In mammalian seminiferous tubules, Sertoli cells are the primary target for the hormones that control the development and maintenance of the spermatogenic process. Yet the responsiveness of these cells to FSH and B-adrenergic stimulation appears to be present only for a short time during the lifespan of the male gonad. Hormones that markedly stimulate several functions in the immature Sertoli cell are no longer effective in stimulating intracellular events of cells present in the mature testis. In addition, the responsiveness of the Sertoli cell undergoes a cycle that is sinchronized with the development and differentiation of the adjacent germ cells. The overall objective of this research proposal is to study the mechanisms involved in these changes of responsiveness of the Sertoli cell. Our preliminary observations demonstrate that FSH regulates cAMP-phosphodiesterase in vivo and in vitro. We plan to study how hormones control the activity of these cyclic nucleotide hydrolyzing enzymes present in the Sertoli cell. The role of this phosphodiesterase regulation in the control of cAMP intracellular levels and in the refractoriness of the Sertoli cell to hormone will also be investigated. In order to establish the physiological importance of phosphodiesterase regulation and cell refractoriness, the effect of an impaired cAMP accumulation by cultured Sertoli cell will be related to changes in steroid biosynthesis and protein secretion. finally, the mechanisms that produce the acute FSH refractoriness will be compared with a) the age-dependent refractoriness and b) the changes of response that occur during different stages of the spermatogenic cycle. The proposed work will improve the understanding of the gonadotropic modulation of the Sertoli cell and will provide new insight into the mechanisms regulating mammalian spermatogenesis.