Finding Molecular Answers to the Mysteries of Preterm Birth

 Sam Mesiano, PhD

Imagine the lifesaving impact of a prophylactic treatment that could be taken once daily by pregnant women to greatly reduce the risk of preterm birth--which still occurs for one of every ten babies born in the United States alone. Current molecular research into the power of the human hormone progesterone, now in the discovery phase, may hold the key to making this idea a reality.

During pregnancy, progesterone is produced in large amounts by the placenta and, as its name implies is “pro-gestational”--it functions to promote pregnancy mainly by keeping the uterine muscle relaxed and quiescent. At the end of pregnancy, something changes, and though the progesterone is still present, it no longer prevents the uterus from beginning to contract. For a typical pregnancy this happens between 37-42 weeks. If earlier, it is preterm or premature birth.

“We know that simply adding more progesterone to the system isn’t effective for nearly half of the women at risk for preterm birth,” said Sam Mesiano, PhD, Research Scientist in the Department of Obstetrics & Gynecology at University Hospitals MacDonald Women’s Hospital and Professor of Reproductive Biology at Case Western Reserve University School of Medicine. “As we suspected when we started these studies, the mechanism is more complex than that—when childbirth is triggered, it is because the progesterone receptors have stopped responding to the presence of progesterone in the same way. Our data suggests that applying the right therapeutic compound might prevent the receptors from changing, therefore keeping the uterus in ‘quiet mode’ to term.”

Dr. Mesiano’s work is part of the March of Dimes Prematurity Research Center Ohio Collaborative, a transdisciplinary and cross-institutional network of researchers breaking down traditional institutional research barriers in order to advance scientific research into the causes of premature birth. Together, the collaborative has developed novel cell line models for individual types of cells believed to play a role in the onset of labor.  Dr. Mesiano’s group focuses on the myometrium, or smooth muscle cells of the middle layer of the uterus. Other laboratories focus on modeling of other cell types, such as those in the cervix. The teams exchange animal models, simulations, and data to compare notes and find synergies.

“The prevailing assumption when investigating progesterone was that it impacts every cell type the same way,” Dr. Mesiano explained. “However, we’ve found that it does specific things in specific cells depending on location—the uterus or elsewhere. By understanding how it impacts a smooth muscle cell we can target therapies specifically to those cells. In this case, we may be able to keep the muscles from contracting.” 

The team also seeks to shorten the development pipeline by simultaneously studying the impacts of therapeutic compounds on these pathways. The hunt for effective therapeutics is supported by the Global Alliance to Prevent Prematurity and Stillbirth (GAPPS), an initiative supported by the Bill and Melinda Gates Foundation.

 “What we learn from unraveling the molecular mechanisms feeds our research into therapeutics, and likewise, our observations of how compounds interact with the receptors at the molecular level can feed our understanding of the mechanisms at work. We are very much in a discovery phase but are already identifying promising compounds and starting to drill down to understand how progesterone functions in the pregnancy uterus,” concluded Dr. Mesiano.

With the global estimate at nearly 15 million preterm births each year and rising, the need for answers and treatments grows more desperate every day. While Dr. Mesiano and colleagues focus on the workings of the smallest of molecules, their findings may have some of the biggest implications for the future of maternal and fetal health during pregnancy.