Undescended Testes☆ Ritzén E Martin, Karolinska Institute, Stockholm, Sweden r 2018 Elsevier Inc. All rights reserved. Glossary Cryptorchidism A testis that is not correctly descended in the scrotum, although it is located in the normal pathway, contrary to an ectopic testis. Ectopic testis The testis is found outside the normal path of decent from the abdomen to the scrotum. Orchidopexy Surgical transfer of a testis from a suprascrotal position to the scrotum. Spermatogenesis The complete sequence of events of cell division and cell maturation that leads from spermatogonia to fully developed spermatozoa. Spermatogonia Stem cells of spermatogenesis and the earliest stages of germ cell maturation, in the absence of which no sperm can be produced. Spermatogonia are present in the normal testis throughout childhood and adulthood. Testicular descent The normal transposition of the testis during fetal or the ﬁrst six postnatal months of life from the lower abdomen, through the inguinal canal, to the scrotum. Undescended testes Synonymous with nondescended testes, cryptorchidism, retained testes, and retentio testis. Introduction With very few exceptions, the testicles of mammals are located in a sac on the outside of the body cavity, exposed to potential trauma rather than protected inside the pelvis or abdomen. From a developmental perspective, this seems to be a risk factor for securing fertility, which should be an absolutely vital strategy for survival of a species. Thus, this location must offer other developmental beneﬁts. The most obvious is the lower temperature in the scrotum than in the abdomen (21C or 31C, depending on the species). In fact, it has been shown that this seemingly minor difference in temperature is crucial for completion of spermatogenesis; in most mammals, failure of the testes to descend from the abdominal cavity to the scrotum leads to infertility. On the other hand, this does not mean that spermatogenesis occurs in all testes that are brought into the scrotum; the non-descent can be secondary to an abnormal development of the testis that might impair spermatogenesis. Another possible beneﬁt of the low scrotal temperature may relate to the incidence of mutations of the genome. A reduced temperature in the testis, the organ with the highest cell proliferation in the male body, will reduce the incidence of mutations that will be transmitted to offspring to a level that is optimal for long-term development (mutations with positive effects are beneﬁcial) but not so high that it compromises fertility or that the occurrence of malformations is at an unacceptable level for the development of the species. Nomenclature and Differential Diagnosis One conventional deﬁnition is that normal testicular descent has occurred when the location of the testis is below the border between scrotal and abdominal skin in a resting, standing position. However, this “resting” state may not be present during examination in the clinic—the cremasteric reﬂex will retract the testes when the examiner's hand approaches. A practical way to circumvent this is to pull the testis down gently, hold it for approximately 30 s until the cremasteric reﬂex has been exhausted, and then release it. The position of the released testis approximates the resting position. If a testis is in a supra-scrotal position at the start of the examination but after manipulation remains in the scrotum, it is called a retractile testis. This condition is thought not to need any further attention. For clinical studies, a more exact location of the testes than “scrotal,” “sub-inguinal,” or “inguinal” should be used, preferably by measuring the distance in millimeters between the testis and a deﬁned point (e.g., the pubic tubercle or the external inguinal oriﬁce). The term cryptorchidism is often used to describe the condition of undescended testes. This term implies that the testes are “hidden,” that they can neither be seen nor palpated. Since in clinical practice even inguinal or sub-inguinal (pre-scrotal) palpable testes should be considered undescended, the term cryptorchidism is not always correct. “Non-descended” and “retained” (Latin: retentio testis) are synonyms of undescended testes that are sometimes used (Fig. 1). In approximately 10%–20%, both testes are found above the scrotum. Even after successful treatment, the prospect for future fertility is worse (approximately 65%) in bilateral than unilateral cryptorchidism (approximately 90%) (Lee, 2005). Untreated bilateral cryptorchidism in adulthood is not compatible with fertility. ☆ Change History: December, 2017. Ritzén E Martin updated the text and added new ﬁgure. This chapter is an update of E. Martin Ritzén, Undescended Testes, In Encyclopedia of Endocrine Diseases, edited by Luciano Martini, Elsevier, New York, 2004, Pages 651–655. Encyclopedia of Endocrine Diseases, Second Edition, Volume 5 doi:10.1016/B978-0-12-801238-3.65347-3 521 522 Undescended Testes Fig. 1 A schematic drawing of the various locations where a testis can be found along its natural path of descent from the abdomen through the inguinal canal to the scrotum. If no testis is palpable, it is important to consider a possible disorder of sex development (DSD), especially if combined with hypospadias of any degree. Such patients should be referred to a DSD team immediately after birth, since the new born might be a virilized girl with congenital adrenal hyperplasia; a possibly life-threatening condition. If both testes undergo atrophy after that male sex differentiation is completed, the boy is born with normal male sex organs but will need testosterone substitution at puberty. The term ectopic testis has been coined to describe a position of the testis that is outside the normal path of the testis during descent. Only during surgery can the true differentiation between a low inguinal and an ectopic testis be made. It is difﬁcult to distinguish bilaterally retained abdominal testicles from testicular atrophy. The differentiation between the two may be aided by a human chorionic gonadotropin (hCG) stimulation test. Signiﬁcantly increased testosterone levels indicate the presence of testicles. Measurement of inhibin B in serum is valuable since in boys this hormone is only produced in Sertoli cells. Acquired Cryptorchidism Acquired cryptorchidism is a term that is used in cases when a testis at some stage (most often during the ﬁrst 6 months of age) has been found in the scrotum, but later in a supra-scrotal or inguinal position. This is found to be the case in about one of ﬁve testes that are undescended at birth, but descend during the ﬁrst 3–6 months (Kollin et al., 2013). Thus, this group of boys should be followed at annual examinations and treated if found to be ascended. Such examinations can be done by the parents, after proper instructions. Secondary ascensus may explain why many studies ﬁnd about 1% undescended testes at age 6 months, but up to 3% of all boys are eventually operated for cryptorchidism. Incidence of Cryptorchidism The classical epidemiological studies by Scorer (1956) in England are often cited. Using his quite strict deﬁnitions, 2.7% of boys with a birth weight of 42.5 kg had undescended testes at birth, but testicular descent proceeded during the ﬁrst postnatal months so that at age 3 months only 0.9% were considered to have incompletely descended testes. In premature infants, the incidence was much higher (21% if o2.5 kg), reﬂecting the late normal descent in utero. When Scorer's study was repeated 20 years later using the same methodology, the incidence at birth and at 3 months was 3.4% and 1.4%, respectively, suggesting a negative trend in fetal testicular development during this period. This has been paralleled by a similar increase in the incidence of testicular cancer, suggesting a possible common environmental cause of testicular maldevelopment. Undescended Testes 523 The term “testicular dysgenesis syndrome” has been coined to describe a common cause for cryptorchidism, hypospadias, testicular cancer and future impaired spermatogenesis (Skakkebaek et al., 2001). Early on, exposure of mother and fetus to environmental estrogenic compounds was suspected to impair testicular function, but later many other such “endocrine disruptors” have been identiﬁed. A recent meta-analysis (Bonde et al., 2017) of publications that examine a possible link between individual endocrine disruptors and testicular dysgenesis in boys failed to show convincing evidence to prove such a relation, although animal experiments have proven that prenatal exposure to compounds such as phthalates and bisphenol A deﬁnitely can cause impaired testicular function. The authors of the meta-analysis conclude that “the current epidemiological evidence is compatible with a small increased risk of male reproductive disorders following prenatal and postnatal exposure to some persistent environmental chemicals classiﬁed as endocrine disruptors but the evidence is limited.” The possibility of a “cocktail effect” of many simultaneous exposures to endocrine disruptors is difﬁcult to study and can presently not be excluded. Mechanisms of Testicular Descent The translocation of the fetal testicles from the lower abdominal wall to their ﬁnal destination in the scrotum is lead through the inguinal canal by the gubernaculum, one end of which is anchored in the epididymal tail and the other in what is to become the bottom of the scrotum. Initially, the gubernaculum ﬁlls the canal, and through successive shortening and swelling of its intra- and extracanalicular parts it is believed to aid the testis through the canal. The precise hormonal regulation of this series of events is incompletely known. In addition to non-hormonal homeobox genes, some endocrine factors have been suggested to have a crucial role in one or several of the events leading to testicular descent. Undescended testicles are often found in boys with hypogonadotropic hypogonadism or androgen insensitivity. Thus, deﬁciency of androgenic hormones is important for the ﬁnal passage through the inguinal canal. Patients with persistent Müllerian duct syndrome due to a loss of function of anti-Müllerian hormone or its receptor also have retained testicles. Therefore, this hormone has been suggested to be a key factor for testicular descent. However, since in this syndrome the testes are closely linked to the uterus and fallopian tubes, this may in itself hinder descent. It has been found that in mice the newly described Insl3 gene is important for gubernacular development and testicular descent from its proximal abdominal position to the internal opening of the inguinal canal. No human disease has yet been ascribed to this factor. Abnormal Functions of Undescended Testicles Spermatogenesis Numerous animal experiments have proven that spermatogenesis is blocked at a pre-meiotic stage if the testes are retained in or moved into the abdomen at any time after birth. This spermatogenic arrest is reversed if the testes are transferred to the scrotum or even if they are cooled in an abdominal position with a cooling device. These experiments prove that a temperature o371C is needed to complete spermatogenesis. In man, the difference between abdominal and scrotal temperature is 21C or 31C. Germ cells, including spermatogonia and spermatocytes, seem to be the most temperature-sensitive cells, but impaired Sertoli cell function at 371C may also be of importance. On the other hand, not all undescended testicles will attain normal spermatogenesis if they are transferred to the scrotum by surgery or by hormonal treatment. As many as 40% of successfully treated men with primary bilaterally undescended testicles are reported to have grossly subnormal sperm quality (Lee, 2005). Although the treatment itself may be harmful to the testis, this suggests that a number of undescended testicles have other deﬁciencies in spermatogenesis that are unrelated to their abdominal or inguinal position. However, it is not possible to distinguish the testes with primary defects in spermatogenesis from those that will normalize when put in a scrotal position. Steroidogenesis Animal experiments have demonstrated that even if the testes are translocated to the abdomen, normal blood levels of testosterone can be maintained. However, there is a subtle difference: The Leydig cells are enlarged and have a lower sensitivity to stimulation by Lutropin (synonyms: luteinizing hormone, LH, interstitial cell-stimulating hormone) or human Chorionic Gonadotropin (hCG). It is not known whether this is due to a primary effect of temperature on the Leydig cells or if it is secondary to damage to the seminiferous tubules, causing an abnormal paracrine hormonal milieu. In man, normal testosterone levels in blood are generally seen even when the testicles are undescended. Thus, a stimulation test with hCG can be used to differentiate between bilaterally nonpalpable retained testicles and the complete absence of testes (testicular atrophy). It is important to remember that even a small testis that has a poor prognosis with regard to spermatogenesis should only be removed if the other testis is present and functioning. This small testis may mean the difference between life long testosterone replacement and no need for medication. 524 Undescended Testes Malignancies It is frequently cited that undescended testicles often develop malignancies and therefore should either be placed into the scrotum or removed. The basis for this assumption lies in the ﬁnding of an overrepresentation of undescended testicles (with or without successful treatment) in cohorts of patients with testicular cancer. Five to ten percent of men with testicular tumors have a history of undescended testes. However, the true incidence of testicular cancer in a group of men with undescended testes has not been well documented. In a Swedish retrospective study (Pinczowski et al., 1991) all 3000 boys with undescended testes from a deﬁned geographical area underwent orchidopexy. These patients, as well as 30,000 boys operated on for inguinal hernia, were searched for in the Swedish Cancer Registry when they were adults. In the previously cryptorchid cohort, four cases of testicular cancer occurred versus 0.54 expected, yielding a relative risk of 7.4 (95% conﬁdence interval, 2.0–19.0). The hernia controls had no increased risk. The most prevalent testicular cancer was seminoma, which has a good prognosis following modern treatment. Thus, the absolute risk (4/3000) does not motivate special follow-up of patients operated for cryptorchidism. However, it is recommended that an undescended testis should be brought into a palpable position so that tumor formation can be detected at an early stage, even in cases in which there is little hope of spermatogenesis. Since testosterone production might be maintained even in a small and soft testicle, it should not be removed unless the contralateral testis is normal. Treatment There is much controversy regarding the methods of treatment of undescended testicles, despite the numerous articles that have been published. The major controversies relate to the method (hormonal or surgical) and the most suitable age of treatment. Hormonal Treatment Based on the common ﬁnding of undescended testicles in boys with hypogonadotropic hypogonadism or androgen insensitivity, stimulation of the testes through administration of hCG or gonadotropic-releasing hormone (GnRH) has been advocated as the logical treatment. Direct systemic administration of testosterone has the drawback of treating the whole body as much as the testis and its surroundings and in a few trials has not been shown to be very effective. Human chorionic gonadotropin In many countries, injection of hCG for 3–5 weeks is the recommended treatment of undescended testicles. The following is a typical treatment regimen: injection of 500 IU hCG intramuscularly twice weekly for 5 weeks for boys younger than 6 years and doubling the dose for older boys. In uncontrolled studies, this treatment is reported to result in testicular descent in approximately 50% of patients; the non-responders are referred for surgery. However, meta-analyses of randomized controlled studies indicates that the success rate is only 19%, compared to 5% for placebo groups. The short-term side effects of hCG treatment include pain of injections, increased frequency of erections, and sometimes development of pubic hair. Animal experiments and some clinical observations have raised concern regarding possible long-term adverse effects of hCG on the testis. Thus, impaired spermatogenesis has been noted in dogs treated with hCG at the time of puberty. In rats, injection of hCG or LH causes an acute inﬂammatory response in the testicular interstitium, with increased intratesticular pressure, extravasation of leukocytes, and signs of edema. A similar histological picture has been reported in testicular biopsies taken within a few days after completed unsuccessful hCG treatment. Furthermore, it has been shown that the number of apoptotic spermatogonia is markedly increased following a course of hCG treatment when compared to the degree of apoptosis in biopsies taken from boys operated on without prior hCG treatment. In a small study, a positive correlation was found between the number of apoptotic spermatogonia within 1 month after treatment in childhood and the follitropin (follicle-stimulating hormone, FSH) levels as adults, approximately 20 years later. Testicular volume in adulthood was negatively correlated with the initial degree of spermatogonial apoptosis, suggesting an impaired spermatogenesis secondary to the post-hCG apoptosis (Dunkel et al., 1997). In conclusion: hCG treatment is not very effective and there are concerns about its safety. Gonadotropin-releasing hormone When this hormone became available as a therapeutic modality, several publications reported good results on undescended testicles. However, later controlled studies were unable to repeat these results, and it has been concluded that GnRH treatment is most successful in boys with retractile or high scrotal testes. If results of the professional examination during the neonatal period are available, such information is of great help for predicting whether hormonal treatment (hCG or GnRH) will be effective: only boys who had palpable testes at birth will respond to hormonal treatment. Also, success is rare if the testicle is not palpable at the time of later examination. The mechanism of action seems to be through increased release of pituitary gonadotropins that stimulate secretion of testosterone in a mode similar to hCG but with a more moderate stimulation of Leydig cell testosterone production. Thus, it can be considered similar to a mild hCG treatment. No side effects of GnRH treatment of undescended testes have been reported. Undescended Testes 525 Surgery (Orchidopexy) Open surgery is the most direct way of transferring an abdominal or inguinal testis into the scrotum. This method has been used for a very long time. The major complications are surgical: in addition to the small risk of general anesthesia, the blood supply to the testis might be damaged during surgery. A high incidence of testicular atrophy after surgical orchidopexy has been reported from departments in which “scrotal and inguinal surgery” (including orchidopexy and hernia repair) is considered to be an activity for surgeons in training. In skilled hands, this complication should be rare if the testis is not situated very high in the abdomen. Surgery has the added advantage that it provides opportunities for direct observation of the testis and, in selected cases, biopsy for microscopical investigations. Comparison Between Hormonal and Surgical Treatment The main advantages of hormonal treatment are that it is inexpensive and that hospitalization and the trauma of anesthesia and surgery are avoided (when successful). This method also provides an opportunity to test the capacity of the non-palpable testicles to produce testosterone if blood samples are taken at the end of hormone administration. The major reason for treating undescended testicles is to save future fertility. Unfortunately, there are no published studies in which patients have been randomized to surgical or hormonal treatment and followed up into adulthood. Therefore, a scientiﬁcally based conclusion regarding the advantages of the two approaches in terms of future fertility cannot be made. The possible adverse effects of hCG on future spermatogenesis and the poor efﬁcacy of hCG or GnRH argue against this as the ﬁrst-line therapy; instead, a primary surgical approach is favored, provided that a skilled surgeon is available. Age at Which Undescended Testicles Should be Treated Again, the scientiﬁc foundations for recommendations are weak. The single classical report by the Swiss pathologist Hedinger (1979) is generally referred to as an argument for early treatment. He compared sections from undescended and normally descended testicles of boys who had died suddenly. The number of spermatogonia per seminiferous tubular cross section was determined. He noted that in normally descended testicles, there was a steady decline in the number of spermatogonia from birth until one or two years of age, followed by a slow increase that continued until puberty. In the undescended testes, the initial decline was similar, but the normal increase in spermatogonia after age 2 years did not occur. The Hedinger study seems to show that undescended testes should be brought into the scrotum before the age of 2 years. It is assumed that spermatogenesis will be improved after successful treatment. Repeat follow-up biopsies have been studied in only two publications: one showed improved spermatogenesis, one did not. It is not known whether the catch-up of spermatogenesis is more complete after early rather than after later treatment. Nevertheless, treatment before age two has become the standard of treatment in many countries. If this approach is followed, initial surgery is to be preferred rather than hormonal treatment since the latter seems to be even less effective at ages younger than 4 years. Final recommendations about the most suitable age for treatment of undescended testes must await results of controlled, randomized studies of treatment at various ages. The ﬁnal outcome to be evaluated in such studies should be spermatogenesis and fertility in adulthood. This requires very long-term prospective studies. Careful measurements of testicular size during the ﬁrst years after treatment may to some extent predict spermatogenesis and should be performed in future studies. Conclusions The condition of undescended testicles is the most common inborn developmental abnormality in boys, affecting approximately 1% of the entire male population. The cause may be hormonal deﬁciencies or, in most cases, unknown. Untreated, undescended testicles always have severely impaired spermatogenesis, but testosterone production is generally acceptable. The risk of malignancy in undescended testicles is increased. If the testes are moved into the scrotum, future spermatogenesis will be improved but not to the full extent. The risk of malignancies is reduced by orchidopexy before puberty. Both the choice of treatment (hormonal or surgical) and the most appropriate age of treatment (1–4 years) are controversial. However, based on current knowledge, skilled surgery at an early age, rather than hormonal treatment, seems to be advisable. See also: Association of Endocrine Disrupting Chemicals With Male Reproductive Health 526 Undescended Testes References Bonde, J.P., Meulengracht Flachs, E., Rimborg, S., Glazer, C.H., Giwercman, A., Høst Ramlau-Hansen, C., Sørig Hougaard, K.S., Bjerre Høyer, B., Keglberg Hærvig, K., Bondo Petersen, S., Rylander, L., Olmer Specht, I., Toft, G., Vaclavik Bräuner, E., 2017. The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: A systematic review and meta-analysis. Human Reproduction Update 23, 104–125. Dunkel, L., Taskinen, S., Hovatta, O., Tilly, J.L., Wikstrom, S., 1997. Germ cell apoptosis after treatment of cryptorchidism with human chorionic gonadotropin is associated with impaired reproductive function in the adult. The Journal of Clinical Investigation 100, 2341–2346. Hedinger, C., 1979. Histological data in cryptorchidism. In: Job, J.-C. (Ed.), Cryptorchidism: Diagnosis and treatment. Pediatric and adolescent endocrinologyVol. 6. New York: Karger, pp. 3–13. Kollin, C., Granholm, T., Nordenskjöld, A., Ritzén, E.M., 2013. Growth of spontaneously descended and surgically treated testes during early childhood. Pediatrics 131, e1174–1180. Lee, P.A., 2005. Fertility after cryptorchidism: Epidemiology and other outcome studies. Urology 66, 427–431. Pinczowski, D., McLaughlin, J.K., Läckgren, G., Adami, H.O., Persson, I., 1991. Occurrence of testicular cancer in patients operated on for cryptorchidism and inguinal hernia. The Journal of Urology 146, 1291–1294. Scorer, C.G., 1956. The incidence of incomplete descent of the testicle at birth. Archives of Disease in Childhood 31, 198–202. Skakkebaek, N.E., Rajpert-De Meyts, E., Main, K.M., 2001. Testicular dysgenesis syndrome: An increasingly common developmental disorder with environmental aspects. Human Reproduction 16, 972–978. Further Reading Kolon, T.F., Herndon, C.D., Baker, L.A., Baskin, L.S., Baxter, C.G., Cheng, E.Y., Diaz, M., Lee, P.A., Seashore, C.J., Tasian, G.E., Barthold, J.S., American Urological Assocation, , 2014. Evaluation and treatment of cryptorchidism: AUA guideline. The Journal of Urology 192 (2), 337–345. Radmayr, C., Dogan, H.S., Hoebeke, P., Kocvara, R., Nijman, R., Stein, R., Undre, S., Tekgul, S., 2016. Management of undescended testes: European Association of Urology/ European Society for Pediatric Urology Guidelines. Journal of Pediatric Urology 12, 335–343. Ritzén, E.M., Bergh, A., Bjerknes, R., Christiansen, P., Cortes, D., Haugen, S.E., Jörgensen, N., Kollin, C., Lindahl, S., Läckgren, G., Main, K.M., Nordenskjöld, A., Rajpert-De Meyts, E., Söder, O., Taskinen, S., Thorsson, A., Thorup, J., Toppari, J., Virtanen, H., 2007. Nordic consensus on treatment of undescended testes. Acta Paediatrica 96, 638–643.