Synergistic Interactions of Somatomed in-C with Adenosine 3′ ,5′-Cyclic Monophosphatedependent Granulosa Cell Agonists1

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Abstract
Recent studies have demonstrated the ability of somatomedin-C (Sm-C) to synergize with follicle-stimulating hormone (FSH) in the activation of cultured rat granulosa cell progesterone biosynthesis as well as the induction of luteinizing hormone (LH) receptors. Neither effect could be attributed to Sm-C-enhanced granulosa cell survival or replication, but could be accounted for, in part, by increased adenosine 3'',5''-cyclic monophosphate (cAMP) generation. The present study was undertaken to determine if the synergistic property of Sm-C is FSH-selective and hence limited in relevance to follicular maturation, as well as to clarify further the role of cAMP in Sm-C-amplified agonist action. To this end, the ability of Sm-C to modulate the hormonal action of a series of physiologic as well as pharmacologic granulosa cell agonists was examined in vitro using cultured granulosa cells from immature, hypophysectomized, diethylstilbestrol-treated rats. Concurrent treatment with highly purified Sm-C (50 ng/ml) resulted in marked increases over controls in the LH-stimulated [1 ng human chorionic gonadotropin (hCG)]-and .beta.2-adrenergic-stimulated (10-6 M terbutaline) accumulation of cAMP (3.8- and 2.6-fold, respectively and progesterone 3.2- and 7.4-fold, respectively). Similarly, concurrent treatment with Sm-C also augmented the vasoactive intestinal peptidergic stimulation of granulosa cell cAMP generation (4.1-fold) and progesterone biosynthesis (2.1-fold). In contrast, Sm-C was incapable of enhancing progesterone accumulation in response to stimulation with rat prolactin, a cAMP-independent granulosa cell agonist. Concurrent application of increasing concentrations of Sm-C (0.1-50 ng/ml) also produced dose-dependent increments in the choleragen (1 ng/ml)-stimulated accumulation of extracellular cAMP and progesterone with apparent median effective doses (ED50s) of 5.5 .+-. 0.6 and 6.1 .+-. 0.6 ng/ml, and maximal responses 9.7- and 23.8-fold greater than those induced by choleragen alone. Qualitatively similar results were obtained with prostaglandin E2 (PGE2). Taken together, these findings suggest that the synergistic potential of Sm-C is not FSH selective, that it may be observed with other granulosa cell agonists for which cAMP may be a second messenger, and that it is closely linked to the ability of Sm-C to affect cAMP generation. These observations also raise the prospect that Sm-C may not be relevant to early follicular maturation alone, but it may also play a role in modulating LH/hCG and .beta.2-adrenergic input concerned with the initiation and maintenance of the ovarian corpus luteum.

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