Infertility

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Cryptorchidism may be a prominent cause of male infertility. Although there are no truly accurate indicators of male infertility, this number has been inferred from the portion of infertile couples whose infertility is believed to result from a male factor. It is estimated that 13 to 14% of couples in which the female partner is less than 45 yr of age are infertile (excluding those who are surgically sterile) (143). In US studies, it is not possible to estimate what portion of these cases result from male factors, because all studies involve selected populations. However, a study from Great Britain evaluated a random sample of couples in a regional health district. In that study, 26% of the infertility was ascribed to problems with the man (144). Applying this percentage to the 13 to 14% of couples in the United States who are infertile suggests that approx 3.5% of men are infertile (143). Because the prevalence of cryptorchidism is estimated to be 0.7 to 2% of men after infancy (11,17,42), this condition could account for a substantial portion of all infertile men.

There are multiple potential etiologies of cryptorchidism, and the different etiologies could result in varying potential for sperm production. Consequently, there may be considerable variation in the indices of fertility in different studies. Furthermore, it is not clear that treatment alters the potential for fertility. It has been considered an established fact that bilateral cryptorchidism is associated with infertility when the testes remain undescended beyond puberty. However, there are some interesting exceptions to this idea. Although testicular location is a potential key factor in relation to infertility, this may apply primarily to abdominal but not to lower positioned testes. Bilateral abdominal testes remaining in this location after puberty are universally associated with infertility.

Until recently, the prevalence of infertility after bilateral cryptorchidism has not been clearly documented, nor has it been shown that treatment during childhood has any beneficial effect (113). A meta-analysis of 27 published studies (113) indicated that no men with untreated bilateral cryptorchidism had normal fertility potential based on sperm density, whereas 25% of those who were treated had normal sperm density. In patients with bilateral cryptorchidism who were treated during childhood, similar percentages of patients had azoospermia and oligospermia (density <20 million/mL), regardless of the type or age at treatment. This report, however, did not include men who were treated during infancy or early childhood.

Testicular sperm extraction (TESE) and testicular sperm aspiration (TESA) with intracytoplasmic sperm injection (ICSI) may be attempted in men who were formerly cryptorchid. Success with TESE and ICSI was reported in a man with prepubertal bilateral orchiopexy and azoospermia (45). It is possible that these techniques may be successful, even for men with untreated bilateral intra-abdominal cryptorchidism.

Risk Factors

It has been hypothesized that disruption of the blood-testis barrier caused by testic-ular biopsy or by the placement of a suture through the testis to anchor it in the scrotum may have a detrimental effect on spermatogenesis, resulting from the development of antisperm antibodies. However, a study searching for antisperm antibodies in the semen of men who had had testicular biopsy at puberty failed to demonstrate antibodies (146). An assessment of the Children's Hospital of Pittsburgh cohort of men who were formerly cryptorchid also found no increase in the prevalence of sperm antibodies in boys who were operated on during childhood (unpublished data). An earlier analysis seeking risk factors for infertility in this same cohort found evidence of an increased risk in association with the placement of a testicular suture (RR 7.56, 95% Cl 1.66-34.39) (147). However, subsequent analyses of the entire cohort failed to confirm this increased risk. Other risk factors for infertility were bilateral cryptorchidism (when compared within the entire cohort), the presence of a varicocele, hCG treatment for cryptoorchidism, and a partner with a fertility problem.

Germ Cell Counts (Unilateral and Bilateral)

Reports relating germ cell counts on biopsy at the time of orchiopexy to indices of fertility in adulthood are inconsistent, suggesting that germ cell number and maturation alone do not predict fertility potential or sperm density. Germ cell counts have correlated positively with sperm density and combined testicular volume and negatively with FSH levels in men who had bilateral orchiopexy between 10 and 16 yr of age

(148,149). The greatest sperm density was found in the men with testes in the superficial inguinal pouch. However, in another biopsy study, the percentage of the sections that contained spermatogonia (tubular fertility index) did not predict sperm density in adulthood (150).

A more recent assessment involved a group of men who had orchiopexy for either unilateral or bilateral cryptorchidism before 2 yr of age (94,95), of whom two-thirds had normal sperm density. In these men, testicular biopsy at the time of orchiopexy revealed that germ cells had undergone the second stage of maturation to adult dark (Ad) spermatogonia. Conversely, the remaining one-third of men who had low sperm densities had evidence for impaired germ cell maturation 20-25 yr earlier. Again, low sperm densities do not necessarily mean lack of paternity.

Most concerning are the prepubertal boys with cryptorchidism who have a complete lack of germ cells on biopsy. Although they are a minority of the total group, the absence of germ cells represents a significant independent risk of subsequent infertility (97). An age relationship is present with all patients who had a biopsy at orchiopexy before 2 yr of age having germ cells, but an increased risk for germ cell absence with orchiopexy at older ages (151). Overall, 30% of the bilateral cryptorchids and 20% of the unilateral group had no germ cells visualized. Conversely, 19% of the bilateral and 83% of the unilateral group had normal sperm densities.

Age at Treatment and Fertility

It has been hypothesized that earlier treatment decreases the risk of infertility, but this has not been demonstrated convincingly. A 1975 report of 79 men found that fertility was greater when patients were younger at the time of orchiopexy (152). Another study of men with bilateral cryptorchidism also reported an inverse correlation between age at orchiopexy and sperm concentration (148). However, a meta-analysis (113) found no difference in the percentage of men with azoospermia or oligospermia with unilateral or bilateral cryptorchidism who were treated before vs. after 9 yr of age. Unfortunately, no patients in the meta-analysis were treated during the first few years of life. Efficacy of early therapy has been questioned, particularly for unilateral cryptorchidism. The percentage of men with azoospermia or oligospermia in the uni-laterals was similar after surgical, hormonal, both treatments, or no treatment. A study of 329 men, including 66 married men, also failed to show a relationship between age of treatment and fertility, but, once again, the youngest age at therapy was 7 yr (153). Another study comparing patients who had surgery between 2 and 7 yr of age with those treated between 10 and 12 yr of age found no difference in fertility potential in adulthood based on testicular volume, LH, FSH and testosterone levels, and semen analyses (97). Finally, in the Pittsburgh study of men who had either unilateral or bilateral cryptorchidism corrected in childhood, sperm density did not correlate with age at surgery (133).

Successive analyses of the Children's Hospital of Pittsburgh Male Fertility Study seeking a relationship between age of orchiopexy and fertility parameters have also failed to show any such relationship (115,139,154). These analyses have involved men who had orchidopexy throughout childhood, including 23 men who had surgery before age 2 yr. No relationship was demonstrated between the age of orchiopexy and successful attempts at paternity, gonadotropin levels, or semen characteristics. Although the subjects in the unilateral group who had attempted paternity included 23 men who had had orchiopexy before 2 yr of age, paternity may not be a sufficiently sensitive or specific index for the relationship between age of orchiopexy and fertility (115,155) partly because of fertility issues in the partner. However, this study remains incomplete, because only a portion of the men have attempted paternity (359 of 609 in the unilateral cohort) and even fewer (105 of the 359) have been available for physical examination, hormone, and semen studies.

Interestingly, in the Pittsburgh cohort, a relationship is suggested between age at orchiopexy and testosterone levels in the unilateral group (1). Although all men evaluated had circulating testosterone levels within the adult male range, there was an inverse relationship between testosterone and age at orchiopexy. This subtle finding is surprising and implies a risk of diminished Leydig cell function, with the retention of the testis after infancy. The finding is also consistent with the finding of Leydig cell atrophy in the cryptorchid testis (156).

Spermatogenesis

According to the World Health Organization (WHO) classification, sperm density greater than 20 x 106/mL is considered to be normal; oligospermia is defined as less than 20 x 106 sperm/mL, and azoospermia is 0 sperm/mL. Early reports of relatively small series suggested that sperm counts are higher in both unilateral and bilateral groups after hCG treatment than after surgery (157), a large percentage of men who had unilateral cryptorchidism have subnormal sperm density (158), and the fertility and potential for fertility are compromised more than suggested by recent studies. However, it is unclear whether patients with retractile testes accounted for a large portion of those treated with hCG, whether those in the hCG treatment group were less severely affected, or whether a large portion had surgical complications. Changes in surgery and surgical techniques were not considered.

Using semen analyses as an index of fertility, variable results in men who had cryptorchidism suggest considerable differences in fertility potential. In the Children's Hospital of Pittsburgh study, the sperm density was normal in only 4% of men with bilateral maldescent and in 23% with unilateral cryptorchidism (133). Other studies have found normal sperm density in 0 to 20% of men who had bilateral cryptrochidism, with 23 to 36% demonstrating oligospermia, and 45 to 77% having azoospermia (114,130). The outcome of patients with a history of unilateral cryptorchidism was better as a group than those with bilateral but was still largely abnormal (60,113,159). Two-thirds of men with unilateral cryptorchidism have decreased sperm counts (73,160), with normal density reported in only 35 to 72% (114,130). Oligospermia was found in 21 to 27%, with 0 to 8% having azoospermia (114,130). Sperm density results in the Children's Hospital of Pittsburgh Cryptorchid group are shown in Fig. 8.

In an attempt to determine the importance of age at orchiopexy, a study was conducted of patients who were operated on for unilateral or bilateral cryptorchidism at an older age of 7-13 yr (153). That study found no improvement with earlier age at orchiopexy, although a relationship with pretreatment testicular position was present, with the lower testis resulting in better semen parameters. In the unilateral group, approximately two-thirds of the 40 men had normal semen volume, sperm density, morphology, and motility. In the bilateral group, 30% had normal sperm density.

An early assessment of sperm density in men with unilateral cryptrochidism from the Children's Hospital of Pittsburgh cohort revealed lower values than among control

Testosterone Levels

Fig. 8. Sperm density in men who were formerly cryptorchid shows diminished levels in all men who were formerly bilaterally cryptorchid, whereas the majority from the unilateral group are normal. Note that control men are men who did not have cryptorchidism but may have reproductive abnormalities. Solid line depicts the median, the shaded area the interquartile range, and the cross-lines the minimum and maximum values.

Fig. 8. Sperm density in men who were formerly cryptorchid shows diminished levels in all men who were formerly bilaterally cryptorchid, whereas the majority from the unilateral group are normal. Note that control men are men who did not have cryptorchidism but may have reproductive abnormalities. Solid line depicts the median, the shaded area the interquartile range, and the cross-lines the minimum and maximum values.

men (131), as well as an inverse correlation with circulating FSH levels. However, subsequent analyses with an enlarged cohort (see Fig. 9) found no significant difference in sperm density between men who had or had not been successful at paternity. This is likely to result from the considerable variation in values in both the cryptorchid and the control group (115). The successful fathers in the men who were formerly cryptorchid had a sperm density of 45.2 ± 40.2 x 106/mL (M ± SD), whereas in those who were unsuccessful, the value was 27.0 ± 30.1 x 106/mL. The control group of men in this study also had wide variation in sperm density (82.3 ± 82.8 x 106/mL), primarily because some men had high densities (115). In addition to the wide ranges in both groups, the findings in the cryptorchid group attest to the fact that men with "subnormal" sperm counts can father children and that multiple other factors are involved in fertility. Only a limited number of men in this cohort had bilateral cryptorchidism; however, there were no men with normal sperm density, and counts ranged from azoospermia to 13.3 x 106/mL (39).

It has been suggested that after unilateral cryptorchidism, the formerly undescended testis may have little sperm production, with most or all of the mature sperm arising from the contralateral testis. Two reports of men who had had unilateral cryptorchidism va

Cryptorchidism Testosterone
Fig. 9. Sperm density in fertile and infertile men in TE control group or with unilateral cryptorchidism. Solid line depicts the median, the shaded area the interquartile range, and the cross-lines the minimum and maximum values.

assessed semen samples after unilateral vasectomy of the contralateral testis (161,162). These reports of men who had fathered children suggest that previously undescended testes produce relatively few sperm and that orchiopexy may, therefore, have little effect on sperm output. In one of these reports, 8 of 12 subjects had azoospermia after vasectomy of the contralateral testis, and the remainder had sperm densities of 2.2-9 x 106/mL (162). These studies can be criticized, because surgery was done at a relatively old age. Nonetheless, the findings suggest that paternity derives primarily from the descended testis, with the previously undescended testis having poor function or severe abnormalities of the epididymis. Such an interpretation agrees with the finding that fertility is not different between men who have unilateral cryptorchidism and successful orchiopexy and men who had an absent or atrophic testis or who required orchioectomy during surgery for unilateral cryptorchidism (114,163). It should also be considered that with current infertility treatments, orchiopexy may permit testicular sperm retrieval to be followed by ICSI.

Paternity

If accurately reported, paternity is the most valid index of fertility. A significant percentage of normal fertile men have sperm counts that are within the range considered as oligospermia (<20 x 106/mL) (164,165). In addition, sperm motility and morphology may be better indicators of paternity but are more difficult to accurately define than is the sperm count. For example, Vietnam veterans with agent-orange exposure were found to have decreased sperm counts but normal paternity rates (166).

Older studies of paternity in men with a history of unilateral cryptorchidism indicated that 71 to 92% of married men reported fathering one or more children (73,167-171). Overall, a composite assessment of these data indicates that 212 (80.9%) of the 262 married subjects reported children. Therefore, sperm density is not predictive of paternity.

In the recent studies of the cohort of men living in Allegheny County, Pennsylvania, during childhood (Children's Hospital of Pittsburgh male fertility study), men with unilateral cryptorchidism have paternity rates (see Fig. 10) that are not different from those of a control group (2,115,154,172). The entire cohort included 609 men who had had orchiopexy for unilateral cryptorchidism. Each subject completed a detailed questionnaire concerning general health, marriages, cohabitation, use of birth control, frequency of intercourse, information on all children conceived in a committed relationship of 1 yr or longer, and several lifestyle factors, including alcohol, drug, and tobacco use and exposure to chemicals and irradiation. In this group, 359 men indicated that they had attempted paternity. Of these men, 89.7% had been successful in fathering one or more children, with this value not significantly different from the control group in which 93.7% were successful (115). The control group consisted of men who did not have cryptorchidism or major illness. Of the 708 men, 443 completed the questionnaire, indicating that they either had fathered one or more children or had attempted paternity for more than 12 mo. A sensitive measure of fertility is time to conception; the median time was 3 mo for both the formerly unilateral and control groups, and the mean (±SD) was 7.1 ± 0.7 mo for the unilateral group and 6.9 ± 2.3 mo for the control group.

In exploring factors relevant to paternity in the men in the Pittsburgh cohort, no correlation was found between paternity and either age at orchiopexy or testicular size at

Testicular Size Age

Fig. 10. Paternity data from a meta-analysis of reported cases and patients from the Pittsburgh cohort. The first two columns are from men who were formerly unilaterally cryptorchid, the next two from men who were formerly bilateral cryptorchid, and the final column the control group from the Pittsburgh study.

Fig. 10. Paternity data from a meta-analysis of reported cases and patients from the Pittsburgh cohort. The first two columns are from men who were formerly unilaterally cryptorchid, the next two from men who were formerly bilateral cryptorchid, and the final column the control group from the Pittsburgh study.

orchiopexy (115,173). Although no statistically significant differences in paternity rates were found when analyzed by preoperative testicular location, men who had an abdominal testis had the lowest success rate (83.3%), and the lowest likelihood (60%) of achieving conception within 12 mo (115). Increased risk of failure at attempted paternity was found for the presence of varicocele (7.1), major illness (3.6), and marijuana use (2.1), whereas no increased risk was found for history of mumps, prostate problems, sexually transmitted disease, or tobacco or alcohol use.

Paternity rates are significantly lower in men with a history of bilateral when compared to unilateral cryptorchidism or normal men (see Fig. 10). Paternity rates from various reports indicate that 33 to 62% of married men who were formerly bilaterally cryptorchid father children (169,170,171,174). In the Pittsburgh cohort, we likewise found a markedly diminished paternity rate in this group (3,154). In the bilateral group, only 65.3% of men were successful at paternity, compared with the 89.7% in the unilateral group and 93.2% in the control group (140). In this group of men, no relationship was found between preoperative testis location and success at attempted paternity, except that the failure rate was high for bilateral but not unilateral men with an abdominal testis location. Also supportive is that time to conception was increased significantly, compared with control men and those with unilateral cryptorchidism (175).

Fertility in Untreated Males

There are isolated case reports of fertility, based on paternity, in men with bilateral cryptorchidism not corrected until after puberty. One man who had palpable testes of normal volume located in the superficial inguinal ring until corrected at 23 yr of age subsequently fathered 4 children (176). Although reported, this is clearly the exception rather than rule, and nearly all would agree that patients with untreated bilateral cryp-torchidism are infertile.

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