Continuously Proliferative Stem Germ Cells Partially Repopulate the Aged, Atrophic Rat Testis after Gonadotropin-Releasing Hormone Agonist Therapy1

Aging in the male human is accompanied by testicular atrophy, although relatively little is known about the mechanisms underlying germ cell loss. Testicular 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 cells. However, examination of testicular cross-sections from 27-mo-old Brown Norway rats indicated that approximately 14% of type A spermatogonia were stem cells. Furthermore, using bromodeoxyuridine labeling, we found that approximately 47% of these stem cells were actively dividing, with a cell cycle 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 testicular atrophy in other models of germ cell loss, also partially restored spermatogenesis in the aged Brown Norway rat. The extent of testicular atrophy varied considerably, not only within the control and leuprolide-treatment 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 comparisons showed that significantly fewer leuprolide-treated animals and testes contained < or = 1% populated tubules, indicating that GnRH agonist therapy stimulates differentiation of type A spermatogonia. An increase in the ratio of soluble to membrane stem cell factor mRNA levels was present in aged rats and partially reversed following leuprolide therapy.