Physiology and Pathophysiology of Steroid Biosynthesis, Transport and Metabolism in the Human Placenta

Abstract

The steroid hormones progestagens, estrogens, androgens, and glucocorticoids as well as their precursor cholesterol are required for successful establishment and maintenance of pregnancy and proper development of the fetus. The human placenta forms at the interface of maternal and fetal circulation. It participates in biosynthesis and metabolism of steroids as well as their regulated exchange between maternal and fetal compartment. This review outlines the mechanisms of human placental handling of steroid compounds. Cholesterol is transported from mother to offspring involving lipoprotein receptors such as low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SRB1) as well as ATP-binding cassette (ABC)-transporters, ABCA1 and ABCG1. Additionally, cholesterol is also a precursor for placental progesterone and estrogen synthesis. Hormone synthesis is predominantly performed by members of the cytochrome P-450 (CYP) enzyme family including CYP11A1 or CYP19A1 and hydroxysteroid dehydrogenases (HSDs) such as 3β-HSD and 17β-HSD. Placental estrogen synthesis requires delivery of sulfate-conjugated precursor molecules from fetal and maternal serum. Placental uptake of these precursors is mediated by members of the solute carrier (SLC) family including sodium-dependent organic anion transporter (SOAT), organic anion transporter 4 (OAT4), and organic anion transporting polypeptide 2B1 (OATP2B1). Maternal–fetal glucocorticoid transport has to be tightly regulated in order to ensure healthy fetal growth and development. For that purpose, the placenta expresses the enzymes 11β-HSD 1 and 2 as well as the transporter ABCB1. This article also summarizes the impact of diverse compounds and diseases on the expression level and activity of the involved transporters, receptors, and metabolizing enzymes and concludes that the regulatory mechanisms changing the physiological to a pathophysiological state are barely explored. The structure and the cellular composition of the human placental barrier are introduced. While steroid production, metabolism and transport in the placental syncytiotrophoblast have been explored for decades, few information is available for the role of placental-fetal endothelial cells in these processes. With regard to placental structure and function, significant differences exist between species. To further decipher physiologic pathways and their pathologic alterations in placental steroid handling, proper model systems are mandatory.

Neonatal HDL Counteracts Placental Vascular Inflammation via S1P–S1PR1 Axis

“…Human pregnancy is accompanied by hyperlipidemia (particularly during the last trimester), with a rise in triglycerides and cholesterol levels in HDL and LDL particles, to meet the cholesterol demand of the fetus [26]. LDL particles represent the major cholesterol carrier in the maternal circulation, where they also serve as a substrate for placental progesterone synthesis [27,28]. Conversely, in cord blood circulation the HDL particle is the cholesterol carrier [29], suggesting a specific and distinct role of the cord blood-derived particles compared to the adult ones.…”

Maternal 25-Hydroxyvitamin D Deficiency Promoted Metabolic Syndrome and Downregulated Nrf2/CBR1 Pathway in Offspring

“…In light of Nrf2 and CBR1 expression reduction in 25(OH) D deficient maternal placenta (Figure 4), we explored the role of the placenta in the process of maternal 25(OH)D deficiency induced MetS in offspring. The placenta is a multifunctional organ enabling optimal fetal growth (Chatuphonprasert et al, 2018). The fetus develops in the womb and depends on the placenta for receiving nutrients from the mother.…”

Functional polymorphisms in the MED13L and SLC4A7 genes are associated with pregnancy-induced hypertension

“…Many studies have investigated the consequences of the mutations of the CYP450 superfamily. Though Chatuphonprasert et al found the association between PE and altered expression of CYP27A1 protein in placenta, maternal, and/or fetal serum [41], another research conducted in a Korean population detected no significant association between polymorphisms in CYP1A1gene and PE [42]. Also, a Spanish study included 500 Caucasians from the region of Asturias indicated that the variation in CYP3A5, CYP3A4, and CYP21A2 did not contribute to the risk for PIH [43].…”