Functional maturation of the primate fetal adrenal in vivo: I. Role of insulin-like growth factors (IGFs), IGF-I receptor, and IGF binding proteins in growth regulation.

Abstract

The rapid growth of the primate fetal adrenal from midgestation until term is regulated by ACTH secreted by the fetal pituitary. Previous studies suggest that the trophic actions of ACTH are mediated by insulin-like growth factor II (IGF-II) synthesized by fetal adrenal cortical cells. To characterize further the role of IGF-II in the regulation of fetal adrenal growth, we investigated the expression of the messenger RNAs (mRNAs) encoding IGF-I, IGF-II, IGF-I receptor (IGF-IR) and IGF binding protein (IGFBP) 1-6 in the fetal rhesus monkey adrenal in vivo from 109 days of gestation until term (165 +/- 5 days) using in situ hybridization. To assess the role of ACTH in the regulation of expression of the IGF system in vivo, we administered metyrapone (3-7 days) to late gestation fetal rhesus monkeys (n = 4) in utero to increase fetal pituitary ACTH secretion. IGF-II mRNA was abundant in the definitive, transitional and fetal zones of the adrenal cortex from 109 days until term. IGF-IR mRNA was expressed in the definitive, transitional and fetal zones and decreased to nondetectable levels at term. IGFBP-2 and IGFBP-6 mRNAs were expressed in the definitive, transitional, and fetal zones, whereas IGFBP-1, -3, -4, and -5 were not detected in adrenal cells. The effects of increasing ACTH secretion on the growth of the specific zones of the adrenal were determined using morphometric techniques. Metyrapone treatment approximately doubled adrenal weight, which was due to an increase in the area of the definitive, transitional, and fetal zones with decreased cell density of the definitive, transitional, and fetal zones compared with controls and not due to a change in total cell number. Therefore, the increase in adrenal weight after metyrapone treatment was due to hypertrophy of the three cortical zones; there was no effect on adrenal medullary growth. The relative abundance of the mRNAs encoding IGF-II and the IGF-IR was increased after metyrapone treatment, whereas the localization and relative abundance of IGFBP 1-6 mRNAs were not altered by metyrapone treatment. We conclude that the ontogenetic increase in adrenal growth may be regulated, at least in part, by locally synthesized IGF-II, and the cessation of adrenal growth that occurs at term may be mediated by the decrease in the IGF-IR. The adrenal cortical expression of IGFBP-2 and IGFBP-6 suggests that these IGFBPs may modulate the IGF-IGF-IR interaction. Metyrapone treatment, which likely increased fetal pituitary ACTH secretion, causes a coordinated increase in expression of IGF-II and IGF-IR in fetal adrenal cortical cells, which may be an important mechanism of regulation of fetal adrenal cortical growth.

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

“…Disruption of the hypothalamo-pituitary axis in the human fetus results in a failure of the fetal zone to grow after 15 weeks gestation 11 and dexamethasone administration to pregnant rhesus monkeys in late gestation, to suppress fetal hypothalamo-pituitary secretion, results in atrophy of the fetal zone. 12,13 There is also substantial evidence that the actions of ACTH on fetal adrenal growth in vivo may be mediated by intra-adrenal growth factors, including insulin-like growth factor (IGF)-II [14][15][16] (for a review, see Mesiano and Jaffe 2 ). After birth, there is a rapid remodelling of the fetal zone of the adrenal cortex and it has therefore been suggested that the placenta may play a role in the differentiation, maintenance or growth of this zone.…”

“…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.…”

Expression of the IGF System in Human Adrenal Tissues from Early Infancy to Late Puberty: Implications for the Development of Adrenarche

“…In contrast, in human adult adrenal cortex, IGF-2 mRNA expression is very low but IGF-1 mRNA is readily detected (12). Type 1 IGF receptor (IGF-R1) mRNA is also expressed abundantly in the definitive zone, transitional zone, and FeZ of the rhesus monkey fetus, but its expression decreases to undetectable levels at term (13). No information is available on the ontogenesis of IGFs and of IGF-R1 in human adrenal cortex from the neonatal period throughout adulthood.…”

Developmental expression of cell cycle regulators in the baboon fetal adrenal gland

“…Thus, there is marked atrophy of the fetal adrenal gland when pituitary ACTH release is suppressed by administration of synthetic corticosteroids in the human (Mesiano & Jaffe 1992), baboon (Leavitt et al 1997, Aberdeen et al 1998, and rhesus monkey (Challis et al 1974). Depending upon the experimental conditions employed in culture studies, however, ACTH had either inhibitory (Ramachandran & Suyama 1975, Hornsby & Gill 1977, Simonian & Gill 1981, stimulatory (Kahri & Halinen 1974, Roos 1974), or limited (Di Blasio et al 1990) effects on the proliferation of human fetal adrenocortical cells, and caused hypertrophy of the primate fetal adrenal cortex (Coulter et al 1996). Other peptides of placental or fetal origin, e.g.…”