Obstentrics_Williams

Obstentrics_Williams. As the amnionic sac expands, the compactness of the mesenchymal cells is progressively reduced, and they become sparsely distributed. Early in pregnancy, amnionic epithelium replicates at a rate appreciably faster than mesenchymal cells. At term, these cells form a continuous uninterrupted epithelium on the fetal amnionic surface. Conversely, mesenchymal cells are widely dispersed, being connected by a ine lattice network of extracellular matrix with the appearance of long slender ibrils.


Obstentrics_Williams

Obstentrics_Williams. he apical surface of the amnionic epithelium is replete with highly developed microvilli. This structure relects its function as a major site of transfer between amnionic luid and amnion. This epithelium is metabolically active, and its cells synthesize tissue inhibitor of MMP-l, prostaglandin E2 (PGE2), and fetal ibronectin (FN) (Rowe, 1997). Although epithelia produce FN, recent studies suggest that ibronectin functions in the underlying mesenchymal cells. Here, FN promotes synthesis of MMPs that break down the strength-bearing collagens and enhance prostaglandin synthesis to prompt uterine contractions (Mogami, 2013). This pathway is upregulated in premature rupture of membranes induced by thrombin or infection-induced release of FN (Chigusa, 2016; Mogami, 2014).


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Obstentrics_Williams. Epithelial cells may respond to signals derived from the fetus or the mother, and they are responsive to various endocrine or paracrine modulators. Examples include oxytocin and vasopressin, both of which increase PGE2 production in vitro (Moore, 1988). They may also produce cytokines such as IL-8 during labor initiation (Elliott, 2001).


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Obstentrics_Williams. Amnionic epithelium also synthesizes vasoactive pep tides, including endothelin and parathyroid hormone-related protein (Economos, 1992; Germain, 1992). he tissue produces brain natriuretic peptide (BNP) and corticotropin-releasing hormone (CRH), which are peptides that invoke smooth-muscle relaxation (Riley, 1991; Warren, 1995). BNP production is positively regulated by mechanical stretch in fetal membranes and is proposed to function in uterine quiescence. Epidermal growth factor, a negative regulator ofBNP, is up regulated in the membranes at term and leads to a decline in BNP-regulated uterine quiescence (Carvaj al, 2013). It seems reasonable that vasoactive peptides produced in amnion gain access to the adventitial surface of chorionic vessels. hus, the amnion may be involved in modulating chorionic vessel tone and blood low. Amnionderived vasoactive peptides function in both maternal and fetal tissues in diverse physiological processes. AOter their secretion, these bioactive


Obstentrics_Williams

Obstentrics_Williams. chorionic vessel tone and blood low. Amnionderived vasoactive peptides function in both maternal and fetal tissues in diverse physiological processes. AOter their secretion, these bioactive agents enter amnionic luid and thereby are available to the fetus by swallowing and inhalation.


Obstentrics_Williams

Obstentrics_Williams. Mesenchymal cells of the amnionic ibroblast layer are responsible for other major functions. Synthesis of interstitial collagens that compose the compact layer of the amnion-the major source of its tensile strength-takes place in mesenchymal cells (Casey, 1996). At term the generation of cortisol by l1�-hydroxysteroid dehydrogenase may contribute to membrane rupture via reduction of collagen abundance (Mi, 2017). Mesenchymal cells also synthesize cytokines that include IL-6, IL-8, and MCP-I. Cytokine synthesis rises in response to bacterial toxins and IL-1. his functional capacity of amnion mesenchymal cells is an important consideration in amnionic fluid study of labor-associated accumulation of inlammatory mediators (Garcia-Velasco, 1999). Finally, mesenchymal cells may be a greater source of PGE2 than epithelial cells, especially in the case of premature membrane rupture (Mogami, 2013; Whittle, 2000).


Obstentrics_Williams

Obstentrics_Williams. During tests of tensile strength, the decidua and then the chorion laeve give way long before the amnion ruptures. Indeed, the membranes are elastic and can expand to twice normal size during pregnancy (Benirschke, 2012). The amnion tensile strength resides almost exclusively in the compact layer, which is composed of cross-linked interstitial collagens I and III and lesser amounts of collagens V and VI. Collagens are the primary macromolecules of most connective tissues. Collagen I is the major interstitial collagen in tissues characterized by great tensile strength, such as bone and tendon. In other tissues, collagen III is believed to contribute to tissue integrity and provides both tissue extensibility and tensile strength. For example, the ratio of collagen III to collagen I in the walls of a number of highly extensible tissues-amnionic sac, blood vessels, urinary bladder, bile ducts, intestine, and gravid uterus-is greater than that in nonelastic tissues a efrey, 1991).


Obstentrics_Williams

Obstentrics_Williams. Amnion tensile strength is regulated in part by fibrillar collagen assembly. his process is influenced by the interaction fibrils with proteoglycans such as decorin and biglycan (Chap. 21, p. 409). Reduction of these proteoglycans is reported to perturb fetal membrane function (Horgan, 2014; Wu, 2014). Fetal membranes overlying the cervix have a regional shift in gene expression and lymphocyte activation that set in motion an inflammatory cascade (Marcellin, 2017). his change may contribute to tissue remodeling and loss of tensile strength in the amnion (Moore, 2009).


Obstentrics_Williams

Obstentrics_Williams. The amnion is metabolically active, is involved in solute and water transport for amnionic fluid homeostasis, and produces an impressive array of bioactive compounds. The amnion is responsive both acutely and chronically to mechanical stretch, which alters amnionic gene expression (Carvajal, 2013; Nemeth, 2000). This in turn may trigger both autocrine and paracrine responses that include production of MMPs, IL-8, and collagenase (Bryant-Greenwood, 1998; Mogami, 2013). Such factors may modulate changes in membrane properties during labor.


Obstentrics_Williams

Obstentrics_Williams. he yolk sac and the umbilical vesicle into which it develops are prominent early in pregnancy. At irst, the embryo is a lattened disc interposed between amnion and yolk sac (see Fig. 5-9). Its dorsal surface grows faster than the ventral surface, in association with the elongation of its neural tube. Thus, the embryo bulges into the amnionic sac, and the dorsal part of the yolk sac is incorporated into the embryo body to form the gut. The allantois projects into the base of the body stalk from the caudal wall of the yolk sac and later, from the anterior wall of the hindgut.


Obstentrics_Williams

Obstentrics_Williams. As pregnancy advances, the yolk sac becomes smaller and its pedicle relatively longer. By the middle of the third month, the expanding amnion obliterates the extraembryonic coelom, fuses with the chorion laeve, and covers the bulging placental disc and the lateral surface of the body stalk. The latter is then called the umbilical cord-or funis. A more detailed description of this cord and potential abnormalities is found in Chapter 6 (p. 117). he cord at term normally has two arteries and one vein (Fig. 5-17). The right umbilical vein usually disappears early during fetal development, leaving only the original left vein.


Obstentrics_Williams

Obstentrics_Williams. he cord at term normally has two arteries and one vein (Fig. 5-17). The right umbilical vein usually disappears early during fetal development, leaving only the original left vein. The umbilical cord extends from the fetal umbilicus to the fetal surface of the placenta, that is, the chorionic plate. Blood flows from the umbilical vein toward the fetus. Blood then takes a path of least resistance via two routes within the fetus. One is the ductus venosus, which empties directly into the inferior vena cava (Fig. 7-9, p. 130). The other route consists of numerous smaller openings into the hepatic circulation. Blood from the liver flows into the inferior vena cava via the hepatic vein. Resistance in the ductus venosus is controlled by a sphincter that is situated at the origin of the ductus at the umbilical recess and is innervated by a vagus nerve branch.


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Obstentrics_Williams. Blood exits the fetus via the two umbilical arteries. These are anterior branches of the internal iliac artery and become obliterated after birth to form the medial umbilical ligaments. FIGURE 5-17 Cross-section of umbilical cord. The large umbilical vein carries oxygenated blood to the fetus (right). To its left are the two smaller umbilical arteries, carrying deoxygenated blood from the fetus to the placenta. (Used with permission from Dr. Mandolin S. Ziadie.) The production of steroid and protein hormones by human trophoblasts is greater in amount and diversity than that of any single endocrine tissue in all of mammalian physiology. A compendium of average production rates for various steroid hormones in nonpregnant and in near-term pregnant women is given in Table


Obstentrics_Williams

Obstentrics_Williams. It is apparent that alterations in steroid hormone production that accompany normal human pregnancy are incredible. he human placenta also synthesizes an enormous amount of protein and peptide hormones, summarized in Table 5-2. Another remarkable feature is the successful TABLE 5-1 . Steroid Production Rates in Nonpregnant and Near-Term Pregnant Women aEstrogens and progesterone are produced by placenta. Aldosterone is produced by the maternal adrenal in response to the stimulus of angiotenoin II. Deoxycorticosterone is produced in extraglandular tissue sites by way of the 21-hydroxylation of plasma progesterone. Cortisol production during pregnancy is not increased, even though the blood levels are elevated because of decreased clearance caused by increased cortisol-binding globulin. physiological adaptations of pregnant women to the unique endocrine milieu, and this is discussed throughout Chapter 4 (p. 49).


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Obstentrics_Williams. physiological adaptations of pregnant women to the unique endocrine milieu, and this is discussed throughout Chapter 4 (p. 49). Chorionic gonadotropin is a glycoprotein with biological activity similar to that of LH, and both act via the same LH-hCG receptor. hCG has with a molecular weight of 36,000 to 40,000 Da and has the highest carbohydrate content of any human hormone-30 percent. The carbohydrate component, and especially the terminal sialic acid, protects the molecule from catabolism. As a result, the 36-hour plasma half-life of intact hCG is much longer than the 2 hours for LH. he hCG molecule is composed of two dissimilar subunits termed . and � subunits. hese are noncovalently linked and are held together by electrostatic and hydrophobic forces. Isolated subunits are unable to bind the LH-hCG receptor and thus lack biological activity.


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Obstentrics_Williams. hCG is produced almost exclusively in the placenta, but low levels are synthesized in the fetal kidney. Other fetal tissues produce either the �-subunit or intact hCG molecule (McGregor, 1981,i1983). The hCG hormone is structurally related to three other glycoprotein hormones-LH, FSH, and TSH. All four glycoproteins share a common a-subunit. However, each of their 3-subunits, although sharing certain similarities, is characterized by a distinctly diferent amino acid sequence.


Obstentrics_Williams

Obstentrics_Williams. Synthesis of the .-and 3-chains of hCG is regulated separately. A single gene located on chromosome 6 encodes the a-subunit. Seven genes on chromosome 19 encode for the �-hCG-3-LH family of subunits. Six genes code for 3-hCG and one for 3-LH (Miller-Lindholm, 1997). Both subunits are synthesized as larger precursors, which are then cleaved by endopeptidases. Intact hCG is then assembled and rapidly released by secretory granule exocytosis (Morrish, 1987). There are multiple forms of hCG in maternal plasma and urine that vary enormously in bioactivity and immunoreactivity. Some result from enzymatic degradation, and others from modifications during molecular synthesis and processing.


Obstentrics_Williams

Obstentrics_Williams. Before 5 weeks, hCG is expressed both in the syncytiotrophoblast and in cytotrophoblasts (Mamo, 1992). Later, in the irst trimester when maternal serum levels peak, hCG is produced almost solely in the syncytiotrophoblast (Beck, 1986; Kurman, 1984). At this time, mRNA concentrations of both .-and 3-subunits in the syncytiotrophoblast are greater than at term (Hoshina, 1982). This may be an important consideration when hCG is used as a screening procedure to identiy abnormal fetuses.


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Obstentrics_Williams. Circulating free levels of 3-subunit are low to undetectable throughout pregnancy. In part, this is the result of its rate-limiting synthesis. Free a-subunits that do not combine with the 3-subunit are found in placental tissue and maternal plasma. Levels of the a-subunit rise gradually and steadily until they plateau at approximately 36 weeks' gestation. At this time, they account for 30 to 50 percent of hormone (Cole, 1997). Thus, .-hCG secretion roughly corresponds to placental mass, whereas secretion of complete hCG molecules is maximal at 8 to 10 weeks. TABLE 5-2. Protein Hormones Produced by the Human Placenta Primary Non-placental Shares Structural or Hormone Site of Expression Function Similarity Functions LH, FSH,lTSH GH, prolactin


Obstentrics_Williams

Obstentrics_Williams. TABLE 5-2. Protein Hormones Produced by the Human Placenta Primary Non-placental Shares Structural or Hormone Site of Expression Function Similarity Functions LH, FSH,lTSH GH, prolactin The combined hCG molecule is detectable in plasma of pregnant women 7 to 9 days after the midcycle surge of LH that precedes ovulation. hus, hCG likely enters maternal blood at the time of blastocyst implantation. Plasma levels rise rapidly, doubling every 2 days in the first trimester (Fig. 5-18). Appreciable fluctuations in levels for a given patient are observed on the same day.


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Obstentrics_Williams. Intact hCG circulates as multiple highly related isoforms with variable cross-reactivity between commercial assays. hus, calculated serum hCG levels can vary considerably among the more than a hundred available assays. his emphasizes the need to use the same assay type when clinically measuring serial hCG levels. Peak maternal plasma levels reach approximately 50,000 to 100,000 mIU/mL between the 60th and 80th days after menses. At 10 to 12 weeks' gestation, plasma levels begin to decline, and a nadir is reached by approximately 16 weeks. Plasma levels are maintained at this lower level for the remainder of pregnancy. The pattern of hCG appearance in fetal blood is similar to that in the mother. Fetal plasma levels, however, are only about 3 percent of those in maternal plasma. Amnionic fluid hCG concentration early in pregnancy is similar to that in maternal plasma. As pregnancy progresses, hCG concentration in Aids maternal adaptation to fetal energy requirements


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Obstentrics_Williams. Aids maternal adaptation to fetal energy requirements Relaxes smooth-muscle; initiates parturition? Promotes fetal and maternal glucocorticoid production Regulates trophoblast hCG production Regulates transfer of calcium and other solutes; regulates fetal mineral homeostasis nizing hormone; TSH = thyroid-stimulating hormone. amnionic fluid declines, and near term the levels are approximately 20 percent of those in maternal plasma. Maternal urine contains the same variety of hCG degradation products as maternal plasma. The principal urinary form is the terminal product of hCG degradation, namely, the 500 400 300�I 0E , 200£:) 100 , ..--, , , , I I 4, , I :t > II II ,, 3.1 c 40 I \ , , c I \, " , , 2 FIGURE 5-18 Distinct profiles for the concentrations of human chorionic gonadotropin (hCG), human placental lactogen (hPL), and corticotropin-releasing hormone (CRH) in serum of women throughout normal pregnancy.


Obstentrics_Williams

Obstentrics_Williams. �-core fragment. Concentrations of this fragment follow the same general pattern as that in maternal plasma, peaking at approximately 10 weeks' gestation. Importantly, the so-called �-subunit antibody used in most pregnancy tests reacts with both intact hCG-the major form in the plasma, and with fragments of hCG-the major forms found in urine. Placental gonadotropin-releasing hormone (GnRH) is likely involved in the regulation of hCG formation. Both GnRH and its receptor are expressed by cytotrophoblasts and by the syncytiotrophoblast (Wolfahrt, 1998). GnRH administration elevates circulating hCG levels, and cultured trophoblasts respond to GnRH treatment and raise hCG secretion (Iwashita, 1993; Siler-Khodr, 1981). Pituitary GnRH production also is regulated by inhibin and activin. In cultured placental cells, activin stimulates and inhibin inhibits GnRH and hCG production (Petraglia, 1989; Steele, 1993).


Obstentrics_Williams

Obstentrics_Williams. Renal clearance of hCG accounts for 30 percent of its metabolic clearance. he remainder is likely cleared by metabolism in the liver (Wehmann, 1980). Clearances of�-and .-subunits are approximately 10-and 30-fold, respectively, greater than that of intact hCG. In pregnancies complicated by chronic renal disease, hCG clearance can be markedly decreased. Both hCG subunits are required for binding to the LH-hCG receptor in the corpus lute un and the fetal testis. LH-hCG receptors are present in various other tissues, but their roles there are less defined.


Obstentrics_Williams

Obstentrics_Williams. he best-known biological function of hCG is the so-called rescue and maintenance of corpus luteum function-that is, continued progesterone production. This is only an incomplete explanation for the physiological function of hCG in pregnancy. For example, maximum plasma hCG concentrations are attained well after hCG-stimulated corpus luteum secretion of progesterone has ceased. Speciically, luteal progesterone synthesis begins to decline at about 6 weeks despite continued and increasing hCG production.


Obstentrics_Williams

Obstentrics_Williams. A second hCG role is stimulation of fetal testicular testosterone secretion. This is maximum approximately when hCG levels peak. hus, at a critical time in male sexual diferentiation, hCG enters fetal plasma from the syncytiotrophoblast. In the fetus, it acts as an LH surrogate to stimulate Leydig cell replication and testosterone synthesis to promote male sexual differentiation (Chap. 3, p. 35). Before approximately 110 days, there is no vascularization of the fetal anterior pituitary from the hypothalamus. Thus, pituitary LH secretion is minimal, and hCG acts as LH before this time. hereafter, as hCG levels fall, pituitary LH maintains modest testicular stimulation.


Obstentrics_Williams

Obstentrics_Williams. The maternal thyroid gland is also stimulated by large quantities of hCG. In some women with gestational trophoblastic disease, biochemical and clinical evidence of hyperthyroidism sometimes develops (Chap. 20, p. 391). This once was attributed to formation of chorionic thyrotropins by neoplastic trophoblasts. It was subsequently shown, however, that some forms ofhCG bind to TSH receptors on thyrocytes (Hershman, 1999). And, treatment of men with exogenous hCG increases thyroid activity. The thyroid-stimulatory activity in plasma of irst-trimester pregnant women varies appreciably from sample to sample. Modiications of hCG oligosaccharides likely are important in the capacity of hCG to stimulate thyroid function. For example, acidic isoforms stimulate thyroid activity, and some more basic isoforms stimulate iodine uptake (Kraiem, 1994; Tsuruta, 1995; Yoshimura, 1994). Finally, the LH-hCG receptor is expressed by thyrocytes, which suggests that hCG stimulates thyroid activity via the


Obstentrics_Williams

Obstentrics_Williams. isoforms stimulate iodine uptake (Kraiem, 1994; Tsuruta, 1995; Yoshimura, 1994). Finally, the LH-hCG receptor is expressed by thyrocytes, which suggests that hCG stimulates thyroid activity via the LH-hCG receptor as well as by the TSH receptor (Tomer, 1992).


Obstentrics_Williams

Obstentrics_Williams. Other hCG functions include promotion of relaxin secretion by the corpus luteum (Duy, 1996). LH-hCG receptors are found in myometrium and in uterine vascular tissue. It has been hypothesized that hCG may promote uterine vascular vasodilatation and myometrial smooth muscle relaxation (Kurtzman, 2001). Chorionic gonadotropin also regulates expansion of dNK cell numbers during early stages of placentation, thus ensuring appropriate establishment of pregnancy (Kane, 2009).


Obstentrics_Williams

Obstentrics_Williams. here are several clinical circumstances in which substantively higher maternal plasma hCG levels are found. Some examples are multifetal pregnancy, erythroblastosis fetalis associated with fetal hemolytic anemia, and gestational trophoblastic disease. Relatively higher hCG levels may be found in women carrying a fetus with Down syndrome. This observation is used in biochemical screening tests (Chap. 14, p. 281). The reason for the elevation is not clear, but reduced placental maturity has been speculated. Various malignant tumors also produce hCG, sometimes in large amounts-especially trophoblastic neoplasms (Chaps. 9, p. 159 and 20, p. 391).


Obstentrics_Williams

Obstentrics_Williams. Relatively lower hCG plasma levels are found in women with early pregnancy wastage, including ectopic pregnancy (Chap. 19, p. 373). hCG is produced in very small amounts in normal tissues of men and nonpregnant women, perhaps primarily in the anterior pituitary gland. Nonetheless, the detection of hCG in blood or urine almost always indicates pregnancy (Chap. 9, p. 158). This is a single, nonglycosylated polypeptide chain with a molecular weight of 22,279 Da. The sequences of hPL and of human growth hormone (hGH) are strikingly similar, with 96-percent homology. Also, hPL is structurally similar to human prolactin (hPRL), with a 67-percent amino acid sequence similarity. Because of these similarities, it was called human placental lactogen or chorionic growth hormone. Currently, human placental lactogen is used by most.


Obstentrics_Williams

Obstentrics_Williams. here are ive genes in the growth hormone-placental lactogen gene cluster that are linked and located on chromosome 17. hPL is concentrated in syncytiotrophoblast, but similar to hCG, hPL is demonstrated in cytotrophoblasts before 6 weeks (Grumbach, 1964; Maruo, 1992). Within 5 to 10 days after conception, hPL is demonstrable in the placenta and can be detected in maternal serum as early as 3 weeks. Levels of mRNA for hPL in syncytiotrophoblast remain relatively con stant throughout pregnancy. his inding supports the idea that the hPL secretion rate is proportional to placental mass. Levels rise steadily until 34 to 36 weeks' gestation. The hPL produc tion rate near term-approximately 1 g/d-is by far the great est of aRY known hormone in humans. The hal-life of hPL in maternal plasma is between 10 and 30 minutes (Walker, 1991). In late pregnancy, maternal serum concentrations reach levels of5 to 15 �g/mL (see Fig. 5-18).


Obstentrics_Williams

Obstentrics_Williams. In late pregnancy, maternal serum concentrations reach levels of5 to 15 �g/mL (see Fig. 5-18). Very little hPL is detected in fetal blood or in the urine of the mother or newborn. Amnionic fluid levels are somewhat lower than in maternal plasma. hPL is secreted primarily into the maternal circulation, with only very small amounts in cord blood. hus, its role in pregnancy is believed to be mediated through actions in maternal rather than in fetal tissues. None theless, interest continues for the possibility that hPL serves select functions in fetal growth. cesses. First, hPL promotes maternal lipolysis with increased circulating free fatty acid levels. This provides an energy source for maternal metabolism and fetal nutrition. In vitro cytiotrophoblast (Coya, 2005). Prolonged maternal starvation in the irst half of pregnancy leads to higher hPL plasma con centrations.


Obstentrics_Williams

Obstentrics_Williams. Second, hPL may aid maternal adaptation to fetal energy requirements. For example, increased maternal insulin resistance ensures nutrient flow to the fetus. It also favors protein synthesis and provides a readily available amino acid source to the fetus. To counterbalance the greater insulin resistance and prevent maternal hyperglycemia, maternal insulin levels are increased. Both hPL and prolactin signal through the prolactin receptor to increase maternal beta cell proliferation to augment insulin secretion (Georgia, 2010). In animals, prolactin and hPL upregulate serotonin synthesis, which increases beta cell proliferation (Kim, 2010). Short-term changes in plasma glucose or insulin, however, have relatively little efect on plasma hPL levels. In vitro studies of syncytiotrophoblast suggest that hPL synthesis is stimulated by insulin and insulin-like growth factor-1 and inhibited by PGE2 and PGF2: (Bhaumick, 1987; Genbacev, 1977).


Obstentrics_Williams

Obstentrics_Williams. Last, hPL is a potent angiogenic hormone. It may serve an important function in fetal vasculature formation (Corbacho, 2002). capacity to synthesize numer ous peptide hormones, including some that are analogous or related to hypothalamic and pituitary hormones. In contrast to their counterparts, some of these placental peptide/protein hormones are not subject to feedback inhibition. he known hypothalamic-releasing or -inhibiting hormones include GnRH, CRH, thyrotropin-releasing hormone (TRH), growth hormone-releasing hormone, and somatostatin. For each, there is an analogous hormone produced in the human placenta (Petraglia, 1992; Siler-Khodr, 1988).


Obstentrics_Williams

Obstentrics_Williams. GnH in the placenta shows its highest expression in the first trimester (Siler-Khodr, 1978, 1988). Interestingly, it is found in cytotrophoblasts, but not syncytiotrophoblast. Pla centa-derived GnRH functions to regulate trophoblast hCG ofMMP-2 and MMP-9 (Peng, 2016). Placenta-derived GnRH is also the likely cause of elevated maternal GnRH levels in pregnancy (Siler-Khodr, 1984). CH is a member of a larger family of CRH-related pep tides that includes CRH and urocortins (Dautzenberg, 2002). Maternal serum CRH levels increase from 5 to 10 pmollL in the nonpregnant woman to approximately 100 pmollL in the early third trimester of pregnancy and to almost 500 pmollL abruptly during the last 5 to 6 weeks (see Fig. 5-18). Urocortin also is produced by the placenta and secreted into the maternal circulation, but at much lower levels than seen for CRH (Flo rio, 2002). After labor begins, maternal plasma CRH levels rise even further (Petraglia, 1989, 1990).


Obstentrics_Williams

Obstentrics_Williams. he biological function of CRH synthesized in the placenta, membranes, and decidua has been somewhat deined. CRH receptors are present in many tissues including placenta. Trophoblast, amniochorion, and decidua express both CRH-R1 and CRH-R2 receptors and several variant receptors (Florio, 2000). Both CRH and urocortin enhance trophoblast secretion of adrenocorticotropic hormone (ACTH), supporting an autocrine-paracrine role (Petraglia, 1999). Large amounts of trophoblast CRH enter maternal blood.


Obstentrics_Williams

Obstentrics_Williams. Other proposed biological roles include induction of smooth-muscle relaxation in vascular and myometrial tissue and immunosuppression. The physiological reverse, however, induction of myometrial contractions, has been proposed for the rising CRH levels seen near term. One hypothesis suggests that CRH may be involved with parturition initiation (Wadhwa, 1998). Some evidence suggests that urocortin 2 expression is induced at term and induces expression of pro inlammatory markers and prostaglandin F receptor expression in the placenta and myometrium (Voltolini, 2015). Prostaglandin formation in the placenta, amnion, chorion laeve, and decidua is increased with CRH treatment Oones, 1989b). hese observations further support a potential action in parturition timing.


Obstentrics_Williams

Obstentrics_Williams. Glucocorticoids act in the hypothalamus to inhibit CRH release, but in the trophoblast, glucocorticoids stimulate CRH gene expression Oones, 1989a; Robinson, 1988). hus, there may be a novel positive feedback loop in the placenta by which placental CRH stimulates placental ACTH to stimulate fetal and maternal adrenal glucocorticoid production with quent stimulation of placental CRH expression (Nicholson, 2001; Riley, 1991). Growth hormone-releasing hormone has an unknown role (Berry, 1992). Ghrelin is another regulator of hGH secretion that is produced by placental tissue (Horvath, 2001). Trophoblast ghrelin expression peaks at midpregnancy and is a paracrine regulator of diferentiation or is a potential regulator of human growth hormone variant production, described next (Fuglsang, 2005; Gualillo, 2001).


Obstentrics_Williams

Obstentrics_Williams. ACTH, lipotropin, and �-endorphin, which are all proteolytic products of pro-opiomelanocortin, are recovered from placental extracts (Genazzani, 1975; Odagiri, 1979). he physiological action of placental ACTH is unclear. As discussed, placental CRH stimulates synthesis and release of chorionic ACTH.


Obstentrics_Williams

Obstentrics_Williams. A human growth hormone variant (hGH-J that is not expressed in the pituitary is expressed in the placenta. The gene encoding hGH-V is located in the hGH-hPL gene cluster on chromosome 17. Sometimes referred to as placental growth hormone, hGH-V is a 191-amino-acid protein that difers in 15 amino acid positions from the sequence for hGH. Although hGH-V retains growth-promoting and antilipogenic functions similar to those of hGH, it has reduced diabetogenic and lactogenic functions relative to hGH (Vickers, 2009). Placental hGH-V presumably is synthesized in the syncytiotrophoblast. It is believed that hGH-V is present in maternal plasma by 21 to 26 weeks' gestation, rises in concentration until approximately 36 weeks, and remains relatively constant thereafter. There is a correlation between the levels of hGH-V in maternal plasma and those of insulin-like growth factor-I. lso, hGH-V secretion by trophoblast in vitro is inhibited by glucose in a dosedependent manner (Patel, 1995).


Obstentrics_Williams

Obstentrics_Williams. between the levels of hGH-V in maternal plasma and those of insulin-like growth factor-I. lso, hGH-V secretion by trophoblast in vitro is inhibited by glucose in a dosedependent manner (Patel, 1995). Overexpression ofhGH-V in mice causes severe insulin resistance, making it a likely candidate to mediate insulin resistance of pregnancy (Liao, 2016).


Obstentrics_Williams

Obstentrics_Williams. Expression of relaxin has been demonstrated in human corpus luteum, decidua, and placenta (Bogic, 1995). This peptide is synthesized as a single, 105-amino-acid preprorelaxin molecule that is cleaved to A and B molecules. Relaxin is structurally similar to insulin and insulin-like growth factor. Two of the three relaxin genes-H2 and H3-are transcribed in the corpus luteum (Bathgate, 2002; Hudson, 1983, 1984). Decidua, placenta, and membranes express H 1 and H2 (Hansell, 1991).


Obstentrics_Williams

Obstentrics_Williams. The rise in maternal circulating relaxin levels seen in early pregnancy is attributed to corpus luteum secretion, and levels parallel those of hCG. Relaxin, along with rising progesterone levels, may act on myometrium to promote relaxation and the quiescence of early pregnancy (Chap. 21, p. 407). In addition, the production of relaxin and relaxin-like factors within the placenta and fetal membranes may play an autocrine-paracrine role in postpartum regulation of extracellular matrix remodeling (Qin, 1997a,b). One important relaxin function is enhancement of the glomerular iltration rate (Chap. 4, p. 66).


Obstentrics_Williams

Obstentrics_Williams. In pregnancy, circulating parathyroid hormone-related protein (PTH-rP) levels are significantly elevated within maternal but not fetal circulation (Bertelloni, 1994; Saxe, 1997). Many functions of this hormone have been proposed. PTH-rP synthesis is found in several normal adult tissues, especially in reproductive organs that include myometrium, endometrium, corpus luteum, and lactating mammary tissue. PTH-rP is not produced in the parathyroid glands of normal adults. Placentaderived PTH-rP may have an important function to regulate genes involved in transfer of calcium and other solutes. It also contributes to fetal mineral homeostasis in bone, amnionic luid, and the fetal circulation (Simmonds, 2010).


Obstentrics_Williams

Obstentrics_Williams. This hormone is normally secreted by adipocytes. It functions as an antiobesity hormone that decreases food intake .through its hypothalamic receptor. It also regulates bone growth and immune unction (Cock, 2003; La Cava, 2004). In the placenta, leptin is synthesized by both cytotrophoblasts and syncytiotrophoblast (Henson, 2002). Relative contributions of leptin from maternal adipose tissue versus placenta are currently not well defined, although recent evidence highlights a key regulatory role of placental leptin in placental amino acid transport and fetal growth (Rosario, 20 16a). Maternal serum levels are significantly higher than those in nonpregnant women. Fetalileptin levels correlate positively with birth weight and likely function in fetal development and growth. Studies suggest that reductions in leptin availability contribute to adverse fetal metabolic programing in intrauterine growth-restricted ofspring (Nusken, 2016).


Obstentrics_Williams

Obstentrics_Williams. This 36-amino-acid peptide is widely distributed in brain. It also is found in sympathetic neurons innervating the cardiovascular, respiratory, gastrointestinal, and genitourinary systems. Neuropeptide Y has been isolated from the placenta and localized in cytotrophoblasts (Petraglia, 1989). Trophoblasts possess neuropeptide Y receptors, and treatment of these with neuropeptide Y causes CRH release (Robidoux, 2000).


Obstentrics_Williams

Obstentrics_Williams. hese glycoprotein hormones are expressed in male and female reproductive tissues and belong to the transforming growth factor-� family Gones, 2006). Inhibin is a heterodimer made up of one a-subunit and one of two distinct �-subunits, either �A or �B. his yields either inhibin A or inhibin B, respectively. Activin is formed by the combination of the two �-subunits. Activin, inhibin, and their respective receptors are expressed in the placenta. Both activin and inhibin A have proposed functions during cytotrophoblast fusion into the syncytiotrophoblast (Debieve, 2000; Jones, 2006). Activin also stimulates production of placental hormones such as hCG, hPL, progesterone, and estrogen (Luo, 2002; Morrish, 1991; Petraglia, 1989; Song, 1996). Inhibin A opposes activin action in the placenta to inhibit production of hCG and steroidogenesis (Petraglia, 1989). Abnormal levels of inhibin or activin correlate with placental pathologies. For example, elevation in inhibin A levels in the second


Obstentrics_Williams

Obstentrics_Williams. inhibit production of hCG and steroidogenesis (Petraglia, 1989). Abnormal levels of inhibin or activin correlate with placental pathologies. For example, elevation in inhibin A levels in the second trimester is indicative of fetal Down syndrome. Further, low inhibin levels early in pregnancy may indicate pregnancy failure (Prakash, 2005; Wallace, 1996). Elevations in circulating inhibin and activin levels are reported in women with preeclampsia (Bersinger, 2003).


Obstentrics_Williams

Obstentrics_Williams. After 6 to 7 weeks' gestation, little progesterone is produced in the ovary (Diczfalusy, 1961). Surgical removal of the corpus luteum or even bilateral oophorectomy during the 7th to 10th week does not decrease excretion rates of urinary pregnanediol, 100.0 50.0 10.0 n ..) 5.0 1.0 ):l u 0.5 0.1 0.05


Obstentrics_Williams

Obstentrics_Williams. FIGURE 5-19 Plasma levels of progesterone, estradiol, estrone, estetrol, and estriol in women during the course of gestation. (Modified and redrawn with permission from Mesiano S: The endocrinology of human pregnancy and fetoplacental neuroendocrine development. In Strauss JF, Barbieri RL (eds) Yen and Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 6th ed. Philadephia, Saunders, 2009.) the principal urinary metabolite of progesterone. Before this time, however, corpus luteum removal will result in spontaneous abortion unless an exogenous progestin is given (Chap. 63, p. 1198). After approximately 8 weeks, the placenta assumes progesterone secretion, resulting in a gradual increase in maternal serum levels throughout pregnancy (Fig. 5-19). By term, these levels are 10 to 5000 times those found in nonpregnant women, depending on the stage of the ovarian cycle.


Obstentrics_Williams

Obstentrics_Williams. The daily production rate of progesterone in late, normal, singleton pregnancies approximates 250 mg. In mulrifetal pregnancies, the daily production rate may exceed 600 mg. Progesterone is synthesized from cholesterol in a two-step enzymatic reauiuI1. r.l�., L-l1UI:�L:lUl ;� C0il v'ci'tC. tv plcg.cidciC ';;ithi� the mitochondria, in a reaction catalyzed by cytochrome P450 cholesterol side-chain cleavage enzyme. Pregnenolone leaves the mitochondria and is converted to progesterone in the endoplasmic reticulum by 33-hydroxysteroid dehydrogenase. Progesterone is released immediately through a process of difusion.


Obstentrics_Williams

Obstentrics_Williams. Although the placenta produces a prodigious amount of progesterone, the syncytiotrophoblast has a limited capacity for cholesterol biosynthesis. Radiolabeled acetate is incorporated into cholesterol by placental tissue at a slow rate. he rate-limiting enzyme in cholesterol biosynthesis is 3-hydroxy3-methylglutaryl coenzyme A (HMG-CoA) reductase. Because of this, the placenta must rely on an exogenous source, that is, maternal cholesterol, for progesterone formation. he tro biosynthesis (Simpson, 1979, 1980). This mechanism difers from placental production of estrogens, which relies principally on fetal adrenal precursors. Although there is a relationship between fetal well-being and placental estrogen production, this is not the case for placen tal progesterone. Thus, placental endocrine function, including the formation of protein hormones such as hCG and proges terone biosynthesis, may persist for weeks after fetal demise.


Obstentrics_Williams

Obstentrics_Williams. he metabolic clearance rate of progesterone in pregnant women is similar to that found in men and nonpregnant women. During pregnancy, the plasma concentration of 5a-dihydroprogesterone disproportionately rises due to syn progesterone and fetus-derived precursor (Dombroski, 1997). hus, the concentration ratio of this progesterone metabolite to progesterone is elevated in pregnancy. The mechanisms for this are not deined completely. Progesterone also is converted to the potent mineralocorticoid deoxycorticosterone in preg nant women and in the fetus. The concentration of deoxy corticosterone is strikingly higher in both maternal and fetal compartments (see Table 5-1). The extraadrenal formation of most of its production in pregnancy (Casey, 1982a,b).


Obstentrics_Williams

Obstentrics_Williams. During the first 2 to 4 weeks of pregnancy, rising hCG levels maintain production of estradiol in the maternal corpus luteum. Production of both progesterone and estrogens in the maternal ovaries drops signiicantly by the 7th week of pregnancy. At this time, there is a luteal-placental transition. By the 7th week, more than half of estrogen entering maternal circulation is produced in the placenta (MacDonald, 1965a; Siiteri, 1963,i1966). Subsequently, the placenta produces a continually increasing magnitude of estrogen. Near term, normal human pregnancy is a hyperestrogenic state, and syncytiotrophoblast is producing estrogen in amounts equivalent to that produced in 1 day by the ovaries of no fewer than 1000 ovulatory women. This hyperestrogenic state terminates abruptly after delivery of the placenta.


Obstentrics_Williams

Obstentrics_Williams. In human trophoblast, neither cholesterol nor, in turn, proges :e�8!e :�� �e�.'e !s F"�C�!!S0!" For �'tr0g�n hi)"ynth�."is. Thi� is because steroid 17a-hydroxylasel1,20-yase (CP17Al) is not expressed in the human placenta. This essential enzyme converts 17-0H progesterone (a C2I steroid) to androstenedione, which is a C'9 steroid and an estrogen precursor. Consequently, the conversion of C2I steroids to C'9 steroids is not possible. However, dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) are also C'9 steroids and are produced by maternal and fetal adrenal glands. These two steroids can serve as estrogen precursors (Fig. 5-20). Ryan (1959a) found that the placenta had an exceptionally high capacity to convert appropriate C'9 steroids to estrone and estradiol. The conversion of DHEA-S to estradiol requires placental expression of four key enzymes


Obstentrics_Williams

Obstentrics_Williams. FIGURE 5-20 Schematic presentation of estrogen biosynthesis in the human placenta. Dehydroepiandrosterone sulfate (DHEAS), secreted in prodigious amounts by the fetal adrenal glands, is converted to 16a-hydroxydehydroepiandrosterone sulfate (16aOHDHEAS) in the fetal liver. These steroids, DHEAS and 16aOHDHEAS, are converted in the placenta to estrogens, that is, 17�-estradiol (E) and estriol (E3). Near term, half of E2 is derived from fetal adrenal DHEAS and half from maternal DHEAS. On the other hand, 90 percent of E3 in the placenta arises from fetal 16aOHDHEAS and only 10 percent from all other sources.


Obstentrics_Williams

Obstentrics_Williams. that are located principally in syncytiotrophoblast (Bonenfant, 2000; Salido, 1990). First, the placenta expresses high levels of steroid sulfatase (STS), which converts the conjugated DHEAS to DHEA. DHEA is then acted upon by 33-hydroxysteroid dehydrogenase type 1 (33HSD) to produce androstenedione. Cytochrome P450 aromatase (CYP19) then converts androstenedione to estrone, which is then converted to estradiol by 173-hydroxysteroid dehydrogenase type 1 (173HSDl). DHEA-S is the major precursor of estrogens in pregnancy (Baulieu, 1963; Siiteri, 1963). However, maternal adrenal glands do not produce suicient amounts of DHA-S to account for more than a fraction oftotal placental estrogen biosynthesis. he fetal adrenal glands are quantitatively the most important source of placental estrogen precursors in human pregnancy. hus, estrogen production duringpregnancy relects the unique interactions among fetal adrenal glands, fetal liver, placenta, and maternal adrenal glands.


Obstentrics_Williams

Obstentrics_Williams. More than 90 percent of estradiol and estriol formed in syncytiotrophoblast 'enters maternal plasma (Gurpide, 1966). And, 85 percent or more of placental progesterone enters maternal plasma, and little maternal progesterone crosses the placenta to the fetus (Gurpide, 1972). his directional movement ofnewly formed steroid into the maternal circulation stems from basic characteristics of hemochorioendothelial placentation. In this system, steroids secreted from syncytiotrophoblast can enter maternal blood directly. Steroids that leave the syncytium do not enter fetal blood directly. hey must irst traverse the cytotrophoblast layer and then enter the stroma of the villous core and then fetal capillaries. From either ofthese spaces, steroids can reenter the syncytium. he net result of this hemochorial arrangement is that entry of steroids into the maternal circulation is substantially greater than that into fetal blood.


Obstentrics_Williams

Obstentrics_Williams. Morphologically, functionally, and physiologically, the fetal adrenal glands are remarkable. At term, the fetal adrenal glands weigh the same as those of the adult. More than 85 percent of the fetal gland is composed of a unique fetal zone, which has a great capacity for steroid biosynthesis. Daily steroid production of fetal adrenal glands near term is 100 to 200 mg/d. This compares with resting adult steroid secretion of 30 to 40 mg/d. The fetal zone is lost in the irst year of life and is not present in the adult. In addition to ACTH, fetal adrenal gland growth is influenced by factors secreted by the placenta. This is exempliied by the continued growth of the fetal glands throughout gestation and by rapid involution immediately after birth and placental delivery.


Obstentrics_Williams

Obstentrics_Williams. Estradiol is the primary placental estrogen product at term. In addition, significant levels of estriol and estetrol are found in the maternal circulation, and levels also rise, particularly late in gestation (see Fig. 5-19). hese hydroxylated forms of estro gen derive from the placenta using substrates formed by the combined eforts of the fetal adrenal gland and fetal liver. For this, high levels of fetal hepatic 16a-hydroxylase act on adre nal-derived steroids. Ryan (1959b) and MacDonald and Siiteri (1965b) found that 16a-hydroxylated C19 steroids, particu larly 16a-hydroxydehydroepiandrosterone (16-0HDHEA), were converted to estriol by placental tissue. Thus, the dispro portionate increase in estriol formation during pregnancy is accounted for by placental synthesis of estriol principally from plasma-borne 16-0HDHEA-sulfate. Near term, the fetus is the source of 90 percent of placental estriol and estetrol precur sors in normal human pregnancy.


Obstentrics_Williams

Obstentrics_Williams. Maternal estriol and estetrol are produced almost solely by fetal steroid precursors. hus, in the past, levels of these steroids were used as an indicator of fetal well-being. However, the low sensitivity and speciicity of such tests have caused them to be discarded. The precursor for fetal adrenal steroidogenesis is cholesterol. he steroid biosynthesis rate in the fetal gland is so great that its steroidogenesis alone is equivalent to a fourth of the total daily LDL cholesterol turnover in adults. Fetal adrenal glands synthesize cholesterol from acetate. All enzymes involved in cholesterol biosynthesis are elevated compared with those of the adult adrenal gland (Rainey, 2001). Thus, the de novo cholesterol synthesis rate by fetal adrenal tissue is extremely high. Even so, it is insuicient to account for the steroids produced by fetal adrenal glands. Therefore, cholesterol must be assimilated from the fetal circulation and mainly from LDL (Carr, 1980, 1981 b, 1982; Simpson, 1979).


Obstentrics_Williams

Obstentrics_Williams. Most fetal plasma cholesterol arises by de novo synthesis in the fetal liver (Carr, 1984). The low LDL cholesterol level in fetal plasma is not the consequence of impaired fetal LDL synthesis, but instead results from the rapid use ofLDL by the fetal adrenal glands for steroidogenesis (Parker, 1980, 1983). Several fetal disorders alter the availability of substrate for placental steroid synthesis and thus highlight the interdependence of fetal development and placental function. Fetal demise is followed by a striking reduction in urinary estrogen levels. Similarly, after ligation of the umbilical cord with the fetus and placenta left in situ, placental estrogen production declines markedly (Cassmer, 1959). However, as previously discussed, placental progesterone production is maintained. In sum, an important source of precursors of pla cental estrogen-but not progesterone-biosynthesis is elimi nated with fetal death. Anencephalic etuses have markedly atrophic adrenal glands.


Obstentrics_Williams

Obstentrics_Williams. Anencephalic etuses have markedly atrophic adrenal glands. his stems from absent hypothalamic-pituitary function, which precludes adrenal stimulation by ACTH. With absence of the adrenal cortex fetal zone, the placental formation of estrogen-especially estriol-is severely limited because of diminished availability of C19 steroid precursors. Indeed, uri nary estrogen levels in women pregnant with an anencephalic fetus are only about 10 percent of those found in normal preg nancy (Frandsen, 1961). With an anencephalic fetus, almost all estrogens produced arise from placental use of maternal plasma DHEA-S. Fetal adrenal cortical hypoplasia occurs in perhaps 1 in 12,500 births (McCabe, 2001). Estrogen production in these pregnan cies is limited, which suggests the absence of C19 precursors.


Obstentrics_Williams

Obstentrics_Williams. Fetal adrenal cortical hypoplasia occurs in perhaps 1 in 12,500 births (McCabe, 2001). Estrogen production in these pregnan cies is limited, which suggests the absence of C19 precursors. Fetal-placental suatase diciency is associated with very low estrogen levels in otherwise normal pregnancies (France, 1969). Namely, sulfatase deficiency precludes the hydrolysis of C19 steroid sulfates, the first enzymatic step in the placental use of these circulating prehormones for estrogen biosynthesis. This deficiency is an X-linked disorder, and thus all afected fetuses are male. Its estimated frequency is 1 in 2000 to 5000 births and is associated with delayed labor onset. It also is associated with the development of ichthyosis in afected males later in life (Bradshaw, 1986).


Obstentrics_Williams

Obstentrics_Williams. Fetal-placental aromatase diciency is a rare autosomal recessive disorder in which individuals cannot synthesize endogenous estrogens (Grumbach, 2011; Simpson, 2000). To recall, fetal adrenal DHA-S is converted in the placenta to androstenedione, but in cases of placental aromatase deiciency, androstenedione cannot be converted to estradiol. Rather, androgen metabolites of DHEA produced in the placenta, including androstenedione and some testosterone, are secreted into the maternal or fetal circulation, or both. This can cause virilization of the mother and the female fetus (Belgorosky, 2009; Harada, 1992; Shozu, 1991). Trisomy 21-Down syndrome screening searches for abnormal levels ofhCG, alpha-fetoprotein, and other analytes (Chap. 14, p. 281). It was discovered that serum unconjugated estriol levels low in women with Down syndrome fetuses (Benn, 2002). The likely reason for this is inadequate formation of C19 steroids in the adrenal glands of these trisomic fetuses.


Obstentrics_Williams

Obstentrics_Williams. Fetal eythroblastosis in some cases of severe fetal D-antigen alloimmunization can lead to elevated maternal plasma estrogen levels. A suspected cause is the greater placental mass from hypertrophy, which can be seen with such fetal hemolytic anemia (Chap. 15, p. 300). Glucocorticoid treatment can cause a striking reduction in placental estrogen formation. Glucocorticoids inhibit ACTH secretion from the maternal and fetal pituitary glands. This diminishes maternal and fetal adrenal secretion of the placental estrogen precursor DHEA-S. With Addison disease, pregnant women show lower estrogen levels, principally estrone and estradiol levels (Baulieu, 1956). The fetal adrenal contribution to estriol synthesis, particularly in later pregnancy, is quantitatively much more important.


Obstentrics_Williams

Obstentrics_Williams. Maternal androgen-producing tumors can present the placenta with elevated androgen levels. Fortunately, placenta is extraordinary eicient in the aromatization of C19 steroids. For example, Edman and associates (1981) found that virtually all androstenedione entering the intervillous space is taken up by syncytiotrophoblast and converted to estradiol. None of this C19 steroid enters the fetus. Second, a female fetus is rarely virilized if there is a maternal androgen-secreting tumor. The placenta eiciently converts aromatizable C19 steroids, including testosterone, to estrogens, thus precluding transplacental passage. Indeed, virilized female fetuses of women with an androgenproducing tumor may be cases in which a nonaromatizable C19 steroid androgen is produced by the tumor-for example, 5a-dihydrotestosterone. Another explanation is that testosterone is produced very early in pregnancy in amounts that exceed the placental aromatase capacity at that time.


Obstentrics_Williams

Obstentrics_Williams. Complete hydatidiorm mole and gestational trophoblastic neoplasias lack a fetus and also a fetal adrenal source of C19 steroid precursors for trophoblast estrogen biosynthesis. Consequently, placental estrogen formation is limited to the use of C 19 steroids from the maternal plasma, and therefore estradiol is principally produced (MacDonald, 1964, 1966). Abel MH: Prostanoids and menstruation. In Baird DT, Michie EA (eds): Mechanisms of Menstrual Bleeding. New York, Raven, 2002


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Obstentrics_Williams. Albrecht ED, Pepe GJ: Steroid hormone regulation of angiogenesis in the primate endometrium. Front Biosci 8:0416, 2003 Ancelin M, Buteau-Lozano H, Meduri G, et al: A dynamic shift of VEGF isoforms with a transient and selective progesterone-induced expression of VEGF189 regulates angiogenesis and vascular permeability in human uterus. Proc Nad Acad Sci USA 99:6023,r2002 Aplin JD: MUC-l glycosylation in endometrium: possible roles of the apical glycocalyx at implantation. Hum Reprod 2:17,r2003 Apps R, Sharkey A, Gardner L, et al: Ex vivo functional responses to HLA-G difer between blood and decidual NK cells. Mol Hum Reprod 17(9):577, 2011 Arici A, Head JR, MacDonald pc, et al: Regulation of interleukin-8 gene expression in human endometrial cells in culture. Mol Cell Endocrinol 94:195,r1993 Arici A, MacDonald Pc' Casey ML: Regulation of monocyte chemotactic protein-l gene expression in human endometrial cells in cultures. Mol Cell Endocrinol 107:189, 1995 Amholdt H, Meisel F, Fandrey


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Obstentrics_Williams. Arici A, MacDonald Pc' Casey ML: Regulation of monocyte chemotactic protein-l gene expression in human endometrial cells in cultures. Mol Cell Endocrinol 107:189, 1995 Amholdt H, Meisel F, Fandrey K, et al: Proliferation of villous trophoblast of the human placenta in normal and abnormal pregnancies. Virchows Arch B Cell Pathol Incl Mol PathoIr60:365, 1991 Baker T: A quantitative and cytological study of germ cells in human ovaries. Proc R Soc Lond B BioI Sci 158:417, 1963 Bathgate A, Samuel CS, Burazin TC, et al: Human relxin gene 3 (H3) and the equivalent mouse relaxin (M3) gene. Novel members of the relaxin peptide family. J BioI Chem 277:1148, 2002 Baulieu EE, Bricaire H, Jayle MF: Lack of secretion of -hydroxycorticosteroids in a pregnant woman with Addison's disease. J Clin Endocrinol 16:690, 1956 Baulieu EE, Dray F: Conversion of3H-dehydroepiandrosterone (3Beta-hydroxydelta5-androsten-17-one) sulfate to 3H-estrogens in normal pregnant women. J Clin Endocrinol 23: 1298, 1963


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Obstentrics_Williams. Beck T, Schweikhart G, Stolz E: Immunohistochemical location of HPL, SPI and beta-HCG in normal placentas of varying gestational age. Arch Gynecol 239:63, 1986 Belgorosky A, Guercio G, Pepe C, et al: Genetic and clinical spectrum of aromatase deficiency in infancy, childhood and adolescence. Horm Res 2(6):321,r2009 Benirschke K, Burton GJ, Baergen RN: Pathology of the Human Placenta, 6th ed. Heidelberg, Springer, 2012 Benn PA: Advances in prenatal screening for Down syndrome: 1. General principles and second trimester testing. Clin Chim Acta 323: 1, 2002 Berry SA, Srivastava CH, Rubin LR, et al: Growth hormone-releasing hormone-like messenger ribonucleic acid and immunoreactive peptide are present in human testis and placenta. J Clin Endocrinol Metab 75:281, 1992


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Obstentrics_Williams. Bersinger NA, Smarason AK, Muttukrishna S, et al: Women with preeclampsia have increased serum levels of pregnancy-associated plasma protein A (PAPP-A), inhibin A, activin A and soluble E-selectin. Hypertens Pregnancy 22(1):45, 2003 Bertelloni S, Baroncelli GI, Pelletti A, et al: Parathyroid hormone-related protein in healthy pregnant women. Calcif Tissue Int 54: 195, 1994 Bhaumick B, Dawson EP, Bala RM: he efects of insulin-like growth factorI and insulin on placental lactogen production by human term placental explants. Biochem Biophys Res Commun 144:674, 1987 BIeker 0, Kloostermans G, Mieras 0, et al: Intervillous space during uterine contractions in human subjects: an ultrasonic study. Am J Obstet Gynecol ,1975 Bogic LV, Mandel M, Bryant-Greenwood GO: Relaxin gene expression in human reproductive tissues by in situ hybridization. J Clin Endocrinol Metab 80:130, 1995


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Obstentrics_Williams. Bogic LV, Mandel M, Bryant-Greenwood GO: Relaxin gene expression in human reproductive tissues by in situ hybridization. J Clin Endocrinol Metab 80:130, 1995 Bonagura TW, Babischkin JS, Aberdeen GC, et al: Prematurely elevating estradiol in early baboon pregnancy suppresses uterine artety remodeling and expression of extravillous placental vascular endothelial growth factor and albl integrins. Endocrinology ,2012 Bonenfant M, Provost PR, Drolet R, et al: Localization of type 1 beta-hydroxysteroid dehydrogenase mRNA and protein in syncytiotrophoblasts and invasive cytotrophoblasts in the human term villi. J Endocrinol 165:217, 2000 Borell U, Fernstrom I, Westman A: An arteriographic study of the placental circulation. Geburrshilfe Frauenheilkd 18:1, 1958 Bourne GL: he Human Amnion and Chorion. Chicago, Year Book, 1962 Boyd JD, Hamilton ): The Human Placenta. Cambridge, England, Hefer, 1970


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Obstentrics_Williams. Bourne GL: he Human Amnion and Chorion. Chicago, Year Book, 1962 Boyd JD, Hamilton ): The Human Placenta. Cambridge, England, Hefer, 1970 Bradshaw KD, Carr BR: Placental sulfatase deficiency: maternal and fetal expression of steroid sulfatase deiciency and X-linked ichthyosis. Obstet Gynecol Surv 41:401,r1986 Brosens I, Dixon H: he anatomy of the maternal side of the placenta. Eur J Endocrinol 73:357, 1963 Bryant-Greenwood GO: he extracellular matrix of the human fetal membranes: structure and function. Placenta 19:1, 1998 Carr BR, Ohashi M, Simpson ER: Low density lipoprotein binding and de novo synthesis of cholesterol in the neocortex and fetal zones of the human fetal adrenal gland. Endocrinology 110: 1994, 1982 Carr BR, Porter JC, MacDonald Pc, et al: Metabolism of/ow density lipoprotein by human fetal adrenal tissue. Endocrinology 107: 1034, 1980


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Obstentrics_Williams. Carr BR, Porter JC, MacDonald Pc, et al: Metabolism of/ow density lipoprotein by human fetal adrenal tissue. Endocrinology 107: 1034, 1980 Carr BR, Sadler RK, Rochelle DB, et al: Plasma lipoprotein regulation of progesterone biosynthesis by human corpus luteum tissue in organ culture. J Clin Endocrinol Metab 52:8 5, 1981a Carr BR, Simpson ER: Cholesterol synthesis by human fetal hepatocytes: efect of lipoproteins. Am J Obstet Gynecol 150:551, 1984 Carr BR, Simpson ER: Lipoprotein utilization and cholesterol synthesis by the human fetal adrenal gland. Endocr Rev 2:306, 1981 b Carson DO: he glycobiology of implantation. Front Biosci 7:dI535, 2002 Carvajal JA, Delpiano AM, Cuello A, et al: Mechanical stretch increases brain natriuretic peptide production and secretion in the human fetal membranes. Reprod Sci 20(5):597,r2013


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Obstentrics_Williams. Carvajal JA, Delpiano AM, Cuello A, et al: Mechanical stretch increases brain natriuretic peptide production and secretion in the human fetal membranes. Reprod Sci 20(5):597,r2013 Casey ML, Delgadillo M, Cox A, et al: Inactivation of prostaglandins in human decidua vera (parietalis) tissue: substrate speciicity of prostaglandin dehydrogenase. Am J Obstet Gynecol 160:3, 1989 Casey ML, Hemsell DL, MacDonald Pc, et al: NAD+ -dependent 15-hydroxyprostaglandin dehydrogenase activity in human endometrium. Prostaglandins 19:115,r1980 Casey ML, MacDonald PC: Extraadrenal formation of a mineralocorticosteroid: deoxycorticosterone and deoxycorticosterone sulfate biosynthesis and metabolism. Endocr Rev 3:396, 1982a


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Obstentrics_Williams. Casey ML, MacDonald PC: Extraadrenal formation of a mineralocorticosteroid: deoxycorticosterone and deoxycorticosterone sulfate biosynthesis and metabolism. Endocr Rev 3:396, 1982a Casey ML, MacDonald PC: Metabolism of deoxycorticosterone and deoxycorticosterone sulfate in men and women. J Clin Invest 70:312, 1982b Casey ML, MacDonald PC: The endothelin-parathyroid hormone-related protein vasoactive peptide system in human endometrium: modulation by transforming growth factor-beta. Hum Reprod 11(SuppI2):62, 1996 Cassmer 0: Hormone production of the isolated human placenta. Studies on the role of the foetus in the endocrine functions of the placenta. Acta Endocrinol Suppl 32(SuppIr45):1, 1959 Cervar M, Blaschitz A, Dohr G, et al: Paracrine regulation of distinct trophoblast functions in vitro by placental macrophages. Cell Tissue Res 295:297, 1999


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Obstentrics_Williams. Cervar M, Blaschitz A, Dohr G, et al: Paracrine regulation of distinct trophoblast functions in vitro by placental macrophages. Cell Tissue Res 295:297, 1999 Chennazhi, Nayak NR: Regulation of angiogenesis in the primate endometrium: vascular endothelial growth factor. Semin Reprod Med 27(1):80, 2009 Chigusa Y, Kishore AH, Mogami H, et al: Nrf2 activation inhibits efects of thrombin in human amnion cells and thrombin-induced preterm birth in mice. J Clin Endocrinol Metab 101(6):2612,r2016 Cock TA, Auwerx]: Leptin: cL1Cting the fat off the bone. Lancet 362: 1572, 2003 Cole A: Immunoassay of human chorionic gonadotropin, its free subunits, and metabolites. Clin Chen 43:2233, 1997 Conneely OM, Mulac-]ericevic B, DeMayo F, et al: Reproductive functions of progesterone receptors. Recent Prog Horm Res 57:339, 2002


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Obstentrics_Williams. Conneely OM, Mulac-]ericevic B, DeMayo F, et al: Reproductive functions of progesterone receptors. Recent Prog Horm Res 57:339, 2002 Corbacho M, Martinez DL, Clapp C: Roles of prolactin and related members of the prolactin/growth hormone/placental lactogen family in angiogenesis. J Endocrinol 173:219, 2002 Coya R, Manul P, Algortar], et al: Progesterone and human placental lactogen inhibit leptin secretion on cultured trophoblast cells from human placentas at term. Gynecol Endocrinol 21 :27, 2005 Crawford]: A study of human placental growth with observations on the placenta in erythroblastosis foetalis. BjOG 66:855, 1959 Critchley HO, Kelly RW, Baird DT, et al: Regulation of human endometrial function: mechanisms relevant to uterine bleeding. Reprod Bioi Endocrinol 4 Suppl 1 :S5, 2006


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Obstentrics_Williams. Critchley HO, Kelly RW, Baird DT, et al: Regulation of human endometrial function: mechanisms relevant to uterine bleeding. Reprod Bioi Endocrinol 4 Suppl 1 :S5, 2006 Cuny TE Jr, Smith MF: Impact of extracellular matrix remodeling on ovulation and the folliculo-luteal transition. Semin Reprod Med 24(4):228, 2006 Dautzenberg FM, Hauger RL: he CRF peptide family and their receptors: yet more partners discovered. Trends Pharmacol Sci 23:71, 2002 Debieve F, Pampfer S, Thomas K: Inhibin and activin production and subunit expression in human placental cells cultured in vitro. Mol Human Reprod 6(8): 43, 2000 Diczfalusy E, Troen P: Endocrine functions of the human placenta. Vitam Horm 19:229, 1961 Dombroski A, Casey ML, MacDonald PC: 5-Alpha-dihydroprogestetone formation in human placenta from 5alpha-pregnan-3beta/alpha-ol-20-ones and 5-pregnan-3beta-yl-20-one sulfate. j Steroid Biochem Mol Bioi 63: 155, 1997


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Obstentrics_Williams. DuY DM, Hutchison jS, Stewart DR, et al: Stimulation of primate luteal function by recombinant human chorionic gonadotropin and modulation of steroid, but not relaxin, production by an inhibitor of 3 beta-hydroxysteroid dehydrogenase during simulated early pregnancy. j Clin Endocrinol Metab 81:2307,r1996 Duncan WC, McNeilly AS, Fraser HM, et al: Luteinizing hormone receptor in the human corpus luteum: lack of down-regulation during maternal recognition of pregnancy. Hum Reprod 11 :2291, 1996 Dunn CL, Critchley HO, Kelly RW: IL-15 regulation in human endometrial stromal cells. j Clin Endocrinol Metab 87:1898, 2002 Economos K, MacDonald pc, Casey ML: Endorhelin-1 gene expression and protein biosynthesis in human endometrium: potential modulator of endometrial blood flow. J Clin Endocrinol Metab 74: 14, 1992


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Obstentrics_Williams. Economos K, MacDonald pc, Casey ML: Endorhelin-1 gene expression and protein biosynthesis in human endometrium: potential modulator of endometrial blood flow. J Clin Endocrinol Metab 74: 14, 1992 Edman CD, Toofanian A, MacDonald PC, et al: Placental clearance rate of maternal plasma androstenedione through placental estradiol formation: an indirect method of assessing uteroplacental blood flow. Am J Obstet Gynecol 141:1029, 1981 Elliott CL, Allport Vc, Loudon jA, et al: Nuclear factor-kappa B is essential for up-regulation of interleukin-8 expression in human amnion and cervical epithelial cells. Mol Hum Reprod 7:787,r200r1 Evans J, Salamonsen A: Inflammation, leukocytes and menstruation. Rev Endocr Metab Disord 13(4):277,r2012 Faas MM, de Vos P: Uterine NK cells and macrophages in pregnancy. Placenta 56:44,r2017 Faddy Mj, Gosden RG, Gougeon A, et al: Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod 7:1342, 1992


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