Continuously proliferative stem germ cells partially repopulate the aged, atrophic rat testis after gonadotropin-releasing hormone agonist therapy

Aging in the male human is accompanied by testicular atrophy, although rela tively little is known about the mechanisms underlying germ cell loss. Test icular atrophy in the aged Brown Norway rat, an animal model for studies of aging in the human, has been attributed to a loss of spermatogonial stem c ells. However, examination of testicular cross-sections from 27-mo-old Brow n Norway rats indicated that approximately 14% of type A spermatogonia were stem cells. Furthermore, using bromodeoxyuridine labeling, we found that a pproximately 47% of these stem cells were actively dividing, with a cell cy cle time of approximately 12.6 days. Both serum and testicular interstitial fluid testosterone levels were depressed in the aged rat. Therapy with the GnRH agonist, leuprolide, which has been empirically shown to reverse test icular atrophy in other models of germ cell loss, also partially restored s permatogenesis in the aged Brown Norway rat. The extent of testicular atrop hy varied considerably, not only within the control and leuprolide-treatmen t groups but also between the left and right testes of the same animals. No significant difference was found between the mean percentage of populated tubules in 31-mo-old control animals (16.2 +/- 28%, mean +/- SD) and 31-mo- old leuprolide-treated animals (20.9 +/- 19.8%), but categorical comparison s showed that significantly fewer leuprolide-treated animals and testes con tained less than or equal to1% populated tubules, indicating that GnRH agon ist therapy stimulates differentiation of type A spermatogonia. An increase in the ratio of soluble to membrane stem cell factor mRNA levels was prese nt in aged rats and partially reversed following leuprolide therapy.