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Genetic Variant Linked to Polycystic Ovary Syndrome Treatment Response

NEW YORK (GenomeWeb News) – New research suggests that at least one genetic variant influences whether women with polycystic ovary syndrome ovulate while taking a drug called metformin.

Researchers in the National Institute of Child Health and Human Development Reproductive Medicine Network analyzed DNA samples from women with PCOS who were taking one of two drugs — or a combination therapy — to look for SNPS linked to better treatment response. They found a genetic variant that roughly predicted whether women ovulated while taking one of the drugs, metformin.

The results, published in the March issue of the Journal of Clinical Endocrinology and Metabolism, may eventually lead to personalized PCOS treatments, especially for women who are trying to conceive  

PCOS is an endocrine disorder often characterized by numerous cysts on the ovaries, excessive masculinizing hormones, and insulin resistance — the need for more insulin than usual to decrease blood sugar levels. Common symptoms include irregular menstrual periods, acne, excess hair growth, and obesity. PCOS is also a leading cause of infertility and can contribute to long-term complications such as heart disease, diabetes, and endometrial cancer.

Although it affects roughly eight to 15 percent of American women, PCOS is poorly understood and — due to the wide range of symptoms and severity — there is no universal treatment. Clomiphene citrate, a drug that triggers the release of some hormones; metformin, a drug that increases insulin sensitivity and lowers blood sugar levels; and combinations of the two are among the treatment options, particularly for those trying to induce ovulation and increase fertility.

Even so, these drugs are not always effective. For instance, in a multi-center, randomized, double-blind clinical trial of 626 PCOS women, lead author Richard Legro, a reproductive endocrinologist at Pennsylvania State University, and his colleagues found that many women — between about a quarter and 45 percent — did not ovulate while taking one or both drugs over the course of the study, which lasted up to seven and a half months.

In an effort to determine whether specific genetic variations are associated with good treatment outcomes, the team looked for polymorphisms in a subset of 312 PCOS women.

Specifically, they evaluated SNPs in a set of candidate genes with anticipated effects on drug response: ESR1, an estrogen receptor 1 gene; two genes, CYP2C9 and CYP2D6, coding for cytochrome P450; and STK11, a serine-threonine kinase gene expressed in the liver. They also looked for a previously identified PCOS microsatellite marker in a fibrillin 3 gene called FBN3.

Overall, the researchers reported that about 63 percent of women ovulated when taking metformin alone. In contrast, about 85 to 86.6 percent ovulated while taking clomiphene alone or both metformin and clomiphene in combination. The number of ovulations per subject, on average, was also highest in those receiving the combination treatment.

Interestingly, though, the researchers detected a negative association between a specific C allele in STK11 and ovulation within the metformin alone treatment group. Those who had two copies of the C allele were least likely to ovulate while taking metformin, while those with two copies of the G allele instead were most likely to ovulate.

A full 79 percent of G/G women ovulated, compared to 48 and 67 percent of C/C and C/G women, respectively. The team also saw a similar trend, though not statistically significant, in the clomiphene-alone group.

Though they note that the results need to be verified in larger trials, the authors and others say this work may pave the way for more personalized PCOS treatments.

“This finding is the first step in the development of a test that can distinguish women who are likely to benefit from the [metformin] treatment from those who are not,” Duane Alexander, director of the NICHD, one of the funding agencies for the study, said in a statement.

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