Hirsutism

INTRODUCTION

¡@

Background: Although hirsutism is broadly defined as excessive hairiness, the common clinical use of the term is in reference to women with excess growth of terminal hair in a male pattern. In this sense, hirsutism is one of the most common endocrine disorders, affecting approximately 10% of women in the US. In these women, the hairiness implies the presence of abnormal androgen action, which may represent a serious or, more likely, a nonserious medical problem. Regardless of the etiology, hirsutism can produce mental trauma and emotional anguish. Even mild cases of hirsutism may be viewed by the patient and others as a presumptive loss of femininity. In more severe cases, it can be a cosmetic catastrophe. The major objectives in the management of hirsutism are to rule out a serious underlying medical condition and to devise a plan of treatment.

¡@

Pathophysiology: Both hormones and the intrinsic characteristics of the hair follicle determine the quality of hair growth. Vellus hairs are fine, unpigmented hairs that cover most of the body before puberty. Pubertal androgens promote the conversion of these vellus hairs to coarser pigmented terminal hairs. The level and duration of exposure to androgens, the local 5 alpha-reductase activity, and the intrinsic sensitivity of the hair follicle to androgen action determine the extent of conversion from vellus to terminal hair. Some terminal-hair growth, however, is androgen-independent, eg, scalp, eye brows, and lashes.

The development of terminal hair or reversion back to a vellus pattern may not immediately be evident because of the characteristics of the hair cycle. This cycle has 2 phases that include active hair growth (anagen phase) and a resting period (telogen phase), which follows the anagen phase. During the resting period, the hair shaft separates from the dermal papillae at the follicle base and no further growth takes place. Eventually, growth restarts and the old hair is pushed out by the new hair shaft formed by the reactivated papillae. The cycle may take months to complete, and this causes a delay in hair-growth response to changes in the androgen milieu.

Dihydrotestosterone is the androgen that acts on the hair follicle to produce terminal hair. This hormone is derived from both the blood stream and local conversion of a precursor, testosterone. The local production of dihydrotestosterone is determined by 5 alpha-reductase activity in the skin. Differences in the activity of this enzyme may explain why women with the same plasma levels of testosterone can have different degrees of hirsutism.

Frequency:
¡@

• In the US: Hirsutism affects approximately 10% of women in the US.

• Internationally: The prevalence rates of hirsutism in northern Europe are similar to those in the US; in other places they are not known with certainty.

Mortality/Morbidity: The mortality and morbidity of hirsutism are determined by the underlying cause. The majority of women with idiopathic hirsutism have no associated mortality or morbidity. On the other extreme, a small number of women may have malignant disease with a grave prognosis.

Race: Ethnic origin has a large effect on terminal hair growth in normal women. Northern, fair-skinned Europeans have the least terminal hair, whereas southern, dark-skinned Mediterranean women have the greatest amount of terminal hair. The difference in the racial patterns of normal terminal hair growth may be related to genetic differences of 5 alpha-reductase activity in the skin. With the exception of congenital adrenal hyperplasia (CAH), the prevalence of diseases causing hyperandrogenism and hirsutism has not been shown to be different among races.

Sex: As a medical problem, hirsutism predominates in women. While hirsutism can occur in men, it is more difficult to recognize because of the wide variability of healthy male terminal-hair growth. Hirsutism in prepubertal children occurs equally in both sexes, usually is a sign of precocious puberty, and may signify a serious underlying disease. This discussion, however, focuses on adult women.

Age: The age of onset of hirsutism depends on the etiology.

• Most forms of nonneoplastic hirsutism become evident around puberty. This includes polycystic ovary syndrome (PCOS), CAH, and idiopathic hirsutism.
• Hirsutism also may develop after weight gain and cessation of the use of oral contraceptives in young women.

• Normally, terminal-hair growth becomes apparent after adrenarche and accelerates after puberty. Terminal hair continues to develop gradually in healthy women, until after menopause when loss of ovarian androgen leads to a loss of hair.

• Rapidly worsening hirsutism, especially in older women, should raise the suspicion of an androgen-secreting tumor.

CLINICAL

¡@

History: An accurate history of the patient’s onset of hirsutism and developmental milestones can be helpful in the etiologic diagnosis.

• Age of onset

• Idiopathic hirsutism and the other less-serious causes of hirsutism usually begin at puberty.

• Conversely, hirsutism occurring in middle-aged or older women should suggest an adrenal or ovarian tumor.

• Family history

• A patient with a family history of hirsutism is consistent with CAH; however, idiopathic hirsutism and PCOS can also be familial.

• Severity and rapidity of progression of the hirsutism

• The history of a benign form of hirsutism usually is characterized by pubertal onset with slow progression over many years.

• When a history of rapid severe hirsutism or other signs of virilization is obtained, an androgen-secreting tumor is a possibility.

• Adrenarche and puberty

• Because the development of pubic hair depends on adrenal androgens, early development points toward CAH. In contrast, ovarian hyperandrogenism is associated with normal adrenarche and delayed menarche or irregular menses.

• Excess androgens either can be from an exogenous or endogenous source.

• Exogenous androgens usually can be elicited by history; however, surreptitious androgen use has been reported in women athletes, especially those at a high level of competition.

• Endogenous androgens originate from 1 of 2 sources, either the adrenal cortex or the ovary. Therefore, the evaluation of androgen excess can focus on disorders of these 2 glands. The principal possibilities are tumors of the ovary or the adrenal cortex, Cushing syndrome, CAH, and PCOS. Idiopathic hirsutism is the most common etiology, but it is a diagnosis of exclusion, so seek other causes first.

• The initial task in evaluating hirsutism on physical examination is to quantitate the disorder. The task requires that terminal hair, which is dependent on androgen, be differentiated from vellus hair, which is androgen independent.
  • As mentioned above, vellus hair is fine, soft, and nonpigmented. An excess of vellus hair, called hypertrichosis, is associated with metabolic disorders, such as hyperthyroidism, anorexia nervosa, and porphyria, and with some medications (eg, phenytoin, diazoxide, minoxidil, glucocorticoids, cyclosporine, hexachlorobenzene).
  • By contrast, terminal hair is coarse, curly, and pigmented. Because small amounts of terminal hair are normal in women, quantitation is important.
• The best method of quantitation employs the Ferriman and Gallway scale. In this approach, hair growth is judged in each of 11 androgen-sensitive areas (see Picture 1).
  • The grade for each area ranges from 0 (no terminal hair) to 4 (frankly virile).
  • Areas such as the axilla and pubis are not included because terminal-hair growth occurs in these places at normal androgen levels in women.
  • The total score correlates roughly with the elevation of androgen levels. A woman with a score of 8 or more is considered to have hirsutism. The majority of women seeking medical attention for the disorder have scores of 15 or more.

• In women with moderate to severe hirsutism (score >15), seek additional signs of hyperandrogenism including temporal hair recession, oily skin, masculine voice, well-developed musculature, enlargement of the clitoris (>35 mm² in surface area), irregular menses, and psychological changes (see Picture 2).
• The degree to which these clinical factors are present suggests the level of androgen overproduction and, thus, determines the degree of suspicion of an underlying disease.

• The extent of evaluation for the cause of hirsutism is greater in women with more severe clinical evidence of masculinization.
• A good abdominal and pelvic examination is important in patients with hirsutism because more than one half of androgen-secreting adrenal and ovarian tumors are palpable.
• Examine the skin for acanthosis nigricans, a manifestation of insulin resistance.
• These patients usually are obese and are thought to be at increased risk for atherosclerosis and coronary heart disease.

Causes: Multiple diseases can cause hyperandrogenism and hirsutism (see Picture 3).

• Adrenal and ovarian tumors: Adrenocortical tumors in patients presenting with hirsutism almost always are malignant. They usually are large and are associated with a very poor prognosis. Ovarian tumors may also be malignant and the threat can be serious.

• Androgen-secreting ovarian tumors are a less-serious threat. The most common among them, accounting for fewer than 1% of all ovarian tumors, is arrhenoblastoma. In this neoplasm, serum testosterone always is elevated, and most patients have amenorrhea and a palpable ovarian mass.

• Gonadoblastomas usually occur in younger persons (aged 10-30 y) who are genetic males with female external genitalia. Nearly one half of these tumors are malignant, and many are bilateral. Pelvic examination is abnormal because internal female genitalia are absent.

  ¡@

• Lipoid cell tumors are of 2 histologic types, with adrenal-like cells in patients who are younger and hilar or Leydiglike cells in patients who are older. These tumors usually are palpable, but they seldom are malignant. Ovarian tumors, even less often encountered, include dysgerminomas, Brenner tumors, and cystic granulose-theca tumors.

• Polycystic ovary syndrome: This syndrome is the most common ovarian disorder associated with hirsutism. Although the cause of PCOS is not known, the etiology is speculated to be multifactorial. By definition, polycystic ovaries have 20 or more subcapsular follicles, ranging from about 1-15 mm in diameter. The follicles are at various states of atresia, and hyperplasia of the theca interna, the anatomic source of ovarian androgens, is present. The basic abnormalities in PCOS, however, are functional rather than anatomic in nature. In particular, levels of luteinizing hormone (LH) are tonically elevated (with LH levels higher than those of follicle-stimulating hormone [FSH]).

• Many women with PCOS have insulin resistance manifest by acanthosis nigricans and elevated plasma insulin levels. Increased insulin levels have been speculated to possibly stimulate androgen production from the ovarian theca interna cells. The importance of insulin resistance is emphasized by the therapeutic effect of insulin-sensitizing medications (eg, metformin, thiazolidinediones), which restore normal ovarian androgen production and ovulation.

• PCOS usually begins at puberty. The incidence has been estimated to be about 5% among adolescent girls and adult women in the US. As noted, the characteristic endocrine abnormality is an elevation in plasma free testosterone that is not suppressed by dexamethasone; however, as many as 50% of patients also show abnormal adrenal androgen secretion.

WORKUP

¡@

Lab Studies:
¡@

• Laboratory studies in hirsutism serve both to confirm the clinical impression of hyperandrogenism and to identify the source of excess androgens, either adrenal or ovarian. The work-up described in Picture 4 uses two visits, a baseline evaluation followed by a two-week dexamethasone treatment period. Specific discussion of the testing is below.

• Testosterone: The most important assay is of serum testosterone, the major circulating androgen. If the results from testing the total serum testosterone are normal, measure the free serum level because hyperandrogenism (and insulin resistance, if present) decreases sex steroid-binding globulin, so that the unbound, biologically active testosterone moiety may be elevated, even if the total level is unremarkable. Extremely high testosterone levels are likely to be associated with adrenal or ovarian tumors, whereas very mild elevations are found in idiopathic and benign etiologies. Indeed, in idiopathic hirsutism, the results from testing androgen levels often are normal. In some of these women, hirsutism is thought to be caused by increased skin sensitivity to androgen or by increased skin 5 alpha-reductase activity. As mentioned above, this enzyme is located in the skin near the hair follicle, and it converts plasma testosterone into the androgen metabolite dihydrotestosterone.

• Dehydroepiandrosterone sulfate: Because testosterone can originate in either the adrenal cortex or the ovary, an elevated testosterone level does not reveal the gland of origin. Accordingly, measurement of elevated plasma levels of DHEAS, an androgen synthesized almost exclusively by the adrenal cortex, can indicate excess adrenal function. Elevations in both testosterone and DHEAS suggest an adrenal origin, whereas an isolated testosterone elevation indicates an ovarian source.

TREATMENT

¡@

Medical Care: The treatment of hirsutism begins with a careful explanation to the patient about the cause of her problem and with reassurance that she is not losing her femininity. Then, direct intervention, if possible, at the underlying disorder. If hirsutism persists (or the patient has idiopathic hirsutism), other cosmetic or systemic treatment may be necessary. In some cases, cosmetic measures may be sufficient. In others, the slow progress of systemic therapy may necessitate more immediate cosmetic treatment. The most effective strategy is to combine systemic therapy, which has a slow onset of effectiveness, with mechanical depilation (shaving, plucking, waxing, and depilatory creams).

Hirsutism requires a careful and systematic clinical evaluation coupled with a rational approach to treatment. Throughout this process, the patient must understand that even though diagnostic testing can be time consuming (and even inconclusive), it sometimes is essential for determining an effective intervention. In other cases, counseling and education may be all that is needed. For the patient who desires treatment, a wide variety of pharmacologic strategies can be followed. Informing the patient that current systemic therapy is imperfect is important. Furthermore, none of the drugs used to treat hirsutism have Food and Drug Administration (FDA) approval for such use. Only initiate therapy in patients who give informed consent after a complete explanation of the potential benefits and risks of a particular treatment and alternative approaches.

• Systemic therapies directed at hirsutism can be divided into those that decrease ovarian or adrenal androgen production and those that inhibit androgen action in the skin.

• Glucocorticoids: Glucocorticoids (dexamethasone or prednisone), which suppress ACTH-dependent adrenal androgen synthesis, have been used with variable success in women with adrenal hirsutism, as in CAH or idiopathic adrenal hyperandrogenism. Usually, 0.5-1 mg of dexamethasone at bedtime is sufficient to suppress ACTH and adrenal androgen production. Unfortunately, some patients gain weight and cushingoid features develop, even on this small of a dose. Further investigations may establish that lower doses (perhaps 0.25 mg) can be effective without adverse effects.

• Oral contraceptives: The drugs most widely used to suppress ovarian androgen production are oral contraceptives (OCs). They probably are the first choice for young women with hirsutism who do not want to become pregnant.
  • OCs are inexpensive, and they promote regular uterine bleeding. In addition, OCs can be used in combination with one of the antiandrogens or other forms of therapy. On the other hand, do not use OCs in women with a history of migraines, known or suspected thrombotic disease, or breast or uterine cancer.
  • Moreover, OCs have a significant failure rate in patients with hirsutism for several reasons. Low-dose OCs and progestin-only minipills fail to suppress ovulation in as many as 50% of women. Ovarian function continues at a variable rate, and ovarian androgens continue to be produced. Second, the progestins in OCs are attenuated derivatives of testosterone and have variable degrees of androgenic activity in women. The degree depends on the type of progestin and, more importantly, on individual susceptibility.

• Spironolactone: Spironolactone, in daily doses of 50-200 mg, blocks androgen receptors. Spironolactone also decreases testosterone production, making it additionally effective for hirsutism. Spironolactone especially is useful in a patient with hypertension or edema because the drug is a mild diuretic.
  • Sexually active women taking spironolactone should ensure that contraceptive measures are adequate. In some cases, spironolactone can be combined with an OC for added effect on the hirsutism.
  • With current systemic therapies for hirsutism, it usually takes 6 months to a year before results are noticeable. Even then, only about one half to three quarters of patients show improvement. The problem partially may lie in the nature of the hair follicle, which will persist for 6 months to a year even after androgen levels have been normalized. Ineffectiveness also may be due to the inability of treatment to completely normalize elevated tissue dihydrotestosterone levels. Newer therapies directed at inhibition of 5 alpha-reductase or blockade of the androgen receptor may improve the ability to treat patients.

• Flutamide: Flutamide, for example, is a potent, nonsteroidal selective antiandrogen without progestational, estrogenic, corticoid, or antigonadotropin activity. Preliminary data indicate that it is effective as therapy for hirsutism (and also acne); however, flutamide is expensive and has caused fatal hepatitis.

  Finasteride: Finasteride is a 5 alpha-reductase inhibitor approved for the treatment of benign prostatic hyperplasia. No adverse effects have been reported in women, and the efficacy is similar to spironolactone; however, the main concern is the risk of ambiguous genitalia in the male fetus exposed to the enzyme inhibitor during the first trimester. Therefore, use this drug only in women who are postmenopausal with no chance of becoming pregnant.

  Cyproterone acetate has been effective in the treatment of hirsutism but is not available in the United States.

• Cosmetic measures for hirsutism (and their disadvantages)

  ¡@

  • Hydrogen peroxide bleaching - Not suitable for severe hirsutism
  • Plucking - Can cause skin irritation, folliculitis, and scarring
  • Low-melting point wax - Can cause skin irritation, folliculitis, and scarring
  • Shaving - May be psychologically unacceptable
  • Chemical depilatories - Can cause skin irritation
  • Electrolysis (This can be painful, and short-wave diathermy can cause scarring.)

MEDICATION

¡@

The most effective strategy in treating hirsutism is to combine systemic therapy, which has a slow onset of effectiveness, with mechanical depilation (shaving, plucking, waxing, depilatory creams).

Systemic therapies directed at hirsutism can be divided into those that decrease ovarian or adrenal androgen production and those that inhibit androgen action in the skin.
¡@

Drug Category: Oral contraceptives -- Inhibit ovarian androgen production. They probably are the first choice for young women with hirsutism who do not want to become pregnant. OCs are inexpensive, and they promote regular uterine bleeding. OCs can be used in combination with antiandrogens or other agents. They have a significant failure rate in hirsutism for several reasons. Low-dose oral contraceptives and progestin-only minipills fail to suppress ovulation in as many as 50% of women. Ovarian function continues at a variable rate, and ovarian androgens continue to be produced. Second, the progestins in OCs are attenuated derivatives of testosterone and have variable degrees of androgenic activity in women. The degree depends on the type of progestin and, more importantly, on individual susceptibility.

Drug Category: Glucocorticoids -- Used to inhibit adrenal androgens. These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Suppress ACTH-dependent adrenal androgen synthesis. Used with variable success in women with adrenal hirsutism, CAH, and idiopathic adrenal hyperandrogenism.

Drug Category: Antiandrogen -- Used to block androgen action.

Drug Category: 5 alpha-reductase inhibitor -- Indicated for treatment of benign prostatic hyperplasia and male pattern baldness. Unlabeled use for treatment of female hirsutism.

FOLLOW-UP

¡@

Prognosis:

• Prognosis depends on etiology of the hirsutism, eg, benign or malignant.

Patient Education:

• Hirsutism requires a careful and systematic clinical evaluation coupled with a rational approach to treatment. Throughout this process, the patient must understand that even though diagnostic testing can be time consuming (and even inconclusive), it sometimes is essential for determining an effective intervention. In other cases, counseling and education may be all that is needed.

• For the patient who desires treatment, a wide variety of pharmacologic strategies can be followed. Informing the patient that current systemic therapy is imperfect is important. Furthermore, none of the drugs used to treat hirsutism has FDA approval for such use. Only initiate therapy in patients who give informed consent after a complete explanation of the potential benefits and risks of a particular treatment and alternative approaches.

MISCELLANEOUS

¡@

Medical/Legal Pitfalls:

• None of the drugs used to treat hirsutism has FDA approval for such use.

• Therapy should be initiated only in patients who give informed consent after a complete explanation of the potential benefits and risks of a particular treatment and alternative approaches.