Age-related decrease in hypothalmic gonadotropin-releasing hormone (GnRH) gene expression, but not pituitary responsiveness to GnRH, in the male brown Norway rat

As is the case in humans, aging male Brown Norway (BN) rats exhibit both pr imary and secondary (hypothalamic/pituitary) testicular failure. We hypothe sized that secondary testicular failure in aging BN rats is due to alterati ons in both hypothalamic and pituitary function. In order to determine whet her gonadotropin-releasing hormone (GnRH) gene expression is altered with a ging, we compared hypothalamic preproGnRH (ppGnRH) mRNA by in situ hybridiz ation histochemistry and GnRH peptide content in microdissected brain areas by radioimmunoassay in intact (or sham-operated) young, middle-aged, and o ld male rats. In addition, we determined hypothalamic-pituitary responsiven ess to the removal of testicular feedback by comparing ppGnRH messenger RNA (mRNA) and gonadotropin levels in sham-operated and orchidectomized young, middle-aged, and old rats. In sham-operated rats, both the cellular ppGnRH mRNA content and the number of neurons expressing ppGnRH mRNA were lower i n old compared with young and middle-aged rats. In addition, GnRH content d ecreased with aging in intact rats in 2 of the 3 brain areas examined, and GnRH content tended to decrease with aging in the third region. Morning ser um luteinizing hormone (LH) levels were unchanged with aging, whereas folli cle-stimulating hormone (FSH) was significantly increased in old compared w ith younger intact rats. The cellular ppGnRH mRNA content also decreased wi th aging in orchidectomized rats, although the number of neurons expressing ppGnRH mRNA was unchanged with aging in these rats. Within age groups, the cellular ppGnRH mRNA content was higher in orchidectomized than in sham-op erated rats, though there was no effect on the number of neurons expressing GnRH. In a second study, we compared pituitary responsiveness to GnRH by m easuring serum LH and FSH levels after GnRH administration in intact BN rat s of different ages. The LH response to GnRH was unchanged with aging, wher eas the FSH response to GnRH tended to increase with aging. Despite similar LH responses, the testosterone (T) response to GnRH declined progressively with aging. A third study assessed age-related changes in the circadian rh ythm of circulating LH, T, and corticosterone (B) levels. LH levels over a 24-hour period decreased with aging and tended to be lower in the morning h ours in all age groups, and circadian rhythmicity was blunted in middle-age d and old compared with young rats. T levels over 24 hours declined progres sively with aging, and these levels showed a bimodal diurnal variation in y oung rats, a variation that was not evident in older animals. B levels over a 24-hour period were lower in old than in younger animals, and with aging , there was dampening of the amplitude of the circadian rhythm of B. Taken together, these findings suggest that secondary testicular failure in aging male BN rats is due in part to decreased GnRH gene expression rather than to decreased pituitary responsiveness to GnRH. This reduction in GnRH gene expression with aging is not dependent on testicular feedback factors. Fina lly, the blunted circadian rhythmicity of LH and T secretion with aging pro vides further evidence of altered hypothalamic regulation of gonadal hormon e secretion in old animals.