Trial Information

Effects of Metformin on Fertility and Pregnancy in Women With Polycystic Ovary Syndrome: a Randomized, Prospective, Placebo-controlled Multicenter Study

Women with PCOS represent about 5-10% of the general female population and one third of the
women treated for infertility. Thus, the development of new therapies to improve the
efficiency of ovulation induction treatments and the outcome of pregnancy, and to reduce the
long-term risks of the syndrome would bring important health benefits.

The central role played by insulin resistance and hyperinsulinemia in PCOS - causing
hyperandrogenism, premature follicular atresia, anovulation, oligo-amenorrhea and
anovulatory infertility - has led to the use of insulin-lowering drugs for the treatment of
this syndrome. The most studied agent is metformin, a biguanide antihyperglycemic drug used
to treat Type 2 diabetes mellitus. It has been shown to improve significantly
hyperinsulinemia and insulin resistance, to decrease androgen levels, and to improve
menstrual pattern and, alone or in addition to clomiphene citrate, to induce ovulation and
improve pregnancy rates in women with PCOS in some studies (1,2). Metformin may also
decrease risks of early spontaneous miscarriage and gestational diabetes in PCOS (3-6). Two
recent RCTs, however, have shown no beneficial effect of metformin compared to placebo as
regards rates of pregnancy, miscarriage or life births in women with PCOS (7,8).

Our hypothesis is that metformin may improve pregnancy rates and decrease miscarriage
occurrence and complications of pregnancy, such as toxemia and gestational diabetes, in
women with PCOS. This multicenter randomized placebo-controlled study is conducted in all
five University Hospitals of Finland (Oulu, Kuopio, Helsinki, Tampere and Turku). Blood
samples are drawn and the oral glucose tolerance test (OGTT) done before and at 3 months of
treatment, after which the treatment with placebo/metformin is continued another 6 months'
period together with the appropriate infertility treatment. If pregnancy occurs, the OGTT is
done at 7-8 weeks of pregnancy and the placebo/metformin treatment is continued until 12
weeks of pregnancy. The study has already started and is estimated to continue at least
until the end of 2009. Power analysis indicated that a minimum of 60 pregnant patients are
needed in each group to decrease the risk of miscarriage from 44% to the normal 15%.