Effect of Metformin on Anovulation and Infertility 2211 Metformin Monotherapy in PCOS

Numerous clinical trials have evaluated the effect of metformin on ovulation in women with PCOS. Nester et al. reported the first randomized, placebo-controlled trial evaluating the use of metformin to reestablish ovulation (11). Sixty-one obese women with PCOS were randomized to metformin 500 mg three times daily or placebo for 35 days. If spontaneous ovulation did not occur, they were entered into the second phase of the study and were given clomiphene 50 mg daily for 5 days while continuing to take the metformin or placebo for another month. During the first 35 days in which metformin monotherapy was compared to placebo, 24% of the women (12 in 35) taking metformin ovulated spontaneously, whereas only 4% (1 in 26) in the placebo group had spontaneous ovulation.

Table 1

Ovulation Rate With Metformin Compared to Placebo or No Treatment

Proportion of women with spontaneous ovulation

Table 1

Ovulation Rate With Metformin Compared to Placebo or No Treatment

Proportion of women with spontaneous ovulation

Study (ref.)

Treatment

Control

Peto odds ratio (95% CI)

Fleming et al., 2002 (14)

37/45

30/47

2.51 (1.01-6.25)

Jakubowicz et al., 2001 (15)

8/28

0/28

9.89 (2.24- 43.61)

Nestler and Jakubowicz, 1996 (7)

5/11

1/13

6.89 (1.12-42.33)

Nestler et al., 1998 (11)

12/35

1/26

5.96 (1.74-20.38)

Ng et al., 2001 (19)

3/9

3/9

1.00 (0.15-6.72)

Vandermolen et al., 2001 (22)

1/12

1/15

1.26 (0.07- 21.72)

Yarali et al., 2002 (23)

6/16

1/16

5.88 (1.13-30.61)

Total (95% CI)

72/156

37/154

3.88 (1.13-30.61)

Adapted from ref. 12.

Adapted from ref. 12.

In the second phase of the study, 19 of 21 women (90%) receiving metformin and clomiphene ovulated, compared with only 2 of 25 women (8%) receiving placebo plus clomiphene. Of note, more women receiving metformin monotherapy for 7 weeks ovulated than those who underwent a single cycle of induction with clomiphene at the 50 mg dose (12% vs 8%, respectively).

Other studies have corroborated the above findings. The Cochrane library has published a systematic review of the use of metformin in PCOS (12). The review included only the most rigorously performed clinical trials for analysis. These included randomized controlled trials comparing insulin-sensitizing drugs to placebo or to an ovulation-induction agent such as clomiphene or gonadotropin. Thirteen trials were included for analysis (7,11,13-24). Almost uniformly across studies, metformin monotherapy showed a beneficial effect on ovulation rates in PCOS (Table 1). Overall, the ovulation rate increased 3.9-fold when metformin was given as monotherapy (p < 0.00001; CI 2.3-6.7). Metformin treatment resulted in spontaneous ovulation in 46% of women, while the ovulation rate was 24% with placebo. Clinical pregnancy rate with metformin was also increased 2.8-fold (p = 0.09; CI 0.9-9.0), but fell short of statistical significance probably as a result of the small number of women included in these studies and the fact that pregnancy was not an outcome measure of these studies. Of note, these studies were short term in nature (most were only up to 3 months in duration) and therefore were biased against showing a positive effect with metformin. Despite a short intervention period, it was evident that metformin was beneficial in improving ovulation in women with PCOS.

Clomiphene citrate has been the initial therapeutic option for the management of anovulatory infertility for many years. Metformin was directly compared to clomiphene in a recent double-blind, placebo-controlled trial in non-obese women (average body mass index [BMI] = 27 kg/m2) with PCOS (24). After progesterone-induced withdrawal bleeds, 100 women with PCOS were randomized to metformin (850 mg twice daily) or clomiphene citrate (150 mg for 5 days on a monthly basis) for 6 months. Although there was no difference in ovulation rates between the metformin and clomiphene groups, the pregnancy rate was higher (15.1% vs 7.2%; p = 0.009) and spontaneous abortion rate lower (9.7% vs 37.5%; p = 0.045) in the metformin group. There was also a favorable trend for the live-birth rate with metformin compared to clomiphene (83.9% vs 56.3%; p = 0.07).

2.2.1.2. Metformin in Clomiphene-Resistant Women

Although clomiphene citrate has been historically the primary agent for ovulation induction in PCOS, obese women with PCOS often have an inadequate response to clomiphene. This is likely due to a high degree of insulin resistance and concomitant hyperinsulinemia (25). Obese patients with PCOS often require progressively increased doses and multiple courses of clomiphene for successful

Table 2

Ovulation Rate With Metformin Combined With Ovulation-Induction Agent Compared With Induction Agent Alone

Proportion of women with ovulation

Study (ref.)

Treatment

Control

Peto odds ratio (95% CI)

Clomiphene resistant:

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