Dapagliflozin improves erectile dysfunction in patients with type 2 diabetes mellitus: An open-label, non-randomized pilot study.

INTRODUCTION: The role of dapagliflozin on erectile dysfunction (ED), a condition widely affecting patients with type 2 diabetes mellitus (T2DM), has not yet been studied. AIM: The aim of the study was to evaluate the effects of dapagliflozin alone or in combination with tadalafil on ED in patients with T2DM. METHODS: This was an open-label, non-randomized pilot study involving 30 Caucasian male patients with T2DM and severe ED. They were equally divided into three groups, assigned to treatment with tadalafil 5 mg/day (Group 1), tadalafil 5 mg/day plus dapagliflozin 10 mg/day (Group 2) and dapagliflozin 10 mg/day (Group 3) for 3 months. The presence and the severity of ED were evaluated at enrolment and after treatment, by the International Index of Erectile Function 5-item (IIEF-5) questionnaire and the dynamic penile echo colour Doppler ultrasound (PCDU) examination. RESULTS: At the end of treatment, the three groups showed a significant improvement in IIEF-5 score, by 294%, 375% and 197%, in Groups 1, 2 and 3, respectively. PCDU evaluation showed a significant increase in peak systolic velocity by 178.9%, 339% and 153%; acceleration time was significantly shortened in Group 2 (-26.2%) and was significantly lower than in Group 1 and 3 (-7.2% and -6.6%), while no significant difference was found in end-diastolic velocity after treatment. The greatest rates of improvement were observed in Group 2 for all the end points. CONCLUSIONS: Dapagliflozin improves ED in patients with T2DM and enhances the efficacy of tadalafil. Further studies are needed to confirm our results explain the mechanism(s) by which dapagliflozin exerts its effects on ED.

Sperm epigenetics and sperm RNAs as drivers of male infertility: truth or myth?

Male infertility represents a complex clinical condition that often challenges the ability of reproductive specialists to find its etiology and then propose an adequate treatment. The unexplained decline in sperm count, as well as the association between male infertility and mortality, morbidity, and cancer, has prompted researchers toward an urgent need to better understand the causes of male infertility. Therefore, molecular biologists are increasingly trying to study whether sperm epigenetic alterations may be involved in male infertility and embryo developmental abnormalities. In this context, research is also trying to uncover the hidden role of sperm RNAs, both coding and non-coding. This narrative review aims to thoroughly and comprehensively present the relationship between sperm epigenetics, sperm RNAs, and human fertility. We first focused on the technological aspects of studying sperm epigenetics and RNAs, relating to the complex role(s) played in sperm maturation, fertilization, and embryo development. Then, we examined the intricate connections between epigenetics and RNAs with fertility measures, namely sperm concentration, embryo growth and development, and live birth rate, in both animal and human studies. A better understanding of the molecular mechanisms involved in sperm epigenetic regulation, as well as the impact of RNA players, will help to tackle infertility.

Relationship between degree of methylation of sperm long interspersed nuclear element-1 (LINE-1) gene and alteration of sperm parameters and age: a meta-regression analysis.

INTRODUCTION: The long interspersed nuclear element-1 (LINE1) gene is a retrotransposon whose methylation status appears to play a role in spermatogenesis, the outcome of assisted reproductive techniques (ART), and even in recurrent pregnancy loss (RPL). Advanced paternal age appears associated with altered sperm parameters, RPL, poor ART outcomes, and compromised offspring health. The methylation status of LINE1 has been reported to be affected by age. The latest meta-analysis on the LINE1 methylation pattern in spermatozoa found no significant differences in methylation levels between infertile patients and fertile controls. However, to the best of our knowledge, no updated meta-analysis on this topic has been published recently. Furthermore, no comprehensive meta-regression analysis was performed to investigate the association between sperm LINE1 methylation pattern and age. OBJECTIVES: To provide an updated and comprehensive systematic review and meta-analysis on sperm LINE1 gene methylation degree in patients with abnormal sperm parameters compared to men with normal sperm parameters and to probe the association between sperm LINE1 methylation status and age and/or sperm concentration. METHODS: This meta-analysis was registered in PROSPERO (registration n. CRD42023397056). It was performed according to the MOOSE guidelines for Meta-analyses and Systematic Reviews of Observational Studies and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P). Only original articles evaluating LINE1 gene methylation in spermatozoa from patients with infertility or abnormalities in one or more sperm parameters compared to fertile or normozoospermic men were included. RESULTS: Of 192 abstracts evaluated for eligibility, only 5 studies were included in the quantitative synthesis, involving a total of 340 patients and 150 controls. Our analysis showed no significant difference in LINE1 gene methylation degree in patients with infertility and/or abnormal sperm parameters compared to fertile controls and/or men with normal sperm parameters, although there was significant heterogeneity across studies. No significant evidence of publication bias was found, and no study was sensitive enough to alter the results. In meta-regression analysis, we found that the results were independent of both ages and sperm concentration. A sub-analysis examining patients and controls separately was also conducted and we found a trend for a positive correlation between LINE1 methylation and sperm concentration in the control group only. CONCLUSIONS: The results of this systematic review and meta-analysis do not suggest a determining role of sperm LINE1 gene methylation degree in patients with infertility and/or abnormal sperm parameters. Therefore, we do not suggest including LINE1 in the genetic panel of prospective studies aimed at identifying the most representative and cost-effective genes to be analyzed in couples undergoing ART cycles.

H19 Sperm Methylation in Male Infertility: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis summarize the difference in the methylation of the H19 gene in patients with abnormal versus normal conventional sperm parameters. It also evaluates the effects of age and sperm concentration on H19 methylation in spermatozoa using meta-regression analysis. It was performed according to the MOOSE guidelines for meta-analyses and Systematic Reviews of Observational Studies and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). The quality of the evidence reported in the studies included was assessed using the Cambridge Quality Checklists. A total of 11 articles met our inclusion criteria. Quantitative analysis showed that H19 methylation levels were significantly lower in the group of infertile patients than in fertile controls. The reduction in methylation was much more pronounced in patients with oligozoospermia (alone or associated with other sperm parameter abnormalities) and in those with recurrent pregnancy loss. Meta-regression analysis showed the results to be independent of both patient age and sperm concentration. Therefore, the H19 methylation pattern should be evaluated among couples accessing assisted reproductive techniques (ART), in order to gain prognostic information on ART outcome and offspring health.

Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series.

Congenital hypogonadotropic hypogonadism (cHH)/Kallmann syndrome (KS) is a rare genetic disorder with variable penetrance and a complex inheritance pattern. Consequently, it does not always follow Mendelian laws. More recently, digenic and oligogenic transmission has been recognized in 1.5-15% of cases. We report the results of a clinical and genetic investigation of five unrelated patients with cHH/KS analyzed using a customized gene panel. Patients were diagnosed according to the clinical, hormonal, and radiological criteria of the European Consensus Statement. DNA was analyzed using next-generation sequencing with a customized panel that included 31 genes. When available, first-degree relatives of the probands were also analyzed to assess genotype-phenotype segregation. The consequences of the identified variants on gene function were evaluated by analyzing the conservation of amino acids across species and by using molecular modeling. We found one new pathogenic variant of the CHD7 gene (c.576T>A, p.Tyr1928) and three new variants of unknown significance (VUSs) in IL17RD (c.960G>A, p.Met320Ile), FGF17 (c.208G>A, p.Gly70Arg), and DUSP6 (c.434T>G, p.Leu145Arg). All were present in the heterozygous state. Previously reported heterozygous variants were also found in the PROK2 (c.163del, p.Ile55*), CHD7 (c.c.2750C>T, p.Thr917Met and c.7891C>T, p.Arg2631*), FLRT3 (c.1106C>T, p.Ala369Val), and CCDC103 (c.461A>C, p.His154Pro) genes. Molecular modeling, molecular dynamics, and conservation analyses were performed on three out of the nine variants identified in our patients, namely, FGF17 (p.Gly70Arg), DUSP6 (p.Leu145Arg), and CHD7 p.(Thr917Met). Except for DUSP6, where the L145R variant was shown to disrupt the interaction between ß6 and ß3, needed for extracellular signal-regulated kinase 2 (ERK2) binding and recognition, no significant changes were identified between the wild-types and mutants of the other proteins. We found a new pathogenic variant of the CHD7 gene. The molecular modeling results suggest that the VUS of the DUSP6 (c.434T>G, p.Leu145Arg) gene may play a role in the pathogenesis of cHH. However, our analysis indicates that it is unlikely that the VUSs for the IL17RD (c.960G>A, p.Met320Ile) and FGF17 (c.208G>A, p.Gly70Arg) genes are involved in the pathogenesis of cHH. Functional studies are needed to confirm this hypothesis.

Effects of Follicle-Stimulating Hormone on Human Sperm Motility In Vitro.

To evaluate whether the follicle-stimulating hormone (FSH) receptor (FSHR) is expressed in human spermatozoa and the effects of FSH incubation on sperm function. Twenty-four Caucasian men were recruited. Thirteen patients had asthenozoospermia, and the remaining 11 had normal sperm parameters (controls). After confirming FSHR expression, spermatozoa from patients and controls were incubated with increasing concentrations of human purified FSH (hpFSH) to reassess FSHR expression and localization and to evaluate progressive and total sperm motility, the mitochondrial membrane potential, and protein kinase B (AKT) 473 and 308 phosphorylation. FSHR is expressed in the post-acrosomal segment, neck, midpiece, and tail of human spermatozoa. Its localization does not differ between patients and controls. Incubation with hpFSH at a concentration of 30 mIU/mL appeared to increase FSHR expression mainly in patients. Incubation of human spermatozoa with hpFSH overall resulted in an overall deterioration of both progressive and total motility in patients and controls and worse mitochondrial function only in controls. Finally, incubation with FSH increased AKT473/tubulin phosphorylation to a greater extent than AKT308. FSHR is expressed in the post-acrosomal region, neck, midpiece, and tail of human spermatozoa. Contrary to a previous study, we report a negative effect of FSH on sperm motility and mitochondrial function. FSH also activates the AKT473 signaling pathway.

Insulin-like Growth Factor 1, Growth Hormone, and Anti-Müllerian Hormone Receptors Are Differentially Expressed during GnRH Neuron Development.

Gonadotropin-releasing hormone (GnRH) neurons are key neuroendocrine cells in the brain as they control reproduction by regulating hypothalamic-pituitary-gonadal axis function. In this context, anti-Müllerian hormone (AMH), growth hormone (GH), and insulin-like growth factor 1 (IGF1) were shown to improve GnRH neuron migration and function in vitro. Whether AMH, GH, and IGF1 signaling pathways participate in the development and function of GnRH neurons in vivo is, however, currently still unknown. To assess the role of AMH, GH, and IGF1 systems in the development of GnRH neuron, we evaluated the expression of AMH receptors (AMHR2), GH (GHR), and IGF1 (IGF1R) on sections of ex vivo mice at different development stages. The expression of AMHR2, GHR, and IGF1R was assessed by immunofluorescence using established protocols and commercial antibodies. The head sections of mice were analyzed at E12.5, E14.5, and E18.5. In particular, at E12.5, we focused on the neurogenic epithelium of the vomeronasal organ (VNO), where GnRH neurons, migratory mass cells, and the pioneering vomeronasal axon give rise. At E14.5, we focused on the VNO and nasal forebrain junction (NFJ), the two regions where GnRH neurons originate and migrate to the hypothalamus, respectively. At E18.5, the median eminence, which is the hypothalamic area where GnRH is released, was analyzed. At E12.5, double staining for the neuronal marker ß-tubulin III and AMHR2, GHR, or IGF1R revealed a signal in the neurogenic niches of the olfactory and VNO during early embryo development. Furthermore, IGF1R and GHR were expressed by VNO-emerging GnRH neurons. At E14.5, a similar expression pattern was found for the neuronal marker ß-tubulin III, while the expression of IGF1R and GHR began to decline, as also observed at E18.5. Of note, hypothalamic GnRH neurons labeled for PLXND1 tested positive for AMHR2 expression. Ex vivo experiments on mouse sections revealed differential protein expression patterns for AMHR2, GHR, and IGF1R at any time point in development between neurogenic areas and hypothalamic compartments. These findings suggest a differential functional role of related systems in the development of GnRH neurons.

Impact of seminal low-risk human papillomavirus infection on sperm parameters of adult men.

Aim: We aimed to evaluate the impact of seminal low-risk human Papillomavirus (LR-HPV) infection on sperm conventional parameters.Material and methods: This was a retrospective case-control study including patients attending to our center for infertility. Patients with evidence for high risk (HR)-HPV infection previously or at the time of enrollment, and/or with severe oligozoospermia (sperm concentration <5 mil/ml) were ruled out. Twenty selected patients positive for a LR-HPV and 20 control subjects with no evidence of HPV DNA and with available results of sperm analysis were consecutively enrolled.Results: Patients positive for LR-HPV had a mean age of 31.0 + 11.0 years, while controls were 35.0 + 8.0-year-old (p > .05). Sperm concentration, total sperm count, sperm progressive motility, morphology, and leukocyte concentration did not differ between patients and controls. However, the prevalence of oligozoospermia was significantly higher in patients than controls (50% vs. 15%). No difference in the prevalence of astenozoospermia (30% vs. 40%) or teratozoospermia (15% vs. 15%) was found.Conclusion: We found no difference in sperm conventional parameters in LR-HPV infected patients than in controls. These data might prompt to research the impact on LR-HPV genotype on male fertility. Particularly, evidence on sperm DNA fragmentation (SDF) and pregnancy outcome is needed.

ANXA2, SP17, SERPINA5, PRDX2 genes, and sperm DNA fragmentation differentially represented in male partners of infertile couples with normal and abnormal sperm parameters.

This study aims to evaluate the expression of genes associated with the fertilisation potential and embryo development, sperm DNA fragmentation (SDF), and acrosome reaction in male partners of infertile couples with different sperm parameters compared to fertile men. First, male partners of infertile couples with abnormal (N = 25) and normal sperm parameters (N = 25), and fertile men (N = 10) were included in experimental groups I, II, and controls respectively. The mRNA levels of the Annexin A2 (ANXA2), Sperm protein 17 (SP17), Plasma serine protease inhibitor (SERPINA5), and Peroxiredoxin-2 (PRDX2) genes and SDF were evaluated. To evaluate the maturity of the sperm and oxidative stress, the acrosome reaction, the lipid peroxidation, and total antioxidant were measured. As result, SP17 showed a significantly lower expression in both experimental groups. SERPINA5 was significantly down-regulated in experimental group I that was aligned with the low rate of acrosome reaction. Significant overexpression of PRDX2 was found between experimental group II and controls. Significant higher rates of SDF were seen in both experimental groups compared to the controls. Finally, our data suggest that differentially gene expression of SP17 is a potential diagnostic biomarker in infertile men either with normal or abnormal sperm parameters. SDF is one of the causes of male infertility, independent of the sperm parameters.

Obesity and Male Reproduction: Do Sirtuins Play a Role?

Obesity is a major current public health problem of global significance. A progressive sperm quality decline, and a decline in male fertility, have been reported in recent decades. Several studies have reported a strict relationship between obesity and male reproductive dysfunction. Among the many mechanisms by which obesity impairs male gonadal function, sirtuins (SIRTs) have an emerging role. SIRTs are highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases that play a role in gene regulation, metabolism, aging, and cancer. SIRTs regulate the energy balance, the lipid balance, glucose metabolism, and adipogenesis, but current evidence also indicates a role for SIRTs in male reproduction. However, the majority of the studies have been conducted in animal models and very few have been conducted with humans. This review shows that SIRTs play an important role among the molecular mechanisms by which obesity interferes with male fertility. This highlights the need to deepen this relationship. It will be of particular interest to evaluate whether synthetic and/or natural compounds capable of modifying the activity of SIRTs may also be useful for the treatment of obesity and its effects on gonadal function. Although few studies have explored the role of SIRT activators in obesity-induced male infertility, some molecules, such as resveratrol, appear to be effective in modulating SIRT activity, as well as counteracting the negative effects of obesity on male fertility. The search for strategies to improve male reproductive function in overweight/obese patients is a challenge and understanding the role of SIRTs and their activators may open new interesting scenarios in the coming years.

Resistance to Thyroid Hormones: A Case-Series Study.

The aim of the study is to describe the clinical features of two unrelated patients with resistance to thyroid hormones (RTH), the first, a total thyroidectomized patient, and the second, a pregnant woman. We report the features found in her newborn who also showed RTH. Patient 1 is a 38-year-old man with total thyroidectomy managed for excessive thyroid stimulating hormone (TSH) production, which poorly responded to the replacement therapy. He was found with a THRß c.1378G>A p.(Glu460Lys) heterozygous mutation, which was also present in other members of his family (son, brother, and father). Interestingly, Patient 1 had hypertension, dyslipidemia, and hepatic steatosis, which have been recently suggested as RTH-related comorbidities. Patient 2 is a 32-year-old pregnant woman with multinodular goiter, and the THRß heterozygous variant c.959G>C, that, to the best of our knowledge, has been reported in literature only once. Her newborn had tachycardia and increased thyroid hormone levels, and showed the same mutation. After delivery, high parathyroid hormone (PTH) and calcium serum levels were found in Patient 2 and the scintigraphy showed the presence of adenoma of a parathyroid gland. This case-series study provides a practical example of the management of RTH in a thyroidectomized patient, a pregnant woman, and a newborn. A novel RTH pathogenic mutation is described for the second time in literature. Furthermore, the importance of metabolic assessment in patients with RTHß has been highlighted and the possible correlation between RTH and primary hyperparathyroidism is discussed.

A study of gene expression by RNA-seq in patients with prostate cancer and in patients with Parkinson disease: an example of inverse comorbidity.

BACKGROUND: Prostate cancer (PCa) is one of the leading causes of death in Western countries. Environmental and genetic factors play a pivotal role in PCa etiology. Timely identification of the genetic causes is useful for an early diagnosis. Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder; it is associated with the presence of Lewy bodies and genetic factors are involved in its pathogenesis. Several studies have indicated that the expression of target genes in patients with PD is inversely related to cancer development; this phenomenon has been named "inverse comorbidity". The present study was undertaken to evaluate whether a genetic dysregulation occurs in opposite directions in patients with PD or PCa. METHODS AND RESULTS: In the present study, next-generation sequencing transcriptome analysis was used to assess whether a genetic dysregulation in opposite directions occurs in patients with PD or PCa. The genes SLC30A1, ADO, SRGAP2C, and TBC1D12 resulted up-regulated in patients with PD compared to healthy donors as controls and down-regulated in patients with PCa compared with the same control group. CONCLUSIONS: These results support the hypothesis of the presence of inverse comorbidity between PD and PCa.

CCR3 gene overexpression in patients with Down syndrome.

Chromosome 21 trisomy or Down syndrome (DS) is the most common genetic cause of intellectual disability (ID). DS is also associated with hypotonia, muscle weakness, autoimmune diseases, and congenital heart disease. C-C chemokine receptor type 3 (CCR3) plays a role in inflammatory, autoimmune, and neuronal migration mechanisms. The present study aimed to evaluate the expression of the CCR3 gene by NGS and qRT-PCR in patients with DS and normal controls (NC). The CCR3 gene was over-expressed in DS patients compared to NC. These data suggest that an over-expression of the CCR3 gene is associated with the phenotype of patients with DS.

The Role of Resveratrol Administration in Human Obesity.

Obesity is a widespread disease that is associated with numerous and serious comorbidities. These include metabolic syndrome, diabetes mellitus, cardiovascular-cerebrovascular disease, hypertension, obstructive sleep apnea syndrome, cancer, and sexual and hormonal disorders. The treatment of obesity has therefore become a goal of great clinical and social relevance. Among the therapeutic strategies against obesity, resveratrol has aroused great interest. This polyphenol has anticancer and antioxidant properties and cytoprotective and anti-inflammatory effects. Other favorable effects attributed to resveratrol are anti-lipid, anti-aging, anti-bacterial, anti-viral, and neuroprotective actions. Administration of resveratrol appears to improve the metabolic profile in obese and/or insulin-resistant patients. This article aims to review the main results of clinical studies evaluating the effects of administering resveratrol alone in overweight/obese patients.

Anti-Müllerian Hormone, Growth Hormone, and Insulin-Like Growth Factor 1 Modulate the Migratory and Secretory Patterns of GnRH Neurons.

Anti-Müllerian hormone (AMH) is secreted by Sertoli or granulosa cells. Recent evidence suggests that AMH may play a role in the pathogenesis of hypogonadotropic hypogonadism (HH) and that its serum levels could help to discriminate HH from delayed puberty. Moreover, the growth hormone (GH)/insulin-like growth factor 1 (IGF1) system may be involved in the function of gonadotropin-releasing hormone (GnRH) neurons, as delayed puberty is commonly found in patients with GH deficiency (GHD) or with Laron syndrome, a genetic form of GH resistance. The comprehension of the stimuli enhancing the migration and secretory activity of GnRH neurons might shed light on the causes of delay of puberty or HH. With these premises, we aimed to better clarify the role of the AMH, GH, and IGF1 on GnRH neuron migration and GnRH secretion, by taking advantage of previously established models of immature (GN11 cell line) and mature (GT1-7 cell line) GnRH neurons. Expression of Amhr, Ghr, and Igf1r genes was confirmed in both cell lines. Cells were then incubated with increasing concentrations of AMH (1.5-150 ng/mL), GH (3-1000 ng/mL), or IGF1 (1.5-150 ng/mL). All hormones were able to support GN11 cell chemomigration. AMH, GH, and IGF1 significantly stimulated GnRH secretion by GT1-7 cells after a 90-min incubation. To the best of our knowledge, this is the first study investigating the direct effects of GH and IGF1 in GnRH neuron migration and of GH in the GnRH secreting pattern. Taken together with previous basic and clinical studies, these findings may provide explanatory mechanisms for data, suggesting that AMH and the GH-IGF1 system play a role in HH or the onset of puberty.

The Role of Resveratrol in Human Male Fertility.

Resveratrol (RSV) (3,4',5 trihydroxystilbene) is a natural non-flavonoid polyphenol widely present in the Mediterranean diet. In particular, RSV is found in grapes, peanuts, berries, and red wine. Many beneficial effects of this molecule on human health have been reported. In fact, it improves some clinical aspects of various diseases, such as obesity, tumors, hypertension, Alzheimer's disease, stroke, cardiovascular diseases, and diabetes mellitus. However, little is known about the relationship between this compound and male fertility and the few available results are often controversial. Therefore, this review evaluated the effects of RSV on human male fertility and the mechanisms through which this polyphenol could act on human spermatozoa.

Complete Androgen Insensitivity Syndrome: From the Relevance of an Accurate Genetic Diagnosis to the Challenge of Clinical Management. A Case Report.

Introduction: Androgen insensitivity syndrome (AIS), an X-linked recessive disorder of sex development (DSD), is caused by variants of the androgen receptor (AR) gene, mapping in the long arm of the X chromosome, which cause a complete loss of function of the receptor. Case presentation: We report a patient diagnosed with complete AIS (CAIS) at birth due to swelling in the bilateral inguinal region. Transabdominal ultrasound revealed the absence of the uterus and ovaries and the presence of bilateral testes in the inguinal region. The karyotype was 46,XY. She underwent bilateral orchiectomy at 9 months and was given estrogen substitutive therapy at the age of 11 years. Genetic analysis of the AR gene variants was requested when, at the age of 20, the patient came to our observation. Methods: The genetic testing was performed by next-generation sequence (NGS) analysis. Results: The genetic analysis showed the presence of the c.2242T>A, p.(Phe748Ile) variant in the AR gene. To the best of our knowledge, this variant has not been published so far. Furthermore, the patient has a heterozygous c.317A>G, p.(Gln106Arg) variation of the gonadotropin-releasing hormone receptor (GNRHR) gene, a heterozygous c.2273G>A, p.Arg758His variation of the chromodomain helicase DNA binding protein 7 (CHD7) gene, and compound heterozygous c.875A>G, p.Tyr292Cys, and c.8023A>G, p.Ile2675Val variations of the Dynein Axonemal Heavy Chain 11 (DNAH11) gene. Conclusions: The case herein reported underlines the importance of an accurate genetic analysis that has to include karyotype and AR gene variant analysis. This is useful to confirm a clinical diagnosis and establish the proper management of patients with CAIS. Numerous variants of the AR gene have not yet been identified. Moreover, several pitfalls are still present in the management of these patients. More studies are needed to answer unresolved questions, and common protocols are required for the clinical follow-up of patients with CAIS.

Urogenital dysfunction in male patients with Charcot-Marie-Tooth: a systematic review.

INTRODUCTION: Charcot-Marie-Tooth (CMT) is the most common inherited polyneuropathy. Polyneuropathies are likely to affect the urogenital system. Urogenital dysfunction is rarely investigated and may be underestimated in CMT patients. AIM: The aim of the present study was to perform a systematic review of the literature to collect all the available evidence on the presence of urogenital dysfunction and in patients with CMT. METHODS: Data sources were MEDLINE, Pubmed, Scopus, and Google Scholar. All types of studies describing the presence of lower urinary tract dysfunction, erectile dysfunction (ED), anejaculation, and other sexual disorders in male patients with CMT were included. RESULTS: Among 131 records identified, five articles were included in the qualitative synthesis. Lower urinary tract dysfunction, neurogenic bladder, ED, and other sexual dysfunctions have been reported in patients with CMT. One case of anejaculation has been described. CONCLUSION: Urogenital dysfunction occurs in patients with CMT. Therefore, uro-andrologic counseling should be performed in the aging male with CMT. This might positively impact on his quality of life.

FSH therapy for idiopathic male infertility: four schemes are better than one.

OBJECTIVE: The aim of this article is to propose an algorithm that aids the clinician to choose the best therapeutic scheme of follicle-stimulating hormone (FSH) in the treatment of men with idiopathic infertility, based on testicular volume (TV) and serum total testosterone concentrations; highlighting the potential role of additional therapy with hCG in a sequential temporal scheme. MATERIALS AND METHODS: We subdivided patients in four clinical groups: patients with normal TV and serum testosterone concentrations (A); patients with normal TV and reduced serum testosterone concentrations (B); patients with reduced TV and serum testosterone concentration (C); patient with low TV e normal serum testosterone concentrations (D). Then, we administered to each group a specific therapeutic scheme. Group A: treated with FSH alone for at least 3 months; group B: treated with hCG alone twice a week for 3 months and addition of FSH for poor responders (unmodified sperm parameters); group C: treated ab initio with FSH and hCG until the pregnancy was reached; group D: treated with FSH alone for 3 months and addition of hCG for moderate poor responders (increased TV but unmodified sperm parameters) or second cycle of FSH for 3 months for severe poor responders (unmodified TV and sperm parameters). After 6 months we evaluated the therapeutic response in term of sperm parameters normalization rate, spontaneous pregnancy rate, and sperm DNA fragmentation normalization rate. RESULTS: 40% of patients became normozoospermic after treatment, while 30% achieved spontaneous pregnancy. B was the group that best responded to treatment in terms of normalization of seminal parameters; while the highest spontaneous pregnancy rate was obtained from the D group. B group also obtained the highest sperm DNA fragmentation normalization rate. CONCLUSIONS: To date, no reliable predictors of response to treatment with FSH exist, but TV and serum testosterone concentrations can help the clinician to choose the best therapeutic scheme for men with idiopathic infertility. The groups treated with a sequential temporal scheme (B and D groups) showed better clinical results compared with two groups treated with conventional schemes (A and C groups).

Consequences on aging process and human wellness of generation of nitrogen and oxygen species during strenuous exercise.

Impairment of antioxidant defense system and increase in metabolic rate and production of reactive oxygen species have been demonstrated in strenuous exercise. Both at rest and during contractile activity, skeletal muscle generates a very complex set of reactive nitrogen and oxygen species; the main generated are superoxide and nitric oxide. The nature of the contractile activity influences the pattern and the magnitude of this reactive oxygen and nitrogen species (ROS) generation. The intracellular pro-oxidant/antioxidant homeostasis undergoes alteration owing to strenuous exercise and the major identified sources of intracellular free radical generation during physical activity are the mitochondrial electron transport chain, polymorphoneutrophil, and xanthine oxidase. Reactive oxygen species increased tissue susceptibility to oxidative damage and pose a serious threat to the cellular antioxidant defense system. The possible dangerous consequences of the aging process and human wellness are emphasized in this review.