Steroid hormoneTo establish and successfully maintain a human pregnancy requires the coordinated secretion of hormones within and between the methandienone 10mg cycle, mother, and placenta. The placenta synthesizes and steroidd steroid and peptide hormones that regulate hormonogenesis by endocrine glands in both the mother and the fetus. Moreover, the placenta metabolizes the large quantities of steroid hormones produced by the steroid hormone secreted by ovaries and placenta endocrine glands to protect the fetus and to orchestrate the timing and development of fetal organ systems, the fetal pituitary-adrenocortical axis in particular. Clearly, placental hormonogenesis and metabolism are among the most important determinants of a successful pregnancy; however, despite the numerous advances in our understanding of placental-fetal function, our knowledge of the factors acting and interacting to regulate these processes during human pregnancy remains incomplete. The purpose of this chapter is to review the classic and more recent concepts regarding:
Steroid Endocrinology of Pregnancy | GLOWM
To establish and successfully maintain a human pregnancy requires the coordinated secretion of hormones within and between the fetus, mother, and placenta. The placenta synthesizes and secretes steroid and peptide hormones that regulate hormonogenesis by endocrine glands in both the mother and the fetus. Moreover, the placenta metabolizes the large quantities of steroid hormones produced by the maternal endocrine glands to protect the fetus and to orchestrate the timing and development of fetal organ systems, the fetal pituitary-adrenocortical axis in particular.
Clearly, placental hormonogenesis and metabolism are among the most important determinants of a successful pregnancy; however, despite the numerous advances in our understanding of placental-fetal function, our knowledge of the factors acting and interacting to regulate these processes during human pregnancy remains incomplete.
The purpose of this chapter is to review the classic and more recent concepts regarding: Because the study of maternal-fetal-placental function during human pregnancy is necessarily limited by ethical constraints, this chapter draws heavily on relevant information derived from in vivo experiments conducted in nonhuman primate models. Finally, because of its broad scope, this chapter provides a more general review, rather than an in-depth analysis, of the factors important to pregnancy maintenance, parturition, and fetal development.
More in-depth reviews of key aspects of placental and fetal adrenocortical-gonadal development have recently been published. Development of the Embryo The union of individual male and female gametes represents an orderly and highly regulated sequence of events collectively termed fertilization. At the 8-cell stage, blastomeres begin to form gap and tight junctions, 23 , 24 a process that initiates segregation of inner cells from outer cells and marks the onset of embryo differentiation.
Enders 32 , 33 has concluded that prior to attachment to the uterine epithelium, mononucleated cytotrophoblast cells of the trophectoderm fuse to form a syncytiotrophoblast layer.
The syncytiotrophoblast appears to initially interact with and adhere to the endometrium. Only after the embryo is totally embedded in the endometrium do cytotrophoblast cells begin to move from the trophoblastic shell to invade the uterus and the uterine vasculature.
The human preimplantation blastocyst 5 days after conception. The innercell mass, the cells destined to form embryonic structures, is seen between 3 and 6 o'clock. The remainder consists of the trophectoderm. Biologic and morphologic development of donated human ova recovered by nonsurgical uterine lavage. Am J Obstet Gynecol Preparation of the Uterus for Implantation As the embryo blastocyst is developing and moving through the fallopian tubes into the uterus, the endometrium undergoes extensive differentiation ultimately to permit embryo attachment i.
In virtually all mammals, preparation of the uterus for implantation is regulated by the coordinated actions of estrogen and progesterone 37 produced and secreted by the ovary-corpus luteum and perhaps by the developing embryo itself.
During this interval, and presumably under the influence of estrogen and progesterone, the uterine endometrium is thickened and highly secretory in nature and becomes rich in glycogen and lipids. Changes in the composition of the uterine glycocalyx have also been observed during the peri-implantation period. For example, the levels of two transmembrane glycoproteins, mucin MUC-1 and keratan sulfate, increase on the endometrial glandular surface during the early luteal phase, 9 , 47 , 48 then decrease as the window for implantation opens.
Epithelial integrins have been proposed as markers for the window of implantation in the human. A similar distribution of endometrial integrins and extracellular matrix proteins has been described across the menstrual cycle and early pregnancy in the baboon. A similar role for LIF in humans and nonhuman primates has not been confirmed.
Growth factors and their receptors in human endometrium during the menstrual cycle. Tissue levels shown are relative to the proliferative phase of the cycle. Giudice LC, Saleh W: Growth factors in reproduction. Trends Endocrinol Metab 6: Almost immediately after fertilization, the embryo secretes platelet-activating factor PAF , interleukins-1 and -6, and early pregnancy factor.
Although inhibition of PAF activity in vivo prevented implantation in rodents, 60 a similar role in primate pregnancy has not been demonstrated. By the 8-cell stage, the blastocyst apparently secretes a number of cytokines and growth factors including chorionic gonadotropin hCG , long recognized as one embryonic factor that is essential for early pregnancy in primate species.
The high levels of hCG secreted into the maternal circulation during early gestation apparently are sufficient to bind to the thyroid-stimulating hormone TSH receptor and thereby to increase maternal thyroid hormone production. Although the physiologic role of most of these factors remains to be defined, CRH may play a role in parturition, 76 , 77 modulation of uterine blood flow, 78 and regulation of maternal pituitary ACTH production.
Mean serum hCG levels throughout normal pregnancy: Arithmetic scale used on ordinate. Serum human chorionic gonadotropin levels throughout normal pregnancy. Current perspective on the endocrine and local mechanisms activated during rescue of the corpus luteum at the start of pregnancy in primate species.
Solid lines indicate established pathways, whereas dotted lines indicate proposed pathways. Embryo-derived hCG, perhaps regulated by locally produced GnRH or other factors, prevents the typical regression of the corpus luteum at the end of the nonfertile ovarian cycle. Therefore, the corpus luteum continues to produce progesterone, which sustains intrauterine pregnancy until the luteal-placenta shift.
Embryo-maternal interactions during the establishment of pregnancy in primates. In Charlton HM [eds]: Oxford Reviews of Reproduction Biology. Oxford, Oxford University Press, The steroid biosynthetic pathway for the conversion of substrate cholesterol to the progestogens, androgens, and estrogens.
Placental steroidogenesis in primate pregnancy. In Knobil E, Neill J [eds]: Encyclopedia of Reproduction, Vol 3, pp — Boston, Academic Press, The human decidua that represents the maternal component of the placenta is composed primarily of the decidua basalis, underlying the site of implantation, the decidua capsularis that initially overlies the gestational sac but gradually disappears with advancing gestation, and the decidua vera that lines the remainder of the uterine cavity.
In humans, as well as the baboon, 82 the decidua produces and secretes a variety of factors that include the hormones relaxin and prolactin, the IGF-binding protein IGF-BP-1 , and a variety of other proteins e. In the human, IGF-BP-1 is secreted by the stromal cells that surround the spiral arteries during the late luteal phase, whereas in the baboon, IGF-BP-1 is secreted by the endometrial glands in response to progesterone.
IGF-BP-1 levels increase rapidly during early gestation in parallel with decidualization, then transiently decline before increasing again in late pregnancy. Glycodelin, synthesized by the uterine glandular epithelium, shares homology with the B-lactoglobulins and retinol-binding proteins 89 and has been implicated as an immunosuppressive agent.
In the baboon, although the pattern of uterine glycodelin mRNA and protein expression mimics that in the human, glycodelin production is regulated by hCG, 95 perhaps by direct action on the endometrium. Decidual prolactin production begins on day 22 of the idealized human menstrual cycle approximately 8 days after ovulation 96 and prolactin mRNA and protein expression is observed in the epithelial cells of the deep basal glands of the baboon uterus during the late luteal phase.
Decidual prolactin expression increases markedly with advancing gestation and is stimulated by progesterone in both the human 97 , 98 and baboon. Although the precise role s of decidual prolactin remains unclear, it has been proposed that the hormone may enhance uterine contractility, an action also apparently antagonized by decidual relaxin.
Both processes depend on the ability of the primordial stem-cell cytotrophoblasts to take either the villous pathway where they remain in the fetal compartment and differentiate morphologically into the syncytiotrophoblast or the extravillous pathway where they proliferate, aggregate into cell columns of the anchoring villi, and invade the endometrial stroma Fig.
Placental villous and extravillous trophoblast pathways during primate pregnancy. Human cytotrophoblasts adopt a vascular phenotype as they differentiate: A strategy for successful endovascular invasion? J Clin Invest The vascular network within the placental villous core develops by in situ differentiation of fetal mesenchymal cells into vessels vasculogenesis and proliferation of existing vessels angiogenesis resulting in secondary and tertiary villi equipped with a functional arterio-capillary-venous system.
In humans, placental vasculogenesis begins at approximately 21 days of gestation and continues through at least the 26th week of pregnancy. In Tie-2 null mice, endothelial cells develop and assemble into tubes, but vessels are immature, lacking branching networks, encapsulation by periendothelial support cells, and proper organization into small and large vessels. During early human pregnancy, angiopoietin-1 is localized to the cytotrophoblast and syncytiotrophoblast, angiopoietin-2 to the cytotrophoblast, and Tie-2 receptor to the endothelium, , observations that are consistent with the proposed role of the angiopoietin-Tie-2 system in development of the placental circulation.
At the same time the vascular system is developing within the chorionic villi, a select population of extravillous cytotrophoblasts migrate and invade the spiral arteries of the uterine endometrium at the placental-decidual junction see Fig.
Consequently, the structure of spiral arteries and the dynamics of blood flow within them are modified by cytotrophoblast invasion, presumably to facilitate implantation and placentation.
As cytotrophoblasts differentiate into cells capable of invading the uterine stroma and blood vessels, their expression of adhesion molecules changes in the human, 8 , , , , , baboon, and rhesus monkey. Migratory cytotrophoblast cells also express specific adhesion molecules, specifically vascular cell adhesion molecule VCAM and cadherins e. MMP-9 promotes cytotrophoblast invasion; the capacity of human cytotrophoblast to invade is completely inhibited by MMP-9 antibody in vitro.
This area of research is of intense interest and clinically relevant. Abnormal expression of several of these components has been observed in cytotrophoblasts of women who develop preeclampsia and in whom endovascular invasion is superficial. As a result of extensive hydroxylation of c19 steroids within the fetus, large quantities of estriol are produced by the placenta during human pregnancy.
A fourth estrogen, estetrol, is also produced uniquely but in relatively low levels during human pregnancy. Molecular structures of the estrogens. The basic carbon estrane nucleus, shared by estrone, estradiol, and estriol, is modified for each by differences in the number and arrangement of hydroxyl groups. Plasma concentrations of estrone, estradiol, and estriol increase as human pregnancy progresses Fig.
It would appear that in both human and nonhuman primate pregnancy, estrogen is produced in considerable excess. Levitz M, Young BK: Because pregnancy with an anencephalic fetus is associated with very low levels of urinary estrogen and fetal adrenal hypoplasia, Frandsen and Stakeman suggested that the fetal adrenal may provide the requisite androgen precursors for placental estrogen production.
The biosynthesis of estrone E 1 , estradiol E 2 , and estriol E 3 by the human fetal-placental unit.
Placental steroid hormone biosynthesis in primate pregnancy. Once secreted by the fetal adrenal gland, DHA is rapidly sulfated in the fetal liver to form DHAS and subsequently hydroxylated at carbon 16 to form hydroxy DHAS, the primary precursor for estriol formation. On arrival in the placenta, sulfurylated c19 steroids precursors are desulfurylated by the enzyme sulfatase to yield unconjugated DHA and hydroxy DHA.
Although the regulation of sulfatase is unknown, prolactin and oxytocin stimulate enzyme activity in decidual cells isolated before the onset of human labor. The subsequent conversions of androstenedione and testosterone to estrone and estradiol and hydroxyandrostenedione to estriol see Fig. The entire three-step process is catalyzed at one active site by a single cytochrome P species. Recent studies have shown that the CYP19 gene encoding human cytochrome Parom is located on chromosome 15 and consists of 9 exons and two polyadenylation sites in the last coding exon downstream from the terminating stop codon that gives rise to the 3.
Although the entire intron sequences remain to be mapped, the CYP19 gene is at least 70 kb long and is the largest cytochrome P gene characterized to date reviewed elsewhere Novy and colleagues , demonstrated that reductions in uteroplacental perfusion caused by graded reductions in maternal distal aortic blood flow in the pregnant baboon resulted in corresponding decreases in the placental clearance of DHA through estradiol formation.
Mean metabolic clearance rate of dehydroepiandrosterone sulfate DHEA-S in normal primigravidas studied sequentially throughout gestation. Study of the metabolic clearance rate of dehydroisoandrosterone sulfate in pregnancy. Fetal Adrenal c19 Steroids The fetal adrenal is a major source of the c19 steroids required for estrogen production; growth and function of the gland therefore greatly influence the production of estrogen.
In fetal baboons, acute stress induced by hypoxemia results in a marked increase in fetal adrenal csteroid secretion and results in a corresponding rise in placental estrogen production.