The prevalence of cryptorchidism is 2–9% in full-term infants [7–14]. Among premature infants, the prevalence is as high as 21%, but diminishes with advancing gestational age and increasing birthweight. It is also noteworthy that there is an increased prevalence of both cryptorchidism and hypospadias among those born early and with low birthweights, although these findings may be more likely to be associated with a more pervasive development defect [15]. As a consequence of spontaneous descent after birth in both the term and premature infant, the prevalence of cryptorchidism decreases to approximately 1–2% by 3 months of age (Table 10.1) [14, 16]. Spontaneous descent is more likely among boys who weigh <2500 g at birth or are gestational age <37 weeks [8]. The likelihood of descent in the 3 months after birth is greater for bilateral maldescent and if the scrotum is large and well developed at birth [7, 9].

After the age of one year, the prevalence of non-descent ranges from 0.7 to 2.0% of males with unilateral and bilateral cryptorchid testes [3, 7, 9, 14, 17, 18], similar to the 0.82% found among untreated Nigerian schoolboys aged 5–13 years [19].

The incidence of cryptorchidism and other urogenital malformations has been reported to have increased in recent decades. The estimated prevalence varies considerably in different regions [20, 21], however, perhaps from different levels of exposure to anti-androgenic chemicals, with hormone-disrupting actions, such as pesticides and phthalates [22]. Increasing incidence trends have been reported from Denmark and the United Kingdom [9, 10, 14, 23, 24]. These studies used rather similar diagnostic criteria for the ascertainment of cryptorchidism, the children having been prospectively examined by trained researchers.

Testicular development involves a cascade of sequential steps under the control of numerous genes [25]. Several transcription factors are known to contribute to the initial development of the adrenogenital primordium [26, 27] including EMX2 (Empty Spiracles 2), LHX1 (Lim Homeobox Gene 1), WT1 (Wilms Tumor 1), and WNT4 (Wingless–type MMTV Integration Family Member 4). Mutations in these genes cause agenesis or dysgenesis of the gonads, adrenal glands, and the urogenital system. Further development to the bipotential gonad requires LHX9 (Lim Homeobox Gene 9), NR5A (Nuclear Receptor Subfamily 5 Group A Member; previously called SF1, Steroidogenic Factor 1), GATA4 (GATA Binding Protein 4), DMRT1/2 (Doublesex– and Mab3–related transcription factor), and CBX2 (Chromobox Homolog 2).

The primordial germ cells (PGCS) migrate from the epiblast to the developing gonadal ridge under the guidance of Kit ligand and c-Kit receptor interaction [28]. Soon thereafter, testicular differentiation of the gonad is initiated by the SRY gene product (Sex determining region of the Y–chromosome) [29]. Expression starts in the somatic cells that differentiate into Sertoli cells forming the seminiferous cords [30]. Peritubular myoid cells surround the cords, and Leydig cells develop in the interstitial space. The Sertoli cells regulate testicular development. SRY regulates SOX9 (SRY–box Containing Gene 9) in the Sertoli cells which determines the gonadal structure [31]. If SRY is missing (as in 46, XX), WNT4 and RSPO1 (R–spondin 1) lead the gonadal development toward the ovary [32]. FOXL2 (Forkhead box L2) is necessary for the maintenance of the ovary. SOX9 regulates the production of fibroblast growth factor 9 (FGF9) and prostaglandin D2 (PGD2) in Sertoli cells, and these reciprocally stimulate SOX9 expression. SOX9 and FGF9 together inhibit the ovarian genes WNT4, RSPO1 and FOXL2 that, in turn, suppress SOX9. Thus, there is a complex gene interaction network in the gonads securing normal development, and if this fails, gonads may become dysgenetic [32].

Sertoli cells secrete growth factors that influence Leydig and peritubular myoid cell differentiation, such as Desert hedgehog (DHH) and platelet-derived growth factors (PDGF). After differentiation, Leydig cells start to secrete testosterone and insulin-like peptide 3 (INSL3) which masculinize the genital structures and regulate testicular descent into the scrotum. Placental human chorionic gonadotropin and pituitary luteinizing hormone stimulate Leydig cell differentiation, proliferation, and hormone production.

Sertoli cells also secrete anti-Müllerian hormone (AMH) from the 7th week of gestation [33], which leads to the involution of Müllerian ducts. AMH is an excellent marker of the presence of testicular tissue in an infant.

Testicular descent [34, 35] occurs after a morphologic reorientation repositions the testis caudally at the level of the lower pole of the metanephric kidney. Then, trans-abdominal migration relocates the testis from the posterior abdominal wall to the inguinal region, accomplished by 15 weeks of fetal life, followed by trans-scrotal migration. Cranial suspensory ligament regression allows both relative intra-abdominal testicular repositioning and trans-inguinal migration. Androgen control of this process is implied by the persistence of intra-abdominal testes in patients with androgen insensitivity syndrome [36], failure of regression in animals treated with an anti-androgen [37], and cranial ligament regression in female animals treated in utero with androgens [38].

Trans-inguinal migration through the inguinal canal to the base of the scrotum occurs after 26 weeks of fetal life [39]. Descent is usually accomplished by the 32nd week but may not be fully complete until post-natal life. Concomitantly, the testis carries the processus vaginalis into the scrotum. Leydig cell-derived insulin-like peptide 3 (INSL3) regulates gubernacular development and regression together with androgens [40]. This androgen-dependent phase involves the gubernaculum, cremaster muscles, the genitofemoral nerve, neurotransmitters, cytokines, intra-abdominal pressure, and epididymal maturation. Some patients with maldescent fail to have attachment of the epididymis to the testes [41]. The gubernaculum, which is intertwined with cremaster muscle, plays a role [42, 43], regressing, perhaps creating a relative negative pressure toward the inguinal canal, concomitant with trans-inguinal migration [42].

It is recognized that the factors causing testicular descent are complex and incompletely understood. Androgen stimulation involves paracrine factors and catabolic enzymes such as acid phosphatase that stimulate gubernacular regression [44]. Animal studies suggest a role for the genitofemoral nerve [45]. In spite of these potential genetic regulators, identifiable genetic causes of cryptorchidism are rare. While INSL3 plays a role in establishing gonadal position in animals [46], mutations in the coding region of the INSL3 gene do not appear to commonly cause human cryptorchidism [47]. It has been shown that RXFP2 (relaxin family peptide receptor 2), a receptor of INSL3, is required for gubernacular development and is necessary for testicular descent [48]. Polymorphisms in the RXFP2 gene may play a role in undescent [49]. Systemic factors may be more frequent with bilateral cryptorchidism while paracrine regulators may be disrupted when only one testis is undescended. Anatomic problems precluding descent could include a detached epididymis [40], testicular-splenic, or testicular hepatic fusion [50]. Inguinal hernia is a common finding with cryptorchidism and is more likely a result than a cause of maldescent.

A hormonal role (gonadotropin-stimulated testosterone production) in testicular descent has been postulated for many years, [51] although factors controlling testicular descent are clearly more complicated. Animal data are consistent with time-specific androgen stimulation of both the abdominal and inguinal phases of descent [52, 53]. Orchidectomy will halt gubernacular regression, and estrogen treatment prevents testicular descent in animals, perhaps via down-regulation of INSL3 expression [54–57].

The testis secretes AMH by the 8–9th fetal week, followed within a week by Leydig cell testosterone production, and by week 12, the hypothalamic-pituitary-testicular (HPT) axis is functional to play a crucial role in final testicular descent [58]. After a decline from about week 17 to term, the HPT axis is reactivated in the first few months after birth, with near adult circulating levels of testosterone at one to three months of age although much of the circulating testosterone is bound to sex hormone binding globulin, with values approaching those seen in men, at this stage of development [59]. This may stimulate spontaneous descent of undescended testes occurring at this age. Failure of spontaneous descent after 6 months of age may be related to diminished hormone levels.

There are contradictory reports of hormonal levels in boys with cryptorchid testes. Early studies reported decreased testosterone levels in cryptorchid infants [60] or preterm cryptorchid infants [61] compared with babies without cryptorchidism, possibly a result of diminished LH secretion [62, 63]. However, more recent research using more sensitive assays has not confirmed that result [64]. A prospective study that compared hormone levels at 3 months of age during “minipuberty” in cryptorchid and control boys reported different results between Danish and Finnish boys. The Finnish group of cryptorchid boys had slightly elevated LH and FSH levels but lower inhibin B levels as compared with non-cryptorchid boys, while among the Danish neonates with cryptorchidism, only FSH levels were significantly higher than in non-cryptorchid boys. Inhibin B levels were lower in both Danish cryptorchid and control newborns than in boys in Finland [65] while testosterone levels did not differ between the groups. When androgen bioactivity was measured in a recombinant cell bioassay, however, all 3-month-old boys with measurable bioactivity had fully descended testes, while all 16 boys with testicular position in the inguinal canal or higher had unmeasurable androgen bioactivity [66]. The explanation for these provocative findings is unclear but may relate to the sensitivity of the testosterone radioimminoassay or differences between populations, and deserves further study. AMH levels have also been reported to be diminished among boys with cryptorchidism [67], suggesting a role for AMH in testicular descent or a consequence of dysfunctional testis. During childhood after the completion of minipuberty, physiologically low LH, FSH, and testosterone levels among cryptorchid boys are not different from values in boys without cryptorchidism [64].

An older report of diminished LH responses to GnRH stimulation among prepubertal boys with undescended testes [68] has led to the unsubstantiated suggestion of mild hypogonadotropic hypogonadism (HH) among cryptorchid boys during childhood. Although patients with congenital HH often do have cryptorchidism, HH is rare among adults with a history of cryptorchidism [69]. Elevated FSH levels during the peripubertal period in some cryptorchid boys suggest instead partial gonadal failure [70], perhaps a consequence of maldescent during childhood. Inhibin B levels vary considerably among boys, and those with cryptorchidism generally have levels within the reference range [71].

At birth, the numbers of germ cells in cryptorchid testes has been reported to be similar to those in descended testes [72, 73]. However, after the transformation of gonocytes into adult dark (AD) spermatogonia which begins between 3 and 9 months of age, the undescended testis has fewer AD spermatogonia. This apparent diminished transformation resulting in diminished germ cells provides the primary rationale for early surgical intervention [74]. Further, regarding the risk of tumor development, intra-tubular germ cell neoplasia in situ (GNIS) in the second and third decades contain enzymatic markers similar to neonatal gonocytes, suggesting that failure of transformation into AD spermatogonia may result in testicular tumors. Testes that remain cryptorchid beyond infancy acquire a progressively more abnormal microscopic appearance [75–79] with progression with increasing age [80]. Comparison of findings at 9 months and 3 years (see below) confirm these differences and document that orchidopexy at the earlier date reverses the process [81]. The poorer growth of the cryptorchid testis that results in diminished volume compared with descended testes is also reversed by spontaneous or surgical descent [82].

The study comparing germ cells in testes with orchidopexy at 9 versus 36 months [81, 82] is the most compelling evidence for the age of recommended surgery for the congenital cryptorchid testis, even though this study could not be fully controlled since cryptorchidism is an outcome of a set of heterogenous disorders [83]. The recommendation for orchidopexy is between 6 and 12 months of age because spontaneous descent is unlikely to occur after 6 months of age while there is progressive loss of germ cells after 12 months of age. The dramatic reduction in germ cell number between 9 and 36 months of age (Fig. 10.2) provides a clear indication for earlier surgery that is beneficial for testicular growth and germ cell development [84, 85]. Other studies have verified these results [86–88]. An assessment of hormones and semen in adult men born with cryptorchidism who had bilateral biopsies at orchidopexy found that more severe histopathology tended to be associated with lower sperm density and higher FSH levels [89], although the association was not statistically significant perhaps because of the small sample size and wide age range at surgery. In clinical practice, biopsy at orchidopexy has not been shown to have value in predicting future fertility.

It has been theorized for some time that diminished germ cells of the undescended testis might be a consequence of relative gonadotropin deficiency, and hence, GnRH might be a beneficial adjunct therapy after orchidopexy. Pooled effect estimates in a meta-analysis of comparative clinical trials indicated that cryptorchid children treated with GnRH had a higher number of germ cells per seminiferous tubule at various prepubertal ages after biopsy when compared with controls [90]. This suggests that some boys with cryptorchidism may benefit from GnRH treatment as adjunctive to orchidopexy in improving the fertility index. However, longer outcome follow-up is necessary to determine if fertility is increased.

Ascent during childhood of a previously normally descended testis (acquired undescended testis) occurs when the testis becomes tethered above the scrotum in an unacceptable position. Acquired UDT is seen in 1–3% of boys during childhood. This may occur among some boys with a retractile testis due to spasticity of the cremaster muscle, or as a consequence of improper elongation of the spermatic cord due to fibrous remnant of the processus vaginalis [23, 91–96]. It is now widely accepted that testes may ascend from the full scrotal position during early- or mid-childhood years inasmuch as boys with undescended testes have been reported whose medical records clearly documented descended or retractile testes that become persistently above the scrotal location [97–100]. The age distribution at orchidopexy is bimodal, with an initial and larger peak within the first five years of life, and a second peak between 8 and 11 years of age. This distribution could be a consequence of acquired cryptorchidism or ascending testes [101]. The pathogenesis of the acquired undescended testis is unclear. It has been suggested that ascending testis may occur more frequently among boys born with undescended testes that undergo spontaneous descent in early infancy by 3 months of age [102]. There is also a suggestion that altered feeding patterns (decreased breast feeding and use of soy formulas) may increase the incidence of ascending cryptorchidism [103], although this has not been confirmed.

Previously, it was felt that ascending testes had the potential for normal function. Since most boys with ascending cryptorchidism have spontaneous testicular descent during puberty [104, 105], surgery was traditionally deferred and performed only in those boys in whom spontaneous descent failed to occur at puberty [106]. One retrospective study involved 2 groups of adult men with a history of ascending testes: group 1 had orchidopexy for lack of spontaneous descent at ages 4.75–17.8 years (n = 26) while group 2 represented men with spontaneous testicular descent during puberty (n = 32) [107]. Overall, men who had unilateral ascent had smaller testes, lower sperm concentration and progressive sperm motility, and softer testicular consistency than control men. No significant differences in fertility parameters were found between men with spontaneous descent versus those with orchidopexy. Those who had bilateral ascent also had smaller mean testicular volume and softer testicular consistency, but also a lower paternity rates, higher LH and FSH and lower inhibin B levels, and reduced sperm concentrations and progressive motility than control men. This latter group was not different from men who had bilateral congenital cryptorchidism. Testicular volume, reproductive hormones, semen quality (better for unilateral than bilateral), and successful paternity rates did not differ between the groups. Small testicular size for age of ascending testes was noted at surgery [108]. Testicular volumes smaller than normal for age by ultrasonography were observed at follow-up after operation in boys and men who had previously been treated with orchidopexy at diagnosis of uni- or bilateral ascended cryptorchidism (n = 155) [109]. Testicular size of ascended undescended testes estimated by orchidometer after spontaneous descent at puberty (n = 494) or after pubertal orchidopexy (n = 85) found that >90% had volumes within normal limits, while in over 50% of unilateral cases the affected testis was smaller at follow-up than the other testis that had always been descended [110]. An evaluation of men with unilateral cryptorchidism who delayed surgery until age 20–30 years found severe maturation arrest (22%), germinal cell aplasia (70%), or tubular atrophy (8%) in the orchidectomy specimens, and no differences in semen parameters or testosterone levels before or after surgery suggesting that testicular function by this age was essentially from the descended testis [111].

A reduced number of germ cells per tubule have been reported in unilaterally ascended testis and also in the normally descended contralateral testis [112], which is interpreted as an innate defect in testicular development in both testes in unilateral as well as bilateral cryptorchidism. By contrast, when a testis is found to be absent, the contralateral descended testis often has an increased volume, increased germ cell proliferation, and dissimilar maturation patterns compared with the contralateral descended testis of patients with unilateral cryptorchidism. These findings do not suggest an underlying endocrinopathy or other testicular defect, or risk of infertility for patients with a solitary testes [113]. In a systematic follow-up of testicular growth in puberty, testes that had been cryptorchid (either unilateral or bilateral) grew slower and remained smaller than descended testes, and there was no compensatory growth in the contralateral testis as compared with control [114]. In contrast, testes of monorchid boys were larger than control.

An evaluation and treatment guideline for cryptorchidism was recently published by the American Urological Association [120]. Imaging for cryptorchidism is not recommended prior to referral, which should occur by 6 months of age. Orchidopexy is the most successful therapy to relocate the testis into the scrotum, while hormonal therapy is not recommended. Successful scrotal repositioning of the testis may reduce but does not prevent the potential long-term issues of infertility and testis malignancy. Appropriate counseling and follow-up of the patient is essential.

A Nordic consensus on treatment of undescended testes was published in 2007 summarizing current information and making treatment recommendations [119]. These include a recommendation against hormonal treatment based upon poor results and the possibility of long-term adverse effects upon spermatogenesis, and recommend orchidopexy between 6 and 12 months of age, or at diagnosis, if later, to be performed by pediatric urologist/surgeons with pediatric anesthesiologists.

The rationale for treatment of cryptorchidism includes the increased risk of infertility and testicular cancer and the need to correct hernias and decrease the risk of torsion. While bilateral cryptorchidism is associated with infertility if the testes remain undescended beyond puberty, the beneficial effect on fertility of orchidopexy during childhood has not been definitively shown [121]. However, the benefit of reducing the risk of malignancy is assumed. For boys with unilateral cryptorchidism, it has been questioned whether treatment to bring the testis into a scrotal location influences fertility since the percentages of men with azoospermia or oligospermia have been reported to be similar for men with surgical treatments or no treatment [121]. However, the question of whether early surgery is beneficial has not been verified since outcome data are for those whose surgery was generally at ages considerably older than is recommended currently. While semen analysis may be abnormal, evidence (see below) suggests that paternity rates have not been shown to differ from control men [122].