In companion studies we have shown that chronic uremic male rats are infertile and hypoandrogenic and have lowered basal LH levels. Fertility was restored by either human CG (hCG) or testosterone treatment. Testicular steroidogenic responses to hCG in vivo and in vitro were normal or excessive, indicating that hypothalamic-pituitary dysfunction was the predominant early lesion in uremic hypogonadism. Further studies were undertaken to characterize the nature of the central defects in regulation of pituitary LH secretion. Uremic rats have reduced MCRs for rat LH (rLH) (61%), rat FSH (rFSH) (47%), and LHRH (41%). Pituitary gonadotropin and hypothalamic LHRH content were unchanged in uremic rats. Pituitary rLH and rFSH responses to LHRH stimulation in vivo and in vitro were quantitatively normal or excessive, with delayed peaks suggesting that uremic pituitary gonadotrope secretion is deficient due to lack of appropriate hypothalamic LHRH drive rather than intrinsic pituitary defects. Despite reduced pituitary gonadotropin secretion in intact uremic rats, castration induced paradoxical excessive increases in pituitary LHRH binding, serum rLH, and rFSH beyond those of nonuremic controls. Paradoxical postcastration hyperresponses of serum rLH and rFSH were not due to circulating immunoreactive fragments of gonadotropins or undernutrition. Dysfunction of the uremic hypothalamus was further characterized in vivo by lack of rLH responsiveness to naloxone and hypersensitivity to negative testicular feedback in castrate-steroid-replaced and intact rats. These data demonstrate that uremic hypogonadism is principally due to aberrant hypothalamic regulation of pituitary LH secretion resembling those of the immature rat or seasonally regressed animal. This recrudescence of the inactive regulatory state in a disease model suggests that common mechanisms are operative in orderly gonadal withdrawal under hostile or inappropriate environments and may underly the reversibility of human uremic hypogonadism with successful renal transplantation.