Steroids, Pregnancy and Fetal Development

Abstract

Maternal glucocorticoids critically rise during pregnancy reaching up to a 20-fold increase of mid-pregnancy concentrations. Concurrently, another steroid hormone, progesterone, increases. Progesterone, which shows structural similarities to glucocorticoids, can bind the intracellular glucocorticoid receptor, although with lower affinity. Progesterone is essential for the establishment and continuation of pregnancy and it is generally acknowledged to promote maternal immune tolerance to fetal alloantigens through a wealth of immunomodulatory mechanisms. Despite the potent immunomodulatory capacity of glucocorticoids, little is known about their role during pregnancy. Here we aim to compare general aspects of glucocorticoids and progesterone during pregnancy, including shared common steroidogenic pathways, plasma transporters, regulatory pathways, expression of receptors, and mechanisms of action in immune cells. It was recently acknowledged that progesterone receptors are not ubiquitously expressed on immune cells and that pivotal features of progesterone induced-maternal immune adaptations to pregnancy are mediated via the glucocorticoid receptor, including e.g., T regulatory cells expansion. We hypothesize that a tight equilibrium between progesterone and glucocorticoids is critically required and recapitulate evidence supporting that their disequilibrium underlie pregnancy complications. Such a disequilibrium can occur, e.g., after maternal stress perception, which triggers the release of glucocorticoids and impair progesterone secretion, resulting in intrauterine inflammation. These endocrine misbalance might be interconnected, as increase in glucocorticoid synthesis, e.g., upon stress, may occur in detriment of progesterone steroidogenesis, by depleting the common precursor pregnenolone. Abundant literature supports that progesterone deficiency underlies pregnancy complications in which immune tolerance is challenged. In these settings, it is largely yet undefined if and how glucocorticoids are affected. However, although progesterone immunomodulation during pregnancy appear to be chiefly mediated glucocorticoid receptors, excess glucocorticoids cannot compensate by progesterone deficiency, indicating that additional und still undercover mechanisms are at play.

COVID-19 in pregnancy and the puerperium: A review for emergency physicians

“…The RECOVERY trial, which demonstrated a mortality benefit of dexamethasone in patients with COVID-19 who required respiratory support, did include pregnant and breastfeeding patients and reported no pregnancy-associated adverse outcomes [ 37 ]. Use of high doses of dexamethasone in early pregnancy has been associated with poor pregnancy outcomes in mice, mares, and dogs [ 38 ]. These outcomes included early pregnancy termination, impaired fetal growth, and abnormal placentation [ 38 ].…”

“…Use of high doses of dexamethasone in early pregnancy has been associated with poor pregnancy outcomes in mice, mares, and dogs [ 38 ]. These outcomes included early pregnancy termination, impaired fetal growth, and abnormal placentation [ 38 ]. However, the RECOVERY trial utilized dexamethasone 6 mg daily, which is not high dose [ 37 ].…”

The Role(s) of Eicosanoids and Exosomes in Human Parturition

“…Before the parturition process starts, a relaxation state of the myometrium with minimum sensitivity to stimulatory uterotonins, such as PGs, is controlled by progesterone ( Mesiano, 2004 ; Ilicic et al, 2020 ). Progesterone is a key player in the establishment and maintenance of pregnancy and its role and regulation have been extensively studied in human and experimental models ( Arck et al, 2007 ; Forde et al, 2009 ; Solano and Arck, 2020 ). Progesterone withdrawal usually indicates the initiation of the parturition process with changes in the contractile activity of the myometrium.…”

Secretory phospholipase A2-X (Pla2g10) is a novel progesterone receptor target gene exclusively induced in uterine luminal epithelium for uterine receptivity in mice

“…Irregular actions of these hormones may provide various causes of RIF. P 4 play critical roles for the establishment and maintenance of pregnancy by not only its endocrine but also immunological effects [14,15]. P 4 -PR transcriptional network along with estrogen signaling promotes spatiotemporal regulation of various target genes for achieving uterine receptivity in the uterus [16].…”