[Association between maternal peri-conceptional exposures and risk of hypospadias and cryptorchidism in offspring].

Objective: To investigate the relationship between maternal exposures to peri-conceptional risk factors and the risk of hypospadias and cryptorchidism in offspring. Methods: Pregnant women who delivered male newborns and participated in the China birth cohort study between February 2018 and December 2020 at the research center of Beijing Obstetrics and Gynecology Hospital, Capital Medical University were selected for the study. All were enrolled at 6-13+6 weeks of their gestation. Baseline risk factor information was collected by questionnaire survey. Information on the outcome of hypospadias and cryptorchidism was obtained by clinical examination at birth and ultrasonography. Logistic regression was used to analyze the Odds Ratio (OR) and 95% Confidence Interval (95%CI) of each factor with respect to the onset of the outcome. Results: A total of 15, 833 pregnant women with an average age of (31.81±3.84) years were included. Among their offsprings, 113 were diagnosed as hypospadias or cryptorchidism (42 hypospadias, 69 cryptorchidism, and 2 both hypospadias and crypterchidism), with an incidence of 7.14‰. The results of multivariate logistic regression analysis showed that mothers with pregnancy history of birth defects (OR=3.01, 95%CI: 1.09-8.35), with preconception Hepatitis B infection (OR=4.74, 95%CI: 1.10-20.42), fetal growth restriction (OR=4.02, 95%CI: 2.10-7.68), multivitamin use since preconception (OR=1.98, 95%CI: 1.12-3.52), and never cook and eat at home (OR=2.17, 95%CI: 1.23-3.82) were risk factors for hypospadias and cryptorchidism (all P<0.05). Conclusions: Obesity in early pregnancy, preconception Hepatitis B infection, pregnancy history of birth defects, fetal growth restriction, multivitamin use before pregnancy, and rarely cook and eat at home were associated with an increased risk of hypospadias or cryptorchidism in their offsprings.

Diagnoses and Treatment of Acquired Undescended Testes: A Review.

Acquired undescended testes were once considered a sporadic disease. In recent years, reports suggest that they are not uncommon, with an incidence rate about 3 times that of congenital undescended testes. The etiology of acquired undescended testes remains inconclusive, clinical diagnostic standards are unclear, and treatment approaches are still controversial. There is ongoing debate about the mechanism of testicular ascent. The prevailing view is that acquired undescended testes occur due to the partial absorption of the gubernaculum, which forms part of the parietal peritoneum. The residual gubernacular fibers continuously pull on the spermatic cord, preventing the spermatic cord from elongating proportionately to somatic growth, leading to a re-ascent of the testis. Acquired undescended testes may increase the risk of testicular cancer, but this is still debated. The preferred treatment method is also controversial. However, surgical fixation has an immediate effect; no studies have proven that early surgery improves fertility in patients. The etiology of acquired undescended testes is closely related to the continuous pull of the residual gubernacular fibers on the spermatic cord, which prevents the cord from extending proportionately to body growth. There are no clear diagnostic standards for acquired undescended testes yet, and spontaneous descent is possible, so testicular fixation surgery may not be the preferred treatment method.

Obliteration of the Processus Vaginalis After Testicular Descent

The testis develops in the abdominal cavity and descends into the scrotum. Although numerous theories have been proposed, the mechanism of descent and the reason for its inhibition remain unknown. Furthermore, none of the explanations account for the other occurrences related to the descent, such as failed obliteration of the processus vaginalis, or the reasons for the decrease in fertility and increase in the risk of malignancy associated with an undescended testis. The gubernaculum is a primitive mesenchymal tissue that was first described in 1786. However, the role of the gubernaculum in the descent process remains obscure. The testis descends through the processus vaginalis. Although the processus vaginalis (PV) is usually defined as a simple peritoneal protrusion, it actively develops into the gubernaculum. The gubernaculum gives rise to the smooth muscles that surround the processus vaginalis. The striated cremaster muscle (CM) is also derived from the gubernaculum. Because the testis descends through the processus vaginalis, the muscles develop to propel the testis. After propelling the testis, the smooth muscle (SM) undergoes programmed cell death. The initiation of programmed cell death through the intrinsic pathway requires activation of phospholipase C. A transient shift in the autonomic balance via a decrease in the sympathetic tonus and an increase in the parasympathetic tonus is essential for initiating this programmed cell death. Programmed cell death in the SM is the physiological pathway for the obliteration of the processus vaginalis. Differences in the timing, intensity, or duration of this physiological pathway result in pathological conditions. A shift before testicular descent diminishes the SM content that is required to propel the testis, and thus inhibits descent. The early shift persists throughout childhood and results in the decrease in fertility and increase in the risk of malignancy because of the differences in signal transduction. Despite a successful descent, persistence of the shift alters the contractility of the CM by increasing the cytosolic calcium levels. Contracted CMs retracts or even ascends the testis. Inadequate intensity or duration of the shift of autonomic tonus causes failure of the programmed cell death. Persistence of the SM hinders the obliteration of PV and gives rise to hydroceles or inguinal hernias depending on the amount of residual smooth muscles. Similar findings from different countries support these explanations. Thus, our proposed mechanism satisfactorily explains the process of descent while considering all the factors related to the process of testicular descent.

Low placental weight may be involved in the etiology of congenital cryptorchidism in neonatal boys.

INTRODUCTION: Several factors have been reported to be associated with the etiology of cryptorchidism; however, clear evidence regarding the risk factors for cryptorchidism is elusive. In the present study, we evaluated the clinical characteristics of cryptorchidism using the common neonatal intensive-care unit (NICU) database of the National Hospital Organization and explored one of possible factors associated with the development of cryptorchidism. METHODS: A total of 7882 male neonates were included in this study. We separated them into two groups: those without cryptorchidism (n = 7852) and those with cryptorchidism (n = 30) at the time of discharge from the NICU. Cryptorchidism was defined as a condition in which the testis was located out of the scrotum on the route of descent at the time of NICU discharge. The associations between cryptorchidism and the maternal, placental, and neonatal information were analyzed. Analyses were performed statistically to compare nominal variables between the groups using Fisher's direct establishment calculation method and logistic regression analyses. RESULTS: Univariate analyses showed the placental weight <10% tile (odds ratio 3.31, 95% confidence interval [CI] 1.18-8.64), birth height <-2 standard deviations (SD) (odds ratio 3.65, 95% CI 0.92-10.6), birth weight <-2SD (odds ratio 4.06, 95% CI 1.55-9.51), and small for gestational age (odds ratio 3.82, 95% CI 1.46-8.97) were significantly associated with the development of cryptorchidism. Multivariate analyses showed that placental weight <10th percentile (odds ratio 2.86, 95% CI 1.11-7.44) was significantly associated with the development of cryptorchidism. DISCUSSION: Although, this study population was limited to infants admitted to the ICU, the data indicated a possible association between low placental weight and the development of cryptorchidism in neonatal boys.

Mapping of referral patterns for undescended testes - Risk factors for referral of children with normal testes.

BACKGROUND: Accurate referral of boys with suspected undescended testes (UDT) is of importance to preserve fertility and reduce risk of future testicular cancer. While late referral is well studied, there is less knowledge about incorrect referrals, hence, referral of boys with normal testes. OBJECTIVE: To evaluate the proportion of UDT referrals that did not lead to surgery or follow-up, and to assess risk factors for referral of boys with normal testes. STUDY DESIGN: All UDT referrals to a tertiary center of pediatric surgery during 2019-2020 were retrospectively assessed. Only children with suspected UDT in the referral (not suspected retractile testicles) were included. Primary outcome was normal testes at examination by a pediatric urologist. Independent variables were age, season, region of residence, referring care unit, referrer's educational level, referrer's findings, and ultrasound result. Risk factors for not needing surgery/follow-up were assessed with logistic regression and presented as adjusted odds ratios with a 95% confidence interval (aOR, [95% CI]). RESULTS: A total of 378 out of 740 included boys (51.1%) had normal testes. Patients >4 years (aOR 0,53, 95% CI [0,30-0,94]), referrals from pediatric clinics (aOR 0.27, 95% CI [0.14-0.51]) or surgery clinics (aOR 0.06, 95% CI [0.01-0.38]) had lower risk of normal testes. Boys referred during spring (aOR 1.80, 95% CI [1.06-3.05]), by a non-specialist physician (aOR 1.58, 95% CI [1.01-2.48]) or referrer's description of bilateral UDT (aOR 2.34, 95% CI [1.58-3.45]), or retractile testes (aOR 6.99, 95% CI [3.61-13.55]) had higher risk of not needing surgery/follow-up. None of the referred boys that had normal testes had been re-admitted at the end of this study (October 2022). DISCUSSION: Over 50% of boys referred for UDT had normal testes. This is higher or equal to previous reports. Efforts to reduce this rate should in our setting probably be directed towards well-child centers and training in examination of testicles. The main limitation of this study is the retrospective design and the rather short follow-up time, which however should have very modest effect on the main findings. CONCLUSION: Over 50% of boys referred for UDT have normal testes. A national survey regarding the management and examination of boys testicles has been launched and directed at well-child centers to further evaluate the findings of the current study.

Congenital male genital malformations and paternal health: An analysis of the US claims data.

OBJECTIVE: To investigate the potential association between paternal health and male genital malformations in the offspring. MATERIALS AND METHODS: We analyzed data from 2007 to 2016 derived from the IBM MarketScan Research database, which reports on reimbursed private healthcare claims in the United States. The association between paternal comorbidities (defined as individual and combined measures) and genital malformations in male offspring was analyzed. RESULTS: Of 376,362 male births, 22% of fathers had at least one component of metabolic syndrome (≥1) prior to conception. Totals of 2880 cases of cryptorchidism (0.77%) and 2651 cases of hypospadias (0.70%) were identified at birth. While 0.76% of sons born to fathers with no metabolic syndrome components were diagnosed with cryptorchidism, 0.82% of sons with fathers with multiple metabolic syndrome components had cryptorchidism. Similarly, 0.69% versus 0.88% of sons had hypospadias when fathers had 0 or 2+ components of metabolic syndrome. After adjusting for maternal and paternal factors, the odds of a son being diagnosed with hypospadias increased with two or more paternal metabolic syndrome components (Odds ratio [95% confidence interval]: 1.27 [1.10-1.47]). Specific components of paternal metabolic syndrome were not generally more associated with a son's genital malformations. When we performed a subgroup analysis where genital malformations were defined based on surgical correction, the association with hypospadias persisted. CONCLUSIONS: Fathers with multiple components of metabolic syndrome in the preconception period were observed to be at increased risk for having sons born with hypospadias. The results support the association between a man's andrological and overall health.

Environmental Impacts on Male Reproductive Development: Lessons from Experimental Models.

BACKGROUND: Male reproductive development in mammals can be divided into a gonadal formation phase followed by a hormone-driven differentiation phase. Failure of these processes may result in Differences in Sex Development (DSD), which may include abnormalities of the male reproductive tract, including cryptorchidism, hypospadias, infertility, and testicular germ cell cancer (TGCC). These disorders are also considered to be part of a testicular dysgenesis syndrome (TDS) in males. Whilst DSDs are considered to result primarily from genetic abnormalities, the development of TDS disorders is frequently associated with environmental factors. SUMMARY: In this review, we will discuss the development of the male reproductive system in relation to DSD and TDS. We will also describe the experimental systems, including studies involving animals and human tissues or cells that can be used to investigate the role of environmental factors in inducing male reproductive disorders. We will discuss recent studies investigating the impact of environmental chemicals (e.g., phthalates and bisphenols), lifestyle factors (e.g., smoking) and pharmaceuticals (e.g., analgesics) on foetal testis development. Finally, we will describe the evidence, involving experimental and epidemiologic approaches, for a role of environmental factors in the development of specific male reproductive disorders, including cryptorchidism, hypospadias, and TGCC. KEY MESSAGES: Environmental exposures can impact the development and function of the male reproductive system in humans. Epidemiology studies and experimental approaches using human tissues are important to translate findings from animal studies and account for species differences in response to environmental exposures.

Aryl hydrocarbon receptor activity in human breast milk and cryptorchidism: A case-control study within the prospective Norwegian HUMIS cohort.

BACKGROUND: The etiology of cryptorchidism remains poorly understood. Endocrine disrupting chemicals can impact estrogen signaling by interacting with aryl hydrocarbon receptor (AhR) activity. OBJECTIVE: To evaluate whether AhR activity in breast milk samples is associated with cryptorchidism. METHOD: We conducted a case-control study based on 199 mother-child pairs (n = 91 cases/108 controls) selected from the Norwegian Human Milk Study (2002-2009). We defined cases for cryptorchidism based on maternal reports at 1-, 6-, 12-, and 24- months after birth. Chemically- and biologically stable AhR activity (pg 2,3,7,8-TCDD equivalent (TEQ)/g lipid) was determined by DR- CALUX® assay in the mothers' milk collected at a median of 33 (10th-90th percentile: 18-57) days after delivery. We used multivariate logistic regression to compare AhR activity levels between cases and controls, and linear regression separately, to establish the relationship with the presence of 27 potential EDCs measured in breast milk and AhR activity. RESULTS: The average estimated daily intake (EDI) of dioxin and (dioxin-like (dl)-compounds via breast milk is 33.7 ± 17.9 pg TEQ/kg bodyweight per day among Norwegian children. There were no significant differences in AhR activation in breast milk samples between cases with cryptorchidism and controls. Among the 27 chemicals measured in breast milk, AhR activity was (borderline) significantly associated with all dl-PCBs, three non-dioxin-like (ndl)-PCBs (PCB-74, PCB-180, PCB-194) and two organochlorine pesticides (OCPs; HCB, ß-HCH). No associations between AhR activity and brominated flame retardants (PBDEs) or poly- and perfluoroalkyl substances (PFASs). CONCLUSION: No association between AhR activity and cryptorchidism was found among Norwegian boys. The average EDI of dioxin and dl-compounds in exclusively breastfed Norwegian infants remains above the safety threshold and, therefore requires further reduction measures. Consistent with a possible role in the observed AhR activity, all dl-PCBs were associated with AhR activity whereas the association was null for either PBDEs or PFASs.

Identification of the Bisphenol A (BPA) and the Two Analogues BPS and BPF in Cryptorchidism.

Objective: to explore the association of plasma concentrations of bisphenol A (BPA), bisphenol S (BPS), and bisphenol F (BPF) with unilateral cryptorchidism. In addition, to analyze selected demographic and intraoperative characteristics. Design: Retrospective analysis to determine plasma concentrations of total BPA, BPS and BPF using gas chromatography - mass spectrometry (GC-MS) among prepubertal boys with cryptorchidism and prebupertal male control subjects. During operation, the size, turgor and location of the cryptorchid testes were assessed. Main Outcome Measure: Plasma concentrations of total BPA, BPS and BPF. Results: In children with cryptorchidism, plasma levels of BPA, BPS and BPF were significantly higher compared to the control subjects. For BPA, it was: median value: 9.95 ng/mL vs. 5.54 ng/mL, p<0.05. For BPS, it was: median value: 3.93 ng/mL vs. 1.45 ng/mL, p<0.001. For BPF, it was: median value: 3.56 ng/mL vs. 1.83 ng/mL, p<0.05. In cryptorchid group, BPA was detected in 61.4% samples, BPS in 19.3% and BPF in 19.3%. All the three bisphenols were detected in plasma samples of both the healthy subjects and the study cohort. In the latter group, we found significant higher levels of BPA in boys from urban areas. We found a weak positive correlation between the levels of BPS and BPF and reduced turgor of the testes. Furthermore, results showed weak positive correlations between BPA and BPS levels and the age of the children as well as between BPS and BPF concentrations and the place of residence. Conclusions: Results provide a first characterization of prepubertal boys suffering from cryptorchidism and exposed to different kind of bisphenols. Our study suggests that cryptorchid boys are widely exposed to BPA and, to a lesser extent, also to its alternatives, such as BPS and BPF.

Proximal Hypospadias and Acquired Cryptorchidism: Incidence, Morphology and Potential Clinical Implications.

PURPOSE: We identified the incidence of acquired cryptorchidism among patients with proximal and mid shaft hypospadias, predictors of acquired cryptorchidism, and the prevalence of testis-epididymis nonfusion with ascended testes. We hypothesized that proximal hypospadias would be associated with higher incidence of acquired cryptorchidism than mid shaft hypospadias, and that ascended testes would exhibit increased prevalence of testis-epididymis nonfusion similar to anatomical findings in an undescended testis. MATERIALS AND METHODS: A retrospective cohort study of patients who underwent primary proximal and mid shaft hypospadias repair from 2010 to 2016 was conducted. Clinical and operative notes were reviewed. Patients with congenitally undescended testes or differences of sex development were excluded. RESULTS: A total of 175 patients were identified. Those with proximal hypospadias (14/104, 13%) were more likely than those with mid shaft hypospadias (1/71, 1%) to develop acquired cryptorchidism (p=0.04). Among proximal hypospadias patients, increased risk of acquired cryptorchidism was associated with pre-term birth (p <0.01) and penoscrotal transposition (p=0.01) but not with testis position on initial examination (p >0.99). In the 14 proximal hypospadias patients with acquired cryptorchidism, 21 ascended testes underwent orchiopexy. Operative notes adequately described testis-epididymis anatomy for 8/21 ascended testes. Testis-epididymis nonfusion was described in 6/8 ascended testes. CONCLUSIONS: Risk of acquired cryptorchidism is increased among patients with proximal hypospadias. Operative notes revealed a high rate of epididymal nonfusion with ascended testes, suggesting these testes morphologically resemble undescended testes. Close followup of testis position is needed in these patients, and the threshold to perform orchiopexy may need to be lower in select patients.