Striatin knock out induces a gain of function of INa and impaired Ca2+ handling in mESC-derived cardiomyocytes.

AIM: Striatin (Strn) is a scaffold protein expressed in cardiomyocytes (CMs) and alteration of its expression are described in various cardiac diseases. However, the alteration underlying its pathogenicity have been poorly investigated. METHODS: We studied the role(s) of cardiac Strn gene (STRN) by comparing the functional properties of CMs, generated from Strn-KO and isogenic WT mouse embryonic stem cell lines. RESULTS: The spontaneous beating rate of Strn-KO CMs was faster than WT cells, and this correlated with a larger fast INa conductance and no changes in If. Paced (2-8 Hz) Strn-KO CMs showed prolonged action potential (AP) duration in comparison with WT CMs and this was not associated with changes in ICaL and IKr. Motion video tracking analysis highlighted an altered contraction in Strn-KO CMs; this was associated with a global increase in intracellular Ca2+, caused by an enhanced late Na+ current density (INaL) and a reduced Na+/Ca2+ exchanger (NCX) activity and expression. Immunofluorescence analysis confirmed the higher Na+ channel expression and a more dynamic microtubule network in Strn-KO CMs than in WT. Indeed, incubation of Strn-KO CMs with the microtubule stabilizer taxol, induced a rescue (downregulation) of INa conductance toward WT levels. CONCLUSION: Loss of STRN alters CMs electrical and contractile profiles and affects cell functionality by a disarrangement of Strn-related multi-protein complexes. This leads to impaired microtubules dynamics and Na+ channels trafficking to the plasma membrane, causing a global Na+ and Ca2+ enhancement.

Obesity and sexual health: focus on postmenopausal women.

Menopause is a cardiometabolic transition with many women experiencing weight gain and redistribution of body fat. Hormonal changes may affect also several dimensions of well-being, including sexual function, with a high rate of female sexual dysfunction (FSD), which displays a multifactorial etiology. The most important biological factors range from chronic low-grade inflammation, associated with hypertrophic adipocytes that may translate into endothelial dysfunction and compromised blood flow through the genitourinary system, to insulin resistance and other neuroendocrine mechanisms targeting the sexual response. Psychosocial factors include poor body image, mood disorders, low self-esteem and life satisfaction, as well as partner's health and quality of relationship, and social stigma. Even unhealthy lifestyle, chronic conditions and putative weight-promoting medications may play a role. The aim of the present narrative review is to update and summarize the state of the art on the link between obesity and FSD in postmenopausal women, pointing to the paucity of high-quality studies and the need for further research with validated end points to assess both biomarkers of obesity and FSD. In addition, we provide general information on the diagnosis and treatment of FSD at menopause with a focus on dietary interventions, physical activity, anti-obesity drugs and bariatric surgery.

Omics sciences and precision medicine in testicular cancer.

Background: Cancer, a potentially fatal condition, is one of the leading causes of death worldwide. Among males aged 20 to 35, the most common cancer in healthy individuals is testicular cancer, accounting for 1% to 2% of all cancers in men. Methods: Throughout this review, we have employed a targeted research approach, carefully handpicking the most representative and relevant articles on the subject. Our methodology involved a systematic review of the scientific literature to ensure a comprehensive and accurate overview of the available sources. Results: The onset and spread of testicular cancer are significantly influenced by genetic changes, including mutations in oncogenes, tu-mor suppressor genes, and DNA repair genes. As a result of identifying these specific genetic mutations in cancers, targeted medications have been developed to disrupt the signaling pathways affected by these genetic changes. To improve the diagnosis and treatment of this disease, it is crucial to understand its natural and clinical histories. Conclusions: In order to comprehend cancer better and to discover new biomarkers and therapeutic targets, oncologists are increasingly employing omics methods, such as genomics, transcriptomics, proteomics, and metabolomics. Targeted medications that focus on specific genetic pathways and mutations hold promise for advancing the diagnosis and management of this disease.

Omics sciences and precision medicine in prostate cancer.

Abstract: In the last decade, Prostate Cancer (PCa) has emerged as the second most prevalent and serious medical condition, and is considered one of the leading factors contributing to global mortality rates. Several factors (genetic as well as environmental) contribute to its development and seriousness. Since the disease is usually asymptomatic at early stages, it is typically misdiagnosed or over-diagnosed by the diagnostic procedures currently in use, leading to improper treatment. Effective biomarkers and diagnostic techniques are desperately needed in clinical settings for better management of PCa patients. Studies integrating omics sciences have shown that the accuracy and dependability of diagnostic and prognostic evaluations have increased because of the use of omics data; also, the treatment plans using omics can be facilitated by personalized medicine. The present review emphasizes innovative multi-omics methodologies, encompassing proteomics, genomics, microbiomics, metabolomics, and transcriptomics, with the aim of comprehending the molecular alterations that trigger and contribute to PCa. The review shows how early genomic and transcriptomic research has made it possible to identify PCa-related genes that are controlled by tumor-relevant signaling pathways. Proteomic and metabolomic analyses have recently been integrated, advancing our understanding of the complex mechanisms at play, the multiple levels of regulation, and how they interact. By applying the omics approach, new vulnerabilities may be discovered, and customized treatments with improved efficacy will soon be accessible.

Testicular volume in 268 children and adolescents followed-up for childhood obesity-a retrospective cross-sectional study.

CONTEXT: Prevalence of obesity in childhood has increased over the past few decades. The impact of obesity and of obesity-related metabolic disorders on testicular growth is unknown. OBJECTIVE: To evaluate the impact of obesity, hyperinsulinemia, and insulin resistance on testicular volume (TV) in pre-pubertal (<9 years), peri-pubertal (9-14 years), and post-pubertal (14-16 years) periods. METHODS: We collected data on TV, age, standard deviation score (SDS) of the body mass index (BMI), insulin, and fasting glycemia in 268 children and adolescents followed-up for weight control. RESULTS: Peri-pubertal boys with normal weight had a significantly higher TV compared to those with overweight or obesity. No difference was found in the other age ranges when data were grouped according to BMI. Pre- and post-pubertal children/adolescents with normal insulin levels had significantly higher TV compared to those with hyperinsulinemia. Peri-pubertal boys with hyperinsulinemia had significantly higher TV compared to those with normal insulin levels. Post-pubertal adolescents with insulin resistance had lower TV and peri-pubertal boys had higher TV compared to those without insulin resistance. No difference was found in pre-puberty. CONCLUSIONS: Closer control of the body weight and the associated metabolic alterations in childhood and adolescence may maintain testicular function later in life.

Sexual functioning in women with functional hypothalamic amenorrhea: exploring the relevance of an underlying polycystic ovary syndrome (PCOS)-phenotype.

PURPOSE: To study sexual function and distress in women with functional hypothalamic amenorrhea (FHA) compared to women with FHA and an underlying polycystic ovary syndrome (PCOS)-phenotype, considering also their psychometric variables. As a secondary aim, we explored the relationship between sexual functioning and hormonal milieu in these women. METHODS: This is a retrospective cross-sectional study conducted on 36 women with typical FHA and 43 women with FHA + PCOS-phenotype. The following validated psychometric questionnaires were administered: Female Sexual Functional Index (FSFI), Female Sexual Distress Scale-Revised (FSDS-R), Body Attitude Test (BAT), Bulimia Investigation Test (BITE), State Anxiety Inventory (STAI), Beck Depression Inventory (BDI), Multidimensional Perfectionism Scale (MPS). Available hormones to formulate FHA diagnosis in the standard routine were considered. RESULTS: Women with typical FHA reported a significantly lower FSFI total score than women with FHA + PCOS-phenotype (95% CI for median 16-21.3 vs. 21.1-24.1, p = 0.002), whereas the FSDS-R score was similar in the two groups (95% CI for median 6-16 vs. 6-16.3). No statistically significant differences were evident in body attitude, state and trait anxiety, depression, bulimic risk, and perfectionism between the two groups, confirming the two FHA groups were superimposable from a psychometric perspective. State anxiety correlated negatively with the FSFI total score in both typical FHA (rho: - 0.33, p = 0.05) and FHA + PCOS-phenotype (rho: - 0.40, p = 0.009). In the entire study population, a positive correlation was found between luteinizing hormone, androstenedione, and 17ß-estradiol and the total FSFI score (rho: 0.28, p = 0.01; rho: 0.27, p = 0.01, rho: 0.27, p = 0.01, respectively). CONCLUSION: Women with FHA showed a very high rate of sexual symptoms as part of their condition, but those with a typical diagnosis displayed a more severe sexual impairment as compared with the FHA + PCOS-phenotype, in spite of a similar psychometric profile. Sexual distress was equally present in both groups (approximately 4 out of 10 women). Further studies should be designed to investigate the potential role of sex hormones, mainly LH-driven androstenedione, in influencing women's sexual functioning.

Congenital adrenal hyperplasia, disorders of sex development, and infertility in patients with POR gene pathogenic variants: a systematic review of the literature.

BACKGROUND: P450 oxidoreductase (POR) deficiency (PORD) is characterized by congenital adrenal hyperplasia (CAH) and disorders of sex development (DSD) in both sexes. PORD can also associate with skeletal defects. However, the prevalence of these phenotypes is unknown. AIM: To evaluate the prevalence of CAH, DSD, and infertility of patients with POR gene pathogenic variants by a systematic review of the literature. METHODS: The literature search was performed through PubMed, MEDLINE, Cochrane, Academic One Files, Google Scholar, and Scopus databases. All studies reporting information on CAH, DSD, testicular adrenal rest tumor (TARTs), and fertility in patients with POR gene pathogenic variants were included. Finally, the prevalence of abnormal phenotypes was calculated. RESULTS: Of the 246 articles initially retrieved, only 48 were included for a total of 119 (46 males and 73 females) patients with PORD. We also included the case of a male patient who consulted us for CAH and TARTs but without DSD. This patient, found to be a carrier of combined heterozygous POR mutation, reached fatherhood spontaneously. All the patients found had CAH. The presence of DSD was found in 65.2%, 82.1%, and 82.1% of patients with compound heterozygosity, homozygosity, or monoallelic heterozygous variants, respectively. The prevalence was significantly higher in females than in males. The prevalence of TARTs in patients with PORD is 2.7%. Only 5 women with PORD became pregnant after assisted reproductive techniques and delivered a healthy baby. Except for the recently reported proband, no other studies focused on male infertility in patients with POR gene variants. CONCLUSION: This systematic review of the literature reports the prevalence of CAH, DSD, and TARTs in patients with PORD. The unknown prevalence of POR gene pathogenetic variants and the paucity of studies investigating fertility do not allow us to establish whether PORD is associated with infertility. Further studies on both women and men are needed to clarify this relationship.

Adult- and late-onset male hypogonadism: the clinical practice guidelines of the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE).

PURPOSE: To provide the evidence-based recommendations on the role of testosterone (T) on age-related symptoms and signs remains. METHODS: The Italian Society of Andrology and Sexual Medicine (SIAMS) and the and the Italian Society of Endocrinology (SIE) commissioned an expert task force to provide an updated guideline on adult-onset male hypogonadism. Derived recommendations were based on Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. RESULTS: Clinical diagnosis of adult-onset hypogonadism should be based on a combination of clinical and biochemical parameters. Testosterone replacement therapy (TRT) should be offered to all symptomatic subjects with hypogonadism after the exclusion of possible contraindications. T gels and the long-acting injectable T are currently available preparations showing the best efficacy/safety profile. TRT can improve all aspects of sexual function, although its effect is limited in more complicated patients. Body composition (reducing fat mass and increasing lean mass) is improved after TRT, either in subjects with or without metabolic syndrome or type 2 diabetes. Conversely, the role of TRT in improving glycometabolic control is more conflicting. TRT can result in increasing bone mineral density, particularly at lumbar site, but no information on fracture risk is available. Limited data support the use of TRT for improving other outcomes, including mood frailty and mobility. CONCLUSIONS: TRT can improve sexual function and body composition particularly in less complicated adult and in aging subjects with hypogonadism. When hypogonadism is adequately diagnosed, T appropriately prescribed and subjects correctly followed up, no short-term increased risk of adverse events is observed. Longer and larger studies are advisable to better clarify TRT long-term efficacy/safety profile.

Adult- and late-onset male hypogonadism: the clinical practice guidelines of the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE)

To provide the evidence-based recommendations on the role of testosterone (T) on age-related symptoms and signs remains. The Italian Society of Andrology and Sexual Medicine (SIAMS) and the and the Italian Society of Endocrinology (SIE) commissioned an expert task force to provide an updated guideline on adult-onset male hypogonadism. Derived recommendations were based on Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. Clinical diagnosis of adult-onset hypogonadism should be based on a combination of clinical and biochemical parameters. Testosterone replacement therapy (TRT) should be offered to all symptomatic subjects with hypogonadism after the exclusion of possible contraindications. T gels and the long-acting injectable T are currently available preparations showing the best efficacy/safety profile. TRT can improve all aspects of sexual function, although its effect is limited in more complicated patients. Body composition (reducing fat mass and increasing lean mass) is improved after TRT, either in subjects with or without metabolic syndrome or type 2 diabetes. Conversely, the role of TRT in improving glycometabolic control is more conflicting. TRT can result in increasing bone mineral density, particularly at lumbar site, but no information on fracture risk is available. Limited data support the use of TRT for improving other outcomes, including mood frailty and mobility. TRT can improve sexual function and body composition particularly in less complicated adult and in aging subjects with hypogonadism. When hypogonadism is adequately diagnosed, T appropriately prescribed and subjects correctly followed up, no short-term increased risk of adverse events is observed. Longer and larger studies are advisable to better clarify TRT long-term efficacy/safety profile.

What hides beneath the scar: sexuality and breast cancer what women don't say: A single-center study.

Background: Breast is a symbol of femininity, motherhood and sexuality. Breast cancer (BC) is the leading cause of cancer death in women worldwide and most frequent cancer in Italy: in 2019, 53.500 new cases were diagnosed. BC and its treatment, the disturbances of body image, and mental health problems such as anxiety and depression could influence sexuality. Very often the aspect of sexuality in BC is likely not to be fully investigated: cultural barriers may also contribute to lack of attention to these issues. In Italy, there are very few Breast Units that provide the figure of the sexologist and psycho-oncologist. Methods: We enlisted 141 BC patients (pts), mean age was 54 years afferent to Breast Unit S. Maria Goretti Hospital, Latina, from March 2019 to March 2020. All pts had undergone surgical intervention. Participants were invited to complete a structured questionnaire, which included four close-up questions regarding self-image, sexual activity, sexual satisfaction, analyzing these aspects before and after BC and its treatments. Finally the participants were asked if they needed the sexologist and psycho-oncologist. Results: Only 2/141 pts (1.41%) refused to participate in our study. Of 139 participants, 68 (48.92%) had disturbances of body image, 26 (18.7%) had sexuality greatly negatively affected, and 103 (74.1%) every kind of sexual dissatisfaction after BC. 38 pts (27.3%) would require the help of the sexologist. 135 ( 97%) would require the help of the psycho-oncologist. Despite the negative influence in their body-image and sexuality, few pts require the help of the sexologist, but nearly all pts require the help of the psycho-oncologist. Conclusion: In our study nearly all pts require the help of the psycho-oncologist, but few pts of the sexologist. Further studies will be needed to understand the reasons for this disparity: at the moment we are carrying out another project following this illustration, with the aim of understanding why this disparity.

First baseline data of the Klinefelter ItaliaN Group (KING) cohort: clinical features of adult with Klinefelter syndrome in Italy.

BACKGROUND: Klinefelter syndrome (KS) is frustratingly under-diagnosed. KS have a broad spectrum of clinical features, making it difficult to identify.  OBJECTIVE: We describe KS clinical presentation in a large Italian cohort. DESIGN: This is the first observational cohort study within a national network, the Klinefelter ItaliaN Group (KING). Primary outcomes were to describe the basic clinical features and the actual phenotype of KS in Italy. Secondary outcomes were to determine age at diagnosis and geographical distribution. METHODS: We performed a basic phenotyping and evaluation of the hormonal values of 609 adult KS patients. RESULTS: Mean age at diagnosis was 37.4 ± 13.4 years. The overall mean testicular size was 3 ml, and 2.5 ml in both testes in untreated KS group. BMI was 26.6 ± 5.8 kg/m2, and 25.5% of KS had metabolic syndrome (MetS). LH and FSH were increased, and mean total testosterone were 350 ± 9.1 ng/dl. A descriptive analysis showed that 329 KS patients were evaluated in Northern Italy, 76 in Central and 204 in Southern Italy. Analysis of variance demonstrated significant statistical differences (p < 0001) between the age at diagnosis of the three geographical groups. Compared with the expected number among male patients matched for age in Italy, only 16% of KS patients received a diagnosis. CONCLUSIONS: These data are the results of the only national database available that collects the clinical and hormonal data of the KS patients, currently referred at the KING centers. In Italy the typical KS patient is overweight, with small testes, and elevated LH and FSH. Only 25.5% of them are diagnosed with MetS. Early detection and timely treatment are mandatory.

Management of male factor infertility: position statement from the Italian Society of Andrology and Sexual Medicine (SIAMS) : Endorsing Organization: Italian Society of Embryology, Reproduction, and Research (SIERR).

PURPOSE: Infertility affects 15-20% of couples and male factors are present in about half of the cases. For many aspects related to the diagnostic and therapeutic approach of male factor infertility, there is no general consensus, and the clinical approach is not uniform. METHODS: In the present document by the Italian Society of Andrology and Sexual Medicine (SIAMS), endorsed by the Italian Society of Embryology, Reproduction, and Research (SIERR), we propose evidence-based recommendations for the diagnosis, treatment, and management of male factor infertility to improve patient and couple care. RESULTS: Components of the initial evaluation should include at minimum medical history, physical examination, and semen analysis. Semen microbiological examination, endocrine assessment, and imaging are suggested in most men and recommended when specific risk factors for infertility exist or first-step analyses showed abnormalities. Full examination including genetic tests, testicular cytology/histology, or additional tests on sperm is clinically oriented and based on the results of previous investigations. For treatment purposes, the identification of the specific cause and the pathogenetic mechanism is advisable. At least, distinguishing pre-testicular, testicular, and post-testicular forms is essential. Treatment should be couple-oriented, including lifestyle modifications, etiologic therapies, empirical treatments, and ART on the basis of best evidence and with a gradual approach. CONCLUSION: These Guidelines are based on two principal aspects: they are couple-oriented and place high value in assessing, preventing, and treating risk factors for infertility. These Guidelines also highlighted that male infertility and in particular testicular function might be a mirror of general health of a man.

Pediatric leiomyoma of the glans: a case report.

OBJECTIVE: The leiomyoma is a benign mesenchymal tumor originating from smooth muscle cells therefore its location is ubiquitous. The genitourinary system is not a common site and the glans localization in pediatric age has been described only three times in the literature to date. CASE REPORT: We describe a case of an 11-year-old boy who presented with a painless, non-bleeding or itchy tumor of the glans. The surgical procedure consisted in the total removal of the mass. The histological study showed spindle cells with an eosinophilic cytoplasm while the immunohistochemical studies proved cells stained strongly positive for smooth muscle actin. The clinical follow-up for more than 5 years after surgery demonstrates the absence of recurrence and discomfort for the patient and a good aesthetic appearance of the glans. RESULTS: Leiomyoma is a benign tumor that can originate anywhere there is smooth muscle. However, localization at the level of the glans can be treated with a total excision due to the presence of a cleavage plane with the surrounding tissues that allows a good reconstruction of the glans itself. CONCLUSIONS: We propose that leiomyoma ought to be considered in the differential diagnosis of any glans mass in children.

From Myo-inositol to D-chiro-inositol molecular pathways.

OBJECTIVE: Inositol is a carbocyclic sugar polyalcohol. By epimerization of its hydroxyl groups, nine possible stereoisomers can be generated, two of major physiological and clinical relevance: myo-inositol and D-chiro-inositol. Myo-inositol and D-chiro-inositol are normally stored in kidney, brain and liver and are necessary for functions, such as signal transduction, metabolic flux, insulin signaling, regulation of ion-channel permeability, stress response and embryo development. In this narrative review, we summarize the mechanisms by which myo-inositol and D-chiro-inositol can be synthesized and absorbed and their possible role in the etiopathogenesis of neural tube defects. MATERIALS AND METHODS: We performed an online search in the PubMed database using the following keywords: "inositol", "D-chiro-inositol", "myo-inositol", "neural tube defects and inositol". RESULTS: Inositol requirements are partly met by dietary intake, while the rest is synthesized endogenously. Inositol deficiency may be involved in the pathogenesis of diseases, such as metabolic syndrome, spina bifida (a neural tube defect), polycystic ovary syndrome and diabetes. Supplementation of the two inositol stereoisomers, D-chiro-inositol and myo-inositol is important to prevent these conditions. CONCLUSIONS: Inositol is fundamental for signal transduction in the brain, kidneys, reproductive organs and other tissues in response to neurotransmitters, hormones and growth factors. Various genes are involved in inositol metabolism and associated pathways. Altered inositol concentrations are observed in several diseases. Analysis of the genes involved in inositol metabolism may provide important information for the clinical management of these conditions.

Leukocytospermia in late adolescents: possible clinical interpretations.

BACKGROUND: No data are currently available on the implication of amicrobial leukocytospermia in male adolescents. Therefore, the primary aim of this study was to evaluate the prevalence of amicrobial leukocytospermia among non-smoker late adolescents who were exposed to other risky lifestyles for the andrological health. The main andrological clinical features of adolescents with leukocytospermia were also reported. METHODS: This is a cross-sectional study carried out in 80 boys. Each adolescent underwent a physical examination, and to the assessment of sperm conventional parameters, seminal leukocytes concentration and immature germ cell evaluation. A possible correlation between seminal leukocytes and immature germ cells and testicular volume (TV) was tested. RESULTS: The adolescents enrolled in this study had 18.0 ± 0.4 (range 18.1-18.9) years. Unprotected sexual intercourse was referred by 38% of them. Sexual dysfunctions were found in 25% and isolated hypoactive sexual desire in 12.5% of boys. Low TV and penile length in flaccidity were found in 44% and 30% of them, respectively. Only 41% had normozoospermia at the sperm analysis, whereas 19% had isolated oligozoospermia, 15% oligo-asthenozoospermia, and 25% oligo-astheno-teratozoospermia. Leukocytospermia occurred in 25% (20 out of 80) of adolescents. No seminal infection was detected in 19% (15 out of 80) of them. Adolescents with leukocytospermia had lower progressive sperm motility, percentage of normal forms, TV, and a higher percentage of immature germ cells compared to those without leukocytospermia. Semen leukocyte concentration correlated negatively with TV and positively with the percentage of immature germ cells in the ejaculate. CONCLUSION: Leukocytospermia, increased immature germ cell number, and low TV identify a distinct phenotype suggestive of testicular tubulopathy. Primary prevention of male infertility and the counselling for andrological risky lifestyles is mandatory and should be started as early as possible.

The European Academy of Andrology (EAA) ultrasound study on healthy, fertile men: Scrotal ultrasound reference ranges and associations with clinical, seminal, and biochemical characteristics.

BACKGROUND: Scrotal color Doppler ultrasound (CDUS) still suffers from lack of standardization. Hence, the European Academy of Andrology (EAA) has promoted a multicenter study to assess the CDUS characteristics of healthy fertile men (HFM) to obtain normative parameters. OBJECTIVES: To report and discuss the scrotal organs CDUS reference ranges and characteristics in HFM and their associations with clinical, seminal, and biochemical parameters. METHODS: A cohort of 248 HFM (35.3 ± 5.9years) was studied, evaluating, on the same day, clinical, biochemical, seminal, and scrotal CDUS following Standard Operating Procedures. RESULTS: The CDUS reference range and characteristics of the scrotal organs of HFM are reported here. CDUS showed a higher accuracy than physical examination in detecting scrotal abnormalities. Prader orchidometer (PO)- and US-measured testicular volume (TV) were closely related. The US-assessed TV with the ellipsoid formula showed the best correlation with the PO-TV. The mean TV of HFM was ~ 17 ml. The lowest reference limit for right and left testis was 12 and 11 ml, thresholds defining testicular hypotrophy. The highest reference limit for epididymal head, tail, and vas deferens was 12, 6, and 4.5 mm, respectively. Mean TV was associated positively with sperm concentration and total count and negatively with gonadotropins levels and pulse pressure. Subjects with testicular inhomogeneity or calcifications showed lower sperm vitality and concentration, respectively, than the rest of the sample. Sperm normal morphology and progressive motility were positively associated with epididymal head size/vascularization and vas deferens size, respectively. Increased epididymis and vas deferens sizes were associated with MAR test positivity. Decreased epididymal tail homogeneity/vascularization were positively associated with waistline, which was negatively associated with intratesticular vascularization. CDUS varicocele was detected in 37.2% of men and was not associated with seminal or hormonal parameters. Scrotal CDUS parameters were not associated with time to pregnancy, number of children, history of miscarriage. CONCLUSIONS: The present findings will help in better understanding male infertility pathophysiology, improving its management.

TSH lowering effects of metformin: a possible mechanism of action.

Preliminary clinical evidence suggests that metformin has TSH lowering effects in patients with T2DM and hypothyroidism or in those with TSH serum levels in the upper normal value. Also, metformin may exert a protective role against thyroid nodules growth in patients without insulin-resistance. The cross-talk between tyrosine kinase receptors and the G protein-coupled receptors (which the TSHR belongs to) has been already shown and IRS1 may represent the hub link between TSHR and IR pathways. By influencing IRS1 phosphorylation pattern, metformin may sensitize TSHR to TSH, thus explaining the findings of clinical studies. However, the existence of this molecular pathway must be confirmed through proper studies and further prospective randomized placebo-controlled studies are needed to confirm this hypothesis.

PET-guided Switch from Immunotherapy to Targeted Therapy in a Metastatic Melanoma Patient: a personalized approach.

An early identification of non-responders in oncology is of crucial importance to rapidly switch treatment regimens. Here we report a positron emission tomography, (PET)-guided switch from immunotherapy to targeted therapy in a patient affected by metastatic melanoma. We describe the case of a 78-years-old male patient diagnosed with nodular melanoma, submitted to baseline PET/CT with 18fluorodeoxyglucose (18F-FDG) that showed cutaneous and skeletal metastases (stage IV). The patients started immunotherapy with pembrolizumab. A PET/CT performed 3 months after the start of immunotherapy demonstrated progressive metabolic disease both at skeletal and cutaneous level, confirmed also by the biopsy. As patients resulted positive for BRAF V600k mutation, treatment regimen was rapidly switched to combined anti-BRAF/MEK targeted therapy. The PET/CT performed 3 months later, showed almost complete metabolic response. Ten months after the beginning of targeted therapy, the patient continues to present a durable metabolic response. PET/CT with 18F-FDG may help in monitoring the response to treatment in metastatic melanoma thus defining personalized therapeutic pathways.