Spermatogenesis D.M.de Kretser1, K.L.Loveland, A.Meinhardt, D.Simorangkir and N.Wreford Institute of Reproduction and Development, Monash University, 246 Clayton Road, Clayton, Victoria 3168, Australia *To whom correspondence should be addressed Downloaded from https://academic.oup.com/humrep/article/13/suppl_1/1/788755 by guest on 30 September 2021 Spermatogenesis is a complex process involving (i) the multiplication of spermatogonia by the mitotic cell division, meiosis and the process of process of mitosis; (ii) meiosis, which reduces the spermiogenesis. The regulation of spermato- chromosome number from diploid to haploid and genesis involves both endocrine and paracrine commences with the entry of type B spermatogonia mechanisms. The endocrine stimulation of into the prophase of the first meiotic division. spermatogenesis involves both follicle stimulat- These cells, now called primary spermatocytes, ing hormone (FSH) and luteinizing hormone, divide to form secondary spermatocytes, and then the latter acting through the intermediary divide again to form round spermatids; (iii) the testosterone, produced by the Leydig cells in successful transformation of the round spermatid the testis. Since the germ cells do not possess into the complex structure of the spermatozoon, receptors for FSH and testosterone, the hor- this phase being called spermiogenesis. monal signals are transduced through the Sertoli Each of these steps represents a key element in cells and peritubular cells by the production of the spermatogenic process. Defects which occur signals that have yet to be defined. Although in any of them can result in the failure of the entire the hormonal signals are essential for successful process and lead to the production of defective spermatogenesis, there is increasing evidence spermatozoa and reduction or absence of sperm that a multiplicity of growth factors and cyto- production. It is therefore essential that our under- kines are involved in local control mechanisms standing of these processes is expanded to provide influencing stem cell renewal by mitosis and the information concerning the regulatory mechan- complicated process of the two meiotic cell isms. Many of the studies required to achieve this divisions. The final complex metamorphosis understanding are not possible in the human, and which converts a round cell into the complex consequently we are dependent on studies in structures of the spermatozoa is well defined rodents and primates for the experimental para- at a structural level, but the control systems digms to provide this crucial knowledge. regulating this process still remain to be elucidated. Regulation of spermatogenesis Key words: Sertoli cell/spermatids/spermatocytes/ Advances in the management of male infertility spermatogenesis/spermatogonia will only occur when our understanding of the regulation of spermatogenesis has progressed further. There are considerable data emerging to indicate that this regulation occurs at two major Introduction levels: (i) hormonal and endocrine and (ii) para- Male fertility requires the production by the testis crine/autocrine. It is not possible, in a review of of large numbers of normal spermatozoa through this size, to cover these topics in depth; our a complex process known as spermatogenesis. This intention therefore is to emphasize emerging con- process can be subdivided into three major steps: cepts and to indicate major references in key areas. Human Reproduction Volume 13 Supplement 1 1998 European Society for Human Reproduction & Embryology 1 D.M.de Kretser et al. of germ cells proceeding successfully through the mitotic and meiotic phases of spermatogenesis. Using replacement therapy in the gonadotrophin- deficient (hpg) mouse model in which GnRH is not secreted, Singh et al. (1995) suggested that FSH may not be, required in this species and that the requirement of testosterone for meiosis maybe even more crucial than its requirement for sperm- Downloaded from https://academic.oup.com/humrep/article/13/suppl_1/1/788755 by guest on 30 September 2021 iogenesis. The recent study by Kumar et al. (1997) TIGHT in which the FSH p-subunit gene was knocked out JUNCTION in mice, rendering them FSH deficient, showed that spermatogenesis could proceed to completion, albeit in the presence of smaller testes. These mice were fertile and the results lend support to the Figure 1. The relationships between the the Sertoli cells (S) work of Singh et al. (1995). Other data suggest and the germ cells: spermatogonia (SG), primary that FSH may play a role in stimulating mitotic spermatocytes (PS), round spermatids (RS) and elongated spermatids are illustrated. Where two adjacent Sertoli cells and meiotic DNA synthesis in type B spermato- abut a tight junction is formed which limits intercellular gonia and preleptotene spermatocytes as well as transport and represents the morphological basis of the blood in preventing apoptosis of pachytene spermatocytes testis barrier. Testosterone (T), produced by the Leydig cells and round spermatids (Henriksen et al, 1996; (LC) under the stimulation of luteinizing hormone, acts through receptors on the Sertoli cells to modulate Shetty et al, 1996). McLachlan et al. (1995) spermatogenesis. Follicle stimulating hormone (FSH) acts on demonstrated that FSH alone could partially restore the Sertoli cells and possibly directly on spermatogonia. spermatogenesis in GnRH-immunized rats and Lerchl et al. (1993) observed a similar effect in Hormonal control the photo-inhibited hypogonadotrophic Djungarian The past decade has seen an intense investigation hamster. These data, taken together with studies of the hormonal mechanisms involved in the con- showing the unique testicular localization of the trol of rat spermatogenesis. These studies have FSH receptor in monkeys (Dankbar et al, 1995) more carefully defined the stages at which testos- and its stage-specific expression (Kliesh et al, terone and follicle stimulating hormone (FSH) act 1992) provide compelling evidence for a specific and, from these data, the difficulty of creating role. models to evaluate FSH deficiency has emerged Whether data in the rat can be extrapolated (Figure 1). These problems arise from the ability directly to man is questionable. Several studies of high doses of testosterone to stimulate FSH have indicated the need for both testosterone and concentrations, even in states of gonadotrophin- FSH for the successful completion of spermatogen- releasing hormone (GnRH) deficiency (McLachlan esis and further data in primates are required to et al, 1994). Nevertheless, these studies have confirm these views. It is important to emphasize shown that, in the absence of testosterone, there is that, although testosterone and FSH represent hor- a loss of round spermatids between steps 7-8 of monal prerequisites for spermatogenesis, germ spermatogenesis (O'Donnell et al, 1994). More cells are devoid of receptors for these substances, recent data indicate that this loss is due to failure although FSH binding has been described in of Sertoli cells to produce the adhesion molecule spermatogonia. Consequently these hormones exert N-cadherin, the production of which appears to their effects through Sertoli cells which contain require both FSH and testosterone (Perryman et al, receptors for both FSH and testosterone, through 1996). Testosterone also impacts on normal sperm- mechanisms that still remain unclear. atogonial mitosis and the successful completion of meiosis (Sun et al, 1989, 1990). Spermatogonial renewal In the rat, the role of FSH is more difficult to The spermatogonial population in the mammalian define, but this hormone may modulate the number testis arises from the primordial germ cells which Spermatogenesis migrate into the developing testis during fetal life. Many earlier studies have shown that up to 35% They become associated with the mesenchymal of spermatogonia degenerate, and recent studies cells which are the forerunners of the Sertoli cells, have implicated apoptosis as a principal process by and seminiferous cords are formed. In this setting, which these cells are removed from the epithelium. they transform into gonocytes which remain cent- However, survival of both spermatogonia and sper- rally placed, being surrounded by the immature matocytes appears to be regulated by c-kit/SCF Sertoli cells. Following a period of multiplication, binding (Packer et al, 1995) and, while our under- the gonocytes migrate to the basement membrane standing of spermatogonial division has been Downloaded from https://academic.oup.com/humrep/article/13/suppl_1/1/788755 by guest on 30 September 2021 of the tubule, where they divide to form type enhanced from the study of c-kit/SCF, little is A spermatogonia. The number of spermatogonial known of the regulatory mechanisms controlling types that have been identified varies between apoptosis. Contact with the basement membrane species, but in the human, A pale, A dark and B has been proposed as a key regulator of this process spermatogonial forms can be distinguished (Heller based on studies of germ cell survival in culture. and Clermont, 1964). In the rodent testis, multiple The addition of FSH to rat tubule cultures also has type A spermatogonia, intermediate and type B been shown to influence germ cell apoptosis, spermatogonia have been identified, and their initial affecting both mitotic and meiotic cell populations appearance within the developing testis is con- (Henriksen et al, 1996; Shetty et al, 1996). trolled in a temporal