Diagnosis and Management of Cryptorchidism

EUROPEAN UROLOGY SUPPLEMENTS 11 (2012) 2–9

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Diagnosis and Management of Cryptorchidism Evi Comploj *, Armin Pycha Department of Urology, Central Hospital of Bolzano, Bolzano, Italy

Article info

Abstract

Keywords: Cryptorchidism Therapy Undescended testis

Among males born at full term or prematurely, 1–30% are affected by cryptorchidism. Approximately 70% of cryptorchid testes will spontaneously descend by 3 mo. The cause of cryptorchidism is multifactorial. A prerequisite for testicular descent is a normal hypothalamic-pituitary-gonadal axis. In addition, an undisturbed interaction with the anatomic structures is required, as well as the appropriate hormonal milieu and environmental conditions. Hereditary factors also play a major role. The Kaplan classification distinguishes between palpable testes (80%) and nonpalpable testes (20%). The nonpalpable group includes intra-abdominal, inguinal, and absent (vanishing) testes, whereas palpable testes can be between the internal and external inguinal ring, high scrotal, or in a superficial pouch between the oblique and the Scarpa fascia in the so-called Denis Browne pouch. Therapy for undescended testis (UDT) is usually carried out when a child is between 6 and 12 mo; individuals with high UDT especially benefit from an early orchidopexy. The lower the pretreatment position, the more chance there is of spontaneous descent as well as better results of surgical intervention. Although the management of a palpable testis is standardized, there are no guidelines for the management of boys with a nonpalpable testis. It seems that both preoperative and postoperative hormonal treatment may have a beneficial effect on fertility later in life. Because of the increased risk of testicular malignancy, lifelong follow-up is mandatory. # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, General Hospital of Bolzano, Lorenz Bo¨hler Street 5, 39100 Bolzano, Italy. Tel. +39 0471 908686; Fax: +39 0471 909738. E-mail address: [email protected] (E. Comploj).

1.

Introduction

Cryptorchidism (from the Greek kryptos, meaning ‘‘hidden,’’ and orchis, meaning ‘‘testis’’) refers to the absence of the testis from the scrotum and is a term that is used interchangeably with the term undescended testis (UDT). Isolated cryptorchidism is the most common congenital abnormality of the male genitalia identified at birth and occurs in 1–4% of full-term and 15–30% of premature male infants [1–4]. The incidence is age dependent, and unilateral cryptorchidism is more than twice as common as bilateral

cryptorchidism; the right side is affected more often than the left (70% compared with 30%, respectively) [5]. Approximately 70% of cryptorchid testes will spontaneously descend, usually by 3 mo of age [6,7]. Testicular descent can be divided into three phases: 1. The transabdominal migration of the testis to the internal inguinal ring occurs during the sixth gestational week. The key structure in humans is the gubernaculum (or caudal genital ligament); it is stimulated by the testis hormone insulin-like factor 3 (INSL3), which causes

1569-9056/$ – see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.eursup.2012.01.005

EUROPEAN UROLOGY SUPPLEMENTS 11 (2012) 2–9

[(Fig._1)TD$IG]

Fig. 1 – Normal testicular descent. CNS = central nervous system; FSH = follicle-stimulating hormone; LH = luteinizing hormone; LHRH = luteinizing hormone-releasing hormone.

masculinizing outgrowth of the male gubernacula [5]. By the 12th week of gestation, the testis is positioned at the internal inguinal ring. 2. The development of the processus vaginalis and the inguinal canal during the third and seventh months of gestation distends the inguinal canal and scrotum [8]. 3. The transinguinal descent of the testis into the scrotum [6] occurs between the 24th and 35th weeks of gestation. The cause of cryptorchidism remains little understood. It seems that endocrine and genetic disorders can cause maldescent of the testis, but, in the majority of cases, no distinct etiology can be determined; therefore, etiology of the condition is multifactorial. A normal hypothalamic– pituitary–gonadal axis is usually a prerequisite for testicular descent to occur [9] (Fig. 1). Complex interactions among the following factors affect the risk for UDT:  Anatomy (mechanical factors such as the gubernaculum [10], processus vaginalis [8], and possibly also the epididymis [11–13] and intra-abdominal pressure [14,15])  Heredity [16]  Hormonal milieu (androgens [17,18], INSL3 [19,20], estrogens [21,22], and anti–mu¨llerian-inhibiting substance) [23,24]  Epidermal growth factor [25]  Calcitonin gene–related peptide [26]  Environmental conditions (pesticides, estrogen, plastic additives, or natural phytoestrogens [27]). 2.

Definitions and classification

Normal testicular descent is defined as a testis that remains stationary within the dependent portion of the scrotum

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[28]; the process is usually complete between the 30th and 32nd weeks of gestation. It is sometimes difficult to accurately classify the position, integrity, and presence of a UDT. Body habitus, testicular position, and compliance of the child during the examination can significantly complicate the clinical evaluation and result in diagnostic error. Although a number of classification systems have been devised, Kaplan [29] proposed the most popular system, which categorizes cryptorchid testes as either palpable or nonpalpable. In 80% of cases, the testis is palpable: the true undescended and ectopic testis [5]. Approximately 20% of all cryptorchid testes are nonpalpable: the intra-abdominal, inguinal, and absent (vanishing) testes [5]. An intra-abdominal testis is usually located just inside the internal ring, commonly within a few centimeters, although intra-abdominal testes have been observed anywhere along a line between the lower pole of the kidney and the internal ring [28]. The inguinal or intracanicular testis is occasionally difficult to palpate and by definition lies within the inguinal canal, between the internal and external rings [28]. The most common ectopic location is within a superficial pouch between the external oblique fascia and Scarpa fascia, a structure that has been termed the Denis Browne pouch. Other abnormal locations include transverse scrotal, femoral, perineal, and prepenile ectopic [28]. 3.

Consequences and indications for treatment

In 1987, Hadziselimovic et al [30] showed that the development of normal germ cells during childhood is a continuous process that ends at puberty. They also demonstrated that the higher the testes are located, the more pronounced impairment in germ cell development of UDT is, although newborns with intra-abdominal testes have a normal number of germ cells [30]. The histopathologic hallmarks associated with cryptorchidism are evident at between 1 and 2 yr and include decreased numbers of Leydig cells, degeneration of Sertoli cells, delayed disappearance of gonocytes, delayed appearance of adult dark (Ad) spermatogonia, failure of primary spermatocytes to develop, and reduced total germ cell counts [31–33]. Beyond 18 mo, both light and electron microscopy demonstrate histologic changes suggesting deterioration of the germ cell population of the testis [32,33]. Huff et al reported that the earliest postnatal histologic abnormality in cryptorchid testes was hypoplasia of the Leydig cells, which was observed from the first month of life [34]. In 1989, Huff et al documented the significantly defective maturation of gonocytes in bilateral testicular biopsy specimens from unilaterally cryptorchid boys aged 1–13 yr, as well as decreased numbers of germ cells from the first year of life [35]. In addition, the transformation of gonocytes to Ad spermatogonia, which is normally complete at 6 mo (priming phase, minipuberty), and the transformation of Ad spermatogonia to primary spermatocytes, which is normally complete at 3 yr, were delayed, defective, or both [35,36].

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Clinically, decreased fertility is a well-recognized consequence of cryptorchidism. Although histologic deterioration was thought to be worse with higher-positioned testes, paternity may be similar in both abdominal and extraabdominal unilateral UDT [37]. Lee, in 2005 [38], showed a lower serum level of inhibin B in boys with a history of UDT, which predicts impaired spermatogenesis later in life. It is still not clear whether early orchidopexy ultimately improves fertility, but serum inhibin B levels are suggestive of this trend [39]. This important phase in spermatogenesis, which is probably androgen dependent and associated with the blunting of the normal surges in gonadotropins and testosterone, has prompted investigators to treat children with gonadotropin-releasing hormone (GnRH) in hopes of improving their fertility index [28]. Hadziselimovic and Herzog showed in 1997 that postoperative GnRH treatment after successful orchidopexy resulted in a significant improvement in the fertility index in adulthood, although those patients were treated preoperatively with human chorionic gonadotropin (hCG) [40]. Neoadjuvant GnRH therapy in prepubescent boys with cryptorchidism may also have a positive effect on future fertility, with the highest fertility indices reported with therapy at <2 yr [41]. Jallouli et al suggest in their study that preoperative GnRH therapy be considered in every child with cryptorchidism, regardless of age, for maximal transformation of gonocytes to Ad spermatogonia to promote the first postnatal maturation step of the germ cells [42]. In their small study, Cortes et al argued against the use of hormone therapy in UDT and reported the benefit of surgery alone over adjuvant hormone therapy [43] using hCG. Another consequence of cryptorchidism is the increased risk of testicular malignancy. Approximately 10% of all testicular tumors arise from UDTs [44]. The relative risk is approximately 40 times greater than in the general population [45]. In all patients with UDT, the relative risk for testicular cancer is 2.75–8, with a lower risk (2–3) in patients who underwent prepubertal orchidopexy [46]. Wood and Elder showed a higher risk in patients with bilateral UDT, associated genitourinary anomalies, or late (>10 to 12 yr) or uncorrected UDT. The contralateral, normally descended testis, however, has no increased risk. The most common testicular tumor in untreated UDT is seminoma, whereas the most common type in successfully treated testes is the embryonal carcinoma [44,46,47]. The higher the position of the UDT, the greater the risk of development of a malignancy [46,48]. The cause of the increased risk for malignant degeneration of a UDT is at present theoretical: increased temperature [47,48] or prevalence of carcinoma in situ (CIS) in UDT [49–51]. The prevalence of CIS is 1.7% in patients with cryptorchidism [49]. In addition, Parkinson et al [52] observed no evidence for histologic premalignant changes occurring before the onset of puberty. Therefore, routine testicular biopsy during childhood orchidopexy appears to have no predictive value for the development of later malignant degeneration, and biopsy is only recommended

for patients with prune belly syndrome, abnormal karyotype, ambiguous genitalia, or age >12 yr [53]. In >90% of patients with UDT, a patent processus vaginalis was found [54]; epididymal anomalies were more frequent in individuals with UDT (72%) than in individuals with descended testes (34%) [55]. Zilberman et al [56] in 2006 showed that testicular torsion occurs more frequently than normal in undescended abdominal testes and is associated with poor surgical salvage rates. Torsion of a UDT, though rare, should be considered in any child with abdominal or groin pain and an empty ipsilateral hemiscrotum. These consequences do not include the psychological effects of an empty scrotum for a prepubertal boy. 4.

Treatment

Determination of whether the testis is present on physical examination is critically important because it guides further work-up and treatment. The work-up begins with a thorough history that includes (1) preterm and maternal history, including the use of gestational steroids; (2) perinatal history, including documentation of a scrotal examination at birth; (3) the child’s medical and previous surgical history; and (4) family history of cryptorchidism or syndromes. The physical examination ideally requires a relaxed child first observed in the supine position (inspection of any penile malformations or asymmetric scrotum). Examination for the UDT is best performed with warm hands and soapy water on the fingertips to reduce skin friction. If only one testis is descended, this gonad should be carefully examined for size, turgor, any palpable paratesticular anomalies, and the presence of hernia or hydrocele. As Huff et al [57] showed in 1992, in the case of a unilateral nonpalpable testis, contralateral testicular hypertrophy of the normally descended testes has been suggested to represent the absence of the ipsilateral testes. The mean volume of the descended testis with an absent contralateral testis was greater than that of boys with an intra-abdominal testis at all ages. This criterion, however, was not reliable for differentiating the two conditions. Therapy for UDT is usually carried out between 6 mo and 1 yr because spontaneous descent rarely occurs at >6 mo [6], and in patients with a high UDT, there may be surgical advantages to orchidopexy within the first 12 mo [58]. The lower the pretreatment position, the better the success rate [59]. Hrebinko and Bellinger showed an overall accuracy of radiologic testing in 44% [60]. The study of Tasian and Copp [61] showed that abdominal-scrotal ultrasonography is unnecessary in the preoperative evaluation of boys with nonpalpable testes, because the results would not change the surgical management. The management of bilateral nonpalpable testes merits special consideration because the condition may be life threatening if associated with either hypospadias or ambiguous genitalia. Endocrinologic evaluation is

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necessary and may help determine whether one or both testes are present. The hCG stimulation test is widely used to evaluate testicular function. However, all boys with nonpalpable testes and normal serum gonadotropin levels must undergo surgical exploration regardless of the results of the hCG stimulation test. Although surgical orchidopexy remains the gold standard for managing cryptorchidism, it is obvious that hormone therapy has a positive effect in testes histology and fertility potential [40–42]. 4.1.

Nonsurgical therapy/hormonal therapy

Hormonal treatment of cryptorchidism is based on the hormonal dependence of testicular descent [59]. The aim of hormonal therapy was, and still is, to induce testicular descent. Both hCG and GnRH or luteinizing hormone–releasing hormone (LHRH) have been used to induce testicular descent but showed a descent rate of 25% with hCG and 18% with GnRH [59,62]. The complete testicular descent rate with LHRH is approximately 20% [63]. Adverse effects of hormonal treatment include increased rugation and pigmentation of the scrotum; penile enlargement; frequent erections; increased appetite and weight gain; development of pubic hair, which regresses after cessation of therapy; and rarely, aggressive behavior [5]. Regular reexamination of children treated with hormonal therapy is indicated because reascent has been reported in up to 25% of patients. Hormonal treatment is used as neoadjuvant therapy in UDT to improve testis histology and fertility potential [40–42]. The hormonal therapy (neoadjuvant GnRH spray, 1.2 mg/d for 1 mo) should be started at 6 mo [41] to restore a normal endocrine milieu and maximize future fertility potential. For Riccabona, there is no indication for hormonal therapy as a routine in every boy with UDT. This therapy should be used in boys <1 yr; boys with a bilateral UDT; and boys >1 yr with smaller testes seen on ultrasonography, a high inguinal or abdominal testis, or a single testis or a contralateral testis that had been damaged before (eg, after testicular torsion) (pers. comm., M. Riccabona, Vienna, Austria). 4.2.

Surgical therapy/treatment

After the induction of general or regional anesthesia, it is useful to examine the boy to reaffirm testicular position or to attempt to establish testicular position in the case of a previously nonpalpable testis. 4.2.1.

Surgical therapy for palpable testes

Palpable testes were treated with a standard open inguinal orchidopexy (Petrivalsky/Schoemaker technique) [64,65]. The key steps are the complete mobilization of the testes and spermatic cord, the repair of the patent processus vaginalis by high ligation of the hernia sac, the skeletonization of the spermatic cord without scarifying vascular integrity to achieve tension-free placement of the testes

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within the dependent position of the scrotum, and the creation of a superficial pouch within the hemiscrotum to receive the testes. The ilioinguinal nerve is carefully preserved, and typically, any testicular or epididymal appendages are excised. If the cord is still short, preventing a tension-free orchidopexy, the internal inguinal ring is opened laterally, and the peritoneum is bluntly elevated off the testicular vessels. In case of the further persistence of a short cord, a Prentiss maneuver [66] may be performed. The procedure is generally performed on an outpatient basis. Antibiotic prophylaxis or longer immobilization is not required. Complications after standard orchidopexy are testicular atrophy in 0.3% of patients and recurrence (reascent) in 4% of patients [67]. 4.2.2.

Surgical therapy for nonpalpable testis

Occasionally, for a high UDT, greater mobilization of the proximal spermatic cord structures does not provide adequate length to allow tension-free placement of the testes within the scrotum. Greater cord length can be obtained by mobilizing the spermatic vessels medially; a Prentiss maneuver [66] may be performed. A high inguinal approach or Jones incision [68] is an open surgical alternative for a high canalicular or intra-abdominal testis. This extraperitoneal approach uses a higher incision than the standard inguinal orchidopexy, extending from the anterior superior iliac spine medially. This procedure shares similar indications and surgical principles with the laparoscopic orchidopexy and was the popular surgical approach before the advent of laparoscopic management of the intra-abdominal testis [28]. Principles include preservation of the spermatic vessels, high retroperitoneal mobilization of the spermatic vessels, and passage of the testes directly through the abdominal wall at the pubic tubercle [66]. If anatomic conditions prevent adequate spermatic vessel length from being achieved during primary orchidopexy or if, under unusual circumstances, a two-stage procedure is undertaken with planned preservation of the spermatic vessels, a staged orchidopexy can be performed as described by Persky and Albert [69]. In the first step, the testis is fixed, without tension, to the lowest possible site (periosteum over the pubis, pubic symphysis) after maximal mobilization. The testis and the spermatic cord can be wrapped with a Silastic sheath to reduce adhesion formation and facilitate dissection during the second-stage procedure [70]. The second procedure is performed 6–12 mo later. For short testicular vessels, a Fowler-Stephens orchidopexy is useful [71]; this technique involves clipping and transecting the testicular vessels. This technique was originally a one-stage procedure, but it may also be performed in two stages. The authors recommended the ligation (clipping) of the spermatic artery as high as possible to preserve the collateral channels between the vessel and spermatic artery. The main disadvantage of the one-stage Fowler-Stephens orchidopexy is that the deferential artery might be so small that if it goes into vasospasm, testes

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atrophy is very probable [1,72,73]. The concept of the staged Fowler-Stephens orchidopexy is based on the development of collateral circulation via the vessels accompanying the deferential artery; this procedure is intended to decrease the risk of testicular atrophy but has the disadvantage of requiring two general anesthesia procedures within 3–8 mo [74]. Both steps can be done as a laparoscopic procedure [75]. The easiest and most accurate way of locating an intraabdominal testis is by diagnostic laparoscopy [76]. Radiographic imaging studies carry unacceptable false-negative and false-positive rates [60]. Magnetic resonance imaging has been shown to be an effective method of detection in only 37% of cases [77]. Laparoscopy has attained its greatest degree of general acceptance, both diagnostically and therapeutically, in the realm of pediatric urology for the management of a nonpalpable testis. Examination of the groin under anesthesia is the first step in laparoscopic orchidopexy, because 18% of nonpalpable testes become palpable under anesthesia [78]. Contraindications to laparoscopy include prior abdominal surgery with potential peritoneal adhesions or a body habitus that will not allow for proper placement of abdominal wall ports and laparoscopic instruments. Potential major complications include vascular injury and bowel and bladder perforation; however, these complications become rare when an open technique is used for trocar placement. The minor complications, which would not necessarily require termination or conversion of the laparoscopic procedure, include abdominal wall injury, such as hematoma, and subcutaneous insufflation. Diagnostic laparoscopy has become the gold standard [1] for the exploration of nonpalpable testes. The accuracy of testicular localization by diagnostic laparoscopy is reported to be >95% [76]. Possible anatomic findings on the side of the nonpalpable testis include the following [78]: (1) the spermatic vessels enter the inguinal canal (40%), (2) a canalicular or peeping testis is found (11.2%), (3) the spermatic vessels end blinding (9.8%), and (4) a viable intra-abdominal testis is identified (37%). Diagnostic laparoscopy helps in determining intraabdominal testicular anatomy and the feasibility of a single- or two-stage orchidopexy. If the testis is abnormal, laparoscopy help determine whether orchiectomy is indicated. There are three laparoscopic procedures that are commonly performed to treat the intra-abdominal testis: (1) primary one-stage orchidopexy with preservation of the spermatic vessels, (2) orchiectomy, and (3) division of the spermatic vessels as the first stage of a two-stage FowlerStephens orchidopexy [79]. In addition to these procedures, laparoscopic-assisted microvascular autotransplantation has been described [80]. In 1992, Jordan and Winslow first described primary, nonstaged laparoscopic orchidopexy and the first staged procedures in 1994 [81]. Mathews and Docimo [82] described how laparoscopic orchidopexy has to be performed.

Laparoscopic orchidopexy includes the following advantages [5]:  The ability to achieve an extensive vascular dissection to the origin of the gonadal vessels  Dissection of the proximal vessels without disturbance to the peritoneum between the vas deferens and the distal spermatic cord, thus preserving the option of a FowlerStephens approach  High (15) magnification and improved visualization during mobilization of the proximal spermatic vessels and gubernaculum  The ability to create a new internal ring medial to the inferior epigastric vessels and thus achieve a straight vascular course to the scrotum  Minimal morbidity in older children and adolescents. A number of series have demonstrated laparoscopic orchidopexy as having a higher success rate than has been historically reported for the open technique. In 1995, Docimo [1] reported an 81.3% success rate for open orchidopexy in patients with intra-abdominal testes. In contrast, open-staged orchidopexy has a success rate of 64–71% [1,73]. The success rate of the one-step FowlerStephens procedure is between 67% and 100%, but most studies report good results in <85% of patients [73,83,84]. Neissner et al concluded that the single-stage approach is a reliable, safe, and effective treatment modality for intraabdominal testes. However, the two-stage procedure including testicular vessel ligation should be restricted to high abdominal testes with very short vessels [85]. A review of the current publications dealing with laparoscopic staged Fowler- Stephens orchidopexy shows a success rate of 95% [73,83]. Guo et al [86] recently showed that although the stay in the hospital is shorter in laparoscopic orchidopexy, there is no significant advantage over open surgery for treating nonpalpable testes. Silber and Kelly [87] first reported the description of microsurgical testicular autotransplantation. The procedure requires plastic surgical anastomosis of the testicular vessels to the ipsilateral inferior epigastric artery and vein [1,88] and should be reserved for use in specialized centers, at which, in experienced hands, there is a success rate of approximately 80% [1,73]. 5.

Outcome and functional consequences

Outcome in orchidopexy is mainly assessed by testicular position and size [1]. Other factors that should be assessed later in life include fertility and risk of testicular cancer (see section 3). The most important surgical complication of orchidopexy is testicular atrophy, which occurs when testicular vascularity is unable to maintain viability of the testis [73,83]. Testicular atrophy occurs as a result of one or more of the following factors: aggressive skeletonization of testicular vessels, postoperative edema, inflammation, inadvertent torsion of the spermatic vessels when passing the testis into the scrotum, and undue tension on the

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spermatic vessels [72,84,89]. Other complications of orchidopexy include testicular retraction, hematoma formation, ilioinguinal nerve injury, postoperative torsion (either iatrogenic or spontaneous), and damage to the vas deferens. Parents should also be informed about the possibility of placing a silicone gel–filled prosthesis. Testicular prostheses have been shown to eliminate adverse psychosexual effects and markedly improve patient self-confidence [90].

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[10] Wensing CJ. The embryology of testicular descent. Horm Res 1988;30:144–52. [11] Frey HL, Rajfer J. Epididymis does not play an important role in the process of testicular descent. Surg Forum 1982;33:617. [12] Baikie G, Hutson J. Wolffian duct and epididymal agenesis fails to prevent testicular descent. Pediatr Surg Int 1990;5:458–62. [13] Mollaeian M, Mehrabi V, Elahi B. Significance of epididymal and ductal anomalies associated with undescended testis: study in 652 cases. Urology 1994;43:857–60. [14] Gier HT, Marion GB. Development of mammalian testes and genital ducts. Biol Reprod 1969;1(Suppl 1):1–23.

6.

Conclusions

The etiology of cryptorchidism remains little understood. It seems that endocrine and genetic disorders can cause maldescent of the testes, but, in the majority of cases, no distinct etiology can be determined; therefore, etiology of the condition is multifactorial. Treatment can be through hormonal manipulation or surgery. In all cases it should be performed when the patient is aged between 6 mo and 1 yr because spontaneous descent rarely occurs at >6 mo [6]. Surgery for the palpable testis remains most commonly an inguinal approach. The nonpalpable testis is most commonly approached laparoscopically, and the success rate of laparoscopic orchidopexy may exceed that of more traditional open approaches.

[15] Quinlan DM, Gearhart JP, Jeffs RD. Abdominal wall defects and cryptorchidism: an animal model. J Urol 1988;140:1141–4. [16] Elert A, Jahn K, Heidenreich A, Hofmann R. The familial undescended testis. Klin Padiatr 2003;215:40–5. [17] Hutson JM, Donahoe PK. The hormonal control of testicular descent. Endocr Rev 1986;7:270–83. [18] Husmann DA, McPhaul MJ. Reversal of flutamide-induced cryptorchidism by prenatal time-specific androgens. Endocrinology 1992; 131:1711–5. [19] Nef S, Parada LF. Cryptorchidism in mice mutant for Ins13. Nat Genet 1999;22:295–9. [20] Zimmermann S, Steding G, Emmen JM, et al. Targeted disruption of the Ins13 gene causes bilateral cryptorchidism. Mol Endocrinol 1999; 13:681–91. [21] Bernstein L, Pike MC, Depue RH, Ross RK, Moore JW, Henderson BE. Maternal hormone levels in early gestation of cryptorchid males: a case-control study. Br J Cancer 1988;58:379–81. [22] Gill WB, Schumacher GF, Bibbo M, Straus II FH, Schoenberg HW. Association of diethylstilbestrol exposure in utero with cryptorchi-

Conflicts of interest

dism, testicular hypoplasia and semen abnormalities. J Urol 1979; 122:36–9.

The authors have nothing to disclose.

[23] Guerrier D, Tran D, Vanderwinden JM, et al. The persistent mu¨ller-

Funding support

[24] Josso N, Picard JY, Imbeaud S, Carre´-Euse`be D, Zeller J, Adamsbaum

ian duct syndrome: a molecular approach. J Clin Endocrinol Metab 1989;68:46–52. C. The persistent mu¨llerian duct syndrome: a rare cause of crypt-

None.

orchidism. Eur J Pediatr 1993;152(Suppl 2):S76–8. [25] Cain MP, Kramer SA, Tindall DJ, Husmann DA. Alterations in maternal epidermal growth factor (EGF) effect testicular descent and

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