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.
Progesterone
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).
Estrogens
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.
