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ShareMar. 31, 2008 — NIH-sponsored researchers have discovered that women who have polycystic ovary syndrome (PCOS) are less likely to ovulate in response to a promising new drug treatment for the condition if they have a variation in a particular gene.
The gene, known as STK (serine-threonine kinase) 11 is involved in controlling blood sugar levels. Along with infertility and cyst-like structures in the ovaries, women with PCOS often have insulin resistance, a pre-diabetic condition in which higher-than-normal amounts of insulin are required to reduce blood sugar levels.
Because the drug metformin lowers blood sugar levels, researchers have studied it as a treatment for the infertility associated with the condition. However, the results of these studies were conflicting.
"The current study offers a possible explanation for the conflicting results seen by the numerous research teams who studied metformin as a treatment for polycystic ovary syndrome," said Duane Alexander, M.D., director of the NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development, which provided much of the funding for the study. "This finding is the first step in the development of a test that can distinguish women who are likely to benefit from the treatment from those who are not."
The study was conducted by a team of researchers from the NICHD Reproductive Medicine Network, who were led by Richard S. Legro, M.D., Professor of Obstetrics and Gynecology at the Penn State University College of Medicine.
PCOS is the leading cause of infertility in women, affecting 8 to 15 percent of American women of reproductive age, said Dr. Legro.
In addition to infertility, PCOS can also cause pelvic pain, excess hair growth and acne. Women who are obese are more likely to develop the syndrome. Women with PCOS are also at higher risk of other conditions like diabetes, heart disease and high blood pressure.
To conduct the study, Dr. Legro and his coworkers analyzed DNA from 312 women who participated in a larger study. That study compared the effectiveness of metformin to the drug clomiphene at helping women with PCOS achieve pregnancy.
In the current study, the researchers found that women were less likely to ovulate after receiving metformin if they had a particular variation of the gene for STK11. As with most genes, individuals have two copies of the STK11 gene. The women's response to metformin was dependent on how many copies of the variant gene they possessed. Of the possible combinations, women had either one variant together with one typical copy of the gene, two copies of the variant, or two typical copies of the gene.
Of the women with one copy of the variant STK11 gene, 67 percent ovulated in response to the treatment (32 women out of 48). For women with two copies of the variant gene, only 48 percent ovulated in response to the treatment (10 of 21). Of the women who did not have the variant gene, 79 percent (15 of 19) ovulated in response to metformin.
The researchers also found that women were less likely to ovulate if they had a higher body mass index (BMI). BMI, which takes into account a person's weight and height, is used to gauge whether an individual is overweight or obese.
Dr. Legro explained that the next step is to conduct a genetic analysis on a large sample of women, to try to find out how frequently the gene variant occurs in the population. Once the researchers find the prevalence of the gene, the next step would be to begin work on a test to distinguish women who would be unlikely to ovulate in response to metformin from those likely to ovulate.
The study was published on line in the Journal of Clinical Endocrinology & Metabolism. Additional funding for the study was provided by NIH's National Center for Research Resources.
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