Management of Hirsutism

A. Alsantali, MD and J. Shapiro, MD, FRCPC

Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

ABSTRACT
Hirsutism is a relatively common condition affecting about 5%-10% of women of childbearing age. Herein, we present an overview of hirsutism with emphasis on its etiology and therapeutic options.

Key Words:
antiandrogens, hirsutism, insulin-sensitizing agents, oral contraceptives, PCOS, polycystic ovary syndrome

Hirsutism is defined as excessive terminal hair growth in women, which has a typical male pattern distribution. It should be differentiated from hypertrichosis, a generalized excessive hair growth that may be hereditary or result from some drugs, such as cyclosporine. Hirsutism is a relatively common disorder that affects about 5%-10% of women of reproductive age.¹ Unwanted hair growth can be associated with significant psychosocial consequences that negatively affect patients’ quality of life.

Causes

More than 70% of hirsutism is caused by polycystic ovary syndrome (PCOS).² PCOS is the most common endocrinopathy in females, affecting 5%-10% of women of childbearing age.² According to the Rotterdam criteria for diagnosis of PCOS,³ the diagnosis could be achieved if 2 of the following 3 criteria are present:

• Oligo- or anovulation (menstrual cycles longer than 35 days or fewer than 10 menses a year).
• Clinical (hirsutism, acne, androgenetic alopecia) or biochemical evidence of hyperandrogenism.
• Polycystic ovaries (=12 follicles in each ovary measuring 2-9mm in diameter and/or increased ovarian volume to >10ml) on ultrasound examination.

Other less common causes include idiopathic hirsutism (i.e., with no other clinical or biochemical abnormalities) (23%), nonclassic adrenal hyperplasia (4.3%), ovarian or adrenal androgen secreting tumors (0.2%), Cushing’s syndrome, acromegaly, hyperprolactinemia, and drugs.

Diagnostic Approach

Clinical history, thorough physical examination and laboratory investigations can be crucial in the correct evaluation of hirsutism. The history should include the onset and progression of hirsutism, the pattern of menstruation, weight gain, and the use of androgenic drugs, such as anabolic and androgenic steroids, and valproic acid.

A rapid progression of hirsutism and evidence of virilization (e.g., clitoromegaly, an increase in muscle mass, and a deepening of the voice) can be noted with rare androgen secreting tumors.

The severity of hirsutism can be measured objectively using the Ferriman-Gallwey hirsutism scoring system.⁴ A score of 8 or more has been used to define the presence of hirsutism. As the response of a pilosebaceous follicle to androgen varies considerably, the hirsutism score does not correlate well with the androgen level.

A thorough abdominal and pelvic examination may rarely show a palpable ovarian mass.

According to the Endocrine Society Clinical Practice Guidelines,⁵ testing for androgen is recommended in women with moderate-to-severe hirsutism or hirsutism of any degree when it is associated with any of the following: sudden onset, rapid progression menstrual irregularity, infertility, central obesity, clitoromegaly, or acanthosis nigricans. The initial tests for hirsutism should include early morning plasma total testosterone and free testosterone. If testosterone levels are more than 1.5-2 times the upper normal limit, or if a history of rapid virilization is found, dehydroepiandrosterone sulphate (DHEA-S) and androstenedione should be measured to identify an adrenal or ovarian source of hyperandrogenemia.

In patients with a positive family history of congenital adrenal hyperplasia or in members of high risk ethnic groups such as Ashkenazi Jews, Hispanics, and Slavics, measurement of an early morning follicular phase level of 17-hydroxyprogesterone is recommended.
If there are features of Cushing’s syndrome, thyroid dysfunction, acromegaly or hyperprolactinemia, an endocrine workup should be carried out accordingly. Transvaginal ultrasonographic imaging of the ovaries is recommended for patients with either menstrual disturbances or clinical or biochemical hyperandrogenism.

Treatment

The therapeutic options of hirsutism can be divided into systemic, topical, and dermato-cosmetic therapies. Patients should be informed that the response to systemic agents is slow; occurring over 3-6 months after therapy has begun.

Systemic Treatment

Oral Contraceptives

Oral contraceptive (OC) agents are considered to be the first-line therapy for hirsutism in premenopausal women.⁵ This treatment option has the advantage of regulating the menstrual cycle and providing contraception. Oral contraceptive pills commonly contain ethinyl estradiol (EE), in combination with a progestin. The most androgenic progestins are norgestrel and levonorgestrel, whereas the least androgenic progestins are norgestimate and desogestrel. Other progestins, such as cyproterone acetate and drospirenone, work as androgen receptor antagonists. The recommended OC includes a combination of EE with either 2mg of cyproterone acetate (Diane-35®, Schering) or 3mg drospirenone (Yasmin®, Bayer Healthcare).

The mechanisms by which OCs improve hirsutism include the suppression of luteinizing hormone secretion, resulting in the inhibition of ovarian androgen biosynthesis, stimulation of sex hormone binding globulin production (effectively decreasing serum free androgen concentrations), and a mild reduction in adrenal androgen synthesis. OCs should not be prescribed to women with a history of venous thrombosis.

Antiandrogens

Spironolactone (Aldactone®, Pfizer), an aldosterone antagonist, has several actions including inhibition of the androgen receptor, suppression of adrenal androgen biosynthesis, and inhibition of the 5á-reductase enzyme. A recent Cochrane review of trials comparing spironolactone 100mg/d with placebo showed a significant subjective improvement in hair growth (odds ratio 7.18, 95% confidence interval [CI] 1.96 to 26.28). The Ferriman-Gallwey score, however, did not validate these findings (weighted mean difference 7.20, 95% CI -10.98 to -3.42).6 Spironolactone is generally well tolerated with few side-effects, such as menorrhagia, lethargy and stomach upset. A clinically significant hypotension and increased serum potassium levels are rare if spironolactone has been used at doses of 100mg/day. In the first months of treatment, measurements of blood pressure and serum potassium levels every 4 weeks are recommended. Spironolactone should not be prescribed to patients with renal insufficiency or hyperkalemia. As spironolactone usually causes feminization of the male fetus as well as menstrual alterations, it is best to add oral contraceptive pills.

Cyproterone acetate (CA) is a progestin with antiandrogenic activity that interferes with the binding of dihydrotestosterone to the androgen receptor and inhibits the secretion of gonadotropin, thereby reducing ovarian and adrenal androgen production. CA (2mg) combined with EE has been shown to be more effective than placebo, but not better than other antiandrogens.7 A small randomized controlled study⁸ showed that CA when combined with EE at a dosage of 0.01mg/d for the first week, 0.02mg/d for the second week, 0.01mg/d for the third week, followed by a pause of 7 days, and 12.5mg CA/d added during the first 10 days of every month for 12 months seems to be the most effective treatment to reduce the hirsutism score when compared with flutamide 250mg/d, finasteride 5mg/d, and ketoconazole 300mg/d. The recommended dose is 12.5-100mg/d added to the first 10 days of each calendar pack of oral contraceptives. Side-effects of CA include weigh gain, loss of libido, depression, headache, mastodynia, and feminization of the male fetus.

Flutamide is a pure nonsteroidal antiandrogen that acts as an androgen receptor blocker. Studies have shown that flutamide 250-500mg/d is more effective than finasteride⁹ and triptorelin,¹⁰ a long acting gonadotropin-releasing hormone antognist. A systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the efficacy of different antiandrogens for the treatment of hirsutism reported that when compared with metformin, flutamide reduced the hirsutism score by 5 (95% CI 3.0-7.0; I²=0%). Spironolactone reduced the score by 1.3 (95% CI 0.03-2.6).¹¹ Due to its propensity for severe hepatotoxicity, which is occasionally fatal, flutamide should not be used as first-line therapy for hirsutism.

Finasteride is a potent inhibitor of the type 2 isoenzyme of 5-á-reductase, which blocks the conversion of testosterone to 5-á-dihydrotestosterone. Finasteride has been shown to lower hirsutism scores by 30%-60% in addition to reducing the average hair diameter.¹² In comparative studies, finasteride demonstrated efficacy similar to that of other antiandrogens with fewer adverse effects.¹³ Other trials suggested that spironolactone and flutamide were more effective than finasteride.^14,15 In women with hirsutism, finasteride is used in doses of 2.5-7.5mg/d. Doses of 2.5mg and 5mg seem to be equally effective.¹⁶ As with the other antiandrogens, the use of finasteride requires a reliable method of contraception in order to avoid a pregnancy given the potential risk of feminization of the male fetus.

Insulin-Sensitizing Drugs

Metformin lowers hepatic glucose production and decreases insulin levels. Thiazolidinediones (rosiglitazone and pioglitazone) sensitize end organs to insulin through their action on the peroxisome-proliferator-activated receptor-ã. Meta-analyses of RCTs of insulin sensitizers for the treatment of hirsutism concluded that insulin sensitizers provide limited or no improvement for women with hirsutism.¹⁷

Gonadotropin-Releasing Hormone (GnRH) Agonists

GnRH agonists suppress luteinizing hormone, and to a lesser degree follicle stimulating hormone secretion, leading to a decline in ovarian androgen production. GnRH agonist therapy seems to have no therapeutic advantage over OC and antiandrogens.^18,19 As GnRH agonist therapy is expensive, requires injections, and estrogen needs to be added to the therapy, its use should be reserved for severe forms of hyperandrogenemia, such as patients with ovarian hyperthecosis who have a suboptimal response to OCs and antiandrogens.

Glucocorticoids

Glucocorticoids can be prescribed to women who:

• have hirsutism that is due to nonclassic congenital adrenal hyperplasia
• have a suboptimal response to OCs and/or antiandrogens
• exhibit poor tolerance to OCs
• are seeking ovulation induction.

Topical Treatment

Eflornithine hydrochloride cream 13.9% (Vaniqa®, Skin Mediea) has been approved by the US FDA for the reduction of unwanted facial hair in women. Noticeable results take about 6-8 weeks. Adverse effects include itching and skin dryness.

Direct Hair Removal Methods

A wide range of hair removal methods have been advocated over the years with varying degrees of success. These modalities can be divided into temporary methods of hair removal and permanent methods of hair reduction. Temporary methods of hair removal include plucking, waxing, shaving and chemical depilatory agents. Although not a method of hair removal, bleaching serves to lighten the color of the external hair shafts so that they are less noticeable. Permanent methods of hair reduction include photoepilation (using laser and intense pulse light [IPL]) and electrolysis. Photoepilation seems to be superior to the conventional methods, such as shaving, waxing and electrolysis. A Cochrane review of photoepilation of unwanted hair growth showed that alexandrite and diode lasers are more effective, whereas little evidence was obtained for the effect from IPL, Nd:YAG, or ruby lasers.²⁰ However, some longer wavelength lasers (Nd:YAG), or IPL, appear to provide benefits in patients who have darker skin types and therefore have less risk of burning and dyspigmentation. Paradoxical hypertrichosis is a possible, but rare, adverse effect of photoepilation, particularly in dark-skinned individuals.^21,22

Conclusion

Hirsutism is usually a benign, but extremely distressing condition. Although several treatment options exist, we recommend the use of OCs with antiandrogenic activity as first-line therapy for the majority of premenopausal women. An antiandrogen can be added if the response to OCs is suboptimal after 6 months of use. Laser/photoepilation are the preferred direct hair removal methods. Logical combinations tailored to the individual clinical profile can accomplish the best results in most patients.

References

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