Endocrinology, Vol 137, 4487-4498, Copyright © 1996 by Endocrine Society

ARTICLES

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

CL Coulter, PC Goldsmith, S Mesiano, CC Voytek, MC Martin, VK Han and RB Jaffe
Reproductive Endocrinology Center, University of California, San Francisco 94143, USA.

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.

This article has been cited by other articles:

				H. Ishimoto, K. Minegishi, T. Higuchi, M. Furuya, S. Asai, S. H. Kim, M. Tanaka, Y. Yoshimura, and R. B. Jaffe The Periphery of the Human Fetal Adrenal Gland Is a Site of Angiogenesis: Zonal Differential Expression and Regulation of Angiogenic Factors J. Clin. Endocrinol. Metab., June 1, 2008; 93(6): 2402 - 2408. [Abstract] [Full Text] [PDF]

				J. T. Ross, I. C. McMillen, F. Lok, A. G. Thiel, J. A. Owens, and C. L. Coulter Intrafetal Insulin-Like Growth Factor-I Infusion Stimulates Adrenal Growth But Not Steroidogenesis in the Sheep Fetus during Late Gestation Endocrinology, November 1, 2007; 148(11): 5424 - 5432. [Abstract] [Full Text] [PDF]

				A. Dumitrescu, G. W Aberdeen, G. J Pepe, and E. D Albrecht Developmental expression of cell cycle regulators in the baboon fetal adrenal gland J. Endocrinol., January 1, 2007; 192(1): 237 - 247. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				R. Sirianni, K. S. Rehman, B. R. Carr, C. R. Parker Jr., and W. E. Rainey Corticotropin-Releasing Hormone Directly Stimulates Cortisol and the Cortisol Biosynthetic Pathway in Human Fetal Adrenal Cells J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 279 - 285. [Abstract] [Full Text] [PDF]

				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]

				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]

				A. HOEFLICH, M. M. WEBER, T. FISCH, S. NEDBAL, C. FOTTNER, M. W. ELMLINGER, R. WANKE, and E. WOLF Insulin-like growth factor binding protein 2 (IGFBP-2) separates hypertrophic and hyperplastic effects of growth hormone (GH)/IGF-I excess on adrenocortical cells in vivo FASEB J, November 1, 2002; 16(13): 1721 - 1731. [Abstract] [Full Text] [PDF]

				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]

				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]

				H. Zhang, T. Hatta, J. Udagawa, K. Moriyama, R. Hashimoto, and H. Otani Induction of Ectopic Corticotropic Tumor in Mouse Embryos by Exo Utero Cell Transplantation and Its Effects on the Fetal Adrenal Gland Endocrinology, July 1, 1998; 139(7): 3306 - 3315. [Abstract] [Full Text] [PDF]

				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]

				M. G. Leavitt, G. W. Aberdeen, M. G. Burch, E. D. Albrecht, and G. J. Pepe Inhibition of Fetal Adrenal Adrenocorticotropin Receptor Messenger Ribonucleic Acid Expression by Betamethasone Administration to the Baboon Fetus in Late Gestation Endocrinology, July 1, 1997; 138(7): 2705 - 2712. [Abstract] [Full Text] [PDF]

				S. Mesiano and R. B. Jaffe Developmental and Functional Biology of the Primate Fetal Adrenal Cortex Endocr. Rev., June 1, 1997; 18(3): 378 - 403. [Abstract] [Full Text]