–Measurements of serum electrolytes, testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), müllerian-inhibiting hormone (MIH), and adrenal hormones and metabolites (17-hydroxyprogesterone).

–A stimulation test using intramuscular human chorionic gonadotropin (hCG) can be done to check for evidence of testosterone production by the gonads.

–Pelvic ultrasound is useful in infants with bilateral nonpalpable testes not only to look for gonads but also to exclude the presence of a uterus.

–Ultrasonography, computed tomography or magnetic resonance imaging, are not sensitive or specific enough to detect the majority of intra-abdominal testes and surgical exploration or laparoscopy is required.

24.2Embryology and Normal Testicular Development and Descent

•Embryologically, the testes develop in the abdomen along the gonadal ridge from the primitive (indifferent) gonad. This is under the influence of several male genes.

•This occurs at about the sixth week of gestation under the influence of the SRY gene.

–The SRY gene is located on the short arm of the Y-chromosome (Yp11.3). It is responsible for initiating sex differentiation by downstream regulation of sexdetermining factors.

–This involves expression of several genes including WT1, CBX2 (M33), SF1, GATA4/ FOG2 is critical to SRY activation.

–The SOX9 gene, located on 7q24.3-25.1, is essential for early testis development.

•The second step in male sex differentiation involves internal and external genitalia differentiation.

•During the third to fifth months of intrauterine development, the cells in the testes differentiate into testosterone-producing Leydig cells, and anti-Müllerian hormone-producing

Sertoli cells. The germ cells become fetal spermatogonia.

–The developed testes have two types of cells:

•The Leydig cells

•The Sertoli cells

–The Sertoli cells produce the anti-Müllerian hormone (AMH).

–The Leydig cells produce testosterone.

–The AMH acts on its receptor in the Müllerian ducts and causes their regression.

–Testosterone acts in a critical concentrationdependent and time-dependent manner to induce male sexual differentiation.

–Testosterone acts on the androgen receptor in the Wolffian ducts to induce the formation of:

•Epididymis

•Ejaculatory ducts

•Seminal vesicles.

–The Leydig cells also produce insulin-like factor 3 (INSL3, relaxin-like factor), which play a role in the descent of testes to the scrotum.

–Testosterone is also converted to dihydrotestosterone (DHT) under the influence of 5-alpha reductase enzyme, which acts on the androgen receptor of the prostate and external genitalia to cause its masculinization.

–Binding of Testosterone and DHT to androgen receptors is necessary for androgen effect.

•The testes remain high in the abdomen until the seventh month of gestation, when they start descending from the abdomen through the inguinal canals into their final position in the scrotum.

•It has been proposed that testicular descent from the abdomen into the scrotum occurs in two phases, under control of somewhat different factors.

–The first phase:

•This involves descent of the testes from the abdomen to the entrance of the inguinal canal.

•This phase is under the influence of the anti-Müllerian hormone (AMH).

–The second phase:

•This involves descent of the testes through the inguinal canal into the scrotum.

•This phase under the influence of androgens (testosterone).

•It was shown experimentally that androgens induce the genitofemoral nerve to release calcitonin gene-related peptide (CGRP), which causes rhythmic contractions of the gubernaculum that help facilitates testicular descend into the scrotum.

•It was also suggested that the testes secret a hormone called descendin which through a paracrine effect help in testicular descent.

•In many infants with inguinal testes, further descent of the testes into the scrotum occurs in the first 6 months of life. This is attributed to the postnatal surge of gonadotropins and testosterone that normally occurs between the first and fourth months of life.

•Factors that can affect testicular descent include:

–Maldevelopment of the gubernaculum

–Deficiency or insensitivity to AMH

–Deficiency or insensitivity to androgen

–Anatomical factors that interfere with testicular descent

•Spermatogenesis continues after birth.

–In the third to fifth months of life, some of the fetal spermatogonia residing along the basement membrane become type A spermatogonia.

–More gradually, other fetal spermatogonia become type B spermatogonia and primary spermatocytes by the fifth year after birth.

–Spermatogenesis arrests at this stage until puberty.

24.3Classification

of Undescended Testes

•A testis absent from the normal scrotal position can be found any were along the “path of descent” from high in the posterior (retroperitoneal)

abdomen, just below the kidney, to the upper part of the scrotum.

–In the abdomen: These are not palpable

–In the inguinal canal

–Just above the scrotum

•Retractile testis: A testis that can easily move between the scrotum and inguinal canal.

•Ectopic testis: A testis that descended but have “wandered” from the normal path of descent to lie outside the inguinal canal.

–In the superficial inguinal pouch

–Under the skin of the thigh

–In the perineum

–Prepenile are

–In the opposite scrotum

–In the femoral canal

•Undeveloped (hypoplastic) testis

•Severely abnormal (dysgenetic) testis

•Vanished testis: This is most likely secondary to intrauterine torsion of testes with infarction and necrosis

•Ascent testis: A testis observed in the scrotum in early infancy can occasionally “reascend” (move back up) into the inguinal canal.

•Most normal-appearing undescended testis are also normal by microscopic examination, but reduced spermatogonia can be found. The tissue in undescended testes becomes more markedly abnormal (“degenerates”) in microscopic appearance between 2 and 4 years after birth. There is some evidence that early orchidopexy reduces this degeneration.

24.4Causes of Undescended Testes and Risk Factors

•In the majority of undescended testes, no definite cause can be found

•Several factors may contribute to the development of cryptorchidism including genetics, maternal health and other environmental factors. These include:

–Parents’ exposure to some pesticides

–Diabetes and obesity in the mother

–Exposure to regular alcohol consumption during pregnancy

–Cigarette smoking

–Family history of undescended testicle

–The use of cosmetics by the mother

–Preeclampsia

–Prenatal exposure to a chemical called phthalate (DEHP) which is used in the manufacture of plastics

–Exposure to mild analgesics by pregnant mothers

•Premature infants and low birth weight infants are known to have a higher incidence of undescended testes.

•Intra-abdominal pressure also appears to play a role in testicular descent.

–Conditions associated with decreased pressure include:

•Prune belly syndrome

•Cloacal exstrophy

•Omphalocele

•Gastroschisis

–Each is associated with an increased risk of undescended testes.

•The effect of decreased intra-abdominal pressure is most significant during transinguinal migration to the scrotum, probably in conjunction with androgens and a patent processus vaginalis.

•Epididymal abnormalities often accompany undescended testes, but the causal relationship has not been established.

•Cryptorchidism occurs at a much higher rate in a large number of congenital malformation syndromes including:

–Down syndrome

–Prader–Willi syndrome

–Noonan syndrome

–Kallmann’s syndrome

–Laurence-Moon-Biedl syndrome

–Sever penoscrotal or perineal hypospadias (Figs. 24.4 and 24.5)

–Prune belly syndrome (Fig. 24.6)

–Spigelian hernia (Figs. 24.7, 24.8, 24.9, and 24.10)

–Omphaloceles (Figs. 24.11 and 24.12)

–Gastroschesis and Cloacal exstrophy (Figs. 24.13 and 24.14)

24.5Histopathology

•There are several histopathological changes in undescended testes.

•A significant decrease in the number of spermatogonia per tubule (S:T ratio) in undescended testes is seen as early as the second year of life.

•Undescended testes also have atrophic Leydig cells, supporting the observation that testosterone secretion is impaired in cryptorchidism during early infancy.

•Patients with poor testicular histology (S:T ratio less or equal to 0.1) and at high risk for impairment of fertility may benefit from treatment with Buserelin, a luteinizing, hormone-releasing hormone (LHRH) analogue.

•There was a significant increase in mean S:T ratio in testes rebiopsied after orchiopexy and 6 months treatment with Buserelin, while there was no change seen following orchiopexy alone.

•Although the retractile testicle is considered a normal variant, some studies suggest that not all retractile testes have a benign course.

–Some ascend into the undescended position and these require orchidopexy

–Others show volume loss and histological abnormalities that are similar but less severe than those found in cryptorchid testes.

–There are also reports of infertile adults with persistent retractile testicles who have improved sperm counts after scrotal orchiopexy.

24.6Classification of Abnormal Testes

•Normally both testes are present in their normal intra-scrotal position at the time of birth.

•A testis that is absent from the normal intrascrotal position can be:

–True undescended testis: The testis can be found anywhere along the “path of testicular descent”.

•High in the posterior (retroperitoneal) abdomen

•Below the kidney

•At the inguinal ring

•In the inguinal canal

•At the upper scrotum

–Ectopic testis: This is a testis that “wandered” from the normal path of descent. Ectopic testes exit the external inguinal ring and are then misdirected away from the normal course of descent. This can be found:

•Outside the inguinal canal

•Under the skin of the thigh

•The perineum

•The opposite scrotum

•The femoral canal

•Prepenile

–Hypoplastic testis

–Dysgenetic testis

–Vanished (anorchia) testis

•The vanishing testicle is thought to be caused by intrauterine testicular torsion.

•This is most likely during late gestation since most of these testicular remnants are found below the internal inguinal ring.

•Only 20–40 % of nonpalpable testes are absent upon surgical exploration.

–Ascent testis: A testis that descended normally in the scrotum can occasionally “reascend” back up into the inguinal canal.

–Retractile testis: A testis which can move up and down between the scrotum and inguinal canal. These testes can be manipu-

lated into the scrotum and there is a high risk of ascent.

•About 70–80 % of undescended testis are unilateral.

•10–20 % of undescended testes are bilateral.

•Approximately 80 % of undescended testes are palpable and 20 % are nonpalpable.

•In 90 % of undescended testes, the testis can be felt in the inguinal canal.

•About one half of nonpalpable testes are found to be intra-abdominal, while the rest represent absent (vanishing) or atrophic testes.

•A patent processus vaginalis is found in more than 90 % of patients with undescended testis

•30–80 % of undescended testes are associated with some type of epididymal abnormality (Figs. 24.15, 24.16, 24.17, and 24.18).

Fig. 24.15 Intraoperative photograph in child with undescended testis. Note the vas looping before it joined the testis. Note also the abnormal epididymis

Fig. 24.17 Intraoperative photograph showing bilateral undescended testes which are small in size. Note also the abnormal epididymis

Fig. 24.16 Intraoperative photograph showing undescended testis. Note the abnormal epididymis