FUNCTIONAL MATURATION OF THE PRIMATE FETAL ADRENAL IN-VIVO .1. ROLE OF INSULIN-LIKE GROWTH-FACTORS (IGFS), IGF-I RECEPTOR, AND IGF BINDING-PROTEINS IN GROWTH-REGULATION

The rapid growth of the primate fetal adrenal from midgestation until term is regulated by ACTH secreted by the fetal pituitary. Previous st udies 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 express ion of the IGF system in vivo, we administered metyrapone (3-7 days) t o late gestation fetal rhesus monkeys (n = 4) in utero to increase fet al pituitary ACTH secretion. IGF-II mRNA was abundant in the definitiv e, transitional and fetal zones of the adrenal cortex from 109 days un til term. IGF-IR mRNA was expressed in the definitive, transitional an d fetal zones and decreased to nondetectable levels at term. IGFBP-2 a nd IGFBP-6 mRNAs were expressed in the definitive, transitional, and f etal zones, whereas IGFBP-1, -3, -4, and 5 were not detected in adrena l cells. The effects of increasing ACTH secretion on the growth of the specific zones of the adrenal were determined using morphometric tech niques. Metyrapone treatment approximately doubled adrenal weight, whi ch was due to an increase in the area of the definitive, transitional, and fetal zones with decreased cell density of the definitive, transi tional, 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 zon es; there was no effect on adrenal medullary growth. The relative abun dance 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 conclu de that the ontogenetic increase in adrenal growth may be regulated, a t least in part, by locally synthesized IGF-II, and the cessation of a drenal growth that occurs at term may be mediated by the decrease in t he IGF-IR. The adrenal cortical expression of IGFBP-2 and IGFBP-6 sugg ests that these IGFBPs may modulate the IGF-IGF-IR interaction. Metyra pone treatment, which likely increased fetal pituitary ACTH secretion, causes a coordinated increase in expression of IGF-II and IGF-IR in f etal adrenal cortical cells, which may be an important mechanism of re gulation of fetal adrenal cortical growth.