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Preterm Birth without Progesterone Withdrawal in 15-Hydroxyprostaglandin Dehydrogenase Hypomorphic Mice

Departments of Pediatrics and Obstetrics and Gynecology and Center for Preterm Birth Research (J.D.R., M.A., L.J.M.), Washington University School of Medicine, St. Louis, Missouri 63110; and Department of Pharmaceutical Sciences (M.T., H.-H.T.), College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536

Address all correspondence and requests for reprints to: Louis J. Muglia, M.D., Ph.D., Washington University School of Medicine, 660 South Euclid Avenue, Box 8208, St. Louis, Missouri 63110. E-mail: Muglia_L{at}kids.wustl.edu.

Parturition is a complex mammalian physiological process whose fundamental determinants have remained elusive. The increasing incidence of human preterm birth, a leading cause of infant mortality, highlights the importance of further understanding mechanisms regulating the timing of birth. Parturition is initiated in most nonprimate mammals, including mice, through a decrease in circulating progesterone caused by elevated prostaglandins. In humans, other higher primates, and guinea pigs, no consistent decrease in circulating progesterone occurs before the onset of labor. The divergence in endocrine control of labor initiation between most mammals compared with the great apes and guinea pigs gives rise to the question: how could a mechanism for the initiation of labor not requiring the withdrawal of progesterone evolve? Here, we genetically modulate prostaglandin signaling to determine the role of prostaglandin catabolism in the timing of birth. We find spontaneous preterm labor in the absence of progesterone withdrawal in 15-hydroxyprostaglandin dehydrogenase hypomorphic mice. The onset of labor in these hypomorphic mice is preceded by prematurely increased concentrations of prostaglandin E₂ and F₂. Moreover, genetic crosses demonstrate a role for fetal genotype in birth timing. Together, these findings demonstrate a 15-hydroxyprostaglandin dehydrogenase-dependent shift in the physiology of murine parturition to one resembling the physiology of higher primates. Thus, endocrine control of labor has the capacity to plastically adapt to changes in genetically determined prostaglandin signals.

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Ligands:   Progesterone