Somatomedin-C/Insulin-Like Growth Factor I as an Enhancer of Androgen Biosynthesis by Cultured Rat Ovarian Cells*

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Abstract
The ovarian granulosa cell has recently been shown to be a site of somatomedin-C/insulin-like growth factor I (Sm-C/IGF-I) production, reception, and action. These observations have generally been interpreted to suggest the existence of an autocrine loop concerned with granulosa cell physiology. It is the objective of the in vitro studies reported herein to extend these observations by evaluating the interaction of Sm-C/IGF-I with the adjacent thecal-interstitial cell. Treatment of collagenase-processed whole ovarian dispersates or highly enriched (> 90%) thecal-interstitial cells from immature rats with Sm-C/IGF-I (50 ng/ml) or hCG (1 ng/ml), resulted in 2.1- and 4.0-fold increments in the acucmulation of androsterone (3.alpha.-hydroxy-5.alpha.-androstane-17-one), the main androgenic steroid identified in culture media. However, combined treatment with both agents unmasked a synergistic interaction producing a 3.3-fold increase in the hCG-stimulated accumulation of androsterone, an effect consequent to enhanced androgen biosynthesis rather than diminished degradation. Unaccounted for by an increase in viable ovarian cell numbers and independent of the hCG dose (0.1-10 ng/ml) used, the Sm-C/IGF-I effect proved time and dose dependent, with a projected minimal effective dose of 3 ng/ml and a minimal time requirement of 72 h. [125I]Iodo-Sm-C/IGF-I binding to untreated highly enriched thecal-interstitial cells proved saturable, with a single class (Hill coefficient = 0.98 .+-. 0.01) of high affinity (Kd = 3.0 nM), low capacity (maximum binding = 10,840 .+-. 2,108 sites/cell) binding sites. Limited specificity studies using related peptides produced a rank order of competitive potency of: Sm-C/IGF-I > multiplication stimulating activity > insulin, a pattern compatible with the presence of type I IGF receptors. Other related peptides, such as porcine proinsulin and porcine desoctapeptide insulin, proved weakly effective in inhibiting Sm-C/IGF-I binding to its receptor, unrelated peptides such as porcine relaxin and erythropoietin were without effect. Taken together, these findings suggest that 1) the thecal-interstitial cell, like the granulosa cell, may be a site of Sm-C/IGF-I reception and action, and 2) the ability of high dose insulin to stimulate ovarian androgen biosynthesis may be due to its capacity to act as a Sm-C/IGF-I surrogate, its high dose requirements reflecting cross-interaction with the type I receptor. Moreover, these observations raise the possibility that Sm-C/IGF-I of granulosa cell origin may constitute one of several signals through which the granulosa cell may communicate in a paracrine fashion with the adjacent thecal-interstitial cell compartment. In doing so, the granulosa cell may exert some control over its own destiny by enhancing ovarian androgen provision to suit its aromatizing capabilities and the estrogen requirements of the developing follicle as a whole.