Undescended testis: The underlying mechanisms and the effects on germ cells that cause infertility and cancer

doi:10.1016/j.jpedsurg.2013.02.001

Journal of Pediatric Surgery

Volume 48, Issue 5, May 2013, Pages 903-908

https://doi.org/10.1016/j.jpedsurg.2013.02.001 Get rights and content

Abstract

Testicular descent is a complex morphological process that occurs in at least 2 stages, with different hormonal control. Insl3 controls the first step of gubernacular enlargement, although the abnormality long gubernacular cord in persistent Műllerian duct syndrome remains unexplained. Androgens control inguinoscrotal migration, which may be triggered by local signalling from the mammary line, and which requires the genitofemoral nerve. However, there is still much to learn about this phase, which when abnormal frequently leads to cryptorchidism. Orchidopexy is being recommended in the first year of age, because increasing research suggests that the stem cells for spermatogenesis form between 3 and 9 months, with surgery aiming to permit this normally, although this is not yet proven. Acquired cryptorchidism is now becoming accepted and is likely to be caused by inadequate elongation of the postnatal spermatic cord. It is not yet known whether orchidopexy is always needed, as this remains controversial.

Section snippets

The stages of testicular descent

At the onset of sexual development at about 7–8 weeks in a human, the ambisexual gonad is on the front of the urogenital ridge. As the mesonephros regresses posterior to the gonad, this leaves it on a mesentery, the so-called mesorchium or mesovarium. The onset of testicular development with production of hormones triggers regression of the Műllerian duct by Műllerian inhibiting substance or anti-Műllerian hormone (MIS/AMH), while the testosterone diffuses down the Wolffian duct and triggers

Evolution of testicular descent and the role of the mammary line

What triggers the genito-inguinal ligament to suddenly become motile and elongate out of the abdominal wall? Further, what controls the elongation process and what regulates the direction of migration? A search for the answers to these questions has taken us on an astounding journey, which begins in early vertebrate evolution [19].

Two hundred million years ago marsupials and early mammals diverged from other vertebrates, but kept two anatomical features in common: breasts and testes descended

The role of the GFN and CGRP

Lewis (1948) [29] first showed that the GFN was important for inguinoscrotal migration in rodents, as cutting the nerve at birth stopped migration. We have spent a lot of effort studying the GFN and the neurotransmitter we eventually localised in its sensory fibres, calcitonin gene-related peptide (CGRP), as described in previous reviews [19], [30]. Here I will just highlight some key features. The rat gubernaculum contains CGRP receptors and contracts rhythmically like cardiac muscle in

Cryptorchidism

The aetiology of cryptorchidism has been discussed in many recent reviews, so I won't reiterate all the evidence and controversy [10]. Most reviews focus on hormonal deficiency, but I think it is still quite likely that somewhere in the complex remodelling of the gubernaculum and its migration to the scrotum are many more possible causes of cryptorchidism.

A more topical issue is determining the time to operate on undescended testes. In the 1950's surgery was done in 10–15 year olds as pediatric

Normal germ cell development and the time for orchidopexy

The neonatal gonocyte moves from the centre of the cord to reach the basement membrane and transforms into an adult dark spermatogonium around 6/12 (and this step is inhibited in UDT) [40]. Some adult dark spermatogonia (AD-S) remain as the putative stem cells for later spermatogenesis, and some continue developing into type B spermatogonia (B-S) and then into primary spermatocytes (PS), which appear in the tubule about 3–4 years of age. Not all gonocytes transform into AD-S, suggesting a

Acquired cryptorchidism

This variant has been gradually accepted over the last 20 years, following the realisation that postnatally the spermatic cord must double its length between birth and puberty. Acquired UDT occurs when this elongation fails, so that the initially descended testis gets left behind as the scrotum moves further from the groin as the boy enlarges. We have previously suggested that this is secondary to a fibrous remnant of the processus vaginalis [44], which links acquired UDT to hydrocele and

Conclusions

Testicular descent is a very complex process, and we are still a long way from a full understanding of the normal process, let alone the causes of cryptorchidism, despite recent progress. However, it is becoming clearer that the prognosis and timing of surgery depend on understanding germ cell development, which will be an area of active research in the next few years.

On the knowledge we currently have, we can say that congenital UDT probably needs surgery in the first year (perhaps 3–9 months),

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Cited by (53)

Testicular blood supply and growth in children with high cryptorchidism treated with gubernaculum preserving vs. cutting laparoscopic orchiopexy: A pilot trial
2021, Journal of Pediatric Urology
Citation Excerpt :
Cryptorchidism is a common urinary system disease in children that may cause declined semen quality and a higher risk of testicular germ cell tumor [1–4,16]. Hutson et al. [17,18] studied the regulation process of testicular descent, the potential mechanism of testicular descent to cause infertility and tumor, and its impact on germ cells through animal experiments. Hormone therapy is the conventional treatment for patients under 1 year of age, and patients failing to respond to hormone therapy and over 1 year of age should receive surgical treatment as early as possible [3,4,19], with the purpose to not only restore the testis to its normal anatomical position but also enable the testis to grow and function properly.
It is still controversial whether the frenum of testis should be retained in laparoscopic testicular fixation.
It is a prospective experiment to study testicular preservation on testicular growth in children with high cryptorchidism.
From January 2018 to June 2020, 120 children with high cryptorchidism in Inner Mongolia Maternal and Child Health Care Hospital and The Fourth Hospital of Baotou were randomly divided into retention group (60 cases in group P, aged 1–3 years, average 1.85 ± 0.58) and cutting group (60 cases in group C, aged 1–3 years, average 1.75 ± 0.66) (P = 0.52). PSV, EDV, RI and testicular volume were measured by color Doppler ultrasound before operation and 1,3,6,12 months after operation. No, there was significant difference between the two groups (P > 0.05).
There is no significant difference in testicular blood supply and growth between laparoscopic testicular fixation and frenulum amputation in children with high cryptorchidism.
Guideline implementation for the treatment of undescended testes: Still room for improvement
2018, Journal of Pediatric Surgery
Citation Excerpt :
The loss of time after referral until surgery was in median 39 days (range: 5–1114) in the congenital cases and 38 days (range: 10–3215) in the acquired cases (Fig. 4C). The underlying reasons for the recommendation of early surgical therapy in congenital UDT are the estimated higher risk for testicular cancer in UDT [12] and the possible histomorphological changes of the testicular architecture with negative effects on semen quality in adulthood [13] and the reduced paternity rates in bilateral cases [14,15]. In order to guarantee a timely therapy if needed, in Germany the testicular position is documented in the pediatric screening examinations.
Early orchidopexy (OP) around the age of 1 year is recommended in boys with congenital undescended testis (UDT) worldwide since decades. Former retrospectives studies did not distinguish congenital from acquired UDT with a consecutive negative bias concerning the age at surgery.
In a retrospective analysis, data of all boys who underwent OP in eight pediatric surgery institutions from 2009 to 2015 were analyzed. Congenital or acquired UDT were differentiated. Patients were categorized into 3 groups of age at surgery: (1) < 12 months, (2) 12–24 months, (3) > 24 months. Data of one institution were analyzed in detail: exact age of first referral, exact age at surgery, intraoperative findings.
Out of 4448 boys, 3270 boys had congenital UDT. In 81% (2656 cases) surgery was performed beyond the age of 1 year, in 54.4% (1780) beyond the age of 2 years. chi-Square statistics showed a higher rate of early operations in hospitals compared to outpatient services and in Germany compared to Switzerland. In 694 congenital detailed cases, median age at referral was 13 months [range 0–196], median age at surgery was 15 months [range 0–202].
Delayed referral is the main reason for guideline non-conform delayed surgery in UDT.
Clinical Research paper.
Level III: Treatment Study.
INSL3 and AMH in patients with previously congenital or acquired undescended testes
2017, Journal of Pediatric Surgery
In previous reports no differences in Leydig and Sertoli cell function were found between congenital undescended testis (CUDT) and acquired UDT (AUDT) on the basis of serum levels of LH, testosterone, FSH or inhibin B. This study tried to detect differences in Leydig and Sertoli cell function between CUDT and AUDT using insulin-like peptide 3 (INSL3) and anti-Müllerian hormone (AMH).
118 men with a history of UDT (CUDT N = 55 (6/55 bilateral), AUDT N = 63 (15/63 bilateral)) were investigated. Differences between CUDT and AUDT, influence of age at surgery in CUDT, and effect of spontaneous descent or orchiopexy in AUDT were evaluated.
For INSL3, no significant differences were found. AMH levels in bilateral CUDT were significantly lower compared with bilateral AUDT (6.4 (1.7–11.4) vs 13.2 (6.1–30.1) μg/l, p = 0.02). AMH levels in unilateral CUDT were significantly higher than in bilateral CUDT (12.1 (2.4–43.7) vs. 6.4 (1.7–11.4) μg/l, p = 0.02).
No differences in Leydig cell function on the basis of INSL3 levels between the different UDT groups were found. Sertoli cell function evaluated by AMH, was more negatively affected in bilateral CUDT in comparison with bilateral AUDT and unilateral CUDT.
Level III Treatment Study.
A rare case of male pseudohermaphroditism-persistent mullerian duct syndrome with transverse testicular ectopia – Case report and review of literature
2017, International Journal of Surgery Case Reports
Citation Excerpt :
PMDS is characterized by the persistence of these structures in their primitive form in male children. PMDS is caused by defects in the gene that encodes the synthesis or action of Mullerian inhibiting Factor or Antimullerian hormone [4–8]. AMH is secreted by the sertoli cells of the developing testes by 7 weeks of gestation.
Persistent Mullerian duct syndrome (PMDS) is a rare type of male pseudohermaphroditism. Transverse testicular ectopia (TTE) is characterized by one testis moving to the opposite side and both testes traversing the same inguinal canal.
An 11-month-old boy presented with bilateral cryptorchidism. The left testis was not palpable; the right testis was canalicular with a right inguinal hernia. Ultrasound showed both testes located in the right inguinal canal. Right inguinal exploration revealed two testes with intact spermatic cords. A primitive uterus with fallopian tubes was also identified on opening the processus vaginalis. After herniotomy, bilateral orchidopexy was carried out (left orchidopexy through a trans-septal approach). Karyotyping confirmed a male gender (46XY). One year after the operation, ultrasound showed both testes to be in good condition.
PMDS is caused by defects in the gene that encodes Antimullerian hormone(AMH). Treatment aims to correct cryptorchidism and ensure appropriate scrotal placement of the testes. Malignant transformation is as likely as the presence of abdominal testes in an otherwise normal man. Failing early surgical correction, gonadectomy must be offered to prevent malignancy. Division of the persistent mullerian duct structures is indicated only in patients where persistence interferes with orchidopexy.
TTE should be suspected in patients presenting with inguinal hernia on one side and cryptorchidism on the other side. Herniotomy and bilateral orchidopexy is optimal. Removal of mullerian structures may injure the artery to vas deferens and is hence not recommended. Follow-up for fertility assessment in the latter years should be counselled.
Testicular atrophy following paediatric primary orchidopexy: A prospective study
2016, Journal of Pediatric Urology
Citation Excerpt :
The current consensus is for orchidopexy to be performed between 6 and 12 months of age, as outlined in the British Association of Paediatric Urologists and the Nordic consensus statement on the treatment of undescended testes [1,2]. The evidence in the literature supports performing orchidopexy at a younger age, in order to facilitate gonocyte maturation and, thereby, improve fertility [3]. Some have expressed concern regarding the potential for increased risk of damage to the testis and its surrounding structures with the younger proposed age of orchidopexy [4].
With the Nordic consensus statement advocating orchidopexy at an earlier age, the present study sought to investigate the outcomes of primary paediatric orchidopexy at a tertiary UK centre.
To prospectively assess testicular atrophy following primary orchidopexy for undescended testes in a paediatric population. Secondary outcomes were complication rates and whether outcomes were dependent on grade of operating surgeon.
Prospective data regarding age at operation, classification of the undescended testis, length of follow-up, and subjective comparison of intraoperative and postoperative testicular volumes compared with the contralateral testis were collected. Testicular atrophy was defined as >50% loss of testicular volume or a postoperative testicular volume <25% of the volume of the contralateral testis. Patients were excluded for incomplete data and follow-up <6 months.
Data for 234 patients were analysed. Testicular atrophy occurred in 2.6% of cases. There was no reported testicular re-ascent. All secondary acquired cases underwent a previous ipsilateral hernia repair. There was no significant difference in outcomes comparing the grade of surgeon (consultant n = 8, trainee/staff-grade surgeon n = 7–8). There was a trend towards postoperative catch-up growth in approximately one fifth of cases.
Previous studies have reported a testicular atrophy rate of 5%. The present study reported a similar rate of 2.6%. In agreement with a previous publication, it was also found that testicular atrophy was not dependent on the grade of operating surgeon. The mechanism for testicular catch-up growth is not well understood. Animal studies have supported the hypothesis that increased temperature has a detrimental effect on testicular volume. However, follow-up in the present cohort was short (median 6.9 months), making interpretation of this finding difficult.
It is acknowledged that clinical palpation alone to determine testicular volume potentially introduces intra-observer and inter-observer error. However, prospective studies using ultrasound to determine testicular volumes following orchidopexy have reported catch-up growth.
This study represented one of the larger collections of prospective assessments of outcomes following primary orchidopexy. It was acknowledged that subjectively assessing testicular volume is not ideal; however, the data correlated with similar studies.
Laparoscopic treatment of nonpalpable testicle. Factors predictive for diminished size
2016, Journal of Pediatric Surgery
The purposes of this study were to demonstrate the usefulness of laparoscopy in intraabdominal testicle (IAT) and to determine factors associated with diminished size during the final outcome after laparoscopic orchidopexy.
This is a retrospective analysis of consecutive patients from 1999 to 2013 with a minimum follow-up of 1 year. Patient and testicular factors were related to diminished size.
Sixty one patients, and 92 testicles were included. Median age at operation was 42 months. Initially we found 66 normal sized testes (71.7%), 22 hypotrophic (23.9%) and four atrophic (4.3%). Eighty seven testes were brought down laparoscopically, 50 in one surgical stage and 37 in two stages. Mean follow-up was 40.2 months and the final outcome was success: 73.5% and diminished size: 26.5%. Variables associated with diminished size were hypotrophy during initial evaluation, short spermatic vessels, section of spermatic vessels, two-stage surgery and tension to reach contralateral inguinal ring. Multivariate analysis showed that initial hypotrophy (odds ratio [OR] 4.96, confidence interval 95% [CI] 1.36–18.10) and tension to reach contralateral ring (OR 4.11, 95% CI 1.18–14.34) were associated with diminished size.
Laparoscopy is useful in treating IAT. Initial size and tension to reach contralateral ring are factors associated with diminished size.

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Journal of Pediatric Surgery-Sponsored Fred McLoed LectureUndescended testis: The underlying mechanisms and the effects on germ cells that cause infertility and cancer

Abstract

Section snippets

The stages of testicular descent

Evolution of testicular descent and the role of the mammary line

The role of the GFN and CGRP

Cryptorchidism

Normal germ cell development and the time for orchidopexy

Acquired cryptorchidism

Conclusions

Lancet

J Biol Chem

J Pediatr Surg

J Pediatr Surg

Semin Pediatr Surg

J Pediatr Surg

J Pediatr Surg

J Pediatr Surg

J Pediatr Surg

J Urol

J Pediatr Surg

J Pediatr Surg

J Pediatr Surg

J Urol

J Urol

J Urol

J Urol

J Pediatr Surg

J Pediatr Surg

The history of ideas about testicular descent

Pediatr Surg Int

Cryptorchidism in common eutherian mammals

Reproduction

The molecular basis of cryptorchidism

Mol Hum Reprod

Human testicular insulin-like factor 3: in relation to development, reproductive hormones and andrological disorders

Int J Androl

Journal of Pediatric Surgery-Sponsored Fred McLoed Lecture
Undescended testis: The underlying mechanisms and the effects on germ cells that cause infertility and cancer