Thyroid diseases and female sexual dysfunctions.

INTRODUCTION: Female sexual dysfunctions (FSDs) have received little attention in the context of thyroid diseases, despite the high prevalence of both conditions. OBJECTIVES: This review aims to update and summarize the state of knowledge on the association between thyroid diseases and FSDs and to investigate the complex mechanisms through which thyroid hormone imbalance can impact female sexual health in the context of the biopsychosocial model. METHODS: A comprehensive literature search was performed through the PubMed, MEDLINE, and Scopus databases, using the following keywords: "female sexual function," "sexual dysfunction," "hypoactive sexual desire disorder," "thyroid disease," "thyroiditis," "hypothyroidism," and "hyperthyroidism." RESULTS: To date, well-designed studies that describe the relationship between FSDs and thyroid disorders are lacking. However, despite the limitations on available studies, current data indicate that sexual alterations are frequently associated with thyroid diseases in women. A complex interplay of direct and indirect hormonal and nonhormonal mechanisms has been hypothesized, including hormonal changes, neurotransmitter imbalance, reduced nitric oxide release, mood disorders, and other systemic consequences of both hypothyroidism and hyperthyroidism. Thyroid hormone receptors have also been identified in the genitourinary system. CONCLUSIONS: In a clinical setting, physicians should investigate the sexuality of patients consulting for thyroid disease. At the same time, an evaluation of thyroid function should be performed in patients presenting with FSD, especially after menopause, when the risk of thyroid diseases and FSDs increases strongly.

Obesity and male fertility disorders.

Often associated with obesity, male infertility represents a widespread condition that challenges the wellbeing of the couple. In this article, we provide a comprehensive and critical analysis of studies exploring the association between obesity and male reproductive function, to evaluate the frequency of this association, and establish the effects of increased body weight on conventional and biofunctional sperm parameters and infertility. In an attempt to find possible molecular markers of infertility in obese male patients, the numerous mechanisms responsible for infertility in overweight/obese patients are reviewed in depth. These include obesity-related functional hypogonadism, insulin resistance, hyperinsulinemia, chronic inflammation, adipokines, irisin, gut hormones, gut microbiome, and sperm transcriptome. According to meta-analytic evidence, excessive body weight negatively influences male reproductive health. This can occurr through a broad array of molecular mechanisms. Some of these are not yet fully understood and need to be further elucidated in the future. A better understanding of the effects of metabolic disorders on spermatogenesis and sperm fertilizing capacity is very useful for identifying new diagnostic markers and designing therapeutic strategies for better clinical management of male infertility.

Impact of COVID-19 on testicular function: a systematic review and meta-analysis.

INTRODUCTION: Studies investigating the effects of SARS-CoV-2 on male reproductive function are few and heterogeneous, and results are often conflicting. This systematic review and meta-analysis was carried out on studies conducted in men with active or anamnestic SARS-CoV-2 infection to evaluate its consequences on the male sex hormone profile and semen parameters. MATERIALS AND METHOD: This meta-analysis follows the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) protocols. PubMed, Scopus, Cochrane, and Embase databases were searched to identify relevant studies. We originally selected 3553 articles. After the eligibility phase, 16 articles met our inclusion criteria encompassing 11 case-control studies and 5 cohort studies (2 prospective and 3 retrospective studies). We performed the quantitative analysis with Comprehensive Meta-Analysis Software. Cochran-Q and heterogeneity (I2) indexes were used to assess statistical heterogeneity. Sensitivity analysis and publication bias tests were also performed. RESULTS: Overall, 1250 patients with active or recent (up to 80 days before) COVID-19 infection and 1232 matched healthy controls were included. Sperm concentration, total sperm count, and total motility were significantly lower in patients compared with controls. Patients also showed lower levels of total testosterone and follicle-stimulating hormone, and higher levels of luteinizing hormone, 17ß-estradiol, and prolactin compared with healthy controls. None of the included studies found the presence of SARS-CoV-2 mRNA in the semen of infected patients. CONCLUSION: The present systematic review and meta-analysis suggests the presence of an association between SARS-CoV-2 infection and primary testicular damage manifested with a picture of altered steroidogenesis and worsening spermatogenesis. The absence of the virus in the seminal fluid indicates a low possibility of sexual transmission of the infection to partners and offspring. However, our findings mostly show short-term follow-up, while few studies have considered the long-term consequences of the viral infection, thus further studies are needed to evaluate the long-term consequences on male reproductive health.

Antioxidants for male infertility: therapeutic scheme and indications. A retrospective single-center real-life study.

BACKGROUND: This single-center real-life study was conducted to evaluate the most effective combination of nutraceuticals and the most appropriate indications for the treatment of male infertile patients. METHODS: Infertile patients aged 20-55 years were treated with a combination of antioxidants (Androlen®; Enfarma, Misterbianco, Catania, Italy) (group A), with Androlen® (Enfarma) and a mixture of fibrinolytic molecules (Lenidase®, Enfarma) (group B), or Androlen® (Enfarma) and other molecules different from those used for the patients of the group B (group C). Patients were also subdivided according to the presence of varicocele, mild testicular hypotrophy, idiopathic infertility, and chronic male accessory gland infection. RESULTS: Forty-three patients were enrolled. In the overall analysis, only progressive motility significantly improved after therapy. Subgroup analysis showed a significant increase in progressive motility, total motile sperm count (TMSC), and in the percentage of alive spermatozoa after treatment in the group A. Progressive motility improved significantly in patients with varicocele, while the TMSC in patients with varicocele and those with idiopathic infertility. The percentage of alive spermatozoa increased in patients with testicular hypotrophy. CONCLUSIONS: Treatment with antioxidants increased progressive sperm motility, especially in patients with varicocele or idiopathic 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.

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.

The Role of Irisin throughout Women's Life Span.

Since its discovery, much attention has been drawn to irisin's potential role in metabolic and reproductive diseases. This narrative review summarizes and updates the possible role played by this fascinating molecule in different physiological (puberty and menopause) and pathological (polycystic ovary syndrome (PCOS), functional hypothalamic amenorrhea (FHA), endometriosis, and gestational diabetes) conditions that can affect women throughout their entire lives. Irisin appears to be an important factor for the hypothalamic-pituitary-gonadal axis activation, and appears to play a role in the timing of puberty onset. Serum irisin levels have been proposed as a biomarker for predicting the future development of gestational diabetes (GDM). Its role in PCOS is still controversial, although an "irisin resistance" mechanism has been hypothesized. In addition to its impact on metabolism, irisin also appears to influence bone health. Irisin levels are inversely correlated with the prevalence of fractures in postmenopausal women. Similar mechanisms have also been postulated in young women with FHA. In clinical settings, further controlled, prospective and randomized clinical trials are needed to investigate the casual relationship between irisin levels and the conditions described and, in turn, to establish the role of irisin as a prognostic/diagnostic biomarker or a therapeutic target.

Relationship between Iron Deficiency and Thyroid Function: A Systematic Review and Meta-Analysis.

Objective: Iron deficiency (ID) is the most prevalent nutritional deficiency worldwide. Low levels of serum ferritin (SF) could affect the thyroid gland and its functioning. The purpose of this systematic review and meta-analysis is to summarize the main currently available evidence and analyze data on the relationship between ID and thyroid function. Methods: This study included all articles evaluating the relationship between ID and thyroid function. Quality assessment was performed using Cambridge Quality Checklists. The search strategy included the following combination of Medical Subjects Headings terms and keywords: "iron deficiency", "thyroid function", "thyroid disease", "thyroid dysfunction", and "hypothyroidism". A meta-analysis was performed to evaluate whether thyroid stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) levels differed between patients with ID and healthy controls without ID. For statistical comparison between cases and controls, the mean difference (MD) was calculated, and a subgroup analysis of pregnant and non-pregnant women was performed. Cochran's Q testing and heterogeneity indices (I2) were used to assess statistical heterogeneity. Sensitivity analysis and publication bias analyses were also performed, both qualitatively and quantitatively. Finally, a meta-regression analysis was performed to evaluate the correlation between serum TSH or FT4 levels and SF in the study population. Results: Ten cross-sectional studies were identified and reviewed. Patients with ID showed TSH (MD: -0.24 mIU/L; 95% CI -0.41, -0.07; I2 = 100%, p = 0.005), FT4 (MD: -1.18 pmol/L; 95% CI -1.43, -0.94; I2 = 99%, p < 0.000001), and FT3 (MD: -0.22 pmol/L; 95% CI -0.32, -0.12; I2 = 99%, p < 0.00001) levels that were significantly lower. Subgroup analysis confirmed significantly lower TSH, FT4, and FT3 levels in pregnant women. Non-pregnant women showed significantly lower serum FT4 and FT3 levels but no difference in TSH values. Meta-regression analysis showed that serum TSH and FT4 levels were positively correlated with SF levels. Our systematic review of the literature found that ID significantly increases the prevalence of thyroid autoantibody (anti-thyroglobulin antibodies and anti-thyroid peroxidase antibodies) positivity both individually and collectively. Conclusion: Studies currently published in the literature indicate a possible relationship between ID, thyroid function, and autoimmunity, especially in some patient groups. Data analysis shows that thyroid hormone levels are lower in patients with ID and, in particular, in pregnant women. Further studies are needed to understand the role played by iron in thyroid metabolism.

Testosterone replacement therapy and vascular thromboembolic events: a systematic review and meta-analysis.

ABSTRACT: To evaluate the relationship between testosterone replacement therapy (TRT) and arterial and/or venous thrombosis in patients with pre-treatment total testosterone (TT) <12 nmol l-1, we performed a meta-analysis following the Population Intervention Comparison Outcome model. Population: men with TT <12 nmol l-1 or clear mention of hypogonadism in the inclusion criteria of patients; intervention: TRT; comparison: placebo or no therapy; outcomes: arterial thrombotic events (stroke, myocardial infarction [MI], upper limbs, and lower limbs), VTE (deep vein thrombosis [DVT], portal vein thrombosis, splenic thrombosis, and pulmonary embolism), and mortality. A total of 2423 abstracts were assessed for eligibility. Twenty-four studies, including 14 randomized controlled trials (RCTs), were finally included, with a total of 4027 and 310 288 hypotestosteronemic male patients, from RCTs and from observational studies, respectively. Based on RCT-derived data, TRT did not influence the risk of arterial thrombosis (odds ratio [OR] = 1.27, 95% confidence interval [CI]: 0.47-3.43, P = 0.64), stroke (OR = 1.34, 95% CI: 0.09-18.97, P = 0.83), MI (OR = 0.51, 95% CI: 0.11-2.31, P = 0.39), VTE (OR = 1.42, 95% CI: 0.22-9.03, P = 0.71), pulmonary embolism (OR = 1.38, 95% CI: 0.27-7.04, P = 0.70), and mortality (OR = 0.70, 95% CI: 0.20-2.38, P = 0.56). Meanwhile, when only observational studies are considered, a significant reduction in the risk of developing arterial thrombotic events, MI, venous thromboembolism, and mortality was observed. The risk for DVT remains uncertain, due to the paucity of RCT-based data. TRT in men with TT <12 nmol l-1 is safe from the risk of adverse cardiovascular events. Further studies specifically assessing the risk of DVT in men on TRT are needed.

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.

Glycometabolic outcomes in adult type 1 diabetic patients switching to closed-loop systems.

OBJECTIVE: This study aimed to evaluate glycometabolic outcomes in AID technology-naïve T1D patients after switching to Hybrid Closed Loop (HCL) and Advanced Hybrid Closed Loop (AHCL) systems. RESEARCH DESIGN AND METHODS: This was a 12-month, prospective, observational, two-center study on 54 type 1 diabetes (T1D) patients aged 19-65 years managed with multiple daily injections (MDI) or Continuous Subcutaneous Insulin Infusion (CSII) in open-loop to evaluate the superiority in terms of effectiveness and safety of Automated Insulin Delivery (AID) systems. RESULTS: HbA1c levels significantly improved at the end of the study. Time spent with glucose levels in target range (TIR70-180 mg/dL, 3.9-10 mmol/L) increased from 50.5 ± 15.6% at baseline to 73.6 ± 8.0% at 12 months (p < 0.001); time spent above range (TAR180-250 mg/dL, 10-13.9 mmol/L and TAR≥250 mg/dL, 13.9 mmol/L) decreased from 30.6 ± 9.0% and 14.2 ± 10.2 at baseline to 19.3 ± 5.3% and 4.8 ± 3.3% at 12 months (p < 0.001 for both), respectively; time spent below range (TBR54-69 mg/dL, 3-3.8 mmol/L and TBR<54 mg/dL, 3.0 mmol/L) decreased from 3.5 ± 2.6% and 1.2 ± 1.4% at baseline to 1.9 ± 1.5% and 0.4 ± 0.7% at the end of the study (p < 0.001 for both); coefficient of variation (CV) decreased from 35.9 ± 7.8% at baseline to 33.0 ± 5.3% (p < 0.05). Satisfaction with the new technology was scored as high. CONCLUSION: AID-naïve T1D patients switching to HCL/AHCL systems have significantly and safely improved their glycometabolic outcomes with their high satisfaction with the new type of treatment.

Lifestyle and sexual habits of students in a Southern Italian region.

BACKGROUND: Incorrect or harmful lifestyle during youth may impact negatively gonadal function later in life. To reduce the development of risky behaviors a series of health prevention and intervention campaigns have been conducted in Italy. The present study is part of a Sicily Region (Italy) health surveillance program that was carried out on a sample of late adolescents. METHODS: Between March 2022 to December 2022, we enrolled 718 adolescents (15-26 years old) attending the last two years of high school (278 males and 440 females) in the districts of Syracuse, Ragusa, Catania, and Agrigento (Sicily, Italy). All adolescents were invited to complete a questionnaire that explored their lifestyles and the student's knowledge of sexually transmitted diseases (STDs) and the main andrological diseases. RESULTS: Our analysis revealed that 43% of students smoke cigarettes, with a similar gender distribution; one-third of the students use illicit drugs, with a higher prevalence of males than females. More than two-thirds of youngsters reported drinking alcohol with a statistically significant difference between genders. 68.2% of students do not have sexual difficulties and males have a greater tendency to sexual promiscuity than females and only about half of them use condoms. 92% of students surf the Internet every day; boys tend to visit pornographic sites more often than girls. CONCLUSIONS: This survey revealed statistically significant differences between the two genders in terms of lifestyle and sexual habits. In particular, the survey shows that the prevalence of risky behaviour is still extremely high among late adolescents and young adults and that much still needs to be done in terms of prevention and information. Adequate prevention campaigns, to be proposed in the early years of adolescence, should be initiated in order to provide youngsters with adequate preparation in terms of healthy lifestyle habits.

Investigational follicle-stimulating hormone receptor agonists for male infertility therapy.

INTRODUCTION: According to estimates by the World Health Organization, about 17.5% of the adult population - roughly 1 in 6 globally - experience infertility. The causes of male infertility remain poorly understood and have yet to be fully evaluated. Follicle-stimulating hormone (FSH) represents an available and useful therapeutic strategy for the treatment of idiopathic infertility. AREAS COVERED: We provide here an overview of the molecular mechanisms by which FSH stimulates Sertoli cells and the schemes, dosages, and formulations of FSH most prescribed so far and reported in the literature. We also evaluated the possible predictor factors of the response to FSH administration and the indications of the latest guidelines on the use of FSH for the treatment of male infertility. EXPERT OPINION: FSH therapy should be considered for infertile male patients with oligoasthenoteratozoospermia and normal serum FSH levels to quantitatively and qualitatively improve sperm parameters and pregnancy and birth rates. The grade of evidence is very low to low, due to the limited number of randomized controlled studies and patients available, the heterogeneity of the studies, and the limited effect size. To overcome these limitations, preclinical and clinical research is needed to evaluate the most effective dose and duration of FSH administration.

Predictive role of 17α-hydroxy-progesterone serum levels of response to follicle-stimulating hormone in patients with abnormal sperm parameters.

OBJECTIVES: To study the possible role of serum 17α-hydroxy-progesterone (17αOH-P) levels in predicting favorable responses to follicle-stimulating hormone (FSH) administration in patients with normal serum FSH levels and idiopathic abnormal sperm parameters. DESIGN: Prospective cohort study. SETTING: University-affiliated fertility center. PATIENTS: Fifty patients with oligozoospermia, asthenozoospermia, and/or teratozoospermia and normal serum levels of gonadotropins and total testosterone (TT). INTERVENTION: Treatment with exogenous FSH is administered subcutaneously at a dose of 150 IU 3 times a week for 3 consecutive months. MAIN OUTCOME MEASURE(S): Luteinizing hormone levels, FSH levels, TT levels, 17αOH-P levels, testicular volume, conventional sperm parameters, and seminal spermatid concentration were evaluated before and after therapy. To evaluate the predictive role of pretreatment serum 17αOH-P levels on FSH responsiveness, the doubling of sperm concentration at the end of the FSH administration was considered a positive outcome. RESULTS: After therapy, patients showed a significant increase in sperm concentration, total sperm count (TSC), progressive motility, percentage of normal forms, FSH levels, TT levels, and testicular volume. There was a negative correlation between pretreatment 17αOH-P levels and the posttreatment increase in sperm concentration, TSC, progressive motility, and normal morphology, and a positive correlation with the posttreatment increase in spermatids. Predictive analysis showed that 17αOH-P levels (<1.18 ng/mL) foretold a doubling of sperm concentration with a sensitivity of 90.0% and a specificity of 73.3%, and of TSC with a sensitivity of 91.3% and a specificity of 81.48%. CONCLUSION: The results of this study suggest that pretreatment serum levels of 17αOH-P, a marker of steroidogenic function, appear to be able to predict the success of subcutaneous administration of exogenous FSH in terms of spermatogenesis improvement. Receiver operating characteristic curves indicated that 17αOH-P levels (<1.18 ng/mL) predict a doubling of sperm concentration and TSC after exogenous FSH administration to patients with idiopathic abnormal sperm parameters and normal gonadotropin levels.

Red Wine and Sexual Function in Men: An Original Point of View.

Red wine is a rich source of nutrients whose biological properties have inspired numerous scientific studies. Indeed, it has been widely reported that there is a correlation between the positive health effects of moderate consumption of red wine and its phenolic content, which, due to its antioxidant activity, has proved to be useful in the improvement of various diseases, such as cardiovascular diseases, metabolic syndrome, cognitive disorders, depression, and cancer. It is a common opinion that the antioxidant activity of red wine is to be ascribed to its entire content of polyphenols, which act synergistically and not as a single component. Furthermore, this health-promoting effect of red wine can also be linked to its ethanol content, which has shown a wide array of biological properties. Beyond this evidence, very little is known about a possible correlation between moderate consumption of red wine and male sexual function. This brief review aimed to evaluate the effects of moderate consumption of red wine on erectile function. To accomplish this, Pubmed and Google Scholar databases were searched to retrieve the most relevant studies on this topic. The evidence so far collected has shown that red wine, if consumed in moderation, can be potentially beneficial for patients with erectile dysfunction as well as can positively influence reproductive function through mechanisms that depend on the vasorelaxant properties of red wine and its antioxidant properties.

Mechanisms Suggesting a Relationship between Vitamin D and Erectile Dysfunction: An Overview.

Vitamin D deficiency (VDD) and erectile dysfunction (ED) heavily burden the male population. The higher prevalence of both conditions in the elderly suggests a possible relationship between the two conditions. In addition, in vitro, animal, and human studies have revealed several mechanisms that may relate VDD to ED. The main mechanism by which vitamin D might exert its action on sexual function appears to be through the regulation of endothelial function. Indeed, VDD correlates with several markers of endothelial function. The action of vitamin D on the endothelium would be exercised both indirectly through its intervention in inflammatory processes and through the production of oxygen free radicals, and directly through the regulation of vascular stiffness, the production of nitric oxide, and the regulation of vessel permeability. Furthermore, the ubiquitous distribution of the vitamin D receptor in the human body means that this hormone can also exert a beneficial effect on erectile function by interfering with those comorbidities significantly associated with ED, such as hypertension, diabetes mellitus, hypercholesterolemia, chronic kidney disease, and hypogonadism. In this review, we thoroughly and carefully presented the evidence and mechanisms that would appear to relate vitamin D levels to erectile function. Furthermore, we have summarized the meta-analytic evidence for and against this association to provide a true representation of this topic. Data published to date suggest that low levels of vitamin D could contribute to worsening erectile function through several mechanisms. Therefore, vitamin D levels should be measured in patients with ED and maintained at adequate levels by specific supplementation in case of deficiency. However, the low quality and heterogeneity of clinical trials evaluating the effects of vitamin D administration on erectile function and ED-associated comorbidities do not allow for a univocal conclusion, and indicate the need for further studies to analyze these aspects.

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.

Is It Time for Andrology and Endocrinology Professionals in Assisted Reproduction Centers?

Epidemiologists indicate that about half of the couple's infertility cases are due to a male factor. Despite this, the role of andrologists or endocrinologists in assisted reproductive technique (ART) centers is still underestimated. According to our literature review, this reduces the chance of a thorough clinical evaluation of the male partners, which, sometimes consists only in a mere semen analysis, usually performed by laboratory technicians. A more complete diagnostic process could lead to the identification of potentially treatable causes of infertility, the recognition of diseases that require immediate treatment, and to the discovery of genetic diseases and, therefore, transmissible to the offspring. It can also increase the success rate of ART resulting in less psychological and financial burden for both public health resources and infertile couples. The presence of medical personnel with andrological and endocrinological skills in the ART centers represents the first step in creating 'precision medicine'. We hope that the guidelines of the various scientific societies will clearly contemplate this possibility.

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.