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Approach to Patients With HirsutismROLAND SAKIYAMA, MD, Los Angeles, California

Hirsutism is a common medical condition that in most women is due to the polycystic ovary syndromeor is idiopathic. For a few women, hirsutism signals a serious underlying disorder such as an ovarianor adrenal tumor, congenital adrenal hyperplasia, or Cushing's syndrome. A detailed medical historyand examination can identify women in whom a serious disease is suspected and for whom laboratoryevaluation is warranted. Measurements of serum testosterone, dehydroepiandrosterone, and 1 7a-hy-droxyprogesterone levels, and 24-hour urinary cortisol concentrations are important screening tests.Therapy is directed at suppressing ovarian or adrenal androgen production, inhibiting the conversionof 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 affectingabout 5% of women in the United States.! All too

often, physicians dismiss hirsutism as a concern that doesnot deserve their clinical acumen. Perhaps this responseis due to a lack of knowledge of the proper evaluation andmanagement of hirsutism or the notion that hirsutism ismerely a cosmetic problem. For most women, hirsutismis 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 seriousunderlying problem. Appropriate management can bedetermined after a carefully directed history, physicalexamination, and limited laboratory testing.*

Hirsutism is defined as the excessive growth of andro-gen-responsive terminal hair in women. Therefore, formost women, hirsutism is a cutaneous manifestation ofandrogen excess. True hirsutism must be distinguishedfrom hypertrichosis-that is, excessive growth of vellusor non-androgen-responsive hair. Vellus is fine, downyhair that is usually unpigmented. Terminal hairs are dark,thick, and found in the sex hormone-responsive areas ofthe pubis, axilla, back, face, chest, and abdomen.Androgens promote an increase in the number and thick-ness of terminal hairs in these areas. Women with andro-gen-dependent hirsutism either have exposure to exces-sive androgens or manifest a heightened androgen-recep-tor sensitivity to normal circulating levels of androgen.For other women, hirsutism is a non-androgen-depen-dent abnormality-that is, an adverse effect to certaindrugs or a genetic characteristic, such as in women ofMediterranean 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, "WhatWe See Most, We Understand Least," on pages 392-393 of this issue.

gens as defined by their ability to interact with theandrogen receptor. Testosterone binds to cell receptors,enters the cell cytoplasm, and is converted to dihy-drotestosterone by a 5a-reductase enzyme. Dihydro-testosterone, in turn, is bound to specific cytoplasmicreceptors. Potential androgens are dependent on a con-

version to testosterone and include dehydroepiandros-terone (DHEA) and androstenedione. Dehydroepi-androsterone is the major adrenal androgen that can beconverted to testosterone, or sulfated to DHEAS beforesecretion. Measuring the DHEAS level is the preferredplasma test of adrenal androgen production becauseDHEA shows a circadian and menstrual rhythm notfound with DHEAS. Androstenedione is the major C19steroid produced by the ovaries, although the ovaries are

also able to secrete testosterone and dihydrotestosterone.In normal women, two thirds of plasma testosterone isderived from the adrenal cortex through peripheral for-mation from DHEA and androstenedione.

Causes of HirsutismCauses of hirsutism can be classified as ovarian,

adrenal, drug-related, idiopathic, or genetic (Table 1).2Ovarian disorders include the polycystic ovary syn-drome and ovarian tumors. Adrenal disorders includecongenital adrenal hyperplasia, Cushing's syndrome,and adrenal tumors. Hirsutism may also occur with theingestion of anabolic steroids or as an adverse effect ofa limited group of medications (see Table 1). Idiopathichirsutism is defined by normal androgen concentrationsand a lack of any identifiable underlying disorder. It hasbeen proposed that idiopathic hirsutism results from an

increased androgen-receptor sensitivity to normal andro-gen 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.

Patients With Hirsutism-Sakiyama 387

tic ovary syndrome.3The polycystic ovary syndrome is the most common

identifiable cause of androgen hypersecretion in women.The underlying defect in this syndrome is postulated tobe a nontumorous dysfunction of luteinizing hormone(LH) hypersecretion, with a subsequent stimulation ofthecal and stromal ovarian cells to produce androgens.The polycystic ovary syndrome encompasses a widespectrum of clinical manifestations. Patients may pre-

sent with classic "polycystic ovary disease"-obesity,hirsutism, anovulation, and enlarged multicystic ovaries.On the opposite end of the spectrum, women with mildpolycystic ovarian syndrome may not be obese and haveregular ovulatory cycles and normal ovaries, with onlysubtle hormonal aberrations and hirsutism. Luteinizinghormone levels are frequently elevated in the polycysticovary syndrome, but often to such a modest degree thatits absolute value remains within the normal referencerange. If the ratio of LH to follicle-stimulating hormone(FSH) is measured, however, it is frequently increased to2.5 or greater in women with the polycystic ovary syn-

drome (most normal ovulatory women have an LH:FSHratio of 1.0). Total plasma testosterone levels are elevat-ed in 40% to 60% of women with this syndrome. In theother women, levels of total testosterone are normal, butthose of free testosterone are elevated. Free testosteronerepresents the nonprotein-bound hormone that is thoughtto most closely reflect cellular hormonal actions. Themajor binding protein for testosterone is sex hor-mone-binding globulin (SHBG), which is decreased inwomen with the polycystic ovary syndrome andaccounts for elevated levels of free testosterone despitenormal total testosterone levels.

Ovarian and adrenal tumors are uncommon causes ofhirsutism. Adrenal carcinomas are typically large by thetime they produce excessive androgens. Adrenal adeno-mas can produce androgens and are typically small anddifficult to localize. Ovarian tumors include Sertoli-Leydig cell tumors, hilar cell tumors, lipoid cell tumors,and adrenal rest tumors. Elevations in DHEAS levelssuggest an adrenal origin of androgen production,whereas greatly elevated testosterone concentrationssignal a possible ovarian or adrenal tumors.3

Cushing's syndrome is caused by the chronic over-

production of glucocorticoids and, to a lesser extent,adrenal androgens. Skin findings due to excessive andro-gen production include hirsutism, acne, and temporalhair recession, in addition to glucocorticoid-associated

TABLE 1.-Causes of Hirsutisrn*

General Specific Ca;,-se

Ovarian .. Polycvstic ovary syndromeNeoplasms

Sertoli-Leydig cell tuimorsHilar cell tunmorsLipoid cell tUmnorsAdrenal rest tumors

Adrenal Congenital adrenal hyperplasia

21-Hydroxylase deficiency11 [i-Hydroxyiase deficieincy31[-Hydroxysteroid dehydrogenasedeficlency

CLushings syndromeNeoplasmsAdrenal carcinoma

Adrenal adenomaDrUgs (proprietary name) ..... Cyclosporine (Sandimmune)

Danazol (Danocrine)Phenytoin (Dilantin)

GlucocorticoidsMinoxidil (Loniten)Diazoxide (Hyperstat)Anabolic steroids

IdiopathicGenetic

findings of thin skin and purple striae. Classic congeni-tal adrenal hyperplasia presents in infancy and is due toa deficiency of 21 -hydroxylase, 11 -hydroxylase, or 3 -

hydroxysteroid dehydrogenase adrenal enzymes. Anattenuated or nonclassic form of congenital adrenalhyperplasia may present in adolescence or young adult-hood.4'5 A partial deficiency of the 21-hydroxylaseenzyme is the most common form of nonclassic congen-ital adrenal hyperplasia. Decreased 21-hydroxylaseactivity leads to increased concentrations of 1 7a-hydroxyprogesterone, which in turn is converted totestosterone.

Idiopathic hirsutism is found in 50% of women eval-uated for hirsutism. Idiopathic hirsutism is defined bynormal physical and laboratory findings in women withthe onset of excessive hair growth in puberty or youngadulthood. They do not have signs of virilization andmanifest a slow progression of their hirsutism. Increasedsensitivity of the hair follicles to normal circulatingandrogens is thought to cause the hirsute state.

History and Physical Examination

The primary goal of the history and physical exami-nation is to identify patients in whom hirsutism is thecutaneous manifestation of a serious underlying disease.Hirsutism due to the polycystic ovary syndrome or idio-pathic causes typically begin between the ages of 15 and25 years and progresses slowly. Symptoms starting laterin life, coupled with a rapid progression, suggest a more

serious underlying disorder, such as an ovarian or adren-al tumor or Cushing's syndrome. The exception is peri-

ABBREVIATIONS USED IN TEXTACTH = adrenocorticotropic hormone, corticotropinCT = computed tomographyDHEA = dehydroepiandrosteroneDHEAS = sulfated form of DHEAFDA = Food and Drug AdministrationFSH = follicle-stimulating hormoneGnRH = gonadotropin-releasing hormoneLH = luteinizing hormoneMRI = magnetic resonance imagingSHBG = sex hormone-binding globulin

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menopausal women who may have more hair growth intheir perimenopausal years due to an increased produc-tion of adrenal androgens. Women with greater eleva-tions in androgen levels have virilizing symptoms suchas balding, deepening of the voice, increased libido, ordecreased body fat. Virilization is not typical of idio-pathic hirsutism or the polycystic ovary syndrome andsuggests a more serious disorder. Women should becarefully questioned about symptoms associated withspecific underlying diseases. For example, those withthe polycystic ovary syndrome may have amenorrhea,oligomenorrhea, infertility, or obesity. A recent weightgain with a cushingoid body habitus and hypertensionsuggests Cushing's syndrome, whereas flank pain or amass coupled with weight loss may be due to an adren-al cancer. Finally, the use of prescribed medications oranabolic steroids should be carefully reviewed.

The examination is directed at documenting theextent and distribution of terminal hair and uncoveringany clues as to an underlying cause. Hirsutism can bequantitated by the use of the Ferriman and Gallweyscore.' The extent of hirsutism is evaluated in nine bodyareas-upper lip, chin, chest, upper arms, upperabdomen, lower abdomen, thighs, and upper and lowerback-and each area is given a point score of 0 (no hir-sutism) to 4 (overtly virile). A total score of 8 or higheris consistent with the diagnosis of hirsutism. Physicalfindings of virilization include receded temporal hair,increased laryngeal size, decreased body fat, atrophiedbreasts, masculine musculature, and clitoromegaly (aclitoris of greater than 1.0 cm in diameter). Patients withCushing's syndrome may have acne, purple striae, orcentripetal obesity. A bimanual pelvic examination isdone to exclude an ovarian mass, which is found inabout half of women with ovarian tumors, or enlargedovaries (polycystic ovary syndrome).

Laboratory EvaluationIn women who are presumed to have the polycystic

ovary syndrome or idiopathic hirsutism, only a limitedlaboratory evaluation is required. For women with sus-picious historical or physical findings, a more extensivelaboratory evaluation is done to exclude androgen-secreting adrenal or ovarian tumors, Cushing's syn-drome, or the nonclassic form of congenital adrenalhyperplasia. The two most important screening tests aremeasurements of total serum testosterone and DHEASlevels. Testosterone levels of greater than 7 nmol perliter (2.0 ng per ml) suggest the presence of an andro-gen-secreting ovarian or adrenal tumor, and DHEASlevels of greater than 19 ,imol per liter (700 [ig per dl)suggest an adrenal tumor.7 Elevations of testosterone andDHEAS levels to this degree are not specific for a neo-plastic cause, as they can also be found in 50% ofwomen with benign disorders. Testosterone and DHEASlevels below these thresholds, however, essentiallyexclude an androgen-secreting tumor. For women withabnormally elevated testosterone levels and normalDHEAS levels, a search for an ovarian tumor is begun

with ultrasonography, computed tomography (CT), ormagnetic resonance imaging (MRI) of the pelvis. If bothtestosterone and DHEAS levels are abnormally elevated,then a radiologic evaluation of the adrenal glands is per-formed with MRI or CT.

To exclude the possibility of Cushing's syndrome, a24-hour urine specimen is collected and submitted forfree cortisol determination. A urine free cortisol concen-tration of greater than 275 nmol per day (100 ,ug per 24hours) is considered abnormal. Alternatively, the patientmay be given an overnight dexamethasone suppressiontest in which 1 mg of dexamethasone (2 mg for obesewomen) is given orally at 11 PM, with a serum cortisollevel measured at 8 AM the next morning. Normally, dex-amethasone will suppress cortisol values to less than 140nmol per liter (5 ,ug per dl). Women having a nonsup-pressed serum cortisol level or abnormal urinary freecortisol concentrations are referred for completeendocrinologic evaluation. To evaluate for 21-hydroxy-lase-deficient nonclassic congenital adrenal hyperpla-sia, a morning plasma 17a-hydroxyprogesterone level ismeasured. A 17a-hydroxyprogesterone level of 6.0nmol per liter (2.0 ng per ml) or lower rules out thisadrenal gland deficiency.5 A women with a 17a-hydroxy-progesterone level above 6.0 nmol per liter should bereferred for adrenocorticotropic hormone (ACTH; corti-cotropin)-stimulated testing.

The diagnosis of the polycystic ovary syndrome canbe confirmed with laboratory determinations of serumtestosterone, DHEAS, LH, and FSH levels. In the poly-cystic ovarian syndrome, the total testosterone level ismodestly elevated in 40% to 60% of patients. In womenfound to have normal testosterone levels, the levels offree testosterone will usually be elevated. The DHEASlevel is normal or occasionally slightly elevated, and theLH:FSH ratio is usually greater than 2.5. Pelvic ultra-sonography is not required unless an ovarian mass isfound on pelvic examination; however, in obese womenin whom the pelvic examination is difficult, an ultra-sonogram may be helpful. Enlarged polycystic ovariesare found infrequently and usually in women who man-ifest other features of the polycystic ovary syndrome,such as obesity, oligomenorrhea, or amenorrhea.

TreatmentMechanical methods of hair removal are an effective

adjunct for the control of hirsutism and may be the mostappropriate therapy for women with limited areas ofunwanted hair growth. For women with widespread hir-sutism, combining medical therapy with shaving, pluck-ing, waxing, or electrolysis can result in a more rapidresponse. In addition, women who have previouslyabandoned these physical methods may wish to resumethese measures after medical therapy has slowed the rateof new hair growth. The most common adverse effectsare skin irritation (bleaching, chemical depilatories), pit-ting or scarring (electrolysis), or folliculitis (plucking,waxing). Shaving is considered the safest method oftemporary hair removal and, contrary to popular belief,

Patients With Hirsutism-Sakiyama388 WJM, December 1996-Vol 165, No. 6

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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 non-

classic congenital adrenal hyperplasia, appropriate refer-ral should be made for specific therapy. Most women'shirsutism will be caused by the polycystic ovary syn-

drome or idiopathic causes, and medical therapy can beoffered. Treatment is more effective at preventing furtherhair growth than reversing long-established hirsutism,and therefore, women with the recent onset of hirsutismare more likely to respond to treatment than those withlong-standing hirsutism. In addition, because hair growthis inherently a slow process, patients are advised that an

observable response may not be evident in the first threeto six months. Finally, determining a therapeuticresponse is often difficult. Although the Ferriman-Gallwey score is useful, it is often cumbersome andhampered by the concomitant use of mechanical methodsof hair removal. A patient's subjective evaluation of herhair growth may be the only measure of successful ther-apy, with often the most useful measure of success beinga reduction in the time a woman spends removingunwanted hair.

Medical therapy for hirsutism may be directed at sev-

eral levels (Table 2). Drugs can suppress ovarian or

adrenal androgen secretion or block the action of andro-gens in target hair follicles. If a hormone abnormalityhas been determined, then therapy is directed at revers-

ing that abnormality. For example, a woman with an ele-vated testosterone level is given drugs that suppress

ovarian androgen production. Women with normaltestosterone concentrations are presumed to have an

increased end-organ sensitivity to androgens and there-fore are more likely to respond to drugs that antagonizethe tissue effects of androgens.

Suppressing Ovarian Androgen ProductionOral contraceptives are the most commonly used

method to suppress ovarian androgen production.Progestins inhibit gonadotropin secretion, therebyreducing ovarian-stimulated androgen secretion. Theestrogen component stimulates the hepatic synthesis ofSHBG, which binds circulating testosterone, and lowersthe amount of free testosterone available to hair follicles.This is especially helpful in women with the polycysticovary syndrome who often have lower SHBG levels.

When prescribing oral contraceptives, clinicians mustbe aware of the possible androgenic activity of the prog-estational component. 19-Nortestosterone derivatives,such as norgestrel, norethindrone, levonorgestrel, and toa lesser extent, ethynodiol diacetate and lynestrenol,show partial androgen activity, especially at higherdoses.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 inDemulen 1/35 has often been recommended for this rea-

son. Newer progestins, such as desogestrel, gestogen,and norgestimate, have no important androgenic activity

TABLE 2.-Medical Management of Hirsutism

Diagnosis Medicatioon (Proprietary Namree)

Ovarian androgen suppression .... Oral contraceptivesGnRH agonistDepot leuprolide (Lupron Depot)Nafarelin acetate (Synarel)

Cyproterone acetate* (Androcur,Diane)

Adrenal androgen suppression .... Glucocorticoids5ox-Reductase inhibitorst ........ Finasteride (Proscar)Antiandrogens ........... ... Spironolactone (Aldactone)

Cyproterone acetate* (AndrocurDiane)

GnRH = gonadotropin-releasing hormone

*Not available in the United States.tlnhibition of testosterone to dihYdrotestosterone.

and should be advantageous in treating hirsute women.Oral contraceptives combining low-dose estrogen andthese nonandrogenic progestins include Desogen,Ortho-Cept, Ortho-Cyclen, and Ortho Tri-Cyclen.Although these oral contraceptives offer a theoreticadvantage, comparisons of different oral contraceptiveswith regards to their effects on hirsutism are lacking.

The response to oral contraceptive use varies, but it ismore likely to occur in women with elevated testos-terone levels. The efficacy of oral contraceptive use forthe treatment of hirsutism has recently been questioned.9It may be that a few hirsute women will have substantialimprovement with oral contraceptive treatment alone.Until further studies are available, oral contraceptivescontinue to be a first-line treatment for the majority ofwomen with hirsutism. These hormones have the addedbenefits of regulating menses and ensuring contracep-tion in women taking antiandrogens.

Gonadotropin-releasing hormone (GnRH) agonistsused long term can suppress ovarian androgen produc-tion in hirsute women. The long-term use of these ago-nists alone, however, often leads to hypoestrogenic sideeffects such as hot flashes, osteoporosis, and urogenitalatrophy. Therefore, they are combined with oral contra-ceptives or conjugated estrogens and progestins in thetreatment of hirsutism.'0"' The GnRH agonists used inthe treatment of hirsutism include nafarelin acetate as anintranasal spray given 400 ,ug twice a day, or depotleuprolide acetate, 3.75 mg monthly. The use of GnRHagonists for the treatment of hirsutism is severely limit-ed by cost, and therefore therapy with GnRH agonistsshould be reserved for moderate to severe hirsutism thatis unresponsive to oral contraceptive alone or combinedwith antiandrogens.

Adrenal Androgen SuppressionGlucocorticoids are used to suppress ACTH-stimulat-

ed adrenal androgen production and therefore are usefulfor patients with the nonclassic form of congenitaladrenal hyperplasia. Treatment may be initiated withdexamethasone, 0.25 to 0.5 mg; prednisone, 2.5 to 5.0

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mg; or hydrocortisone, 10 to 20 mg. Glucocorticoids areadministered in the evening or at bedtime to suppress thenightly ACTH surge.

Sa-Reductase InhibitorsFinasteride is the only Sa-reductase inhibitor avail-

able in the United States. Finasteride blocks the conver-sion of testosterone to dihydrotestosterone, therebyinhibiting the androgen effects on the hair follicle.Finasteride has been approved by the Food and DrugAdministration (FDA) for the treatment of benign pro-static hypertrophy, but not for hirsutism. Studies havecompared the use of finasteride with that of spironolac-tone (an antiandrogen) and found them to have equaleffectiveness in the treatment of hirsutism.'2 The use ofboth finasteride and spironolactone decreased terminalhair diameters by 14% and improved the Ferriman-Gallwey scores by 11%. Finasteride use is well tolerat-ed, but studies of animals have reported ambiguous gen-italia in male offspring of treated females, and thereforefinasteride should not be used during pregnancy andshould be combined with a reliable method of contra-ception, such as oral contraceptives.

AntiandrogensOne of the most useful group of medications for the

treatment of hirsutism are the antiandrogens. These drugscompetitively inhibit the binding of testosterone anddihydrotestosterone to their respective receptors. Themost commonly used antiandrogen is spironolactone,which is an aldosterone antagonist commonly used as apotassium-sparing diuretic. Spironolactone has the addi-tional property of competitively binding to dihy-drotestosterone receptors, thus limiting the response oftissues to endogenous androgens. Although not approvedby the FDA for the treatment of hirsutism, several stud-ies have shown it to be an effective drug for this indica-

tion.'3"4 Therapy is started with a dosage of 50 mg twicea day, which is then increased to 100 mg twice a day ifno response is seen after three months. Half to three quar-ters of women will have a noticeable improvement withspironolactone. Adverse effects are more common athigher doses and include irregular menses (25%), gas-trointestinal cramping, diarrhea, nausea, lethargy, andheadache. Hyperkalemia may occur, especially in elderlywomen, in women with diabetes mellitus, or if taken withother drugs that may increase serum potassium levels(angiotensin-converting enzyme inhibitors). Therefore,periodic monitoring of serum potassium levels is recom-mended. Spironolactone should not be used in pregnan-cy, and appropriate contraception must be recommended.Combinations of oral contraceptives and spironolactoneare, therefore, commonly prescribed for the treatment ofhirsutism, to ensure contraception, and to regulate themenses.

Flutamide is a potent, nonsteroidal, selective antian-drogen without progestational or estrogenic activity thathas been effective in the treatment of hirsutism.9Flutamide is given at a dosage of 250 mg twice a daycombined with an estrogen-containing oral contracep-tive. Adverse effects include dry skin and increasedappetite. A major concern with flutamide is a potential-ly fatal drug-induced hepatitis that occurs in 0.5% ofpatients given this drug. Flutamide use can also causeambiguous genitalia in male offspring, and therefore,contraception must be maintained. Its use is not recom-mended for the routine treatment of hirsutism due to itsexpense and possible toxic side effects.

Cyproterone acetate has properties of both a potentprogestin and a moderately potent antiandrogen.Cyproterone acetate, therefore, acts at two levels in thepathophysiologic process of hirsutism. It competitivelyinhibits the binding of dihydrotestosterone to its cyto-plasmic receptor and also inhibits gonadotropin secre-

TABLE 3.-Guidelines for the Treotment of Hirsutism

lnitial Therapy Doseae* Alternative Thercipy Doscage*

Polycystic ovary syndrome ...... .

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

Nonclassic congenital adrenal hyperplasia ...

Cushing's syndrome ...................

Adrenal tumor .............. .

Ovarian tumor .......................

Drug-induced .........e

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

Glucocorticoids: prednisone, 5 mg qhs; or dexamethasone, 0.25 mg qhsSurgical excision of ACTH-secreting pituitary adenoma or ectopicACTH-secreting tumor; adrenalectomy for adrenal hyperplasiaSurgical excisionSurgical excisionDiscontinue medication

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

Finasteride (Proscar), 5 mg qd

GnRH agonist (Lupron Depot),3.75 mg monthly

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 rngof leuprolide acetate.

Diagnosis

390 WJM, December 1996-Vol 165, No. 6 Patients With Hirsutism-Sakiyama

Patients With Hirsutism-Sakiyama 391

tion because of its progestational properties.'5'6 An oralcontraceptive using cyproterone acetate as the progestinwould appear to be well suited for the treatment of hir-sutism. Cyproterone acetate is not available in theUnited States in any form, but it is available as a singleagent (Androcur) or combined with estrogen in an oralcontraceptive (35 or 50 ,ug of ethinyl estradiol and 2 mgof cyproterone acetate) in Europe, Canada, and Mexico(see Table 2). Drug-induced hepatitis is a rare complica-tion that may require periodic monitoring of liverenzyme levels.

Treatment GuidelinesInitial therapy for women with hirsutism due to the

polycystic ovary syndrome or idiopathic causes can bestarted with spironolactone or oral contraceptives (Table3). Certainly, in women with menstrual irregularities or

contraceptive concerns, oral contraceptives are consid-ered a first-line agent. Spironolactone is generally welltolerated and usually efficacious. Women who are intol-erant or nonresponsive to spironolactone use may begiven a trial of finasteride combined with an estrogen-containing oral contraceptive. In women with severe hir-sutism who are not responsive to the use of antiandro-gens, oral contraceptives, and finasteride, the use ofGnRH agonists should be considered. Finally, if hir-sutism continues or worsens despite these treatmentmodalities, the clinician should consider reevaluating fora serious underlying disorder.

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ovaries in normal women and what is their significance for fertility of the popula-tion? Clin Endocrinol (Oxf) 1992; 37:127-134

2. Carr BR: Disorders of the ovary and female reproductive tract, chap 12, InWilson 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-hydroxy-lase deficiency mimicking idiopathic hirsutism or polycystic ovarian disease. AnnIntem Med 1982; 96:143-148

5. Azziz R, Dewailly D, Owerbach D: Nonclassic adrenal hyperplasia: Currentconcepts. J Clin Endocrinol Metab 1994; 78:810-814

6. Ferriman D, Gallwey JD: Clinical assessment of body hair growth inwomen. J Clin Endocrinol Metab 1961; 21:1440-1447

7. Derksen J, Nagesser SK, Meinders E, Haak HR, van de Velde CJH: Identifi-cation 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 contracep-tives in treatment of androgen excess symptoms. J Clin Endocrinol Metab 1990;71:5-7

9. Rittmaster RS: Medical treatment of androgen-dependent hirsutism. J ClinEndocrinol Metab 1995; 80:2559-2563

10. Azziz R, Ochoa TM, Bradley EL, Potter HD, Boots LR: Leuprolide and es-trogen versus oral contraceptive pills for the treatment of hirsutism: A prospectiverandomized study. J Clin Endocnnol Metab 1995; 80:3406-3411

11. Heiner JS, Greendale GA, Kawakami AK, et al: Comparison of go-nadotropin-releasing hormone agonist and low dose oral contraceptive given aloneor 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: Aprospective randomized trial comparing finasteride to spironolactone in the treat-ment 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 ClinJ Med 1990; 57:285-287

15. Hammerstein J, Moltz L, Schwartz U: Antiandrogens in the treatment ofacne and hirsutism. J Steroid Biochem 1983; 19:591-597

16. Rubens R: Androgen levels during cyproterone acetate and ethinyl treat-ment of hirsutism. Clin Endocrinol (Oxf) 1984; 20:313-325

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