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Supportive care in early pregnancy is associated with a significant beneficial effect on pregnancy outcome. Prophylactic hormonal supplementation can be.
Table of contents

Like progesterone, estrogen is secreted by the corpus luteum until the placenta takes over. This pregnancy hormone plays a key role in the development of the fetus , and it triggers the growth of several organs and other bodily systems in the fetus. The role of estrogen is super-important: It helps to stimulate hormone production in the fetus's adrenal gland, it stimulates growth of the adrenal gland, and it enhances the mother's uterus, enabling it to respond to oxytocin another pregnancy hormone; see below.

It also prepares your breasts for milk production by enlarging the milk ducts. Once you've reached the end of the first trimester, your body has higher levels of circulating estrogen, and then the levels plateau. Some women, however, are lucky enough to experience the upside of a pregnancy 'glow,' which is largely attributed to estrogen levels. Relaxin is believed to be responsible for loosening the ligaments that hold the pelvic bones together and for relaxing the uterine muscle.

The Down Side: You may feel that your ligaments are 'looser,' including your shoulders, knees, hips, and ankles, which can result in aches, pain , inflammation, and even clumsy tendencies. Oxytocin is also the hormone that stretches the cervix and stimulates the nipples to produce milk. Many women believe oxytocin is the hormone that triggers labor.

Pitocin, the drug usually given to induce labor , is the synthetic form of oxytocin. In the days and weeks immediately before delivery, many women experience mild euphoria and strong nesting behavior inexplicably washing walls, baking and so on , and this may be linked to oxytocin as well as to other hormones and steroids. During delivery, huge bursts of oxytocin run through the brain.

After delivery, when a woman holds her newborn, she develops what's called "baby lust," a chemical reaction that happens when a baby's pheromones stimulate the production of additional oxytocin—thus augmenting the mother-baby bond. This milk-producing hormone has a tranquilizing effect. Prolactin prepares breast tissues for lactation and the release of milk.

A Cheat Sheet to Pregnancy Hormones. By Lambeth Hochwald. Pin FB ellipsis More. Image zoom. Popular in Pregnancy Emotions. In particular, the total abundance of circulating leukocytes, monocytes, granulocytes and T lymphocytes increase in the mother in response to pregnancy Groen et al. However, expression of major histocompatibility complex class II by circulating monocytes is reduced in the mother, which would decrease antigen presentation and stimulation of T cells during pregnancy and prevent the maternal immune system from mounting an unwanted response against fetal antigens Groen et al.

The total number of circulating natural killer cells and secretion of pro-inflammatory cytokines IFN-gamma is also reduced in the pregnant state Veenstra Van Nieuwenhoven et al. However, close to parturition, the maternal immune system shifts to a pro-inflammatory state, particularly locally within the uterus, to promote labor Mor and Cardenas, ; Edey et al.

There are also specific changes in the numbers of different leukocyte populations in the maternal thymus and spleen during pregnancy Clarke and Kendall, ; Kendall and Clarke, ; Norton et al. The spleen, which also has functions in hematopoiesis, enlarges due to an expansion of the splenic red pulp during pregnancy Maroni and De Sousa, ; Norton et al. Neurological changes must also occur during pregnancy to increase maternal nursing behavior and enable the mother to properly care for her newborn infant Bridges et al.

For instance, there is increased activation of the prefrontal cortex and neurogenesis of the forebrain olfactory bulb Shingo et al. In addition, formation of lobulo-alveolar units in the mammary gland commences during pregnancy, in preparation for lactational support of the neonate.

The placenta is a highly active endocrine organ during gestation; secreting a variety of hormones with physiological effects in the mother. Placental hormones include members of the prolactin and growth hormone family, steroid hormones and neuroactive hormones. The function of these hormones in driving physiological changes during pregnancy has been assessed in two main ways.

First, the expression and activity of the hormones have been manipulated in vivo by either exogenously administering or genetically manipulating the expression of hormones and hormone receptors to study the physiological consequences for the animal. Secondly, hormones have been manipulated similarly in cultured cells and tissue explants to inform on the cellular and molecular mechanisms by which they modulate function.

Members of this family consist of prolactin PRL Handwerger et al. Between mammalian species, there are differences in the number and type of family members expressed by the placenta [reviewed elsewhere Linzer and Fisher, ; Soares, ; Soares et al. In mice and rats, expression of the individual PRL-GH family members vary spatially and temporally in the placenta Dai et al.

The anterior pituitary also produces PRL and GH; however this is diminished by mid-pregnancy, when placental hormone production predominates Bridges, In several species including rodents and humans, PRL is additionally produced by the decidua during pregnancy. As the PRL-GH members also exert similar functions, these have been presented in a grouped fashion in the text and tables Tables 1 , 2. However, where possible, the roles of individual family members of the PRL-GH in physiological changes have been described.

Studies performed both in vivo and in vitro support a role for the PRL-GH family in mediating maternal metabolic adaptations to pregnancy Tables 1 , 2. GH may also be important for modulating pancreatic insulin production Billestrup and Nielsen, ; Brelje et al. Placental GH reduces insulin receptor expression and signaling, as well as, diminishes the abundance of the insulin-sensitive glucose-transporter, GLUT-4, in the skeletal muscle Barbour et al.

Insulin receptor abundance and signaling in the liver is also reduced in response to increased GH abundance in transgenic mice Dominici et al. In white adipose tissue, GH also disrupts the insulin signaling pathway, and inhibits insulin action on glucose uptake and lipid accumulation Del Rincon et al.

In part, the effects of GH may be mediated through insulin-like growth factor-1 IGF1 , which is primarily secreted from the liver in response to GH and exerts lipolytic effects during pregnancy Randle, ; Sferruzzi-Perri et al. Taken together, the production of PRL-GH family of hormones by the placenta appears to be important in regulating both insulin production and sensitivity of the mother in response to pregnancy. In non-pregnant animals, GH is important for controlling body weight and composition such as adiposity; Farmer et al.

The effect of PRL on weight gain and body adiposity is even less clear; with both no effect and an increase reported for non-pregnant and pregnant rodents. Taken together, members of the PRL-GH family appear to promote changes in maternal glucose metabolism, behavior and mammary gland function which are expected to be important for supporting the growth of offspring during pregnancy and lactation.

The placenta is a primary source of steroid hormones during pregnancy. Placental steroid hormones include estrogens and progesterone Costa, ; Edey et al. In species like rodents, the corpus luteum continues to contribute to the circulating pool of steroid hormones during pregnancy, whereas in other species such as humans and ruminants, the placenta serves as the main source Costa, Physiological effects of progesterone are mediated predominately by nuclear receptors PR-A, PR-B although membrane bound-type receptors mPR enable non-genomic actions.

Steroid hormones are implicated in pregnancy complications such as gestational diabetes and preeclampsia. High progesterone and estrogen concentrations have been reported for women with gestational diabetes Branisteanu and Mathieu, ; Qi et al. Studies performed in vivo , suggest placental steroid hormones may be important in driving the changes in insulin sensitivity and glucose metabolism of the mother during pregnancy Table 3.

Hyperinsulinemic-euglycemic clamp studies in women and rodents highlight a role for progesterone in reducing maternal insulin sensitivity during pregnancy.

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Progesterone administration decreases the ability of insulin to inhibit glucose production by the liver, and diminishes insulin-stimulated glucose uptake by skeletal muscle and to a lesser extent in the adipose tissue of non-pregnant animals Table 3 ; Progesterone; Leturque et al. In contrast, exogenous estrogen increases whole body insulin sensitivity in non-pregnant state Table 3 ; Estrogen; Ahmed-Sorour and Bailey, Loss of the estrogen receptor or estrogen production is also associated with increased body weight, adiposity and hepatic lipogenesis Table 3 ; Estrogen; Takeda et al.

Progesterone and estrogen also exert opposite effects on food intake in vivo Table 3. In particular, estrogen depresses food intake in part via induction of leptin production by adipose tissue, whereas progesterone increases food intake by enhancing NPY and reducing CART expression by the hypothalamus Table 3 ; Fungfuang et al. Therefore, both estrogen and progesterone play roles in regulating insulin and glucose homeostasis, lipid handling and appetite regulation, which may be important in promoting metabolic changes in the mother during pregnancy.

Work conducted both in vitro and in vivo indicate that estrogen and progesterone may also facilitate some of the cardiovascular changes that accompany pregnancy Tables 3 , 4. Estrogen attenuates the vasoconstrictor responses of blood vessels, impairs vascular smooth muscle cell proliferation and calcium influx, and increases vasodilatory nitric oxide synthase activity in vitro Table 4 ; Estrogen; Takahashi et al.

It also increases uterine artery angiogenesis and amplifies the vasodilatory impact of vascular endothelial growth factor on isolated rat uterine vessels Storment et al. Conversely, estrogen supplementation appears to protect the heart and vasculature from pressure overload or vessel injury Zhang et al. Progesterone also exerts cardiovascular effects. It stimulates nitric oxide synthesis by human umbilical vein endothelial cells in vitro and by rat abdominal aorta and mesenteric arteries in vivo Tables 3 , 4 ; Progesterone; Chataigneau et al.

It also decreases blood pressure, when infused into ovariectomised ewes and protects against vascular injury in non-pregnant mice Pecins-Thompson and Keller-Wood, ; Zhang et al. In culture, progesterone induces hypertrophy and inhibits apoptosis of rodent cardiomyocytes Morrissy et al. Thus, via its impacts on cardiomyocytes, progesterone may mediate the pregnancy-induced growth of the mother's heart in vivo.

In late pregnancy, the murine heart shifts to use fatty acids, rather than glucose and lactate, as a metabolic fuel. In part, this metabolic shift is proposed to be mediated by progesterone during pregnancy, which inhibits pyruvate dehydrogenase activity in ventricular myocytes Liu et al. Thus, placental-derived progesterone and estrogen may mediate part of the changes in the maternal cardiovascular system during pregnancy.

In many mammalian species, progesterone levels decline just before parturition and this is associated with the initiation of labor. Indeed, in rodents, inhibition of progesterone synthesis or administration of a progesterone antagonist results in premature delivery of the neonate Table 3 ; Progesterone; Fang et al. In humans, circulating progesterone levels continue to be high until birth. Commencement of labor is therefore proposed to be related to a functional withdrawal of progesterone activity in the myometrium of women Brown A. In experimental animals, progesterone reduces the production of prostaglandins and decreases the expression of contraction-associated genes including oxytocin and prostaglandin receptors, gap junction proteins and ion channels in the myometrium Table 3 ; Progesterone; Fang et al.

Together, these progesterone-mediated actions decrease contractility of uterine smooth muscle cells and maintain uterine quiescence until term. In contrast to progesterone, estrogen levels rise prior to term and estrogen promotes the expression of contraction-associated genes and contraction of the myometrium Table 4 ; Estrogen; Nathanielsz et al. Therefore, in many species, the high ratio of estrogen to progesterone in the maternal circulation is thought to contribute the onset of labor.

Progesterone also decreases the ability of LPS to induce pro-inflammatory cytokine secretion by human myometrium and placental explants Youssef et al. It also diminishes the ability of estrogen to induce the infiltration of macrophages and neutrophils into the uterus, and decreases LPS-induced leukocyte adhesion to human umbilical vein cells Simoncini et al.

Thus, it is perhaps not surprising that progesterone receptor null mice demonstrate chronic uterine inflammation, particularly in response to estrogen treatment Table 3 ; Estrogen; Lydon et al. There is also evidence that placental steroids participate in cervical softening, by regulating the expression of matrix remodeling enzymes as well as leukocyte infiltration and function Chinnathambi et al. In addition to regulating the events leading to parturition, recent data suggest that during the course of pregnancy, both estrogen and progesterone contribute to the maternal tolerance of the fetus by modulating proliferation and cytokine expression of CD4 and CD8 T cells and enhancing the suppressive function of T-regulatory cells Mao et al.

Additionally, both estrogen and progesterone are key stimulators of mammary gland development. For instance, progesterone stimulates proliferation of mammary stem cells and mammary epithelium Tables 3 , 4 ; Progesterone; Joshi et al. In mice, deficiency of the progesterone receptor restricts mammary gland development, whereas exogenous progesterone induces ductal side branching and lobuloalveolar differentiation and development Table 3 ; Progesterone; Plaut et al.

In addition, both estrogen and progesterone may have indirect effects on mammary gland development by regulating prolactin secretion from the pituitary gland Rezaei et al. Maternal behavior during and after birth are regulated by the steroid hormones. Estrogen stimulates maternal nurturing behavior in numerous species, including rats, mice, sheep and primates Bridges, Findings from animal models suggest that progesterone plays a role in regulating anxiety and depression-related behavior.

For instance, exogenous progesterone stimulates anti-anxiety and anti-depressive actions in mouse dams Table 3 ; Progesterone; Koonce and Frye, In contrast, progesterone withdrawal increases these types of behaviors Gulinello et al. Thus, placental-derived steroids may modulate several aspects of maternal physiology which are beneficial to both pregnancy and post-partum support of the offspring.

One major target of placental hormones is the maternal brain and related neuroendocrine organs such as the hypothalamus and pituitary glands. These neuroendocrine effects enable the mother to respond and adapt accordingly to her environment, so as to mitigate the adverse effects of stress and maintain homeostasis Voltolini and Petraglia, In addition to their impact on the maternal neuroendocrine system, these hormones have additional functions in vivo and in vitro functions as well, which are detailed in Tables 5 , 6 , respectively.

Melatonin and its precursor, serotonin, are tryptophan-derived hormones with well-known neuroendocrine impacts. In humans, circulating concentrations of melatonin and serotonin increase as pregnancy advances Lin et al. In the non-pregnant state, melatonin and serotonin are primarily produced by the pineal gland and the brain, respectively.

However, the enzymes involved in melatonin and serotonin biosynthesis are also expressed by the human placenta throughout gestation Iwasaki et al. The mouse placenta similarly expresses the enzymes needed for serotonin synthesis Wu et al. The rat placenta does not produce melatonin de novo due to the lack of synthesizing enzymes Tamura et al.

However, the same study demonstrated that conditioned medium from cultured term rat placentas stimulated melatonin release by the maternal pineal gland Tamura et al.

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These findings suggest that placental-derived factors may indirectly regulate melatonin levels by the mother during pregnancy. Placental expression of melatonin, serotonin and their respective enzymes, also remains to be investigated in other species such as rabbits and sheep, which are commonly used in pregnancy-related studies. Mouse models that result in deficiencies or reduced bioactivity of these hormones demonstrate altered sleep patterns, melancholic behavior, hyperactivity and aggression in the non-pregnant state Table 5 ; Serotonin and Melatonin; Weil et al.

There is some evidence that serotonin and melatonin may also impact maternal feeding behavior. For example, increased serotonin signaling reduces food intake in pregnant cows Laporta et al. Similarly, exogenous melatonin lowers food intake in pregnant rats Nir and Hirschmann, ; Jahnke et al. These negative effects on maternal food intake suggest that peak serotonin and melatonin concentrations in late pregnancy may serve to control the maternal appetite and prevent excessive weight gain. Another key function of melatonin and serotonin is glucose homeostasis and the regulation of steroid synthesis Table 5 ; Serotonin and Melatonin.

In mice, loss of melatonin or serotonin signaling leads to glucose intolerance and insulin resistance, with consequences for blood glucose and insulin concentrations in both the non-pregnant and pregnant state Contreras-Alcantara et al. However, these neuroactive hormones appear to have differential effects on the pancreas Table 6 ; Serotonin and Melatonin. Non-pregnant mice with deficient serotonin signaling have impaired lipid handling and excessive lipid accumulation in association with reduced adipose aromatase expression and circulating estrogen Zha et al.

Similarly, treating placental-derived trophoblast cells with norfluoxetine, a selective serotonin-reuptake inhibitor, inhibits aromatase activity and estrogen secretion in vitro Hudon Thibeault et al. Supplementation of melatonin in non-pregnant humans reduces circulating triglycerides and cholesterol levels, but effects of lipid handling in pregnancy are unknown Mohammadi-Sartang et al. Melatonin also modulates steroid production. For instance, melatonin treatment in pregnant cows reduces circulating estrogen and progesterone Brockus et al.

Melatonin can either enhance or reduce uterine myometrial contractility depending on the species Table 6 ; Melatonin; Ayar et al. Both melatonin and serotonin are also important for lactation, specifically for mammary gland development and milk nutrient content Okatani et al. For instance, mammary gland proliferation and calcium transport is impaired in pregnant mice with genetically-induced serotonin deficiency Laporta et al. Conversely, supplementation of a serotonin precursor increases mammary calcium transporter expression and milk calcium content in lactating mice and cows Laporta et al.

In contrast to serotonin, increased melatonin signaling is associated with reduced ductal growth and branching, as well as impaired terminal end bud formation in the non-pregnant state Xiang et al. Thus, during lactation, these mice with increased melatonin signaling have impaired mammary gland lobulo-alveolar development and reduced milk protein content, which reduces the weight of suckling pups Xiang et al. Nevertheless, melatonin supplementation during pregnancy confers significant beneficial neuroprotective effects on the fetus and enhances maternal antioxidant capacity Miller et al.

Therefore, while melatonin supplementation shows promise for use in the clinic, particularly for enhancing the neurodevelopmental outcomes of offspring in growth compromised pregnancies, the potential adverse outcomes for both mother and child must also be considered and should be assessed in further studies. Another key neuroendocrine factor is oxytocin. Oxytocin is widely known for its role in triggering maternal nursing behavior Bosch and Neumann, This is mediated by oxytocin's actions on the maternal brain, as well as, the mammary glands.

Indeed, a greater rise in circulating oxytocin concentrations from early to late pregnancy in pregnant women, is associated with a stronger bond between a mother and her infant Levine et al. Concurrently, placental expression of oxytocin also peaks at term in humans Kim S. The rat placenta also produces oxytocin Lefebvre et al. Reduced oxytocin signaling decreases maternal nurturing behavior such as pup retrieval in rats Van Leengoed et al.

It also decreases the willingness of female voles to care for, groom and lick unrelated pups Keebaugh et al. Low oxytocin signaling can additionally impair social bonding in voles and mice Ferguson et al. Moreover, a lack of oxytocin disrupts mammary gland proliferation and lobuloalveolar development, which impairs milk release from the mammary tissues in mice Nishimori et al.

Therefore, high oxytocin levels enable the mother to bond better and protect her newborn, when it is most vulnerable. Oxytocin is also important in the process of parturition Table 6 ; Oxytocin ; it stimulates the contraction of smooth muscle cells in the myometrium Ayar et al. Cardiovascular effects of oxytocin include its ability to significantly lower blood pressure in non-pregnant rats Petersson et al. There is also some evidence that oxytocin induces anti-inflammatory and antioxidant effects in the heart under hypoxic conditions in non-pregnant rats Gutkowska and Jankowski, Nevertheless, the specific cardiovascular effects of oxytocin in pregnancy remain to be explored.

Studies performed in non-pregnant rodents show that oxytocin also affects metabolic function in vivo Table 5 ; Oxytocin. In particular, loss of oxytocin reduces glucose and insulin tolerance and increases adiposity Camerino, , whereas exogenous oxytocin has the reverse effect Deblon et al. Studies are however, required to determine whether the rise in oxytocin in late pregnancy Levine et al. There is some evidence that oxytocin may additionally play a role in controlling energy expenditure and thermoregulation during pregnancy.

Even with a similar diet and activity level to control mice, oxytocin-deficient mice become obese due to reduced energy expenditure from poor thermoregulation in the non-pregnant state Chaves et al. Furthermore, exogenous oxytocin in non-pregnant mice causes a rise in body temperature Mason et al. Nevertheless, whether oxytocin may play a role in controlling heat dissipation due to the increased maternal energy expenditure during pregnancy requires exploration. Exogenous oxytocin also reduces food intake in non-pregnant rats Arletti et al.

However, the role of oxytocin in appetite regulation during pregnancy remains to be explored. There is also evidence for oxytocin's possible involvement in maternal bone metabolism and calcium homeostasis during pregnancy and lactation. For instance, oxytocin stimulates both bone resorption and bone formation by osteoclasts and osteoblasts respectively in vitro Tamma et al. Moreover, oxytocin administration in rats reduces circulating calcium with an overall skew toward bone formation Elabd et al. These findings may suggest that the peak in circulating oxytocin toward term promote the restoration of depleted maternal skeletal calcium stores.

In addition to the aforementioned melatonin, serotonin and oxytocin, the human placenta also produces neuroactive hormones such as kisspeptin and thyrotropin-releasing hormone TRH , which may function in adapting maternal physiology to support pregnancy Bajoria and Babawale, ; De Pedro et al.

In humans, circulating kisspeptin rises throughout pregnancy to concentrations 10,fold that of the non-pregnant state, with the placenta speculated as a major source Horikoshi et al. In the non-pregnant state, kisspeptin can both stimulate and impede glucose stimulated insulin secretion in mice Bowe et al. The nature of the effect may partly relate to differences in the actions of kisspeptin isoforms on pancreatic islets Bowe et al. Kisspeptin may also have effects on the maternal cardiovascular system, given its reported vasoconstrictive effects on vascular smooth muscle cells and fibrotic effects on the heart in non-pregnant rats Mead et al.

Studies in humans highlight the importance of regulating kisspeptin production during gestation; increased placental kisspeptin is associated with pre-eclampsia Whitehead et al. Like the human, the murine placenta produces kisspeptin. Although a kisspeptin-deficient mouse has been established, previous work has been focused on feto-placental outcomes, with no examination of maternal physiology Herreboudt et al. Studies are required to determine the consequences of abnormal placental kisspeptin on the maternal physiology during pregnancy.

In the non-pregnant state, hypothalamic TRH stimulates release of thyroid-stimulating hormone and PRL from the pituitary Hershman et al. However, during pregnancy, the placenta serves as an additional source of TRH Bajoria and Babawale, Excess TRH in pregnancy raises blood concentrations of thyroid-stimulating hormone and PRL in humans, rhesus monkeys, sheep and rats Thomas et al. Thyroid hormones are necessary for optimal brain development as well as thyroid function Miranda and Sousa, Impaired TRH signaling is associated with anxiety-like and depressive-like behavior in non-pregnant mice Zeng et al.

However, whether any direct causal relationship between placental hormones, like TRH and perinatal depression remains unclear. Additionally, TRH is implicated in glucose homeostasis and appetite regulation. For example, mice with TRH deficiency are hyperglycaemic, due to an impaired insulin response to glucose Yamada et al.

Reduced TRH signaling also impedes leptin production and ghrelin acylation, which results in less energy conservation during fasting and a lower body mass in the non-pregnant state Groba et al. Investigations are warranted to identify whether TRH may contribute to the regulation of glucose handling and appetite in the mother during pregnancy. The placenta also produces numerous other hormones with pleiotropic effects. Several key ones, which have been implicated in pregnancy failure or disorders of pregnancy such as hypertension, hyperglycemia and hypercalcemia, are discussed here.

The hormones presented here are by no means exhaustive and were selected primarily on their major associations with abnormal maternal physiology during pregnancy. In women, hCG is secreted from the trophoblast from very early in gestation and is thought to be the first placental hormone to act on the mother Ogueh et al. Indeed, maternal circulating hCG concentrations peak in the first trimester and then decline toward term Ogueh et al.

In early pregnancy, hCG maintains corpus luteum allowing the continued secretion of ovarian progesterone and estrogens until the steroidogenic activity of the fetal-placental unit can compensate for maternal ovarian function Fournier et al. In particular, hCG increases the abundance of low-density lipoprotein receptor and thus uptake of cholesterol for steroidogenesis. There is also some evidence which suggests hCG may inhibit factors that promote luteal demise, such as the prostaglandins. The high levels of hCG in early pregnancy are also sufficient to bind to the TSH receptor and may act to increase maternal thyroid hormone production, which as mentioned previously, may exert effects in the mother and fetus.

CG may also play important autocrine and paracrine roles at the maternal-fetal interface. Administration of hCG antisera prevents implantation in marmoset in vivo Hearn et al. Recent proteomic analysis of estrogen and hCG treated human endometrial epithelial cells demonstrates that hCG targets pathways involved in metabolism, basement membrane and cell connectivity, proliferation and differentiation, cellular adhesion, extracellular-matrix organization, developmental growth, growth factor regulation and cell signaling Greening et al.

Such pathways are likely to be important for placental development, as attenuating hCG signaling disrupts trophoblast differentiation in vitro Shi et al. In contrast, supplementing human trophoblast cells with hCG increases their differentiation, migration, invasion and adhesion to uterine epithelial cells, and decreases their leptin secretion in vitro Table 8 ; hCG; Shi et al. Furthermore, hCG is key in suppressing the maternal immune system from mounting a response against paternal antigens carried by the allogenic conceptus.

Administration of hCG in a mouse model of spontaneous abortion significantly reduces the number of fetal resorptions due to improved immune tolerance of the fetus Schumacher et al. In vitro , hCG enhances proliferation of immunosuppressive uterine natural killer cells Kane et al.

In pregnancy, hCG additionally inhibits the contractile function of smooth muscle cells in the uterus to help sustain myometrial quiescence Ambrus and Rao, ; Eta et al. Glycosylation of hCG affects its biological activity and half-life Fournier et al. Given its involvement with multiple systems, it is perhaps unsurprising that abnormal concentrations of hCG and hCG glycoforms have been linked with pregnancy complications such as fetal growth restriction and preeclampsia Chen et al. However, whether the abnormal concentrations of hCG are cause or consequence of the disorders remains to be determined.

Activin signaling promotes the decidualization, as well as, apoptosis of endometrial stroma cells Table 8 ; Activins; Tessier et al. Additionally, activin A enhances steroid production, invasion and apoptosis of human trophoblast in vitro Ni et al. However, activins may also be of importance in modulating the physiology of the mother during pregnancy Table 7 ; Activins.

In normal human pregnancy, activin A concentrations gradually rise during gestation and peak at term Fowler et al. The placenta is thought to be the main source of activin A in the maternal circulation during pregnancy, given the rapid clearance after delivery of the placenta Muttukrishna et al.

A similar rise of activin in the maternal circulation is observed in pregnant ewes Jenkin et al. Nevertheless, in mice, impaired activin signaling leads to poor pregnancy outcomes such as fewer viable pups Clementi et al. However, there is evidence that an increase in activin may also be pathological and detrimental to pregnancy outcome. For instance in pregnant mice, infusion of activin A or plasmid overexpression of activin A results in the development of a preeclamptic phenotype; dams display hypertension and proteinuria, in addition to growth restriction and greater in utero deaths Kim et al.

The maternal hypertension observed likely results from pathological concentrations of activin A inducing vascular endothelial dysfunction Yong et al. In the non-pregnant state, activins are also important for renal glomeruli development Maeshima et al. The possible contributions of activin to these latter functions in pregnancy are currently unclear. Therefore, the impact of activin signaling on these other body systems during pregnancy remains to be determined. Relaxin is a potent vasodilator Danielson et al. In pregnant women, circulating relaxin concentration peaks in the first trimester, declines in the second trimester and is maintained until delivery in the third trimester Quagliarello et al.

In contrast, circulating relaxin peaks toward term in mice, rats, guinea pigs and hamsters O'byrne and Steinetz, ; O'byrne et al. In pregnant mice, relaxin deficiency leads to proteinuria, suggesting a particular role of relaxin in modulating renal function during pregnancy O'sullivan et al. In addition, relaxin-deficient mice remain sensitive to vasoconstrictors such as angiotensin and endothelin, and are hypertensive during pregnancy Marshall et al. During pregnancy, relaxin-deficient mice also display stiffer uterine vessels and fetal growth is retarded Gooi et al.

Relaxin also enhances capillarisation and glucose uptake of skeletal muscles in non-pregnant mice Bonner et al. Taken together, these data highlight the importance of relaxin in mediating changes in maternal vascular function that serve to promote blood flow to the gravid uterus during pregnancy. Relaxin may play additional roles within the uterus that are important for implantation, placentation and pregnancy maintenance Tables 7 , 8 ; Relaxin. In vitro , relaxin increases decidual cell insulin-like growth factor binding protein-1 expression, a marker of decidualization Mazella et al.

It also enhances survival and proliferation of cultured human trophoblast cells Lodhi et al. During early mouse pregnancy, relaxin modulates the uterine expression of genes involved in angiogenesis, steroid hormone action and remodeling Marshall et al. Indeed in pregnant marmosets, exogenous relaxin improves uterine and placental growth Einspanier et al.

Relaxin infusion also alters the endometrial lymphocyte number in vivo Goldsmith et al. Relaxin impedes spontaneous contractility of myometrium in humans, rats and pigs Maclennan and Grant, ; Longo et al. In mice with a deficiency in relaxin signaling, obstructed deliveries occur at a higher rate due to poor maturation of the cervix Zhao et al.

Conversely in hamsters, the rise in circulating relaxin toward term coincides with cervical ripening in preparation for delivery O'byrne et al. Insufficient relaxin signaling also impedes mammary development through excessive duct dilation and reduces the nursing of offspring in mice Zhao et al. Conversely, overexpression leads to hypertrophy of the nipples in non-pregnant mice Feng et al. Hence, relaxin is important in driving changes at the maternal-fetal interface that establish pregnancy, adapts the cardiovascular system of the mother to support the pregnancy and prepares the mother for lactation post-partum.

PTHrP concentrations in the maternal blood rise throughout gestation in humans Gallacher et al. PTHrP increases maternal bone resorption, thereby enabling calcium transfer from mother to fetus for bone development Salles, Thus, it is perhaps not surprising that complete knockout of PTHrP in mice is lethal at birth in association with abnormal bone development Karaplis et al. Carrying one defective PTHrP copy is enough to also impede bone development and reduce snout length in mice Amizuka et al.

Mammary-specific PTHrP deletion increases maternal bone mass and protects against lactation-associated bone loss by reducing bone turnover in mice Williams et al.

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However, deleting bone-specific PTHrP increases skeletal fragility, both in the non-pregnant and pregnant state Kirby et al. PTHrP infusion of lactating goats increases mammary gland uptake calcium, phosphorous and magnesium for transfer in milk to the neonate Barlet et al. These findings imply that a fine balance of PTHrP production by gestational and maternal tissues must be achieved for appropriate regulation of maternal bone metabolism and offspring calcium requirements during pregnancy and lactation.

Placental-derived PTHrP may also exert additional effects on the placenta and the mother which are beneficial for offspring development and growth. In vivo , blocking PTHrP signaling during mouse pregnancy leads to excessive uterine growth and decidualization in association with a decrease in decidual cell apoptosis Williams et al. These studies highlight a possible important regulatory role of PTHrP in the control of decidualization and mammary gland development in vivo. It also increases renal plasma flow and glomerular filtration rate, and exerts proliferative effects on renal glomerular and tubule cells in rodents Izquierdo et al.

However, the significance of PTHrP on glucose-insulin dynamics and renal and vascular function of the mother during pregnancy remains to be investigated. Leptin is an abundant circulating hormone involved in regulating appetite. In the non-pregnant state, the adipose tissue is the exclusive source of circulating leptin. During pregnancy in humans, baboons and mice, concentrations of leptin rapidly rise throughout gestation, peaking toward term Highman et al.

The rise in leptin positively correlates with increases in maternal body fat Highman et al. In humans, blood leptin rapidly falls to non-pregnant concentrations within 24 h of delivery, indicating that the placenta contributes to the main rise of leptin in pregnancy Masuzaki et al. In particular, leptin is produced by the human placental trophoblast cells Masuzaki et al.

A similar post-pregnancy decline and placental trophoblast expression is seen in baboons Henson et al. However, this is not the case for mice, as the murine placenta does not produce leptin Malik et al. Nevertheless, leptin studies in mice still provide useful knowledge about pregnancy-related effects of leptin Table 7 ; Leptin. For instance, leptin in pregnancy helps prepare the mother for lactation, as a deficiency results in impaired mammary gland development, which is detrimental for lactation post-delivery Mounzih et al.

Another significant effect of leptin in pregnancy observed through mouse studies is leptin resistance, whereby the dam increases her food intake in mid-pregnancy to meet increased energy demands despite an increase in circulating leptin, which in the non-pregnant state would lead to satiety Mounzih et al. In contrast, excessive leptin significantly decreases maternal food intake and restricts feto-placental growth Yamashita et al.

Leptin exposure of rat and human islets and cultured insulinoma cells significantly decreases insulin production in vitro , demonstrating that leptin may be directly involved in glucose metabolism Table 8 ; Leptin; Kulkarni et al. Further in vitro studies on placental explants or trophoblast cultures highlight a potential for leptin to be involved in immune modulation and placental hormone production, given its stimulatory effects on HLA-G and hCG expression Table 8 ; Leptin; Chardonnens et al.

Additional effects of leptin on the placenta are thoroughly reviewed elsewhere Schanton et al. Therefore, placental leptin can have systemic effects on the mother in pregnancy. Pregnancy represents a unique physiological paradigm; there are dynamic and reversible changes in the function of many organ systems in the mother that are designed to support offspring development. In part, these changes are signaled via the placental secretion of hormones, which in turn, alter in abundance, interact with one another and exert wide effects on maternal tissues during pregnancy.

For instance, steroid hormones modulate most systems of the mother throughout pregnancy. However, they also alter the production of other hormones, such as prolactin and placental lactogens, which in turn, may contribute to the physiological changes in the mother Figure 2. However, further work is required to better define how placental hormones elicit their actions in the mother, as well as, identify the extent to which they interplay with hormones produced by maternal tissues.

As the endocrine and metabolic state of the mother is also influenced by her environment, maternal conditions such as poor nutrition and obesity may modulate placental hormone production and pregnancy adaptations. Further studies are nonetheless needed to assess the interaction of the maternal environment with placental endocrine function. Placental hormones are also released into the fetal circulation, where they may have direct impacts on fetal growth and development Freemark, Investigations exploring the importance of placental endocrine function on fetal growth, independent of the mother, will require future examination.

Collectively, further studies on the nature and role of placental endocrine function in maternal adaptations and fetal growth will undoubtedly provide novel insights into understanding of the potential causes of obstetrical syndromes such as gestational diabetes and preeclampsia that are marked by maternal physiological maladaptation. Figure 2. Summary of expression profiles, interactions and maternal physiological effects of placental-derived hormones.

TN and HY substantially contributed to the conception of the work, drafting and revision of the manuscript, preparation of the tables and approved of the final version. JL-T substantially contributed to the conception of the work, drafting and revision of the manuscript, preparation of the figures and approved of the final version. AS-P substantially contributed to the conception of the work, critical revision of the manuscript for intellectual content and approved of the final version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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