Michael C. Lu, Calvin J. Hobel
Women undergo major endocrinologic and metabolic changes that establish, maintain, and terminate pregnancy. The aim of these changes is the safe delivery of an infant who can survive outside of the uterus. The maturation of the fetus and the adaptation of the mother are regulated by a variety of hormones. This chapter deals with the properties, functions, and interactions of the most important of these hormones as they relate to pregnancy and parturition.
The concept of the fetoplacental unit is based on observations of the interactions of hormones of fetal and maternal origin. The fetoplacental unit largely controls the endocrine events of the pregnancy.Although the fetus, the placenta, and the mother all provide input, the fetus appears to play the most active and controlling role of the three in its growth and maturation, and probably also in the events that lead to parturition.
The adrenal gland is the major endocrine component of the fetus. In mid-pregnancy, it is larger than the fetal kidney. The fetal adrenal cortex consists of an outer definitive, or adult, zone and an inner, fetal, zone. The definitive zone later develops into the three components of the adult adrenal cortex: the zona fasciculata, the zona glomerulosa, and the zona reticularis. During fetal life, the definitive zone secretes primarily glucocorticoids and mineralocorticoids. The fetal zone, at term, constitutes 80% of the fetal gland and primarily secretes androgens during fetal life. It involutes following delivery and completely disappears by the end of the first year of life. The fetal adrenal medulla synthesizes and stores catecholamines, which play an important role in maintaining fetal homeostasis. The role of the fetal adrenal during fetal growth and maturation is not completely understood.
The placenta produces both steroid and peptide hormones in amounts that vary with gestational age. Precursors for progesterone synthesis come from the maternal circulation. Because of the lack of the enzyme 17α-hydroxylase, the human placenta cannot directly convert progesterone to estrogen but must use androgens, largely from the fetal adrenal gland, as its source of precursor for estrogen production.
The mother adapts to pregnancy through major endocrinologic and metabolic changes. The ovaries produce progesterone in early pregnancy until its production shifts to the placenta. The maternal hypothalamus and posterior pituitary produce and release oxytocin, which causes uterine contractions and milk letdown. The anterior pituitary produces prolactin, which stimulates milk production. Several important changes in maternal metabolism are described later in the chapter.
The fetoplacental unit produces a variety of hormones to support the maturation of the fetus and the adaptation of the mother.
Human Chorionic Gonadotropin
Human chorionic gonadotropin (hCG) is secreted by trophoblastic cells of the placenta and maintains pregnancy. This hormone is a glycoprotein with a molecular weight of 40,000 to 45,000 and consists of two subunits: alpha (α) and beta (β). The α subunit is shared with luteinizing hormone (LH) and thyroid-stimulating hormone (TSH). The specificity of hCG is related to its β subunit (β-hCG), and a radioimmunoassay that is specific for the β subunit allows positive identification of hCG. The presence of hCG at times other than pregnancy signals the presence of an hCG-producing tumor, usually a hydatidiform mole, choriocarcinoma, or embryonal carcinoma (a germ cell tumor).
During pregnancy, hCG begins to rise 8 days after ovulation (9 days after the midcycle LH peak). This provides the basis for virtually all immunologic or chemical pregnancy tests. With continuing pregnancy, hCG values peak at 60 to 90 days and then decline to a moderate, more constant level. For the first 6 to 8 weeks of pregnancy, hCG maintains the corpus luteum and thereby ensures continued progesterone output until progesterone production shifts to the placenta. Titers of hCG are usually abnormally low in patients with an ectopic pregnancy or threatened abortion and abnormally high in those with trophoblastic disease (e.g., moles or choriocarcinoma). This hormone may also regulate steroid biosynthesis in the placenta and the fetal adrenal gland and stimulate testosterone production in the fetal testicle. Although immune suppression has been ascribed to hCG, this effect has not been verified.
Human Placental Lactogen
Human placental lactogen (hPL) originates in the placenta. It is a single-chain polypeptide with a molecular weight of 22,300, and it resembles pituitary growth hormone and human prolactin in structure. Maternal serum concentrations parallel placental weight, rising throughout gestation to maximum levels in the last 4 weeks. At term, hPL accounts for 10% of all placental protein production. Low values are found with threatened abortion and intrauterine fetal growth restriction. Human placental lactogen antagonizes the cellular action of insulin and decreases maternal glucose utilization, which increases glucose availability to the fetus. This may play a role in the pathogenesis of gestational diabetes.
During pregnancy the major source of corticotropin-releasing hormone (CRH) is the placenta, and it can be measured as early as 12 weeks of gestation when it passes into the fetal circulation. This 41–amino acid peptide stimulates fetal adrenocorticotropic hormone (ACTH) secretion, which in turn stimulates the fetal adrenal to secrete dehydroepiandrosterone sulfate (DHEA-S), an important precursor of estrogen production by the placenta. The fetal adrenal gland early in pregnancy does not have the enzymes to produce cortisol, but as gestational age increases, it becomes more responsive. Fetal cortisol stimulates placental CRH release, which then stimulates fetal ACTH secretion, completing a positive feedback loop that plays an important role in the activation and amplification of labor, both preterm and term. Elevated levels of CRH in mid-gestation have been found to be associated with an increased risk for subsequent preterm labor.
Prolactin is a peptide from the anterior pituitary with a molecular weight of about 20,000. Normal nonpregnant levels are about 10 ng/mL. During pregnancy, maternal prolactin levels rise in response to increasing maternal estrogen output that stimulates the anterior pituitary lactotrophs. The main effect of prolactin is stimulation of postpartum milk production. In the second half of pregnancy, prolactin secreted by the fetal pituitary may be an important stimulus of fetal adrenal growth. Prolactin may also play a role in fluid and electrolyte shifts across the fetal membranes.
Progesterone is the most important human progestogen. In the luteal phase, it induces secretory changes in the endometrium, and in pregnancy, higher levels induce decidual changes. Up to the 6th or 7th week of pregnancy, the major source of progesterone (in the form of 17-OH progesterone) is the ovary. Thereafter, the placenta begins to play the major role. If the corpus luteum of pregnancy is removed before 7 weeks and continuation of the pregnancy is desired, progesterone should be given to prevent spontaneous abortion. Circulating progesterone is mostly bound to carrier proteins, and less than 10% is free and physiologically active.
The myometrium receives progesterone directly from the venous blood draining the placenta. Progesterone prevents uterine contractions and may also be involved in establishing an immune tolerance for the products of conception. Progesterone also suppresses gap junction formation, placental CRH expression, and the actions of estrogen, cytokines, and prostaglandin. This steroid hormone therefore plays a central role in maintaining uterine quiescence throughout most of pregnancy.
The fetus inactivates progesterone by transformation to corticosteroids or by hydroxylation or conjugation to inert excretory products. However, the placenta can convert these inert materials back to progesterone. Steroid biochemical pathways are shown in Figure 5-1.
FIGURE 5-1 Main pathways of steroid hormone biosynthesis. Adrenal DHEA is largely transported as its sulfate, DHEA-S, which can also be formed from steroid sulfates starting with cholesterol sulfate. LDL, low-density lipoprotein.
Both fetus and placenta are involved in the biosynthesis of estrone, estradiol, and estriol. Cholesterol is converted to pregnenolone and pregnenolone sulfate in the placenta. These precursors are converted to DHEA-S largely in the fetal, and to a lesser extent the maternal, adrenals. The DHEA-S is further metabolized by the placenta to estrone (E1) and, through testosterone, to estradiol (E2). Estriol (E3), the most abundant estrogen in human pregnancy, is synthesized in the placenta from 16α-hydroxy-DHEA-S, which is produced in the fetal liver from adrenal DHEA-S. Placental sulfatase is required to deconjugate 16α-hydroxy-DHEA-S before conversion to E3 (Figure 5-2). Steroid sulfatase activity in the placenta is high except in rare cases of sulfatase deficiency.
FIGURE 5-2 Formation of estriol in the fetal-placental unit.
A sudden decline of estriol in the maternal circulation may indicate fetal compromise in neurologically intact fetuses. Anencephalic fetuses lack a hypothalamus and have hypoplastic anterior pituitary and adrenal glands; thus, estriol production is only about 10% of normal.
During pregnancy, androgens originate mainly in the fetal zone of the fetal adrenal cortex. Androgen secretion is stimulated by ACTH and hCG, the latter being effective primarily in the first half of pregnancy, when it is present in high concentration. The fetal adrenal favors production of DHEA over testosterone and androstenedione. Fetal androgens enter the umbilical and placental circulation and serve as precursors for estradiol and estriol (see Figure 5-1).
The fetal testis also secretes androgens, particularly testosterone, which is converted within target cells to dihydrotestosterone (DHT), which is required for the development of male external genitalia. The main trophic stimulus appears to be hCG.
Cortisol is derived from circulating cholesterol (see Figure 5-1). Maternal plasma cortisol concentrations rise throughout pregnancy, and the diurnal rhythm of cortisol secretion persists. The plasma level of transcortin rises in pregnancy, probably stimulated by estrogen, and the plasma-free cortisol concentration doubles.
Both the fetal adrenal and the placenta participate in cortisol metabolism. The fetal adrenal is stimulated by ACTH, originating from the fetal pituitary, to produce both cortisol and DHEA-S. In contrast to DHEA-S, which is produced in the fetal zone, cortisol originates in the definitive zone (see Figure 5-1). Toward the end of pregnancy cortisol promotes differentiation of type II alveolar cells and the biosynthesis and release of surfactant into the alveoli. Surfactant decreases the force required to inflate the lungs. Insufficiency of surfactant leads to respiratory distress in the premature infant, which can cause death. Cortisol also plays an important role in the activation of labor, increasing the release of placental CRH and prostaglandins.
OTHER HORMONES AND TRANSMITTERS
The oxytocic prohormone, which originates in the supraoptic and paraventricular nuclei of the maternal hypothalamus, migrates down the nerve fibers, and oxytocin accumulates at the nerve endings in the posterior pituitary. Oxytocin is a nonapeptide, which is released from the posterior pituitary by various stimuli, such as distention of the birth canal and mammary stimulation. Oxytocin causes uterine contractions, but impairment of oxytocin production, as in diabetes insipidus, does not interfere with normal labor. Fluctuations in circulating oxytocin levels before the onset of labor do not correspond to changes in uterine activity. Maternal serum oxytocin levels rise only during the first stage of labor. Oxytocin can be administered to induce labor, especially in term pregnancies, or to increase the frequency and strength of contractions during spontaneous labor.
Relaxin is a peptide hormone that originates mostly from the ovary. In the human, it reaches its peak concentration in the maternal circulation at the 10th week of pregnancy and then declines. Relaxin is associated with the softening of the cervix, which is one of the anatomic signs of pregnancy. Its primary function appears to be in promoting implantation of the embryo by facilitating angiogenesis.During hyperstimulation of the ovaries of women undergoing in vitro fertilization (IVF), the ovaries produce excessive levels of relaxin. This excess of relaxin has been shown to be associated with shortening of the cervix and an increased risk for preterm labor.
Prostaglandins and Leukotrienes
Prostaglandins are a family of ubiquitous, biologically active lipids that are involved in a broad range of physiologic and pathophysiologic responses. They are not true hormones in that they are not synthesized in one gland and transported through the circulating blood to a target organ. Rather, they are synthesized at or near their site of action. Prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α), prostacyclin, and thromboxane A2 are synthesized in the endometrium, myometrium, the fetal membranes, decidua, and placenta. PGE2 and PGF2α cause contraction of the uterus. Their receptors in the myometrium are downregulated during pregnancy. Prostaglandins can also cause contraction of other smooth muscles, such as those of the intestinal tract. Hence, when used pharmacologically, prostaglandins may give rise to undesirable side effects such as nausea, vomiting, and diarrhea. The amniotic fluid concentrations of PGE2 and PGF2α rise throughout pregnancy and increase further during spontaneous labor. Levels are lower in women who require oxytocin for induction of labor than in women going into spontaneous labor. Administration of PGE2 or PGF2α by various routes induces labor or abortion at any stage of gestation. Various synthetic prostaglandin derivatives are currently in use to terminate pregnancy at any stage and to induce labor at term.
Prostaglandins are thought to play a major role in the initiation and control of labor. Prostaglandin synthesis begins with the formation of arachidonic acid, an obligatory precursor of the prostaglandins of the “2” series (i.e., PGE2, PGF2α). Arachidonic acid is stored in esterified form as glycerophospholipid in the trophoblastic membranes. The initial step is the hydrolysis of glycerophospholipids, which is catalyzed by phospholipase A2 or C. Phospholipase A2 preferentially acts on chorionic phosphatidyl ethanolamine to release arachidonic acid (Figure 5-3). Free arachidonic acid does not accumulate. Labor appears to be accompanied by a cascade of events in the chorion, amnion, and decidua that releases arachidonic acid from its stored form and converts it to active prostaglandins. 17β-Estradiol stimulates several enzymes active in the synthesis of prostaglandins from arachidonic acid.
FIGURE 5-3 Diagram of prostaglandin and leukotriene biosynthesis.
There are two cyclooxygenase isoenzymes referred to as COX-1, or PGHS-1, and COX-2, or PGHS-2. These isoenzymes originate from separate genes. COX-1 is expressed in quiescent cells, whereas COX-2 is inducible and is expressed at sites of inflammation upon cell activation and potentiates the inflammatory process. COX-1 mRNA expression is low in fetal membranes and does not change with gestational age, whereas COX 2 mRNA expression in the amnion increases with gestational age.
Increased phospholipase A2 activity may lead to premature labor. Endocervical, intrauterine, or urinary tract infections are often associated with premature labor. Many of the organisms producing these infections have phospholipase A2 activity, which could produce free arachidonic acid, followed by prostaglandin synthesis, which could trigger labor.
Prostaglandin synthetase inhibitors can prolong gestation. Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit phospholipase A2, whereas aspirin-like drugs inhibit cyclooxygenase. Because PGE2 keeps the ductus arteriosus open, premature closure of the ductus may occur after ingestion of NSAIDs or aspirin in large amounts or for a prolonged period of time, resulting in fetal pulmonary hypertension and death.
An additional pathway for arachidonic acid metabolism is the conversion of arachidonic acid to leukotrienes (see Figure 5-3). Both prostaglandins and leukotrienes induce decidualization, which means that they initiate changes in the endometrium to facilitate implantation of the fertilized ovum.
Although PGF2α is more potent in producing uterine contractile activity, PGE2 is the most potent prostaglandin for ripening the cervix by inducing changes in the connective tissue. Hence, PGE2 and its synthetic derivatives are clinically useful for cervical ripening before the induction of labor or abortion.
Changes in Maternal Metabolism
Maternal metabolism adapts to pregnancy through endocrinologic regulation, as described subsequently.
Aldosterone is a mineralocorticoid synthesized in the zona glomerulosa of the adrenal cortex. The main source in pregnancy is the maternal adrenal. The fetal adrenal and the placenta do not participate significantly in aldosterone production, although the fetal adrenal is capable of synthesizing it. Aldosterone secretion is regulated by the renin-angiotensin system. Increased renin formed in the kidney converts angiotensinogen (renin-substrate) to angiotensin I, which is further metabolized to angiotensin II, which in turn stimulates aldosterone secretion. Aldosterone stimulates the absorption of sodium and the secretion of potassium in the distal tubule of the kidney, thereby maintaining sodium and potassium balance. Renin-substrate (a plasma protein) concentration rises in pregnancy. It is thought that the high concentrations of progesterone and estrogen present during pregnancy stimulate renin and renin-substrate formation, thus giving rise to increased levels of angiotensin II and greater aldosterone production. Aldosterone secretion rates decline in pregnancy-induced hypertension and, in some cases, may fall below nonpregnant levels.
Although calcium absorption is increased in pregnancy, total maternal serum calcium declines. The fall in total calcium parallels that of serum albumin because about half of the total calcium is bound to albumin. Ionic calcium, the physiologically important calcium fraction, remains essentially constant throughout pregnancy because of increased maternal production of parathyroid hormone. In late pregnancy, coinciding with maximal calcification of the fetal skeleton, increased serum parathyroid hormone enhances both maternal intestinal absorption of calcium and bone resorption. The latter counteracts the inhibition of bone resorption caused by increased circulating estrogen. Urinary calcium excretion is decreased.
Calcium ions are actively transported across the placenta, and fetal serum levels of total as well as ionized calcium are higher than maternal levels in late pregnancy. High fetal ionic calcium suppresses fetal parathyroid hormone production, and parathyroid hormone does not cross the placenta. Furthermore, calcitonin production is stimulated, thus providing the fetus with ample calcium for calcification of the skeleton. In the first 24 to 48 hours postpartum, the total serum calcium concentration in the neonate usually falls, while the phosphorus concentration rises. Both adjust to adult levels within 1 week.
Parturition means childbirth, and labor is the physiologic process by which a fetus is expelled from the uterus to the outside world.
BIOCHEMICAL BASIS OF CONTRACTION
Muscle contraction is brought about by the sliding of actin and myosin filaments fueled by adenosine triphosphate (ATP) and calcium. Although skeletal muscle requires innervation, contraction of smooth muscles such as the myometrium is triggered primarily by hormonal stimuli. Hormonal receptors have been found in the myometrial cell membrane.
The binding of oxytocin and prostaglandins to their respective receptors activates phospholipase C, which hydrolyzes phosphatidylinositol bisphosphate, a lipid present in the cell membrane, to inositol trisphosphate and diacylglycerol (Figure 5-4). Inositol trisphosphate induces release of calcium from the sarcoplasmic reticulum, an intracellular calcium storage area. The resulting high intracellular free calcium concentration enables the myofibrils of the myometrium to contract. Subsequently, the calcium is pumped back into the sarcoplasmic reticulum with the help of ATP, and more calcium may enter from the extracellular fluid through both voltage-operated and receptor-operated channels that open briefly.
FIGURE 5-4 Diagram of inositol trisphosphate formation.
Unlike the heart, in which the bundle of His is present, no anatomic structures for synchronization of contractions have been found in the uterus. Instead, contraction spreads as current flows from cell to cell through areas of low resistance. Such areas are associated with gap junctions, which become especially prominent at parturition. Estradiol and prostaglandins promote the appearance of gap junctions, whereas progesterone opposes this action of estradiol.
HORMONAL CONTROL OF GESTATIONAL LENGTH AND INITIATION OF LABOR
Gestational length is under the hormonal control of the fetus in most species. Each species, however, has not only a unique gestational length, but also unique mechanisms for controlling the length of gestation. Thus, although animal models provide important insight, they do not provide specific information concerning the control of the human gestational length or the mechanisms controlling initiation of labor.
Most studies have been conducted in the sheep, where the fetus appears to control the onset of labor. The fetal hypothalamus stimulates the fetal pituitary to secrete ACTH, which brings about a surge of cortisol from the fetal adrenal. The cortisol surge induces the placental enzyme 17α-hydroxylase and formation of androgens, which are estrogen precursors (see Figure 5-1), simultaneously decreasing progesterone formation. The rise in the estrogen-to-progesterone ratio leads to (1) greater secretion of prostaglandins; (2) formation of myometrial gap junctions, which provide areas of low resistance to current flow and increase coordinated uterine contractions; (3) cervical ripening; and (4) the onset of labor. Administered ACTH, glucocorticoids, or dexamethasone can also initiate parturition. Removal of the fetal pituitary or adrenal, both of which are required for the cortisol surge, results in prolonged pregnancy.
In a breed of Guernsey cows with a genetic defect resulting in fetal pituitary and adrenal dysfunction, pregnancy is prolonged, and normal vaginal delivery does not occur. In the rabbit, parturition directly follows a decline in progesterone production secondary to a decline in corpus luteum function. Abortion can be prevented by administration of progesterone.
The process of normal spontaneous human parturition can be divided into four phases.
PHASE 0: QUIESCENCE
Throughout the majority of pregnancy, the uterus remains relatively quiescent. Myometrial activity is inhibited during pregnancy by various substances, but progesterone appears to play a central role in maintaining uterine quiescence. Rare uterine contractions that occur during the quiescent phase are of low frequency and amplitude and are poorly coordinated; these are commonly referred to as Braxton-Hicks contractions in women. The poor coordination of these contractions is primarily due to an absence of gap junctions in the pregnant myometrium.
PHASE 1: ACTIVATION
Normally, the signals for myometrial activation can come from uterine stretch as a result of fetal growth, or from activation of the fetal hypothalamic-pituitary-adrenal (HPA) axis as a result of fetal maturation, or both. Uterine stretch has been shown in animal models to increase gap junctions and contraction-associated proteins in the myometrium. It is currently thought that once fetal maturity has been reached (as determined by as yet unknown mechanisms), the fetal hypothalamus increases CRH secretion, which in turn stimulates ACTH expression by the fetal pituitary and cortisol and androgen production by the fetal adrenals. Recent data from pregnant mice suggest that the fetus signals the initiation of labor by secreting a major lung surfactant protein, SP-A, into the amniotic fluid.
These data support a critical role for the fetal HPA axis in the initiation of parturition because surfactant protein synthesis is stimulated by glucocorticoids. The concept of a role for the fetal lung in the initiation of parturition is particularly attractive because the fetal lung is the last major organ to mature.
PHASE 2: STIMULATION
Phase 2 involves a progressive cascade of events leading to a common pathway of parturition, and involving uterine contractility, cervical ripening, and decidual/fetal membrane activation. This cascade probably begins with placental production of CRH. Placental CRH synthesis is stimulated by glucocorticoids, in contrast to the inhibitory effect of glucocorticoids on maternal hypothalamic CRH synthesis. Placental CRH enters into the fetal circulation and, in turn, promotes fetal cortisol and DHEA-S production. This positive feedback loop is progressively amplified, thereby driving the process forward from fetal HPA activation to parturition and the placental production of estrogens.
For most of pregnancy, uterine quiescence is maintained by the action of progesterone. At the end of pregnancy in most mammals, maternal progesterone levels fall, and estrogen levels rise. In human and nonhuman primate pregnancies, progesterone and estrogen concentrations continue to rise throughout pregnancy until delivery of the placenta. A functional progesterone withdrawal may occur in women and nonhuman primates by alterations in progesterone receptor (PR) expression. There are two progesterone receptors (PRA and PRB) in the human myometrium. In contrast to PRB, which increases progesterone action, PRA inhibits progesterone action. The ratio of PRA to PRB in the myometrium in labor is increased, which in effect results in a progesterone withdrawal.
Functional progesterone withdrawal results in functional estrogen predominance, in part as a result of the increase in placental estrogen production. The expression of estrogen receptor (ER) isoform, ERα, is normally suppressed by progesterone, but as the expression of PRA increases relative to that of PRB, so does the expression of ERα in the laboring myometrium. The rising expression of ERα facilitates increased estrogen action. Increasing estrogen levels also enhance expression of many estrogen-dependent contraction associated proteins (CAPs), including connexin 43 (gap junctions), oxytocin receptor, prostaglandin receptors, COX-2 (which results in prostaglandin production), and myosin light-chain kinase (MLCK), which stimulate myometrial contractility and labor.
The progressive cascade of biological processes leads to a common pathway of parturition, involving cervical ripening, uterine contractility, and decidual/fetal membrane activation. Cervical ripening is largely mediated by the actions of prostaglandins, uterine contractility by the actions of gap junctions and MLCK, and decidual/fetal membrane activation by the actions of enzymes such as metalloproteinases, which ultimately lead to rupture of the membranes.
PHASE 3: INVOLUTION
During expulsion of the fetus, there is a dramatic increase in the release of maternal oxytocin, which facilitates the initiation of the final phase of labor. Phase 3 involves placental separation and continued uterine contractions. Placental separation occurs by cleavage along the plane of the decidua basalis. Uterine contraction is essential to prevent bleeding from large venous sinuses that are exposed after delivery of the placenta and is primarily affected by oxytocin. This is further supported by oxytocin letdown during early breastfeeding.
To summarize, labor is a release from the state of functional quiescence maintained during pregnancy due, in large part, to the lack of myometrial gap junctions and the actions of progesterone. It is hoped that future research in this important area will further our knowledge and improve our ability to prevent premature labor and delivery, currently the leading cause of perinatal mortality.
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