Medical & Surgical Management of Male Infertility Ashok Agarwal, Botros RMB Rizk, Nabil Aziz, Edmund Sabanegh Jr
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1Physiology2

The Testis: Development and StructureChapter 1

Deborah M Spaine,
Sandro C Esteves
 
INTRODUCTION
The testis is functionally compartalized into the gamete and endocrine sectors; the process of spermatogenesis occurs in the first where the haploid germ cell is generated, androgen production takes place in the second which is the site of testosterone biosynthesis.1
 
TESTIS DEVELOPMENT
 
Embryonic Development of the Gonadal Sex
The presumptive gonad is only a mass of mesoderm that will eventually differentiate into the somatic elements of the testis. Prior the 7th week of human development, the urogenital tract is identical in both sexes. Genetic males and females have both Wolffian and Mullerian duct systems. At the end of this indifferent phase of phenotypic sexual differentiation, the dual duct system constitutes the primordium of the internal accessory organs of reproduction.2 Most of the gonad's cell types are derived from the mesoderm of the urogenital ridges. However, the primordial germ cells originate outside the area of the presumptive gonad and are initially identifiable in the endoderm of the yolk sac; they are derived from the primitive ectodermal cells of the inner cell mass.3 At the 4th week of development, human primordial germ cells are well recognized in the hind-gut epithelium while at the 5th week they are found at the coelomic angle's dorsal mesentery and in the forming germinal ridge after migration. At 6th week of development, most primordial germ cells have already migrated to the gonad and are usually surrounded by and in close association with adjacent somatic cells.4 The human primordial germ cells are characterized by their large and round nucleus and the presence of considerable number of lipid droplets in the cytoplasm. Histochemically, they have a high content of alkaline phosphatase and glycogen.5
The testis arises from the primitive gonad on the medial surface of the embryonic mesonephros. Primitive germ cells, which migrate to this region from the yolk sac, induce coelomic epithelial cells proliferation and formation of the sex cords. Formation of the sex cords gives to this region a raised contour that is called the genital ridge. By the 7th week of fetal development, proliferation of the mesenchyme has split the sex cords from the underlying coelomic epithelium. During the 16th week, the sex cords become U-shaped and their ends anastomose to form the rete testis.6,7 The chronology of the male reproductive tract development is depicted in Figure 1.1.
 
Sex Differentiation
Normal male sex differentiation involves a complex mechanism that depends on both genetic and hormonal control. The mechanism by which the germ cells differentiate is not fully understood, but it is known that the process begins early since primordial germ cells can be recognized in the 4 to 5 day-old human blastocyst.8 At the beginning of the 4th week of development, germ cells begin to migrate by amoeboid movement through the gut endoderm into the mesentery's mesoderm, finally ending up in the coelomic epithelium of the gonadal ridges.5 The formation of the gonadal blastema is completed during the 5th week of human embryogenesis; at this time the primitive and undifferentiated gonad is composed of three distinct cell types:
  1. Germ cells
  2. Supporting cells of the gonadal's ridge coelomic epithelium that either give rise to the testicular Sertoli cells or ovarian granulosa cell
  3. Stromal (interstitial) cells derived from the mesonchyme of the gonadal ridge.
Sex differentiation is determined by the presence and expression of DNA sequences normally carried on by the Y-chromosome. All placental mammals have an XX female XY male sex determining system although the Y-chromosome differs morphologically and genetically between species.9 In mammals, both male sex determination and spermatogenesis are controlled by genes located on the Y-chromosome. The testis-determining factor (TDF) is responsible for the transformation of the undifferentiated gonad to a differentiated testis.10 TDF is produced by the sex-determining gene (SRY) that is located in the short arm of Y-chromosome (Yp). SRY is the first gene known to be involved in the differentiation process and undoubtedly is the main initiator of the gene interactions cascade that determine the development of the testis from the undifferentiated gonad.11 The biochemical mechanism by which SRY determines testis differentiation appears to involve the binding to A/TAACAAT that is located within a minor DNA groove.12 It was originally suggested that SRY directly activates other genes in the testis-determining pathway.4
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Figure 1.1: Embryologic events in male sex differentiation. The line depicts the increase in serum testosterone concentrations. The word activity refers indirectly to the action of anti-Mullerian hormone in causing Mullerian duct regression and androgens to induce male sex differentiation. (Adapted from Endocrinology 142(8), Hughes, Minireview: sex differentiation, page 3282, copyright 2001, with permission from the publisher, Association for the Study of Internal Secretions)
SOX9 plays a crucial role in the differentiation because it is up-regulated by SRY and SF1 to initiate differentiation of pre-Sertoli to Sertoli cells.13 The development of the undifferentiated gonad within the genital ridge is controlled by autossomal genes, such as WT-1, LIM-1, SF-1, DAZ-1, DMTR1/DMTR-2, which act as transcription factors.14
 
Descent of the Testis
In most mammals the testes migrate from their original site. In many, including the humans, they pass through the abdominal wall into an evagination of the peritoneum that forms the scrotum.15 The descent of the testis occurs in two morphologically and hormonally distinct phases termed transabdominal and inguinoscrotal phases.16 During the first phase the testis remains anchored to the retroperitoneal inguinal area by the swollen gubernaculum, which prevents its ascent as the fetus enlarges. The gubernaculum is a cylindrical and gelatinous structure attached to the inguinal canal. Prior to the descent of the testis, an increase in the length of the intra-abdominal gubernaculum occurs. The increase of the gubernaculum wet mass plays an important role in the descent of the testis through the inguinal canal while the relative mass of the testis remains constant during this period.17 The testis receives its neurovascular supply at approximately the T10 medular level. During the 3rd trimester of development, it slips down the posterior wall dragging its neurovascular leash.18 In the second phase the testis descends from the inguinal area into the scrotum guided by the gubernaculum. The inguinoscrotal phase is androgen-dependent and is possibly mediated indirectly by the release of the neuropeptide calcitonin gene-related peptide (CGRP) from the genitofemoral nerve.19 The role of the peptide INSL3 (Leydig cell protein product) in the control of testis descent in humans is not fully understood.20 At the sixth -month of fetal development, the tip of the gubernaculum protrudes through the external inguinal ring. By the 7th month, it is at the level of the presumptive internal ring of the inguinal canal. Soon thereafter, the lower anterior abdominal wall is evaginated to form the scrotal sac. By birth, or shortly thereafter, the testis has moved into its definitive extra-abdominal location and is covered by the processus vaginalis of the peritoneum.
It appears that the descent of the testis is a time-dependent embryological phenomenon similar to other important events of fetal development. It takes place between the 6th month of intra-uterine life and the first six weeks post-delivery. Thereafter, the forces that drive descent, which have already been diminishing fairly rapidly, fail altogether.21 Several congenital problems may arise if this development sequence does not proceed normally. For instance, failure in the closure of the superior portion of the processus vaginalis may lead to a congenital inguinal hernia.18 Cryptorchidism is associated with impaired germ cell development.15 Androgens are still produced when the testis does not descend properly but the secretion rate is lower than normal particularly if the conditional is unilateral because there is no compensatory stimulation by increased levels of luteinizing hormone (LH).
 
TESTIS STRUCTURE
 
Anatomy
The human testis is an ovoid mass that lies within the scrotum. The testes in all mammals are paired encapsulated organs consisting of seminiferous tubules separated by interstitial tissue. The testis weight increases many fold at puberty and it decreases slightly with age.22 There are very few detailed studies of the spermatogenic function of the testis in aging men. The average testicular 5volume is 20 cubic centimeters in young men but decreases with age. The right testis is usually 10 percent larger than the left. Normal longitudinal length of the testis is approximately 4.5–5.1 cm. The average weight of human testis is 15 to 19 g with a specific gravity of 1.038 g/mL.23 Measurement of testicular size is critical in the clinical assessment of the infertile man since seminiferous tubules correspond to approximately 90percent of the testicular volume. Spermatogenesis probably decreases parallel to the decline in the overall testicular size.24 Testicular consistency is also of value in determining fertility capacity. A soft testis is likely to reflect degenerating or shrunken spermatogenic components within the seminiferous tubules.
The layers covering the testis and their derivations (Fig. 1.2) are as follows:
  • Skin
  • Dartos fascia which is a continuation of Scarpa's fascia over the scrotum
  • External spermatic fascia, derived from the external oblique aponeurosis
  • Cremasteric muscle, derived from the internal oblique muscle
  • Internal spermatic fascia, derived from fascia transversalis.
  • Tunica vaginalis, derived from the processus vaginalis of the abdominal peritoneum.25 The testis projects into the abdominal peritoneum from the retroperitoneum as it descends into the scrotum. It therefore explains the existence of double tunica vaginalis layers, an outer parietal and an inner visceral, surrounding the testis. Normally, there is a small amount of fluid between the visceral and parietal layers; a hydrocele is an excessive accumulation of fluid between these layers.
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Figure 1.2: Schematic representation of the male reproductive organs and their related structures
The testicular parenchyma is surrounded by a capsule containing blood vessels, smooth muscle fibers and nerve fibers sensitive to pressure. This capsule is often referred to as the tunica albuginea and it consists of fibroblasts and bundles of collagen and smooth-muscle cells.26 The tunica albuginea is a tough fibrous covering which is composed of three layers:
  1. An outer layer of visceral peritoneum—the tunica vaginalis
  2. The tunica albuginea itself
  3. The tunica vasculosa which is a subtunical extension of the interstitial tissue consisting of blood vessels and some Leydig cells in a loose connective tissue. The functional role of the testicular capsule is unknown but may relate to movement of fluid out through the rete testis or to maintain the interstitial pressure inside the testis.
 
Structure of the Seminiferous Tubules
In the male, the tunica albuginea and the rete testis combined comprise about 20percent of the testicular size of young men; this value increases with age.27 Most of the testis is made up by the seminiferous tubules, where the spermatozoa are formed, and interstitial cells. The seminiferous tubules are long V-shaped tubules; both ends drain toward the central superior and posterior regions of the testis, the rete testis which has a flat cuboidal epithelium. These cells appear to form a valve or plug which may prevent the passage of fluid from the rete into the tubule. The rete lies along the epididymal edge of the testis and coalesces in the superior portion of the testis, just anterior to the testicular vessels, to form 5 to 10 efferent ductules. The ductules leave the testis and travel a short distance to enter the head or caput region of the epididymis providing a connecting conduit to sperm transport to the epididymis. The seminiferous tubules are arranged in about 300 lobules each containing between one and four tubules. The rete testis is located in close proximity to the testicular artery that has part of its course on the surface of the testis. The interstitial tissue fills up the spaces between the seminiferous tubules and contains all the blood and lymphatic vessels and nerves of the testicular parenchyma.
 
Vasculature
The first description of the human testicular vasculature is dated of 1677. The author demonstrated that the gonadal artery divides into two branches just above the testis. One of them supplies the epididymis and the other branch enters the testis posteriorly, descends to the inferior pole and turns back superiorly along the anterior surface. This classical description remained substantially correct over time.28 The testes receive their blood supply from the testicular, cremasteric and deferential arteries. The testicular artery is the primary testis blood supply; it arises from the abdominal aorta just inferior to the origin of the renal arteries and courses the retroperitoneum toward the pelvis. By the time the artery reaches the testicular surface, it is comparatively thin-walled to the portion that will course along the surface of the testis. The testicular artery pierces the tunica albuginea at the posterior aspect of the superior pole, courses down to the inferior pole, and then ascends along the anterior surface, just under the tunica albuginea, giving off several branches that course into the testicular parenchyma.6
zoom view
Figures 1.3A and B: Illustration of the venous and arterial testicular vasculature
The highest density of surface arteries is concentrated in the anterior, medial and lateral surfaces of the inferior pole and the lowest density is found in the medial and lateral aspects of the superior pole. It has been suggested that a myogenic response of subcapsular artery to increases in blood pressure may have an important role in the auto-regulation of the testicular blood supply.29 The cremasteric arteries, also referred to as the external spermatic arteries, are branches of inferior epigastric artery and originate as branches of the external iliac arteries. The deferential arteries are branches of the internal iliac arteries and traverse much of the length of the vas deferens and supply it with blood (Figs 1.3A and B).
The venous anatomy of the testis is a particularly important feature of the male reproductive tract. The veins emerging from the testis form a dense network of intercommunicating branches known as the pampiniform plexus which extends through the scrotum and into the spermatic cord. The arteries supplying the testis pass through this plexus of veins in route to the testis. The venous blood (33°C) cools the arterial blood coming from the abdomen at a temperature of 37°C by the countercurrent heat exchange mechanism. After traversing the inguinal canal, the venous plexus disperses into veins that follow the arterial supply of the testis. The blood drains off the testis via the internal spermatic and the external pudendal veins (Fig. 1.3). There are no cross communication between the right and left spermatic venous system in the scrotal, retropubic and pelvic regions.30 The right testicular vein empties into the inferior vena cava. In contrast, the left testicular vein normally enters the left renal vein (Fig. 1.4).
Anatomic dissections in several species have shown that the autonomic nerve supply to the testis is derived from the spermatic plexus, which is composed of nerve fibers originating at the T10-L11 vertebral levels.
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Figure 1.4: Illustration depicting the venous drainage of right and left testes. The right testicular vein empties into the inferior vena cava while the left testicular vein normally enters the left renal vein
7
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