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Introduction Primary squamous cell carcinoma of the prostate is rare, and genetic profiling of this disease has not been established yet. Case presentation We present a case of primary squamous cell carcinoma in a patient with testicular dysgenesis syndrome. The patient was diagnosed with prostate squamous cell carcinoma following intractable dysuria, and his serum prostate‐specific antigen level was low. The patient had multiple lymph node and lung metastases, which led to administration of platinum‐based chemotherapy. Additionally, targeted next‐generation genome sequencing was performed to detect CDK12 mutations. Conclusion Early imaging studies should be considered, even if the patient's prostate‐specific antigen level is low when dysuria persists despite medical treatment. To the best of our knowledge, this is the first reported case of primary squamous cell carcinoma with a CDK12 mutation in a patient with TDS.

Introduction 45,X/46,XY mosaicism is a rare anomaly in sexual differentiation, presenting with diverse phenotypes and often leading to infertility due to abnormal gonadal development. Aims This report aims to present a case study of a 45,X/46,XY mosaic male patient with an ejaculatory disorder attributed to seminal vesicle dysplasia. Methods In this case study, diagnostic procedures encompassed blood tests, semen analysis, chromosomal examination, and imaging studies to assess gonadal morphology. Treatment strategies included attempted varicocelectomy, pharmacological intervention with amoxapine, and surgical testicular sperm extraction. Additionally, the patient underwent assisted reproductive techniques, specifically intracytoplasmic sperm injection (ICSI), to facilitate pregnancy for his wife. Results A 32-year-old man could not ejaculate, with post-orgasmic urinalysis revealing minimal sperm presence. Chromosomal analysis confirmed 45,X/46,XY mosaicism. Despite undergoing microsurgical varicocelectomy for clinical varicocele and receiving tricyclic antidepressants, no improvement in semen volume occurred. Imaging studies indicated ejaculatory disorder due to prostate and seminal vesicle aplasia. Consequently, surgical retrieval of testicular sperm was performed, leading to successful pregnancy via ICSI for his wife. Conclusion Our approach has effectively addressed ejaculatory disorder in 45,X/46,XY mosaic men, resulting in successful pregnancy. [ABSTRACT FROM AUTHOR]

Introduction CHARGE syndrome is a rare disorder that causes congenital abnormalities in multiple organs, including secondary hypogonadism. We report, herein, a unique case of CHARGE syndrome with both primary and secondary hypogonadism and discuss the possible causes and pathogenesis in this patient. Case presentation A 15‐year‐old boy with delayed secondary sexual characteristics and non‐palpable testes was referred to our hospital. Physical examination and detection of a chromodomain‐helicase‐deoxyribonucleic acid‐binding protein 7 gene mutation confirmed CHARGE syndrome. Hormone stimulation tests suggested both primary and secondary hypogonadism. Laparoscopic bilateral orchiectomy was performed because of decreased testosterone production and atrophy in both testes. Pathological examination of the testes revealed maturation arrest, germ cell neoplasm in situ, and decreased expression of steroid synthase. Conclusion This appears to be the first report of CHARGE syndrome with both primary and secondary hypogonadism demonstrated in endocrinological and histological examinations.

There is an abundance of epidemiological evidence and animal experiments concerning the correlation between cadmium exposure and adverse male reproductive health outcomes. However, the evidence remains inconclusive. We conducted a literature search from PubMed, Embase, and Web of Science over the past 3 decades. Pooled r and 95% confidence intervals (CIs) were derived from Cd levels of the type of biological materials and different outcome indicators to address the large heterogeneity of existing literature. Cd was negatively correlated with semen parameters (r = − 0.122, 95% CI − 0.151 to − 0.092) and positively correlated with sera sex hormones (r = 0.104, 95% CI 0.060 to 0.147). Among them, Cd in three different biological materials (blood, semen, and urine) was negatively correlated with semen parameters, while among sex hormones, only blood and urine were statistically positively correlated. In subgroup analysis, blood Cd was negatively correlated with semen density, sperm motility, sperm morphology, and sperm count. Semen Cd was negatively correlated with semen concentration. As for serum sex hormones, blood Cd had no statistical significance with three hormones, while semen Cd was negatively correlated with testosterone. In summary, cadmium exposure might be associated with the risk of a decline in sperm quality and abnormal levels of sex hormones. [ABSTRACT FROM AUTHOR]

Environmental oestrogens (EEs) as environmental pollutants have been paid much attention due to their impact on congenital malformation of male genitourinary system. Exposure to EEs for prolonged time could hinder testicular descent and cause testicular dysgenesis syndrome. Therefore, it is urgent to understand the mechanisms by which EEs exposure disrupt testicular descent. In this review, we summarize recent advances in our understanding of the process of testicular descent, which is regulated by intricate cellular and molecular networks. Increasing numbers of the components of these networks such as CSL and INSL3 are being identified, highlighting that testicular descent is a highly orchestrated process that is essential to human reproduction and survival. The exposure to EEs would lead to the imbalanced regulation of the networks and cause testicular dysgenesis syndrome such as cryptorchidism, hypospadias, hypogonadism, poor semen quality and testicular cancer. Fortunately, the identification of the components of these networks provides us the opportunity to prevent and treat EEs induced male reproductive dysfunction. The pathways that play an important role in the regulation of testicular descent are promising targets for the treatment of testicular dysgenesis syndrome. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: It has been suggested that antenatal exposure to environmental endocrine disruptors is responsible for adverse trends in male reproductive health, including male infertility, impaired semen quality, cryptorchidism and testicular cancer, a condition known as testicular dysgenesis syndrome. Anogenital distance (AGD) is an anthropomorphic measure of antenatal exposure to endocrine disruptors, with higher exposure levels leading to shortened AGD. We hypothesized that exposure to endocrine disruptors could lead to changes in DNA methylation during early embryonic development, which could then persist in the sperm of infertile men with shortened AGD. Results: Using fluorescence activated cell sorting based on staining with either YO-PRO-1 (YOPRO) or chromomycin-3 (CMA3), we isolated four sperm fractions from eleven infertile men with short AGD and ten healthy semen donors. We examined DNA methylation in these sorted spermatozoa using reduced representation bisulfite sequencing. We found that fractions of spermatozoa from infertile men stained with CMA3 or YOPRO were more likely to contain transposable elements harboring an estrogen receptor response element (ERE). Abnormal sperm (as judged by high CMA3 or YOPRO staining) from infertile men shows substantial hypomethylation in estrogenic Alu sequences. Conversely, normal sperm fractions (as judged by low CMA3 or YO-PRO-1 staining) of either healthy donors or infertile patients were more likely to contain hypermethylated Alu sequences with ERE. Conclusions: Shortened AGD, as related to previous exposure to endocrine disruptors, and male infertility are accompanied by increased presence of hormonal response elements in the differentially methylated regulatory sequences of the genome of sperm fractions characterized by chromatin decondensation and apoptosis. [ABSTRACT FROM AUTHOR]

Summary: Background: Hypospadias affects around 1/200 newborn males. Intrauterine testicular dysfunction may underlie a subset of cases. The long-term endocrine and reproductive outcomes in these men remain largely unknown. Methods: Cross-sectional study in Ghent and Vienna University Hospitals to assess the endocrine and seminal parameters of young adult men (16–21 years) born with non-syndromic hypospadias (NSH) (n = 193) compared to healthy typical males (n = 50). Assessments included physical exam, semen analysis, hormone assays and exome-based gene panel analysis (474 genes). Findings: All participants had experienced a spontaneous puberty, in spite of higher LH and INSL3 levels than typical males. Oligo- or azoospermia was observed in 32/172 (18·6%; 99%-CI: 12·2–27·4%) of NSH men; but in 5/16 (31·3%; 99%-CI: 11·1;62·4%) of complex NSH men and in 13/22 (59·1%; 99%-CI: 33·2–80·7%) of those born small for gestational age (SGA). No (likely) pathogenic coding variants were found in the investigated genes. Suboptimal statural growth affected 8/23 (34·8%; 99%-CI: 15·4–61·0%) of men born SGA with NSH. Interpretation: Spermatogenesis is significantly compromised in NSH men, especially in those born SGA or those with complex NSH. Long-term andrological follow-up is recommended, including end-pubertal semen analysis. No clear monogenic causes could be demonstrated in our cohort even in proximal or complex NSH. Being born SGA with NSH is frequently associated with poor catch-up growth, requiring growth hormone therapy in some. Funding: Research grants from the European Society of Paediatric Endocrinology, the Belgian Society of Pediatrics, the Belgian Society of Pediatric Endocrinology and Diabetology and the Research Foundation Flanders (FWO).

Endocrine disruptors are chemicals that interfere with the body's endocrine system and cause adverse effects in biological systems. Phthalates are a group of man-made chemicals which are mainly used as plasticizers and classified as endocrine disruptors. They are also used in cosmetic and personal care products as color or smell fixators. Moreover, phthalates are present in inks, adhesives, sealants, automobile parts, tools, toys, carpets, medical tubing and blood storage bags, and food packages. Pathological condition known as "testicular dysgenesis syndrome" (TDS) or "phthalate syndrome" is usually linked to phthalate exposure and is coined to describe the rise in alterations in reproductive health in men, such as reduced semen quality (decrease in sperm counts, sperm motility and increase in abnormal sperms), hypospadias, cryptorchidism, reduced anogenital distance and early-life testicular cancer. Phthalates are suggested to cause direct effect on gonadal and non-gonadal tissues, impair the differentiation and morphogenesis of seminiferous tubules and accessory sex organs and testicular cells (both Sertoli and Leydig cells), alter estradiol and/or testosterone levels, decrease insulin-like 3 (INSL3) peptide production, impair spermatogenesis and lead to epigenetic alterations, all of which may lead to TDS. This review will mainly focus on phthalates as causes of TDS and their mechanisms of action.

The steroidogenic cells in the testicle, Leydig cells, located in the interstitial compartment, play a vital role in male reproductive tract development, maintenance of proper spermatogenesis, and overall male reproductive function. Therefore, their dysfunction can lead to all sorts of testicular pathologies. Spermatogenesis failure, manifested as azoospermia, is often associated with defective Leydig cell activity. Spermatogenic failure is the most severe form of male infertility, caused by disorders of the testicular parenchyma or testicular hormone imbalance. This review covers current progress in knowledge on Leydig cells origin, structure, and function, and focuses on recent advances in understanding how Leydig cells contribute to the impairment of spermatogenesis. [ABSTRACT FROM AUTHOR]

Increasing rates of infertility associated with declining sperm counts and quality, as well as increasing rates of testicular cancer are contemporary issues in the United States and abroad. These conditions are part of the Testicular Dysgenesis Syndrome, which includes a variety of male reproductive disorders hypothesized to share a common origin based on disrupted testicular development during fetal and neonatal stages of life. Male reproductive development is a highly regulated and complex process that relies on an intricate coordination between germ, Leydig, and Sertoli cells as well as other supporting cell types, to ensure proper spermatogenesis, testicular immune privilege, and endocrine function. The eicosanoid system has been reported to be involved in the regulation of fetal and neonatal germ cell development as well as overall testicular homeostasis. Moreover, non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics with abilities to block eicosanoid synthesis by targeting either or both isoforms of cyclooxygenase enzymes, have been found to adversely affect male reproductive development. This review will explore the current body of knowledge on the involvement of the eicosanoid system in male reproductive development, as well as discuss adverse effects of NSAIDs and analgesic drugs administered perinatally, focusing on toxicities reported in the testis and on major testicular cell types. Rodent and epidemiological studies will be corroborated by findings in invertebrate models for a comprehensive report of the state of the field, and to add to our understanding of the potential long-term effects of NSAID and analgesic drug administration in infants.

Background: Cryptorchidism is one of the most common urogenital malformations. Cryptorchidism prevalence varies greatly in different countries and populations. The aim of the current study was to determine and analyse cryptorchidism prevalence in Estonia. Materials and methods: During 2012–2015, all consecutively born 5014 boys at Tartu University Hospital were examined for cryptorchidism. All the subjects with cryptorchidism were followed up for at least 6 months to assess spontaneous testicular descent. Results: Note that 2.1% cases had one or both testicles undescended at birth, 1.6% cases at expected date of birth, 1% cases at 3 months of age, and 0.8% cases at the age of 6 months had cryptorchidism. Cryptorchidism prevalence at birth was higher in preterm boys (11.9%), boys of low birth weight (16.7%) and boys small for gestational age (14%) but was lower in full‐term newborn boys (1.1%). During follow‐up, testes descended spontaneously in 61.6% of boys, more commonly in prematurely born boys (92%) and boys with low gestational weight (93%) as compared to full‐term cryptorchid boys (29.2%) and cryptorchid boys with normal birth weight (34%). At the age of 6 months, cryptorchidism prevalence was equalized in preterm boys (0.9%) and boys with low birth weight (1%) as compared to full‐term boys (0.7%) and boys with normal birth weight (0.7%). Boys SGA required surgical intervention more commonly than boys with normal birth weight. Ethnically, cryptorchidism prevalence at birth was similar among Estonians and non‐Estonians. Conclusion: Our data revealed that cryptorchidism prevalence, especially in full‐term boys, is lower in Estonia than reported in the other Nordic‐Baltic countries and worldwide. [ABSTRACT FROM AUTHOR]

This work describes the relevance of toxicology studies of environmental chemicals, with a focus on phthalates, for a hypothesis that certain human male reproductive disorders and diseases have a common etiology of disturbance of normal development in utero. The "Testicular Dysgenesis Syndrome" hypothesis in humans has parallels in male reproductive tract abnormalities and microscopic lesions reported for phthalate toxicity in rats. Additionally, this work describes the histological findings of abnormal testicular development (testicular dysgenesis) in rats as compared to those in humans, as well as potential findings in rats at different ages, from the embryo to the adult. [ABSTRACT FROM AUTHOR]

Objective:We aimed to determine the predictive value of additional parameters for differentiating benign-malign tumors and to identify optimal patients for partial orchiectomy in unilateral, small (≤2 cm) testicular masses.Methods:The data of 31 patients who underwent radical orchiectomy between January 2010 and December 2017 due to unilateral and small testicular masses were retrospectively analyzed. Demographic data, histopathological tumor types, serum tumor markers, neutrophil/lymphocyte ratio (NLR), monocyte/ lymphocyte ratio (MLR), platelet/lymphocyte ratio (PLR), mean platelet volume (MPV), red cell distribution width (RDW), the presence of testicular dysgenesis syndrome (TDS) and its components, postoperative follow-up outcomes were recorded. Patients were divided into two groups as benign and malignant.Results:There was no significant difference between groups in terms of AFP (p=0.116), β-hCG (p=0.205), LDH (p=0.606), MPV (p=0.087) and RDW (p=0.266); while MLR (p=0.001), NLR (p=0.036) and PLR (p=0.001) were significantly higher in malignant group. The presences of testicular microlithiasis (p=0.719), undescended testis (p=0.254), hypospadias (p=0.645), atrophic testis (p=0.409) were not different between groups; while the rate of disorders of semen parameters (p=0.043) and presence of TDS (p=0.043) were significantly higher in malignant cases. In multivariate analysis, MLR and PLR were found as predictive factors for benign-malign distinction of small testicular masses.Conclusion:In the patients in whom preoperative malignancy suspicion could not be excluded, we think that PLR, MLR, NLR, disorders of semen parameters and presence of TDS may have high predictive value for benign-malign distinction. Partial orchiectomy may be recommended in patients with suspicion of benign lesions according to these parameters.

Study Question: Is anogenital distance (AGD) shorter in testicular cancer (TC) survivors than in men from the general population, and is AGD affected by testosterone replacement therapy in adulthood?Summary Answer: AGD, measured as distance from anus to scrotum (AGDas), is shorter in TC survivors and does not change as a result of testosterone replacement therapy.What Is Known Already: Animal studies have shown that AGD is a postnatal 'read-out' of foetal androgen action, and short AGD in male offspring is considered a sign of feminization caused by in utero disruption of the reproductive system. Likewise, measurement of AGD in human studies has suggested AGD to be part of the testicular dysgenesis syndrome hypothesis, which proposes that male reproductive disorders, such as hypospadias, cryptorchidism, some cases of impaired semen quality and TC, all share a common foetal origin.Study Design, Size, Duration: The aim was to assess AGD in men with a history of TC and controls, and furthermore to examine AGD during testosterone replacement therapy in adulthood. Study participants were TC survivors with a mild Leydig cell insufficiency who participated in a randomized double-blind study of testosterone replacement therapy versus placebo for 52 weeks (N = 69). Men from the general population were prospectively included from a study on testicular function as controls (N = 67).Participants/materials, Setting, Methods: We measured two variants of AGD; as our primary outcome the anoscrotal distance (AGDas) measured from the centre of the anus to the posterior base of the scrotum, and secondarily the anopenile distance (AGDap) measured from the anus to the cephalad insertion of the penis. Using multiple regression analysis, the mean difference in AGD between TC survivors and men from the general population was assessed, adjusted for height, BMI and examiner. Next, AGD was measured before and after 52 weeks of treatment with testosterone or placebo, and with covariance analysis differences between the two groups at follow-up was assessed after adjustment for baseline AGD, examiner, BMI and change in BMI during treatment.Main Results and the Role Of Chance: TC survivors had a shorter AGDas (-0.84 cm, 95% CI: -1.31; -0.37) compared to men from the general population, and AGDas did not differ between the testosterone and placebo treated group at follow-up (0.11 cm, 95% CI: -0.22; 0.44). In contrast, AGDap was not shorter in TC survivors after adjustment (0.05 cm, 95% CI: -0.30; 0.39), and was 0.48 cm longer (95% CI: 0.13; 0.82) at follow-up in the testosterone treated compared to the placebo-treated group.Limitations, Reasons For Caution: A limitation of the study is that the number of included men was limited, and results need confirmation in a larger study. Furthermore, TC survivors were significantly older than controls. For the comparison of AGD in TC survivors and controls, it was not possible to conduct the examinations with the examiner being blinded to which group he was examining, and it cannot be excluded that this can cause a bias.Wider Implications Of the Findings: The shorter AGDas in TC survivors compared to controls, which did not change upon adult testosterone replacement therapy, supports the hypothesis that reduced AGD is part of the testicular dysgenesis syndrome and may be a marker of disrupted foetal testicular development. By contrast, AGDap was not shorter in TC survivors and might be modestly sensitive to adult testosterone treatment, and thus inferior to AGDas as a constant postnatal marker of the foetal androgen environment.Study Funding/competing Interest(s): Expenses were paid by the Department of Oncology, Copenhagen University Hospital, Rigshospitalet. Kiowa Kirin International covered expenses for Tostran and placebo. The Danish Cancer Society, The Danish Cancer Research Foundation, the Preben & Anna Simonsen Foundation, and Rigshospitalet have supported the study. L.P. was financed by the Research Fund of the Capital Region of Denmark. The authors have no competing interests.Trial Registration Number: Part of the study is based on men participating in a randomized controlled trial registered at ClinicalTrials.gov, NCT02991209, 25 November 2016. [ABSTRACT FROM AUTHOR]

Background: It is not known if impaired fertility in men with hypospadias is caused by decreased semen quality or other factors. Semen quality in men born with hypospadias may be impaired due to effects of androgens or testicular dysgenesis but has been very little studied. Objectives: To study semen quality in men with hypospadias using dizygotic twinning rates as an epidemiological indicator. We further aimed to study men treated for cryptorchidism, given a hypothesized mutual etiology for decreased semen quality. Materials and methods: We conducted a population‐based study using national Swedish registers. A total of 4,363,165 births between 1964 and 2013 were included. The association between hypospadias and cryptorchidism, and fathering dizygotic multiple births was estimated using logistic regression and presented as odds ratios. The main analyses excluded births conceived using assisted reproductive technology (ART). Results: We identified a total of 5317 births with fathers with hypospadias, including 26 dizygotic births conceived unassisted. No significant association was found between hypospadias and dizygotic twinning (OR 1.10, 0.75–1.61). We estimated a significantly increased odds for dizygotic multiple births in men treated for cryptorchidism (OR 1.35, 1.01–1.81) which was decreased after exclusion of ART, but the estimate was not significant (OR 0.75, 0.48–1.18). Discussion: Using dizygotic twinning rates as an indicator of semen quality, we did not find any difference between fathers with hypospadias and controls. Due to sample size, we could not analyze phenotypes separately and can therefore not exclude impaired semen quality in severe hypospadias. We could not demonstrate any association between dizygotic twinning and cryptorchidism. Men treated for cryptorchidism were more likely than controls to use ART to conceive. Conclusion: Men with hypospadias who conceived without ART were not shown to have impaired semen quality using dizygotic twinning as an epidemiological indicator. [ABSTRACT FROM AUTHOR]

Abstract Background Over the last 40 years, there has been a significant increase in the incidence of testicular cancer. The epidemiologic evidence to understand this phenomenon is unclear, however exogenous estrogen exposure is thought to be a driver in the development of testicular cancer. This is of particular importance in the transgender population because utilization of exogenous estrogen therapy is an essential aspect of the transition process. Case We present the case of a 38-year-old Caucasian male to female transgender patient who presented with metastatic testicular cancer 15 months after initiating estrogen therapy. She presented to our emergency department with worsening back pain and fatigue. A clinical examination revealed a right-sided testicular mass. A computed tomography scan of her abdomen/pelvis identified a right groin lesion measuring 6.4 cm, a retroperitoneal mass causing right-sided hydronephrosis, an extensive deep vein thrombosis, and pathologic abdominal lymphadenopathy. Germ cell tumor markers revealed an alpha-fetoprotein of

Objective: The incidence of bilateral testicular germ cell tumours (TGCT) is low and constitutes 0.5%-7% of all testicular tumours. We aimed to evaluate the clinical and pathological features of unilateral and bilateral TGCT, as well as prognostic factors in bilateral cases that may have an impact on oncological outcomes. Materials and Methods: Bilateral TGCT were detected in 10 (11.4%) of 87 patients between January 2010 and July 2016. Patients with 68 unilateral and 10 bilateral tumours (4 synchronous, 6 metachronous) had completely accessible data. We retrospectively evaluated their clinical-pathological data and postoperative follow-up results. Results: Four patients with bilateral synchronous tumours had a seminoma and three (75%) of them had a stage III disease. At a median follow-up of 31.50 (29-37) months, local recurrence, distant metastasis and death were observed in two patients with stage III disease. No recurrence or metastasis was seen in six patients with unilateral TGCT at 33 (24-50) months of follow-up, but metachronous tumours occurred in the contralateral testicles. At a median follow-up of 25 (11-39) months after metachronous tumour development, local recurrence, distant metastasis and death were observed in the contralateral testis of patients with stage III disease. There was no significant difference in bilateral and unilateral cases for disease-free survival, progression-free survival (PFS) and overall survival (OS). PFS and OS were significantly shorter (p=0.039) in bilateral synchronous tumours than in metachronous tumours. Moreover, stage III disease was more common (75% vs 33.3%) in synchronous tumours. Family history (OR: 6.556, p=0.035), testicular dysgenesis syndrome (OR: 3.876, p=0.031), disorders of semen parameters (OR: 2.879, p=0.037), undescended testis (OR: 2.561, p=0.026), monocyte/lymphocyte ratio >0.31 [odds rotio (OR): 2.234, p=0.022], testicular microlithiasis (OR: 2.015, p=0.015) and neutrophil/lymphocyte ratio >3.23 (OR: 1.348, p=0.025) increased the risk of contralateral tumour development. Conclusion: Bilateral synchronous tumours are detected at a more advanced stage and have lower PFS and OS durations, but survival rates are similar to those of unilateral tumours. Long-term follow-up is necessary for patients with unilateral TGCT having certain risk factors due to the possibility of metachronous tumour development in the contralateral testis. [ABSTRACT FROM AUTHOR]

• DINP exposure in the MPW (e15.5–18.5) does not result in effects known for DBP. • DINP exposure in the MPW has no effect ADG on e21.5. • Leydig cell aggregates on e17.5 and e21.5 were not increased. • DINP exposure in the MPW does not induce focal testicular dysgenesis. This study investigates possible effects of in utero exposure of rats to a low dose (125 mg/kg bw/day) and a high dose (750 mg/kg bw/day) of Diisononyl phthalate (DINP) during the masculinisation programming window (MPW) which is embryonic days 15.5–18.5 (e15.5 - e18.5). Dibutyl phthalate (DBP) was used at a high dose level (750 mg/kg bw/day) as an established positive control substance for anti-androgenic effects on the developing male reproductive tract. We focussed on the MPW and measured a multitude of biological endpoints at various life stages and applied state of the art histopathology staining techniques to refine the characterization of potential changes to the testis, beyond what is currently available with DINP. If DINP can mediate testicular dysgenesis (TDS) disorders, this exposure window would be sufficient to induce androgen impacts and alter male reproductive tract development as shown earlier in this validated experimental model with DBP. Overall, the results of this systematic comparison provide convincing evidence on the differences between the effects occurring with DBP and DINP. In contrast to what was seen with DBP, DINP did not cause cryptorchidism or hypospadias, had no effect on anogenital distance/anogenital index (AGD/AGi) and Leydig cell aggregates on e17.5 and e21.5 did not increase. With DINP no reduction of intratesticular testosterone, no effects on sperm motility and sperm count and no effect on adult testosterone or luteinizing hormone (LH) levels were seen. Our results demonstrate that DINP does not cause the adverse reproductive effects known to occur with DBP, a well-established endocrine disruptor. [ABSTRACT FROM AUTHOR]

• Penile length and width measurements in neonates depicted high intra-rater reliability. • Inverse association between penile width and MCPP was not confirmed on multivariate analysis. • No statistically significant associations were identified between phthalate metabolite concentrations and penile length. Our objective was to determine if maternal first trimester urinary phthalate concentrations are associated with reduced penile length (PL) or width (PW) at birth in full term singletons. First trimester phthalate metabolite urinary concentrations were obtained from mothers participating in a Canadian pregnancy cohort study (MIREC). PL and PW were measured shortly after birth in the male offspring. Univariate and multivariable linear regressions were performed to study associations between maternal phthalate exposure and penile measurements, adjusting for confounders. On univariate analysis of 170 mother-infant pairs, PW showed an inverse relationship with the concentration of mono-3-carboxypropyl phthalate (MCPP-p = 0.016), which was not confirmed on multivariable analysis. On multivariable analysis controlling for infant's size and other confounders, no statistically signficant associations between phthalate metabolite concentrations and PL or PW were identified. In this population of Canadian women, there was no strong evidence to suggest an association between maternal first trimester urinary phthalates with PL or PW in term singletons. [ABSTRACT FROM AUTHOR]

• Three histological patterns according to lesion severity can be seen. • Vasculitis and atherosclerosis have been reported for the first time. • Cross-sex hormone therapy should be provided in specialized units. The volume of ubiquitous chemicals with estrogenic properties is on the rise and some reports relate the increase in hormonal diseases to these compounds. A morphological and immunohistochemical analysis has been performed on 42 bilateral orchiectomy specimens from adult individuals who underwent gender reassignment surgery after receiving crossed-sex hormone therapy to give insight into vascular, inflammatory and epididymal changes following long-term treatment with estrogens and antiandrogens and raise awareness of the consequences of hormone therapy. The present study confirms previously reported findings in testicular parenchyma and epididymis, such as identification of three histological patterns according to lesion severity and cell dedifferentiation, and reports for the first time vascular and inflammatory lesions (atherosclerosis and vasculitis), both on testicle and epididymis. Cross-sex hormone therapy should be provided in specialized units in order to systematize treatments and ensure adequate follow-up. [ABSTRACT FROM AUTHOR]

Introduction. There is evidence that disturbed spermatogenesis is associated with impaired Leydig cell function and that it may be the result of testicular dysgenesis during fetal/infant development. Sertoli cell-only syndrome (SCOS) is defined by complete lack of germ cells in the seminiferous epithelium. The pathogenesis of SCOS is still not well understood. The aim of the study is to evaluate testes with SCOS focusing on morphometric signs of testicular dysgenesis and markers of Leydig cell (LC) function in relation to hormonal status of studied infertile men. Materials and methods. Forty-nine testicular biopsies of patients with SCOS and 15 controls with normal spermatogenesis (NOR) were studied. In each biopsy the seminiferous tubule diameter (STD), thickness of tubular membrane (TM), area fraction of intertubular space (AFIS) were measured and semi-quantitative assessment of the LC number was performed (LC-score). The results of histological examination were correlated with serum levels of FSH, LH, testosterone (T) and T/LH ratio. Results. In SCOS group testicular volume (median [M]: 16.0 vs. 29.5; p < 0.001) and STD (M: 141.7 vs. 190.2; p < 0.001) were lower, while TM (M: 9.8 vs. 6.4; p < 0.001) and AFIS (M: 47.6 vs. 27.6; p < 0.001) were significantly higher in comparison to NOR group. LC-score was higher in SCOS than in NOR group (M: 2.2 vs. 1.1; p < 0.001). Abnormal AFIS and STD were present in 43% of SCOS biopsies and among them in 81% the increased LC-score was found. In SCOS group, the subjects had significantly higher levels of both gonadotropins (FSH, M: 19.9 vs. 3.4; p < 0.001; LH, M: 7.1 vs. 4.2; p < 0.001). Total serum testosterone level did not differ between studied groups; however, T/LH ratio was significantly lower in SCOS group (M: 2.3 vs. 3.8; p < 0.001). Negative correlation between LC-score and STD was observed in SCOS group (r = -0.48; p < 0.001). AFIS correlated positively with serum FSH level in NOR (r = 0.53; p < 0.05) and SCOS (r = 0.41; p < 0.05) group, while with LH, and negatively with T/LH ratio, only in SCOS (LH, r = 0.37; p < 0.05; T/LH, r = -0.36; p < 0.05) group. Conclusions. We have shown that substantial number of testes from subjects with SCOS presented abnormal morphometric features, which are recognized as the signs of testicular dysgenesis. Additionally, an increased number of Leydig cells simultaneously with abnormal T/LH ratio were found, which suggests an impaired function of these cells. Increased serum levels of LH and also FSH, may reflect dysfunction of Leydig cells. It seems that reproductive hormones levels reflect also the condition of testicular structure, and that FSH may be related to the changes in intertubular space area independently of impaired Leydig cell function. [ABSTRACT FROM AUTHOR]

Testicular microlithiasis (TM) is one of the symptoms of testicular dysgenesis syndrome (TDS). TM is particularly interesting as an informative marker of testicular germ cell tumors (TGCTs). KIT ligand gene (KITLG), BCL2 antagonist/killer 1 (BAK1), and sprouty RTK signaling antagonist 4 (SPRY4) genes are associated with a high risk of TGCTs, whereas bone morphogenetic protein 7 gene (BMP7), transforming growth factor beta receptor 3 gene (TGFBR3), and homeobox D cluster genes (HOXD) are related to TDS. Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, we investigated allele and genotype frequencies for KITLG (rs995030, rs1508595), SPRY4 (rs4624820, rs6897876), BAK1 (rs210138), BMP7 (rs388286), TGFBR3 (rs12082710), and HOXD (rs17198432) in 142 TGCT patients, 137 TM patients, and 153 fertile men (control group). We found significant differences in the KITLG GG_rs995030 genotype in TM (P = 0.01) and TGCT patients (P = 0.0005) compared with the control. We also revealed strong associations between KITLG_rs1508595 and TM (G allele, P = 0.003; GG genotype, P = 0.01) and between KITLG_rs1508595 and TGCTs (G allele, P = 0.0001; GG genotype, P = 0.0007). Moreover, there was a significant difference in BMP7_rs388286 between the TGCT group and the control (T allele, P = 0.00004; TT genotype, P = 0.00006) and between the TM group and the control (T allele, P = 0.04). HOXD also demonstrated a strong association with TGCTs (rs17198432 A allele, P = 0.0001; AA genotype, P = 0.001). Furthermore, significant differences were found between the TGCT group and the control in the BAK1_rs210138 G allele (P = 0.03) and the GG genotype (P = 0.01). KITLG and BMP7 genes, associated with the development of TGCTs, may also be related to TM. In summary, the KITLG GG_rs995030, GG_rs1508595, BMP7 TT_rs388286, HOXD AA_rs17198432, and BAK1 GG_rs210138 genotypes were associated with a high risk of TGCT development.

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Study Question: When should 'not so rare' Leydig cell tumors (LCTs) of the testis be suspected, diagnosed, and treated?Summary Answer: LCTs are more frequent than generally believed, are associated with male infertility, cryptorchidism and gynecomastia, and should be treated conservatively (in compliant patients) with active surveillance, which appears to be a safe alternative to surgical enucleation.What Is Known Already: Increasing referrals for testicular imaging have led to an increase in findings of LCTs. The features and natural history of these tumors remain largely unknown, as the available studies are small and heterogeneous. LCTs were previously treated aggressively and follow-up data are lacking.Study Design, Size, Duration: A case-cohort study of consecutive patients diagnosed with LCTs over a 10-year period was prospectively enrolled from 2009 to 2018 and compared to matched cohorts of patients with seminomas or no testicular lesions screened in the same timeframe.Participants/materials, Setting, Methods: Of the 9949 inpatients and outpatients referred for scrotal ultrasound, a total of 83 men with LCTs were included. Enrolled subjects underwent medical history and clinical examination and were asked to undergo routine blood tests, hormone investigations (FSH, LH, total testosterone, estradiol, inhibin B, sex hormone-binding globulin (SHBG), prolactin), and semen analysis. Patients who consented also underwent contrast-enhanced ultrasound, elastography, gadolinium-enhanced scrotal magnetic resonance imaging, and hCG stimulation test (5000 IU i.m.) with serum total testosterone and estradiol measured at 0, 24, 48, and 72 hours.Main Results and the Role Of Chance: In total, 83 patients diagnosed with LCTs were compared against 90 patients diagnosed with seminoma and 2683 patients without testicular lesions (NoL). LCTs were diagnosed by enucleation (48.2%), orchiectomy (13.3%), or clinical surveillance (38.5%). Testicular volume, sperm concentration, and morphology were lower (P = 0.001, P = 0.001, and P < 0.001, respectively) in patients with LCTs than in the NoL group. FSH, LH, and SHBG were higher and the testosterone/LH ratio was lower in LCTs than in the NoL group (P < 0.001). The LCT group showed higher SHBG (P = 0.018), lower sperm concentration (P = 0.029), and lower motility (P = 0.049) than the seminoma group. Risk factors for LCTs were cryptorchidism (χ2 = 28.27, P < 0.001), gynecomastia (χ2 = 54.22, P < 0.001), and low testicular volume (χ2 = 11.13, P = 0.001). Five cases were recurrences or bilateral lesions; none developed metastases during follow-up (median, 66 months).Limitations, Reasons For Caution: This study has some limitations. First, hCG and second-line diagnostic investigations were not available for all tumor patients. Second, ours is a referral center for infertility, thus a selection bias may have altered the baseline features of the LCT population. However, given that the comparison cohorts were also from the same center and had been managed with a similar protocol, we do not expect a significant effect.Wider Implications Of the Findings: LCTs are strongly associated with male infertility, cryptorchidism, and gynecomastia, supporting the hypothesis that testicular dysgenesis syndrome plays a role in their development. Patients with LCTs are at a greater risk of endocrine and spermatogenesis abnormalities even when the tumor is resected, and thus require long-term follow-up and prompt efforts to preserve fertility after diagnosis.LCTs have a good oncological prognosis when recognized early, as tissue-sparing enucleation is curative and should replace orchiectomy. Conservative surgery and, in compliant patients, active surveillance through clinical and radiological follow-up are safe options, but require monitoring of testicular failure and recurrence.Study Funding/competing Interest(s): The project was funded by the Ministry of University and Research Grant MIUR 2015ZTT5KB. There are no conflicts of interest.Trial Registration Number: ALCeP trial (ClinicalTrials.gov Identifier: NCT01206270). [ABSTRACT FROM AUTHOR]

Les perturbateurs endocriniens (PE) pourraient être impliqués dans les cancers de la prostate et du testicule, les malformations urogénitales et les troubles de la fertilité. L'objectif de cet article était de réaliser une mise au point sur les PE en urologie et de rapporter les messages clés que l'on peut communiquer à nos patients. Une revue de la littérature a été réalisée sur la base de données PubMed en mars 2019 en utilisant les mots clés : « endocrine disruptor; urology; patient; prostate cancer; testicular cancer; testicular dysgenesis syndrome; malformation; fertility ». Les PE sont des substances d'origine naturelle ou artificielle capables d'interférer avec le système endocrinien à chaque étape du fonctionnement hormonal. L'ensemble de la population est exposé quotidiennement à de multiples PE mais les études en milieu professionnel sont plus nombreuses étant donné l'exposition plus importante dans ce contexte. L'exemple historique du chlordécone, insecticide utilisé dans les bananeraies antillaises illustre l'implication des PE dans le cancer de la prostate. Il existe peu de données concernant le cancer du testicule mais il semblerait que l'exposition in utero aux PE constituerait une fenêtre de susceptibilité. L'altération des qualités du sperme ces dernières décennies pourrait être liée à une exposition croissante aux PE mais les données disponibles reposent sur des études de faible niveau de preuve. Enfin, plusieurs équipes ont rapporté une association entre syndrome de dysgénésie testiculaire et exposition in utero et néonatale aux PE. Les données préliminaires concernant l'effet des PE en urologie rapportent une implication possible dans le cancer de la prostate, du testicule, les malformations urogénitales et les troubles de la fertilité. L'urologue doit être en mesure d'informer et d'aider les patients à se prémunir contre cette exposition. Endocrine disruptors may be involved in prostate and testicular cancers, urogenital malformations and fertility disorders. The purpose of this article was to provide an update on endocrine disruptors in urology and to report key messages that can be communicated to our patients. A review of the literature was conducted on the PubMed database in March 2019 using the keywords: "endocrine disruptor; urology; patient; prostate cancer; testicular cancer; testicular dysgenesis syndrome; malformation; fertility". Endocrine disrupters are substances of natural or artificial origin that can interfere with the endocrine system at each stage of hormonal function. The entire population is exposed to multiple endocrine disrupters on a daily basis, but more studies are being conducted in the workplace because of the higher exposure in this context. The historical example of chlordecone, an insecticide used in Caribbean banana plantations, illustrates the involvement of endocrine disrupters in prostate cancer. There are few data on testicular cancer, but it would appear that in utero exposure to endocrine disruptors would provide a window of susceptibility. The deterioration in sperm quality in recent decades may be linked to increasing exposure to endocrine disrupters, but the available data are based on studies with a low level of evidence. Finally, several teams have reported an association between testicular dysgenesis syndrome and in-utero and neonatal exposure to endocrine disruptors. Preliminary data on the effect of endocrine disruptors in urology report possible involvement in prostate cancer, testicular cancer, urogenital malformations and fertility disorders. The urologist must be able to inform and help patients to guard against this exposure. [ABSTRACT FROM AUTHOR]

Study Question: Does cord blood androgen level obtained at birth affect the AGD in human newborns?Summary Answer: In human newborns, though males have a significantly longer AGD compared to females (as early as 22 weeks of gestation) the AGD is not affected by androgen levels at birth in both the sexes.What Is Known Already: Animal studies have reported a critical time period in early fetal life, termed the masculinization programming window (MPW) during which AGD is fixed by in utero androgen action and is unaffected by testosterone levels later during gestation. Thus, AGD may serve as a lifelong biomarker of androgen exposure during this window. This MPW is hypothesized to occur in humans at 8-14 weeks of gestation during which AGD is fixed. The effect of androgens (testosterone) on AGD after the MPW in humans is not known. Furthermore, altered AGD has been associated with various human reproductive health disorders in both males and females.Study Design, Size, Duration: A prospective descriptive cohort study was performed using data from randomly selected neonates (n = 205) born at a single center over a period of 1 year (August 2015 to August 2016).Participants/materials, Setting, Methods: AGDs in male (n = 117) and female infants (n = 88) together with penile width, glans girth and stretched penile length were measured by trained caregivers. Gestation ranged from 22 to 41 weeks and infants were examined within 24 h of birth (within 48-72 h in very sick preterm infants after clinical stabilization). AGD-1 was measured from the center of the anus to the posterior base of scrotum in males or to the posterior fourchette in females. AGD-2 was measured from the center of the anus to the anterior base of the penis in males or to the clitoris in females. Sex steroid hormones (testosterone, 17-OH progesterone (17-OHP) and androstenedione) were measured in serum prepared from umbilical cord blood samples taken at birth, using liquid chromatography-tandem mass spectrometry.Main Results and the Role Of Chance: Males had a significantly lower gestational age (mean ± SD; 34.6 ± 4.9 versus 36.1 ± 4.1 weeks, P = 0.04), and a significantly longer AGD-1 (mean ± SD; 21.6 ± 6.0 versus 12.7 ± 3.8 mm, P < 0.001) and AGD-2 (41.9 ± 8.7 versus 33.9 ± 7.1 mm, P = 0.004) compared to female infants, respectively. The cord serum testosterone levels were significantly higher for male than female infants [median, interquartile range; 13.0 (7.3, 20.5) versus 4.1 (2.5, 5.9), ng/dl, P < 0.001]. There was no difference in levels of 17-OHP (P = 0.697) or androstenedione (P = 0.601) between the two sexes. On multiple regression analysis after adjusting for potential confounders, none of the AGD's in both males and females correlated with any sex steroid hormonal levels. We also provide normative charts for penile length, penile width and glans girth in preterm and term infants.Limitations, Reasons For Caution: No data were collected on family history of genital malformation, infertility or hormonal disorders, parental endocrine-disrupting chemical exposure or diet pattern, any of which might have influenced the AGD and/or sex steroid hormone levels in the offspring.Wider Implications Of the Findings: Our results suggest that AGD in humans, like animals, is fixed in early gestation (likely during the hypothesized MPW) and is unaffected by androgen levels thereafter. Thus, AGD can serve as a biomarker of in utero androgen action during early gestation (likely 8-14 weeks) in humans. As such, causes of human newborn and adult reproductive health disorders, such as endocrine disruptors, should be explored during early gestation. However, further larger studies are needed to help corroborate these findings.Study Funding/competing Interests: No specific funding was obtained for this study, and all authors have no conflict of interest to declare. [ABSTRACT FROM AUTHOR]

Despite concerns of the scientific community regarding the adverse effects of human exposure to exogenous man-made chemical substances or mixtures that interfere with normal hormonal balance, the so called “endocrine disruptors (EDs)”, their production has been increased during the last few decades. EDs' extensive use has been implicated in the increasing incidence of male reproductive disorders including poor semen quality, testicular malignancies and congenital developmental defects such as hypospadias and cryptorchidism. Several animal studies have demonstrated that exposure to EDs during fetal, neonatal and adult life has deleterious consequences on male reproductive system; however, the evidence on humans remains ambiguous. The complexity of their mode of action, the differential effect according to the developmental stage that exposure occurs, the latency from exposure and the influence of the genetic background in the manifestation of their toxic effects are all responsible factors for the contradictory outcomes. Furthermore, the heterogeneity in the published human studies has hampered agreement in the field. Interventional studies to establish causality would be desirable, but unfortunately the nature of the field excludes this possibility. Therefore, future studies based on standardized guidelines are necessary, in order to estimate human health risks and implement policies to limit public exposure. [ABSTRACT FROM AUTHOR]

Cryptorchidism and hypospadias are the most common congenital anomalies of the genitourinary tract in males, but their etiology remains unclear. Placental insufficiency has been suggested to be linked to both conditions. Placental weight is a commonly used proxy measure for placental insufficiency; thus, we examined placental weight and other placental characteristics in relation to cryptorchidism and hypospadias in the Collaborative Perinatal Project, a US mother-child cohort study. Pregnant women were recruited between 1959 and 1965. The analysis contrasted boys with cryptorchidism (n = 413) and boys with hypospadias (n = 145) with boys without cryptorchidism (n = 23,799) and boys without hypospadias (n = 22,326). Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. In categorical analyses in which the middle tertile was the referent, cryptorchidism was inversely associated with placental weight (odds ratio = 0.66, 95% confidence interval: 0.46, 0.95) among white boys and positively associated with the lowest tertile of placental weight among black boys (odds ratio = 1.70, 95% confidence interval: 1.11, 2.59). We conclude that lower placental weight may be related to risk of cryptorchidism. Further investigation of placental functioning may offer insights into the etiology of cryptorchidism. [ABSTRACT FROM AUTHOR]

Testicular dysgenesis syndrome is a testicular development disorder that can lead to congenital malformations in boys (hypospadias, cryptorchidism) but also an increased risk of testicular cancer and poor semen quality at adulthood. First described in 2001 by Niels Skakkebaek's team, several pathophysiological hypotheses have been proposed but environmental factors constitute main determinants, especially during fetal life. This article reviews all the publications concerning the pathophysiological data concerning the testicular dysgenesis syndrome. [ABSTRACT FROM AUTHOR]

The period of the first to second trimester transition in human pregnancy represents a sensitive window for fetal organogenesis, particularly in regard to the development of the male reproductive system. This is a time of relative analytical inaccessibility. We have used a large national biobank of amniotic fluid samples collected at routine amniocentesis to determine the impacts of exogenous endocrine disruptor load on specific fetal biomarkers at this critical time. While adrenal and testicular steroids are highly correlated, they are also mostly positively influenced by increasing phthalate load, represented by the metabolites 7cx-MMeHP and 5cx-MEPP, by perfluorooctane sulfonate (PFOS) exposure, and by smoking, suggesting an adrenal stress response. In contrast, the testis specific biomarkers insulin-like peptide 3 (INSL3) and androstenedione are negatively impacted by the phthalate endocrine disruptors. Using a case--control design, we show that cryptorchidism and hypospadias are both significantly associated with increased amniotic concentration of INSL3 during gestational weeks 13--16, and some, though not all steroid biomarkers. Cases are also linked to a specifically increased variance in the Leydig cell biomarker INSL3 compared to controls, an effect exacerbated by maternal smoking. No influence of phthalate metabolites or PFOS was evident on the distribution of cases and controls. Considering that several animal and human studies have shown a negative impact of phthalate load on fetal and cord blood INSL3, respectively, the present results suggest that such endocrine disruptors may rather be altering the relative dynamics of testicular development and consequent hormone production, leading to a desynchronization of tissue organization during fetal development. Being born small for gestational age appears not to impact on the testicular biomarker INSL3 in second trimester amniotic fluid. [ABSTRACT FROM AUTHOR]

Progressive increases in the incidence of male reproductive disorders inclusive of hypospadias, cryptorchidism, poor semen quality, and testicular germ cell cancer (TGCC) have been observed in recent times. The central hypothesis of this study asserted that these disorders may all collectively signify testicular dysgenesis syndrome (TDS). This review aimed to provide evidence verifying the reality of TDS based on four key aspects: environmental endocrine-disrupting chemicals (EDCs), genetic factors, intrauterine growth disorders and lifestyle factors. Although TDS might result from genetic polymorphisms or aberration, recent evidence has highlighted links indicating the conditions associations to both environmental and lifestyle factors due to the rapid temporal changes in the clinical symptoms observed over recent decades. Based on our review of genetic and environmental factors, a key observation of our study suggested that there is an urgent need to prioritize research in reproductive physiology and pathophysiology, particularly in highly industrialized countries facing decreasing populations. At present, current research has yet to elucidate the mechanisms of TDS, in addition to the lack of genuine consideration of a variety of potentially key factors and TDS mechanisms. In conclusion, our study revealed that environmental exposures owing to modern lifestyles are primary factors involved in the associated trends of the syndrome, which are capable of affecting the adult endocrine system via direct means or through epigenetic mechanisms. [ABSTRACT FROM AUTHOR]

Environmental chemical (EC) exposure may be impacting male reproductive health. The translationally relevant biosolids treated pasture (BTP) sheep model was used to investigate gestational low-level EC mixture exposure on the testes of F1 male offspring. Adult rams from ewes exposed to BTP 1 month before and throughout pregnancy had more seminiferous tubules with degeneration and depletion of elongating spermatids, indicating possible "recovery" from previously reported testicular dysgenesis syndrome-like phenotype in neonatal and pre-pubertal BTP lambs. Expression of transcription factors CREB1 (neonatal) and BCL11A and FOXP2 (pre-pubertal) were significantly higher in the BTP exposed testes, with no changes seen in adults. Increased CREB1 , which is crucial for testes development and regulation of steroidogenic enzymes, could be an adaptive response to gestational EC exposure to facilitate the phenotypic recovery. Overall, this demonstrates that testicular effects from gestational exposure to low-level mixtures of ECs can last into adulthood, potentially impacting fertility and fecundity. • Testis development affected by gestational environmental chemical mixture exposure. • Adult phenotypic "recovery" from TDS-like phenotype in neonatal and pre-pubertal. • mTOR signalling a repeat finding in foetal, neonatal, pre-pubertal and adult testes. • HIF1α activation highest in neonatal, then pre-pubertal, but absent in adult testes. • Higher testes expression of CREB1 (neonatal) and BCL11A and FOXP2 (pre-pubertal). [ABSTRACT FROM AUTHOR]

Study Question: What is the familial childhood mortality in first-degree (FDR) and second-degree relatives (SDR) of patients undergoing semen analysis (SA)?Summary Answer: The relationship between infertility and congenital malformations (CM) in offspring is complex, with an increased risk of death due to CM in FDR, but not SDR, of men with lower semen parameters.What Is Known Already: Semen quality is an established predictor of men's somatic health. We can gain a better understanding of possible genetic or environmental determinants of the infertility phenotype by exploring familial aggregation of childhood mortality in relatives of men with poor semen quality.Study Design, Size, Duration: Retrospective cohort study from the Subfertility, Health and Assisted Reproduction study (cohort compiled 1996-2011) linked with patient/familial information from the Utah Population Database (UPDB). Index cases included a clinic-referred sample of 12 889 men who underwent SA and had adequate familial and follow-up data in the UPDB. Parameters of semen quality included: semen concentration, sperm count, motility, total motile count, sperm head morphology, sperm tail morphology and vitality.Participants/materials, Setting, Methods: SA data were collected from two tertiary medical center andrology laboratories that have captured ~90% of all SA performed in Utah since 2004. Age- and sex-matched fertile controls were selected to create the comparison group for determining risk of childhood death (to age 20 years) in family members. A total of 79 750 siblings and 160 016 aunts/uncles were used to investigate the familial aggregation of childhood mortality. The main outcome was childhood mortality in FDR and SDR of men with SA and their matched controls. All-cause and cause-specific Cox proportional hazard models were used to test the association between semen quality and childhood mortality in family members. Cause-specific models were considered for cancer and CM.Main Results and the Role Of Chance: In the cohort of men with SA, there were 406 (1.0%) deaths in FDR and 772 (1.1%) deaths in SDR due to any cause. There was no significant difference in the risk of all-cause childhood mortality between the relatives of men with SA and the fertile control group [hazard ratio (HR)Female = 1.08, 95% CI = 0.88, 1.32; HRMale = 0.88, 95% CI = 0.75, 1.04]. We found no association between semen quality and risk for childhood cancer mortality in FDR or SDR (HRFDR = 0.98, 95% CI = 0.62, 1.54; HRSDR = 1.12, 95% CI = 0.83, 1.50). The FDR of men with SA and fertile controls were followed on average for 19.71 and 19.73 years, respectively. During this period of follow-up, FDR of men with SA had an unadjusted 40% relative risk of increased CM-related death. After stratifying by semen parameters and adjusting for birth year, we found FDR of men with worse semen quality, and notably azoospermic men (HR = 2.69, 95% CI = 1.24,5.84), were at higher risk of CM-related death.Limitations Reasons For Caution: A large proportion of men with SA in the study had normal semen parameters. It is important to note that these men themselves may not be subfertile, but they were subfertile at the couple level (i.e. the female partner may be infertile). In addition, care is needed when interpreting our results, as we do not have semen measures on our sample of fertile men. Second, we were unable to include potential confounders such as medical comorbidities, smoking status, or environmental exposures. Third, men with SA were seen at the University of Utah or Intermountain Health Care clinics for a fertility evaluation thereby suggesting a more select population. Fourth, we chose to categorize morphology into equally distributed quartiles as a response to the fact that the World Health Organization threshold for normal motility changed multiple times during our study period. Lastly, we do not know the proportion of female partners with diagnosed infertility. We chose not to subcategorize each infertile male by infertile diagnosis because our goal was to understand how semen parameters influenced familial childhood mortality.Wider Implications Of the Findings: We are not the first study to show a relationship between fertility and CMs. Children conceived through ART may be at higher risk of birth defects, however it is not known if the relationship is causal or if there is some underlying factor linking infertility and birth outcomes. This study provides further evidence that the increased risk of congenital birth defects may not be due to the ART, but rather genetic or environmental factors that link the two outcomes. We encourage further research in order to confirm a relationship between semen quality and increased risk for CM.Study Funding/competing Interests: This work was supported by the National Institutes of Health - National Institute of Aging [Grant numbers 1R21AG036938-01, 2R01 AG022095 and 1K12HD085852-01]. Authors have no competing interests to disclose.Trial Registration Number: Not applicable. [ABSTRACT FROM AUTHOR]

Study Question: What is the relationship between maternal paracetamol intake during the masculinisation programming window (MPW, 8-14 weeks of gestation) and male infant anogenital distance (AGD), a biomarker for androgen action during the MPW?Summary Answer: Intrauterine paracetamol exposure during 8-14 weeks of gestation is associated with shorter AGD from birth to 24 months of age.What Is Already Known: The increasing prevalence of male reproductive disorders may reflect environmental influences on foetal testicular development during the MPW. Animal and human xenograft studies have demonstrated that paracetamol reduces foetal testicular testosterone production, consistent with reported epidemiological associations between prenatal paracetamol exposure and cryptorchidism.Study Design, Size, Duration: Prospective cohort study (Cambridge Baby Growth Study), with recruitment of pregnant women at ~12 post-menstrual weeks of gestation from a single UK maternity unit between 2001 and 2009, and 24 months of infant follow-up. Of 2229 recruited women, 1640 continued with the infancy study after delivery, of whom 676 delivered male infants and completed a medicine consumption questionnaire.Participants/materials, Setting, Method: Mothers self-reported medicine consumption during pregnancy by a questionnaire administered during the perinatal period. Infant AGD (measured from 2006 onwards), penile length and testicular descent were assessed at 0, 3, 12, 18 and 24 months of age, and age-specific Z scores were calculated. Associations between paracetamol intake during three gestational periods (<8 weeks, 8-14 weeks and >14 weeks) and these outcomes were tested by linear mixed models. Two hundred and twenty-five (33%) of six hundred and eighty-one male infants were exposed to paracetamol during pregnancy, of whom sixty-eight were reported to be exposed during 8-14 weeks. AGD measurements were available for 434 male infants.Main Results and the Role Of Chance: Paracetamol exposure during 8-14 weeks of gestation, but not any other period, was associated with shorter AGD (by 0.27 SD, 95% CI 0.06-0.48, P = 0.014) from birth to 24 months of age. This reduction was independent of body size. Paracetamol exposure was not related to penile length or testicular descent.Limitations, Reasons For Caution: Confounding by other drugs or endocrine-disrupting chemicals cannot be discounted. The cohort was not fully representative of pregnant women in the UK, particularly in terms of maternal ethnicity and smoking prevalence. There is likely to have been misclassification of paracetamol exposure due to recall error.Wider Implications Of the Findings: Our observational findings support experimental evidence that intrauterine paracetamol exposure during the MPW may adversely affect male reproductive development.Study Funding/competing Interests: This work was supported by a European Union Framework V programme, the World Cancer Research Fund International, the Medical Research Council (UK), the Newlife Foundation for Disabled Children, the Evelyn Trust, the Mothercare Group Foundation, Mead Johnson Nutrition, and the National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre. The authors declare no conflict of interest. [ABSTRACT FROM AUTHOR]