Combination Oral Contraceptives for Treatment of Polyendocrine Metabolic Ovarian Syndrome

Editor’s note: Before 2026, polyendocrine metabolic ovarian syndrome, or PMOS, was known as polycystic ovary syndrome, or PCOS. We use the updated terminology here, but readers should be aware that older articles on the Embryo Project Encyclopedia use the term 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.

1. PMOS: Some Important Background
2. Combination Oral Contraceptives: How They Work
3. Combination Oral Contraceptives: History and Evolution
4. Connecting PMOS to Specific Hormonal Changes
5. Standardizing Diagnostic Criteria and Treatment
6. Impacts

PMOS: Some Important Background

The recognition that PMOS is a hormonal disorder, one that can be treated with contraceptives, came slowly. Researchers did not categorize PMOS beyond a cluster of unrelated symptoms until 1935. In that year, Irving F. Stein and Micheal L. Leventhal, physicians and researchers in endocrinology from the US, published a paper associating the symptoms of hirsutism, enlarged cystic ovaries, and irregularities in the menstrual cycle titled “Amenorrhea Associated with Bilateral Polycystic Ovaries.” Hirsutism is the presence of male-pattern hair growth in areas such as the face, chest, and back in women. In their article, Stein and Leventhal suggest that the mechanisms that cause the collection of symptoms they saw are hormonal in nature. Later research supported that hypothesis by showing that women with PMOS have high levels of androgens compared to women without PMOS.

As of 2026, researchers know that one main cause of the elevated androgens, or hyperandrogenism, characteristic of PMOS is the action of certain gonadotropins, or pituitary hormones that affect the reproductive system. Luteinizing hormone, or LH, is one of those hormones. LH is a hormone that, when present at high levels, triggers ovulation and stimulates the production of androgens in women. Ovulation is the phase of the menstrual cycle in which a mature egg is released from the ovary to be fertilized. Another gonadotropin, follicle-stimulating hormone, or FSH, stimulates the process of synthesizing estrogens from androgens. When one has a high level of LH and a low level of FSH, androgens do not convert to estrogen due to the lack of FSH. The androgens build up in the blood, and that can cause hyperandrogenism. Individuals with hyperandrogenism as a symptom of PMOS tend to have ratios of LH to FSH that are larger than what physicians consider normal.

Another factor that contributes to hyperandrogenism in women with PMOS is the levels of sex-hormone-binding globulin, or SHBG, in the blood. SHBG is a protein that binds to sex hormones, including androgens, which renders them inactive. The androgens that don’t bind to SHBG are free androgens, which can cause symptoms that accompany hyperandrogenism, including hirsutism. Those with PMOS tend to have lower levels of SHBG and higher levels of free androgens than what physicians consider normal. Hyperandrogenism is more dependent on the number of free androgens than total androgens.

Combination Oral Contraceptives: How They Work

Combination oral contraceptives have gone through several iterations since their first release in 1960, but they all contain progestin, or a synthetic hormone that imitates progesterone. Progesterone is a naturally occurring sex hormone, also categorized as a steroid hormone, that regulates the menstrual cycle and is present during early pregnancy. Progestin has a slightly different chemical composition than progesterone, but it functions similarly in the body. When a woman takes progestin without being pregnant, it exaggerates progesterone’s effects, ultimately causing the uterus to respond as it would during early pregnancy. During that stage, the uterus prevents sperm from reaching the uterus and LH levels decrease, which halts ovulation.

Some oral contraceptives contain only progestin, but combined oral contraceptives contain a combination of estrogen and progestin. In 1960, the first commercially available birth control pill, Enovid, was a combination oral contraceptive. Progestin-only pills appeared on the market in 1973. The mechanisms of contraception are similar between progestin-only and combination pills. However, combination pills can have antiandrogenic benefits for those with PMOS, as estrogen can help to address irregular menstruation cycles. Doctors do not recommend that women with medical histories of blood clots or high blood pressure take combination pills, as the estrogen makes one more prone to potentially fatal blood clots, so for them progestin-only pills are a better option.

Combination Oral Contraceptives: History and Evolution

The understanding that combined oral contraceptives could be useful in treating PMOS emerged in tandem with developments within endocrinology, or the study of hormones, and medicinal chemistry, beginning with work on progesterone. In 1943, Russell Marker, a researcher working at Pennsylvania State University in State College, Pennsylvania, synthesized the first progesterone from Mexican yams. He created a method of deriving that steroid hormone from the plants, although he was not aware of progesterone’s effects on pregnancy. He left Pennsylvania in 1943 and became the co-founder of a company called Syntex in Mexico City, Mexico, in 1944, which produced various steroid hormones, including progesterone, using his synthesis process. In 1951, Carl Djerassi, a researcher working in Mexico City at the same company, later created norethindrone, which was the first progestin. Syntex became a major distributor of synthetic steroid hormones in South America soon after Djerassi’s synthesis of progestin, as they were one of the only companies supplying steroids for birth control pills when the FDA approved of them in 1960. In 1953, chemist Frank Colton synthesized a different type of progestin, which he called norethynodrel, for G.D. Searle, a pharmaceutical company based in the US. Both Colton and Djerassi were aware of progestin’s role in treating irregular menstruation, which is why people used the medication at the time, but they were unaware of its contraceptive abilities.

Margaret Sanger helped bridge the gap between commercially available progestins and the creation of the first-ever combination birth control pill. Sanger was a nurse and birth control activist in New York from the 1910s until her death in 1966 who pushed for the creation of an oral contraception pill. Before she pursued activism, she spent most of her time as a nurse delivering infants in the lower-income parts of New York. Sanger witnessed several of her patients employ unsafe methods of abortion, which led to either significant bodily injury or death. When she worked there, people from those parts of New York requested contraception methods from Sanger, explaining that poverty was the reason for doing so. She left nursing in 1912 and started the first birth control clinic in the US in 1916, which influenced the creation of the Planned Parenthood Federation of America, or PPFA.

The path to the development of the first birth control pill started with the meeting of Sanger and Gregory Pincus, an independent scientist working in Massachusetts. Prior to meeting Sanger in 1951, Pincus conducted research on reproductive hormone regulation at an independent research institute he co-founded, the Worcester Foundation for Experimental Biology. After the two met and discussed the creation of a birth control pill, PPFA granted Pincus a small amount of money to perform research towards the development of a hormone-based oral contraceptive. Soon after, Sanger was able to secure Pincus a larger amount of funding in 1953 through Katherine McCormick, a friend of Sanger who was a member of the McCormick family. Pincus chose G. D. Searle’s progestin, as opposed to Syntex’s, to conduct research on potential options for birth control, and he helped G. D. Searle develop Enovid, the first birth control pill on the US market. Enovid became available to US consumers in 1957 as a medication for menstrual issues, such as irregular menstruation. In 1960, the US Food and Drug Administration, or FDA, approved Enovid for birth control purposes.

In the 1960s, researchers learned more about how Enovid works, including how it affects hormone profiles. In 1965, researcher Victor Alexander Drill published a review of those studies, titled “Endocrine Properties and Long-term Safety of Oral Contraceptives.” In the article, Drill highlights that, in studies that he conducted, Enovid worked to prevent pregnancy by inhibiting pituitary hormones that affect the uterus. Enovid did not affect the uterus’s tissue, solely the hormones that act on the uterus. In particular, Drill highlighted that Enovid lowered levels of the hormone LH. Lowering the level of LH means that there is no surge of LH that traditionally triggers ovulation, effectively preventing pregnancy.

Connecting PMOS to Specific Hormonal Changes

A shift in PMOS diagnostic criteria occurred in the late 1950s that linked LH levels with the disorder. Before the late 1950s, doctors studying PMOS mostly focused on observable physical symptoms, such as the presence of cysts in the ovaries, hirsutism, and infertility. Then, in 1957, William C. Keettel, a researcher working at University of Iowa Hospitals & Clinics, in Iowa City, Iowa, and his colleagues published a study that suggested the hormonal mechanism behind hirsutism. The researchers measured levels of LH in thirty-six women who did not have any symptoms and in thirteen women they suspected to have what the authors called Stein-Leventhal syndrome, an earlier name for PMOS. To do that, the researchers used a method called a bioassay, which is a measurement of the presence of certain chemicals in substances through their effect on living cells. The bioassay involved injecting the urine samples of the women into rats and observing if the rat’s physiological response to the injection was typical of an injection with a high amount of LH, which would show as an excess blood supply to the theta interna. The theta interna is the part of the ovary that produces androgens. Using that method, they noted that of the eleven women they suspected of having Stein-Leventhal syndrome, ten had elevated LH levels. According to Eli Adashi, a researcher in gynecology working at Brown University in Providence, Rhode Island, the correlation between Stein-Leventhal syndrome and an abnormally large LH to FSH ratio made in that article likely constituted the first suggestion of hormonal diagnostic criteria for PMOS.

In the 1970s, researchers in New York developed an alternative method to measure precise quantities of hormones called a radioimmunoassay, which helped to measure hormones such as LH, FSH, and SHBG. The ability of doctors to obtain exact measurements of hormones helped to create quantitative biochemical specifications for PMOS diagnostic criteria. Radioimmunoassays quantitatively measure hormones like LH and FSH, and proteins like SHBGs, by detecting the amount in a sample of blood. According to Adashi, the development of radioimmunoassays was useful for subsequent research about hormonal abnormalities associated with PMOS. In particular, radioimmunoassays allowed for landmark trials quantitatively measuring the abnormally high LH and FSH levels in those with PMOS. Adashi states that those trials then influenced different landmark trials measuring the abnormally low levels of SHBG in those with PMOS.

In 1974, William E. Easterling, a researcher studying PMOS at the University of North Carolina, Chapel Hill, in Chapel Hill, North Carolina, and his colleagues published the results of one of the first studies on the effect of combination oral contraceptives on the symptoms of those with PMOS. By that time, there were several studies supporting the case that SHBG is abnormally low in those with PMOS. To address that, Easterling and his colleagues prescribed combination oral contraceptives to subjects with symptoms of PMOS and healthy subjects. Thirty-nine women participated in the study, fifteen with PMOS and twenty-four without PMOS. The researchers gave all women combination oral contraceptives and completed radioimmunoassays to determine the contraceptives’ effects on levels of an androgen called testosterone. Easterling and his colleagues found that, in women with PMOS, the amount of SHBG increased by four, whereas for healthy women, the amount of SHBG increased by two. That suggested that the combination birth control pill was helpful in reducing hyperandrogenism in PMOS patients. While that study did not standardize the use of combination contraceptives as a treatment for PMOS, it was among the first studies to support its use as treatment.

Standardizing Diagnostic Criteria and Treatment

Developments in PMOS diagnostic criteria helped facilitate the widespread use of combined oral contraceptives as treatment. According to Jacob P. Christ, a physician and researcher studying reproductive endocrinology in San Francisco, California, a 1990 conference at the National Institutes of Health, or NIH, was the first national conference in the US with the primary goal of reaching an agreement amongst physicians and researchers in endocrinology and gynecology on the diagnostic criteria for PMOS. The consensus from the conference was that two criteria were necessary to diagnose someone with PMOS. Those were clinical evidence of hyperandrogenism, which often involves a biochemical analysis using radioimmunoassay, and ovulatory dysfunction, which is irregular or absent ovulation that often affects the patient’s fertility. Those criteria further solidified the hormonal mechanisms behind the disorder. With the specified criteria, diagnoses of PMOS increased after the conference. From 1990 to 2021, the number of women diagnosed with PMOS across the world went from around thirty-five million to around sixty-five million.

Although researchers and physicians had documented the effectiveness of combination oral contraceptives in treating those with PMOS decades before, it was only in 2013 that a national organization suggested it officially as a first-line treatment. In the 2013 publication “Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline,” from the Endocrine Society, the authors, who consisted of physicians and other scientists with clinical expertise in PMOS, asserted that combined oral contraceptives should be a first-line treatment addressing the irregular menstruation and hyperandrogenism present in those with PMOS. Its suggestion of oral contraceptives for PMOS treatment codified their usage as a first-line treatment for the first time by a national organization.

Impacts

Oral contraception continues to be a first-line treatment for PMOS in 2026. In 2023, the American Society for Reproductive Medicine published an updated version of their international guidelines for treatment, having published the first version in 2018, and they continue to recommend combined oral contraceptives to treat hyperandrogenism and an irregular menstrual cycle. But, while physicians still consider it to be a first-line medication, some researchers point out certain side effects of the treatment for those with PMOS. In particular, Marco Calcagno, a researcher working at Santo Spirito Hospital in Rome, Italy, and his colleagues published an article in 2024 calling for the consideration of both risks and benefits of taking oral contraceptives. Calcagno and his colleagues also point out that contraceptives often only address the symptoms of the disorder, rather than the root cause. They highlight that while contraceptives are useful for regulating some symptoms, those with PMOS often have other symptoms, such as insulin resistance, that contribute to a higher risk of complications such as thromboembolism. Thromboembolism is when blood clots form in blood vessels and prevent blood flow to other parts of the body, which can be fatal. Researchers suggest that patients with insulin resistance take an inositol supplement, to address that aspect of the disorder.

As of 2026, physicians continue to prescribe combined oral contraceptives to treat the symptoms of PMOS, but some also critique that symptom-based approach, instead pushing for a more holistic approach to treatment.

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