Progesterone from maternal circulation binds to progestin receptors in fetal brain

Abstract

Steroid hormones activate nuclear receptors which, as transcription factors, can regulate critical aspects of neural development. Many regions of the rat forebrain, midbrain and hindbrain express progestin receptors (PR) during perinatal life, suggesting that progesterone may play an important role in the development of the brain. An immunohistochemical approach using two antibodies with differential recognition of ligand-bound PR was used to examine whether fetuses are exposed to maternal progesterone during pregnancy and whether progesterone from maternal circulation can bind to PR within the fetal brain. Findings demonstrate that maternal and fetal serum progesterone levels are positively correlated at the end of gestation, suggesting a common source of progesterone in mothers and fetuses (e.g., the maternal ovary). Additional findings suggest that administration of exogenous progesterone to mothers not only increases fetal serum progesterone levels within 2 h, but appears to increase ligand-bound PR in fetal brain. These findings suggest that progesterone of maternal origin may play a previously overlooked role in neural development. In addition, there are implications for the ongoing prophylactic use of synthetic progestins in pregnant women for the prevention of premature birth. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 767-774, 2017.

Administration of Progesterone Throughout Pregnancy Increases Maternal Steroids Without Adverse Effect on Mature Oligodendrocyte Immunostaining in the Guinea Pig

“…One possibility to explain this delayed rise is the ability of exogenous progesterone to be stored in fat and undergo delayed release into the circulation. Alternatively, a recent study found that administration of exogenous progesterone to mothers increased fetal serum progesterone levels within 2 hours of dosing 28 ; based on this, it is possible that we missed measuring our peak progesterone levels, as our measurement of fetal plasma in the preterm cohort was 24 hours after the final dose. Similarly, our measurements of salivary progesterone in the mother taken throughout gestation were obtained 24 hours after each daily dose, so the levels we see are not indicative of peak levels but rather closer to the baseline level achieved.…”

“…26,27 Further studies not only showed that progesterone transferred to the fetal circulation but that it also bound to nuclear progesterone receptors in the developing fetal brain. 28 These data and the ability of progesterone to transfer from the maternal to the fetal circulation suggest that increased progesterone exposure can affect fetal steroid levels and the fetal brain. This work highlights the need to further investigate the effects that progesterone therapy during pregnancy may have on the vulnerable developing fetal brain.…”

Progesterone Actions During Central Nervous System Development

“…Progesterone is essential for the maintenance of pregnancy and its circulating levels in pregnant women increase between sixfold and eightfold when compared with non-pregnant subjects due to placental secretion (Lee et al, 2017). Existing evidence from pregnant rats indicates that progesterone from the maternal circulation enters the fetal bloodstream and reaches the developing CNS, binding to its intracellular receptors (Wagner and Quadros-Mennella, 2017). Additionally, progesterone from the human placenta was proposed to contribute to adequate neurodevelopment, having specific roles in neuroprotection and the development of neural circuits.…”

Progesterone through Progesterone Receptor B Isoform Promotes Rodent Embryonic Oligodendrogenesis

“…This is plausible because the expression of PR and the expression and activity of the enzymes required for progesterone synthesis have been found from the early embryo ages of the mammalian development in several regions of the developing CNS [61]. Additionally, pregnancy is characterized by an increase in maternal progesterone levels, and there is evidence that progesterone from the maternal circulation enters the embryo/fetal circulation and binds its PR in the developing rat CNS [62]. Remarkably, the levels of progesterone in fetal circulation and in the brain progressively increases throughout pregnancy, especially during late pregnancy [63], coinciding with the time in which the CNS undergoes critical processes such as neural circuits organization and myelination [64].…”