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INTRODUCTION

The endocrinology of human pregnancy involves endocrine and metabolic changes that result from physiological alterations at the boundary between mother and fetus. Known as the feto-placental unit (FPU), this interface is a major site of protein and steroid hormone production and secretion (Figure 1). Many of the endocrine and metabolic changes that occur during pregnancy can be directly attributed to hormonal signals originating from the FPU. The initiation and maintenance of pregnancy depends primarily on the interactions of neuronal and hormonal factors. Proper timing of these neuro-endocrine events within and between the placental, fetal and maternal compartments is critical in directing fetal growth and development as well as the coordinating the timing of parturition. Maternal adaptations to hormonal changes that occur during pregnancy directly reflect the development of the fetus and placenta. Gestational adaptations that take place in pregnancy include implantation and the maintenance of early pregnancy; modification of the maternal system in order to provide adequate nutritional support for the developing fetus; and preparation for parturition and subsequent lactation.

Figure 1. The interface between mother and fetus, known as the feto-placental unit (FPU), is a major site of protein and steroid hormone production and secretion.

Pregnancy-related proteins can be found in maternal circulation shortly after conception. For example, a platelet activating (PAF)-like substance, produced by the fertilized ovum, is present almost immediately (1-4). After ovulation and fertilization, the embryo remains in the ampullary portion of the fallopian tube for up to 3 days. The developing conceptus travels toward the uterus, through the isthmic portion of the tube, for approximately 10 hours, and then enters the uterus as an embryo at the 2- to 8-cell stage (5-6). With further development, between 3-6 days after conception, the embryo becomes a blastocyst floating unattached in the endometrial cavity (6). A schematic representation of the pre-implantation phase of pregnancy is shown in Figure 2. Before implantation, the blastocyst also secretes specific substances that enhance endometrial receptivity. Successful implantation requires precise synchronization between blastocyst development and endometrial maturation.

Figure 2. A diagrammatic summary of the ovarian cycle, fertilization, and embryo development as it occurs during the first week after conception. (From ref. 7, with permission)

To date, little information exists regarding regulation of steroid production in the embryo. The early embryo and its surrounding cumulus cells secrete detectable estradiol and progesterone well before the time of implantation (8,9). Mechanical removal of these cells results in the cessation of steroid secretion, while return of the removed cells through co-culture results in restoration of steroid secretion (8). Given this finding, steroid production by the conceptus is thought to be negligible by the time it has reached the endometrial cavity, since it is gradually denuded of cumulus cells as it travels through the fallopian tube.

Conceptus-secreted progesterone may itself affect tubal motility as the conceptus is carried to the uterus (10). Progesterone, by action mediated through catecholamines and prostaglandins (PG), is believed to relax utero-tubal musculature. Moreover, progesterone is thought to be important in tubal-uterine transport of the embryo to the uterine cavity, since receptors for progesterone are found in highest concentrations in the mucosa of the distal one third of the fallopian tube. Estradiol, also secreted by these structures, may balance the progesterone effect so as to maintain the desired level of tubal motility and tone (10). Progesterone antagonizes estrogen-augmented uterine blood flow through depletion of estrogen receptors in the cytoplasm (11). Likewise, estrogen and progesterone also appear to balance one another in the maintenance of blood flow at the implantation site.

IMPLANTATION PHASE

Human chorionic gonadotropin (hCG) messenger ribonucleic acid (mRNA) is detectable in the blastomeres of 6- to 8-cell embryos; however, it is not detectable in blastocyst culture media until the 6th day (12-14). After implantation is initiated, hCG is detectable in maternal serum. However, due to the absence of direct vascular communication, secretion of hCG into the maternal circulation is initially limited (15). Thus, during the process of implantation the embryo is actively secreting hCG, which can be detected in maternal serum as early as the 8th day after ovulation. The primary role of hCG is to prolong the biosynthetic activity of the corpus luteum, which allows continued progesterone production and maintenance of the gestational endometrium. As implantation progresses, the conceptus continues to secrete hCG and other pregnancy-related proteins, and resumes detectable steroid production (8,9,16).

Termed trophectoderm, blastomeres lining the periphery of the blastocyst are destined to form the placenta and can be identified at 5 days post-conception. The main structural and functional units of the placenta are the chorionic villi, which increase significantly in number during the first trimester of pregnancy. The structure of the chorionic villi is pictured in Figure 3. The villous structure provides a tremendous absorptive surface to facilitate exchange between the maternal and fetal circulation. The maternal blood arrives from the spiral arteries and circulates through the intervillous space. Fetal blood moves in the core of the chorionic villi within the villous vessels; thus, fetal and maternal blood is never mixed in this system. The key cells inside the chorionic villi are the cytotrophoblasts. They have the ability to proliferate, invade and migrate or to differentiate, through aggregation and fusion, to form a syncytial layer of multi-nucleate cells lining the placental villi, known as the syncytiocytotrophoblasts.

By 10 days post-conception, 2 distinct layers of invading trophoblasts have formed. The inner layer, the cytotrophoblasts, is composed of individual, well-defined and rapidly dividing cells. The outer layer, the syncytiocytotrophoblasts, is a thicker layer comprised of a continuous cell mass lacking distinct cell borders. Syncytiocytotrophoblasts line the fetal side of the intervillous space opposite the decidualized endometrium of the maternal side. Immunohistochemically, cytotrophoblasts stain for hypothalamic-like protein hormones: gonadotropin releasing hormone (GnRH), corticotrophin releasing hormone (CRH), and thyrotropin releasing hormone (TRH) (17-29). Juxtaposed syncytotrophoblasts stain immunohistochemically for the corresponding pituitary-like peptide hormones: human chorionic gonadotropin (hCG; analogous to pituitary luteinizing hormone, LH), adrenocorticotropic hormone (ACTH) and human chorionic thyrotropin (hCT). Anatomically, this arrangement suggests that these 2 layers mirror the paracrine relationship of the hypothalamic-pituitary axis (17-29).

Syncytiocytotrophoblasts, the principal site of placental steroid and protein hormone biosynthesis, have a large surface area and line the intervillous space which exposes them directly to maternal bloodstream without the vascular endothelium and basement membrane which separates them from the fetal circulation (Figure 3). This anatomic arrangement explains why placental proteins are secreted almost exclusively into the maternal circulation in concentrations much higher than those in the fetus are (30). The syncytiocytotrophoblast layer contains the abundant subcellular machinery characteristic of cells primarily responsible for hormone synthesis. Amino acids of maternal origin are assembled into pro-hormones. Pro-hormones are then packaged into early secretory granules and transferred across the trophoblastic cell membranes as mature granules. Mature granules become soluble as circulating hormones in maternal blood as they pass through the intervillous space (30).

Figure 3. A. A depiction of a blastocyst implanting in the uterus. B. A longitudinal section of a chorionic villus at the feto-maternal interface at about 10 weeks' gestation. The villous serves as a bridge between maternal and fetal compartments. C. Human placental ultra-structure seen in cross section. Syncytiocytotrophoblasts line the fetal surface of the intervillous space and interact with the maternal blood supply to secrete placental hormones directly into the circulation. Decidua lines the maternal surface of the intervillous space and secretes protein hormones.  (From ref. 31, with permission)

PROLONGATION OF CORPUS LUTEUM FUNCTION

Primary steroid products of the corpus luteum are progesterone, 17a-progesterone, estradiol and androstenedione. Low-density lipoprotein (LDL) cholesterol is the main precursor responsible for corpus luteum progesterone production. (32) Between 6 and 7 weeks gestation, corpus luteum function naturally begins to decline. During this luteal-placental transition period, production of progesterone shifts to the developing placenta (Figure 4).
Removal of the corpus luteum before 6 weeks of gestation increases the risk of abortion. Thus, regarding early pregnancy, progesterone is considered the most important steroid product in this group because progesterone alone can maintain a pregnancy that would otherwise abort in a lutectomized woman (33). For example, exogenous progesterone, given to an agonadal woman pregnant through egg-donor in vitro fertilization (IVF), maintains the pregnancy through the first trimester until placental progesterone secretion is established (34). For this reason, in patients with corpus luteum dysfunction or in whom the corpus luteum has been removed surgically, supplementation with exogenous progesterone is frequently initiated and extended beyond, approximately 10 weeks of gestation, the critical period of the luteal-placental shift.

Figure 4. A shift in progesterone production from the corpus luteum to the placenta occurs at approximately the 7th to 9th week of gestation. The small, shaded area represents the estimated duration of this functional transition.  (From ref. 35, with permission)

In women with first-trimester threatened abortion, progesterone concentrations at the time of initial evaluation are often predictive of ultimate outcome (36). Abortion will occur in approximately 80% of those with progesterone concentrations under 10 ng/mL; viable pregnancies are virtually never observed at concentrations of <5.0 ng/mL (37).

DECIDUA AND DECIDUAL HORMONES

The decidua is the endometrium of pregnancy. Decidualized endometrium is a site of maternal steroid and protein biosynthesis that relates directly to the maintenance and protection of the pregnancy from immunologic rejection. For instance, decidual tissue secretes cortisol, and in combination with hCG and progesterone secreted by the conceptus, cortisol produced by the decidua acts to suppress the maternal immune response conferring the immunologic privilege required by the implanting conceptus (38,39).

Decidual Prolactin

Decidual prolactin is a peptide hormone having chemical and biological properties identical to pituitary prolactin (40). Prolactin, derived from decidualized endometrium, is first detectable in the endometrium at a time corresponding to implantation-cycle day 23. Progesterone is known to induce decidual prolactin secretion (41). Scant decidual prolactin enters the fetal or maternal circulation after it is transported across the fetal membranes from the adherent decidua and is released into the amniotic fluid (42). Unaffected by bromocriptine administration, decidual production of prolactin takes place independent of dopaminergic control (40).

Decidual prolactin secretion rises in parallel with the gradual rise in maternal serum prolactin seen until 10 weeks gestation, when it rises rapidly until 20 weeks, and then falls as term approaches (43). Decidua-derived prolactin serves to regulate fluid and electrolyte flux through fetal membranes by reducing permeability of the amnion in the fetal-to-maternal direction (40-42,44-48). Unlike decidual prolactin, circulating prolactin, in the fetus, is secreted by the fetal pituitary gland, while prolactin found in the maternal circulation is secreted by the maternal pituitary under the influence of estrogens. These circulating levels are both suppressed by maternal ingestion of bromocriptine.

Decidual Insulin-like Growth Factor Binding Protein-1 (IGFBP-1)

IGF binding protein-1 (IGFBP-1) is a peptide hormone that originates from decidual stromal cells. In non-pregnant women, circulating IGFBP-1 does not change during cycling of the endometrium. During pregnancy, however, there is a several-fold increase in serum IGFBP-1 levels that begins during the first trimester, peaks during the second trimester, and falls briefly only to peak a second time before term (49). IGFBP-1 inhibits the binding of insulin-like growth factor (IGF) to receptors in the decidua.

Decidual Pregnancy Protein-14 (PP14)

Pregnancy protein-14 is a glycoprotein hormone synthesized by secretory and decidualized endometrium that is detectable around cycle day 24 (50). In serum, it rises sharply around cycle day 22 to 24, reaching its peak value at the onset of menstruation; if pregnancy occurs, levels remain high (51). In pregnancy, PP14 rises in parallel with hCG (49). Like hCG, PP14 is thought to have immunosuppressant properties in pregnancy (50). Pregnancy protein-14 levels are often low in those patients with conditions, such as ectopic pregnancy, in which there is little decidual tissue produced.

PLACENTAL COMPARTMENT

The endocrine system, a system that is functional from the time of intrauterine existence through old age, is one of the first systems to develop during fetal life. Unique to mammals, the placenta plays a major role in the growth and development of these fetal systems. Without question, the placenta is one of the most amazing endocrine organs of all. The fetus develops in an environment where respiration, alimentation and excretory functions are provided by the placenta. The placenta has, no doubt, evolved over the course of time as a means or system through which viviparity or livebirth could take place with dependable success. Likewise, it may exist, in part, as a hypothalamic-pituitary-end organ-like entity owing to the inherent ability of this type of system, with its stimulatory and inhibitory feedback mechanisms, to dynamically regulate factors that affect the growth and development of the fetus under a variety of conditions. The presence of the placenta has allowed humans and other mammals to compete successfully, in evolution, through adaptation to their environment and reproduction at a competitive rate.

Both adaptation and procreation, to a large extent, are dependent on neuro-endocrine control systems; in adaptation, the most important role of these systems is homeostasis, and in the case of reproduction it is cyclicity. Moreover, communication and coordination of neural and endocrine systems helps to ensure a sustained ability to adapt to ever-changing environments, whether in utero or ex utero. Endocrine systems are tailored to take care of the daily needs, but for certain situations the endocrine feedback system works too slowly. Neural systems are adapted toward instant transmission of the body's metabolic needs, regardless of their location. In the fully developed hypothalamic-pituitary-end organ schema of humans, neural inputs to the hypothalamus serve to regulate to secretion of hypothalamic releasing hormone peptides. However, in the placenta there are no such direct neural inputs, and the exact mechanisms responsible for regulation of the secretion of hypothalamic-like placental peptides is unknown. Nonetheless, as a combined entity the neuro-endocrine system is well suited for adaptation to ever-changing metabolic and physiologic requirements; therefore, it may not be too surprising that the placenta has evolved as, and functions in many ways like, the mature hypothalamic-pituitary-end organ endocrine system.

Changes in maternal hormone concentrations play a critical role in modulating the metabolic and immunologic changes required for successful outcome in pregnancy. The fetus and placenta produce and secrete peptides and steroids into the maternal circulation as well as stimulate maternal hormone production. The origins and amounts of the fetal and placental hormones secreted during pregnancy changes dramatically over the course of the gestational period. Some of the pregnancy-related protein hormones previously discussed are, in part, responsible for the altered steroid concentrations typical of pregnancy.

Placental Maturation

As pregnancy advances, the relative numbers of trophoblasts increase as feto-maternal exchange begins to dominate the placenta's secretory functions. Later, throughout the second and third trimester, the placenta adapts its structure to reflect its function such that near term, the villi consist mainly of fetal capillaries with sparse supporting stroma beyond that which is required to maintain its anatomic integrity. In contrast to the early placental villus where trophoblasts are abundant as part of a continuous layer of basal cytotrophoblasts, the term placenta's membranous interface between the fetal and maternal circulation is extremely thin (30). Thus, as the gestation progresses toward term, the number of cytotrophoblasts declines and the remaining syncytial layer becomes thin and barely visible. This structural arrangement facilitates transport of compounds across the feto-maternal interface.

Placental Steroid Hormones

Placental Progesterone
The placenta is the main source of progesterone during pregnancy. From the luteal phase to term, maternal progesterone levels rise six- to eight-fold. (Figures 5 and 8) Although, progesterone originates almost entirely from the corpus luteum before 6 weeks' gestational age, its production shifts more to the placenta after the 7th week. Beyond 12 weeks, the placenta is definitively the major source of progesterone (53,54).

While the placenta produces large amounts of progesterone, it has a limited capacity to synthesize cholesterol de novo (Figure 7). Maternal cholesterol in the form of low-density lipoprotein (LDL) cholesterol is the principal source of precursor for biosynthesis of progesterone during pregnancy (32,53,55). Progesterone concentrations are less than 1 ng/mL during the follicular phase of the normal menstrual cycle (56,57). However, in the luteal phase of conception cycles, progesterone concentrations rise from about 1-2 ng/mL on the day of the LH surge to a plateau of approximately 10-35 ng/mL over the subsequent 7 days. Concentrations remain within this luteal-phase range from the 10th week from the last menstrual flow, and then show a sustained rise that continues until term. At term, progesterone concentrations can range from 100-300 ng/mL (53).

Figure 5. Relative values of circulating concentrations (mean ąSEM) of progesterone and 17a-progesterone during the course of human pregnancy from conception to term. The data displayed demonstrates values before and after the luteinizing hormone (LH) surge. Gestational ages are calculated from last menstrual flow. (From ref. 58, with permission)

Progesterone functions to promote endometrial decidualization; inhibit smooth muscle contractility; decrease prostaglandin (PG) formation, which helps maintain myometrial quiescence and prevent the onset uterine contractions; and inhibit immune responses like those involved in graft rejection. It is believed to work in concert with hCG and decidual cortisol to inhibit T-lymphocyte-mediated tissue rejection and confer immunologic privilege to the implanted conceptus and developing placenta (59,60). In animal models, progesterone extends the survival of transplanted human trophoblasts, and high intervillous concentrations of progesterone are of major importance in blocking the cellular immune rejection of the foreign protein originating from the pregnancy (60).

Placental 17a-Progesterone
Like progesterone, during the first several weeks of gestation, and through the time of the luteal-placental shift, 17a-hydroxyprogesterone concentrations primarily reflect the steroidogenic status of corpus luteum (61). However, unlike progesterone, the ovaries continue to be a significant source of 17a-hydroxyprogesterone throughout pregnancy. During the third trimester the placenta also uses fetal D5-sulfoconjugated precursors to secrete increasing amounts of 17a-hydroxyprogesterone, and the placenta is the major source of this hormone at term (61).

Concentrations of 17a-hydroxyprogesterone are less than 0.5 ng/mL during the follicular phase of normal menstrual cycles. In conception cycles, 17a-hydroxyprogesterone concentrations rise to about 1 ng/ml on the day of the LH surge, decline slightly for about 1 day, and rise again over the subsequent 4-5 days reaching a level of 1-2 ng/ml. Concentrations then increase slightly to a mean of approximately 2 ng/ml (luteal phase levels) by the end of the 12th week. This level remains stable until a gestational age of about 32 weeks at which time begins an abrupt, sustained rise, at about 37 weeks, to approximately 7 ng/ml, a level that persists until term (61) (Figures 5 and 8). The rise in 17a-hydroxyprogesterone that begins at 32 weeks strongly correlates with the fetal maturational processes known to begin at this time.

Placental 17b-estradiol
The corpus luteum is the principal source of estrogens during early pregnancy, after which time nearly all of the estrogen is derived from the placenta Figure 7. Thus, for the first 5-6 weeks of gestation, 17b-estradiol originates almost exclusively from the maternal ovary (53). After the first trimester, the placenta is the major source of circulating 17b-estradiol (53). The rate of estrogen production and the level of circulating estrogens increase markedly during pregnancy. Concentrations of 17b-estradiol are less than 0.1 ng/mL during the follicular phase of the cycle and reach about 0.4 ng/mL during the luteal phase of normal menstrual cycles (56). Following conception, 17b-estradiol increases gradually to a range of 6-30 ng/mL at term (57) (Figures 6 and 8). Because it is deficient in 17-hydroxylase enzyme activity, the placenta is unable to convert progestogens to estrogens. Thus, the placenta relies on androgen precursors produced by the fetal and maternal adrenal glands. Sources of estrogen biosynthesis by the maternal-fetal-placental unit are depicted in Figure 8. The major source of fetal adrenal DHEAS is LDL-cholesterol circulating in the fetal blood. A minor source of fetal adrenal DHEAS is derived from pregnenolone secreted by the placenta. Twenty percent of fetal cholesterol is derived from the maternal compartment. Since amniotic fluid cholesterol levels are negligible, the main source of cholesterol is the fetal liver. As gestation advances, increasing quantities of 17b-estradiol are synthesized from the conversion of circulating maternal and fetal dihydroepiandrostenedione sulfate (DHEAS). At term, approximately equal amounts of estrogens are produce from circulating maternal DHEAS and fetal DHEAS (53,62).

Figure 6. Relative values of circulating concentrations (mean ąSEM) of 17b-estradiol, estriol and estrone during the course of human pregnancy from conception to term. Data displayed demonstrate values before and after the luteinizing hormone (LH) surge. Gestational ages are calculated from last menstrual flow. (From ref. 63, with permission)

With regard to the function of estrogens in pregnancy, they are known to augment uterine blood flow. For example, in animal models, direct estrogen injection into the uterine arteries produces striking increases in blood flow. Without question, 17b-estradiol is the most potent estrogen in this role. Estriol and estrone, however, though less active, also produce this effect (64). Because the exposure of the utero-placental bed to direct estriol secretion is enormous, estriol may be the principal up-regulator of uterine blood flow. This may be the dominant role of estriol in human pregnancy (64). Estrogen regulated mechanisms may also allow the fetus to govern production and secretion of progesterone during the third trimester. In primates, estrogen regulates the biosynthesis of placental progesterone by regulating the availability of LDL-cholesterol for conversion to pregnenolone and its downstream steroid products (65).

Placental Estriol
Estriol is first detectable in maternal serum at 9 weeks of gestation (53,62,66,67). This temporal relationship closely corresponds to the early stages of steroidogenic maturation in the fetal adrenal cortex (53). Hence, the continued production of estriol is, therefore, dependent upon the presence of a living fetus. Concentrations of estriol are less than 0.01 ng/ml in non-pregnant women. First detectable at approximately 0.05 ng/ml by 9 weeks, estriol increases gradually to a range of approximately 10-30 ng/ml at term (53,54,66,68). Between 35 and 40 weeks gestational age, estriol concentrations increase sharply in a pattern that reflects a final surge of intrauterine steroidogenesis just prior to term (Figures 6 and 8).

Figure 7. Synthesis of estrogen and progesterone within and between the maternal, placental and fetal compartments.  (From ref. 69, with permission)

Figure 8. Circulating maternal steroid hormone levels throughout early pregnancy. The first-trimester relationship of these steroid hormones to human chorionic gonadotropin (hCG) is shown. Progestogens Progesterone -o-o-o- 17-a-hydroxyprogesterone -D-D-D- Estrogens 17-b-estradiol -l-l-l- Estriol -o-o-o- Estrone -x-x-x- Human chorionic gonadotropin (hCG) -s-s-s-  (From ref. 70, with permission)

Placental Estrone
For the first 4-6 weeks of pregnancy, estrone originates primarily from maternal sources such as the ovaries, adrenals, or peripheral conversion (57). Later, the placenta secretes increasing quantities of estrone from the conversion of circulating maternal and fetal DHEAS. The placenta continues to be the major source of circulating estrone for the remainder of the pregnancy (53). Estrone concentrations are less than 0.1 ng/mL during the follicular phase and may reach a maximum of 0.3 ng/mL during the luteal phase of a normal menstrual cycle. Following conception, estrone concentrations remain within the luteal phase range through weeks 6-10 of gestation (54). Subsequently there is a gradual increase to a wide range of 2-30 ng/ml at term (53,54,57) (Figures 6 and 8).

Placental Peptide Hormones: Hypothalamic-like Hormones

Placental Gonadotropin Releasing Hormone (GnRH)
Gonadotropin releasing hormone derived from the placenta is biologically and immunologically similar to the hypothalamic decapeptide GnRH (19). Gonadotropin releasing hormone activity has been localized to the cytotrophoblast cells along the outer surface of the syncytiocytotrophoblast layer. Human chorionic gonadotropin (hCG) has been localized to the adjacent syncytiocytotrophoblast layer. Its production peaks at about 8 weeks gestation and then decreases as the pregnancy advances in gestational age (19-22). Furthermore, gonadotropin releasing hormone levels parallel those of hCG in both the placenta and maternal circulation (22).

Placental GnRH stimulates hCG release through a dose-dependent, paracrine mechanism (71). There is little augmentation of hCG secretion by GnRH, in first trimester placental culture, because hCG production is already close to maximum (22). In contrast, at mid-trimester there is a marked dose-dependent GnRH augmentation of hCG release, in vitro, with this effect diminishing in the term placenta. Likely due to the low affinity of placental GnRH receptors and dilution affect of the maternal circulation, intravenous administration of GnRH during pregnancy does not increase serum hCG. Thus, it seems most likely that locally produced placental GnRH is responsible for stimulation of placental hCG production (71).

Placental Corticotrophin Releasing Hormone (CRH)
Placental CRH is structurally similar to the hypothalamic peptide, CRH (72,73). Due to this similarity, it is easily measured by in amniotic fluid as well as fetal and maternal plasma. Pro-CRH mRNA is present in cytotrophoblasts (74). The production of CRH is most prominent in first trimester cytotrophoblasts and then diminishes toward term (18). CRH is also intensely immunoreactive in the decidua (18). Detection of CRH in maternal plasma increases sharply beginning in the 20th week of gestation, but reaches its highest levels at term (75). Although concentrations of CRH in fetal plasma are lower than those found in maternal plasma, there exists a significant correlation between maternal and fetal plasma CRH (75). There is a 3-fold rise, in amniotic fluid, between the second and third trimester (75,76). Placenta-derived CRH stimulates placental ACTH release in a dose-dependent manner in vitro (77,78). Corticotrophin releasing hormone and ACTH are both released into fetal and maternal circulation; their activity is moderated by maternal CRH binding proteins (75).

Placental CRH participates in the surge of fetal glucocorticoids associated with late third trimester fetal maturation (75,77,79). When uterine blood flow is restricted, secretion of both CRH and ACTH is increased. Corticotrophin releasing hormone is a potent utero-placental vasodilator (80,81). Corticotrophin releasing hormone is released into the fetal circulation in response to fetal stress and in conditions leading to fetal growth restriction (82-84). High circulating maternal CRH is believed to be responsible for the elevated plasma ACTH and cortisol found in pregnancy, which renders them unresponsive to feedback suppression of plasma cortisol (75-77,79,85). Corticotrophin releasing hormone stimulates prostaglandin synthesis in fetal membranes and placenta. In pre-eclampsia, fetal asphyxia, premature labor, and other conditions leading to fetal growth restriction CRH is frequently elevated (82-84).

Placental Thyrotropin Releasing Hormone (TRH)
Thyrotropin releasing hormone is found in the cytotrophoblast layer; however, this molecule is different from the tripeptide produced by the hypothalamus (86). Since hCG is regarded as the principal placenta-derived thyroid stimulator, a significant role for TRH is uncertain (87).