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

Abstract

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.

Spermatogonial stem cell enrichment using simple grafting of testis and in vitro cultivation

“…Rathi et al and Schoenfeld et al reported that testicular stem cells continuously proliferated in the aging testis after grafting3435. In the present study, we introduced a testis tissue grafting method for the enrichment of SSCs from adult testis connected with the simultaneous cultivation of these cells because tissue grafting is potentially be a better strategy for germ cell preservation and transplantation in humans than the cryptorchid or hyperthermia-exposed methods.…”

Inhibition of Recovery of Spermatogenesis in Irradiated Rats by Different Androgens

“…That study led to the conclusion that the inhibitory factor must be T or an androgenic metabolite of T. Other studies showed that suppression of androgens, using GnRH analogs, also stimulated spermatogonial differentiation in rats after spermatogenesis had been inhibited by procarbazine (6), hexanedione (37), heat treatment (38), or aging (39). GnRH-antagonist treatment also stimulated spermatogonial differentiation in juvenile spermatogonial depletion (jsd) mutant mice, which are depleted of all germ cells except A spermatogonia (40,41).…”

Expression of a K48R Mutant Ubiquitin Protects Mouse Testis from Cryptorchid Injury and Aging

“…This decrease in testosterone may result from dysregulation at the hypothalamic-pituitary axis, in addition to age-related changes in Leydig cells. [17][18][19] Along with hormonal changes, alterations in testis vasculature may contribute to injury. In Sprague Dawley rats, aged testes have a significant reduction in blood vessel volume; 6-month and 24-month-old testes had 71% and 31% of the blood vessel volume, respectively, when compared to 3-month-old controls.…”