The Protein Hormones Of Pregnancy
The placenta is a very rich source of both protein and steroid hormones, only a few of which are unique to pregnancy (Fig. 18.1). These placental hormones are responsible for almost all the maternal and some of the fetal adaptations to pregnancy.
Human chorionic gonadotropin
Human chorionic gonadotropin (hCG) is a dimeric protein hormone whose structure is closely related to luteinizing hormone (LH) (Chapter 1). It is among the earliest products of the trophoblast cells of the embryo and is necessary to signal the maternal organism that conception has occurred. β-hCG mRNA can be detected in an eight-cell embryo, although intact hCG is not detectable in the maternal blood- stream or urine until 6 days after fertilization. hCG secretion is quantitatively related to the total mass of trophoblast in the placenta. Its concentration in the maternal serum approximately doubles every 2–3 days in early pregnancy; this can be used as a screen to differentiate normal from abnormal pregnancies. Failure of the hCG concentrations to increase appropriately may indicate an abnormal implantation such as an ectopic (tubal) pregnancy or a nonviable intrauterine gestation. Higher than expected levels of hCG are seen with multiple gestations (Chapter 35) and molar pregnancies (Chapter 45).
The major biologic role of hCG is to “rescue” the corpus luteum of the ovary from its programmed demise 12–14 days after ovulation. Because of the close structural relationship of hCG to LH, hCG is able to bind to the LH receptor on luteal cells. hCG can therefore substitute for LH, supporting the corpus luteum when a pregnancy is present. Maintenance of the corpus luteum allows continued secretion of ovarian progesterone after day 14 postovulation and maintenance of the early pregnancy. Surgical removal of the corpus luteum without progesterone supplementation before the 9th menstrual week of pregnancy will result in a pregnancy loss. Administration of an antiprogestin such as RU-486 will have similar results. By 9 weeks’ gestation (7 weeks after conception), the placenta has typically acquired sufficient cellular mass to supply the large amounts of progesterone necessary for pregnancy maintenance. Progesterone production is taken over by the placenta at this point and the corpus luteum could be removed without adverse effect on pregnancy maintenance. At the end of the first trimester, hCG also stimulates the fetal gonads to make the steroid hormones responsible for differentiation of the internal and external genitalia (Chapters 5 and 6).
Many of the hormones produced within the placenta result from a two-cell system that mimics the interactions between the neuroendo- crine hypothalamus and the pituitary gland (Fig. 18.2a). For instance, gonadotropin-releasing hormone (GnRH) can be synthesized and secreted by the cytotrophoblast cells of the placenta. GnRH from the cytotrophoblast stimulates hCG production by the syncytiotrophoblast. As pregnancy progresses and the placenta becomes the major site of progesterone production, hCG’s primary role changes from maintenance of the corpus luteum to maintenance of progesterone production by the syncytiotrophoblast. The serum level of hCG reflects this change by increasing to a maximum at about the 9th or 10th menstrual week of pregnancy and then decreasing to a much lower steady state level for the remainder of the pregnancy.
Human placental lactogen
Human placental lactogen (hPL) is a protein hormone produced exclusively by the placenta. It is structurally related to both prolactin and growth hormone (GH). When the peptide was originally isolated from the placenta, its biologic activity was assessed in animal models, where it has lactogenic activity. Although it was designated as a lactogen, lactogenic activity has not been clearly demonstrated in the human. Instead, hPL appears to function in metabolism (Fig. 18.2b). Its metabolic activities closely mimic those of GH, with which it shares 96% structural homology. Its effects on fat and carbohydrate metabolism include inhibition of peripheral glucose uptake, stimulation of insulin release by the pancreas and an increase in plasma free fatty acids. Prolonged fasting and hypoglycemia increase hPL production. During pregnancy, blood glucose decreases, insulin secretion increases and peripheral insulin resistance is enhanced. These metabolic changes are consistent with the presence of increased GH-like activity, possibly the effects of hPL. Another name for hPL is human chorionic somatomammotropin (hCS).
In theory, the decreased maternal glucose utilization induced by hPL would ensure that a steady supply of glucose is available for fetal utilization. There is growing evidence that hPL is involved in regulating glucose homeostasis in the mother so that she can meet the nutritional demands of the fetus; however, successful pregnancies have been reported in the absence of hPL production by the placenta. In normal pregnancies, hPL production is directly proportional to placental mass and therefore rises steadily throughout pregnancy. At the end of gestation, over 1 g/day of hPL is produced by the placenta. This amount surpasses the production levels of any other protein hormone in either men or women.
Pituitary growth hormone of either maternal or fetal origin is not necessary for normal fetal growth. In fact, anencephalic fetuses lacking a pituitary gland and the offspring of women with GH deficiency will grow normally in utero. The placenta produces its own variant of GH protein, known as placental growth hormone (PGH). PGH is a candidate hormone for regulating fetal growth. The placenta also produces somatotropin release inhibiting factor (SRIF), also known as somatostatin, that appears to affect HPL secretion by the placenta.
The cytotrophoblast cells and the syncytiotrophoblast secrete cor- ticotropin-releasing hormone (CRH), neuropeptide Y (NPY), a CRH secretagogue, pro-opiomelanocortin (POM-C), the precursor to adrenocorticotropic hormone (ACTH) and melanocyte stimulating hormone (MSH). Maternal CRH levels and placental CRH content rise in the last month of pregnancy. Glucocorticoids enhance CRH mRNA production by the placenta, suggesting a positive feed- back system. It is hypothesized that placental CRH and ACTH may be involved in the timing of the onset of parturition. MSH appears to promote maturation of the fetal hypothalamic-pituitary-adrenal axis and has the secondary effect of darkening the maternal skin pigments. MSH induced darkening of the skin on the forehead, nose and cheeks of some pregnant women produces a mask-like appearance known as cholasma.
Maternal production of protein hormones Placental hormones exert dramatic effects on the production and activities of nonplacental maternal protein hormones. For example, placental estrogen production stimulates the production of many hepatic proteins. Among these is thyroid-binding globulin (TBG). The increase in circulating TBG in the pregnant woman leaves less thyroid hormone free to circulate. Because free thyroid hormone exerts central negative feedback, this decrease in free thyroid hormone frees the hypothalamus to release thyroid-releasing hormone (TRH). Maternal pituitary thyroid-stimulating hormone (TSH) secretion increases in response to TRH and the maternal thyroid gland produces enough T3 and T4 to return the circulating levels to normal. Pregnant women therefore have higher levels of TBG, total T3 and T4, but normal amounts of free T3 and T4. This can cause confusion when interpreting thyroid function tests in pregnancy. It also means that pregnant women taking hormone replacement for thyroid gland deficiency often need to increase their dosage to maintain adequate free hormone levels.
Pituitary production of prolactin also increases dramatically as a result of estrogen stimulation in the pregnant woman. The number of lactotrophs in the pituitary gland doubles, thereby almost doubling the size and blood supply of the pituitary gland. This increase in size makes the pituitary gland particularly vulnerable to ischemic damage. Therefore, if postpartum hemorrhage and shock are not promptly treated, pituitary gland failure (Sheehan syndrome) may develop.