Steroid hormone synthesis in pregnancy
Section snippets
Substrate for steroid hormone synthesis
The precursor for all steroid hormone synthesis is the 27 carbon-containing cholesterol molecule, a lipid that is composed of four fused rings (the 17 carbon-containing cyclopentanoperhydrophenanthrene backbone) with associated side chains (Fig. 1). Cholesterol substrate, a major component of cell membranes, can be obtained from cholesterol-laden lipoproteins in human plasma, de novo cholesterol synthesis in steroidogenic tissues, and intracellular lipid droplets that store cholesterol esters
Overview of steroidogenesis in pregnancy
Measurement of steroid hormone production in pregnancy demonstrates a placenta that produces vast quantities of progesterone (250 mg/d at term [78]) and estriol (35–45 mg/d [79], [80], [81]) and lesser amounts of estrone, estradiol, and estetrol (Fig. 2) [16], [82]. The secretion of all placental estrogens increases throughout gestation [83]. The relative concentrations of estrogens in the maternal serum (estradiol > estriol) do not reflect placental production; this is reflected better by the
Cholesterol availability to p450 side chain cleavage system
The acute stimulation of steroidogenesis in the adrenals and gonads is triggered by trophic hormone-induced generation of cyclic adenosine monophosphate (cAMP), with subsequent activation of phosphorylation and gene transcription by the cAMP-dependent protein kinase A. The first committed step in steroid hormone synthesis is the side-chain cleavage of cholesterol to form pregnenolone, a step that is catalyzed by the side-chain cleavage enzyme system (P450scc/CYP11A1), which is located on the
The steroidogenic pathways in human pregnancy
The current understanding of steroid hormone synthesis during human pregnancy is depicted (see Fig. 2). The placental syncytiotrophoblast readily converts cholesterol substrate (largely, but not exclusively, derived from maternal LDL) to pregnenolone by way of the P450scc enzyme [118], [119], [120]. Required for this reaction are two cofactors: a flavoprotein reductase (ferredoxin/adrenodoxin reductase) and an iron sulfoprotein (ferredoxin/adrenodoxin); together, these ensure reducing
Questions and controversies regarding human steroid hormone production in pregnancy
From the above-mentioned physiology, one can explain the integrated process that results in placental production of progesterone, estrone, estradiol, and estriol. Several important issues warrant further investigation.
When and how does the fetal adrenal first produce glucocorticoids and mineralocorticoids? Prevailing theory has supported the notion that fetal deficiency of 3β-HSD ensures increased production of fetal DHEAS (the substrate for placental estrogens) and precludes significant
Acknowledgments
The author is deeply grateful to Dr. Richard Hochberg for the critical review of this manuscript and for assistance in the preparation of the figures.
References (175)
- et al.
The utilization of circulating dehydroisoandrosterone sulfate for estrogen synthesis during human pregnancy
Steroids
(1963) - et al.
Differential actions of progesterone and cortisol on lymphocyte and monocyte interaction during lymphocyte activation–relevance to immunosuppression in pregnancy
J Reprod Immunol
(1983) - et al.
Tolerance to the foeto-placental ‘graft’: ten ways to support a child for nine months
Curr Opin Immunol
(2000) - et al.
Embryo-maternal signalling: how the embryo starts talking to its mother to accomplish implantation
Reprod Biomed Online
(2003) - et al.
Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone
FEMS Immunol Med Microbiol
(2003) - et al.
Endocrine basis for the initiation, maintenance and termination of pregnancy in humans
Psychoneuroendocrinology
(1988) - et al.
The effects of a progesterone metabolite, 5 beta-dihydroprogesterone, on oxytocin receptor binding in human myometrial membranes
BJOG
(2003) - et al.
The involvement of progesterone in the onset of human labour
Eur J Obstet Gynecol Reprod Biol
(2003) - et al.
Mechanisms modulating estrogen-induced uterine vasodilation
Vascul Pharmacol
(2002) - et al.
Circulatory responses to systemic infusions of estrone and estradiol-17alpha in nonpregnant, oophorectomized ewes
Am J Obstet Gynecol
(1978)
The relationship between the timing of luteectomy and the incidence of complete abortions
Am J Obstet Gynecol
The de novo synthesis of sterols and steroids from acetate by preparations of human term placenta
Steroids
Cholesterol synthesis by human fetal hepatocytes: effect of lipoproteins
Am J Obstet Gynecol
Transport of cholesterol across a BeWo cell monolayer: implications for net transport of sterol from maternal to fetal circulation
J Lipid Res
Regulated expression of the trophoblast alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein. Differentiation and cAMP modulate protein and mRNA levels
J Biol Chem
Metabolism of modified LDL by cultured human placental cells
Atherosclerosis
Structure and localization of the human gene encoding SR-BI/CLA-1. Evidence for transcriptional control by steroidogenic factor 1
J Biol Chem
Selective cholesteryl ester uptake from high density lipoprotein by human first trimester and term villous trophoblast cells
Placenta
Uterine and placental expression of steroidogenic genes during rodent pregnancy
Mol Cell Endocrinol
Presence of CLA-1 and HDL binding sites on syncytiotrophoblast brush border and basal plasma membranes of human placenta
Placenta
The efficient cellular uptake of high density lipoprotein lipids via scavenger receptor class B type I requires not only receptor-mediated surface binding but also receptor-specific lipid transfer mediated by its extracellular domain
J Biol Chem
Dimerization of the scavenger receptor class B type I: formation, function, and localization in diverse cells and tissues
J Lipid Res
SR-BI and cholesterol uptake into steroidogenic cells
Trends Endocrinol Metab
Oestriol binding to plasma proteins
J Steroid Biochem
The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR)
J Biol Chem
Unveiling the mechanism of action and regulation of the steroidogenic acute regulatory protein
Mol Cell Endocrinol
Studies on ACTH action in perfused bovine adrenals: site of action of ACTH corticosteroidogenesis
Arch Biochem Biophys
Cytochrome P-450scc-substrate interactions. Studies of binding and catalytic activity using hydroxycholesterols
J Biol Chem
Protein synthesis and adrenocorticotropin responsiveness
J Biol Chem
Acute ACTH regulation of adrenal corticosteroid biosynthesis. Rapid accumulation of a phosphoprotein
J Biol Chem
Placental estrogen biosynthesis during human pregnancy
J Clin Endocrinol Metab
Placental biosynthesis and metabolism of steroid hormones in primates
Contrib Primatol
The formation of progesterone by the human placenta
Am J Obstet Gynecol
Developmental and functional biology of the primate fetal adrenal cortex
Endocr Rev
Steroid metabolism in the human foeto-placental unit
Acta Endocrinol (Copenh)
Novel signaling pathways that control ovarian follicular development, ovulation, and luteinization
Recent Prog Horm Res
The effects of estrogen on the expression of genes underlying the differentiation of somatic cells in the murine gonad
Endocrinology
Progesterone as a mediator of gonadotrophin action in the corpus luteum: beyond steroidogenesis
Hum Reprod Update
The road to ovulation: the role of oestrogens
Reprod Fertil Dev
Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes
Development
Progesterone and maintenance of pregnancy: is progesterone nature's immunosuppressant?
Ann N Y Acad Sci
Cytokine regulation of trophoblast steroidogenesis
J Clin Endocrinol Metab
Steroids as immunosuppressants in pregnancy
Immunol Rev
Actions of placental and fetal adrenal steroid hormones in primate pregnancy
Endocr Rev
Immunological relationship between the mother and the fetus
Int Rev Immunol
Microarray analysis of genes controlled by progesterone in human endometrial stromal cells in vitro
Gynecol Endocrinol
Uterine contraction and physiological mechanisms of modulation
Am J Physiol
The physiological basis of uterine contractility: a short review
Exp Physiol
Regulation of myometrial smooth muscle functions
Curr Pharm Des
Estrogen selectively up-regulates eNOS and nNOS in reproductive arteries by transcriptional mechanisms
J Soc Gynecol Investig
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