Researchers Studying Diabetes Find a Possible Cause of Infertility
For about one in 10 couples that cannot conceive a child, their reproductive problem falls under the broad category of "idiopathic infertility," meaning the cause remains to be determined. But these idiopathic problems are gradually giving way to discovery and, in the February issue of the journal Endocrinology, scientists at the National Institutes of Health and colleagues report that in the course of animal studies to understand diabetes, they may have uncovered a previously unknown cause of infertility in women.
The scientists report that some female reproductive problems might involve the so-called dense core vesicles, the protein packaging that encases insulin and other secreted hormones. Whereas researchers traditionally have been most interested in the hormonal content of the vesicles, the team discovered the structural components of the vesicles play a subtle and until now overlooked role in the secretion of reproductive hormones from the pituitary gland that stimulate the release of eggs from the ovaries, or ovulation.
The researchers said this finding is potentially important because, when they deleted genes that encode two major proteins in the protective outer membrane of these vesicles, female mice were born infertile. "What's particularly interesting is the deleted proteins, called IA-2 and IA-2 beta, also are structurally important for dense core vesicles in people," said Dr. Abner Notkins, a scientist at NIH's National Institute of Dental and Craniofacial Research (NIDCR) and senior author on the paper. "That's why it's very likely that alterations in these and possibly other genes that are needed to produce well functioning dense core vesicles would have similar effects in people."
Dense core vesicles are key components of our neuroendocrine cells, or cells that secrete hormones and other signaling proteins into the bloodstream. Under a laboratory microscope, these hormone-containing vesicles look like tiny granular specks that shuttle from the cytoplasm to the cell membrane. There, the vesicles aggregate until the appropriate signal arrives to stimulate the release of their hormone content into the circulation. The release of hormones from these vesicles marks an important, tightly controlled event in regulating a variety of biological processes, including blood glucose and reproductive cycles.
This month's finding is a classic case of an experiment taking an unexpected scientific twist. According to Notkins, his laboratory has a longstanding research interest in the IA-2 and IA-2 beta proteins. In the mid 1990s, his group first reported that increased levels of autoantibodies against IA-2 in particular are strongly associated with an increased risk for Type I diabetes. Today, research laboratories around the world use the measurement of autoantibobies, including those to IA-2, to predict a person's likelihood of developing Type I diabetes.
However, the precise function of these proteins has remained unclear. To solve this issue, Notkins and colleagues created "knockout" mice, a standard laboratory strategy in which a specific gene of choice is inactivated. In this case, they created litters of mice that lacked the IA-2 gene, IA-2 beta gene, or both. The hope was the mice would have some obvious visual manifestation of what happens when the gene is lacking, offering a clue into each gene's normal function in the body.
"When knockout mice are born, we routinely examine them for a variety of biological features, including fertility," said Dr. Atsutaka Kubosaki, an NIDCR scientist and lead author on the paper. "We found most of the female mice that lacked both the 1A-2 and IA-2 beta genes not only had some characteristics of disordered glucose metabolism, they failed to ovulate and were essentially infertile. That's when we decided to halt some of our other studies and try to find out why the knockout mice produced so few offspring."
In collaboration with Drs. Anne Clark and John Morris, scientists at Oxford University in England and authors on the paper, the NIH researchers found these mice had totally abnormal reproductive cycles and could not ovulate. This raised the possibility that changes in the dense core vesicle caused the pituitary gland to secrete insufficient luteinizing hormone to trigger ovulation. They soon found this was the case and, when they treated the knockout mice with luteinizing hormone, ovulation did occur.
"Although we need to define further the roles of IA-2 and IA-2 beta in the secretion of dense core vesicles in the pituitary gland, our results do suggest an important role for these proteins in the control of ovulation, which should be considered in women with an unsolved reproductive problem" said Dr. John Morris.