Pediatr Surg Int DOI 10.1007/s00383-015-3714-z

LETTER TO THE EDITOR

Re: Regulation of testicular descent F. Hadziselimovic1

Accepted: 20 April 2015 Ó Springer-Verlag Berlin Heidelberg 2015

Introduction A recent review on the regulation of testicular descent by Hutson and coauthors published in this journal [1] ignored that the epididymis descends into the scrotum together with the testis. However, epididymal, not testicular, descent is the typical strategy of recently evolved mammalian species [2]. The main reason for descent is that the epididymis has to be localized in the scrotal position to enable superfluity of ejaculations within a short time period [2].

No Wolffian duct—no descent In cryptorchid boys, the height of the epithelium, muscular wall, and lumen of the undescended epididymis were reduced at every age studied [3]. In addition, retarded growth of the undescended epididymis was observed during the entire prepubertal period [3] and non-fusion anomalies of the epididymis are typical findings in cryptorchid boys [4– 7]. The highest incidence of severe epididymal developmental delay was observed in bilateral high positioned testes. Only complete non-fusion of the epididymis seems to reliably interfere with epididymo-testicular descent [6]. An identical finding was also observed in August-Copenhagen-

Irish rats having a congenital defect that frequently causes arrested development of a single ipsilateral Wolffian duct [8]. If the Wolffian duct fails to form in its early developmental stage, the testis does notdescend [8] (Fig. 1).

Androgens and fibroblast growth factor receptor 1 (FGFR1) The primary factors regulating epididymal development and function are androgens. However, there is now a large body of evidence suggesting that growth factors play important roles in the regulation and maintenance of the epididymis. Fibroblast growth factor signaling is involved in the development and normal functioning of male reproductive organs, such as the testis and epididymis [9]. At later stages of embryonic development, the undifferentiated mesenchyme is a specific domain for FGFR1 expression [10]. Mutations of the FGFR1 gene have been described in cases of idiopathic hypogonadotropic hypogonadism with a functioning olfactory bulb and normal sense of smell and cryptorchidism [11, 12]. In 2010, we reported that the undescended testis in unilateral cryptorchid boys has impaired expression of FGFR1 when compared with its descended partner [13]. This indicated that FGFR1 is involved in the process of epididymo-testicular descent.

This comment refers to the article available at doi:10.1007/s00383-015-3673-4. An author’s reply to this comment is available at doi:10.1007/s00383-015-3715-y. & F. Hadziselimovic [email protected] 1

Institute for Cryptorchidism Research, Kindermedizinisches Zentrum, Bahnhofplatz 11, 4410 Liestal, Switzerland

Role of the gubernaculum: the proximal part is not important for descent; while, the ‘‘distal’’ part is scrotal component The schematic synopsis of testicular descent by Bartezko and Jakob implied that a gubernaculum in a 120-mm crown–rump length (CRL) fetus actively glides over both

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Pediatr Surg Int

Fig. 1 Sagittal plane of the newborn August-Copenhagen-Irish rat (ACI) with agenesis of the Wolffian duct show testis localized in an undescended high intra-abdominal position. c In contrast, newborn ACI rats with epididymis have epididymo-testicular union localized

ducts to form direct contact to the testis [14]. Investigations of serial sagittal sections made during the process of descent show that the gubernaculum is always attached proximally to the epididymis and never to the testis [15] (Figs. 2, 3). Therefore, the name gubernaculum testis is misleading. Since the gubernaculum inserts into the epididymis and not the testis, the gubernaculum testis should be called the gubernaculum epididymis [7, 15]. In 1984, Frey and Rajfer [16] reported that the distal gubernaculum is an absolute prerequisite for testicular descent, and they attempted to prove this by dissecting this part of the gubernaculum, as done by Bergh et al. [17]. This structure represents inguinal cone known to be a part of scrotum since its description by Klaatsch [18] in 1890. If the scrotum is stunted in its development, then the descent cannot take place. This experiment does not explain idiopathic congenital cryptorchidism where the scrotum is developed despite crypto-epididymis. If the proximal gubernaculum is transected, epididymo-testicular descent is completed [17]. It is the tail of the developing epididymis, and not gubernaculum elongation, which enlarges and carries the testis towards the developing scrotum in the process of ‘‘inguinal’’-scrotal descent (Fig. 1).

Mu¨llerian inhibiting substance (MIS) and insulinlike factor 3 (INSL3) Male LH receptor knockout mice exhibited bilateral cryptorchidism, which was corrected by testosterone replacement therapy (TRT). The TRT reversed all the

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at ventral abdominal wall. The epididymis is carrying the testis (T) while the tail of the epididymis is preceding the testis. d Figure is from Ref. [8] with permission

Fig. 2 Epididymo-testicular descent in the mouse. The course of descent is S-shaped from dorsal-superior to ventral-inferior. The gubernaculum epididymis (arrow) never inserts directly in the testis and there is no extra-abdominal swelling of the gubernaculum. The ‘‘bulb’’ is a part of the scrotum inverted into the abdominal cavity and is swollen at the 19th embryonic day, everting completely at postnatal day 1, while the gubernaculum is now a small thread. The urogenital anlage (U), Wolffian duct (W), testis (T) and mesonephros (M) are indicated. Testicular enlargement starts postnatal, after epididymal enlargement. Figure is from Ref. [24] with permission. Magnification 911.5

Pediatr Surg Int

Fig. 3 Sagittal serial histological sections of the gubernaculum in a fetus of 125 mm CRL. From distal (left above) to proximal (right down). The gubernaculum (G) is a thick cord composed of loose mesenchymal tissue with irregularly arrayed thin fibers. At its proximal end, (AG) the gubernaculum is connected to the tail of the epididymis (TE, arrow). Short testicular ligament (TL) is connecting

the tail of the epididymis to the testis (T). Noticeably, there is no active gliding and insertion of the gubernaculum from the epididymis into the testis, as suggested by Barteczko and Jakob [20]. Deep inguinal ring and processus vaginalis (asterisk), transversus muscle fascia (T, arrow), internal oblique muscle fascia (IO), external oblique muscle fascia (EO), body of the epididymis (BE), deferent duct (VD)

morphological and gene expression changes except INSL3, suggesting that testosterone, not INSL3 facilitates the completion of testicular descent [19]. Nef and Parada considered the development of the epididymis to be normal in INSL3-deficient mice, with no influence on descent [20]. We could not confirm this observation; on the contrary, we found absent smooth musculature around the epididymal duct of INSL3 mutant mice [21]. This developmental malformation of the epididymis resulted in a high intraabdominal undescended position [21]. Our results, therefore, support the importance of an intact epididymis for descent of the epididymo-testicular unit. Emmen et al. [22] found that Insl3 is not essential for growth of the Wolffian duct and MIS has no influence on gubernaculum growth. Moreover, in 2014 Hutson [23] acknowledged that MIS has no obvious effect on testicular descent in mice.

2. Bedford M (1978) Anatomical evidence for epididymis as a prime mover in the evolution of the scrotum. Am J Anat 152:483–486 3. De Miguel MP et al (2001) Epididymal growth and differentiation are altered in human cryptorchidism. J Androl 22(2):212–225 4. Michelson L (1949) Congenital anomalies of the ductus deferens and epididymis. J Urol 61:384–390 5. Va´zquez Medrano A et al (1993) Complete separation between epididymis and testis associated with cryptorchism. Presentation of a case and review of the literature. Arch Esp Urol 46(6):479–480 6. Rachmani E et al (2012) Complete testis-epididymis fusion anomaly: a typical association with cryptorchid testis. Urol Int 89(3):355–357 7. Caterino S et al (2014) Epididymal-testicular fusion anomalies in cryptorchidism are associated with proximal location of the undescended testis and with a widely patent processus vaginalis. J Anat 225(4):473–478 8. Hadziselimovic F (1984) Mechanism of testicular descent. Urol Res 12(3):155–157 9. Denise R et al (2009) Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. Genesis 47(1):40–48. doi:10.1002/dvg.20453 10. Basilico C, Moscatelli D (1992) The FGF family of growth factors and oncogenes. Adv Cancer Res 59:115–165

References 1. Hutson JM et al (2015) Regulation of testicular descent. Pediatr Surg Int. doi:10.1007/-015-3673-4

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Pediatr Surg Int 11. Dode´ C et al (2003) Loss-of function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 33:463–465 12. Pitteloud N et al (2006) Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci USA 103:6281–6286 13. Hadziselimovic NO et al (2010) Decreased expression of FGFR1, SOS1, RAF1 genes in cryptorchidism. Urol Int 84(3):353–361 14. Barteczko KJ, Jacob MI (2000) The testicular descent in human. Origin, development and fate of the gubernaculum Hunteri, processus vaginalis peritonei, and gonadal ligaments. Adv Anat Embryol Cell Biol 156:1–98 15. Hadziselimovic F, Herzog B (1993) The development and descent of the epididymis. Eur J Pediatr 152(Suppl 2):S6–S9 16. Frey HL, Rajfer J (1984) Role of the gubernaculum and intraabdominal pressure in the process of testicular descent. J Urol 131:574–579 17. Bergh A, Helander HF, Wahlqvist L (1978) Studies on factors governing testicular descent in the rat—particularly the role of gubernaculum testis. Inter J Androl 1:342–356

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¨ ber den Descensus testiculorum. Mor18. Klaatsch H (1890) U phologisches Jahrbuch 16:587–646 19. Yuan FP et al (2006) Cryptorchidism in LhrKO animals and the effect of testosterone-replacement therapy. Hum Reprod 21:936–942 20. Nef S, Parada LF (1999) Cryptorchidism in mice mutant for Insl3. Nat Genet 22:295–299 21. Hadziselimovic F, Adham I (2007) Insulin 3-like hormone and its role in epididymo-testicular descent. Int Braz J Urol 33:407–411 22. Emmen JM et al (2000) Hormonal control of gubernaculum development during testis descent: gubernaculum outgrowth in vitro requires both insulin-like factor and androgen. Endocrinology 141(12):4720–4727 23. Hutson J (2014) Reply to the Editor. J Pediatr Surg 49(7):1188 24. Hadziselimovic F (ed) (1983) Cryptorchidism management and implications. Springer, Berlin

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