Hirsutism and Hyperandrogenism

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[edit] Hirsutism and Hyperandrogenism

James C. Shaw

In both men and women, hair growth on the face and other androgen-sensitive areas is a clinical marker for androgen effect. In the absence of androgens, terminal hair does not develop in these areas. Lifetime patterns of hair growth in women are highly variable, are influenced by genetic factors, and may or may not be considered abnormal depending on social custom. Some increase in the quantity and coarseness of hair typically occurs with aging.

Idiopathic hirsutism refers to increased androgen-mediated hair growth without an identifiable disease. Clinical presentations within the idiopathic category also include acne, androgenic alopecia, and menstrual irregularities. Since advances in hirsutism research have identified hyperandrogenism in most cases, the designation idiopathic hirsutism will likely become less useful.

[edit] ETIOLOGY AND PATHOPHYSIOLOGY

Androgen-mediated hair growth is a complex process that is influenced primarily by circulating levels of testosterone and its precursors or metabolites. Sources of androgens in women are the ovaries, adrenal glands, and those from target tissue metabolism of androgen precursors. In adult women, ovaries are most often the source of androgens. Anovulation with loss of cyclic menstrual function leads to increased androgen production by the ovaries, a condition called functional ovarian hyperandrogenism; the most severe form is full-blown polycystic ovary syndrome. Adrenal hyperandrogenism is much less common and occurs in the setting of late-onset adrenal hyperplasia.

[edit] PATIENT EVALUATION

[edit] History.

The most common clinical history in hirsute women is irregular menses, onset of hirsutism during the teenage years or early 20s, and gradual worsening of the condition. Acne is frequently associated with worsening hirsutism. The rapidity of development of hirsutism is important. A woman who develops hirsutism after age 25 and demonstrates rapid progression of masculinization over several months may have an androgen-producing tumor. Other less common causes that may be addressed in the history include Cushing's syndrome, acromegaly, and pregnancy. Drugs can stimulate hair growth by both androgen-mediated and non-androgen-mediated mechanisms (e.g., methyltestosterone, anabolic steroids, danazol, phenytoin, diazoxide). Hypertrichosis refers to increased nonsexual hair and may be associated with porphyrias and environmental factors that produce chronic irritation or reactive hyperemia of the skin.

[edit] Physical Examination.

Increased hair growth in patients with hirsutism and hyperandrogenemia ranges from fine vellus hair on the face to marked terminal (full-sized) hair on the face, breasts, genitalia, lower abdomen, and extremities. Other physical findings that suggest hyperandrogenemia include acne, increased oiliness of the skin, and androgenic alopecia. Masculinizing features such as clitorimegaly, android muscle distribution, and a deep voice are only seen in women with severe hyperandrogenemia.

[edit] DIAGNOSIS

Women with normal menses and mild hirsutism require little or no hormonal evaluation. Women with hirsutism, obesity, and menstrual irregularities may benefit from an endocrinologic evaluation for polycystic ovary syndrome, diabetes, or Cushing's syndrome. In women with rapid onset of hirsutism and in those with oligomenorrhea, hormonal evaluation is indicated to rule out androgen-secreting tumors and other endocrine causes. A basic evaluation to screen for androgen-secreting tumors includes plasma total testosterone, dehydroepiandrosterone sulfate (DHEAS), and 17-hydroxyprogesterone (17-OHP), which is used optionally to diagnose late-onset adrenal hyperplasia. An expanded evaluation for women with more severe disease usually includes total testosterone, free testosterone, DHEAS, luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, adrenocorticotropic hormone (ACTH) stimulation, and glucose tolerance tests.

[edit] Testosterone Level.

Plasma testosterone levels (normal 20 to 80 ng/dl [0.69 to 2.8 nmol/L]) are primarily a measure of ovarian testosterone production and are elevated in the majority of women (70%) with anovulation and hirsutism. Individual variation is great, largely because of the changes in the testosterone-binding capacity of sex hormone–binding globulin (SHBG) in the blood. Measuring the free testosterone (a technically difficult and expensive assay) is not necessary. A routine testosterone assay adequately screens for testosterone-secreting tumors because these tumors are associated with testosterone levels in the male range and do not rely on fine discrimination of the free testosterone level. If the testosterone level exceeds 200 ng/dl (7 nmol/L), an androgen-producing tumor must be suspected.

[edit] DHEAS Level.

DHEAS is derived almost exclusively from the adrenal gland. It is a direct measure of adrenal androgen activity and correlates clinically with urinary 17-ketosteroid levels. The upper limit of normal in most laboratories is 350 μg/dl (9.5 μmol/L). A random sample of DHEAS is sufficient for the evaluation of hirsutism because a slow turnover rate results in a large and stable pool in the blood with insignificant variation. Elevated levels of DHEAS contribute to the clinical problem of hirsutism because DHEAS is a prehormone in hair follicles, providing substrate for the hair follicle synthesis of androgens.

When the DHEAS level is normal, adrenal disease is unlikely, and the source of excess androgen production is most likely the ovaries. Rare cases of adrenal tumors with normal DHEAS levels have been reported; testosterone levels are elevated in these patients. Late-onset adrenal hyperplasia is not usually associated with increased DHEAS. Moderately elevated DHEAS levels are frequently found in patients with anovulation and polycystic ovaries.

[edit] 17-OHP Level.

17-OHP is elevated in the setting of late-onset adrenal hyperplasia. The normal baseline 17-OHP level is less than 200 ng/dl (6 nmol/L). Levels greater than 800 ng/dl are diagnostic of 21-hydroxylase deficiency. Levels between 200 and 800 ng/dl require ACTH testing to determine the degree of 21-hydroxylase deficiency (see Chapter 98 ).

[edit] Differential Diagnosis

Several conditions can cause hirsutism associated with hyperandrogenemia. Idiopathic hirsutism and polycystic ovary syndrome account for more than 90% of cases, and because of the heterogenous nature of polycystic ovary syndrome, functional ovarian hyperandrogenism is used to describe these patients' condition. Less common causes of hirsutism include congenital adrenal hyperplasia, late-onset adrenal hyperplasia, Cushing's syndrome, androgen-producing tumors of the ovary or adrenal gland, and luteoma associated with pregnancy.

[edit] MANAGEMENT

Treatment options for hirsutism are mechanical hair removal and medical therapy, including androgen receptor blockers and suppression of ovaries and adrenal glands (Box 36-1). Frequently a combination of mechanical and medical therapy is used.

[edit] Mechanical Therapy

Hair removal by shaving, plucking, waxing, or electrolysis temporarily reduces hirsutism. Most patients experience a recurrence and require ongoing use of these modalities. A new approach uses lasers of several types, with longer-lasting results. It is not clear which wavelength of laser will produce the best results.

[edit] Pharmacologic Therapy

[edit] Systemic Therapy.

All systemic therapies are hormonal and are designed (1) to suppress the production of androgens in either the ovaries or the adrenals or (2) to block the end-organ effect of androgens. Hirsutism responds slowly to treatment. Because the hair growth cycle is long, change takes time. Patients should be informed that at least 6 months of hormonal suppression is necessary before reduced hair growth can be observed. Some patients return after a period of treatment expressing disappointment because hair is still present. The effect of treatment (prevention of new hair growth) may not be apparent unless previously established hair is removed. Ovarian suppression to prevent new hair growth combined with electrolysis or laser therapy to remove the old hair may be most effective.

After 1 to 2 years the medication should be stopped and the patient observed for a return of ovulatory cycles. Even in patients who continue to be anovulatory, testosterone suppression continues for 6 months to 2 years after discontinuing treatment. If anovulation is still present, hirsutism will eventually return.

[edit] Ovarian Suppression

[edit] Oral Contraceptives.

Suppression of ovarian androgens is usually accomplished with oral contraceptives (OCs). In addition to suppressing ovarian activity, OCs increase SHBG levels, thus decreasing circulating testosterone. The pro gestins in OCs also inhibit the activity of 5α-reductase, the enzyme that converts testosterone to the more active dihydrotestosterone (DHT). Low-dose OCs are as effective as the higher-dose formulations in treating hirsutism and suppressing free testosterone levels. Multiphasic formulations appear to be equally effective. Well-designed studies are needed to determine whether the newer OCs with less androgenic progestins (norgestimate, desogestrel) have more effect on hirsutism than other OCs.

When OCs are contraindicated or unwanted, good results can be achieved with medroxyprogesterone acetate, either 150 mg intramuscularly every 3 months or 30 mg orally every day. The mechanism of action of medroxyprogesterone acetate is slightly different from that of the combination OC. Since suppression of gonadotropins is less intense, ovarian follicular activity continues. LH suppression is significant, however, and testosterone production is decreased, although to a lesser degree than with combined OCs. In addition, testosterone clearance from the circulation is increased. This latter effect is caused by induction of liver enzyme activity. Although medroxyprogesterone acetate decreases SHBG, resulting in a relative increase in free testosterone, suppression of total testosterone production is so great that the net amount of free testosterone is decreased. The overall effect yields a clinical result comparable to that achieved with the combination OC.

[edit] Cyproterone Acetate.

Cyproterone acetate has been successfully used worldwide to treat hirsutism and acne. It is a steroidal progestin with androgen receptor–blocking activity that is used alone or as the progestin in OCs. Cyproterone acetate is not available in the United States.

[edit] Gonadotropin-releasing Hormone (GnRH) Agonists.

Because ovarian androgen production is LH dependent, suppression of the pituitary with chronic GnRH agonist treatment improves hirsutism. A higher dose of GnRH agonist is required to suppress ovarian androgen production than to suppress estradiol secretion. Therefore treatment should be monitored with testosterone levels. Leuprolide, 3.75 mg/month, is effective. To avoid problems associated with estrogen deficiency, therapy with an OC containing estrogen and progestin should be initiated after the GnRH agonist maintenance dose has been established. This method of treatment is relatively complicated and expensive and should be reserved for severe cases of ovarian hyperandrogenism.

[edit] Adrenal Suppression.

Suppression of endogenous ACTH secretion is used in women who have an adrenal enzyme deficiency with resultant adrenal hyperplasia. Dexamethasone is given nightly (to achieve maximal suppression of the central nervous system adrenal axis, which peaks during sleep) at a dose of 0.5 mg. The equivalent dose of prednisone is 5 to 7.5 mg. If this treatment suppresses the morning plasma cortisol level below 2.0 μg/dl (56 nmol/L), the dose should be reduced to avoid an inability to react to stress. Fortunately, adrenal androgen secretion is more sensitive to suppression by dexamethasone than is cortisol secretion. Patients with classic (congenital) adrenal hyperplasia may require higher doses to normalize the steroid blood levels. With higher doses, alternative day therapy can still accomplish significant adrenal androgen suppression without affecting cortisol secretion.

[edit] Antiandrogens (Androgen Receptor Blockers)

[edit] Spironolactone.

Although spironolactone is well known for its use as an aldosterone-antagonist diuretic in hypervolemic states, it also produces hormonal effects, including competitive androgen receptor blockade, inhibition of ovarian and adrenal steroidogenesis, and inhibition of 5α-reductase activity. The peripheral receptor blockade is responsible for most of the clinical antiandrogen effect. Spironolactone has been successful in the treatment of hirsutism in doses ranging from 50 to 200 mg/day. Usually some response is noted within 3 months, but longer treatment may be required before change is evident. Side effects are usually minimal and dose related. Potential side effects include a diuresis in the first few days of use, occasional complaints of fatigue, dysfunctional uterine bleeding, and breast tenderness. Spironolactone is contraindicated in pregnancy because of a potential feminizing effect on a developing male fetus. Concomitant OC use prevents this potential complication, prevents menstrual irregularities, and corrects the common underlying steady state of anovulation.

[edit] Flutamide.

Flutamide is a nonsteroidal antiandrogen that blocks androgen receptors at peripheral tissue. Although its primary use is treatment of prostate cancer, flutamide has been used successfully in women with hirsutism. Doses range from 125 mg twice a day to 250 mg three times a day. Flutamide is generally well tolerated, but fatal hepatotoxicity has been reported with its use in men in doses of 750 mg or more per day, and close monitoring of liver function is important.

[edit] Finasteride.

Finasteride inhibits 5α-reductase and is indicated for use in benign prostatic hypertrophy and androgenetic alopecia in men. Finasteride is somewhat effective in women with hirsutism, but less so than spironolactone and cyproterone acetate. Because of potential effects on developing male fetuses, finasteride is not recommended for women of childbearing age.

[edit] ADDITIONAL READINGS

• JH Barth, CA Cherry, F Wojnarowaka, RP Dawber: Spironolactone is an effective and well tolerated systemic anti-androgen therapy for hirsute women. J Clin Endocrinol Metab 1989; 68:966.
• E Carmina, RA Lobo: The addition of dexamethasone to antiandrogen therapy for hirsutism prolongs the duration of remission. Fertil Steril 1998; 69:1075.
• M Erenus, D Yucelten, F Durmusoglu,et al.: Comparison of finasteride versus spironolactone in the treatment of idiopathic hirsutism. Fertil Steril 1997; 68:1000.
• B Kohn,et al.: New MI, late-onset steroid 21-hydroxylase deficiency: a variant of classical congenital adrenal hyperplasia. J Clin Endocrinol Metab 1982; 55:817.
• RA Lobo: Hirsutism in polycystic ovary syndrome: current concepts. Clin Obstet Gynecol 1991; 34:817.
• JAM Marcondes,et al.: Treatment of hirsutism in women with flutamide. Fertil Steril 1992; 57:543.
• RS Rittmaster: Differential suppression of testosterone and estradiol in hirsute women with the superactive gonadotropin-releasing hormone agonist leuprolide. J Clin Endocrinol Metab 1988; 67:651.
• RS Rittmaster: Hirsutism. Lancet 1997; 349:191.
• RS Rittmaster: Hyperandrogenism--what is normal?. N Engl J Med 1992; 327:194.(editorial)
• JC Shaw: Spironolactone in dermatologic therapy. J Am Acad Dermatol 1991; 24:236.
• JC Shaw: Antiandrogen therapy in dermatology. Int J Dermatol 1996; 85:770.
• PC White, MI New, B Dupont: Congenital adrenal hyperplasia. N Engl J Med 1987; 316:1519.