Preterm births—births before 37 weeks of pregnancy—are medically labelled ‘idiopathic,’ when they arise from unexplained, spontaneous labor. Preterm births are linked to an array of illnesses and increased risk of death in infancy. Idiopathic preterm birth (iPTB) is linked to maternal depression and post-traumatic stress disorder but the exact molecular mechanism that links maternal stress to preterm birth has been unclear.

A new preclinical study conducted at the Morsani College of Medicine Department of Obstetrics and Gynecology, University of South Florida Health (USF Health), has uncovered a mechanism to help explain how psychological or physiological stress in pregnant women triggers iPTB.

Reduced progesterone production or function signals labor. The new research shows how the stress increases the expression of the stress-responsive protein, FKBP51, in the decidual cells lining the wall of the uterus and its binding to progesterone P4 receptors to inhibit progesterone receptor function in the uterus. This reduces progesterone receptor activity and stimulates labor.

These findings are reported in the Proceedings of the National Academy of Sciences (PNAS) article, “Decidual cell FKBP51–progesterone receptor binding mediates maternal stress–induced preterm birth.”

Ozlem Guzeloglu-Kayisli
Ozlem Guzeloglu-Kayisli, PhD, an associate professor of obstetrics and gynecology at USF Health, co-led the preclinical study showing that FKBP51-progesterone receptor binding plays a critical role in maternal stress-induced preterm birth. [USF Health/University of South Florida]
“This new study fills in some longstanding mechanistic gaps in our understanding of how normal labor begins and how stress causes preterm birth,” says the paper’s senior author Charles J. Lockwood, MD, senior vice president of USF Health, dean of the USF Health Morsani College of Medicine, and a professor of obstetrics and gynecology specializing in maternal-fetal medicine.

Lockwood is a co-principal investigator on the study along with the paper’s lead author Ozlem Guzeloglu-Kayisli, PhD, a USF Health associate professor of obstetrics and gynecology. Nihan Semerci, MSc, a senior biological scientist, shares the lead authorship with Guzeloglu-Kayisli.

“Prevention of idiopathic preterm birth by extending gestation even two or three weeks can benefit the newborn, because it provides critical time needed for the fetus’s lungs and brain to mature,” says Guzeloglu-Kayisli . “Our research indicates the importance of investigating the potential use of FKBP51 inhibitors as a targeted therapy to reduce the risk of stress-related preterm birth.”

 Charles J. Lockwood, MD,
The preclinical study providing molecular insights into maternal stress and preterm birth of unknown cause was co-led by Charles J. Lockwood, MD, senior vice president of USF Health, dean of the USF Health Morsani College of Medicine, and a professor of obstetrics and gynecology specializing in maternal-fetal medicine. [USF Health/University of South Florida]
Earlier studies have linked elevated FKBP51 expression to an increased risk for stress-related disorders. Previous work by the USF Health team showed that normal human labor starting at term (between 37 and 42 weeks of pregnancy) was associated with reduced expression of progesterone receptors and increased expression of FKBP51, specifically in decidual cells lining the uterus.

In the current study, the researchers combined experiments in human maternal decidual cells and a mouse model in which FKBP5, the gene that makes FKBP51, has been deleted.

The analysis reveals a previously unknown functional progesterone withdrawal mechanism, mediated by maternal stress-induced uterine FKBP51 overexpression and enhanced FKPB51-progesterone receptor binding, that triggers preterm birth.

Pregnancy is abnormally prolonged in Fkbp5 knockout mice accompanied by slower decline of serum progesterone levels and resistance to stress-induced preterm birth, the authors report.

“Collectively, these results suggest that FKBP51 plays a pivotal role both in term labor and stress-associated preterm parturition (birth) and that inhibition of FKBP51 may prove to be a novel therapy to prevent idiopathic preterm birth,” the authors conclude.

The study also reports enhanced FKPB51 levels and FKPB51 binding to progesterone receptors in the decidual cells of women with iPTB, compared to decidual cells of gestational age-matched controls.

Currently progesterone injection is the only therapeutic recommendation approved to  prevent preterm birth in high-risk women who have had a previous preterm birth. However, its effectiveness was not confirmed by a recent large clinical trial, sparking debate in the healthcare community. These current findings, that progesterone receptor activity is reduced in iPTB, may explain the apparent lack of effectiveness of supplemental progesterone.