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 5-1. It is apparent that alterations in steroid hormone production that accompany normal human pregnancy are incredible. The human placenta also synthesizes an enormous amount of protein and peptide hormones as summarized in Table 5-2. It is understandable, therefore, that yet another remarkable feature of human pregnancy is the successful physiological adaptations of pregnant women to the unique endocrine milieu as discussed throughout Chapter 4 (Reproductive Tract).
TABLE 5-1Steroid Production Rates in Nonpregnant and Near-Term Pregnant Women ||Download (.pdf) TABLE 5-1 Steroid Production Rates in Nonpregnant and Near-Term Pregnant Women
| ||Production Rates (mg/24 hr) |
|Steroida ||Nonpregnant ||Pregnant |
|Estradiol-17β ||0.1–0.6 ||15–20 |
|Estriol ||0.02–0.1 ||50–150 |
|Progesterone ||0.1–40 ||250–600 |
|Aldosterone ||0.05–0.1 ||0.250–0.600 |
|Deoxycorticosterone ||0.05–0.5 ||1–12 |
|Cortisol ||10–30 ||10–20 |
TABLE 5-2Protein Hormones Produced by the Human Placenta ||Download (.pdf) TABLE 5-2 Protein Hormones Produced by the Human Placenta
|Hormone ||Primary Nonplacental Site of Expression ||Shares Structural or Function Similarity ||Functions |
|Human chorionic gonadotropin (hCG) ||— ||LH, FSH, TSH ||Maintains corpus luteum function |
Regulates fetal testis testosterone secretion
Stimulates maternal thyroid
|Placental lactogen (PL) ||— ||GH, prolactin ||Aids maternal adaptation to fetal energy requirements |
|Adrenocorticotropin (ACTH) ||Hypothalamus ||— || |
|Corticotropin-releasing hormone (CRH) ||Hypothalamus ||— ||Relaxes smooth-muscle; initiates parturition? |
Promotes fetal and maternal glucocorticoid production
|Gonadotropin-releasing hormone (GnRH) ||Hypothalamus ||— ||Regulates trophoblast hCG production |
|Thyrotropin (TRH) ||Hypothalamus ||— ||Unknown |
|Growth hormone-releasing hormone (GHRH) ||Hypothalamus ||— ||Unknown |
|Growth hormone variant (hGH-V) ||— ||GH variant not found in pituitary ||Potentially mediates pregnancy insulin resistance |
|Neuropeptide Y ||Brain ||— ||Potential regulates CRH release by trophoblasts |
|Parathyroid hormone-releasing protein (PTH-rp) ||— ||— ||Regulates transfer of calcium and other solutes; regulates fetal mineral homeostasis |
|Inhibin ||Ovary/testis ||— ||Potentially inhibits FSH-mediated ovulation; regulates hCG synthesis |
|Activin ||Ovary/testis ||— ||Regulates placental GnRH synthesis |
Human Chorionic Gonadotropin
This so-called pregnancy hormone is a glycoprotein with biological activity similar to luteinizing hormone. Both act via the same plasma membrane LH-hCG receptor. Although hCG is produced almost exclusively in the placenta, low levels are synthesized in the fetal kidney. Other fetal tissues produce either the β-subunit or intact hCG molecule (McGregor, 1981, 1983).
Various malignant tumors also produce hCG, sometimes in large amounts—especially trophoblastic neoplasms (Chap. 20, Hydatidiform Mole—molar Pregnancy). Chorionic gonadotropin is produced in very small amounts in 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, Breast and Skin Changes).
Chorionic gonadotropin is a glycoprotein with a molecular weight of 36,000 to 40,000 Da. It 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. The 36-hour plasma half-life of intact hCG is much longer than the 2 hours for LH. The hCG molecule is composed of two dissimilar subunits termed α and β subunits. These 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.
This hormone is structurally related to three other glycoprotein hormones—LH, FSH, and TSH. All four glycoproteins share a common α-subunit. The β-subunits, although sharing certain similarities, are characterized by distinctly different amino-acid sequences. Recombination of an α- and a β-subunit of the four glycoprotein hormones gives a molecule with biological activity characteristic of the hormone from which the β-subunit was derived.
Syntheses of the α- and β-chains of hCG are regulated separately. A single gene located on chromosome 6 encodes the α-subunit common to hCG, LH, FSH, and TSH. Seven genes on chromosome 19 encode for the β-hCG–β-LH family of subunits. Six genes code for β-hCG and one for β-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.
Before 5 weeks, hCG is expressed in both syncytiotrophoblast and cytotrophoblast (Maruo, 1992). Later, in the first 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 α- and β-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 identify abnormal fetuses.
Circulating free β-subunit levels are low to undetectable throughout pregnancy. In part, this is the result of its rate-limiting synthesis. Free α-subunits that do not combine with the β-subunit are found in placental tissue and maternal plasma. These levels increase gradually and steadily until they plateau at about 36 weeks’ gestation. At this time, they account for 30 to 50 percent of hormone (Cole, 1997). Thus, α-hCG secretion roughly corresponds to placental mass, whereas secretion of complete hCG molecules is maximal at 8 to 10 weeks.
Concentrations of hCG in Serum and Urine
The combined hCG molecule is detectable in plasma of pregnant women 7 to 9 days after the midcycle surge of LH that precedes ovulation. Thus, hCG likely enters maternal blood at the time of blastocyst implantation. Plasma levels increase rapidly, doubling every 2 days in the first trimester (Fig. 5-21). Appreciable fluctuations in levels for a given patient are observed on the same day—evidence that trophoblast secretion of protein hormones is episodic.
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.
Intact hCG circulates as multiple highly related isoforms with variable cross-reactivity between commercial assays. Thus, there is considerable variation in calculated serum hCG levels among the more than a hundred available assays. Peak maternal plasma levels reach approximately 100,000 mIU/mL between the 60th and 80th days after menses. At 10 to 12 weeks, 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 (see Fig. 5-21).
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 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 degradation hCG product—the β-core fragment. Its concentrations follow the same general pattern as that in maternal plasma, peaking at about 10 weeks. It is important to recognize that the so-called β-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.
Regulation of hCG Synthesis and Clearance
Placental gonadotropin-releasing hormone (GnRH) is likely involved in the regulation of hCG formation. Both GnRH and its receptor are expressed by cytotrophoblasts and syncytiotrophoblast (Wolfahrt, 1998). GnRH administration elevates circulating hCG levels, and cultured trophoblast cells respond to GnRH treatment with increased 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).
Renal clearance of hCG accounts for 30 percent of its metabolic clearance. The remainder is likely cleared by metabolism in the liver (Wehmann, 1980). Clearances of β- and α-subunits are approximately 10-fold and 30-fold, respectively, greater than that of intact hCG.
Biological Functions of hCG
Both hCG subunits are required for binding to the LH-hCG receptor in the corpus luteum and the fetal testis. LH-hCG receptors are present in various other tissues, but their role there is less defined. The best-known biological function of hCG is the so-called rescue and maintenance of corpus luteum function—that is, continued progesterone production. Bradbury and colleagues (1950) found that the progesterone-producing life span of a corpus luteum of menstruation could be prolonged perhaps for 2 weeks by hCG administration. 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. Specifically, progesterone luteal synthesis begins to decline at about 6 weeks despite continued and increasing hCG production.
A second hCG role is stimulation of fetal testicular testosterone secretion, which is maximum approximately when hCG levels peak. Thus, at a critical time in male sexual differentiation, 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. 7, Mechanisms of Gender Differentiation). 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. Thereafter, as hCG levels fall, pituitary LH maintains modest testicular stimulation.
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, Diagnosis). This once was attributed to formation of chorionic thyrotropins by neoplastic trophoblasts. It was subsequently shown, however, that some forms of hCG 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 first-trimester pregnant women varies appreciably from sample to sample. Modifications 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 LH-hCG receptor as well as by the TSH receptor (Tomer, 1992).
Other hCG functions include promotion of relaxin secretion by the corpus luteum (Duffy, 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 uterine natural killer cell numbers during early stages of placentation, thus ensuring appropriate establishment of pregnancy (Kane, 2009).
Abnormally High or Low hCG Levels
There 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 at midtrimester in women carrying a fetus with Down syndrome—an observation used in biochemical screening tests (Chap. 14, Serum Analytes). The reason for this is not clear, but reduced placental maturity has been speculated. Relatively lower hCG plasma levels are found in women with early pregnancy wastage, including ectopic pregnancy (Chap. 19, Beta Human Chorionic Gonadotropin).
Prolactin-like activity in the human placenta was first described by Ehrhardt (1936). Because of its potent lactogenic and growth hormone-like bioactivity, as well as an immunochemical resemblance to human growth hormone (hGH), it was called human placental lactogen or chorionic growth hormone. Currently, human placental lactogen is used by most.
Grumbach and Kaplan (1964) showed that this hormone, like hCG, was concentrated in syncytiotrophoblast. It is detected as early as the second or third week after fertilization. Also similar to hCG, hPL is demonstrated in cytotrophoblasts before 6 weeks (Maruo, 1992).
Chemical Characteristics and Synthesis
Human placental lactogen is a single, nonglycosylated polypeptide chain with a molecular weight of 22,279 Da. It is derived from a 25,000-Da precursor. The sequence of hPL and hGH is strikingly similar, with 96-percent homology. Also, hPL is structurally similar to human prolactin (hPRL), with a 67-percent amino-acid sequence similarity. For these reasons, it has been suggested that the genes for hPL, hPRL, and hGH evolved from a common ancestral gene—probably that for prolactin—by repeated gene duplication (Ogren, 1994).
There are five genes in the growth hormone–placental lactogen gene cluster that are linked and located on chromosome 17. Two of these—hPL2 and hPL3—encode hPL, and the amount of mRNA in the term placenta is similar for each.
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. Maternal plasma concentrations are linked to placental mass, and they rise steadily until 34 to 36 weeks’ gestation. The hPL production rate near term—approximately 1 g/day—is by far the greatest of any known hormone in humans. The half-life of hPL in maternal plasma is between 10 and 30 minutes (Walker, 1991). In late pregnancy, maternal serum concentrations reach levels of 5 to 15 μg/mL (see Fig. 5-21).
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. Because hPL is secreted primarily into the maternal circulation, with only very small amounts in cord blood, it appears that its role in pregnancy is mediated through actions in maternal rather than in fetal tissues. Nonetheless, there is continuing interest in the possibility that hPL serves select functions in fetal growth.
Regulation of hPL Biosynthesis
Levels of mRNA for hPL in syncytiotrophoblast remain relatively constant throughout pregnancy. This finding supports the idea that the hPL secretion rate is proportional to placental mass. There are very high plasma levels of hCG in women with trophoblastic neoplasms, but only low levels of hPL in these same women.
Prolonged maternal starvation in the first half of pregnancy leads to increased hPL plasma concentrations. Short-term changes in plasma glucose or insulin, however, have relatively little effect 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 PGF2α (Bhaumick, 1987; Genbacev, 1977).
Placental lactogen has putative actions in several important metabolic processes. 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 studies suggest that hPL inhibits leptin secretion by term trophoblast (Coya, 2005).
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 increased 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). Recent animal studies provide insight into the mechanism by which lactogenic hormones drive beta cell expansion. Specifically, prolactin and hPL upregulate serotonin synthesis via regulation of the rate-limiting enzyme, tryptophan hydroxylase-1, which in turn increases beta cell proliferation (Kim, 2010).
Last, hPL is a potent angiogenic hormone. It may serve an important function in fetal vasculature formation (Corbacho, 2002).
Other Placental Protein Hormones
The placenta has a remarkable capacity to synthesize numerous peptide hormones, including some that are analogous or related to hypothalamic and pituitary hormones. In contrast to their counterparts, the placental peptide/protein hormones are not subject to feedback inhibition. Examples include pro-opiomelanocortin-derived peptides, growth hormone variant V, and gonadotropin-releasing hormone.
Adrenocorticotropic hormone (ACTH), lipotropin, and β-endorphin—all proteolytic products of pro-opiomelanocortin—are recovered from placental extracts (Genazzani, 1975; Odagiri, 1979). The physiological action of placental ACTH is unclear. Placental corticotropin-releasing hormone stimulates synthesis and release of chorionic ACTH. Placental CRH production is positively regulated by cortisol, producing a novel positive feedback loop. As discussed later, this system may be important for controlling fetal lung maturation and parturition timing.
The placenta expresses a growth hormone variant (hGH-V) that is not expressed in the pituitary. 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 differs in 15 amino-acid positions from the sequence for hGH. Although hGH-V retains growth-promoting and antilipogenic functions similar to hGH, it has reduced diabetogenic and lactogenic functions relative to hGH (Vickers, 2009). Placental hGH-V presumably is synthesized in the syncytium. However, its pattern of synthesis and secretion during gestation is not precisely known because antibodies against hGH-V cross-react with hGH. It is believed that hGH-V is present in maternal plasma by 21 to 26 weeks’ gestation, increases 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-1. Also, hGH-V secretion by trophoblasts in vitro is inhibited by glucose in a dose-dependent manner (Patel, 1995). Overexpression of hGH-V in mice causes severe insulin resistance, and thus it is a likely candidate to mediate insulin resistance of pregnancy (Barbour, 2002).
Hypothalamic-Like Releasing Hormones
The known hypothalamic-releasing or -inhibiting hormones include GnRH, CRH, thyroid-releasing hormone (TRH), growth hormone-releasing hormone (GHRH), and somatostatin. For each, there is an analogous hormone produced in the human placenta (Petraglia, 1992; Siler-Khodr, 1988). Many investigators suggest this indicates a hierarchy of control in chorionic trophic-agent synthesis.
There is a reasonably large amount of immunoreactive GnRH in the placenta (Siler-Khodr, 1978, 1988). Interestingly, it is found in cytotrophoblasts, but not syncytiotrophoblast. Gibbons and coworkers (1975) and Khodr and Siler-Khodr (1980) demonstrated that the human placenta could synthesize both GnRH and TRH in vitro. Placental-derived GnRH functions to regulate trophoblast hCG production, hence the observation that GnRH levels are higher early in pregnancy. Placental-derived GnRH is also the likely cause of elevated maternal GnRH levels in pregnancy (Siler-Khodr, 1984).
This hormone is a member of a larger family of CRH-related peptides that includes CRH, urocortin, urocortin II, and urocortin III (Dautzenberg, 2002). Maternal serum CRH levels increase from 5 to 10 pmol/L in the nonpregnant woman to approximately 100 pmol/L in the early third trimester of pregnancy and to almost 500 pmol/L abruptly during the last 5 to 6 weeks (see Fig. 5-21). Urocortin also is produced by the placenta and secreted into the maternal circulation, but at much lower levels than seen for CRH (Florio, 2002). After labor begins, maternal plasma CRH levels increase further by two- to threefold (Petraglia, 1989, 1990).
The biological function of CRH synthesized in the placenta, membranes, and decidua has been somewhat defined. CRH receptors are present in many tissues: placenta, adrenal gland, sympathetic ganglia, lymphocytes, gastrointestinal tract, pancreas, gonads, and myometrium. Some findings suggest that CRH can act through two major families—the type 1 and type 2 CRH receptors (CRH-R1 and CRH-R2). Trophoblast, amniochorion, and decidua express both CRH-R1 and CRH-R2 receptors and several variant receptors (Florio, 2000). Both CRH and urocortin increase trophoblast ACTH secretion, supporting an autocrine-paracrine role (Petraglia, 1999). Large amounts of trophoblast CRH enter maternal blood. That said, there also is a large concentration of a specific CRH-binding protein in maternal plasma, and the bound CRH seems to be biologically inactive.
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). Prostaglandin formation in the placenta, amnion, chorion laeve, and decidua is increased with CRH treatment (Jones, 1989b). This latter observation further supports a potential action in parturition timing.
Glucocorticoids act in the hypothalamus to inhibit CRH release, but in the trophoblast, glucocorticoids stimulate CRH gene expression (Jones, 1989a; Robinson, 1988). Thus, 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 subsequent stimulation of placental CRH expression (Nicholson, 2001; Riley, 1991).
Growth Hormone-Releasing Hormone
The role of placental GHRH is not known (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 potential regulator of hGH-V production or a paracrine regulator of differentiation (Fuglsang, 2005; Gualillo, 2001).
Other Placental Protein Hormones
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). Other tissues, including decidua, placenta, and membranes, express H1 and H2 (Hansell, 1991).
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, Myometrial Cell-to-Cell Communication). 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 degradation (Qin, 1997a,b). One important relaxin function is enhancement of the glomerular filtration rate (Chap. 4, Renal Function Tests).
Parathyroid Hormone–Related Protein
In pregnancy, circulating parathyroid hormone-related protein (PTH-rP) levels are significantly elevated within maternal but not fetal circulation (Bertelloni, 1994; Saxe, 1997). Many potential 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. Based on insights from parathyroid hormone-related protein null mice, placental-derived 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 fluid, and the fetal circulation (Simmonds, 2010).
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 function (Cock, 2003; La Cava, 2004). In the placenta, leptin also is synthesized by both cytotrophoblast and syncytiotrophoblast (Henson, 2002). Relative contributions of leptin from maternal adipose tissue versus placenta are currently not well defined. Maternal serum levels are significantly higher than those in nonpregnant women. Fetal leptin levels correlate positively with birthweight and likely play an important function in fetal development and growth. Studies suggest that leptin inhibits apoptosis and promotes trophoblast proliferation (Magarinos, 2007).
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). There are receptors for neuropeptide Y on trophoblast, and treatment of placental cells with neuropeptide Y causes CRH release (Robidoux, 2000).
Inhibin is a glycoprotein hormone that acts preferentially to inhibit pituitary FSH release. It is produced by human testis and by ovarian granulosa cells, including the corpus luteum. Inhibin is a heterodimer made up of an α-subunit and one of two distinct β-subunits, βA or βB. All three are produced by trophoblast, and maternal serum levels peak at term (Petraglia, 1991). One function may be to act in concert with the large amounts of sex steroid hormones to inhibit FSH secretion and thereby inhibit ovulation during pregnancy. Inhibin may act via GnRH to regulate placental hCG synthesis (Petraglia, 1987).
Activin is closely related to inhibin and is formed by the combination of the two β-subunits. Its receptor is expressed in the placenta and amnion. Activin A is not detectable in fetal blood before labor but is present in umbilical cord blood after labor begins. Petraglia (1994) found that serum activin A levels decline rapidly after delivery. It is not clear if chorionic activin and inhibin are involved in placental metabolic processes other than GnRH synthesis.
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, 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, Sonography). After approximately 8 weeks, the placenta assumes progesterone secretion, resulting in a gradual increase in maternal serum levels throughout pregnancy (Fig. 5-22). By term, these levels are 10 to 5000 times those found in nonpregnant women, depending on the stage of the ovarian cycle.
The daily production rate of progesterone in late, normal, singleton pregnancies is approximately 250 mg. In multifetal pregnancies, the daily production rate may exceed 600 mg/day. Progesterone is synthesized from cholesterol in a two-step enzymatic reaction. First, cholesterol is converted to pregnenolone within 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 3β-hydroxysteroid dehydrogenase. Progesterone is released immediately through a process of diffusion.
Although the placenta produces a prodigious amount of progesterone, there is limited capacity for trophoblast cholesterol biosynthesis. Radiolabeled acetate is incorporated into cholesterol by placental tissue at a slow rate. The rate-limiting enzyme in cholesterol biosynthesis is 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. Because of this, the placenta must rely on exogenous cholesterol for progesterone formation. Bloch (1945) and Werbin and colleagues (1957) found that after intravenous administration of radiolabeled cholesterol to pregnant women, the amount of radioactivity of urinary pregnanediol was similar to that of plasma cholesterol. Hellig and associates (1970) also found that maternal plasma cholesterol was the principal precursor—as much as 90 percent—of progesterone biosynthesis. The trophoblast preferentially uses LDL cholesterol for progesterone biosynthesis (Simpson, 1979, 1980). In studies of pregnant baboons, when maternal serum LDL levels were reduced, there was a significant drop in placental progesterone production (Henson, 1997). Thus, placental progesterone is formed through the uptake and use of a maternal circulating precursor. This mechanism is unlike the placental production of estrogens, which relies principally on fetal adrenal precursors.
Progesterone Synthesis and Fetal Relationships
Although there is a relationship between fetal well-being and placental estrogen production, this is not the case for placental progesterone. Fetal demise, ligation of the umbilical cord with the fetus and placenta remaining in situ, and anencephaly are all conditions associated with very low maternal plasma levels and low urinary excretion of estrogens. In these circumstances, there is not a concomitant decrease in progesterone levels until some indeterminate time after fetal death. Thus, placental endocrine function, including the formation of protein hormones such as hCG and progesterone biosynthesis, may persist for long periods (weeks) after fetal demise.
Progesterone Metabolism During Pregnancy
The metabolic clearance rate of progesterone in pregnant women is similar to that found in men and nonpregnant women. During pregnancy, the plasma concentration of 5α-dihydroprogesterone disproportionately increases due to synthesis in syncytiotrophoblast from both placenta-produced progesterone and fetal-derived precursor (Dombroski, 1997). Thus, the concentration ratio of this progesterone metabolite to progesterone is increased in pregnancy. The mechanisms for this are not defined completely. Progesterone also is converted to the potent mineralocorticoid deoxycorticosterone in pregnant women and in the fetus. The concentration of deoxycorticosterone is increased strikingly in both maternal and fetal compartments (see Table 5-1). The extraadrenal formation of deoxycorticosterone from circulating progesterone accounts for most of its production in pregnancy (Casey, 1982a,b).
Placental Estrogen Production
The placenta produces huge amounts of estrogens using blood-borne steroidal precursors from the maternal and fetal adrenal glands. Near term, normal human pregnancy is a hyperestrogenic state. The amount of estrogen produced each day by syncytiotrophoblast during the last few weeks of pregnancy is equivalent to that produced in 1 day by the ovaries of no fewer than 1000 ovulatory women. The hyperestrogenic state of human pregnancy is one of continually increasing magnitude as pregnancy progresses, terminating abruptly after delivery.
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 decreases significantly 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, 1966). These studies support the transition of a steroid milieu dependent on the maternal corpus luteum to one dependent on the developing placenta.
Placental Estrogen Biosynthesis
The estrogen synthesis pathways in the placenta differ from those in the ovary of nonpregnant women. Estrogen is produced during the follicular and luteal phases through the interaction of theca and granulosa cells that surround the follicles. Specifically, androstenedione is synthesized in ovarian theca cells and then is transferred to adjacent granulosa cells for estradiol synthesis. Estradiol production within the corpus luteum of nonpregnant women and in early pregnancy continues to require interaction between the luteinized theca and granulosa cells. However, in human trophoblast, neither cholesterol nor progesterone can serve as precursor for estrogen biosynthesis. A crucial enzyme necessary for sex steroid synthesis—steroid 17α-hydroxylase/17, 20-lyase (CYP17)—is not expressed in the human placenta. Consequently, the conversion of C21-steroids to C19-steroids—the latter being the immediate and obligatory precursors of estrogens—is not possible.
Dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) are C19-steroids. Although these are often called adrenal androgens, these steroids can also serve as estrogen precursors (Fig. 5-23). Ryan (1959a) found that the placenta had an exceptionally high capacity to convert appropriate C19-steroids to estrone and estradiol. The conversion of DHEA-S to estradiol requires placental expression of four key enzymes that are located principally in syncytiotrophoblast (Bonenfant, 2000; Salido, 1990). First, the placenta expresses high levels of steroid sulfatase (STS), which converts the conjugated DHEA-S to DHEA. DHEA is then acted upon by 3β-hydroxysteroid dehydrogenase type 1 (3βHSD) to produce androstenedione. Cytochrome P450 aromatase (CYP19) then converts androstenedione to estrone, which is then converted to estradiol by 17β-hydroxysteroid dehydrogenase type 1 (17βHSD1).
Schematic presentation of estrogen biosynthesis in the human placenta. Dehydroepiandrosterone sulfate (DHEA-S), secreted in prodigious amounts by the fetal adrenal glands, is converted to 16α-hydroxydehydroepiandrosterone sulfate (16αOHDHEA-S) in the fetal liver. These steroids, DHEA-S and 16αOHDHEA-S, are converted in the placenta to estrogens, that is, 17β-estradiol (E2) and estriol (E3). Near term, half of E2 is derived from fetal adrenal DHEA-S and half from maternal DHEA-S. On the other hand, 90 percent of E3 in the placenta arises from fetal 16αOHDHEA-S and only 10 percent from all other sources.
Plasma C19-Steroids as Estrogen Precursors
Frandsen and Stakemann (1961) found that urinary estrogens levels in women pregnant with an anencephalic fetus were only about 10 percent of that found in normal pregnancy. The adrenal glands of anencephalic fetuses are atrophic because of absent hypothalamic-pituitary function, which precludes ACTH stimulation. Thus, it seemed reasonable that fetal adrenal glands might provide substance(s) used for placental estrogen formation.
In subsequent studies, DHEA-S was found to be a major precursor of estrogens in pregnancy (Baulieu, 1963; Siiteri, 1963). The large amounts of DHEA-S in plasma and its much longer half-life uniquely qualify it as the principal precursor for placental estradiol synthesis. There is a 10- to 20-fold increased metabolic clearance rate of plasma DHEA-S in women at term compared with that in men and nonpregnant women (Gant, 1971). This rapid use results in a progressive decrease in plasma DHEA-S concentration as pregnancy progresses (Milewich, 1978). However, maternal adrenal glands do not produce sufficient amounts of DHEA-S to account for more than a fraction of total placental estrogen biosynthesis. The fetal adrenal glands are quantitatively the most important source of placental estrogen precursors in human pregnancy. A schematic representation of the estrogen formation pathways in the placenta is presented in Figure 5-23. As shown, the estrogen products released from the placenta are dependent on the substrate available. Thus, estrogen production during pregnancy reflects the unique interactions among fetal adrenal glands, fetal liver, placenta, and maternal adrenal glands.
Directional Secretion of Steroids from Syncytiotrophoblast
More than 90 percent of estradiol and estriol formed in syncytiotrophoblast as shown in Table 5-1 enters maternal plasma (Gurpide, 1966). And 85 percent or more of placental progesterone enters maternal plasma, with little maternal progesterone crossing the placenta to the fetus (Gurpide, 1972).
The major reason for directional movement of newly formed steroid into the maternal circulation is the nature 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. They must first traverse the cytotrophoblasts and then enter the stroma of the villous core and then fetal capillaries. From either of these spaces, steroids can reenter the syncytium. The net result of this hemochorial arrangement is that there is substantially greater entry of steroids into the maternal circulation compared with the amount that enters fetal blood.