Genetic and molecular diagnostics of male infertility in the clinical practice.

Male infertility represents one of the clearest examples of complex phenotype with substantial genetic basis. It is indeed well established that genetic causes account for 10-15% of infertility cases, including chromosomal abnormalities and single-gene mutations. However, a large proportion of infertile males does not receive a clear diagnosis and thus they are reported as idiopathic or unexplained. Male (in)fertility is commonly based on standard semen analysis, which, however, cannot clearly distinguish fertile from infertile populations and therefore fails to detect any abnormality in many cases. Abnormal sperm function or specific molecular defects can be hypothesized in these cases. This review considers practical genetic and molecular diagnostic tests for male infertility, reporting on the most frequent genetic causes of male infertility and on the pros and cons of most commonly used techniques for genetic, molecular and functional sperm evaluation. Finally, this review will discuss recent advances in pharmacogenetics and new developments on sperm analysis that will form the basis for future research

Gonadal Function in Male Patients With Metastatic Renal Cell Cancer Treated With Sunitinib

Background/aim: Single-agent tyrosine kinase inhibitors are still prescribed as first-line treatment to a relevant subgroup of patients with metastatic renal cell carcinoma (mRCC). These agents are known to cause disfunction of many endocrine glands (e.g., thyroid). In this two-step trial, we aimed to assess gonadal function among male patients with mRCC treated with sunitinib. Patients and methods: We enrolled a first cross-sectional cohort of pre-treated (>6 months) patients and a subsequent cohort of treatment-naïve patients who were prospectively followed-up. All patients were screened for hypogonadism and received a Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire at study entry and after 6 months of therapy. Patients who were candidates for testosterone replacement therapy (TRT) also received a FACT-G questionnaire at baseline and 3 months after supplementation. Results: Among the 30 enrolled patients, the prevalence of hypogonadism was found to be higher in those receiving sunitinib for a longer period (27.3% at baseline, 41.7% in the first 6 months, and 68.4% after 9 months of therapy). The testosterone level of patients correlated with quality of life (R=0.32). A total of six patients received TRT, with a significant improvement in their global quality of life after the first 3 months of treatment. Conclusion: An increasing prevalence of hypogonadism was seen among male patients who received long-term treatment with sunitinib. TRT was associated with relevant improvements in quality of life. These findings corroborate similar published observations and encourage the assessment of gonadal function in male patients with mRCC under treatment with sunitinib

Testis transcriptome analysis in male infertility: new insight on the pathogenesis of oligo-azoospermia in cases with and without AZFc microdeletion

<p>Abstract</p> <p>Background</p> <p>About 10% of cases of male infertility are due to the presence of microdeletions within the long arm of the Y chromosome (Yq). Despite the large literature covering this critical issue, very little is known about the pathogenic mechanism leading to spermatogenesis disruption in patients carrying these microdeletions. In order to identify the presence of specific molecular pathways leading to spermatogenic damage, testicular gene expression profiling was carried out by employing a microarray assay in 16 patients carrying an AZFc microdeletion or affected by idiopathic infertility. Hierarchical clustering was performed pooling the data set from 26 experiments (16 patients, 10 replicates).</p> <p>Results</p> <p>An intriguing and unexpected finding is that all the samples showing the AZFc deletion cluster together irrespectively of their testicular phenotypes. This cluster, including also four patients affected by idiopathic infertility, showed a downregulation of several genes related to spermatogenesis that are mainly involved in testicular mRNA storage. Interestingly, the four idiopathic patients present in the cluster showed no testicular expression of <it>DAZ </it>despite the absence of AZFc deletion in the peripheral blood.</p> <p>Conclusions</p> <p>Our expression profiles analysis indicates that several forms of infertility can be triggered by a common pathogenic mechanism that is likely related to alterations in testicular mRNA storage. Our data suggest that a lack of testicular DAZ gene expression may be the trigger of such mechanism. Furthermore, the presence of AZFc deletions in mosaic or the loss of function of AZFc genes in absence of Yq deletion can perhaps explain these findings. Finally, based on our data, it is intriguing to hypothesize that <it>DAZ </it>gene dysfunctions can account for a larger number of previously thought "idiopathic" infertility cases and investigation of such testicular gene dysfunction can be important to reveal the molecular determinant of infertility than are undetected when only testing Yq deletions in peripheral blood.</p

Global warming and testis function: A challenging crosstalk in an equally challenging environmental scenario

Environmental pollution, accounting for both chemical and physical factors, is a major matter of concern due to its health consequences in both humans and animals. The release of greenhouse gases with the consequent increase in environmental temperature is acknowledged to have a major impact on the health of both animals and humans, in current and future generations. A large amount of evidence reports detrimental effects of acute heat stress on testis function, particularly on the spermatogenetic and steroidogenetic process, in both animal and human models, wich is largely related to the testis placement within the scrotal sac and outside the abdomen, warranting an overall scrotal temperature of 2°C–4°C lower than the core body temperature. This review will provide a thorough evaluation of environmental temperature’s effect on testicular function. In particular, basic concepts of body thermoregulation will be discussed together with available data about the association between testis damage and heat stress exposure. In addition, the possible association between global warming and the secular decline of testis function will be critically evaluated in light of the available epidemiological studies

Plasma metabolomics in male primary and functional hypogonadism

Metabolomics proposes to unveil the molecular machinery involved in each specific disease by the comprehensive analysis of low-molecular-weight metabolites in a biological sample. This narrative mini-review analyzes previous studies applying ultra-high-performance liquid chromatography–high-resolution mass spectrometry (HRMS)-based metabolomics to highlight different metabolic pathways involved in male hypogonadism and testosterone replacement therapy, both in the case of insulin-sensitive patients with primary hypogonadism and in the case of insulin-resistant patients with functional hypogonadism. In functional hypogonadism, metabolomics revealed that different biochemical pathways are affected. In detail, glycolysis is the most important biochemical process involved in these patients. Glucose metabolism is fueled by amino acid degradation, and gluconeogenesis is widely stimulated. Some important pathways, including glycerol, are compromised. Furthermore, mitochondrial electron transport is influenced, namely, by a decrease in ATP production. On the contrary, beta-oxidation of short- and medium-chain fatty acids does not represent an energy source in hypogonadal patients. Both lactate and acetyl-CoA are converted into ketone bodies, which increased immensely. However, carnosine and β-alanine are greatly reduced. These metabolic changes are associated with increased fatigue and mental confusion. After testosterone replacement therapy, a complete restoration is achieved for only a part of the metabolites. It is of note that only in patients with functional hypogonadism treated with testosterone are ketone bodies produced at high levels, so the symptoms sometimes reported by these patients after the beginning of the therapy (difficulty in concentrating, depressed mood, brain fog, and memory impairment) might represent a specific “keto flu-like” syndrome, related to the metabolic ketonic state

Unicompartmental knee arthroplasty: current perspectives and trends in Brazil

OBJECTIVE: The aim of this study was to evaluate the approaches and procedures used by Brazilian orthopedic surgeons for treating osteoarthrosis by means of unicompartmental knee arthroplasty and high tibial osteotomy of the knee. METHODS: A questionnaire with 14 closed questions was developed and applied to Brazilian knee surgeons during the three days of the 43rd Brazilian Congress of Orthopedics and Traumatology. RESULTS: A total of 113 surgeons filled out the questionnaire completely and became part of the sample analyzed. In this study, the majority of the surgeons performed fewer than five unicompartmental knee arthroplasty procedures/year (61.1%) and between 5 and 15 high tibial osteotomy procedures/year (37.2%). Use of computerized navigation systems during surgery remains uncommon in our environment, since only 0.9% of the specialists were using it. 65.5% of the surgeons reported that they had chosen to use total knee arthroplasty rather than partial arthroplasty due to lack of familiarity with the surgical technique. When asked about the possibility that the number of unicompartmental prostheses used in Brazil would grow as surgeons in this country become increasingly familiar with the technique, 80.5% of the respondents believed in this hypothesis. In this sample, we found that the greater the surgeon's experience was, the greater the numbers of unicompartmental prostheses and tibial osteotomies performed annually were (r = 0.550 and r = 0.465, respectively; p < 0.05). CONCLUSIONS: There is a clear evolutional trend towards treatment of unicompartmental osteoarthritis using partial knee arthroplasty in Brazil. However, further prospective controlled studies are needed in order to evaluate the clinical and scientific benefits of these trends.OBJETIVO: O objetivo deste estudo é avaliar as condutas e procedimentos realizados pelos cirurgiões de joelho do Brasil no tratamento da osteoartrose com artroplastia unicompartimental e osteotomia tibial alta do joelho. MÉTODOS: Um questionário de 14 questões fechadas foi elaborado e aplicado a cirurgiões brasileiros de joelho durante os três dias do 43º Congresso Brasileiro de Ortopedia e Traumatologia. RESULTADOS: Um total de 113 cirurgiões de joelho preencheram completamente o questionário e fizeram parte da amostra analisada. Neste estudo, a maioria dos cirurgiões realizava menos de cinco artroplastias unicompartimentais do joelho/ano (61,1%) e entre cinco e 15 osteotomias tibiais altas/ano (37,2%). A utilização de navegação computadorizada no intraoperatório é ainda infrequente em nosso meio, sendo realizada por apenas 0,9% dos especialistas. A opção pelo uso da artroplastia total do joelho em detrimento da parcial devido à falta de familiaridade com a técnica cirúrgica foi relatada por 65,5% dos cirurgiões. Quando arguidos sobre a possibilidade de crescimento no número de próteses unicompartimentais no Brasil com o aumento da familiaridade com a técnica pelos cirurgiões do País, 80,5% dos entrevistados responderam que acreditam nesta hipótese. Nesta amostra, constatamos que quanto maior a experiência do cirurgião maior o número de próteses unicompartimentais e osteotomias tibiais realizadas anualmente (r = 0,550 e r = 0,465, respectivamente, e p < 0,05). CONCLUSÕES: Existem claras tendências em evolução no tratamento da osteoartrose unicompartimental com artroplastia parcial do joelho no Brasil. No entanto, mais estudos prospectivos controlados são necessários para avaliar o benefício clínico e científico destas tendências.Universidade Federal de São Paulo (UNIFESP) Departamento de Ortopedia e Traumatologia Centro de Traumatologia do EsporteUniversidade Federal de São Paulo (UNIFESP) Departamento de Ortopedia e TraumatologiaUNIFESP, Depto. de Ortopedia e Traumatologia Centro de Traumatologia do EsporteUNIFESP, Depto. de Ortopedia e TraumatologiaSciEL

European academy of andrology guidelines on Klinefelter syndrome : endorsing organization : European Society of Endocrinology

Background Knowledge about Klinefelter syndrome (KS) has increased substantially since its first description almost 80 years ago. A variety of treatment options concerning the spectrum of symptoms associated with KS exists, also regarding aspects beyond testicular dysfunction. Nevertheless, the diagnostic rate is still low in relation to prevalence and no international guidelines are available for KS. Objective To create the first European Academy of Andrology (EAA) guidelines on KS. Methods An expert group of academicians appointed by the EAA generated a consensus guideline according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. Results Clinical features are highly variable among patients with KS, although common characteristics are severely attenuated spermatogenesis and Leydig cell impairment, resulting in azoospermia and hypergonadotropic hypogonadism. In addition, various manifestations of neurocognitive and psychosocial phenotypes have been described as well as an increased prevalence of adverse cardiovascular, metabolic and bone-related conditions which might explain the increased morbidity/mortality in KS. Moreover, compared to the general male population, a higher prevalence of dental, coagulation and autoimmune disorders is likely to exist in patients with KS. Both genetic and epigenetic effects due to the supernumerary X chromosome as well as testosterone deficiency contribute to this pathological pattern. The majority of patients with KS is diagnosed during adulthood, but symptoms can already become obvious during infancy, childhood or adolescence. The paediatric and juvenile patients with KS require specific attention regarding their development and fertility. Conclusion These guidelines provide recommendations and suggestions to care for patients with KS in various developmental stages ranging from childhood and adolescence to adulthood. This advice is based on recent research data and respective evaluations as well as validations performed by a group of experts