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Placental Human Chorionic Gonadotropin (hCG) As mentioned previously, hCG mRNA is detectable in embryos as early as the 6- to 8-cell stage (12). After implantation of the conceptus, hCG is detectable in the syncytiocytotrophoblast layer (outer trophectoderm layer) (22,25-27). Human chorionic gonadotropin is secreted by the syncytiocytotrophoblasts of the placenta into both the fetal and maternal circulation. Plasma levels increase, doubling in concentration every 2-3 days between 60 and 90 days of gestation. At 3-4 weeks' gestation, the mean doubling time of dimeric hCG is 2.0 ±1.0 days and increases to about 3.5 ±1.5 days at 9-10 weeks (22). The average peak hCG level is approximately 110,000 mIU/mL and occurs at 10 weeks gestation (22). Between 12 and 16 weeks, average hCG decreases rapidly with the concentration halving every 2.5 ±1.0 days before reaching 25% of first trimester peak values. Levels continue to fall from 16 to 22 weeks at a slower rate (mean halving rate of 4.0 ±2.0 days) to become approximately 10% of peak first trimester values (22). During the third trimester mean hCG levels rise in gradual, yet significant, manner from 22 weeks until term (22). Human chorionic gonadotropin secretion is related directly to the mass of hCG-secreting trophoblastic tissues. In vivo, the release of hCG has been correlated with the widths of trophoblast tissue from 4 to 20 weeks and with placental weight from 20 to 38 weeks, respectively (22). The rapidly rising hCG seen between 3-4 and 9-10 weeks gestation coincides with the proliferation of immature trophoblastic villi and the extent of the syncytial layer (22). As expected, declining hCG levels are associated with a relative reduction in the mass of the syncytiocytotrophoblast and cytotrophoblast tissue. From 20-22 weeks until term a gradual increase in dimeric hCG corresponds with a similar increase in placental weight and villus volume (22). Thus, in early gestation rising hCG levels reflect the histological finding of a rapidly proliferating and increasingly invasive placenta. Later in pregnancy, declining hCG levels are associated with a relative reduction in the number and mass of trophoblasts; therefore, hCG levels mirror the placenta's morphologic transformation from an organ of invasion to an organ of transfer (22). Levels of the b subunit of hCG mirror those of dimeric hCG. The a subunit, undetectable until around 6 weeks' gestation, rises in a sigmoid fashion to reach peak levels at 36 weeks. Levels of the individual subunits are very low relative to dimeric hCG; they are approximately 2,000-fold to 150-fold less than dimeric forms at 6 and 35 weeks, respectively) (22). With respect to the regulation of hCG production and secretion, hCG secretion appears to be related to placental GnRH release (71). In vitro, hCG is released in pulses at a frequency and amplitude that correlates with the release of placental GnRH (71). In addition, hCG production is stimulated by glucocorticoids and suppressed by DHEAS (77). In vitro, cyclic AMP (cAMP) analogues augment hCG secretion. In humans, decidual inhibin and prolactin inhibit hCG production by term trophoblasts whereas decidua-derived activin augments it (88,89). Human chorionic gonadotropin, known as the major factor involved in supporting and maintaining the corpus luteum, ensures the continual secretion of progesterone until the placenta can perform this function (90). It has immunosuppressive properties, likely involving maternal T-lymphocyte function and it possesses thyrotropic activity (91). Human chorionic gonadotropin stimulates both adrenal and placental steroidogenesis by providing the fetal testes with increasing levels of testosterone that induce virilization and sexual differentiation in males (92,93). The functions of hCG are summarized in Figure 9.
Placental Growth Hormone (GH) The rate of secretion of pituitary GH is known to change rapidly, depending on the net result of multiple stimulatory and inhibitory input. The regulation of placental GH is quite different. The rate of synthesis of placental GH, and thus the maternal circulating levels, increases with the growth of the placenta (102). Growth hormone releasing hormone (GHRH) does not modulate placental GH expression in vitro, in vivo, or in the presence of glucose (103,104). Figure 10 shows both the stimulatory and inhibitory mediators of maternal pituitary GH output, including the influence of placental growth hormone. Production of maternal IGF-I is regulated by placental growth hormone. Insulin-like growth factor-I concentrations in the maternal plasma, studied in a large number of pregnancies, correlate with the corresponding placental GH. Insulin-like growth factor-I levels do not vary significantly during the first weeks of gestation, but then increase gradually from 165 ±44.5 mg/L at about 24-25 weeks' gestation, and reach levels of 330.5 ±63.5 mg/L in a manner similar to the increases seen in placental GH. It should be noted that circulating maternal IGF-I levels also reflect placental IGF-I secretion. This growth factor, however, does not appear to be strongly expressed in human placenta; in particular; it is not expressed in the syncytiocytotrophoblast cell layer (105). The biologic activities of GH and related peptide hormones can be classified into two general categories: somatogenic and lactogenic. Somatogenic activities are related to linear bone growth and alterations in carbohydrate metabolism (106,107). Changes in carbohydrate metabolism are mediated, in part, by the release of local and hepatic insulin-like growth factor-I (IGF-I). The lactogenic activities of these peptides involve the stimulation of lactation and the modulation of other reproductive functions.
Placental Adrenocorticotropic Hormone (ACTH) Placental ACTH stimulates an increase in circulating maternal free cortisol that is resistant to dexamethasone suppression (122,125). Thus, relative hypercortisolism in pregnancy occurs despite high-normal ACTH concentrations. This situation is possible due to two main differences in endocrine relationships during pregnancy. First, the maternal response to exogenous CRH is blunted (125). Second, a paradoxical relationship exists between placental CRH, ACTH, and their end-organ product, cortisol; glucocorticoids augment placental CRH and ACTH secretion, not suppress it (78,123). This positive feedback mechanism allows an increase in glucocorticoid secretion in times of stress in excess of the amount necessary if the mother were not pregnant (78). Placental Human Placental Lactogen (hPL), [Human Chorionic
Somatomammotropin (hCS)] Since hPL is secreted primarily into the maternal circulation, most of its functions occur at sites of action in maternal tissues. Human placental lactogen is thought to be responsible for the marked rise in maternal plasma insulin-like growth factor-1 (IGF-1) concentrations as the pregnancy approaches term (128-130). Human placental lactogen exerts metabolic effects during pregnancy, via insulin-like growth factor-I (IGF-I). It is associated with insulin resistance, enhances insulin secretion which stimulates lipolysis, increases circulating free fatty acids, and inhibits gluconeogenesis; in effect, it antagonizes insulin action, induces glucose intolerance, as well as lipolysis and proteolysis in the maternal system (40). In response to fasting and glucose loading, hPL levels rise and fall (129). These metabolic effects favor the transport of glucose, amino acids and fatty acids to the fetus in an effort to provide nutrition. Pregnancy is associated with profound alterations in maternal metabolism. The fetal-maternal relationship favors glucose use by the fetus and forces the maternal tissues to increase their use of alternative energy sources. The endocrine hallmark of this hormonal environment is insulin resistance. Several hormones prevalent during pregnancy are believed to responsible for this altered milieu: estrogens, progesterone, glucocorticoids, human placental lactogen (hPL) and human chorionic somatomammotropin (hCS). Circulating levels of glucose and amino acids are reduced, while levels of free fatty acids, ketones, and triglycerides are increased. The secretion of insulin is augmented in response to a glucose load. The fuel requirements of the developing fetus are met primarily by glucose. It provides the energy needed for protein synthesis and serves as a precursor for the fat synthesis and glycogen formation. Fetal blood glucose levels are generally 10-20 mg/100 ml below those of the maternal circulation; thus, diffusion and facilitated transport favor the net movement of glucose from mother to fetus. Placental Human Chorionic Thyrotropin (hCT) Placental Peptide Hormones: Growth Factors Placental Inhibin/Activin In the maternal circulation, dimeric inhibin begins to increase above non-pregnant levels by 12 days post-conception, dramatically increasing at about 5 weeks' gestation to peak at 8-10 weeks. Subsequently, levels decrease at 12-13 weeks and stabilize until around 30 weeks before they rise again as term approaches (134). The early fluctuations in inhibin levels reflect release from the corpus luteum, whereas the increase seen in the third trimester originates from the placenta and decidua. After delivery, inhibin is undetectable. Levels of the inhibin a dimer exhibit a similar pattern throughout pregnancy (136). Through a paracrine mechanism placental inhibin is inhibits the release of placenta-derived GnRH and hCG (89,137). Alternatively, activin is known to stimulate the release of GnRH and hCG. Decidual inhibin and activin are likely to have similar effects, and function to allow maternal tissues to modulate placental GnRH and hCG production and release. Placental Insulin-like Growth Factors-I and-II (IGF-I and IGF-II) Placental Peptide Hormones: Other placental peptides In addition to the pregnancy-related proteins produced analogous to hypothalamic and pituitary glycoproteins, the placenta also produces several other proteins that have no known analogues in the non-pregnant state. These proteins have been isolated and identified from serum drawn during pregnancy or purified from placental tissue. Figure 11 shows the changes in concentration of each of these pregnancy-related proteins throughout gestation. Placental Pregnancy-Specificb1-Glycoprotein (SP1) Placental Pregnancy-Associated Plasma Protein-A (PAPP-A) Placental Protein-5 (PP5)
The regulation of the fetal endocrine system, as is true for the
placenta, is not entirely independent but relies, to some extent, on
precursors secreted by the placenta or maternal tissues. As the fetus
develops, its endocrine system begins matures and eventually becomes
more independent, preparing the fetus for extrauterine life. Fetal Hypothalamus and Pituitary The fetal hypothalamus differentiates from the forebrain during the first few weeks of fetal life. By 12 weeks' gestation, hypothalamic development is well advanced. Most of the hypothalamic-releasing hormones, including gonadotropin-releasing hormone (GnRH), thyrotropin-releasing hormone (TRH), corticotrophin-releasing hormone (CRH), as well as dopamine, norepinephrine, and somatostatin, can be identified as early as 6-8 weeks of gestation. The portal-vessel system that delivers the releasing hormones to the anterior pituitary is fully developed by 18 weeks of gestation. The anterior pituitary cells that develop from those cells lining Rathke's pouch are capable of secreting growth hormone (GH), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and adrenocorticotropic hormone (ACTH), in vitro, as early as 7 weeks of fetal life (Figure 12).
The placenta is relatively impermeable to thyroid-stimulating hormone (TSH) and thyroxine (T4), so the fetal hypothalamic-pituitary-thyroid axis develops and functions independently of the mother's. The levels of TSH and T4 are relatively low in fetal blood until mid-gestation. At 24-28 weeks' gestation, serum T4 and reverse tri-iodothyronine (rT3) concentrations begin to rise progressively until term while the TSH concentration peaks. At birth, there is an abrupt release of TSH, T4, and T3. The relative hyperthyroid state of the newborn is believed to facilitate thermoregulatory adjustments for extrauterine life. The pattern of luteinizing hormone (LH) levels in fetal plasma parallels that of follicle-stimulating hormone (FSH). The decline in pituitary gonadotropin content, and plasma concentration of gonadotropins after mid-gestation is believed to result from the maturation of the hypothalamic-pituitary-gonadal axis. The hypothalamus becomes progressively more sensitive to sex steroids originating from the placenta, and circulating in fetal blood. Occurring at 7 weeks' gestation in the male, fetal testosterone secretion begins soon after differentiation of the gonad into the testis and Leydig cells. Maximum levels of fetal testosterone are observed at about 15 weeks and decrease thereafter. Early secretion of fetal testosterone is important in initiating sexual differentiation in males. Human chorionic gonadotropin (hCG), supplemented by fetal LH, is believed to be the primary stimulus effecting the early development and growth of Leydig cells as well as stimulating the subsequent peak of testosterone production. In females, the fetal ovary is involved primarily in the formation of follicles and germ cells and less involved in hormone secretion. The human fetal adrenal gland is a remarkable organ due to its incredible capacity for steroid biosynthesis in utero, and because of its unique morphologic features. The human fetal adrenals are disproportionately large, and at mid-pregnancy their size exceeds that of the fetal kidneys. At term, the adrenals are as large as those of adults are, weighing 10 grams or more. The region that ultimately develops into the adult adrenal cortex, the outer or definitive zone, accounts for only about 15% of the fetal gland (Figure 13). The unique inner or fetal zone comprises 80-85% of the volume of the adrenal in utero, and is largely responsible for the tremendous secretory capacity of this organ. The fetal zone rapidly undergoes involution at parturition and by one year it has completely disappeared (152). Changes in the fetal adrenal volume throughout fetal life and into young adulthood are graphically depicted in Figure 14. The adrenal function of 10 preterm infants of gestational age 27-34 weeks was assessed for up to 80 days after delivery. The changes in steroid excretion with time in preterm infants of gestation over 28 weeks reflect involution of the fetal adrenal zone at a similar rate to term infants. These findings are consistent with the removal at birth of the inhibitory effects of oestrogen on the 3 beta-hydroxysteroid dehydrogenase enzyme. The continued function of the adrenal fetal zone beyond the first month in preterm infants of less than 28 weeks gestation may however be due to persistence of some other fetal regulatory adrenal mechanism. This suggests that it is gestation that determines fetal zone activity rather than birth (153). The fetal adrenal gland secretes large quantities of steroid hormones (up to 200-mg daily) near term. The rate of steroidogenesis is 5-times that observed in the adrenal glands of adults at rest. The principal steroids secreted are C-19 steroids (mainly DHEAS), which serve as substrates for estrogen biosynthesis by the placenta (Figure 13). The fetal adrenal gland contains a zone, unique to in-utero fetal life, that accounts for the rapid growth of the adrenal gland; this zone regresses during the first few weeks after birth. In addition to the fetal zone, an outer layer of cells forms the adrenal cortex (definitive zone). The fetal zone differs not only histologically, but also biochemically from the cortex (i.e., the fetal zone is deficient in 3b-hydroxysteroid dehydrogenase enzyme activity and, therefore, secretes C-19 steroids (mainly DHEAS); the cortex secretes primarily cortisol).
Research involving the fetal adrenal gland has attempted to determine the factors that stimulate and regulate fetal adrenal growth and steroidogenesis. Other work has focused on the mechanisms responsible for fetal zone atrophy after delivery. All investigations have shown that, in vitro, adrenocorticotropic (ACTH) stimulates steroidogenesis. Furthermore, there is clinical evidence that, in vivo, ACTH is the major trophic hormone of the fetal adrenal gland. For example, in anencephalic fetuses, the plasma levels of ACTH are very low and the fetal zone is markedly atrophic. Maternal glucocorticoid therapy suppresses fetal adrenal steroidogenesis by suppressing fetal ACTH secretion. Despite these observations, ACTH -related peptides, growth factors and other hormones have been proposed as possible trophic hormones for the fetal zone. After birth, the adrenal gland shrinks in size by more than 50% because of the regression of fetal zone cells. Fetal Parathyroid Glands and Calcium Homeostasis In the fetus calcium concentrations, are regulated by the movement of calcium, across the placenta, from the maternal compartment. In order to maintain fetal bone growth, the maternal compartment undergoes adjustments that provide a net transfer of sufficient calcium to the fetus. Maternal compartment changes that permit calcium accumulation include increases in maternal dietary intake, increases in maternal 1,25-dihydroxyvitamin D3 levels, and increases in parathyroid hormone levels. Actually, levels of total calcium and phosphorus decline in maternal serum, but ionized calcium levels remain unchanged. A placental calcium pump creates a gradient of calcium and phosphorus that favors the fetus. Thus, circulating fetal calcium and phosphorus levels increase steadily throughout gestation. Furthermore, fetal levels of total and ionized calcium, as well as phosphorus, exceed maternal levels at term. By 10-12 weeks' gestation, the fetal parathyroid glands secrete parathyroid hormone (PTH). Fetal plasma levels of parathyroid hormone are low during gestation, but increase after delivery. In contrast to unchanged maternal calcitonin levels, the fetal thyroid gland produces increasing levels of calcitonin. Since there is no transfer of parathyroid hormone across the placenta, changes noted in fetal calcium levels are related to changes in these hormones (PTH and calcitonin), and consistent with an adaptation to conserve and stimulate bone growth within the fetus. After birth, neonatal serum calcium and phosphorus levels fall. Parathyroid hormone levels start to rise within 48 hours after birth. Calcium and phosphorus levels steadily increase over the following several days, with some dependence on dietary intake of milk. The fetal pancreas appears during the 4th week of fetal life. The alpha cells, which contain glucagon, and the beta cells, which contain somatostatin, develop before the beta cells differentiate; however, insulin can be recognized in the developing pancreas before beta cell differentiation is apparent. Human pancreatic insulin and glucagon concentrations increase with advancing fetal age, and are higher than concentrations found in the adult pancreas. In vivo studies of umbilical cord blood obtained at delivery and fetal scalp blood samples obtained at term show that fetal insulin secretion is low and tends to be relatively unresponsive to acute changes in glucose. In contrast, fetal insulin secretion, in vitro, is responsive to amino acids and glucagon as early as 14 weeks' gestation. In maternal diabetes mellitus, fetal islet cells undergo hypertrophy such that the rate of insulin secretion increases. Alpha-fetoprotein is a glycoprotein synthesized, in sequence, by the yolk sac, gastrointestinal tract and fetal liver (156,157). After entering the fetal urine, it is readily detected in amniotic fluid. Amniotic fluid AFP (afAFP) peaks between 10-13 weeks gestation, and then declines from 14-32 weeks. In the fetus, AFP peaks at 12-14 weeks, and steadily decreases until term (158). The fall in fetal plasma AFP (fpAFP) is most likely due to the combination of increasing fetal blood volume and a decline in fetal production. The concentration gradient between fpAFP and msAFP is approximately 150- to 200-fold. Detectable as early as 7 weeks' gestation, msAFP reaches peak concentrations between 28-32 weeks (158). The seemingly paradoxical rise in msAFP in association with decreasing afAFP and fetal serum levels can be accounted for by the increasing placental permeability to fetal plasma proteins that occurs with advancing gestational age (158). Alpha-fetoprotein acts as an osmoregulator to help adjust fetal intravascular volume (158). It may also be involved in certain immunoregulatory functions (159). Amniotic fluid AFP and maternal serum AFP are clinically important because they are elevated in association conditions such as neural tube defects (160). Additionally, msAFP is decreased in pregnancies in which the fetus has Down syndrome (trisomy 21) (161). Maternal Hypothalamus and Pituitary Little information is definitively known about the endocrine alterations of the maternal hypothalamus during pregnancy. Thought to result from estrogen stimulation, the anterior pituitary undergoes a 2- to 3-fold enlargement during pregnancy, primarily because of hyperplasia and hypertrophy of lactotroph cells. Thus, plasma prolactin levels parallel the increase in pituitary size throughout gestation. In contrast to the lactotrophs, the size of the other pituitary cells decreases or remains unaltered during pregnancy. In line with these findings, maternal levels of growth hormone (GH) are low and the level of thyroid-stimulating hormone (TSH) remains unchanged. Adrenocorticotrophic hormone (ACTH) levels do increase with advancing the gestation. Corticotrophin-releasing hormone (CRH) in the maternal plasma increases during pregnancy due to increased placental secretion, but alterations in binding-protein concentrations prevent increased biologic activity of this releasing hormone. Maternal plasma arginine vasopresssin (AVP) levels remain low throughout gestation and are not believed to play a pivotal role in human pregnancy. Maternal oxytocin levels are low and do not vary much throughout pregnancy, until they increase during the later stages of labor. As a result of increased vascularity and glandular hyperplasia, the thyroid gland increases slightly in size during pregnancy; however, true goiter is not usually present. During gestation the mother remains in an euthyroid state. Total thyroxine (T4) and tri-iodothyronine (T3) levels increase but do not result in hyperthyroidism because there is a parallel increase in T4-binding globulin that results from estrogen exposure (Figure 15). The increase seen in binding-protein concentrations is similar to that observed in women who use oral contraceptives (OC). A modest increase in the basal metabolic rate (BMR) rate occurs during pregnancy secondary to increasing fetal requirements. Some T4 and T3, but no TSH, are transferred across the placenta.
The maternal adrenal gland does not change morphologically during pregnancy. Plasma adrenal steroid levels increase with advancing gestation. The increase in total plasma cortisol is due, principally, to a concomitant increase in cortisol-binding globulin. There is a slight increase in plasma and urinary free cortisol, but pregnant women do not exhibit any overt signs of hypercortisolism. Levels of renin and angiotensin rise during pregnancy, which leads to elevated angiotensin II levels and markedly elevated levels of aldosterone. A dual-hormone secretion mechanism is partially responsible for the metabolic adaptation of pregnancy in which glucose is spared for the fetus by the maternal endocrine pancreas. Compared to the non-pregnant state, in response to a glucose load, there is a greater release of insulin from the beta cells and a greater suppression of glucagon release from the alpha cells. Associated with the increased release of insulin, the maternal pancreas undergoes beta-cell hyperplasia and islet-cell hypertrophy, with an accompanying increase in blood flow to the endocrine pancreas. During pregnancy, when fasting blood glucose levels fall, they rise to a greater extent in response to a glucose load than do levels in non-pregnant women. The increased release of insulin is related to insulin resistance due to hPL, which spares transfer of glucose to the fetus. Glucagon levels are also suppressed in response to a glucose load, with the greatest suppression occurring near term. REGULATION OF FETO-MATERNAL STEROIDOGENESIS Using in vitro investigations utilizing placental tissue explants as well as, in vivo, catheterized primate models to study steroidogenic regulation in pregnancy, researchers have determined LDL-cholesterol, fetal pituitary hormones, intra-placental regulators, and intra-adrenal regulators act as the primary modulators of feto-placental steroid production (163-165). Regulation by Low-density Lipoprotein Cholesterol (LDL) A limiting factor in adrenal steroid output is the availability of, LDL-cholesterol, the primary lipoprotein used in fetal adrenal steroid steroidogenesis (Figure 16). Circulating LDL-cholesterol accounts for 50-70% of the cholesterol utilized for fetal adrenal steroidogenesis (166-168). The fetal adrenal is known to contain high affinity, low capacity LDL binding sites. The presence of ACTH increases this binding capacity (167,169,170). Within the adrenal, hydrolysis of LDL makes cholesterol available for conversion to steroids. The majority of fetal LDL-cholesterol is made, de novo, in the fetal liver (171). In addition, cortisol from the fetal adrenal cortex and estradiol (aromatized from fetal DHEAS) augment this de novo synthesis within the fetal liver. These systems interact in a manner that is linked, self-perpetuating, and serves to increase steroid production to meet the needs of the maturing fetus (171).
Regulation by Fetal Pituitary Hormones Fetal ACTH regulates steroidogenesis in both adrenal zones. Adrenocorticotropic hormone receptor activity is diminished in the fetal zone of the cortex during the early second trimester when other factors, such as hCG, are more important in the maintenance of this zone (171). In vitro studies, in human fetal adrenal tissue, demonstrate that ACTH stimulates the release of D5 pregnenolone sulfate and DHEAS, whereas in adult adrenal cortex secretes only cortisol when stimulated by ACTH (171). Moreover, ACTH can act on its own adrenal-cell membrane receptor to express a direct stimulatory effect on steroidogenic enzymes (171). Adrenocorticotropic hormone extracted from the human fetal pituitary gland has been shown, in vitro, to stimulate the production of DHEAS and cortisol (173,174). Interestingly, concentrations of ACTH throughout the gestation do not correlate with the increasing mass of the fetal adrenal cortex or the increasing steroidogenic function that are hallmarks of the third trimester (170). Fetal pituitary ACTH is detectable by 9 weeks gestation (174,179). Thereafter, levels of ACTH increase steadily until 20 weeks gestation. The levels remain stable until approximately 34 weeks, when a significant decline is initiated and persists until term (170). Prolactin may act as a co-regulator, along with ACTH, hCG and certain growth factors, in fetal adrenal steroid production (177,178). Both in vitro and in vivo, prolactin augments ACTH-stimulated adrenal androgen production (165). Fetal pituitary prolactin is detectable at 10 weeks gestation (179). Umbilical cord prolactin levels increase with advancing gestational age and rise in parallel with increased fetal adrenal mass (180). Regulation by Intra-placental Mechanisms The placenta is an important co-regulator of the fetal adrenal zone due its ability to secrete hCG, placental CRH, progesterone and estradiol (181). In vitro and in vivo, hCG receptor activity is present in the fetal zone, and hCG stimulates fetal adrenal production of DHEAS (181,182). However, after the 20th week of gestation ACTH primarily influences the fetal zone of the adrenal, and at this time, hCG plays only a minor role. Placental CRH, acts in a paracrine relationship with placental ACTH, to complement the actions of the fetal hypothalamus and pituitary in producing the surge in fetal glucocorticoids notable in the late third trimester as fetal growth and maturity become increasingly important (184,185). Placental progesterone inhibits D5 to D4 steroid transformations in the fetal zone of the adrenal (56,186). This effect is another explanation for fetal adrenal 3bHSD deficiency. Placental estradiol modifies the production and metabolism of corticosteroids and progesterone. In vivo, the placenta regulates the inter-conversion of maternal cortisol to cortisone, and the fetal pituitary production of ACTH (179,184). Modulation of the transfer of maternal cortisol across the placenta, into the fetus, is the primary mechanism through which this effect occurs. Regulation by Intra-adrenal Mechanisms With advancing gestational age, the fetal adrenal becomes more sensitive to circulating ACTH (165). Between 32 and 36 weeks gestation, the fetal adrenal mass increases (187-189). Blood flow to the fetal adrenal is affected by many factors that, in turn, affect the exposure of the fetal adrenal receptors of the different trophic stimuli. Growth factors modulate adrenal steroid pathways just as they do in the adult adrenal cortex. The fetal adrenal produces IGF-I and IGF-II; ACTH originating from either the fetal pituitary or the placenta can stimulate production of their respective mRNAs (190,191). Active labor is characterized by a dramatic increase in the number of oxytocin receptors in the myometrium. Once begun, the process appears to be self-perpetuating. The level of maternal catecholamines increases, resulting in the liberation of free fatty acids, including arachadonic acid; there is also an increase in the level of maternal or fetal cortisol, which decreases the production of uterine smooth muscle prostacyclin. It is unlikely that oxytocin is the initiator of labor despite the fact that oxytocin receptors are present in the myometrium and increase before labor, and it stimulates decidual prostaglandin E2 and prostaglandin F2a production. Therefore, the prostaglandins (PG) are thought to play the central role. For years, it has been known that rupture, stripping or infection of the fetal membranes, as well as instillation of hypertonic solutions into the amniotic fluid, results in the onset of labor. These facts have led to the hypothesis that a fetal-amniotic fluid-fetal membrane complex is a metabolically active unit that triggers the onset of labor. Evidence supporting a causative role of prostaglandins in the labor process is present since PGs induce myometrial contractions in all stages of gestation. However, direct evidence relating endogenous PGs to labor is not clear. Important to this hypothesis is the understanding that at least one mechanism in the onset of parturition is the release of stored precursors of PGs from the fetal membranes. The major precursor for PGs is arachadonic acid, which is stored in glycerophospholipids. The fetal membranes are enriched with two major glycerophospholipids, phosphatidylinositol and phosphatidylethanolamine. As gestation advances, the progressively increasing levels of estrogen stimulate the storage, in fetal membranes, of these glycerophospholipids containing arachadonic acid. A series of fetal membrane lipases, including phospholipase A2 and Phospholipase C control the release of arachadonic acid from storage in fetal membrane phospholipids. Once in a free state, arachadonic acid is available for conversion to PG. Additional factors that augment and accentuate the normal process of labor include the liberation of corticosteroid by the mother and fetus, resulting in a decrease in the production of myometrial prostacyclin, a smooth muscle relaxant. There is no reduction in maternal or fetal progesterone levels during spontaneous labor. Undoubtedly, progesterone is important in uterine quiescence because in the first trimester removal of the corpus luteum leads rapidly to myometrial contractions (33). Likewise, labor ensues following the administration of progesterone receptor antagonists in the third trimester (192). The anti-progesterone agents occupy progesterone receptors and inhibit the action of progesterone, which is clearly essential for maintenance of uterine quiescence. Yet, progesterone administration to women, except for very large doses, does not suppress uterine contractions once begun (192). The ratios of estradiol and progesterone in various animal models are closely related to the stimulation of myometrial gap-junction formation (193). With decreasing progesterone relative to estradiol, gap junctions permit cell-cell communication for the synchronized myometrial smooth muscle contractions required for labor. Progesterone and the estrogens are antagonistic in the parturition process. Progesterone produces uterine relaxation, stabilizing lysosomal membranes and inhibiting prostaglandin synthesis and release. By contrast, estrogens destabilize lysosomal membranes and augment the synthesis of prostaglandin and their release (194). Although gradual increase in umbilical cord DHEAS and maternal estriol occurs toward term, there is no corresponding drop in either fetal or maternal progesterone concentrations (195). The roles of estrogen include regulation of events leading to parturition because pregnancies are often prolonged when estrogen levels in maternal blood and urine are low, as in placental sulfatase deficiency or when associated with anencephaly. Feto-placental estrogens are closely linked to myometrial irritability, contractility, and labor. In primates, estrogens ripen the cervix, initiate uterine activity, and established labor (196). Estrogens also increase the sensitivity of the myometrium to oxytocin by augmenting prostaglandin biosynthesis (194,197). Because placental release of estrogens is linked to the fetal hypothalamus, pituitary, adrenals, and placenta the fetal pituitary adrenal axis appears to fine-tune parturition timing in part through its effect on estrogen production. In human studies, there is a correlation in uterine activity with circulating maternal estrogens and progesterone as labor approaches (198-200). There is firm evidence of increasing, rhythmical fetal adrenal and placental steroid output over the 5 weeks just before term that is important in preparing human pregnancy for the final cascade of oxytocin and prostaglandins that stimulate labor (194,197-201). |
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