Descent Of The Testis

Testicular development begins at conception under complicated genetic direction (22). This involves a cascade of sequential steps under the control of numerous genes, most of which are yet to be identified. Key to testicular differentiation is the sex-determining region Y (SRY) gene. Genetic components upstream from SRY that are essential for gonadal development include splicing factor 1 (SF1), Wilm's tumor 1 gene (WT1), and Double sex and MAb-3-Related Transcription Factor 1 (DMRT1). Downstream from SRY are DAX1 (associated with dosage sensitive sex reversal), Wnt-4 (Wingless-type MnTV Integration Site Family, Member 4 (in which duplication is associated with XY sex reversal), and sex-related box (SOX9), in which mutations cause XY sex reversal and duplication with XX sex reversal. A scheme that may regulate downstream testicular differentiation is hypothesized to involve SRY suppression of Wnt-4, expression that, in turn, suppresses DAX1 expression, allowing for SOX9 expression, and leading to testicular differentiation. This would be normal sequence in the 46XY male, resulting in normal testicular development. Conversely, in the absence of SRY, Wnt-4 and DAX1 are expressed, inhibiting SOX9 expression and abolishing testicular differentiation, as in the 46XX female.

With the appropriate genetic direction and substrates, primitive sex cords become testicular cords to provide the framework for the developing testis. Primitive mes-enchyme cells differentiate into Sertoli cells that can be seen in the testicular cords by 7 wk of gestation, with Leydig cells recognizable by 8 wk. Testosterone production also begins at this time. Concomitantly, primitive germ cells from the endoderm of the yolk sac first appear in the genital ridge. After this, Leydig cells proliferate and the testicular cords become canalized forming seminiferous tubules. Hence, the primordial gonad begins its differentiation into a testis in early fetal life and becomes functional by the middle of the first trimester with testosterone synthesis and release. Testosterone secretion is necessary for the subsequent development of the testis and the accessory male reproductive structures, as well as for the normal descent of the testes (23).

Concomitant with this early testicular differentiation is a series of other key developmental events that relate to testicular descent. Early in gestation, tissues begin to organize to form the associated ducts, the gubernaculum, and the tunica vaginalis (the serous membrane eventually covering a portion of the testes and epididymis). By 5 wk after conception, the initial concentrations of the mesenchyme begin to organize and develop into the ligamentous band of tissue that will develop into the gubernaculum. This structure eventually connects the lower end of the epididymis and the base of the scrotum. By 10 wk of fetal life, a small invagination that will become the processus vaginalis can be found next to the internal inguinal ring. This peritoneal outpocketing, adjacent to the gubernaculums, elongates progressively through the inguinal canal. The testicular ductal system develops under testosterone stimulation, beginning at week 7 to 8. The paired Wolffian ducts become rete testes, adjacent to the testes with the ejacu-latory ducts at the distal end. Concomitantly, the testes secrete Mullerian-inhibiting hormone, precluding further differentiation of the paired Mullerian ducts. Externally, there is concomitant male differentiation of the genitalia under the control of dihy-drotestosterone (DHT) that is essentially completed by 12 wk of fetal life.

Testicular descent in the developing male fetus is a complex process that is only understood partially. Descent has been described as consisting of either two or three phases (24,25), each with different regulatory mechanisms. Three phases are described: (1) repositioning of the testis, (2) transabdominal descent, and (3) trans-scrotal migration. The three-phase model includes an initial phase of morphologic reorientation that is the same in both sexes and involves repositioning of the testis cau-dally, concomitant with regression of the mesonephros as the metanephros migrates cranially. At this point early in gestation, the position of the testis is at the level of the lower pole of the metanephric kidney. It is unclear whether adjacent anatomic structures or hormonal factors are involved in the relative repositioning of the testis in phases 1 and 2 that occurs between the 8th and 26th wk to a posterior position at the level of the anterior iliac supine. Transabdominal migration culminates in the testis locating to a position that is clearly different from that of the ovary, the shift occurs from the posterior abdominal wall to the inguinal region. This movement is accomplished primarily between 10 and 15 wk of fetal life.

The cranial suspensory ligaments that are attached to the developing gonad anteriorly may play a role in testicular descent. Normally, these ligaments regress in males but persist in females. Regression allows both the relative intra-abdominal testicular repositioning and the transinguinal migration. Persistence of these ligaments in humans and mice with androgen insensitivity syndrome (24,26), failure of regression in male rats treated prenatally with anti-androgen (27), and regression of these ligaments and a more caudal ovarian location in newborn female rats treated in utero with androgens (28), together suggest that regression of these ligaments is under androgenic control. Because androgens play a role in the regression of these ligaments and such regression is important in both the abdominal and the transinguinal migration phases of testicular descent, androgens are crucial for both of these phases. Although Mullerian-

inhibiting hormone has been hypothesized to participate in the transabdominal phase, this has not been verified.

The final phase of descent is called transinguinal migration, occurring after 26 wk of fetal life and lasting 4 to 6 wk. During this time, the testes pass through the inguinal canal (29) to the bottom of the scrotum. Thus, complete descent is generally accomplished by the 32nd wk of gestation but may not be fully complete until the first few months of postnatal life.

During this final phase, the testis carries the processus vaginalis (the peritoneal-lined outpocket into the inguinal canal) into a scrotal position. This phase has long been considered to be androgen dependent and to involve the gubernaculum, the cremaster muscle, the genitofemoral nerve, neurotransmitters, cytokines, intra-abdominal pressure, and epididymal maturation. The specific roles of the epididymis and the gubernaculum (the fetal ligament attached to the lower end of the epididymis and the bottom of the scrotum) are unclear. Epididymides with no attachment to the testes have been reported in some patients with maldescent (30). This defect may not only play a role in the lack of descent but also will cause infertility.

The anatomical changes and position of the gubernaculum led to the suggestion that this structure plays a role in the migration of the testis from the abdomen into the inguinal canal, although it is unclear whether an active or a passive process is involved (31,32). Before the transinguinal migration phase, the gubernaculum increases in size from the 15 th to 24th wk of gestation. Gubernacular growth is characterized by mes-enchymal cell hyperplasia and hypertrophy, with a marked increase of the extracellular matrix related to the hydrophilic properties of hyaluronic acid. The cremaster muscle is intertwined in the gubernaculum. Concomitant with the transinguinal migration phase is a phase of regression of the gubernaculum (29). During testicular migration, the gubernacular connective tissue changes into a fibrous structure containing considerable collagen and elastic fibers. These changes result in its decreased size (33). This regression may also cause a relative negative pressure, drawing the testis through the inguinal canal. An active process involving the cremaster muscle pulling the testis is unlikely. Most likely, the gubernaculum plays an important passive role by guiding the testis along the channel of descent. As shown in Fig. 1, testes may have an ectopic location. There are usually five points of attachment of the gubernaculum, with the primary one at the base of the scrotum. The mechanism for ectopic locations is likely to be an abnormal primary attachment of the gubernaculum to structures other than the base of the scrotum, such as laterally or medially in the femoral, penile, or perineal area.

Although transinguinal migration is clearly under androgenic control, such stimulation directs a cascade of metabolic responses involving paracrine factors and catabolic enzymes, such as acid phosphatase, which stimulate gubernacular regression (34). A role for the genitofemoral nerve is suggested from animal studies in which division of the nerve during early fetal life results in premature regression of the gubernaculum and prevents testicular descent (25,35). It has been hypothesized that this nerve secretes the neuropeptide, calcitonin gene-related peptide (CGRP) that has been found in its nucleus. The control of CGRP secretion by the genitofemoral nerve may reside in spinal cord nuclei, a hypothesis consistent with the increased prevalence of cryp-torchidism in patients with spina bifida and in rats after spinal cord transection (36). Receptors for CGRP are found in the cremasteric muscle in the rat gubernaculum and are upregulated after denervation of the genitofemoral nerve (37,38). Exogenous

CGRP stimulates gubernacular development, whereas a synthetic CGRP antagonist (CGRP 8-37) delays testicular descent (39,40). Also, in vivo administration of CGRP results in contraction in the gubernaculum in the rat (41). Other factors may include an insulin-like peptide isolated from Leydig cells (42) and an insulin-like factor (INSL)-3/relaxin-like factor (RLF) gene that is expressed in Leydig cells (43).

Even with the many potential genetic regulators of testicular descent, identifible genetic causes of cryptorchidism, or infertility in relation to cryptorchidism, are rare. Human studies have failed to find karyotypic abnormalities or an increased frequency of mutations in males with cryptorchidism (44). There is evidence that INSL-3 (Leydig insulin-like or relaxin-like factor) plays a role in establishing gonadal position and in cryptorchidism in animals (45,46). Although reports differ concerning the association of INSL-3 mutations and human cryptorchidism (47-50), mutations in the coding region of the INSL-3 gene are an uncommon cause of human cryptorchdism (61).

Given the complexity of the process, it is obvious that there may be multiple etiologies for failure of testicular descent. In particular, systemic factors are likely to be important in patients with bilateral cryptorchidism, whereas paracrine regulators may be disrupted when only one testis is undescended. Anatomic problems precluding descent could include a detached epididymis (30), testicular-splenic, or testicular hepatic fusion (52). Etiologies that result in a dysgenetic testis preclude normal function, even with correct scrotal positioning. However, if an anatomic problem has not compromised the vascular supply and can be corrected, the testis may develop normally, with the potential for normal function.

A concomitant inguinal hernia is a common finding with cryptorchidism. It is often unclear whether the hernia is related to the cause or is a result of the maldescent, although the latter has been presumed. If other malformations are present, the likelihood of a common etiology is increased. Almost one-half of cryptorchid fetuses and infants without inguinal hernias had associated diagnoses (e.g., dysplasia of the kidneys, ureters, or spinal column, suggesting a general insult or defect), whereas only approximately one-fifth of those with a hernia had such defects (53).

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