Infertility is common among obese women, but the reasons remain poorly understood and few treatments exist. Now a team of Johns Hopkins Children's Center scientists, conducting experiments in mice, has uncovered what they consider surprising evidence that insulin resistance, long considered a prime suspect, has little to do with infertility in women with type-2 diabetes, polycystic ovary syndrome (PCOS) and metabolic syndrome, all obesity-related conditions in which the body becomes desensitized to insulin and loses the ability to regulate blood sugar.

In a report, published online Nov.10 in the journal Diabetes, the Johns Hopkins scientists say the real culprit appears to be insulin sensitivity in the ovaries and the pituitary.

The Hopkins team said its findings show that these organs escape insulin resistance and, awash with high levels of circulating insulin common in obesity, develop abnormal cell signaling that disrupts ovulation and eventually leads to infertility.

"Our findings suggest that the focus should shift from treating insulin resistance in peripheral tissue to taming insulin sensitivity in the pituitary and ovaries," says lead investigator Sheng Wu, Ph.D., of the Johns Hopkins Children's Center. Scientists traditionally have treated obesity-induced infertility by lowering blood insulin to counter the effects of insulin resistance.

A 2010 study by the same Hopkins team discovered that the pituitary gland, insensitive to insulin in lean mice, became sensitive to elevated levels of insulin seen in human and rodent obesity. By knocking out the insulin receptors in the pituitary glands of obese mice, the researchers were able to partially restore fertility, thus proving that abnormal insulin signaling in the pituitary was only part of the story.

"In the original study, disrupting insulin signaling in the pituitary restored 50 percent of fertility in obese mice, but the search was on for the accomplice," says senior investigator Andrew Wolfe, Ph.D., an endocrinologist at Hopkins Children's. "Our new findings point to the ovaries."

In the pituitary, faulty insulin signaling stimulates increased secretion of luteinizing hormone, the researchers say. In the ovary, it puts testosterone production into overdrive. Both disrupt ovulation, the researchers explain.

In the latest study, lean mice and mice made obese on a three-month high-fat diet, received injections of progressively higher doses of insulin to mimic the effects of high circulating insulin seen in obesity, diabetes and PCOS. In lean mice, the ovaries and pituitaries were insensitive to the hormone at low-dose injections, and responded only when injected with higher doses of insulin. The "trigger" doses corresponded to insulin levels typically seen in obesity. Obese mice with naturally elevated insulin levels exhibited high levels of insulin signaling in their pituitary and ovarian cells. When injected with insulin, the livers and muscles of obese mice showed greatly reduced response to insulin - or insulin resistance. Their ovaries and pituitary glands, however, responded to insulin injections, confirming that in obese mice, these reproductive organs escape the insulin resistance seen in other organs.

To determine insulin sensitivity, the researchers focused on two signaling proteins, IRS-1 and IRS-2, regulators of cell-insulin communication involved in the development of insulin resistance in liver and muscle tissue. The scientists hypothesized that in the pituitary and ovaries, these messenger proteins would remain dormant under normal insulin levels, but would get activated once exposed to high levels of insulin. Indeed, the researchers found, the pituitary glands of obese mice showed higher IRS-2 signaling activity compared with lean mice, while the ovaries of obese mice had higher signaling activity in both IRS-1 and IRS-2 proteins, compared with lean mice.

In a follow-up study now under way, the Hopkins team is trying to determine whether knocking out the insulin receptors in both the ovaries and the pituitary would fully restore fertility in obese mice with high insulin levels.

Other co-investigators on the study included Sara Divall, M.D., and Fred Wondisford, M.D., both of the Johns Hopkins Children's Center.

The research was funded by the Endocrine Fellow Foundation, by The Eunice Kennedy Shriver National Institute of Child Health and Human Development, part of the National Institutes of Health, and by the Baltimore Diabetes Research and Training Center, which is supported by the National Institute for Diabetes and Digestive and Kidney Diseases.