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.

Keywords: cholesterol; estrogens; gestational diabetes mellitus; glucocorticoids; intrauterine growth retardation; oxysterols; preeclampsia; progestagens.

FIGURE 1

The placental barrier. (A) Schematic depiction of the main structural elements of the human placenta. From the chorionic plate (CP), the umbilical cord (UC), and the chorionic villi (CV) originate. The umbilical vein carries oxygen- and nutrient-rich blood from the placenta to the fetus, while two arteries transport deoxygenated blood and waste products from the fetus to the placenta. The intervillous space (IS) is filled with maternal blood that enters this cavity via remodeled and opened maternal spiral arteries (SA) and leaves via uterine veins (UV). Cells in direct contact with maternal blood are the villous trophoblasts (T). The basal plate (BP) contains extravillous trophoblasts and decidual cells. (B,C) Schematic representation of first trimester (B) and term trimester chorionic villi (C) depicting the major cell types and the placental barrier. CTB, cytotrophoblast; M, myometrium of the maternal uterus, pFECs, placental-fetal endothelial cells; STB, syncytiotrophoblast.

FIGURE 2

Structures of the steroid skeleton, cholesterol, and common oxysterols. (A) All steroids have the same basic perhydro-1,2-cyclopentenophenanthrene skeleton. Letters designate each ring, the carbon atoms are numbered. A slight variation in this skeleton or the introduction of functional groups result in various classes of steroids. (B) Unesterified cholesterol contains this skeleton with a hydroxyl group, two methyl groups, and a hydrogen tail. In the esterified form, a fatty acid would be bound to the hydroxyl group by an ester bond. (C) 25-hydroxycholesterol (25-OHC), the most extensively studied oxysterol. (D) Oxysterol 27-hydroxycholesterol (27-OHC). (E) Oxysterol 7-ketocholesterol. Red molecules indicate the positions of hydroxylation (C,D) or oxidation (E) of cholesterol to 25- or 27-OHC, or 7-ketocholesterol, respectively. Oxysterols are intermediates of cholesterol catabolism and act as signaling molecules with regulatory impact on various cellular processes including lipid metabolism.

FIGURE 3

Important steps in cholesterol synthesis and homeostasis. Cholesterol synthesis occurs via the mevalonate pathway and involves over 20 enzymes. It starts from acetyl-CoA in the cytosol, but all steps downstream of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) occur in the smooth endoplasmic reticulum. Lanosterol, the first sterol, feeds either into the Bloch pathway or the Kandutsch–Russell pathway. In these pathways, cholesterol is produced from either desmosterol or 7-dehydrocholesterol (7-DHC), by the enzymes 24-dehydrocholesterol reductase (DHCR24) and 7-dehydrocholesterol reductase (DHCR7), respectively. Gene mutations of the enzyme DHCR7 result in Smith-Lemli-Opitz syndrome, SLOS, with increased levels of cholesterol precursors and reduced levels of cholesterol. In the skin, 7-DHC can be converted to vitamin D by UVB light. Diverse oxysterols are produced enzymatically from cholesterol, its precursors but also during subsequent steroid hormone synthesis. The rate limiting step in cholesterol synthesis is catalyzed by 3 HMG-CoA reductase (HMGR). Cellular homeostasis of cholesterol is maintained by three distinct mechanisms (red arrows). (1) Regulation of HMGR activity and levels to control cholesterol biosynthesis occurs by feed-back inhibition, control of gene expression, rate of enzyme degradation, and phosphorylation–dephosphorylation. For example, the transcription factor sterol regulatory element-binding protein 2 (SREBP2) positively regulates the gene expression of HMGR. Rising cholesterol and oxysterol levels reduce the rate of cholesterol biosynthesis by modulating the activities of insulin-induced gene (INSIG) proteins. When activated, INSIG both promotes the ubiquitination and consequent destabilization of HMGR and inhibits the transcriptional activity of SREBP2 by retaining it in complex with SREBP cleavage-activating protein (SCAP) in the endoplasmic reticulum. (2) Rising cholesterol levels also activate acyl-coenzyme A:cholesterol acyltransferase (ACAT), which esterifies cholesterol leading to its sequestration in cytosolic lipid droplets. Through hydrolysis via the cholesteryl ester hydrolase (CEH) enzyme system, the cholesteryl esters can be reused later. (3) Regulation of cholesterol uptake and export via low-density lipoprotein (LDL)-receptor-mediated uptake and high-density lipoprotein HDL-mediated reverse transport, respectively. Oxysterols activate liver-X receptor (LXR) transcription factors, which positively regulate the transcription of proteins that drive cholesterol efflux from the cell (ABC transporter, ABCA1 and ABCG1), and sequester it in lipoprotein particles containing Apolipoprotein E (ApoE) in the circulatory system. Activation of oxysterol binding protein-related proteins (ORP) by oxysterols negatively regulates cholesterol efflux by promoting ABCA1 ubiquitination and degradation. Following binding of lipoprotein particles (LDL and HDL) to their respective receptors [LDLR, Scavenger receptor class B type 1 (SRB1)], they are internalized into endosomes. Alternatively, HDL particles can transfer cholesteryl esters to the plasma membrane (selective lipid uptake) without requirement for endocytosis. Within endosomes, Niemann-Pick C1 (NPC1) and NPC2 are critical for the egress of internalized cholesterol from endosomes; they act together to redistribute cholesterol to the ER. Statins are HMGR inhibitors. The net result of statin treatment is an increased cellular uptake of LDLs, since the intracellular synthesis of cholesterol is inhibited and cells are therefore dependent on extracellular sources of cholesterol.

FIGURE 4

Proposed model for placental uptake of cholesterol from maternal lipoproteins, cholesterol metabolism, and materno-fetal transport of cholesterol. For detailed information, see text. Solid arrows indicate pathways that have been demonstrated in vitro. Dashed arrows indicate hypothetic routes. Apo, Apolipoprotein; ABC transporters, ATP-binding cassette transporters; CYPs, cytochrome P-450 enzymes; CTB, cytotrophoblast; pFECs, placental-fetal endothelial cells; HDL, high-density lipoprotein; HSP, heat shock protein; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; LRP, lipoprotein receptor-related proteins; LXR, liver X receptor; PDI, protein disulfide isomerase; MTP, microsomal triglyceride transfer protein; RXR, retinoid X receptor; SRB1, scavenger receptor class B type 1; STARD3, StAR-related lipid transfer domain protein 3; STB, syncytiotrophoblast; VLDL, very low-density lipoprotein; VLDLR, very low-density lipoprotein receptor.

FIGURE 5

Structures and interconversion of the sex-steroids progestagens (green), estrogens (red), and androgens (blue) starting from cholesterol. For detailed information, see text. Arrows indicate metabolizing processes by respective enzymes (gray). CYPs, cytochrome P-450 enzymes; HSD, hydroxysteroid dehydrogenase; SULT, sulfotransferase.

FIGURE 6

Proposed model for placental progesterone and estrogen synthesis. For detailed description, see text. Progestagens are shown in green, estrogens in red, and androgens in blue color. Solid arrows indicate enzymatic steps that have been demonstrated in human placenta; respective enzymes are shown in gray. Dashed arrows indicate hypothetic routes of transport of sulfate-conjugated compounds. Dashed purple circles highlight sulfate-conjugated compounds that require transporters for uptake into (SOAT, OAT4, and OATP2B1) and export (ABCG2) from cells. A-dione, androstenedione; ABC transporters, ATP-binding cassette transporters; BCRP, breast cancer resistance protein; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulfate; CYPs, cytochrome P-450 enzymes; E1, estrone; E1-S, estrone sulfate; E2, Estradiol; E2-S, estradiol sulfate; E3, estriol; E3-S, estriol sulfate; ER, endoplasmatic reticulum; pFEC, placental-fetal endothelial cell; -OH-, -Hydroxy-; 17α-OHP, 17α-hydroxyprogesterone; HSD, hydroxysteroid dehydrogenase; OAT4, organic anion transporter 4; OATP2B1, organic anion transporting polypeptide 2B1; SOAT, sodium-dependent organic anion transporter; STS, steroid sulfatase; SULT, sulfotransferase; STB, syncytiotrophoblast; TES, testosterone.

FIGURE 7

Interconversion of cortisol and the inactive metabolite cortisone by 11β-hydroxysteroid dehydrogenases type 1 and 2. 11β-HSD1 exerts mainly reductase activity in vivo, while 11β-HSD2 metabolizes the conversion of cortisol to cortisone. In human placenta, conversion from cortisol to cortisone predominates at all gestational ages, but increasing conversion of cortisone to cortisol in homogenized human placental tissue toward term indicates a predominant reductase activity of 11β-HSD1.

FIGURE 8

Proposed model for placental glucocorticoid (cortisol) function and metabolism. For detailed description, see text. Cortisol can diffuse across cell membranes and regulate target protein expression directly via glucocorticoid receptor (GR) or indirectly via other transcription factors (e.g., Sp1). Placental corticotropin-releasing hormone (CRH) is the major mediator of adaptive response to stressors during pregnancy. Cortisol stimulates placental CRH expression, which regulates placental hormone levels (e.g., hCG, estrogen, progesterone, and 11β-HSD2). Red arrows indicate inhibiting/negative feedback pathways, while green arrows indicate stimulating pathways. ABC transporters, ATP-binding cassette transporters; ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; DHEA, dehydroepiandrosterone; GRE, glucocorticoid response element; HSD, hydroxysteroid dehydrogenase; hCG, human chorionic gonadotropin; pFEC, placental-fetal endothelial cell; PKA, protein kinase A; Sp1, specificity protein 1 transcription factor; STB, syncytiotrophoblast.