AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Androgen excess is the most common endocrine disorder in women of reproductive age. Characterized by an excessive androgen production by the adrenal glands and/or the ovary, androgen excess may result from increased local tissue sensitivity to circulating androgens. Androgen excess affects different tissues and organ systems, causing clinical conditions ranging from acne to hirsutism to frank virilization.

To understand how androgen excess develops and affects organs and systems, the physiology of androgen production and secretion should be briefly reviewed.

Sources of androgens in women

Androgen sources in women are the endocrine glands (adrenal glands and ovaries) and peripheral tissues such as fat and skin. Liver and gut play a minor role in androgen production, particularly in the peripheral conversion of testosterone to the most active form dihydrotestosterone (DHT).

The endocrine glands secrete 5 androgens through a similar pathway (see Media file 1): dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), androstenedione, testosterone, and androstenediol (has both androgenic and estrogenic activity). Testosterone is the only androgen with direct androgenic activity, while DHEAS, DHEA, and androstenedione are all precursors of testosterone.

The ovaries, under the control of luteinizing hormone (LH), produce 50% of the total testosterone that rises to 75% at midcycle. The ovaries also secrete 50% of the total androstenedione and small amounts (20%) of DHEA. Testosterone is used as a marker of ovarian androgen secretion; however, the adrenals, via peripheral conversion of androstenedione to testosterone, also contribute to total testosterone.

The adrenal glands produce all the DHEAS and 80% of the DHEA. The adrenals also secrete 50% of androstenedione and 25% of the circulating levels of testosterone. DHEAS and 11-androstenedione are not secreted by the ovaries and, therefore, are used as markers of adrenal androgen secretion. Their secretion depends on adrenocorticotropic hormone (ACTH); prolactin and estrogen can effect adrenal androgen production.

Skin, fat, liver, and urogenital systems are important peripheral sites of androgen production. Androstenedione, and to some degree DHEA, are converted to testosterone in the skin.

Androgen circulation

Androgen circulates in the blood in a protein-bound and an unbound fashion. Albumin has a low affinity but high capacity for binding steroids. DHEAS, DHEA, and androstenedione are almost entirely bound to albumin. Sex hormone-binding globulin (SHBG) binds steroids with high affinity but low capacity. Testosterone and DHT are bound primarily to SHBG and to a lesser degree, albumin.

In healthy women, 80% of testosterone is bound to SHBG, 19% is bound to albumin, and 1% circulates freely in the blood stream. In women who are hirsute, 79% of testosterone is bound to SHBG, 19% is bound to albumin, and 2% circulates freely. In men, 78% is bound to SHBG, 19% is bound to albumin, and 3% circulates freely.

Androgenicity depends mainly on the unbound fraction and in part on the fraction associated with albumin (bioavailable androgens). The binding capacity is decreased by androgen.

The levels of SHBG increase and decrease based on conditions and medications.

• SHGB levels increase because of the following:
  
  
  • Estrogens
  • Thyroid hormone
  • Pregnancy
  • Estrogen-containing preparations
• SHGB levels decrease because of the following:
  
  
  • Androgens
  • Synthetic progestins (norethindrone, norgestrel, desogestrel, norgestimate)
  • Glucocorticoids
  • Growth hormone
  • Insulin
  • Obesity
  • Acromegaly
  • Hypothyroidism
  • Hyperinsulinemia

Mechanism of androgen action

In the target tissues, androgens enter the cell cytoplasm by simple diffusion across the cell membrane. Once inside the cell, the androgens bind and activate the androgen receptor. The androgen-receptor complex attaches to a specific DNA site and stimulates the production of messenger RNA, which, in turn, stimulates the production of the enzymes and proteins necessary to affect androgen action.

Androgen effects

Androgens induce maleness and are responsible for forming the male external genitalia in the fetus; their absence or the absence of testosterone receptors results in a female phenotype despite the presence of a 46 XY karyotype. Androgens are responsible for the development of the secondary sexual organs and ducts, the seminal vesicles, and the prostate. Postnatal females are not as sensitive as the fetus to androgens, which induce the growth of sexual hair, temporal balding, acne, clitoral growth, sebum production, and a deepening of the voice. Oral androgens decrease high-density lipoprotein (HDL) cholesterol and increase low-density lipoprotein (LDL) cholesterol. With androgen excess, the extent of these changes is dependent on the level of androgens in the blood.

Pathophysiology

Androgen excess affects mainly the pilosebaceous unit (PSU) and the reproductive systems.

The pilosebaceous unit secretes sebum and is the unit from which hair grows. Two types of hair (ie, lanugo or vellus, and terminal hairs) exist. The fine hairs of the fetus are lanugo and the peach fuzz hair of adults is vellus hair. These hairs are fine, short, and nonpigmented. Thick and pigmented hair is referred to as terminal hair. Those hairs of the pubic, axillary, sternal, and facial areas are responsive to androgens and those in other parts of the body are androgen-independent. Their prevalence depends largely on genetics. As androgen levels rise, more vellus hairs in the androgen-sensitive areas are converted into terminal hairs. This results in hirsutism. Androgens prolong the growth phase of hair and promote their conversion from vellus type to terminal. Hirsutism affects 70-80% of women with androgen excess. Sebum production from the pilosebaceous unit is also increased by androgens.

Lesions of the pilosebaceous unit are called acne. Acne can be aggravated or initiated by increased androgen levels as the excess sebum production and the shedding of hyperkeratinized epithelium may occlude the hair follicle. Propionibacterium acne proliferates and triglycerides of sebum are then hydrolyzed by the bacterial lipases to form glycerol and free fatty acids, which are inflammatory. An inflammatory lesion develops. The progressive stages of acne lesions are the following:

• Noninflammatory lesions
  
  
  • Closed comedone (whitehead)
  • Open comedone (blackhead)
• Inflammatory lesions
  
  
  • Papule
  • Pustule
  • Nodule

In polycystic ovarian syndrome (PCOS), the most common cause of androgen excess and hirsutism, the ovarian theca cells increase their ovarian androgen production under the stimulatory activity of the raised LH levels. Hyperinsulinemia due to peripheral insulin resistance is often present in those women and it promotes hyperandrogenemia through the binding of insulin to the IGF-1 receptor. Insulin mimics the action of IGF-1, which augments androgen production by the theca cell in response to LH. Since insulin decreases levels of SHBG, the circulating levels of free testosterone are also increased. Most of those patients are infertile due to anovulation as the increased LH activity causes a defective granulosa cells' aromatization of androgens to estrogens and results in reduced estrogen levels. Spontaneous miscarriages also increase.

Obesity and hyperinsulinemia often present in patients with PCOS can cause abnormal lipid metabolism that can lead to atherosclerosis and a predisposition to coronary artery disease.

The increase of 5a-reductase activity in the peripheral tissues or an increased sensitivity of the androgen receptors could be at the origin of idiopathic hirsutism, the second most common cause of hirsutism. In this condition, the clinical signs do not correspond to an increased level of serum androgens.

An enzyme defect in the adrenal or ovarian steroidogenic pathways can also cause androgen excess. Congenital adrenal hyperplasia (CAH) due to an autosomal-recessive disorder is the most common cause of an enzyme defect. In 90% of cases, the enzyme 21-hydroxylase is missing or defective, whereas in a minority of cases, the 11a-hydroxylase enzyme or the 3a-hydroxy-steroid dehydrogenase enzyme is missing or defective. When these enzymes are missing or functioning at low levels, the body cannot make adequate amounts of the adrenal steroid hormones cortisol and aldosterone.

High levels of ACTH that stimulate adrenal hyperplasia and hypersecretion of androgen precursors for cortisol and aldosterone synthesis ensue. CAH can appear in utero or develop postnatally. Pseudohermaphroditism may be present at birth. The administration of corticosteroids corrects the hyperandrogenism, but failure to take steroids can increase androgen levels in adults and can result in further androgenization and/or virilization.

The 21-hydroxylase deficiency is the most common autosomal-recessive disorder (more common than cystic fibrosis) and manifests itself with elevated levels of 17-hydroxyprogesterone. The 11a-hydroxylase deficiency is characterized by elevated levels of 11-deoxy-cortisol (compound S) and results in elevated levels of deoxycorticosterone (DOC), a mineralocorticoid. Hypertension and hypokalemia can be a prominent feature of 11a-hydroxylase deficiency.

Another form of CAH, 3a-hydroxy-steroid dehydrogenase deficiency, results in elevated levels of pregnenolone, 17-hydroxy-pregnenolone, and DHEA. This condition is lethal if not detected because no corticosteroids are synthesized.

A partial defect in the above enzymes that manifests after puberty results in elevated levels of adrenal steroids via the same mechanism. The elevations are not as marked as they are with the congenital condition and this condition is referred to as nonclassical (maturity-onset or late-onset) CAH.

Ovarian or adrenal tumors are rare causes of hyperandrogenism. These tumors secrete high levels of androgens, causing an abrupt onset of signs of androgen excess and a rapid progression of the symptoms.

Ovarian androgen-secreting tumors

• Sertoli-Leydig cell tumors
• Leydig cell tumors
• Lipoid or lipid cell tumors
• Granulosa-theca cell tumors
• Hilus cell tumors
• Gynandroblastoma
• Steroid cell tumors
• Teratoma
• Gonadoblastoma

Adrenal androgen-secreting tumors

• Carcinoma
• Adenoma

Ingestion of androgens or agents with androgenlike activity can result in hirsutism, acne, and virilization. Oral contraceptive progestins are listed as potentially causing hirsutism because of their derivation from testosterone; however, oral contraceptive progestins are not androgenic in women in clinical doses. Androgenic effects are observed only in high doses in rodents.

Frequency

United States

The incidence rate of androgen excess is 8%.

International

The international incidence rate is dependent on the particular culture, but, essentially, it is similar to that of the United States.

Mortality/Morbidity

No mortality or morbidity exists per se, but androgen excess is associated with insulin resistance, dyslipidemia, hypertension, and vascular diseases; therefore, it is a forerunner for cardiovascular disease (CVD).

• Impaired glucose tolerance and type II diabetes affect about 40% of women with PCOS.
• The presence of PCOS is an independent cardiovascular risk factor and women who have anovulatory PCOS have the greatest cardiovascular risk compared with women who have ovulatory PCOS and idiopathic hyperandrogenism.
• Androgen-secreting tumors are rare and about 30% of them are malignant.

Race

Androgen excess occurs equally in all races. CAH prevalence due to 21-hydroxylase deficiency is greater among those of Ashkenazi Jewish descent.

Sex

CAH occurs equally in both sexes; however, this article focuses on females.

Age

The most common causes of hyperandrogenism begin in early adolescence or in childbearing age. Androgen-producing tumors may rarely affect postmenopausal women.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

A thorough history and focused physical examinations are essential for the androgen excess evaluation. Laboratory tests should serve to confirm the diagnosis.

• Family history and cultural background
• • A patient is not hirsute if she does not notice a difference compared with her relatives.
  • CAH is inherited so a family history is important.
  • A family history of type II diabetes may indicate insulin resistance.
• Patient age at thelarche, adrenarche, and menarche
• • CAH is a genetic condition that causes androgen excess in early childhood.
  • Androgen excess in childhood, if untreated, results in rapid growth and early puberty with short stature in adulthood.
• Detailed history of menstrual pattern: Oligomenorrhea, anovulation, and dysfunctional uterine bleeding are often associated with androgen excess.
• Reproductive history, including miscarriages
• History of galactorrhea or symptoms of thyroid dysfunction
• Detailed history of age at onset and progressions of features of androgen excess
• • Hirsutism, acne, alopecia, excessive sebum, and seborrhea could all be signs of androgen excess.
  • Rapid onset of hirsutism is characteristic of androgen-secreting tumors, whereas slow onset is more likely to be an endocrine disorder of adrenal, ovary, or pilosebaceous unit.
  • Signs of virilization include deepening of voice, temporal balding, clitoromegaly, and changes in bra size.
• Use of androgenic drugs should be excluded.

Physical

• Height, weight, body mass index (BMI) and waist-to-hip ratio (WHR) should be determined. Increased BMI and WHR are associated with increased coronary artery disease and mortality.
• Hirsutism is excessive recognizable hair growth characterized by an increase in the number and length of terminal hairs in androgen-sensitive areas. Racial, familial, genetic, and ethnic differences all affect the occurrence of hirsutism. Hirsutism is difficult to quantitate. The entire body needs to be inspected and the findings must be documented carefully. Particular attention should be directed to the chin, lip, sideburns, breasts, and sternum, the midline between the umbilicus and the pubis and the thigh.
• Ferriman and Gallwey published a rating scale that is illustrated in the table below.¹ This scale allows the physician to measure a response to therapy objectively. This system is the most widely used and evaluates body areas for absent-to-severe hirsutism with scores of 0-4, respectively. Scores of 8 and higher are consistent with a diagnosis of hirsutism. This scale does not measure the thickness of the hair, which is another way of objectively assessing excess hair.
• • Scoring systems are a useful aid in quantifying hirsutism and in evaluating treatment response; however, they remain somewhat subjective. The absolute score does not define hirsutism. Even with scores greater than 8, the patient provides the definition. From a clinical standpoint, the patient can determine if he or she notices a difference. Photographs are helpful for documentation and for following the progress of therapy.
  • Ferriman-Gallwey Scoring System
    
    

    Body Area Evaluated	Score (Graded from 0-4*)
    Upper lip
    Chin
    Upper abdomen
    Lower abdomen
    Upper arm
    Thighs
    Upper back
    Lower back/buttocks

    *0 = No hirsutism, 4 = Severe hirsutism
• Virilization is relatively uncommon; it occurs with extreme hyperandrogenism.
• • Virilization is characterized by temporal balding, breast atrophy, androgenic muscle development, clitoral hypertrophy, amenorrhea, deepening of the voice, and extreme hirsutism.
  • Clitoromegaly is defined when the product of the sagittal and transverse diameters of the glans of the clitoris are greater than 35 mm.
• Acne as an isolated symptom might not be considered a sign of hyperandrogenism.
• • The severity of the acne lesions needs to be assessed, including the number, type, and distribution of the lesions.
  • Several areas of the body need to be examined, including the face, chest, and back. Photographic documentation is helpful.
• Acanthosis nigricans is a skin hyperpigmentation usually present on the back of the neck, under the arms, and in the groin region. The skin is velvety and the color can range from light brown to black. Acanthosis nigricans in the presence of hirsutism raises the suspicion of insulin resistance and hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN) syndrome (see Acanthosis Nigricans).
• The breasts should be examined for presence of galactorrhea and the thyroid gland should be palpated.

Causes

Excessive androgen production by the ovaries, and/or the adrenal glands are the most common causes of androgen excess. An abnormal steroid metabolism, androgen receptor dysfunction, and the use of androgenlike drugs may also be causes.

• Polycystic ovarian syndrome (PCOS) is the most common hyperandrogenic disorder, affecting 5-10% of all women. PCOS involves irregular ovulation in combination with excess androgens and possibly polycystic ovaries. An extreme form, hyperthecosis, can have testosterone levels in the tumor range.
• Tumors of the ovary secrete high levels of testosterone. The testosterone levels exceed 2.0 ng/mL (200 ng/dL, 8.92 nmol/L) or 2.5 times the upper limit of the reference range. Sertoli-Leydig cell tumors, hilus cell tumors, and lipoid cell (adrenal rest) tumors are the most common. Sertoli-Leydig cell tumors reach palpable size at the time of clinical diagnosis, whereas hilar cell and lipoid cell tumors are difficult to detect by any means because of their small size.
• Tumors of the adrenal glands (adenomas, carcinomas), which secrete elevated levels of androgens, are known but rare. They are suspected when DHEAS exceeds 7 μg/mL (18 μmol/L).
• Classical and nonclassical (late-onset) CAH
• Cushing syndrome: Patients with Cushing syndrome secrete elevated androgens, but diagnosing this disease by hyperandrogenic manifestations without the other signs and symptoms of Cushing syndrome would be unusual.
• Hyperandrogenic, insulin resistance, and acanthosis nigricans (HAIR-AN) syndrome
• Mild androgenic disorders: These are common androgenic disorders that do not cause an ovulatory dysfunction.
  
  
  • Ovulatory PCOS - Ovulatory hyperandrogenic patients with polycystic ovary at ultrasonography
  • Idiopathic hyperandrogenism - Ovulatory hyperandrogenic patient but with normal ovaries at ultrasonography
  • Idiopathic hirsutism - Androgenic phenotype with normal androgens
• Factitious: Ingestion of androgens can result in hirsutism, acne, and virilization. Agents such as oral contraceptive progestins are listed as potentially causing hirsutism; however, these agents are not androgenic in women in the doses used clinically. Drugs that can induce hirsutism by their inherent androgenic effects include DHEAS, testosterone, danazol, and anabolic steroids.
• Pregnancy: Testosterone rises throughout the normal pregnancy, reaching values around 600-800 ng/dL by term. The increase in SHBG and the placenta aromatization of androgens to estrogens protect the mother and fetus. Placental aromatase enzyme deficiency can cause hyperandrogenemia in both mother and fetus and causes virilization.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Congenital adrenal hyperplasia
Adrenal tumor
Ovarian tumor
Hyperprolactinemia
Idiopathic
Factitious

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• The selection of a laboratory expert in androgen determination is crucial. Reliable reference range and quality control must ensure reproducible androgen determination over a long period, as long-term therapy for hyperandrogenism is often necessary.
• The purpose of laboratory tests is to detect the specific androgens involved, the degree of hypersecretion, and the origin of the androgens. The following are markers of androgen production:
• • Adrenal glands: Virtually all DHEAS is produced by the adrenal glands.
  • Ovaries: Two thirds of circulating testosterone originates from the ovaries.
  • Peripheral production: 3α-androstanediol glucuronide is a metabolite of DHT and indicates the level of activity of target tissue conversion of testosterone and androstenedione to DHT.
• Follicle-stimulating hormone (FSH), total and free testosterone, 17-hydroxyprogesterone (17-OHP), DHEAS, SHBG, and prolactin should be tested during the initial assessment.
• • The samples should be obtained in the morning because of the diurnal rhythm of adrenal steroids and performed in the early follicular phase.
  • An elevated LH or LH/FSH ratio greater than 2.5 is demonstrable in two thirds of women with PCOS; however, it is not useful in the workup of hirsutism (see Polycystic Ovarian Syndrome).
  • Testosterone levels between the upper limit of the reference range and 2 ng/mL (8.92 nmol/L, 200 ng/dL) or 2.5 times the upper range are consistent with PCOS. Values within the reference range may indicate end-organ sensitivity or genetically determined hirsutism.
  • Serum testosterone level greater than 2 ng/mL (8.92 nmol/L) or 2.5 times the upper limit of the reference range for the laboratory suggests an ovarian tumor. Adrenal tumors that secrete testosterone have been reported, and markedly elevated adrenal androgens can be converted peripherally to testosterone.
  • Not all women with a testosterone level greater than 2 ng/mL have a tumor. To avoid unnecessary surgery and radiographic testing, several samples should be elevated.
  • Testing for free testosterone should be limited to those patients who have a sign of hyperandrogenism in the presence of normal levels of testosterone and DHEAS (idiopathic hirsutism).
  • Obese women may have relatively high testosterone levels because of reduced SHBG due to hyperinsulinemia.
  • 17-OH-progesterone is elevated in the luteal phase, hence the rationale of testing in early follicular phase. CAH due to 21-hydroxylase defect can be screened by measuring 17-OH-progesterone. Tests revealing levels above 2 ng/mL (6.05 nmol/L) need to be repeated and, if elevated, an ACTH stimulation test with 0.25 mg of ACTH (Cortrosyn) must be performed. Levels above 10 ng/mL (30.02 nmol/L) at 1 hour are diagnostic.
  • Elevated DHEAS levels indicate an adrenal cause for androgen excess. An adrenal tumor should be suspected if the value is greater than 7 µg/mL (18 µmol/L), and radiographic studies should be undertaken. If no tumor is suspected, then Cushing syndrome should be ruled out, if clinically indicated. See Cortisol studies. Media file 2 is an algorithm that outlines the workup of an elevated DHEAS.
  • Prolactin is occasionally elevated in hirsutism. When other test results are normal, prolactin testing is recommended to determine if bromocriptine might be useful.
• Fasting glucose and insulin should be tested in women who are obese or have PCOS. An elevated insulin level or, even better, a fasting glucose/insulin ratio less than 4.5 indicates insulin resistance.
• Cortisol studies are indicated if the physical examination is consistent with Cushing syndrome and no other explanation can be found for hirsutism in the patient. A 24-hour urinary free cortisol level or an overnight dexamethasone suppression test should be completed.
• Testing for androstanediol glucuronide is useful when testosterone and DHEAS levels are in the reference range. Levels are frequently elevated in patients with hirsutism and who have normal testosterone levels. This test is most useful when considering the use of finasteride.

• Testosterone level greater than 200 ng/d; DHEAS level normal
• • Possible diagnoses
  • • Ovarian neoplasm
    • Hyperthecosis
  • Workup
  • • CT scan of adrenals
    • Pelvic ultrasonography
    • Ovarian and adrenal venous sampling
• Testosterone level variable; DHEAS level greater than 7µg/mL
• • Possible diagnoses
  • • Adrenal tumor
    • Cushing syndrome
  • Workup
  • • Adrenal CT scan
    • Dexamethasone suppression test
• Testosterone level greater than 70 ng/dL; DHEAS level elevated but less than 7µg/mL
• • Possible diagnoses
  • • PCOS
    • Adrenal hyperplasia
    • Cushing syndrome
  • Workup
  • • No further workup
    • Rule out Cushing syndrome
    • Rule out CAH
• Testosterone level normal; DHEAS level normal
• • Possible diagnoses
  • • End-organ sensitivity
    • Decreased SHBG
  • Workup
  • • Free testosterone
    • 3a-androstanediol glucuronide

Imaging Studies

• Ultrasonography allows an accurate evaluation of the ovaries.
  
  
  • Polycystic ovaries (PCO) are defined on ultrasonography as having 12 or more follicles measuring 2–9 mm in diameter, and/or increased ovarian volume (>10 cm³). The presence of PCO in 1 ovary is sufficient to make a diagnosis. About 20% of healthy patients can have ultrasonographic evidence of PCO and patients with PCOS can have normal looking ovaries.
  • Color-flow Doppler is helpful for tumor detection and localization but small hilar cell tumors can be missed. Ultrasonography helps the diagnosis of ovarian hyperthecosis.
• CT scan helps diagnosis adrenal androgen-secreting tumors. CT scans are rarely useful or necessary for ovarian tumors.
• MRI can detect some ovarian tumors, although it is more useful for adrenal lesions. Because CT scans and ultrasonography are less expensive, they should be performed first.
• Radionuclide studies: Iodomethyl-norcholesterol (NP-59) can light up steroid-secreting areas of the adrenal gland or ovary, and, if available, these studies help to differentiate and locate a tumor when other radiographic studies fail to show a tumor.

Other Tests

Functional tests are used in clinical scenarios when the androgen excess origins cannot be attributed.

• 2-day dexamethasone suppression test
• • DHEAS, testosterone, and cortisol are measured before and after administration of 8 doses of 0.5 mg of dexamethasone given over a period of 48 hours.
  • Adrenal source: Following administration of dexamethasone, testosterone is suppressed more than 40% and DHEAS is suppressed more than 60%.
  • Ovarian source: Following administration of dexamethasone, testosterone is not suppressed while DHEAS and cortisol are suppressed.
  • Combined source: Following administration of dexamethasone, testosterone suppression is less than 40%.
  • If androgens and cortisol fail to suppress following administration of dexamethasone, Cushing syndrome or adrenal cancer must be the cause.
• Synthetic ACTH (Cosyntropin) adrenal stimulation test
• • This test is only indicated if a morning early follicular phase 17-OHP is elevated.
  • This test helps the detection of enzyme deficiencies (eg, 21-hydroxylase deficiency) of the adrenal gland.
• Gonadotrophin-releasing hormone (GnRH) stimulation test
• • This test is useful to confirm the ovarian origin of the hyperandrogenemia.
  • Dexamethasone is used to suppress the adrenal glands while the ovaries are stimulated by GnRH analogue.
  • A 17-hydroxyprogesterone hypersecretion confirms the ovarian origin of androgen excess.
• GnRH antagonist (Cetrolix) suppression test
• • This test helps determine if the androgen production is gonadotrophin dependent.
  • This test is used in the diagnosis of ovarian-secreting tumor.

Procedures

• Ovarian and adrenal vein sampling
  
  
  • Ovarian and adrenal vein sampling are used when laboratory values indicate a tumor but no tumor can be identified by imaging studies.
  • Sampling of the ovarian and adrenal veins helps determine the source of elevated androgen levels and whether 1 or both glands are involved. A single glandular involvement is highly suggestive of a tumor.

TREATMENT

Section 6 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Medical treatment needs to be maintained for a long time because satisfactory clinical effects of drugs appear after several months.

Pharmacologic measures aim to correct symptoms by lowering the serum-free androgen levels and blocking the peripheral androgen action.

• Suppression of ovarian androgens by administration of estrogens and/or progestins (ie, contraceptive pill) or GnRH agonist and add-back estrogen therapy
• Suppression of adrenal androgens by administration of glucocorticoids (dexamethasone, prednisolone)
• Use of antiandrogens (spironolactone, flutamide, cyproterone acetate)
• Use of the 5α-reductase inhibitor (finasteride)
• Use of bromocriptine in hyperprolactinemia
• Use of insulin-sensitizing drugs (metformin, thiazolidinediones)
• • Oral contraceptive (OC) combined with antiandrogens is the first-line approach to nonadrenal hyperandrogenism. OCs alone have limited efficacy in treating androgen excess; however, they provide reliable contraception, help in the treatment of acne, and counteract the risk of endometrial cancer associated with anovulation and unopposed estrogen stimulation. Antiandrogens are best added to OC therapy to maximize the results in hirsutism treatment.
  • Progestins in adequate doses suppress the ovarian function and, therefore, reduce hirsutism. Progestins do not offer additional advantages and are used only in patients in whom combined OCs are not indicated.
  • Adrenal hyperandrogenism (CAH, Cushing syndrome), respond to glucocorticoid treatment with prednisolone or dexamethasone in a low dose. The long-term effect of low-dose glucocorticoid therapy on the bone metabolism and dysmetabolic syndrome is not entirely clear; therefore, the steroid dose should be lowered or discontinued after 3 months.
  • Suppression of androgen secretion has limited efficacy on hair growth and the best results are obtained by using antiandrogens. Antiandrogen drug availability in different countries is inconsistent; the US Food and Drug Administration (FDA) does not approve the use of the antiandrogen cyproterone acetate in hyperandrogenism.
  • Antiandrogens alone or in combination with OC pills are effective treatments of hyperandrogenism. Spironolactone, finasteride, flutamide, and cyproterone acetate have all been demonstrated to be equally effective. Antiandrogens are class D or X in pregnancy; therefore, an effective form of contraception is required when using these drugs. They can cause ambiguous genitalia and feminization of a male fetus.
  • GnRH agonists are effective in severe hirsutism and virilism secondary to ovarian hyperandrogenism. The GnRH agonist suppresses the ovarian androgen production by inhibiting the gonadotrophin secretion. Hormone replacement therapy (HRT) add back can be used to relieve the symptoms of hypoestrogenism. HRT also increases SHBG and decreases free testosterone. The HRT add back can be any HRT, either sequential or continuous combined. For the initial few months, the addition of 100-200 mg/d of spironolactone may help. After improvement of both the serum testosterone values and hirsutism, these patients can stop the GnRH agonist and switch to an OC with or without spironolactone.
  • Insulin-sensitizing drugs have a role in hyperandrogenism associated with PCOS because they decrease hyperinsulinemia and insulin resistance.
• Hirsutism treatment
• • A combination of both mechanical and medical methods best treats hirsutism. Medical therapy does not work on terminal hairs; these should be removed by cosmetic measures including mechanical and chemical methods.
  • OC combined with an antiandrogen is the first-line approach to hirsutism. Depo-Provera or Lunelle are also good choices.
  • The progestin component of the contraceptive pill lowers both the ovarian androgen production and the adrenal DHEAS production. The estrogenic component increases levels of SHBG production, thus lowering the free androgens.
  • A contraceptive pill containing ethinylestradiol and the antiandrogen cyproterone acetate (Diane) is on the market in many countries but not in United States.
  • The efficacy of the new OC Yasmin, which contains the new progestin drospirenone (a 17a-spironolactone derivative), has yet to be demonstrated.
  • A GnRH agonist best manages severe hirsutism and virilism secondary to hyperthecosis.
  • Hirsutism secondary to adrenal hyperandrogenism responds to glucocorticoid treatment with prednisolone or dexamethasone in a low dose.
  • Monotherapy with spironolactone, finasteride, flutamide, and cyproterone acetate is equally effective. An effective form of contraception is required when using these drugs.
  • Spironolactone is the least expensive and most extensively used antiandrogen. A potential side effect is abnormal uterine bleeding; therefore, the use of an OC is advocated. This also protects against the risk of pregnancy and feminization of male fetuses.
  • Cyproterone acetate is a steroid with progestin, antiandrogen, and glucocorticoid activity. It is an effective treatment for hirsutism but not licensed in the United States.
  • The efficacy of insulin-sensitizing drugs on hirsutism appears limited and more studies are needed.
  • Topical eflornithine (Vaniqa) is available for the treatment of facial hirsutism. Eflornithine blocks the ornithine carboxylase in the hair follicle, thus reducing hair growth. Its efficacy has been shown in randomized controlled trials, but the effect rapidly reverses after stopping the treatment.
• Acne treatment
• • Therapy for acne is directed to reduce the sebum production, normalize the keratin production, clear comedones, and eliminate the propionibacterium acne colonization that causes inflammation and infection. Topical and systemic treatment exists. The drugs that decrease hirsutism also decrease acne.
  • In randomized placebo-controlled trials, mild-to-moderate acne has been shown to improve with OCs. A review of the literature indicates that all OCs studied are efficacious. The comparative effectiveness of the OC pill shows no differences in the different progestin components it contains.
  • Topical retinoids help to normalize keratinocyte differentiation and reduce cell proliferation and inflammation. They are the first choices in patients with comedonal acne, but they can cause skin irritation and increase skin photosensitivity and therefore should be applied at bedtime.
  • Oral isotretinoin (Accutane) is useful in severe inflammatory acne and in cases that are unresponsive to other treatments. It is category X and teratogenetic, therefore 2 effective forms of contraception are required.
  • Antibacterial drugs can be used alone or in association with topical retinoid. Azelaic acid (Azelex) topical has been shown to possess antimicrobial activity against Propionibacterium acnes and Staphylococcus epidermidis.
  • Topical or oral tetracycline, erythromycin, and clindamycin can all be used effectively. Oral antibiotics should be given in a short course if absolutely necessary. Tetracycline is the preferred oral antibiotic due to its low cost and high efficacy.
• Ovulatory dysfunction and infertility treatment
• • Androgen excess can cause anovulation and infertility.
  • Ovulation induction with clomiphene citrate 50-200 mg/d for 5 days, commencing on day 2 or 3 of the menstrual cycle is first-line treatment. Of anovulatory women, 25% do not respond to clomiphene and can be treated with gonadotrophins. Clinician experts in assisted reproduction techniques must supervise the treatment because hyperstimulation syndrome and multiple pregnancy rates of up to 25% are recognized complications.
  • A short course of dexamethasone can be added to clomiphene to restore ovulation.
  • Metformin has been shown to increase both spontaneous and clomiphene-induced ovulation rates.

Surgical Care

Ovarian and adrenal tumors need to be removed surgically.

• In severe cases of hyperthecosis and severe hirsutism, oophorectomy may be considered in women older than 35 years who have completed their family. Estrogen replacement therapy following oophorectomy prevents osteoporosis and vasomotor symptoms and improves hyperandrogenic conditions.
• Ovarian drilling by either laser or fulguration is effective in restoring ovulation in patients with PCOS wishing to conceive who are resistant to clomiphene. An ovulation rate of 70% has been reported. Ovarian drilling is not indicated for hirsutism, and a lowering effect on circulating androgens has yet to be fully demonstrated.
• Cosmetic measures include bleaching the hair in white people to make it less noticeable, shaving, waxing, electrolysis, laser removal, and use of depilatory creams to remove hair chemically.

Consultations

• Consultation with the appropriate practitioner for any surgical procedure described above is indicated.
• In complicated cases, consultation with an internal medicine endocrinologist or a reproductive endocrinologist would be appropriate for further workup and treatment and for interpretation of unusual results.

Diet

Decreasing central body fat decreases hyperinsulinemia and increases SHBG, thereby decreasing ovarian androgen production and serum free androgens. Although difficult to achieve, weight loss should be encouraged in all patients, particularly those with PCOS who are obese because they are at risk of metabolic complications.

Weight loss improves menstrual irregularity in as many as 80% of patients and can restore ovulation and fertility.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical treatment of androgen excess is aimed at lowering ovarian or adrenal androgen production, reducing the free androgen level and blocking the peripheral androgen action. However, the treatment of primary symptoms such as hirsutism, acne, and menstrual disorders usually brings the patient with androgen excess to the doctor’s attention.

Hirsutism is best treated by a combination of mechanical and chemical methods. The mechanical methods remove hair immediately, and the chemical methods prevent further differentiation of vellus to terminal hairs.

PCOS associated with insulin resistance can be treated with metformin and/or an OC with or without added antiandrogen (spironolactone). PCOS not associated with insulin resistance is best treated with an OC with or without added spironolactone.

Acne treatment is aimed at decreasing skin sloughing and proliferation of P acnes using topical and systemic agents. Suppression of androgen production decreases production of sebum and reduces acne.

Drug Category: Oral contraceptives

Oral contraceptives (OCs) decrease ovarian androgen production and increase SHBG, therefore reducing free testosterone by approximately 50%. OCs also decrease adrenal androgen production, particularly DHEAS. The reduction in ovarian androgens is in relation to the OCs capacity to inhibit ovulation. Low-strength preparations (20 µg ethinyl estradiol) are less efficient than standard or high-strength preparations in inhibiting ovulation. The presence of less androgenic progestin (desogestrel, norgestimate) in the third generation pills is not associated with better outcome compared with other OCs. By promoting regular bleeding, OCs reduce the incidence of endometrial hyperplasia and cancer.

OCs alone or in combination with antiandrogens are first choice for the treatment of hirsutism in women needing contraception. All strengths of OC pills have been shown to improve acne. The choice of an oral contraceptive should be based solely on personal preference of the health care provider and patient. The new OC pill containing the antiandrogens drospirenone and ethinyl estradiol (Yasmin) has not shown advantages over other preparations.

Drug Name	Drospirenone and ethinyl estradiol (Yasmin)
Description	Drospirenone 3 mg and ethinyl estradiol 30 µg
Adult Dose	1 tab PO qd
Pediatric Dose	Postmenarche: Administer as in adults
Contraindications	Yasmin increases serum potassium level and should not be used in hepatic dysfunction, renal insufficiency or adrenal insufficiency; past and present thromboembolic disorders; cardiovascular and cerebrovascular diseases; documented hypersensitivity; pregnancy; breastfeeding; liver diseases; endometrial and breast cancer; systemic lupus erythematosus; porphyria; undiagnosed vaginal bleeding; smokers older than 35 y
Interactions	The effect is reduced by drugs that induce hepatic enzyme activity (eg, phenobarbital, phenytoin, paramethadione, carbamazepine, troglitazone, rifampicin, and griseofulvin); broad spectrum antibiotics (eg, ampicillin, doxycycline) reduce OC effect; OCs may reduce hypoprothrombinemic effects of anticoagulants
Pregnancy	X - Contraindicated; benefit does not outweigh risk
Precautions	The combined use with other potassium- increasing drugs (NSAID, potassium- sparing diuretics, ACE inhibitors, angiotensin-II receptors antagonists, heparin) must be avoided; obesity, hypertension, smoking, migraines, seizure disorders, cerebrovascular disorders, or family history of thromboembolic disease

Drug Category: Antiandrogens

Spironolactone (Aldactone), cyproterone acetate (Androcur), flutamide (Eulexin), and drospirenone are agents that bind to the androgen receptor and block its action. Finasteride (Proscar) is a 5a-reductase inhibitor that blocks the intracellular conversion of testosterone to DHT prevalently in the skin and in the sebaceous gland. Finasteride is comparable to spironolactone as an effective drug in hirsutism. Only spironolactone, flutamide, and finasteride are available in the United States. Drospirenone (3 mg) is available in combination with 30 µg of ethinyl estradiol as an oral contraceptive (Yasmin). Cyproterone acetate (not available in the US) is available in combination with 35 µg or 50 µg of ethinyl estradiol (Diane-35, Diane-50) and is marketed for acne and other hyperandrogenic conditions. Flutamide is used in prostate cancer and has been used successfully to treat hirsutism. Spironolactone, a potassium-sparing diuretic, has been available for many years and is a safe and effective antiandrogen. Drospirenone and spironolactone are similar in structure. Theoretically, ingestion of any of these agents during pregnancy could result in the feminizing of a male fetus; therefore, effective contraception should be used in conjunction with these agents.

Drug Name	Flutamide (Eulexin)
Description	Nonsteroidal antiandrogen that inhibits androgen uptake or binding of androgen to target tissues.
Adult Dose	250 mg PO qd/tid
Pediatric Dose	Administer as in adults; only administered postmenarche
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	X - Contraindicated; benefit does not outweigh risk
Precautions	Use with contraception; strict monitoring of liver function tests indicated; adverse effects include hepatotoxicity, nausea, gastralgia, dry skin, fatigue, and breast tenderness; flutamide should be used with OCs

Drug Name	Cyproterone acetate (Androcur, Diane-35, Diane-50)
Description	Available in combination with ethinyl estradiol: Diane-35, 2 mg cyproterone acetate and 35 µg ethinyl estradiol, reverse sequential. Diane-50, 2 mg cyproterone acetate and 50 µg ethinyl estradiol, reverse sequential. Powerful antiandrogen usually administered with estrogens to maintain regular menstruation and to prevent conception. Not available in United States.
Adult Dose	50-100 mg/d PO on days 1-10 with oral contraceptive
Pediatric Dose	Administer as in adults; only administered postmenarche
Contraindications	Documented hypersensitivity; children; breastfeeding; same contraindications as other OC agents
Interactions	None reported
Pregnancy	X - Contraindicated; benefit does not outweigh risk
Precautions	Monitor liver function; adverse effects include weight gain, fatigue, loss of libido, mastodynia, nausea, headaches, depression; risk of venous thromboembolism associated with antiandrogen OC use is at least as high as with third-generation oral contraceptive use

Drug Name	Finasteride (Proscar, Propecia)
Description	Predominantly a type 2, 5a-reductase inhibitor. Inhibits the production of DHT. Efficacy in hirsutism is similar to that of spironolactone.
Adult Dose	5 mg/d PO
Pediatric Dose	Administer as in adults; only administered postmenarche
Contraindications	Documented hypersensitivity; breastfeeding; children
Interactions	None reported
Pregnancy	X - Contraindicated; benefit does not outweigh risk
Precautions	Must be used with contraception as it may cause ambiguous genitalia development in male fetus; monitor liver function; monitor patients with severely diminished urinary flow for obstructive uropathy (if possible avoid in these patients)

Drug Category: GnRH agonists/antagonists

These agents, which suppress pituitary LH and FSH secretion, suppress ovarian hormone secretion to a greater degree than OCs. Examples of GnRH agonists in the United States include Lupron, Synarel, and Zoladex. The endometriosis doses are the ones used for hirsutism. Significant osteoporosis may occur if treatment lasts longer than 6 months; in these cases, estrogen add back with HRT or OC pills should be given.

Drug Name	Nafarelin acetate (Synarel)
Description	Suppresses secretion of LH and FSH, which in turn reduces ovarian and testicular steroid production. Available as nasal solution (2 mg/mL).
Adult Dose	1 spray (200 µg) into 1 nostril am and 1 spray into other nostril pm; start treatment between d 2 and 4 of menstrual cycle; may require up to 800 µg if amenorrhea is not achieved or in cases of ovarian hyperthecosis
Pediatric Dose	Administer as in adults; only administered postmenarche
Contraindications	Documented hypersensitivity to GnRH or related products; undiagnosed abnormal vaginal bleeding; pregnancy or women who may become pregnant while receiving drug; pernicious anemia
Interactions	None reported
Pregnancy	X - Contraindicated; benefit does not outweigh risk
Precautions	Ovarian cysts may occur in first 2 mo of therapy, especially in patients with PCOS; cystic enlargements may occur but may resolve spontaneously (generally by 4-6 wk of therapy); caution in patients with risk factors for decreased bone mineral content; consider estrogen add back if therapy continues for more than 6 mo

Drug Name	Goserelin (Zoladex)
Description	Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels.
Adult Dose	3.6 mg SC q28d or 10.8 mg SC q12wk for 6 mo
Pediatric Dose	Administer as in adults; only administer postmenarche
Contraindications	Documented hypersensitivity; undiagnosed vaginal bleeding; spinal cord compression
Interactions	None reported
Pregnancy	X - Contraindicated; benefit does not outweigh risk
Precautions	Urinary tract obstruction, tumor flare, and bone pain may occur; monitor patients for weakness and paresthesias

Drug Category: Corticosteroids

Adrenal hyperandrogenism responds well to low-dose glucocorticoid therapy with dexamethasone or prednisolone. These agents are used with variable success in women with adrenal hirsutism, CAH, and idiopathic adrenal hyperandrogenism. Glucocorticoids have anti-inflammatory properties and cause profound and varied metabolic effects. Changes suggesting Cushing disease may develop in patients receiving long-term therapy.

Drug Name	Prednisone (Deltasone, Sterapred, Orasone)
Description	May reduce steroid hormone production. Decreases immune reactions.
Adult Dose	5-7.5 mg PO qd
Pediatric Dose	Not recommended (until growth finished)
Contraindications	Documented hypersensitivity; active bacterial or fungal infection
Interactions	Coadministration with estrogens may decrease prednisone clearance; when used with digoxin, digitalis toxicity secondary to hypokalemia may increase; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Administer for 3 mo, then dose should be halved or discontinued; monitor for adrenal insufficiency when tapering because abrupt discontinuation of glucocorticoids may cause adrenal crisis; complications of glucocorticoid use include severe infections, hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections

Drug Category: Insulin-sensitizing drugs

Insulin resistance is a metabolic disturbance in hyperandrogenism. Insulin-sensitizing drugs, by reducing the insulin levels, ameliorate hyperandrogenism associated with PCOS. Metformin in many, but not all, studies successfully treated hirsutism in patients with PCOS associated with insulin resistance. Not effective if patient does not have insulin resistance. Troglitazone has been found to cause hepatic damage and has been removed from the marked.

Drug Category: Topical skin products

May use to reduce hair growth in face and adjacent areas under the chin.

Drug Category: Dopamine agonists

Women with hyperandrogenism who also have hyperprolactinemia may benefit from therapy with a dopamine receptor agonist (bromocriptine, cabergoline). These agents improve menstrual cycle, ovulation, and hirsutism in women with PCOS and hyperprolactinemia.

Drug Name	Cabergoline (Dostinex)
Description	Semisynthetic ergot alkaloid derivative; strong dopamine D2-receptor agonist with low affinity for D1 receptors.
Adult Dose	0.25-1 mg PO twice/wk; start with a low dose and increase q4wk based on prolactin levels
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity; ischemic heart disease, uncontrolled hypertension, peripheral vascular disorders; breastfeeding
Interactions	Toxicity may increase with ergot alkaloids; amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, and reserpine may decrease effects
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in renal or hepatic disease; generally stopped during pregnancy but can be restarted if symptoms recur; perform regular visual-field testing during pregnancy to monitor for tumor growth; can cause postural hypotension and nausea

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

Medical therapy for hirsutism requires 3-6 months before any significant effect can be observed. A follow-up visit should be scheduled after 1 month of therapy and then at 3-6 months until stable. Once control has been achieved, annual visits are appropriate.

Prognosis

Unless a reversible cause is identified and treated, androgen excess continues unabated, and, once suppressive therapy is withdrawn, the symptoms return.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Missing an ovarian or an adrenal androgen-secreting tumor is the most important medicolegal pitfall.
• Without mechanical depilation, 3-6 months elapse before a clinical effect of chemical (medical) depilation is noticed because of the life cycle of hair follicles, which is important for both the health care provider and patient to realize.
• Some of the drugs used to treat androgen excess symptoms have not been approved for such use in the United States by the FDA.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Androgen secretion pathway in adrenal glands and ovaries.
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Media type:  Chart

Media file 2:  Algorithm for workup of a dehydroepiandrosterone sulfate (DHEAS) value exceeding 7 mg/mL.
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Media type:  Graph

Media file 3:  Chemical structures of spironolactone and drospirenone. The testosterone core is in black.
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Media type:  Image

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

1. Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endorcrinol Metab. Nov 1961;21:1440-1447. [Medline].
2. Arowojolu AO, Gallo MF, Grimes DA, Garner SE. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev. 2004;(3):CD004425. [Medline].
3. Azziz R, Sanchez LA, Knochenhauer ES, et al. Androgen excess in women: experience with over 1000 consecutive patients. J Clin Endocrinol Metab. Feb 2004;89(2):453-62. [Medline].
4. Balfour JA, McClellan K. Topical eflornithine. Am J Clin Dermatol. 2001;2(3):197-201; discussion 202. [Medline].
5. Barbieri RL. Hyperandrogenic disorders. Clin Obstet Gynecol. Sep 1990;33(3):640-54. [Medline].
6. Carmina E. Mild androgen phenotypes. Best Pract Res Clin Endocrinol Metab. Jun 2006;20(2):207-20. [Medline].
7. Carmina E, Lobo RA. Polycystic ovary syndrome (PCOS): arguably the most common endocrinopathy is associated with significant morbidity in women. J Clin Endocrinol Metab. Jun 1999;84(6):1897-9. [Medline].
8. Falsetti L, De Fusco D, Eleftheriou G. Treatment of hirsutism by finasteride and flutamide in women with polycystic ovary syndrome. Gynecol Endocrinol. Aug 1997;11(4):251-7.