Undescended testis: A roundtable discussion based on clinical scenarios - Part 2.

Undescended testis (UDT, cryptorchidism) is the most frequent genital anomaly in boys. However, its treatment varies widely throughout the world. This second part of our roundtable discussion aims to continue to ask global experts to express their attitudes towards several case scenarios of UDT in order to explore the rationale for their clinical decisions.

Advocating hormonal treatment to prevent adult in-fertility in patients diagnosed with congenital un-descended testes.

In 2007 the Nordic group came to the following unanimous conclusions: In general, hormonal treatment is not recommended, considering the poor immediate results and the possible long-term adverse effects on spermatogenesis. Thus, surgery is to be preferred. However, defective mini puberty inducing insufficient gonadotropin secretion is one of the most common causes of nonobstructive azoospermia in men suffering from congenital isolated unilateral or bilateral cryptorchidism.

Undescended testis: A roundtable discussion based on clinical scenarios - Part 1.

Undescended testis (UDT, cryptorchidism) is the most common congenital anomaly of the genital tract. Despite its high incidence, the management of UDT varies between specialties (urology, pediatric surgery, pediatric urology, pediatric endocrinology). Therefore, as the European Association of Urology - Young Academic Urologists Pediatric Urology Working Group, we requested experts around the world to express their own personal approaches against various case scenarios of UDT in order to explore their individual reasoning.

Epigenetics, cryptorchidism, and infertility.

Background: Cryptorchid boys with defective mini-puberty and impaired differentiation of Ad spermatogonia (high infertility risk) have altered expression of several genes encoding histone methyltransferases compared to patients with intact differentiation of gonocytes into Ad spermatogonia (low infertility risk).

Results: High infertility risk cryptorchid boys display hypogonadotropic hypogonadism, which, together with the diminished expression of histone deacetylases and increased expression of HDAC8 decrotonylase, indicates altered histone marks and, thus, a perturbed histone code. Curative GnRHa treatment induces normalization of histone methyltransferase, chromatin remodeling, and histone deacetylase gene expression.

Low-dose every-second-day LHRH treatment following bilateral orchidopexy in children with bilateral cryptorchidism may improve their fertility outcome.

Introduction/background: Currently the standard treatment for bilateral cryptorchidism is bilateral surgical orchidopexy. Whether a hormonal treatment should be routinely administered postoperatively to increase fertility is debatable. Low-dose postoperative luteinizing hormone releasing hormone (LHRH) can increase spermatogonial numbers, but the effect of native LHRH (Kryptocur®) on adult fertility is unclear.

The Management of Intraabdominal Testis: A Survey of the World Federation of Associations of Pediatric Surgeons (WOFAPS) Practices.

Background And Objective: The optimal treatment protocol of intraabdominal testis is still a matter of debate and until now there are a lot of areas of controversy as regards this challenging subtype. The aim of this report is to document current practice patterns among surgeons from different continents through an online Redcap survey supervised the World Federation of the Association of Pediatric Surgeons (WOFAPS).

Methods: A 16-question-survey related to the management of intraabdominal testis was created and administered RedCap.

A novel role for CFTR interaction with LH and FGF in azoospermia and epididymal maldevelopment caused by cryptorchidism.

Cryptorchidism occurs frequently in children with cystic fibrosis. Among boys with cryptorchidism and abrogated mini-puberty, the development of the epididymis and the vas deferens is frequently impaired. This finding suggests that a common cause underlies the abnormal development of Ad spermatogonia and the epididymis.

Temperature is not a major factor in the differentiation of gonocytes into ad spermatogonia and fertility outcome in congenitally cryptorchid boys.

Spermatogenesis in mammals is a heat-sensitive developmental pathway incompatible with the typical mammalian body temperature of 37 °C. It is thought that this is the reason why the testicles of most mammalian males are outside of the body cavity, in the scrotum, where they function at approximately 33 °C. It has been suggested that the abnormally high temperature environment of cryptorchid testes may lead to impaired testicular development and adult infertility.

Gubernaculum and Epididymo-Testicular Descent: Review of the Literature.

Cryptorchidism is a common disorder in boys that has been widely studied both experimentally and clinically. The role of the gubernaculum, a mesenchymal tissue extending from the fetal testis and epididymis to the developing scrotum, is still unclear. Even the name is debated: 'gubernaculum epididymis' or 'gubernaculum testis'.

Viral infections that alter estrogen levels during pregnancy may contribute to the etiology of cryptorchidism.

Cryptorchidism is as common as type 2 diabetes or celiac disease. Boys with congenital cryptorchidism are at increased risk of infertility and testicular cancer. Zika syndrome, which affects pregnant women, is associated with a high incidence of undescended testes in the infant, accompanied by epididymal anomalies.

Molecular clues in the regulation of mini-puberty involve neuronal DNA binding transcription factor NHLH2.

Gonadotropin releasing hormone agonist (GnRHa) treatment following surgery to correct cryptorchidism restores mini-puberty via endocrinological and transcriptional effects and prevents adult infertility in most cases. Several genes are important for central hypogonadotropic hypogonadism in mammals, including many that are transcribed in both the brain and testis. However, the expression of these genes in prepubertal gonads has not been studied systematically, and little is known about the effect of hormone therapy on their testicular and neuronal expression levels.

Abnormal histology in testis from prepubertal boys with monorchidism.

Background: Little is known about the histology of contralateral descended testes in boys with unilaterally absent testis. We investigated whether absence of one testis is associated with abnormal tissue architecture of the solitary contralaterally descended testis.

Design Setting And Patients: For this retrospective study, we examined the results of biopsies of the contralateral descended testis in 43 boys with monorchidism.

Testicular expression of long non-coding RNAs is affected by curative GnRHa treatment of cryptorchidism.

Background: Cryptorchidism is a frequent endocrinopathy in boys that has been associated with an increased risk of developing testicular cancer and infertility. The condition is curable by combined surgery and hormonal treatment during early pre-pubertal stages using gonadotropin releasing hormone agonist (GnRHa). However, whether the treatment also alters the expression of testicular long non-coding RNAs (lncRNAs) is unknown.

Genes located in Y-chromosomal regions important for male fertility show altered transcript levels in cryptorchidism and respond to curative hormone treatment.

Background: Undescended (cryptorchid) testes in patients with defective mini-puberty and low testosterone levels contain gonocytes that fail to differentiate normally, which impairs the development of Ad spermatogonia and ultimately leads to adult infertility. Treatment with the gonadotropin-releasing hormone agonist GnRHa increases luteinizing hormone and testosterone and rescues fertility in the majority of pathological cryptorchid testes. Several Y-chromosomal genes in the male-specific Y region (MSY) are essential for spermatogenesis, testis development and function, and are associated with azoospermia, infertility and cryptorchidism.

Is Hormonal Treatment of Congenital Undescended Testes Justified? A Debate.

Abnormal germ cell development in cryptorchidism is not a result of a congenital dysgenesis but is preceded by a hormone imbalance and perturbation in germ cell-specific gene expression during abrogated mini-puberty. Adequate treatment with low doses of GnRHa enables 86% of men to achieve a normal sperm count and, most importantly, prevent development of azoospermia. GnRHa treatment induces a significant transcriptional response, including protein coding genes involved in pituitary development, the hypothalamic-pituitary-gonadal axis, and testosterone synthesis.

Histone Methyltransferase mRNA Levels Increase in Response to Curative Hormone Treatment for Cryptorchidism-Dependent Male Infertility.

There is a correlation between cryptorchidism and an increased risk of testicular cancer and infertility. During orchidopexy, testicular biopsies are performed to confirm the presence of type A dark (Ad) spermatogonia, which are a marker for low infertility risk (LIR). The Ad spermatogonia are absent in high infertility risk (HIR) patients, who are treated with a gonadotropin-releasing hormone agonist (GnRHa) to significantly lower the risk of infertility.

Gonadotropin-Releasing Hormone Agonist Corrects Defective Mini-Puberty in Boys with Cryptorchidism: A Prospective Randomized Study.

Introduction: This prospective study investigated the efficacy of a gonadotropin-releasing hormone agonist (LH-RHa) in restoring defective mini-puberty.

Materials And Methods: Boys with isolated bilateral cryptorchidism and defective mini-puberty were randomly divided into two groups. The "surgery only" group underwent a second orchidopexy without hormonal treatment (control).

Histopathology of Unilateral Cryptorchidism.

Defective mini-puberty inducing insufficient gonadotropin secretion is one of the most common causes of nonobstructive azoospermia in men suffering from congenital isolated unilateral or bilateral cryptorchidism. The aim of our study was to determine the risk for azoospermia by histologic criteria in a cohort of unilateral cryptorchid boys undergoing orchidopexy and bilateral testicular biopsy. We performed a retrospective analysis of data available in the library of the Cryptorchidism Research Institute, Liestal, Switzerland.

Curative GnRHa treatment has an unexpected repressive effect on Sertoli cell specific genes.

Background: Follicle stimulating hormone and testosterone stimulate Sertoli cells to support germ cell function and differentiation. During mini-puberty, when gonadotropin (GnRH) stimulates increases in plasma luteinizing hormone (LH) and testosterone levels, gonocytes are transformed into Ad spermatogonia. In cryptorchidism, impaired gonadotropin secretion during mini-puberty results in insufficient LH and testosterone secretion, impaired gonocyte transition to Ad spermatogonia, and perturbed Sertoli cell proliferation.

On the descent of the epididymo-testicular unit, cryptorchidism, and prevention of infertility.

This comprehensive review provides in-depth coverage of progress made in understanding the molecular mechanisms underlying cryptorchidism, a frequent pathology first described in about 1786 by John Hunter. The first part focuses on the physiology, embryology, and histology of epididymo-testicular descent. In the last 20 years epididymo-testicular descent has become the victim of schematic drawings with an unjustified rejection of valid histological data.