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Previous Volume 338:1876-1880 June 25, 1998 Number 26 Next

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ABSTRACT

Background Obese women with the polycystic ovary syndrome are relatively unresponsive to the induction of ovulation by clomiphene. We hypothesized that reducing insulin secretion by administering metformin would increase the ovulatory response to clomiphene.

Methods We performed oral glucose-tolerance tests before and after the administration of 500 mg of metformin or placebo three times daily for 35 days in 61 obese women with the polycystic ovary syndrome. Women who did not ovulate spontaneously were then given 50 mg of clomiphene daily for five days while continuing to take metformin or placebo. Serum progesterone was measured on days 14, 28, 35, 44, and 53, and ovulation was presumed to have occurred if the concentration exceeded 8 ng per milliliter (26 nmol per liter) on any of these days.

Results Twenty-one women in the metformin group and 25 women in the placebo group were given clomiphene because they did not ovulate spontaneously during the first phase of the study. Among the 21 women given metformin plus clomiphene, the mean (±SE) area under the serum insulin curve after oral glucose administration decreased from 6745±2021 to 3479±455 µU per milliliter per minute (40.5±12.1 to 20.9±2.7 nmol per liter per minute, P=0.03), but it did not change significantly in the 25 women given placebo plus clomiphene. Nineteen of the 21 women (90 percent) who received metformin plus clomiphene ovulated (mean peak serum progesterone concentration, 23.8±3.4 ng per milliliter [7.6±10.9 nmol per liter]). Two of the 25 women (8 percent) who received placebo plus clomiphene ovulated (P<0.001). Overall, 31 of the 35 women (89 percent) treated with metformin ovulated spontaneously or in response to clomiphene, as compared with 3 of the 26 women (12 percent) treated with placebo.

Conclusions The ovulatory response to clomiphene can be increased in obese women with the polycystic ovary syndrome by decreasing insulin secretion with metformin.

Clomiphene citrate, an antiestrogenic drug, is the primary therapy used for ovulation induction in women with the polycystic ovary syndrome.^13,14,15 However, obese women with the syndrome often require multiple courses and high doses of clomiphene, and there is a positive correlation between obesity and the dose of clomiphene required to induce ovulation.¹⁵ Since increasing obesity is associated with increasing hyperinsulinemia,¹⁶ the high degree of hyperinsulinemia in obese women with the polycystic ovary syndrome may account for their poor responsiveness to clomiphene.¹³ Hyperinsulinemia could adversely affect folliculogenesis and ovulation by increasing intraovarian androgen production,^6,8,17,18,19 altering gonadotropin secretion,^8,9,20,21,22 or directly affecting follicular development.

The aim of this study was to determine whether reducing hyperinsulinemia with metformin would increase the ovulatory response to clomiphene in obese women with the polycystic ovary syndrome.

Methods

Subjects

We studied 61 obese women (body-mass index [the weight in kilograms divided by the square of the height in meters], >28) with polycystic ovary syndrome in the United States, Venezuela, and Italy. All had oligomenorrhea (fewer than six menstrual periods in the preceding year) and hyperandrogenemia (elevated serum free testosterone concentrations, determined at local clinics), and none had diabetes mellitus. All had normal serum prolactin concentrations and normal thyroid-function tests. Late-onset adrenal hyperplasia was ruled out by the finding of a morning serum 17-hydroxyprogesterone concentration below 200 ng per deciliter (6 nmol per liter). All the women had findings on ultrasonography of the ovaries consistent with the diagnosis of the polycystic ovary syndrome.²³ Thirty-one women had received clomiphene previously, but none had taken it or any other medication for at least two months before the study. The study was approved by the institutional review board at each study site, and each woman gave informed consent.

Experimental Protocol

At the time of entry into the study, all the women were in the equivalent of the follicular phase of the menstrual cycle, as documented by a serum progesterone concentration below 2 ng per milliliter (6.4 nmol per liter), and their last episode of menstrual bleeding had been at least two months earlier.

On day 0, the women came to the hospital after a 12-hour overnight fast, at which time their weight, height, and waist-to-hip ratio were measured. Blood samples were drawn at 8:30, 8:45, and 9 a.m., and equal volumes of serum were pooled for the measurement of insulin, glucose, steroid hormones, and sex hormone–binding globulin. At 9 a.m. 75 g of glucose was given orally, and blood samples were collected after 60 and 120 minutes for the determination of serum glucose and insulin concentrations.

Findings from a previous study⁸ suggested that metformin might increase spontaneous ovulation. Given that a goal of the study was to have an equal number of women in the metformin and placebo groups during the administration of clomiphene, more women were randomly assigned to receive metformin. Thirty-five women were assigned to take 500 mg of metformin (Glucophage, Bristol-Myers Squibb, Princeton, N.J.; Glafornil, North Medicamenta, Caracas, Venezuela; or Metforal, Laboratori Guidotti, Pisa, Italy) orally three times daily, and the remaining 26 women were assigned to receive placebo. The women were asked to abstain from sexual intercourse or to use a barrier method of contraception during the study.

The women took metformin or placebo alone on days 1 to 34 to allow sufficient time for metformin to exert its putative insulin-sensitizing effects. Serum progesterone was measured on days 14, 28, and 35, and ovulation was presumed to have occurred if the value exceeded 8 ng per milliliter (25.6 nmol per liter) on any of these days. All tests performed at base line (day 0) were repeated on day 35.

The 21 women in the metformin group and the 25 women in the placebo group who did not ovulate and had serum progesterone concentrations below 2 ng per milliliter between days 0 and 35 were given 50 mg of clomiphene citrate (Serophene, Teva Pharmaceuticals, Jerusalem, Israel) daily for five days (days 35 to 39), while continuing to receive metformin or placebo through day 53. Serum progesterone was measured on days 44 and 53 to assess the ovulatory response to clomiphene.

Assays

Blood samples were centrifuged as soon as they were obtained, and the serum was stored at –20°C until assayed. Serum hormones and sex hormone–binding globulin (measured as protein) were assayed as previously described,^6,24,25 except for serum free testosterone, the concentration of which was calculated according to the method of Sodergard et al.²⁶ and was predicated on the assumption of a constant serum albumin concentration of 4.0 g per deciliter. To avoid variation between assays, all samples from an individual woman were analyzed in duplicate in a single assay for each hormone. The intraassay coefficient of variation was 5.5 percent for the insulin assay and less than 10 percent for all steroid hormone assays.

Statistical Analysis

We analyzed the serum glucose and insulin responses to oral glucose administration by calculating the areas under the response curves by the trapezoidal rule using absolute values. Fisher's exact test was used to analyze the differences in ovulation rates between the metformin and placebo groups. For other variables, we compared results within a group by testing for normality with the Wilk–Shapiro test and then using Student's two-tailed paired t-test or the Wilcoxon signed-rank test, and we compared results between groups with Student's two-tailed unpaired t-test or the Mann–Whitney rank-sum test.

Results

Treatment with Metformin or Placebo Alone

On entry into the study (day 0), the metformin and placebo groups did not differ with respect to history of clomiphene treatment, anthropometric variables, and biochemical values (Table 1).

View this table: [in this window] [in a new window]   Table 1. Base-Line Characteristics of Women with the Polycystic Ovary Syndrome.

 
In the metformin group, the mean (±SE) area under the serum insulin curve during the oral glucose-tolerance test decreased from 6598±1267 to 3764±317 µU per milliliter per minute (39.6±7.6 to 22.6±1.9 nmol per liter per minute, P=0.002), whereas this value did not change significantly in the placebo group (P=0.20). There was also a small but significant decrease in the waist-to-hip ratio during testing (from 0.89±0.01 to 0.88±0.01, P<0.001) in the metformin group, but not in the placebo group (P=0.60). In neither group was there any change in the body-mass index, serum insulin or glucose concentrations during fasting, or the area under the serum glucose curve during the oral glucose-tolerance test.

During the first 35 days of treatment, serum total testosterone concentrations did not change significantly in either the metformin group (P=0.84) or the placebo group (P=0.53). Serum sex hormone–binding globulin concentrations increased in both the metformin group (from 2.0±0.2 to 2.7±0.3 µg per deciliter [69±7 to 93±10 nmol per liter], P= 0.01) and the placebo group (2.7±0.4 to 3.6±0.5 µg per deciliter [94±13 to 124±17 nmol per liter], P=0.06). As a result, serum free testosterone concentrations decreased in the metformin group, from 1.0±0.1 to 0.8±0.1 ng per deciliter (347±35 to 278±35 pmol per liter, P=0.07), and in the placebo group, from 0.8±0.1 to 0.6±0.1 ng per deciliter (278±35 to 208±35 pmol per liter, P=0.04).

Twelve of the 35 women (34 percent) in the metformin group ovulated spontaneously during treatment with metformin alone, as compared with only 1 of the 26 women (4 percent) in the placebo group (P<0.001). The mean peak serum progesterone concentration in the 12 women in the metformin group who ovulated was 13.0±1.0 ng per milliliter (41.6±3.2 nmol per liter). Two other women in the metformin group had peak serum progesterone concentrations between 4 and 8 ng per milliliter (12.8 to 25.6 nmol per liter) and were not included in the second phase of the study. Figure 1 shows the number of women who had serum progesterone concentrations above 8 ng per milliliter (indicative of ovulation) on days 14, 28, and 35 in the metformin and placebo groups.

View larger version (7K): [in this window] [in a new window]   Figure 1. Number of Women with a Serum Progesterone Concentration above 8 ng per Milliliter on Each Day of the Study on Which It Was Measured. During days 1 to 34 the women were treated with metformin or placebo alone. On day 35, ovulation induction with clomiphene was started while metformin or placebo was continued. Only women whose serum progesterone concentrations were less than 2 ng per milliliter throughout the first phase of the study were included in the ovulation-induction phase of the study.

 
Treatment with Clomiphene and Metformin or Placebo

Twenty-one women in the metformin group and 25 women in the placebo group continued into the second phase of the study, during which they received concurrent clomiphene treatment. The two groups had not differed on study day 0 with respect to the area under the serum insulin curve (6745±2021 µU per milliliter per minute [40.5±12.1 nmol per liter per minute] in the group given metformin and clomiphene, as compared with 6574±1072 µU per milliliter per minute [39.4±6.4 nmol per liter per minute] in the group given placebo and clomiphene; P=0.83), but on day 35, before clomiphene treatment was started, this value was significantly lower in the group given metformin and clomiphene (P=0.03) (Table 2). The difference was due to a 48 percent decrease (P=0.03) in the value in the 21 women in the group given metformin and clomiphene between days 0 and 35, from 6745±2021 to 3479±455 µU per milliliter per minute (40.5±12.1 to 20.9±2.7 nmol per liter per minute). On day 35 the two groups did not differ with respect to history of clomiphene treatment, anthropometric variables, or biochemical values (Table 2).

View this table: [in this window] [in a new window]   Table 2. Characteristics of Women with the Polycystic Ovary Syndrome on Initiation of Ovulation Induction with Clomiphene after the Administration of Metformin or Placebo for 35 Days.

 
Nineteen of the 21 women (90 percent) who received combined metformin and clomiphene ovulated; the mean peak serum progesterone concentration in these 19 women was 23.8±3.4 ng per milliliter (76.1±10.9 nmol per liter). In contrast, only 2 of the 25 women (8 percent) in the group given placebo and clomiphene ovulated (P<0.001); 2 other women in this group had serum progesterone concentrations between 4 and 8 ng per milliliter. Figure 1 shows the number of women who had serum progesterone concentrations above 8 ng per milliliter on days 44 and 53 in the two groups.

Discussion

We conducted this study to determine whether decreasing insulin secretion in obese women with the polycystic ovary syndrome would facilitate the induction of ovulation by clomiphene. We found that treatment with metformin, but not placebo, significantly decreased the serum insulin response to oral glucose administration. Simultaneously with the reduction in serum insulin, the women given metformin had marked increases in both spontaneous ovulation and clomiphene-induced ovulation, as compared with the women given placebo. Thirty-one of the 35 women treated with metformin (89 percent) ovulated either spontaneously or in response to clomiphene, as compared with only 3 of the 26 women in the placebo group (12 percent). These findings support the idea that hyperinsulinemia impedes ovulation in obese women with the polycystic ovary syndrome and that decreasing insulin secretion facilitates both spontaneous ovulation and the induction of ovulation by clomiphene.

Our findings are consistent with those of previous studies that noted an increased frequency of menstruation or ovulation in women with the polycystic ovary syndrome during treatment with metformin^7,8,9 or troglitazone.^11,12 However, the specific effect of insulin reduction on ovulation was not assessed in those studies. In a recent study, several previously infertile women with the polycystic ovary syndrome who were treated with metformin for six months became pregnant.²⁷ However, the study was uncontrolled and was not specifically designed to monitor ovulation, and nearly half the women recruited did not complete the study. None of the studies examined the effect of the reduction in insulin secretion on the induction of ovulation by clomiphene.^{7,8,9,11,12,27}

To assess clomiphene-induced ovulation, we purposefully chose to administer a low daily dose of only 50 mg of clomiphene, because few obese women with the polycystic ovary syndrome would be expected to have a response to this dose.^13,15 For example, in a study of women with the polycystic ovary syndrome who weighed more than 91 kg (200 lb), 50 mg of clomiphene daily for five days resulted in an ovulatory rate of only 20 percent.¹⁵ The rate of clomiphene-induced ovulation was lower in our placebo group, most likely because half the women had not had a response to previous clomiphene therapy.

We chose to use metformin because several previous studies had documented its ability to decrease serum insulin in women with the polycystic ovary syndrome.^7,8,9,10,28 It is classified as a category B drug, which means that no teratogenic effects have been demonstrated in vitro. It is commonly given to premenopausal women with type II diabetes mellitus and simply discontinued when they become pregnant. Metformin was administered to a limited number of South African women with diabetes throughout their pregnancies,²⁸ and no teratogenic effects were reported. It is not known to influence hypothalamic, pituitary, or ovarian function independently, but this possibility cannot be ruled out.

There are two main limitations to our study. First, pregnancy was not an outcome measure, and we do not know whether the increased frequency of ovulation would be accompanied by an increased pregnancy rate or birth rate. Second, we do not know whether the improved ovulatory function in the women given metformin was due to a decrease in intraovarian androgen production, normalization of spontaneous or clomiphene-induced gonadotropin secretion, diminution of the potential direct effects of insulin on ovarian folliculogenesis, or a combination of these processes.

In summary, the frequency of spontaneous ovulation and ovulation induced by clomiphene can be increased in obese women with the polycystic ovary syndrome by decreasing serum insulin concentrations with metformin.

Supported by grants from the National Institutes of Health (R01HD35629 and R01CA64500 [to Dr. Nestler] and M01RR00847). Dr. Nestler is a consultant to Bristol-Myers Squibb, which manufactures metformin, and owns 300 shares of Bristol-Myers Squibb stock.

Source Information

From the Departments of Medicine at the Medical College of Virginia, Virginia Commonwealth University, Richmond (J.E.N.); Hospital de Clinicas Caracas, Caracas, Venezuela (D.J.J.); the University of Virginia, Charlottesville (W.S.E.); and the University of Bologna, Bologna, Italy (R.P.).

Address reprint requests to Dr. Nestler at the Medical College of Virginia, P.O. Box 980111, Richmond, VA 23298-0111.

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