Measurement of PDE5 concentration in human serum: proof-of-concept and validation of methodology in control and prostate cancer patients.

PURPOSE: We aimed to investigate if the type 5 phosphodiesterase (PDE5), an enzyme with cardinal biological functions in sexual and cardiovascular health, can be detected and quantited in human serum. METHODS: Blood samples were collected from control male and female subjects. PDE5 levels were measured by a specific ELISA kit. ROC curves weighted for age and serum levels of PSA (male subjects), or age (female subjects) were used to identify the predictive ability in the detection of PCa. Sensitivity, specificity, PPV and NPV values were determined for cut-off value determined during ROC curve analysis. RESULTS: 41 control male subjects, 18 control female subjects, and 55 consecutive subjects, of which 25 were affected by benign prostatic hypertrophy (BPH) and 30 with histologically confirmed prostate cancer (PCa), were studied. PDE5 serum levels were detectable in all subjects (range: 5 to 65 ng/ml). Analysis by MANCOVA identified a significant difference in serum PDE5 between control subjects or hyperplasia patients and PCa patients. Marginal means of serum PDE5 concentrations showed a significant difference (p < 0.001). The ROC curve demonstrated that PDE5 serum levels can predict men with or without PCa, with 0.806 AUC value (p < 0.0001). Using a 12.705 ng/ml PDE5 serum cut-off yielded sensitivity, specificity, PPV, and NPV of 83.3%, 77.27%, 62.5%, and 91.1% in detecting men with histologically proven PCa, respectively. CONCLUSIONS: We demonstrated, for the first time, that PDE5 levels can be detected in human sera and that PCa patients have significantly higher PDE5 concentration compared to BPH patients or male and female controls. While serum PDE5 level measurement may open new research avenues, the clinical relevance of PDE5 levels in PCa patients deserves further investigation.

Psychosexological correlates of 372 women with vulvodynia, overactive pelvic floor, postcoital cystitis, and interstitial cystitis.

BACKGROUND: Among the plethora of urogynecological conditions possibly affecting women, some of them, less explored, have significant impacts on sexological and psychological health, with a mutual influence. AIM: The aim of this study was to investigate the sexological and psychological correlates of four urogynecological pathologies in a sample of women of childbearing age: overactive pelvic floor, vulvodynia, postcoital cystitis, and interstitial cystitis. Women cured of these conditions were also included, to assess the same aspects after the remission of physical symptoms. METHODS: We recruited 372 women with an average age of 33.5 years through an online platform shared by a popular forum for women with urogynecological pathologies between March and May 2021. The participants filled out a socio-anamnestic questionnaire and a set of psychometric tests. OUTCOMES: Participant data were collected by use of the Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, Toronto Alexithymia Scale-20, Female Sexual Function Index, and Orgasmometer-F, and the SPSS (Statistical Package for Social Sciences) v.26 was used for data analysis. RESULTS: Overactive pelvic floor was reported by 66.4% of the women, vulvodynia by 55%, postcoital cystitis by 58.8%, and interstitial cystitis by 8.3%, and these conditions were often comorbid with each other, with 9.4% and 7% of women reporting having suffered psychological and sexual abuse, respectively. The presence of past abuse was correlated with overactive pelvic floor (P < .05), vulvodynia (P < .01), and major depression (P < .01). Significantly more depression occurred in women with vulvodynia than in the other subgroups (P < .05), except for women with only an overactive pelvic floor. There was no difference between the subgroups in the occurrence of alexithymia, sexual function, and orgasm (P < .05). Interestingly, the prevalence of sexual dysfunction increased in cured women. CLINICAL IMPLICATIONS: The lack of significant differences, except for depression, between the pathological subgroups suggests a similar clinical and psychological relevance of the four pathologies studied. The persistence of sexual dysfunctions in cured women may be related to a residual dysfunctional relational modality with the partner. STRENGTHS AND LIMITATIONS: The evaluation of both psychological and sexological variables in a group of less-explored urogynecological conditions represents a strength of this study, while a lack of a face-to-face assessment could represent a limitation. CONCLUSION: The results of the present study should promote psychosexological interventions in women with these diseases, both during the pathological state and after remission.

Perceived intravaginal ejaculation latency time: The diagnosis of premature ejaculation among Vietnamese men.

INTRODUCTION: Premature ejaculation (PE) is a prevalent sexual dysfunction in men that greatly affects their quality of life. In PE, the duration of sexual performance is considered an important aspect. However, a self-estimated value of intravaginal ejaculation latency time (perceived IELT, PIELT) as a criterion for diagnosis has not been specified. AIM: This study aimed to determine the validity and a threshold value for PIELT in PE diagnosis. METHOD: In our cross-sectional study, we recruited 550 men from March 2019 to January 2020 and interviewed them regarding their general demographic characteristics, sexual habits, PIELT and completed a premature ejaculation diagnostic tool (PEDT) questionnaire. Eventually, a combination of a clinical diagnosis and PEDT score was used, in which those with PEDT ≥ 11 and diagnosed with possible PE were assigned to the final PE(+) group; those with PEDT score ≤ 8 and diagnosed with no PE were included in the final PE(-) group. RESULTS: Men PE(-) had more frequent sexual intercourse (9.74 ± 5.38 vs. 6.69 ± 5.38 episodes per month, p < 0.001) and had higher marriage rate (72.7% vs. 60.4%, p = 0.002) than PE(+) patients. No significant difference was noted regarding age, smoking habit, age of first sexual experience, and number of sexual partners between the two groups. The mean PIELT of control subjects and PE(+) patients were 11.69 ± 6.83 min and 2.01 ± 1.21 min, respectively. On receiver operating characteristic curve analysis, the cut-off value of PIELT of 3.75 min can be used to distinguish PE men (area under the curve = 0.982, sensitivity/specificity = 0.961/0.909), which means that men with a PIELT ≤ 3.5 min is suggestive of PE. CONCLUSION: The impact of PE is dramatic both from a social and a personal perspective. PE(+) patients married significantly less and have significantly lower sexual activity compared to a PE(-) population. Furthermore, a PIELT of ≤ 3.5 min predicts PE demonstrating the need to revise its taxonomy and definition.

The murder of the surgeon Antonio Parrozzani and the relationship between sexual disorders and paranoid thinking.

In this study we aimed to describe the relationship between sexual disorders and paranoid thinking describing the historical case of murder of the famous surgeon Antonio Parrozzani and the pathological personality of his murderer. Parrozzani was killed by Francesco Mancini, his patient in the past. Mancini was obsessed by his sexual problems due to hypothetical injuries after an inguinal hernia surgery, made by Parrozzani. Following treatment, the murderer likely lived his surgery as a traumatic event and developed a paranoid thinking against the surgeon, breaking out with the dramatic homicide. Parrozzani's case highlights the strong relationship between paranoia and sexuality, and likewise this relationship can be considered as a prodromic factor for a psychotic onset. Moreover, this case, supported by two psychiatric assessments of murderer, remembers once again the association between violence and paranoia. Therefore, clinicians should take into account the danger of the possible presence of paranoid obsession together with sexual problems, to prevent psychosis onset or violent acts related to paranoid delusions.

Effect of the new 75-mg orodispersible film of sildenafil on erection and sexual quality of life: insights from an observational study.

Background: The newly devised orodispersible film (ODF) of sildenafil is the first phosphodiesterase type 5 inhibitor (PDE5i) available in a 75-mg dose. This intermediate dose and the particular properties of the ODF formulation can improve the clinical management of erectile dysfunction (ED) patients. Aim: We investigated the effects of the sildenafil ODF 75-mg dose on both sexual quality of life and erectile function based on the results from an observational study in daily practice in Italy. Methods: This study was a post hoc analysis of results from an observational, real-life study carried out in ED patients at 6 treatment centers in Italy. All subjects were asked to take the prescribed dose of sildenafil ODF at inclusion (visit 1) and to return for a control visit (visit 2) to confirm or adapt the prescribed dose after a minimum of 4 weeks. An end of study control visit (visit 3) was performed after additional 4 weeks. Outcomes: Erectile function, assessed by the International Index of Erectile Function-Erectile Function (IIEF-EF) domain; sexual quality of life, measured using the sexual quality of life instrument for men (SQoL-M). Results: Among the 36 subjects initially recruited for the 75-mg dose, 5 patients dropped out of the study (2 at visit 2 and 3 at visit 3), none of whom due to treatment inefficacy or serious adverse events. At visit 2, the mean (SD) IIEF-EF scores significantly increased (∆ = 7.97 [4.71], P < 0.0001) as SQoL-M scores also did (∆ = 10.76 [10.46], P < 0.0001). At visit 3, IIEF-EF and SQoL-M scores were still significantly improved compared to baseline (∆ = 10.64 [7.01], P < 0.0001, and ∆ = 18.15 [12.32], P < 0.0001, respectively). By ANCOVA, we found no significant effects for age, BMI, previous use of PDE5i, presence of metabolic comorbidities, or smoking habits on study outcomes at both visits 2 and 3. Clinical implication: The new 75-mg ODF sildenafil formulation is a safe and effective treatment for ED, significantly improving both erectile function and sexual quality of life in patients undergoing treatment. Strengths and limitations: This is the first study assessing the efficacy of the sildenafil ODF 75-mg dose in a real-life setting. However, the small sample size, possible underlying cultural factors, and limited availability of clinically relevant data may have affected the reliability of our results. Conclusion: The use of the 75 mg ODF formulation for sildenafil represents an effective and safe novel treatment option for ED patients.

Genital Sensitivity and Perceived Orgasmic Intensity in Transgender Women With Gender Dysphoria After Gender-Affirming Surgery: A Pilot Study Comparing Pelvic Floor Evoked Somatosensory Potentials and Patient Subjective Experience.

BACKGROUND: The integrity of the neural pathways that link genital sensitive areas to the brain and the correlation with subjective sensations in transgender women with gender dysphoria after gender affirming surgery (GAS) have not been explored in detail and remain controversial, so far. AIM: To test with electrophysiology the integrity of the nervous paths after GAS, and to explore the relationship between genital sensitivity and self-perceived orgasmic intensity in transgender women after GAS. METHODS: Six patients who underwent GAS between 2016 and 2019 were enrolled in the study, and the evaluation of genital and pelvic neural pathways was performed. OUTCOMES: Genital sensory thresholds (at clitoral, vaginal, and anal sites) investigated by Somatosensory Evoked Potentials (SEP) and the intensity of orgasm (measured by a psychometric tool, the Orgasmometer) were combined to obtain an objective and subjective evaluation. RESULTS: SSEPs confirmed the integrity of the large diameter, dorsal column-lemniscus pathway subserving the genital area after GAS. Perceptual Threshold (PT) values were much lower at the neoclitoris compared to neovagina and anal sites. There was no correlation between Orgasmometer and SEP at anal and neovaginal level, while a trend was found at clitoral level. CLINICAL IMPLICATION: These findings could lead clinicians to a better understanding of postsurgical sexual life in transgender women in order to develop surgical techniques that could focus more on functional aspects of neovagina and neoclitoris. STRENGTHS & LIMITATIONS: Limitations: study very preliminary/exploratory; small number of patients; no long-term follow-up. Strengths: first assessment of sensory pelvic floor innervation in transgender women after GAS; use of objective methods; first attempt at correlating objectives findings to subjective experience of the sexual orgasm. CONCLUSIONS: Our evaluation showed that SSEPs is a good indicator of neural sensitivity, especially in neoclitoris, and that these measurements were consistent with the analysis of self-perceived orgasmic intensity. Canale D, Molinaro A, Marcocci C, et al. Genital Sensitivity and Perceived Orgasmic Intensity in Transgender Women With Gender Dysphoria After Gender-Affirming Surgery: A Pilot Study Comparing Pelvic Floor Evoked Somatosensory Potentials and Patient Subjective Experience. J Sex Med 2022;19:1479-1487.

MAPK activation drives male and female mouse teratocarcinomas from late primordial germ cells.

Germ cell tumors (GCTs) are rare tumors that can develop in both sexes, peaking in adolescents. To understand the mechanisms that underlie germ cell transformation, we established a GCT mouse model carrying a germ-cell-specific BRafV600E mutation with or without heterozygous Pten deletion. Both male and female mice developed monolateral teratocarcinomas containing embryonal carcinoma (EC) cells that showed an aggressive phenotype and metastatic ability. Germ cell transformation started in fetal gonads and progressed after birth leading to gonadal invasion. Early postnatal testes showed foci of tumor transformation, whereas ovaries showed increased number of follicles, multi-ovular follicles (MOFs) and scattered metaphase I oocytes containing follicles. Our results indicate that MAPK (herein referring to Erk1/2) overactivation in fetal germ cells of both sexes can expand their proliferative window leading to neoplastic transformation and metastatic behavior.

The Lost Penis Syndrome: A New Clinical Entity in Sexual Medicine.

INTRODUCTION: The "lost penis syndrome" (LPS) is a term often used in non-clinical settings to describe the subjective perception of the loss of cutaneous and proprioceptive feelings of the male organ during vaginal penetration. Although deserving clinical attention, this syndrome did not receive any consideration in the medical literature. Notwithstanding, it represents a relatively unexceptional condition among patients in sexual medicine clinics, and it is often reported together with other sexual dysfunctions, especially delayed ejaculation, anejaculation, male anorgasmia and inability to maintain a full erection. OBJECTIVES: To draft a new conceptual characterization of the LPS, defined as a lack of penile somesthetic sensations during sexual penetration due to various causes and leading to several sexual consequences in both partners. METHODS: Based on an extensive literature review and physiological assumptions, the mechanisms contributing to friction during penovaginal intercourse, and their correlation to LPS, have been explored, as well as other nonanatomical factors possibly contributing to the loss of penile sensations. RESULTS: Efficient penile erection and sensitivity, optimal vaginal lubrication and trophism contribute to penovaginal friction. Whenever one of these processes does not occur, loss of penile sensation defined as LPS can occur. Sociocultural, psychopathological and age-related (ie, couplepause) factors are also implicated in the etiology. Four types of LPS emerged from the literature review: anatomical and/or functional, behavioral, psychopathological and iatrogenic. According to the subtype, a wide variety of treatments can be employed, including PDE5i, testosterone replacement therapy and vaginal cosmetic surgery, as well as targeted therapy for concomitant sexual comorbidity. CONCLUSION: We held up the mirror on LPS as a clinically existing multifactorial entity and provided medical features and hypotheses contributing to or causing the occurrence of LPS. In the light of a sociocultural and scientific perspective, we proposed a description and categorization of this syndrome hypothesizing its usefulness in daily clinical practice. Colonnello E, Limoncin E, Ciocca G, et al. The Lost Penis Syndrome: A New Clinical Entity in Sexual Medicine. Sex Med Rev 2022;10:113-129.

Ultrasonic testicular size of 24,440 adult Vietnamese men and the correlation with age and hormonal profiles.

Testicular size is an important parameter to investigate male reproductive and sexual functions. However, diagnosis and treatments are hindered by the lack of country-specific standard values for testicular volume. We conducted the present retrospective chart review study on 24,440 men who sought consultation at Andrology and Sexual Medicine-Hanoi Medical University Hospital to provide a reference range of testicular volume and to determine the correlations between testicular volume, age and hormonal profiles. These men were classified into groups being healthy fathers, hypogonadal men, unexplained infertile men, men with unknown fertility, testicular pathologies and other andrological condition groups. Hypogonadal men and unexplained infertile men had significantly smaller testicular sizes compared with healthy fathers. The mean value of testicular volume of healthy subjects was 13.64 ± 3.44 ml (left testis: 13.94 ± 3.72 ml; right testis: 13.34 ± 3.61 ml; p < 0.001). Testicular size of Vietnamese men was negatively correlated with LH and FSH (Rho = -0.16 and -0.33, p < 0.001) and positively correlated with testosterone after adjusting for confounding factors. Testicular volume was independent of the subject's age and smoking habits.

Harm Reduction in Sexual Medicine.

INTRODUCTION: Strategies of harm reduction (HR) include policies and community-based measures aimed to reduce the risk of self-harm while continuing potentially hazardous behaviors, such as illegal drug, alcohol, and tobacco use. OBJECTIVES: To assess whether and to which extent strategies of HR could have beneficial, or harmful, effects on sexual and reproductive health, for general and at-risk populations. METHODS: A literature research was performed between July 2020 and January 2021, investigating the association between harm reduction strategies and sexual and reproductive health. RESULTS: HR strategies are mostly aimed at providing support to at-risk population, such as injection drug users or sex workers. Alcohol and drug use, smoking and high-risk sexual behaviors are among the main targets for HR strategies. Barriers to access, such as stigma, marginalization or lacking awareness, are often present as negative risk factors and require attention from professionals. Preventing sexually transmitted infections (STIs), early/unwanted pregnancies and violence are the most important results HR programs could provide for sexual and reproductive health. However, evidence is limited and often qualitative, rather than quantitative. CONCLUSION: HR strategies are important measures to improve sexual and reproductive health in at-risk populations. Increasing personal and social awareness is a key factor for the success of HR programs. A Sansone, E. Limoncin, E Colonnello, et al. Harm Reduction in Sexual Medicine. Sex Med Rev 2022;10:3-22.

The validity and reliability of the Turkish version of the 6-item female sexual function index (FSFI-6) and the relationship between climacturia and female sexual dysfunction.

This study aims to assess the validity and reliability of the Turkish version of the FSFI-6 questionnaire,an abbreviated version of FSFI-19,a common tool for evaluating female sexual function. The study included 120 female patients aged between 18-65 years who presented to the urology clinic between December 2019 and March 2020. The Turkish version of FSFI-6 was translated from the English version for validation. The abridged FSFI-6 questionnaire consists of questions 2, 4, 7, 11, 16, and 17 of the FSFI-19 form. We recorded the demographic data of the patients. All subjects filled out the FSFI-19 and FSFI-6 questionnaires. The patients were asked to fill out the questionnaires again after two weeks. The mean age of the subjects was 46.58 ± 9.89 years (28-63). The results of the reliability analysis indicated that the intraclass correlation coefficient of the total FSFI-6 score was 0.92 (weighted kappa coefficients of individual items, 0.868-0.975) and the Cronbach's alpha was 0.862. The validity analysis indicated that the mean total FSFI-6 score was strongly correlated with the mean FSFI-19 score (p < 0.001, r = 0.997). In the test-retest analysis,the kappa coefficient was calculated as 0.891. The FSFI-19 and FSFI-6 scores of the patients with (n = 52) and without climacturia (n = 68) were compared, and it was observed that the scores of the patients with climacturia were significantly lower than those without climacturia (p < 0.001). The abbreviated FSFI-6 questionnaire is a valuable tool for screening women with FSD. It can be used more extensively due to being short and easy to apply. Our results approve the Turkish version of the questionnaire as a valid and reliable tool for evaluating FSD.

Sempervirine inhibits RNA polymerase I transcription independently from p53 in tumor cells.

In the search of small molecules that can target MDM2/p53 pathway in testicular germ cell tumors (TGCTs), we identified sempervirine (2,3,4,13-tetrahydro-1H-benz[g]indolo[2,3-a]quinolizin-6-ium), an alkaloid of Gelsemium sempervirens, that has been previously proposed as an inhibitor of MDM2 that targets p53-wildtype (wt) tumor cells. We found that sempervirine not only affects cell growth of p53-wt cancer cells, but it is also active in p53-mutated and p53-null cells by triggering p53-dependent and independent pathways without affecting non-transformed cells. To understand which mechanism/s could be activated both in p53-wt and -null cells, we found that sempervirine induced nucleolar remodeling and nucleolar stress by reducing protein stability of RPA194, the catalytic subunit of RNA polymerase I, that led to rRNA synthesis inhibition and to MDM2 block. As shown for other cancer cell models, MDM2 inhibition by nucleolar stress downregulated E2F1 protein levels both in p53-wt and p53-null TGCT cells with the concomitant upregulation of unphosphorylated pRb. Finally, we show that sempervirine is able to enter the nucleus and accumulates within the nucleolus where it binds rRNA without causing DNA damage. Our results identify semperivirine as a novel rRNA synthesis inhibitor and indicate this drug as a non-genotoxic anticancer small molecule.

Lifestyles and sexuality in men and women: the gender perspective in sexual medicine.

Sexual health is strictly related with general health in both genders. In presence of a sexual dysfunction, the expert in sexual medicine aims to discover the specific weight of the physical and psychological factors can cause or con-cause the sexual problem. At the same time, a sexual dysfunction can represent a marker of the future development of a Non-communicable diseases (NCDss) as cardiovascular or metabolic diseases.In the evaluation phase, the sexual health specialist must focus on these aspects, focusing especially on the risk and protective factors that could impact on both male and female sexuality.This article presents a review of researches concerning healthy and unhealthy lifestyles and their contribute in the development of sexual quality of life in a gender-dependent manner.Among the unhealthy lifestyle, obesity contributes mostly to the development of sexual dysfunctions, due to its negative impact on cardiovascular and metabolic function. Tobacco smoking, alcohol - substance abuse and chronic stress lead to the development of sexual dysfunction in a med-long term.In order to guarantee a satisfying sexual quality of life, sexual health specialists have the responsibility to guide the patient through the adoption of healthy lifestyles, such as avoiding drugs, smoke and excessive alcohol, practicing a regular physical activity, following a balanced diet and use stress-management strategies, even before proposing both pharmaco- and/or psychotherapies.

Regulation of Kit Expression in Early Mouse Embryos and ES Cells.

Kit is a growth factor receptor that regulates proliferation and/or survival of many embryonic and postnatal stem cell types. When mutated, it can induce malignant transformation of the host cells. To dissect the Kit role in the control of ESC pluripotency, we studied its expression during early mouse embryogenesis and during the process of ESC derivation from inner cell mass (ICM) cells. We followed the in vitro development of early mouse embryos obtained from transgenic mice carrying Kit promoter regions fused to EGFP (Kit-EGFP) and found that they initiate EGFP expression at morula stage. EGFP expression is then maintained in the blastocyst, within the ICM, and its levels increase when cultured in the presence of MAPK and GSK3ß inhibitors (2i) plus LIF compared with the LIF-only condition. Kit-EGFP ESCs showed nonhomogeneous EGFP expression pattern when cultured in LIF condition, but they upregulated EGFP expression, as well as that of Sox2, Nanog, Prdm14, when shifted to 2i-LIF culture. Similarly, primordial germ cells (PGCs) in the process of embryonic germ cell (EGC) conversion showed enhanced EGFP expression in 2i-LIF. Kit expression was affected by manipulating Sox2 levels in ESCs. Chromatin immunoprecipitation experiments confirmed that Sox2 binds Kit regulatory regions containing Sox2 consensus sequences. Finally, Kit constitutive activation induced by the D814Y mutation increased ESC proliferation and cloning efficiency in vitro and in teratoma assays in vivo. Our results identify Kit as a pluripotency-responsive gene and suggest a role for Kit in the regulation of ESC proliferation. Stem Cells 2019;37:332-344.

EDEUS, a Real-Life Study on the Users of Phosphodiesterase Type 5 Inhibitors: Prevalence, Perceptions, and Health Care-Seeking Behavior Among European Men With a Focus on 2nd-Generation Avanafil.

INTRODUCTION: Erectile dysfunction (ED) is a multidimensional disorder with an estimated prevalence of 1% to 10% in men younger than 40 years and up to 100% in men in their 70s and 80s. AIM: To evaluate the real-life characteristics and unmet needs of men with ED, its impact on well-being, and treatment rates across Europe. METHODS: Adult men in Belgium, France, Germany, Italy, Poland, Portugal, and Spain were invited to participate in the survey. Men who did not use at least a drug for sexual health in the past 3 months, had cancer or spinal cord injuries, and/or underwent non-nerve-sparing radical prostatectomy were excluded. MAIN OUTCOME MEASURES: The 15-item International Index of Erectile Function (IIEF-15) with study-specific, self-constructed questions was used. RESULTS: Overall, 940 subjects (age = 46.2 ± 13.4 years) were considered. Subjects (n = 778) using on-demand phosphodiesterase type 5 inhibitors (PDE5is) were designated "performers" (60%) without a formal ED diagnosis or "patients" with a medical diagnosis. Patients were older than performers, with more self-reported comorbidities; patients used a higher PDE5i dosage and purchased it from official pharmacies more often than performers did. Of avanafil users (n = 39), no differences in total IIEF or subdomain scores were observed after adjusting for confounders. However, avanafil users less often declared its use without an ED diagnosis and a physician prescription. Overall, the latter condition was associated with higher PDE5i-related satisfaction. CONCLUSION: The survey shows 2 different attitudes toward ED and PDE5i use: for recreational use and without a medical prescription or with a formal diagnosis and medical prescription. Avanafil, a 2nd-generation PDE5i with a good balance between efficacy and tolerability profile, is more frequently prescribed by doctors than self-prescribed compared with other PDE5is. Because the major challenge is to decrease the high dropout of 1st-generation PDE5is, further studies will be needed to clarify this topic. Corona G, Maggi M, Jannini EA. EDEUS, a Real-Life Study on the Users of Phosphodiesterase Type 5 Inhibitors: Prevalence, Perceptions, and Health Care-Seeking Behavior Among European Men With a Focus on 2nd-Generation Avanafil. Sex Med 2018;6:15-23.

SM = SM: The Interface of Systems Medicine and Sexual Medicine for Facing Non-Communicable Diseases in a Gender-Dependent Manner.

INTRODUCTION: Complex non-communicable diseases (NCDs), including cancer, cardiovascular disease, obesity, diabetes, and chronic respiratory disorders, are major causes of morbidity and mortality globally. The complexity of NCDs requires innovative, integrated, and interdisciplinary approaches for diagnosis, treatment, and prevention by adopting the new paradigm called systems medicine. A growing body of evidence suggests that sexual dysfunction in general and erectile and lubrication dysfunctions in particular are, in a sex-dependent manner, efficient predictors of overall systemic well-being. However, the relation between systems medicine and sexual medicine is not well defined. AIM: To demonstrate that in combating the major NCDs, sexual health can be used as a surrogate marker of systemic health and can facilitate the diagnosis, treatment, and prevention of NCDs. METHODS: A comprehensive review of peer-reviewed publications on the topic was performed through a PubMed search. MAIN OUTCOME MEASURES: Because there is a strong biological basis for the developmental origins of health and disease not only in the early phases of development but also later in life, the identification of appropriate biomarkers is essential for monitoring these timelines and trajectories for better understanding NCD processes, risk stratification for NCD intervention, and prevention. RESULTS: In this review, I propose a novel approach in which sexual medicine can be used as a new tool to understand and manage NCDs and as a marker of systemic health. Moreover, the multipronged application of systems medicine to pathophysiologic changes leading to sexual dysfunction might sustain the growth of a young science such as sexual medicine. CONCLUSION: This multilevel approach has the potential to suggest novel avenues for the comprehensive management of NCDs and sexual dysfunction in a sex-dependent manner. Jannini EA. SM = SM: The Interface of Systems Medicine and Sexual Medicine for Facing Non-Communicable Diseases in a Gender-Dependent Manner. Sex Med Rev 2017;5:349-364.

Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome.

Expression of type 5 phosphodiesterase (PDE5), a cGMP-specific hydrolytic enzyme, is frequently altered in human cancer, but its specific role in tumorigenesis remains controversial. Herein, by analyzing a cohort of 69 patients affected by glioblastoma multiforme (GBM) who underwent chemo- and radiotherapy after surgical resection of the tumor, we found that PDE5 was strongly expressed in cancer cells in about 50% of the patients. Retrospective analysis indicated that high PDE5 expression in GBM cells significantly correlated with longer overall survival of patients. Furthermore, silencing of endogenous PDE5 by short hairpin lentiviral transduction (sh-PDE5) in the T98G GBM cell line induced activation of an invasive phenotype. Similarly, pharmacological inhibition of PDE5 activity strongly enhanced cell motility and invasiveness in T98G cells. This invasive phenotype was accompanied by increased secretion of metallo-proteinase 2 (MMP-2) and activation of protein kinase G (PKG). Moreover, PDE5 silencing markedly enhanced DNA damage repair and cell survival following irradiation. The enhanced radio-resistance of sh-PDE5 GBM cells was mediated by an increase of poly(ADP-ribosyl)ation (PARylation) of cellular proteins and could be counteracted by poly(ADP-ribose) polymerase (PARP) inhibitors. Conversely, PDE5 overexpression in PDE5-negative U87G cells significantly reduced MMP-2 secretion, inhibited their invasive potential and interfered with DNA damage repair and cell survival following irradiation. These studies identify PDE5 as a favorable prognostic marker for GBM, which negatively affects cell invasiveness and survival to ionizing radiation. Moreover, our work highlights the therapeutic potential of targeting PKG and/or PARP activity in this currently incurable subset of brain cancers.

Episode-like pulse testosterone supplementation induces tumor senescence and growth arrest down-modulating androgen receptor through modulation of p-ERK1/2, pARser81 and CDK1 signaling: biological implications for men treated with testosterone replacement therapy.

Despite the growing body of knowledge showing that testosterone (T) may not significantly affect tumor progression in hypogonadal patients treated for prostate cancer (Pca), the use of this hormone in this population still remains controversial. The effects of continuous or pulsed T stimulation were tested in vitro and in vivo on androgen-sensitive Pca cell lines in order to assess the differential biological properties of these two treatment modalities. Pulsed T treatment resulted in a greater inhibition than continuous T supplementation of tumor growth in vitro and in vivo. The effects of pulsed T treatment on tumor growth inhibition, G0/G1 cell cycle arrest, and tumor senescence was more pronounced than those obtained upon continuous T treatments. Mechanistic studies revealed that G0/G1 arrest and tumor senescence upon pulsed T treatment were associated with a marked decrease in cyclin D1, c-Myc and SKp2, CDK4 and p-Rb levels and upregulation of p27 and p-ERK1/2. Pulsed, but not continuous, T supplementation decreased the expression levels of AR, p-ARser81 and CDK1 in both cellular models. The in vitro results were confirmed in an in vivo xenografts, providing evidence of a greater inhibitory activity of pulsed supraphysiological T supplementation than continuous treatment, both in terms of tumor volume and decreased AR, p-ARser81, PSA and CDK1 staining. The rapid cycling from hypogonadal to physiological or supra-physiological T intraprostatic concentrations results in cytostatic and senescence effects in preclinical models of androgen-sensitive Pca. Our preclinical evidence provides relevant new insights in the biology of Pca response to pulsed T supplementation.

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.

The International Society for Sexual Medicine's Process of Care for the Assessment and Management of Testosterone Deficiency in Adult Men.

INTRODUCTION: In 2014, the International Society for Sexual Medicine (ISSM) convened a panel of experts to develop an evidence-based process of care for the diagnosis and management of testosterone deficiency (TD) in adult men. The panel considered the definition, epidemiology, etiology, physiologic effects, diagnosis, assessment and treatment of TD. It also considered the treatment of TD in special populations and commented on contemporary controversies about testosterone replacement therapy, cardiovascular risk and prostate cancer. AIM: The aim was to develop clearly worded, practical, evidenced-based recommendations for the diagnosis and treatment of diagnosis and management of TD for clinicians without expertise in endocrinology, such as physicians in family medicine and general urology practice. METHOD: A comprehensive literature review was performed, followed by a structured, 3-day panel meeting and 6-month panel consultation process using electronic communication. The final guideline was compiled from reports by individual panel members on areas reflecting their special expertise, and then agreed by all through an iterative process. RESULTS: This article contains the report of the ISSM TD Process of Care Committee. It offers a definition of TD and recommendations for assessment and treatment in different populations. Finally, best practice treatment recommendations are presented to guide clinicians, both familiar and unfamiliar with TD. CONCLUSION: Development of a process of care is an evolutionary process that continually reviews data and incorporates the best new research. We expect that ongoing research will lead to new insights into the pathophysiology of TD, as well as new, efficacious and safe treatments. We recommend that this process of care be reevaluated and updated by the ISSM in 4 years.