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IntroductionGalectin-3 is a pro-fibrotic β-galactoside binding lectin highly expressed in fibrotic liver and implicated in hepatic fibrosis. Selvigaltin (previously known as GB1211) is a novel orally active galectin-3 small molecule inhibitor that has high affinity for galectin-3 (human KD = 25 nM; rabbit KD = 12 nM) and high oral bioavailability in rabbits and man. In this study the efficacy of selvigaltin was investigated in a high fat diet (HFD) rabbit model of metabolic-associated steatohepatitis (MASH).MethodsMale New Zealand White rabbits were individually caged under standard conditions in a temperature and humidity-controlled room on a 12 h light/darkness cycle. After 1 week of regular diet (RD), rabbits were randomly assigned for 8 or 12 weeks to different groups: RD/vehicle, RD/selvigaltin, HFD (8 weeks), HFD/vehicle and HFD/selvigaltin (0.3, 1.0, 5.0 or 30 mg/kg selvigaltin with vehicle/selvigaltin p.o. dosed therapeutically q.d. 5 days per week from week 9 or 12). Liver inflammation, steatosis, ballooning, and fibrosis was measured via blood metabolic markers, histomorphological evaluation [Oil Red O, Giemsa, Masson’s trichome, picrosirius red (PSR) and second harmonic generation (SHG)], and mRNA and protein expression.ResultsSteatosis, inflammation, ballooning, and fibrosis were all increased from RD to HFD/vehicle groups. Selvigaltin demonstrated target engagement by significantly decreasing galectin-3 levels in the liver as measured via immunohistochemistry and mRNA analysis. Selvigaltin dose-dependently reduced biomarkers of liver function (AST, ALT, bilirubin), inflammation (cells foci), and fibrosis (PSR, SHG), as well as decreasing the mRNA and protein expression of several key inflammation and fibrosis biomarkers (e.g., IL6, TGFβ3, SNAI2, collagen). Doses of 1.0 or 5.0 mg/kg demonstrated consistent efficacy across most biological endpoints supporting the current clinical doses of selvigaltin being investigated in liver disease.DiscussionSelvigaltin significantly reduced hepatic inflammation and fibrosis in an HFD rabbit model of MASH following therapeutic dosing for 4 weeks in a dose-dependent manner. These data support the human selvigaltin dose of 100 mg b.i.d. that has been shown to reduce key liver biomarkers during a clinical study in liver cirrhosis.

Kunyaza is a traditional sexual technique reported in some regions of Central Africa that aims to trigger peri-orgasmic fluid production. A personal narrative experience of a 29-year-old unmarried woman from Kenya suggested that this particular technique may have also been practiced in Kenya for a long time. Indeed, an oral tradition about “how to make Lake Victoria”, a peculiar local expression used to indicate peri-orgasmic fluid production, is reported here. This tradition is transmitted from grandmothers to granddaughters and concerns not only fluid emission but also teachings on personal hygiene, sexual interactions with a partner, and, interestingly, the importance of the woman’s sexual pleasure. In this narrative case report, we compared anecdotes and personal experiences with literature evidence about herbal medicine and traditional practices, suggesting the presence of a particularly woman-centered sexual culture in some more sex-positive ethnic groups in Kenya.

Sperm oxidative stress has been extensively associated to male infertility. However, tests to detect this parameter have not been yet introduced in clinical practice and no definitive data are present on the extent of oxidative stress in male infertility. In this study, we used a novel and reliable flow cytometric method to reveal sperm ROS production in subfertile patients (n = 131) and in healthy donors (n = 31). Oxidative stress was higher in subfertile patients (14.22 [10.21–22.08]%) than in healthy donors (9.75 [8.00–14.90]% (p < 0.01)), but no correlation was found with age, semen quality or sDF. We also failed to detect an increase in sperm ROS production with semen viscosity or leukocytospermia, but a sharp impact of semen bacteria was evident (with bacteria: 31.61 [14.08–46.78]% vs. without bacteria: 14.20 [10.12–22.00]%, p < 0.01). Finally, after establishing a threshold as the 95th percentile in healthy donors, we found that 29% of subfertile patients exceeded this threshold. The percentage decreased to 25.56% when we excluded subjects with bacteriospermia and increased to 60.87% when only these patients were considered. In conclusion, 29% of subfertile patients showed an excessive sperm ROS production. Surprisingly, this parameter appears to be independent from routine semen analysis and even sDF determination, promising to provide additional information on male infertility.

Several clinical laboratories assess sperm DNA fragmentation (sDF) in addition to semen analysis in male infertility diagnosis. Among tests evaluating sDF, TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) and SCD (Sperm Chromatin Dispersion) are widely used. Our lab developed a modified version of TUNEL (TUNEL/PI) able to distinguish two sperm populations (PI Brighter and PI Dimmer) differently associated with sperm viability and reproductive outcomes. The aim of this study was to compare sDF levels detected by SCD and TUNEL/PI in the semen samples from 71 male subjects attending our Andrology Laboratory. Our results demonstrate that SCD is less sensitive in determining sDF compared to TUNEL/PI. The statistically significant positive correlation found between sDF evaluated by SCD and PI Dimmer (consisting of all dead spermatozoa) suggests that SCD mainly detects sDF in unviable spermatozoa. We confirmed that most spermatozoa detected by SCD are unviable by performing SCD after incubation in hypo-osmotic medium to discriminate viable and unviable cells in 52 samples. Such results might explain the lower ability of this test in discriminating couples having successful ART outcomes demonstrated in published metanalyses. Overall, our results indicate that SCD is less sensitive in evaluating sDF for diagnostic purposes.

Background Sexual health is a major concern in women with endometriosis, however only a few controlled studies have examined this with validated instruments. The effect of hormonal treatments on sexual function in endometriosis is also an underrated topic. The aim of this study was to investigate sexual function of patients with endometriosis by a specific tool to better evaluate their sexual function (including different domains), and the influence of hormonal treatment or surgery on these parameters. Methods An observational, cross-sectional, multicentre study was conducted in a group (n=194) of sexually active, women aged 25–45 years old, with surgical or ultrasonographic diagnosis of endometriosis, referred to the Endometriosis Center of Careggi University Hospital or Negrar di Valpolicella. Sexual function was assessed by administering the Female Sexual Function Index (FSFI), which assesses the domains of desire, arousal, lubrication, orgasm, satisfaction and pain. FSFI scores were compared to those of a control group (n=58) and according to the treatment received by patients with endometriosis. Results Ovarian endometriosis was present in 50 patients (25.8%), deep infiltrating endometriosis in 65 patients (33.5%) and both in 79 patients (40.7%). Adenomyosis coexisted in 102 patients (52.6%). Women with endometriosis reported a mean total FSFI score of 18.3 [4.2-25.8] (< 26.55), indicating female sexual dysfunction (FSD) in all patients. At multivariate analysis, after adjusting for confounders (BMI and hormonal therapy), women with endometriosis presented significantly lower scores than controls in all the FSFI (p

The real epidemiology and the possible consequences of anabolic-androgenic steroids (AAS) use still represent a very tricky task due to the difficulties in the quantification and detection of these drugs. Chronic use of AAS, frequently combined with other illicit substances, can induce tremendous negative effects on the reproductive system, but it is also associated with an increased overall and cardiovascular mortality risk. In the present review we summarize and discuss the available evidence regarding the negative impact of AAS on the male reproductive system, providing practical suggestions to manage these problems. For this purpose a meta-analysis evaluating the effects of AAS abusers vs. controls on several hormonal, reproductive and metabolic parameters was performed. In addition, in order to overcome possible limitations related to the combined use of different AAS preparations, we also retrospectively re-analyzed data on animal models treated with supraphysiological dosage of testosterone (T), performed in our laboratory. Available data clearly indicated that AAS negatively affect endogenous T production. In addition, increased T and estradiol circulating levels were also observed according to the type of preparations used. The latter leads to an impairment of sperm production and to the development of side effects such as acne, hair loss and gynecomastia. Furthermore, a worse metabolic profile, characterized by reduced high density lipoprotein and increased low density lipoprotein cholesterol levels along with an increased risk of hypertension has been also detected. Finally sexual dysfunctions, often observed upon doping, represent one the most probable unfavorable effects of AAS abuse.

Benzo(a)pyrene (BaP) is considered one of the most dangerous air pollutants for adverse health effects, including reproductive toxicity. It is found both in male and female reproductive fluids likely affecting spermatozoa after the selection process through cervical mucus, a process mimicked in vitro with the swim-up procedure. In vitro effects of BaP (1, 5, 10 µM) were evaluated both in unselected and swim-up selected spermatozoa after 3 and 24 h of incubation. BaP reduced total, progressive and hyperactivated motility and migration in a viscous medium both in swim-up selected and unselected spermatozoa. Viability was not significantly affected in swim-up selected but was reduced in unselected spermatozoa. In swim-up selected spermatozoa, increases in the percentage of spontaneous acrosome reaction and DNA fragmentation were observed after 24 h of incubation, whereas no differences between the control and BaP-treated samples were observed in caspase-3 and -7 activity, indicating no effects on apoptotic pathways. ROS species, evaluated by staining with CellROX® Orange and Dihydroethidium, did not differ in viable spermatozoa after BaP treatment. Conversely, the percentage of unviable ROS-positive spermatozoa increased. Our study suggests that BaP present in male and female genital fluids may heavily affect reproductive functions of human spermatozoa.

Abstract Female sexual dysfunction (FSD) may be a mirror of a poor cardiometabolic state. In a small pilot study enrolling 71 women with FSD, we previously demonstrated that clitoral Pulsatility Index (PI) evaluated by using color Doppler ultrasound (CDU), reflecting vascular resistance, was associated with cardiometabolic risk factors. Data on uterine CDU in this context are lacking. First, to confirm previously reported data on the direct association between clitoral PI and cardiometabolic risk factors on a larger study population of women consulting for sexual symptoms; second, to investigate eventual similar correlations between cardiometabolic risk factors and CDU parameters of the uterine artery. We also ascertained whether uterine artery PI, similarly to what had previously been observed for clitoral artery PI, was directly related to body image uneasiness and psychopathological symptoms, assessed by validated questionnaires. N = 230 women consulting our clinic for sexual symptoms were examined with clitoral CDU and blood sampling and were asked to fill out the Female Sexual Function Index, the Middlesex Hospital Questionnaire (MHQ) and the Body Uneasiness Test (BUT). In a subgroup of women (n = 164), we also performed transvaginal CDU with measurement of uterine artery parameters. At multivariate analysis, we found a direct association between clitoral PI and body mass index (BMI) (p = 0.004), waist circumference (WC) (p = 0.004), triglycerides (p = 0.006), insulin (p = 0.029) and HOMA-IR (p = 0.009). Furthermore, a correlation between obesity and Metabolic Syndrome (MetS) and a higher clitoral PI was observed (p = 0.003 and p = 0.012, respectively). Clitoral PI was also correlated with MHQ-S (p = 0.010), a scale exploring somatized anxiety symptoms, and BUT-B Positive Symptom Distress Index (p = 0.010), a measure of body image concerns. Similarly, when investigating the uterine artery, we were able to demonstrate an association between its PI and BMI (p

Abstract Male genitourinary tract (MGT) bacterial infections are considered responsible for 15% of male infertility, but the mechanisms underlying decreased semen quality are poorly known. We evaluated in vitro the effect of strains of Gram-negative uropathogenic species (two E.coli strains, three K. pneumoniae strains, P. aeruginosa and E. cloacae) on motility, viability, mitochondrial oxidative status, DNA fragmentation and caspase activity of human spermatozoa. All strains, except P. aeruginosa, reduced significantly sperm motility, with variable effects. Sperm Immobilizing Factor (SIF) was largely responsible for deteriorating effects on sperm motility of E. coli strains since they were completely reverted by knockout of SIF coding recX gene. Sequence alignment for RecX showed the presence of high homologous sequences in K. pneumoniae and E. cloacae but not in P. aeruginosa. These results suggest that, in addition to E.coli, other common uropathogenic Gram-negative bacteria affect sperm motility through RecX products. In addition to sperm motility, the E. coli strain ATCC 35218 also affected sperm viability, and induced caspase activity, oxidative stress and DNA fragmentation suggesting an interspecies variability in the amount and/or type of the produced spermatotoxic factors. In general, our results highlight the need for a careful evaluation of semen infections in the diagnostic process of the infertile man.

BackgroundOxidative stress is defined as the unbalance between reactive oxygen species (ROS) production and antioxidant defences. Whereas low levels of ROS are necessary for physiological sperm functions, high levels impair fertility damaging membranes, proteins and DNA. In this study, we used two probes, CellROX® Orange and Dihydroethidium (DHE), which reveal different intracellular ROS species, to evaluate the association between the percentage of oxidized viable spermatozoa and sperm functions.MethodsThe percentage of oxidized spermatozoa was evaluated by flow cytometry with the two probes concomitantly with standard semen parameters and sperm DNA fragmentation (sDF, by TUNEL/PI). Phosphatidylserine membrane exposure, caspase 3,7 activity, sperm kinematic parameters and hyperactivated motility were evaluated by Annexin V, FLICA™ and CASA system respectively.ResultsOxidized viable spermatozoa, evaluated with both probes, were positively associated with sperm basal parameters and negatively with sDF. Also, we found that a consistent percentage of CellROX® positive viable spermatozoa were selected from whole semen during swim up procedure. Double staining of CellROX® Orange with Annexin V and FLICA™ demonstrated that viable oxidized spermatozoa do not show apoptotic features.ConclusionOverall, our results suggest that CellROX® Orange and DHE allows identification of the viable oxidized sperm fraction related to better performances.

Introduction: Deficiency of the 17β-hydroxysteroid dehydrogenase type 3 (17 β-HSD3) is a rare autosomal recessive 46,XY Difference of sex development (DSD), resulting from pathogenetic variants in the HSD17B3 gene, which lead to absent or reduced ability to convert Δ4-androstenedione to testosterone in the fetal testes. Aim: This study aimed to present the clinical and genetic characteristics of an Italian patient receiving a diagnosis of 17 β-HSD3 deficiency in adulthood. The patient was raised as female and underwent early surgical interventions to correct virilized genitalia, leading to a significant sexual distress. Methods: At the time of the referral, a 20-gene Next Generation Sequencing custom-panel for DSD was performed on patient's genomic DNA. Results: A novel compound heterozygous mutation in HSD17B3 gene was identified, detecting a new variant (c.257_265delAGGCCATTG, p.) Conclusion: Novel genotype causing 17 β-HSD3 deficiency is presented. Furthermore, the patient's clinical history stresses the importance to actively involve these individuals in the decision-making process avoiding surgical intervention when the patient is not able to give fully informed consent.Cocchetti C, Baldinotti F, Romani A, et al. A Novel Compound Heterozygous Mutation of HSD17B3 Gene Identified in a Patient With 46,XY Difference of Sexual Development. Sex Med 2022;10:100522.

Objective: To assess the safety and efficacy of convalescent plasma (CP) transfusion in elderly people with moderate to severe coronavirus disease 2019 (COVID-19) living in a long-term care facility (LTCF). Patients and Methods: Twenty-two consecutive elderly patients with COVID-19 infection living in an LTCF in Lombardy, Italy, who were given CP during May 15 to July 31, 2020, were enrolled in a prospective cohort study. Their clinical, instrumental, and laboratory parameters were assessed following the CP treatment. The overall mortality rate in this group was compared with that recorded in other LTCFs in Lombardy during the 3-month period from March to May 2020. Results: Of the 22 patients enrolled, 68.2% (n=15) received 1 CP unit, 27.3% (n=6) received 2 units, and 4.5% (n=1) received 3 units. Of the CP units transfused, 76.7% (23/30) had a neutralizing antibody titer of 1:160 or greater. No adverse reactions were recorded during or after CP administration. Improvements in clinical, functional, radiologic, and laboratory parameters during the 14 days after CP transfusion were observed in all 19 patients who survived. Viral clearance was achieved in all patients by the end of follow-up (median, 66 days; interquartile range, 48-80 days). The overall mortality rate was 13.6% (3/22), which compared favorably with that in the control group (38.3% [281/733]; P=.02) and corresponded to a 65% reduction in mortality risk. Conclusion: Early administration of CP with an adequate anti–severe acute respiratory syndrome coronavirus 2 antibody titer to elderly symptomatic patients with COVID-19 infection in an LTCF was safe and effective in eliminating the virus, restoring patients’ immunity, and blocking the progression of COVID-19 infection, thereby improving patients’ survival. Trial Registration: ClinicalTrials.gov: NCT04569188.

Cancer impairs spermatogenesis, whereas results on sperm DNA integrity are controversial and no data are available about sperm oxidative stress. In cancer patients, we detected sperm DNA fragmentation (sDF) and both viable (ROS production in viable sperm fraction/viable spermatozoa) and total (ROS production in viable sperm fraction/total spermatozoa) oxidative stress. We found that cancer (22.50 (17.00–26.75)%, n = 85) increased sDF with respect to the control groups in both normozoospermic subfertile patients (NSP) (12.75 (8.63–14.88)%, n = 52, p < 0.001) and in healthy donors (HD) (8.50 (7.00–14.00)%, n = 19, p < 0.001). The induction of viable oxidative stress (n = 96) with cancer was even higher: 36.60 (24.05–58.65)% versus 11.10 (8.63–14.90)% in NSP (p < 0.001) and 9.60 (8.00–14.03)% in HD (p < 0.001). Similar, albeit lower, differences were found for total oxidative stress. SDF sharply correlated to viable oxidative stress when we considered all subjects (cancer patients and controls) (r = 0.591, p < 0.001, n = 134), but no correlation was found when only cancer patients were studied (r = 0.200; p > 0.05, n = 63). In conclusion, cancer significantly increases sDF and sperm oxidative stress levels. Additional mechanisms to oxidative attack might be responsible for increased sDF in cancer patients. Because sperm oxidative stress might affect the outcomes of sperm cryopreservation, of cancer treatments and of sperm epigenoma, the detection of oxidative stress could be of help in managing the reproductive issues of cancer patients.

A dichotomic distinction between “organic” and “functional” hypogonadism is emerging. The former is an irreversible condition due to congenital or “acquired” “organic” damage of the brain centers or of the testis. Conversely, the latter is a potentially reversible form, characterized by borderline low testosterone (T) levels mainly secondary to age-related comorbidities and metabolic derangements, including metabolic syndrome (MetS). Life-style modifications, – here reviewed and, when possible, meta-analyzed –, have documented that weight-loss and physical exercise are able to improve obesity-associated functional hypogonadism and its related sexual symptoms. A rabbit experimental model, of MetS originally obtained in our lab, showed that endurance training (PhyEx) completely reverted MetS-induced hypogonadotropic hypogonadism by reducing hypothalamus inflammation and testis fibrosis eventually allowing for a better corpora cavernosa relaxation and response to sildenafil. Physicians should strongly adapt all the reasonable strategies to remove/mitigate the known conditions underlying functional hypogonadism, including MetS and obesity. Physical limitations, including reduced muscle mass and increased fat mass, along with low self-confidence, also due to the sexual problems, might limit a subject’s propensity to increase physical activity and dieting. A short term T treatment trial, by improving muscle mass and sexual function, might help hypogonadal obese patients to overcome the overfed, inactive state and to become physically and psychologically ready for changing their lifestyle.

Cryopreservation is an expanding strategy to allow not only fertility preservation for individuals who need such procedures because of gonadotoxic treatments, active duty in dangerous occupations or social reasons and gamete donation for couples where conception is denied, but also for animal breeding and preservation of endangered animal species. Despite the improvement in semen cryopreservation techniques and the worldwide expansion of semen banks, damage to spermatozoa and the consequent impairment of its functions still remain unsolved problems, conditioning the choice of the technique in assisted reproduction procedures. Although many studies have attempted to find solutions to limit sperm damage following cryopreservation and identify possible markers of damage susceptibility, active research in this field is still required in order to optimize the process. Here, we review the available evidence regarding structural, molecular and functional damage occurring in cryopreserved human spermatozoa and the possible strategies to prevent it and optimize the procedures. Finally, we review the results on assisted reproduction technique (ARTs) outcomes following the use of cryopreserved spermatozoa.

Adiponectin (ADPN), a hormone produced by adipose tissue, facilitates gastric relaxation and can be a satiety signal in the network connecting peripheral organs and the central nervous system for feeding behavior control. Here, we performed preclinical research by morpho-functional analyses on murine gastric fundus smooth muscle to add insights into the molecular mechanisms underpinning ADPN action. Moreover, we conducted a clinical study to evaluate the potential use of ADPN as a biomarker for eating disorders (ED) based on the demonstrated gastric alterations and hormone level fluctuations that are often associated with ED. The clinical study recruited patients with ED and healthy controls who underwent blood draws for ADPN dosage and psychopathology evaluation tests. The findings of this basic research support the ADPN relaxant action, as indicated by the smooth muscle cell membrane pro-relaxant effects, with mild modifications of contractile apparatus and slight inhibitory effects on gap junctions. All of these actions engaged the ADPN/nitric oxide/guanylate cyclase pathway. The clinical data failed to unravel a correlation between ADPN levels and the considered ED, thus negating the potential use of ADPN as a valid biomarker for ED management for the moment. Nevertheless, this adipokine can modulate physiological eating behavior, and its effects deserve further investigation.

Benzo[a]pyrene (BaP) is a widespread pollutant that can act as an endocrine disrupting compound (EDC) and interferes with reproductive function. The central regulatory network of the reproductive system is mediated by gonadotropin-releasing hormone (GnRH) neurons, which originate in the olfactory placode and, during ontogenesis, migrate into the hypothalamus. Given the importance of the migratory process for GnRH neuron maturation, we investigated the effect of BaP (10 µM for 24 h) on GnRH neuroblasts isolated from the human fetal olfactory epithelium (FNCB4). BaP exposure significantly reduced the mRNA level of genes implicated in FNCB4 cell migration and affected their migratory ability. Our findings demonstrate that BaP may interfere with the central neuronal network controlling human reproduction affecting GnRH neuron maturation.

PCOS is one of the most common endocrine disorders and NAFLD is one of its most dangerous metabolic consequences. The diagnosis of NAFLD is not a practical task and the condition is at risk of being overlooked. The use of simpler but still reliable surrogate markers is necessary to identify women with a high likelihood of NAFLD. The aim of this study was to evaluate the clinical correlates of NAFLD Liver Fat Score (NAFLD-LFS) in women with oligomenorrhea and/or hirsutism. Furthermore, the study aimed to evaluate whether, among the hormonal parameters evaluated in such women, possible hallmarks of NAFLD may be identified. To this purpose, 66 women who attended our Outpatient Clinic for oligomenorrhea and/or hyperandrogenism were included in the study. In order to validate the results obtained in the first cohort, a second independent sample of 233 women evaluated for female sexual dysfunction (FSD) was analyzed. In cohort 1, NAFLD-LFS positively correlated with metabolic and inflammatory parameters. Among the hormone parameters, NAFLD-LFS showed no significant relationships with androgens but a significant negative correlation with SHBG (p

Abstract Background In last years Metabolic Syndrome (MetS) has been closely associated to Benign Prostatic Enlargement (BPE) Aim of our study is to evaluate the effect of MetS and each single MetS parameter on prostate growth in men surgically treated for BPE. Methods Overall, 379 men were prospectively enrolled in two tertiary referral centers. Calculated prostate volume (PV) was measured with transrectal US defining the antero-posterior (AP), the cranio-caudal (CC) and the latero-lateral (LL) diameters through the ellipsoid formula, while raw PV was calculated by suprapubic US. MetS was defined according to the NCEP-ATPIII criteria. Results One-hundred and forty men (36.9%) were affected by MetS. The number of MetS parameters (0 to 5) and the presence of MetS were correlated with the calculated PV. The number of MetS parameters were also directly related to increasing prostate diameters. At the binary logistic regression, MetS resulted associated to high (>60 cc) raw and calculated PV. Moreover, multivariate analysis suggested that AP diameter was mainly correlated with HDL cholesterol (r:-0.3103, p = 0.002) CC diameter with triglycerides (r:-0.191, p = 0.050) and LL diameter with systolic blood pressure (r:0.154, p = 0.044). However, at the binary logistic regression, only low HDL Cholesterol was the main determinant for the enlargement of all diameters and consequently of the whole PV. Conclusions Metabolic factors, specially dyslipidemia, could play a central role in the pathogenesis and progression of BPE/LUTS. Interventional studies are needed to evaluate the impact of early treatment of dyslipidemia on progression of LUTS/BPH.

Metabolic syndrome (MetS) is known to be associated to inflammation and alteration in the hypothalamus, a brain region implicated in the control of several physiological functions, including energy homeostasis and reproduction. Previous studies demonstrated the beneficial effects of testosterone treatment (TTh) in counteracting some MetS symptoms in both animal models and clinical studies. This study investigated the effect of TTh (30 mg/kg/week for 12 weeks) on the hypothalamus in a high-fat diet (HFD)-induced animal model of MetS, utilizing quantitative RT-PCR and immunohistochemical analyses. The animal model recapitulates the human MetS features, including low testosterone/gonadotropin plasma levels. TTh significantly improved MetS-induced hypertension, visceral adipose tissue accumulation, and glucose homeostasis derangements. Within hypothalamus, TTh significantly counteracted HFD-induced inflammation, as detected in terms of expression of inflammatory markers and microglial activation. Moreover, TTh remarkably reverted the HFD-associated alterations in the expression of important regulators of energy status and reproduction, such as the melanocortin and the GnRH-controlling network. Our results suggest that TTh may exert neuroprotective effects on the HFD-related hypothalamic alterations, with positive outcomes on the circuits implicated in the control of energy metabolism and reproductive tasks, thus supporting a possible role of TTh in the clinical management of MetS.

The complex process of sexual differentiation is known to be influenced by biological and environmental determinants. The present review has the aim of summarizing the most relevant studies on the biological basis of sexual development, and in particular, it focuses on the impact of sex hormones and genetic background on the development of sexual differentiation and gender identity. The authors conducted a search of published studies on Medline (from January 1948 to December 2019). The evidence suggests that the sexual dimorphic brain could be the anatomical substrate of psychosexual development, on which gonadal hormones may have a shaping role during prenatal and pubertal periods. Additionally, according to several heritability studies, genetic components may have a role, but a promising candidate gene has not been identified. Even though growing evidence underlines the primary role of biological factors on psychosexual development, further studies are necessary to better explain their complex interactions.

The female orgasm represents one of the most complex functions in the field of human sexuality. The conjunction of the anatomical, physiological, psycho-relational and socio-cultural components contributes to make the female orgasm still partly unclear. The female orgasmic experience, its correlates and the relation with sexual desire, arousal and lubrication as predictors are highly debated in scientific community. In this context, little is known about the impact of female sexual dysfunction (SD) on sexual pleasure expressed by subjective orgasmic intensity, and there are no suitable psychometric tools suited to investigate this dimension. Thus, we validate, in female subjects, a Visual Analogue Scale (VAS) that we named Orgasmometer-F, to verify if SD is accompanied by a lower perceived orgasmic intensity. A total of 526 women, recruited through a web-based platform and from sexological outpatient clinic, were enrolled in the study. They were divided into, on the basis of the Female Sexual Function Index (FSFI) score in two groups: 1) 112women suffering from SD, (SD Group); and 2) 414 sexually healthy women (Control Group). The participants were requested to fill out the Orgasmometer-F, recording orgasmic intensity on a Likert scale from 0 (absence of orgasmic intensity) to 10 (maximum orgasmic intensity experienced). Women with SD experienced significantly lower orgasmic intensity than controls, as measured by the Orgasmometer-F (p < 0.0001). Interestingly, masturbatory frequency was positively correlated with orgasmic intensity, as were the lubrication, orgasm and sexual satisfaction domains of the FSFI. The Orgasmometer-F was well understood, had a good test-retest reliability (ICC = 0.93) and a high AUC in differentiating between women with and without sexual dysfunction (AUC = 0.9; p < 0.0001). The ROC curve analysis showed that a cut-off

Digito-rectal examination (DRE) of the prostate provides useful information on the state of prostate growth and on the presence of suspected peripheral nodules. The aim of this study is to describe the clinical and biochemical correlates of finding an enlarged prostate size at DRE in subjects with sexual dysfunction (SD). A consecutive series of 2379 patients was retrospectively studied. The analysis was focused on a subset of subjects (n = 1823; mean age 54.7 ± 11.4) selected for being free from overt prostatic diseases. Several parameters were investigated. After adjusting for confounders, the presence of an enlarged prostate size at DRE was associated with a higher risk of metabolic syndrome (HR = 1.346 (1.129-1.759); P = 0.030), type 2 diabetes mellitus (HR = 1.489 (1.120-1.980); P = 0.006), increased LDL cholesterol (>100 mg dl−1 ; HR = 1.354 (1.018-1.801); P = 0.037) and increased mean blood pressure (BP) values (HR = 1.017 (1.007-1.027) for each mmHg increment; P = 0.001). Accordingly, enlarged prostate size was also associated with a higher risk of arteriogenic erectile dysfunction (ED), as well as with other andrological conditions, such as varicocele and premature ejaculation (PE). PSA levels were significantly higher in subjects with enlarged prostate size when compared to the rest of the sample (HR = 3.318 (2.304; 4.799) for each log unit increment in PSA levels; P < 0.0001). Arteriogenic ED, according to different criteria, was also associated with increased PSA levels. In conclusion, our data support the need to examine prostate size either by clinical (DRE) or biochemical (PSA) inspection in subjects with SD, in order to have insights into the nature of the SD and the metabolic and cardiovascular (CV) background of the patient.

Erectile dysfunction (ED) is a frequent complication of obesity. The aim of this review is to critically analyze the framework of obesity and ED, dissecting the connections between the two pathological entities. Current clinical evidence shows that obesity, and in particular central obesity, is associated with both arteriogenic ED and reduced testosterone (T) levels. It is conceivable that obesity-associated hypogonadism and increased cardiovascular risk might partially justify the higher prevalence of ED in overweight and obese individuals. Conversely, the psychological disturbances related to obesity do not seem to play a major role in the pathogenesis of obesity-related ED. However, both clinical and preclinical data show that the association between ED and visceral fat accumulation is independent from known obesity-associated comorbidities. Therefore, how visceral fat could impair penile microcirculation still remains unknown. This point is particularly relevant since central obesity in ED subjects categorizes individuals at high cardiovascular risk, especially in the youngest ones. The presence of ED in obese subjects might help healthcare professionals in convincing them to initiate a virtuous cycle, where the correction of sexual dysfunction will be the reward for improved lifestyle behavior. Unsatisfying sexual activity represents a meaningful, straightforward motivation for consulting healthcare professionals, who, in turn, should take advantage of the opportunity to encourage obese patients to treat, besides ED, the underlying unfavorable conditions, thus not only restoring erectile function, but also overall health.

No previous study has evaluated systematically the relationship between metabolic syndrome (MetS) and prostate-related symptoms and signs in young infertile men. We studied 171 (36.5 ± 8.3-years-old) males of infertile couples. MetS was defined based on the National Cholesterol Education Program Third Adult Treatment Panel. All men underwent hormonal (including total testosterone (TT) and insulin), seminal (including interleukin-8 (IL-8), seminal plasma IL-8 (sIL-8)), scrotal and transrectal ultrasound evaluations. Because we have previously assessed correlations between MetS and scrotal parameters in a larger cohort of infertile men, here, we focused on transrectal features. Prostate-related symptoms were assessed using the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and the International Prostate Symptom Score (IPSS). Twenty-two subjects fulfilled MetS criteria. In an age-adjusted logistic ordinal model, insulin levels increased as a function of MetS components (Wald = 29.5, P < 0.0001) and showed an inverse correlation with TT (adjusted r = -0.359, P< 0.0001). No association between MetS and NIH-CPSI or IPSS scores was observed. In an age-, TT-, insulin-adjusted logistic ordinal model, an increase in number of MetS components correlated negatively with normal sperm morphology (Wald = 5.59, P< 0.02) and positively with sIL-8 levels (Wald = 4.32, P < 0.05), which is a marker of prostate inflammation, with prostate total and transitional zone volume assessed using ultrasound (Wald = 17.6 and 12.5, both P < 0.0001), with arterial peak systolic velocity (Wald = 9.57, P = 0.002), with texture nonhomogeneity (hazard ratio (HR) = 1.87 (1.05-3.33), P < 0.05), with calcification size (Wald = 3.11, P< 0.05), but not with parameters of seminal vesicle size or function. In conclusion, in males of infertile couples, MetS is positively associated with prostate enlargement, biochemical (sIL8) and ultrasound-derived signs of prostate inflammation but not with prostate-related symptoms, which suggests that MetS is a trigger for a subclinical, early-onset form of benign prostatic hyperplasia.

Sexual function worsens with advancing menopause status. The most frequently reported symptoms include low sexual desire (40−55%), poor lubrication (25−30%) and dyspareunia (12−45%), one of the complications of genitourinary syndrome of menopause (GSM). Declining levels of sex steroids (estrogens and androgens) play a major role in the impairment of sexual response; however, psychological and relational changes related with aging and an increase in metabolic and cardiovascular comorbidities should also be taken into account. Although first-line therapeutic strategies for menopause-related sexual dysfunction aim at addressing modifiable factors, many hormonal and non-hormonal, local and systemic treatment options are currently available. Treatment should be individualized, taking into account the severity of symptoms, potential adverse effects and personal preferences.

Metabolic syndrome (MetS) is a well-recognized cluster of cardiovascular (CV) risk factors including obesity, hypertension, dyslipidemia, and hyperglycaemia, closely associated with an increased risk of forthcoming cardiovascular disease and type 2 diabetes mellitus. Emerging evidence indicates that benign prostate hyperplasia (BPH) and its related lower urinary tract symptoms (LUTS) represent other clinical conditions frequently observed in subjects with MetS. Several modifiable factors involved in MetS determinism, such as inadequate diet, lack of physical exercise, and smoking and drinking behaviours are emerging as main contributors to the development of BPH. The pathogenetic mechanisms underlying the connection between MetS and BPH have not been completely clarified. MetS and its components, hypogonadism, and prostate inflammation probably play an important role in inducing BPH/LUTS. Although historically considered as a “normal” consequence of the aging process, BPH/LUTS should now be faced proactively, as a preventable disorder of the elderly. Type of diet and level of physical activity are now considered important factors affecting prostate health in the aging male. However, whether physical exercise, weight loss, and modifications of dietary habit can really alter the natural history of BPH/LUTS remains to be determined. Further research is advisable to better clarify these points.

Metabolic disorders are often associated with male hypogonadotropic hypogonadism, suggesting that hypothalamic defects involving GnRH neurons may impair the reproductive function. Among metabolic factors hyperglycemia has been implicated in the control of the reproductive axis at central level, both in humans and in animal models. To date, little is known about the direct effects of pathological high glucose concentrations on human GnRH neurons. In this study, we investigated the high glucose effects in the human GnRH-secreting FNC-B4 cells. Gene expression profiling by qRT-PCR, confirmed that FNC-B4 cells express GnRH and several genes relevant for GnRH neuron function (KISS1R, KISS1, sex steroid and leptin receptors, FGFR1, neuropilin 2, and semaphorins), along with glucose transporters (GLUT1, GLUT3, and GLUT4). High glucose exposure (22 mM; 40 mM) significantly reduced gene and protein expression of GnRH, KISS1R, KISS1, and leptin receptor, as compared to normal glucose (5 mM). Consistent with previous studies, leptin treatment significantly induced GnRH mRNA expression at 5 mM glucose, but not in the presence of high glucose concentrations. In conclusion, our findings demonstrate a deleterious direct contribution of high glucose on human GnRH neurons, thus providing new insights into pathogenic mechanisms linking metabolic disorders to reproductive dysfunctions.

Background Sexual health is a major concern in women with endometriosis, however only a few controlled studies have examined this with validated instruments. The effect of hormonal treatments on sexual function in endometriosis is also an underrated topic. The aim of this study was to investigate sexual function of patients with endometriosis by a specific tool to better evaluate their sexual function (including different domains), and the influence of hormonal treatment or surgery on these parameters. Methods An observational, cross-sectional, multicentre study was conducted in a group (n=194) of sexually active, women aged 25–45 years old, with surgical or ultrasonographic diagnosis of endometriosis, referred to the Endometriosis Center of Careggi University Hospital or Negrar di Valpolicella. Sexual function was assessed by administering the Female Sexual Function Index (FSFI), which assesses the domains of desire, arousal, lubrication, orgasm, satisfaction and pain. FSFI scores were compared to those of a control group (n=58) and according to the treatment received by patients with endometriosis. Results Ovarian endometriosis was present in 50 patients (25.8%), deep infiltrating endometriosis in 65 patients (33.5%) and both in 79 patients (40.7%). Adenomyosis coexisted in 102 patients (52.6%). Women with endometriosis reported a mean total FSFI score of 18.3 [4.2-25.8] (< 26.55), indicating female sexual dysfunction (FSD) in all patients. At multivariate analysis, after adjusting for confounders (BMI and hormonal therapy), women with endometriosis presented significantly lower scores than controls in all the FSFI (p Conclusions Patients with endometriosis are at risk for FSD, encompassing not only dyspareunia, but all domains of sexual function. Hormonal treatments do not result in improvement in sexual symptoms.