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Reproductive Endocrinology Center, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, California 94143-0556
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Abstract |
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 Top Abstract I. IntroductionII. DevelopmentIII. RegulationIV. PhysiologyV. SummaryReferences |
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I. Introduction |
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TopAbstractI. IntroductionII. DevelopmentIII. RegulationIV. PhysiologyV. SummaryReferences |
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Development and function of the primate fetal adrenal cortex are distinct from those in other species. During the latter two thirds of gestation in humans and higher primates, the fetal adrenal glands are disproportionately enlarged and exhibit extraordinary growth and steroidogenic activity in a specialized cortical compartment known as the fetal zone (4, 5, 6, 7). As its name implies, the fetal zone exists only during fetal life; it atrophies soon after birth and has no counterpart postnatally. During midgestation, the fetal zone occupies 80–90% of the cortical volume and produces 100–200 mg/day of the androgenic C19 steroid, dehydroepiandrosterone sulfate (DHEA-S), which is quantitatively the principal steroid product of the primate fetal adrenal gland throughout gestation. The primate fetal adrenal cortex also produces cortisol, which promotes the maturation of fetal organ systems, including the lungs, liver, thyroid, and gut, needed for extrauterine life (1). In some species (e.g. sheep, goats, and rabbits), cortisol produced by the fetal adrenals also regulates the timing of parturition (2, 8); however, a similar role in primates is not apparent.
Experiments of nature in humans (e.g. anencephaly) (9, 10, 11) and studies in pregnant rhesus monkeys (12, 13) indicate that ACTH secreted from the fetal pituitary is the principal trophic regulator of the fetal adrenal cortex. However, several observations indicate that ACTH may not be acting directly. During the latter two thirds of gestation, the fetal zone grows rapidly and produces large amounts of steroid even though circulating ACTH concentrations may be decreasing (14). Furthermore, soon after birth the fetal zone rapidly involutes although exposure to ACTH continues. Thus, other factors, possibly specific to the intrauterine environment, appear to play a role in the regulation of fetal adrenal cortical growth and function. Substances produced by the placenta (e.g. CG) have been implicated (10, 15), and peptide growth factors produced locally within the fetal adrenal (16) are thought to influence fetal adrenal cortical growth and function by mediating and/or modulating the tropic actions of ACTH. Specific nuclear receptor transcription factors also appear to be important regulators of adrenal cortical development by influencing early embryonic differentiation of adrenal cortical progenitors and the maintenance of steroidogenic function (17, 18). Thus, regulation of the primate fetal adrenal cortex is a complex process involving the net effect of a cohort of factors that modulate and/or mediate the trophic actions of ACTH.
Our purpose is to review the literature and synthesize the current understanding of the developmental and functional biology of the primate fetal adrenal cortex. In particular, we will discuss the recent literature concerning the role of growth factors and nuclear receptors and factors emanating from the placenta in the regulation of fetal adrenal cortical growth and function. We will also address recent advances in understanding the function of the fetal adrenal cortex in the regulation of fetal development and parturition.
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II. Development |
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TopAbstractI. IntroductionII. DevelopmentIII. RegulationIV. PhysiologyV. SummaryReferences |
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Development of the primate fetal adrenal cortex differs qualitatively
and quantitatively from that of other species and is characterized by
extraordinarily rapid growth, high steroidogenic activity, and a unique
morphological appearance. For much of gestation, the human fetal
adrenal cortex is composed of two morphologically distinct zones: the
fetal zone and the definitive zone (Fig. 1
). The fetal
zone accounts for the bulk (80–90%) of the cortex and is the primary
site of growth and steroidogenesis. The definitive zone (also referred
to as the adult cortex, neocortex, or permanent zone), occupies the
remainder of the cortex and comprises a narrow band of tightly packed
cells surrounding the fetal zone. Excellent studies of the early
embryonic and fetal development of the human adrenal cortex have been
reported (4, 20, 21, 22, 23, 24, 25). The following description is synthesized from
these works.
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By the eighth week of gestation, the mass of cells migrating into the adrenal blastema organize into anastomosing cords and exhibit ultrastructural characteristics consistent with steroidogenic capability. These cells eventually differentiate into large polyhedral cells and become the primordium of the fetal zone. Uotila (22) reported that the definitive zone is derived about a week later when a separate population of cells in the same area of celomic epithelium migrates to the adrenal blastema and surrounds the primordial fetal zone. Although Crowder (23) also proposed that the fetal and definitive zone are derived from separate populations of cells in the celomic epithelium, that study concluded that the anlage of both zones develops simultaneously in the celomic epithelium and enters the adrenal primordium at the same time but in discrete juxtaposed columns. Conversely, Jirasek (4), concluded that both zones are derived from a single progenitor population and that the entire adrenal blastema is initially made up of small primitive epithelial cells. The cells in the center of the adrenal blastema then differentiate into fetal zone cells, whereas the peripheral cells maintain their small blastematous morphology and eventually form the definitive zone. Despite these differences in the dynamics of fetal and definitive zone formation, it is clear that by the eighth week of human pregnancy the fetus acquires a rudimentary but distinct adrenal cortex made up of two zonal compartments.
At around the ninth week of gestation, the adrenal blastema is completely enclosed by the adrenal capsule, which is composed of specialized mesenchymal cells migrating from the area of Bowman’s capsule. At the same time, an extensive network of sinusoidal capillaries develops between the cords of the fetal zone. This vasculature predominates in the central portion of the fetal zone and persists throughout fetal life (26). Consequently, the adrenal cortex is one of the most highly vascularized organs in the primate fetus. Abundant vascularization is likely required to facilitate access of hormonal products to the circulation.
The medulla is absent from the primate fetal adrenal as a discrete structure throughout most of gestation except for small islands of chromaffin cells scattered through the body of the cortex. Only after the involution of the fetal zone during the first postnatal week do the chromaffin elements coalesce around the central vein and begin to form a rudimentary medulla. By the fourth postnatal week, essentially all of the chromaffin cells have clustered in the center of the gland. However, it is not until 12 to 18 months that the medulla becomes adult-like in appearance (23).
B. Fetal adrenal development
After 10–12 weeks of gestation, the morphology of the adrenal
cortex remains relatively constant. By midgestation (16–20 weeks), the
fetal zone clearly dominates and is composed of large (20–50 µm)
eosinophilic cells that exhibit ultrastructural characteristics typical
of steroid-secreting cells (i.e. large amounts of tubular
smooth endoplasmic reticulum, mitochondria with tubulovesicular
cristae, large Golgi complexes, abundant lipid, and numerous dense
bodies). In the outer regions of the fetal zone, the cells are arranged
in tightly packed cords. However, the cells in the central portion are
more widely spaced into a reticular pattern and separated by many
vascular sinusoids. Clusters of immature neuroblasts that will
aggregate eventually into a functional medulla are also present between
the innermost fetal zone cells (26).
The definitive zone is composed of a narrow band of small (10–20 µm) tightly packed basophilic cells that exhibit structural characteristics typical of cells in a proliferative state (i.e. small cytoplasmic volume containing free ribosomes; small, dense mitochondria with lamelliform cristae and scant lipid). Its inner layers form arched cords that send finger-like columns of cells into the outer rim of the fetal zone. Although definitive zone cells are lipid-poor during midgestation, they accumulate some cytoplasmic lipid and begin to resemble steroidogenically active cells with increasing age. By late gestation, the definitive zone cells may be likened to cells of the adult zona glomerulosa (26).
Ultrastructural studies have also demonstrated a third zone between the
fetal and definitive zones, the cells of which have intermediate
characteristics (27). We have referred to this cortical area as the
‘transitional zone’ (28) (Fig. 1
). Studies in our laboratory
(discussed below) indicate that after midgestation, transitional
zone cells may have the capacity to synthesize cortisol and thus be
analogous to cells of the zona fasciculata of the adult adrenal. By the
30th week of gestation, the definitive zone and transitional zone begin
to take on the appearance of the zona glomerulosa and the zona
fasciculata, respectively (19). Thus, by late gestation the fetal
adrenal cortex resembles a rudimentary form of the adult adrenal
cortex.
C. Neonatal adrenal development
Soon after birth, the primate adrenal cortex dramatically
remodels. Keene and Hewer (20) in 1927 reported that during the first 6
weeks of postnatal life "... The whole gland shrinks owing
to the rapid disappearance of the foetal cortex... " The
demise of the fetal zone was thought to occur by necrosis and
hemorrhage. However, more recent studies have suggested that the
necrosis and hemorrhage were probably artifacts related to the cause of
death and time elapsed before tissue fixation. Detailed studies by
Sucheston and Cannon (19) in humans and by McNulty (29) in rhesus
monkeys, demonstrated that the postnatal remodeling of the primate
adrenal cortex involves a complex wave of differentiation such that the
fetal zone atrophies and the zonae glomerulosa and fasciculata develop.
Recent studies by Spencer et al. (30) indicate that fetal
zone remodeling in the human is an apoptotic process.
It has generally been thought that the adult cortical zones develop from the persistent definitive zone. However, there is no evidence of adrenal cortical insufficiency during the perinatal period and the postnatal remodeling process. Thus, it is likely that the nascent adult cortical zones are present and functional before birth. Indeed, morphological studies have identified rudimentary zonae glomerulosa and fasciculata during late gestation (19). This lends support to the notion that the postnatal remodeling of the primate adrenal cortex involves apoptosis of the fetal zone and the simultaneous expansion of preexisting zonae glomerulosa and fasciculata.
D. Growth
Rapid growth of the human fetal adrenal cortex begins at
approximately the 10th week of gestation and continues to term (Fig. 2). The growth is almost entirely due to enlargement of
the fetal zone and, as a consequence, the gland becomes as large as the
fetal kidney by 20 weeks. Between 20 and 30 weeks, the size and weight
of the fetal adrenal gland doubles, achieving a relative size 10- to
20-fold that of the adult adrenal. A further doubling in fetal adrenal
weight occurs after 30 weeks of gestation such that by term the gland
weighs approximately 3–4 g (4, 20).
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Centripetal migration of lipid-containing cells from the definitive to the fetal zone was first reported by Keene and Hewer (20) and later confirmed by Crowder (23). Jirasek (4) described the daughter cells resulting from mitoses in the definitive zone forming cords that invade into the outer layers of the fetal zone. The disparate level of proliferation between the definitive and fetal zones and evidence of centripetal migration lend support to the migration theory of adrenal cortical cytogenesis and suggest that the definitive zone is the germinal/stem-cell compartment from which the inner cortical zones are derived. Thus, cells proliferate in the definitive zone and then migrate inward to form the fetal zone. This concept is supported by studies in the adult rat and mouse showing that mitotic pressure in the periphery of the adrenal cortex causes centripetal migration of cells from the glomerulosa to the inner cortical compartments (33, 34, 35, 36, 37, 38). The adrenal cortical zones therefore appear to be interdependent and derived from a common pool of cells in the periphery. Thus, growth of the fetal zone not only involves limited proliferation of existing fetal zone cells but also the differentiation and hypertrophy of inwardly migrating cells from the definitive zone.
Apoptosis also may occur in the developing human fetal adrenal cortex.
By morphological criteria, Jirasek (4) detected evidence of cellular
apoptosis primarily in the central portions of the fetal zone and
similarly, Spencer et al. (30) using a technique that
identifies apoptotic cell in situ based on the detection of
increased accumulation of cleaved DNA found that the labeling index of
apoptotic nuclei was greater in the central areas of the fetal zone
than in the definitive zone. In contrast, Albrecht et al.
(39) could not detect evidence of apoptosis during early-, mid-, and
late-gestation in the baboon fetal adrenal. However, in that study
apotosis was assessed by measuring that extent to which genomic DNA
extracted from whole baboon fetal adrenals was cleaved into specific
oligonucleosomes (the DNA-laddering method). The low number of
apoptotic cells detected by Spencer et al. (30) in the
central areas of the cortex probably would not contribute enough
cleaved DNA for detection in the laddering assay. Thus, the primate
(and most likely other species’) fetal adrenal cortex is a dynamic
organ in which cells proliferate in the periphery, migrate
centripetally, differentiate to form the specialized cortical
compartments (and possibly continue to proliferate within the
compartments), and then undergo senescence when they reach the center
of the cortex (Fig. 3). The size of the fetal adrenal
cortex and its constituent zones represents the net effect of forces
that modulate these dynamic parameters of growth.
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1. Ontogeny of steroidogenic activity.
Morphological analyses
indicate that the human fetal adrenal cortex has steroidogenic
capabilities early in gestation. This is first seen at 6–8 weeks when
the cells in the adrenal blastema differentiate and acquire
steroidogenic characteristics (23, 27). In cord blood from human
fetuses between 10 and 20 weeks of gestation, concentrations of
cortisol (40, 41, 42), corticosterone, and aldosterone (40) are greater in
the umbilical artery than in the umbilical vein, indicating that these
steroids are produced by the fetus. Perfusion of previable human
fetuses with radiolabeled progesterone showed that the fetus has the
capacity to produce cortisol from progesterone as early as the 16th
week of gestation (43, 44, 45). Small amounts of aldosterone have been
detected in human amniotic fluid at 9 weeks of gestation (46); however,
it is not certain whether it originates from the maternal or fetal
adrenals at this stage of gestation. At 20 weeks, low levels of
aldosterone can be produced by the previable human fetus perfused with
radiolabeled corticosterone (47, 48).
Estrogens, particularly estriol, in the maternal circulation are indicative of fetal adrenal steroidogenic activity. The placenta, which is the principal source of estrogens during pregnancy, utilizes exogenous androgens supplied to an increasing extent by the fetal adrenal cortex and to a decreasing extent by the maternal adrenal cortex as gestation proceeds (49), as precursors for estrogen synthesis (see Section IV). Low levels of estriol can first be detected in the maternal circulation at the eighth week of gestation, indicating that DHEA-S is being produced by the fetus at this stage. At around the 12th week of gestation, estriol concentrations in the maternal circulation rapidly increase approximately 100-fold (50). This increase coincides with the initiation of fetal zone hypertrophy and ACTH secretion by the fetal pituitary gland (51). In contrast, estriol levels are markedly decreased and sometimes undetectable in women bearing anencephalic fetuses (49, 52), if fetal death occurs (49), or in placental sulfatase deficiency (53, 54). These observations indicate that the human fetal adrenal cortex produces DHEA-S beginning at around 8–10 weeks of gestation in sufficient quantities to effect increases in maternal estrogen levels. Production of DHEA-S by the fetal adrenal cortex continues for the remainder of pregnancy and during the second and third trimesters increases considerably such that by term the human fetal adrenal produces around 200 mg/day (49).
A major unanswered question regarding function of the primate fetal adrenal cortex is the stage of gestation at which the fetal adrenal cortex begins to produce cortisol. Observations of infants with congenital adrenal hyperplasia (CAH) suggest that the fetal adrenal cortex produces cortisol early in gestation. The most common form of CAH is caused by a deficiency of the 21-hydroxylase enzyme (P450c21) (55) and, as a result, the fetal adrenal cortex cannot synthesize adequate amounts of cortisol. The reduced glucocorticoid negative feedback to the hypothalamus and pituitary leads to a compensatory increase in ACTH secretion, the trophic actions of which cause hyperplasia of the fetal adrenal cortex. The elevated ACTH also increases production of DHEA-S, as biosynthesis of this C19 steroid is not affected by P450c21 deficiency. Consequently, the primary manifestations of P450c21 deficiency are those of androgen excess, which are first expressed in utero, resulting in the masculinization of the external genitalia in female fetuses. Inasmuch as differentiation of external genitalia in both sexes begins at week 7 of gestation and is complete by week 10 (Ref. 56 for review), these effects of androgen excess in P450c21 deficiency most likely occur before week 10 of gestation. These observations imply that, under normal circumstances, the fetal adrenal produces cortisol early in gestation which exerts negative feedback control on fetal pituitary ACTH secretion. Moreover, these observations indicate that the human fetal pituitary produces ACTH before 10 weeks of gestation, which regulates fetal adrenal steroidogenesis. Immunohistochemical studies demonstrate the presence of corticotropes in the human fetal pituitary at about this time (51). It is conceivable that cortisol is produced by the fetal adrenal early in gestation to suppress ACTH secretion and prevent overproduction of adrenal androgens during the androgen-sensitive phase of sexual differentiation (particularly in females).
Studies of human fetal adrenal tissue in vitro have provided
more direct evidence of its steroidogenic capability early in
gestation. Incubations with labeled acetate (57) or progesterone (58, 59) and superfusion of human fetal adrenal tissue in vitro
with media containing ACTH (60) indicate that the human fetal adrenal
cortex is responsive to ACTH and produces corticoids and DHEA-S as
early as the tenth week of gestation. The pattern of glucocorticoid
production by the primate fetal adrenal cortex during the rest of
pregnancy is not clear. Expression of key steroid-metabolizing enzymes
suggests that the human fetal adrenal cortex does not produce cortisol
de novo from cholesterol until around week 30 of gestation
(see below). However, this does not preclude the possibility that
cortisol is produced utilizing progesterone as precursor early in
gestation. MacNaughton et al. (45) infused radiolabeled
progesterone into previable human fetuses between 16 and 18 weeks of
gestation and found that it was metabolized to cortisol and that the
rate of metabolism was increased by ACTH. The abundant amount of
progesterone produced by the placenta provides the fetal adrenal cortex
with a potential source of 
4-C21 steroid
substrate for cortisol and aldosterone production even though the
adrenal may not be sufficiently mature to produce these steroids
de novo.
Mineralocorticoid production by the primate fetal adrenal cortex is very low early in gestation but increases during the third trimester. At term, 80% of the aldosterone in human and rhesus monkey fetal blood appears to originate from the fetal adrenal (47, 61). In 18- to 21-week human fetal adrenals, the mineralocorticoid metabolic pathway is localized to the definitive zone, although its activity is very low and unresponsive to secretagogues (62). The angiotensin-II receptors, AT1 and AT2, are present on human fetal adrenal cortical cells after 16 weeks of gestation (63). The AT2 receptor is localized mainly on definitive zone cells, whereas the AT1 receptor is detectable to a lesser extent in cells from both fetal and definitive zones. Thus, during the first and second trimesters, the ability of the human fetal adrenal cortex to synthesize mineralocorticoids is minimal even though the cells express angiotensin-II receptors.
2. Functional zonation and ontogeny of steroidogenic enzyme
expression.
The contributions of the fetal and definitive zones to
human fetal adrenal steroidogenic potential have been studied in
vitro using tissue perfusion and cell culture techniques (60, 64, 65). In response to ACTH, fetal zone cells produce mainly DHEA-S and
little cortisol, whereas definitive zone cells produce mainly
corticoids and little DHEA-S. It was concluded that, during
midgestation, the fetal zone is the site of DHEA-S synthesis and that
the definitive zone is the site of cortisol synthesis (60).
Another approach to assessing the steroidogenic potential of adrenal
cortical zones has been to determine which steroidogenic enzymes are
expressed by the cells of each zone. As the fate of pregnenolone
metabolism is determined by the branch-point enzymes cytochrome P450
17
hydroxylase/17,20 lyase (P450c17) and 3ß-hydroxysteroid
dehydrogenase/4–5 isomerase (3ßHSD), the
steroidogenic potential of cells may be inferred by the pattern of
expression of these two enzymes. Thus, if both enzymes are expressed,
the cells have the potential for cortisol production, whereas if
3ßHSD is expressed and P450c17 is lacking, steroidogenesis would be
directed toward mineralocorticoid synthesis, and conversely, if P450c17
is expressed and 3ßHSD is lacking, steroidogenesis would be limited
to the 5 pathway and be directed toward DHEA-S
synthesis. Thus, expression of 3ßHSD is particularly relevant for the
de novo synthesis of mineralocorticoids and glucocorticoids,
and expression of P450c17 is essential for C19 steroid
(e.g., DHEA) biosynthesis.
The metabolism of radiolabeled progesterone to cortisol by previable
human fetuses indicates that the fetal adrenal cortex expresses the
enzymes downstream from 3ßHSD [i.e. P450c17,
21-hydroxylase (P450c21), and 11ß-hydroxylase (P450c11)] needed for
cortisol synthesis early in gestation. However, studies in the late
gestation fetal rhesus monkey (66) and baboon (67) show that the
conversion of placental progesterone to cortisol by the fetus is
minimal. Expression of 3ßHSD by the primate fetal adrenal cortex is
therefore the critical step in the metabolism of pregnenolone, as it
confers on cells the ability to convert 5-3ß
hydroxysteroids to 4–3-ketosteroids essential for
mineralocorticoid and glucocorticoid production. Data regarding the
expression of 3ßHSD by the human fetal adrenal cortex early in
gestation are conflicting. Goldman et al. (68) first
indicated that 3ßHSD activity is present in the human fetal adrenal
cortex as early as 12 weeks of gestation and that it is localized to
the definitive zone. However, the specificity of their assay is
uncertain. Voutilainen et al. (69) examined 3ßHSD
expression using the highly sensitive technique of RT-PCR and could not
detect mRNA encoding 3ßHSD (either type I or type II) in human fetal
adrenals between 12 and 22 weeks of gestation but could detect its
expression after 22 weeks. In contrast, Parker et al. (70),
using immunohistochemistry, detected 3ßHSD staining exclusively in
the definitive zone between 11 and 15 weeks of gestation. However,
between 15 and 24 weeks, 3ßHSD expression in the human fetal adrenal
cortex decreased to undetectable levels and after 24 weeks was again
detectable in the definitive zone. Thus, although masculinization of
the female fetus with P450c21 deficiency indicates glucocorticoid
production by the fetal adrenal cortex before 10 weeks of gestation,
evidence of its de novo synthesis (based on 3ßHSD
expression) is uncertain.
The steroidogenic potential of each cortical zone in the primate fetal adrenal also has been examined by determining the in situ pattern of cholesterol side chain cleavage (P450 scc) and P450c17 and 3ßHSD expression during midgestation (16–24 weeks) in the human and late-gestation rhesus monkey fetal adrenal by in situ hybridization and immunocytochemistry (28). In those studies, the late-gestation fetal rhesus monkey was used as a model for the late-gestation human fetus, as the growth, structure, and function of its adrenals closely resemble those of the human (26). Moderate levels of P450scc expression were detected in all cortical zones of the human and rhesus monkey fetal adrenals at all gestational ages. Consistent with other studies (70, 71, 72), 3ßHSD was not expressed in any cortical zone in midgestation, i.e. 16–22 weeks. At 22–24 weeks, 3ßHSD staining was detected in the outermost layer of definitive zone cells. Dupont et al. (72) and Parker et al. (70) showed that by 28 weeks, this staining extended inward to encompass all of the definitive and transitional zone cells (cells at the interface between the fetal and definitive zones). At no time in gestation was 3ßHSD expression detected in the fetal zone. This ontogenetic pattern of 3ßHSD expression suggests that the human fetal adrenal cortex cannot synthesize cortisol de novo between 16 and 22 weeks because it cannot convert pregnenolone to progesterone due to the lack of 3ßHSD.
Interestingly, expression of P450c17, although highly abundant in the transitional and fetal zones, was lacking in the definitive zone at all gestational ages (28, 63, 71). The lack of P450c17 in the definitive zone was unexpected and implies that these cells cannot synthesize cortisol in vivo either de novo or from progesterone. Expression of P450c17 was highest in the transitional zone cells which, late in gestation, also expressed 3ßHSD. Therefore, the transitional zone may be the site of de novo glucocorticoid production by the human fetal adrenal cortex and may acquire this capability late in gestation when its cells begin to express 3ßHSD.
Recently, Coulter and Jaffe (C. L. Coulter and R. B. Jaffe, unpublished
data) examined the ontogenetic localization of P450c21 and P450c11
expression in the human (13–24 weeks) and rhesus monkey (109 days to
term) fetal adrenal cortex using immunohistochemistry. In the human and
rhesus fetal adrenals at all gestational ages, P450c21 immunoreactive
staining was detected in all of the cortical zones. Staining for
P450c21 was less intense in the fetal zone than in the definitive and
transitional zones and was increased in adrenals from rhesus monkey
fetuses treated with metyrapone, which was administered to increase
endogenous ACTH secretion. P450c11 peptide was detected with a
polyclonal antibody that also detects P450c11AS (aldosterone synthase).
Staining for P450c11 was detected early in gestation only in the
transitional zone. Later in gestation, P450c11 staining was found in
the definitive and transitional zones and was increased by metyrapone
treatment. These data suggest differential regulation of P450c21 and
P450c11 expression in the primate fetal adrenal cortex. The presence of
P450c21 throughout gestation in all cortical zones suggests that this
is not a rate-limiting step in steroidogenesis. The colocalization of
P450c21 and P450c11 in the transitional zone further implicates this
cortical compartment as the site of de novo glucocorticoid
synthesis. The onset of P450c11 in the definitive zone late in
gestation indicates that this zone does not have the capacity to
synthesize aldosterone until near term. The onset of 3ßHSD expression
in definitive and transitional zone cells late in gestation (73),
coupled with the presence of P450c21 and P450c11, suggests that these
cells acquire the capacity to synthesize mineralocorticoids and
glucocorticoids, respectively. Thus, the ontogeny of 3ßHSD expression
in specific zones allows the functional differentiation of the primate
fetal adrenal cortex. Studies in the fetal rhesus monkey in
vivo suggest that the ontogeny of 3ßHSD in the fetal adrenal
cortical zones is regulated by ACTH (73) (Fig. 4).
Future studies of the ontogeny and localization of P450c21 and P450c11
in the human fetal adrenal cortex will provide valuable information and
should help resolve the issue of whether cortisol is produced de
novo or derived from progesterone early in gestation.
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5-steroid
production, particularly DHEA-S (Fig. 5).
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). Fetal zone cells can be induced to synthesize
cortisol de novo if they are exposed to a sufficiently high
concentration of ACTH. Thus, it is possible that, although fetal zone
cells exhibit some differentiation when placed under culture
conditions, their expression of 3ßHSD in vitro may be due
to exposure to supraphysiological concentrations of ACTH.
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Ligand-induced up-regulation of ACTH receptor expression may be an important adaptive process directed toward optimizing adrenal responsiveness to ACTH in concert with physiological requirements for hypothalamic-pituitary-adrenal activity. This is particularly important for the physiological response to stress and the maintenance of metabolic homeostasis in which the adrenals play a pivotal role. Inhibition, by ligand-induced receptor down-regulation, of mechanisms involved in the response to stress would be detrimental, whereas enhancement by ligand-induced up-regulation would be advantageous by permitting a more efficient and rapid response. Whether such a process is advantageous for fetal development is not clear. It is possible that this up-regulation is part of the process by which the fetus prepares for responding to the stresses of delivery and the perinatal period. Clearly, an efficient and functionally responsive fetal adrenal cortex is essential for survival during the perinatal period.
In summary, functional development of the primate fetal adrenal cortex
is a complex process involving the temporal and spatial expression of
specific steroid-metabolizing enzymes and changes in responsiveness to
ACTH. Early in gestation (8–12 weeks), the glands appear to be capable
of cortisol and DHEA-S synthesis. However, it is not clear whether
cortisol is produced from progesterone or whether the full complement
of enzymes necessary for de novo cortisol synthesis are
expressed. Later in gestation, the ontogenetic expression of 3ßHSD,
first in the definitive zone and subsequently in the transitional zone,
appears to reflect the functional maturation of these zones as analogs
of the zonae glomerulosa and fasciculata, respectively. Throughout
gestation, the fetal zone expresses high levels of P450c17 but lacks
3ßHSD, consistent with its continued production of DHEA-S (Fig. 4).
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III. Regulation |
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TopAbstractI. IntroductionII. DevelopmentIII. RegulationIV. PhysiologyV. SummaryReferences |
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A. The fetal pituitary and ACTH
It is not unexpected that the extraordinary growth and
steroidogenic activity of the primate fetal adrenal cortex are
dependent on an intact fetal pituitary gland as it produces ACTH, the
primary tropic regulator of the adrenal cortex, postnatally. Several
observations firmly establish the pivotal role of ACTH secreted by the
fetal pituitary in primate adrenal cortical regulation: 1) Disruption
of hypothalamic-pituitary function in the human fetus (e.g.
in anencephalics or associated with maternal glucocorticoid treatment)
results in failure of the fetal zone to develop beyond the size
attained at approximately the 15th week of gestation (9, 10, 88, 89)
and is associated with dramatically reduced estrogen concentrations in
the maternal circulation (49, 90). 2) Administration of dexamethasone
to normal human fetuses in utero reduces maternal estrogen
levels (91), and dexamethasone treatment of pregnant rhesus monkeys
during late gestation causes atrophy of the fetal zone and a marked
decrease in maternal plasma estradiol and estrone levels and fetal
plasma cortisol levels (12, 13). Similarly, experimental anencephaly
(produced by fetal decapitation at around day 80 of gestation;
term = 165 ± 5 days) in the fetal rhesus monkey also caused
marked atrophy of the fetal adrenal cortex and decreased maternal
estrogen levels (12, 92); 3) In utero administration of ACTH
to normal human fetuses (91) increases maternal estrogen levels and in
anencephalics (89), partially restores adrenal size. 4) In congenital
adrenal hyperplasia, the fetal zone is markedly enlarged, and adrenal
androgen concentrations are elevated to virilizing levels (93). 5) In
fetal rhesus monkeys, administration of ACTH increases fetal cortisol
and maternal estrone concentrations (12), and increased endogenous ACTH
secretion (induced by metyrapone treatment) increases fetal adrenal
cortical growth and advances functional maturation, as assessed by
3ßHSD expression (Refs 32 and 73 and see Fig. 4).
The mechanism by which ACTH regulates fetal adrenal cortical growth and function is not clearly understood. The actions of ACTH are mediated via its interaction with specific receptors on the cell surface of adrenal cortical cells. A human ACTH receptor has been cloned and characterized (94). This receptor is coupled to heterotrimeric guanine nucleotide-binding proteins that activate adenylate cyclase leading to an increase in intracellular cAMP that activates protein kinase A and initiates the cascade of intracellular signaling events. Consequently, the actions of ACTH can be mimicked by cAMP analogs (e.g. 8-bromo-cAMP) or substances that increase adenylate cyclase activity (e.g. forskolin). The signaling events downstream from the activation of protein kinase A have not been characterized. The contribution of other signaling pathways in adrenal cortical steroidogenic activity has been reviewed by Pepe and Albrecht (87).
Although the principal regulator of fetal adrenal cortical development appears to be ACTH, several observations support the concept that human fetal adrenal growth and function also are influenced by factors that act independently from, or in conjunction with, ACTH. These lines of evidence are as follows: 1) human fetal adrenal cortical growth and steroidogenic activity are maximal during mid- to late gestation even though circulating ACTH concentrations in the fetus appear to be decreasing (14); 2) before 10–15 weeks of gestation, adrenal development in anencephalic fetuses (presumably with markedly reduced ACTH) is normal, but thereafter the fetal zone fails to develop and does not exhibit its characteristic growth and steroidogenic activity (9, 10), indicating that early in gestation fetal zone growth and function are independent of ACTH; 3) in contrast, the definitive zone appears normal in anencephalic fetuses despite the absence of ACTH stimulation (9, 10, 89), suggesting that its growth is not dependent on ACTH at any stage in gestation, although its functional maturation appears to be regulated by ACTH (73); 4) the fetal zone rapidly involutes once the newborn is delivered and separated from the placenta despite relatively unchanged exposure to ACTH (29), indicating that fetal zone growth and function are maintained by a factor(s) specific to intrauterine life, and 5) ACTH is not a growth factor per se and is not a mitogen for adrenal cortical cells in vitro (95, 96). However, it stimulates proliferation of adrenal cortical cells in vivo, suggesting that its proliferative actions may be mediated by growth factor(s).
B. Growth factors
Specific growth factors, acting in an autocrine and/or paracrine
fashion, are likely candidates as mediators and/or modulators of the
trophic actions of ACTH on the primate fetal adrenal cortex. This
notion is not without precedent, as several classic growth-promoting
hormones are known to act through the stimulation of local
autocrine/paracrine growth factors. Studies of growth factor
involvement in the regulation of fetal adrenal development have
addressed: 1) the effects of growth factors on proliferation and
function of cultured fetal adrenal cortical cells; 2) growth factor
expression by the fetal adrenals, and 3) the regulation of this growth
factor expression by the fetal adrenals.
1. Basic fibroblast growth factor (bFGF).
Basic FGF is a
peptide mitogen that stimulates the proliferation of mesodermal- and
neurectodermal-derived cells and also is a potent angiogenic and
neurotrophic agent. It is a member of a family of related peptides that
include acidic FGF, FGF-6, FGF-7, keratinocyte growth factor,
hst, and int (97). Four different FGF receptors
have been identified, each with intrinsic tyrosine kinase activity.
Differential mRNA splicing results in multiple isoforms of each
receptor (98).
The mitogenic effects of bFGF on adrenal cortical cells was first observed in the Y-1 mouse adrenal cortical cell line (99). Gospodarowicz et al. (100) and Hornsby and Gill (101) subsequently reported that bFGF is a potent mitogen for primary cultures of bovine adult adrenal cortical cells, and both groups suggested that it mediates the growth-stimulatory actions of ACTH in vivo. Basic FGF was later purified from adult bovine adrenals (102) and shown to be synthesized by cultured bovine adrenal cortical cells (103). More recently, bFGF has been shown to be involved in the compensatory adrenal growth response to unilateral adrenalectomy in the rat (104).
Crickard et al. (105) examined the effect of bFGF on the proliferation of fetal and definitive zone cells from midgestation human adrenals. Proliferation of both cell types was stimulated by bFGF, a finding that was later confirmed by Hornsby et al. (106). Interestingly, bFGF elicited a greater proliferative response (relative to control) in definitive zone cells (4-fold increase) than in fetal zone cells (2-fold increase). This suggests that the definitive zone may be more sensitive than the fetal zone to the mitogenic actions of bFGF and that bFGF may preferentially influence definitive zone development in vivo.
In light of its potent mitogenic actions on human fetal adrenal cortical cells, we hypothesized that bFGF is a local mediator of the stimulatory effects of ACTH (16). Therefore, we determined whether the human fetal adrenals express bFGF and, if so, whether this expression is regulated by ACTH. Basic FGF bioactivity and mRNA were detected in protein and total RNA extracts, respectively, from midgestation human fetal adrenals. Messenger RNA encoding bFGF also was detected in cultured human fetal adrenal cortical cells and interestingly, its abundance was increased 2- to 3-fold by ACTH. Thus, bFGF, a potent mitogen for human fetal adrenal cortical cells, is expressed by these cells and regulated by ACTH. Therefore, bFGF may be an important mediator of ACTH action in human fetal adrenal development. It is of interest that bFGF also is a potent angiogenic factor (107) and that the adrenal cortex, particularly the fetal zone, is one of the most highly vascularized organs in the human fetus (26, 27). It is possible that bFGF not only affects the growth of the fetal adrenal cortex but also its vascularization and may be an important local mediator of these events in response to ACTH. In this regard, our preliminary data also indicate that vascular endothelial growth factor, a potent stimulator of angiogenesis, may promote vascularization of the developing adrenal cortex (108).
2. Epidermal growth factor (EGF).
The effects of EGF on
primary adrenal cortical cell cultures was first examined by
Gospodarowicz et al. (100) who reasoned that because EGF is
a potent mitogen for granulosa cells (109), and granulosa and adrenal
cortical cells are derived from the same embryonic germ layer,
i.e. the celomic epithelium, it also may be mitogenic for
adrenal cortical cells. Their studies of cultured adult bovine adrenal
cortical cells, however, revealed that EGF was not mitogenic, a finding
that was later confirmed by Hornsby et al. (106). In
contrast to these negative results in bovine adrenal cortical cells,
Crickard et al. (105) found EGF to be a potent mitogen for
cultured fetal and definitive zone cells from midgestation human fetal
adrenals, a finding that was also confirmed by Hornsby et
al. (106). Interestingly, as with their response to bFGF,
definitive zone cells were more responsive to the proliferative action
of EGF than were fetal zone cells, suggesting that EGF (like bFGF)
preferentially regulates definitive zone growth. High-affinity
surface-binding sites, characteristic of EGF receptors, were detected
in both cell types (105). These findings imply that the human fetal
adrenal cortex is a target for EGF (or other EGF receptor ligands).
The effect of EGF treatment on fetal adrenal development in the late gestation rhesus monkey in vivo has been examined (110). Treatment with EGF significantly increased adrenal weight and the width of the definitive zone. Interestingly, Coulter et al. (110) found that cell density in the definitive zone of EGF-treated animals was less than that of controls, indicating that definitive zone enlargement in EGF-treated animals was due to cellular hypertrophy rather than hyperplasia. This finding indicates that EGF stimulated hypertrophy and not hyperplasia of definitive zone cells, an unexpected effect given the potent mitogenic action of EGF on definitive zone cells in vitro. Thus, in vivo EGF may not be a direct mitogen for definitive zone cells but instead may affect its growth by modulating the hypothalamic-pituitary axis and possibly increasing ACTH secretion and/or ACTH responsiveness. EGF has been shown to affect the fetal hypothalamic-pituitary-adrenal axis in other species: in fetal sheep, EGF stimulates secretion of cortisol from the fetal adrenals, corticotropin releasing hormone (CRH) from the hypothalamus, and ACTH from the pituitary (111, 112). Therefore, EGF could affect fetal adrenal development indirectly by modulating the fetal hypothalamic-pituitary axis. This also is suggested by the finding of Coulter et al. (110) that EGF treatment in vivo increased the amount of 3ßHSD protein in definitive and transitional zone cells of fetal rhesus monkeys. Similar effects were reported in fetal rhesus monkeys in which endogenous ACTH secretion was increased by administration of metyrapone (32). Thus, in addition to its potential direct effect on adrenal cortical cell proliferation, EGF also may modulate adrenal growth and functional maturation by affecting the hypothalamic-pituitary-adrenal axis.
EGF is a member of a large family of peptide growth factors that
includes transforming growth factor- (TGF), vaccinia virus growth
factor, amphiregulin, heparin-binding EGF-like factor, and betacellulin
(113). Each of these peptides shares considerable sequence homology
with EGF and, because they all bind to the EGF receptor, have similar
biological activities. Therefore, studies of EGF action on adrenal
development must take into account the multiple ligands for the EGF
receptor and that, although EGF may have effects on cultured cells, it
may not be a biologically significant ligand in vivo. Sasano
et al. (114), aware of this issue, examined the expression
of EGF, TGF, and the EGF receptor in human adult adrenals. They
found that TGF and the EGF receptor were expressed, whereas EGF was
not, and concluded that TGF is the significant locally produced
ligand for the EGF receptor in adult human adrenals. Similar
experiments in human fetal adrenal glands, in which the expression of
EGF, TGF, and the EGF receptor were examined, yielded similar
findings (115). Immunostaining for TGF was greatest in the fetal and
transitional zones and less intense in the definitive zone.
Immunostaining for the EGF receptor was detected in each of the
cortical zones with equal intensity. These data indicate that TGF
may be the predominant locally produced ligand for the EGF receptor in
the developing human fetal adrenal cortex. These observations indicate
that activation of the EGF receptor on human fetal adrenal cortical
cells may be an important component in the regulation of fetal adrenal
development.
3. Insulin-like growth factors I and II (IGF-I and IGF-II).
IGF-I and IGF-II affect growth and function in a wide variety of cell
types and can act as autocrine, paracrine, or endocrine factors (116).
IGF-I (formerly known as somatomedin-C) mediates many of the
somatotropic actions of GH (117). Although the role of IGF-II is less
defined, it is thought to be involved in the regulation of fetal
development because its circulating and tissue levels are highest
during fetal life and decrease postnatally (118). Two IGF receptors,
designated type I and type II, have been identified (119). The type I
receptor is structurally related to the insulin receptor and binds both
IGF-I and IGF-II with high affinity and insulin with lower affinity.
The type II receptor, also known as the mannose-6-phosphate receptor,
binds IGF-II with high affinity but will not bind IGF-I or insulin.
Most of the known actions of IGF-I and -II appear to be mediated via
activation of the type I receptor. Effects mediated via the type II
receptor are not clearly understood, although this receptor is known to
be involved in targeting lysosomal enzymes. The IGF system is made more
complex by the presence of six high-affinity IGF-binding proteins that
associate with the IGF peptides and modulate their biological activity
(120).
The IGF peptides and their receptors have been identified in normal and neoplastic adrenals (121). Growth and differentiated function in several steroidogenic cell types, including granulosa (122, 123), Leydig (124, 125), and adrenal cortical cells (126), are modulated by IGFs. In adult bovine (127) and fetal ovine (128) adrenal cortical cells, IGF-I increases proliferation and enhances the steroidogenic responsiveness to ACTH. IGF-I augments responsiveness of adult bovine adrenal cortical cells to ACTH by increasing ACTH receptors (127). Similar findings were reported by Pham-Huu-Trung et al. (129), who showed that IGF-I modulates steroidogenesis in cultured human adult adrenal cortical cells by enhancing responsiveness to ACTH and the activity of key steroidogenic enzymes, including P450c17. These effects of IGF-I on adrenal cortical cells were most likely mediated via the type I receptor, which has been identified in bovine (126) and human (121, 130, 131) adrenal cortical cells. Penhoat et al. (132) showed that IGF-I is synthesized by adult bovine adrenal cortical cells and that its secretion is enhanced by ACTH, suggesting that it may be a local paracrine/autocrine mediator of ACTH action.
The role of the IGFs in human fetal adrenal development has also been examined. Han et al. (133, 134) studied IGF-I and IGF-II expression in a variety of midgestation human fetal tissues and showed that, consistent with other species, IGF-II is quantitatively the predominant IGF expressed during fetal life. In the fetal adrenals, abundance of mRNA encoding IGF-II was high (second only to the liver), whereas mRNA encoding IGF-I was low. Ilvesmäki et al. (135), using RT-PCR analysis of total RNA extracted from whole adrenals, demonstrated that all of the components of the IGF system (i.e. IGFs, receptors, and binding proteins) are expressed by human fetal adrenals. Interestingly, Han et al. (133), using in situ hybridization analysis, found that mRNAs encoding the IGFs were generally restricted to mesenchymal cells, and in the adrenals were detected only in the capsule. These findings led Han et al. to hypothesize that IGFs produced by the mesenchymal component regulates the growth of associated epithelial elements.
Expression of IGF-I and IGF-II in cultured cortical cells from midgestation human fetal adrenals was first examined by Voutilainen and Miller (136) who found that the high level of IGF-II expression reported by Han et al. (133) in vivo also was present in vitro and could be stimulated by ACTH and factors that increase intracellular cAMP, a finding that we later confirmed (137). This effect of ACTH is inconsistent with IGF-II expression by capsular fibroblasts as suggested by Han et al. (133), insasmuch as fibroblasts are not known to be responsive to ACTH, and their presence in the cell culture preparations was minimal. Instead, the data suggest that IGF-II was expressed by the ACTH-responsive cortical cells. In light of this, we reexamined the localization and regulation of IGF-I and IGF-II expression in midgestation human fetal adrenals (137).
In situ hybridization analysis revealed that IGF-II is expressed by all cortical cells in relatively high abundance, whereas IGF-I is only detectable in the adrenal capsule. Similarly, in cultured human fetal adrenal cortical cells, mRNA encoding IGF-II is highly abundant in the cortical cells and not present in the contaminating fibroblasts, and its abundance in cortical cells is markedly up-regulated by ACTH. In contrast, IGF-I mRNA was not detected in cultured fetal adrenal cortical cells and could not be stimulated with ACTH. These findings recently have been confirmed in the fetal rhesus monkey in vivo in which endogenous ACTH secretion was increased by administration of metyrapone (32). Adrenals of metyrapone-treated fetuses were larger than controls and expressed higher levels of IGF-II but not IGF-I. Taken together, these data strongly implicate IGF-II as an important local regulator of fetal adrenal development and a possible mediator of at least some of the trophic actions of ACTH. Interestingly, cultured adrenal cortical cells from a 6-week human neonate responded to ACTH with increased cortisol production but failed to express IGF-II (138), suggesting that expression of IGF-II by the human adrenal cortex and its regulation by ACTH are unique to fetal life.
The role of the IGFs in human fetal adrenal development was further characterized in studies of their effects on the growth and function of cultured human fetal adrenal cortical cells (137). Both IGF-I and IGF-II are specific mitogens for human fetal adrenal cortical cells. Interestingly, the IGFs act cooperatively with bFGF and EGF, other known mitogens for human fetal adrenal cortical cells (see above), resulting in an additive effect on cell proliferation. That both IGF-I and IGF-II stimulated proliferation in an almost equipotent fashion suggests that their mitogenic actions are mediated through a common receptor, most likely the type-I IGF receptor. In other cell types for which IGF-II is a mitogen, its actions have been found to be mediated via the type-I IGF receptor (139, 140).
In conjunction with its mitogenic activity, IGF-II also affects the
differentiated function of human fetal adrenal cortical cells. In
cultured fetal zone cells, IGF-II augments ACTH-stimulated cortisol and
DHEA-S production (Fig. 7) and ACTH-stimulated
expression of the steroidogenic enzymes P450scc, P450c17, and 3ßHSD
(74, 141) (Fig. 8). As with its mitogenic actions, the
effects of IGF-II on steroid production were mimicked by IGF-I, again
suggesting that the actions of both peptides were mediated by the
type-I IGF receptor. Both IGF-I and IGF-II directly up-regulated basal
expression of P450c17 as assessed by mRNA abundance, but did not affect
basal expression of P450scc or 3ßHSD (Fig. 8). A similar effect of
IGFs on P450c17 activity and expression has been reported in human
adult adrenal cortical cells (129, 142). The increased P450c17 activity
suggests that IGFs may be important regulators of adrenal androgen
production. Activation of the type-I IGF receptor by either IGF-I
(postnatally) or IGF-II (prenatally) may directly augment adrenal
androgen synthetic capacity by augmenting P450c17 expression and
activity. This may be an important mechanism by which adrenal androgen
production is regulated during fetal and postnatal life. Interestingly,
the onset of adrenarche coincides with an increase in circulating IGF-I
(143).
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), indicating that their stimulatory effects on ACTH
responsiveness were exerted at some point distal to ACTH receptor
binding and activation.
4. Activin/inhibins.
Activin and inhibin are homodimeric
(ßA-ßA, ßB-ßB, or ßA-ßB) and heterodimeric (-ßA or
-ßB) glycoproteins, respectively, which are structurally related
to other members of the TGFß family of peptides. Both inhibin and
activin originally were isolated from follicular fluid based on their
ability to modulate FSH secretion from the pituitary (145). Inhibin
suppresses, while activin stimulates, FSH secretion. It is now apparent
that activin’s actions extend beyond the pituitary-gonadal axis to
affect many key biological functions. The amino acid sequence of
activin is strongly conserved between species and is closely related to
that of TGFß, mullerian inhibiting substance, fly decapentaplegic
complex, and bone morphogenesis proteins, all of which are regulators
of development and differentiation of a variety of tissues. Activin may
subserve different functions in the organism depending on the stage of
development. For example, activin induces mesoderm development in
Xenopus during early embryogenesis (146), whereas later in
life it appears to be a significant regulator of ovarian
folliculogenesis (147). A family of activin receptors has been
characterized according to subunit structure. These include the type-I
activin receptor and two homologous type-II receptors (IIA and IIB)
(148).
Activin appears to play a role in the regulation of adrenal cortical
development and function. This is not unexpected as activin has
profound effects on the growth and function of granulosa cells (149),
which originate from the same germ layer as adrenal cortical cells. The
subunits of activin and inhibin (, ßA and ßB) have been
identified in the adrenal glands of the adult rat (150) and the fetal
and adult sheep (151). Interestingly, inhibin knockout mice develop
adrenal tumors, suggesting that inhibin acts as a tumor suppressor gene
in adrenal cortical cells (152). Activin/inhibin subunit localization,
as well as the mitogenic and steroidogenic actions of activin and
inhibin in human fetal and adult adrenals, has been examined (153, 154). Each of the activin/inhibin subunit proteins and their mRNAs were
detected in fetal and adult adrenals by immunohistochemistry. In
midgestation fetal adrenals, specific immunostaining for the
subunits was localized in a scattered pattern in both the fetal and
definitive zones, whereas specific staining for intact activin-A
(ßA-ßA homodimer) was detected predominantly in the definitive and
transitional zones. In cultured fetal adrenal cortical cells, ACTH
stimulated secretion of immunoreactive -subunit. This suggests that
ACTH stimulates inhibin production by fetal adrenal cortical cells, as
the -subunit is only present in the inhibin molecule. ACTH enhances
the abundance of mRNAs encoding the - and ßA-subunits, but not the
ßB-subunit, in cultured fetal adrenal cortical cells. Thus, during
midgestation, the human fetal adrenals express each of the
activin/inhibin subunits and appear to produce immunoreactive activin-A
in the definitive and transitional zones. ACTH stimulates expression of
the - and ßA-subunits, suggesting that fetal adrenal production of
activin and inhibin is under trophic hormone regulation.
In cultured human luteinizing granulosa cells activin stimulates proliferation and steroidogenesis, whereas inhibin has no effect (149). In contrast to its mitogenic affects on granulosa cells, recombinant human activin-A inhibits proliferation of fetal zone cells and, at the same time, increases ACTH-stimulated cortisol production (153, 154). Activin has no effect on DHEA-S production by fetal zone cells or growth and steroidogenesis in definitive zone or adult adrenal cortical cells. Recombinant human inhibin has no effect on proliferation or function of any of the adrenal cortical cell types. Thus, activin acts directly and specifically on fetal zone cells to inhibit their rate of growth and enhance their capacity for cortisol production in response to ACTH. Activin may inhibit fetal zone cell growth by stimulating cellular apoptosis and therefore may be involved in the postnatal demise of the fetal zone, a process involving apoptosis (30). In addition, activin may coordinately stimulate the differentiation of other fetal zone cells into a cortisol-producing phenotype.
5. TGFß.
TGFß is the prototypical peptide of a large
family of growth factor proteins including activin, inhibin, mullerian
inhibiting substance, bone morphogenic protein, and several closely
related proteins designated TGFß2, TGFß3, TGFß4, and TGFß5
(155). Specific receptors for TGFß have been identified on almost all
mammalian cells. The effect of TGFß is variable and appears to be
dependent on the cell type. In general, TGFß stimulates proliferation
of cells of mesenchymal origin and inhibits proliferation of cells of
epithelial or neurectodermal origin (156). TGFß also modulates the
differentiated function of cells and, in particular, has marked effects
on the function of steroid-producing cells. In adult bovine and ovine
adrenal cortical cells, TGFß inhibits basal and ACTH-stimulated
cortisol and agonist-stimulated aldosterone production (157, 158, 159, 160) and
reduces ACTH receptor binding (161). TGFß is produced by, and
interacts with, specific receptors on adult bovine adrenal cortical
cells (162), suggesting that it acts as an intraadrenal
autocrine/paracrine factor.
Several studies have indicated that TGFß is involved in the regulation of human fetal adrenal development. Riopel et al. (163) investigated the effects of TGFß on growth and function of cultured fetal zone cells and found that it significantly inhibits fetal zone cell proliferation but had no effect on steroidogenesis. Subsequently, Spencer et al. (154) confirmed these inhibitory effects of TGFß on fetal zone cell proliferation. Parker et al. (164) later reported that TGFß also inhibits proliferation of definitive zone cells and, in a more detailed study of the effects of TGFß on fetal adrenal steroid production, Stankovic et al. (165) found that both basal and ACTH-, forskolin-, and cAMP-stimulated DHEA-S and cortisol production and expression of P450c17 by fetal and definitive zone cells were inhibited by TGFß. They also showed that TGFß binds to specific sites on human fetal adrenal cortical cells and that these binding sites are regulated by ACTH (166). Lebrethon et al. (167) reported similar findings and, in addition, showed that TGFß has no effects on ACTH receptor and P450scc expression but enhances ACTH-stimulated expression of 3ßHSD, an intriguing finding in light of its inhibitory effects on steroid production. Thus, TGFß inhibits proliferation and steroid production by fetal and definitive zone cells, likely via interaction with specific cell surface-binding sites. Whether TGFß is expressed by human fetal adrenal cortical cells is uncertain. Taken together, these data indicate that TGFß-related peptides (particularly TGFß and activin) are significant negative regulators of human fetal adrenal growth and may play an important role in balancing the positive effects of other growth factors during adrenal development.
C. Nuclear receptors/transcription factors
Nuclear receptors are essential elements in cellular regulation as
they mediate the link between an extracellular signal and the
transcriptional response (Ref. 168 for review). Examples of well
characterized nuclear receptors for which the ligand is known include
the steroid hormone receptors, thyroid hormone receptor, retinoic acid
receptor, and vitamin D receptor. Each of these proteins, when bound to
its cognate ligand, acts on specific sequences of DNA (response
elements) to either promote or inhibit transcription of target genes.
Many transcription factors that share sequence homology (especially in
the DNA- and ligand-binding domains) with classical nuclear receptors
have been identified, but their ligands have not been identified. These
are referred to as "orphan" nuclear receptors. Two of these,
steroidogenic factor-1 (SF-1) and DAX-I, appear to play major roles in
adrenal development and function.
SF-1 is a transcription factor that regulates the expression of genes encoding steroidogenic enzymes [Refs. 169169 and 170170 and see review by Parker and Schimmer (170a)170A in this issue]. Consensus-binding sites for SF-1 have been identified in the promoter regions of genes for most steroidogenic enzymes. In the mouse, SF-1 is expressed in all steroidogenic tissues, including the adrenal gland. Interestingly, SF-1 also is expressed in the embryonic anlage of steroidogenic cells before their acquisition of a steroidogenic phenotype, suggesting that it is involved in the early embryonic development of steroidogenic tissues. To examine the role of SF-1, Luo et al. (18) performed targeted disruption of the Ftz-F1 gene, which encodes SF-1, in intact mice. SF-1 null mice had normal survival in utero but died by postnatal day 8 due to severe adrenal insufficiency. These animals lacked adrenal glands and gonads, and all animals (male and female) had female internal reproductive organs. These findings demonstrate the essential role of SF-1 in the embryonic differentiation of steroidogenic tissues, in particular the embryonic development of the adrenal cortex. Thus, the role of SF-1 in mice extends beyond the regulation of steroidogenic enzyme expression and includes the regulation of fundamental events in adrenal and gonadal differentiation. A similar role of SF-1 in the regulation of adrenal development in humans and higher primates is likely but presently is unproven. Several studies have demonstrated SF-1 expression in human steroidogenic tissues, and a growing body of literature demonstrates a role for SF-1 in the regulation of the genes for human steroidogenic enzymes [see review by Parker and Schimmer (170a)170A in this issue].
Another putative transcription factor (based on its structural homology to other transcription factors) that appears to be an important regulator of adrenal development is DAX-1. Mutations in the DAX-1 gene are responsible for X-linked adrenal hypoplasia congenita (AHC), an inherited disorder in humans that is characterized by hypoplasia of the fetal adrenal glands with absence of the definitive zone and the structural disorganization of the fetal zone (Refs. 171–173 and Ref. 17 for review). The DAX-1 gene was identified by positional cloning and derives its name from its proximity to the dosage-sensitive sex reversal locus and the AHC locus on the X chromosome (173). Like SF-1, DAX-1 also is a member of the nuclear receptor superfamily and as its ligand is not yet known, is considered an orphan nuclear receptor (17). DAX-1 is expressed in the human adrenal gland and testis and, to a lesser extent, in the ovary. Abundance of mRNA encoding DAX-1 is much lower in the adult adrenal than in the fetal adrenal (173), possibly reflecting its more important role in fetal adrenal development. The tissue distribution of DAX-1 expression is similar to that for SF-1 (18, 169, 174), suggesting that these two factors may be coregulators of steroidogenic tissue development and function. Interestingly, putative SF-1 response elements have been identified in the 5'-flanking region of the human DAX-1 (175, 176) gene, suggesting that SF-1 is involved in the regulation of DAX-1 expression and that SF-1 is proximal to DAX-1 in the regulatory cascade. The complete absence of adrenals and gonads associated with SF-1 deficiency, but not with DAX-1 deficiency, suggests that SF-1 is absolutely required for adrenal and gonadal development, whereas the requirement for DAX-1 is partial; DAX-1 appears to be required for the development of the definitive zone but not the fetal zone. The molecular mechanism underlying the actions of DAX-1 are not yet fully characterized.
D. Placental factors
The rapid disappearance of the fetal zone when the newborn and
placenta separate at birth suggests that substances produced by the
placenta play a role in fetal zone development and/or maintenance. The
human placenta produces a large variety of hormones and growth factors,
including EGF (177), bFGF (178), and IGF-I and -II (179), which may
influence fetal adrenal growth and function. However, the roles of
these factors in vivo as endocrine regulators of adrenal
development are uncertain.
1. Human CG (hCG).
Placental production of CG appears to be
unique to primate species and is thought to act primarily as a
luteotropin to ensure maintenance of the corpus luteum and its
production of progesterone during the early stages of pregnancy before
the onset of placental progesterone synthesis. In humans, hCG
production peaks at around the 10th week of gestation and gradually
declines thereafter, reaching a nadir of around 20 IU/ml in the
maternal plasma at 17–20 weeks (180). The involvement of hCG in the
regulation of human fetal adrenal development was first proposed by
Lanman (181). Studies by Lauritzen and Lehmann (182) showed that
administration of hCG to human infants during the first week of
postnatal life (when fetal zone remnants persist) significantly
increases urinary excretion of DHEA, suggesting that it may regulate
steroid production by the fetal zone. Interestingly, there was no
concomitant rise in 17-hydroxycorticosteroids in response to hCG,
whereas in response to ACTH both DHEA and corticosteroid levels
increased. Moreover, Lauritzen and Lehmann found that the excretion of
DHEA in response to hCG was greater in premature infants than in
infants born at term. Based on those data, they proposed that hCG is an
adrenocorticotrophic hormone in the human fetus and that it regulates
the supply of fetal adrenal DHEA-S as precursor for placental estrogen
production. Similar results were obtained by Jaffe et
al. (6) who found that hCG sustained DHEA-S production by the
rhesus monkey adrenal gland when administered during the first
postpartum month. Consistent with these in vivo
findings, Pabon et al. (183) recently demonstrated that
the zona reticularis of the human adult adrenal cortex (which may be
analogous to the fetal zone) expresses the hCG receptor. In contrast,
hCG had no effect on fetal adrenal steroid production when administered
to human anencephalic (89) or rhesus monkey fetuses during midgestation
(12) probably because the fetal adrenal was already maximally
stimulated. Several studies have examined the effects of hCG on
cultured fetal adrenal cortical cells. Serón-Ferré
et al. (15), using superfusion techniques on fetal zone
tissue derived from human fetuses between 12 and 17 weeks of gestation,
found that DHEA-S production increased significantly when hCG was added
to the perfusing medium. Lehmann and Lauritzen (184) also found that
hCG increased the production of DHEA by slices of human fetal adrenal
tissue obtained from 14- to 22-week abortuses. Interestingly,
Abu-Hakima et al. (185) found that hCG obtained from a
commercial source stimulated DHEA-S production by cultured fetal zone
cells, whereas hCG obtained from the NIH was without effect. They
suggested that the effect seen with the less pure commercial hCG was
due to contaminants in the preparation. However, the robust stimulation
of fetal zone DHEA-S production by hCG reported by
Serón-Ferré et al. (15) was obtained using
NIH hCG (preparation CR-21). These inconsistent and conflicting data
have not yet been resolved, and consequently the role of hCG in primate
fetal adrenal development remains uncertain.
2. Placental CRH and ACTH.
The human placenta produces CRH,
which has identical immunoreactivity and bioactivity to that produced
by the hypothalamus (186, 187, 188, 189, 190, 191, 192, 193, 194). Interestingly, immunoassayable and
bioassayable ACTH activity also has been detected in human placental
tissue and dispersed trophoblasts (195), and cultured human placental
trophoblastic cells synthesize a high molecular weight protein with
physicochemical similarities to POMC (196). Placental CRH can stimulate
production of POMC and some of its derivatives, including ACTH, MSH,
and ß-endorphin in syncytiotrophoblast cells (194). Thus, it is
possible that CRH produced by syncytio- and cytotrophoblast (189)
stimulates the production of POMC-derived peptides, including ACTH from
the syncytiotrophoblast, which then can influence the fetal adrenal
cortex. Although the extent to which placental ACTH contributes to the
regulation of the fetal adrenal cortex is not known, it would appear
that it is not sufficient to maintain fetal adrenal growth and function
in anencephalics, suggesting that its role in the regulation of fetal
adrenal development is minor. It is more likely that placental CRH
influences the fetal adrenal cortex by modulating the fetal
pituitary-adrenal axis. Placental CRH is secreted into the fetal
circulation resulting in elevated CRH levels in the fetus throughout
gestation (197, 198). Thus, CRH produced by the placenta may modulate
fetal adrenal growth and function. Other physiological roles of
placental CRH are discussed below.
3. Indirect effect of placental glucocorticoid metabolism.
Based on a series of studies in the baboon, Pepe and Albrecht (Refs. 87
and 199 for review) proposed that the placenta, via its capacity to
metabolize glucocorticoids of maternal origin, influences ACTH
secretion by the fetal pituitary and therefore indirectly affects fetal
adrenal development and function. Studies in late gestation humans and
rhesus monkeys showed that although maternal cortisol freely traverses
the placenta, it is efficiently oxidized to cortisone, a less active
glucocorticoid, by the placenta before it can gain access to the fetal
circulation (200, 201, 202, 203, 204). Thus, the placenta can protect the fetus from
the relatively high maternal cortisol concentrations. Pepe and Albrecht
(205) examined the metabolism of maternal cortisol by the baboon
placenta in vivo at various times in gestation and found
that, as with the human near term, cortisol is preferentially oxidized
to cortisone. However, during midgestation they found that the
reduction of cortisone to cortisol was substantial and exceeded the
oxidation of cortisol to cortisone. They proposed that during
midgestation, the baboon placenta permits maternal cortisol to enter
the fetal circulation. The maternal cortisol then can act on the fetal
hypothalamus and pituitary to suppresses ACTH secretion. These
investigators proposed that factors other than ACTH (possibly CG)
maintain fetal adrenal cortical growth and function during the period
when maternal glucocorticoids suppress ACTH production by the fetal
pituitary. As pregnancy proceeds, the placental metabolism of maternal
cortisol becomes oxidative, leading to decreased cortisol
concentrations in the fetal circulation and a concomitant rise in ACTH
secretion by the fetal pituitary. The increased ACTH then can stimulate
growth of, and DHEA-S production by, the fetal adrenal cortex (Ref. 199
for review).
4. Placental estrogens.
Interestingly, in the baboon,
oxidation of cortisol to cortisone by the placenta is induced by
estrogen (206, 207). As placental estrogens are derived from DHEA-S,
this represents a positive feedback loop whereby further increases in
placental estrogens lead to increased conversion of cortisol to
cortisone, decreasing circulating cortisol in the fetus and leading to
increased secretion of ACTH by the fetal pituitary. This, in turn,
could stimulate increased DHEA-S production by the fetal adrenal
cortex, providing more substrate for placental estrogen formation. The
increased ACTH eventually could promote functional maturation of
definitive and transitional zones and the ability to synthesize
cortisol de novo. The production of cortisol by the fetal
adrenal suppresses ACTH secretion by the fetal pituitary and
effectively interrupts the loop. This intriguing hypothesis is
supported by an extensive amount of data, and Pepe and Albrecht (Refs.
87 and 199 for review) have proposed that this mechanism may underlie
the rapid growth and high level of DHEA-S production by the primate
fetal adrenal cortex during midgestation.
Estrogens also directly influence steroid production by primate fetal adrenal cortical cells. Several studies have shown that estradiol suppresses ACTH-stimulated cortisol and augments ACTH-stimulated DHEA-S production by human fetal adrenal cortical cells (141, 208, 209, 210). Fujieda et al. (210) postulated that placental estrogens influence fetal zone function by inhibiting 3ßHSD expression and proposed that ACTH and estradiol interact to cause fetal zone cells to exhibit their characteristic steroidogenic phenotype. However, although estradiol inhibited cortisol production, it did not inhibit the expression of P450scc, P450c17, or 3ßHSD (141). Hirst et al. (211) showed that the fetal zone of midgestation rhesus monkeys does not express estrogen receptors, suggesting that any effects of estrogens on fetal zone function are not mediated via classic estrogen receptor interactions. These data indicate that effects of estradiol on fetal zone steroidogenesis are exerted at the level of the activity of steroidogenic enzymes rather than their gene transcription, and that although estradiol restores fetal zone phenotype with respect to cortisol synthesis, it does not inhibit expression of 3ßHSD.
In contrast to the stimulatory effects of estrogen on DHEA-S production by cultured midgestation human fetal adrenal cortical cells in response to ACTH, Pepe and Albrecht and colleagues (212, 213, 214) have demonstrated a negative feedback loop in the baboon whereby placental estrogens inhibit DHEA production by the fetal adrenal cortex. Interestingly, this attenuation of DHEA production by estrogen occurred at midgestation but not near term in vitro (213) and in vivo (214). These investigators proposed that estrogen down-regulates DHEA-S production by the fetal adrenal cortex to maintain a physiologically normal balance of estrogen production during primate pregnancy (Ref. 199 for review).
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IV. Physiology |
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TopAbstractI. IntroductionII. DevelopmentIII. RegulationIV. PhysiologyV. SummaryReferences |
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A. Placental estrogen formation
The primate placenta has a high level of aromatase activity and
produces large amounts of estrogens (216). Studies in the 1950s showed
that, although radiolabeled cholesterol administered to pregnant women
is converted to estrogens by the placenta, human placental tissue
in vitro does not produce estrogens de novo from
acetate or cholesterol and cannot convert pregnenolone or progesterone
into C19 steroids because it lacks the P450c17 enzyme
(Refs. 217–219 for review). Thus, the estrogen synthetic pathway in
the primate placenta is incomplete. The involvement of the fetus in
placental estrogen production was first demonstrated by Cassmer (220),
who found that maternal estrogens decreased sharply when the umbilical
cord was cut, whereas progesterone, the other major steroid produced by
the placenta, was unchanged until the placenta was delivered.
Involvement of the fetal adrenal cortex in placental estrogen
production was first suggested by Fransden and Stakemann (52) who found
markedly reduced estrogen concentrations in women bearing anencephalic
fetuses. Siiteri and MacDonald (49), Bolté et al.
(221), and Baulieu and Dray (222) subsequently demonstrated that the
human placenta produces estrogens by the aromatization of
C19 precursors, particularly DHEA-S and its 16-hydroxylated
metabolite produced by the fetal liver and adrenal cortex. Thus, the
primate placenta is capable of converting C19 steroids to
estrogens but cannot produce C19 steroids from pregnenolone
or progesterone because it lacks the P450c17 enzyme. In contrast, the
fetal adrenal cortex expresses high levels of P450c17 and produces
large amounts of the C19 steroid DHEA-S. Siiteri and
MacDonald (49) estimated DHEA-S production by the fetal adrenal during
the third trimester to be around 200 mg/day. The combination of these
two incomplete steroidogenic pathways in these two disparate organs
results in a complete estrogen-synthesizing system. Thus, one of the
physiological functions of the primate fetal adrenal cortex is to
provide C19 substrate to the placenta for the formation of
estrogens. This strategy for estrogen formation in pregnancy is unique
to primate species and is accomplished by the ‘feto-placental unit’
(223).
The principal placental estrogen of human pregnancy is estriol.
Inasmuch as the placenta lacks the 16-hydroxylase enzyme, it can only
produce estriol from 16-hydroxylated C19 steroid precursor
(223). Most of the DHEA-S produced by the fetal zone is converted to
16-hydroxy-DHEA-S by the fetal liver and to a lesser extent within
the adrenal itself (224). In the placenta, the sulfatase enzyme removes
the sulfate moiety from DHEA-S and 16-hydroxy DHEA-S producing DHEA
and 16-hydroxy DHEA, respectively, which are then aromatized to
estradiol, estrone, and estriol after further metabolism and
19-hydroxylation.
In other species, the fetal adrenal cortex also influences placental estrogen production. As with the human placenta, the sheep placenta lacks P450c17 for most of gestation and produces estrogens (mainly as sulfoconjugates) primarily from androstenedione supplied by the fetal adrenal cortex. Late in gestation, the prenatal rise in cortisol secretion by the sheep fetal adrenals induces increased expression of P450c17 in the placenta, which results in the conversion of progesterone to androstenedione and subsequently to estrone and estradiol. The consequence of this is that during the final days before parturition in sheep, placental production of progesterone declines as its conversion to androstenedione and estrogen increases (Refs. 2 and 3 for review). In most species, an increase in the estrogen/progesterone ratio occurs at the end of pregnancy (225). In general, progesterone maintains pregnancy by sustaining uterine quiescence, whereas estrogens stimulate events necessary for parturition, e.g. formation of myometrial gap junction, cervical effacement and dilatation, and uterine contractions (Ref. 199 for review). A rise in estrogens and a decrease in progesterone at the end of pregnancy therefore are requisite for parturition in most species. In primates, the placenta lacks P450c17 throughout gestation; therefore, progesterone production does not decline at the end of pregnancy as it does in sheep. However, toward the end of pregnancy, increased DHEA-S production by the fetal adrenal cortex results in increased substrate available to the placenta for estrogen production and a rise in maternal estrogen levels. Unlike the sheep, maternal estrogen concentrations in the pregnant woman (226), rhesus monkey (12), and baboon (227) rise gradually over several weeks prepartum. The physiological roles of estrogens in primate pregnancy are diverse (Ref. 199 for review) and beyond the scope of this review; however, it is clear that the fetal adrenal cortex is essential for the production of placental estrogens.
B. Timing of parturition and fetal maturation
The pioneering work of Liggins and colleagues (Refs. 2 and 3 for
review) in sheep first demonstrated that increased activity of the
fetal hypothalamic-pituitary-adrenal axis triggers the initiation of
parturition and stimulates the maturation of the fetal organ systems
essential for extrauterine life. In this species, increased secretion
of cortisol from the fetal adrenal glands during the final week of
pregnancy initiates a cascade of events that culminates in the birth of
a viable neonate. In most mammalian species, including humans, cortisol
also stimulates events associated with preparation for extrauterine
life, e.g. surfactant production by the fetal lungs,
activity of enzyme systems in the fetal gut, retina, pancreas, thyroid,
and brain, and deposition of glycogen in the fetal liver (Refs. 1 and
228 for review). As in the sheep, the primate fetal adrenal cortex must
produce cortisol de novo toward the end of gestation to
ensure fetal maturation and neonatal competence. Clearly, perinatal
survival is dependent on the timely initiation of labor when organ
systems necessary for extrauterine life are sufficiently mature to
allow the newborn to live outside of the uterus and independent of the
placenta. Thus, in a number of species, regulation of fetal maturation
and the timing of parturition are controlled by a single hormone,
cortisol, produced by the fetal adrenals, which appears to coordinate
these processes such that fetal maturation proceeds appropriately
before parturition.
The discoveries by Liggins and colleagues in sheep caused excitement among clinicians seeking to understand the physiological basis for the timing of parturition and to develop strategies to deal with the problems of preterm labor in humans. However, it was soon realized that fundamental differences exist between sheep and humans with regard to the regulation of parturition and that, although fetal adrenal cortisol clearly orchestrates the initiation of parturition in sheep, a similar role for cortisol in primates was not apparent.
In anencephalics and infants with congenital abnormalities that prevent glucocorticoid synthesis, pregnancy is not significantly prolonged, on average, although labor occurs over a wider time interval (10, 89, 229). Similarly, adrenalectomy (230) or experimental anencephaly (92) of fetal rhesus monkeys does not prevent parturition but increases the window of time in gestation during which birth occurs. Treatment of rhesus monkey fetuses with dexamethasone does not lead to premature induction of parturition, as it does in sheep, but instead results in prolonged pregnancy (231). As glucocorticoid treatment inhibits ACTH production by the fetal pituitary leading to a decrease in DHEA-S production and suppression of the feto-placental unit, these findings implicate the feto-placental unit in the regulation of primate parturition. Interestingly, fetectomy of the rhesus monkey at midgestation results in delivery of the placenta postterm (232) and alters the rhythm of uterine activity (233). Recently, Nathanielsz and colleagues (234) infused androstenedione, which is readily aromatized by the placenta to estrogen, into pregnant rhesus monkeys late in gestation to assess the effect of augmented placental estrogen synthesis on parturition. Androstenedione infusion increased maternal estrogen and nocturnal oxytocin concentrations and induced cervical dilation and normal parturition. These investigators proposed that, in primates, androgen produced by the fetal adrenals as a source of aromatizable substrate for estrogen synthesis by the placenta is the link between the fetus and mother in the initiation of parturition. However, studies in the baboon have provided conflicting data. Albrecht et al. (235) found that fetectomy in baboons does not prolong gestation of the placenta. Interestingly, administration of estradiol prevented placental delivery and prolonged gestation in fetectomized animals, indicating that in this species the feto-placental unit may actually inhibit parturition. Moreover, human aromatase deficiency does not appear to be associated with abnormal length of gestation (236), although as Mecenas et al. (234) point out, the patient with aromatase deficiency was treated frequently with tocolytic agents between 24 and 35 weeks, and it is unclear whether membrane rupture was spontaneous or induced. Based on this literature, the role of the feto-placental unit in the regulation of primate (especially human) parturition is unclear.
Studies of CRH production by the primate placenta have led to novel
theories regarding the mechanism by which the feto-placental unit is
involved in the regulation of parturition. A role for placental CRH in
the regulation of the fetal hypothalamic-pituitary-adrenal axis and
parturition was suspected when it was found that concentrations of CRH
in the fetal (197, 237, 238) and maternal (197, 237, 239, 240)
peripheral circulation and abundance of mRNA encoding CRH in the human
placenta (189) increase sharply from 28 weeks of gestation until
delivery. Interestingly, Majzoub and colleagues (241, 242) found that,
unlike its effects on the hypothalamic CRH production, glucocorticoid
increases CRH expression by the human placenta. The marked increase of
CRH expression and maternal circulating concentrations at the end of
gestation, and the capacity of glucocorticoids to enhance placental CRH
expression, led these investigators to propose that the rise in
placental CRH that precedes parturition could result from the rise in
fetal glucocorticoids that occurs at this time. The increase in
placental CRH may stimulate, via stimulation of fetal pituitary ACTH
(243, 244, 245), a further rise in fetal glucocorticoids, completing a
positive feedback loop that would be terminated by delivery. They also
postulated that environmental stresses may stimulate fetal
hypothalamic, as well as placental, CRH production, leading to
increases in fetal ACTH production and activation of the positive
feedback loop (Fig. 9). Subsequent studies showing that
CRH receptors are present in the myometrium and fetal membranes (246, 247) and that CRH stimulates the release of prostaglandins from human
decidua and amnion in vitro (248) and can potentiate the
action of oxytocin and prostaglandin F2 in
vitro (249, 250) and in vivo (251) provide further
circumstantial evidence that placental CRH may be directly involved in
the regulation of human parturition by increasing myometrial
contractility associated with labor.
|
), concomitant stimulation of fetal cortisol and
DHEA by placental CRH would couple the glucocorticoid effects on fetal
organ maturation with the timing of parturition which, as they note, is
of obvious benefit for postnatal survival. McLean et al (240) recently proposed that placental CRH is associated with a ‘placental clock,’ which is active beginning at least by the 16th week of pregnancy, and which participates in the determination of the length of pregnancy and the timing of parturition. They found that concentrations of CRH in the maternal circulation, presumably secreted by the placenta, are predictive of the subsequent length of gestation. Maternal plasma CRH concentrations were predictive of those women who were destined to have normal term, preterm, or postterm delivery. The CRH curve in women who delivered preterm was shifted to the left by a magnitude of 6 weeks, which was equivalent to the degree of prematurity later observed at delivery in this group. Conversely, in women who delivered postterm, the CRH curve was shifted to the right by a magnitude of 2 weeks, which corresponded to the extent of postmaturity that was observed subsequently.
The exponential rise in maternal plasma CRH concentrations with advancing pregnancy is associated with a concomitant fall in the concentrations of the CRH-binding protein in late pregnancy. These reciprocal concentration curves suggest that there is a rapid increase in circulating levels of bioavailable CRH concurrent with the onset of parturition. The causal relationship between the increase in unbound CRH and the timing of parturition remains to be elucidated.
Clearly, the role of the fetal adrenal cortex in the regulation of parturition in primates is highly complex and different from that in other species. In addition, the primate may have several redundant mechanisms that may regulate parturition. This is not surprising given the critical nature of the timing and occurrence of this event.
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V. Summary |
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TopAbstractI. IntroductionII. DevelopmentIII. RegulationIV. PhysiologyV. SummaryReferences |
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Elegant experiments during the 1950s and 1960s demonstrated the central role of the primate fetal adrenal cortex in establishing the estrogenic milieu of pregnancy. Those findings were among the first indications of the function and physiological role of the human fetal adrenal cortex and led Diczfalusy and co-workers to propose the concept of the feto-placental unit, in which DHEA-S produced by the fetal adrenal cortex is used by the placenta for estrogen synthesis. Tissue and cell culture techniques, together with improved steroid assays, revealed that the fetal zone is the primary source of DHEA-S, and that its steroidogenic activity is regulated by ACTH.
In recent years, function of the human and rhesus monkey fetal adrenal cortical zones has been reexamined by assessing the localization and ontogeny of steroidogenic enzyme expression. The primate fetal adrenal cortex is composed of three functionally distinct zones: 1) the fetal zone, which throughout gestation does not express 3ßHSD but does express P450scc and P450c17 required for DHEA-S synthesis; 2) the transitional zone, which early in gestation is functionally identical to the fetal zone but late in gestation (after 25–30 weeks) expresses 3ßHSD, P450scc, and P450c17, and therefore is the likely site of glucocorticoid synthesis, and 3) the definitive zone, which lacks P450c17 throughout gestation but late in gestation (after 22–24 weeks) expresses 3ßHSD and P450scc, and therefore is the likely site of mineralocorticoid synthesis. Indirect evidence, based on effects of P450c21 deficiency and maternal estriol concentrations, indicate that the fetal adrenal cortex produces cortisol and DHEA-S early in gestation (6–12 weeks). However, controversy exists as to whether cortisol is produced de novo or derived from the metabolism of progesterone, as data regarding the expression of 3ßHSD in the fetal adrenal cortex early in gestation are conflicting.
During the 1960s, Liggins and colleagues demonstrated that in the sheep, cortisol secreted by the fetal adrenal cortex late in gestation regulates maturation of the fetus and initiates the cascade of events leading to parturition. Those pioneering discoveries provided insight into the mechanism underlying the timing of parturition and therefore were of particular interest to obstetricians and perinatologists confronted with the problems of preterm labor. However, although cortisol emanating from the fetal adrenal cortex promotes fetal maturation in primates as it does in sheep, its role in the regulation of primate parturition, unlike that in sheep, appears minimal. More recently, Nathanielsz and colleagues have proposed, based on studies in the rhesus monkey, that the feto-placental unit plays a role in regulating the timing of parturition in primates. These investigators provided strong evidence supporting the hypothesis that estrogens produced by the placenta from C19 precursor supplied by the fetal adrenal cortex influence the timing of parturition in the rhesus monkey. However, studies by Albrecht and colleagues indicated that estrogens are not involved in the regulation of parturition in the baboon. These conflicting data may be due to species differences, and further studies are required to resolve this intriguing issue and to elucidate the role of the fetal adrenal cortex in the regulation of primate parturition.
In all mammalian species studied to date, growth and function of the
fetal adrenal cortex are primarily regulated by ACTH secreted from the
fetal pituitary. Studies in humans and non-human primates have clearly
demonstrated the dependence of the fetal adrenal cortex, particularly
the fetal zone, on the fetal hypothalamic-pituitary axis and on ACTH.
As ACTH is not a growth factor per se, we have proposed that
at least some of its trophic actions are mediated by locally expressed
growth factors. Several growth factors including bFGF, EGF, IGF-I and
-II, TGF and -ß, and the activins/inhibins can modulate the growth
and function of primate fetal adrenal cortical cells. Moreover, the
expression of some of these growth factors, e.g. bFGF and
IGF-II, by fetal adrenal cortical cells is up-regulated by ACTH,
suggesting that they act as local mediators of ACTH action.
The placenta also may influence fetal adrenal development. In pregnant baboons, Pepe and Albrecht have proposed that the placenta modulates fetal adrenal cortical development indirectly by limiting the amount of maternal cortisol passing into the fetal circulation, which could inhibit ACTH secretion by the fetal pituitary. They also found that placental estrogens promote the conversion of maternal cortisol to cortisone and inhibit DHEA-S production by the fetal adrenal. More recently, the primate placenta was found to produce CRH and ACTH. It has been hypothesized that placental CRH influences fetal adrenal cortical growth and function by stimulating ACTH secretion from either the fetal pituitary or within the placenta itself. The human placenta produces very large quantities of CRH late in gestation that may stimulate ACTH secretion from the fetal pituitary. Interestingly, cortisol can stimulate CRH production by the placenta, suggesting that a positive feedback loop develops whereby placental CRH stimulates ACTH secretion from the fetal pituitary, which then augments cortisol production by the fetal adrenal, which stimulates further CRH production by the placenta. Some investigators have proposed that this regulatory feedback mechanism may be involved in the regulation of parturition. Although Serón-Ferré et al. showed that hCG increases DHEA-S production by human fetal zone cells, other workers have not detected an effect of hCG on fetal adrenal cortical function; therefore, its role in fetal adrenal cortical development remains uncertain.
In conclusion, development and function of the primate fetal adrenal cortex are unique among mammalian species. Much effort has been directed at elucidating the mechanism by which fetal adrenal growth and function are regulated, and significant progress has been made in understanding the mechanism by which ACTH exerts its trophic actions and the role of growth factors in this process. In addition, studies of adrenal cortical function based on the expression of steroidogenic enzymes have provided new insight into the functional zonation of the fetal adrenal cortex. However, despite these advances, we still do not fully understand the physiological role of the primate fetal adrenal cortex and its possible involvement in the regulation of parturition. This problem is made more intriguing by the recent discovery that the primate placenta produces CRH. This finding puts a new and exciting perspective on the concept of the feto-placental unit and broadens our understanding of the physiological interaction between the placenta and fetal adrenal. Future studies directed at this issue will likely contribute significantly to understanding the developmental and functional biology of the primate fetal adrenal cortex.
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Footnotes |
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1 This work was supported in part by NIH Research Grant R01 HD-08478. 
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References |
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TopAbstractI. IntroductionII. DevelopmentIII. RegulationIV. PhysiologyV. SummaryReferences |
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-hydroxylase/17,20-lyase, and 3ß-hydroxysteroid dehydrogenase
isomerase steroidogenic enzymes in the human and rhesus fetal adrenal
gland: reappraisal of functional zonation. J Clin Endocrinol Metab 77:1184–1189
,21-trihydroxypregn-5-en-20-one by the intact human foetus at
midpregnancy. Biochim Biophy Acta 152:648–650[Medline]
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deoxycorticosterone. Endocrinology 69:354–372
5-4 isomerase (3ß-HSD) in human
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75:R7–R10
5-androsten-17-one) sulfate to
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H. Ishimoto, M. O. Muench, T. Higuchi, K. Minegishi, M. Tanaka, Y. Yoshimura, and R. B. Jaffe Midkine, a Heparin-Binding Growth Factor, Selectively Stimulates Proliferation of Definitive Zone Cells of the Human Fetal Adrenal Gland J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 4050 - 4056. [Abstract] [Full Text] [PDF]
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C. Torres-Farfan, V. Rocco, C. Monso, F. J. Valenzuela, C. Campino, A. Germain, F. Torrealba, G. J. Valenzuela, and M. Seron-Ferre Maternal Melatonin Effects on Clock Gene Expression in a Nonhuman Primate Fetus Endocrinology, October 1, 2006; 147(10): 4618 - 4626. [Abstract] [Full Text] [PDF]
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H. Ishimoto, D. G. Ginzinger, T. Matsumoto, Y. Hattori, M. Furuya, K. Minegishi, M. Tanaka, Y. Yoshimura, and R. B. Jaffe Differential Zonal Expression and Adrenocorticotropin Regulation of Secreted Protein Acidic and Rich in Cysteine (SPARC), a Matricellular Protein, in the Midgestation Human Fetal Adrenal Gland: Implications for Adrenal Development J. Clin. Endocrinol. Metab., August 1, 2006; 91(8): 3208 - 3214. [Abstract] [Full Text] [PDF]
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H. Ishimoto, D. G. Ginzinger, and R. B. Jaffe Adrenocorticotropin Preferentially Up-Regulates Angiopoietin 2 in the Human Fetal Adrenal Gland: Implications for Coordinated Adrenal Organ Growth and Angiogenesis J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1909 - 1915. [Abstract] [Full Text] [PDF]
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 K. Watterberg Fetal Adrenal Development: Implications For Lung Development and Postnatal Disease NeoReviews, March 1, 2006; 7(3): e135 - e142. [Full Text] [PDF]
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 N. Weintrob, J. Drouin, S. Vallette-Kasic, E. Taub, D. Marom, Y. Lebenthal, G. Klinger, E. Bron-Harlev, and M. Shohat Low Estriol Levels in the Maternal Triple-Marker Screen as a Predictor of Isolated Adrenocorticotropic Hormone Deficiency Caused by a New Mutation in the TPIT Gene Pediatrics, February 1, 2006; 117(2): e322 - e327. [Abstract] [Full Text] [PDF]
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K. L. Watterberg, M. L. Shaffer, J. S. Garland, E. H. Thilo, M. C. Mammel, R. J. Couser, S. W. Aucott, C. L. Leach, C. H. Cole, J. S. Gerdes, et al. Effect of Dose on Response to Adrenocorticotropin in Extremely Low Birth Weight Infants J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6380 - 6385. [Abstract] [Full Text] [PDF]
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R. Zhou, I. M. Bird, D. A. Dumesic, and D. H. Abbott Adrenal Hyperandrogenism Is Induced by Fetal Androgen Excess in a Rhesus Monkey Model of Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6630 - 6637. [Abstract] [Full Text] [PDF]
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M.-C. Battista, M. Otis, M. Cote, A. Laforest, M. Peter, E. Lalli, and N. Gallo-Payet Extracellular Matrix and Hormones Modulate DAX-1 Localization in the Human Fetal Adrenal Gland J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5426 - 5431. [Abstract] [Full Text] [PDF]
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 J. S. Leeder, R. Gaedigk, K. A. Marcucci, A. Gaedigk, C. A. Vyhlidal, B. P. Schindel, and R. E. Pearce Variability of CYP3A7 Expression in Human Fetal Liver J. Pharmacol. Exp. Ther., August 1, 2005; 314(2): 626 - 635. [Abstract] [Full Text] [PDF]
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 W. Wu, H. Kamma, M. Fujiwara, Y. Yano, H. Satoh, H. Hara, T. Yashiro, E. Ueno, and Y. Aiyoshi Altered Expression Patterns of Heterogeneous Nuclear Ribonucleoproteins A2 and B1 in the Adrenal Cortex J. Histochem. Cytochem., April 1, 2005; 53(4): 487 - 495. [Abstract] [Full Text] [PDF]
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E. D. Albrecht, G. W. Aberdeen, and G. J. Pepe Estrogen Elicits Cortical Zone-Specific Effects on Development of the Primate Fetal Adrenal Gland Endocrinology, April 1, 2005; 146(4): 1737 - 1744. [Abstract] [Full Text] [PDF]
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G. D. Hammer, K. L. Parker, and B. P. Schimmer Minireview: Transcriptional Regulation of Adrenocortical Development Endocrinology, March 1, 2005; 146(3): 1018 - 1024. [Abstract] [Full Text] [PDF]
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 J Liu, X-D Li, A Vaheri, and R Voutilainen DNA methylation affects cell proliferation, cortisol secretion and steroidogenic gene expression in human adrenocortical NCI-H295R cells J. Mol. Endocrinol., December 1, 2004; 33(3): 651 - 662. [Abstract] [Full Text] [PDF]
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K. L. Watterberg, J. S. Gerdes, C. H. Cole, S. W. Aucott, E. H. Thilo, M. C. Mammel, R. J. Couser, J. S. Garland, H. J. Rozycki, C. L. Leach, et al. Prophylaxis of Early Adrenal Insufficiency to Prevent Bronchopulmonary Dysplasia: A Multicenter Trial Pediatrics, December 1, 2004; 114(6): 1649 - 1657. [Abstract] [Full Text] [PDF]
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J Liu, X-D Li, A Ora, P Heikkila, A Vaheri, and R Voutilainen cAMP-dependent protein kinase activation inhibits proliferation and enhances apoptotic effect of tumor necrosis factor-{alpha} in NCI-H295R adrenocortical cells J. Mol. Endocrinol., October 1, 2004; 33(2): 511 - 522. [Abstract] [Full Text] [PDF]
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M. Thomas, M. Keramidas, E. Monchaux, and J.-J. Feige Dual Hormonal Regulation of Endocrine Tissue Mass and Vasculature by Adrenocorticotropin in the Adrenal Cortex Endocrinology, September 1, 2004; 145(9): 4320 - 4329. [Abstract] [Full Text] [PDF]
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L. Lu, T. Suzuki, Y. Yoshikawa, O. Murakami, Y. Miki, T. Moriya, M. H. Bassett, W. E. Rainey, Y. Hayashi, and H. Sasano Nur-Related Factor 1 and Nerve Growth Factor-Induced Clone B in Human Adrenal Cortex and Its Disorders J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 4113 - 4118. [Abstract] [Full Text] [PDF]
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 K.E. Warnes, I.C. McMillen, J.S. Robinson, and C.L. Coulter Differential Actions of Metyrapone on the Fetal Pituitary-Adrenal Axis in the Sheep Fetus in Late Gestation Biol Reprod, August 1, 2004; 71(2): 620 - 628. [Abstract] [Full Text] [PDF]
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K. K. Ong, N. Potau, C. J. Petry, R. Jones, A. R. Ness, J. W. Honour, F. de Zegher, L. Ibanez, and D. B. Dunger Opposing Influences of Prenatal and Postnatal Weight Gain on Adrenarche in Normal Boys and Girls J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2647 - 2651. [Abstract] [Full Text] [PDF]
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A.-M. Lefrancois-Martinez, J. Bertherat, P. Val, C. Tournaire, N. Gallo-Payet, D. Hyndman, G. Veyssiere, X. Bertagna, C. Jean, and A. Martinez Decreased Expression of Cyclic Adenosine Monophosphate-Regulated Aldose Reductase (AKR1B1) Is Associated with Malignancy in Human Sporadic Adrenocortical Tumors J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 3010 - 3019. [Abstract] [Full Text] [PDF]
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 C. Torres-Farfan, H. G. Richter, A. M. Germain, G. J. Valenzuela, C. Campino, P. Rojas-Garcia, M. L. Forcelledo, F. Torrealba, and M. Seron-Ferre Maternal melatonin selectively inhibits cortisol production in the primate fetal adrenal gland J. Physiol., February 1, 2004; 554(3): 841 - 856. [Abstract] [Full Text] [PDF]
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I. Virtanen, M. Korhonen, N. Petajaniemi, T. Karhunen, L.-E. Thornell, L. M. Sorokin, and Y. T. Konttinen Laminin Isoforms in Fetal and Adult Human Adrenal Cortex J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4960 - 4966. [Abstract] [Full Text] [PDF]
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D. Rosenberg, L. Groussin, E. Jullian, K. Perlemoine, S. Medjane, A. Louvel, X. Bertagna, and J. Bertherat Transcription Factor 3',5'-Cyclic Adenosine 5'-Monophosphate-Responsive Element-Binding Protein (CREB) Is Decreased during Human Adrenal Cortex Tumorigenesis and Fetal Development J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3958 - 3965. [Abstract] [Full Text] [PDF]
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E. Lalli and P. Sassone-Corsi DAX-1, an Unusual Orphan Receptor at the Crossroads of Steroidogenic Function and Sexual Differentiation Mol. Endocrinol., August 1, 2003; 17(8): 1445 - 1453. [Abstract] [Full Text] [PDF]
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J. Ratcliffe, M. Nakanishi, and R. B. Jaffe Identification of Definitive and Fetal Zone Markers in the Human Fetal Adrenal Gland Reveals Putative Developmental Genes J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3272 - 3277. [Abstract] [Full Text] [PDF]
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A. M. Blanks, M. Vatish, M. J. Allen, G. Ladds, N. C. J. de Wit, D. M. Slater, and S. Thornton Paracrine Oxytocin and Estradiol Demonstrate a Spatial Increase in Human Intrauterine Tissues with Labor J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3392 - 3400. [Abstract] [Full Text] [PDF]
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F. Beuschlein, B. D. Looyenga, S. E. Bleasdale, C. Mutch, D. L. Bavers, A. F. Parlow, J. H. Nilson, and G. D. Hammer Activin Induces x-Zone Apoptosis That Inhibits Luteinizing Hormone-Dependent Adrenocortical Tumor Formation in Inhibin-Deficient Mice Mol. Cell. Biol., June 1, 2003; 23(11): 3951 - 3964. [Abstract] [Full Text] [PDF]
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M. Fassnacht, S. Hahner, I. A. Hansen, T. Kreutzberger, M. Zink, K. Adermann, F. Jakob, J. Troppmair, and B. Allolio N-Terminal Proopiomelanocortin Acts as a Mitogen in Adrenocortical Tumor Cells and Decreases Adrenal Steroidogenesis J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2171 - 2179. [Abstract] [Full Text] [PDF]
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 M. D. Payet, L. Bilodeau, L. Breault, A. Fournier, L. Yon, H. Vaudry, and N. Gallo-Payet PAC1 Receptor Activation by PACAP-38 Mediates Ca2+ Release from a cAMP-dependent Pool in Human Fetal Adrenal Gland Chromaffin Cells J. Biol. Chem., January 10, 2003; 278(3): 1663 - 1670. [Abstract] [Full Text] [PDF]
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J. Lafont, M. Laurent, H. Thibout, F. Lallemand, Y. Le Bouc, A. Atfi, and C. Martinerie The Expression of novH in Adrenocortical Cells Is Down-regulated by TGFbeta 1 through c-Jun in a Smad-independent Manner J. Biol. Chem., October 18, 2002; 277(43): 41220 - 41229. [Abstract] [Full Text] [PDF]
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S. Kiiveri, J. Liu, M. Westerholm-Ormio, N. Narita, D. B. Wilson, R. Voutilainen, and M. Heikinheimo Differential Expression of GATA-4 and GATA-6 in Fetal and Adult Mouse and Human Adrenal Tissue Endocrinology, August 1, 2002; 143(8): 3136 - 3143. [Abstract] [Full Text] [PDF]
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C. L. Coulter, I. C. McMillen, I. M. Bird, and M. D. Salkeld Steroidogenic Acute Regulatory Protein Expression Is Decreased in the Adrenal Gland of the Growth-Restricted Sheep Fetus During Late Gestation Biol Reprod, August 1, 2002; 67(2): 584 - 590. [Abstract] [Full Text] [PDF]
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V. E. Murphy, T. Zakar, R. Smith, W. B. Giles, P. G. Gibson, and V. L. Clifton Reduced 11{beta}-Hydroxysteroid Dehydrogenase Type 2 Activity Is Associated with Decreased Birth Weight Centile in Pregnancies Complicated by Asthma J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1660 - 1668. [Abstract] [Full Text] [PDF]
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E. Chamoux, A. Narcy, J.-G. Lehoux, and N. Gallo-Payet Fibronectin, Laminin, and Collagen IV as Modulators of Cell Behavior during Adrenal Gland Development in the Human Fetus J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1819 - 1828. [Abstract] [Full Text] [PDF]
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P. S. Babu, D. L. Bavers, F. Beuschlein, S. Shah, B. Jeffs, J. L. Jameson, and G. D. Hammer Interaction Between Dax-1 and Steroidogenic Factor-1 in Vivo: Increased Adrenal Responsiveness to ACTH in the Absence of Dax-1 Endocrinology, February 1, 2002; 143(2): 665 - 673. [Abstract] [Full Text] [PDF]
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A. J. Ginther, A. A. Carlson, T. E. Ziegler, and C. T. Snowdon Neonatal and Pubertal Development in Males of a Cooperatively Breeding Primate, the Cotton-Top Tamarin (Saguinus oedipus oedipus) Biol Reprod, February 1, 2002; 66(2): 282 - 290. [Abstract] [Full Text] [PDF]
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C. Martinerie, C. Gicquel, A. Louvel, M. Laurent, P. N. Schofield, and Y. Le Bouc Altered Expression of novH Is Associated with Human Adrenocortical Tumorigenesis J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3929 - 3940. [Abstract] [Full Text] [PDF]
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 R. C. Ribeiro, F. Sandrini, B. Figueiredo, G. P. Zambetti, E. Michalkiewicz, A. R. Lafferty, L. DeLacerda, M. Rabin, C. Cadwell, G. Sampaio, et al. An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma PNAS, July 31, 2001; 98(16): 9330 - 9335. [Abstract] [Full Text] [PDF]
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N. Hiroi, G. P. Chrousos, B. Kohn, A. Lafferty, M. Abu-Asab, S. Bonat, A. White, and S. R. Bornstein Adrenocortical-Pituitary Hybrid Tumor Causing Cushing's Syndrome J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2631 - 2637. [Abstract] [Full Text] [PDF]
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E. Chamoux, L. Bolduc, J.-G. Lehoux, and N. Gallo-Payet Identification of Extracellular Matrix Components and Their Integrin Receptors in the Human Fetal Adrenal Gland J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 2090 - 2098. [Abstract] [Full Text]
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N. A. Hanley, W. E. Rainey, D. I. Wilson, S. G. Ball, and K. L. Parker Expression Profiles of SF-1, DAX1, and CYP17 in the Human Fetal Adrenal Gland: Potential Interactions in Gene Regulation Mol. Endocrinol., January 1, 2001; 15(1): 57 - 68. [Abstract] [Full Text]
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R. Gitau, N. M. Fisk, J. M. A. Teixeira, A. Cameron, and V. Glover Fetal Hypothalamic-Pituitary-Adrenal Stress Responses to Invasive Procedures Are Independent of Maternal Responses J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 104 - 109. [Abstract] [Full Text]
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 T. J. Rosol, J. T. Yarrington, J. Latendresse, and C. C. Capen Adrenal Gland: Structure, Function, and Mechanisms of Toxicity Toxicol Pathol, January 1, 2001; 29(1): 41 - 48. [Abstract] [PDF]
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 L. Ibáñez, J. DiMartino-Nardi, N. Potau, and P. Saenger Premature Adrenarche--Normal Variant or Forerunner of Adult Disease? Endocr. Rev., December 1, 2000; 21(6): 671 - 696. [Abstract] [Full Text]
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L. Breault, E. Chamoux, J.-G. LeHoux, and N. Gallo-Payet Localization of G Protein {{alpha}}-Subunits in the Human Fetal Adrenal Gland Endocrinology, December 1, 2000; 141(12): 4334 - 4341. [Abstract] [Full Text] [PDF]
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J. R.G. Challis, S. G. Matthews, W. Gibb, and S. J. Lye Endocrine and Paracrine Regulation of Birth at Term and Preterm Endocr. Rev., October 1, 2000; 21(5): 514 - 550. [Abstract] [Full Text]
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P. C. White and P. W. Speiser Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency Endocr. Rev., June 1, 2000; 21(3): 245 - 291. [Abstract] [Full Text]
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F. Wilkin, N. Gagné, J. Paquette, L. L. Oligny, and C. Deal Pediatric Adrenocortical Tumors: Molecular Events Leading to Insulin-Like Growth Factor II Gene Overexpression J. Clin. Endocrinol. Metab., May 1, 2000; 85(5): 2048 - 2056. [Abstract] [Full Text]
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 P C Ng The fetal and neonatal hypothalamic-pituitary-adrenal axis Arch. Dis. Child. Fetal Neonatal Ed., May 1, 2000; 82(3): 250F - 254. [Full Text]
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C. L. Coulter, D. A. Myers, P. W. Nathanielsz, and I. M. Bird Ontogeny of Angiotensin II Type 1 Receptor and Cytochrome P450c11 in the Sheep Adrenal Gland Biol Reprod, March 1, 2000; 62(3): 714 - 719. [Abstract] [Full Text]
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M. C. Zatelli, R. Rossi, and E. C. degli Uberti Androgen Influences Transforming Growth Factor-{beta}1 Gene Expression in Human Adrenocortical Cells J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 847 - 852. [Abstract] [Full Text]
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E. Chamoux Involvement of the Angiotensin II Type 2 Receptor in Apoptosis during Human Fetal Adrenal Gland Development J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4722 - 4730. [Abstract] [Full Text]
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E. D. Albrecht, J. S. Babischkin, W. A. Davies, M. G. Leavitt, and G. J. Pepe Identification and Developmental Expression of the Estrogen Receptor {alpha} and {beta} in the Baboon Fetal Adrenal Gland Endocrinology, December 1, 1999; 140(12): 5953 - 5961. [Abstract] [Full Text]
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A. Chakravorty, S. Mesiano, and R. B. Jaffe Corticotropin-Releasing Hormone Stimulates P450 17{alpha}-Hydroxylase/17,20-Lyase in Human Fetal Adrenal Cells via Protein Kinase C J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3732 - 3738. [Abstract] [Full Text] [PDF]
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M. G. Leavitt, E. D. Albrecht, and G. J. Pepe Development of the Baboon Fetal Adrenal Gland: Regulation of the Ontogenesis of the Definitive and Transitional Zones by Adrenocorticotropin J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3831 - 3835. [Abstract] [Full Text] [PDF]
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T. Tajima, X.-M. Ma, S. R. Bornstein, and G. Aguilera Prenatal Dexamethasone Treatment Does Not Prevent Alterations of the Hypothalamic Pituitary Adrenal Axis in Steroid 21-Hydroxylase Deficient Mice Endocrinology, July 1, 1999; 140(7): 3354 - 3362. [Abstract] [Full Text]
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R. B. Billiar, M. G. Leavitt, P. Smith, E. D. Albrecht, and G. J. Pepe Functional Capacity of Fetal Zone Cells of the Baboon Fetal Adrenal Gland: A Major Source of {alpha}-Inhibin Biol Reprod, July 1, 1999; 61(1): 142 - 146. [Abstract] [Full Text]
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M. Freemark Editorial: The Fetal Adrenal and the Maturation of the Growth Hormone and Prolactin Axes Endocrinology, May 1, 1999; 140(5): 1963 - 1965. [Full Text]
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M. M. Weber, C. Fottner, P. Schmidt, K. M. H. Brodowski, K. Gittner, H. Lahm, D. Engelhardt, and E. Wolf Postnatal Overexpression of Insulin-Like Growth Factor II in Transgenic Mice Is Associated with Adrenocortical Hyperplasia and Enhanced Steroidogenesis Endocrinology, April 1, 1999; 140(4): 1537 - 1543. [Abstract] [Full Text]
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S. J. Spencer, S. Mesiano, J. Y. Lee, and R. B. Jaffe Proliferation and Apoptosis in the Human Adrenal Cortex during the Fetal and Perinatal Periods: Implications for Growth and Remodeling J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 1110 - 1115. [Abstract] [Full Text]
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P. J. Burton and B. J. Waddell Dual Function of 11ß-Hydroxysteroid Dehydrogenase in Placenta: Modulating Placental Glucocorticoid Passage and Local Steroid Action Biol Reprod, February 1, 1999; 60(2): 234 - 240. [Abstract] [Full Text] [PDF]
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C. L. Coulter and R. B. Jaffe Functional Maturation of the Primate Fetal Adrenal in Vivo: 3. Specific Zonal Localization and Developmental Regulation of CYP21A2 (P450c21) and CYP11B1/CYP11B2 (P450c11/Aldosterone Synthase) Lead to Integrated Concept of Zonal and Temporal Steroid Biosynthesis Endocrinology, December 1, 1998; 139(12): 5144 - 5150. [Abstract] [Full Text] [PDF]
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R. Smith, S. Mesiano, E.-C. Chan, S. Brown, and R. B. Jaffe Corticotropin-Releasing Hormone Directly and Preferentially Stimulates Dehydroepiandrosterone Sulfate Secretion by Human Fetal Adrenal Cortical Cells J. Clin. Endocrinol. Metab., August 1, 1998; 83(8): 2916 - 2920. [Abstract] [Full Text]
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N. Boulle, A. Logié, C. Gicquel, L. Perin, and Y. Le Bouc Increased Levels of Insulin-Like Growth Factor II (IGF-II) and IGF-Binding Protein-2 Are Associated with Malignancy in Sporadic Adrenocortical Tumors J. Clin. Endocrinol. Metab., May 1, 1998; 83(5): 1713 - 1720. [Abstract] [Full Text]
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J. L. Shifren, S. Mesiano, R. N. Taylor, N. Ferrara, and R. B. Jaffe Corticotropin Regulates Vascular Endothelial Growth Factor Expression in Human Fetal Adrenal Cortical Cells J. Clin. Endocrinol. Metab., April 1, 1998; 83(4): 1342 - 1347. [Abstract] [Full Text]
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G. W. Aberdeen, M. G. Leavitt, G. J. Pepe, and E. D. Albrecht Effect of Maternal Betamethasone Administration at Midgestation on Baboon Fetal Adrenal Gland Development and Adrenocorticotropin Receptor Messenger Ribonucleic Acid Expression J. Clin. Endocrinol. Metab., March 1, 1998; 83(3): 976 - 982. [Abstract] [Full Text]
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G. Cao, C. K. Garcia, K. L. Wyne, R. A. Schultz, K. L. Parker, and H. H. Hobbs Structure and Localization of the Human Gene Encoding SR-BI/CLA-1. EVIDENCE FOR TRANSCRIPTIONAL CONTROL BY STEROIDOGENIC FACTOR 1 J. Biol. Chem., December 26, 1997; 272(52): 33068 - 33076. [Abstract] [Full Text] [PDF]
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