Preeclampsia, Fetal Development Problems May Be Linked To Low Levels Of Hormone

The findings also suggest that the hormone, adrenomedullin, plays a key role in maternal susceptibility to preeclampsia, a serious pregnancy complication that occurs in the third trimester. Preeclampsia affects roughly one in fifteen pregnant women and is the leading cause of death among expectant mothers.

The UNC researchers demonstrated that pregnant mice with low adrenomedullin levels had reduced litter sizes, and while embryos implanted normally in the uterus, their spacing was overcrowded and resulted in poor growth. Because the low hormone levels were caused by a genetic mutation affecting adrenomedullin production, similar genetic changes could be linked to problems in human pregnancy, the researchers said.

"Our study provides the first genetic evidence to suggest that a modest reduction in human adrenomedullin expression during pregnancy may cause profound defects during pregnancy," said Dr. Kathleen M. Caron, senior study author and an assistant professor in the departments of cell and molecular physiology and genetics at the UNC School of Medicine.

Among the potential problems are poor implantation of the embryo, failure of the placenta to establish blood flow between mother and fetus and restricted fetal growth, Caron said. "The clinical implications are that women who have mutations in the gene responsible for expressing adrenomedullin might have greater susceptibility to these pregnancy problems, including preeclampsia."

The study was published online Sept. 14 in the Journal of Clinical Investigation and will appear in the Oct. 2 print edition.

Discovered in 1993, adrenomedullin is a powerful blood vessel dilator that is essential for life. Secreted by cells throughout the body, it is involved in more than a dozen physiological functions such as metabolism, heart rate control, gastric control, thirst and appetite control, stress response, blood vessel growth, antibacterial activity and nerve transmission.

The hormone also plays a role in a number of diseases and cardiovascular conditions. For example, blood levels of adrenomedullin double in cancer, kidney failure, congestive heart failure, hypertension and diabetes. According to Caron, one of the greatest increases occurs during the course of a normal pregnancy, when the placenta secretes adrenomedullin -- levels reach four to five times higher than normal by the third trimester before rapidly returning to pre-pregnancy values after delivery.

But in women who experience complications such as preeclampsia, spontaneous abortion, and gestational diabetes, hormone levels do not increase as they normally would in pregnancy. "It's possible that the inability to increase adrenomedullin during pregnancy might be a cause of preeclampsia and other problems," Caron said.

Caron, who has studied adrenomedullin's role in the body for several years, first noticed the link between the hormone and fertility while working as a postdoctoral researcher with UNC professor Dr. Oliver Smithies. Caron discovered that mice with a genetic mutation causing a 50 percent reduction in adrenomedullin levels had poor fertility and small litter sizes.

Caron's latest research establishes that reduced litter sizes are due to low adrenomedullin levels in the mother and not the father. The study also found that although embryos implanted normally, their spacing in the wall of the mouse uterus was "overcrowded," which was associated with poorer subsequent growth. This overcrowding also was linked to abnormal placentas and a high rate of twinning.

The UNC researchers showed that both mother and embryo make an effort to increase the level of adrenomedullin at the embryo's implantation site in the uterus. "And when mom's level is 50 percent lower than normal, implantation goes awry, as does fetal growth," Caron said.

Study co-authors include Dr. Terry R. Magnuson, Sarah Graham Kenan professor, chair of genetics and director of the Carolina Center for Genome Sciences; Dr. Manyu Li, first author and postdoctoral scientist and veterinarian in Caron's lab; and Della Yee, research technician.

Funding was provided by the Burroughs Wellcome Fund and the National Institutes of Health.