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A new study published in PNAS, the Proceedings of the National Academy of Sciences of the United States of America, looked at how maternal stress triggers preterm birth.

“Our study focused on uncovering the cellular mechanisms underlying preterm birth triggered by maternal stress,” study lead author and co-principal investigator, Ozlem Guzeloglu-Kayisli told us. “We combined results obtained from human studies and a mouse model. We wanted to understand the role of the stress-responsive protein FKBP51 in the uterus – whether FKBP51 levels were increased by maternal stress and how such enhanced FKBP51 expression might cause preterm birth.”

Guzeloglu-Kayisli, PhD, is associate professor of obstetrics and gynecology at the USF Health Morsani College of Medicine at the University of South Florida, in Tampa, Florida. The study’s other co-principal investigator (and paper’s senior author) was Charles J. Lockwood, MD, dean of the USF Health Morsani College of Medicine and professor of obstetrics and gynecology.

“We hypothesized that maternal stress increases FKBP51 expression in the uterus,” Guzeloglu-Kayisli told us. “Furthermore, this enhanced uterine FKBP51 promotes functional progesterone withdrawal by inhibiting progesterone receptor activity, which results in preterm birth.”

The preterm birth rate in the U.S. remains unacceptably high, Guzeloglu-Kayisli explained, comprising about 10% of all births. It remains the leading cause of infant death and illness.

“We know maternal stress linked to depression and post-traumatic stress disorder and/or fetal stress has been strongly implicated in idiopathic preterm births, particularly those occurring between 34 weeks and 37 weeks of gestation (pregnancy), which account for the bulk of idiopathic cases,” Guzeloglu-Kayisli told us. “However, the underlying molecular causes of stress-associated preterm births remain unclear.”

The aim nationwide is to reduce the rates of preterm birth. Guzeloglu-Kayisli said the findings are crucial for developing inhibitors to potentially treat stress-related elevation of FKBP51 in high-risk pregnant women and thereby reduce the incidence of preterm birth.

FKBP51 is an important mediator of the stress response and implicated as a cause of stress-related disorders. Since maternal stress is known to trigger preterm birth, researchers first measured the levels of FKBP51 in women with idiopathic (unknown) preterm birth and in gestational age-matched controls. Then, they combined the human studies with results obtained from an Fkbp5-deficient (knockout) mouse model.

“We observed that maternal stress upregulates FKBP51 levels and enhances binding of FKBP51 to progesterone receptors,” Guzeloglu-Kayisli told us. “Moreover, FKBP51 binding to progesterone receptors reduces progesterone receptor activity by causing functional progesterone withdrawal to induce preterm birth. Wild type mice (normal-control) are responsive to maternal stress-induced preterm birth and display shorter gestation under stress.”

In contrast, Fkbp5-deficient mice are resistant to maternal stress-induced preterm birth and exhibit prolonged gestation. Collectively, these results revealed a novel functional progesterone withdrawal mechanism mediated by maternal stress-induced uterine FKBP51 over-expression and enhanced FKPB51-progesterone receptor binding that elicited idiopathic preterm birth.

“We were surprised that mice deficient in Fkbp5 display a prolonged gestational length – which we reported for the first time,” Guzeloglu-Kayisli told us. “We were even more surprised that, in the wild type mice, stress-induced uterine levels of the progesterone metabolizing enzyme Akr1c18 contributed to preterm birth. The increased local progesterone metabolism, together with enhanced FKBP51-progesterone receptor interaction, blocks progesterone receptor-regulated cell signaling. The Akr1c18 finding helped us complete the story of how maternal stress triggers preterm birth at the uterine receptor level.”

The researchers’ next step is to identify inhibitors (drug candidates) that reduce FKBP51 levels to delay or prevent idiopathic preterm birth. This is important because babies born too early have more health problems at birth and face greater risks for long-term health complications including childhood lung, heart and neurological disorders.

Considered together, these findings suggest that FKBP51 plays a pivotal role both in term labor and stress-related preterm birth, and that inhibition of FKBP51 is likely to prove to be a novel therapy to prevent idiopathic preterm birth.