Metformin hydrochloride, hereafter metformin, is a medication that doctors prescribe to treat type 2 diabetes, a condition where the body fails to respond effectively to the hormone insulin, leading to high blood sugar levels. In 1922, Emil Werner and James Bell, chemists working at Trinity College in Dublin, Ireland, were among the first to synthesize a compound with metformin’s modern chemical formula, namely dimethylbiguanide. At first, physicians didn’t recognize the compound’s ability to lower high blood sugar levels. However, the drug found other uses: physicians prescribed it to treat malaria and flu in the 1940s. Metformin as a treatment for diabetes became popular in the 1990s. In addition to type 2 diabetes, physicians also prescribe metformin to those with polycystic ovary syndrome, or PCOS, as some of its symptoms are similar to those of diabetes. Treating PCOS helps to reduce infertility caused by irregular or no ovulation. Metformin’s wide range of uses has helped hundreds of millions of people across the globe in managing diabetes, but also in treating PCOS and malaria.

In 1935, US-based physicians Irving Freiler Stein and Michael Leo Leventhal published “Amenorrhea Associated with Bilateral Polycystic Ovaries,” hereafter “Amenorrhea,” in the American Journal of Obstetrics and Gynecology based on their clinical experience with seven female patients. In their article, Stein and Leventhal report finding a correlation between a lack of menstruation for a prolonged period, or amenorrhea, in the women and the presence of bilateral polycystic ovaries, in which cysts form in both ovaries. Stein and Leventhal theorize that such cysts form due to hormonal imbalances, which makes their presence indicative of an endocrine, or hormonal, disorder. That explanation contested a widely held belief at the time that inflammation caused amenorrhea. “Amenorrhea” was one of the first publications to propose a hormonal explanation for bilateral polycystic ovaries and to describe the cluster of symptoms that became the basis for diagnosing what later became known as polycystic ovarian syndrome, or PCOS, an endocrine disorder that affects five to eleven percent of women globally per year.

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 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.

For women with polyendocrine metabolic ovarian syndrome, or PMOS, combination oral contraceptives are a first-line treatment. PMOS is a reproductive hormonal disorder that affects roughly one in ten women of reproductive age and causes symptoms such as an irregular menstrual cycle and hyperandrogenism, or an excess of male-typical hormones called androgens. Combination oral contraceptives are medications containing a mix of synthetic female hormones that women often use as a means of birth control. In the 1970s, researchers found that the synthetic female hormones in combination oral contraceptives can reduce excess androgens in women experiencing PMOS. Several medical conferences in the 1990s and early 2000s created a diagnostic standard for PMOS, which led to an increase in diagnoses across the world and expanded the number of women who were receiving combined oral contraceptives for PMOS management. By relieving hyperandrogenism, combination oral contraceptives help women manage the symptoms of PMOS and reduce their risk of long-term health problems.