Testicular volume at puberty in boys with congenital cryptorchidism randomised to treatment at different ages.

AIM: To assess testicular volume at puberty for boys who underwent orchidopexy at 9 or at 36 months compared to boys with spontaneous postnatal descent. METHODS: At age 6 months, boys with congenital unilateral cryptorchidism were randomised to surgery at 9 or 39 months of age and followed to 16 years in parallel with boys with spontaneous postnatal descent. Ultrasound was done at 11 and 16 years to determine testicular volume. The ratio of the initially undescended testis to its scrotal counterpart was used to assess testicular growth. RESULTS: At age 16, the ratio was lower (p < 0.00) in the late group compared to the early group. At 16 years, the spontaneously descended testes were significantly smaller than their scrotal counterparts but larger than the operated groups (early p < 0.01 and late p < 0.00). CONCLUSION: Our data at 16 years show that orchidopexy at 9 months results in better testicular growth compared to 3 years but did not reach the corresponding volumes of their scrotal counterparts. This indicates that earlier surgery is beneficial to testicular growth. At age 16, the postnatally descended testes were not only larger than the surgically treated testes but also exhibited impaired testicular growth.

Effect of an interactive mobile health support system and daily weight measurements for pediatric obesity treatment, a 1-year pragmatical clinical trial.

BACKGROUND: Pediatric obesity lifestyle treatment is not always successful. Frequent clinical visits are of major importance to certify sufficient effect but are difficult due to the associated costs and the great demands on families. We hypothesized that an interactive digital support may reduce the need for frequent physical visits. The aim of the study was to assess 1-year weight outcome for patients using a digital support system compared with standard care. METHODS: An obesity lifestyle treatment with a digital support system was implemented in one clinic in Stockholm, Sweden. Measurements from a custom-made body scale without digits for daily home measurement of weights were transferred via Bluetooth to a mobile application, where BMI Z-score was calculated and presented graphically with an individualized weight loss target curve. An automatic transfer of data to the web-based clinic interface enables a close monitoring of treatment progress, and frequent written communication between the clinical staff and families via the application. One-year outcome was compared with a randomly retrieved, age and sex matched control group from the Swedish childhood obesity treatment register (BORIS), which received standard treatment at other clinics. Main outcome was change in BMI Z-score and missing data was imputed. RESULTS: 107 children were consecutively included to digi-physical treatment and 321 children to standard care. Age range 4.1-17.4 years (67% males). The attrition rate was 36% and 46% respectively, p = 0.08. After 1 year, the mean ± SD change in BMI Z-score in the treatment group was -0.30 ± 0.39 BMI Z-score units and in the standard care group -0.15 ± 0.28, p = 0.0002. The outcome was better for both sexes and all age groups in the digi-physical treated group. CONCLUSION: A digital support system with a personalized weight-loss target curve and daily weight measurements shared by the family and the clinic is more effective than a standard care childhood obesity treatment. GOV ID: NCT04323215.

Pathway analysis supports association of nonsyndromic cryptorchidism with genetic loci linked to cytoskeleton-dependent functions.

STUDY QUESTION: What are the genetic loci that increase susceptibility to nonsyndromic cryptorchidism, or undescended testis? SUMMARY ANSWER: A genome-wide association study (GWAS) suggests that susceptibility to cryptorchidism is heterogeneous, with a subset of suggestive signals linked to cytoskeleton-dependent functions and syndromic forms of the disease. WHAT IS KNOWN ALREADY: Population studies suggest moderate genetic risk of cryptorchidism and possible maternal and environmental contributions to risk. Previous candidate gene analyses have failed to identify a major associated locus, although variants in insulin-like 3 (INSL3), relaxin/insulin-like family peptide receptor 2 (RXFP2) and other hormonal pathway genes may increase risk in a small percentage of patients. STUDY DESIGN, SIZE, DURATION: This is a case-control GWAS of 844 boys with nonsyndromic cryptorchidism and 2718 control subjects without syndromes or genital anomalies, all of European ancestry. PARTICIPANTS/MATERIALS, SETTING, METHODS: All boys with cryptorchidism were diagnosed and treated by a pediatric specialist. In the discovery phase, DNA was extracted from tissue or blood samples and genotyping performed using the Illumina HumanHap550 and Human610-Quad (Group 1) or OmniExpress (Group 2) platform. We imputed genotypes genome-wide, and combined single marker association results in meta-analyses for all cases and for secondary subphenotype analyses based on testis position, laterality and age, and defined genome-wide significance as P = 7 × 10(-9) to correct for multiple testing. Selected markers were genotyped in an independent replication group of European cases (n = 298) and controls (n = 324). We used several bioinformatics tools to analyze top (P < 10(-5)) and suggestive (P < 10(-3)) signals for significant enrichment of signaling pathways, cellular functions and custom gene lists after multiple testing correction. MAIN RESULTS AND THE ROLE OF CHANCE: In the full analysis, we identified 20 top loci, none reaching genome-wide significance, but one passing this threshold in a subphenotype analysis of proximal testis position (rs55867206, near SH3PXD2B, odds ratio = 2.2 (95% confidence interval 1.7, 2.9), P = 2 × 10(-9)). An additional 127 top loci emerged in at least one secondary analysis, particularly of more severe phenotypes. Cytoskeleton-dependent molecular and cellular functions were prevalent in pathway analysis of suggestive signals, and may implicate loci encoding cytoskeletal proteins that participate in androgen receptor signaling. Genes linked to human syndromic cryptorchidism, including hypogonadotropic hypogonadism, and to hormone-responsive and/or differentially expressed genes in normal and cryptorchid rat gubernaculum, were also significantly overrepresented. No tested marker showed significant replication in an independent population. The results suggest heterogeneous, multilocus and potentially multifactorial susceptibility to nonsyndromic cryptorchidism. LIMITATIONS, REASONS FOR CAUTION: The present study failed to identify genome-wide significant markers associated with cryptorchidism that could be replicated in an independent population, so further studies are required to define true positive signals among suggestive loci. WIDER IMPLICATIONS OF THE FINDINGS: As the only GWAS to date of nonsyndromic cryptorchidism, these data will provide a basis for future efforts to understand genetic susceptibility to this common reproductive anomaly and the potential for additive risk from environmental exposures. STUDY FUNDING/COMPETING INTERESTS: This work was supported by R01HD060769 (the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD)), P20RR20173 (the National Center for Research Resources (NCRR), currently P20GM103464 from the National Institute of General Medical Sciences (NIGMS)), an Institute Development Fund to the Center for Applied Genomics at The Children's Hospital of Philadelphia, and Nemours Biomedical Research. The authors have no competing interests to declare.

Phenotype specific association of the TGFBR3 locus with nonsyndromic cryptorchidism.

PURPOSE: Based on a genome-wide association study of testicular dysgenesis syndrome showing a possible association with TGFBR3, we analyzed data from a larger, phenotypically restricted cryptorchidism population for potential replication of this signal. MATERIALS AND METHODS: We excluded samples based on strict quality control criteria, leaving 844 cases and 2,718 controls of European ancestry that were analyzed in 2 separate groups based on genotyping platform (ie Illumina® HumanHap550, version 1 or 3, or Human610-Quad, version 1 BeadChip in group 1 and Human OmniExpress 12, version 1 BeadChip platform in group 2). Analyses included genotype imputation at the TGFBR3 locus, association analysis of imputed data with correction for population substructure, subsequent meta-analysis of data for groups 1 and 2, and selective genotyping of independent cases (330) and controls (324) for replication. We also measured Tgfbr3 mRNA levels and performed TGFBR3/betaglycan immunostaining in rat fetal gubernaculum. RESULTS: We identified suggestive (p ≤ 1× 10(-4)) association of markers in/near TGFBR3, including rs9661103 (OR 1.40; 95% CI 1.20, 1.64; p = 2.71 × 10(-5)) and rs10782968 (OR 1.58; 95% CI 1.26, 1.98; p = 9.36 × 10(-5)) in groups 1 and 2, respectively. In subgroup analyses we observed strongest association of rs17576372 (OR 1.42; 95% CI 1.24, 1.60; p = 1.67 × 10(-4)) with proximal and rs11165059 (OR 1.32; 95% CI 1.15, 1.38; p = 9.42 × 10(-4)) with distal testis position, signals in strong linkage disequilibrium with rs9661103 and rs10782968, respectively. Association of the prior genome-wide association study signal (rs12082710) was marginal (OR 1.13; 95% CI 0.99, 1.28; p = 0.09 for group 1), and we were unable to replicate signals in our independent cohort. Tgfbr3/betaglycan was differentially expressed in wild-type and cryptorchid rat fetal gubernaculum. CONCLUSIONS: These data suggest complex or phenotype specific association of cryptorchidism with TGFBR3 and the gubernaculum as a potential target of TGFß signaling.

Cryptorchidism: a clinical perspective.

Incomplete descent of the testes is the most common genital anomaly in newborn boys. The prevalence varies with apparent geographical differences. The etiology of cryptorchidism is considered to be multifactorial (genetic, maternal, and environmental factors), and it occurs most often as an isolated disorder with no obvious cause. Cryptorchidism should not be left untreated, since there is an increased risk of developing testicular cancer and infertility/subfertility. However, the mode and timing of treatment, as well as the risks of subfertility and testicular cancer have long been controversial. There is increasing evidence that treatment should be performed early in life. Randomized volumetric and histological studies have shown that early treatment before the age of one year is beneficial for testicular development and future spermatogenesis compared to later treatment. It remains to be proven that this difference persists into adulthood. Due to the low efficacy rate and the possible adverse effects of hormonal treatment, surgery is preferred. The exact optimal time for orchidopexy is not known, but it should probably be before one year of age, at centers with expertise in pediatric anesthesiology and pediatric surgery/urology. The risk of testicular cancer is also reduced if orchidopexy is performed before puberty; however it remains to be proven if treatment in early infancy reduces the risk even further.

Growth of spontaneously descended and surgically treated testes during early childhood.

OBJECTIVE: To investigate whether in congenital unilateral cryptorchidism the growth of a spontaneously descended testis is normal, compared with the contralateral scrotal testis or similar to the growth of testes that failed to descend spontaneously and later underwent orchidopexy. METHODS: Ninety-one boys with congenital unilateral cryptorchidism with later spontaneous descent of the initially retained testis were followed from birth (0-3 weeks) up to 5 years of age and compared with boys randomized to surgery at either 9 months (n = 78) or 3 years (n = 85) of age. Testicular volume was determined with ultrasonography. RESULTS: Eighty-two percent of spontaneous descent occurred before 2 months of age. Twenty-two percent of these descended testes were later again found in a retained position. The spontaneously descended testis was smaller than its scrotal counterpart at all ages (P < .001). We also showed a significant difference in the testicular volume between the early and late treated boys from age 2 years and onward. At 2, 4, and 5 years of age, the volumes of the spontaneously descended testes were significantly larger than those of boys operated on at 3 years but similar to those operated on at 9 months. CONCLUSIONS: We have shown that in boys with congenital unilateral cryptorchidism with later spontaneous descent, the originally retained testes show impaired growth compared with its scrotal counterpart from birth and onwards. Also, they are prone to later ascent to a retained position. Furthermore, the longer testes remain untreated the more they exhibit impaired growth.

Management of undescended testes: how and when?

Incomplete descent of one or both testicles from the abdominal cavity, through the inguinal canal into the scrotum is the most common abnormality in new-born boys; 3-5% are affected. Although a majority of these retained testes will descend spontaneously during the first few months after birth, about one percent of all boys will require some sort of treatment in order to achieve best possible testicular function. Thousands of publications deal with different aspects on cryptorchidism - most of them try to improve the mode of treatment; why, when and how should treatment be delivered? In order to summarize the present state of the art, a consensus conference with experts from the Nordic countries was called in August 2006. The conclusions and the appropriate literature reviews can be found in the May issue of Acta Paediatrica 2007.

Surgical treatment of unilaterally undescended testes: testicular growth after randomization to orchiopexy at age 9 months or 3 years.

PURPOSE: We compared the growth of congenital, unilaterally undescended testes following orchiopexy at age 9 months or 3 years. MATERIALS AND METHODS: Patients were randomized to surgery at age 9 months (72) or 3 years (83). Testicular volume was measured by ultrasonography at ages 6, 12, 24, 39 and 48 months. RESULTS: Orchiopexy at age 9 months resulted in an increase in testicular volume at subsequent measurements at ages 2, 3 and 4 years compared to the volume at 6 months (p <0.001). In contrast, no significant growth was noted in the group treated at age 3 years. The improved testicular growth after early orchiopexy was also demonstrated by a gradual increase in the ratio of the previously retained testis and the scrotal testis in individual boys from 6 months to 4 years (0.68 to 0.81, p <0.001). For the late treatment group a significant decrease in this ratio was noted during the same period (0.68 to 0.56, p <0.01). CONCLUSIONS: Surgical treatment at 9 months resulted in partial catch-up of testicular growth until at least age 4 years compared to surgery at 3 years, clearly indicating that early surgery has a beneficial effect on testicular growth. Since testicular volume is an approximate indirect measure of spermatogenic activity, this gives hope that orchiopexy at this age may improve future spermatogenesis.

Testicular growth from birth to two years of age, and the effect of orchidopexy at age nine months: a randomized, controlled study.

AIM: To study whether surgical treatment at age 9 mo in boys with congenital unilaterally palpable undescended testes (cryptorchidism) is followed by improved growth of the previously retained testes compared to non-treatment. METHODS: At the age of 6 mo, 70 boys were randomized to surgical treatment at 9 mo and 79 boys to treatment at 3 y of age. The boys were then followed at 12 and 24 mo. Ultrasonography was used to determine testicular volume. RESULTS: After orchidopexy, the previously retained testes resumed growth and were significantly larger than the non-operated testes at 2 y (0.49 ml vs 0.36 ml, p<0.001). Testicular growth after orchidopexy was also demonstrated by a higher mean ratio between the previously retained and the scrotal testes of the individual boys at 2 y: 0.84 for the surgically treated group, compared to 0.63 for the untreated group (p<0.001). CONCLUSION: Surgery at 9 mo has a beneficial effect on the growth of previously undescended testes.