Plasma progestagens as markers of feto-placental health

Abstract

The pregnant mare produces many metabolites of progesterone (progestagens) which are present in high concentrations in maternal plasma in late gestation. Progesterone (P4) itself is undetectable during the second half of pregnancy. The role of these progestagens is not known but it is thought that they may regulate myometrial activity. The source of progestagens has been identified using mares which have had chronic catheters placed in fetal, umbilical and uterine blood vessels. The P4 precursor, pregnenolone (P5) is produced by the fetus and rapidly metabolised by the placenta/endometrium into P4 and other metabolites, notably 5α-pregnane-3,20-dione (5α-DHP). These metabolites reenter the fetal circulation and are then further metabolised by the fetus and placenta and excreted into the maternal circulation. Because the enzymes necessary to metabolise progestagens are present in both the fetus and placenta/endometrium, an intact and healthy feto-placental unit is necessary for their production and, presumably, for maintenance of myometrial quiescence. In healthy Thoroughbred (TB) and pony mares, total progestagen concentrations gradually increase during the last week(s) pre-partum and then decline 24 h before delivery. However, in mares which have placental damage and associated premature mammary development, total progestagen concentrations often are raised precociously and remain elevated until abortion or pre-term delivery. Many of their foals, although delivered before full term, demonstrate adrenocortical activity suggesting a relationship between adrenal development and maternal plasma progestagen concentrations. This relationship has been confirmed by studies in which fetuses or mares injected sequentially with adrenocorticotrophic hormone (ACTH), exhibit raised maternal progestagen concentrations. Because the fetus produces P5, possibly by the adrenal, metabolism of progestagens may be altered or enhanced if there is fetal stress and / or placental damage. In order to test this hypothesis, blood samples were collected from mares (7 TB, 1 pony) in late gestation (250-280 days) with clinical conditions such as placentitis, premature mammary development, vaginal discharge or colic. Specific progestagen profiles measured quantitatively using gas chromatography - mass spectrometry showed detectable levels of P4 and elevated metabolites (5α-DHP, ββ-diol, 20α-5P, βα-diol) compared with control mares at the same stage of pregnancy. Maternal PS was not elevated. Progestagens were low in 2 mares which aborted within 72 h. These results suggest that the progestagen pathway may be blocked in the placenta whilst an alternative route for 5α-DHP production may exist in the fetus. Low maternal P5 concentrations do not preclude enhanced fetal P5 production, but low progestagen concentrations overall were associated with fetal demise. A specific marker of feto-placental stress was not identified but different progestagen profiles were observed between healthy and compromised pregnant mares.