Hormonal and genetic control of germ cell apoptosis in the testis

Programmed cell death is an evolutionarily conserved cell death process tha t plays a major role during normal development and homeostasis. In many cas es, the ordered execution of this internal death programme leads to typical morphological and biochemical changes that have been termed apoptosis. The crucial role of this mode of cell death in the pathogenesis of diverse hum an diseases including cancer, acquired immunodeficiency syndrome, neuro-deg eneratives disorders, atherosclerosis and cardiomyopathy is now supported b y a wealth of data. In adult mammals, including humans, germ cell death is conspicuous during normal spermatogenesis and plays a pivotal role in sperm output. Withdrawal of gonadotrophins and testosterone further enhances the degeneration of germ cells in the testis. The availability of a quantitati ve method for analysing the testicular DNA fragmentation and in situ method s to localize specific germ cells undergoing apoptosis, either spontaneousl y or in response to a variety of death triggering signals, opens new avenue s in the understanding of the significance of germ cell apoptosis during no rmal and abnormal states of spermatogenesis. A growing body of evidence dem onstrates that both spontaneous (during normal spermatogenesis) and acceler ated germ cell death triggered by deprivation of the gonadotrophic support or moderately increased scrotal temperature in adult rats occur almost excl usively via apoptosis. Although there has been spectacular progress in the understanding of the molecular mechanisms of apoptosis in various systems o ther than spermatogenesis, elucidation of the biochemical and molecular mec hanisms by which germ cell apoptosis is regulated has only just begun. It i s likely that germ cell apoptosis is controlled in a cell-type specific fas hion, but the basic elements of the death machinery may be universal. In ad dition, there is increasing evidence that homozygous disruption of a number of genes in mice results in infertility through accelerated germ cell apop tosis. Manipulation of spermatogenesis by survival factor(s) deprivation or increases in extrinsic death signals in loss-of-function or gain-of-functi on mouse models provides a basis for further attempts to define the intrins ic regulation of various death-related genes by external death signals. Suc h information is crucial for effective management of male factor infertilit y as well as more targeted approaches to male contraception.