Insulin Sensitizing Agents

Insulin resistance with compensatory hyperinsulinemia is a prominent feature of PCOS diagnosed in both lean and obese patients (see Chapter 24). The exact mechanisms for abnormalities of insulin action in the syndrome have yet to be elucidated (65). However, hyperinsulinemia has been show to increase ovarian androgen biosynthesis (66) and decrease hepatic synthesis of SHBG (67), leading to increased bioavailability of free androgens. The increase in local ovarian androgen production mediated by hyperinsulinemia can also result in premature follicular atresia and anovulation (68).

The strong association between PCOS and insulin resistance and the role of hyperinsulinemia in hyperandrogenism and disrupted folliculogenesis provide the rationale for the use of insulin sensitizers in the treatment of the syndrome. It seems logical that the therapeutic interventions directed at increasing insulin sensitivity, thereby decreasing hyperinsulinemia, would ameliorate the hyperandrogenism and improve ovulatory dysfunction in women with PCOS. Indeed, insulin sensitizers are becoming widely used in PCOS, both as single ovulatory agents and as an adjuvant to other ovulation-induction drugs, principally clomiphene. However, we should note that not all women with PCOS have documented insulin resistance, and no measure of insulin sensitivity is included in the current diagnostic criteria of PCOS. Moreover, there are no generally acknowledged guidelines or criteria for the clinical quantification of insulin resistance (69). Nevertheless, up to 65% of patients with PCOS can actually be classified as having insulin resistance (70-72).

A number of insulin-sensitizing agents with different mechanisms of action have been used in the setting of PCOS. These medications include biguanide oral hypoglycemic agents such as metformin and thiazolidinediones such as troglitazone, rosiglitazone, and pioglitazone.

2.2.3.1. Metformin

Metformin is the most extensively used insulin-sensitizing agent for ovulation induction in PCOS (73). Metformin is a biguanide antihyperglycemic that has been used to treat type 2 diabetes mellitus since the early 1970s in Europe and was introduced (actually reintroduced) in the United States in 1994. The glucose-lowering effects of metformin are mainly a consequence of reduced hepatic glucose output (primarily through inhibition of gluconeogenesis and, to a lesser extent, glycogenolysis) and increased insulin-stimulated glucose uptake in skeletal muscle and adipocytes. By increasing insulin sensitivity, metformin reduces peripheral and hepatic insulin resistance, insulin secretion, and hyperinsulinemia (74).

There has been increasing interest in the use of metformin for the treatment of PCOS since the first report by Velazquez et al. (75) in 1994. Recently, the effects of metformin for ovulation induction were assessed in a meta-analysis including 13 randomized controlled trials and 543 participants (73). The dose range of the metformin used in these trials was 1500-1700 mg/day. There was a significant effect of metformin in achieving ovulation in women with PCOS, with odds ratios (OR) of 3.88 (95% confidence interval [CI] 2.25-6.69, p < 0.00001) for metformin vs placebo and 4.41 (95% CI 2.378.22, p < 0.00001) for metformin plus clomiphene vs clomiphene alone (73). The overall ovulation rate achieved by metformin, or metformin and clomiphene, was reported as 57%. The data from this meta-analysis suggested that metformin acts relatively quickly to improve ovulation, with significant treatment effects reported after 2 months. We should note that there was a significant correlation between trial length and the proportion of patients ovulating on placebo, suggesting that the treatment effect of metformin will appear less with the longer trials becaus of the higher rate of spontaneous ovulation in the placebo arm (73). Alternatively, and in contrast to its beneficial effect in clomiphene-resistant patients, metformin does not enhance ovulatory or pregnancy rates in gonado-tropin ovulation-induction cycles (76,77) or in vitro fertilization (78), although current data are limited.

It has been suggested that metformin could be used as a first-line agent for ovulation induction in women with PCOS, instead of clomiphene. Recently, Palomba et al. (79) reported the results of a randomized controlled trial comparing metformin with clomiphene as the first-line treatment for ovulation induction in non-obese PCOS patients (Table 1). One hundred non-obese PCOS patients were enrolled and randomized to metformin (850 mg twice daily) plus placebo or clomiphene (150 mg for 5 days from the third day of a progesterone withdrawal bleeding) plus placebo for 6 months. At the end of the study, the ovulation rate was not significantly different between the two treatment groups, whereas patients receiving metformin demonstrated a higher continuing pregnancy rate (15.1 vs 7.2%, respectively, p = 0.009) and a lower miscarriage rate (9.7 vs 37.5%, respectively, p = 0.045) compared to clomiphene. These promising results remain to be confirmed in larger studies. Additionally, it is important to note that ovulation and pregnancy rates are surrogate outcomes, and live birth

Table 1

Ovulation and Pregnancy Rates in PCOS Women Randomized to Treatment

With Metformin Cloridrate or Clomiphene Citrate (CC) During Each Cycle of Treatment

Ovulation rate Pregnancy rate

[No. ovulatory cycles/no. cycles (%)] [No. pregnancies/no. cycles (%)]

Table 1

Ovulation and Pregnancy Rates in PCOS Women Randomized to Treatment

With Metformin Cloridrate or Clomiphene Citrate (CC) During Each Cycle of Treatment

Ovulation rate Pregnancy rate

[No. ovulatory cycles/no. cycles (%)] [No. pregnancies/no. cycles (%)]

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