Recent research has begun to shed light on the genetics behind polycystic ovary syndrome (PCOS), paving the way for potential new therapies.

PCOS affects up to 20% of women, leading to disrupted ovarian function characterized by at least two of the following: irregular or absent periods, elevated male hormones like testosterone, and the accumulation of immature eggs within cyst-like ovaries. Consequently, it can result in fertility challenges.

While the exact causes remain unclear, PCOS is believed to correlate with changes in the gut microbiome and hormonal imbalances during prenatal development. The condition also appears to have a hereditary component, with studies indicating that 70% of the risk is genetic. However, researchers have only pinpointed about 25 genetic mutations impacting sex hormone production and ovarian function, explaining roughly 10% of an individual’s risk.

To address this knowledge gap, Qiao Shigang and colleagues at Shandong University in Jinan, China, conducted a genomic study involving over 440,000 women from China and Europe, out of which 25,000 were diagnosed with PCOS, marking the largest gene analysis related to the condition to date.

The researchers discovered 94 genetic variants that appear to contribute to PCOS risk, with 73 being previously unrecognized. Notably, one mutation affects the gene responsible for the mitochondrial ribosomal protein S22, essential for mitochondrial function, an area that Zhao points out has connections in earlier studies discussing the link between PCOS and mitochondrial dysfunction.

Another newly identified variant impacts sex hormone-binding globulin, a protein that moderates the activity of sex hormones and is often found at reduced levels in women with PCOS.

Several of the remaining variants influence the function of granulosa cells in the ovaries, responsible for producing estrogen and progesterone and aiding in egg development during the menstrual cycle. This supports the hypothesis that PCOS is genetically influenced by fluctuations in sex hormone levels, according to Zhao.

In summary, the research indicated that these 94 mutations account for around 27% of the risk variation in PCOS among European participants and about 34% in the Chinese cohort.

“This study is significant because it enhances our understanding of the genetic factors associated with this condition,” remarks Elisabeth Stenner-Victorin from Karolinska Institutet, Sweden. Furthermore, it underscores the necessity of including diverse ancestral backgrounds in PCOS genetic research, according to Zhao.

Ultimately, the team identified medications that could modify the pathways affected by the recognized mutations. Some of these, like clomiphene, are already used for PCOS treatment; they stimulate ovulation which is often hampered by the syndrome. Additionally, the team discovered that betaine—sometimes utilized for homocystinuria treatment—might also benefit PCOS patients. Future studies using mice exhibiting PCOS-like symptoms could explore this treatment potential.

“Current treatments focus on alleviating symptoms, as there aren’t any medications that can cure PCOS,” states Stenner-Victorin. Typical interventions include clomiphene, contraceptive pills to manage periods, and metformin, a type 2 diabetes medication that may enhance fertility. However, effectiveness varies among individuals. “Identifying genetic clusters that affect PCOS risk will be essential for developing more targeted treatment strategies for these women,” she adds.