Polycystic ovary syndrome: 3 key challenges

Note however, that obese women often require higher doses of clomiphene to induce ovulation.²⁶ Although I give obese patients the same starting dose of clomiphene, I raise daily levels up to 200 mg in this patient population.

Using metformin to enhance ovulation. Pretreatment with metformin may enhance ovulation induction with clomiphene. In a multinational, randomized, placebo-controlled trial, obese women with PCOS were given metformin or placebo for 5 weeks.²⁷ The ovulation rates were 34% (12/35) in the metformin group and 4% (1/26) in the placebo group. The women who did not ovulate were then given 50 mg of clomiphene per day for 5 days in addition to placebo or metformin. In the clomiphene-metformin group, the ovulation rate was 90% (19/21) versus 8% (2/25) in the placebo-metformin group.

Even modest weight loss can improve insulin resistance and enhance ovulation.

Metformin also appears to be effective in women with clomiphene resistance. One randomized, placebo-controlled trial examined women with PCOS and clomiphene-resistant anovulation at a dosage of 150 mg/d. Participants were given a thrice-daily dose of 500 mg metformin or placebo for 7 weeks, followed by clomiphene, starting at 50 mg/d with increasing doses until ovulation occurred or a dosage of 150 mg/d was achieved.²⁸ The rate of ovulation was 75% (9/12) in the metformin-clomiphene group versus 27% (4/15) in the placebo-clomiphene group.

More investigation is needed to determine the effects of combination therapies, including various oral hypoglycemic agents, in the treatment of women with PCOS. An NIH-funded clinical trial is currently comparing the effectiveness of ovulation induction with clomiphene alone, metformin alone, and the two agents in combination.

3. Address hirsutism

Hirsutism is the presence of terminal hair on a woman’s face, chest, lower abdomen, suprapubic area, upper arms, thighs, or back. PCOS is the most common cause of hirsutism in women of reproductive age. Most women with PCOS have elevated serum levels of luteinizing hormone and total and free testosterone, which results in hirsutism.

Patients should be counseled that their response to therapy will likely be slow and subtle.

Counsel the patient. Treating this condition is difficult; it is best approached with a combination of medical and mechanical means. Patients should be counseled that their response to therapy will likely be slow and subtle. In fact, noticeable changes may not occur for as long as 6 months.

Unfortunately, there is no accepted method for assessing a patient’s response to therapy. Even baseline assessment can be difficult, because many patients camouflage hirsutism with depilatories and cosmetics.

I ask patients if they shave and, if so, how often. I also ask if they use any other method of hair removal. In addition, I use a modified Ferriman-Gallwey scale and a pictogram to document hair growth. At followup, I ask if they have noticed any changes in their hair growth or if they are shaving less often.

Medical therapy. Begin by treating the patient’s anovulation and androgen production. Next, antagonize androgenic effects at the level of the pilosebaceous unit. This can be done using compounds that antagonize the binding of androgen to its receptor or that inhibit the enzyme 5α-reductase, which metabolizes the conversion of testosterone to dihydrotestosterone (TABLE 2).

• Androgen-receptor antagonists. Among the androgen-receptor antagonists is spironolactone, which not only competitively binds to the androgen receptor, but also inhibits the 5α-reductase enzyme. It also has been used in combination with oral contraceptives. Oral contraceptives are helpful because they reduce ovarian androgen production by decreasing luteinizing hormone and stimulating the production of sex-hormone binding globulin, which binds testosterone and reduces free testosterone. Oral contraceptives also ensure effective contraception.
  
• 5α-reductase inhibitors. The 5α-reductase enzyme exists in 2 forms. Type I occurs predominately in the skin, and type II occurs mainly in the prostate. Finasteride, which inhibits both forms, is approved for the treatment of prostate cancer at a daily dose of 5 mg and male alopecia at a daily dose of 1 mg.
  

Overall, the literature suggests that both flutamide and finasteride are effective against PCOS-associated hirsutism. One randomized, placebo-controlled clinical trial involving 40 women utilized both the Ferriman-Gallwey score and hair-shaft diameter to assess clinical effectiveness of these agents. In that study, 5 mg/d of finasteride was shown to be as effective as 100 mg/d of spironolactone or 250 mg/d of flutamide.²⁹ (Note that 5α-reductase inhibitors should not be used during pregnancy.)

• Eflornithine, a topical agent, was recently approved for the treatment of facial hair. This compound is available in a cream that the patient applies twice daily. Eflornithine inhibits ornithine decarboxylase, an enzyme that is important in the function of the pilosebaceous unit. In one trial, the first signs of effectiveness were noted after 8 weeks of therapy; one third of patients improved after 24 weeks of use.³⁰
  
• As a first-line agent I rely on spironolactone, simply because it has been on the market longest and I have more clinical experience with it. I also have used finasteride. Unfortunately, there are no data to aid in patient selection.
  
• Electrolysis, the application of a galvanic current to achieve chemical destruction of the hair follicle.
  
• Thermolysis, which utilizes alternating current and the generation of heat to destroy the hair follicle.