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Endocrinology of Pregnancy and Parturition
Clincal Keys for This Chapter
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The hormonal and nonhormonal changes that occur during pregnancy and parturition are regulated through a physiological mechanism referred to as the fetoplacental unit. A series of hormones and transmitters are produced by each of the components of this unit, and they have multiple effects within and between the fetus, the placenta and the mother.
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The fetal component of the fetoplacental unit plays the major role in the regulation of pregnancy and parturition. Most of the activity in the fetal component takes place in the fetal adrenal gland which is larger than the fetal kidney by mid-gestation. The fetal zone of the fetal adrenal gland primarily secretes androgens during fetal life and these androgens act as precursors for estrogen production in the placenta. The overall role of the fetal adrenal is not completely understood.
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The placental trophoblasts are the source of human chorionic gonadotropin (hCG), which “rescues” the corpus luteum very early in pregnancy. The placenta also produces large amounts of steroid and peptide hormones. Because the placenta lacks the enzyme 17α-hydroxylase, it cannot convert progesterone to estrogen. The placenta instead uses androgens from the fetal adrenal as precursors for the production of estrogens that are needed to maintain the pregnancy. In addition to estrogens, progesterone and the corticosteroid, cortisol, are produced in the placenta. Peptide hormones include human placental lactogen (hPL), corticotropin-releasing hormone (CRH), and prolactin. Other important hormones and transmitters include oxytocin, relaxin, prostaglandins, leukotrienes, and parathyroid hormone–related peptide.
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Maternal adaptation and regulation of pregnancy and parturition start with the secretion of 17-hydroxyprogesterone (17-OHP) from the ovarian corpus luteum. If the maternal ovary is deficient in progesterone production, the pregnancy is likely to miscarry. Placental function assures adequate amounts of estrogen (mostly estriol or E3) to increase uterine blood flow for uterine growth, and progesterone to maintain the quiescent state of the uterus throughout most of the gestational period. The absence of myometrial gap junctions facilitates the action of progesterone.
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Labor (which initiates the parturition process) is a release from the state of functional uterine quiescence maintained during pregnancy. This quiescence is due, in large part, to the lack of gap junctions before the onset of labor and the actions of progesterone. Three additional phases of parturition follow the first phase of quiescence, as follows. Phase 1: activation is initiated by uterine stretch and fetal hypothalamic-pituitary-adrenal (HPA) activity. Phase 2: stimulation most likely begins with placental production of CRH. This phase continues with cervical ripening, uterine contractility, and decidual/fetal membrane activation. Phase 3: involution involves expulsion of the fetus with a dramatic increase in oxytocin release and a decrease in parathyroid hormone–related peptide (PTHrP) expression. This phase also involves placental separation and continued uterine contractions.
Women undergo major endocrinologic and metabolic changes that establish, maintain, and end pregnancy. The aim of these changes is the safe delivery of an infant that can survive outside of the uterus. The maturation of the fetus and the adaptation of the mother are regulated by a variety of hormones and transmitters ( Table 5-1 ). This chapter deals with the properties, functions, and interactions of the most important of these hormonal and nonhormonal substances as they relate to pregnancy and parturition.
TABLE 5-1
Hormones and Transmitters of Pregnancy and Parturition
| Hormone/Transmitter | Source | Function(s) | Clinical Comments |
|---|---|---|---|
| Human chorionic gonadotropin (hCG) | Placental trophoblastic tissue | Prevents regression of (rescues) the corpus luteum of pregnancy; increases T-cells that affect immunity | A likely regulator of a process that provides immune tolerance for the fetus; other trophic activities |
| Human placental lactogen (hPL) | Placenta | Antagonizes maternal glucose use so more is available for the fetus | Low values found in pregnancy loss; normal levels may increase risk of gestational diabetes |
| Corticotropin-releasing hormone (CRH) | Placenta | Stimulates fetal adrenocorticotropic hormone (ACTH) secretion, which allows the fetal adrenal to secrete DHEA-S for progesterone production; CRH may facilitate vasodilation |
Fetal cortisol stimulates placental CRH release and fetal ACTH secretion; elevated levels may predict an increased risk of preterm birth |
| Prolactin | Maternal and fetal (late pregnancy) anterior pituitary glands | Stimulation of postpartum milk production | May play a role in fetal adrenal growth, as well as fluid and electrolyte membrane transfer |
| Progesterone (P4) | Placenta; precursors come from the maternal circulation | Prevents uterine contractions; suppresses gap junction formation | Maintains uterine quiescence |
| 17-Hydroxyprogesterone (17-OHP) | Corpus luteum | Supports early pregnancy until placental production of P4 begins | Corpus luteum function is essential in early pregnancy |
| Estrogens Estriol (E3), estrone (E1), and estradiol (E2) |
Placenta; conversion of androgens (DHEA, DHEA-S) from the fetal adrenal into estrogens | Estriol (E3) is the main estrogen of pregnancy; it increases uterine blood flow and prepares the breast for lactation | Placenta cannot convert progesterone to estrogen; lacks the enzyme 17α-hydroxylase; has role in lung surfactant production |
| Androgens Dehydroandrosterone (DHEA) and its sulfate (DHEA-S) Dihydrotestosterone (DHT) |
During pregnancy, androgens originate mostly in the fetal adrenal cortex | DHEA production is favored, and is a precursor for placental estrogen production | Fetal testis produces testosterone, which is converted to DHT; this is needed for development of male external genitalia; hCG stimulates testosterone production |
| Cortisol | Derived from circulating cholesterol | Plays a major role in the activation of labor by increasing placental release of CRH and prostaglandins | Late in pregnancy, cortisol promotes the production of lung surfactant |
| Oxytocin | Maternal hypothalamus and posterior pituitary | Can cause uterine contractions; possible effects on emotion and well-being | Related to uterine contractions, but not the natural initiation of labor; facilitator of childbirth and breastfeeding |
| Relaxin | Corpus luteum and placenta | Primary function is to promote implantation; also causes uterine relaxation | Too much relaxin can result in a shortened cervix and increased risk of premature labor; too little can interfere with implantation |
| Prostaglandins PGE 2 PGF 2α |
Placental production from arachidonic acid | Thought to play a major role in the initiation of labor | Not true hormones; act at or close to the site of production; prostaglandin synthetase inhibitors can prolong labor |
| Leukotrienes | Placental production from arachidonic acid | Initiate changes in the endometrium that allow for implantation | Not true hormones; act at or close to the site of production |
| Parathyroid hormone–related peptide (PTHrP) | Uterus and other organs | Relaxes the uterus and allows for stretch without contractions | Allows for fetal growth during pregnancy; gene that activates PTHrP is off during parturition |
Fetoplacental Unit
The concept of the fetoplacental unit is based on observations of the interactions between hormones of fetal, placental, and maternal origin. The fetoplacental unit largely controls the endocrinologic 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 in its growth and maturation, and probably also in the events that lead to parturition.
Fetus
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 overall role of the fetal adrenal during fetal growth and maturation is not completely understood.
Placenta
The placenta, which functions as an “extra brain” during pregnancy, is unique because it contains genes from both the mother and father. In addition, it is the source of a brain peptide, corticotropin-releasing hormone (CRH), which has a very important regulatory role in pregnancy. Thus, the placenta produces both steroids 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.
Mother
The mother adapts to pregnancy through major endocrinologic and metabolic changes. The ovarian corpus luteum produces progesterone (mostly 17-hydroxyprogesterone) 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.
Hormones
The fetoplacental unit produces a variety of hormones to support the maturation of the fetus and the adaptation of the mother.
Peptide Hormones
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. Newer immunoassays for hCG are able to accurately measure low levels of hCG based on the entire molecule and not just the beta subunit. 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 may be 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. Early pregnancy is characterized by an increase in regulatory T cells (Tregs), which are known to facilitate maternal immune tolerance of the fetus. Recent animal research has shown that hCG acts as a central regulator of this immune tolerance during pregnancy.
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 CRH is the placenta and it can be measured as early as 12 weeks' 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 capable. 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 of subsequent spontaneous preterm labor.
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