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Table of Contents

Published February 13, 2004

Priya
Chinnappa, MD

Adi
Mehta, MD

Department of
Endocrinology

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     Definition

     Epidemiology

     Etiology and
     Pathogenesis

     Signs and
     Symptoms

     Diagnosis

     Therapy

     Conclusion

     References

Overall, the prevalence of hirsutism is unknown but it may be as high as 50%. It is said that "even a single hair casts a shadow," so that in cultures where a lack of hair is a classic feature of female beauty, minimal hirsutism is considered a disorder while in other cultures where some excess hair growth is acceptable, a significant change in the pattern and texture of the hair is needed before it is deemed a problem. In a classic British study of 430 normal women there was no hair seen on the upper back or abdomen indicating that the presence of hair in these areas is indeed abnormal. In this study, 10% had hair on their chest, 22% had chin hair, and 49% had hair on the upper lip. The distribution of hair was very scanty in all these areas. Hence, the ethnic environment as well as distribution and density of hair growth determine the degree of hirsutism. The practicing physician must place the patient in the spectrum of individuals in the locality in which he or she practices to be able to fairly assess the severity of hirsutism. In addition, the age of onset and rate of growth and progression may also determine the severity of the problem.

Androgens are a prerequisite for sexual hair development. Hirsutism may arise from increased androgen production or increased sensitivity of the hair follicles to circulating androgens.

Testosterone is the most important circulating androgen because of its relatively high plasma concentration and greater potency at the target organ level. Circulating testosterone is the sum of the secretion from the ovaries (35 to 40%) and adrenals (40%) in response to the trophic hormones luteinizing hormone (LH) and adrenocorticotrophic hormone (ACTH), respectively. The remaining circulating testosterone is derived from the conversion of androgenic precursors, mainly androstenedione (derived from the ovaries and adrenals) and dihydroepiandrosterone (DHEA—derived almost exclusively from the adrenals).^2-4 Peripheral conversion of androgenic prohormones to testosterone occurs in the liver, the skin, and adipose tissue.³ Testosterone is present in the circulation as the free or conjugated form. Close to 98 to 99% of plasma testosterone is bound to steroid hormone binding globulin (SHBG), cortisol binding globulin, or nonspecifically to albumin and other proteins and is biologically inactive. The free portion of testosterone is the biologically active portion. In the hair follicles, testosterone is converted to its biologically active form, dihydrotestosterone, by the enzyme 5-alpha reductase.^5-7 Sex hormones work independently at the liver to control SHBG production. Estrogens increase while androgens decrease the production of SHBG. Thus, in hyperandrogenic states SHBG is lowered, thereby allowing for a greater amount of free androgen levels, so that hyperandrogenism begets hyperandrogenism.

Pilosebaceous Unit:

The pilosebaceous unit (PSU) consists of a piliary component and a sebaceous component. Each PSU has the capacity to either form a terminal hair (a dark, pigmented, large medullated hair) as its prominent structure or a sebaceous follicle (in which the hair remains vellus and the sebaceous gland is most prominent). Androgens play a key role in the development of the PSU.

Prior to the onset of puberty, in androgen-sensitive areas the hair is vellus and sebaceous glands small. When androgen levels increase during puberty or hyperandrogenic states, PSUs form terminal hairs in sexual areas and sebaceous glands in sebaceous areas. The former when excessive leads to hirsutism and excess of the latter causes the development of acne.⁸

Mechanism of Action of Androgens in the PSU:

The hair follicle is one of the androgen-sensitive appendages in the skin and is a major site for the formation of testosterone from its precursors. The 5-alpha reductase enzyme present in the outer root sheath cells converts testosterone to its active metabolite dihydrotestosterone. The dermal papilla cells are thought to be the target cells that release growth factors that act on other cells of the hair follicles.

PSU Sensitivity to Androgens:

Development of hirsutism is determined by androgen levels and sensitivity of the PSU to androgens. Increase in sensitivity is thought to be due to exaggerated peripheral 5-alpha reductase activity, androgen receptor polymorphisms, or altered androgen metabolism.⁹

Causes of Androgen-Mediated Hirsutism:

Polycystic ovarian syndrome (PCOS) and idiopathic hirsutism account for 90% of the cases.^10,11 The androgen source is a mixture of contributions from ovaries and adrenal glands. The various other conditions can be classified according to the source of excess androgens. Ovarian causes are mainly ovarian tumors and hyperthecosis. Adrenal causes include Cushing's syndrome, androgen-producing tumors, and congenital adrenal hyperplasia (CAH), most commonly due to 21-hydroxylase deficiency. Other causes of CAH are 11-beta-hydroxylase deficiency and 3-beta hydroxysteroid dehydrogenase deficiency. Hyperprolactinemia by increasing adrenal DHEA-S production may cause hirsutism. Exogenous androgens can cause hirsutism and their use needs to be excluded. Androgenic preparations mainly estrogen-testosterone combinations have been approved for the treatment of postmenopausal symptoms, and need to be rule out as of tibolone, a steroid with estrogenic, progestogenic, and androgenic effects.¹²

Valproic acid, a commonly used antiepileptic agent, has been associated with PCOS. History of the use of this medication should be specifically asked about in the evaluation of women with hirsutism.^13,14

While insulin resistance is a feature of PCOS, severe insulin resistance syndromes like maturity onset diabetes of the young and lipodystrophies are rarer causes of hirsutism.

Hirsutism can occur in older women beginning a few years before menopause and can continue for a few years after menopause. Ovarian estrogen secretion declines rapidly whereas ovarian androgen production continues for a few years after menopause. Androgen production after menopause is gonadotrophin dependent and when excessive can lead to the development of hirsutism.^15-17

History should include the following:

Age of onset—idiopathic hirsutism typically begins at the peri-pubertal age.

Rate of progression—hirsutism due to malignant lesions progresses rapidly.

Virilization—Presence of virilizing signs such as change in voice, male-pattern balding, clitoromegaly, change in muscle distribution, and increase in libido make the presence of a serious underlying disorder likely.

Family history, race, and ethnicity persons of Mediterranean, Middle Eastern, and South Asian descent are more hirsute.

Current medication—screen for the use of androgenic steroids.

The amount and distribution of hair are an index of androgen effect. As mentioned above, before puberty most of the body is covered by fine unpigmented, nonmedullated hairs called vellus hair. In the presence of androgens these hair are converted to coarse, pigmented medullated terminal hair. Terminal hair on the face, around the areola, and on the abdomen below the level of the umbilicus is present in 10% of "normal" women. Terminal hairs of the upper back, shoulders, sternum, and upper abdomen suggest a more marked androgen effect.

Grading of hirsutism is done using the Ferriman and Gallwey scale,¹⁸ which semiquantitatively measures the amount of hair growth. It is subject to large observer variability, however.

Examination should include a search for signs of virilization like male-pattern baldness, increased voice pitch, muscle bulk, and clitoromegaly (length >10 mm or clitoral index which is the product of the length and the width >35 sq mm). Signs of insulin resistance (acanthosis nigricans, abdominal obesity), Cushing's syndrome, and the presence of ovarian enlargement should be sought during the examination.

The goals of biochemical assessment are to evaluate the source of hyperandrogenism and to rule out the presence of a malignancy. Some authors recommend no further evaluation in patients with mild hirsutism and regular, ovulatory menses because these patients do not have a serious underlying disorder.^7,8

The major biochemical parameters tested include:

1. Testosterone—total and free. In the majority of patients with hirsutism, especially associated with abnormal periods, the testosterone levels are either high normal or just above the upper limit of normal. The free testosterone level is also similarly affected. Values of total testosterone greater than 200 ng/ml are suggestive of an androgen-producing tumor.¹⁹

2. DHEA-S. Marginal elevations of DHEA-S are common. Elevated values suggest an adrenal source of androgens. Values greater than 700 µg/dl are suggestive of an androgen-producing adrenal tumor. These patients should undergo further evaluation with computed tomography or magnetic resonance imaging to check for a tumor.

3. 17-Hydroxyprogesterone, a precursor of cortisol, should be measured to screen for adult-onset CAH. The measurement should be done between 0700 and 0900 hours in the early follicular phase of the menstrual cycle. Levels less than 200 ng/dl excludes the disease. Mildly increased levels between 300 and 1,000 ng/dl require an ACTH stimulation test. Cosyntropin (synthetic ACTH), 250 µg, is administered intravenously, and levels of 17-hydroxyprogesterone are measured before and 1 hour after the injection. Post-stimulation values that exceed 1,000 ng/dl constitute a positive test.

4. Twenty-four hour urine free cortisol should be measured in women with signs and symptoms of Cushing's syndrome.

5. Prolactin levels should be measured because an occasional woman with hirsutism and irregular menses could have hyperprolactinemia due to hypothalamic disease or a pituitary tumor. Levels may also be mildly elevated in up to 20% of patients with PCOS.

6. Serum follicle-stimulating hormone (FSH) should be measured if ovarian failure is a consideration, but it otherwise is of minimal help.

7. Serum LH. Women with PCOS tend to have higher serum LH levels and a ratio of LH to FSH levels greater than 3. This is thought to be significant by some, but most authorities do not consider this a requirement for the diagnosis of PCOS. Ratios less than 3 do not exclude the diagnosis. Measurements of FSH and LH are therefore not needed.

8. While not necessary for the diagnosis of PCOS, fasting plasma glucose and lipid profiles in patients suspected to have PCOS and/or insulin resistance are helpful to define the presence of metabolic risk, which in the long term is of great significance to an individual's morbidity and mortality.

Principles:

The underlying cause should be treated. These treatment guidelines refer to the treatment of hirsutism due to PCOS and idiopathic hirsutism. Hirsutism is a cosmetic and psychological problem, not a life-threatening illness. Therefore the risks and benefits of treatment have to be weighed.

Before beginning treatment women should be warned that they might not see improvement in hair growth for 3 to 9 months. Drug treatment affects the growth of new hair follicles but the half-life of established follicles is up to 6 months, hence it takes that much time to see its effect.

Nonpharmacologic Therapy:

Because of the significant association of insulin resistance and obesity with PCOS, therapy to reduce insulin resistance is appropriate. Diet, exercise, and weight loss should be prescribed to all women with PCOS. Diet therapy consisting of a decreased total caloric intake with appropriately mixed high fiber diet in addition to a daily exercise program so as to induce weight loss has been shown to reduce androgen production. Modest weight loss of 7 to 15 lbs with the appropriate exercise program is all that is needed to improve menstrual and biochemical abnormalities.²⁰

Mechanical hair removal can be achieved by shaving, waxing, or plucking or the use of depilatory creams. These treatments do not compound the problem. Bleaching may mask hair growth. Electrosurgical methods include electrosurgical epilation and laser treatment. Electrosurgical epilation was the only commercially available method of long-term hair removal until the availability of laser treatment. This method is time consuming, causes discomfort, and requires multiple treatments. There is a small but definite risk of punctate scarring and postinflammatory skin color change. Laser treatment was introduced to effectively remove hairs over larger areas with as few complications as possible. There are several different methods used and further studies are needed to determine which is ideal.^21,22

Pharmacologic Therapy:

Antiandrogens
This group of agents is effective in the treatment of hirsutism. The main effect of antiandrogens is to inhibit the binding of testosterone and dihydrotestosterone to the androgen receptor.^23,24 They all share the potential risk of teratogenicity to the developing fetus and should always be used with adequate contraception in females of child-bearing age.

Spironolactone is a potent antiandrogen. Its primary action is to inhibit the binding of testosterone and dihydrotestosterone to the androgen receptor. In addition, it may inhibit ovarian testosterone synthesis.²⁵ The starting dose is 50 mg twice daily and may be increased to a total daily dose of 200 mg per day. It takes at least 6 months to see its effect. Numerous studies have shown its efficacy in the treatment of hirsutism. Side effects include nausea, fatigue, headaches, mastodynia, and irregular menses. There is a theoretical risk of increase in serum potassium levels. Renal insufficiency may predispose patients to this adverse effect. This drug may interfere with the masculinization of the female fetus and we strongly recommend use of spironolactone along with oral contraceptives. In addition to protecting against pregnancy (and therefore against potential teratogenic effects) the oral contraceptives overcome irregular menses, a side effect of spironolactone.

Cyproterone acetate is a potent progestin and a moderately potent antiandrogen. Like spironolactone, it inhibits the binding of dihydrotestosterone to the androgen receptor and suppresses gonadotrophins. Side effects include nausea, breakthrough bleeding, decreased libido, and depression. It is generally used in combination with ethinyl estradiol. Cyproterone may cause fatal hepatitis and has not been licensed for use in the United States.

Flutamide is another androgen receptor blocker used more commonly for the hormonal treatment of prostate cancer. Flutamide has been shown to be as effective as spironolactone, though some studies suggest that it is more potent. Doses of 125 to 500 mg per day are effective for hirsutism. Flutamide is not licensed for the treatment of hirsutism and because of the significant risk of hepatoxicity, off-label use in hirsutism is discouraged by the Food and Drug Administration.

Cimetidine is a weak antiandrogen and is rarely used in the treatment of hirsutism.

Inhibitors of 5-Alpha Reductase
Finasteride is a topical agent that inhibits 5-alpha reductase. Its efficacy is similar to cyproterone but it can cause fatal hepatitis and hence is rarely used.

Others
Eflornithine cream (Vaniqa®) is another topical agent. It is thought to inhibit hair growth by inhibiting an enzyme involved in keratin synthesis. The cream is applied to the face twice a day. Gradual improvement is seen in 4 to 6 weeks. Patients should be advised to use mechanical hair removal methods along with this treatment. Eight weeks stopping this agent, hair growth reappears (without change from pretreatment appearance).²⁶

Ovarian Suppression:

Oral Contraceptive Pills²⁷
Estrogen/progesterone combinations act by reducing gonadotrophin secretion and thereby reducing ovarian androgen production. They also increase levels of SHBG resulting in lower levels of free testosterone, and they inhibit adrenal androgen production.²⁸ Oral contraceptive pills (OCPs) with progestins that are low in androgenic activity should be used. Those OCPs with norgestrel and levonorgestrel are more androgenic than others and must be avoided. The newer progestins such as norgestimate, norethindrone, and desogestrel have a lower androgenic potential and are preferable. We recommend starting with a pill containing 35 µg of ethinylestradiol and one of the progestins mentioned above. If there is no response in biochemical parameters like testosterone after two to three cycles of treatment the pill can be changed to one with 50 µg ethinylestradiol.

These agents are also effective in controlling hirsutism in the older woman around menopause.²⁹

Yasmin® is a newer contraceptive pill that contains 3 mg of drospirenone as the progestin and has been shown to have the antiandrogenic action of spironolactone. This antiandrogen effect is equivalent to 25 mg of spironolactone.

Gonadotrophin-Releasing Hormone (GnRH Agonists )
Long-acting GnRH analogs decrease gonadotrophin secretion and therefore reduce ovarian stimulation and hence testosterone. Estrogen production is also reduced, so therapy is usually used in combination with an oral contraceptive pill containing estrogen and progestin. This therapy is parenteral and expensive and is reserved for women with severe hirsutism who do not respond to a combination of an oral contraceptive pill and antiandrogen.

Adrenal Suppression:

Glucocorticoids
Oral glucocorticoids lead to a fall in androgen levels in the majority of women. We suggest a dose of prednisone 2.5 mg or dexamethasone 0.25 mg at bedtime. Side effects at these doses are small. Higher doses are associated with significant side effects including a cushingoid habitus; weight gain; osteoporosis; glucose, lipid, and blood pressure abnormalities; and possible vascular disease. These drugs have a definite role in the treatment of hirsutism secondary to CAH. In other forms of hirsutism they are best if combined with antiandrogens and should be reserved for severe cases where the risk-benefit ratio is appropriate.

Hirsutism is a distressing condition for most women. While it may sometimes be the harbinger of a more serious metabolic disorder, it is often not associated with significant underlying pathology. The principles of treatment include patience to wait and see the efficacy of treatment and a combination of nonpharmacologic and pharmacologic measures. Combining pharmacologic measures like OCPs and antiandrogenic therapy yields the best results, making the problem more acceptable to the patient so that over time she is usually able to balance the need for treatment with the cosmetic benefit of treatment.

Return to Medicine Index

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