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Testosterone Acts Directly at the Pituitary to Regulate Gonadotropin-Releasing Hormone-Induced Calcium Signals in Male Rat Gonadotropes¹

Department of Physiology, Monash University, Clayton, Victoria 3168, Australia; Research Unit for Molecular Reproductive Endocrinology, Department of Chemical Pathology, University of Cape Town, South Africa

Address all correspondence and requests for reprints to: Dr. B. J. Canny, Department of Physiology, Monash University, Clayton, Victoria 3168, Australia. E-mail ben.canny{at}med.monash.edu.au

We have recently shown that castration alters GnRH-induced calcium (Ca²⁺) signaling in the gonadotropes of male rats. Instead of generating spike-plateau Ca²⁺ responses to high concentrations of GnRH (100 nM), the majority of gonadotropes from castrated rats have oscillatory Ca²⁺ responses, which are generally only seen with low concentrations of GnRH in the gonadotropes of intact rats. This change in the nature of GnRH-induced Ca²⁺ responses is prevented by in vivo testosterone treatment. The aims of the present study were, therefore, to determine if testosterone acts directly at the pituitary or via the regulation of hypothalamic GnRH secretion. Accordingly, castrated male rats were treated with a GnRH antagonist to ablate the effects of increased GnRH secretion at the pituitary gland. GnRH antagonist treatment (10 µg/100 g BW, twice daily for 7 days from the time of castration) decreased the concentration of LH in the serum of castrated rats (0.4 ± 0.1 ng/ml vs. 11.2 ± 0.4 ng/ml in untreated castrated rats, mean ± SEM) but had no effect on the proportion of gonadotropes having oscillatory Ca²⁺ responses to 100 nM GnRH when compared with untreated castrated rats (63% in antagonist-treated castrated rats vs. 70% in untreated castrated rats). The GnRH antagonist treatment did not, however, interfere with the ability of in vivo testosterone treatment (100 µg/100 g body weight/day) to decrease the proportion of gonadotropes having oscillatory Ca²⁺ responses to 100 nM GnRH (26% in testosterone-treated rats vs. 25% in testosterone and antagonist-treated rats). These findings indicate that testosterone acts directly at the pituitary, and not by altered GnRH secretion, to modulate GnRH-induced Ca²⁺ signals. To confirm this suggestion, cultured gonadotropes of castrated male rats were treated in vitro with 10 nM testosterone. Testosterone treatment for twelve, but not 4 h, restored the proportion of gonadotropes having oscillatory Ca²⁺ responses to that seen in gonadotropes from intact rats. The in vitro effects of testosterone over 12 h were prevented by concomitant treatment with the protein synthesis inhibitor cycloheximide (10 µM), which, when given alone, had no effect on GnRH-induced Ca²⁺ signals in cells from castrate male rats. Taken together, these findings suggest that testosterone has a direct genomic action at the pituitary to regulate GnRH-induced Ca²⁺ signals, via a process that involves new protein synthesis.

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