Progestin withdrawal at parturition in the mare

Mammalian pregnancies need progestogenic support and birth requires progestin withdrawal. The absence of progesterone in pregnant mares, and the progestogenic bioactivity of 5 alpha-dihydroprogesterone (DHP), led us to reexamine progestin withdrawal at foaling. Systemic pregnane concentrations (DHP, allopregnanolone, pregnenolone, 5 alpha-pregnane-3 beta, 20 alpha-diol (3 beta, 20 alpha DHP), 20 alpha-hydroxy-5 alpha-dihydroprogesterone (20 alpha DHP)) and progesterone) were monitored in mares for 10 days before foaling (n = 7) by liquid chromatography-mass spectrometry. The biopotency of dominant metabolites was assessed using luciferase reporter assays. Stable transfected Chinese hamster ovarian cells expressing the equine progesterone receptor (ePGR) were transfected with an MMTV-luciferase expression plasmid responsive to steroid agonists. Cells were incubated with increasing concentrations (0-100 nM) of progesterone, 20 alpha DHP and 3 alpha, 20 beta DHP. The concentrations of circulating pregnanes in periparturient mares were (highest to lowest) 3 alpha, 20 beta DHP and 20 alpha DHP (800-400 ng/mL respectively), DHP and allopregnanolone (90 and 30 ng/mL respectively), and pregnenolone and progesterone (4-2 ng/mL). Concentrations of all measured pregnanes declined on average by 50% from prepartum peaks to the day before foaling. Maximum activation of the ePGR by progesterone occurred at 30 nM; 20 alpha DHP and 3 alpha, 20 beta DHP were significantly less biopotent. At prepartum concentrations, both 20 alpha DHP and 3 alpha, 20 beta DHP exhibited significant ePGR activation. Progestogenic support of pregnancy declines from 3 to 5 days before foaling. Prepartum peak concentrations indicate that DHP is the major progestin, but other pregnanes like 20 alpha DHP are present in sufficient concentrations to play a physiological role in the absence of DHP. The authors conclude that progestin withdrawal associated with parturition in mares involves cessation of pregnane synthesis by the placenta.