Ovarian folliculogenesis entails proliferation as well as differentiation of the developing granulosa cell (GC). Although the central role of gonadotropins in this process is well established, the variable fate of follicles afforded comparable gonadotropic stimulation, suggests the existence of additional intraovarian modulatory mechanism(s). Amongst potential novel modulators of GC ontogeny, Somatomedin-C (Sm-C) appears uniquely suited to the task, combining replicative and cytodifferentiative properties. Although Sm-C was previously shown to stimulate bovine GC proliferation, the reciprocal nature of proliferation and differentiation precluded demonstration of its cytodifferentiative potential. To overcome this limitation, preliminary studies reported herein mad use of rat GCs of limited growth potential in vitro, thereupon revealing that Sm-C is capable of synergizing with FSH in the induction of progesterone biosynthesis and LH receptors. Significantly, this direct cytodifferentiative effect of Sm-C is distinct from its replicative property, and may thus represent a novel biologic effect of this polypeptide. These observations, coupled with the demonstration of GC immunoreactive Sm-C release, suggest the existence of a novel intraovarian autocrine control mechanism, wherein Sm-C may serve as the central signal, and the granulosa cell its site of production, reception, and action. According to this view, Sm-C of GC origin may play an autocrine role at or adjacent to its site of synthesis, interacting with GC """"""""autoreceptors"""""""" to amplify for attenuate gonadotropic control of GC ontogeny. To test this hypothesis, in vitro studies are proposed on the role and regulation of GC immunoreactive Sm-C release, the characteristics and regulation of GC Sm-C receptors, as well as the mechanism(s) and site(s) of action of Sm-C in GC differentiation. In these experiments, the role(s) of endogenously produced Sm-C will be deduced from immunoneutralization studies, using a monoclonal antibody to Sm-C. Similarly, the identity of the receptor mediating the cytodifferentiative effect of Sm-C, will be evaluated through selective blockade of Sm-C receptors with an anti-receptor monoclone. The long term objectives of this investigation include studies of the in vivo ontogeny of ovarian Sm-C and its receptor, the identification of ovarian Sm-C-producing cells other than the GC, the role of Sm-C in intraovarian paracrine interaction, and its linkage with defined physiologic processes.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Modified Research Career Development Award (K04)
Project #
5K04HD000697-04
Application #
3073309
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1986-07-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Adashi, E Y; Resnick, C E; Hurwitz, A et al. (1992) The intra-ovarian IGF system. Growth Regul 2:10-5
Adashi, E Y; Resnick, C E; Hurwitz, A et al. (1991) Insulin-like growth factors: the ovarian connection. Hum Reprod 6:1213-9
Adashi, E Y; Resnick, C E; Hernandez, E R et al. (1991) Insulin-like growth factor I as an intraovarian regulator: basic and clinical implications. Ann N Y Acad Sci 626:161-8
Adashi, E Y; Resnick, C E; Jastorff, B (1990) Blockade of granulosa cell differentiation by an antagonistic analog of adenosine 3',5'-cyclic monophosphate (cAMP): central but non-exclusive intermediary role of cAMP in follicle-stimulating hormone action. Mol Cell Endocrinol 72:1-11
Adashi, E Y; Resnick, C E; Croft, C S et al. (1989) Tumor necrosis factor alpha inhibits gonadotropin hormonal action in nontransformed ovarian granulosa cells. A modulatory noncytotoxic property. J Biol Chem 264:11591-7
Payne, D W; Holtzclaw, W D; Adashi, E Y (1989) A convenient, unified scheme for the differential extraction of conjugated and unconjugated serum C19 steroids on Sep-Pak C18-cartridges. J Steroid Biochem 33:289-95
Adashi, E Y; Resnick, C E; Hernandez, E R et al. (1989) Ovarian transforming growth factor-beta (TGF beta): cellular site(s), and mechanism(s) of action. Mol Cell Endocrinol 61:247-56
Adashi, E Y; Resnick, C E; Hernandez, E R et al. (1988) Characterization and regulation of a specific cell membrane receptor for somatomedin-C/insulin-like growth factor I in cultured rat granulosa cells. Endocrinology 122:194-201
Payne, D W; Holtzclaw, W D; Adashi, E Y (1988) The steroidogenic characteristics of primary testicular cell cultures from adult hypophysectomized rats: enhanced formation of C21 steroids. Biol Reprod 39:581-91
Adashi, E Y; Resnick, C E; Hernandez, E R et al. (1988) Insulin-like growth factor-I as an amplifier of follicle-stimulating hormone action: studies on mechanism(s) and site(s) of action in cultured rat granulosa cells. Endocrinology 122:1583-91

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