Anogenital distance in a cohort of 169 infant boys with uni- or bilateral cryptorchidism including 18 boys with vanishing testes.

STUDY QUESTION: Do different boys with different types of cryptorchidism exhibit different anogenital distances (AGDs)? SUMMARY ANSWER: Length of AGD seemed to differ in different groups of patients with cryptorchidism. WHAT IS KNOWN ALREADY: AGD, which is used as an indicator of prenatal androgen action, tends to be shorter in boys with cryptorchidism compared to unaffected boys. Shorter AGDs have also been reported in boys with hypospadias, in men with poor semen quality, and in men with testicular cancer. STUDY DESIGN, SIZE, DURATION: A prospective descriptive cohort study was performed using data from consecutively selected boys with cryptorchidism (n = 169) operated in a single center over a period of 3 years (September 2019 to October 2022). PARTICIPANTS/MATERIALS, SETTING, METHODS: AGD was measured in 169 infant boys, at 3 to 26 months of age, during anesthesia with a vernier caliper measuring the distance from the anus to the base of the scrotum (AGDAS) and from the anus to the anterior base of the penis (AGDAP) in two body positions according to the methods by 'The Infant Development and the Environment Study' (TIDES) and 'Cambridge Baby Growth Study', resulting in four mean values per patient (TIDES AGDAS/AP and Cambridge AGDAS/AP). Normal values for AGD by age were set by our hospital Department of Growth and Reproduction based on a large cohort of healthy infant boys (n = 1940). Testicular biopsies were performed at orchidopexy as a clinical routine. The germ cell number (G/T) and type Ad spermatogonia number (AdS/T) per cross-sectional tubule of at least 100 and 250 tubules, respectively were measured and related to normal samples. Blood samples were obtained by venipuncture for measuring serum LH, FSH, and inhibin B. They were analyzed in our hospital Department of Growth and Reproduction where the normal reference was also established. Correlations between the four mean AGD measurements for each boy were evaluated by Spearman rank correlation analyses. The AGD measurement of every boy was transferred to the multiple of the median (MoM) of the normal AGD for age and named MoM AGD. MAIN RESULTS AND THE ROLE OF CHANCE: There were 104 boysoperated for unilateral, and 47 boys operated for bilateral, undescended testes, whereas 18 boys had vanished testis including one boy with bilateral vanished testes. Only 6% of cases with vanished testes had a MoM AGD higher than the normal median compared to 32% with undescended testes (P < 0.05). MoM AGD increased with the age at surgery for boys with vanished testis (Spearman r = 0.44), but not for boys with undescended testes (Spearman r = 0.14). Boys with bilateral cryptorchidism had longer AGDs and more often had hypogonadotropic hypogonadism than boys with unilateral cryptorchidism (P < 0.005) and (P < 0.000001). LIMITATIONS, REASONS FOR CAUTION: Although being the largest published material of AGD measurements of infant boys with cryptorchidism, one limitation of this study covers the quite small number of patients in the different groups, which may decrease the statistical power. Another limitation involves the sparse normal reference material on G/T and AdS/T. Finally, there are currently no longitudinal studies evaluating AGD from birth to adulthood and evaluating childhood AGD in relation to fertility outcome. Our study is hypothesis generating and therefore the interpretation of the results should be regarded as exploratory rather than reaching definite conclusions. WIDER IMPLICATIONS OF THE FINDINGS: The study findings are in agreement with literature as the total included group of boys with cryptorchidism exhibited shorter than normal AGDs. However, new insights were demonstrated. Boys with vanished testis had shorter AGDs compared to unaffected boys and to boys with undescended testes. This finding challenges the current concept of AGD being determined in 'the masculinization programming window' in Week 8 to 14 of gestation. Furthermore, boys with bilateral cryptorchidism had longer AGDs and more often had hypogonadotropic hypogonadism than boys with unilateral cryptorchidism, suggesting that the lack of fetal androgen in hypogonadotropic hypogonadism is not that significant. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used and no competing interests are declared. TRIAL REGISTRATION NUMBER: The trial was not registered in an ICMJE-recognized trial registry.

The Inhibin-B Level at Orchidopexy and Follow-up of 280 Boys With Non-syndromic Unilateral Cryptorchid Testes.

PURPOSE: An impaired germ cell number per tubular cross-section (G/T) at orchidopexy indicates a high risk of infertility. A recent study in boys with bilateral cryptorchidism showed a very high predictive value for a low serum inhibin-B level, indicating bilateral impaired G/T. Several other studies have shown a fairly strong correlation between inhibin-B and G/T. We aimed to evaluate if inhibin-B levels at orchidopexy improved at follow-up in boys with unilateral cryptorchidism. METHODS: We included 280 boys with unilateral non-syndromic cryptorchidism at the median age of 1 year (4 months-9 years) who underwent orchidopexy. They were evaluated for serum FSH, LH and inhibin-B levels at surgery and at follow-up (median 16 months later), including multiple of the median (MoM) estimations of inhibin-B due to the age dependency of normal levels. RESULTS: The inhibin-B MoM score improved significantly at follow-up. At orchidopexy, 59 (21%) boys had inhibin-B levels below the normal 2.5-percentile indicating impaired G/T bilaterally. At follow-up, 36% of the boys still had low inhibin-B. At orchidopexy, 221 (79%) boys had inhibin-B levels above normal 2.5-percentile and only 5% had low inhibin-B levels at follow-up. The risk of low inhibin-B levels at follow-up was significantly different between the two groups (p < 0.0001). At follow-up, totally, 32 (11%) boys had low inhibin-B levels, hereof only 3 patients with increased FSH. CONCLUSIONS: Orchidopexy benefits the fertility potential. About 10% of boys with unilateral non-syndromic cryptorchidism may have a bilateral testicular disease reducing their fertility potential. Insufficient gonadotropin stimulation may possibly be the cause.

The fate of germ cells in cryptorchid testis.

Cryptorchidism in males constitutes a notable risk factor for both infertility and testicular cancer. Infertility in adulthood is closely linked to the germ cell status in childhood. Furthermore, the significance of germ cell status is important as more than 95% of all reported testicular malignancies are germ cell tumors. The review aims to elucidate the pathogenesis of germ cells in cryptorchid testes concerning their association with infertility and testicular malignancies. Impaired germ cell numbers are evident in cryptorchid testes even during antenatal and neonatal stages. In cryptorchidism there is a rapid decline in germ cell number within the first year of life, partially attributed to physiologic gonocyte apoptosis. Additionally, germ cells fail to differentiate normally during mini-puberty leading to reduced germ cell proliferation and delayed clearance of gonocytes from the seminiferous epithelium. Absence of germ cells in testicular biopsies occurs already 10 months of age and germ cell deterioration progressively worsens with approximately 50% of persisting cryptorchid testes lacking germ cells during puberty. The deficient germ cell maturation and proliferation leads to later infertility. Elevated temperature in the cryptorchid testes and also hormonal deficiency contribute to this phenomenon. Germ cell neoplasia in situ (GCNIS) originating during fetal development may manifest in rare cases associated with disorders of sexual development, chromosomal abnormalities in boys, specific syndromes, and teratomas that include cryptorchidism. In adults, the presence of GCNIS predominantly represents a new histology pattern before invasive germ cell cancer is demonstrated and is neither congenital nor related to abnormal gonocyte transformation.

The positive predictive value of using fsh and Inhibin-B serum levels to diagnose gonadotropin insufficiency in bilateral cryptorchid boys is high.

AIM OF STUDY: Despite early surgery, many boys with bilateral cryptorchidism at surgery have a reduced number of germ cells per tubular cross-section (G/T) in testicular biopsies and/or low inhibin-B with no elevated follicle-stimulating hormone (FSH) as expected based on a normal gonadotropin feed-back mechanism. Such boys have a high risk of later infertility because of insufficient gonadotropin stimulation and may benefit from adjuvant hormonal treatment. Testicular biopsies are not always wanted or accepted. The study aim was to investigate the value of a low inhibin-B and normal FSH to identify patients that might benefit from adjuvant hormonal treatment avoiding the need for testicular biopsy. METHODS: A series of boys with cryptorchidism were evaluated with serum levels of inhibin-B and FSH in relation to G/T in testicular biopsies, which were compared to previously published age-matched normal control values. RESULTS: A total of 365 boys who underwent bilateral orchidopexy between 0.4 and 7.8 (median: 2) years of age were included. Twenty-seven (7%) patients had increased FSH and low G/T, whereas 11 of these also had low inhibin-B indicating hypergonadotropic hypogonadism. Moreover, 85 (23%) patients between 0.75 and 7.5 (median: 2) years of age had both low G/T (median: 0.3) and low inhibin-B (median: 56 pg/ml) but normal FSH (median: 0.6 U/l) indicating a gonadotropin insufficiency. Three patients with normal FSH and low inhibin B had normal G/T. DISCUSSION: Our study shows that if surgeons prefer to avoid testicular biopsies and only wish to rely on hormonal parameters (low inhibin-B and normal FSH) in order to diagnose a gonadotropin insufficiency as the cause of hypogonadism, they will identify only about 30% of such cases and overlook about 70% of patients sharing the same endocrinopathy. In addition, if surgeons treat patients for gonadotropin insufficiency only based on low inhibin-B and normal FSH they will solely treat patients with gonadotropin insufficiency and would not overtreat patients. CONCLUSION: Adjuvant hormonal treatment was indicated by a gonadotropin insufficiency discerned in 23% of boys with bilateral cryptorchidism. Without histology, the clinicians are left with more difficult clinical judgments to identify patients for adjuvant hormonal treatment. The positive predictive value of low inhibin-B and normal FSH corroborated by low G/T was 0.97 (85/85 + 3), but the sensitivity was low (0.30).

Organotypic Culture of Testicular Tissue from Infant Boys with Cryptorchidism.

Organotypic culture of human fetal testis has achieved fertilization-competent spermatids followed by blastocysts development. This study focuses on whether the organotypic culture of testicular tissue from infant boys with cryptorchidism could support the development of spermatogonia and somatic cells. Frozen-thawed tissues were cultured in two different media, with or without retinoic acid (RA), for 60 days and evaluated by tissue morphology and immunostaining using germ and somatic cell markers. During the 60-day culture, spermatocytes stained by boule-like RNA-binding protein (BOLL) were induced in biopsies cultured with RA. Increased AR expression (p < 0.001) and decreased AMH expression (p < 0.001) in Sertoli cells indicated advancement of Sertoli cell maturity. An increased number of SOX9-positive Sertoli cells (p < 0.05) was observed, while the percentage of tubules with spermatogonia was reduced (p < 0.001). More tubules with alpha-smooth muscle actin (ACTA, peritubular myoid cells (PTMCs) marker) were observed in an RA-absent medium (p = 0.02). CYP17A1/STAR-positive Leydig cells demonstrated sustained steroidogenic function. Our culture conditions support the initiation of spermatocytes and enhanced maturation of Sertoli cells and PTMCs within infant testicular tissues. This study may be a basis for future studies focusing on maintaining and increasing the number of spermatogonia and identifying different factors and hormones, further advancing in vitro spermatogenesis.

Sertoli and Germ Cells Within Atrophic Seminiferous Tubules of Men With Non-Obstructive Azoospermia.

Background: Infertile men with non-obstructive azoospermia (NOA) have impaired spermatogenesis. Dilated and un-dilated atrophic seminiferous tubules are often present in the testes of these patients, with the highest likelihood of active spermatogenesis in the dilated tubules. Little is known about the un-dilated tubules, which in NOA patients constitute the majority. To advance therapeutic strategies for men with NOA who fail surgical sperm retrieval we aimed to characterize the spermatogonial stem cell microenvironment in atrophic un-dilated tubules. Methods: Testis biopsies approximately 3x3x3 mm3 were obtained from un-dilated areas from 34 patients. They were classified as hypospermatogenesis (HS) (n=5), maturation arrest (MA) (n=14), and Sertoli cell only (SCO) (n= 15). Testis samples from five fertile men were included as controls. Biopsies were used for histological analysis, RT-PCR analysis and immunofluorescence of germ and Sertoli cell markers. Results: Anti-Müllerian hormone mRNA and protein expression was increased in un-dilated tubules in all three NOA subtypes, compared to the control, showing an immature state of Sertoli cells (p<0.05). The GDNF mRNA expression was significantly increased in MA (P=0.0003). The BMP4 mRNA expression showed a significant increase in HS, MA, and SCO (P=0.02, P=0.0005, P=0.02, respectively). The thickness of the tubule wall was increased 2.2-fold in the SCO-NOA compared to the control (p<0.05). In germ cells, we found the DEAD-box helicase 4 (DDX4) and melanoma-associated antigen A4 (MAGE-A4) mRNA and protein expression reduced in NOA (MAGE-A: 46% decrease in HS, 53% decrease in MA, absent in SCO). In HS-NOA, the number of androgen receptor positive Sertoli cells was reduced 30% with a similar pattern in mRNA expression. The γH2AX expression was increased in SCO as compared to HS and MA. However, none of these differences reached statistical significance probably due to low number of samples. Conclusions: Sertoli cells were shown to be immature in un-dilated tubules of three NOA subtypes. The increased DNA damage in Sertoli cells and thicker tubule wall in SCO suggested a different mechanism for the absence of spermatogenesis from SCO to HS and MA. These results expand insight into the differences in un-dilated tubules from the different types of NOA patients.

Necessity of Prophylactic Extrapleural Chest Tube During Primary Surgical Repair of Esophageal Atresia: A Systematic Review and Meta-Analysis.

Background: Esophageal atresia is corrected surgically by anastomosing and recreating esophageal continuity. To allow the removal of excess fluid and air from the anastomosis, a prophylactic and temporary intraoperative chest tube (IOCT) has traditionally been placed in this area during surgery. However, whether the potential benefits of this prophylactic IOCT overweigh the potential harms is unclear. Objective: To assess the benefits and harms of using a prophylactic IOCT during primary surgical repair of esophageal atresia. Data Sources: We conducted a systematic review with a meta-analysis. We searched Cochrane Central Register of Controlled Trials (2021, Issue 12), MEDLINE Ovid, Embase Ovid, CINAHL, and Science Citation Index Expanded and Conference Proceedings Citation Index-(Web of Science). Search was performed from inception until December 3rd, 2021. Study Selection: Randomized clinical trials (RCT) assessing the effect of a prophylactic IOCT during primary surgical repair of esophageal atresia and observational studies identified during our searches for RCT. Data Extraction and Synthesis: Two independent reviewers screened studies and performed data extraction. The certainty of the evidence was assessed by GRADE and ROBINS-I. PROSPERO Registration: A protocol for this review has been registered on PROSPERO (CRD42021257834). Results: We included three RCTs randomizing 162 neonates, all at overall "some risk of bias." The studies compared the placement of an IOCT vs. none. The meta-analysis did not identify any significant effect of profylacitic IOCT, as confidence intervals were compatible with no effect, but the analyses suggests that the placement of an IOCT might lead to an increase in all-cause mortality (RR 1.66, 95% CI 0.76-3.65; three trials), serious adverse events (RR 1.08, 95% CI 0.58-2.00; three trials), intervention-requiring pneumothorax (RR 1.65, 95% CI 0.28-9.50; two trials), and anastomosis leakage (RR 1.66, 95% CI 0.63-4.40). None of our included studies assessed esophageal stricture or pain. Certainty of evidence was very low for all outcomes. Conclusions: Evidence from RCTs does not support the routine use of a prophylactic IOCT during primary surgical repair of esophageal atresia.

Characterization and Survival of Human Infant Testicular Cells After Direct Xenotransplantation.

Background: Cryopreservation of prepubertal testicular tissue preserves spermatogonial stem cells (SSCs) that may be used to restore fertility in men at risk of infertility due to gonadotoxic treatments for either a malignant or non-malignant disease. Spermatogonial stem cell-based transplantation is a promising fertility restoration technique. Previously, we performed xenotransplantation of propagated SSCs from prepubertal testis and found human SSCs colonies within the recipient testes six weeks post-transplantation. In order to avoid the propagation step of SSCs in vitro that may cause genetic and epigenetic changes, we performed direct injection of single cell suspension in this study, which potentially may be safer and easier to be applied in future clinical applications. Methods: Testis biopsies were obtained from 11 infant boys (median age 1.3 years, range 0.5-3.5) with cryptorchidism. Following enzymatic digestion, dissociated single-cell suspensions were prelabeled with green fluorescent dye and directly transplanted into seminiferous tubules of busulfan-treated mice. Six to nine weeks post-transplantation, the presence of gonocytes and SSCs was determined by whole-mount immunofluorescence for a number of germ cell markers (MAGEA, GAGE, UCHL1, SALL4, UTF1, and LIN28), somatic cell markers (SOX9, CYP17A1). Results: Following xenotransplantation human infant germ cells, consisting of gonocytes and SSCs, were shown to settle on the basal membrane of the recipient seminiferous tubules and form SSC colonies with expression of MAGEA, GAGE, UCHL1, SALL4, UTF1, and LIN28. The colonization efficiency was approximately 6%. No human Sertoli cells were detected in the recipient mouse testes. Conclusion: Xenotransplantation, without in vitro propagation, of testicular cell suspensions from infant boys with cryptorchidism resulted in colonization of mouse seminiferous tubules six to nine weeks post-transplantation. Spermatogonial stem cell-based transplantation could be a therapeutic treatment for infertility of prepubertal boys with cryptorchidism and boys diagnosed with cancer. However, more studies are required to investigate whether the low number of the transplanted SSC is sufficient to secure the presence of sperm in the ejaculate of those patients over time.

Serial Inhibin B Measurements in Boys with Congenital Monorchism Indicate Compensatory Testicular Hypertrophy in Early Infancy.

AIM: Congenital monorchism is considered a condition in which an initially normal testis has existed but subsequently atrophied and disappeared due to a third trimester catastrophe (presumably torsion). Since inhibin B concentrations appear related to Sertoli and germ cells number, we evaluated pre- and postoperative inhibin B of boys with congenital monorchism to determine whether the well-known hypertrophy of the contralateral testis was reflected in inhibin B concentrations. MATERIALS AND METHODS: Twenty-seven boys consecutively diagnosed with congenital monorchism (median age 12 months) underwent follow-up with reproductive hormones 1 year postoperatively (median age 25 months). The results were compared with inhibin B of 225 boys with congenital nonsyndromic unilateral cryptorchidism, by converting values to multiple of the median (MoM) for age in normal boys. RESULTS: Ten boys (37%) had blind-ending vessels and ductus deferens (vanished testis) and the remaining (63%) had testicular remnants. At the time of diagnostic procedure, monorchid boys did not have significantly lower inhibin B (median 114, range 20-208) than unilateral cryptorchid boys (136, 47-393) (p = 0.27). During follow-up, MoM values of inhibin B increased in monorchid boys (median 0.59 to 0.98) and in unilateral cryptorchid boys (0.69 to 0.89) (both p < 0.0001). Compared with the concentration at surgery, an additional 44% monorchid boys had inhibin B MoM values higher than 1.0, whereas only additional 23% of unilateral cryptorchid boys exhibited such values (p = 0.04). CONCLUSION: Generally, inhibin B MoM values were normalized during follow-up in boys with congenital monorchism, reflecting compensatory hypertrophy within the first 2.5 years of life. The compensatory capacity to increase was better in monorchism than in unilateral cryptorchidism.

The Majority of Boys Having Orchidopexy for Congenital Nonsyndromic Cryptorchidism during Minipuberty Exhibited Normal Reproductive Hormonal Profiles.

INTRODUCTION: The activation of the hypothalamic-pituitary-gonadal axis that occurs in male minipuberty during the first 5 months of life is important for early germ cell development. Orchidopexy during minipuberty may improve fertility potential as the germinative epithelium may benefit from the naturally occurring gonadotropin stimulation. We hypothesize that most boys with congenital nonsyndromic cryptorchidism display normal reproductive hormonal profiles and histological findings during minipuberty. METHODS: We included boys with congenital nonsyndromic cryptorchidism who underwent orchidopexy at less than 160 days of age, having no potential for spontaneous resolution clinically. At surgery, testicular biopsies and reproductive hormones were collected and compared with normal reference values. We measured the germ cells (G/T) and type A dark spermatogonia number per tubule. RESULTS: Thirty-five boys aged 37 to 159 (median age: 124) days at orchidopexy were included, five were bilateral. G/T was below the normal lower range in 26% (9/35) of the cases. In six of these cases, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were above 97.5 percentile, whereas one case had FSH below 2.5 percentile. Totally, 97% (33/34, one FSH was missing) exhibited a normal LH/FSH ratio. LH was more often above 97.5 percentile than FSH: 34% (12/35) versus 3% (1/34, p < 0.001). Inhibin B was below 2.5 percentile in 17% (6/35) of cases who all proved FSH above normal mean and four had LH above normal mean. CONCLUSION: Generally, reproductive hormonal profiles of the cryptorchid boys exhibited normal minipubertal pattern. Thus, 26% of the boys had reduced germ cell number, and transient hypogonadotropic hypogonadism could be suspected in few cases.

Fertility preservation in boys facing gonadotoxic cancer therapy.

Patient survival following childhood cancer has increased with contemporary radiation and chemotherapy techniques. However, gonadotoxicity associated with treatments means that infertility is a common consequence in survivors. Novel fertility preservation options are emerging, but knowledge about these options amongst urologists and other medical professionals is lacking. Pre-pubertal boys generally do not produce haploid germ cells. Thus, strategies for fertility preservation require cryopreservation of tissue containing spermatogonial stem cells (SSCs). Few centres worldwide routinely offer this option and fertility restoration (including testicular tissue engraftment, autotransplantation of SSCs and in vitro maturation of SSCs to spermatozoa) post-thaw is experimental. In pubertal boys, the main option for fertility preservation is masturbation and cryopreservation of the ejaculate. Assisted ejaculation using penile vibratory stimulation or electroejaculation and surgical sperm retrieval can be used in a sequential manner after failed masturbation. Physicians should inform boys and parents about the gonadotoxic effects of cancer treatment and offer fertility preservation. Preclinical experience has identified challenges in pre-pubertal fertility preservation, but available options are expected to be successful when today's pre-pubertal boys with cancer become adults. By contrast, fertility preservation in pubertal boys is clinically proven and should be offered to all patients undergoing cancer treatment.

During infancy low levels of follicle-stimulating hormone may result in high rate of germ cell apoptosis.

PURPOSE: It has been suggested that follicle-stimulating hormone (FSH) plays a role in preventing germ cell apoptosis. We aimed to compare apoptotic rate of boys with cryptorchidism having different levels of FSH in order to investigate its role in apoptosis. METHODS: Hormonal profiles and testicular biopsies from 30 boys with unilateral cryptorchidism (age range: 4-14 months) were included. Based on FSH level, the boys were grouped into three (3 × 10) having high (>97.5percentile), low (<2.5percentile), or within normal range. Sections underwent immunohistochemical staining to analyze the number of germ cells and type A dark spermatogonia per cross-sectional tubule. One section was co-stained with immunofluorescent antibodies against an apoptotic marker (cleaved caspase-3), proliferation marker (Ki67), Sertoli cell marker (anti-Müllerian hormone) and processed by confocal imaging for analysis. Germ cell apoptosis was calculated as the apoptosis index (percentage caspase-3+ germ cells/total germ cell number). RESULTS: Fifty percent (5/10) of the boys with low FSH had an apoptosis index above 90% compared with 15% (3/20) of the boys with normal or high FSH (p = 0.04). Caspase-3+ germ cells were most likely to be located on the basement membrane (p<0.05). CONCLUSION: Our findings lead to trends proposing that FSH may play a role in preventing apoptosis. TYPE OF STUDY: Prognosis Study LEVEL OF EVIDENCE: III.

The impact of early and successful orchidopexy on hormonal follow-up for 208 boys with bilateral non-syndromic cryptorchidism.

PURPOSE: Inhibin-B is produced by Sertoli cells and decreased values might be associated with impaired fertility potential. The aim of the study was to evaluate the impact of bilateral orchidopexy on serum inhibin-B and follicle-stimulating hormone (FSH). METHODS: A cohort study including 208 bilateral cryptorchid boys (median age: 1.7 year) was evaluated with serum inhibin-B and FSH in relation to histological parameters. Based on the fertility potential, the boys were divided into three subgroups. At follow-up (median age: 2.7 years) the boys were evaluated with FSH and in case of inhibin-B using multiple of the median (MoM). RESULTS: Inhibin-B MoM improved significantly at follow-up. In 32 boys with high FSH at orchidopexy 63% normalized FSH and 59% increased MoM inhibin-B, but 31% had impaired inhibin-B at follow-up. In 105 boys with transient hypogonadotropic hypogonadism, 52% increased inhibin-B MoM but 31% had impaired inhibin-B at follow-up. In 71 boys with normal FSH, inhibin-B, and G/T, 54% increased inhibin-B MoM and 15% had impaired inhibin-B at follow-up. The effect of the surgery was best in patients younger than 1 year. CONCLUSION: Orchidopexy, especially before 1 year of age, improves the fertility potential in bilateral cryptorchidism. At follow-up, 26% (54/208) had a risk of infertility based on inhibin-B.

Evaluation of boys with daytime incontinence by combined cystourethroscopy, voiding cystourethrography and urodynamics.

Objects: Approximately, 1% of school children have daytime urinary incontinence. The symptoms may be caused by an overactive bladder (OAB). In the evaluation of boys with OAB complaints, one should consider a possible urethral cause. The aim of the study was to evaluate the value of a diagnostic regime with cystourethroscopy, voiding cystourethrography (VCUG) and urodynamic pressure-flow studies in boys with OAB complaints after unsuccessful urotherapy and pharmacological therapy. Materials and Methods: Seventy-five boys (5-14 years old) were investigated with cystourethroscopy and within 24 h thereafter VCUG followed by urodynamic combined cystometry and pressure-flow study. All boys had daytime incontinence and urgency. Results: Sixty-one boys had no suspected urethral valves at cystoscopy or VCUG, and urodynamics showed no obstructed Pdet-Qmax. All 61 boys had detrusor overactivity. Two boys had late diagnosed urethral valves. In four boys, the initial cystourethroscopy was described as normal. The VCUG indicated presence of posterior urethral valves, but urodynamics showed no obstructed Pdet-Qmax. In eight boys, the initial cystourethroscopy was described as normal whereas urodynamics showed obstructed Pdet-Qmax. In four of these boys, VCUG showed abnormalities in the sphincter area but they were not described as suspected urethral valves. At repeat cystourethroscopy, urethral valves could still not be identified. Patient follow-up regarding achievement of continence after investigation guided treatment was in accordance with the literature. Conclusions: Boys can be safely evaluated by cystourethroscopy followed by urodynamics in search for a possible urethral problem. It is our suggestion, that VCUG can be restricted to those boys where urodynamics indicates obstruction or the findings by cystourethroscopy are uncertain.

Fertility Potential is Impaired in Boys with Bilateral Ascending Testes.

PURPOSE: Ascending testes have been documented to be descended in the scrotum within the first year of life and then reascended. The aim of this study was to investigate to what extent the fertility potential was impaired in boys with such testes compared to the fertility potential of boys with late referral congenital cryptorchidism. MATERIALS AND METHODS: A total of 153 consecutive boys underwent bilateral orchiopexy at age 2 to 7 years (median 3.9) between 2011 and 2018. Of the patients 67 were diagnosed with bilateral ascended testes and 86 with late referral bilateral congenital cryptorchidism. We assessed serum levels of inhibin B and gonadotropins and histological parameters, number of germ cells per tubule cross-section and number of type A dark (Ad) spermatogonia per tubule cross-section. All values were compared to our normal material. RESULTS: Number of germ cells per tubule cross-section of boys with ascended testes (median 0.50, range 0 to 2.29) was not significantly higher compared to boys with congenital cryptorchidism (median 0.37, range 0 to 2.57; p=0.11). Mean number of germ cells per tubule cross-section was below normal range in 40 boys with ascending testes (60%) vs 57 boys with late referral congenital cryptorchidism (66%, p=0.40). Biopsies absent of Ad spermatogonia were noted in 31% of boys with ascending testes (21 of 67) vs 34% of boys with congenital cryptorchidism (29 of 86, p=0.76). Serum levels of inhibin B and gonadotropins did not differ between the 2 groups. CONCLUSIONS: The fertility potential of boys with bilateral ascended testes was impaired to almost the same level as that of boys with bilateral congenital cryptorchidism and should therefore be surgically corrected as soon as the diagnosis of ascended testes is settled.

Sexual functions and fertility outcomes after hypospadias repair.

Hypospadias is a common abnormality of the urogenital tract with a wide range of variety in its presentation and severity. The primary aim to correct hypospadias is to restore normal penile function and appearance. Although it can be corrected at any age, early correction between the 6 and 18 months of life is recommended. The functional and cosmetic outcomes have been very-well presented in the literature, although the aspects of sexuality and fertility of hypospadias repair in the long term are vague. In this narrative review, we aimed to gather the data around the sexuality and fertility outcomes of hypospadias repair and acknowledge urologists and parents of boys with hypospadias who will have a correction surgery about future sexual and fertility concerns.

Germ cells positive for PLAP and c-Kit in 11-16 year old normal boys with ongoing spermatogenesis.

INTRODUCTION: Positive staining of testicular germ cells for PLAP and c-Kit beyond infancy may be associated with the presence of GCNIS (Germ Cell Neoplasia In Situ). We recently reported our findings of positive staining of normal, infantile germ cells for PLAP, and c-Kit up to 2 years of age, contrary to previous studies. The present study aims to elucidate whether otherwise normal testes of boys undergoing puberty express PLAP, c-Kit, Oct3/4, or D2-40. MATERIALS AND METHODS: Biopsies were taken from 31 boys (11.5-16.5 years of age, mean and median of 13.5 years), who underwent surgery either for torsion of the testis (15) or a history suspicious of intermittent torsion of the testis (16). 21 were biopsied on both sides, making a total of 52 biopsies. Four testes were necrotic. The biopsies were fixed in Stieve's medium, cut into 2 µm sections, and mounted on coated slides. One slide was processed for H-E, and the others incubated with primary antibody for PLAP, c-Kit, D2-40, and Oct3/4. RESULTS: 87% of the boys stained positive for both PLAP and c-Kit. None were positive for either D2-40 or Oct3/4. None had any histological features characteristic of GCNIS. Only two boys showed no signs of having initiated spermatogenesis. Those positive for PLAP were likewise for c-Kit, and vice versa, except 2; one boy, 13 years, was positive for PLAP, but negative for c-KIT, another, 16 years, was negative for PLAP and positive for c-Kit. Three boys stained positive for PLAP and c-Kit on the right side, and negative on the left. One boy was negative for c-Kit on the right side, positive on the left, and positive for PLAP bilaterally. CONCLUSION: Positive staining of testicular germ cells for PLAP and c-Kit seems to be a normal finding in boys not having completed puberty. Rather than indicating pre-malignant transformation, the positivity is indicative of an ongoing maturational process of the germ cells.