ANATOMY OF THE MALE SEX ORGANS
The male sex organs consist of testes, epididymides, ductus deferentes, accessory sex glands, and penis (Figure 1.1). The testes differentiate in the fetus from indifferent gonads after expression of the SRY gene on the short arm of the Y chromosome. Fetal Leydig cells then secrete androgens that induce differentiation of the mesonephric (or Wolffian) duct into the epididymis and ductus deferens and some of the accessory sex glands and the indifferent external genitalia into a penis (Meniru 2004).
The testes are two oval structures that normally lie in the scrotum (Figure 1.2). Caudal migration of testes from the abdomen takes place late in fetal life (around week 25–30). Testicular descent into a cool environment may have evolved to minimize the mutation rate in male germ cells (Setchell & Breed 2006). Each testis measures 4–6 cm in length and has a volume of about 25 mL. Testes are encased by a tough fibrous capsule, the tunica albuginea. This comprises an outer layer of visceral peritoneum made up of mesothelial cells, and inside this there is a layer of fibroblasts, collagen fibers, and bundles interspersed by smooth muscle cells.
Testes produce spermatozoa and testosterone (the male hormone). A mature spermatozoon is shown in Figure 1.3. The spermatozoon carries a copy of the man's genetic makeup, the chromosomes, from the site of production in the testis, through the male and female genital tracts, to the oocyte so that fertilization may occur. The spermatozoon carries this genetic material in the headpiece. The rest of the spermatozoon is made up of the mid-piece, which supplies the energy, and the tail, which propels the sperm forward.
Seminiferous tubules are contained within the testis (Figure 1.4). The seminiferous tubules contain germ cells and somatic Sertoli cells that have essential nutritive and physiological functions essential for the developing germ cells. Contractions of the peritubular myoid cells surrounding the seminiferous tubules are responsible for moving the luminal fluid and spermatozoa out of the seminiferous tubules through the rete and the efferent ducts into the epididymis. The interstitial spaces between the seminiferous tubules contain the blood and lymph vessels, macrophages, and Leydig cells. Both ends of each seminiferous tubule open into tubuli recti and then to the rete testis. In humans, up to six seminiferous tubules can join a single tubulus rectus. The rete testis is linked to the epididymal duct by the efferent ducts (ductuli efferentes). These ducts form a cord that is anatomically differentiated into a proximal (initial) zone, where the individual ducts run roughly parallel to each other, and a distal zone (Setchell & Breed 2006).
The epididymis consists of a single highly convoluted duct that develops from the mesonephric (or Wolffian) duct. It measures 5–6 cm and connects the tubules of the testis to the vas deferens. Sperm transport along the epididymal duct is affected by its tunic of smooth muscle. The vas deferens is 35–45 cm long. It originates in the scrotum and courses upward to the groin. It then enters the body cavity through the inguinal canal and joins the duct of the seminal vesicle on that side to form the ejaculatory duct. Spermatozoa reaching the ejaculatory duct from the vas deferens of each side are ejected from the penis, together with secretions from the accessory sex glands at the time of ejaculation. Table 1.1 shows the location and role of the tubules the sperm pass through in the male reproductive tract.
The accessory sex glands arise in part from the mesonephric or Wolffian duct and in part from the prostatic and penile urethra. Vesicular glands (seminal vesicles) and ampullary glands develop as diverticula from the mesonephric duct. The prostate and bulbourethral (Cowper's gland) glands arise from the proximal and distal urethra, respectively, as compound tubular alveolar secretory glands. The secretion of the accessory sex glands contains various substances (e.g. fructose, citric acid, zinc, and acid phosphatase) that are added to semen at ejaculation. The prostate surrounds the urethra at the neck of the bladder and is the largest accessory sex gland.
The penis is an intromittent organ by which semen is deposited in the female reproductive tract. Man has a vascular penis that contains two corpora cavernosa that are united by a septum and, inferiorly, a single corpus spongiosum that surrounds the urethra. The corpora cavernosa are covered by a tunica albuginea with trabeculae of elastic fibers and smooth muscle passing inward to subdivide the cavernous bodies into endothelial-lined cavities that are continuous with blood vessels. Upon erection, these cavities become filled with blood and the blood vessels extend. The distal ends of the corpora cavernosa are covered by the glans, which is an extension of the corpus spongiosum. Caudally, the corpus spongiosum is enlarged to form the urethral bulb, which is surrounded by a bulbocavernosus muscle, whereas the root of the corpora cavernosa is surrounded by ischiocavernosus muscles.
The scrotum is an outpouching of skin. It lacks subcutaneous fat and has abundant sweat glands. Beneath the skin there is a layer of smooth muscle, the tunica dartos that contracts in response to cold and draws the testes up toward the body wall, whereas in a warm environment it relaxes to increase the surface area of the scrotum by up to 20% (Setchell & Breed 2006).
BLOOD SUPPLY OF THE MALE SEX ORGANS
The vascular supply and innervations of the male reproductive system are important because interruption of either the blood supply or the innervation leads to disturbances of reproductive function.
The blood supply to the testis is via the long and convoluted testicular artery. It is surrounded by the multiple veins of the pampiniform plexus. The testicular artery originates from the abdominal aorta. The vascular arrangement of the spermatic cord facilitates a countercurrent heat exchange that cools the descending arterial blood by 2–6°C before its entry into the testis. The countercurrent heat exchange between the arterial and venous blood keeps the testes and epididymides cool.
In approximately 15% of humans, the veins of the pampiniform plexus dilate to form a varicocele, and the incidence is appreciably higher in men attending infertility clinics. Varicocele is more common on the left side. It is often ligated in an attempt to treat male infertility, but results have been inconclusive (Setchell & Breed 2006).
The blood supply to the epididymis is derived from two sources, with anastomoses in the corpus. The caput is supplied by branches of an epididymal artery and the cauda is supplied by the deferential artery, a branch of the internal iliac or hypogastric artery that runs alongside and also supplies the ductus deferens. Lymphatic vessels drain the whole length of the epididymis and the ductus deferens.
The blood supply to the accessory glands is derived from the internal iliac (hypogastric) artery. The prostatic (superior vesical) artery runs dorsal to the vesicular gland, where it branches to supply the ventral and dorsolateral prostate, the vesicular gland, together with the anterior prostate, with some branches from the inferior vesical artery. The veins from the ventral and dorsolateral prostate drain into a single, large, circular anastomosis around the neck of the bladder.
The arterial supply to the penis is derived from a branch of the hypogastric artery, the internal pudendal artery that divides to form three arteries of the penis: the bulbourethral, dorsal, and cavernosal arteries. Three sets of veins, superficial, intermediate, and deep, drain the blood from the penis. The scrotum is supplied by the external pudendal vessels.
INNERVATION OF THE MALE SEX ORGANS
The organs of the male reproductive tract receive a visceral afferent and efferent nerve supply, derived from a group of ganglia near the spinal cord, the celiac, aortic, caudal mesenteric, hypogastric, and pelvic ganglia. The scrotum and external cremaster muscle also receive somatic innervations.
The testis is supplied by the superior and inferior spermatic nerves. If the spinal cord is injured, male infertility may result with decreases in sperm production and motility but no effect on morphology. Contrary to earlier suggestions, these effects do not appear to be related to changes in scrotal temperature or serum gonadotropin levels. The nerve supply to the epididymis and ductus deferens is derived largely from the inferior (caudal) mesenteric ganglion and pelvic plexus via the hypogastric and then the inferior and middle spermatic nerves.
The penis is supplied by sympathetic, parasympathetic, and somatic fibers, which are carried in the dorsal and cavernous nerves. The cavernous nerve runs along the posterolateral aspect of the prostate, it is often damaged during prostatectomy, leading to erectile problems. The scrotum is supplied by branches from the genitofemoral (cranial and caudal inguinal) nerves, the superficial (superior) perineal nerve, and the caudal scrotal nerve. In the scrotal skin, there are thermal receptors that transmit information on scrotal temperature to neurons in the thalamus, hypothalamus, and cortex.
GERM CELL DEVELOPMENT AND PRODUCTION OF SPERMATOZOA
The testes originally lie in the abdomen of the developing male fetus but descend into the scrotum during the later part of pregnancy. Cells that will eventually produce spermatozoa (called primordial germ cells) are deposited in the testes in the early stage of testicular development. These primordial germ cells arise in the yolk sac of the embryo and migrate, between the 4th and 6th week of pregnancy, to the genital ridge that eventually forms the testes. The primordial germ cells develop into spermatogonia and lie dormant until the boy reaches puberty when the spermatogonia resume cell division and further development. The testes do not become depleted of spermatogonia unlike the situation in the female (Meniru 2004).
The various germ cell types, from the immature diploid spermatogonia to mature haploid spermatids, are described on the basis of the morphological changes that occur during maturation (Table 1.2). Spermatogonia undergo a series of mitotic divisions to produce a large number of germ cells available for entry into meiosis. The first and second meiotic divisions yield secondary spermatocytes and haploid round spermatids, respectively. Spermiogenesis is the process by which the round spermatid transforms, without further division, into the specialized elongated spermatid via a series of complex cytodifferentiative steps. Spermiation is the final step of spermatogenesis and involves removal of spermatid cytoplasm to yield the streamlined spermatozoon capable of motility, retraction of the Sertoli cell away from the spermatid, and finally, the release of the mature spermatid into the tubule lumen (O'Donnell et al. 2006; Figure 1.5). There are six stages of spermatogenesis in the human, and it takes approximately 64 days to produce spermatozoa from spermatogonia (Heller & Clermont 1963, Russell et al. 1990).
ORGANIZATION OF SPERMATOGENESIS
Male fertility depends on the continuous daily production of millions of spermatozoa. Spermatogenesis involves a coordinated series of mitotic and meiotic divisions, elaborate cytodifferentiative steps, and constantly changing intercellular interactions, all overseen by an extraordinary interplay of autocrine, paracrine, and endocrine factors.
The endocrine regulation of spermatogenesis is accomplished via a classic negative feedback loop (Figure 1.6) involving interactions between the hypothalamus, pituitary, and testis. The production of spermatozoa is dependent on stimulation by the pituitary gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), which are secreted in response to hypothalamic gonadotropin-releasing hormone (GnRH).
LH stimulates androgen synthesis by the Leydig cells of the testis, which acts locally to regulate sperm production and feeds back on the hypothalamus and pituitary to affect GnRH and LH production in a self-limiting loop. FSH stimulates Sertoli cells to secrete inhibin B that has a negative feedback effect on the pituitary to limit FSH synthesis (O'Donnell et al. 2006).
ABILITY OF THE TESTIS TO RESPOND TO ENDOCRINE SIGNAL: HORMONE RECEPTOR EXPRESSION
An important function of the Sertoli and Leydig cells of the testis is the ability to ‘receive’ endocrine signals from the bloodstream and to transmit these signals in an appropriate manner to the developing germ cells.
Androgens are produced by the Leydig cells and regulate spermatogenesis by binding to intracellular androgen receptors (ARs). Testosterone, or its 5α-reduced metabolite dihydrotestosterone, bind to cytosolic ARs, which subsequently dimerise, translocate to the nucleus, and bind to androgen response elements in the promoters of androgen-responsive genes to modulate gene transcription.
FSH exerts its biological effect on the testis via FSH receptors (FSH-R) present on the plasma membrane of the Sertoli cell. FSH plays a key role in the development of the immature testis, particularly by controlling the size of the Sertoli cell population, which is set early in postnatal life. FSH is the primary endocrine hormone regulating Sertoli cell function and proliferation. FSH acts at multiple sites in the spermatogenic process and is required for quantitatively normal spermatogenesis. The frequent requirement for FSH in the establishment of spermatogenesis in congenitally and completely hypogonadotropic men points to the need for FSH to induce permanent maturational effects on the Sertoli cell/seminiferous epithelium, as during normal puberty (O'Donnell et al. 2006).
The expression of LH receptors is generally accepted to be restricted to the Leydig cells where it mediates LH actions on the Leydig cell number, function, LH-responsiveness, and, importantly, steroidogenesis. There is an absolute requirement for LH and androgens for the initiation and maintenance of spermatogenesis.
ANDROGEN REGULATION OF SPERMATOGENESIS
In the adult, testosterone maintains the size and function of the male reproductive sex organs and is important for the production of spermatozoa. Testosterone is essential for the initiation and maintenance of spermatogenesis, and due to its local synthesis by the Leydig cells, it has an exceedingly high testicular concentration being 50- to 100-fold greater than in the circulation.
Testosterone is also essential for the completion of spermiogenesis. The final event of spermiogenesis, spermiation (the release of mature sperm from the Sertoli cell), is impaired by FSH suppression, although this process is also affected by testosterone suppression, suggesting that FSH and testosterone have synergistic roles in this process. It seems that FSH and testosterone act cooperatively by exerting effects at different stages of spermatogenesis and, therefore, acting in collaboration to allow complete germ cell development (O'Donnell et al. 2006).
HORMONAL DEPENDENCY OF HUMAN SPERMATOGENESIS
Both FSH and testosterone have been shown to play important roles in the initiation of spermatogenesis at puberty and are essential for quantitatively normal spermatogenesis in adulthood.
The term hypogonadotropic hypogonadism is applied to a range of clinical disorders due to deficiency of hypothalamic GnRH drive or intrinsic pituitary FSH and LH secretory ability, which feature poor sexual development (if prepubertal in onset), or infertility and androgen deficiency in adulthood.
In terms of spermatogenesis in males congenitally deficient in GnRH, germ cells do not proceed beyond the immature state in which only a few spermatogonia are seen (de Kretser et al. 1968). Acquired gonadotropin deficiency after puberty leads to testicular regression and marked oligospermia (i.e. reduced but detectable numbers of sperm in the ejaculate) or azoospermia (i.e. an absence of spermatozoa from the ejaculate) and may result from disorders of the hypothalamic-pituitary-testicular axis or from treatment.
When gonadotropin depletion is partial, qualitatively normal spermatogenesis may occur with a reduced total sperm output but in sufficient quantity to maintain fertility. When the hormonal depletion is more marked, spermatogenesis fails to progress due to inhibition of several key steps and infertility results (O'Donnell et al. 2006).
The main function of spermatozoa is to fertilize an oocyte to form a zygote. The spermatozoon cell must locate the oocyte, penetrate its protective layers, and then finally fuse its genetic material with the oocyte. For successful fertilization to take place, a spermatozoon must first penetrate various layers surrounding the oocyte to reach its protective glycoprotein coat, the zona pellucida (ZP). This is accomplished by the release of powerful enzymes contained in the acrosome of the spermatozoon head. The release of these enzymes begins the acrosomal process. Once a spermatozoon nears an oocyte, capacitation and hyperactivity occur. The spermatozoon begins to swim more rapidly and forcefully. Hyperactivity is linked to a sudden influx of calcium ions into the tail of the spermatozoon. Once a spermatozoon is capacitated and reaches the oocyte, enzymes are released from the acrosome to dissolve cell junctions and the ZP coat.
The ZP is an extracellular glycoprotein matrix, which surrounds all mammalian oocytes. There are four human zona glycoproteins (ZP1, ZP2, ZP3, and ZP4), which participate at several steps in the fertilization pathway. Recent studies employing recombinant and immunoaffinity purified human zona glycoproteins revealed that in addition to ZP3, capacitated acrosome-intact spermatozoa also bind ZP4. Human ZP2 primarily binds to the acrosome-reacted spermatozoa, supporting its role as secondary sperm receptor. Both human ZP3 and ZP4 induce dose-dependent acrosomal exocytosis in capacitated spermatozoa. In humans, ZP3 and ZP4 are involved in binding of the spermatozoa to the oocyte and subsequent induction of acrosome reaction. The contribution, if any, of human ZP1 during these stages of fertilization remains to be elucidated (Gupta et al. 2009).
ZP3 is the species-specific spermatozoon receptor on the oocyte surface that functions in the initial binding and induction of the spermatozoon acrosomal reaction. Once the spermatozoon has bound to ZP3, the fused section of the membranes opens and the head of the spermatozoon is transferred to the oocyte cytoplasm, followed by entry of the whole spermatozoon into the oocyte.
Problems with spermatozoa production or any of the parameters by which semen is assessed may lead to infertility. There are also specific syndromes that affect male fertility, such as immotile cilia syndrome, an autosomal recessive defect, which causes immotility or poor motility of the cilia of the airways and sperm. Consequently, an oocyte cannot be fertilized and male infertility results. In azoospermia, no spermatozoa are present in the semen. Impairment of sperm transport, such as obstruction of the epididymis or vas deferens and cystic fibrosis, may also cause male infertility.
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