And It's About Time There Was Some Support For Cushing's!
From Clinician Reviews ®
Hirsutism in Women: Diagnosis and Treatment of a Common Symptom
R. Mimi Clarke Secor, MS, MEd, RN, CS-FNP
Hirsutism is an androgen excess-related condition that commonly affects women. Persistent anovulation, characterized by hirsutism of gradual onset, irregular menses, and obesity, is the most common cause (accounting for as many as 95% of cases). Rapid-onset hirsutism may indicate an androgen-producing tumor or other aggressive condition that requires the patient's prompt referral to an endocrine specialist. Because of its potentially serious complications -- infertility, diabetes, hypertension, and heart disease -- persistent anovulation must be managed appropriately. Pharmacologic options include low-androgen combination oral contraceptives, medroxyprogesterone acetate, antiandrogens, glucocorticoids, and/or insulin-sensitizing agents -- sometimes enhanced by cosmetic modalities.
Hirsutism, or excessive growth of facial and body hair, is an androgen excess-related condition that often causes significant emotional distress in women who are affected by it. Because it is a cutaneous manifestation of androgen excess, hirsutism is a symptom, not a disease. The condition is relatively common in women of Mediterranean or East Indian ancestry. Female hirsutism has a variety of causes; however, approximately 95% of hirsute women are believed to suffer from persistent anovulation, also known as polycystic ovary syndrome or Stein-Leventhal syndrome. Hirsutism can also be an adverse effect of certain medications. Idiopathic hirsutism may actually be a mild form of persistent anovulation or may indicate hypersensitivity to androgens.
Less common but potentially serious causes include Cushing's syndrome, congenital adrenal hyperplasia, adrenal or ovarian tumors, a luteoma (a pregnancy-related benign tumor), anorexia nervosa, hypothyroidism, porphyria, and hyperprolactinemia, as well as ovarian hyperthecosis in postmenopausal women.[3,4]
Regardless of the specific cause, hirsutism results from excessive activity of androgens (testosterone and androstenedione), leading to abnormal hair growth.
Hair grows in long cycles over many months, beginning with an active phase (anagen) that is followed by a resting phase (telogen); during the telogen phase, the shaft separates from the follicle base and falls out.[4,5] Both the biology of normal hair growth and the pathophysiology of abnormal hair growth are influenced by several hormonal factors.
Among the androgens, testosterone stimulates growth, increasing size and intensifying pigmentation of the hair follicle. Hair follicle sensitivity to androgens is determined by 5a-reductase activity, which converts testosterone to its follicle-active form, dihydrotestosterone. Because of the variation in levels of 5a-reductase activity, it is possible for women with similar androgen levels to have varied degrees and patterns of hair growth.
Estrogens act in the opposite manner to androgens, slowing growth and producing finer, less highly pigmented hair; progesterone has little effect on hair.
The diagnostic goal of the hirsutism evaluation is to identify the most likely cause and to exclude rare pathology.
Persistent anovulation is characterized by onset of hirsutism during a woman's teens or in her early 20s, with a gradual worsening of the condition over many years. This process is accompanied by a long history of irregular menses, usually since menarche. Most of these women are obese. So common is this presentation that the history alone may be sufficient to establish an accurate clinical diagnosis.
As many as 70% of women with a history of persistent anovulation develop hirsutism. Hirsutism is an early symptom of androgen excess; later symptoms include acne, increasingly oily skin, increased libido, and masculinization.
Masculinization and virilism are terms used to describe the most extreme androgen-excess state. This is characterized by male hair pattern (balding), clitoral enlargement of greater than 1 cm, deepening of the voice, increased muscle mass, and general male body habitus.[2,4]
History and Physical Examination<
The hirsutism evaluation requires a thorough history of the present illness or complaint. This includes time and rapidity of onset, associated symptoms (eg, obesity, acne), progression of symptoms, history of unprotected coitus without pregnancy, age at menarche, and subsequent menstrual history -- especially oligomenorrhea, amenorrhea, and sporadic episodes of abnormal vaginal bleeding. All of these are commonly associated with persistent anovulation.
To help identify less common causes of hirsutism, a review of systems and of past medical, social, family, and medication history are also obtained.
Medications that may cause hirsutism include methyltestosterone (topical or oral), danazol, and anabolic drugs, such as nonprescription dehydroepiandrosterone -- an agent that is used by an increasing number of female athletes.[3,4] Medications that may cause hypertrichosis (ie, non-androgen-dependent and non-endocrine-related hirsutism) include metronidazole, corticosteroids, and cyclosporine.
Phenytoin, diazoxide, and minoxidil may cause increased growth of fine hair (referred to as vellus growth).[3,4] Low-dose oral contraceptives (OCs) including the "mini-pill" (progestins only), do not cause hirsutism; however, testosterone replacement therapy may.
A complete physical examination is also helpful in identifying the likely cause of hirsutism. The practitioner should pay special attention to the following factors: height and weight (including body mass index exceeding 27 kg/m2); elevated blood pressure; stigmata of Cushing's syndrome (central obesity, bruising, high blood pressure); masses in, or enlargement of, the thyroid; and abdominal and pelvic masses suggestive of unilateral or bilateral ovarian enlargement.
A thorough skin assessment should be performed. Note the distribution of hair and areas of coarse hair: the upper lip, chin, chest, upper arms, upper and lower abdomen, thighs, and back. Hirsutism is graded according to the distribution, quantity, and quality of hair (see Figure,).
Hirsutism grading, 0 (absent) to 4 (virile)
Source: Delaney ML. Hirsutism (Figure 20-1). In: Carr PL, Freund KM, Somani S, eds. The Medical Care of Women. Philadelphia, Pa: WB Saunders Co, 1995:183. Adapted with permission of the author.
Acanthosis nigricans, a marker of insulin resistance associated with persistent anovulation, may be present. This gray-brown, velvety, and sometimes verrucous skin discoloration usually appears on the neck, groin, lower abdomen, and/or axillae.
In pregnant women, signs of virilization should raise suspicion for a luteoma, a benign tumor that generally resolves after pregnancy.
Determining the speed of hirsutism onset is key to establishing an accurate diagnosis. Gradual onset of symptoms over a number of years since adolescence (often since menarche) is most likely indicative of persistent anovulation. Women believed to have persistent anovulation do not require further diagnostic testing unless other causes are suspected; this is because results of diagnostic tests for this condition are often within normal range and do not help clarify the diagnosis. In addition, enlarged ovaries are not required for a diagnosis of persistent anovulation, nor do enlarged ovaries indicate it; many normal women have asymptomatic cystic ovaries. When persistent anovulation is suspected, current recommendations advise testing for insulin resistance and diabetes mellitus (see Table 1[1,4] ).
In contrast to hirsutism of gradual onset, rapid-onset hirsutism (ie, over a matter of months) in a woman older than 25 years suggests a more aggressive underlying cause (eg, an androgen-producing tumor or other adrenal condition). Such a patient should be referred promptly to an endocrine specialist. Few if any diagnostic tests are required before referral.
When rapidity of hirsutism onset is unclear, certain diagnostic tests, listed in Table 1[1,4] may be considered.
The most important goal in treating women with persistent anovulation-related hirsutism is to prevent potentially serious complications of infertility, diabetes, hypertension, and heart disease. Hirsutism treatment is directed at interrupting the steady state of persistent anovulation characterized by tonic luteinizing hormone (LH) elevations, excess androgen production, and low levels of sex hormone-binding globulin (SHBG). Cosmetic improvement is an important but secondary goal.
Patients with a clinical diagnosis of persistent anovulation who wish to become pregnant should be referred to a gynecologic specialist for ovulation induction, combined with an insulin-sensitizing agent (metformin or troglitazone) and weight loss.
Those with persistent anovulation or idiopathic hirsutism who are not seeking to conceive should be advised to lose weight and may also be started on low-dose combination OCs. Oral contraceptives suppress ovarian steroid production, which in turn curbs LH levels. Low-dose OCs, especially those containing new-generation, low-androgen progestins (norgestimate and desogestrel), raise levels of SHBG for greater androgen-binding capacity, thus reducing circulating testosterone levels. In addition, 5a-reductase (at the skin level) is inhibited by the progestin component in OCs.
These actions gradually correct hirsutism, acne, and amenorrhea -- in addition to preventing the complications previously mentioned. Low-dose and multiphasic OCs are as effective as higher-dose preparations.
Therapy must continue for 6 to 12 months and may be required for many years, especially if obesity is not corrected. Therefore, weight loss is a key component of therapeutic regimens intended to resolve symptoms and prevent complications. Significant weight loss, it should be noted, is the only long-term solution to obesity-related hirsutism.
When OCs are contraindicated (eg, in extremely obese patients) or not desired, good cosmetic effects may be obtained with medroxyprogesterone acetate (MPA), either in a 150-mg intramuscular injection every 3 months, or by 10 to 20 mg/d PO.4 In contrast with OCs, MPA reduces testosterone levels by inducing liver enzyme activity, mild LH suppression, and reduction of total testosterone production. Surprisingly, this is accomplished without raising SHBG levels.
Treatment with either OCs or progesterone may be continued for 1 to 2 years, then discontinued to observe the patient for spontaneous (though unlikely) return of ovulatory cycles. If anovulation recurs, hirsutism will as well, and treatment must be resumed.
If no improvement is noted after 8 to 12 months of treatment, the patient should be referred to an endocrinologist. Severe hirsutism, too, may require a consultation or referral.
Various other antiandrogen medications may also be used to treat hirsutism. Spironolactone, an aldosterone-antagonist diuretic (50 to 200 mg/d), inhibits ovarian and adrenal production of androgens. Flutamide (250 mg/d, given in divided doses) acts by competing with androgen receptors; however, hepatotoxicity is a concern. Finasteride (1 to 5 mg/d), by contrast, blocks the conversion of testosterone to dihydrotestosterone by inhibiting 5a-reductase; however, because this agent is highly teratogenic, effective contraception is required.
To maximize their therapeutic effect and to prevent pregnancy, these antiandrogen medications may be given in combination with OCs.
Gonadotropin-releasing hormone analogs include leuprolide (a 3.75-mg intramuscular injection, given monthly) and nafarelin (400 µg bid intranasally).
Cyproterone acetate (CPA) is a potent, long-acting progestin that blocks androgen action and inhibits gonadotropin production. Not yet approved in the United States, CPA is used extensively in the United Kingdom to treat hirsutism; the oral contraceptive "Diane-35" (also unavailable in the United States) combines low-dose CPA with ethinyl estradiol for the effectiveness of standard-dose CPA with a significant reduction in adverse effects.[1,4]
Glucocorticoids offer only a modest effect by suppressing adrenal androgen production. These include dexamethasone (0.25 to 0.5 mg), prednisolone (5.0 to 7.5 mg), and hydrocortisone (10 to 20 mg) -- each administered in a single nightly dose.
Great optimism surrounds the insulin-sensitizing agents (troglitazone [400 mg/d or bid] and metformin [850 mg/d, then bid]), which reduce ovarian androgen production by suppressing levels of LH and follicle-stimulating hormone; they also lower plasma insulin levels. According to current data, they may be effective not only to treat, but to prevent persistent anovulation-associated and/or idiopathic hirsutism. Though a good option for women who must avoid estrogens, insulin-sensitizing agents are expensive and associated with significant adverse effects.
In actuality, all the medications described may be associated with multiple and serious adverse effects, high cost, and possible teratogenic risk (especially finasteride).[2,4,7] They must be prescribed carefully and only after a thorough review of relevant prescribing information.
The only permanent or semipermanent treatments for previously established coarse hair are electrolysis, thermolysis, and various laser systems. Recent research indicates the most promising effects from long-pulsed ruby laser. These cosmetic modalities should be considered only after 6 months of medical management, whether with monotherapy or combination treatment.
Because hirsutism is often very distressing to patients and because of the complications associated with persistent anovulation, supportive counseling and comprehensive education are essential (see Table 2[2,9]).
Female hirsutism is a common endocrine problem, which is very distressing to most patients and is generally caused by one of several underlying conditions. The most common cause, persistent anovulation, may be diagnosed by a detailed history and a thorough physical examination. Carefully selected diagnostic tests are useful to rule out less common and rare causes and to clarify cases in which speed of hirsutism onset is unclear.
Short-term management options include various OC preparations or MPA -- sometimes enhanced by cosmetic measures. It is important for clinicians and patients to understand that significant weight loss currently provides the only long-term, nonpharmacologic solution for obesity-related hirsutism.
Fasting glucose-to-insulin ratio. A calculation of less than 4.5 suggests insulin resistance.
2-Hour glucose level after a 75-g glucose load. A measurement below 140 mg/dL is normal. Levels of 140 to 199 mg/dL indicate impaired glucose tolerance; and of 200 mg/dL or higher, type 2 diabetes mellitus.
Serum thyroid-stimulating hormone (TSH). This test is performed to rule out thyroid disease. Normal range is 0.32 to 5 µIU/L.
Serum testosterone. A normal level is 90 ng/dL or less. Levels are normal or slightly elevated in persistent anovulation or benign adrenal conditions. A level exceeding 200 ng/dL suggests an adrenal tumor.
17a-Hydroxyprogesterone (17-OHP) in the morning. Levels below 200 mg/dL are considered normal; those between 200 and 800 mg/dL require adrenocorticotropic hormone testing. A 17-OHP level higher than 800 mg/dL is diagnostic of late-onset adrenal hyperplasia.
24-Hour urinary free cortisol excretion. Normal excretion is 10 to 90 µg/dL. A late-evening plasma cortisol level of less than 15 µg/dL rules out Cushing's syndrome.
Prolactin should be measured in patients with amenorrhea, especially those who also experience galactorrhea. Levels of 10 to 25 ng/mL are normal.
Pelvic ultrasonography should be performed if an ovarian tumor or a luteoma is suspected, or if the pelvic examination is hindered by obesity.
The clinician's most important responsibilities are to:
Hirsutism is the most common endocrine-related symptom in women. Its primary mechanism is an excessive increase in androgen levels. An estimated 95% of cases are the result of persistent anovulation.
Hair growth is influenced by a number of hormonal factors. Androgens, including testosterone, stimulate the hair follicle and affect the hair's size and pigmentation; to what extent depends on 5a-reductase activity. Estrogens act in the opposite manner. During pregnancy, women may experience alternating intervals of hair growth and hair loss.
Identifying the most likely cause of hirsutism and ruling out rare pathology are the clinician's chief goals.
The most common presentation -- gradual-onset hirsutism, irregular menses, and obesity -- is associated with persistent anovulation. In such patients, the history alone may suffice to establish an accurate clinical diagnosis. As many as 70% of women with persistent anovulation may develop hirsutism; other symptoms of androgen excess are acne, oily skin, increased libido, and masculinization.
Less common causes of hirsutism include use of certain medications, Cushing's syndrome, congenital adrenal hyperplasia, and adrenal or ovarian tumors.
In a case of hirsutism, the history includes rapidity of hirsutism onset, associated symptoms and their progression, and menstrual history. Past medical, social, family, and medication history help identify less common causes of hirsutism.
Key points during the physical examination are body mass index, blood pressure, and abdominal or pelvic masses. A thorough skin assessment includes distribution and texture of hair, the possible presence of acanthosis nigricans, and characteristics of masculinization.
Determining the speed of hirsutism onset is essential to an accurate diagnosis. Persistent anovulation is almost always associated with gradual onset. Rapid-onset hirsutism suggests more aggressive underlying causes (eg, an androgen-producing tumor) and requires immediate referral to an endocrine specialist.
In women whose hirsutism onset is unclear, it is important to rule out adrenal or ovarian tumors, late-onset adrenal hyperplasia, and Cushing's syndrome -- and to test for diabetes mellitus and insulin resistance. Other testing may include serum testosterone, morning levels of 17a-hydroxyprogesterone, 24-hour urinary free cortisol excretion, prolactin, and pelvic ultrasonography.
Treatment for persistent anovulation is important to prevent potentially serious complications: infertility, diabetes, hypertension, and heart disease. Correcting hirsutism, acne, and amenorrhea is a secondary goal.
Unless they wish to become pregnant (in which case these patients should be referred to a gynecologic specialist for ovulation induction), women with persistent anovulation or idiopathic hirsutism may be given low-dose combination oral contraceptives. Other pharmacologic options include medroxyprogesterone acetate, antiandrogens, glucocorticoids, gonadotropin-releasing hormone analogs, and insulin-sensitizing agents. As with all medications, practitioners must consider potential adverse effects and high costs before prescribing.
Weight loss is an essential component of therapy, both in resolving symptoms and preventing complications. If hirsutism is extreme or fails to improve, referral to an endocrine specialist may be required.
Comprehensive information and supportive counseling are essential to managing women with hirsutism.
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