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Diabetes mellitus (DM) is a global health burden, affecting about 463 million of the adult population worldwide. Approximately 94% of diabetic male individuals develop varying degrees of testicular disorders (TDs), which usually result in hypogonadism, hypotestosteronemia and defective spermatogenesis and steroidogenesis. Short chain fatty acids (SCFAs) have shown potential benefits in metabolic health. However, its effect on TD associated with DM is not clear. Howbeit, the present study investigated the hypothesis that SCFAs, acetate would ameliorate TD accompanying DM, possibly by suppressing proprotein convertase subtilisin/kexin type 9 (PCSK9). Male Wistar rats (210–240 g) were allotted into groups (n = 6/group): control (vehicle; po), DM with/without 200 mg/kg (po) of sodium acetate (SAc). Diabetes was induced by streptozotocin 65 mg/kg (iv) after a dose of nicotinamide (110 mg/kg). Semen/biochemical and histological analyses were performed with appropriate methods. In addition to hyperglycemia, hyperinsulinemia and reduced insulin sensitivity, DM led to increased serum and testicular triglyceride or total cholesterol/high-density lipoprotein cholesterol ratio, low-density lipoprotein cholesterol, malondialdehyde, TNF-α, IL-6 and PCSK9 as well as reduced high-density lipoprotein cholesterol and glutathione. Moreover, DM caused TD which is characterized by altered sperm parameters, disrupted tissue architecture, atrophied seminiferous tubules, deleterious spermatogonia, disappearance of lumen and cellular degeneration as well as decreased luteinizing hormone and testosterone. However, the administration of SAc attenuated these alterations. The study demonstrates that DM-induced TD is accompanied by elevated PCSK9. The results however suggest that SAc rescues testicular disorder/dysfunction associated with DM by suppression of PCSK9 and improvement of insulin sensitivity.

Graphical abstract, Diabetes mellitus is a well-known danger element for the progression of male reproductive dysfunctions. Available evidence supports oxidative stress to be the underlying mechanism for the manifestation of testicular dysfunctions during diabetes, and this relation represents an attractive target to antagonize these complications. Artemisia judaica L. is known to have antidiabetic and antioxidant characteristics. The possible protective effect of Artemisia judaica against diabetes-induced testicular disorders was not explored. In this investigation, we planned to estimate the possible protective effect of Artemisia judaica extract against diabetes-induced testicular disorders in male rats. The blood levels of insulin, glucose, glycosylated hemoglobin, testosterone, luteinizing hormone and follicle stimulating hormone were evaluated in rats after 12 weeks of Artemisia judaica treatment. Further, oxidative stress markers were determined in their testicular tissue. Epididymal fluid and testicular histological changes were also assessed. Expression of proliferating cell nuclear antigen has been evaluated in testis. Testicular mRNA expression of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 as the significant transcription factors in controlling antioxidant system were evaluated by real-time polymerase chain reaction. Artemisia judaica extracts have the ability to ameliorate the elevation in the serum glucose and blood glycosylated hemoglobin and the reduction in insulin, testosterone, follicle stimulating hormone and luteinizing hormone caused by streptozotocin-induced diabetes. It induced a significant recovery of the testicular oxidative stress markers, sperm characteristics and improved histopathological findings of the testes. Treatment with Artemisia judaica extracts led to an increase in proliferating cell nuclear antigen protein expression. Reduction of testicular oxidative stress potential in streptozotocin-treated groups was confirmed by upregulation of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1.

ContextMale infertility is defined as the inability to conceive following 1 year of regular unprotected intercourse. It is the causative factor in 50% of couples and a leading indication for assisted reproductive techniques (ART). Testicular failure is the most common cause of male infertility, yet the least studied to date.Evidence AcquisitionThe review is an evidence-based summary of male infertility due to testicular failure with a focus on etiology, clinical assessment, and current management approaches. PubMed-searched articles and relevant clinical guidelines were reviewed in detail.Evidence Synthesis/ResultsSpermatogenesis is under multiple levels of regulation and novel molecular diagnostic tests of sperm function (reactive oxidative species and DNA fragmentation) have since been developed, and albeit currently remain as research tools. Several genetic, environmental, and lifestyle factors provoking testicular failure have been elucidated during the last decade; nevertheless, 40% of cases are idiopathic, with novel monogenic genes linked in the etiopathogenesis. Microsurgical testicular sperm extraction (micro-TESE) and hormonal stimulation with gonadotropins, selective estrogen receptor modulators, and aromatase inhibitors are recently developed therapeutic approaches for men with the most severe form of testicular failure, nonobstructive azoospermia. However, high-quality clinical trials data is currently lacking.ConclusionsMale infertility due to testicular failure has traditionally been viewed as unmodifiable. In the absence of effective pharmacological therapies, delivery of lifestyle advice is a potentially important treatment option. Future research efforts are needed to determine unidentified factors causative in “idiopathic” male infertility and long-term follow-up studies of babies conceived through ART.

Male Breast Carcinoma (MBC) is a rare condition accounting for risk factor includes hormonal imbalance, Klinefelter syndrome, testicular disorders, radiation exposure, alcoholism and antiandrogenic medication. MBC clinically manifests as painless palpable mass sometimes masquerading gynecomastia. Compared with female breast cancer, male breast carcinoma presents slightly older age at diagnosis with large tumor size and most of the tumors hormone receptor positive. We come across chronic alcoholic male presented with fungating growth over left breast. Cytology revealed neuroendocrine type of infiltrating ductal carcinoma cells, whereas biopsy showed various histological patterns in sections from different areas making this case interesting one. Immunohistochemically, it was positive for estrogen and progesterone receptor but negative for Her2neu marker. Keywords: Male Breast Carcinoma, Comedocarcinoma, Neuroendocrine, Cribriform, Schirrous, Mucinous.

Objectives: The 46,XX disorders of sex development (DSD) is a rare genetic cause of male infertility and possible misdiagnosis of this condition has never been reported. We aim to investigate clinical characteristics and laboratory results of infertile males with possibly misdiagnosed 46,XX DSD. Methods: Between January 2008 and December 2017, a retrospective case series study was performed involving sixteen 46,XX DSD males without azoospermia factor (AZF) deletion. Demographics, clinical features, laboratory results and assisted reproductive technology (ART) outcomes of these patients were depicted, and the underlying accurate diagnosis was also discussed. Results: The mean age was 30.06 ± 5.40 years old. Thirteen patients (81.25%) merely obtained secondary school education. Gynaecomastia occurred in one case, and cryptorchidism appeared in two cases. Testicular volumes were equal to 15 mL on two sides in one patient who had severe asthenozoospermia. Thirteen patients (81.25%) had bilateral atrophic testes which were below 5 mL. The majority of patients were observed with elevated levels of gonadotropic hormones and decreased testosterone values. Neither AZF region nor sex-determining region Y gene was absent among all patients. Twelve patients had normal ejaculatory function, whereas four were diagnosed with ejaculatory dysfunction. Eleven patients (68.75%) were diagnosed with azoospermia. Testicular sperm aspiration was performed in six subjects (37.50%). The pathological results showed that Leydig cell hyperplasia with spermatic failure was found in each case, and no sperm was found in testicular tissue. ART with donor sperm was conducted in 15 patients. Live birth was achieved in three cases through artificial insemination by donor and in one case using in-vitro fertilization by donor. Conclusions: Chromosomal analysis rarely yields 46,XX karyotype combined with no deletion of AZF in infertile males. Under this condition, molecular analysis should be conducted to avoid potential misdiagnosis and false interpretation of other findings.

Cisplatin is widely used as one of the most effective anticancer agents in the treatment of some neoplasms. Reproductive toxicity is the most common outcome associated with cisplatin testicular damage. Alternative natural medicines for treating male testicular disorders and infertility have received extensive attention in research. Natural products, medicinal herbs, and their secondary metabolites have been shown as promising agents in the management of testicular damage induced by chemotherapy drugs. This study aimed to review the research related to natural substances that are promising in mitigation of the cisplatin-induced toxicity in the reproductive system. PubMed and Scopus were searched for studies on various natural products for their potential protective property against reproductive toxicity induced by cisplatin from 2000 to 2020. Eligibility was checked based on selection criteria. Fifty-nine articles were included in this review. Mainly in animal studies, several natural agents have positively affected cisplatin-reproductive-toxicity factors, including reactive oxygen species, inflammatory mediators, DNA damage, and activation of the mitochondrial apoptotic pathway. Most of the natural agents were investigated in short-term duration and high doses of cisplatin exposure, considering their antioxidant activity against oxidative stress. Considering antioxidant properties, various natural products might be effective for the management of cisplatin reproductive toxicity. However, long-term recovery of spermatogenesis and management of low-dose-cisplatin toxicity should be considered as well as the bioavailability of these agents before and after treatment with cisplatin without affecting its anticancer activity.

The testicular disorder of sex development (TDSD) is a rare condition characterized by a male appearance with a female karyotype. The most frequent cause of TDSD is misplacement of the sex determining region Y (SRY) gene on the X chromosome. Here, we report the generation of an induced pluripotent stem cell (iPSC) line from peripheral blood mononuclear cells of a patient with SRY-positive 46,XX TDSD. This cell line offers an unprecedented cellular model to investigate the profound manifestations like infertility of the male sex reversal patients, and serves as a useful tool to develop therapies for the disease.

En la mayoría de los casos, la diferenciación sexual masculina ocurre con la participación del gen SRY. Sin embargo, se pueden presentar otros genotipos excepcionales, como en el caso que se presenta en este reporte.Se trata de un paciente adulto de sexo masculino atendido en el Servicio de Paternidades del Instituto de Genética de la Universidad Nacional de Colombia. Se le hicieron los análisis del gen de la amelogenina y de repeticiones cortas en tándem (Short Tandem Repeat, STR) específicas para el gen SRY con estuches comerciales de identificación humana, así como los de cariotipo convencional e hibridación in situ fluorescente del SRY, y el estudio de microdeleciones del cromosoma Y mediante reacción en cadena de la polimerasa (PCR). Se le hizo la evaluación clínica y se le brindó asesoramiento genético.El paciente no presentaba ambigüedad genital, su cariotipo era 46 XX, y el perfil molecular era negativo para el gen SRY y positivo para el ZFY. Se le diagnosticó un trastorno de diferenciación sexual 46 XX testicular no sindrómico, una rara condición genética. Solo el 20 % de los pacientes con este diagnóstico son negativos para SRY y exhiben perfiles moleculares diversos. La información disponible parece indicar que el ZFY está relacionado con la diferenciación sexual masculina, aún en ausencia del gen SRY.

Health outcomes among men are poorer than women and little efforts have been made by health organizations to promote men’s health. Testicular disorders can have a negative effect on men’s health and are rarely addressed in pre-existing men’s health policies. Findings from the empirical literature on men’s awareness of testicular disorders suggest that men’s knowledge of testicular disorders is lacking and their intentions to seek timely medical attention for testicular symptoms are low. This paper aims to introduce the concept of ‘testicular awareness’ and explore its implications for health research, practice, and education. The key attributes of ‘testicular awareness’ include: (i) familiarity with own testes; (ii) knowing what is normal versus abnormal; (iii) ability to detect an abnormality; and (iv) knowing own risk factors. Testicular awareness is an all-encompassing concept since it helps men become familiar with a body part that is seldom discussed and enables them to detect testicular abnormalities and to seek timely medical attentions for testicular symptoms, regardless of the ultimate diagnosis. Testicular awareness can be promoted using a number of strategies; these include but are not limited to: (i) involving men in drafting men’s health policies that address testicular awareness; (ii) partnering with men to develop and test interventions promoting testicular awareness; (iii) being cognizant of the learning needs of men who are at risk of health disparities including those with low literacy and health literacy; (iv) promoting testicular awareness in clinical practice and health education; and (v) using men’s daily spheres of information (e.g. workplaces, universities, gyms, and community organizations) to promote testicular awareness.

SRY-negative 46,XX testicular disorders of sex development (DSD) are very rare conditions. Recently, we identified a novel heterozygous NR5A1 mutation, p.Arg92Trp (c.274C>T, p.R92W), in 2 unrelated cases of 46,XX testicular/ovotesticular DSD. We report the clinical course from infancy to puberty in a Japanese male with SRY-negative 46,XX testicular DSD, carrying this p.Arg92Trp mutation in NR5A1. The patient naturally acquired the development of a penis and pubic hair during puberty. However, hypergonadotropic hypogonadism subsequently developed. More clinical cases will be needed to fully understand the effects of the p.Arg92Trp mutation on the ability to maintain testosterone secretion in 46,XX testicular DSD.

The purpose of this paper was to analyse the aetiology and methods of diagnosing reproductive disorders in male dromedary camels. Male camel infertility manifests as one of three conditions: post-coital infertility (IG), inability to copulate (IC) and lack of sexual desire (LSD). IG is mainly a testicular disorder that is linked to a deteriorated seminogram, arrested spermatogenesis, Sertoli cell-only syndrome and testicular degeneration. For IG diagnosis, semen analysis, testicular biopsy and fine-needle aspiration are gold standards. Testicular ultrasonography was generally inefficient. High serum FSH was found in IG camels with oligo- and azoospermia, implying primary spermatogenesis defects. The testis-expressed protein (TEX101) and the epididymis-expressed protein (ECM1) are reliable biomarkers for distinguishing between obstructive and non-obstructive azoospermia. IC manifests in two forms: phimosis (PHI) and erectile dysfunction (ED). PHI is frequently linked to preputial and penile pathologies, as well as leucocytosis, neutrophilia and elevated nitric oxide metabolites. The majority of camels with ED have normal genital organs, and the condition is associated with an increase in cardiac troponin I. LSD is a rare disorder brought on by hormonal imbalances, high temperatures, stress and debilitating diseases. In conclusion, IG diagnosis necessitates semen analysis, testicular biopsy or fine-needle aspiration, and FSH testing, whereas IC diagnosis requires preputial and penile examinations. Diagnostic aids include serum and seminal biomarkers.

Acquired testicular disorders are a spectrum of disease characterized by the presence of testicular damage that may recognize traumatic etiology or, less frequently, may be due to environmental pollutants or drug adverse reactions, i.e., antiandrogens or corticosteroids. Even if traumatic disorders may often affect young adolescents, they are rather frequent also in adult life, while post-infective disease is more frequent in adult and elderly men. Recognizing clinical signs, diagnosis, and treatment options is important for clinicians to prevent infertility and associated sexual disturbances in most cases. This chapter will discuss most important features for diagnosing acquired testicular disease and its treatment.

Herein, for the first time, the potential relationships between the cytoskeleton-associated proteins DAAM1 and PREP with different testicular disorders, such as classic seminoma (CS), Leydig cell tumor (LCT), and Sertoli cell-only syndrome (SOS), were evaluated. Six CS, two LCT, and two SOS tissue samples were obtained during inguinal exploration in patients with a suspect testis tumor based on clinical examination and ultrasonography. DAAM1 and PREP protein levels and immunofluorescent localization were analyzed. An increased DAAM1 protein level in CS and SOS as compared to non-pathological (NP) tissue was observed, while LCT showed no significant differences. Conversely, PREP protein level increased in LCT, while it decreased in CS and SOS compared to NP tissue. These results were strongly supported by the immunofluorescence staining, revealing an altered localization and signal intensity of DAAM1 and PREP in the analyzed samples, highlighting a perturbed cytoarchitecture. Interestingly, in LCT spermatogonia, a specific DAAM1 nuclear localization was found, probably due to an enhanced testosterone production, as confirmed by the increased protein levels of steroidogenic enzymes. Finally, although further studies are needed to verify the involvement of other formins and microtubule-associated proteins, this report raised the opportunity to indicate DAAM1 and PREP as new potential markers, supporting the cytoskeleton dynamics changes occurring during normal and/or pathological cell differentiation.

The risk of a gonadal tumor is high in testicular disorder of sexual development (DSD) with the Y chromosome, but cases of DSD without the Y chromosome are extremely rare. We reported a gonadal tumor in a phenotypically male individual with 46, XX testicular DSD. A testicular tumor was incidentally found in a 32-year-old phenotypic male who was presented to the hospital with male infertility. A diagnosis of 46, XX testicular DSD was made by the presentation of karyotype analysis of 46, XX with the sex-determining region of the Y chromosome (SRY) positive and gonadal tissue without female gonads. Surgery was performed due to a gradually growing tumor. The partial orchidectomy was performed with the diagnosis of a benign Leydig cell tumor in frozen biopsy.

The follicle-stimulating hormone receptor (FSH-R) expression was always considered human gonad-specific. The receptor has also been newly detected in extragonadal tissues. In this finding, we evaluated FSH-R expression in the human male early genital tract, in testicular tumors, and in sperm from healthy and varicocele patients. In sperm, we also studied the mechanism of FSH-R action. Immunohystochemistry and Western blot analysis showed FSH-R presence in the first pathways of the human genital tract, in embryonal carcinoma, and in sperm, but it was absent in seminoma and in lower varicocele. In sperm, FSH/FSH-R activity is mediated by G proteins activating the PKA pathway, as we observed by using the H89. It emerged that increasing FSH treatments induced motility, survival, capacitation, and acrosome reaction in both sperm samples. The different FSH-R expression in tumor testicular tissues may be discriminate by tumor histological type. In spermatozoa, FSH-R indicates a direct action of FSH in these cells, which could be beneficial during semen preparation for in vitro fertilization procedures. For instance, FSH positive effects could be relevant in idiopathic infertility and in the clinic surgery of varicocele. In conclusion, FSH-R expression may be considered a molecular marker of testicular disorders.

International audience; Testicular disorder of sex development (TDSD) is a rare condition, characterised by a female karyotype, male phenotype, small testes and cryptorchidism. Only a few studies have investigated the genetic causes of male sex reversal. This is the clinical report of an Iranian 46,XX patient presented with TDSD and associated with hypospadias. Whole-exome sequencing (WES) of the patient ascertained the heterozygous missense variant (c.274C>T) in the NR5A1 gene, resulting in a substitution of arginine with tryptophan. The arginine 92 residue was located in a highly conserved region of steroidogenic factor 1 (SF1), which is crucial for its interaction with DNA. Our finding is in line with previous reports, which highlighted the role of p.(Arg92Trp) variant in TDSD individuals. As far as we are aware, this is the first report of TDSD with p.(Arg92Trp) variant in the Iranian population.

Testicular cancer is the most common cancer among men younger than 50, and benign testicular disorders such as torsion and epididymitis can be life-threatening if left untreated. Men’s awareness of testicular disorders is lacking, and their intentions to see help for symptoms of testicular disease are low. This study aimed to describe the development, feasibility, and usability of a virtual reality (VR) intervention designed to enhance men’s awareness of testicular disorders (E-MAT). We designed E-MAT as a three-level VR experience and tested its feasibility and usability with 15 men recruited from a university. Following exposure to the intervention, participants filled a 43-item questionnaire. Participants agreed that the technology was comfortable to use, testicular disorders were well represented, the use of light humor was appropriate, and the scientific facts were easy to understand. Participants also agreed that the intervention was suited for men from different sociodemographic backgrounds and felt confident using VR. Overall, participants perceived the intervention as user-friendly, enjoyable, and aesthetically appealing. To the best of our knowledge, VR has not been used to promote men’s health in the past, let alone increasing their awareness and help seeking for testicular disorders. We recommend testing the effectiveness of E-MAT and making it available on public platforms that men can access at their own leisure. VR can be used in future interventions to educate men about various health topics.

Aims As nitric oxide (NO) production is essential for insulin signaling, glucose uptake, endothelial function, and regulation of apoptosis, the loss of bioavailable NO may be a mechanism underlying the development of diabetes complication. Dietary nitrate acts as a substrate for NO generation, thus serving as a physiological source of NO. This study evaluated the therapeutic effects of nitrate supplementation on the apoptosis-induced testicular disorders in diabetic rats. Main methods Fifty male Wistar rats were divided into five groups; control, control with 100 mg/L nitrate in distilled drinking water, diabetes, diabetes treated with 2–4 U/day NPH insulin, diabetes treated with 100 mg/L nitrate in distilled drinking water. After 8 weeks, blood samples, testis, and epididymis were collected to assess the apoptosis process and the stereology of testis tissue, sperm motility, morphology and DNA fragmentation, and also mRNA expression of miR-449a, p53, Pdcd4, and Pacs2 mRNA, as well as serum glucose, insulin, and NOx levels were investigated. Key findings The results of this study indicated that nitrate treatment ameliorated the sperm parameters, testicular morphometrical and stereological alterations, reduced blood glucose, the number of TUNEL positive cells and tubules, and testicular expressions of p53, Pdcd4, and Pacs2 mRNA as well as increased body weight, serum insulin and NOx levels, and testicular expression of miR-449a in streptozotocin-induced diabetic rats. Significance Our in vivo evidence revealed that nitrate treatment may has a favorable effect as an exogenous NO donor on experimental diabetic testicular damages in which NO bioavailability is impaired.

Testicular tumours are the most common neoplasms in male dogs accounting for approximately 90% of all tumours affecting the genitourinary tract. Gray-scale ultrasonography in combination with colour and power Doppler imaging has been well accepted as an accurate technique for assessing scrotal lesions and vascularization of the testis. Colour Doppler sensitivity for low blood flows appears promising in the study of testicular disorders. The aim of this study was to assess if colour and power Doppler ultrasound is a good tool for the investigation of testicular lesions in dogs, to report the sonographic features of lesions and to measure colour and power Doppler parameters such as resistive index (RI), pulsatility index (PI), hypovascularization and hypervascularization (VI) determining if they can be used to distinguish testicular neoplasms from the wide spectrum of non-neoplastic pathological findings. In this study, 50 male dogs of various breeds, aged between 7 and 14 years, presented with testicular disorders were selected. RI and PI were calculated. Mean RI values for neoplastic, inflammatory and degenerative lesions were 0.54, 0.45 and 0.58, respectively. Mean PI values were 0.62, 0.55 and 0.63, respectively. Hypovascularization and hypervascularization of the lesion were evaluated throughout the vascularity index (VI). Vascular signals in neoplasms were significantly intensified around and inside the mass if compared with those measured during inflammatory and degenerative lesions. VI markedly increased in solid tumours. Pathological testes were removed; macroscopical, histological and immunoistochemical evaluations were carried out. Colour Doppler showed increased intralesional and peripheral flows in all neoplastic lesions analysed. No flows were detected around cysts.

Background The incidence of benign and malignant testicular disorders is on the rise. Three literature reviews and one qualitative study found that men’s awareness of testicular disorders was lacking, and their intentions to seek help for symptoms of testicular disease were low. Objectives The aim of the study was to enhance men’s awareness of testicular disorders, help-seeking intentions for testicular symptoms, and intention and behavior to feel their testes. Methods Men aged 18–50 years were recruited from a university and asked to engage in a three-level, educational, virtual reality experience. The Medical Research Council framework guided the development and pilot testing of the intervention. Knowledge, awareness, perceived risk, implementation intentions, help-seeking intentions, and behaviors were measured at pretest (T0), immediately posttest (T1), and 1 month posttest (T2). Results Data were available from 49 participants. In comparison to T0, a significant increase in knowledge (mean difference [ MD ] = 3.5, 95% CI [2.8, 4.26]); testicular awareness ( MD = 0.2, 95% CI [0.01, 0.41]); implementation intentions ( MD = 0.6, 95% CI [0.33, 0.90]); and help-seeking intentions for testicular swelling ( MD = 0.3, 95% CI [0.12, 0.51]), lumpiness ( MD = 0.3, 95% CI [0.08, 0.46]), and pain ( MD = 0.6, 95% CI [0.25, 1.01]) was noted at T1. This increase was maintained at T2. Participants who expressed an intention to feel their testes at T0 were more likely to report performing this behavior at T2. Discussion The intervention succeeded in promoting knowledge, testicular awareness, implementation intentions, help-seeking intentions, and behaviors. A randomized controlled trial of the Enhancing Men’s Awareness of Testicular Disorders intervention with a larger sample size is warranted.

Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal (MIM # 610644) is a clinically distinctive form of SRY-negative 46,XX disorder of sex development. It is a rare autosomal recessive disorder caused due to biallelic loss of function mutations in RSPO1 gene. RSPO1 acts by activating the canonical β-catenin pathway and is one of the most important genes controlling female gonadal differentiation. RSPO1-associated disorders of sex development have been described only in three instances in the past. We report fourth such case with additional findings and perform a comparative review of previous phenotypic descriptions, thereby expanding the clinical phenotype of this syndrome.

Background: Inhibin B is a hormone produced by the Sertoli cells that can provide important information for the investigation of disorders of sex development (DSD) with 46,XY karyotype. The aim of this study is to compare two enzyme-linked immunosorbent assay (ELISA) assays for dosage of serum inhibin B in patients with 46,XY DSD with normal testosterone secretion. Methods: Twenty-nine patients with 46,XY DSD and normal testosterone secretion (partial androgen insensitivity syndrome [PAIS] [n=8]; 5α-reductase deficiency [n=7] and idiopathic 46,XY DSD [n=14]) were included. Molecular analysis of the AR and SRD5A2 genes were performed in all patients and the NR5A1 gene analysis in the idiopathic group. Measurements of inhibin B were performed by two second-generation ELISA assays (Beckman-Coulter and AnshLabs). Assays were compared using the interclass correlation coefficient (ICC) and the Bland-Altman method. Results: ICC was 0.915 [95% confidence interval (CI): 0.828–0.959], however, a discrepancy was observed between trials, which is more evident among higher values when analyzed by the Bland-Altman method. Conclusions: It is recommended to perform the inhibin B measurement always using the same ELISA kit when several evaluations are required for a specific patient.

Testicular XX disorder of sex development (XX DSD, SRY -negative), causing sterility, is quite frequently diagnosed in pig populations, however, its molecular background is still unknown. This disorder may affect carcass quality (boar taint) due to the presence of testicular tissue in animals with ambiguous female external genitalia. A chromosome fragment encompassing the SOX9 gene was previously considered as a candidate region in functional and association studies. We analyzed distribution of polymorphic variants in 5’UTR and in 3’-flanking regions of the SOX9 gene in a cohort of 12 XX DSD pigs and a panel of 116 normal females. Altogether, 8 previously known polymorphic sites were analyzed and no significant association under Bonferroni correction (P>0.0063) between DSD phenotype and identified SNPs was found. The region harboring the SOX9 gene was also searched for the presence of copy number variation (CNV) by fluorescence in situ hybridization technique (FISH), using a set of 7 BAC probes. A potential CNV region, manifested by size variation (large and small) of fluorescence signals, produced by a single BAC probe hybridizing downstream (approx. 500 kb) of the SOX9 gene, was observed in 4 DSD cases. We conclude, that a new CNV polymorphism in the region harboring SOX9 gene can be considered as a promising marker for the DSD phenotype.

Purpose: We aimed to identify the genetic cause in a cohort of 11 unrelated cases and two sisters with 46,XX SRY-negative (ovo)testicular disorders of sex development (DSD). Methods: Whole-exome sequencing (n = 9), targeted resequencing (n = 4), and haplotyping were performed. Immunohistochemistry of sex-specific markers was performed on patients' gonads. The consequences of mutation were investigated using luciferase assays, localization studies, and RNA-seq. Results: We identified a novel heterozygous NR5A1 mutation, c.274C>T p.(Arg92Trp), in three unrelated patients. The Arg92 residue is highly conserved and located in the Ftz-F1 region, probably involved in DNA-binding specificity and stability. There were no consistent changes in transcriptional activation or subcellular localization. Transcriptomics in patient-derived lymphocytes showed upregulation of MAMLD1, a direct NR5A1 target previously associated with 46,XY DSD. In gonads of affected individuals, ovarian FOXL2 and testicular SRY-independent SOX9 expression observed. Conclusions: We propose NR5A1, previously associated with 46,XY DSD and 46,XX primary ovarian insufficiency, as a novel gene for 46,XX (ovo)testicular DSD. We hypothesize that p.(Arg92Trp) results in decreased inhibition of the male developmental pathway through downregulation of female antitestis genes, thereby tipping the balance toward testicular differentiation in 46,XX individuals. In conclusion, our study supports a role for NR5A1 in testis differentiation in the XX gonad. Genet Med 19 4, 367–376.

Ovotesticular or testicular disorder of sexual development in dogs with female karyotype and lack of SRY (XX DSD) is a common sexual anomaly diagnosed in numerous breeds. The molecular background, however, remains unclear, and epigenetic mechanisms, including DNA methylation, have not been studied. The aim of our study was comparative methylation analysis of CpG islands in promoters of candidate genes for XX DSD: SOX9, SOX3, and WNT4. Methylation studies were performed on DNA extracted from formalin-fixed/paraffin-embedded or frozen gonads from 2 dogs with ovotesticular and 2 dogs with testicular XX DSD as well as control females (n = 4) and males (n = 2). Bisulfite-converted DNA was used for CpG methylation analysis using quantitative pyrosequencing. Promoter regions of SOX9 and WNT4 showed similar CpG methylation in each group, ranging from 0 to 5.5% and from 39 to 74%, respectively. The SOX3 promoter showed significantly higher methylation in the ovotesticular XX DSD cases and the testicular XX DSD and control males, suggesting that SOX3 methylation may play a role in canine XX DSD pathogenesis.

Made available in DSpace on 2019-10-06T16:26:50Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-08-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Cryptorchidism (CPT), the most common male congenital abnormality, is variably associated with other male reproductive tract problems. We evaluated if cryptorchid rats develop enhanced testicular susceptibility to dibutyl phthalate (DBP) or acrylamide (AA) after extended exposure. Three studies with rats were performed: (1) in utero and postnatal exposure to DBP or AA; (2) establishment of CPT and orchiopexy; and (3) in utero and postnatal exposures to DBP or AA associated with CPT/orchiopexy. Seminiferous tubules were histologically scored according to the severity of lesions: (1) Rats exposed to DBP (score 1.5) or AA (score 1.1) presented mostly preserved spermatogenesis. Some seminiferous tubules showed vacuolated germinative epithelium, germ cell apoptosis, and a Sertoli cell-only (SCO) pattern. (2) CPT (score 3.3) resulted in decreased absolute testes weights, degenerated and SCO tubules, and spermatogenesis arrest that were reversed by orchiopexy (score 1.1). (3) Exposure to DBP or AA with CPT/orchiopexy led to atrophic testes, spermatogenesis arrest, germ cell exfoliation/multinucleation, and SCO tubules (both chemicals score 2.5). Exposure to chemicals such as DBP or AA prevented the recovery of cryptorchid testes by orchiopexy. The possible role of environmental contaminants should be considered when looking for factors that modulate human testicular disorders associated with CPT. Department of Pathology Center for Evaluation of the Impact of the Environmental on Human Health (TOXICAM) Botucatu Medical School Botucatu Campus Sao Paulo State University (UNESP) Department of Physiology Polytechnic Centre Federal University of Paraná Department of Pathology and Microbiology and the Fred and Pamela Buffett Cancer Center University of Nebraska Medical Center Havlik-Wall Professor of Oncology University of Nebraska Medical Center Department of Pathology Center for Evaluation of the Impact of the Environmental on Human Health (TOXICAM) Botucatu Medical School Botucatu Campus Sao Paulo State University (UNESP) CNPq: 132667/2013-4

Disorders of sexual development (DSD) in wild mammals are rarely described. A male South African giraffe (Giraffa camelopardalis giraffa) was identified with bilateral cryptorchidism. The testes were intra-abdominal, smaller and less ovoid than in normal male giraffes. The right testis was situated more cranially than the left and connected to a longer deferent duct with normal ampullae. One distended vesicular gland filled with mucoid material was identified. A short penis, situated in the perineal area, was directed caudally and presented hypospadias. Histologically, testicular hypoplasia was present; the epididymis tubules contained no spermatozoa and the deferent duct and vesicular gland were inflamed. The blood testosterone concentration was 16.27 nmol/L and oestrone sulphate concentration was 0.03 ng/mL. The aetiology of the abnormalities is unknown.

Rationale Chromosome karyotype analysis and SRY (sex determined region of Y chromosome) gene detection are routines for the diagnosis of growth hormone deficiency (GHD), but further whole exome gene sequencing occasionally leads to subversive results and unexpected conclusions. Patient concerns We report a single case of a 7-year-old Chinese boy who had stunted growth since he was 1 year old. He was short in height (height Standard Deviation Score (SDS) was less than 2.9), bilateral scrotal dysplasia and delayed bone age. Diagnosis His growth hormone (GH) stimulation tests showed GHD. His karyotype analysis and polymerase chain reaction (PCR) analyses indicated a 46, XX disorder of sex development (DSD) without the presence of the SRY gene. Nevertheless, considering that female gonad was not observed in the chest and abdominal magnetic resonance imaging, the whole exome gene sequencing was performed. Sequencing data confirmed the presence of SRY gene sequence and two copies of chromosome X. Later, using different primer sequences for PCR, it showed that the SRY gene was positive. The final diagnosis was a rare case of "46, XX (SRY positive) testicular DSD with GHD". Interventions The boy's parents agreed to use recombinant human growth hormone (rhGH) for GHD treatment, the starting dose was 0.035 mg / kg / day. But they disagreed with molecular diagnostics and genomic analysis of the Y chromosome. Outcomes The boy was treated with rhGH for 3 months and his height increased by 2.2 cm. The patient will be followed-up until the end of his puberty. Lessons In summary, whole exome gene sequencing overturned the preliminary diagnosis results of karyotype analysis and SRY gene detection, and found that there may be a certain correlation between testicular DSD and GHD.

Virilisation of the XX foetus is the result of androgen excess, resulting most frequently from congenital adrenal hyperplasia in individuals with typical ovarian differentiation. In rare cases, 46,XX gonads may differentiate into testes, a condition known as 46,XX testicular disorders of sex development (DSD), or give rise to the coexistence of ovarian and testicular tissue, a condition known as 46,XX ovotesticular DSD. Testicular tissue differentiation may be due to the translocation of SRY to the X chromosome or an autosome. In the absence of SRY, overexpression of other pro-testis genes, e.g. SOX family genes, or failure of pro-ovarian/anti-testis genes, such as WNT4 and RSPO1, may underlie the development of testicular tissue. Recent experimental and clinical evidence giving insight into SRY-negative 46,XX testicular or ovotesticular DSD is discussed.

Testicular or ovotesticular disorder of sex development (DSD) in genetic females (78,XX; SRY-negative) has been reported quite frequently in numerous dog breeds and is usually diagnosed due to the presence of female external genitalia with an enlarged clitoris. The molecular background of this disorder, diagnosed also in human and other mammals, is not fully understood. However, it has recently been proposed that a copy number variation (CNV) in the region upstream of the SOX9 gene is associated with it. We described a rare case of this disorder in a French Bulldog with abdominal testes and male external genitalia (a slightly malformed penis). FISH studies showed a female karyotype, lack of a translocation involving the Y chromosome, and a distinct size variation in the CNV region (CNVR) upstream of the SOX9 gene, located on chromosome 9 (CFA9). A large FISH variant on a single CFA9 and a lack of the variant on its homologue was observed. Surprisingly, in the mother of this DSD dog, 2 normal-sized variants were identified which means that the CNV in the DSD dog was de novo. Our observations are in agreement with earlier suggestions that a high number of copies at the CNVR upstream of SOX9 may be associated with this type of DSD.

A custom CGH microarray that covers the SOX9 regulatory region. Log2 ratio scatterplot showing individual data points. Blue box highlights copy number gain with 3' breakpoint region magnified.

46,XX testicular disorder of sexual development (DSD) is characterized by male phenotype with 46,XX karyotype. The incidence rate is 1:25,000 in male newborn. Infants with ambiguous external genitals will be confronted with issue of gender assigment and may result in a stressful condition in the parents. Since gender assignment is inevitable, several factors should be considered in DSD management. The management approach for children born with DSD is individualized and multidisciplinary. Gender assignment aims to facilitate the patient to obtain the best quality of life. Adaptation of children with 46,XX testicular DSD as a determinant of quality of life is also influenced by psychological and family conditions. The purpose of this report was to observe medical growth and development aspects of the child with 46,XX terticular DSD as indicated by the aspects of growth and development, and health related quality of life, as well as the influential aspects. PA, 18 months, was diagnosed with 46,XX testicular DSD. The patient routinely visited to endocrinology clinic, urologic surgery, and child psychiatry clinic from the age of 6 months. The parents decided to raise patient as male. The patient had undergone surgery for hypospadias correction, hormone injections, child growth monitoring, and psychological monitoring (medical records of Dr. Soetomo Hospital, Surabaya in 2015). Management should consider individual and multidiciplinary accompaniment of the patient and parents, the importance of group support, and follow-up to adulthood, as well as possible longterm outcomes that will occur in the future so that the patients and the parents need to be prepared.

Molecular diagnosis is rarely established in 46,XX testicular (T) disorder of sex development (DSD) individuals with atypical genitalia. The Wilms' tumour factor-1 (WT1) gene is involved in early gonadal development in both sexes. Classically, WT1 deleterious variants are associated with 46,XY disorders of sex development (DSD) because of gonadal dysgenesis. We report a novel frameshift WT1 variant identified in an SRY-negative 46,XX testicular DSD girl born with atypical genitalia. Target massively parallel sequencing involving DSD-related genes identified a novel heterozygous WT1 c.1453_1456del; p.Arg485Glyfs*14 variant located in the fourth zinc finger of the protein which is absent in the population databases. Segregation analysis and microsatellite analysis confirmed the de novo status of the variant that is predicted to be deleterious by in silico tools and to increase WT1 target activation in crystallographic model. This novel and predicted activating frameshift WT1 variant leading to the 46,XX testicular DSD phenotype includes the fourth zinc-finger DNA-binding domain defects in the genetic aetiology of 46,XX DSD.

Background Health outcomes among men are markedly poorer than women. Testicular disorders can be life-threatening if left untreated. Few studies promoting awareness of testicular disorders have been underpinned by theory. Theory-based interventions are more likely to achieve positive health outcomes than interventions that lack a theoretical foundation. Objectives The purpose of the study is to present a theory-focused analysis of the preconscious awareness to action framework (PAAF), developed to enhance testicular awareness and help-seeking intentions and behaviors among men. Methods The following approach was used to develop the PAAF: The empirical literature on men’s awareness of testicular disorders was reviewed. A qualitative study was conducted to explore men’s awareness of testicular disorders, help-seeking intentions for testicular symptoms, and preferred learning strategies in relation to testicular disorders and symptoms. An iterative narrative review process of the theoretical literature on health promotion and symptom appraisal was undertaken. Results The PAAF comprises seven steps: preconscious awareness, unconscious awareness, conscious awareness, unconscious appraisal, conscious appraisal, intention, and behavior. The concept of testicular awareness was developed to familiarize men with their own testes and promote timely help-seeking. Discussion Researchers are encouraged to use the PAAF to design health-promoting interventions aimed at enhancing testicular awareness, symptom appraisal, and help-seeking.

Background: Testicular cancer (TC) is commonly diagnosed among men aged 15-40 years. The incidence of TC is on the rise. Benign testicular disorders such as testicular torsion and epididymitis can lead to testicular ischemia, sepsis, and infertility if left untreated. This systematic review aims to evaluate the effectiveness of studies promoting men’s knowledge and awareness of testicular disorders and/or self-examination, behaviours and/or intentions to examine their testes, and help-seeking behaviours and/or intentions for testicular symptoms. Methods: Academic Search Complete, Medline, CINAHL, PsychINFO, ERIC, the Cochrane Library, the World Health Organisation International Clinical Trials Registry Platform, Clinicaltrials.gov, Grey Literature Report, and Open Grey were searched for studies published between November 2014 and April 2018. The methodological quality and level of evidence per outcome were assessed. Results: There were five papers included: two were experimental studies, two were systematic reviews, and one was an integrative review. The majority of the reviewed interventions were successful in increasing men’s awareness of TC and self-examination. Examples include a television show featuring a celebrity with TC, a university campaign, and interactive educational sessions. The impact of the reviewed interventions on health beliefs (i.e. perceived susceptibility, severity, benefits, barriers, and self-efficacy) varied across the reviewed literature. Studies promoting help-seeking for testicular symptoms and awareness of benign testicular disorders were lacking. Conclusions: This review highlights the importance of evaluating educational interventions aimed at younger men, whilst raising their awareness of testicular disorders and increasing their help-seeking intentions for testicular symptoms. Given the lack of consensus around scheduled testicular self-examination among younger men, clinicians are encouraged to instruct men to familiarise themselves with the look and feel of their own testes and to seek timely medical attention for abnormalities. Registration: The review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42018093671.

Men Breast Cancer (MBC) is uncommon and occurs after the age of 60 years. Among men Prognosis is poor as Prognosis a course of a medical condition is discovered at a late stage. where Infiltrating ductal carcinoma accounts for (70-90%) of male breast cancers. In situ but not invasive carcinoma is exclusively ductal, and it accounts only 7% of the breast cancer cases in males. It is observed that 50-75% of breast cancer cases are spread to lymph nodes. The etiology of male breast cancer is unknown. An excess risk has been associated with the testicular disorders, benign breast disease including gynecomastia, Klinefelter syndrome, etc., Preliminary evidence suggests that BRCA2 is a strong cause. The carriers of the males with BRCA2 mutation have an increased lifetime risk of breast cancer with 80-fold in it. It is also known that there is also a risk of breast cancer associated with undescended testes and it is also related to orchiectomy, orchitis, testicular injury, etc., with an increasing number of children the decreasing trend in risk was observed gradually. Where It is also known that Liver cirrhosis is associated with increased levels of estrogens possibly via high levels of endogenous estrogens.