Cryptorchidism is a common genital anomaly diagnosed at birth or during childhood. Genetic and/or environmental factors that alter expression or function of hormones crucial for testicular descent, insulin-like 3, and testosterone, may contribute to cryptorchidism. When identified at birth, surgical treatment is indicated by 6 months of age if testes fail to descend, or at the time of diagnosis in older children. A laparoscopic approach is preferred for abdominal testes. Early surgical therapy may reduce the risk of subfertility and/or malignancy.
Cryptorchidism or undescended testis is the most common disorder of the male endocrine glands in children. Up to one-third of boys with true cryptorchidism have bilaterally cryptorchid testes. The main reasons for treatment of cryptorchidism include increased risks of progressive infertility, testicular malignancy, torsion, and/or associated inguinal hernia, and because of cosmetic concerns. The current standard of therapy in the United States is orchidopexy, or surgical repositioning of the testis within the scrotal sac; hormonal therapy has fewer advocates. However, successful relocation of the testis may reduce but does not prevent these potential long-term sequelae in susceptible individuals.
Epidemiology/pathogenesis
The incidence of cryptorchidism is 1% to 4% in full-term newborns and in up to 45% of preterm male babies. A small increase in the prevalence of cryptorchidism in prepubertal boys has been reported by several investigators but is not consistent in all populations. This condition is an associated finding in hundreds of clinical syndromes, with the ratio of nonsyndromic to syndromic cryptorchidism reported to be greater than 6:1. However, confounding factors such as variations in diagnosis of cryptorchidism between observers, in study populations, and in study design complicate estimates of true prevalence. Advanced maternal age, maternal obesity, maternal diabetes, family history of cryptorchidism, preterm birth, low birth weight or small for gestational age, breech presentation, and consumption of cola-containing drinks during pregnancy have all been suggested as possible risk factors for cryptorchidism.
Spontaneous testicular descent in infancy may occur as a result of the normal gonadotropin surge (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) that occurs around 60 to 90 days of life. Gendrel and colleagues and Job and colleagues reported blunting of this surge in boys with cryptorchidism that remain undescended in the first year of life. They reported a significant difference in the polynomial regression curves comparing the testosterone levels of persistently cryptorchid testes with those having delayed spontaneous descent. However, the positive predictive value that bilateral cryptorchidism will have abnormally low testosterone levels is only about 23%. Subsequent studies have been inconsistent, with reduced or normal serum testosterone levels and normal or relatively increased LH levels, when comparing patients with cryptorchidism and controls.
Studies have suggested genetic susceptibility for cryptorchidism does exist, but this is likely polygenic and multifactorial. In a recent population-based study by Schnack and colleagues more than 1 million male births were reviewed. Risk ratios for cryptorchidism were 10.1 in twins, 3.5 in brothers, and 2.3 in offspring of fathers who had an undescended testis. Previous data on this subject suggested a 5-fold increased risk in offspring of affected fathers and a 7- to 10-fold increased risk in those with an affected brother compared with patients with no family history of the disorder.
The possibility that environmental chemicals alter normal reproductive tract development has been debated in the recent literature. There is significant potential concern that endocrine-disrupting chemicals that may be linked to the testicular dysgenesis syndrome, described as linked male reproductive tract anomalies, including cryptorchidism, that may have a common cause. Concerns about a connection between an endocrine-disrupting chemical and cryptorchidism developed because of a reported higher risk related to early maternal exposure to diethylstilbestrol. However, only 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. Some question whether epidemiologic data truly support the existence of a clinical testicular dysgenesis syndrome.
The hormonal pathways that are crucial for testicular descent were largely elucidated by studies of animal models. The obvious anatomic differences between human and rodent has incited controversy as to how to interpret the data from such research. Nonetheless, some observers believe the species have sufficient similarity to warrant translational studies of these models. Based on murine models, Hutson and Hasthorpe have proposed that testicular descent occurs in 2 phases. The initial transabdominal descent accompanied by enlargement of the gubernaculum is controlled by the Leydig cell hormone, insulin-like 3 (INSL3). Transgenic mice with deletion of Insl3 are viable but show a severe cryptorchidism phenotype 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 to 17 weeks’ gestation just after the peak in testosterone production at 14 to 16 weeks’ gestation. In vitro, these hormones cause proliferation of gubernacular cells. Animal models suggest that inguinoscrotal descent is androgen mediated, via the genitofemoral nerve (GFN) and/or by activation of androgen receptors in the gubernaculum. The GFN releases calcitonin gene-related peptide (CGRP) on stimulation to produce rhythmical 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).
Androgen Receptor Signaling
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) caused by 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 boys with isolated cryptorchidism suggests that longer alleles of the GGN (polyglycine) repeat polymorphism are more common in cases compared with controls but no association of cytosine-adenosine-guanine (CAG) repeat length or variants in other AR exons with isolated cryptorchidism.
INSL3/RXFP2 Signaling
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 1 of these genes exist in 3% of cases of cryptorchidism. However, it is not clear at present which genetic variants are functionally significant. 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.
Other Genetic Risk Factors for Isolated Undescended Testis
Two posterior HOX genes have been identified as possible candidates for cryptorchidism from murine genetic knockout phenotypes because loss of either Hoxa10 or Hoxa11 is associated with a nonsyndromic cryptorchid phenotype in transgenic mice. However, no variants of these genes are consistently associated with cryptorchidism in human studies. Similarly, mixed results were obtained in studies of the association of the estrogen receptor alpha ( ESR1 ) gene in clinical cryptorchidism.
Diagnosis
Traditionally, testicular position at birth was used to determine the presence or absence of undescended testis. However, in recent decades new evidence supports the concept that some testes that are documented as descended at birth are no longer intrascrotal at a subsequent time. This situation is frequently called acquired cryptorchidism, but it more likely represents primary failure of complete testicular descent, and is associated with similar histopathology to that observed in cases discovered at birth. Although the incidence of acquired maldescent in the general population of boys with normally positioned testes at birth seems to be low in longitudinal studies, the risk in boys with retractile testes is 7% to 45%.
History and Physical Examination
Potential risk factors include prematurity, birth weight, breech presentation, maternal diabetes, maternal use/exposure to exogenous hormones (estrogens), lesions of the central nervous system (myelomeningocele or cerebral palsy), and previous inguinal surgery. Family history of cryptorchidism or other genital anomalies, congenital syndromes, infertility, and consanguinity are relevant. It is also important to note if the testes were ever palpable in the scrotum at the time of birth or within the first year of life.
Classification is based on testicular location, either along the normal line of descent (abdomen, inguinal canal, external ring, prescrotal, upper scrotal) or in an ectopic position (usually in the superficial inguinal pouch or perineal; rarely perirenal). An important distinction is whether or not the testis is palpable, and whether the cryptorchidism is isolated or a component of a syndrome, as these classifications may affect treatment plans and provide further direction to evaluate for other associated urologic conditions. It is important to document associated findings such as hernia, hydrocele, penile size, and meatal position.
The patient should be examined supine with legs abducted initially. With warmed hands, check the size, location, and texture of the contralateral descended testis. Begin examination of the undescended testis at the anterior superior iliac spine and sweep the groin from lateral to medial with the nondominant hand. Once the testis is palpated, grasp it with the dominant hand and continue to sweep the testis toward the scrotum with the other hand. Assess testicular mobility, size, consistency, and spermatic cord tension. Maintain the position of the testis in the scrotum for a minute, so that the cremaster muscle is fatigued. Release the testis, and if it remains in place for a short time but then retracts, it is considered retractile. The key to distinguishing a retractile from an undescended testis is success of delivery and stability of the testis within the scrotum. The retractile testis will remain intrascrotal after overstretching of the cremaster muscle, whereas a low cryptorchid testis will return to its undescended position after being released. If there is any question, a follow-up examination is indicated. An experienced examiner should evaluate patients with retractile testes on a yearly basis.
For patients who are difficult to examine because of obesity, lack of cooperativity, and/or a hyperactive cremasteric reflex, the cross-legged or baseball catcher’s position can also help relax the cremaster muscle. Wetting the fingers of the nondominant hand with lubricating jelly or soap can increase the sensitivity of the fingers in palpating the small mobile testis. Usually the cryptorchid testis is palpable (∼80%), as reported in large contemporary series.
When the testis is truly nonpalpable, possible findings include complete testicular atrophy (vanishing testis or testicular regression syndrome), an abdominal or peeping (in and out of the internal ring) testis and extra-abdominal location but not palpable because of patient factors or small testicular size. A vanishing testis can be found anywhere along the normal path to the scrotum. The cause is prenatal vascular thrombosis or torsion because of the frequent identification of hemosiderin associated with the testicular remnant. Hypertrophy of the contralateral descended testis (>1.8–2 mL) in combination with a palpable scrotal nubbin and absence of palpable scrotal appendages (sac, gubernaculums, or cord structures) indicates a high likelihood of monorchism as a result of testicular regression. If abnormal penile and/or urethral development occurs with unilateral or bilateral cryptorchidism, further diagnostic studies may be indicated to evaluate for hypogonadism or disorders of sexual differentiation.
Imaging and Laboratory Tests
The use of imaging studies to aid in the diagnosis in cases of nonpalpable testis is controversial. Ultrasound (US), computed tomography (CT) scan and magnetic resonance imaging (MRI) have been applied in this clinical scenario but the accuracy of these studies in identifying intra-abdominal testes may be low. Hrebinko and Bellinger found that the most reliable mode of examination has been the physical examination by a pediatric urologist (84%) compared with a referring physician (53%). The accuracy of imaging studies in this series was 44% and imaging did not influence management decisions in any of the cases. Similarly, Elder reported that US has limited usefulness when an experienced surgeon examines a patient with cryptorchidism. In contrast, other studies suggest that if an experienced surgeon evaluates a child and determines the testis to be nonpalpable, the sensitivity of US can be as high as 95% to 97% for an inguinal testis, and even identify an abdominal testis in certain cases. Thus, US may be useful in certain cases of nonpalpable testes to aid in planning for either laparoscopic or inguinal approaches. Furthermore, MRI may be useful in identifying an ectopic abdominal testis, if not found by laparoscopy or open exploration. Yeung and colleagues identified 100% of canalicular and 96% of intra-abdominal testes using gadolinium-enhanced MR angiography. However, this technique is expensive, requires sedation, and the results have not been reproduced.
In boys with bilateral nonpalpable testes or associated hypospadias, chromosomal and endocrine evaluation may be useful. In infants with bilateral nonpalpable testes, the postnatal testosterone surge is absent if anorchia is present. After 3 months of age, a human chorionic gonadotropin (hCG) stimulation test can aid in the diagnosis of anorchia, most frequently showing a low serum testosterone level and increased LH and FSH levels. However, in mid-childhood low baseline gonadotropin levels and poor response to hCG may occur in anorchia. Serum levels of anti- Müllerian hormone (AMH) or inhibin B can also document the presence of testicular tissue.
Diagnosis
Traditionally, testicular position at birth was used to determine the presence or absence of undescended testis. However, in recent decades new evidence supports the concept that some testes that are documented as descended at birth are no longer intrascrotal at a subsequent time. This situation is frequently called acquired cryptorchidism, but it more likely represents primary failure of complete testicular descent, and is associated with similar histopathology to that observed in cases discovered at birth. Although the incidence of acquired maldescent in the general population of boys with normally positioned testes at birth seems to be low in longitudinal studies, the risk in boys with retractile testes is 7% to 45%.
History and Physical Examination
Potential risk factors include prematurity, birth weight, breech presentation, maternal diabetes, maternal use/exposure to exogenous hormones (estrogens), lesions of the central nervous system (myelomeningocele or cerebral palsy), and previous inguinal surgery. Family history of cryptorchidism or other genital anomalies, congenital syndromes, infertility, and consanguinity are relevant. It is also important to note if the testes were ever palpable in the scrotum at the time of birth or within the first year of life.
Classification is based on testicular location, either along the normal line of descent (abdomen, inguinal canal, external ring, prescrotal, upper scrotal) or in an ectopic position (usually in the superficial inguinal pouch or perineal; rarely perirenal). An important distinction is whether or not the testis is palpable, and whether the cryptorchidism is isolated or a component of a syndrome, as these classifications may affect treatment plans and provide further direction to evaluate for other associated urologic conditions. It is important to document associated findings such as hernia, hydrocele, penile size, and meatal position.
The patient should be examined supine with legs abducted initially. With warmed hands, check the size, location, and texture of the contralateral descended testis. Begin examination of the undescended testis at the anterior superior iliac spine and sweep the groin from lateral to medial with the nondominant hand. Once the testis is palpated, grasp it with the dominant hand and continue to sweep the testis toward the scrotum with the other hand. Assess testicular mobility, size, consistency, and spermatic cord tension. Maintain the position of the testis in the scrotum for a minute, so that the cremaster muscle is fatigued. Release the testis, and if it remains in place for a short time but then retracts, it is considered retractile. The key to distinguishing a retractile from an undescended testis is success of delivery and stability of the testis within the scrotum. The retractile testis will remain intrascrotal after overstretching of the cremaster muscle, whereas a low cryptorchid testis will return to its undescended position after being released. If there is any question, a follow-up examination is indicated. An experienced examiner should evaluate patients with retractile testes on a yearly basis.
For patients who are difficult to examine because of obesity, lack of cooperativity, and/or a hyperactive cremasteric reflex, the cross-legged or baseball catcher’s position can also help relax the cremaster muscle. Wetting the fingers of the nondominant hand with lubricating jelly or soap can increase the sensitivity of the fingers in palpating the small mobile testis. Usually the cryptorchid testis is palpable (∼80%), as reported in large contemporary series.
When the testis is truly nonpalpable, possible findings include complete testicular atrophy (vanishing testis or testicular regression syndrome), an abdominal or peeping (in and out of the internal ring) testis and extra-abdominal location but not palpable because of patient factors or small testicular size. A vanishing testis can be found anywhere along the normal path to the scrotum. The cause is prenatal vascular thrombosis or torsion because of the frequent identification of hemosiderin associated with the testicular remnant. Hypertrophy of the contralateral descended testis (>1.8–2 mL) in combination with a palpable scrotal nubbin and absence of palpable scrotal appendages (sac, gubernaculums, or cord structures) indicates a high likelihood of monorchism as a result of testicular regression. If abnormal penile and/or urethral development occurs with unilateral or bilateral cryptorchidism, further diagnostic studies may be indicated to evaluate for hypogonadism or disorders of sexual differentiation.
Imaging and Laboratory Tests
The use of imaging studies to aid in the diagnosis in cases of nonpalpable testis is controversial. Ultrasound (US), computed tomography (CT) scan and magnetic resonance imaging (MRI) have been applied in this clinical scenario but the accuracy of these studies in identifying intra-abdominal testes may be low. Hrebinko and Bellinger found that the most reliable mode of examination has been the physical examination by a pediatric urologist (84%) compared with a referring physician (53%). The accuracy of imaging studies in this series was 44% and imaging did not influence management decisions in any of the cases. Similarly, Elder reported that US has limited usefulness when an experienced surgeon examines a patient with cryptorchidism. In contrast, other studies suggest that if an experienced surgeon evaluates a child and determines the testis to be nonpalpable, the sensitivity of US can be as high as 95% to 97% for an inguinal testis, and even identify an abdominal testis in certain cases. Thus, US may be useful in certain cases of nonpalpable testes to aid in planning for either laparoscopic or inguinal approaches. Furthermore, MRI may be useful in identifying an ectopic abdominal testis, if not found by laparoscopy or open exploration. Yeung and colleagues identified 100% of canalicular and 96% of intra-abdominal testes using gadolinium-enhanced MR angiography. However, this technique is expensive, requires sedation, and the results have not been reproduced.
In boys with bilateral nonpalpable testes or associated hypospadias, chromosomal and endocrine evaluation may be useful. In infants with bilateral nonpalpable testes, the postnatal testosterone surge is absent if anorchia is present. After 3 months of age, a human chorionic gonadotropin (hCG) stimulation test can aid in the diagnosis of anorchia, most frequently showing a low serum testosterone level and increased LH and FSH levels. However, in mid-childhood low baseline gonadotropin levels and poor response to hCG may occur in anorchia. Serum levels of anti- Müllerian hormone (AMH) or inhibin B can also document the presence of testicular tissue.
Treatment
Hormonal Therapy
Primary hormonal therapy with hCG or gonadotropin-releasing hormone (GnRH or LH-releasing hormone [LHRH]) have been used for many years, especially in Europe. The exact mechanism of action of gonadotropin on postnatal testicular descent is not known but may involve effects on the spermatic cord and/or cremaster muscle. Divergent results have been reported likely because of suboptimal study design, differences in patient age and treatment schedules, possible inclusion of retractile testes, and variable follow-up. However, several meta-analyses of this published literature suggest that the effectiveness of primary hormonal therapy in cryptorchidism is less than 20%. A recent consensus statement discourages use of hormone therapy for cryptorchidism.
Some data suggest that spermatogonia/tubule (S/T) ratios may improve after treatment with low dose LHRH analogue therapy. However, caution is advised when evaluating these data because of retrospective, nonrandomized study design and patient heterogeneity.
Surgery
Palpable testis
Standard inguinal orchidopexy involves several steps after repeat examination under anesthesia to reconfirm testicular location. A transverse inguinal incision is made along Langer lines and Scarpa fascia is 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 transcapsular sutures.
A primary scrotal approach to orchidopexy is described in cases in which the testis is palpable and is either close to the scrotum or can be easily drawn into the sac. 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% to 2%, and postoperative hernia has been noted in 2% to 3% of cases with follow-up in these series ranging from 1 month to 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 used 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) allows 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 orchidopexy 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 to 12 months later.
Nonpalpable testis
Exploration for a nonpalpable testis may occur through an extended inguinal incision, an abdominal incision, or, more commonly, via 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 nonpalpable because of the size of the testis or patient’s body habitus. 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 use 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. 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 theoretic 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, but laparoscopic orchidopexy is often the procedure of choice with high success rates reported. 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. 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% to 100%, 71% to 97% and 84% to 96%, respectively.
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