]]. Reprints are not available from the authors. taining levonorgestrel, norethindrone, and norgestrel tend TABLE 3
Causes of Hirsutism, Associated Laboratory Findings, and Recommended Additional Testing
17-OHP = 17␣-hydroxyprogesterone; LH = luteinizing hormone; FSH = follicle-stimulating hormone; DHEAS = dehydroepiandrosteronesulfate; 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, norgestimate, and desogestrel 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 virilization (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 ovarian tumor.2,9 positive family history of the disorder.4 Key elements ofhistory and physical examination are noted in Table 5.6,8Methods the patient has used to treat hirsutism should be noted, including hair removal methods, to provide some Signs of Virilization
semiquantitative measure for evaluating severity and pro-gression of hair growth. Discussion of the psychosocial effects of hirsutism as well as the patient’s infertility con- Physical examination should distinguish normal amounts of hair growth from hirsutism and hypertri- chosis. Amounts, characteristics, and distribution of hair 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 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 medication history adrenal hyperplasia.2,6 For diagnostic purposes, serum levels of testosterone and 17-OHP are usually sufficient.6 A diag- nostic algorithm is provided in Figure 1.6,8 For patients with irregular menses, anovulation, PCOS, late-onset adrenal hyperplasia, and idiopathic hirsutism, Physical examination
prolactin levels and thyroid function tests may be consid- Height, weight, blood pressure (may suggest condition of ered to identify thyroid dysfunction and pituitary tumors.
androgen excess related to adrenal enzyme deficiencies) Testing of glucose, testosterone, and 17-OHP levels should Documentation of hair amount, distribution, and characteristics be considered, along with careful breast examination to Skin changes (i.e., acne, acanthosis nigricans)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 adrenal neoplasm. Diagnostic testing should examine levelsof 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- (24.3 nmol per L) are strongly indicative of virilizing cologic endocrinology and infertility. 6th ed. Baltimore: LippincottWilliams & 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 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 shaving 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 oftenineffective for dark hair growth, and skin irritation mayoccur. Chemical depilatories produce results similar toshaving, but skin irritation is common. Electrolysis is one Identification of serious underlying disorders is 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 However, electrolysis is costly and time consuming, andlargely has been supplanted by use of laser techniques.
Hirsutism
Evaluation of Hirsutism
FIGURE 1. Algorithm showing the evaluation of hirsutism. (ACTH = adrenocorticotropic hormone; CAH = congenitaladrenal 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. that all preparations are comparable in efficacy.24 These Laser hair removal methods work best on dark agents increase the level of SHBG and therefore decreaseovarian androgen production while decreasing the risk of hair growth, although post-treatment hyperpig- endometrial hyperplasia often seen in anovulatory Antiandrogens 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 combination therapy,27 but data have the development of laser therapy for hirsutism. Several dif- shown that combined therapy is not significantly better than ferent lasers 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 ovulation.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 flutamide (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 spironolactone; however, hepatic function must apy works best on dark hair, although post-treatment be monitored.28 Finally, finasteride (Proscar), a competitive 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 hormones. 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 diabetes mellitus and cardiovascular disease.6 such as leuprolide (Lupron) should be reserved for use inwomen 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- 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. Metformin (Glucophage) has been Eflornithine (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.
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 glucocorticoid 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, gestodene (not available in the United States), 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, TABLE 6
Medications Commonly Used in the Treatment of Hirsutism
heparin, potassium supplements, potassium sparing diuretics.
Hot flushes, decreased bone Pregnancy category X. Use with Skin adverse effects include Pregnancy category C FDA approval for reduction No significant drug interaction (rare with mortality nearly Resumption of ovulation may 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 = hormone therapy; 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. Hirsutism
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19. Dierickx CC. Hair removal by lasers and intense pulsed light effective in the treatment of hirsutism. Severe side effects, sources. Semin Cutan Med Surg 2000;19:267-75.
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and at periodic intervals during prolonged treatment.
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