An investigational drug that helps insulin to function more efficiently appears to combat infertility in women with polycystic ovary syndrome (PCOS), the most common cause of female infertility, according to a research team funded in part by the National Institute of Child Health and Human Development (NICHD). The drug, D-chiro-inositol, occurs naturally in fruits and vegetables and appears to have no side effects in the comparatively small number of PCOS patients who took part in this preliminary trial.

The study, conducted by researchers at Virginia Commonwealth University (VCU) in Richmond, appears in the April 29 issue of The New England Journal of Medicine.

"These early results show a lot of promise," said Dr. Donna Vogel, Associate Chief for Clinical Research in NICHD's Reproductive Sciences Branch and NICHD program officer for the study. "Dr. Nestler and his colleagues have shown that a substance naturally produced by the body to assist in insulin action promotes ovulation in the majority of PCOS patients who take it."

PCOS affects from 5 to 10 percent of American women of reproductive age (as many as 5 million in all), explained the study's principal investigator, John E. Nestler, M.D., Chairman of Endocrinology at VCU's Medical College of Virginia. The ovaries of women with PCOS appear to be filled with numerous small cysts. The cyst-like appearance results from an accumulation of immature ovarian follicles, the bubble-like structures which, upon maturation, rupture and give rise to the egg cell.

The features of PCOS may include failure to ovulate or menstruate, abnormally high levels of insulin, obesity, high blood pressure, hardening of the arteries, and high triglyceride levels. (Triglycerides are fatty substances used for energy storage, and high triglyceride levels may increase the risk for coronary artery disease.) PCOS patients also have high levels of the male hormone testosterone, which may cause them to grow excess facial or body hair.

"PCOS is not just a reproductive disorder; it's a major health concern for women who are affected," Dr. Nestler said. "This is a promising new drug because not only does it dramatically improve ovulation, it improves a woman's overall health."

Dr. Nestler added that, traditionally, physicians have been able to treat only the symptoms of PCOS, and not eliminate its cause. For example, antiandrogens were prescribed to block the action of testosterone and reduce excessive hair growth. Birth control pills were used to regulate the menstrual cycle, and when the women sought to have children, they were treated with fertility drugs -- either alone or in combination with in vitro fertililzation.

Roughly two years ago, however, Dr. Nestler and his colleagues were successful in reducing the PCOS symptoms of a group patients by treating them with the drug metformin, used to treat insulin resistance in patients with adult onset (type II) diabetes. (Insulin resistance is the failure of cells to respond to insulin properly). Metformin increases the body's sensitivity to insulin and allows the body to use insulin more efficiently. Troglitazone, another insulin-sensitizing agent, has similar effects in PCOS patients.

Although both drugs do restore ovulation, both have a number of side effects. Metformin, for example, may cause diarrhea, nausea, and loss of appetite, and Troglitazone may be toxic to the liver.

The current findings strongly suggest that PCOS results from a failure to use insulin properly. Presumably, Dr. Nestler said, this failure causes insulin levels to rise. The high insulin levels, in turn, cause a variety of other effects, such as high blood pressure, hardening of the arteries, and high triglyceride levels. Insulin also appears to have an effect on the ovaries, causing them to produce high levels of testosterone and similar compounds, which halt egg maturation and interfere with the menstrual cycle.

In the current study, the researchers followed 44 obese women with PCOS; half received D-chiro-inositol, and half received a placebo. Of the 22 women who received the study drug, 86 percent ovulated, compared with only 27 percent of the women in the placebo group. Women who received D-chiro-inositol also saw improvements in insulin, blood sugar, blood pressure, testosterone and triglyceride levels. No side effects were reported.

Dr. Nestler explained that the body uses D-chiro-inositol to manufacture the D-chiro-inositol mediator, which allows the cell to process glucose after insulin binds to the cell's surface. According to Dr. Nestler, the research offers insight into the possible cause of insulin resistance in women with PCOS, which previously had been unknown. A PCOS patient's insulin resistance could be due, in part, to a D-chiro-inositol deficiency.

NICHD is currently funding a trial of D-chiro-inositol in a large number of patients to further ascertain its safety and effectiveness. The drug is also being tested in patients with type 2 diabetes.

The study drug is manufactured by INSMED Pharmaceuticals, Inc., which develops products to detect and treat insulin resistance. The research is funded by an NIH Small Business Innovation Research Grant. These grants are given to independently owned and operated U.S. companies that have fewer than 500 employees.