Endocrinology of Pregnancy and Parturition

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.

Corticotropin-Releasing Hormone

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

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

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.

Estrogens

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.

Androgens

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.

Glucocorticoids

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.

Oxytocin

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

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 F_2α (PGF_2α), prostacyclin, and thromboxane A₂ are synthesized in the endometrium, myometrium, the fetal membranes, decidua, and placenta. PGE₂ and PGF_2α 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 PGF_2α 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 PGF_2α 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, PGF_2α). 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 PGF_2α 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.

Animal Models

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 Human

The process of normal spontaneous human parturition can be divided into four phases.