Undescended testis, or "cryptorchidism", is a very common anomaly in male infants and pre-adolescent boys, with about 1 in 20 boys undergoing treatment by the time they reach puberty. Not only is it prevalent, but also there remain unresolved questions about prognosis in adult life. It is not known yet whether the dramatic changes in recommended age for surgery (from 15 years of age in the 1950's, to six months old now) will decrease the risk of infertility or testicular cancer. However, current treatment is based on the assumption that early surgery will prevent germ cell degeneration during childhood, leading to improved fertility and fewer tumors.

Our understanding of the embryology has advanced rapidly in recent years, with new theories and experimental evidence supporting a complex anatomical process controlled directly and indirectly by hormones. The classification of cryptorchidism also is changing, with the recent recognition of acquired anomalies. With so much change in the way we view and treat cryptorchidism, endocrinologists will need to keep checking on the controversies described in this chapter.

The testes descend prenatally from their initial intra-abdominal location on the urogenital ridge into the low-temperature environment of the scrotum via a complex multi-stage mechanism (1). Prior to 7-8 weeks of development, the gonadal position is similar in both sexes. With the onset of sexual differentiation, the fetal testis begins producing Mullerian inhibiting substance (MIS) (also called anti-Mullerian hormone, AMH) from the Sertoli cells, as well as androgen and insulin-like hormone 3 (INSL3) from the Leydig cells. These hormones are involved in controlling descent of the male gonad, which is held by the cranial suspensory ligament at the upper pole, and the genito-inguinal ligament or gubernaculum at the lower pole (2).

During the initial phase of descent, regression of the cranial ligament and thickening of the gubernaculum allows the testis to be held near the inguinal region (3). By contrast, in the female the cranial ligament persists while the gubernaculum remains thin, which holds the ovary higher on the posterior abdominal wall as the fetal abdomen enlarges. The inguinal canal forms by the abdominal wall muscles developing around the caudal, gelatinous end of the gubernaculum. By 15 weeks the testis is attached by a short stout and gelatinous gubernaculum to the future internal inguinal ring, while the ovary is higher in the pelvis (4).

After 20-25 weeks a diverticulum of the peritoneal membrane, known as the processus vaginalis, begins to elongate within the gubernaculum, which retains a central connection with the epididymal tail and the lower pole of the testis. The caudal end of the gubernaculum grows out of the abdominal wall and elongates towards the scrotum, extending the processus vaginalis eventually to the scrotum. Between 25-30 weeks the testis descends rapidly through the inguinal canal, and then more slowly across the pubic region and into the scrotum, followed by obliteration of the proximal processus vaginalis (5). Descent within this peritoneal diverticulum is complete by 35 weeks. The gubernaculum is not anchored to adjacent structures during inguino-scrotal migration, but becomes secondarily attached to the scrotum after descent is complete.

Figure 1.

The two main phases of descent appear to be controlled independently by hormones. [Fig. 1]. INSL3 is the major factor controlling gubernacular enlargement (6), and recent evidence suggests (7,8,9,10), androgens, particularly DHT, MIS and (possibly) relaxin appear to play minor roles in this "swelling reaction" of the gubernaculum. Under the influence of the hormones mentioned above, the caudal end of the gubernaculum, where it attaches to the inguinal abdominal wall, enlarges by proliferation of the embryonic mesenchyme as well as deposition of extracellular matrix. Androgens also are responsible for regression of the cranial suspensory ligament, but they are not sufficient alone for descent. The phase of gubernacular migration is controlled both directly and indirectly by androgens, with the aid of the genitofemoral nerve releasing calcitonin gene-related peptide (CGRP) (11, 12). The number of sensory neurones and the amount of CGRP in the genitofemoral nerve of rats are significantly less after exposure to the anti-androgen, flutamide, consistent with androgens stimulating structural and functional changes in the nerve. The nerve is proposed as the means of orienting the direction of gubernacular migration, while the physical force needed for elongation of the processus vaginalis is probably provided by intra-abdominal pressure (13). CGRP released from the nerve stimulates mitosis and cremaster muscle development in the gubernacular tip, enabling elongation to the scrotum (6). Estrogens have a minor inhibitory role in normal gubernacular development, but may be responsible in larger doses for cryptorchidism secondary to suppression of the "swelling reaction".

Any anomaly in either the hormonal control or the anatomical processes in normal testicular descent will cause cryptorchidism (14). Hormonal defects in INSL3, MIS or androgenic action are identified only rarely, suggesting that mechanical anomalies are more common. These patients may present with rare disorders of sexual development with cryptorchidism as part of the complex genital anomaly. The first or "transabdominal" phase involves little movement of the testis and this may explain the low frequency (5-20%) of intra-abdominal testes. The inguinoscrotal migration phase requires very significant mechanical and anatomical re-arrangements, and consequently, anomalies are common: over 60% of testes are found just outside the external inguinal ring, consistent with anomalous or arrested gubernacular migration. Transient deficiency of androgen production in utero perhaps related to deficiency of gonadotropin production by the fetal pituitary or the placenta (15), may account for some, particularly where there is intra uterine growth retardation. Anomalies of the genitofemoral nerve also may cause undescended testes. For example, perineal testes may be caused by an anomalous location of the genitofemoral nerve (1).

Inherited syndromes frequently are associated with cryptorchidism. Hypothalamic dysfunction, connective tissue disorders, neurogenic (eg spina bifida) and mechanical anomalies (eg arthrogryposis multiplex congenita) may all cause disruption in testicular descent (16-18). Cryptorchidism is also common in infants with abdominal wall defects, such as exomphalos or omphalocele, gastroschisis and extrophy of the bladder (19).

There is much current interest in the potential adverse effects of environmental estrogens on the incidence of both cryptorchidism and hypospadias(20) . In addition there are data on the effect of diethylstilbestrol (DES) of cryptorchidism in male offspring of exposed mothers (21). In the latter case there is supporting evidence from animal models (22) although in the former, the cause and effect relationship is more tenuous, because the level of exposure is less clear, and the epidemiology may not have allowed for changes in diagnostic criteria over recent decades. More work is needed before we can ascertain a proven cause-and-effect link with synthetic molecules in the environment.The body of the epididymis is hypoplastic and frequently is not tightly adherent to the cryptorchid testis (23). This is more common in high intra-abdominal testes and probably indicates significantly decreased androgen production. Whether epididymal-testicular separation is the cause or the result of cryptorchidism is not known (24). In addition, its effect on fertility is uncertain, even though the rete testis is nearly always still connected to the head of the epididymis.

Up to 4-5% of newborn males show cryptorchidism, but this falls to 1-2% by 12 weeks after term, following normal (but postnatal) descent in premature infants, and delayed postnatal descent in some term babies. Beyond 12 weeks, spontaneous testicular descent is believed to be rare (25). Geographic differences in prevalence of cryptorchidism have been reported, with 9% of Danish boys with undescended testes at birth, compared with only 2% of males from Finland (25).

An undescended testis is best defined as a testis that cannot be manipulated into the bottom of the scrotum (without excess tension on the spermatic cord) by 12 weeks of age. Most testes (about 85%) are near the neck of the scrotum, or just lateral to the external inguinal ring, described by Denis Browne as the "superficial inguinal pouch(26) .

A few cryptorchid testes are within the inguinal canal, making them impalpable unless they can be squeezed out of the external inguinal ring by compression. 10% of testes are intra-abdominal or absent (presumed to be secondary to prenatal, intra-abdominal torsion). Ectopic cryptorchid testes are rare (< 5%), and occur in the perineum, prepubic region, thigh, or the contralateral inguinal canal (transverse testicular ectopia) (27).

The aim of clinical examination is to locate the gonad, if palpable, and determine its lowest position without causing painful traction on the spermatic cord (which probably corresponds to the caudal limit of the tunica vaginalis) (42). In infants, the diagnosis is straightforward because the scrotum is thin and pendulous. Hypoplasia of the hemiscrotum indicates it does not contain a testis. The inguinal testis is within its tunica vaginalis which gives it significant mobility.Ultrasound, CT or MRI have been proposed for diagnosis of the impalpable testis, but generally are not contributory. This is because absence of the testis (secondary to possible perinatal torsion) is common, and also because intra abdominal testes are concealed by the bowel and other viscera (43). A simple and reliable approach is to use laparoscopy, which readily locates the testis itself (or blind-ending gonadal vessels), and allows orchidopexy in experienced hands (44).

The complication rate after orchidopexy is less than 5% in experienced hands (53). Wound infection is common in infants secondary to external contamination of the wound, although there is a very low risk of atrophy of the testis which is greatest when intra-abdominal testes are pulled down under tension. Laparoscopy, with or without ligation of the testicular vessels (Fowler-Stephens procedure) (54), shows increasing success for high intra-abdominal gonads (55-57).

The prognosis for fertility, the primary aim of orchidopexy, remains uncertain (25,58-60). However, extensive review of the recent literature suggests improved outcomes with very early surgery (60), Now that early germ cell maturation in the first year is known to be deranged, improved fertility is to be expected with very early orchidopexy (59,60). Unfortunately, it will be a few more years before the outcome of this new policy is known.

The risk of malignancy was previously calculated to be 5 -10 times greater than normal for a man with a history of unilateral cryptorchidism (61-65). The risk in a future generation for men who underwent orchidopexy in infancy is unknown at present, but is anticipated to be lower than in the past, as supported by preliminary evidence (66).

Some clinical features are associated with statistically better outcomes, and include testes near the neck of the scrotum, and ascending or retractile testes (see below), where malignancy risk is now thought to be similar to normal men (25,60). Poor prognostic factors are primary testicular or epididymal dysplasia, intra-abdominal or intra-canalicular position, associated strangulated inguinal hernia and (possibly) surgery late in childhood or adolescence (67).

Retraction of the testis out of the scrotum secondary to reflex contraction of the cremaster muscle is both normal and common, and is involved in temperature control and protecting the testis from trauma. The reflex is absent or weak at birth and becomes more active after one year, reaching a peak in 5-10 year-old boys (68).

Many testes are erroneously described as "retractile" when they can be pulled down into the scrotum during the physical examination, but retract back out of the scrotum on release. This retractability is assumed to be secondary to cremasteric activity, but an alternative explanation has been proposed recently, which is that the malposition may be caused by failure of the spermatic cord to elongate with age (69). Since the distance from external inguinal ring to the bottom of the scrotum increases from 5 cm at birth to 8-10 cm at 10 years of age, the spermatic cord must double in length to keep the testis in the scrotum during the first decade. Preliminary evidence suggests that failure of complete obliteration of the processus vaginalis may prevent normal postnatal elongation of the vas and vessels (70) [Fig. 2].

Figure 2.

The ascending testis is a special variant of acquired maldescent, in which there is delayed postnatal descent of the testis in the first three months after birth (71, 72). Follow-up studies suggest that subsequent "ascent" of the testis is common later in childhood (73-75). The cause for ascending testes is not resolved, with the only well-documented cause being neuronal dysfunction as seen in children with cerebral palsy (76). In normal children, the explanation is likely to be persistence of the processus vaginalis, either patent or as a fibrous remnant (77).

Both “retractile” and ascending testes are likely to be different names for what is, in effect, acquired cryptorchidism caused by persistence of the processus vaginalis (78-81). The normal spermatic cord elongates gradually with growth, and hence acquired cryptorchidism develops insidiously, presenting mostly between 5 and 10 years of age (82). Orchidopexy is required once the testis can no longer reside spontaneously in the scrotum, and can be performed in the standard manner or by a scrotal approach (83). Once the fibrous remnant of the processus vaginalis is divided, the testis can reach the scrotum easily.

The prognosis for this special group is probably much better than for congenital cryptorchidism, as the testis is normally located in the scrotum during infancy (60, 84,85), when germ cell maturation is occurring.. Unfortunately, previous studies of outcome for fertility and malignancy have not discriminated between congenital and acquired cryptorchidism, but recent studies suggest a mild suppression of fertility and little risk of malignancy (25,60) The frequency of acquired cryptorchidism, like the concept itself, still remains controversial, but may account for up to half of all children coming to orchidopexy (82,86).