The Steroid Hormones Of Pregnancy
Steroid hormone production during pregnancy requires cooperation among maternal, fetal and placental organs and enzyme pathways (Fig. 19.1a). The fetus and the placenta each lack key steroidogenic enzymes and would be unable to synthesize certain steroid molecules if they existed in isolation. Interplay among fetus, placenta and the mother are essential to produce the full spectrum of steroidal products necessary for pregnancy maintenance. For example, the fetal adrenal gland has diminished 3β-hydroxysteroid dehydrogenase: Δ4–5 isomerase activity and therefore it secretes large amounts of the progesterone precursors, pregnenolone and dehydroepiandrosterone, and very little progesterone (Chapter 2). Because the fetus can synthesize so very little progesterone directly, it obtains its supplies from the placenta.
Because the syncytiotrophoblast layer of the placenta lacks a key enzyme, it cannot synthesize cholesterol from circulating acetate. To synthesize progesterone, the placenta requires cholesterol or pregnenolone from maternal or fetal sources. The vast majority arises from the maternal system and is transported to the placenta in the form of low density lipoprotein (LDL) cholesterol.
In contrast to the mother and placenta, the fetus has a remarkable ability to rapidly conjugate steroids with sulfates. Sulfation creates less potent steroids with more rapid clearance, characteristics that allow the fetus to be safely exposed to the high levels of circulating steroids seen during pregnancy. The fetal liver can efficiently hydroxylate steroid precursors and thereby provides the placenta with those hydroxylated steroids necessary for estrogen production. The placenta has almost no 17α-hydroxylase or 17, 20 desmolase activity. For this reason, the precursors of the estrogens produced by the placenta must be supplied by the fetal or maternal systems. The placenta exhibits a robust ability to cleave sulfate groups from steroids. Placental sulfatase is integral to the formation of estrogens from fetal sulfated precursors. As the placenta lacks 17-α hydroxylase, all estriol produced during pregnancy arises from 17-α hydroxylated fetal precursors.
The corpus luteum of the ovary supplies progesterone until about 10 weeks’ gestation. This supports pregnancy until placental progesterone production takes over in weeks 7–9 of gestation. The levels of 17α-hydroxyprogesterone produced by the corpus luteum rise in early pregnancy but fall by 10 weeks’ gestation. After that time, placental production of progesterone dominates the maternal system and the placenta exhibits almost no 17α-hydroxylase activity.
Unlike other steroid-producing glands, the placenta lacks the enzymes to form cholesterol from acetate; therefore, progesterone produced by the syncytiotrophoblast is dependent on maternal cholesterol. hCG produced by the placenta supports the synthesis and secretion of progesterone within the placenta. Estrogens may also promote progesterone production by stimulating cholesterol uptake by the placenta and placental enzymatic conversion of cholesterol to pregnenolone. As a result, very large amounts of progesterone are produced and secreted by the placenta into the maternal bloodstream. This progesterone is active locally within the uterus, where it maintains the decidual lining of the uterus and relaxes the smooth muscle cells of the myometrium. It also has peripheral effects upon vascular smooth muscle and other organs that must adapt to the demands of pregnancy (Chapters 20 and 21).
The placenta can efficiently aromatize androgen precursors to estrogens because it expresses abundant amounts of the enzyme aromatase. All three of the major estrogens, estrone (E1), estradiol (E2) and estriol (E3), are produced in the placenta; however, their androgen precursors arise from different sources (Fig. 19.2). Because placental aromatase is so abundant, it is not rate-limiting. Therefore, the relative amounts of each estrogen produced are determined by the amounts of substrate delivered to the placenta. The major androgen precursor for placental estrogen production is dehydroepiandrosterone sulfate (DHEA-S). DHEA-S is an adrenal androgen and the majority supplied to the placenta originates in the maternal adrenal gland. In the placenta, DHEA-S is converted to DHEA by the abundant placental sulfate-cleaving enzyme, sulfatase. Maternal DHEA is then converted to androstenedione, then testosterone and finally to estrone and estradiol (Chapter 2). A very small amount of fetal DHEA-S is also utilized by the placenta to produce estrone and estradiol. However, the majority of fetal DHEA-S is converted to estriol in the placenta. To accomplish this, most of the fetal DHEA-S first undergoes 16-hydroxylation in the fetal liver. When the fetal 16α-OH-DHEA-S reaches the placenta, the placental sulfatase cleaves the sulfate side chain. 16α-OH DHEAis further metabolized and aromatized within the placenta to estriol. Estriol, which is not produced by the human ovary, is a relatively weak estrogen, but when produced at the high levels seen in pregnancy it can have dramatic estrogenic effects. The amount of estriol produced by the placenta far exceeds that of estrone and estradiol, making placental estriol of fetal origin the major placental estrogen.
Like progesterone, most of the estrogen produced by the placenta is found in the maternal compartment (uterus and bloodstream). Unlike its other estrogenic activities, estriol appears to be as effective as estradiol and estrone in increasing uteroplacental blood flow. Its relatively weak estrogenic effects on other organ systems make it highly effective in this single important pregnancy function. Its unique production from a fetal substrate also permits fetal regulation of uteroplacental blood flow. Uteroplacental blood flow is an important determinant of fetal growth and well-being.
Fetal adrenal physiology
By about 9 weeks’ gestation, the fetal adrenal gland has developed an inner fetal zone and a very thin outer definitive zone. The latter will develop into the adrenal cortex in the adult. Approximately 80% of the gland is composed of the inner fetal zone. The fetal adrenal gland functions independently of adrenocorticotropic hormone (ACTH) until nearly 15–16 weeks’ gestation. During this pre-ACTH phase, the fetal adrenal is thought to respond to hCG. After this time, it is control- led by ACTH secreted by the fetal pituitary gland. The fetal adrenal gland increases in size until about 24 weeks’ gestation. It undergoes another impressive growth spurt at 34–35 weeks. 3β-hydroxysteroid dehydrogenase activity is limited in the fetal zone and therefore its major secretory products are DHEA and DHEA-S. These serve as the major substrates for circulating maternal estrogens. In fact, circulating maternal estrogen levels reflect the size of the fetal adrenal. Fetal ACTH control of its adrenals is assured by the presence of high levels of estrogen during pregnancy (Fig. 19.1b). Placental estrogens activate placental 11β-hydroxysteroid dehydrogenase. This in turn metabolizes maternal cortisol, allowing little to reach the fetal circulation.
Maternal adrenal function and salt metabolism
During pregnancy, the zona fasciculata of the maternal adrenal gland increases in size at the expense of the other adrenal cortical zones. In response, maternal glucocorticoid secretion increases, with significant elevations in maternal levels of circulating cortisol. Elevated estrogen levels also drive an increase in the production of cortisol-binding globulin. Still, an increase in the level of circulating free cortisol accompanies the increase in total cortisol. An increase in maternal plasma renin activity and angiotensinogen production results in an increase in plasma aldosterone levels during pregnancy. This results in elevated sodium retention and is partially responsible for the notable increase in maternal vascular volume.