The possibility that environmental chemicals alter normal reproductive tract development has been debated in the literature. There is significant potential concern that endocrine-disrupting chemicals may be linked to the “testicular dysgenesis syndrome” [17.18]. Concerns for a connection between endocrine-disrupting chemical and cryptorchidism developed because of a reported higher risk related to early maternal exposure to diethylstilbestrol . Currently, indirect correlations and suggestive data have been found correlating exposure to endocrine-disrupting chemicals such as pesticides, flame retardants, and phthalates and the occurrence of cryptorchidism [20-24]. Some question whether epidemiologic data truly support the existence of a clinical testicular dysgenesis syndrome .
The hormonal pathways that are crucial for testicular descent have been mainly studied in animal models. Some observers feel the species have sufficient similarity to warrant translational studies of these models . Based on murine models, Hutson has proposed that testicular descent occurs in two phases . The initial transabdominal descent accompanied by enlargement of the gubernaculum is controlled by the Leydig cell hormone insulin-like 3 (INSL3) [28,29]. Transgenic mice with deletion of Insl3 are viable but show a severe cryptorchidism phenotype [30,31], suggesting the crucial nature of INSL3 in the process of testicular descent. In addition, these mice have developmental abnormalities of the gubernaculum, abnormal spermatogenesis and infertility. In human fetuses, Leydig cell production of INSL3 peaks at 15-17 weeks’ gestation just after the peak in testosterone production at 14-16 weeks’ gestation. In vitro, these hormones cause proliferation of gubernacular cells [29,32]. Animal models suggest that inguinoscrotal descent is androgen-mediated, via the genitofemoral nerve (GFN) and/or by activation of androgen receptors in the gubernaculum [27,28]. The GFN releases calcitonin gene-related peptide (CGRP) upon stimulation to produce rhythmic contractions of the murine gubernaculum, which aids migration of the testis and gubernaculum into the scrotum. In addition, androgens may also alter the composition of the gubernaculum resulting in the appropriate swelling and elasticity that promotes testicular descent through the masculinized inguinal canal . Indeed, cryptorchidism has been noted in rodent models exposed to androgen receptor blockade, with defective innervation (the cryptorchid TS rat) and/or with altered muscle-specific gene expression in the gubernaculum (the Long-Evans orl rat) [33,34].
The role for androgens in testicular descent is readily observed in clinical human correlates. Cryptorchidism is a common component of complete or partial androgen insensitivity syndrome (CAIS, PAIS) due to mutations of the androgen receptor (AR) gene . The role of AR gene mutations in isolated forms of hypospadias or cryptorchidism is less clear. Analysis of this gene in males with isolated cryptorchidism suggests that longer alleles of the GGN (polyglycine) repeat polymorphism are more common in cases as compared to controls but no association of CAG (cytosine-adenosine-quanine) repeat length or variants in other AR exons with isolated cryptorchidism [35-40].
Several investigators have examined the role of genetic variants of INSL3 and its receptor, RXFP2 (relaxin/insulin-like family peptide receptor 2, also known LGR8 and GREAT) in the etiology of cryptorchidism. Binding of the INSL3 protein to RXFP2, which is highly expressed in the gubernaculum, results in increased cAMP production and downstream signaling important in gubernacular development . Several genetic studies have examined the INSL3-RXFP2 pathway to determine the frequency of mutations in either gene in patients with cryptorchidism. The available data suggest that variants of one of these genes exist in 3% of cryptorchid cases . However, it is not clear at present which genetic variants are functionally significant [43-45]. As yet unidentified genetic and/or environmental factors could also alter expression of INSL3 and/or RXFP2 protein during a critical period of testicular descent. Indeed, a recent study suggests that levels of INSL3 are reduced in cord blood of boys with persistent cryptorchidism after birth . Further studies are needed to elucidate the role of this important signaling pathway in the pathogenesis of cryptorchidism in man.
Two posterior HOX genes have been identified as possible candidates for cryptorchidism from murine genetic knockout phenotypes as loss of either Hoxa10 or Hoxa11 is associated with a nonsyndromic cryptorchid phenotype in transgenic mice [47,48]. However, no variants of these genes are consistently associated with cryptorchidism in human studies [49-51]. Similarly, mixed results were obtained in studies of the association of the estrogen receptor alpha (ESR1) gene in clinical cryptorchidism [52-55].
Retractile testes are commonly confused with undescended testes. The key to distinguishing them from undescended testes is the physical exam. All retractile and many undescended testes can be delivered into the scrotum. The retractile testis will stay in the scrotum after the cremaster muscle has been overstretched. The low undescended testis will immediately pop back to its undescended position after being released. Atrophic or “vanishing” testes are found anywhere along the normal path to the scrotum. They are believed to be due to neonatal vascular ischemia. The contralateral descended testis can be hypertrophied in these boys, but this is not a reliable diagnostic sign. Upon complete evaluation, 80% of nonpalpable testes are present in either the abdomen or in the inguinal canal. A child with bilateral nonpalpable testes should have an endocrine evaluation to rule out anorchia or disorder of sex development (DSD or intersex). Cryptorchidism associated with hypospadias should also raise the possibility of DSD states, which occurs in 30% to 40% of patients, mainly consisting of defects in gonadotropin or testosterone synthesis.
Hormone Therapy Patients with undescended testes should be referred for surgical evaluation no later than 6 months of age. Hormonal therapy, including gonadotropin-releasing hormone and human chorionic gonadotropin, has been widely used in Europe for inducing descent of undescended testes. Treatment is most successful for low undescended testes. Divergent results have been reported likely due to suboptimal study design, differences in patient age and treatment schedules, possible inclusion of retractile testes and variable follow-up. Several meta-analyses of this published literature suggest that the effectiveness of primary hormonal therapy in cryptorchidism is less than 20% [60-62]. A recent consensus statement discourages use of hormone therapy for cryptorchidism . The use of hormonal therapy after orchiopexy to improve semen analyses in high-risk patients with very poor germ cell development has been reported to be helpful in investigations in Europe and the United States.
The goals in bringing the testis into the scrotum include: prevent ongoing thermal damage to the testis, treat the associated patent hernia sac, prevent testis torsion/injury against the pubic bone, and achieve a good cosmetic result (avoid the psychological effects of an empty scrotum) to allow easy future palpation of the testis (testicular self-exam for cancer).
Standard inguinal orchidopexy involves several steps after repeat examination under anesthesia to reconfirm testicular location. A transverse inguinal incision is made along Langer’s lines and Scarpa’s fascia incised with care to avoid injury to a testis in the superficial inguinal pouch. The testis is mobilized after incision of the gubernacular remnant. The cremasteric muscle fibers are transected and the hernia sac isolated, transected, mobilized to the internal inguinal and ligated. After division of lateral fascial bands, the testis is placed in the scrotum in a subcutaneous or subdartos pouch without trans-capsular sutures.
A primary scrotal approach to orchidopexy is described in cases where the testis is palpable and is either close to the scrotum or can be easily drawn into the sac [64-66]. Successful mobilization of the testis and ligation of the hernia sac at the level of the external or internal ring is described; alternatively a secondary inguinal incision is made if needed. Many series report use of testicular fixation sutures within the dartos pouch to maintain the testis in a dependent scrotal position. Testicular retraction or atrophy has been reported at 0-2%, while postoperative hernia has been noted in 2-3% of cases with follow up in these series ranging from 1 month-3 years. Thus, this approach may be a viable option in select cases of cryptorchidism when testes are distal to the external ring.
Further maneuvers may be employed to obtain adequate length of a high inguinal testis. Passing the testis behind the inferior epigastric artery and vein after opening the transversalis fascia (the Prentiss maneuver) will allow more medial positioning of the cord. Dividing the internal oblique muscles with lengthening the incision as needed allows further opening of the internal ring and additional dissection of the lateral spermatic fascia in the retroperitoneal space.
A Fowler-Stephens orchiopexy, or division of the internal spermatic artery, can be performed if extensive dissection between the vas and cord has not occurred, as testicular survival then relies on the deferential and external spermatic blood supply. An alternative for the high testis is microvascular autotransplantation to the ipsilateral inferior epigastric artery and vein. Rarely, a 2-stage orchiopexy may be used without division of the spermatic vessels when the Prentiss maneuver and cord dissection fail to provide adequate length . The testis is anchored in its most dependent position or the spermatic cord may be wrapped in a protective sheath  for ease of the second stage, generally 6-12 months later.
Exploration for a nonpalpable testis may occur through an extended inguinal incision, an abdominal incision, or by diagnostic laparoscopy. At the time of exploration, the most likely findings are intra-abdominal or “peeping” testis just at the internal ring (25-50%), vanishing testis most commonly distal to the internal ring (15-40%) or cord structures (vessels and vas) that enter the internal ring in the presence of a viable testis that is non-palpable due to the size of the testis or patient’s body habitus [68-70]. Absence of visible spermatic vessels warrants further full exploration of the retroperitoneum to document testicular agenesis, which is extremely rare. The finding of cord vessels entering the ring warrants inguinal exploration for identification of a distal viable or vanishing testis. Some surgeons us a primary transscrotal approach when a palpable scrotal nubbin is present and confirm the diagnosis of vanishing testis by visualizing a black area containing hemosiderin [71,72]. However, if findings are questionable using this approach, laparoscopy is warranted. Although controversial, fixation of the solitary testis should be considered to protect against the theoretical risk of torsion.
Options for treatment of an intra-abdominal testis are varied depending on the patient’s age, testis size, contralateral testis, and the skills of the surgeon. Goals are to mobilize all structures extending distal to the internal ring, transect the peritoneum lateral to the spermatic vessels and distal to the vas, and to mobilize these vessels proximally while maintaining collateral blood supply with the vas should a Fowler-Stephens maneuver be required. Adequate length is defined by mobilization of the testis to the contralateral internal ring. A new hiatus is created by retrograde passage of a clamp or port at the level of the medial umbilical ligament. Formal closure of the dissected internal ring is not necessary [73,74]. If dissection does not allow for adequate length to reach the scrotum, the spermatic vessels are clipped, followed by a 1- or 2-stage operation to bring the testis into the scrotum. The typical success rates of contemporary series for standard, 1-stage and 2-stage Fowler-Stephens laparoscopic orchiopexy are 90-100%, 71-97% and 84-96%, respectively [75-78].
If a testicular nubbin is found within the scrotum, some surgeons recommend contralateral scrotal testis fixation since the possibility of a previously unrecognized torsion may have occurred.
Surgery cannot reverse the maturational failure of the undescended testis, but it can prevent ongoing thermal injury. Parents are often concerned about future fertility. Arrested development of spermatogonia is a common finding in cryptorchid testes and has been recognized for over 40 years . Very low Ad spermatogonia per tubule (Ad/T) ratios are associated with increased risk for infertility [80,81]. However, failure to establish an adequate Ad spermatogonia population in cryptorchid testes appears to correlate more closely with sperm counts in adulthood than total Ad/T count alone [82,83]. A reduced number of Leydig/interstitial cells in undescended as compared to contralateral descended testis  and with increasing age at orchidopexy  is also reported. In addition, there is disruption of morphology, failure of maturation at puberty and evidence for reduced number of Sertoli cells after 4 months of age in the cryptorchid testis [86-89].
In patients who have undergone orchiopexy at an early age, abnormal semen quality is common, with reduced sperm counts reported in 75-100% and 18-43% of formally bilaterally and unilaterally cryptorchid men, respectively [90-93]. However, 90% of boys with unilateral cryptorchidism and 65% with bilateral cryptorchidism will achieve paternity. Patients who are interested in their risk for infertility may have a semen analysis performed at age 18.
The increased risk of germ cell tumor (GCT) arising in a cryptorchid testis may be related to persistence of gonocytes, which as precursors of testicular carcinoma in situ (CIS) may then evolve into frank GCT . Recent analyses by Wood and Elder critically evaluated several concerns surrounding the topic of cryptorchidism and testicular cancer . They determined from their review that previous estimates of cancer risk in cryptorchid testes were too high (at 26-40 times greater risk) and are more likely 2.5-8 overall, with a decreased relative risk of 2-3 if prepubertal orchidopexy is performed. In their review of the risk of malignancy in contralateral descended testes, they noted that studies suggesting such a risk demonstrated significant flaws in study design. In contrast, in a recent meta-analysis Akre et al derived a significantly increased relative risk of tumor in the contralateral testis of 1.7 (95% C.I. 1.01-2.98) in males with a history of unilateral cryptorchidism .
Recent data suggest that risk of malignant degeneration may be 2-6 times higher in men who underwent orchidopexy after puberty as compared to those having surgery at an earlier age [97,98]. Orchiectomy is the best option for post-pubertal males up to age 50 since these gonads have poor fertility potential and increased risk, while nonoperative treatment is recommended in men over 50 since their cancer risk has never been defined . Finally, the malignant tumor developing in persistently cryptorchid testes is most commonly seminoma (74%) while after orchiopexy two-thirds of malignancies are non-seminoma . Approximately 15% of tumors arise in the contralateral descended testis.
All patients should be taught proper monthly testicular self-exam at the time of puberty. Some patients with cryptorchidism are at a higher risk of cancer (prune belly syndrome, ambiguous genitalia, karyotypic abnormalities, or the postpubertal boy). After successful orchiopexy, patients are examined at 6 to 12 months to check on testicular size and position. They are rechecked at puberty to explain the technique and need for monthly testis self-exam concerning early recognition of testis cancer. Patients with retractile testes should be examined annually until age 7, because about 5% will be found to have a testis out of the scrotum.
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