Spermatogenesis is the development of spermatogonia into spermatozoa and this process takes place in the seminiferous tubule of the adult testis. Three central processes encompasses spermatogenesis: mitotic replication of spermatogonia, meiotic proliferation of spermatocytes, in which genetic material is recombined and segregated, and post-meiotic differentiation into spermatozoa, also termed spermiogenesis (Russell et al., 1990a), (Soares et al., 2009) (Fig 1.1).
The functional morphology of the seminiferous tubule depicts the different phases of the spermatogenesis (Courot et al., 1970). Myoid cells and fibroblasts encompass the external part of the basement membrane. The blood supply of the testis is confined to the interstitial tissue by the basement membrane, and therefore does not enter the seminiferous tubule itself (Pelletier and Byers, 1992). Groups of Leydig cells are situated between the tubules as a part of the interstitial tissue. They are the central component of the endocrine portion of the testis and synthetises testosterone, which is the androgen hormone that drives the spermatogenesis (Hooker, 1970),(Hall, 2006).
Somatic Sertoli cells are positioned on the internal side of the basal membrane of the seminiferous tubule. They are cylindrical in shape with an elusive outline of the cell membrane and contain an irregularly shaped nuclei located close to the basement membrane, which contains a small amount of chromatin and a distinct nucleolus (Foote et al., 1972), (Russell et al., 1990a). The Sertoli cells provide nutritional and physical support for the germinal cells and therefore extent all through the layers of the seminiferous epithelium, in order to be in close connection to all the different phases of germinal cells in the spermatogenesis (Griswold, 1998). Tight cell junctions, adherent junctions and gap junctions between the Sertoli cells form the blood-testis barrier and separate the seminiferous tubules into a basal and a luminal compartment (Pelletier and Byers, 1992, p. -). This sustains a specialized environment in the luminal compartment and dissociates the germ cells of the meiotic and spermiogenic phases from the immune system (Hochereau-de Reviers et al., 1990), (Pelletier and Byers, 1992). The junctions between the Sertoli cells form around puberty and are androgen-dependent, like the adherence between Sertoli cells and germinal cells (Holdcraft and Braun, 2004a).
Spermatogenesis can be classified based on changes in the shape of the spermatid nucleus, the location of spermatids and spermatozoa in regard to the basement membrane, presence of meiotic figures and the release of spermatozoa from the lumen of the tubule (Foote et al., 1972). These stages can also be identified based on the development of the acrosome system and the morphology of developing spermatids (Russell et al., 1990b), (Soares et al., 2009) as well as tubular morphology, in which the shape and location of the spermatid nucleus are the main aspects of consideration (Courot et al., 1970).
The epithelium of the seminiferous tubule appears as concentric layers of Sertoli cells, spermatogonia, spermatocytes, and spermatids (Parkinson, 2009) (Fig. 1.2)
Numerous generations of spermatogonia, the immature germinal stem cell, are situated along the basement membrane. These undergo several rounds of mitosis to form a reservoir of stem cells, of which some will later undergo meiosis, differentiating spermatogonia, and form spermatozoa (Russell et al., 1990a).
The A-spermatogonia is the least differentiated of the germ cells, and after several rounds of mitosis it gives rise to intermediate spermatogonia, that eventually form B-spermatogonia. The B-spermatogonia move closer to the lumen of the seminiferous tubule and therefore has significantly reduced connection to the basement membrane (Kerr et al., 2006).
After the last round of mitosis the B-spermatogonia give rise to preleptotene primary spermatocytes, which initiates the prophase of the first meiotic cell division, by developing into leptotene primary spermatocytes. They enter the zygotene phase with pairing of homologous chromosomes, and then later the pachytene phase with genetic recombination of the paired chromosomes. Finally the primary spermatocytes undergo diakinesis, the separation phase of meiosis, and give rise to short-lived secondary spermatocytes, which go through another round of meiotic cell division to produce round spermatids (Russell et al., 1990a), (Parkinson, 2009).
Next step in the development of spermatozoa is the maturation of spermatids, termed spermiogenesis. This process consists of the synthesis of the acrosome and the formation of the tail from the centrioles. One centriole forms the piece connecting the neck and the head of the sperm, while the other one forms the axial filament of the tail (Kerr et al., 2006).
Late in the spermiogenesis a helix of mitochondria densify around the proximal part of the flagellum, forming the mid-piece of the spermatozoa.
Just before spermiation, the release of spermatozoon into the lumen of the seminiferous tubule, the Sertoli cell phagocytizes the remaining of the cytoplasm of the spermatid (Fouquet, 1974).
1.2 Endocrine Regulation of Spermatogenesis
Endocrinological control of the testes is regulated by the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). They are both synthesized and secreted from the anterior pituitary gland upon stimulation from the gonadotropin-releasing hormone (GnRH), which is produced in the hypothalamus in the brain (van Sluijs, 1996) (Parkinson, 2009). Furthermore, paracrine and autocrine intratesticular factors play a significant role in the endocrine regulation within the testes (Parkinson, 2009).
Expression of FSH receptors is confined to testicular Sertoli cells in males (Rannikki et al., 1995), while expression of LH receptors are found in Leydig cells, primarily, although receptor staining in spermatogenic cells has also been observed (Eblen et al., 2001), (Lei et al., 2001).
GnRH is produced by neurons in the hypothalamus and transferred via the hypothalamic-hypophyseal portal blood to the pituitary where it stimulates the release of gonadotropes (Lincoln, 1979) (Fig 1.3). LH is secreted in a pulsatile fashion and acts upon Leydig cells to stimulate testosterone synthesis, (Günzel-Apel et al., 1990a), (O’Donnell et al., 2006). It appears that LH has only one function within the testes and that is the essential regulation of androgen production (Holdcraft and Braun, 2004a).
Peaks of LH are followed by peaks testosterone 30-40 minutes later (Günzel-Apel et al., 1990a). When LH stimulates testosterone production in the Leydig cells, it is mainly mediated through adenylate cyclase, which conducts the conversion of cholesterol to pregnenolone. This is the rate-limiting point of testosterone synthesis, in a course of intermediate steps (Hall, 2006).
Testosterone binds to androgen receptors (AR), which are found in Leydig, Sertoli and myoid cells (Holdcraft and Braun, 2004a) but not in germinal cells.
Testosterone has several functions in and outside the testis. First of all it drives the spermatogenesis in the seminiferous tubules, but it is also necessary for the following maturation of the spermatozoa in the epididymis, and for the action of the accessory sex glands. Libido and the development of secondary male characteristics are also features controlled by testosterone (Parkinson, 2009).
When FSH is released from the pituitary gland it stimulates Sertoli cells to synthesize and secret androgen-binding protein (ABP) (Gunsalus et al., 1981). Through adenylate-cyclase-linked enzyme systems Sertoli cells also aromatize testosterone into oestrogens (O’Donnell et al., 2006). FSH is furthermore responsible for inducing genes in the Sertoli cell that control and support spermatogenesis (Walker and Cheng, 2005).
Sertoli cells and accessory sex glands are responsible for the metabolism of testosterone, in which it is converted by 5α-reduction to 5α-dihydrotestosterone (DHT) (Bardin et al., 1994). DHT is not prone to aromatization like testosterone, and it is a more potent androgen and seems to be the main androgen associated with the spermatogenesis (Walker and Cheng, 2005).
Both testosterone and DHT are bound to androgen-binding protein (ABP) and thereby a high concentration of androgen hormone is sustained in the seminiferous tubule and the epididymis (Parkinson, 2009).
Another factor that is important for the number of spermatozoa in the adult testis is the number of Sertoli cells (Knobil et al., 2006). Studies in rodents have shown that the pre-pubertal proliferation of Sertoli cells is stimulated by FSH (Heckert and Griswold, 2002).
In general, it is believed that FSH is not secreted in a pulsatile fashion like LH, but a few studies appear to reveal an episodic pattern of FSH secretion (Lumpkin et al., 1984), (Culler and Negro-Vilar, 1987), (Pau et al., 1991).
Testosterone exerts negative feedback on the synthesis and release of GnRH from the hypothalamus and gonadotropins from the pituitary gland, both directly and after the transformation into DHT and oestradiol (Jackson et al., 1991), (Tilbrook et al., 1991), (Tilbrook and Clarke, 2001). Oestradiol and inhibin both exert negative feedback on the secretion of gonadotropins (Baird et al., 1991). Sertoli cells synthesize and secret inhibin, and it inhibits the secretion of FSH from the pituitary gland (Tilbrook et al., 1993), but has limited impact on the LH secretion (Tilbrook et al., 1995).
There are different types of inhibin, but inhibin B is the major form in most males of domestic species (McNeilly et al., 2002). Furthermore Sertoli cells synthesize and secret activin, which both stimulate FSH synthesis in the pituitary gland but also acts as a paracrine hormone within the testis (De Kretser et al., 2004).
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