Activation and regulation of Leydig cell function is exerted primarily by LH, which is secreted in pulses of high biological activity and interacts with membrane receptors. Other hormones and factors secreted by the Leydig cell or from the tubular compartment can influence Leydig cell differentiation and acute or chronic actions of LH on steroidogenesis. Conversely, hormones produced in the Leydig cell could modulate tubular function (e.g. beta-endorphin, oxcytocin). The LH receptor has been purified to homogeneity in sufficient quantities to allow its peptide sequence to be determined and its gene structure to be elucidated as well as functional reconstitution studies to be performed. The LH receptor subunit of Mr 90,000 can be phosphorylated by cAMP-dependent protein kinase. The native receptor appears to exist in the membrane as a dimer of identical subunits associated by noncovalent interactions. It is likely that receptor dimerization and further aggregation are necessary for signal transduction to occur, and receptor phosphorylation by one or more kinases may be involved in regulating gonadotropin action. Stimulation of the androgen pathway occurs mainly through a cAMP-mediated mechanism. The stimulatory event can be negatively influenced by the action of certain peptide hormones through the guanyl nucleotide inhibitory subunit of adenylate cyclase. Such an inhibitory action of angiotensin has further emphasized the importance of the cAMP pathway in the Leydig cell. The hormone also appears to facilitate androgen production by a cAMP-independent mechanism located at the plasma membrane or intracellular sites. A Ca2+ sensitive kinase system is present in the Leydig cell membranes. The presence of nM amounts of Ca2+ induces membrane phosphorylation of a protein Mr 45,000. Adenylate cyclase activation also is affected by Ca2+. Membrane phosphorylation may be a modifier of LH-stimulated adenylate cyclase activity and possibly other LH-induced actions in the activated Leydig cell membrane. In the adult rat testis, the ability of Leydig cells to respond to sustained gonadotropic stimulation with increased androgen production is limited by the development of a refractory state associated with loss of LH receptors and steroidogenic enzymes. Gonadotropin-induced steroidogenic lesions in adult rat testes include a late steroidogenic lesion at the site of conversion of progesterone to androgen and an early lesion before pregnenolone formation that leads to a decreased in vitro pregnenolone and testosterone response to hCG.