Role of Hypothalamic-Pituitary Axis in EGF Action on Maturation of Adrenal Gland in Fetal Rhesus Monkey In Vivo

Abstract

We determined the route of action of epidermal growth factor (EGF) [intraperitoneal (IP) versus intraamniotic administration] on adrenal development and whether its effects are mediated via the fetal hypothalamic-pituitary axis in the fetal rhesus monkey in vivo. EGF (40 g) was administered IP (n ϭ 9) or intraamniotic (n ϭ 6) at 121, 123, 125, and 127 d gestation (term, approximately 165 Ϯ 10 d gestation). In addition, a competitive corticotropin-releasing factor antagonist ([D-phenylalanine 12 , Norleucine 21,38 ] corticotropin-releasing factor 12-41 to block fetal pituitary ACTH secretion; 400 g IP) and metyrapone (11␤-hydroxylase inhibitor to block adrenal cortisol synthesis; 15 mg IP and 15 mg intraamniotic) were administered, in combination with EGF (EGFϩBLOCK; 40 g IP; n ϭ 4 fetuses). Control fetuses (n ϭ 6) received saline injections in an equivalent volume. On gestational d 128, a hysterotomy was performed, and fetal adrenals were collected for morphometric analyses and immunocytochemical localization of 3␤-hydroxysteroid dehydrogenase (3␤HSD) and cytochrome P-450 11␤-hydroxylase/ aldosynthase. Definitive zone (DZ) width and cortical width of 3␤HSD staining were significantly greater (p Ͻ 0.05) in the EGF IP-treated fetuses compared with controls and EGFϩBLOCK. With EGF IP, 3␤HSD was increased in the DZ and induced extensively in the transitional zone of the fetal adrenal cortex, and cytochrome P-450 11␤-hydroxylase/aldosynthase immunoreactivity was induced to detectable levels in the DZ. The administration of EGFϩBLOCK inhibited the expression of 3␤HSD in the transitional zone, but 3␤HSD expression was still increased in the DZ and cytochrome P-450 11␤-hydroxylase/ aldosynthase immunoreactivity was induced in the DZ. EGF intraamniotic administration had no significant effect on the width of the DZ or cortical width of 3␤HSD staining compared with controls. These data suggest that EGF acts via the hypothalamic-pituitary axis to modulate adrenal cortical growth and functional maturation of the transitional zone (the putative zona fasciculata), whereas EGF can act independently of the hypothalamic-pituitary axis to stimulate functional maturation of the DZ (the putative zona glomerulosa The development of the steroidogenic capacity of the fetal adrenal gland is necessary for the maintenance of intrauterine homeostasis, development of enzyme systems necessary for extrauterine life, and, at least in some species, the timing of

Variations in Adrenal Androgen Production Among (Nonhuman) Primates

“…107 Epidermal growth factor induces maturation of the definitive zone of the rhesus fetal adrenal cortex. 108,109 Except for inferences drawn from estrogen secretion during pregnancy; however, the functional capacity for androgen synthesis of the nonhuman primate FZ remains essentially unexplored in most species.…”

“…107,[110][111][112] ACTH administration increased the width and expression of 3b-HSD in the transitional zone, and betamethasone inhibited P450c17 and 3b-HSD expression in the fetal adrenal cortex of the baboon 107 and rhesus. 108,109 Cytochrome b5 expression in the fetal adrenal cortex has been examined only in the rhesus monkey. 112 Although identifiable in the earliest organizational stages, it is largely absent through most of adrenal development during pregnancy, but expression increases in the cells of the outer FZ immediately before birth.…”

Functional Biology of the Primate Fetal Adrenal Gland: Advances in Technology Provide New Insight

“…The functional capacity of the fetal adrenal cortex has been investigated by examining the spatial and temporal localization of steroidsynthesizing enzymes in the human and rhesus monkey fetal adrenal. [14][15][16][34][35][36] In our initial studies, we chose to investigate the expression of three enzymes, namely cytochrome P450 cholesterol side-chain cleavage (CYP11A1), cytochrome P450 17 ␣ hydroxylase (CYP17) and 3 ␤ hydroxysteroid dehydrogenase (3 ␤ HSD), which play a pivotal role in sthe teroidogenesis pathway and define the steroidogenic potential of the different zones in the adrenal cortex. 35,36 As further factors have been identified as being necessary for complete adrenal steroidogenic function, such as steroidogenic factor-1(SF-1), steroidogenic acute regulatory protein (StAR), adrenocortical cytochrome b5 and DHEAsulphotransferase, additional studies have been undertaken to examine their spatial and temporal localization.…”

“…35,36 Based on the functional capacities of the definitive zone, transitional zone and fetal zone, we proposed that these three zones are analogous to the zona glomerulosa, zona fasciculata and zona reticularis, respectively, of the mature adrenal cortex. 2,[14][15][16][34][35][36] Given the small size of the fetal rhesus monkey and the hyperreactivity of the primate uterus to intervention, few studies have investigated the in vivo responsiveness of the fetal pituitary-adrenal axis. In our studies, we were able to demonstrate that the functional maturation of the fetal adrenal cortex is paralleled by a maturation of the fetal cortisol response to intrauterine stress.…”

Enucleation-Induced Rat Adrenal Gland Regeneration: Expression Profile of Selected Genes Involved in Control of Adrenocortical Cell Proliferation

“…Another growth factor—Egf—stimulates adrenocortical growth and functional maturation and this action is connected with induction of expression of 11beta-hydroxylase (Cyp11b) and 3beta-hydroxysteroid dehydrogenase (3bHsd) in the fetal rhesus monkey [48]. In our experiments expression of Egf gene has not significantly changed during adrenal regeneration (microarray data, not shown).…”