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

Abstract

Progesterone is administered to pregnant women at risk of premature labor, despite systematic reviews showing conflicting outcomes regarding its use, highlighting doubt over the effectiveness of the therapy. Progesterone can be rapidly metabolized into a number of steroids, but to date, there has been a lack of investigation into the fetal steroid profiles following administration and whether this impacts fetal neurodevelopment. The objective of this study was to determine the effect of progesterone treatment on allopregnanolone and cortisol levels in the fetus and on a marker of myelination in the fetal brain. We used a guinea pig model where pregnant dams were administered vehicle (β-cyclodextrin) or progesterone orally throughout pregnancy (GA29-61). Maternal and fetal fluids and tissues were collected at both preterm (GA61) and term (GA68) ages. Maternal and fetal progesterone and cortisol were analyzed by enzyme immunoassay and allopregnanolone by radioimmunoassay. Measurement of myelination of fetal brains (hippocampus, cingulum, and subcortical white matter) at preterm and term ages was performed by immunohistochemistry staining for myelin basic protein. We found that dams receiving progesterone had significantly elevated progesterone and cortisol concentrations, but there was no effect on allopregnanolone. Interestingly, the increased cortisol concentrations were not reflected in the fetuses, and there was no effect of progesterone treatment on myelination. Therefore, we conclude that in our guinea pig model, maternal administration of progesterone has no effect on cortisol levels or markers of mature oligodendrocytes in the fetus and suggest this is potentially due to the protective cortisol barrier in the placenta.

Placental endocrine function shapes cerebellar development and social behavior

“…Similar sex-dependent MBP changes were previously described in the cerebellum of guinea pigs delivered preterm 9 . In addition, a migration downshift of MAG on western blots was observed in plKO males but not females (Fig.…”

“…8 Wellcome Centre for Integrative Neuroimaging (WIN), Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK. 9 Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Pittsburgh, PA, USA. 10 The George Washington University School of Medicine and Health Sciences, Pediatrics, Washington, DC, USA.…”

Progestin therapy to prevent preterm birth: History and effectiveness of current strategies and development of novel approaches

“…No significant beneficial effect of vaginal P4 prophylaxis on the rate of spontaneous PTB (< 34 weeks) was detected by the OPPTIMUM trial regardless of PTB risk factor (29). Follow-up analyses showed that vaginal P4 had no detectable adverse effects on the infants up to 2 years of age (30) which is consistent with studies in animals showing that P4 therapy during pregnancy has no adverse effect on fetal or neonatal neurodevelopment (31).…”

NTP Research Report on the Scoping Review of Prenatal Exposure to Progestogens and Adverse Health Outcomes

“…The reported results across the same outcome were, however, often inconsistent. For example in animal studies, whole brain (or a specific region of brain) weight was higher in some studies (Ahmad and Zamenhof 1979;Menzies et al 1982;van Marthens et al 1979) and unaffected in others (Coyle et al 1976;Shaw et al 2017;Snyder and Hull 1980). Some studies of prenatal progesterone exposure reported greater performance in the learning and cognition domain in exposed versus unexposed children (Dalton 1968;1976), while other studies reported no difference from controls (Lynch et al 1978;McNamara et al 2015;Norman et al 2016).…”