Feb. 14, 2001 St. Louis, Feb. 8, 2001 — There may be new hope for women who are infertile due to polycystic ovary syndrome (PCOS). A study published in the February issue of the journal Fertility and Sterility reveals that the drug metformin, when combined with the commonly used fertility drug clomiphene citrate, increases ovulation and the likelihood of pregnancy in patients who are unresponsive to clomiphene alone. The study was a joint effort between researchers from four medical centers, including Washington University School of Medicine in St. Louis.
Four percent to 6 percent of reproductive-age women suffer from PCOS, a condition that prevents regular ovulation. Many of these women ovulate so infrequently that conception is extremely challenging. Clomiphene citrate is a pill that has been used with relative success – about two-thirds of women who take the pill ovulate, and roughly one-third become pregnant. For those who do not respond, the only viable alternatives today are surgery and injectable fertility drugs, both of which have potentially dangerous side effects.
"We don’t want to cause dangerous situations in women who are otherwise very healthy," says Valerie S. Ratts, M.D., an assistant professor of obstetrics and gynecology at the School of Medicine. "It would be nice to have an alternative way to treat these women safely and effectively."
Research suggests that many of these women also have a type of insulin resistance similar to that seen in type 2 diabetes. The body produces excess insulin to ensure that all cells are sufficiently fueled. Researchers believe that increased levels of insulin may interrupt normal communication between the pituitary gland and the ovary.
"Normally, the ovary and pituitary glands talk to each other," explains Ratts. "We think that insulin interferes with the signals, like static. So maybe we should be attacking this problem by helping these women lower their insulin levels to get the cells to work properly." Once insulin levels are in balance, she says, patients may be more responsive to clomiphene citrate.
She and her colleagues tested the potential of metformin, a drug widely used to treat patients with type 2 diabetes. Women with infertility due to PCOS who were resistant to clomiphene citrate were randomly assigned to either an experimental group or a control group. Each patient in the experimental group received 500 mg of metformin three times a day for seven weeks. She then continued to take metformin and also was given 50 mg of clomiphene citrate a day. If she did not ovulate, the dose of clomiphene citrate was increased by 50 mg for the next cycle, up to 150 mg. Patients continued this pattern for six months or until they became pregnant.
Women in the control group received an inert substance instead of metformin but followed the same dosage and procedure for clomiphene citrate.
Of the 11 participants who received metformin, eight ovulated and six became pregnant. Of the 14 participants who received the inert substance, only three ovulated and one conceived. Therefore both ovulation and conception were significantly more likely in the experimental group than in the control group.
"By using metformin in PCOS patients, we decreased insulin levels so the ovaries could function more normally and therefore could respond to clomiphene citrate," Ratts says. "It’s exciting because metformin is much cheaper than injectable fertility drugs and doesn’t present the risk of side effects. And it seems to work."
The research team now hopes to identify factors that predict which patients will respond to the new therapy and which will not.
Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma SW, Nestler JE. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients resistant to clomiphene alone. Fertility and Sterility, 75:2, 310-315, February, 2001.
Funding from the National Institute of Child Health and Human Development supported this research.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
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