We studied the involvement of major histocompatibility (MHC) class I antigens on the mechanism of LH/hCG receptor activation. For this purpose we investigated the effects of anti-MHC class I antibodies on hormone-receptor interaction, signal transduction, and MHC class I antigen-receptor interaction. Monoclonal antibodies against MHC class I antigen were able to stimulate testosterone production in mouse Leydig cells with the same potency as LH. This biological effect depends on the concentration of antibody used and could be abolished by a LH antagonist. There is a perfect parallelism, for each monoclonal antibody, between the specificity for a particular haplotype and the response of the target cells from the strains carrying such a haplotype. The same antibodies were able to precipitate the soluble LH/hCG receptors, as both a hormone-receptor complex and a free receptor. The results suggest that bound hormone triggers an association of the MHC class I antigen with the LH/hCG receptor, resulting in activation of the target cell.

Flutamide is a nonsteroidal antiandrogen that blocks androgen receptors, with a consequent increase in serum immunoreactive LH (I-LH) in the presence of high testosterone concentrations. Several studies suggested that the gonadal steroids also play an important role in the regulation of LH bioactivity (B-LH). Therefore, it seems difficult to understand how the blockade of pituitary androgen receptors leads to the increase in testosterone levels. The present study was designed to elucidate the effect of flutamide on serum I-LH, B-LH and testosterone, as well as on in vitro stimulation of pituitaries by gonadotropin-releasing hormone (GnRH), in intact and androgen-treated castrated rats. In intact animals, a dose of flutamide as low as 0.5 mg/day provoked a 7- to 8-fold increase in serum I-LH levels over the vehicle-injected controls, whereas B-LH and testosterone were unaffected. However, higher doses significantly increased serum B-LH to values similar to those obtained in vehicle-injected castrated animals, resulting in high testosterone levels. Flutamide treatment provoked a decrease in I-LH and B-LH pituitary content; this effect was significantly higher under in vitro GnRH stimulation. The releasable I-LH under GnRH stimulation was not affected by flutamide treatment; however, a marked decrease was observed in B-LH. The results presented here show that (1) the interference of androgen action by flutamide is as efficient as castration to affect I-LH and B-LH; (2) androgens may act directly at the pituitary level; (3) androgens modulate the action of GnRH in the pituitary gland, and (4) the effect of androgens on the pituitary can be observed at two distinct levels, depending on the androgen concentration, that is on LH synthesis and release, and on LH bioactivity. In addition, our results confirm that high doses of flutamide are not enough to abolish the biological action of androgens, due to the increase in LH bioactivity resulting in high androgen concentrations.

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