INTRODUCTION
The evolutionary advent of viviparity necessitated changes in the maternal metabolic, hormonal and immunological systems. To compensate for the increased and altered demands of an intracorporeal pregnancy, a new organ—the placenta—developed and a series of hormones were secreted. These hormones allow invasion of a half foreign tissue into the maternal system that not only tolerates but also actively nourishes and protects the growing fetus.
The past half a century has seen dramatic advances in our understanding of mammalian pregnancy and fetal development. Endocrine systems are involved in every aspect of pregnancy—implantation, placentation, maternal adaptation, fetal development, parturition, fetal adaptation to extrauterine life and lactation. The endocrine functions of the placenta have begun to be unraveled.
The production of steroid and protein hormones by human trophoblast is greater in amount and diversity than that of any other endocrine tissue known in all mammalian physiology.1 In its key location as a way station between the mother and fetus, the placenta can utilize precursors from either of the two to circumvent its own enzymatic deficiencies. The placental steroid hormones are produced from both fetal and maternal substrates. The protein hormones are generated from amino acids of maternal origin.
No class of steroid hormones other than estrogens and progesterone appear to be formed or secreted by the placenta. There is no evidence of placental synthesis of glucocorticoids or mineralocorticoids.
The placental villus is composed of trophoblast, mesenchymal cells and fetal blood vessels. There are 2 main trophoblast layers-cytotrophoblast and syncytiotrophoblast. The cytotrophoblast is the basic placental stem cell from which the syncytiotrophoblast arises by differentiation. The syncytiotrophoblast represents the functional cells of the placenta and is the major site of hormone and protein production. Control of this important cellular differentiation is still not understood. However, the process is influenced by human chorionic gonadotropin (HCG) and, undoubtedly, by a variety of cytokines and growth factors.2
The surface of the syncytiotrophoblast is in direct contact with maternal blood in the intervillus space. This ‘hemochorioendothelial’ placenta dictates that placental proteins and steroids are secreted preferentially into the mother. More than 90 percent of the estradiol and estriol and 85 percent or more of the progesterone are secreted into the maternal compartment.3,4 In contrast, the syncytiotrophoblast is separated from fetal blood by several layers of tissue. Consequently, the net transfer of steroids to fetal circulation is only about 1/10th the transfer to maternal blood. For the same reason placental proteins are secreted preferentially into the mother.
STEROID HORMONES
Progesterone Formation in the Placenta
Progesterone is largely produced by the corpus luteum until about 10 weeks of gestation when the placenta takes over. Indeed, up to 7 weeks, the continuation of pregnancy is dependent upon the corpus luteum. The period of 7 to 10 weeks is a transition time of shared function.
The placenta derives progesterone from circulating maternal low density lipoprotein (LDL)-cholesterol.5,6 Normally the fetus does not contribute precursors for placental progesterone production.
De novo synthesis of cholesterol from acetate is also low in the placenta. The entry of LDL-cholesterol from maternal bloodstream to trophoblast by endocytosis is enhanced by estrogen. Figure 1.1 summarizes the steps in placental progesterone production.
Some authors believe that the fetal liver may also contribute cholesterol for placental progesterone secretion.7
In contrast to estrogens, progesterone production by the placenta is largely independent of the quality of precursors available, the uteroplacental perfusion, fetal well-being and even the presence of a live fetus. This is because the fetus contributes essentially no precursors, the majority being derived from maternal cholesterol. At term, a small fraction of the progesterone, about 3 percent, is derived from maternal pregnenolone.
Progesterone serves as a substrate for fetal adrenal production of glucocorticoids or mineralocorticoids. The fetus lacks significant activity of the 3β-hydroxysteroid dehydrogenase, Δ4–5 isomerase system. Unable to produce progesterone, the fetus must borrow from the placenta to circumvent this lack in order to synthesize corticosteroids. In return, the fetus supplies what the placenta lacks—19-carbon compounds to serve as precursors of estrogen.
Estrogen Formation During Pregnancy
In early pregnancy estrogen, like progesterone, is mainly produced in the corpus luteum of the maternal ovary. After the first 3 to 4 weeks of human gestation, nearly all of the estrogens (estradiol and estriol) begins to be produced in the syncytiotrophoblast. As early as 7th week, more than 50 percent of estrogen in maternal circulation is placental in origin8,9
In human placenta neither acetate nor cholesterol, nor even progesterone, can serve as precursor for estrogen biosynthesis. The enzyme for sex steroid synthesis, steroid 17α-hydroxylase (CYP17), is not expressed in human placenta, Consequently, C21-steroids cannot be converted to C19-steroids in trophoblast. C19-steroids are the immediate and obligate precursors of estrogen. However, the placenta has a remarkable capacity for the aromatization of C19-steroids and androstenedione, testosterone and dehydroepiandrosterone, are all efficiently converted to estrogen. Figure 1.2 summarizes the synthesis of estriol by the placenta in advanced pregnancy.
The androgen compounds utilized for estrogen synthesis are derived from maternal bloodstream in early pregnancy. But by the 20th week, the vast majority of estrogen is derived from fetal androgens; 90 percent of estriol can be accounted for by dehydroepiandrosterone sulfate (DHEAS) production by fetal adrenal glands.9,10
A second feature of estrogen formation in human pregnancy is that the amount of estriol in the blood and urine of pregnant women is elevated disproportionately, as compared with the amount of estrone and estradiol in the blood and urine of non-pregnant women. In the non-pregnant, estriol is totally derived from metabolism of estrone and estradiol, whereas estriol in pregnancy is secreted directly by the syncytiotrophoblast by a pathway involving desulfuration of plasma 16α-hydroxydehydroepiandrosterone sulfate,9,11 and aromatization of the 16α-hydroxyandrostenedione formed by action of 3β-hydroxysteroid dehydrogenase.
During pregnancy, estrone and estradiol excretion is increased about 100 times over non-pregnant state. However, maternal estriol excretion is about 1000-fold. Because of high concentration, estriol is an important hormone in pregnancy. Incidentally, estriol is not secreted by the ovaries of the non-pregnant woman.
Near term, 50 percent estradiol synthesized in the placenta is derived from precursors in fetal circulation and the rest from precursors in the maternal circulation.
Fig. 1.2: Overall pathway of estriol synthesis in late pregnancy (DHEAS = Dehydroepiadrosterone sulfate, 16α-OH-DHEAS = 16α-hydroxy-DHEAS)
In contrast, 90 percent estriol in near-term pregnant women is produced from 16α-hydroxydehydroepiandrosterone sulfate in fetal plasma. DHEAS is synthesized in fetal adrenal cortex and is converted to 16α-hydroxydehydroepiandrosterone sulfate in fetal adrenals and liver. Steroid sulfatase activity in the placenta is high. The principal precursors for fetal adrenal steroid biosynthesis is LDL-cholesterol.
Role of Progesterone
Progesterone is regarded as the main pregnancy hormone. Exogenous support is required in early pregnancy achieved following assisted reproductive technology till 10 weeks.12
- Tubal motility: The preimplantation conceptus with its surrounding corona cells secretes progesterone that affects tubal motility as the conceptus is carried to the uterus.13 Estrogen may balance the progesterone effect, producing optimum motility.
- Induces decidualization of the endometrium in preparation to receive the conceptus.
- Progesterone inhibits T-lymphocyte mediated tissue rejection and is believed to work in concert with HCG and decidual cortisol.14,15 This may confer an immunological privilege to the conceptus. Siiteri et al14 pointed out that progesterone has aptly been called ‘the hormone of pregnancy’ and pregnancy is terminated by antiprogestins.
- Breasts: Growth of ducts and lobules and inhibition of prolactin and lactalbumin synthesis.
- Relaxation of smooth muscle of uterus, blood vessels and the gastrointestinal and urinary tracts. Using measurements of uterine resistance index, Jauniaux et al16 found that both estradiol and progesterone contributed to the downstream fall in resistance to blood flow with advanced gestational age.
- Vasodilatation, particularly in the kidney and skin.
- Natriuretic activity: Stimulation of sodium and water loss.
- Hyperventilation, lowering arterial pCO2.
- Thermogenic, raising basal body temperature.
- Increase in thirst, appetite and fat deposition.
- Role in parturition: An obligatory role for progesterone in the maintenance of human pregnancy can neither be established nor refuted. It is likely 6that both estrogens and progesterone are involved as components of a broader-based fail-safe biomolecular system that implements and maintains contractile unresponsiveness during pregnancy.1
Role of Estrogens
- Stimulates growth of uterus and uterine blood flow (angiogenesis and vasodilatation).17
- Stimulates growth of alveoli and ducts of breast.
- Stimulates hepatic synthesis of angiotensinogen (precursor of angiotensin I and II). Together with progesterone stimulates secretion of renin, which catalyzes formation of angiotensin I from angiotensinogen. The net effect is enhanced secretion of angiotensin II which in turn stimulates aldosterone secretion from the adrenal glands. The maternal vasculature, however, remains refractory to angiotensin II (mediated by vasodilatory prostaglandins and perhaps nitric oxide). The resultant sodium and water retention, leads to expansion of maternal blood volume, an important adaptation in pregnancy.
- Stimulation of protein synthesis and cholesterol metabolism in the liver.
- Polymerization of ground substance, especially in skin and cervix which become hygroscopic, soft and stretchable, and in joints (specially pelvic) which become more mobile.
- Estrogen regulated mechanisms may allow the fetus to govern production and secretion of progesterone during the third trimester. In the baboon, estrogen regulates the biosynthesis of placental progesterone by regulating the availability of LDL-cholesterol.18
Clinical Implications
Measurements of Estrogen in Pregnancy
Since 90 percent of maternal estriol is derived from fetal precursors after placental processing, for years (1960s and 1970s), 24-hour urinary estriol was a standard hormonal method of assessing fetal well-being. This was replaced by radioimmunoassay of unconjugated estriol in the plasma22 because of the latter's short half-life and less variability.
The differential diagnosis of extremely low estriol includes:
- Hydatidiform mole, Down's syndrome in early pregnancy.
- In late pregnancy, impending or present fetal demise.
- Adrenal hypofunction e.g. anencephaly.
- Placental sulfatase deficiency.
- Placental aromatase deficiency.
- Drug related effects e.g. maternal corticosteroid intake.
In pregnancies complicated by Rh-isoimmunization and maternal diabetes, the estriol levels maybe higher than in comparable normal pregnancies.
Biophysical tests, however, have now taken over the biochemical tests for fetal well-being because the latter are more expensive and have a low predictive value for adverse fetal outcome.23
There has been resurgence in measurement of unconjugated estriol (uE3) as a screening procedure for Down's syndrome. Current recommendations are summarized in Table 1.1.
In women with first trimester threatened abortion, low progesterone concentrations are predictive of poor outcome.25 Progestins were extensively used therapeutically. Nowadays we do not administer progesterone to these cases and ultrasonography (USG) in threatened abortion cases is extensively employed for predicting outcome.
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Progesterone concentrations are lower in women with ectopic pregnancy. Single serum progesterone levels have been utilized in diagnostic algorithms with serum HCG and USG in diagnosis of ectopic pregnancies without laparoscopy. A value of 25 ng/ml or more is associated with normal intrauterine pregnancy in 98 percent of cases. Progesterone levels less than 5 ng/ml are diagnostic of fetal death in first trimester.26 Curettage is helpful in these cases and presence/absence of chorionic villi will determine location of pregnancy in place of an unnecessary laparoscopy. The great majority of ectopic pregnancies have serum progesterone levels between 10 to 20 ng/ml, limiting the clinical usefulness of progesterone measurement.27
Although not useful clinically, serum progesterone levels are elevated in hydatidiform mole and Rh-isoimmunization in pregnancy. Formation of progesterone and protein hormones, such as HCG, may persist after fetal death. This is unlike in the case of estriol.
Protein Hormones
Right from the time of conception, proteins are released into the maternal system by the newly formed conceptus, first, to announce its arrival, and then to orchestrate the maternal immune, metabolic and endocrine responses. The production of proteins reflects the demands that each developmental stage of gestation brings. Table 1.2 depicts the proteins associated with pregnancy, of which the placental list is the longest.
The list of proteins made by the placenta is ever-increasing, unlike the steroids which comprise only estrogens and progesterone. The only hormone not made by either the trophoblast or the fetal membranes, seems to be prolactin, which is derived from maternal pituitary, fetal pituitary and uterine decidua.
One extensively reviewed and attractive hypothesis suggests that the hypothalamus-like placental peptides (GnRH, CRH, TRH, GHRH), located in the cytotrophoblast, stimulate the pituitary-like placental peptides (HCG, ACTH, HCT, GH), located in the adjacent syncytiotrophoblast.28 Thus placental protein hormones are no longer seen as autonomous; an increasing number of in vitro studies point to endogenous placental regulation of its hormonal products simulating a miniature hypothalamic-pituitary-target hormone unit.29
Although the placenta produces numerous protein hormones, we shall restrict our discussion to the 2 most abundant peptides, namely HCG and human placental lactogen (HPL).
The latter has also been called human chorionic somatomammotropin.
Human Chorionic Gonadotropin
HCG is a glycoprotein with the highest carbohydrate (30%) content of any human hormone. It bears structural similarity to follicle stimulating hormone (FSH), luteinizing hormone (LH) and thyroid stimulating hormone (TSH). Like other glycoprotein hormones, HCG is composed of α and β-subunits. The β-subunit differs just enough to confer unique biological activity and specificity in immunoassays. The α-subunit is common to all the above glycoprotein hormones.
HCG is sometimes referred to as ‘surrogate’ LH because it binds to the cell membrane LH/HCG receptor and mimics the action of LH. The long half-life of HCG, approximately 24 hours, as compared with 2 hours for LH, is due mainly to a greater sialic acid content. All human tissues appear to make HCG, but the placenta is unique in having the ability to glycosylate the protein, thus conferring a longer half-life and greater biological activity.
HCG can be detected with very sensitive kits in normal men and women where it comes probably from the pituitary gland.30,31
The complete HCG molecule is synthesized primarily in the syncytiotrophoblast. Yet, immunoreactive HCG has been localized in cytotrophoblast before 6 weeks of gestation. Thereafter, it is found only in the syncytiotrophoblast. There is thus a cellular shift in HCG formation at about 6 weeks. A similar event is seen with HPL.32
The greatest rate of HCG secretion coincides in time with the maximal abundance of cytotrophoblast in placenta. Because cytotrophoblast is the progenitor of the syncytiotrophoblast, the correlation may reflect increased conversion of cyto to syncytiotrophoblast. Alternatively, the cytotrophoblast is the site of synthesis of GnRH; thus a paracrine control may cause GnRH of cytotrophoblast origin to act on syncytiotrophoblast to stimulate production of HCG.
The secretion of HCG is detectable in the plasma of pregnant women around the 8th day after ovulation, one day after implantation. Biomolecular technique has demonstrated HCG in the 8-cell stage.33 The maternal plasma HCG is about 100 IU/l at the time of expected but missed menses. A peak level of about 100,000 IU/l is reached at 8 to 10 weeks of gestation. Thereafter it decreases to about 10,000 to 20,000 IU/l by 18 to 20 weeks and remains at this level till term (Fig. 1.3).
The maternal circulation contains some 20 to 30 isoforms of HCG depending on the stage of pregnancy and presence of gestational trophoblastic disease. HCG is not a single molecule; it is a mixture of regular HCG (MW ≈ 36,000), large carbohydrate variants or hyperglycosylated HCG (MW ≈ 41,000), nicked HCG (MW ≈ 36,000), HCG missing the β subunits C-terminal peptide (MW ≈ 29,000), free b subunits (MW > 22,000), nicked free β subunit (MW 22,000) and multiple combination of these variants. The same 6 molecules plus β core fragments (MW 10,000) are detected in urine samples. In gestational trophoblastic disease any one of these variants maybe the principal molecule in blood samples. Considering the heterogeneity it is essential to use an HCG test that measures all forms of HCG.34
Phantom HCG or false positive HCG values: Rarely, women have persistently elevated HCG levels which are false positive, sometimes after receiving chemotherapy or surgery for presumed gestational trophoblastic disease (GTD). Most patients with false positive HCG have low level HCG elevations.35 False positivity results from interference with the HCG immunometric sandwich assays, most often caused by heterophile antibodies in the patient's sera.
Fig. 1.3: Profile of human chorionic gonadotropin (HCG) and human placental lactogen (HPL) levels in maternal serum through gestation. The differential peaks of the 2 hormones in early and late pregnancy is to be noted
False positive HCG may also appear after evacuation of a hydatidiform mole or following an ectopic pregnancy. False positivity should be suspected if HCG values plateau at relatively low level and do not respond to therapeutic maneuvers such as methotrexate. Evaluation should include checking serum HCG using a variety of assay techniques at serial dilutions of patient's serum combined with urinary HCG levels (heterophile antibodies are not excreted in urine).36
Hyperglycosylated HCG is a new and invaluable marker for monitoring GTD. It is only produced by invasive cytotrophoblast and can distinguish invasive (malignant) and non-invasive disease, determining the need for treatment or only follow-up.34
Higher plasma levels of HCG are found in multiple pregnancies, with erythroblastic fetus and in some women with diabetes. Relatively higher levels of plasma HCG in mid-trimester maybe used as a part of triple screen for Down's syndrome.
HCG levels approximately double every 2 days in early normal intrauterine pregnancies and a lesser increase is associated with ectopic pregnancies and spontaneous abortions.37 Titers greater than 1000 to 1500 IU/l should enable visualization of intrauterine gestation by transvaginal sonography. Failure to demonstrate a sac suggests ectopic pregnancy. Declining levels of HCG are also helpful in monitoring ectopic pregnancies after effective medical or conservative surgical treatment.
Very high levels of HCG maybe associated with features of hyperthyroidism, for instance in gestational trophoblastic disease. Many patients of hyperemesis gravidarum, with high levels of HCG may also have transient hyperthyroidism.38
Physiological Role of HCG
- To rescue and support the corpus luteum, taking over from LH on about the 8th day after ovulation.
- HCG stimulates steroidogenesis in the early fetal testis by entering the fetal plasma from syncytiotrophoblast. Testosterone secreted by LH-like action of HCG ensures initial male sexual differentiation. The fetal pituitary starts LH secretion after first trimester and effects later development. HCG may similarly regulate DHEAS production by the fetal zone of the adrenal gland during first trimester.
- HCG has thyroid stimulating activity as it can bind to the TSH receptor of thyroid cells. There is also evidence that LH/HCG receptors are expressed in the thyroid.39
- HCG may act in vivo to promote relaxin secretion by corpus luteum.
- LH/HCG receptors occur in the myometrium and in myometrial blood vessels and HCG may promote myometrial smooth muscle relaxation or myometrial vasodilatation.40
- HCG is immunosuppressive and maybe involved in the immunological tolerance of the fetus by the mother.
Human Placental Lactogen
HPL is a single chain, non-glycosylated, polypeptide of 191 amino acids with 96 percent homology to human growth hormone (GH) which consists of 188 amino acids. HPL has only 3 percent of the growth promoting activity of GH. Incidentally, HPL also has some structural similarity to prolactin, with about 67 percent homology in amino acid sequence.
The genes coding for prolactin, GH and HPL are closely related, with the prolactin gene being presumed to be the ancestral gene.41 The five genes of the GH-HPL family are located on the long arm of chromosome 17.42
Although HPL has about 50 percent of the lactogenic activity of sheep prolactin in certain bioassays, its lactogenic contribution in human pregnancy is uncertain.7,29
HPL is detectable in the trophoblast within 5 to 10 days after fertilization. It is demonstrable in maternal serum 3 weeks after fertilization. As with HCG, HPL is identified before 6 weeks in the cytotrophoblast but after that the HPL synthesis shifts to the syncytiotrophoblast.32 Its level increases steadily up to 34 to 36 weeks when maximal levels of 5 to 15 μg/ml are reached (Fig. 1.3). There is no circadian variation, the hormone is secreted primarily into the maternal circulation, and its half-life is only 10 to 30 minutes.43 The serum level correlates with fetal and placental weights, high levels being found in multiple pregnancies. The daily secretion of 1 to 2 g is greater than any other known hormone either during or outside pregnancy.44
Fig. 1.4: Schematic representation of neurohormones and their potential interactions in the placenta. [Abbreviations: ACTH = Adrenocorticotrophic hormone; CRH = Corticotropin releasing hormone; GHRH = Growth hormone releasing hormone; GHRIH = Growth hormone release inhibiting hormone (somatostatin); GnRH = Gonadotropin releasing hormone; HCC = Human chorionic corticotropin (ACTH); HCG = Human chorionic gonadotropin; HPL = Human placental lactogen; MSH = Melanocyte stimulating hormone; NPY = Neuropeptide Y]Adapted from: Jaffe RB. Neuroendocrine—metabolic regulation of pregnancy. In: Yen SSC, Jaffe RB, Barbieri RL. Reproductive Endocrinology (4th edn). Philadelphia: WB Saunders, 1999; 767.
Like other peptide hormones, the synthesis of HPL is probably regulated by placental growth factors, cytokines and perhaps by hypothalamic hormones produced in the cytotrophoblast layer.29
Physiological Role of HPL
The main action of HPL is to reset the maternal carbohydrate and fat metabolism so as to furnish adequate substrates, glucose and amino acids, for fetal nutrition. In normal pregnancy insulin resistance develops, glucose and free fatty acid levels are increased, providing fetal energy substrates. Recently, tumor necrosis factor α, leptin and resistin have also been implicated in insulin resistance in pregnancy in addition to HPL, estrogen, progesterone, prolactin and corticosteroids.45
In the fasting state, as glucose decreases, HPL stimulates lipolysis increasing free fatty acids. Thus a different fuel is provided for the mother so that glucose and amino acids are spared for the fetus.
In the fed state, increased glucose levels lead to hyperinsulinemia that causes lipogenesis, glucose utilization, decreased gluconeogenesis, and decreased free fatty acid levels. HPL secretion is depressed with hyperglycemia.
In the mother HPL stimulates insulin secretion and insulin-like growth factor-I (IGF-I) production, and induces insulin resistance and carbohydrate intolerance. In the second half of pregnancy, when the HPL level rises 10 times, it may contribute to gestational diabetes in susceptible individuals.
The small amounts of HPL in fetal circulation, in synergy with insulin, may affect fetal growth. Thus in anencephaly, where fetal GH is deficient, the fetus grows normally.
Low plasma levels of HPL have been described with otherwise normal pregnancies.46 HPL may thus be one important mechanism of a fail-safe system to ensure nutrient supply to the fetus during times of starvation.
Clinical Implications
Test of fetal well-being: In view of its high serum levels, short half-life and correlation with placental mass, plasma HPL levels were used as a measure of placental function, and indirectly fetal well-being. Levels less than 4 μg/ml in last trimester were taken to suggest placental insufficiency. The positive predictive value of plasma HPL in terms of perinatal mortality is however poor and probably not even as good as estriol. Both have been superseded by biophysical parameters.
Gestational trophoblastic disease: Intact molar 11pregnancies can have elevated levels of both HPL and HCG.47 Because of the short half-life of 20 minutes (compared to 24 hours for HCG) aborting molar pregnancies are likely to show low HPL with elevated HCG.
CONCLUSION
There is a continuing interplay between the fetoplacental and maternal endocrine system progressively modifying the internal milieu in both mother and fetus during different stages of pregnancy. The interaction of these hormones appears to be more complex, now that the role of gene expression and intermediary chemokines and cytokines are gradually being unraveled. Understanding physiology is important in distinguishing normal from abnormal in a pregnant woman.
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