|Standard Therapy More Effective Than Diabetes
Drug for Achieving Pregnancy in Common Fertility Disorder
Metformin, a drug used to treat diabetes and thought to hold great
promise at overcoming the infertility associated with polycystic
ovary syndrome (PCOS), is less useful for helping women with the
condition achieve pregnancy than is the standard treatment with
the infertility drug clomiphene, report researchers in an NIH research
This study is the largest, most comprehensive effort yet to compare
the two drugs in helping women with PCOS achieve successful pregnancy.
The finding appears in the February 8, 2007 issue of the New
England Journal of Medicine.
“The results of this study underscore the need to test any new
treatment rigorously, no matter how promising it may seem initially,” said
Duane Alexander, M.D., Director of the National Institute of Child
Health and Human Development, which supported the study, along
with the National Center for Research Resources. Both NICHD and
NCRR are part of NIH.
Polycystic ovary syndrome (PCOS) affects seven to eight percent
of women in the United States and may be the most common cause
of female infertility, the study authors wrote. With PCOS, an excess
of male hormones interferes with ovulation. The ovaries become
enlarged and fill with cysts. In addition to infertility, PCOS
symptoms include irregular menstrual periods, excessive body and
facial hair, acne, and obesity.
Women with PCOS frequently experience insulin resistance, a prediabetic
condition in which higher-than-normal amounts of insulin are required
to allow glucose to enter tissues. Earlier studies had shown that
drugs such as metformin, which make the body more sensitive to
insulin, could increase ovulation in PCOS patients. Similarly,
several smaller studies had suggested that metformin, alone or
when taken together with the drug clomiphene, could result in greater
fertility rates for PCOS patients than could clomiphene taken alone.
Clomiphene fosters ovulation by stimulating the release of hormones
needed for ovulation to occur.
To conduct the study, the researchers randomly assigned 626 infertile
women with PCOS to one of three groups, explained the study’s lead
investigator, Richard. S. Legro, M.D., of the Department of Obstetrics
and Gynecology at Penn State College of Medicine in Hershey, Pennsylvania.
The first group received clomiphene and a placebo, the second group
received metformin and a placebo, and the third group received
both metformin and clomiphene. The women took the treatments for
up to six months. The researchers tested the women’s levels of
the hormone progesterone to gauge when the women were ovulating.
The researchers found that fewer women in the metformin only group
had given birth than had women in either of the clomiphene groups.
In the metformin only group, 15 out of 208 women had given birth,
or 7.2 percent. In the clomiphene only group, 47 out of 209 women
had given birth, or 22.5 percent. In the combined clomiphene-metformin
group, 56 out of 209 women had given birth (26.8 percent). The
difference in the number of births between the clomiphene only
group and the combined clomiphene-metformin group was not statistically
significant. The researchers also found that, compared to the other
women in the study, obese women were less likely to conceive during
the course of the study and less likely to ovulate in response
The researchers noted that women in the combination therapy group
ovulated more frequently than did the women in either the clomiphene-alone
or the metformin-alone groups. However, the tendency to ovulate
more frequently did not translate into a significantly greater
number of pregnancies for the combination group.
Dr. Legro said that these findings were consistent with earlier
studies that also reported an increase in ovulation from the combined
therapy and that these early observations had led to researchers’ initial
enthusiasm for metformin as a potential treatment for PCOS. He
theorized that although the combination of the two drugs might
stimulate more cycles of ovulation than clomiphene alone, these
extra cycles might result in a higher number of eggs that are not
capable of fertilization or development.
“Our results show that you can’t use ovulation as a surrogate
for pregnancy,” Dr. Legro said “An ovulation on clomiphene treatment
is twice as likely to result in pregnancy as an ovulation on metformin,
thus all ovulations are not alike.”
The researchers also reported that women in the clomiphene groups
had more occurrences of multiple pregnancy: 6.4 percent for the
clomiphene-only group, 3.3 percent for the combination group and
0 percent for the metformin group. Clomiphene is known to stimulate
the release of more than one egg at a time. Dr. Legro noted that
the rate of multiple pregnancy seen in the study for women treated
with clomphene was less than the multiple pregnancy rate after
in vitro fertilization, which averages about 33 percent.
The study authors noted that while metformin alone did not improve
the chances for pregnancy, it was useful for lowering the high
blood testosterone levels that occur with PCOS.
“In summary, our study supports the use of clomiphene citrate
alone as first-line therapy for infertility in women with PCOS,” the
study authors wrote.
NCRR provides laboratory scientists and clinical researchers with
the environments and tools they need to understand, detect, treat,
and prevent a wide range of diseases. With this support, scientists
make biomedical discoveries, translate these findings to animal-based
studies, and then apply them to patient-oriented research. Ultimately,
these advances result in cures and treatments for both common and
rare diseases. Through collaborations and networks, NCRR connects
researchers with one another, and with patients and communities
across the nation. These connections bring together innovative
research teams and the power of shared resources, multiplying the
opportunities to improve human health. For more information, visit www.ncrr.nih.gov.
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.