Unbalanced progesterone signals may cause some pregnant women to experience either preterm labor or prolonged labor, according to new research by NIEHS scientists and their academic collaborators.

The study in mice — published Mar. 16 in the Proceedings of the National Academy of Sciences — provides novel insights for developing treatments and was the subject of a March 11 NIEHS news release.

Preterm birth and prolonged labor can affect the health of the mother, the infant at birth, and the infant after birth, according to the researchers. (Photo courtesy of Prostock-studio / Shutterstock.com)

Promoting and preventing contraction

During pregnancy, the hormone progesterone helps to prevent the uterus from contracting and going into labor prematurely. This occurs through molecular signaling involving progesterone receptor types A and B (PGR-A and PGR-B). In this first-of-its-kind study, the scientists showed how unbalanced PGR-A and PGR-B signaling can affect pregnancy duration.

DeMayo noted that preterm birth occurs in about 10% of pregnancies. “One hormone critical for maintaining pregnancy is progesterone,” he said. (Photo courtesy of Steve McCaw / NIEHS)

“We used genetically engineered mouse models to alter the ratio of PGR-A and PGR-B in the muscle compartment of the uterus, called the myometrium,” said senior author Francesco DeMayo, Ph.D., head of the NIEHS Reproductive and Developmental Biology Laboratory. “Our team found that PGR-A promotes muscle contraction and PGR-B prevents such contraction, and we identified the biological pathways influenced by both forms.”

High costs of preterm birth, prolonged labor

Previous research showed that PGR-A helps initiate childbirth and that PGR-B affects molecular pathways related to maintaining the normal course of pregnancy. This study builds on those findings, revealing that the relative abundance of PGR-A and PGR-B may be critical in promoting healthy pregnancy. The public health implications are significant.

Preterm birth, when the baby is born before 37 weeks of pregnancy, affects 10% of all pregnancies and is the primary cause of neonatal morbidity and mortality worldwide, according to the researchers. For example, infants born preterm are at greater risk for disorders ranging from blindness to cerebral palsy. Care for preterm deliveries can result in high social and economic costs.

Prolonged labor — which increases risk of infection, rupture of the uterus, and neonatal distress — can harm both mother and infant and lead to cesarean delivery.

“Hormone signaling in pregnancy is complicated and involves both the hormone levels and the types of receptors in the uterus that sense the hormones,” said co-first author Mary Peavey, M.D., from the University of North Carolina at Chapel Hill. “This publication sheds light on how hormones influence labor and can thus be used to help women when the uterus goes into labor too soon or for a prolonged period.”

Paving the way for therapies

Wu pointed to research showing that abnormally slow or protracted labor accounts for 25-55% of first-time cesarean deliveries. (Photo courtesy of Steve McCaw / NIEHS)

Progesterone treatment aimed at preventing premature labor can help a subset of patients, but for other individuals, confounding factors may reduce effectiveness, noted Steve Wu, Ph.D., the other co-first author and a staff scientist in DeMayo’s Pregnancy and Female Reproduction Group.

Wu said that the research team found novel molecules that control uterine muscle contraction and could serve as future therapeutic targets. He added that the current study also may help to advance treatment for labor dystocia, which is the clinical name for abnormally slow or protracted labor.

“Although labor stimulation by oxytocin infusion is an approved measure to mitigate labor dystocia, serious side effects have been associated with this treatment,” said Wu. “Novel proteins that we identified as being part of progesterone signaling could serve as a key molecular switch of uterine contraction, through drug-dependent regulation of their activities,” he explained.

Citation: Peavey MC, Wu S-P, Li R, Liu J, Emery OM, Wang T, Zhou L, Wetendorf M, Yallampalli C, Gibbons WE, Lydon JP, DeMayo FJ. 2021. Progesterone receptor isoform B regulates the Oxtr-Plcl2-Trpc3 pathway to suppress uterine contractility. Proc Natl Acad Sci USA 118(11):e2011643118.

(Jesse Saffron, J.D., is a media relations coordinator for the NIEHS Office of Communications and Public Liaison.)