Women Not Interested in Fertility

The medical treatment for menstrual regulation and hirsutism is summarized in Table 3.

Menstrual Regulation

The lack of menstrual regularity predisposes women with PCOS to a threefold risk of endometrial cancer (46). Data from the Cancer and Steroid Hormone study found a fivefold increased risk of endometrial cancer in women with PCOS [Odds ratio (OR) 5.4; 95% confidence interval (CI) 2.4-12.3] (47). This increased risk is attributed to prolonged periods of unopposed estrogens, resulting in mito-genic stimulation of the endometrium. Peripheral aromatization into estrone and low circulating SHBG levels, resulting in increased free estradiol concentrations, further contributes to the chronic estrogen action on the endometrium. Fortunately, most cases of endometrial cancer are detected at an early stage with well-differentiated histology and good prognosis (48). Nonetheless, women with PCOS who are not interested in fertility should be treated with oral contraceptive pills (OCPs) or a 14-d course of cyclic progestin each month to induce regular withdrawal bleed and prevent endometrial hyperplasia (49).

A newer alternative is metformin, which is a dimethyl biguanide and an antihyperglycemic agent. It has been in clinical use since 1957 but was only recently approved by the Food and Drug Administration for the treatment of type 2 DM. Metformin decreases hepatic gluconeogenesis, increases peripheral glucose uptake, and decreases free fatty acid oxidation (50,51). The first study describing its use in women with PCOS showed a 29% decrease in total testosterone, 39% decrease in free testosterone, 50% increase in SHBG, and menstrual regulation with evidence of ovulation (52).

Table 3

Drugs Used for Menstrual Regulation and Hirsutism in PCOS

Drug

Indication

Dose

Adverse effects

Efficacy

Oral contraceptives Menstrual regulation Low-dose, third-generation

OCPs

Hirsutism

Progestins (medroxy- Menstrual regulation 10 mg qd x 12-14 d each month progesterone acetate) Glucophage

Hirsutism

Spironolactone Hirsutism

Menstrual regulation 500 mg tid

50-200 mg qd

Flutamide

Finasteride Eflornithine HCl 13.9%

Hirsutism

Hirsutism Hirsutism

250 mg tid 1 mg qd

Apply thin layer to face bid

Weight gain, nausea, vomiting, gallbladder disease, migraine

Bloating, depression

Abdominal discomfort, nausea, diarrhea

Hyperkalemia, irregular bleeding, light- headedness, gynecomastia Diarrhea, cystitis, rectal bleeding, liver injury Sexual dysfunction, breast tenderness Redness, rash, burning, tingling

OCP, oral contraceptive pill.

a-, no efficacy; +, low; ++, moderate; +++, high; +/-, unkown.

There are few randomized studies comparing the long-term outcomes in women treated with OCPs versus metformin. In one study, women randomized to metformin showed a decrease in BMI, fasting glucose, and testosterone levels compared with the ethinyl estradiol-cyproterone acetate group (53). Although an improvement in menstrual cyclicity was noted in six of eight subjects on metformin, the efficacy of this treatment in preventing endometrial hyperplasia and cancer needs to be evaluated.

Hirsutism

Because the response to medical treatment is slow (owing to the long hair growth cycle), therapy needs to be continued for 1-2 yr and combined with mechanical methods of hair removal such as plucking, waxing, laser phototherapy, and electrolysis. Medical treatment of hirsutism includes ovarian suppression with OCPs, progestins, or GnRH analogs or antiandrogen compounds such as spironolactone, flutamide, and finasteride. In addition to decreasing LH-dependent ovarian androgen production, the estrogenic component of OCPs also acts directly on the liver to increase SHBG. Furthermore, the progestins in OCPs can directly inhibit 5a-reductase, which converts testosterone to dihydro-testosterone. The response to low dose OCPs is comparable to that observed with higher doses in patients with hirsutism (54). Similarly, progestational agents including third-generation preparations such as desogestrel, gestodene, and norgestimate when used alone have effects similar to those of low-dose OCPs.

Spironolactone, an aldosterone antagonist and antidiuretic, is the next most commonly used drug. It competes for androgen receptors in the hair follicle, inhibits the enzyme 5a-reductase, and may have a direct effect on inhibiting ovarian steroid synthesis. The recommended doses are 50-200 mg daily, but the response to this agent is also slow (6 mo). Spironolactone can cause irregular menses and is teratogenic; hence it is usually prescribed in combination with OCPs, although this may not significantly improve the outcome (55).

Flutamide inhibits the androgen receptor directly but has limited use because of the severe hepatotoxicity reported in a small number of cases (56). Finasteride inhibits 5a-reductase activity, hence decreasing the conversion of testosterone to dihydrotestosterone, and has fewer side effects. A prospective randomized trial compared the efficacy of flutamide, finasteride, ketoconazole, and ethinyl-estra-diol-cyproterone acetate over a period of 360 d. Although an improvement in a modified Ferriman-Gallwey score was noted in all four groups, there was no statistically significant difference between groups (57). Another randomized prospective trial compared the efficacy of spironolactone, flutamide, and finasteride and showed similar effectiveness at 6 mo (58).

Eflornithine hydrochloride (HCl) cream (VANIQA(r)) is a topical medication that can irreversibly block ornithine decarboxylase (ODC), an enzyme responsible for regulating hair growth. This results in a decrease in the rate of hair growth as well as thinning of the hair. In a 24-wk randomized clinical trial, women using eflornithine cream showed significant improvement in a four-point physician global assessment with minimal side effects (59). In an 8-wk follow-up study, it was found that the benefits diminished with discontinuation of the cream. The long-term efficacy and side effects from this drug, as well as its concomitant use with some of the above-mentioned agents, need to be examined.

Metabolic Syndrome

The metabolic syndrome seen in women with PCOS is associated with hyper-lipidemia, early-onset diabetes, and hypertension and macrovascular coronary artery syndrome. This underscores the importance of early intervention and treatment. Lifestyle modifications including weight loss and nutritional and exercise counseling remain the mainstay of therapy. In a recent multicenter, randomized, prospective trial sponsored by the NIH, intensive lifestyle modifications in individuals with impaired glucose tolerance reduced the risk of progressing to diabetes by 58%, and metformin reduced the risk of diabetes by 31% over a follow-up period of 3 yr (60; see also Chapter 5). Similar results for lifestyle changes were reported in the recent Finnish Diabetes Prevention Study (61). However, it is still unclear whether and how this applies to specific populations of women with PCOS.

The treatment of women with PCOS diagnosed with diabetes during the preliminary workup is clear; however, the treatment of women who have hyper-insulinemia or a glucose/insulin ratio less than 4.5 remains controversial. In a randomized control trial of 29 adolescents with hyperinsulinemia and obesity, treatment with metformin resulted in an improvement in the fasting glucose and insulin levels and a decrease in BMI (62). These authors concluded that metformin may complement dietary and exercise counseling in selected patients with increased risk for diabetes.

In summary, women with PCOS who are not interested in fertility should be prescribed steroid hormones to regulate their menstrual cycles. If they present with a prolonged duration of amenorrhea, an endometrial biopsy should be performed prior to starting medical therapy. Periodic screening tests should include blood pressure checks, fasting lipids, glucose, and insulin. If they are obese or hyperinsulinemic, they should be aggressively counseled regarding weight loss and the use of insulin-sensitizing agents.

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