The regulatory effect of sex steroids on the RhoA/ROCK pathway in the rat distal vagina.

BACKGROUND: Sex steroids have been demonstrated as important modulators of vaginal function. The RhoA/ROCK calcium-sensitizing pathway plays a role in genital smooth muscle contractile mechanism, but its regulation has never been elucidated. AIM: This study investigated the sex steroid regulation of the vaginal smooth muscle RhoA/ROCK pathway using a validated animal model. METHODS: Ovariectomized (OVX) Sprague-Dawley rats were treated with 17ß-estradiol (E2), testosterone (T), and T with letrozole (T + L) and compared with intact animals. Contractility studies were performed to test the effect of the ROCK inhibitor Y-27632 and the nitric oxide (NO) synthase inhibitor L-NAME. In vaginal tissues, ROCK1 immunolocalization was investigated; mRNA expression was analyzed by semiquantitative reverse transcriptase-polymerase chain reaction; and RhoA membrane translocation was evaluated by Western blot. Finally, rat vaginal smooth muscle cells (rvSMCs) were isolated from the distal vagina of intact and OVX animals, and quantification of the RhoA inhibitory protein RhoGDI was performed after stimulation with NO donor sodium nitroprusside, with or without administration of the soluble guanylate cyclase inhibitor ODQ or PRKG1 inhibitor KT5823. OUTCOMES: Androgens are critical in inhibiting the RhoA/ROCK pathway of the smooth muscle compartment in the distal vagina. RESULTS: ROCK1 was immunolocalized in the smooth muscle bundles and blood vessel wall of the vagina, with weak positivity detected in the epithelium. Y-27632 induced a dose-dependent relaxation of noradrenaline precontracted vaginal strips, decreased by OVX and restored by E2, while T and T + L decreased it below the OVX level. In Western blot analysis, when compared with control, OVX significantly induced RhoA activation, as revealed by its membrane translocation, with T reverting it at a level significantly lower than in controls. This effect was not exerted by E2. Abolishing NO formation via L-NAME increased Y-27632 responsiveness in the OVX + T group; L-NAME had partial effects in controls while not modulating Y-27632 responsiveness in the OVX and OVX + E2 groups. Finally, stimulation of rvSMCs from control animals with sodium nitroprusside significantly increased RhoGDI protein expression, counteracted by ODQ and partially by KT5823 incubation; no effect was observed in rvSMCs from OVX rats. CLINICAL IMPLICATIONS: Androgens, by inhibiting the RhoA/ROCK pathway, could positively contribute to vaginal smooth muscle relaxation, favoring sexual intercourse. STRENGTHS AND LIMITATIONS: This study describes the role of androgens in maintaining vaginal well-being. The absence of a sham-operated animal group and the use of the only intact animal as control represented a limitation to the study.

Sexual Dysfunction as a Harbinger of Cardiovascular Disease in Postmenopausal Women: How Far Are We?

BACKGROUND: Female sexual dysfunction (FSD) affects 40-50% of women in the general population, resulting from the interaction among organic, psychological, sociocultural and relational factors; differently from men, in women definitive clinical evidence suggesting a connection between cardiovascular (CV) diseases (CVDs) and female sexual function is still lacking. AIM: To focus on the current scientific support for an association between CV diseases and/or risk factors and FSD, focused primarily on postmenopausal women. METHODS: This is a narrative review based on an extensive literature search of peer-reviewed publications on the associations between CV diseases and/or risk factors and FSD and their underlying mechanisms, which was performed using the PubMed database. OUTCOMES: We present a summary of the evidence from clinical and preclinical studies and discuss the possible mechanisms providing the pathophysiologic bases of vasculogenic FSD. RESULTS: Growing evidence shows that female sexual function, especially arousal, is significantly affected by genital vascular impairment, which can lead to FSD. For many cardiometabolic risk factors and diseases, such as hypertension, diabetes, dyslipidemia and metabolic syndrome, an adverse impact on endothelial function as well as an association with FSD have been recognized. In this scenario, similarly to penile Doppler blood flow studies in men, clitoral Doppler ultrasound can represent an innovative and useful tool to early reveal the presence of CV risk factors and sexual dysfunction. Notably, although the prevalence of CVDs as well as of FSD increases as a function of menopause and aging, middle-aged women have shown a higher prevalence of distressing sexual problems than older and younger women. CLINICAL IMPLICATIONS: It becomes clinically relevant to assess particularly postmenopausal women for FSD and CVDs, since both disorders still remain underdiagnosed and sub-optimally untreated. Clitoral Doppler ultrasound could represent a useful technique to diagnose the presence of underlying CVD, which along with risk factors could predict sexual dysfunction in women. STRENGTHS & LIMITATIONS: This review focuses on a very important and innovative topic, providing a context for describing, elaborating and evaluating the relevant theory that sexual dysfunction could be a harbinger for CVDs also in women. However, its narrative nature as well as the lack of specifically designed studies to assess a definitive association between FSD and CVDs represent the principle limitations of this paper. CONCLUSION: Postmenopausal women, particularly those in the middle-age range, should be assessed for CV risk factors and FSD, so that both CVDs and sexual problems do not persist unnoticed. Cipriani S, Simon JA. Sexual Dysfunction as a Harbinger of Cardiovascular Disease in Postmenopausal Women: How Far Are We? J Sex Med 2022;19:1321-1332.

Physical Activity and Female Sexual Dysfunction: A Lot Helps, But Not Too Much.

BACKGROUND: Research on the relationship between physical activity (PA) and female sexual dysfunction (FSD) is lacking. AIM: To investigate the clinical, psychological, and sexual correlates of PA in women with FSD. METHODS: 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. OUTCOMES: 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, Female Sexual Distress Scale-Revised, Body Uneasiness Test, and Middlesex Hospital Questionnaire. RESULTS: At multivariate analysis, women engaging in PA (67.4%, n = 217) scored significantly higher in several Female Sexual Function Index domains - including desire, arousal and lubrication - 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. Mediation analysis demonstrated that the negative association between PA and HSDD was partly mediated by body image concerns (Body Uneasiness Test Global severity index), psychopathological symptoms (Middlesex Hospital Questionnaire total score) and sexual distress (Female Sexual Distress Scale-Revised score). These latter 2 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 and histrionic/hysterical symptoms), even compared to a sedentary lifestyle. CLINICAL IMPLICATIONS: Women consulting for FSD may gain benefits on desire, arousal, lubrication and sex-related distress from regular PA; however, physicians should remain alert to the downsides of excessive exercise. STRENGTHS & LIMITATIONS: The main strength lies in the novelty of the findings. The main limitations are the cross-sectional nature, the clinical setting, the small sample size of the different PA groups, and the use of self-reported instruments for the evaluation of PA. CONCLUSION: 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. Maseroli E, Rastrelli G, Di Stasi V, et al. Physical Activity and Female Sexual Dysfunction: A Lot Helps, But Not Too Much. J Sex Med 2021;18:1217-1229.

Neuroprotective Effects of Testosterone in the Hypothalamus of an Animal Model of Metabolic Syndrome.

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.

Obesity and hormonal contraception: an overview and a clinician's practical guide.

BACKGROUND: The growing prevalence of obesity among the fertile female population poses a considerable problem to contraceptive providers. Obese women, who are more at risk for venous thromboembolism and cardiovascular events due to their condition, might be at an even higher risk of developing thromboembolic events when on medical contraception. Combined hormonal contraceptives might be less effective in obese women and may lead to unacceptable metabolic side effects for this population. In addition, the lack of safety data for weight loss drugs and the higher risk for complications during and after pregnancy require a close surveillance of the fertility status of obese patients. OBJECTIVE: The aim of this narrative review is to summarize the available medical contraceptive options and to give the readers a practical guidance for a wise contraceptive choice with regards to obesity. METHODS: A general literature review of peer-reviewed publications on the topic "obesity and contraception" was performed using the PubMed database. RESULTS: Nowadays, there are many useful tools that help clinicians in choosing among the wide range of therapeutic possibilities, such as the World Health Organization (WHO) Medical Eligibility Criteria for contraceptive use. Furthermore, the great diversity of hormonal contraceptive formulations (combined hormonal formulations; progestin-only methods) and active substances (different estrogens and progestins) allow physicians to tailor therapies to patients' clinical peculiarities. CONCLUSION: Long-acting reversible contraceptives [progestin-only implants, levonorgestrel-intra-uterine devices (IUDs) and copper IUDs] and progestin-only methods in general are excellent options for many categories of patients, including obese ones. LEVEL OF EVIDENCE: V, narrative review.

Impact of Metabolically Healthy Obesity in Patients with Andrological Problems.

BACKGROUND: Although the pathogenic role of metabolically complicated obesity (MCO) in erectile dysfunction (ED), major adverse cardiovascular events (MACE), and male infertility has been widely studied, that of metabolically healthy obesity (MHO) has been poorly investigated. AIM: To assess the role of MHO in the pathogenesis of ED, prediction of MACE, and male reproductive health. METHODS: A consecutive series of 4,945 men (mean age, 50.5 ± 13.5 years) with sexual dysfunction (SD) (cohort 1) and 231 male partners of infertile couples (mean age, 37.9 ± 9.1 years; cohort 2) were studied. A subset of men with SD (n = 1,687) was longitudinally investigated to evaluate MACE. All patients underwent clinical, biochemical, erectile function, and flaccid penile color Doppler ultrasound (PCDU) assessment. Infertile men also underwent scrotal and transrectal ultrasound; semen analysis, including interleukin (IL-) 8; and prostatitis-like symptom assessment. MHO was defined as body mass index >30 kg/m2 with high-density lipoprotein cholesterol level >40 mg/dL and absence of diabetes or hypertension. The rest of the obesity sample was defined as MCO. MHO or MCO were compared with the rest of the sample, defined as normal weight (NW) individuals. OUTCOMES: Clinical, biochemical, erectile, and PCDU assessment in MHO, MCO and NW men in both cohorts; longitudinal MACE incidence assessment in cohort 1. RESULTS: In cohort 1, 816 men (16.5%) were obese, 181 (3.7%) were MHO, and 635 (12.8%) were MCO. In cohort 2, 68 men (28.4%) were obese, 19 (8.2%) were MHO, and 49 (21.2%) were MCO. After adjusting for confounders, in both samples, the men with MHO and MCO had lower total testosterone levels and worse PCDU parameters compared with the NW men. However, only MCO men had worse erectile function compared with NW men. In the longitudinal study, both MHO and MCO men independently had a higher incidence of MACE compared with NW men (P < .05 for both). In cohort 2, MHO and MCO men had a larger prostate volume, and MCO men also had higher ultrasound and biochemical (IL-8) features of prostatic inflammation compared with NW men, but no differences in prostatitis-like symptoms or seminal parameters. CLINICAL IMPLICATIONS: MHO men should be considered at high cardiovascular risk like MCO men and followed-up for erectile dysfunction and prostate abnormalities overtime. STRENGTHS & LIMITATIONS: The study simultaneously examined several endpoints with validated instruments within 2 different male populations, 1 with SD and 1 with infertility. As for limitations, there is no consensus in the scientific community regarding the definition of MHO, and the results are derived from patients with SD or infertility, which could have different characteristics than the general male population. CONCLUSION: MHO is associated with subclinical ED, increased cardiovascular risk, and prostate enlargement. Lotti F, Rastrelli G, Maseroli E, et al. Impact of Metabolically Healthy Obesity in Patients with Andrological Problems. J Sex Med 2019:16;821-832.

Sex hormone-binding globulin is associated with androgen deficiency features independently of total testosterone.

OBJECTIVE: It is recognized that total testosterone (TT) does not sufficiently describe androgen status when sex hormone-binding globulin (SHBG) is altered. However, in humans, evidence supporting the existence of a hypogonadism due to low T bioactivity is scanty. The aim of the study was to assess whether changes in SHBG levels, independently of TT, are associated with subjective and objective androgen-dependent parameters. DESIGN: Cross-sectional observation. PATIENTS: Two thousand six hundred and twenty-two men (aged 51.1 ± 13.5 years) attending a Sexual Medicine and Andrology Outpatient Clinic for sexual dysfunctions. MEASUREMENTS: All patients underwent a standardized diagnostic protocol before starting any treatment. Clinical and biochemical parameters have been collected. Higher ANDROTEST score has been used as a comprehensive marker of more severe hypogonadal symptoms. Prostate-specific antigen (PSA) and haematocrit have been used as objective surrogate markers of T bioactivity. RESULTS: After adjusting for TT and lifestyle, SHBG showed a significant positive association with ANDROTEST score (B = 0.79 [0.61; 0.96], P < .0001). Conversely, higher SHBG, independently of TT, was negatively related to PSA (B = -0.86 [-0.83; -0.89]; P < .0001) and haematocrit (B = -0.64 [-0.88; -0.40]; P < .0001), after adjustment for the aforementioned confounders along with age and body mass index. Furthermore, a relationship between SHBG and lipids or blood pressure was found, with lower SHBG levels associated with a worse metabolic profile, independently of TT. CONCLUSIONS: Higher SHBG, independently of TT, is associated with either subjective or objective androgen deficiency features. This indicates that besides a hypogonadism due to an impaired T production, a hypogonadism due to a lower biological activity of T does exist.

Outcome of Medical and Psychosexual Interventions for Vaginismus: A Systematic Review and Meta-Analysis.

INTRODUCTION: Although vaginismus is a condition with a great impact on psychosexual well-being, the evidence on the efficacy of interventions is lacking. AIM: To review all information on vaginismus treatment, including data from randomized clinical trials (RCTs) and observational studies. METHODS: A systematic search was conducted of MEDLINE, EMBASE, PsycINFO, and ClinicalTrials.gov. 2 Independent meta-analyses of RCTs and observational studies were performed. For RCTs, only those having no treatment as the comparator were considered eligible. MAIN OUTCOME MEASURE: The primary outcome was the success rate (number of successes/total sample) in the completion of sexual intercourse. RESULTS: 43 Observational studies (n = 1,660) and 3 RCTs (n = 264) were included in the final analyses, respectively. In the meta-analysis of RCTs, the use of psychological interventions showed a trend toward a significantly better result vs waiting list control (OR 10.27 [95% CI 0.79-133.5], P = .075). The combination of the results obtained from the observational studies showed that treating vaginismus is associated with the completion of sexual penetrative intercourse in 79% of cases, independently of the therapy used (success rate 0.79 [0.74-0.83]). When only moderate- or strong-quality studies were considered, the success rate was 0.82 (0.73-0.89). As for the different definitions of vaginismus, studies with unconsummated marriage as the inclusion criterion showed the worst success rate (0.68). The origin of vaginismus (primary, secondary, or both), its duration, the mean age of the participants, the involvement of the partner in the intervention, or the geographic setting did not exert a significant effect on the outcome. Studies enrolling women with unconsummated marriage showed a significantly worse success rate. CLINICAL IMPLICATIONS: No approach is superior to the others in allowing the achievement of penetrative intercourse in women with vaginismus. STRENGTH & LIMITATIONS: Only studies specifically enrolling patients with vaginismus were selected, and analyses were performed on an intention-to-treat approach. The main limitations are the small number of trials in the meta-analysis of RCTs and the lack of a comparison group in the meta-analysis of observational studies, which cannot rule out a placebo effect. Due to the limited evidence available, great caution is required in the interpretation of results. Further well-designed trials, with more appropriate outcomes than penetrative sex, are required. CONCLUSION: The meta-analysis of RCTs documented a trend toward higher efficacy of active treatment vs controls, whereas the meta-analysis of observational studies indicated that women with vaginismus benefit from a range of treatments in almost 80% of cases. Maseroli E, Scavello I, Rastrelli G, et al. Outcome of Medical and Psychosexual Interventions for Vaginismus: A Systematic Review and Meta-Analysis. J Sex Med 2018;15:1752-1764.

Psychosexual Correlates of Unwanted Sexual Experiences in Women Consulting for Female Sexual Dysfunction According to Their Timing Across the Life Span.

BACKGROUND: Comparative data on the psychopathologic and sexual correlates of unwanted sexual experiences (USEs) occurring during childhood, adolescence, or adult life are lacking. AIM: To investigate the prevalence of USEs in a setting of female sexual dysfunction (FSD) and to examine whether they are associated with different psychosexual parameters depending on the timing of occurrence. METHODS: A consecutive series of 200 heterosexual women attending our clinic for FSD was consecutively recruited. MAIN OUTCOME MEASURE: Patients underwent a structured interview and completed the Female Sexual Function Index, the Middlesex Hospital Questionnaire, the Female Sexual Distress Scale-Revised, the Body Uneasiness Test, and the Childhood Experience of Care and Abuse questionnaire. USEs were classified as occurring in adult life (≥17), adolescence (<17 and ≥14), or childhood (<14 years). RESULTS: 47 women (23.5%) reported USEs, occurring in childhood, adolescence, and adult life in 38.3% (n = 18), 31.9% (n = 15), and 29.8% (n = 14) of cases, respectively. We observed an association between history of lifetime USEs and indexes of psychopathology, specifically diagnosis of psychiatric diseases, use of psychiatric medications, and anxiety symptoms (Middlesex Hospital Questionnaire free-floating anxiety score). USEs were associated with lower orgasm ability (Female Sexual Function Index orgasm domain), higher sexually related distress levels (Female Sexual Distress Scale-Revised total score), and higher body image concerns (Body Uneasiness Test) including depersonalization symptoms. Notably, women exposed to USEs in adolescence reported a stronger impairment of arousal, orgasm, and satisfaction domains and higher sexual distress when compared to women without a history of USEs or reporting USEs in childhood. Women exposed to USEs in childhood exhibited higher body image concerns and depersonalization symptoms when compared to those not reporting USEs. CLINICAL IMPLICATIONS: USEs should be investigated in women consulting for FSD because patients who had USEs may require unique strategies to optimize the diagnostic and therapeutic work-up of their sexual symptoms. STRENGTH & LIMITATIONS: Our main contribution is that we addressed the different impacts of USEs depending on their timing across the life span. However, the cross-sectional nature of the study does not allow determination of the cause-and-effect nature of the associations, and the selectivity of the sample (women consulting for FSD) limits the generalizability of the results. CONCLUSION: The negative outcomes of USEs vary according to their timing of occurrence: adolescence appears as the most sensitive temporal window for USEs to exert their deleterious effects on female sexuality, whereas childhood USEs are more tightly related to a severe body uneasiness in adult life. Maseroli M, Scavello I, Campone B, et al. Psychosexual Correlates of Unwanted Sexual Experiences in Women Consulting for Female Sexual Dysfunction According to Their Timing Across the Life Span. J Sex Med 2018;15:1739-1751.

Psychobiological Correlates of Vaginismus: An Exploratory Analysis.

BACKGROUND: Evidence concerning the determinants of vaginismus (V), in particular medical conditions, is inconclusive. AIM: To investigate, in a cohort of subjects consulting for female sexual dysfunction, whether there is a difference in medical and psychosocial parameters between women with V and women with other sexual complaints. METHODS: A series of 255 women attending our clinic for female sexual dysfunction was consecutively recruited. V was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. Lifelong and acquired V cases were included. OUTCOMES: Patients underwent a structured interview and physical, gynecologic, laboratory, and clitoral ultrasound examinations; they completed the Female Sexual Function Index (FSFI), the Middlesex Hospital Questionnaire, the Female Sexual Distress Scale-Revised (FSDS), and the Body Uneasiness Test. RESULTS: V was diagnosed in 20 patients (7.8%). Women with V were significantly younger than the rest of the sample (P < .05). No differences were found for traditional risk factors such as a history of sexual abuse, relational parameters, or gynecologic diseases or for newly investigated parameters (ie, neurologic, hormonal, and metabolic alterations). Women with V showed significantly higher histrionic-hysterical symptoms and traits (as detected by MHQ-H score; P < .05) compared with subjects with other sexual complaints. When the scores of all MHQ subscales were simultaneously introduced in a logistic model, the association between V and MHQ-H score was confirmed (P = .013). Women with V also showed higher FSFI pain and FSDS total scores, even after adjusting for age (P < .05). In an age-adjusted model, FSDS total score increased as a function of the years of duration of V (P = .032) but not as a function of its severity. All observations were confirmed in a case-control study (ratio = 1:3). CLINICAL IMPLICATIONS: Our data demonstrate that some novel contributors of V should be investigated, namely histrionic-hysterical traits. This psychological comorbidity could offer valuable insights for intervention and managing complications. STRENGTHS AND LIMITATIONS: This is the first study to assess the role of many metabolic and hormonal parameters as potential determinants of V. The main limitation is its exploratory and cross-sectional nature; our data need to be confirmed in larger, more systematic analyses. CONCLUSION: V was associated with histrionic-hysterical traits, FSFI pain domain, and sex-related distress. A history of abuse, relational parameters, gynecologic diseases, and hormonal and metabolic alterations do not seem to play a role in the development of V. Maseroli E, Scavello I, Cipriani S, et al. Psychobiological Correlates of Vaginismus: An Exploratory Analysis. J Sex Med 2017;14:1392-1402.

High Triglycerides Predicts Arteriogenic Erectile Dysfunction and Major Adverse Cardiovascular Events in Subjects With Sexual Dysfunction.

INTRODUCTION: The atherogenic role of triglycerides (TG) remains controversial. The aim of the present study is to analyze the contribution of TG in the pathogenesis of erectile dysfunction (ED) and to verify the value of elevated TG in predicting major adverse cardiovascular events (MACE). METHODS: An unselected series of 3,990 men attending our outpatient clinic for sexual dysfunction was retrospectively studied. A subset of this sample (n = 1,687) was enrolled in a longitudinal study. MAIN OUTCOME MEASURES: Several clinical, biochemical, and instrumental (penile color Doppler ultrasound; PCDU) factors were evaluated. RESULTS: Among the patients studied, after adjustment for confounders, higher TG levels were associated with arteriogenic ED and a higher risk of clinical and biochemical hypogonadism. Conversely, no association between TG and other sexual dysfunctions was observed. When pathological PCDU parameters-including flaccid acceleration (<1.17 m/sec(2)) or dynamic peak systolic velocity (PSV <35 cm/sec)-were considered, the negative association between impaired penile flow and higher TG levels was confirmed, even when subjects taking lipid-lowering drugs or those with diabetes were excluded from the analysis (OR = 6.343 [1.243;32.362], P = .026 and 3.576 [1.104;11.578]; P = .34 for impaired acceleration and PSV, respectively). Similarly, when the same adjusted models were applied, TG levels were associated with a higher risk of hypogonadism, independently of the definition criteria (OR = 2.892 [1.643;5.410], P < .0001 and 4.853 [1.965;11.990]; P = .001 for total T <12 and 8 nM, respectively). In the longitudinal study, after adjusting for confounders, elevated TG levels (upper quartile: 162-1686 mg/dL) were independently associated with a higher incidence of MACE (HR = 2.469 [1.019;5.981]; P = .045), when compared to the rest of the sample. CONCLUSION: Our data suggest an association between elevated TG and arteriogenic ED and its cardiovascular (CV) risk stratification. Whether the use of TG lowering drugs might improve ED and its associated CV risk must be confirmed through specific trials.

The Role of Somatic Symptoms in Sexual Medicine: Somatization as Important Contextual Factor in Male Sexual Dysfunction.

INTRODUCTION: An important feature of somatic symptom disorder is the subjective perception of the physical symptoms and its maladaptive interpretation. Considering that psychological distress is often expressed through somatic symptoms, it is possible that they underlie at least a part of the symptoms in subjects complaining of sexual dysfunction. Nevertheless, studies on the impact of somatoform disorders in sexual dysfunction are scanty. AIM: To define the psychological, relational, and organic correlates of somatic symptoms in a large sample of patients complaining of sexual problems. METHODS: A consecutive series of 2833 men (mean age 50.2 ± 13.5 years) was retrospectively studied. MAIN OUTCOME MEASURES: Somatic symptoms were assessed using the "somatized anxiety symptoms" subscale of the Middlesex Hospital Questionnaire (MHQ-S). Several clinical, biochemical, psychological, and relational parameters were studied. Patients were interviewed with the previously validated Structured Interview on Erectile Dysfunction (SIEDY), and ANDROTEST (a structured interview for the screening of hypogonadism in patients with sexual dysfunction). RESULTS: Among the 2833 patients studied, subjects scoring higher on somatic symptoms were older, more obese, reporting unhealthy lifestyle (current smoking, alcohol consumption), and a lower education (all P < .05). Moreover, they reported a general impairment of their sexuality more often, including erectile problems (spontaneous or sexual-related), low sexual desire, decreased frequency of intercourse, and perceived reduction of ejaculate volume (all P < .005). Interestingly, we observed a significant association between MHQ-S scoring with a reduced testosterone level and hypogonadism symptoms (both P < .05). Finally, we found a significant association between somatic symptoms and both SIEDY Scales 1 (organic domain of ED) and 3 (intrapsychic domain of ED) (both P < .0001). CONCLUSION: The present study demonstrates that the presence of somatic symptoms can represent an important contextual factor in the determination of or in the exacerbation of male sexual dysfunction. High levels of somatic symptoms in subjects with sexual dysfunction can be related to the sexual symptom itself. The consequences of this pattern have great clinical relevance in a sexual medicine setting, considering their severe impact on sexuality.

Cardiometabolic Risk and Female Sexuality: Focus on Clitoral Vascular Resistance.

INTRODUCTION: The relation between sexual and cardiovascular health in women is not well defined. Clitoral color Doppler ultrasound (CDU) with assessment of the pulsatility index (PI), reflecting resistance to blood flow, has been proposed as an objective measurement of sexual functioning. AIM: To investigate associations between clitoral PI and cardiometabolic risk factors, sexual and intrapsychic parameters, and self-perception of body image. METHODS: Seventy-one adult heterosexual women in a stable relationship attending our clinic for sexual dysfunction were consecutively recruited. MAIN OUTCOME MEASURES: Patients underwent physical, laboratory, and clitoral color Doppler ultrasound examinations and completed the Female Sexual Function Index, the Middlesex Hospital Questionnaire, and the Body Uneasiness Test (BUT). RESULTS: Clitoral PI was positively correlated with body mass index (r = 0.441, P < .0001), waist circumference (r = 0.474, P < .0001), glycemia (r = 0.300, P = .029), insulin (r = 0.628, P = .002), homeostatic model assessment index (r = 0.605, P = .005), triglycerides (r = 0.340, P = .011), total cholesterol (r = 0.346, P = .010), and low-density lipoprotein cholesterol (r = 0.334, P = .016). All relations, with the exception of glycemia, retained statistical significance after adjusting for age, smoking habit, and years since menopause (P < .0001 for body mass index, waist circumference, and triglycerides; P < .05 for all other associations). Analysis of covariance, after adjusting for confounders, showed that women with obesity or metabolic syndrome (MetS) showed significantly higher PI values (obesity: F = 17.79, P = .001; MetS: F = 7.37, P = .019). In particular, a stepwise increase of PI was found as a function of increasing MetS components (ß = 0.434, P = .007). Clitoral PI was negatively associated with Female Sexual Function Index arousal (ß = -0.321, P = .014) and satisfaction (ß = -0.289, P = .026) scores and positively associated with Middlesex Hospital Questionnaire somatized anxiety symptoms, even after adjusting for age, smoking habit, years since menopause, and current use of psychiatric medication (ß = 0.354, P = .011). A positive association also was observed between PI and the BUT positive symptom distress index (ß = 0.322, P = .039) and BUT for dislike of the womb, genitals, and breast (ß = 0.538, P < .0001; ß = 0.642, P < .0001; ß = 0.549, P < .0001, respectively). After introducing waist circumference as another covariate, the associations between clitoral PI and the BUT positive symptom distress index and BUT dislike of the womb, genitals, and breast retained statistical significance (P = .038 for positive symptom distress index; P < .0001 for dislike of womb, genitals, and breast). CONCLUSION: Clitoral vascular resistance is positively associated with MetS (in particular insulin resistance), decreased sexual arousal, body image concerns, and increased somatized anxiety symptoms. Further studies are needed to establish whether treatment of metabolic abnormalities might improve clitoral color Doppler ultrasound indices and sexual outcomes.

Prevalence of endocrine and metabolic disorders in subjects with erectile dysfunction: a comparative study.

INTRODUCTION: Alterations of gonadal, thyroid, and pituitary hormones, along with metabolic disorders, might be involved in causing erectile dysfunction (ED). AIM: The prevalence of endocrine abnormalities in two different cohorts from the general and the symptomatic populations of Florence was compared. METHODS: The first group is a general population sample derived from a Florentine spin-off of the European Male Aging Study (EMAS cohort; n = 202); the second group is a series of n = 3,847 patients attending our clinic for ED (UNIFI cohort). RESULTS: Both primary and secondary hypogonadism were more often observed in the UNIFI than in the EMAS cohort (2.8 vs. 0%; P < 0.05 and 18.9 vs. 8%; P < 0.001, respectively). However, only the second association retained statistical significance after adjusting for age. Compensated hypogonadism was more common in the EMAS cohort (4.4 vs. 8.1%; P < 0.05). No statistically significant difference in the prevalence of overt thyroid disorders was observed. Conversely, subclinical hyperthyroidism was more prevalent in the EMAS cohort (2 vs. 4.1%, P < 0.05). No significant difference in the prevalence of hyperprolactinemia was detected, while the prevalence of hypoprolactinemia was significantly higher in the UNIFI than in the EMAS cohort (28.2% vs. 17.8%, P = 0.001), even after the adjustment for age, BMI, and testosterone (P = 0.001). Central obesity (waist ≥102 cm), impaired fasting glucose (IFG), and type 2 diabetes mellitus (T2DM) were more often detected in UNIFI patients (31.7 vs. 22.8%, P < 0.05; 44.5 vs. 33.3%, P < 0.05; 20.1% vs. 1.0%, P < 0.001 in the UNIFI and EMAS cohort, respectively), even after adjusting for age. In contrast, the prevalence of overweight and obesity did not differ between the two groups. CONCLUSION: T2DM, IFG, central obesity, secondary hypogonadism, and hypoprolactinemia are more frequent in subjects consulting for ED than in the general population of the same geographic area. Our data suggest that these conditions could play a central role in determining consultation for ED.

Why couple infertility is historically a female-driven problem?

BACKGROUND: The history of studies in the field of infertility represents a chapter of great interest in gender issues. OBJECTIVES: This paper aims to delve deep into the historical roots of the aspect of gender inequality related to couple infertility, with a journey back in time, from classical antiquity to the contemporary age, reporting junctions and metaphors linked to particular historical moments as well as to cultural and religious constructs. METHODS: This is a narrative review based on an extensive literature search of publications regarding the role of women in couple infertility over the centuries. RESULTS: Rarely in the ancient world, male infertility was taken into consideration, and the sources deal with it mainly indirectly. This attitude of "blaming" the woman for the lack of children had, in fact, strong social implications, which only the scientific research of recent years has managed to bring back into the context of a more egalitarian approach. CONCLUSIONS: In the "journey" narrated in this article, the reader starts from the responsibility of couple infertility attributed exclusively to women in some ancient societies, whose central role was determined by their ability to procreate, going up to the medicalization of infertility in the contemporary age, which contributed to sharing with men this participation in the impossibility of having children.

An evaluation of bremelanotide injection for the treatment of hypoactive sexual desire disorder.

INTRODUCTION: Female sexual response implies a deep intertwining between psychosocial and neurobiological mediators. Regulation of central melanocortin signaling may enhance sexual desire. In premenopausal women with hypoactive sexual desire disorder (HSDD), melanocortin receptor agonist bremelanotide (Vyleesi) has been hypothesized to trigger excitatory brain pathways. AREAS COVERED: Hereby we summarize bremelanotide's proposed mechanism of action, pharmacokinetics, efficacy and safety data derived from clinical trials. A literature search of peer-reviewed publications on the current evidence on the pharmacotherapy with bremelanotide was performed using the PubMed database. EXPERT OPINION: Bremelanotide appears to be moderately safe and well-tolerated; the most common adverse reaction is nausea (40%). Although data from clinical trials demonstrated a significant change in validated questionnaires, the overall clinical benefit appears to be modest. However, these results should be interpreted in the light of the dramatic challenges in conducting well-designed clinical trials for female sexual dysfunction, due to the significant placebo effect of pharmacotherapy, and the frequent use of outcome measures that are likely to be highly susceptible to expectation biases, such as long periods of recall of sexual and emotional response.

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

BACKGROUND: Transrectal ultrasound (TRUS) parameters are not standardized, especially in men of reproductive age. Hence, the European Academy of Andrology (EAA) promoted a multicenter study to assess the TRUS characteristics of healthy-fertile men (HFM) to establish normative parameters. OBJECTIVES: To report and discuss the prostate and seminal vesicles (SV) reference ranges and characteristics in HFM and their associations with clinical, seminal, biochemical parameters. METHODS: 188 men (35.6 ± 6.0 years) from a cohort of 248 HFM were studied, evaluating, on the same day, clinical, biochemical, seminal, TRUS parameters following Standard Operating Procedures. RESULTS: TRUS reference ranges and characteristics of the prostate and SV of HFM are reported herein. The mean PV was ∼25 ml. PV lower and upper limits were 15 and 35 ml, defining prostate hypotrophy and enlargement, respectively. PV was positively associated with age, waistline, current smoking (but not with T levels), seminal volume (and negatively with seminal pH), prostate inhomogeneity, macrocalcifications, calcification size and prostate arterial parameters, SV volume before and after ejaculation, deferential and epididymal size. Prostate calcifications and inhomogeneity were frequent, while midline prostatic cysts were rare and small. Ejaculatory duct abnormalities were absent. Periprostatic venous plexus size was positively associated with prostate calcifications, SV volume and arterial peak systolic velocity. Lower and upper limits of SV anterior-posterior diameter after ejaculation were 6 and 16 mm, defining SV hypotrophy or dilation, respectively. SV total volume before ejaculation and delta SV total volume (DSTV) positively correlated with ejaculate volume, and DSTV correlated positively with sperm progressive motility. SV total volume after ejaculation was associated negatively with SV ejection fraction and positively with distal ampullas size. SV US abnormalities were rare. No association between TRUS and time to pregnancy, number of children or history of miscarriage was observed. CONCLUSIONS: The present findings will help in better understanding male infertility pathophysiology and the meaning of specific TRUS findings.

The European Academy of Andrology (EAA) ultrasound study on healthy, fertile men: An overview on male genital tract ultrasound reference ranges.

BACKGROUND: So far, male genital tract color-Doppler ultrasound (MGT-CDUS) was not standardized. Recently, the European Academy of Andrology (EAA) published the results of a multicenter study assessing the CDUS characteristics of healthy-fertile men (HFM) to obtain normative parameters. OBJECTIVES: To report the EAA US study (i) standard operating procedures (SOPs) for assessing MGT-CDUS, (ii) main MGT-CDUS normative parameters, and (iii) compare the EAA and previously published "normal" CDUS values. METHODS: A cohort of 248 HFM (35.3 ± 5.9 years) was studied, evaluating MGT-CDUS before and after ejaculation following SOPs. RESULTS: SOPs for MGT-CDUS assessment are summarized here. All subjects underwent scrotal CDUS and 188 men underwent transrectal ultrasound before and after ejaculation. The main CDUS reference ranges and characteristics of the HFM-MGT are reported here. The mean testicular volume was ∼17 mL. The lower limit for right and left testis was 12 and 11 mL, defining testicular hypotrophy. The upper limit for epididymal head, body, tail, and vas deferens was 11.5, 5, 6, and 4.5 mm, respectively. Testicular and epididymal arterial reference ranges are reported. The EAA varicocoele classification is reported. CDUS-varicocoele was detected in ∼37% of men. Prostate mean volume was ∼25 mL, while lower and upper limits were 15 and 35 mL, defining hypotrophy and enlargement, respectively. Prostate arterial reference ranges are reported. Prostate calcifications and inhomogeneity were frequent; midline prostatic cysts were rare and small. Ejaculatory duct abnormalities were absent. The upper limit for periprostatic venous plexus was 4.5 mm. Lower and upper limits of seminal vesicles (SV) anterior-posterior diameter were 6 and 16 mm, defining hypotrophy or dilation, respectively. Seminal vesicle volume and ejection fraction reference ranges are reported. SV-US abnormalities were rare. Deferential ampullas upper limit was 6 mm. A discussion on the EAA and previously published "normal" CDUS values is reported here. CONCLUSIONS: The EAA findings will help in reproductive and general male health management.

SHBG as a Marker of NAFLD and Metabolic Impairments in Women Referred for Oligomenorrhea and/or Hirsutism and in Women With Sexual Dysfunction.

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<0.0001) that therefore appeared as a candidate hallmark for pathologic NAFLD-LFS. The ROC analysis showed a significant accuracy (81.1%, C.I.69.1-93.0, p <0.0001) for SHBG in identifying women with a pathological NAFLD-LFS. In particular, a SHBG 33.4 nmol/l was recognized as the best threshold, with a sensitivity of 73.3% and a specificity of 70.7%. In order to validate this SHBG as a marker of metabolic impairment possible related with the presence of NAFLD, we tested this threshold in cohort 2. FSD women with SHBG <33.4 nmol/l had worse metabolic parameters than women with SHBG ≥33.4 nmol/l and a significantly higher NAFLD-LFS even after adjusting for confounders (B=4.18 [2.05; 6.31], p=0.001). In conclusion, this study provides a new evidence in the diagnostic process of NAFLD, showing that the measurement of SHBG, which is routinely assessed in the workup of women referred for possible PCOS, could identify women at higher metabolic risk, thus detecting those who may deserve further targeted diagnostic assessment.

Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients.

BACKGROUND: The pandemic of new severe acute respiratory syndrome (SARS) due to coronavirus (CoV) 2 (SARS-CoV-2) has stressed the importance of effective diagnostic and prognostic biomarkers of clinical worsening and mortality. Epidemiological data showing a differential impact of SARS-CoV-2 infection on women and men have suggested a potential role for testosterone (T) in determining gender disparity in the SARS-CoV-2 clinical outcomes. OBJECTIVES: To estimate the association between T level and SARS-CoV-2 clinical outcomes (defined as conditions requiring transfer to higher or lower intensity of care or death) in a cohort of patients admitted in the respiratory intensive care unit (RICU). MATERIALS AND METHODS: A consecutive series of 31 male patients affected by SARS-CoV-2 pneumonia and recovered in the respiratory intensive care unit (RICU) of the "Carlo Poma" Hospital in Mantua were analyzed. Several biochemical risk factors (ie, blood count and leukocyte formula, C-reactive protein (CRP), procalcitonin (PCT), lactate dehydrogenase (LDH), ferritin, D-dimer, fibrinogen, interleukin 6 (IL-6)) as well as total testosterone (TT), calculated free T (cFT), sex hormone-binding globulin (SHBG), and luteinizing hormone (LH) were determined. RESULTS: Lower TT and cFT were found in the transferred to ICU/deceased in RICU group vs groups of patients transferred to IM or maintained in the RICU in stable condition. Both TT and cFT showed a negative significant correlation with biochemical risk factors (ie, the neutrophil count, LDH, and PCT) but a positive association with the lymphocyte count. Likewise, TT was also negatively associated with CRP and ferritin levels. A steep increase in both ICU transfer and mortality risk was observed in men with TT < 5 nmol/L or cFT < 100 pmol/L. DISCUSSION AND CONCLUSION: Our study demonstrates for the first time that lower baseline levels of TT and cFT levels predict poor prognosis and mortality in SARS-CoV-2-infected men admitted to RICU.