Effects of Metformin on Spontaneous and Clomiphene-Induced Ovulation in the Polycystic Ovary Syndrome by John E. Nestler, Daniela J. Jakubowicz, William S. Evans, and Renato Pasquali

In 1998, physician John E. Nestler and colleagues published “Effects of Metformin on Spontaneous and Clomiphene-Induced Ovulation in the Polycystic Ovary Syndrome,” hereafter “Metformin,” in the New England Journal of Medicine. Polycystic ovary syndrome, or PCOS, is an endocrine, or hormone-related, disorder that affects one in ten women of reproductive age, is characterized by symptoms such as an irregular menstrual cycle and high androgen levels, and can lead to infertility, or the inability to become pregnant. In the article, the authors report on the results of a randomized control trial they conducted in which they administered the insulin-lowering medication metformin to a group of thirty-five obese infertile female patients with PCOS, and compared them to twenty-six similar women receiving a placebo, to see if metformin could improve spontaneous or drug-induced ovulation rates. They found that it could. As of 2026, “Metformin” is one of the most cited articles supporting metformin’s usage as a second-line treatment for infertility in women with PCOS.

PCOS: Some Relevant Background

As a hormonal disorder, PCOS often leads to insulin resistance, or when the body is less responsive to insulin. Insulin is a hormone produced by the pancreas that regulates glucose, or blood sugar, levels in the body. While the presence of insulin resistance isn’t necessary for a diagnosis of PCOS, it is a prevalent symptom. Insulin resistance is often accompanied by hyperinsulinemia, or when the body produces extra insulin to compensate for reduced insulin sensitivity. Individuals with PCOS who exhibit hyperinsulinemia tend to have complications with weight management and a high risk of developing prediabetes. That is why insulin resistance and hyperinsulinemia are symptoms of the disorder that are more common in obese or overweight individuals.

Nestler and his collaborators hypothesized that elevated insulin levels may impede the function of medications, such as clomiphene citrate, which doctors prescribe to treat infertility. As of 2026, clomiphene as a first-line treatment for those with PCOS who experience infertility. The medication helps women ovulate, which is a stage of the menstrual cycle when an egg cell is released from the ovary to the uterus, where it is able to be fertilized. Successful ovulation is not necessarily indicative of whether or not a woman will be able to conceive and give birth without complications. Nevertheless, many women who are infertile and have PCOS do not ovulate regularly or at all. Inducing ovulation with medication allows for a greater chance of conceiving and giving birth. The authors hypothesized that metformin, a drug known to help control blood sugar and increase insulin responsiveness in people with diabetes, might help women with PCOS respond better to clomiphene.

One reason why women with PCOS may not ovulate regularly is because they tend to have high levels of androgens circulating in their blood, termed hyperandrogenism. Hyperandrogenism disrupts regular ovarian function, which can lead to not only irregular menstrual cycles, but also to irregular ovulation cycles. To better understand the role of hyperandrogenism in the women, Nestler and his colleagues measured serum hormone binding globulin, or SHBG. SHBG is a hormone found in blood that binds to sex hormones, rendering them inactive. Androgens in their active, unbound form are what causes hyperandrogenism. Because total androgen levels are not consistent indicators of hyperandrogenism, the study authors measured both SHBG-bound androgen and total androgen levels to evaluate the relationship between the number of inactive androgens, total androgens, and the physical symptoms of hyperandrogenism.

Author Background and Study Context

At the time of publication, Nestler was a physician with a focus in obstetrics and gynecology, or the medical subfield concerned with female reproductive health, and in endocrinology at the Medical College of Virginia in Richmond, Virginia. In the 1990s, he researched hyperinsulinemia and its association with hyperandrogenism in women with PCOS. He often collaborated with Daniela J. Jakubowicz on that research. At the time of publication, Jakubowicz was a physician in internal medicine at the Hospital De Clinicas Caracas in Caracas, Venezuela. The other co-authors of “Metformin” are William S. Evans and Renato Pasquali, who at the time were physicians studying metabolism and endocrinology at the University of Virginia in Charlottesville, Virginia, and the University of Bologna in Bologna, Italy, respectively.

In the 1980s, researchers started to recognize that some women with PCOS were exhibiting metabolic symptoms, namely insulin resistance and hyperinsulinemia. The researchers observed those symptoms to be more prevalent in women with PCOS who were obese, which made sense because insulin resistance and hyperinsulinemia promote fat storage rather than usage. During the late 1990s, a few researchers had published studies in support of using metformin to manage those symptoms. For example, in 1994, one study titled “Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy” by researchers at the University of the Andes in Merida, Venezuela, and the Cholesterol Center of the Jewish Hospital of Cincinnati in Cincinnati, Ohio, found metformin effective at addressing the metabolic aspect of the disorder. The authors of “Metformin” cite those studies and point out that not many studies had looked at whether metformin could help support regular ovulation in obese women with PCOS. In a previous article published in 1996, the two main authors, Nestler and Jakubowicz, suggest that insulin resistance can exacerbate hyperandrogenism, and that in turn negatively affects ovulation.

Detailed Breakdown of the Article’s Contents

“Metformin” contains four sections. In an untitled introduction section, the authors state their hypothesis that metformin will facilitate ovulation in obese women with PCOS. In “Methods.” the researchers describe the study participants, who were sixty-one obese women with PCOS. They then explain that they administered metformin or a placebo to all subjects at first. If the subjects did not spontaneously ovulate in thirty-four days, the researchers administered clomiphene alongside metformin or the placebo. Throughout the study, they took blood samples to check for hormonal responses to the medication. In the next section, titled “Results,” the researchers compare the differences in serum insulin, or insulin in the blood, and sex hormones between the group that received only metformin or a placebo, and the group that received metformin or a placebo and clomiphene, at different time intervals in the study. In “Discussion,” they conclude that addressing the hyperinsulinemia in obese women with PCOS helps to facilitate ovulation.

In the untitled introduction, the physicians note that chronic anovulation due to PCOS affects around six percent of women of reproductive age, and they note that it is the most common reason for infertility in women in the US. They then suggest that there is likely a correlation between insulin resistance and hyperandrogenism, as studies show that androgen levels decrease in women with PCOS when insulin levels are decreased. The authors note that there is not much research studying the correlation between metformin usage and the reduction of infertility. They mention how obese women with PCOS who experience infertility often need higher doses of clomiphene compared to their non-obese counterparts in order to induce ovulation. They suggest that the reason for that phenomenon is because hyperinsulinemia exacerbates hyperandrogenism, which adds another layer that makes ovulation more difficult. That leads them to hypothesize that reducing the levels of insulin in the women will allow for spontaneous ovulation or for the proper functioning of clomiphene.

The researchers split the second section, “Methods,” into four subsections, starting with “Subjects,” where they introduce the criteria that the subjects had to meet. The subjects were patients at the hospitals where the authors worked. The women who participated in the study were obese according to the body mass index, or BMI, which is a method of measuring body fat based on body weight and height. The subjects also had oligomenorrhea and elevated levels of androgens in the serum samples the physicians took via blood test at the beginning of the study. Oligomenorrhea is when a woman has infrequent menstrual periods due to larger gaps between menstrual cycles. Typically, physicians consider twenty-eight to thirty-five days in between cycles to be normal, but those with oligomenorrhea may have longer gaps between menstrual cycles. That means women who have oligomenorrhea tend to have fewer cycles throughout the year. The researchers do not explicitly state that the subjects were anovulatory, but oligomenorrhea accompanied with PCOS often suggests infertility.

The next subsection, “Experimental Protocol,” elaborates on how the subjects were separated into metformin and placebo groups and evaluated after 53 days to determine metformin’s efficacy. The researchers note that the women were at a similar stage in their menstrual cycle, which they determined by measuring serum for levels of progesterone, a hormone that regulates the menstrual cycle and prepares the uterus for pregnancy. The day before the study started, the researchers measured the subjects’ serum to determine levels of insulin, glucose, sex hormones, and SHBG. The physicians then state that the experiment involved two groups: an experimental group and a placebo group. In the experimental group, the women took 500 milligrams of metformin orally three times daily, and in the placebo group, the women took a placebo pill three times a day as well. Both groups continued that regimen for fifty-three days. There were thirty-five women in the metformin group and twenty-six in the placebo group. Nestler and his colleagues measured serum progesterone levels three times throughout the study to check for ovulation, as higher progesterone levels are indicative of ovulation. They gave fifty milligrams of clomiphene alongside the metformin or the placebo to those who did not ovulate after the first thirty-four days. They did so to test if the clomiphene would have a different response than it has traditionally had for obese women with insulin resistance, now that the subjects’ insulin levels had decreased.

In the “Results” section, Nestler and his colleagues use subsections to describe the measurements they took of each group with varying treatments. In the subsection “Treatment with Metformin or Placebo Alone,” they first address the group that received metformin or a placebo but did not receive clomiphene. In those who received metformin from that group, the serum insulin decreased by forty-three percent, while the researchers deemed the change in serum insulin for those who received the placebo insignificant. While the levels of total serum testosterone didn’t change, the levels of SHBG increased in the metformin group by thirty-five percent and in the placebo group by thirty-one percent. Because SHBG binds to free hormones in the blood, the levels of active serum testosterone decreased in both groups, decreasing by twenty percent in the metformin group and twenty-five percent in the placebo group. On day thirty-four, the researchers note that twelve of the women from the metformin group ovulated spontaneously, or without further medication, while only one from the placebo group ovulated spontaneously. At that point, the researchers stopped treatment for those who began to ovulate and started the second phase of the study.

The next subsection in the “Results,” “Treatment with Clomiphene and Metformin or Placebo,” describes the second phase of the study, in which the researchers gave fifty milligrams of clomiphene daily to the women who did not spontaneously ovulate. They continued administering metformin and placebo treatments. They first note that, at the start of the second phase, the metformin group had decreased levels of serum insulin compared to the placebo group. By the end of the second phase of the study, which lasted nineteen days, nineteen women from the clomiphene and metformin group ovulated, and two women from the clomiphene and placebo group ovulated.

In the “Discussion” section, the physicians highlight that the metformin treatment was effective at reducing serum insulin levels and facilitating ovulation in thirty-one of the thirty-five total subjects in that group. The placebo group did not demonstrate comparable ovulation rates, as only three subjects from the group ovulated during the study. Nestler and his colleagues note that while there have been studies exploring the relationship between metformin usage and return of ovulation or a regular menstrual cycle, there had not been a study that explored the mechanism behind that change, namely how insulin levels affect the ability for ovulation to occur. They then mention that they administered a smaller dosage of clomiphene in the group that moved onto the second phase of the study than physicians traditionally prescribe. They explain that the reason for that decision was to compare their results with previous studies that displayed lower ovulation rates with clomiphene usage in obese women experiencing infertility with the same, smaller dosage. The researchers attribute the increased ovulation rates in their study to metformin usage.

In the “Discussion” section, the researchers address some limitations of the study. The first limitation they mention is that while they measured whether or not the subjects were ovulating, they did not look at whether or not the women got pregnant after ovulation. Ovulation is not the only factor determining whether women are able to conceive or have a safe pregnancy if they are able to conceive. The researchers also mention that they still do not know what exactly allowed the subjects to ovulate. They state that they are unsure if it was due to the decrease in production of androgens, the decrease in insulin, an increase in production of hormones that regulate the menstrual cycle, or a combination of them.

Impacts

As of 2026, “Metformin” has around 1,200 citations according to Google Scholar. One of those citations includes the “Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS),” which is a report from the 2003 international conference for PCOS, sponsored by the American Society for Reproductive Medicine and the European Society for Human Reproduction and Embryology, in Rotterdam, Netherlands. According to Jacob P. Christ, a researcher in reproductive endocrinology, those diagnostic guidelines serve as a standard for physicians to diagnose PCOS, and it has around 6,800 citations as of 2026. While there was limited mention of treatments, as the researchers focused on diagnostic criteria, the report referred to “Metformin” as a landmark clinical trial in the development of treatment for PCOS, which means that it was an important trial that affected the trajectory of treatment for women with PCOS.

After the conference, a 2003 systematic review of multiple studies on metformin’s efficacy in treating infertility, titled “Metformin in polycystic ovary syndrome: systematic review and meta-analysis,” supported Nestler and his colleagues’ findings. A systematic review is a method of analyzing a group of studies asking similar questions. In the systematic review, alongside “Metformin,” there were six other studies that the researchers included. The authors of the systematic review, Jonathan M. Lord, Robert J. Norman, and Ingrid H. K. Flight, who are physicians in reproductive health, and a researcher in public health, respectively, state that the results they obtained support the use of metformin as a first-line medication for PCOS. As of 2026, the article has around one-thousand citations.

In 2007, another systematic review of studies in metformin’s efficacy in treating fertility, titled “The role of metformin in polycystic ovary syndrome: a systematic review,” provided support for Nestler and his colleagues findings, but suggested that metformin should not be a first-line treatment for infertile women with PCOS. The authors, Etelka Moll, Fulco van der Veen and Madelon van Wely, are researchers in reproductive endocrinology from the University of Amsterdam, in Amsterdam, Netherlands. While they observe that the studies they include support a higher birth rate among women who took metformin to induce ovulation, they note that there was no evidence favoring metformin over clomiphene. The researchers argue that clomiphene should continue to be a first-line treatment, and state that metformin is a useful medication to take alongside clomiphene for those who are clomiphene-resistant. As of 2026, that article has around 300 citations.

The first official guideline on PCOS treatment, published in 2013, reflects the shift from understanding metformin as a first-line treatment, to more of a second-line treatment for infertility. In the guideline, the researchers report that clomiphene is a first-line treatment, and that metformin does not show as much efficacy in treating infertility as clomiphene. As of 2026, the American Society of Reproductive Medicine, an international nonprofit reproductive research organization, continues to uphold the recommendation that physicians should prescribe metformin as a second-line infertility treatment.

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