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Approach to Patients With Hirsutism

ROLAND SAKIYAMA, MD, Los Angeles, California

Hirsutism is a common medical condition that in most women is due to the polycystic ovary syndrome or is idiopathic. For a few women, hirsutism signals a serious underlying disorder such as an ovarian or adrenal tumor, congenital adrenal hyperplasia, or Cushing's syndrome. A detailed medical history and examination can identify women in whom a serious disease is suspected and for whom laboratory evaluation is warranted. Measurements of serum testosterone, dehydroepiandrosterone, and 1 7a-hydroxyprogesterone levels, and 24-hour urinary cortisol concentrations are important screening tests. Therapy is directed at suppressing ovarian or adrenal androgen production, inhibiting the conversion of testosterone to dihydrotestosterone, or antagonizing the effects of androgens at the receptor level. (Sakiyama R: Approach to patients with hirsutism. West J Med 1996; 165:386-391)
Hirsutism is a common clinical condition affecting about 5% of women in the United States.! All too often, physicians dismiss hirsutism as a concern that does not deserve their clinical acumen. Perhaps this response is due to a lack of knowledge of the proper evaluation and management of hirsutism or the notion that hirsutism is merely a cosmetic problem. For most women, hirsutism is not a manifestation of a serious disorder, but rather a possible source of emotional disability. For some women, hirsutism is a warning sign of a more serious underlying problem. Appropriate management can be determined after a carefully directed history, physical examination, and limited laboratory testing.* Hirsutism is defined as the excessive growth of androgen-responsive terminal hair in women. Therefore, for most women, hirsutism is a cutaneous manifestation of androgen excess. True hirsutism must be distinguished from hypertrichosis-that is, excessive growth of vellus or non-androgen-responsive hair. Vellus is fine, downy hair that is usually unpigmented. Terminal hairs are dark, thick, and found in the sex hormone-responsive areas of the pubis, axilla, back, face, chest, and abdomen. Androgens promote an increase in the number and thickness of terminal hairs in these areas. Women with androgen-dependent hirsutism either have exposure to excessive androgens or manifest a heightened androgen-receptor sensitivity to normal circulating levels of androgen. For other women, hirsutism is a non-androgen-dependent abnormality-that is, an adverse effect to certain drugs or a genetic characteristic, such as in women of Mediterranean or East Indian origin. Testosterone and dihydrotestosterone are true andro*See also the editorial by S. J. Agarwal, MB,BS, and H. L. Judd, MD, "What We See Most, We Understand Least," on pages 392-393 of this issue.

defined by their ability to interact with the androgen receptor. Testosterone binds to cell receptors, enters the cell cytoplasm, and is converted to dihydrotestosterone by a 5a-reductase enzyme. Dihydrotestosterone, in turn, is bound to specific cytoplasmic receptors. Potential androgens are dependent on a conversion to testosterone and include dehydroepiandrosterone (DHEA) and androstenedione. Dehydroepiandrosterone is the major adrenal androgen that can be converted to testosterone, or sulfated to DHEAS before secretion. Measuring the DHEAS level is the preferred plasma test of adrenal androgen production because DHEA shows a circadian and menstrual rhythm not found with DHEAS. Androstenedione is the major C19 steroid produced by the ovaries, although the ovaries are also able to secrete testosterone and dihydrotestosterone. In normal women, two thirds of plasma testosterone is derived from the adrenal cortex through peripheral formation from DHEA and androstenedione.
gens as

Causes of Hirsutism
Causes of hirsutism can be classified as ovarian, adrenal, drug-related, idiopathic, or genetic (Table 1).2 Ovarian disorders include the polycystic ovary syndrome and ovarian tumors. Adrenal disorders include congenital adrenal hyperplasia, Cushing's syndrome, and adrenal tumors. Hirsutism may also occur with the ingestion of anabolic steroids or as an adverse effect of a limited group of medications (see Table 1). Idiopathic hirsutism is defined by normal androgen concentrations and a lack of any identifiable underlying disorder. It has been proposed that idiopathic hirsutism results from an increased androgen-receptor sensitivity to normal androgen levels. More than 95% of women with hirsutism are found to have either idiopathic hirsutism or the polycys-

From the Division of Family Medicine, University of Califomia, Los Angeles (UCLA), School of Medicine.

Reprint requests to Roland Sakiyama, MD, Division of Family Medicine, UCLA School of Medicine, 200 UCLA Medicine Plaza, Ste 220, Los Angeles, CA 90095-1628.

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ABBREVIATIONS USED IN TEXT ACTH = adrenocorticotropic hormone, corticotropin CT = computed tomography DHEA = dehydroepiandrosterone DHEAS = sulfated form of DHEA FDA = Food and Drug Administration FSH = follicle-stimulating hormone GnRH = gonadotropin-releasing hormone LH = luteinizing hormone MRI = magnetic resonance imaging SHBG = sex hormone-binding globulin

TABLE 1.-Causes of Hirsutisrn*

General
Specific Ca;,-se
..

Ovarian

Polycvstic ovary syndrome Neoplasms Sertoli-Leydig cell tuimors Hilar cell tunmors Lipoid cell tUmnors Adrenal rest tumors
Congenital
adrenal

Adrenal

hyperplasia

tic ovary syndrome.3 The polycystic ovary syndrome is the most common identifiable cause of androgen hypersecretion in women. The underlying defect in this syndrome is postulated to be a nontumorous dysfunction of luteinizing hormone (LH) hypersecretion, with a subsequent stimulation of thecal and stromal ovarian cells to produce androgens. The polycystic ovary syndrome encompasses a wide spectrum of clinical manifestations. Patients may present with classic "polycystic ovary disease"-obesity, hirsutism, anovulation, and enlarged multicystic ovaries. On the opposite end of the spectrum, women with mild polycystic ovarian syndrome may not be obese and have regular ovulatory cycles and normal ovaries, with only subtle hormonal aberrations and hirsutism. Luteinizing hormone levels are frequently elevated in the polycystic ovary syndrome, but often to such a modest degree that its absolute value remains within the normal reference range. If the ratio of LH to follicle-stimulating hormone (FSH) is measured, however, it is frequently increased to 2.5 or greater in women with the polycystic ovary syndrome (most normal ovulatory women have an LH:FSH ratio of 1.0). Total plasma testosterone levels are elevated in 40% to 60% of women with this syndrome. In the other women, levels of total testosterone are normal, but those of free testosterone are elevated. Free testosterone represents the nonprotein-bound hormone that is thought to most closely reflect cellular hormonal actions. The major binding protein for testosterone is sex hormone-binding globulin (SHBG), which is decreased in women with the polycystic ovary syndrome and accounts for elevated levels of free testosterone despite normal total testosterone levels. Ovarian and adrenal tumors are uncommon causes of hirsutism. Adrenal carcinomas are typically large by the time they produce excessive androgens. Adrenal adenomas can produce androgens and are typically small and difficult to localize. Ovarian tumors include SertoliLeydig cell tumors, hilar cell tumors, lipoid cell tumors, and adrenal rest tumors. Elevations in DHEAS levels suggest an adrenal origin of androgen production, whereas greatly elevated testosterone concentrations signal a possible ovarian or adrenal tumors.3 Cushing's syndrome is caused by the chronic overproduction of glucocorticoids and, to a lesser extent, adrenal androgens. Skin findings due to excessive androgen production include hirsutism, acne, and temporal hair recession, in addition to glucocorticoid-associated

21 -Hydroxylase deficiency 11 [i-Hydroxyiase deficieincy

31[-Hydroxysteroid dehydrogenase
deficlency
CLushings syndrome

DrUgs (proprietary name)

.....

Neoplasms Adrenal carcinoma Adrenal adenoma Cyclosporine (Sandimmune) Danazol (Danocrine)

Phenytoin (Dilantin)

Glucocorticoids

Minoxidil (Loniten) Diazoxide (Hyperstat) Anabolic steroids

Idiopathic
Genetic

findings of thin skin and purple striae. Classic congenital adrenal hyperplasia presents in infancy and is due to a deficiency of 21 -hydroxylase, 11 -hydroxylase, or 3 hydroxysteroid dehydrogenase adrenal enzymes. An attenuated or nonclassic form of congenital adrenal hyperplasia may present in adolescence or young adulthood.4'5 A partial deficiency of the 21-hydroxylase enzyme is the most common form of nonclassic congenital adrenal hyperplasia. Decreased 21-hydroxylase activity leads to increased concentrations of 1 7ahydroxyprogesterone, which in turn is converted to
-

testosterone.

Idiopathic hirsutism is found in 50% of women evaluated for hirsutism. Idiopathic hirsutism is defined by normal physical and laboratory findings in women with the onset of excessive hair growth in puberty or young adulthood. They do not have signs of virilization and manifest a slow progression of their hirsutism. Increased sensitivity of the hair follicles to normal circulating androgens is thought to cause the hirsute state.
History and Physical Examination The primary goal of the history and physical examination is to identify patients in whom hirsutism is the cutaneous manifestation of a serious underlying disease. Hirsutism due to the polycystic ovary syndrome or idiopathic causes typically begin between the ages of 15 and 25 years and progresses slowly. Symptoms starting later in life, coupled with a rapid progression, suggest a more serious underlying disorder, such as an ovarian or adrenal tumor or Cushing's syndrome. The exception is peri-

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menopausal women who may have more hair growth in their perimenopausal years due to an increased production of adrenal androgens. Women with greater elevations in androgen levels have virilizing symptoms such as balding, deepening of the voice, increased libido, or decreased body fat. Virilization is not typical of idiopathic hirsutism or the polycystic ovary syndrome and suggests a more serious disorder. Women should be carefully questioned about symptoms associated with specific underlying diseases. For example, those with the polycystic ovary syndrome may have amenorrhea, oligomenorrhea, infertility, or obesity. A recent weight gain with a cushingoid body habitus and hypertension suggests Cushing's syndrome, whereas flank pain or a mass coupled with weight loss may be due to an adrenal cancer. Finally, the use of prescribed medications or anabolic steroids should be carefully reviewed. The examination is directed at documenting the extent and distribution of terminal hair and uncovering any clues as to an underlying cause. Hirsutism can be quantitated by the use of the Ferriman and Gallwey score.' The extent of hirsutism is evaluated in nine body areas-upper lip, chin, chest, upper arms, upper abdomen, lower abdomen, thighs, and upper and lower back-and each area is given a point score of 0 (no hirsutism) to 4 (overtly virile). A total score of 8 or higher is consistent with the diagnosis of hirsutism. Physical findings of virilization include receded temporal hair, increased laryngeal size, decreased body fat, atrophied breasts, masculine musculature, and clitoromegaly (a clitoris of greater than 1.0 cm in diameter). Patients with Cushing's syndrome may have acne, purple striae, or centripetal obesity. A bimanual pelvic examination is done to exclude an ovarian mass, which is found in about half of women with ovarian tumors, or enlarged ovaries (polycystic ovary syndrome).

Laboratory Evaluation
In women who are presumed to have the polycystic ovary syndrome or idiopathic hirsutism, only a limited laboratory evaluation is required. For women with suspicious historical or physical findings, a more extensive laboratory evaluation is done to exclude androgensecreting adrenal or ovarian tumors, Cushing's syndrome, or the nonclassic form of congenital adrenal hyperplasia. The two most important screening tests are measurements of total serum testosterone and DHEAS levels. Testosterone levels of greater than 7 nmol per liter (2.0 ng per ml) suggest the presence of an androgen-secreting ovarian or adrenal tumor, and DHEAS levels of greater than 19 ,imol per liter (700 [ig per dl) suggest an adrenal tumor.7 Elevations of testosterone and DHEAS levels to this degree are not specific for a neoplastic cause, as they can also be found in 50% of women with benign disorders. Testosterone and DHEAS levels below these thresholds, however, essentially exclude an androgen-secreting tumor. For women with abnormally elevated testosterone levels and normal DHEAS levels, a search for an ovarian tumor is begun

with ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI) of the pelvis. If both testosterone and DHEAS levels are abnormally elevated, then a radiologic evaluation of the adrenal glands is performed with MRI or CT. To exclude the possibility of Cushing's syndrome, a 24-hour urine specimen is collected and submitted for free cortisol determination. A urine free cortisol concentration of greater than 275 nmol per day (100 ,ug per 24 hours) is considered abnormal. Alternatively, the patient may be given an overnight dexamethasone suppression test in which 1 mg of dexamethasone (2 mg for obese women) is given orally at 11 PM, with a serum cortisol level measured at 8 AM the next morning. Normally, dexamethasone will suppress cortisol values to less than 140 nmol per liter (5 ,ug per dl). Women having a nonsuppressed serum cortisol level or abnormal urinary free cortisol concentrations are referred for complete endocrinologic evaluation. To evaluate for 21-hydroxylase-deficient nonclassic congenital adrenal hyperplasia, a morning plasma 17a-hydroxyprogesterone level is measured. A 17a-hydroxyprogesterone level of 6.0 nmol per liter (2.0 ng per ml) or lower rules out this adrenal gland deficiency.5 A women with a 17a-hydroxyprogesterone level above 6.0 nmol per liter should be referred for adrenocorticotropic hormone (ACTH; corticotropin)-stimulated testing. The diagnosis of the polycystic ovary syndrome can be confirmed with laboratory determinations of serum testosterone, DHEAS, LH, and FSH levels. In the polycystic ovarian syndrome, the total testosterone level is modestly elevated in 40% to 60% of patients. In women found to have normal testosterone levels, the levels of free testosterone will usually be elevated. The DHEAS level is normal or occasionally slightly elevated, and the LH:FSH ratio is usually greater than 2.5. Pelvic ultrasonography is not required unless an ovarian mass is found on pelvic examination; however, in obese women in whom the pelvic examination is difficult, an ultrasonogram may be helpful. Enlarged polycystic ovaries are found infrequently and usually in women who manifest other features of the polycystic ovary syndrome, such as obesity, oligomenorrhea, or amenorrhea.

Treatment Mechanical methods of hair removal are an effective adjunct for the control of hirsutism and may be the most appropriate therapy for women with limited areas of unwanted hair growth. For women with widespread hirsutism, combining medical therapy with shaving, plucking, waxing, or electrolysis can result in a more rapid response. In addition, women who have previously abandoned these physical methods may wish to resume these measures after medical therapy has slowed the rate of new hair growth. The most common adverse effects are skin irritation (bleaching, chemical depilatories), pitting or scarring (electrolysis), or folliculitis (plucking, waxing). Shaving is considered the safest method of temporary hair removal and, contrary to popular belief,

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once hair is shaved, it does not return in a darker or thicker state. For women found to have an ovarian or adrenal tumor, Cushing's syndrome, or 21-hydroxylase-deficient nonclassic congenital adrenal hyperplasia, appropriate referral should be made for specific therapy. Most women's hirsutism will be caused by the polycystic ovary syndrome or idiopathic causes, and medical therapy can be offered. Treatment is more effective at preventing further hair growth than reversing long-established hirsutism, and therefore, women with the recent onset of hirsutism are more likely to respond to treatment than those with long-standing hirsutism. In addition, because hair growth is inherently a slow process, patients are advised that an observable response may not be evident in the first three to six months. Finally, determining a therapeutic response is often difficult. Although the FerrimanGallwey score is useful, it is often cumbersome and hampered by the concomitant use of mechanical methods of hair removal. A patient's subjective evaluation of her hair growth may be the only measure of successful therapy, with often the most useful measure of success being a reduction in the time a woman spends removing unwanted hair. Medical therapy for hirsutism may be directed at several levels (Table 2). Drugs can suppress ovarian or adrenal androgen secretion or block the action of androgens in target hair follicles. If a hormone abnormality has been determined, then therapy is directed at reversing that abnormality. For example, a woman with an elevated testosterone level is given drugs that suppress ovarian androgen production. Women with normal testosterone concentrations are presumed to have an increased end-organ sensitivity to androgens and therefore are more likely to respond to drugs that antagonize the tissue effects of androgens.

TABLE 2.-Medical Management of Hirsutism

Diagnosis

Medicatioon (Proprietary Namree)

Ovarian androgen suppression .... Oral contraceptives GnRH agonist Depot leuprolide (Lupron Depot) Nafarelin acetate (Synarel) Cyproterone acetate* (Androcur, Diane) Adrenal androgen suppression .... Glucocorticoids 5ox-Reductase inhibitorst ........ Finasteride (Proscar) Antiandrogens ........... ... Spironolactone (Aldactone) Cyproterone acetate* (Androcur Diane)
GnRH = gonadotropin-releasing hormone
*Not available in the United States. tlnhibition of testosterone to dihYdrotestosterone.

Suppressing Ovarian Androgen Production Oral contraceptives are the most commonly used method to suppress ovarian androgen production. Progestins inhibit gonadotropin secretion, thereby reducing ovarian-stimulated androgen secretion. The estrogen component stimulates the hepatic synthesis of SHBG, which binds circulating testosterone, and lowers the amount of free testosterone available to hair follicles. This is especially helpful in women with the polycystic ovary syndrome who often have lower SHBG levels. When prescribing oral contraceptives, clinicians must be aware of the possible androgenic activity of the progestational component. 19-Nortestosterone derivatives, such as norgestrel, norethindrone, levonorgestrel, and to a lesser extent, ethynodiol diacetate and lynestrenol, show partial androgen activity, especially at higher doses.8 The dose of these progestins should be kept to a minimum. The use of a combination of ethinyl estradiol (35 ,ug) and ethynodiol diacetate (1 mg) found in Demulen 1/35 has often been recommended for this reason. Newer progestins, such as desogestrel, gestogen, and norgestimate, have no important androgenic activity

and should be advantageous in treating hirsute women. Oral contraceptives combining low-dose estrogen and these nonandrogenic progestins include Desogen, Ortho-Cept, Ortho-Cyclen, and Ortho Tri-Cyclen. Although these oral contraceptives offer a theoretic advantage, comparisons of different oral contraceptives with regards to their effects on hirsutism are lacking. The response to oral contraceptive use varies, but it is more likely to occur in women with elevated testosterone levels. The efficacy of oral contraceptive use for the treatment of hirsutism has recently been questioned.9 It may be that a few hirsute women will have substantial improvement with oral contraceptive treatment alone. Until further studies are available, oral contraceptives continue to be a first-line treatment for the majority of women with hirsutism. These hormones have the added benefits of regulating menses and ensuring contraception in women taking antiandrogens. Gonadotropin-releasing hormone (GnRH) agonists used long term can suppress ovarian androgen production in hirsute women. The long-term use of these agonists alone, however, often leads to hypoestrogenic side effects such as hot flashes, osteoporosis, and urogenital atrophy. Therefore, they are combined with oral contraceptives or conjugated estrogens and progestins in the treatment of hirsutism.'0"' The GnRH agonists used in the treatment of hirsutism include nafarelin acetate as an intranasal spray given 400 ,ug twice a day, or depot leuprolide acetate, 3.75 mg monthly. The use of GnRH agonists for the treatment of hirsutism is severely limited by cost, and therefore therapy with GnRH agonists should be reserved for moderate to severe hirsutism that is unresponsive to oral contraceptive alone or combined with antiandrogens.
Adrenal Androgen Suppression Glucocorticoids are used to suppress ACTH-stimulated adrenal androgen production and therefore are useful for patients with the nonclassic form of congenital adrenal hyperplasia. Treatment may be initiated with dexamethasone, 0.25 to 0.5 mg; prednisone, 2.5 to 5.0

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mg; or hydrocortisone, 10 to 20 mg. Glucocorticoids are administered in the evening or at bedtime to suppress the nightly ACTH surge.

Sa-Reductase Inhibitors Finasteride is the only Sa-reductase inhibitor available in the United States. Finasteride blocks the conversion of testosterone to dihydrotestosterone, thereby inhibiting the androgen effects on the hair follicle. Finasteride has been approved by the Food and Drug Administration (FDA) for the treatment of benign prostatic hypertrophy, but not for hirsutism. Studies have compared the use of finasteride with that of spironolactone (an antiandrogen) and found them to have equal effectiveness in the treatment of hirsutism.'2 The use of both finasteride and spironolactone decreased terminal hair diameters by 14% and improved the FerrimanGallwey scores by 11%. Finasteride use is well tolerated, but studies of animals have reported ambiguous genitalia in male offspring of treated females, and therefore finasteride should not be used during pregnancy and should be combined with a reliable method of contraception, such as oral contraceptives.
Antiandrogens One of the most useful group of medications for the treatment of hirsutism are the antiandrogens. These drugs competitively inhibit the binding of testosterone and dihydrotestosterone to their respective receptors. The most commonly used antiandrogen is spironolactone, which is an aldosterone antagonist commonly used as a potassium-sparing diuretic. Spironolactone has the additional property of competitively binding to dihydrotestosterone receptors, thus limiting the response of tissues to endogenous androgens. Although not approved by the FDA for the treatment of hirsutism, several studies have shown it to be an effective drug for this indica-

tion.'3"4 Therapy is started with a dosage of 50 mg twice a day, which is then increased to 100 mg twice a day if no response is seen after three months. Half to three quarters of women will have a noticeable improvement with spironolactone. Adverse effects are more common at higher doses and include irregular menses (25%), gastrointestinal cramping, diarrhea, nausea, lethargy, and headache. Hyperkalemia may occur, especially in elderly women, in women with diabetes mellitus, or if taken with other drugs that may increase serum potassium levels (angiotensin-converting enzyme inhibitors). Therefore, periodic monitoring of serum potassium levels is recommended. Spironolactone should not be used in pregnancy, and appropriate contraception must be recommended. Combinations of oral contraceptives and spironolactone are, therefore, commonly prescribed for the treatment of hirsutism, to ensure contraception, and to regulate the menses. Flutamide is a potent, nonsteroidal, selective antiandrogen without progestational or estrogenic activity that has been effective in the treatment of hirsutism.9 Flutamide is given at a dosage of 250 mg twice a day combined with an estrogen-containing oral contraceptive. Adverse effects include dry skin and increased appetite. A major concern with flutamide is a potentially fatal drug-induced hepatitis that occurs in 0.5% of patients given this drug. Flutamide use can also cause ambiguous genitalia in male offspring, and therefore, contraception must be maintained. Its use is not recommended for the routine treatment of hirsutism due to its expense and possible toxic side effects. Cyproterone acetate has properties of both a potent progestin and a moderately potent antiandrogen. Cyproterone acetate, therefore, acts at two levels in the pathophysiologic process of hirsutism. It competitively inhibits the binding of dihydrotestosterone to its cytoplasmic receptor and also inhibits gonadotropin secre-

TABLE 3.-Guidelines for the Treotment of Hirsutism

Diagnosis
lnitial Therapy Doseae*
ovary

Alternative Thercipy Doscage*

Polycystic

syndrome

...... .

Oral contraceptives (Demulen 1/35, Desogen, Ortho-Cept, Ortho-Cyclen, or Ortho Tri-Cyclen) Spironolactone (Aldactone), 50 to 100 mg bid Oral contraceptives (Demulen 1/35, Desogen, Ortho-Cept, Ortho-Cyclen, or Ortho Tri-Cyclen) Spironolactone (Aldactone), 50 to 100 mg bid
...

Finasteride (Proscar), 5 mg qd GnRH agonist (Lupron Depot), 3.75 mg monthly

Idiopathic.. .............

Finasteride (Proscar), 5

mg

qd

GnRH agonist (Lupron Depot), 3.75 mg monthly

Nonclassic congenital adrenal hyperplasia

Cushing's syndrome

...................

Adrenal tumor .............. Ovarian tumor ....................... Drug-induced .........e

Glucocorticoids: prednisone, 5 mg qhs; or dexamethasone, 0.25 mg qhs Surgical excision of ACTH-secreting pituitary adenoma or ectopic ACTH-secreting tumor; adrenalectomy for adrenal hyperplasia . Surgical excision Surgical excision Discontinue medication

ACTH = adrevocorticotropic hormonie, bid = twice a day, CrrRH - gorradorropiro-releasirig hiormone, qd = dailv qhs - every night at bedtimne *Proprietary names are given in parentheses. Demulen 35-21 (CD Searle & Co) contaiiis vthyriodiol diacetate, rig, and eth.nyl estradol, 35 itg9 Desogen (Organori Inc) coritains desogestrel, 0.15 rig, arid ethinyl estradiol, 0.03 mg. Ortho-Cept 21 (Ortho PharmaceLitical Corp) containis desogestrel 015 rng, arid ethinvI estradiol, 0.03 rng. Ortho-Cycleri 21 (Ortho Pharmaceutical Corp' contains riorgestimrate, 0.25 eng, and etlhinyl estradiol, 0.035 ong. Ortlro-Tricycleii (Ortho PharmaceLitical Comi contains rnorgertimate, 0.18 m-g, and ethinrsil estradiol, 0.035 ing. Lupror Depot (TAP Pharmnaceuticaisl) contains 3.75 rng of leuprolide acetate.

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tion because of its progestational properties.'5'6 An oral contraceptive using cyproterone acetate as the progestin would appear to be well suited for the treatment of hirsutism. Cyproterone acetate is not available in the United States in any form, but it is available as a single agent (Androcur) or combined with estrogen in an oral contraceptive (35 or 50 ,ug of ethinyl estradiol and 2 mg of cyproterone acetate) in Europe, Canada, and Mexico (see Table 2). Drug-induced hepatitis is a rare complication that may require periodic monitoring of liver enzyme levels.

REFERENCES
1. Clayton RN, Ogden V, Hodgkinson J, et al: How common are polycystic ovaries in normal women and what is their significance for fertility of the population? Clin Endocrinol (Oxf) 1992; 37:127-134 2. Carr BR: Disorders of the ovary and female reproductive tract, chap 12, In Wilson JD, Foster DW (Eds): Williams Textbook of Endocrinology, 8th edition. Philadelphia, Pa, WB Saunders, 1992, pp 776-780 3. McKenna TJ: Screening for sinister causes of hirsutism. N Engl J Med 1994; 331:1015-1016 4. Chrousos GP, Loriaux DL, Mann DL, Cutler GB Jr: Late-onset 21-hydroxylase deficiency mimicking idiopathic hirsutism or polycystic ovarian disease. Ann Intem Med 1982; 96:143-148 5. Azziz R, Dewailly D, Owerbach D: Nonclassic adrenal hyperplasia: Current concepts. J Clin Endocrinol Metab 1994; 78:810-814 6. Ferriman D, Gallwey JD: Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961; 21:1440-1447 7. Derksen J, Nagesser SK, Meinders E, Haak HR, van de Velde CJH: Identification of virilizing adrenal tumors in hirsute women. N Engl J Med 1994; 331:968-973 8. Pang S: Relevance of biologic properties of progestogen of oral contraceptives in treatment of androgen excess symptoms. J Clin Endocrinol Metab 1990; 71:5-7 9. Rittmaster RS: Medical treatment of androgen-dependent hirsutism. J Clin Endocrinol Metab 1995; 80:2559-2563 10. Azziz R, Ochoa TM, Bradley EL, Potter HD, Boots LR: Leuprolide and estrogen versus oral contraceptive pills for the treatment of hirsutism: A prospective randomized study. J Clin Endocnnol Metab 1995; 80:3406-3411 11. Heiner JS, Greendale GA, Kawakami AK, et al: Comparison of gonadotropin-releasing hormone agonist and low dose oral contraceptive given alone or together in the treatment of hirsutism. J Clin Endocrinol Metab 1995; 80:3412-3418 12. Wong IL, Morris RS, Chang L, Spahn MA, Stanczyk FZ, Lobo RA: A prospective randomized trial comparing finasteride to spironolactone in the treatment of hirsute women. J Clin Endocrinol Metab 1995; 80:233-238 13. Shapiro G, Evron S: A novel use of spironolactone: Treatment of hirsutism. J Clin Endocrinol Metab 1980; 51:429-432 14. Cumming DC: Use of spironolactone in treatment of hirsutism. Cleve Clin J Med 1990; 57:285-287 15. Hammerstein J, Moltz L, Schwartz U: Antiandrogens in the treatment of acne and hirsutism. J Steroid Biochem 1983; 19:591-597 16. Rubens R: Androgen levels during cyproterone acetate and ethinyl treatment of hirsutism. Clin Endocrinol (Oxf) 1984; 20:313-325

Treatment Guidelines Initial therapy for women with hirsutism due to the polycystic ovary syndrome or idiopathic causes can be started with spironolactone or oral contraceptives (Table 3). Certainly, in women with menstrual irregularities or contraceptive concerns, oral contraceptives are considered a first-line agent. Spironolactone is generally well tolerated and usually efficacious. Women who are intolerant or nonresponsive to spironolactone use may be given a trial of finasteride combined with an estrogencontaining oral contraceptive. In women with severe hirsutism who are not responsive to the use of antiandrogens, oral contraceptives, and finasteride, the use of GnRH agonists should be considered. Finally, if hirsutism continues or worsens despite these treatment modalities, the clinician should consider reevaluating for a serious underlying disorder.