Germ Cell Development In The Cryptorchid Testis

Germ cell numbers and testicular and epididymal weights, but not body weights, were lower in stillborns with cryptorchidism than in those with full testicular descent (53). Twenty-three percent of these fetuses had decreased numbers of germ cells per tubular cross-section. Furthermore, in contrast to the descended testis, germ cells in the cryptorchid testis were reduced in number with increasing fetal age.

Figure 2 shows that germ cells in cryptorchid testes at birth do not differ in number from those in descended testes (53,76). Although not verified, it is generally assumed that such a testis has a normal potential for spermatogenesis. However, it is clear that testes that remain cryptorchid beyond infancy acquire a progressively more abnormal microscopic appearance. Although the histological appearance of the unilateral unde-scended testis cannot be distinguished from a normal testis based on germ cell number at birth (77), changes are apparent by the second or third month, with defective transformation of gonocytes into adult dark spermatogonia (78). Untransformed gonocytes persist until the second half of the first year of life; then secondary degeneration occurs, decreasing the total germ cell count. As illustrated in Fig. 2, germ cell number in the cryptorchid testes is reduced by age 1 yr and consistently so by 2 yr of age (53,76,77,79-83), with a further decrease with increasing age (84). Progression is apparent when the percentage of boys with abnormally low germ cell numbers is ana lyzed as a function of age; 22% of boys with cryptorchidism have values below the normal range during the first year of life, compared to 92% in the 1- to 3-yr-old group (53). During the first 5 yr of life, there is no difference in the number of germ cells between undescended testes that are intra-abdominal or canalicular (85), consistent with the lack of correlation between pretreatment testicular location and fertility in adulthood (86).

The number of germ cells in undescended testes from birth to 1 yr of age was statistically less among boys without an inguinal hernia than with a hernia, the latter being not different from normal (53). This difference was lost by 3 yr of age.

Key steps in the maturation of the descended testis include the disappearance of gonocytes (the fetal stem cell pool), with the subsequent appearance of adult dark sper-matogonia (the adult stem cell pool) by 3 mo of age and the appearance of primary spermatocytes at the onset of meiosis by age 5 yr. Both of these steps are impaired in the undescended testis. Total and differential germ cell counts in testicular biopsies of cryptorchid testes in boys under 1 yr of age indicate that the adult stem cell pool is not yet fully established. This delay or defect is further reflected in the biopsies from boys 4 to 5 yr of age, which demonstrate a lack of primary spermatocytes; only approx 20% of contralateral testes contain these cell forms (87).

However, in the undescended testes of boys older than 5 yr of age, seminiferous tubules decrease progressively in size, with Sertoli cell hypoplasia, a marked reduction in spermatogonia number and peritubular hyalinization with thickening and fibrosis of the lamina propria (88). Biopsies of cryptorchid testes from boys aged 13 to 18 yr demonstrate changes that are similar to those of prepubertal boys, except for the development of Leydig cells and more Sertoli cell junctions. Cryptorchid testes from 19- to 27-yr-old men had changes ranging from complete spermatogenesis to isolated spermatogonia, mature to hyperplastic Sertoli cells, and normal to thickened lamina propria. A normal lamina propria was associated with mature Sertoli cells, whereas thickening involved peritubular cell alterations.

Reports conflict concerning the status of germ cells in the scrotal testis contralateral to an undescended testis. No differences in comparison with control descended testes have been reported (89). However, abnormal maturation and germ cell numbers have been reported in the scrotal testis that is contralateral to the unilaterally undescended testis. The contralateral testis has more germ cells than the undescended testis but fewer germ cells than in age-matched normal testes (90). There is variation between subjects, because in another report, 30% of contralateral testes had diminished numbers of germ cells, with a few testes demonstrating severe reduction (31). Histological changes have also been described in the contralateral testes of prepubertal boys who had unilateral torsion and atrophy, with decreased numbers and delay in maturation of germ cells, with variably diminished tubular diameter and Sertoli cell hyperplasia (91). As in unilateral cryptorchidism, contralateral changes could represent either an acquired immunological or congenital defect. Although it is unclear to what extent the altered testicular histology of the undescended testis is reversible and whether differences result from maturational lag or permanent damage, some postpubertal cryp-torchid testes are devoid of germ cells.

The findings presented here are the basis for the current recommendation for treatment of cryptorchidism before 18 mo of age, even as young as age 6 mo. Based primarily on the findings of decreased germ cell numbers with age, the recommended age for treatment has declined progressively throughout the past 40 yr to the current young age. For decades, it was believed that orchiopexy should be performed at early puberty if spontaneous descent had not occurred. This reasoning was consequent to the inaccurate perception that the testes are inert during childhood. The recommended treatment age progressively declined as the risk of diminished testicular function, primarily reduced germ cell numbers with increasing age, was realized (92). The most recent recommendation is for treatment around 9 mo of age, because testes are not likely to descend spontaneously after the first 3 to 4 mo of life and germ cells are already declining by this age (80,86), with greater and earlier decreases with bilateral than with unilateral maldescent (80). Indeed, it was shown that orchiopexy was safe at age 1 yr (93). Although a study failed to find any improvement of germ cell numbers (30), more outcome data are needed to determine if fertility is improved by earlier treatment.

To determine if hormonal therapy will affect germ cell development, two studies suggested that orchiopexy followed by long-term gonadotropin stimulation improves germ cell numbers and subsequent fertility (94,95). Furthermore, a GnRH analog administered once daily in a nasal spray to stimulate rather than inhibit gonadotropins has also been reported to induce testicular descent and increase numbers of germ cells (96).

Evaluation based on numbers of germ cells alone may be insufficient. A study of young adult men who had undergone orchiopexy and testicular biopsy before 2 yr of age included semen for analysis. All men who had surgery before 6 mo of age had a normal number of germ cells on biopsy, whereas those older than 6 mo of age at the time of surgery had reduced germ cell numbers (94). Two thirds of the men provided semen for analysis as adults, but these findings did not correlate with the total number of germ cells at childhood biopsy. However, a diminished sperm count was found in men who did not have adult (dark) spermatogonia on biopsy 20 to 25 yr earlier. This finding implies irreparable damage rather than simply delayed maturation.

Another cohort of adult men who had a biopsy at orchiopexy at ages 10 to 12 yr has been studied (97). A positive correlation was found between the number of spermatogonia at biopsy and sperm count, volume of the operated testis, and total testicular volume. Negative correlations were found between FSH levels and testicular volume, sperm concentration, and total sperm count.

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