Endocrine Aspects Of Testicular Descent

A role for hormones in testicular descent was demonstrated more than 70 yr ago when a urinary extract from pregnant monkeys (containing hCG) was used to treat monkeys with cryptorchidism (54). It remains unclear whether that was a direct gonadotropin effect or an indirect effect from increased testosterone production. The factors controlling testicular descent are clearly more complicated than hormone insufficiency alone, because only a portion of hypogonadotropic patients with Kallmann syndrome have cryptorchidism. Furthermore, most patients with congenital primary hypogonadism (e.g., Klinefelter's syndrome) do not have cryptorchidism. Although the absence of cryp-torchidism as a universal finding may be a consequence of the amount of gonadotropin or androgen present during differentiation, these examples are further evidence that many factors are involved in testicular descent, most of which are not yet understood.

There is a similar lack of understanding of the role of androgen action in testicular maldescent in 46XY patients with mutations in the LH receptor and those with androgen receptor defects producing complete androgen insensitivity syndrome. In these patients, the testes descend as far as is anatomically possible, because the absence of a scrotum precludes further descent. Thus, such examples fail to provide evidence for or against the role of androgens in testicular descent.

The available animal data are consistent with androgen stimulation of both the abdominal and the inguinal phases of descent (55,56). Although the androgenic effect is limited to a specific time period (56). Orchiectomy will halt gubernacular regression in the dog, a finding that is reversible with testosterone treatment (57,58). This property may be related to testosterone itself, rather than to DHT, because administration of a 5-a reductase inhibitor had little effect on testicular descent (59). Estrogen treatment prevents testicular descent in newborn rats (60,61). However, androgen and gonadotropin replacement were unable to reverse this effect in mice, raising the possibility of a direct estrogenic effect rather than via suppression of the hypothalamic-pituitary axis (62). Estrogen also been proposed to prevent testicular descent through downregulation of INSL-3 expression. In humans, a case-control study found no association between cryptorchidism and either exogenous estrogen exposure or pregnancy-related variables that are hypothesized to be indirect indicators of endogenous estrogens (63).

The hypothalamic-pituitary-testicular axis differentiates by midgestation. Testosterone, gonadotropins, and Mullerian-inhibiting hormone are present in the fetal circulation, and each could play a crucial role in testicular descent. During the first few months after birth, the hypothalamic-pituitary-testicular axis is active, with near-adult circulating levels of testosterone that peak between 1 to 3 mo of age. Thereafter, concentrations diminish gradually to low childhood levels by 6 mo of age (64). This neonatal testosterone rise is likely to be related to "imprinting" maleness and may be critical for normal differentiation of germ cells, as well as the spontaneous descent of undescended testes that occurs during the first 6 mo of life in males born with maldescent. These observations and the testosterone secretion pattern are also consistent with the finding that testes that fail to descend within the first 6 mo of life are unlikely to descend spontaneously thereafter.

Decreased testosterone levels have been reported in cryptorchid infants (65), consistent with diminished LH secretion (66,67), with lower levels in both the postnatal week and the second month of life in preterm infants with cryptorchidism, when compared to those without cryptorchidism (68). Although antipituitary antibodies have been found in mothers of cryptorchid infants, no correlation was found with postnatal testosterone levels (67).

Mullerian-inhibiting hormone, associated with regression of the Mullerian duct, is produced by Sertoli cells. Diminished levels in boys with cryptorchidism (69) led to the hypothesis that Mullerian-inhibiting hormone plays a role in testicular descent. Lower levels have also been reported in boys with bilateral than in unilateral cryp-torchidism, and this difference has been interpreted to suggest that Mullerian-inhibiting hormone could be involved in the transabdominal phase of descent (70). Circumstantial evidence supporting this idea is that this phase occurs concurrent with the highest Mul-lerian-inhibiting hormone levels. However, animal data do not support this hypothesis insofar as male offspring of female rabbits immunized against Mullerian-inhibiting hormone had persistent Mullerian duct derivatives but descended testes (71).

During childhood, LH, FSH, and testosterone levels in boys with cryptorchidism are low and are similar to those of boys without cryptorchidism. Diminished LH responses to gonadotropin-releasing hormone (GnRH) stimulation have been reported in prepubertal boys with undescended testes (72). These and other data support the diagnosis of

Fsh Testosterone

Fig. 2. Germ cell numbers vs age in young boys with unilateral cryptorchidism and in their contralateral descended testes.

Fig. 2. Germ cell numbers vs age in young boys with unilateral cryptorchidism and in their contralateral descended testes.

mild hypogonadotropic hypogonadism in boys with cryptorchidism during childhood. However, hypergonadotropism, particularly involving FSH, is common in affected adults, whereas hypogonadotropism is rare in adults with a history of cryptorchidism (73). Elevated FSH levels may become apparent as puberty approaches, suggesting at least partial gonadal failure (74). On the other hand, inhibin-B levels are within the normal range in boys with either unilateral or bilateral cryptorchidism (75).

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