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Obesity and male hypogonadism (HG) are often associated, as demonstrated in all cross-sectional studies. Prospective studies have indicated that i) having HG at baseline increases the risk of visceral obesity (and metabolic syndrome) and that ii) obesity induces incident HG. Hence, there is a bidirectional relationship between the two conditions. This is the main topic of this review, along with some pathogenic considerations. Meta-analysis of intervention studies indicates that treating obesity is a very efficient treatment for obesity-induced HG. The mechanism by which obesity induces HG has not yet been completely understood, but dietary-induced hypothalamic inflammation, along with a decreased GnRH release, is plausible. Among patients seeking medical care for obesity, the proportion of HG is relatively high. The prevalence of obesity among patients referring for sexual dysfunction is also elevated. Hence, in symptomatic, obese, hypogonadal subjects, testosterone supplementation (TS) can be considered. Whereas long-term uncontrolled register studies suggest that TS could decrease weight, analysis of controlled studies only support a parallel increase in lean mass and decrease in fat mass, with a resulting null effect on weight. Considering that T induces an increase in muscle mass, it is conceivable that the amount of activity obese people can undertake after TS will increase, allowing a closer adherence to physical exercise programs. Some studies, here meta-analyzed, support this concept. [ABSTRACT FROM AUTHOR]

Background:Epidemiological data indicate that lower urinary tract symptoms (LUTS)/BPH can be associated with metabolic syndrome (MetS). Chronic inflammation has been proposed as a candidate mechanism at the crossroad between these two clinical entities.Aim of study is to examine the correlation among pre-operatory LUTS/BPH severity, MetS features and inflammatory infiltrates in prostatectomy specimens.Methods:A total of 271 consecutive men treated with simple prostatectomy were retrospectively selected for this study in two tertiary referral centers for LUTS/BPH. Prostate diameters and volume were measured by transrectal ultrasound, LUTS scored by International Prostate Symptom Score (IPSS) and obstruction by uroflowmetry. The International Diabetes Federation and American Heart Association and the National Heart, Lung and Blood Institute was used to define MetS. The inflammatory infiltrate was investigated combining anatomic location, grade and extent of flogosis into the overall inflammatory score (IS); the glandular disruption (GD) was used as a further marker.Results:Eighty-six (31.7%) men were affected by MetS. Prostatic volume and anterior-posterior (AP) diameter were positively associated to the number of MetS components. Among MetS determinants, only dyslipidaemia (increased serum triglycerides and reduced serum high-density lipoprotein) was associated with an increased risk of having a prostatic volume >60 cm3 (hazard ratio (HR)=3.268, P<0.001). A significant positive correlation between the presence of MetS and the IS was observed. MetS patients presented lower uroflowmetric parameters as compared with those without MetS (Maximum flow rate (Qmax): 8.6 vs 10.1, P=0.008 and average flow rate (Qave): 4.6 vs 5.3, P=0.033, respectively), and higher obstructive urinary symptoms score (P=0.064). A positive correlation among both IS-GD and IPSS Score was also observed (adjusted r=0.172, P=0.008 and adjusted r=0.128, P=0.050).Conclusions:MetS is associated with prostate volume, prostatic AP diameter and intraprostatic IS. The significantly positive association between MetS and prostatic AP diameter could support the observation that MetS patients presented lower uroflowmetric parameters. In conclusion, MetS can be regarded as a new determinant of prostate inflammation and BPH progression. [ABSTRACT FROM AUTHOR]

Hypoxia is a normal, physiological condition in penile tissue, which is interrupted by reoxygenation associated to sleep-related erections. We previously described in the rat that a penile fibrosis and overexpression of the pro-fibrotic endothelin-1 type B receptor (ETB) are associated to prolonged (3 months) hypoxia induced by the bilateral surgical resection of the cavernous nerves (bilateral cavernous neurotomy (BCN)). The aim of the present study was to define the time frame in which BCN induces hypoxia and ETB overexpression in the penile tissue. In addition, we studied the time-dependency of the rescuing effect of an acute administration of the phosphodiesterase type 5 inhibitor, sildenafil. We found that BCN induced penile hypo-oxygenation (immunohistochemistry for Hypoxyprobe), penile ETB mRNA overexpression (quantitative real-time reverse transcriptase polymerase chain reaction) and hypersensitivity to the ETB agonist IRL-1620 (in vitro contractility study). Sildenafil treatment was able to counteract all these alterations (penile hypoxygenation, hyper-sensitivity to IRL-1620 and ETB overexpression), with its effect being more evident the earlier it was administered.International Journal of Impotence Research (2008) 20, 60–67; doi:10.1038/sj.ijir.3901596; published online 16 August 2007 [ABSTRACT FROM AUTHOR]

An abstract of the article "Effects of chronic treatment with tadalafil in monocrotaline-induced pulmonary hypertensive rat model" by L. Vignozzi and colleagues is presented.

The vagina is traditionally thought of as a passive organ in the female reproductive system, serving primarily as a passageway for menstrual blood, sexual intercourse and childbirth. However, recent research has shed light on the vagina's role as an endocrine organ that plays a crucial role in female hormonal balance and overall health. Particularly, growing evidence shows that the human vagina can be considered both as source and target of androgens, in view of the novel concept of 'intracrinology'. Besides the well-known role of estrogens, androgens are also crucial for the development and maintenance of healthy genitourinary tissues in women. As androgen levels decline with age, and estrogen levels fall during the menopausal transition, the tissues in the vagina, together with those in the urinary tract, become thinner, drier and less elastic, leading to a variety of uncomfortable and sometimes painful symptoms, clustered in the genitourinary syndrome of menopause (GSM). Given the lack of testosterone-based or androstenedione-based products approved by regulatory agencies to treat GSM, the possibility of using intravaginal prasterone, which works by providing a local source of dehydroepiandrosterone (DHEA) to the vaginal tissues, appears to be a targeted treatment. Further studies are needed to better assess its safety and efficacy. [ABSTRACT FROM AUTHOR]

Introduction: Adenosine (ADO) is a purinergic neuromodulator that in the male exerts a positive effect on penile erection by controlling smooth muscle (SM) relaxation. However, its role in the relaxant/contractile pathways in the vagina is yet to be investigated. Objective: The aim of this study was to characterize the effect of ADO stimulation on SM activity in distal vagina, evaluating its possible effect on the regulation of nitric oxide (NO) pathway using a validated animal model of female Sprague-Dawley rats. Methods: The immunolocalization of ADORA2A and ADORA2B in distal vagina tissues was detected by immunohistological staining. In vitro contractility studies on noradrenaline (NA)-precontracted vaginal strips from intact Sprague-Dawley rats were performed; rat smooth muscle cells (rvSMCs) from distal vagina of intact animals were stimulated with ADO for cyclic adenosine monophosphate (cAMP) quantification. mRNA (messenger ribonucleic acid) isolated from vaginal tissue was analyzed by semi-quantitative Reverse Transcriptase-Polymerase Chain Reaction. Results: All ADORAs mRNA were expressed in the vaginal tissue, with a significant prevalence of ADORA2B; furthermore, ADORA2A and ADORA2B immunolocalization highlighted that both receptors are highly expressed in the epithelium, in blood capillaries of the vascular bed and in the smooth muscle bundles of vagina wall. In vitro ADO stimulation induced a dose-dependent relaxation (IC50=31.9±2.38 μM), which was significantly reduced by the administration of NO-synthase inhibitor L-NAME; similar effects were observed after the mechanical ablation of endothelium and in vitro administration of the soluble guanylate cyclase inhibitor ODQ, highlighting the pivotal contribution of NO signaling to the ADO relaxant activity. In vitro stimulation with increasing doses of the selective ADO receptor ADORA2A agonist CGS2-1680 induced a dose-dependent relaxation (IC50=132.6±3.47 nM); a similar but less potent relaxant effect was observed with ADORA2B selective agonist BAY60-6583. The relaxing effect induced by ADO on NA-precontracted vaginal strips was completely counteracted by the stimulation with the re-spectively selective ADORA2A and ADORA2B antagonists SHC-442416 and PSB603; a similar effect was induced by ADORA1 selective antagonist SLV320, but not by ADORA3 selective antagonists VUF5574. The mRNA relative expression of enzymes regulating the ADO turnover [adenosine deami-nase (ADA), 5′-nucleotidase (5NTD), AMP deaminase type 1 and type 2 (AMPD1, AMPD2) and adenosine kinase (ADK)] showed a higher expression of genes regulating the de novo ADO/cAMP syn-thesis (ADK, 5NTD), compared to those acting on ADO degradation (ADA, AMPD1, AMPD2). Finally, stimulation of rvSMCs with increasing doses of ADO induced a significant production of intracellular cAMP after 3 minutes (1 and 10 μM). Conclusions: These data show that ADO acts as an important relaxant modulator of the vagina through the activation of its receptors, specifically ADORA2A, and the consequent cAMP-dependent adenylate cyclase re-sponse. However, in vitro studies show that ADO also acts trough the NO-dependent pathway. These results therefore demonstrate for the first time a new relaxant pathway in distal vagina, ADO signaling, that results deeply intertwined with the well-known NO pathway. This finding unravels new biological mechanisms underlying vagina physiology that need to be further studied in future research. Disclosure: No. [ABSTRACT FROM AUTHOR]

Introduction: Gender disparity persists in the relationship between sexual dysfunction and cardiovascular risk (CV). It is well- known that erectile dysfunction (ED) represents a sign of subclinical CV pathology and that alterations in color Doppler penile ultrasound parameters serve as predictive markers of major CV events. Female sexual dysfunction (FSD) is a complex condition that involves psychological and organic components, including the cardiovascular system, and affects the quality of life of over a third of women. However, despite its high prevalence, little attention has been paid to the vascular system responsible for blood supply to the female genital apparatus. In men, the hypothesis of penile artery size is a proposed pathophysiological mechanism to address the relationship between the onset of ED symptoms and cardiovascular disease. In recent years, it has also been highlighted that compromised genital vascularization may be a precursor to cardiovascular diseases in women. Objective: Our ami gas to investigate the association between clitoral pulsatility index (PI), evaluated through Clitoral color Doppler ultrasound (CDU), and cardiometabolic risk factors in women referred to the Andrology, Women's Endocrinology and Gender Incongruence Unit, Careggi University Hospital, Florence, Italy. Methods: In an observational study, a total of 361 women with a mean age of 45.1 (±13.3) years were evaluated. All patients underwent a thorough medical history assessment, an evaluation of anthropometric parameters, blood sampling for measurement of metabolic and hormonal parameters and a Doppler ultrasound of the clitoral cavernous artery to measure the PI. Results: 23.5% of the patients were overweight and 11.6% were obese, 16.3% had hypertension, and 18.6% had metabolic syndrome. In the multivariate analysis, after adjusting for age, the PI was positively correlated with body mass index (BMI) (ß=0.160, p=0.003) and waist circumference (ß=0.186, p=0.002). Furthermore, all women underwent cardiovascular risk assessment, as indicated by Progetto CUORE, assigning a score based on the presence of risk factors (blood pressure, cholesterol levels, smoking, diabetes, age, gender) to estimate the absolute global cardiovascular risk over the next 10 years. We observed that, particularly in women of reproductive age, the clitoral PI was positively correlated with the Progetto CUORE score (r=0.136, p=0.035). Conclusions: Clitoral PI increases in relation to several cardiometabolic risk factors. It is therefore relevant to understand how common cardiometabolic alterations may influence vascular function in the female genital tract and whether treating these alterations leads to an improvement in clitoral ultrasound indices, especially in young premenopausal women. Disclosure: No. [ABSTRACT FROM AUTHOR]

Introduction: Adenosine (ADO) is a purinergic neuromodulator that in the male exerts a positive effect on penile erection by controlling smooth muscle (SM) relaxation. However, its role in the relaxant/contractile pathways in the vagina is yet to be investigated. Objective: The aim of this study was to characterize the effect of ADO stimulation on SM activity in distal vagina, evaluating its possible effect on the regulation of nitric oxide (NO) pathway using a validated animal model of female Sprague-Dawley rats. Methods: The immunolocalization of ADORA2A and ADORA2B in distal vagina tissues was detected by immunohistological staining. In vitro contractility studies on noradrenaline (NA)-precontracted vaginal strips from intact Sprague-Dawley rats were performed; rat smooth muscle cells (rvSMCs) from distal vagina of intact animals were stimulated with ADO for cyclic adenosine monophosphate (cAMP) quantification. mRNA (messenger ribonucleic acid) isolated from vaginal tissue was analyzed by semi-quantitative Reverse Transcriptase-Polymerase Chain Reaction. Results: All ADORAs mRNA were expressed in the vaginal tissue, with a significant prevalence of ADORA2B; furthermore, ADORA2A and ADORA2B immunolocalization highlighted that both receptors are highly expressed in the epithelium, in blood capillaries of the vascular bed and in the smooth muscle bundles of vagina wall. In vitro ADO stimulation induced a dose-dependent relaxation (IC50=31.9±2.38 μM), which was significantly reduced by the administration of NO-synthase inhibitor L-NAME; similar effects were observed after the mechanical ablation of endothelium and in vitro administration of the soluble guanylate cyclase inhibitor ODQ, highlighting the pivotal contribution of NO signaling to the ADO relaxant activity. In vitro stimulation with increasing doses of the selective ADO receptor ADORA2A agonist CGS2-1680 induced a dose-dependent relaxation (IC50=132.6±3.47 nM); a similar but less potent relaxant effect was observed with ADORA2B selective agonist BAY60-6583. The relaxing effect induced by ADO on NA-precontracted vaginal strips was completely counteracted by the stimulation with the re-spectively selective ADORA2A and ADORA2B antagonists SHC-442416 and PSB603; a similar effect was induced by ADORA1 selective antagonist SLV320, but not by ADORA3 selective antagonists VUF5574. The mRNA relative expression of enzymes regulating the ADO turnover [adenosine deami-nase (ADA), 5′-nucleotidase (5NTD), AMP deaminase type 1 and type 2 (AMPD1, AMPD2) and adenosine kinase (ADK)] showed a higher expression of genes regulating the de novo ADO/cAMP syn-thesis (ADK, 5NTD), compared to those acting on ADO degradation (ADA, AMPD1, AMPD2). Finally, stimulation of rvSMCs with increasing doses of ADO induced a significant production of intracellular cAMP after 3 minutes (1 and 10 μM). Conclusions: These data show that ADO acts as an important relaxant modulator of the vagina through the activation of its receptors, specifically ADORA2A, and the consequent cAMP-dependent adenylate cyclase re-sponse. However, in vitro studies show that ADO also acts trough the NO-dependent pathway. These results therefore demonstrate for the first time a new relaxant pathway in distal vagina, ADO signaling, that results deeply intertwined with the well-known NO pathway. This finding unravels new biological mechanisms underlying vagina physiology that need to be further studied in future research. Disclosure: No. [ABSTRACT FROM AUTHOR]

Introduction: Gender disparity persists in the relationship between sexual dysfunction and cardiovascular risk (CV). It is well- known that erectile dysfunction (ED) represents a sign of subclinical CV pathology and that alterations in color Doppler penile ultrasound parameters serve as predictive markers of major CV events. Female sexual dysfunction (FSD) is a complex condition that involves psychological and organic components, including the cardiovascular system, and affects the quality of life of over a third of women. However, despite its high prevalence, little attention has been paid to the vascular system responsible for blood supply to the female genital apparatus. In men, the hypothesis of penile artery size is a proposed pathophysiological mechanism to address the relationship between the onset of ED symptoms and cardiovascular disease. In recent years, it has also been highlighted that compromised genital vascularization may be a precursor to cardiovascular diseases in women. Objective: Our ami gas to investigate the association between clitoral pulsatility index (PI), evaluated through Clitoral color Doppler ultrasound (CDU), and cardiometabolic risk factors in women referred to the Andrology, Women's Endocrinology and Gender Incongruence Unit, Careggi University Hospital, Florence, Italy. Methods: In an observational study, a total of 361 women with a mean age of 45.1 (±13.3) years were evaluated. All patients underwent a thorough medical history assessment, an evaluation of anthropometric parameters, blood sampling for measurement of metabolic and hormonal parameters and a Doppler ultrasound of the clitoral cavernous artery to measure the PI. Results: 23.5% of the patients were overweight and 11.6% were obese, 16.3% had hypertension, and 18.6% had metabolic syndrome. In the multivariate analysis, after adjusting for age, the PI was positively correlated with body mass index (BMI) (ß=0.160, p=0.003) and waist circumference (ß=0.186, p=0.002). Furthermore, all women underwent cardiovascular risk assessment, as indicated by Progetto CUORE, assigning a score based on the presence of risk factors (blood pressure, cholesterol levels, smoking, diabetes, age, gender) to estimate the absolute global cardiovascular risk over the next 10 years. We observed that, particularly in women of reproductive age, the clitoral PI was positively correlated with the Progetto CUORE score (r=0.136, p=0.035). Conclusions: Clitoral PI increases in relation to several cardiometabolic risk factors. It is therefore relevant to understand how common cardiometabolic alterations may influence vascular function in the female genital tract and whether treating these alterations leads to an improvement in clitoral ultrasound indices, especially in young premenopausal women. Disclosure: No. [ABSTRACT FROM AUTHOR]

Introduction: It has been previously demonstrated that testosterone (T) has a pivotal role in controlling vaginal relaxation through the related molecular machinery, i.e., improving the nitric oxide (NO)/protein kinase G (PKG)/cyclic guanosine monophosphate (cGMP) vaginal signaling and maintaining the integrity of the muscular wall. Adenosine (ADO) is a purinergic neuromodulator that, in the male, shows a positive effect on penile erection by controlling smooth muscle relaxation and local blood flow increase. However, the role, if any, of T on the ADO-induced relaxation signaling is yet to be investigated. Objective: The aim of this study was to evaluate the effect of sex steroids on ADO-mediated vaginal relaxation using a validated animal model of ovariectomized (OVX) and sex steroid supplemented Sprague-Dawley rats. Methods: Subgroups of OVX rats were treated with 17β-estradiol (E2; 10 mg/kg/die), testosterone (T; 30 mg/kg/week), or testosterone and letrozole (T+L, 2.5 mg/kg/die) for 6 weeks. The experimental groups were compared with a group of intact rats. In vitro contractility studies were performed on noradrenaline (NA) pre-contracted distal vaginal strips, isolated from each experimental group, stimulated with increasing doses of ADO (1 μM - 1 mM), with or without NO-synthase inhibitor L-NAME (100 μM) pretreatment, or treated with ADORA2A selective agonist CGS21680 (10 Pm-100 μM). Messenger ribonucleic acid (mRNA) isolated from vaginal tissue was analyzed by semi-quantitative Reverse Transcriptase-Polymerase Chain Reaction. Results: The results showed that OVX resulted in a decreased responsiveness to ADO, completely restored by T supplementation, with or without letrozole. In contrast, E2 did not affect the hyporesponsiveness to ADO in OVX rats. Likewise, ADO induced dose-dependent relaxation was significantly reduced by in vitro L-NAME (100 μM) only in the OVX animals treated with T or T+L. Accordingly, vagina expressed all ADO receptors (ADORA1, ADORA2A, ADORA2B, ADORA3) mRNAs, with pro-relaxant ADORA2A (ADO receptor coupled to adenylyl cyclase activation) being significantly modulated by hormonal treatments: OVX significantly reduced ADORA2A mRNA expression, an effect counteracted by either T or T+L administration, but not by E2. These data are supported by the observed T-induced upregulation of cyclic adenosine monophosphate (cAMP)-dependent genes, where T, but not E2, treatment upregulated the mRNA expression of the ubiquitous isoform of ADCY (ADCY4), protein kinase A (PKA) catalytic subunit b (PKAcb), PKA regulatory subunit 2b (PKAr2b) and cAMP responsive element modulator (CREM). Finally, as further demonstration of the functional activity of ADO signaling in distal vagina, stimulation by increasing doses of CGS21680, a selective agonist of ADORA2A receptor, enhanced the relaxant effect induced by T and T+L treatments but not by E2. Conclusions: Our data demonstrated for the first time a novel ADO-mediated relaxant mechanism in vagina and suggested that T positively modulates the responsiveness to ADO stimulation, thus confirming this process as a major player in the relaxant mechanism regulation of muscle contractility in vagina. Disclosure: No. [ABSTRACT FROM AUTHOR]

Introduction: HSDD (Hypoactive Sexual Desire Disorder) is one of the most common sex-related disorders among women. Despite its considerable prevalence, factors affecting sexual desire as well as therapeutic outcomes of treatment of HSDD in women have been scarcely studied. According to the Dual Control Model (DCM), for years female sexual desire has been identified as the result of two mainly centrally acting brain processes: excitation or inhibition towards sexual cues. In this context, the SIS (Sexual Inhibition Scale)/SES (Sexual Excitation Scale) validated questionnaire could represent an useful tool for the clinician to better characterize patients' lack of desire. Objective: This study was aimed at exploring both the inhibitory and excitatory components of sexual desire in women referring to our Clinic for sexual dysfunction, in order to find a cut-off value in the SIS/SES score predicting a diagnosis of HSDD. A secondary aim was also to identify clinical, relational and biochemical parameters significantly associated with these two dimensions of sexual desire. Methods: We retrospectively recruited a consecutive series of 133 women consulting for Female Sexual Dysfunction (FSD). Patients underwent clinical and biochemical evaluation, a structured interview and completed several self-administered questionnaires, including SIS/SES, Female Sexual Function Index (FSFI), Female Sexual Distress Scale-Revised (FSDS-R), Body Uneasiness Test (BUT), Emotional Eating Scale (EES) and Middlesex Hospital Questionnaire (MHQ). Results: The ROC curve for SES score showed an accuracy of 0.687 ± 0.05 (p<0.0001) in identifying HSDD; considering a cut-off value of 47.5, the sensitivity and specificity for HSDD detection were 70.5% and 55.6%, respectively. In addition, the best cut-off value for SIS1 to diagnose HSDD was 32.5, with 0.664 ± 0.048 AUC (p=0.002), 68.2% sensitivity and 53.3% specificity. We next stratified FSD women according to these SES/SIS1 cut-off values, thus identifying patients with pathological (pSES, pSIS1) or non-pathological (npSES, npSIS1) scores and the following 4 different subgroups: group 1 npSES/npSIS1; group 2 npSES/pSIS1; group 3 pSES/npSIS1; group 4 pSES/pSIS1. Among the 4 groups we did not find any statistically significant difference concerning the main characteristics explored, including lifestyle, hormonal and metabolic factors, with the exception of age, which was associated with a progressive worsening of either SES and SIS1 scores (F=4.299, p=0.006). Concerning relational factors, we demonstrated that the longer the duration of the relationship, the more pathological the excitatory/inhibitory scores, even when adjusted for age (F=5.588, p=0.001). Noteworthy, with exception for FSFI orgasm (FSFI-O) and satisfaction (FSFI-S) domains, all others FSFI domains scores showed similar significant differences with the worst values observed in pSES subgroups, independently from the presence of pSIS1. In contrast, FSDS-R score showed a highly significant variation among subgroups, but with the pSIS1 subgroup displaying the worst distress score independently from the presence of pSES. Among endocrinological factors, only total testosterone levels showed significant variation among groups (F=5.952, p<0.001), with the lower level observed in FSD women with pSES or pSIS1, in whatever combination as compared to npSES/npSIS1, even after age-adjustment (F=3.176, p=0.027). Regarding psychopathological factors, in an age-adjusted model, we found a significantly different MHQ total score among the 4 groups, with the worst value associated with the pSIS1 group combined or not with pSES. We also explored eating disorder symptoms. The 4 groups reported significantly different values in the EES, with pSES/pSIS1 group showing the highest score, even after adjusting for age (F=3.316, p=0.023). We then investigated the relevance of stratifying HSDD patients according to SIS1 and SES np/p scores in predicting the beneficial effects of treatments for HSDD (improvement yes/no). Interestingly, we found that SES, but not SIS scores, could predict HSDD treatment outcome after 6 months; in particular, the lower the level of SES at baseline, the higher the improvement in FSFI-D domain during treatment is predictable. Finally, we explored which were the main determinants for SES/SIS1 scores in the study population. Noteworthy, a significantly stepwise increase of SES score was observed as a function of total testosterone levels (r=0.192, p=0.049). Conclusions: In conclusion, the cutoffs of SIS1/SES found in this study could help characterizing HSDD women and identifying subgroups of patients with the highest probability to benefit from testosterone treatment. From a broader viewpoint, our study suggests that women diagnosed with HSDD should be evaluated by using more appropriate tools, including those not routinely employed in clinical practice, so that different "nuances" of this sexual disorder could be recognized and consequently adequately treated in a tailored therapy perspective. Disclosure: No. [ABSTRACT FROM AUTHOR]

Introduction: It has been previously demonstrated that testosterone (T) has a pivotal role in controlling vaginal relaxation through the related molecular machinery, i.e., improving the nitric oxide (NO)/protein kinase G (PKG)/cyclic guanosine monophosphate (cGMP) vaginal signaling and maintaining the integrity of the muscular wall. Adenosine (ADO) is a purinergic neuromodulator that, in the male, shows a positive effect on penile erection by controlling smooth muscle relaxation and local blood flow increase. However, the role, if any, of T on the ADO-induced relaxation signaling is yet to be investigated. Objective: The aim of this study was to evaluate the effect of sex steroids on ADO-mediated vaginal relaxation using a validated animal model of ovariectomized (OVX) and sex steroid supplemented Sprague-Dawley rats. Methods: Subgroups of OVX rats were treated with 17β-estradiol (E2; 10 mg/kg/die), testosterone (T; 30 mg/kg/week), or testosterone and letrozole (T+L, 2.5 mg/kg/die) for 6 weeks. The experimental groups were compared with a group of intact rats. In vitro contractility studies were performed on noradrenaline (NA) pre-contracted distal vaginal strips, isolated from each experimental group, stimulated with increasing doses of ADO (1 μM - 1 mM), with or without NO-synthase inhibitor L-NAME (100 μM) pretreatment, or treated with ADORA2A selective agonist CGS21680 (10 Pm-100 μM). Messenger ribonucleic acid (mRNA) isolated from vaginal tissue was analyzed by semi-quantitative Reverse Transcriptase-Polymerase Chain Reaction. Results: The results showed that OVX resulted in a decreased responsiveness to ADO, completely restored by T supplementation, with or without letrozole. In contrast, E2 did not affect the hyporesponsiveness to ADO in OVX rats. Likewise, ADO induced dose-dependent relaxation was significantly reduced by in vitro L-NAME (100 μM) only in the OVX animals treated with T or T+L. Accordingly, vagina expressed all ADO receptors (ADORA1, ADORA2A, ADORA2B, ADORA3) mRNAs, with pro-relaxant ADORA2A (ADO receptor coupled to adenylyl cyclase activation) being significantly modulated by hormonal treatments: OVX significantly reduced ADORA2A mRNA expression, an effect counteracted by either T or T+L administration, but not by E2. These data are supported by the observed T-induced upregulation of cyclic adenosine monophosphate (cAMP)-dependent genes, where T, but not E2, treatment upregulated the mRNA expression of the ubiquitous isoform of ADCY (ADCY4), protein kinase A (PKA) catalytic subunit b (PKAcb), PKA regulatory subunit 2b (PKAr2b) and cAMP responsive element modulator (CREM). Finally, as further demonstration of the functional activity of ADO signaling in distal vagina, stimulation by increasing doses of CGS21680, a selective agonist of ADORA2A receptor, enhanced the relaxant effect induced by T and T+L treatments but not by E2. Conclusions: Our data demonstrated for the first time a novel ADO-mediated relaxant mechanism in vagina and suggested that T positively modulates the responsiveness to ADO stimulation, thus confirming this process as a major player in the relaxant mechanism regulation of muscle contractility in vagina. Disclosure: No. [ABSTRACT FROM AUTHOR]

Introduction: HSDD (Hypoactive Sexual Desire Disorder) is one of the most common sex-related disorders among women. Despite its considerable prevalence, factors affecting sexual desire as well as therapeutic outcomes of treatment of HSDD in women have been scarcely studied. According to the Dual Control Model (DCM), for years female sexual desire has been identified as the result of two mainly centrally acting brain processes: excitation or inhibition towards sexual cues. In this context, the SIS (Sexual Inhibition Scale)/SES (Sexual Excitation Scale) validated questionnaire could represent an useful tool for the clinician to better characterize patients' lack of desire. Objective: This study was aimed at exploring both the inhibitory and excitatory components of sexual desire in women referring to our Clinic for sexual dysfunction, in order to find a cut-off value in the SIS/SES score predicting a diagnosis of HSDD. A secondary aim was also to identify clinical, relational and biochemical parameters significantly associated with these two dimensions of sexual desire. Methods: We retrospectively recruited a consecutive series of 133 women consulting for Female Sexual Dysfunction (FSD). Patients underwent clinical and biochemical evaluation, a structured interview and completed several self-administered questionnaires, including SIS/SES, Female Sexual Function Index (FSFI), Female Sexual Distress Scale-Revised (FSDS-R), Body Uneasiness Test (BUT), Emotional Eating Scale (EES) and Middlesex Hospital Questionnaire (MHQ). Results: The ROC curve for SES score showed an accuracy of 0.687 ± 0.05 (p<0.0001) in identifying HSDD; considering a cut-off value of 47.5, the sensitivity and specificity for HSDD detection were 70.5% and 55.6%, respectively. In addition, the best cut-off value for SIS1 to diagnose HSDD was 32.5, with 0.664 ± 0.048 AUC (p=0.002), 68.2% sensitivity and 53.3% specificity. We next stratified FSD women according to these SES/SIS1 cut-off values, thus identifying patients with pathological (pSES, pSIS1) or non-pathological (npSES, npSIS1) scores and the following 4 different subgroups: group 1 npSES/npSIS1; group 2 npSES/pSIS1; group 3 pSES/npSIS1; group 4 pSES/pSIS1. Among the 4 groups we did not find any statistically significant difference concerning the main characteristics explored, including lifestyle, hormonal and metabolic factors, with the exception of age, which was associated with a progressive worsening of either SES and SIS1 scores (F=4.299, p=0.006). Concerning relational factors, we demonstrated that the longer the duration of the relationship, the more pathological the excitatory/inhibitory scores, even when adjusted for age (F=5.588, p=0.001). Noteworthy, with exception for FSFI orgasm (FSFI-O) and satisfaction (FSFI-S) domains, all others FSFI domains scores showed similar significant differences with the worst values observed in pSES subgroups, independently from the presence of pSIS1. In contrast, FSDS-R score showed a highly significant variation among subgroups, but with the pSIS1 subgroup displaying the worst distress score independently from the presence of pSES. Among endocrinological factors, only total testosterone levels showed significant variation among groups (F=5.952, p<0.001), with the lower level observed in FSD women with pSES or pSIS1, in whatever combination as compared to npSES/npSIS1, even after age-adjustment (F=3.176, p=0.027). Regarding psychopathological factors, in an age-adjusted model, we found a significantly different MHQ total score among the 4 groups, with the worst value associated with the pSIS1 group combined or not with pSES. We also explored eating disorder symptoms. The 4 groups reported significantly different values in the EES, with pSES/pSIS1 group showing the highest score, even after adjusting for age (F=3.316, p=0.023). We then investigated the relevance of stratifying HSDD patients according to SIS1 and SES np/p scores in predicting the beneficial effects of treatments for HSDD (improvement yes/no). Interestingly, we found that SES, but not SIS scores, could predict HSDD treatment outcome after 6 months; in particular, the lower the level of SES at baseline, the higher the improvement in FSFI-D domain during treatment is predictable. Finally, we explored which were the main determinants for SES/SIS1 scores in the study population. Noteworthy, a significantly stepwise increase of SES score was observed as a function of total testosterone levels (r=0.192, p=0.049). Conclusions: In conclusion, the cutoffs of SIS1/SES found in this study could help characterizing HSDD women and identifying subgroups of patients with the highest probability to benefit from testosterone treatment. From a broader viewpoint, our study suggests that women diagnosed with HSDD should be evaluated by using more appropriate tools, including those not routinely employed in clinical practice, so that different "nuances" of this sexual disorder could be recognized and consequently adequately treated in a tailored therapy perspective. Disclosure: No. [ABSTRACT FROM AUTHOR]

In this prospective study, we evaluated the steroid levels in 111 follicular fluids (FF) collected from 13 women stimulated with FSH monotherapy and 205 FF collected from 28 women stimulated with FSH + LH because of a previous history of hypo-responsiveness to FSH. Steroid levels were measured by HPLC/MS–MS and related to ovarian stimulation protocol, oocyte maturity, fertilization and quality of blastocysts, after individually tracking the fate of all retrieved oocytes. 17-Hydroxy-Progesterone, Androstenedione, Estradiol and Estrone were significantly higher in the FSH + LH protocol. Progesterone, 17-Hydroxy-Progesterone and Estradiol were more expressed in FF yielding a mature oocyte (p < 0.01) in the FSH + LH protocol. FF Progesterone concentration was correlated with the rate of normal fertilization in the FSH protocol. None of the FF steroids measured were associated with blastocyst quality and achievement of pregnancy. Our results indicate that LH supplementation in hypo-responsive women modifies ovarian steroid production, mimicking physiological production better and likely contributing to an improved ovarian response. Employing a correct methodological procedure to evaluate the relationship between FF steroid hormones and assisted reproduction outcomes, our study reveals that some steroids in single follicles may be helpful in predicting oocyte maturity and fertilization. [ABSTRACT FROM AUTHOR]

Background: Premature ejaculation (PE) is present in up to 30% of men with erectile dysfunction (ED). Objectives: To assess the clinical features of men complaining of both ED and PE (ED‐PE) as compared to men reporting only ED or PE. Materials and methods: A consecutive series of 4024 men (mean age 51.2 ± 13.2 years) consulting for sexual dysfunction was studied. The population was categorized into ED‐only (n = 2767; 68.8%), PE‐only (n = 475; 1.8%), and ED‐PE (n = 782; 19.4%). Sexual symptoms were evaluated using the structured interviews SIEDY and ANDROTEST. Penile color Doppler ultrasound (PDCU) parameters were also assessed. Results: When compared to PE alone, ED‐PE reported more sexual complaints, including impaired morning erections [OR = 5.8 (4.1; 8.3)], decreased sexual desire [OR = 2.6 (1.8; 3.7)], decreased ejaculate volume [OR = 2.7 (1.8; 4.0)], and reduced frequency of sexual intercourse [OR = 1.4 (1.0; 2.0)]. Conversely, ED‐PE and ED‐only men had a similar prevalence of sexual symptoms. In ED‐PE men, the characteristics of ED were similar to ED‐only men, whereas the characteristics of PE were milder than in PE‐only men. ED‐PE men had a significantly higher prevalence of hypertension, diabetes, and cardiovascular (CV) diseases [OR = 1.8 (1.1; 3.0), 2.7 (1.3; 5.6) and 2.7 (1.1; 6.5), respectively] than PE‐only subjects. Moreover, ED‐PE men showed worse dynamic peak systolic velocity at PDCU [B = −12.0 (−17.7; −6.2)] and a greater 10‐year estimated CV risk [B = 3.8 (2.5; 5.1)] than PE‐only patients. Conversely, comorbidities and PDCU parameters were similar in ED‐PE and ED‐only men. Discussion: The present results suggest that men reporting ED and PE should be considered as patients with ED‐only, at least at first glance. Consequently, the diagnosis—including the CV risk stratification—and treatment should be primarily focused on the erectile problem. Conclusions: Erectile dysfunction‐PE patients present several similarities with those consulting only for ED, whereas their characteristics are different from PE‐only men. In agreement with the guidelines, our results confirm that ED‐PE men might be considered (and managed) primarily as patients with ED. [ABSTRACT FROM AUTHOR]

Introduction: The "Dual control model" of sexual response postulates that sexual desire and associated behaviors depend on the balance between excitation and inhibition. These aspects have not been evaluated in women with sexual dysfunction (FSD). Objectives: The aim of our study was to explore the psychosexual correlates of excitation and inhibition in women with FSD, according to their menopausal state. We also aimed at performing a pre-post analysis in a sub-sample of patients followed for 3-6 months, investigating the possible relationships between excitation and inhibition and the changes in questionnaires related to sexual function. Methods: In an observational, retrospective study, we recruited a consecutive series of 66 women consulting for FSD. Patients underwent a clinical evaluation, a structured interview and completed several self-administered questionnaires, including Sexual Inhibition/Sexual Excitation Scale (SIS/SES), Female Sexual Function Index (FSFI), Female Sexual Distress Scale-Revised (FSDS-R), Body Uneasiness Test (BUT) and Middlesex Hospital Questionnaire (MHQ). A subgroup of patients (n=28) was evaluated at 3-6 months follow-up, using the FSFI and FSDS-R questionnaires. Results: Considering the whole sample, the SES scale was positively correlated with several psychosexual and relational parameters, including masturbation (p=0.005), number of lifetime partners (p=0.004) and histrionic personality traits (p=0.013), and negatively with the presence of a stable relationship (p=0.038) and its length (p=0.026). Sexual inhibition due to the fear of performance failure (SIS1 scale) positively correlated with conflicts within the couple (p=0.012), lack of privacy (p<0.0001), symptoms of general psychopathology (p=0.001; in particular, anxiety) and body image concerns (p=0.015). Regarding sexual parameters, the SES scale was associated with the total FSFI score (p=0.016), and the desire (p=0.011), arousal (p=0.030), lubrication (p=0.046) and orgasm domains (p=0.025), whereas the SIS1 scale was associated with the FSDS-R score (p=0.028). In premenopausal women, the SIS1 scale was associated with the diagnosis of Hypoactive Sexual Desire Disorder (HSDD), even after adjusting for confounders (p=0.047), whereas in postmenopausal women, we found an association between HSDD and the SES scale (p=0.039). Given these correlations, we developed two cut-off values for the SES and SIS1 scales, according to which a score < 49 on the SES (in postmenopausal women) and a score > 34 on the SIS1 (in premenopausal women) accurately identified patients diagnosed with HSDD. In postmenopausal women, the ROC curve for the SES scale showed an accuracy (AUC) of 0.734 +− 0.107, p=0.037, in identifying HSDD; considering a cut-off value of 49, the sensitivity and specificity for HSDD detection were 85.7% and 66.7%, respectively. In premenopausal women, the ROC curve for the SIS1 scale showed an AUC of 0.853 +− 0.081, p=0.007, in identifying HSDD; considering a cut-off value of 34, the sensitivity and specificity for HSDD detection were 78.6% and 75.0%, respectively. The mean change in FSFI total score was not correlated with the SES or SIS2 scales (p=0.214 and p=0.402, respectively), but only with the SIS1 scale (p=0.026). When comparing patients with low excitation (SES scale <49) and high inhibition (SIS1 scale >34) with the rest of the sample, they showed a significantly lower change in FSFI total score (p=0.018). Conclusions: In women consulting for FSD, sexual excitation and inhibition, which may be easily assessed by the SIS/SES questionnaire, emerge as key aspects in both the diagnostic evaluation and planning of therapeutic outcomes, in the perspective of a personalized sexual medicine approach. Disclosure: No. [ABSTRACT FROM AUTHOR]

Data on the role of prolactin (PRL) in the physiologic range in the female sexual response are scanty. We aimed at investigating the association between PRL levels and sexual function, and specifically, with the desire domain as assessed by the Female Sexual Function Index. We also explored the presence of a cut-off level of PRL able to identify women with a diagnosis of Hypoactive Sexual Desire Disorder (HSDD). N=234 pre- and post-menopausal women (mean age 45.2+-12.4 years) consulting for female sexual dysfunction (FSD), and sexually active in the previous 4 weeks, were retrospectively analysed. A clinical, biochemical and pharmacological evaluation was performed. All patients completed the FSFI, the Female Sexual Distress Scale-Revised (FSDS-R), the Middlesex Hospital Questionnaire (MHQ) for the screening of psychopathological symptoms and the Sexual excitation/sexual inhibition scale (SIS/SES). Biochemical assessment included PRL (by luminescent oxygen channeling immunoassay). Only few patients (n=9) had hyperPRL (PRL> 483.0 mU/L) and showed a significantly higher MHQ total score (p=0.043), lower Total (p=0.037), Desire (p=0.002), Arousal (p=0.024) and Satisfaction (p=0.026) FSFI scores and a higher FSDS-R score (p=0.006) compared with women with normoPRL women. At univariate linear regression analysis, we did not find a significant correlation between FSFI total score and PRL levels. Hypothesizing the non-linearity of the association between these 2 variables, we tested different fitting models and found that the quadratic relationship was the best fitting (R2=0.11).When stratifying normoPRL women into tertiles (T1: PRL < 163.55 mU/L; T2= PRL > 163.55 and < 262.0 mU/L; T3: PRL > 262.0 and < 483.0 mU/L), a significant difference emerged in FSFI Desire (p=0.001), Arousal (p=0.033) and Satisfaction (p=0.019) among the 4 groups; however, only the difference in Desire was confirmed (p=0.034) in a multivariate model. A post-hoc analysis showed that only women in the T3 PRL tertile had significantly higher scores in FSFI Desire (p=0.011) and Satisfaction (0.045) vs. women with hyperPRL.After excluding hyperPRL women, we compared PRL between women with (n=35) and without HSDD (n=190) and observed that those with HSDD showed significantly lower PRL levels (p=0.002). ROC curve analysis for PRL levels showed an accuracy of 0.615 +- 0.022, p = 0.040, in predicting HSDD, and when a threshold of PRL<190 mU/L was chosen, sensitivity and specificity for HSDD were both 64.7%. Finally, we compared women with PRL levels > and < 190 mU/L. At multivariate analysis, women with PRL <190 mU/L showed a significantly lower cortisol (p=0.017) and SIS1 score (p=0.049), a scale of sexual inhibition, than women with PRL >190 mU/L (bit still in the normal range). FSD women with hyperPRL showed a worse sexual function than those with normal PRL levels. However, when stratifying normoPRL women based on PRL tertiles, those included in the highest group had the best FSFI profile. Measuring PRL level in women with FSD is important, not only in order to ascertain the presence of a hyperPRL condition, but also to potentially predict the presence of HSDD or of a lower sexual inhibitory trait. No [ABSTRACT FROM AUTHOR]

Female sexual response is a complex phenomenon that involves multiple psychophysiological factors. Sex steroids play a fundamental role in the mechanisms of regulation of sexual arousal, modulating the sexual response and preserving the integrity and functionality of the vaginal tissue. For this reason, imbalances in the sexual environment of steroids in women favor the onset of important pathophysiological conditions such as hypoactive sexual desire disorder (HSDD) and genitourinary syndrome of menopause (GSM). Previous research has focused primarily on the effects of estrogen supplementation on vaginal physiology, but only few studies evaluated the effects of androgen administration, particularly on the vaginal smooth muscle compartment. The calcium sensitizing pathway of RhoA/ROCK may play a role in regulating vaginal contractility but, at present, the regulatory mechanisms of RhoA/ROCK signaling in the female genitourinary tract have yet to be fully elucidated. In particular, no specific research has been conducted on the effects of testosterone (T) on the contractility mechanism of smooth muscle in the vagina. The aim of this study was to evaluate the sex steroid regulation on the distal vagina contractility mechanism, mediated by the RhoA/ROCK pathway, using a validated animal model of female ovariectomized rats. Ovariectomized Sprague-Dawley rats (OVX) were treated with 17β-estradiol (OVX+E), testosterone (OVX+T), or testosterone and letrozole (OVX+T+L) and compared with an intact animals' group (CTRL). In vitro contractility studies were performed on noradrenaline (NA) pre-contracted vaginal strips to investigate the effect of OVX and in vivo treatments on vaginal smooth muscle activity. The mRNA from vagina tissues isolated from each experimental group was analyzed by semi-quantitative RT-PCR, and membrane translocation of RhoA was evaluated by Western blot analysis. Y-27632 induced a dose-dependent relaxation on NA pre-contracted vaginal strips that was significantly decreased by OVX; T, with or without L, further decreased OVX-induced hyporesponsiveness to Y-27632, whilst it was fully restored up to control level by 17β-estradiol (E) supplementation. Accordingly, gene expression analysis indicated that OVX decreased the expression of RhoA/ROCK pathway markers, which was normalized by E. However, at variance with contractility results, androgen receptor (AR) activation upregulated, rather than downregulating, RhoA/ROCK expression. In Western blot analysis, OVX induced activation and membrane translocation of the active form of RhoA as compared to controls. Interestingly, T reverted this effect by reducing RhoA translocation to membrane to a level even significantly below the control one. This effect was not exerted by E administration. Considering that AR activation increases NO signaling (as measured by Prkg1 mRNA expression), we tested the effect of abolishing NO formation through the NO synthase inhibitor L-NAME. Pre-incubation with L-NAME substantially increased Y-27632 responsiveness in the OVX +T group and partially in the CTRL one and, but not in the OVX group. This study confirms that in vagina estrogens increase the expression of the calcium-sensitizing pathway RhoA/ROCK, while androgen administration functionally decreases RhoA/ROCK activity, by hampering RhoA translocation to the membrane, a mechanism which is most probably driven by NO. No [ABSTRACT FROM AUTHOR]

Research on the relationship between physical activity (PA) and female sexual dysfunction (FSD) is lacking. To investigate the clinical, psychological, and sexual correlates of PA in women with FSD. A non-selected series of n=322 pre- and post-menopausal patients consulting for FSD was retrospectively studied. Regular involvement in PA and its frequency (<1 hour/week: sedentary, 1-3 hours/week: active, 4-6 hours/week: very active, >6 hours/week: extremely active) were investigated with a specific question. FSDs, including HSDD (Hypoactive sexual desire disorder) and FGAD (Female genital arousal disorder), were diagnosed according to a structured and clinical interview. Participants underwent a physical examination and a clitoral Doppler ultrasound, and were asked to complete the Female Sexual Function Index (FSFI), Female Sexual Distress Scale-Revised (FSDS-R), Body Uneasiness Test (BUT), and Middlesex Hospital Questionnaire (MHQ). Mean age was 45.1±12.9, mean body mass index was 25.24±6.34 kg/m2 and 46.3% (n=149) of women were post-menopausal. At multivariate analysis, women engaging in PA (67.4%, n = 217) scored significantly higher in several FSFI domains - including desire, arousal and lubrication (see Table 1) - and showed lower sexual distress and lower resistance of clitoral arteries, as compared to sedentary women. A significant, inverse association between PA and HSDD was observed (see Table 1). In the same adjusted model, the association between PA and the vascular resistance of clitoral arteries, expressed by clitoral PI, retained statistical significance. Mediation analysis demonstrated that the negative association between PA and HSDD was partly mediated by body image concerns (BUT Global severity index), psychopathological symptoms (MHQ total score) and sexual distress (FSDS-R score). These latter two factors also partly mediated the association between PA and a reduced risk of FGAD, whilst a lower BMI was a full mediator in the relationship between PA and FGAD. Finally, extreme PA was associated with significantly worse scores in several psychosexual parameters (i,e, sexual satisfaction – see Figure 1) and histrionic/hysterical symptoms), even compared to a sedentary lifestyle. In women with FSD, PA was associated with better sexual function and clitoral vascularization, lower sexual distress and reduced odds of HSDD and FGAD; the benefits of PA on sexuality were mediated by both psychological and organic determinants; excessive PA was related with a poor overall sexual function and with a low sexual satisfaction. Women consulting for FSD may gain benefits from regular PA; however, physicians should remain alert to the downsides of excessive exercise. Work supported by industry: no. [ABSTRACT FROM AUTHOR]

The "Dual control model" of sexual response postulates that sexual desire and associated behaviors depend on the balance between excitation and inhibition. These aspects have not been evaluated in women with sexual dysfunction (FSD). To explore the psychosexual correlates of excitation and inhibition in women with FSD, according to their menopausal state. We also aimed at performing a pre-post analysis in a sub-sample of patients followed for 3-6 months, investigating the possible relationships between excitation and inhibition and the changes in questionnaires related to sexual function. In an observational, retrospective study, we recruited a consecutive series of 66 women consulting for FSD. Patients underwent a clinical evaluation, a structured interview and completed several self-administered questionnaires, including Sexual Inhibition/Sexual Excitation Scale (SIS/SES), Female Sexual Function Index (FSFI), Female Sexual Distress Scale-Revised (FSDS-R), Body Uneasiness Test (BUT) and Middlesex Hospital Questionnaire (MHQ). A subgroup of patients (n=28) was evaluated at 3-6 months follow-up, using the FSFI and FSDS-R questionnaires. In pre-menopausal women, the SIS1 scale (Sexual inhibition due to the fear of performance failure) was associated with the diagnosis of Hypoactive Sexual Desire Disorder (HSDD), even after adjusting for confounders (p=0.047), whereas in post-menopausal women, we found an association between HSDD and the SES scale (total sexual excitation) (p=0.039; see also Figure 1). Given these correlations, we developed two cut-off values for the SES and SIS1 scales, according to which a score < 49 on the SES (in postmenopausal women) and a score > 34 on the SIS1 (in premenopausal women) accurately identified patients diagnosed with HSDD. In post-menopausal women, the ROC curve for the SES scale showed an accuracy (AUC) of 0.734 +- 0.107, p=0.037, in identifying HSDD; considering a cut-off value of 49, the sensitivity and specificity for HSDD detection were 85.7% and 66.7%, respectively (Fig. 2). In premenopausal women, the ROC curve for the SIS1 scale showed an AUC of 0.853 +- 0.081, p=0.007, in identifying HSDD; considering a cut-off value of 34, the sensitivity and specificity for HSDD detection were 78.6% and 75.0%, respectively (Fig. 3). At follow-up, the mean change in FSFI total score was not correlated with the SES or SIS2 scales (p=0.214 and p=0.402, respectively), but only with the SIS1 scale (p=0.026). When comparing patients with low excitation (SES scale <49) and high inhibition (SIS1 scale >34) with the rest of the sample, they showed a significantly lower change in FSFI total score (p=0.018). In women consulting for FSD, sexual excitation and inhibition, which may be easily assessed by the SIS/SES questionnaire, emerge as key aspects in both the diagnostic evaluation and planning of therapeutic outcomes, in the perspective of a personalized sexual medicine approach. Work supported by industry: no. [ABSTRACT FROM AUTHOR]

An abstract of the study "Sexual functioning predicts long term outcome of eating disorders patients: a two years follow up study" by G. Castellini and colleagues is presented.

It has been generally assumed that partner's erectile dysfunction, premature, and delayed ejaculation play a significant role in determining female sexual dysfunction ( FSD). This study aimed to evaluate the role of the male partner's sexual function, as perceived by women, in determining FSD. A consecutive series of 156 heterosexual women consulting our clinic for FSD was retrospectively studied. All patients underwent a structured interview and completed the Female Sexual Function Index ( FSFI). FSFI total score decreased as a function of partner's age, conflicts within the couple, relationship without cohabitation and the habit of engaging in intercourse to please the partner; FSFI total score increased as a function of frequency of intercourse, attempts to conceive and fertility-focused intercourse. FSFI total score showed a negative, stepwise correlation with partner's perceived hypoactive sexual desire (HSD) ( r = −0.327; p < 0.0001), whereas no significant correlation was found between FSFI and erectile dysfunction, premature and delayed ejaculation. In an age-adjusted model, partner's HSD was negatively related to FSFI total score (Wald = 9.196, p = 0.002), arousal (Wald = 7.893, p = 0.005), lubrication (Wald = 5.042, p = 0.025), orgasm (Wald = 9.293, p = 0.002), satisfaction (Wald = 12.764, p < 0.0001), and pain (Wald = 6.492, p = 0.011) domains. Partner's HSD was also significantly associated with somatized anxiety, low frequency of intercourse, low partner's care for the patient's sexual pleasure, and with a higher frequency of masturbation, even after adjusting for age. In patients not reporting any reduction in libido, FSFI total score was significantly lower when their partner's libido was low ( p = 0.041); the correlation disappeared if the patient also experienced HSD. In conclusion, the presence of erectile dysfunction, premature, and delayed ejaculation of the partner may not act as a primary contributing factor to FSD, as determined by FSFI scores; conversely, women's sexuality seems to be mostly impaired by the perceived reduction in their partner's sexual interest. [ABSTRACT FROM AUTHOR]

The benefits of treatment with testosterone (T) in women with loss of desire suggest that low androgens may distinguish women with sexual dysfunction (SD) from others; however, evidence on this point is lacking. To answer the question: is there an association between endogenous levels of androgens and sexual function in women? An extensive search was performed in MEDLINE, Embase and PsycInfo. Four separate meta-analyses were conducted for total T, free T, Free Androgen Index (FAI) and Dehydroepiandrosterone sulphate (DHEAS). Cohort, cross-sectional and prospective studies were included.The main outcome was the association between endogenous androgens and sexual desire. Global sexual function was considered as a secondary outcome. The effect measure was expressed as standardized mean difference (SMD). The meta-analysis on total T included 34 studies involving 3268 women, mean age 36.5 years. In 11 studies, a significant association was found between sexual desire, measured by validated psychometric instruments, and total T [SMD=0.59 (0.29; 0.88), p<0.0001], with a moderate effect. The association with global sexual function (n=12 studies) was also significant [SMD=0.44 (0.21; 0.67), p<0.0001]. Overall, total T was associated with a better sexual function [SMD=0.55 (0.28; 0.82), p<0.0001], with similar results obtained when Poor quality studies were removed. No association was found between total T and sexual function in PCOS or healthy women. Age showed a negative relationship with the overall outcome. No differences were found when stratifying the studies according to menopausal status, relationship status, method for T measurement (immunoassays, radioimmunoassays or mass spectrometry) or phase of the menstrual cycle. The meta-analysis of T derivatives (free T and FAI) also showed a significant, moderate association with sexual desire. In contrast, DHEAS seems not to exert any significant influence on desire, whilst showing a positive association with global sexual function. There appears to be a moderate association between total T levels and sexual desire/global sexual function, which is confirmed, although weak, in studies employing LC-MS. Similar results on desire were obtained for free T and FAI. DHEAS only showed a positive association with global sexual function. More research is needed. No [ABSTRACT FROM AUTHOR]

Several studies have highlighted a strong association between benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) and erectile dysfunction (ED), particularly in elderly men. Many epidemiological trials, such as in vitro and in vivo studies, have reported the emerging role of metabolic syndrome, including abdominal obesity, impaired glucose metabolism, hypertriglyceridemia, low high-density lipoprotein cholesterol, and hypertension, in the development and progression of urinary and sexual symptoms. Moreover, many authors have focused their studies on the identification of all the shared pathogenetic mechanisms of LUTS/BPH and ED, including alteration of cyclic guanosine monophosphate and RhoA-ROCK pathways or vascular and neurogenic dysfunction. All these are potential targets for proposed phosphodiesterase type 5 inhibitors (PDE5-Is). Therefore, several trials have recently been designed to evaluate the role of PDE5-Is alone or in combination with conventional treatment for BPH, such as α-adrenergic blockers, in men affected by LUTS/BPH, with or without ED. Different PDE5-Is are in clinical use worldwide and currently six of them are licensed for the oral treatment of ED. All these compounds differ in pharmacokinetic factors, with influence on drug action, and subsequently in the overall safety and efficacy profile. [ABSTRACT FROM AUTHOR]

Several studies have highlighted a strong association between benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) and erectile dysfunction (ED), particularly in elderly men. Many epidemiological trials, such as in vitro and in vivo studies, have reported the emerging role of metabolic syndrome, including abdominal obesity, impaired glucose metabolism, hypertriglyceridemia, low high-density lipoprotein cholesterol, and hypertension, in the development and progression of urinary and sexual symptoms. Moreover, many authors have focused their studies on the identification of all the shared pathogenetic mechanisms of LUTS/BPH and ED, including alteration of cyclic guanosine monophosphate and RhoA-ROCK pathways or vascular and neurogenic dysfunction. All these are potential targets for proposed phosphodiesterase type 5 inhibitors (PDE5-Is). Therefore, several trials have recently been designed to evaluate the role of PDE5-Is alone or in combination with conventional treatment for BPH, such as α-adrenergic blockers, in men affected by LUTS/BPH, with or without ED. Different PDE5-Is are in clinical use worldwide and currently six of them are licensed for the oral treatment of ED. All these compounds differ in pharmacokinetic factors, with influence on drug action, and subsequently in the overall safety and efficacy profile. [ABSTRACT FROM AUTHOR]

Preclinical studies show that, in the clitoris, testosterone (T) is necessary to maintain a functional contractile and relaxant machinery, which represents the underlying mechanism of the peripheral arousal response. Although there is clinical evidence suggesting that T treatment significantly improves multiple domains of sexual functioning, the vascularization of clitoral tissue and its regulation by sex steroids are still under-investigated. To explore the effects of 6-month systemic T administration on clitoral color Doppler ultrasound (CDU) parameters in women with female sexual dysfunction (FSD). 81 women with FSD were retrospectively recruited. Data on CDU parameters at baseline and after 6 months with four different treatments were available and thus further longitudinally analyzed: local non-hormonal moisturizers (NH group), n=37; transdermal 2% T gel 300 mcg/day (T group), n=23; local estrogens (E group), n=12; combined therapy (T+E group), n=9. Patients underwent physical, laboratory, and genital CDU examinations at both visits and completed different validated questionnaires, including the Female Sexual Function Index (FSFI). At 6-month visit, T therapy significantly increased clitoral artery peak systolic velocity (PSV) when compared to both NH (p < 0.0001) and E (p < 0.0001) groups. A similar increase was found in the T + E group (p = 0.039 vs. E) (Fig.1). In addition, T treatment was associated with significantly higher FSFI desire, pain, arousal, lubrication, orgasm and total scores at 6-month visit vs. baseline. Similar findings were observed in the T + E group. No significant differences in the variations of total and high-density lipoprotein-cholesterol, triglycerides, fasting glycemia, insulin and glycated hemoglobin levels were found among the four groups. No adverse events were observed. In women complaining for FSD, systemic T administration, either alone or combined with local estrogens, was associated with a positive effect on clitoral blood flow and a clinical improvement in sexual function, showing a good safety profile. Work supported by industry: no. [ABSTRACT FROM AUTHOR]

The human vagina is extremely sensitive to hormonal changes occurring during the woman's lifetime, in particular the decline in estrogens that characterizes the menopause is known to induce a range of genital and sexual symptoms (dryness, burning, irritation, lack of lubrication, discomfort, pain), known as "genitourinary syndrome of menopause" (GSM). However, this reduction in estrogen levels is also accompanied by a progressive ageing-dependent decline in androgens for which the role of androgens in the development and treatment of GSM has received more attention. It is known that peripheral tissues compensate for circulating hormonal imbalances through the in-situ production of small quantities of sex hormones deriving from inactive precursors metabolized by specific cellular enzymes. This non-classical production and local activity of hormones is defined as "intracrinology". The aim of the study was to investigate whether the human vagina possesses the specific enzymatic machinery to convert weak androgen precursors, such as DHEA, into active androgens [Δ4-androstenedione (A), testosterone (T) and dihydrotestosterone (DHT)] as already described in other species. In this study, a well established model of human smooth muscle cells (hSMCs), isolated from vagina tissues of women undergoing surgery for benign gynecological diseases, was used. Semi-quantitative RT-PCR was employed in order to evaluate the mRNA expression of the steroidogenic markers in hSMCs and corrispective tissue. The production of androgens was quantified in hSMCs medium by liquid chromatography tandem-mass spectrometry (LC-MS/MS). In vaginal tissues, AR mRNA was significantly less expressed than estrogen receptor α (ERα), whereas in hvSMCs, its mRNA expression was higher than progestin and both estrogen receptors. In hvSMCs and in vaginal tissue, when compared to ovaries, the mRNA expression of pro-androgenic steroidogenic enzymes (HSD3β1/β2, HSD17β3/β5), along with 5α-reductase isoforms and sulfo-transferase, resulted as being more abundant. In addition, enzymes involved in androgen inactivation were less expressed than in the ovaries. The LC-MS/MS analysis revealed that, in hvSMCs, short term DHEA supplementation increased Δ4-androstenedione levels in spent medium, while increasing testosterone (T) and dihydrotestosterone (DHT) secretion after longer incubation. Finally, androgenic signaling activation was evaluated through AR-dependent marker mRNA expression, after DHEA and T stimulation. This study provides evidence for the presence of steroidogenic machinery in the human vagina, supporting, for the first time, the construct of intracrinology in this organ, emphasizing that the vagina is an androgen-dependent organ. These observations suggest the potential mechanism and resulting action of intravaginally administered DHEA, recently indicated for the treatment of GSM and open new perspectives for the treatment of this common and bothersome condition. Work supported by industry: no. [ABSTRACT FROM AUTHOR]

Female sexual response is a result of a complex interplay between central and peripheral mechanisms and the nitric oxide (NO)-mediated relaxation of clitoris and distal vagina vascular bed leads to clitoris tumescence and vagina lubrification. The aim of this study was to evaluate sex steroids regulation of the relaxant/contractile pathway in vagina, using a validated animal model of ovariectomized (OVX) Sprague-Dawley rats. Subgroups of OVX rats were treated with 17β-estradiol (10 mg/kg/die), testosterone (T, 30 mg/kg/week), or testosterone and letrozole (2.5 mg/kg/die) for 6 weeks. The experimental groups were compared with a group of intact rats. In vitro contractility studies were carried out in order to investigate the effect of OVX and in vivo treatments on vaginal smooth muscle activity. RNA from vaginal tissue was analyzed by semi-quantitative RT-PCR. In vitro contractility studies were performed on noradrenaline pre-contracted distal vaginal strips, isolated from each experimental group. Acetylcholine (Ach; 0.001-10 µM) stimulation induced a concentration-dependent relaxation, which was significantly reduced by NO-synthase inhibitor L-NAME (100 µM) and by guanylate cyclase inhibitor ODQ (1 µM). OVX resulted in a decreased responsiveness to Ach, restored by T supplementation, with or without letrozole, but not by 17β-estradiol. Vaginal strips sensitivity to the NO-donor SNP (1 nM - 100 µM) was higher in OVX than in the control. Vardenafil (100 nM), a PDE5 inhibitor, enhanced SNP effect in OVX+T as well as in control, suggesting that T positively modulates PDE5, as supported by RNA expression analysis. In vitro contractility studies and mRNA expression analysis highlight the positive regulation of T on Ach- and NO-dependent muscle relaxation by modulating the NO/cGMP/PKG pathways.Our data demonstrate that testosterone improves the NO-mediated vascular smooth muscle vaginal cells relaxation confirming its critical role in maintaining the integrity of muscular relaxant machinery. Our study confirms the decisive role played by androgens, rather than estrogens, in maintaining the functionality and integrity of the vagina. This study might provide support for the use of androgens in the treatment of genitourinary syndrome of menopause (GSM) and/or sexual arousal disorders related to ageing related-hormonal deficiency. Work supported by industry: no. [ABSTRACT FROM AUTHOR]

Eating and sexual behavior are driven by neurological mechanisms that are extremely intertwined; emerging evidence indicates that their deep relationship can be mediated by the presence of specific psychopathologies. to investigate the relationship between female sexual dysfunction (FSD) and eating disorders (EDs). 123 retrospectively recruited women consulting for FSD underwent physical examination and completed the following validated questionnaires: Female Sexual Function Index (FSFI), Female Sexual Distress Scale-Revised (FSDS-R), Eating Disorder Examination Questionnaire (EDE-Q), Binge Eating Scale (BES), Emotional Eating Scale (EES), Barrat Impulsiveness Scale-11 (BIS-11), Beck Depression Inventory (BDI), State-Trait Anxiety Inventory Y (STAI Y), Symptom Checklist 90-Revised (SCL-90-R), Body Uneasiness Test (BUT), Dyadic Adjustment Scale (DAS) and Sexual Inhibition/Sexual Excitation Scales (SIS/SES). Moreover, demographic, medical and psycho-sexuological data were obtained through a structured interview. in relation to menopausal status, we did not observe any significant difference in all the investigated questionnaires in pre- vs. post-menopausal women. When stratifying patients for BMI (<25, 25-30, >30 kg/m2) we found that all the scores related to EDE-Q subscales were significantly different among the three subgroups (all p<0.001). Furthermore, patients with a history of Unwanted Sexual Experience (USE) had significantly higher BES (p=0.034) and EES (p=0.027) total scores compared with those without. Moreover, when we stratified our patients according to the clinical diagnosis of Hypoactive Sexual Desire Disorder (HSDD), we found that those with HSDD showed a worst psychological profile than those without, in particular a higher score at EDE-Q and BDI (all p<0.05). In contrast, when stratifying patients for the other two main FSD diagnosis, Female Genital Arousal Disorder (FGAD) and Female Orgasm Disorder (FOD), no significant differences among all the investigated questionnaires were observed. To further verify the impact of the different psychopathological aspects on the risk of having HSDD, we found that the only questionnaires scores that contributed to this dysfunction were EDE-Q (OR 1.678, IC [1.164-2.421]; p=0.006), total BDI (OR 1.055, IC [1.006-1.107]; p=0.027) and SIS1 (OR 1.101, IC [1.109-1.190]; p=0.015), after adjustment for age (Fig. 1). After simultaneous analysis in a multivariate model of the three questionnaires, we found that both a higher EDE-Q score and a higher SIS1 score were significant risk factors for HSDD (p=0.007 and p=0.034, respectively). Finally, we subdivided our patients into three groups: no Binge Eating (BE), sporadic BE and frequent BE, observing a significant positive association between frequency of BE and sexual distress, as assessed by FSDS-R total score (Fig. 2). in a population of women affected by FSD, ED traits could negatively affect sexual desire, representing a relevant risk factor for the clinical diagnosis of HSDD. Among all the investigated psychopathological aspects, the psychological alterations related to EDs seem to play a more pronounced effect on HSDD than other commonly accepted risk factors for sexual desire disorders, such as depression and increased inhibitory trait. In a clinical perspective, it would worth to investigate the relative change in FSD and ED after treatment for ED and vice versa. Work supported by industry: no. [ABSTRACT FROM AUTHOR]

Metabolic syndrome (MetS) is a diagnostic category which identifies subjects at high risk for diabetes and cardiovascular diseases, erectile dysfunction (ED) and male hypogonadism. However, MetS impact on male infertility has been poorly studied. We systematically evaluated possible associations between MetS and clinical characteristics in men with couple infertility. Out of 367 consecutive subjects, 351 men without genetic abnormalities were studied. MetS was defined according to the International Diabetes Federation&American Heart Association/National Heart,Lung, and Blood Institute classification. All men underwent physical, hormonal, seminal and scrotal ultrasound evaluation. Erectile and ejaculatory functions were assessed by International Index of Erectile Function-15 erectile function domain (IIEF-15-EFD) and Premature Ejaculation Diagnostic Tool (PEDT), respectively, while psychological symptoms by Middlesex Hospital Questionnaire. Out of 351 patients, 27 (7.7%) fulfilled MetS criteria. Among ultrasound features, in an age-adjusted logistic model, only testis inhomogeneity was significantly associated with increasing MetS factors (HR = 1.36 [ 1.09-1.70]; p < 0.01). In an age-adjusted model, MetS was associated with a stepwise decline in total testosterone (TT) (B = -1.25 ± 0.33; p < 0.0001), without a concomitant rise in gonadotropins. At univariate analysis, progressive motility and normal morphology were negatively related to the number of MetS components (both p < 0.0001), but when age and TT were introduced in a multivariate model, only sperm morphology retained a significant association (B = -1.418 ± 0.42; p = 0.001). The risk of ED (IIEF-15-EFD score <26) increased as a function of the number of MetS factors, even after adjusting for age and TT (HR = 1.45[1.08--1.95]; p < 0.02). No association between PEDT score and MetS was observed. Finally, after adjusting for age and TT, somatization and depressive symptoms were associated with increasing MetS components (B = 0.66 ± 0.03, p < 0.05; B = 0.69 ± 0.03, p < 0.02; respectively). In conclusion, in men with couple infertility, MetS is associated with hypogonadism, poor sperm morphology, testis ultrasound inhomogeneity, ED, somatization and depression. Recognizing MetS could help patients to improve not only fertility but also sexual and overall health. [ABSTRACT FROM AUTHOR]

While the association of Klinefelter’s Syndrome (KS) with infertility is well-known, very few investigations have evaluated the prevalence of sexual dysfunction in KS. The aim of the present study was to systematically analyse the prevalence of KS in a consecutive series of adult male patients consulting for sexual problems and to investigate its specific correlates. Among a consecutive series of 1386 men (mean age 48.9 ± 12.7 years old), 23 (1.7%) subjects with KS were found. Patients with KS were younger and more often hypogonadal when compared with the rest of the sample. Among patients with KS, five (22.7%) subjects reported severe erectile dysfunction, 14 (60.9%) hypoactive sexual desire (HSD), two (9.5%) premature and two (9.5%) delayed ejaculation. Only the association between KS and HSD was confirmed after adjustment for age [HR = 3.2 (1.37–7.5)], however, when patients with KS were compared with age, smoking habit, and testosterone matched controls, even the association between KS with HSD disappeared. In comparison to matched hypogonadal controls, subjects with KS had lower levels of education, a higher frequency of cryptorchidism and poorer pubertal progression. In conclusion, our results indicate that sexual dysfunction present in KS is not specifically associated with the syndrome but is caused by the underlying hypogonadal state. Further studies are needed to evaluate the efficacy of testosterone substitution in ameliorating the hypoactive sexual desire often reported in subjects with KS. [ABSTRACT FROM AUTHOR]

Clitoral Pulsatility Index (PI) evaluated by color Doppler ultrasound (CDU), reflecting vascular resistance, has been proposed as an objective method to assess sexual function. Significant positive associations were observed between clitoral PI and the MHQ scale exploring somatized anxiety symptoms (MHQ-S) and with BUT-B Global measure PSDI (Positive Symptom Distress Index). When evaluating uterine artery, a positive association was observed between uterine PI and BMI, WC, insulin, glycated hemoglobin, and HOMA-IR index. [Extracted from the article]

A nitric oxide (NO)-mediated relaxation of clitoris and distal vagina vascular bed leads to clitoris tumescence and vagina lubrification. Acethylcholine (Ach; 0.001-100 M) induced a concentration-dependent relaxation, which was significantly reduced by nitric oxide (NO)-synthase inhibitor L-NAME (0.1 mM) and by guanylate cyclase inhibitor ODQ (1 M). T treatment upregulated the mRNA expression of NO-mediated, RhoA/ROCK and adenosine pathway genes. [Extracted from the article]

Intracrinology is the science that studies how each peripheral organ, as the vagina, is able to produce intracrine hormones. The vagina produces a small and appropriate amount of both estrogens and androgens from a common inactive precursor, the dehydroepiandrosterone (DHEA), which usually mainly derives from the adrenal glands. Finally, the activation of androgen signaling was observed and assessed by the mRNA expression of STAMP2 after stimulation with DHEA and testosterone. [Extracted from the article]

A subgroup of sexually active patients treated for FSD (n = 81), divided into 4 different regimens (local non-hormonal treatment, n = 37; systemic transdermal T gel 300 mcg/day, n = 23; local estrogens (E) only, n = 12; T + local E, n = 9) was evaluated after 6-months therapy. At follow-up, T treatment was able to significantly increase clitoral peak systolic velocity (PSV) when compared to non-hormonal treatment (p<0.0001) and local E (p<0.0001). Similarly, patients treated with combined therapy (T+E) showed significantly higher FSFI Desire, Arousal, Lubrication and Total Scores compared to baseline (p=0.041; p=0.043; p=0.050; and p=0.028, respectively). [Extracted from the article]

Introduction: It has been hypothesized that leptin's modifications in Eating Disorders (EDs) aren't just a consequence of malnutrition, but they also represent a maintenance factor for pathological reward-related eating behaviours, such as dietary restraint and compensatory physical exercise, due to the role of leptin in the regulation of dopaminergic tone in brain reward circuits. Objectives: To evaluate the role of leptin in maintaining dietary restriction and compensatory exercise in subjects with Anorexia Nervosa (AN) and Bulimia Nervosa (BN). Methods: 56 patients were enrolled, 39 with AN and 17 with BN; 43 healthy controls (HCs) were also recruited. Blood leptin levels were measured and psychometric tests for the evaluation of general psychopathology (SCL-90-R) and of EDs specific pathological behaviours and psychopathology (EDE-Q) were administered. Results: Lower leptin levels were found in subjects withANand BN as compared with HCs. Leptin was negatively associated with the frequency of compensatory exercise, even when adjusting for age and BMI, but only in subjects with EDs. The moderated mediation models confirmed the role of leptin as a complete mediator for the relationship between low BMI and increased dietary restriction and compensatory exercise, but only for high levels of EDs specific psychopathology. Conclusions: These results suggest that for subjects with severe EDs psychopathology a low BMI maintains dietary restraint and compensatory exercise through a decrease in leptin levels, probably because of the role of leptin in reward circuits and due to the presence in EDs patients of an aberrant food-related reward that makes losing weight instead of feeding the desirable aim. [ABSTRACT FROM AUTHOR]

Current guidelines recommend the use of gonadotropin-releasing hormone agonists (GnRHas) as the treatment of choice to suppress puberty in adolescents with Gender Incongruence/Gender Dysphoria (GI/GD). After 6 months of treatment adolescents with GD reported significant lower levels of internalizing problems as well as a decrease of suicide risk and depressive symptoms (p< 0.05). [Extracted from the article]

Exercise and physical activity are recommended for either primary management or prevention of Metabolic syndrome (MetS), a cluster of metabolic and cardiovascular risk factors often associated to hypogonadism in men. PAS-staining fiber typing in SkM cross-sections confirmed a shift from type-I to type-II fibers in HFD, which was normalized by T. Moreover, T significantly increased the expression of both myogenic and muscle metabolism (insulin-dependent signaling, lipid turnover) markers. Conclusions Our results indicate that T could be useful to promote oxidative muscle metabolism altered by MetS, thus improving exercise performance. [Extracted from the article]

This study 1) investigated the steroidogenic genes mRNA expression in human vagina; 2) verified the ability of human vagina smooth muscle cells (hSMCs) to synthesize active androgens from precursor dehydroepiandrosterone (DHEA); 3) evaluated STAMP2 mRNA expression, as readout for androgen receptor stimulation. The main steroidogenic pathway mRNA analysis showed a higher expression of pro-androgenic enzymes (HSD3 1/ 2, HSD17 3/ 5), 5 -reductase isoforms and sulfo-transferase, both in hSMCs and in vaginal tissue, compared to the ovary. The LC-MS/MS analysis revealed that hSMCs DHEA treatment induced both androstenedione and testosterone production, although testosterone was produced at higher doses and longer incubation times. [Extracted from the article]

The most important pathway underlying the penile erection is the nonadrenergic/noncholinergic signalling, which through the release of nitric oxide (NO), leads to an intracellular increase of cyclic GMP (cGMP), the main secondary messenger mediating tumescence in the penis. Interestingly, both cGMP formation and degradation are affected by testosterone (T). In fact, beyond the well-known role of T in regulating sexual desire and NO release, recent experimental evidences from our group showed that T also regulates the expression of phosphodiesterase type 5 (PDE5), the hydrolytic enzyme involved in cGMP breakdown. This antithetic role of T seems to be the main way through which the peripheral hormonal regulation of penile erections occurs, allowing an important synchronization between erectile processes and sexual desire. Hence, erections are still possible in hypogonadal conditions where a decreased cGMP formation, because of impaired NO production, is counterbalanced by a reduced cGMP hydrolysis. The purpose of this review is to describe evidences about the peripheral role of T in regulating penile erection and to justify the importance to test T plasma levels in those patients with erectile dysfunction who do not respond to PDE5 inhibitors. [ABSTRACT FROM AUTHOR]

Oxytocin (OT) is a neurohypophysial hormone with unclear physiological functions in the male. Several previous studies indicated that OT might have a role in the ejaculatory process, stimulating sperm release from the epididymal storage. In this study we investigated on the presence and function of OT receptor (OTR) in rabbit and human epididymis. By using RT-PCR, Western and binding studies, we found that OTR gene and protein is expressed in the human epididymis and stimulates in vitro contractility. The immunolocalization of OTR suggests that the receptor is not only present in the smooth muscle cells of the human epididymis but also in the epithelial compartment. Experiments performed in rabbit epididymal epithelial (rEE) cells in culture indicate that OT induces the release of an other potent stimulator of epididymal contractility, endothelin-1 (ET-1), Blocking the ETA subtype of the ET-1 receptors, by using a specific antagonist (BQ-123), partially counteracts the contractile effect of OT, suggesting positive interactions between the two peptides in regulating epididymal contractility. Finally, to investigate whether an acute OT administration increases sperm release also in humans, we treated oligozoospermic patients with an intravenous bolus of OT (2.5 IU), just before sperm collection. In a small, single blind study, we found that OT almost doubled sperm retrieval when compared with vehicle administration. Our results indicate that OT might have physiological functions also in the male, controlling epididymal motility and sperm progression through the male genital tract. [Copyright &y& Elsevier]

Recently, a monophasic combined oral contraceptive (COC) containing 1.5 mg 17-beta estradiol (E2) and 2.5 mg nomegestrol acetate (NOMAC) has been developed with a 24/4 regimen. Our preliminary Results suggest that NOMAC/E2, differently from other COCs, does not negatively alter the vascular resistance of clitoral arteries. [Extracted from the article]