Irving Freiler Stein Sr. was a physician who studied women’s reproductive health during the twentieth century in the United States. In partnership with his colleague, Michael Leventhal, Stein identified a women’s reproductive disorder related to elevated male sex hormones, or androgens. The syndrome was originally called Stein-Leventhal syndrome and later known as polycystic ovarian syndrome. While studying the syndrome, Stein also helped establish a treatment for the condition, through the surgical removal of ovarian tissues. Stein identified the symptoms related to the condition polycystic ovarian syndrome, a hormonal imbalance estimated to be the most common female reproductive disorder as of 2017.

Amenorrhea is considered a type of abnormal menstrual bleeding characterized by the unexpected absence of menstrual bleeding, lasting three months or longer. Menstrual bleeding typically happens approximately once a month when blood and endometrial tissue, or tissue lining the inside of the uterus, sheds from the uterus through the vagina. Menstruation is expected to stop with pregnancy, breastfeeding, and menopause, or the natural cessation of the menstrual cycle at an older age. However, women may also experience amenorrhea because of an underlying health condition, including low body weight or polycystic ovarian syndrome, that may complicate fertility and contribute to decreased quality of life. According to the American College of Obstetricians and Gynecologists, one in twenty-five women experience amenorrhea as a menstrual disorder within their lives at times.

In 1958, Irving Freiler Stein Sr. published “The Stein-Leventhal Syndrome: A Curable Form of Sterility” documenting his findings on the diagnosis and surgical treatment of Stein-Leventhal syndrome. Stein-Leventhal syndrome, later called polycystic ovarian syndrome (PCOS), affects the reproductive health of women. Common symptoms include excess body hair, a lack of menstrual cycle or amenorrhea, and infertility. As of 2017, polycystic ovarian syndrome is considered the most common reproductive health disorder among women in the United States. In his article, Stein argued that the means of treating infertility and menstruation issues in women with Stein-Leventhal syndrome prior to the 1950s were inferior to surgical removal of ovarian tissue. “The Stein-Leventhal Syndrome: A Curable Form of Sterility” offered a brief view of Stein’s findings over his three decades of research on the syndrome and his opinion on why surgery was the only means of treating the syndrome. The paper’s conclusions allowed later physicians to further their research on the uses of other surgical techniques and medicine to aid in treating the symptoms of the syndrome.

Polycystic ovarian syndrome or PCOS is one of the most common reproductive conditions in women, and its symptoms include cystic ovaries, menstrual irregularities, and elevated androgen or male sex hormone levels. During the 1930s, Irving Freiler Stein and Michael Leventhal identified the syndrome and its symptoms. Women who experience symptoms of PCOS may also experience secondary symptoms, including infertility and diabetes. Though estimates vary and the causes of the syndrome are not clear as of 2017, PCOS affects approximately ten percent of women of reproductive age. Women who suspect they have symptoms of PCOS should see a doctor, as early treatment may help prevent long-term implications such as infertility, diabetes, and some types of cancers.

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 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.