Pediatr Surg Int (2007) 23:625–632 DOI 10.1007/s00383-007-1900-3

REVIEW ARTICLE

Orchidopexy and its impact on fertility Feilim Murphy Æ Thambipillai Sri Paran Æ Prem Puri

Accepted: 9 February 2007 / Published online: 13 March 2007
Springer-Verlag 2007

Abstract We critically analysed the factors known to influence the fertility potential after orchidopexy in children. A comprehensive literature review of all publications in the English language listed in Medline using the words cryptorchidism, undescended testis, orchidopexy, fertility, semen analysis and surgery from 1970 to 2005. In unilateral ectopic, canalicular and emergent testes, as long as the surgery is carried out in early childhood, fertility outcome is good (>90%). The majority of the bilateral abdominal testes are infertile. While unilateral abdominal testes and unilateral absent or vanishing testes have favourable fertility potential, quantification has proven difficult. Despite multiple studies, fertility in crypt orchid tests is still an uncertain issue. Hormonal treatment in conjunction with early surgical correction has not been fully explored. We recommend orchidopexy soon after 6–7 months of age, corrected for term, to maximise the future fertility potential. Keywords Fertility

Undescended testis
Orchidopexy


Introduction The term cryptorchidism is derived from the Greek words ‘‘kryptos’’ and ‘‘orchis’’, meaning ‘‘hidden’’ and ‘‘testis’’. Testicular descent into the cooler environment of the scrotum is necessary to allow for normal spermatogenesis. Testicular decent as proposed by Hutson occurs in two

F. Murphy (&)
T. S. Paran
P. Puri Children’s Research Centre, Our Lady’s Hospital for Sick Children, Crumlin, Dublin 4, Ireland e-mail: [email protected]

sequential phases with the initial transabdominal descent controlled by mullerian inhibiting substances, insulin-3 and testosterone [1]. The testis reaches the internal inguinal ring by the 12th week of gestation. The testis does not change position between 3 and 7 months of life, during which period the inguinal canal and scrotum are distended by the gubernacular swelling [2]. During the transinguinal phase, the gubernaculum migrates towards the scrotum. Androgens and the genitofemoral nerve indirectly control this [3]. The transinguinal descent is known to occur during the 24th and 28th weeks of gestation, and is usually completed by the third trimester [3]. Approximately, two-thirds of neonates born with an undescended testis will undergo spontaneous testicular descent, typically by 4–6 months postnatally. This spontaneous descent is thought to be mediated by a postnatal testosterone surge. Approximately, 33% of premature male infants are cryptorchid. The incidence decreases to 3–5%, for fullterm infants, and by 1 year of age the incidence is approximately 0.8–1% [4]. Most undescended testes that descend spontaneously do so during the first 3–4 months after term, and few will descend after that [5]. The right side (70%) is affected more often than the left (30%) [6]. Cryptorchidism frequently has strong familial clustering with 6–10% incidences within siblings [7, 8]. Of patients with cryptorchidism, 10–25% (1 in 600 males) have bilateral undescended testes. It is estimated that al least 6% of these are due to an endocrine disorder [9, 10]. The bimodal presentation of cryptorchidism with a peak at 2 years and the second around 8–10 years has been observed [11, 12]. Hack et al. have reported that in a significant proportion of these older children, the testes have been documented to be present within the scrotum in early childhood. This is known as acquired undescended testes. The pathogenesis appears to be due to a failure of natural

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elongation of the cord structures in proportion to body growth owing to incomplete disappearance of the processus vaginalis [13, 14]. The fact that these testes initially descended normally and later ascended, mostly into the superficial inguinal pouch, may mean that they have a favourable fertility potential. John Hunter, the renowned eighteenth century Scottish anatomist, was the first to describe the gubernaculum and its effect on the testicular descent. He also postulated that the testis, which failed to descend, is intrinsically abnormal rather than becoming abnormal secondary to failing to descend [15]. This key question still remains, whether there is a primary abnormality of the cryptorchid testis or that progressive injury occurs to the cryptorchid testis due to its abnormal position. The issue of fertility or infertility is fraught with both physiological and emotional difficulties. The undescended testis and the effect of orchidopexy on male fertility are far from clear-cut. What effect orchidopexy has on these patients’ fertility in the long term is complicated by numerous other factors. Issues such as the accuracy of semen analysis, the partner’s fertility, the age at surgery, bilateral versus unilateral, the preoperative testicular site, testicular size, suture placement and or biopsy at the time of surgery are all listed as significant factors in post orchidopexy fertility. What effect does the fixation of the unilateral cyrptorchid testis have on the contralateral testis? A number of statements are frequently presented as truisms such as ‘‘higher testis is always worse’’, ‘‘earlier surgery is better than later’’ and ‘‘bilateral cryptorchidism is worse than unilateral’’. It is difficult to draw conclusions from a significant amount of the research on this topic due to sample size, selection bias and variable end points. In this review, we critically examine the above factors and their influence on fertility following orchidopexy.

Classification A retractile testis is defined as one that is palpable in the normal line of descent, and one that could be manipulated into the dependent scrotum without tension. A vast majority of children referred surgically with a diagnosis of cryptorchidism are diagnosed of retractile testis. These have completed the process of descent, but are found in the groin because of an overactive cremasteric reflex. An accurate diagnosis is challenging, and children with this diagnosis should be monitored, as some may occasionally ascend and become ‘‘undescended’’ [16]. Table 1 summarises the present classification of cryptorchidism and its incidence. Ectopic testis is one that has descended beyond the external inguinal ring into an abnormal position. A vast majority of these are seen in the

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superficial inguinal pouch and are palpable on clinical examination. Truly undescended testes are seen in approximately 23% out of which 10–12% are intracanalicular. Absent testes contribute to the remaining 4–8% [18].

Assessment of fertility If accurately reported, paternity is a more valid index of fertility than sperm density. However, studies of paternity literature in the USA quote that 15–30% of paternity tests reveal that the father named on the birth certificate is not the genetic father, thus paternity results in cryptorchidism must also be interpreted with caution [19, 20]. In the absence of accurate paternity reports, semen analysis, testicular volume, blood hormonal assays and testicular biopsies have all been used to assess the potential for fertility. The World Health Organisation (WHO) defines a normal sperm count to be more than 20 · 106 sperm/ml, with less than this defined as oligopsermia, and the complete absence of sperms as azoospermia [21]. The WHO also recommends a standard method of assessment [22]. However, there is controversy, within the reproductive and physiology departments around the world, on the accuracy of the definition and the methodology of sperm analysis. Indeed, the coefficient of variation for the sperm count alone can exceed 40% between two technicians due to technique, the equipment and the reader [23]. The lack of standardisation in the North American semen analysis has a significant impact on the results [24]. Because of these variables, Keel argues that all laboratories performing the semen analysis should adopt universally accepted performance standards and criteria with external review [25]. The possible decrease of sperm counts in recent decades and significant variability from the WHO normal sperm count further complicate the issue [26]. Testicular aging occurs after a peak at 30 years of age with a natural decrease in spermatozoa and sperm motility and form. Oshio et al. in Japan demonstrated significant variability in the semen of healthy males examined monthly over a yearly period, prompting them to state that multiple semen analysis need to be performed in all situations [27]. Table 1 Classification of undescended testes and their incidence [17] Classification

Incidence (%)

Ectopic testis

77

Intracanalicular and emergent testis

10–12

Intra-abdominal testis

4–6

Vanishing

3

Absent

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In a recent study of fertile men preceding vasectomy revealed that 54.9% had at least one altered parameter in comparison to the minimal values established by WHO [28]. A Danish study of 430 couples found that the probability of conception increased with increasing sperm concentrations up to 40 · 106/ml and that the semen volume and motility were of limited value [29]. Their data demonstrated that WHO guidelines must be used with caution and that men with sperm counts greater than the lower range of normal, as defined by the WHO of 20 · 106/ml, may in fact be subfertile. These controversies have a direct impact on our assessment of the data on post orchidopexy fertility. Other factors of variability include patient selection, the method of sperm collection, analysis, the number of specimens and length of abstinence. There is no test to determine the quality of sperms, although it is implied by motility. It is believed that damage to the germinal epithelium causes both a reduction in sperm number and quality. Hargreave et al. found that cryptorchid men had a worse prognosis than other subfertile men with similar low sperm counts [30]. Mahmoud et al. in Ghent concluded that men with unilateral orchidopexy had severe subfertility in which conventional in vitro fertilisation (IVF) therapy had no role [31]. This was based on 44 couples undergoing assisted reproduction, where the men had a history of unilateral cryptorchidism. This is contrary to Singer et al. in 1987, who found that cryptorchid men had generally normal values for both motility and viability, and they believed that these individuals would be more fertile than the non ‘‘postcryptorchid type oligospermia’’ [32]. Sperm density is variable in both the unilateral and bilateral cryptorchid male (Table 2). Both sperm density and biopsy studies show significant difference between unilateral and bilateral cryptorchidism. Puri et al. performed semen analysis on 142 men with a mean age of 24.7 years, who had undergone orchidopexy at ages 7– 14 years (119 unilateral and 23 bilateral) to reveal normal sperm density in 74% of men with unilateral cryptorchidism, in 68% with a unilateral impalpable testis and only in 30% with bilateral cryptorchidism. Men who had bilateral impalpable testes were azoospermic [37]. Gracia et al. found significant differences in the sperm density between

Table 2 Result variation in sperm analysis in previously cryptorchid men

intra-abdominal and those in the superficial inguinal pouch. Sperm analysis on 140 patients who were at least 18 years old on followup, demonstrating the lack of germ cells at biopsy, correlated with infertility risk of 78–100% in bilateral cryptorchidism [38]. Negri et al. performed testicular biopsies on the testes in 30 men (mean age 34.7 ± 4.4 years) with a previous history of bilateral cryptorchidism who were attending fertility treatment. These men had testicular histology demonstrating mild hypospermatogenesis in ten patients, severe in eight and only pure Sertoli cell syndrome in eight [39]. However, important semen morphology, density and motility may appear, natural paternity and fatherhood is the golden standard to assess the fertility of the cryptorchid male. The Pittsburgh group in 1996 with Coughlin et al. examined delays in conception following orchidopexy. The mean time for conception was found to be longer in those following bilateral orchidopexy as opposed to unilateral and controls 34, 11 and 9 months, respectively. This was based on the questionnaires of 547 men who had orchidopexy in the Children’s Hospital in Pittsburgh from 1955 to 1977, of which 246 attempted conception. Thus, bilateral cryptorchid had significant delays in conceiving as opposed to unilateral patients who were similar to normal controls [40]. Repeatedly, in the post orchidopexy studies, the men who provided semen samples remained a fraction of the overall total number of cases, and one must be concerned about the element of self-selection within these volunteers. Fallon and Kennedy’s long-term followup of cryptorchid patients, in 1985, reveals the problems with assessing fertility and sperm analysis in these patients [41]. In their study, 200 patients had an orchidopexy performed between 1950 and 1960. However, only 64 (34%) responded to their questionnaire, 25 (12%) came for review and 20 (10%) had semen analysis performed.

Testicular volume As the bulk of the testis is composed of seminiferous tubules, testicular volume has been used to estimate tubular function and spermatogenesis. Between 1963 and 1986,

Unilateral Azospermia (%)

Bilateral Oligospermia (%)

Azospermia (%)

Oligospermia (%)

Chilvers [33]

14

31

42

31

Chendron [34]

12

75

88

12

Okuyama [35] Mandat [36]

7

21

77

23

10

37

9

65

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Beltran-Brown et al. classified the position of the cryptorchid prior to orchidopexy in 1,010 patients [42]. They found that 42% of smaller testes (as defined by a measured reduction in volume of 30% in comparison to the contralateral side) had no increase in size on followup. Puri et al. examined the testicular volume in 159 men who underwent orchidopexy at a mean age of 9.8 years (range 7–13.6) [43]. With a mean age at followup of 24.3 years (range 18– 41), they found that the cryptorchid testes were smaller than the contralateral side. The mean testicular volume of the contralateral testis (n = 131) was 21.1 ± 4.4 ml as opposed to 4.9 ± 3.5 for those testes that were originally abdominal in position (n = 19). Testes found in the superficial inguinal pouch were approximately 85% of normal testicular volume and those that were impalpable were substantially smaller. Ku et al. who randomly assessed 1,602 adult male volunteers confirmed this [44]. Of the 36 patients with unilateral cryptorchidism, 29 had undergone surgery 8.9 ± 3.9 years earlier, and the testicular volume of the affected side (n = 25) was significantly smaller than that of the contralateral side. Taskinen et al. assessed 73 men who had previous surgery and found that the mean volume of the cryptorchid testis was 11 ± 6 ml compared to 20 ± 7 ml for the contralateral scrotal side [45]. The results showed no significant correlation between patient age at treatment or original testicular location, except when the surgery occurred after 5 years of age. The high scrotal testicular volume was 16 ± 6 ml as compared to 10 ± 6 ml for intraabdominal testis. They concluded, somewhat controversially, that the lack of significant variations in testicular size implies early orchidopexy at age younger than 2 years was not essential. Lee et al. found no correlation between the position of the cryptorchid, preoperatively, and adult sperm density and paternity [46, 47]. This was based on their findings of 90% paternity in their cohort of 320 previously repaired unilateral cryptorchid patients and sperm analysis from 21 patients with intra-abdominal/internal ring testis. Their results demonstrated paternity rates of 100% for those with testes previously found at the internal inguinal ring and 83.3% for those intra-abdominal. The presence of a unilateral atrophic testis at birth did not affect successful paternity as opposed to those with normal size cryptorchid, 88 versus 89.7%, respectively. On examination of 103 men, they found that the previously cryptorchid testis was always smaller than the contralateral side. Importantly, the mean age at surgery was quite high in this group with 11, 22 and 34% of the 320 men having their surgery between the ages of 3 and 5, 6 and 10, and older than 10 years, respectively. Overall, the balance of evidence implies testicular size is influenced by cryptorchidism. Unilateral crypt orchids can

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have a smaller testis than the contralateral normal testis, and that the higher the cryptorchid the greater the risk of both decreased testicular size and thus the possible paternity rates.

Morphological studies of cryptorchid testis The neonatal germ cells present at birth undergo transformation into a Type A spermatogonium from 3 months of age and are completed by 1 year of age [48]. This step is defective in cryptorchid testes [49]. The decreased number of Type A spermatogonia leads to inadequate stem cells for the spermatogenesis and subsequent low sperm counts and infertility [48]. Whether the germ cell loss is a primary effect, due to an intrinsic developmental abnormality within an undescended testis, or secondary effect, due to the exposure to a higher temperature (37 vs. 33C) remains unknown. Surgery, however, is based on the assumption that the germ cell loss is secondary to the position and, hence, reversible by placement of the testis in the scrotum. Whether this assumption is valid remains to be seen [48]. Cortes et al. in 1995 examined the testes of 35 foetuses with cryptorchidism (intra-abdominal or intra-canalicular) and 16 normal controls that were stillborn, along with 58 boys aged up to 3 years with cryptorchidism [50]. They found that the number of germ cells per tubular cross section was statistically lower in the cryptorchid than the normal at all ages even at birth. The entire weight of the testes in the cryptorchid foetal group was significantly lower than the normal. Interestingly, the germ cell number in the intra-abdominal testes decreased from 28 weeks’ gestation. Hadziselimov et al. histologically assessed 72 intraabdominal testes, which were biopsied at the time of fixation and compared them to 94 normally descended controls in order to assess normal and crypt orchid development [51]. The abdominal testes were histologically normal up to 6 months, then showed a sharp decline in the spermatogonia, with empty interstitium appearing after 2 years and a complete lack of germ cells occurring in 64% of those older than 3 years. Atrophy was also seen in relation to Sertoli cells. Such changes appear to be proportional to the age and to the degree of incomplete testicular descent. Ultrastructural changes such as degeneration of mitochondria, loss of cytoplasmic ribosomes and smooth endoplasmic reticulum appear by the second year of life and are not seen before 1 year of age [52]. Damage to the normally descended contralateral testis has also been seen [53]. Epididymal anomalies were associated with 36–43% of cryptorchid testes [54–56]. Most common (50%) anomaly is abnormal ductal fusion where a flimsy attachment of the

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head of the epididymis to the testis is seen. Complete separation or atresia of the epididymis and atresia of the vas was seen in 5–21% of cases. Other anomalies include abnormal ductal suspension, elongated tail of the epididymis and a long loop vas. These abnormalities together with possible damage secondary to the surgery itself may contribute to the overall incidence of infertility. This would explain the reported success rates in fertility of 40% with testicular sperm extraction in previously cryptorchid patients with azoospermia and normal hormonal status [57].

Hormonal studies of cryptorchid testis Numerous theories have been proposed for the failure of testicular descent and its effect on long-term fertility [1, 49, 58]. It is postulated that there is an early gonadotrophin level decrease at 60–90 gestational days leading to a regression of foetal Leydig cells, which persists to adolescence [58]. A blunted neonatal surge of LH and FSH has been postulated to cause the infertility associated with unilateral cryptorchidism [59]. Other hypotheses on this subject include a mild form of hypogonadotrophic hypogonadism or impaired hormonal priming during infancy [51]. If hormonal changes are the reason for cryptorchidism, then logic implies that hormonal therapy will both induce testicular descent, increase the number of germ cells and improve fertility. One of the greatest controversies relating to hormonal therapy relate to the fact that exogenous gonadotrophins will cause a retractile testis to descend. This makes scientific evaluation of trials of hormone therapy for cryptorchidism difficult, as there is no strictly objective test for retractile testes. Randomised trials have found that human chorionic gonadotropin (hCG) and luteinising-hormonereleasing-hormone (LHRH) are very effective in causing the descent of retractile testis [60]. A randomised double blind trial comparing gonadatrophin releasing hormone with human chorionic hormone in 33 boys (1–5 years old) with cryptorchidism found testicular descent in 13 (19%) of those treated with GRH and only 1 patient (6%) with hCG [61]. A further double blind LHRH versus placebo controlled study of 252 boys with 301 cryptorchids found after 8 weeks of treatment that 8% of the placebo group and 9% of the LHRH group testes had descended with the lowest success rate in the youngest age group of 1–2 years [60]. Hormonal manipulation is proposed to increase testicular size. Schwentner et al. prospectively assessed the effect of GNRH on 44 boys aged 11–100 months for 4 weeks prior to orchidopexy compared to surgery alone [62]. Biopsies were performed at the time of orchidopexy and the mean fertility index of those treated with GNRH was

629

1.05 ± 0.71, as opposed to surgery alone, 0.52 ± 0.39. However, in the Taskinen et al. series, 26 patients who had received human chorionic gonadotropin treatment had a significantly smaller testis (9 ± 5 ml) than the 57 patients treated with surgery alone (12 ± 6 ml) [45]. A meta analysis of all randomised control trials of hormonal therapy for cryptorchidism in 2004 concluded that evidence existed for the advantage of hCG and LHRH treatment, but that due to the small number of trials and with small sample size this treatment modality could not be recommended for all [63]. Zhou found that hCG given to prepubertal mice caused a precocious transformation of the primary spermatocytes to form spermatids, suggesting that hCG treatment of prepubertal cryptorchid boys may initiate premature spermatogenesis which may effect later fertility [64].

Testicular biopsies and fixation Testicular biopsy was introduced for the exploration of male infertility in 1940 [65]. One of the most significant concerns about testicular biopsy at the time of orchidopexy is whether this would increase the risk of testicular malignancy later on in life. It is well documented that cryptorchid testes have an increased incidence of malignancy, even after orchidopexy. The relative risk is estimated to be between 4 and 8 times more than that for normally descended testes [66–69]. Intra-abdominal testes are reported to result in malignancy more so than the others. Swerdlow et al. reviewed 1,075 men who had an orchidopexy performed during 1951 and 1964, which revealed that the relative risk of testicular malignancy increased following biopsy to 66.7, as compared to the normal population [70]. However, Moller et al. highlighted a potential weakness in this study, that is, the criteria for biopsy was unclear in 9% of the testes in the series [71]. They felt that this leaves open the possibility of a selection bias. They went on to investigate a cohort of 830 men, all of whom had a biopsy taken at the time of surgery in their institute over a period of 21 years. They found a moderate increase (about twofold) risk of testicular cancer in the biopsied testes [71]. However, the age at surgery, preoperative testicular location or the details of the control group is not clear from their paper. A meta analysis performed in 2,000 of case control and cohort studies concluded that significant risk factors for testicular malignancy included intra-abdominal testes, orchidopexy after 10 years of age and testicular biopsy [68]. Cortes et al. in 2004 again reviewed their database of now 1,466 patients to assess the effect of surgery and testicular biopsy on the cryptorchid [69]. They found that

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testicular biopsy (3 mm · 3 mm · 3 mm) was not a risk factor for malignancy and recommended biopsy at the time of orchidopexy in those with abnormal karyotype/ambiguous genitalia or intra-abdominal testis. Patel et al. assessed 112 men with a mean age of 19.6 years who had had previous orchidopexy with testicular biopsy, with physical examination, testicular ultrasound and measurement of antisperm antibodies [72]. They found no patients with direct antisperm antibodies and no increase in the rate of testicular microlithasis and thus postulated that testicular biopsy at orchidopexy did not damage the testis. Ward et al. compared the ultrasonographic appearance of the human testis (n = 22) that had suture fixation to those that had sutureless dartos pouch fixation [73]. Sonography revealed no significant parenchymal changes in the sutured group with 14% having an area of subtunical hypoechogenicity and 32% having tunica albuginea calcifications. Sonography of the sutureless fixation revealed normal testes. No significant evidence exists that breaching the testicular capsule in the prepubertal human cryptorchid has any effect on the contralateral testis or on long-term fertility.

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there was a higher rate of azoospermia and abnormal sperm counts in adults. Engeler et al. in 2000 followed up 440 prepubertal boys who had orchidopexies with biopsy and found that the fertility outcome in those with bilateral cryptorchidism correlated with the number of spermatogonia at orchidopexy (P = 0.018), but correlated inversely with the age at orchiopexy (P = 0.021) [79]. However, only 14 patients in this study were operated on prior to the age of two and only a small minority of the cohort reported paternity. Coughlin et al. demonstrated that those men with unilateral cryptorchidism who were orchidopexed before 2 years have higher levels of inhibin B and lower FSH levels, which implies better potential for normal sperm production [80]. As stated previously, ‘‘implied potential’’ for normal sperm production does not equal paternity. Miller et al. reported paternity rates for repaired unilateral cryptorchids (at various ages) at 89.7%, as compared to 93.7% for the normal population, which is not statistically significant [81]. However, in bilateral cryptorchidism, especially with intra-abdominal testes, the decision to operate early is obvious.

Conclusions Timing of orchidopexy and its effect on fertility The recommended age for orchidopexy has steadily fallen over the decades with the evolving understanding of spermatogenesis and improvement in surgical techniques. Ludwig et al. in 1975 demonstrated 90% fertility for those operated on within the first 2 years of life, as opposed to 50% for those operated between 3 and 4 years and 30% for those operated between 9 and 12 years [74]. However, the original position of the testis, which we now know to be a significant factor in fertility outcome, was not taken into account in this report. Hamza et al. followed 84 neonates with undescended testes and found that spontaneous descent occurred prior to 4 months in those born at full term and prior to 6 months for those born preterm [75]. It is generally assumed, at present, that spontaneous descent no longer occurs after approximately 3 months of age in a term baby, and is rare beyond 6 months of age [48, 76]. In 1987, Schindler et al. found that orchidopexy had no effect on germ cell number once the damage was established at least after the age of three [77]. Hadziselimovic et al. observed in a small cohort of 31 boys that although there was a decrease in the germ cells in those who underwent surgery after 6 months as compared to those less than 6 months, there was no statistical difference in the sperm counts between the two groups 20 years later [78]. They also noted that when germ cell maturation was poor at the time of surgery, independent of the age of surgery,

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Given the nature of the male contribution to fertility, it is not surprising that predicting fertility rates with various markers such as sperm analysis, testicular volume, testicular position and hormonal assays would all be fraught with difficulty. Hormonal treatments as an alternative to surgical correction have failed so far. However, hormonal treatments in conjunction with surgical correction have not been explored fully. Overall, it appears that in unilateral canalicular or palpable testes, as long as surgery is carried out by 2–5 years, fertility is approximately 90% of the normal population. If surgery is delayed beyond 12 years, there is a real decrease in fertility in this group. Based on the accounts of morphology and ultrastructural changes noted in undescended testes as early as 3–6 months, it would be logical to operate on these children soon after this period in the hope that germ cell loss can be prevented or minimised. Since bilateral cryptorchids have much lower fertility rates, it is advisable also to operate on these testes early within 3–6 months. Whether such an early surgery could improve fertility outcome remains to be seen in 15– 20 years’ time, when the present generation of children with early orchidopexy reach adulthood.

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