Diabetes drug cures infertility and more

From San Diego, at the Experimental Biology 2000 meeting

Afflicting some 6 percent of U.S. women, polycystic ovary disease is the most common source of infertility. Cases of this inherited disorder usually go undiagnosed, however, notes endocrinologist Charles J. Glueck of the Jewish Hospital in Cincinnati. Most of the affected women don’t ovulate, but he’s found that even among those who become pregnant, half miscarry in the first trimester. That’s five times the normal rate.

In the first of three studies that Glueck now reports, his team restored normal fertility to these women by using the common diabetes drug metformin, also known as glucophage.

Among the first 118 women treated, 91 percent ovulated, and the group became pregnant at the same rate that healthy women do. More importantly, among the 60 women who took the drug throughout their pregnancies, at least 90 percent had healthy babies.

In the December 1999 Metabolism, Glueck’s team unveiled the mechanism by which polycystic ovary disease jeopardizes pregnancies. Affected women make too much plasminogen-activator inhibitor (PAI), a protein that keeps the body from breaking down blood clots. During the first trimester of pregnancy, as the placenta begins connecting a woman’s blood vessels to those in her fetus, small clots can form. If they don’t dissolve, these clots may shut down the fetal oxygen supply.

In a second new study, the researchers showed why enhancing insulin action, as metformin does, fixes the problem. “Polycystic ovary disease is the poster child for insulin resistance,” Glueck says. Although people with the disease produce what should be sufficient insulin, the hormone doesn’t work well enough to clear all the sugar from their bloodstream. The body copes, at least for a while, by increasing its production of insulin. Eventually, he notes, roughly 70 percent of women with polycystic ovary disease develop adult-onset diabetes.

Side effects of extra insulin can include an overproduction of PAI and male hormones. The latter promote excess body hair, weight gain, balding, and a disproportionate accumulation of fat at the waist—all hallmarks of  polycystic ovary disease. But treatment with metformin returns the women’s production of PAI and male hormones to normal, Glueck’s team reports.

This therapy also appears to prevent development of gestational diabetes—diabetic symptoms during pregnancy.

Metformin therapy also offered most of the women an extra benefit: weight loss even though they didn’t cut calories or increase exercise. Prodded by this observation, the researchers undertook a third study, offering the same drug for 24 weeks to 22 morbidly obese, nondiabetic women and men.

These people shed about 6 percent of their weight—usually around 18 pounds—and lost 2 to 3 inches from their waist and hips. Moreover, blood concentrations of their low-densitylipoprotein cholesterol, the so-called bad cholesterol, dropped by 10 percent, and their fasting insulin, even more. In fact, Glueck says, “their reduction in weight appears to have been due almost exclusively to ameliorating insulin resistance.”

He now plans to investigate whether prescribing metformin to apparently healthy people with insulin resistance will keep this high-risk population from developing diabetes.