" Has only one amino acid chain.
b hCS was formerly known as human placental lactogen.
chain) of molecular mass 21.5 kDa. hCS has significant structural homology with growth hormone. Little information is available concerning the production and secretion of hCS by the trophoblasts and placenta.
The major biological roles of hCS are not well-described; its effects on the mobilization and metabolism of maternal fat stores have been described. hCS is also an insulin antagonist and in this role is postulated to be involved in the regulation of maternal blood glucose levels to ensure optimal availability of blood glucose to meet the caloric requirements of the fetus. In addition, hCS has been suggested as being one of the contributory agents to the development of diabetic ketoacidosis in pregnant women who have no prior history of diabetes.
Relaxin (RLX) is a small 6-kDa peptide hormone produced by the corpus luteum of the ovary, particularly during the first and second trimesters of pregnancy. Relaxin is a member of a family of peptides structurally related to insulin and insulin-like growth factors. The primary structure of RLX consists of two peptide chains (designated a and /3) of 22 and 31 amino acid residues, respectively. The a- and /3-chains are covalently linked by two disulfide bonds, with an additional intradisulfide link in the a-chain.
In some species (pig, rat), parturition is preceded by a significant increase in relaxin. In these species, relaxin has been shown to play a role in the softening of the fibrous connective tissue at the cervix. However, in human pregnancy, the role of RLX is not clear; re laxin concentrations are lowest in the third trimester and unchanged during parturition.
Oxytocin is a nonapeptide secreted by the neurohypophysis. An extensive discussion of its chemistry and mode of action is presented in Chapter 4. Milk letdown and milk ejection from the mammary tissue are the chief biological responses. There is also some preliminary evidence to support the action of oxytocin on the uterine endometrium at parturition to stimulate its contraction. High concentrations of oxytocin can be detected in fetal blood.
/. Chorionic Proopiomelanocortin
The placenta also produces proopiomelanocortin (POMC; see Chapter 5) peptides; these include ACTH, /3-endorphin, /3-lipotropin, and three forms of dynor-phin. The levels of plasma ACTH increase during pregnancy, presumably because of production by the placenta. The biological roles of POMC and ACTH in pregnancy are not yet known, but it has been suggested that /3-endorphins and other POMC-derived peptides might have some role in fetal response to stress, hypoxia, and parturition.
g. Neuropeptide Y
The 36-amino acid neuropeptide Y (NPY; see Chapter 8) is found in the cytotrophoblast. The levels of NPY rise in the first trimester and remain elevated through parturition; the levels of NPY fall dramatically after delivery. The biological function of NPY in the placenta is not known, although NPH receptors are known to be present in the placenta.
h. Other Peptide Hormones
Evidence, both chemical and immunochemical, has been presented to indicate that human placental tissue produces and secretes human chorionic thyrotropin (an analog of TSH), chorionic ACTH, GnRH- and TRH-releasing hormones, and proopiomelanocortin (see Figure 14-8).
The steroid hormones generated specifically as a consequence of the circumstances of pregnancy are produced in a number of tissues; these include the maternal-fetal placenta, the maternal and fetal adrenals, and the maternal ovaries and liver. The steroids produced at these sites are tabulated in Table 14-3. Figures 2-20, 2-21, and 2-22 and Table 2-6 should also be consulted for additional details concerning steroid metabolism.
There is a changing pattern of production of steroid hormones throughout the trimesters of pregnancy, so that as the fetus differentiates and develops, the fetal adrenals and liver have an increasing responsibility for steroid metabolism. Immediately following conception through weeks 12-13 of the pregnancy, the principal source of progesterone and estrogen is the corpus lu-teum. By week 7 and until parturition, the placenta produces significant quantities of both estrogens (in the forms of 17/3-estradiol, estriol, estrone, and estetrol)
and progesterone. Both the placental and corpus lu-teum production of progesterone is stimulated by hCG.
Since the placenta does not have the complete array of steroid-metabolizing enzymes to convert cholesterol into estradiol, progesterone, or other steroids, during the second and third trimesters both the maternal adrenal cortex and the fetal adrenal cortex serve as major sources of precursors for placental steroidogenesis. In this regard, dehydroepiandrosterone sulfate from the maternal adrenals is converted by the placenta to estrogens. The fetal adrenal cortex becomes enzymatically competent to produce steroids by day 50 of the pregnancy. In this fetal compartment, many of the steroids are sulfate conjugates. The fetal adrenal also assumes major responsibility for the production of C-19 androgens and sulfoconjugated A5 C-21 steroids such as pregnenolone sulfate in the second and third trimesters.
b. Production of Progesterone
Throughout the course of pregnancy there are three principal forms of the C-21 progestins present: progesterone, 16a-hydroxyprogesterone, and 17a-hydroxyprogesterone. Figure 14-9 summarizes their separate pathways of biosynthesis.
Progesterone is produced largely by the corpus lu-teum up to weeks 5-6 of gestation; by week 12 of gestation the placenta becomes the dominant site of biosynthesis. Thus, the plasma level of progesterone rises from 1-2 ng/ ml at conception to over 100 ng/ml by parturition. The placenta contains all of the enzymes required for the conversion of maternally derived cholesterol into progesterone.
17a-Hydroxyprogesterone levels in the plasma rise from 0.5 ng/ml at conception to a plateau of 50-
TABLE 14-3 Steroid Hormones of Pregnancy and Their Sites of Production
Adrenal cortex Cholesterol
Ovaries (corpus luteum)
Progesterone (after 12 weeks) Estriol
Estradiol, estetrol A5-Pregnenolone
Dehydroepiandrosterone sulfate Cortisol
Pregnenolone sulfate 17a-Hydroxypregnenolone sulfate Dehydroepiandrosterone sulfate 16<*-Dehydroepiandrosterone sulfate A5-Pregnenolone sulfate
Cholesterol (fetal source) 16a-Hy droxy progesterone 17a-Hy droxy progesterone Estetrol
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