Women Interested in Fertility

Medical Treatment

Most women with PCOS ovulate intermittently and can present with infertility. However, only a subset have infertility secondary to anovulation, and most respond to ovulation-inducing agents. The current medical treatment strategy for PCOS patients to regulate menstruation and treat infertility includes use of an estrogen receptor agonist/antagonist such as clomiphene citrate. Clomiphene is typically administered in the follicular phase of the cycle, starting on d 3-5 for a total of 5 d. The starting dose is 50 mg/d, and this may be increased in an incremental manner until ovulation is detected, usually by measuring the midluteal progesterone level. Women are asked to time intercourse every other day for 1 wk starting 5 d after the last dose of clomiphene or to use an ovulation prediction kit. This ovulatory dose is then maintained for three to six cycles. It has been reported that 70% of women will ovulate at the 100-mg dose (63). Furthermore, most clomiphene-initiated conceptions will occur within the first six cycles. The common side effects associated with clomiphene include hot flashes, mood changes, abdominal discomfort, visual symptoms, and a multiple pregnancy rate of 5-8%. If there is no other cause for infertility, the pregnancy rates in this population approach that of the normal population (63). Approximately 20% of women with PCOS fail to ovulate on maximum doses of clomiphene (150-200 mg/d) and are then candidates for combination therapy with metformin or gonadotropins. Also, women who fail to become pregnant after three to six cycles of clomiphene are then treated with combination therapy.

Weight loss counseling is also important. It has been reported that weight loss of 5-7% of body weight will improve menstrual function (64-66). In a randomized trial, weight loss was associated with decrease in total testosterone and insulin levels, and four of six women had documented ovulation (67). In contrast, none of the five women in the control group ovulated. In another study, women with PCOS were placed on a low-calorie diet and randomized to placebo versus metformin (65). After 6 mo, the women in the metformin arm of the study had greater reduction of body weight (mean 9.7 kg) and abdominal fat and a decrease in serum fasting insulin (40%), testosterone (35%), and leptin levels. In addition, they had a significant improvement in menstrual irregularity.

Insulin sensitizers may also have a role in the treatment of infertility in PCOS. Approximately 80% of women with PCOS will respond to clomiphene, but only 50% will become pregnant. Although several studies have examined the role of insulin-sensitizing agents in women with PCOS (68-70), the appropriateness of administering insulin-lowering agents to women with normal fasting insulin remains to be validated (71). Obese PCOS women treated with metformin have a reduction in cytochrome P450c17a activity and a decrease in serum free testosterone (72). Metformin therapy for only 5 wk improves both the spontaneous ovulatory rate (34%) and clomiphene-induced ovulatory response (90%) compared with 4 and 8%, respectively, in controls (69). Laboratory data in the same study showed an improvement in the free testosterone and SHBG levels as well as the insulin area under the curve. A randomized controlled trial conducted over a 6-mo period showed similar improvements in biochemical profiles of women with PCOS administered metformin compared with placebo (n = 23) (58). In the metformin arm of the study, the authors noted an increase in menstrual frequency in 54.8% of women, and ovulation was detected in 74% of these women.

The use of metformin in conjunction with clomiphene will reduce the number of patients who will require gonadotropins for ovulation induction. This has potential benefits owing to the side effects associated with gonadotropin therapy, which include ovarian hyperstimulation syndrome (OHSS) and multiple gestation, as well as the lower cost and decreased patient monitoring requirements. Women who fail to ovulate with clomiphene/metformin combinations can then be treated with low-dose gonadotropins. In a review of14 randomized controlled trials, it was noted that ovulation induction with FSH compared with human menopausal gonadotropin (HMG) resulted in a lower incidence of OHSS (OR 0.2; 95% CI 0.08-0.46) (73) but no significant improvement in pregnancy rate. On the other hand, addition of GnRH analogs to gonadotropin therapy showed a trend toward improved pregnancy rates, but there was a higher risk of overstimulation (OR 3.15; 95% CI 1.48-6.7). The addition of metformin to gonadotropin stimulation has been associated with an orderly growth of follicles and a lower risk of hyperstimulation (74).

The use of metformin in women with PCOS undergoing in vitro fertilization has been recently examined. Women in the metformin arm had fewer follicles (p < 0.005) and lower estradiol levels (p < 0.05) compared with the group that did not receive metformin (75). In addition, the number of mature oocytes and more than 4-cell-stage embryos was higher in the metformin group, suggesting a beneficial effect of metformin on follicular and oocyte development. Troglitazone, a member of the thiazolidinedione class of drugs, is another insulin-sensitizing agent that has been shown to have similar beneficial effects on biochemical parameters and menstrual function. However, troglitazone has been withdrawn for sale in the United States because of potentially fatal hepatotoxicity. The two available thiazolidinediones (rosiglitazone and pioglitazone) may have the same favorable effects on menstrual function as troglitazone.

Surgical Treatment

Modern surgical treatment for PCOS consists of laparoscopic ovarian "drilling." Ovarian wedge resection was the first established treatment for anovulatory PCOS women but was abandoned because of the increased risk of postoperative adhesions (76). As previously mentioned, some women fail to respond to ovulatory agents such as clomiphene and have an exaggerated response to gonadotropins. Hence, there has been an ongoing effort to develop laparoscopic ovarian drilling as a relatively less invasive alternative to wedge resection. Several observational trials have reported an improvement in both the spontaneous ovulatory rate and the response to ovulation-inducing agents. A review of six randomized controlled trials comparing ovarian drilling with gonadotropins failed to show a statistically significant difference between the two treatment groups (77). However, multiple pregnancy rates were significantly reduced in the ovarian drilling arm (OR 0.61; 95% CI 0.17-2.16) This treatment remains an option for women who fail to respond to oral ovulation-inducing agents and cannot afford expensive treatments including gonadotropins and assisted reproductive technologies.

Obstetric Complications

Women with PCOS have an increased risk of miscarriages of unclear etiology (78,79). This has led several authors to recommend (for patients achieving pregnancy on metformin) that the drug be continued at least through the first trimester (80). This is based on the hypothesis that metformin will lower the miscarriage rate by decreasing insulin and PAI-1 levels (81) and increasing glycodelin and IGFBP-1 (81). Women with PCOS also have an increased risk of other obstetric complications including diabetes and risks associated with multiple gestations. In one study (82), the multiple pregnancy rate was 9.1% in women with PCOS compared with 1.1% in controls, and the risk of developing gestational diabetes was 20% in women with PCOS compared with 8.9% in controls. Interestingly, PCOS was an independent predictor of gestational diabetes. In contrast, PCOS was not a predictor of preeclampsia, as had been reported previously (83,84).

In summary, most women with PCOS will achieve a successful pregnancy. However, a subset of these patients may fail to respond to oral ovulation-inducing agents and will hyperrespond when administered gonadotropins. Newer regimens including metformin and letrozole will decrease the number of women with PCOS that will require assisted reproductive technologies.

summary

PCOS is a heterogenous disorder with an appreciable increase in risk of diabetes and cardiovascular complications by the perimenopausal period. Although the short-term benefits of insulin-sensitizing agents are now being defined, it is crucial to determine the long-term effects of these agents on delaying or decreasing the risks of developing diabetes and hypertension.

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