|Gene Variation Predicts Response to Treatment
in Common Infertility Disorder
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
Additional funding for the study was provided by NIH's National
Center for Research Resources.
The study was published on line in the Journal of Clinical
Endocrinology & Metabolism.
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. The release describing the earlier
study is available at http://www.nichd.nih.gov/news/releases/pcos_treatments.cfm.
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
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 NICHD sponsors research on development, before and after birth;
maternal, child, and family health; reproductive biology and population
issues; and medical rehabilitation. For more information, visit
the Institute's Web site at http://www.nichd.nih.gov/.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.