Placental hormones and fetal growth

Fetal growth is controlled by the placenta which mediates fetal nutritional supplies. During pregnancy, the placenta secretes a specific placental growth hormone which replaces the pituitary growth hormone in the maternal circulation. Placental growth hormone is one example of the materno-placental cooperation which is impaired in cases of intra-uterine growth retardation.     

Increase in maternal placental growth hormone during pregnancy and disappearance during parturition in normal and growth hormone-deficient pregnancies

OBJECTIVE: The purpose of this study was to evaluate placental growth hormone levels in maternal circulation throughout pregnancy in normal and growth hormone-deficient women with the use of a specific assay and to determine the clearance of placental growth hormone from maternal circulation after birth. STUDY DESIGN: Seventeen healthy pregnant women and 1 patient with growth hormone deficiency substituted with recombinant growth hormone during pregnancy participated in a longitudinal study from early pregnancy until birth with repetitive blood sampling and measurement of placental growth hormone levels throughout pregnancy. Furthermore, serial blood samples were drawn before, during, and after elective caesarean deliveries in 5 healthy women to calculate the half-life of placental growth hormone. Placental growth hormone was measured with the use of two monoclonal antibodies in a commercially available solid-phase iodine 125-labeled immunoradiometric assay (Biocode, Liège, Belgium). RESULTS: Placental growth hormone levels were detectable from as early as 8 weeks of gestation in some of the women and increased throughout gestation, with a maximum at approximately 35 to 36 weeks of gestation (13.7 ng/mL; range, 5.9-24.4 ng/mL) and large interindividual variations. Placental growth hormone levels did not correlate with birth weight or placental weight. In the patient with isolated growth hormone deficiency, placental growth hormone levels were detectable from 11 weeks of gestation (3.4 ng/mL) and increased throughout pregnancy to 13.9 ng/mL, which is similar to values that are obtained in the healthy pregnant women. Substitution therapy with recombinant human growth hormone did not suppress the increase in placental growth hormone. We found a mean half-life of placental growth hormone of 13.8 minutes (range, 11.5-15.2 minutes) in healthy pregnant women and an apparently similar half-life of placental growth hormone (15.8 minutes) in the growth hormone-deficient patient, assuming a monoexponential disappearance of placental growth hormone during the first 30 minutes after the delivery. After the initial 30 minutes, approximately 75% (range, 65%-89%) of the placental growth hormone had been cleared from the maternal circulation. CONCLUSION: Levels of placental growth hormone in maternal circulation increase throughout pregnancy from as early as 8 weeks of pregnancy, with maximum levels around the week 35 of gestation. The pregnancy-induced rise in placental growth hormone levels in the growth hormone-deficient patient was comparable to the rise seen during normal pregnancies and was not suppressed by the concurrent human growth hormone treatment. We speculate that maternal serum levels of placental growth hormone reflect placental function and fetal growth. However, further studies are needed to evaluate the potential clinical use of placental growth hormone determinations.     

Contribution of maternal circulation to blood-borne progesterone in the fetus. II. Studies on sheep

Catheters were placed in maternal and fetal vessels in four ewes in the last month of gestation. Tritiated progesterone (P) was infused at a constant rate into a maternal peripheral vein. Specific activities and endogenous concentrations of P were measured in blood samples drawn from a maternal artery and either a fetal femoral artery or an umbilical vein. Comparison of the specific activities of P in fetal and maternal samples revealed that direct secretion of the placental hormone into the umbilical vein accounted for 90 to 93 per cent of the hormone in the fetal circulation. Estimates of the rates of production of P in the fetal circulation, obtained by multiplying metabolic clearance rates previously reported and concentrations of P in a fetal femoral artery, indicate that placental P is preferentially secreted toward the maternal circulation.     

胎盘促肾上腺皮质激素释放激素在人类分娩中的作用

在妊娠中、晚期 ,人类胎盘组织能产生和分泌大量的促肾上腺皮质激素释放激素 (CRH)进入母体和胎儿循环中。母体血浆 CRH的水平随着孕周升高 ,分娩前达到高峰 ,且与孕周长短呈正相关。早产孕妇血浆 CRH水平在妊娠中期开始就明显升高 ,治疗有效者 ,血浆 CRH水平明显回落。CRH可通过对胎儿下丘脑 -垂体 -肾上腺轴的作用来促进胎盘其他分娩激素的分泌以及对子宫平滑肌的作用而诱导分娩的启动     

Stress and the female reproductive system

The hypothalamic-pituitary-adrenal (HPA) axis, when activated by stress, exerts an inhibitory effect on the female reproductive system. Corticotropin-releasing hormone (CRH) inhibits hypothalamic gonadotropin-releasing hormone (GnRH) secretion, and glucocorticoids inhibit pituitary luteinizing hormone and ovarian estrogen and progesterone secretion. These effects are responsible for the "hypothalamic" amenorrhea of stress, which is observed in anxiety and depression, malnutrition, eating disorders and chronic excessive exercise, and the hypogonadism of the Cushing syndrome. In addition, corticotropin-releasing hormone and its receptors have been identified in most female reproductive tissues, including the ovary, uterus, and placenta. Furthermore, corticotropin-releasing hormone is secreted in peripheral inflammatory sites where it exerts inflammatory actions. Reproductive corticotropin-releasing hormone is regulating reproductive functions with an inflammatory component, such as ovulation, luteolysis, decidualization, implantation, and early maternal tolerance. Placental CRH participates in the physiology of pregnancy and the onset of labor. Circulating placental CRH is responsible for the physiologic hypercortisolism of the latter half of pregnancy. Postpartum, this hypercortisolism is followed by a transient adrenal suppression, which may explain the blues/depression and increased autoimmune phenomena observed during this period.     

Biologically active corticotropin-releasing hormone in maternal and fetal plasma during pregnancy

Corticotropin-releasing hormone was measured in the plasma of 110 pregnant women and in the umbilical cord plasma of 25 premature infants and 43 infants born at term. Mean maternal plasma corticotropin-releasing hormone was undetectable (less than 41 pg/ml) until mid-second trimester, rose to a mean of 204 +/- 24 pg/ml by 30 weeks' gestation, to 326 +/- 41 by 35 weeks, and then rose sharply near term, with a mean of 2930 pg/ml at 38 to 40 weeks' gestation. Sequential measurements in seven pregnant women confirmed that plasma corticotropin-releasing hormone rose in a predictable pattern, with a dramatic increase in the final weeks of pregnancy. There was little hour-to-hour variability in maternal plasma concentrations. Corticotropin-releasing hormone was also detectable in umbilical cord plasma; mean corticotropin-releasing hormone was 194 +/- 44 in the preterm infants and 150 +/- 19 in the term infants. The corticotropin-releasing hormone extracted from both the maternal and fetal circulation was biologically active in vitro and caused the dose-dependent release of adrenocorticotropic hormone and beta-endorphin from cultured rat anterior pituitary cells. A significant correlation was found between maternal plasma corticotropin-releasing hormone and cortisol levels the morning after betamethasone administration, a finding that supports a physiologic role for maternal plasma corticotropin-releasing hormone. We conclude that the placenta secretes large amounts of biologically active corticotropin-releasing hormone into both the maternal and fetal circulation during pregnancy. We demonstrate that this corticotropin-releasing hormone is secreted into the maternal plasma in a reproducible pattern during normal term pregnancy and suggest that sequential corticotropin-releasing hormone measurements may prove to be of clinical utility. In addition, placental corticotropin-releasing hormone may be an important modulator of the hypothalamic-pituitary-adrenal axis during pregnancy.     

Prostaglandin E2, Fetal Maturation and Ovine Parturition

Summary: The major source of PGE₂ in ovine pregnancy is the placenta, with secretion occurring bidirectionally into fetal and maternal circulations. The placental output of PGE₂ appears to increase when demand on placental function is increased, suggesting that the normally observed increase in its concentration towards term is driven by the growing demands of the fetus. The fetal pituitary is also involved in the control of PGE₂ synthesis. PGE₂ has potent stimulatory actions on the fetal pituitary to increase both the absolute concentration and the bioactive fraction of ACTH-containing peptides in the fetal circulation. It also directly stimulates glucocorticoid secretion from the fetal adrenal gland.
We propose that PGE₂ provides a tonic stimulation of the fetal HPA axis in late gestation, contributing to phenomena such as the apparent insensitivity of the pituitary to Cortisol feedback and the increasing sensitivity of the fetal adrenal. Because of its apparent responsiveness to placental workload, it may transduce stimuli from the placenta and transmit them to the fetal HPA axis, giving a possible biochemical basis to the empirically observed correlation between fetal metabolic demand and gestation length.     

Placental leptin

Placental tissues from humans, rodents and farm animals contain leptin and its receptor. Leptin produced by the human placenta has the same size, charge and immunoreactivity as leptin produced by adipose tissue. However, the expression of human placental leptin appears to be regulated by a placenta-specific upstream enhancer. In this review the occurrence of leptin and its receptor in a range of species and placental types is described, and its significance during pregnancy discussed. Placental leptin contributes to the increase in maternal circulating concentrations of leptin during late pregnancy when it is likely to have an endocrine role in regulating maternal energy balance. Placental leptin may have angiogenic and immunomodulatory activities, which affect the placenta in an autocrine or paracrine manner. It also appears to affect fetal growth and development by binding to leptin receptors present in fetal organs.     

Non-placental causes of intrauterine growth restriction

Placental insufficiency, in some form or fashion, is associated with the majority of cases of intrauterine growth restriction (IUGR). There are numerous causes of IUGR which are not caused primarily by placental insufficiency, but indirectly lead to it. The causes of IUGR can be subdivided into fetal and maternal etiologies. The fetal etiologies consist of genetic diseases, congenital malformations, infections, multiple gestations, and placental/cord abnormalities. The maternal etiologies are categorized as follows: (1) decreased uteroplacental blood flow, (2) reduced blood volume, (3) decreased oxygen carrying capacity, (4) nutrition status, (5) teratogens, and (6) miscellaneous causes such as short interpregnancy intervals, race, maternal age, and low socioeconomic status. Knowledge of the etiologies of fetal growth restriction is essential, so that future care can be targeted at prevention. There are several primary and secondary prevention strategies that can be adopted.     

Partitioning of glutamine synthesised by the isolated perfused human placenta between the maternal and fetal circulations

Introduction

Placental glutamine synthesis has been demonstrated in animals and is thought to increase the availability of this metabolically important amino acid to the fetus. Glutamine is of fundamental importance for cellular replication, cellular function and inter-organ nitrogen transfer. The objective of this study was to investigate the role of glutamate/glutamine metabolism by the isolated perfused human placenta in the provision of glutamine to the fetus.

Methods

Glutamate metabolism was investigated in the isolated dually perfused human placental cotyledon. U–¹³C-glutamate was used to investigate the movement of carbon and ¹⁵N-leucine to study movement of amino-nitrogen. Labelled amino acids were perfused via maternal or fetal arteries at defined flow rates. The enrichment and concentration of amino acids in the maternal and fetal veins were measured following 5 h of perfusion.

Results

Glutamate taken up from the maternal and fetal circulations was primarily converted into glutamine the majority of which was released into the maternal circulation. The glutamine transporter SNAT5 was localised to the maternal-facing membrane of the syncytiotrophoblast. Enrichment of ¹³C or ¹⁵N glutamine in placental tissue was lower than in either the maternal or fetal circulation, suggesting metabolic compartmentalisation within the syncytiotrophoblast.

Discussion

Placental glutamine synthesis may help ensure the placenta's ability to supply this amino acid to the fetus does not become limiting to fetal growth. Glutamine synthesis may also influence placental transport of other amino acids, metabolism, nitrogen flux and cellular regulation.

Conclusions

Placental glutamine synthesis may therefore be a central mechanism in ensuring that the human fetus receives adequate nutrition and is able to maintain growth.     

Growth hormone 24-h serum profiles during pregnancy--lack of pulsatility for the secretion of the placental variant

Serum profiles of growth hormone (GH) were recorded for 24 h in women at different stages of normal pregnancy. Two monoclonal antibodies directed against different epitopes and unaffected by human placental lactogen were used in radioimmunoassays to distinguish the pituitary 22K-GH from the placental GH variant. The 'normal' episodic peak activity of GH in non-pregnant and first trimester pregnant women was dramatically changed into a continuous very stable secretion during late pregnancy. This change was first observed at 17 weeks gestation. It is concluded that during the second half of pregnancy, serum measurements of GH reflect a major contribution from a non-episodically secreted placental GH variant and a concomitant suppression of pituitary GH. This specific signal, i.e. a continuous GH secretion, may be an important regulator of maternal liver metabolism during pregnancy.     

Growth hormone 24-h serum profiles during pregnancy—lack of pulsatility for the secretion of the placental variant

Summary. Serum profiles of growth hormone (GW) were recorded for 24 h in women at different stages of normal pregnancy. Two monoclonal antibodies directcd against different epitopes and unaffected by human placental lactogen were used in radioimmunoassays to distinguish the pituitary 22K-GH from the placental GH variant. The 'normal' episodic peak activity of GH in non-pregnant and first trimester pregnant women was dramatically changed into a continuous very stable secretion during late pregnancy. This change was first observed at 17 weeks gestation. It is concluded that during the second half of pregnancy, serum measurements of GH reflect a major contribution from a non-cpisodically secreted placental GH variant and a concomitant suppression of pituitary GH. This specific signal, i.e. a continuous GH secretion, may be an important regulator of maternal liver metabolism during pregnancy.     

The influence of leptin on placental and fetal volume measured by three-dimensional ultrasound in the second trimester

For a couple of years mechanisms influencing placental and fetal growth and the functioning of leptin, the protein product of the ob/ob gene, have been subjects of intensive research. This study's aim was to investigate whether maternal serum leptin and amniotic fluid leptin have an influence on placental and fetal size measured by three-dimensional ultrasound in the second trimester. To determine this, 40 women with a singleton intrauterine pregnancy at the time of the amniocentesis were included in the study. Placental and fetal volume measurements were obtained and correlated to maternal serum leptin, amniotic fluid leptin, body mass index and gestational age. Multiple regression analysis identified amniotic fluid leptin as an independent negative predictor of placental and fetal volume (r = -2.29, p = 0.032 and r = -0.95, p = 0.011, respectively). In contrast, there was no correlation between maternal serum leptin and placental or fetal volume. The median leptin level in amniotic fluid (9.5 ng/ml) was significantly lower than in maternal blood (18.6 ng/ml). However, there was no significant correlation between maternal serum leptin and amniotic fluid leptin (r = 0.208, n.s.). Body mass index did not reveal any significant influences on placental or fetal volume. The relatively high level of amniotic fluid leptin and its inverse correlation on placental and fetal volume in the second trimester suggest that it possibly plays a role as an anti-placental growth hormone or feedback modulator of substrate supply to the fetus and placenta.     

Contribution of maternal circulation to blood-borne progesterone in the fetus. I. Studies on human subjects

Tritiated progesterone was infused intravenously at a constant rate into three pregnant volunteers in labor, for at least two hours before delivery. Blood samples from a maternal peripheral vein and from unbilical vessels were taken at birth. Comparison of the specific activities of progesterone in these samples indicated that 10 per cent or less of the hormone in fetal circulation is derived from transfer of maternally circulating progesterone. After consideration of reported values of umbilical vein blood flow at term and measured arteriovenous differences in concentrations of progesterone in umbilical vessels, the secretion rate of the placental hormone toward the fetus was estimated to be about 1/10 of the rate of secretion of progesterone toward the maternal circulation. About 1 per cent of the maternally circulating hormone was found to cross the placenta.     

Leptin: roles and regulation in primate pregnancy

Leptin, a hormone produced by adipose tissue and the placenta, is enhanced in the maternal circulation throughout pregnancy in both the human and the baboon ( Papio sp.), a proven nonhuman primate model for the study of human pregnancy. The presence of both leptin and its receptor in the fetus implies a role for the polypeptide as a regulator of in utero development, although localization in the placental trophoblast may relate to autocrine and/or paracrine regulatory functions in this important endocrine tissue. Although regulatory mechanisms remain incompletely defined, it has been suggested that cross talk occurs between the fetus, placenta, and maternal adipose stores. Placental estrogen, which is present in increasing concentrations with advancing gestation, is suggested to influence leptin synthesis in a tissue- and cell type-specific fashion. In this capacity, cellular hypoxia, diabetes, and preeclampsia are conditions that appear to be intimately linked to leptin dynamics. A better understanding of regulatory mechanisms will have direct clinical significance, as leptin has been proposed to impact on those causes of human perinatal morbidity and mortality that are associated with anomalies of fetal maturity and development, general conceptus growth, trophoblast endocrinology, and placental sufficiency.     

Hypoperfusion causes increased production of interleukin 6 and tumor necrosis factor alpha in the isolated, dually perfused placental cotyledon

OBJECTIVE: Our purpose was to determine whether exposure of the isolated, perfused human placental cotyledon to different fetal circuit perfusion rates, and to concomitant pressure differences, alters placental production of interleukin 6 and tumor necrosis factor alpha. STUDY DESIGN: The maternal and fetal circulations of 2 cotyledons from 5 placentas were perfused for 4 hours. The fetal circulation of 1 cotyledon was perfused at a low rate of 1 mL/min, and the other at a high rate of 10 mL/min. The maternal circulation of each cotyledon was perfused at 10 mL/min. Effluents from the fetal circulation were collected at hourly intervals, and concentrations of interleukin 6 and tumor necrosis factor alpha were determined by enzyme-linked immunosorbent assay. Concentrations of interleukin 6, obtained from a prior study with an estimated physiologic fetal circulation rate of 4 mL/min, were compared with the low and high perfusion rate results. RESULTS: Concentrations of interleukin 6 and tumor necrosis factor alpha were greater at the perfusion rate of 1 mL/min, in comparison with the perfusion rate of 10 mL/min, with statistically significant differences achieved at 2 and 4 hours for interleukin 6 and at 4 hours for tumor necrosis factor alpha. Concentrations of both cytokines increased exponentially with time. Placental perfusion pressures were significantly greater at the perfusion rate of 10 mL/min. CONCLUSION: Placental hypoperfusion results in an increased production of both interleukin 6 and tumor necrosis factor alpha. This finding links placental perfusion abnormalities to the myriad of disorders associated with elevated concentrations of inflammatory cytokines, including cerebral palsy.     

Does the physiological acromegaly of pregnancy benefit the fetus?

Pregnancy is accompanied by notable changes in the secretion of growth hormone (GH) and the insulin-like growth factors (IGFs). A GH variant produced by the placenta is discernible in maternal plasma from early pregnancy, rising exponentially until 37 weeks. Meanwhile, pituitary GH gradually drops to near-undetectable levels. While there might be a modest reduction in circulating IGF-I in early pregnancy, IGF-I increases 2- to 3-fold in the second half, again with a peak at around 37 weeks. Thus, placental GH is believed to replace pituitary GH as the primary stimulus for IGF-I secretion in pregnancy. Several IGF-binding proteins (IGFBPs) including IGFBP-3 are proteolyzed, leading to an elevated free (bioavailable) IGF-I fraction. IGF-II concentrations also appear to show a modest (20-25%) increase in the course of pregnancy. The possible clinical manifestations include edema of face and forearms and carpal tunnel symptoms, reminiscent of the symptoms of acromegaly and the side effects of GH/IGF-I treatment. Neither placental GH nor the maternal IGFs cross the placental barrier, yet evidence from preclinical models is accumulating that they promote trophoblast invasion, placenta growth and maturation, transplacental nutrient transport and, ultimately, fetal growth. The ensemble data strongly suggest that 'gestational acromegaly' develops in order to foster fetoplacental growth.     

Somatomedins--insulin-like growth factors

Growth factors act after specific binding with cell membrane receptors, i.e. these factors mediate mitogenic signals. Insulin-like growth factors (IGF) (syn.: somatomedins) as well as insulin have the same biological activity caused by structural homology. But under normal physiological conditions neither IGF I nor IGF II appear to be involved in the regulation of glucose homeostasis, in contrary to insulin IGFs have mostly mitogenic features. On the other side it is possible that under pathophysiological conditions hypoglycemic effects are caused by an increase of free IGF in the circulation. Insulin acts as a regulating factor in the GF-expression. IGF-I and IGF-II are different peptides especially regarding to their biological role. The synthesis of IGF-I secretion in the liver is dependent on growth hormone (GH). GH is secreted by the pituitary under the influence of the growth-hormone releasing factor (GHF) and is inhibited by somatostatin. In response to GH the liver secretes somatomedin which exerts negative feed back effects on the pituitary and stimulates somatostatin release. The IGF-synthesis is dependent on the human placental lactogen (HPL), i.e. IGF-II is mainly responsible for fetal development the estimation of the production of IGFs by the fetus supports investigations about fetal somatomedins to clear fetal growth retardations and diabetic macrosomia respectively.     

Putative role of placental corticotropin-releasing factor in the mechanisms of human parturition.

Corticotropin-releasing factor is a 41-amino-acid neuropeptide synthesized in the paraventricular nucleus of the hypothalamus and released in response to stress. Its major role is the regulation of the hypothalamus-pituitary-adrenal axis by stimulation of ACTH release from the anterior pituitary gland. In addition, corticotropin-releasing factor modulates behavioral, vascular, and immune responses to stress. Corticotropin-releasing factor was first detected in the extracts of human placentas obtained at full term from spontaneous deliveries. Placental corticotropin-releasing factor content and messenger RNA expression progressively increase during normal pregnancy, and corticotropin-releasing factor levels in maternal plasma have a similar time course. The addition of corticotropin-releasing factor to primary trophoblast cell cultures stimulates ACTH secretion in a dose-dependent manner, and its action is mediated by cyclic adenosine monophosphate as second messenger. In addition, corticotropin-releasing factor is a potent local regulator of myometrial contractility and of membrane prostaglandin release. The effects of corticotropin-releasing factor in these various tissues are mediated by specific receptors. Placental corticotropin-releasing factor is also secreted into the fetal circulation and the stimulation of fetal pituitary ACTH and fetal adrenal gland dehydroepiandrosterone sulfate release in vitro has been shown. Recently, urocortin, a new peptide related to corticotropin-releasing factor, has been found in human placenta. Corticotropin-releasing factor and urocortin share some of their biologic effects, acting on the same receptors. A large-molecular-weight corticotropin-releasing factor-binding protein modulates the activity of both these peptides. Plasma corticotropin-releasing factor levels are low in nonpregnant women and become higher during the second trimester of pregnancy, rising steadily until about 35 weeks, and then increasing more rapidly until term. Vaginal delivery is a condition associated with the highest values of maternal corticotropin-releasing factor levels. Corticotropin-releasing factor is also measurable in fetal plasma (20-fold lower than in maternal circulation) and in amniotic fluid. Increased maternal plasma corticotropin-releasing factor levels characterize some gestational diseases. Women with chronic hypertension and preeclampsia have high corticotropin-releasing factor levels, and intrauterine growth retardation is associated with an activation of the hypothalamus-pituitary-adrenal axis, reflected by increased fetal plasma concentrations of ACTH, cortisol, and corticotropin-releasing factor. The role of corticotropin-releasing factor in preterm labor is uncertain, but midgestational plasma corticotropin-releasing factor levels may be higher in women delivering preterm. In these various pathologic states, maternal plasma corticotropin-releasing factor-binding protein levels undergo opposite changes, decreasing to very low levels. The endocrine-paracrine corticotropin-releasing factor/corticotropin-releasing factor-binding protein pathways may play a major role in the mechanism of human parturition.     

Fetal placental vascular responses to corticotropin-releasing hormone in vitro. Effects of variation in oxygen tension

In this study, using the human placenta perfused in vitro with Krebs' bicarbonate solution, we have examined the effects of changes in oxygen tension on the vasoreactivity of fetal placental blood vessels to corticotropin releasing hormone (CRH). Vasodilatory responses to human synthetic CRH were measured during sub-maximal vasoconstriction of the fetal placental circulation with prostaglandin F(2alpha)(PGF(2alpha)) (1-100 micrometer). Decreases in fetal placental arterial perfusion pressure (FAP) were obtained with CRH under conditions of high oxygen or low oxygen tension, >/=450 mmHg and 相似文献