University Hospitals Investigates the Fundamentals of Labor to Prevent Preterm Birth
December 09, 2021
Innovations in Obstetrics & Gynecology | Fall 2021
Preterm birth impacts 10 to 15 percent of pregnancies in the United States and is the leading cause of neonatal mortality. While there are known risk factors and some therapies intended to prevent preterm birth, much remains unknown about its cause and how it can be prevented, says Sam Mesiano, PhD, Vice Chair of Research and Director of the Division of Research in the Department of Obstetrics and Gynecology at University Hospitals Cleveland Medical Center.
Mesiano, who is also the William H. Weir Professor of Reproductive Biology at Case Western Reserve University School of Medicine, leads a research team at University Hospitals that is trying to understand how the process of birth is controlled and use that knowledge to develop more effective therapies to prevent preterm birth.
Nature has provided some clues. Progesterone, often referred to as the pregnancy hormone, is essential for the establishment and maintenance of pregnancy. Clinical trials suggest that treating women with extra progesterone decreases the risk for preterm birth, and this therapy is administered in women with increased risk.
Mesiano’s team is exploring the mechanism by which progesterone acts to block labor and delivery and how its blocking actions are overcome to allow birth.
“We’re trying to tease out the molecular mechanism by which progesterone maintains pregnancy and how it acts on the uterus to keep it from contracting and to keep the cervix closed,” he says. “If we understand how progesterone blocks labor, then we can then start to tease out the signaling pathways that remove its blocking action and trigger labor.”
Some early studies suggested that boosting progesterone activity in pregnant women prevents preterm birth, but more research has since been done. Mesiano reasons that the blocking action of progesterone can be exploited with more potent synthetic compounds that mimic the action of a woman’s natural progesterone.
Uterine Tissue and Mouse Models
At UH, Mesiano is using uterine tissue, cell cultures and mouse models to understand the mechanisms behind labor and to develop novel progesterone-based therapies to prevent preterm birth. They can look at the muscle cells in human uterine tissue to help determine what keeps these cells relaxed and what causes them to contract. In mouse models, the research team is studying preterm birth and testing progesterone-like drugs that could prevent it.
A New Approach
While naturally occurring progesterone may not be the definitive answer to stopping preterm birth, understanding this hormone and altering it may be the key to doing so. In a recent study published in the American Journal of Obstetrics & Gynecology, Mesiano and his team demonstrated promising results with a different form of progesterone in a mouse model.
“We take the progesterone that nature has given us, and we modify it a little bit chemically to make a different structure that will act in a more robust way in the woman,” he says. “Our lead compound was effective at preventing preterm birth in mice treated to simulate human preterm birth, and we are excited to explore its mechanism of action.”
“It is exciting to have proof of concept that preterm birth can indeed be prevented with a progesterone-like compound,” Mesiano says. The team is in the process of obtaining funding to study the same protocol in rhesus monkeys.
While plenty of work remains to be done before this research translates into real-world care, the compound being used in this research has already been in used in humans. It is approved in Europe for the treatment of gynecological disorders such as endometriosis and uterine fibroids. “It is an early stage drug repurposing project,” Mesiano says.
He is collaborating with experts in structural and organic chemistry at Case Western Reserve University to synthesize novel compounds that have the potential to be even more effective.
“We have a pipeline in place to test these compounds on cells and in mice, and we are now modifying what we have to see if we can improve effectiveness,” Mesiano says. “Our research wouldn’t happen as efficiently as it does if it were not for the academic environment that is built around the OB/GYN department at UH and the department of reproductive biology.”