Potential therapeutic target for infertility and contraception

The multiple “litter” births of mice, versus the normal singleton pregnancy of humans, is due to defective processing in mice of a common mammalian protein called bone morphogenetic protein 15 (BMP-15), according to new research from the University of California, San Diego (UCSD) School of Medicine.

Published online the week of April 4, 2005 in Proceedings of the National Academy of Sciences, and appearing in the journal’s April 12, 2005 print edition, the study provides one of the first insights into the physiological mechanisms responsible for multiple births and suggests a potential therapeutic target for infertility and contraception.

“Infertility is a major problem for many couples,” said the study’s senior author, Shunichi Shimasaki, Ph.D., UCSD professor of reproductive medicine. “Based on our findings, it is possible that therapeutic regimens targeting BMP-15 could offer exciting new opportunities for novel treatments for female infertility. On the other side of the coin, BMP-15 could also serve as a new target for non-steroidal contraceptives.”

Recently, scientists have found that BMP-15 produced by eggs developing in the ovary plays an important role in determining ovulation quota, which results in litter size in mammals. In laboratory studies with human and mouse models, the UCSD team found specific differences between mice and humans in the way BMP-15 is produced and secreted by cells.

While BMP-15 was found to be readily produced and normal in humans, its production in mice was degraded before it could become a mature protein. BMP-15 controls the number of follicles that become competent to ovulate, resulting in singleton or twin gestations in humans and sheep. In mice, however, the impaired BMP-15 caused early development of follicles, leading to an increase in egg production and ovulation.

“How humans restrict their pregnancies to single or twin births while many other animals have such large litters is a fundamental aspect of biology that has remained poorly understood,” Shimasaki said. “This research begins to provide some answers to this very basic question of biology.”

The study was funded by the National Institutes of Health (NIH) and the National Institute of Child and Human Development/NIH. The first author was Osamu Hashimoto, Ph.D., a former post doctoral fellow in the UCSD Department of Reproductive Medicine, and an additional author was another former post doctoral fellow, R. Kelly Moore, Ph.D., UCSD Department of Reproductive Medicine.