Apoptosis appears to have an essential role in the control of germ cell number in testes. During spermatogenesis germ cell deletion has been estimated to result in the loss of up to 75% of the potential number of mature sperm cells. At least three factors seem to determine the onset of apoptosis in male germ cells: (1) lack of hormones, especially gonadotropins and androgens; (2) the specific stage in the spermatogenic cycle; (3) and the developmental stage of the animal. Although male germ cell apoptosis has been well characterized in various animal models, few studies are presently available regarding germ cell apoptosis in the human testis. The first part of this review is focused on germ cell apoptosis in testes of prepubertal boys, with special emphasis on apoptosis in normal and cryptorchid testes. A higher percentage of apoptotic spermatogonia was seen in the cryptorchid testes than in the scrotal testes. The hCG-treatment increased the number of apoptotic spermatogonia. The hCG-treatmentinduced apoptosis in spermatogonia had severe long-term consequences in reproductive functions in adulthood. Increased apoptosis after hCG-treatment was associated with subnormal testis volumes, subnormal sperm density and pathologically elevated serum FSH. This finding indicates that increased apoptosis in spermatogonia in prepuberty leads to disruption of testis development. To evaluate the role of apoptosis in human adult testes, apoptosis was induced in seminiferous tubules that were incubated under serum-free conditions in the absence or presence of testosterone. Most frequently apoptosis was identified in spermatocytes. Occasionally some spermatids also showed signs of apoptosis. In short term incubations apoptosis was suppressed by testosterone. Our findings lead to the conclusion that apoptosis is a normal, hormonally controlled phenomenon in the human testis. The role of apoptosis in disorders of spermatogenesis remains to be established.
Antioxidant defenses play a critical role in the regulation of programmed cell death, even when death is induced by nonoxidative stimuli. During spermatogenesis, most of the testicular germ cells degenerate by an apoptotic process that is under hormonal control. However, the exact mechanisms by which hormonal signals are transduced within the cells to direct their life, and whether other effectors of the apoptotic pathway, for example antioxidants, take part in the control of human germ cell survival, are not known. In the present study, testosterone and N-acetyl-L-cysteine (NAC), which is an antioxidant, an inhibitor of apoptosis in several systems, and a survival factor in human semen, were found to suppress programmed cell death in human testicular germ cells in vitro. The samples came from adult men undergoing orchidectomy for prostate cancer. Germ cell death was induced by incubating segments of seminiferous tubules under serum-free culture conditions. This apoptosis, detected by Southern blot analysis of DNA fragmentation, by DNA labeling in situ, and by morphological analysis under the electron microscope, was significantly inhibited by testosterone at concentrations of 10(-6) and 10(-7) mol/L. NAC concentrations of 125, 100, 50, and 25 mmol/L suppressed germ cell death in a dose-dependent manner. This inhibition was effective during 4, 24, and 48 h of incubation. Apoptotic cells were identified mainly as spermatocytes and early spermatids. Programmed cell death was also demonstrated in late spermatids. We conclude that NAC, which is an antioxidant, plays an important role in germ cell survival in the human seminiferous tubules in vitro. We also suggest NAC as a possible new therapeutic factor for some men with idiopathic oligospermia.
In the present study an in vitro model was developed and characterized for evaluation of the role of apoptosis in adult human testes. The samples came from adult men undergoing orchidectomy for prostate or testicular cancer. Segments of seminiferous tubules were isolated and incubated under serum-free conditions in the absence or presence of testosterone. Apoptosis was assessed by low mol wt DNA fragmentation (185-bp multiples) by use of 3'-end-labeled DNA, in situ end labeling, and morphological detection under light and electron microscopy. During the 4-h incubation, a 15-fold increase was seen in apoptotic DNA fragmentation. The extent of low mol wt DNA showed a time-dependent increase and reached a 20-fold intensity in 24 h of incubation compared to the level at 0 h. Apoptosis was significantly suppressed by testosterone concentrations of 10(-7) and 10(-6) mol/L during the first 4 h of incubation. Apoptotic cells were identified mainly as spermatocytes and occasionally as spermatids. We conclude that apoptosis is induced in human seminiferous tubules under serum-free conditions in vitro. That this apoptosis is suppressed by testosterone indicates that testosterone in the human male is a critical germ cell survival factor. The model created in the present study provides a valuable tool for further investigation of hormonal and gene regulation of human germ cell death and survival.
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