Vol. 40 (6): 722-729, November - December, 2014 REVIEW ARTICLE doi: 10.1590/S1677-5538.IBJU.2014.06.02 The importance of the gubernaculum in testicular migration during the human fetal period _______________________________________________ Luciano A. Favorito1, Suelen F. Costa1, Helce R. Julio-Junior1, Francisco J. B. Sampaio1 1Urogenital Research Unit, State University of Rio de Janeiro, Brazil ABSTRACT ARTICLE INFO ______________________________________________________________ ______________________ Objectives: The objective of this review is to study the role of the gubernaculum in the Key words: testicular migration process during the human fetal period. Testicular Diseases; Materials and Methods: We performed a descriptive review of the literature about the Cryptorchidism; Embryology; role of the gubernaculum in testicular migration during the human fetal period. Fetus; Testis Results: In the first phase of testicular migration, the gubernaculum enlarges to hold the testis near the groin and in the second phase the gubernaculum migrates across Int Braz J Urol. 2014; 40: 722-9 the pubic region to reach the scrotum. The proximal portion of the gubernaculum is attached to the testis and epididymis and the presence of multiple insertions in the dis- _____________________ tal gubernaculum is extremely rare. The presence of muscle and nerves in the human gubernaculum is very poor. The gubernaculum of patients with cryptorchidism has Submitted for publication: more fibrous tissue and less collagen and when the patients are submitted to hormonal June 20, 2014 _____________________ treatment, the gubernaculum components alter significantly. Conclusions: The gubernaculum presents significant structural modifications during Accepted after revision: testicular migration in human fetuses. October 31, 2014 INTRODUCTION gubernaculum’s development (1, 11). The guberna- culum seems to be the most important anatomi- Testicular migration is a complex process cal structure in the testicular migration process, of relevant importance for the comprehension by means of contraction and shortening, thus of cryptorchidism. During the human fetal pe- imposing traction strength on the testis (1). riod, the testes migrate from the abdomen to the The objective of this review is to study the scrotum, traversing the abdominal wall and the role of the gubernaculum in the process of tes- inguinal canal between the 15th and the 28th ticular migration during the human fetal period. week post-conception (WPC) (1-4). Several the- ories have been developed to explain testicular MATERIAL AND METHODS migration. The most accepted ones are: (a) the increase in the intra-abdominal pressure (5); (b) In this study we carried out a review of the development of the epididymis, spermatic the Pubmed, Embase and Scielo databases about vessels, deferent ducts and inguinal canal (6-8); the role of the gubernaculum in testicular mi- (c) the stimulus originating in the genito-femoral gration published in the past 40 years by using nerve (9); (d) the hormonal stimulus originating the key expressions “gubernaculum testis” and in the placental gonadotrophin and the testoste- “testicular migration”. We found several papers rone produced by the fetal testes (10); and (e) the in these databases and we included only papers 722 IBJU | GUBERNACULUM AND TESTICULAR MIGRATION in English and excluded case reports, editorials region to reach the scrotum. The androgens sti- and opinions of specialists. mulate growth and differentiation of the muscular part of the gubernaculum bulb, which facilitates RESULTS the movement of the gubernaculum through the inguinal region by the traction resulting from Testicular migration happens in two dis- this growth (6, 12, 15, 16). The gubernaculum has tinct phases: the first phase corresponds to the tes- its own nerve supply, the genito-femoral nerve ticular migration from the abdomen to the internal (GFN), descending on the anteromedial surface of inguinal ring, and the second phase corresponds the psoas muscle from L1-L2 segments (17). The to the transition of the testes through the inguinal second phase of testicular descent is regulated canal until their definitive arrival at the scrotum by androgens and calcitonin gene-related pepti- (1-3). In the first phase, the gubernaculum enlar- de (CGRP), released by the sensory nucleus of the ges to hold the testes near the groin, regulated by genitofemoral nerve (GFN) (10, 18). In rodents, the insulin-like 3 (INLS-3) (12, 13). INSL-3 is secreted active proliferation of the gubernacular tip and by the Leydig cells and controls gubernaculum cremaster muscle, the muscle’s rhythmic contrac- swelling via its receptor, LGR8 (leucine-rich repe- tion, and the chemotactic gradient provided by at containing G protein-coupled receptor 8, also the CGRP together result in migration of the tes- known as GREAT or relaxin receptor 2), a pro- tes into the scrotum. The importance of this me- cess resulting in thickening of the gubernaculum chanism is corroborated by experimental models because of increases in water, glycosaminoglycan where the sectioning of the genitofemoral nerve and hyaluronic acid content (11-14) (Figure-1). leads to cryptorchidism (1, 15, 18). In the second phase of testicular migra- The moment when testicular migration be- tion, the gubernaculum migrates across the pubic gins is controversial. Backhouse (2) reported that Figure 1 - Image of a male fetus aged 22 weeks post-conception with both testes situated in the abdomen. The abdominal wall was dissected to show the position of the testis (T) above the internal ring (IR). The figure shows the gubernaculum (G) and the bladder (B). 723 IBJU | GUBERNACULUM AND TESTICULAR MIGRATION this process starts at about the 24th week post-con- gubernaculum, slowly penetrating its mesenchy- ception, while Heyns (3) and Sampaio & Favorito mal substance. This invagination occurs bilate- (4) described cases where the migration process rally and is considered as the start of the vaginal started as early as the 17th week. An aspect that process. Some authors consider this phenomenon various authors report is that the passage of the to be “active”, involving the invasion of the gu- testis through the inguinal canal occurs very qui- bernaculum by mesothelial cells (19), while others ckly (2-4). Heyns (3) found only 2.6% of the testes advocate that this phenomenon is “passive” and examined in his sample located in the inguinal ca- secondary to the increase in intra-abdominal nal, while Sampaio & Favorito (4), in a sample of pressure (6, 20). 71 human fetuses, found 20.5% of the testes loca- The growth of the vaginal process divides ted there. Furthermore, 73.3% of these testes were the gubernaculum into three parts: (a) the main in fetuses with ages between 21 and 25 WPC, in- gubernaculum, which corresponds to the portion dicating that in this period the migration through covered by the visceral layer of the peritoneum of the inguinal canal intensifies. In the same study, the vaginal process; (b) the vaginal gubernaculum, all the fetuses older than 30 weeks already showd which corresponds to the portion that externally the testes in the scrotum. Other authors, however, surrounds the parietal portion of the vaginal pro- report that the testicular migration is only com- cess, and (c) the infra-vaginal gubernaculum, that pleted after the 32nd week post-conception (1-3). corresponds to the caudal region of the guberna- culum, which has not been invaded by the vaginal Gubernaculum Testis process (19-21). The gubernaculum starts to develop in the Both the gubernaculum and vaginal pro- human fetus during the sixth week of gestation, cess change in harmony during testicular migra- the same period when the germinative cells are tion. The maintenance of this undifferentiated me- arriving at the genital ridge (1, 19). senchyme along the inguinal canal and scrotum is In the eighth week of gestation, the testis essential for the downward extension of the vagi- and mesonephros are linked to the posterior ab- nal process to occur, during which it follows the domen wall by a peritoneal fold. As the mesone- pathway created by dilation of the gubernaculum, phros degenerates, the portion of this fold cranial forming the canal through which the testis will to the testis, called the diaphragmatic ligament, reach the scrotum (1, 2, 19, 21). also degenerates, turning into the cranial portion The gubernaculum is a cylindrical struc- of the gonadal mesentery. This structure is called ture, covered by a peritoneum on all sides except the caudal gonadal ligament, which gives rise to the posterior, where the testicular vessels and vas the gubernaculum testis (3, 19). deferens pass. Macroscopically, it looks like the Cranially, the gubernaculum approaches Wharton’s jelly of the umbilical cord. Histologi- the mesonephric duct, while distally it approaches cally, it is composed of undifferentiated cells with the inguinal region. At this moment, the future elongated shape, surrounded by a large quantity inguinal canal is still only a space in the mus- of extracellular material, where it is impossible to culature of the anterior abdominal wall, where identify smooth or striated muscle cells except in only mesenchyme tissue exists. In this region, the its distal end and in the peripheral portion (22). genital branch of the genitofemoral nerve crosses the abdominal wall and descends to the scrotum Proximal Gubernaculum where it will innervate the cremaster muscle, and The proximal portion of the gubernaculum