Hormone Production Sexual Development and Activity Hormone Production

Testosterone levels are generally normal in men with cryptorchidism, even those who were not treated (73,130). Although testosterone levels are within the normal range in men who were formerly cryptorchid (see Fig. 3) without other problems, a

Hormone Normal Levels
Fig. 4. Testosterone levels (ng/dL) in men who were formerly cryptorchid plotted against age of orchidopexy. These data suggest lower levels in men with orchiopexy at older ages (1).

recent study found an inverse relationship between testosterone levels in adulthood and age at orchiopexy (see Fig. 4), suggesting a subtle progressive detrimental consequence of a nonscrotal testis during childhood (1).

LH levels are generally within the broad normal adult male range, although GnRH stimulation testing may unmask subtle abnormalities. Elevated responses provide evidence for borderline diminished testicular function that likely involves Leydig cells. Results have ranged from an excessive rise in LH levels in more than 50% of men with unilateral and the majority of men with bilateral cryptorchidism in one study (130) to all responses within the broad normal adult male range (131). Both studies also had a small subgroup of men who were formerly bilateral cryptorchid who had subnormal responses, suggesting partial gonadotropin deficiency (130,131).

Although LH regulates Leydig cells, serum levels of inhibin-B and FSH relate more directly to seminiferous tubule function. Increased basal and GnRH-stimulated FSH

Gnrh Stimulation Test

Fig. 5. Circulating follicle-stimulating hormone (FSH) levels in formerly cryptorchid men compared with control men. The majority of men in the unilateral group have FSH levels in the normal range, where almost half of men who had bilateral cryptorchidism had elevated FSH levels. Solid line depicts the median, the shaded area the interquartile range, and the cross-lines the minimum and maximum values.

Fig. 5. Circulating follicle-stimulating hormone (FSH) levels in formerly cryptorchid men compared with control men. The majority of men in the unilateral group have FSH levels in the normal range, where almost half of men who had bilateral cryptorchidism had elevated FSH levels. Solid line depicts the median, the shaded area the interquartile range, and the cross-lines the minimum and maximum values.

levels are a common finding in men who were cryptorchid (73). Basal FSH levels are frequently elevated (see Fig. 5) and are inversely related to sperm density (see Fig. 6) (131,132). GnRH stimulation testing may identify an exaggerated abnormal response, which is more common and more severe in bilateral (88% in one series) than in unilateral (66%) cryptorchidism (130). It is impossible to determine if this abnormality is a consequence of an abnormal cryptorchid testis, operative injury, or both.

Mean inhibin-B levels were lower in men who were formerly cryptorchid than control men (see Fig. 7) (133). These levels correlated inversely with other hormonal markers, including FSH levels when controlled for LH, LH levels when controlled for FSH, GnRH-stimulated LH and FSH levels, testosterone, free testosterone, sperm density, sperm motility, and sperm morphology. In contrast, inhibin-B levels in control men correlated only with FSH and LH. Also, in cryptorchid but not control men, inhibin-B levels were significantly higher in men with normal sperm counts than men with low sperm counts (see Fig. 7). Likewise, men with cryptorchidism who were successful at paternity had higher inhibin-B levels than those who were unsuccessful. This difference was not observed in the control group. Inhibin-B is a sensitive marker of testicular dysfunction, implying diminished Sertoli cell number and/or function, and the findings suggest that a larger portion of the men

Follicle Stimulating Levels Men
Fig. 6. An inverse relationship is apparent between follicle-stimulating hormone (FSH) levels and sperm density in men who were formerly cryptorchid.

who were formerly cryptorchid have compromised testicular function than indicated by paternity data. Elevated FSH and low inhibin-B levels and decreased sperm density are all indicative of a high risk of infertility.

As noted in the above figures, men with treated cryptorchidism have mean hormone levels that are similar to those of normal men (86,131,133,134). Although a minority of unilateral men who formerly had cryptorchidism have elevated FSH and low inhibin-B levels, implying compromised seminiferous tubule function, the majority of men who had orchiopexy for bilateral cryptorchidism had elevated FSH and low inhibin-B levels (139). In 45 men who were reported to have spontaneous bilateral descent after age 10 yr, 58% had elevated FSH levels, 62% had decreased testicular volume, and 53% had a sperm density less than 20 million/mL (135). These data imply diminished function after a nonscrotal location of the testis during childhood years but also document that some men who were formerly cryptorchid have normal parameters.

The Children's Hospital of Pittsburgh study found that men who had orchidopexy for unilateral cryptorchidism had similar FSH, LH, testosterone, and inhibin-B levels

Fig. 7. A direct relationship is present between inhibin-B levels and sperm density in men who were formerly cryptorchid.

to controls (131,133). When the men who had unilateral cryptorchidism were analyzed based on success or lack of success at attempted paternity, no differences were found in these hormone levels (115). Men who had unilateral cryptorchidism have varying degrees of compromised seminiferous tubule function but may nevertheless be able to achieve paternity. Inhibin-B and FSH levels are only two of many markers of fertility and cannot be used to reliably predict infertility. Because numerous factors combine to cause reproductive success or failure, it is not surprising that no single finding short of azoospermia can predict infertility.

Sexual Development

Normal testosterone production in patients with cryptorchidism, even those with unilateral anorchia or an atrophic testis, results in full stimulation of growth and maturation in androgen-responsive tissues. Hence, genital development and pubertal viril-ization are complete and normal, with the exception of diminished testicular volume in previously undescended testes (130,142).

The cryptorchid testis varies considerably in size and may be small, even during the prepubertal years (136). Catch-up growth is more likely after orchiopexy for the palpable than the nonpalpable testis (137) if it is brought to a scrotal location before 18 mo of

Cryptorchid Testicular Volume

Fig. 7. A direct relationship is present between inhibin-B levels and sperm density in men who were formerly cryptorchid.

age (136). However, when adult testicular volume was evaluated in relation to previous germ cell counts at biopsy in prepubertal boys with cryptorchidism, prepubertal testicular size did not predict adult germ cell count (138). There is also a lack of correlation between testicular volume at orchiopexy and paternity, hormone levels, sperm count, and testicular volume in adulthood when studied in both unilateral and bilateral men with cryptorchidism (115,132,139).

Compensatory hypertrophy of the nonaffected testis in unilateral cryptorchidism or in the less affected testis in bilateral cryptorchidism, may occur before puberty, either before or after correction of the cryptorchidism. The mechanism for the hypertrophy is likely to involve decreased inhibin-B and, thereby, increased FSH production, even during the prepubertal years. Testicular volume differences become most significant at mid-puberty, approximately age 14 yr, when increases in testicular volume for the contralateral testis become greater than 15 mL (140).

In infertile men overall, there is a significant correlation between testicular volume and indices of spermatogenesis (sperm density and motility and FSH levels) (141). LH levels are related to testicular volume but not to testosterone levels. Adult previously undescended testes generally have diminished volume (130,142). As a consequence of compensatory hypertrophy of the contralateral descended testis, mean testicular volume for men with corrected unilateral maldescent is usually within the normal adult range (130). Occasionally, combined volume may be greater than expected, suggesting hypertrophy.

Sexual Activity

Although there is no reason to expect a disturbance in sexual activity because men who were formerly cryptorchid have normal development and testosterone levels and a normal interest and abilities for sexual functioning, an early report suggested that "sexual drive seemed to be diminished" (130). Also, men who were formerly cryptorchid have been reported to be less sexually active as adults when judged by frequency of intercourse, although the mean age of onset of masturbation and coitus were not different than normal. It is of interest that a direct relationship was found between frequency of intercourse and both testicular volume and testosterone levels (142). Also, unpublished data from the Children's Hospital of Pittsburgh cohort of formerly cryptorchid men indicate that frequency of intercourse is lower than in control men. These data are not well substantiated.

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