Early traumatic experiences are linked to hypersexual behavior and erectile dysfunction in men through the mediation of body uneasiness and general psychopathology.

BACKGROUND: Childhood traumatic experiences have been associated with hypersexuality and sexual dysfunctions. However, the mediators of the interactions between these variables should be clarified in men. AIM: This study aimed to investigate the interaction of early traumatic experiences, psychopathology, and sexuality with respect to erectile dysfunction (ED) and hypersexual behavior. The hypothesized model expected that traumatic experiences would be associated with hypersexual behavior and reduced sexual functioning through the mediation of body uneasiness and psychological distress. METHODS: The study was cross-sectional and observational. A total of 317 men were enrolled. Male patients with a primary complaint of ED and an indication for psychiatry referral represented the clinical sample (n = 116; mean ± SD age, 42.82 ± 16.89 years). Clinical classification was assessed with the Structured Interview on Erectile Dysfunction. The second sample (n = 201, 30.82 ± 11.94 years) was recruited from the general population. All participants were administered the following questionnaires: Brief Symptom Inventory, Childhood Trauma Questionnaire-Short Form, Hypersexual Behavior Inventory, Body Uneasiness Test-A, and 5-item International Index of Erectile Function. OUTCOMES: Psychopathology and sexual functioning were assessed by a dimensional approach, and a multivariate model was computed by structural equation model analysis. RESULTS: When compared with the sample from the general population, the clinical sample exhibited a higher prevalence of early traumatic experiences, as measured by scores on the Childhood Trauma Questionnaire-Short Form (45.08 ± 14.25 vs 39.03 ± 10.22, F = 17.63, P < .001), and a higher tendency to engage in hypersexual behaviors (34.63 ± 13.55 vs 30.79 ± 12.44, F = 6.97, P < .01). Structural equation model analysis showed excellent fit indices indicating that early traumatic experiences predicted hypersexual behaviors and ED through the exacerbating mediating effect of body uneasiness and psychopathology. CLINICAL IMPLICATIONS: Clinicians should not limit their attention to the behavioral level when assessing sexual dysfunction in men; rather, they should also consider the complex psychopathologic consequences of childhood trauma. Integrated treatments that address the potential presence of childhood trauma with its wider psychological correlates (eg, emotion dysregulation, body uneasiness) might improve treatment response. STRENGTHS AND LIMITATIONS: The study reports novel data on the relationship among childhood maltreatment, male sexuality, and psychopathologic mediators with a dimensional assessment. However, the assessment was cross-sectional, and causality was mainly derived from previous studies. CONCLUSION: The present study enriches the current literature, strengthening the hypothesis that childhood traumatic experiences significantly shape development and sexuality. Body uneasiness and psychopathology can both tax sexual functioning, as assessed by erectile functioning or hypersexuality.

What Women Want? The State of the Art regarding the Treatment of Young Women with Hypoactive Sexual Desire Disorder.

BACKGROUND: Hypoactive sexual desire disorder (HSDD) in premenopausal women involves biological, psychological, and social aspects. In the European Society for Sexual Medicine meeting in Rotterdam in February 2023, several leading experts in the field discussed the multifaceted nature of this disorder and the state of the art regarding treatment at a round table. This review reflects the information discussed at this event and further discusses current controversies. SUMMARY: HSDD is the most prevalent female-estimated sexual disorder reported by 28% of the 40% premenopausal women with sexual dysfunction. Flibanserin and bremelanotide are the only approved medications to treat HSDD in the USA, and none are approved in Europe. Lybrido, Lybridos, and Lorexys are under development. There are several psychological factors with impact in sexual desire, including depression and sexual abuse. Feminine sexual scripts, the pleasure gap, and structural inequalities also affect sexual desire. Evidence strongly supports the value of combining medical and psychological approaches in the treatment of HSDD, but there is ongoing controversy regarding the pharmacological treatment of young women with HSDD. However, some women seem open and would like to have access to drug treatment. KEY MESSAGES: The treatment of HSDD in young women requires a mixed treatment approach that addresses the disorder's complexity. Despite clinicians seeming to be divided between using pharmacological and/or psychosocial approaches, some women might respond better to one type of intervention over the others. This calls for the development of tools that assess the best approach for each person, including their will and informed choice.

Sperm Chromatin Dispersion Test Detects Sperm DNA Fragmentation Mainly Associated with Unviable Spermatozoa and Underestimates the Values with Respect to TUNEL Assay.

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

Internalized transphobia predicts worse longitudinal trend of body uneasiness in transgender persons treated with gender affirming hormone therapy: a 1-year follow-up study.

BACKGROUND: Given the relationship between interiorized stigma and body image, it could be hypothesized that high levels of internalized transphobia (IT) might predict higher levels of body uneasiness in subjects with gender dysphoria (GD) and worse improvement of body image after gender affirming hormone therapy (GAHT). AIM: We sought to evaluate the relationship between IT and body uneasiness in subjects with GD and the role of IT in moderating the improvement of body image after GAHT. METHODS: In total, 200 individuals with GD performed the baseline assessment; 99 were re-evaluated 12 months after starting GAHT. At baseline participants were evaluated through a face-to-face interview and filled self-administered questionnaires to evaluate GD (Utrecht Gender Dysphoria Scale [UGDS]), IT attitudes (Attitudes Toward Transgendered Individuals [ATTI] Scale), body uneasiness (Body Uneasiness Test, part A [BUT-A]), and general psychopathology (Symptom Checklist 90-Revised [SCL 90-R]). The same questionnaires, except ATTI, were readministered at follow-ups. OUTCOMES: Outcomes were based on measures of the associations between IT and baseline characteristics of the sample, the longitudinal trends of GD, body uneasiness, and general psychopathology; and IT as a moderator of the longitudinal trend of body uneasiness. RESULTS: At baseline, IT correlated with lower level of education, higher GD, and more severe body uneasiness. Longitudinal analyses showed significant improvements in GD, body uneasiness, and general psychopathology during GAHT. Moderation analysis confirmed that participants with more transphobic attitudes showed less improvement after GAHT with regard to body uneasiness (bTime*ATTI = -.002, P = .040). The Johnson-Neyman technique revealed that no significant improvement in body uneasiness was found for participants with ATTI scores lower than 71.14. CLINICAL IMPLICATIONS: The presence of IT should be investigated in subjects with GD who require gender affirming treatments to provide specific interventions aimed at targeting this dimension. STRENGTHS AND LIMITATIONS: Strengths of this study include the mixed cross-sectional and longitudinal design and the dimensional evaluation of the investigated constructs. Limitations include the small sample size and the limited follow-up. Furthermore, the effects of gender affirming surgery were not evaluated. CONCLUSION: The association of IT with both baseline body uneasinessand the longitudinal course of this dimension highlighted the clinical significance of body uneasiness and the importance of making continuous efforts to improve education and information to fight societal stigmas.

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.

Cryopreservation of Human Spermatozoa: Functional, Molecular and Clinical Aspects.

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

Effects of Benzo[a]pyrene on Human Sperm Functions: An In Vitro Study.

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

Defining the Molecular Mechanisms of the Relaxant Action of Adiponectin on Murine Gastric Fundus Smooth Muscle: Potential Translational Perspectives on Eating Disorder Management.

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

Are Endogenous Androgens Linked to Female Sexual Function? A Systemic Review and Meta-Analysis.

BACKGROUND: 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. AIM: To answer the question: is there an association between endogenous levels of androgens and sexual function in women? METHODS: 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. OUTCOMES: 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). RESULTS: The meta-analysis on total T included 34 studies involving 3,268 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. Age showed a negative relationship with the overall outcome. No differences were found when stratifying the studies according to menopausal status, type of menopause, age at menopause, use of hormonal replacement therapy, relationship status, method for T measurement, phase of the menstrual cycle or use of hormonal contraception. 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. CLINICAL IMPLICATIONS: Endogenous androgens show a moderate association with a better sexual function in women; however, the role of psychological, relational and other hormonal factors should not be overlooked. STRENGTHS & LIMITATIONS: This represents the first attempt at meta-analyzing data available on the topic. A significant publication bias was found for total T. CONCLUSION: There appears to be a moderate association between total T and sexual desire/global sexual function, which is confirmed, although weak, in studies employing liquid chromatography-mass spectrometry (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. Maseroli E and Vignozzi L. Are Endogenous Androgens Linked to Female Sexual Function? A Systemic Review and Meta-Analysis. J Sex Med 2022;19:553-568.

Avoidant Attachment Style Moderates the Recovery of Healthy Sexuality in Women With Anorexia Nervosa Treated With Enhanced Cognitive Behavior Therapy (CBT-E): A 2-Year Follow-Up Study.

BACKGROUND: Insecure Attachment style has been associated with interpersonal problems in persons with Anorexia Nervosa (AN), and it might moderate the recovery of healthy sexuality in these subjects. AIM: The aim of the present 2-year follow-up study was to evaluate the role of insecure attachment style as a moderator of the recovery of healthy sexuality in women with AN. METHODS: 63 Italian women with AN treated with a multidisciplinary approach including Enhanced Cognitive Behavior Therapy were evaluated by means of a clinical interview and self-administered questionnaires. Individual psychotherapy sessions were administered by experienced psychotherapists over the course of at least 40 weeks (median number of sessions = 43, range: 38-50); trained dieticians provided personalized nutritional counselling to facilitate weight recovery. The assessment was performed at baseline (T0) and after 1 (T1) and 2 (T2) years. OUTCOMES: The administered questionnaires investigated general psychopathology (SCL-90-R), eating disorder-specific psychopathology (EDE-Q), female sexuality (FSFI) and adult attachment style (ECR). RESULTS: At baseline, avoidant attachment style was associated with all domains of sexual dysfunction. Longitudinal analysis showed a significant decrease in both eating disorder-specific psychopathology and sexual dysfunctions at follow-up evaluations. However, only 45% of remitted subjects also recovered healthy sexuality: these women reported significantly lower avoidance scores than those who only recovered from AN. Moderation analysis indicated that sexual desire did not increase in participants with higher levels of avoidant attachment. CLINICAL IMPLICATIONS: These novel findings highlighted the importance of the assessment of adult attachment in the clinical setting, for better characterization and treatment of persons suffering from AN. STRENGTHS & LIMITATIONS: The long follow-up duration, the multidisciplinary nature of the treatment, and the novelty of the topic were major strengths of the study, whereas the limited sample size and the absence of biological data were the main limitations. CONCLUSION: This study highlighted the crucial role of avoidant attachment in the relationship between AN and sexual dysfunctions, underlining the importance of integrating treatments with attachment-focused interventions. Cassioli E, Rossi E, Vizzotto C, et al. Avoidant Attachment Style Moderates the Recovery of Healthy Sexuality in Women With Anorexia Nervosa Treated With Enhanced Cognitive Behavior Therapy (CBT-E): A 2-Year Follow-Up Study. J Sex Med 2022;19:347-355.

Psychological Wellbeing and Perceived Social Acceptance in Gender Diverse Individuals.

BACKGROUND: Over the last few years, the gender binary has been questioned, highlighting the existence of gender diverse people, who identify as neither (exclusively) male nor female. AIM: The present study evaluated the possible differences in terms of psychological wellbeing between binary and gender diverse individuals, as well as the role of perceived social acceptance and religious fundamentalism as possible mediators of psychopathology in gender diverse people. Furthermore, the diversity of gender-affirming hormonal treatment requests according to gender identification was investigated. METHODS: A sample of 563 transgender people aged 18-70 was enrolled (n = 264 assigned female at birth, AFAB and n = 299 assigned male at birth, AMAB), all individuals referring to several Italian gender clinics. A subdivision of the study population based on the gender identity visual analog scale (GI-VAS) median was performed, in order to distinguish between gender diverse and binary transgender individuals. Moreover, a linear regression analysis was performed entering logarithmically transformed GI-VAS (Log GI-VAS) into the models with psychometric scales. OUTCOMES: Psychometric and sociodemographic data, as well as information regarding requests for gender-affirming treatments, were extrapolated from the clinical interviews conducted during the first referral. RESULTS: Gender diverse individuals showed significantly less intense gender dysphoria and higher levels of depression and anxiety compared to binary ones; accordingly, a less binary gender identity correlated with higher levels of depression and anxiety and lower levels of gender dysphoria. The depressive symptomatology in gender diverse people was partially mediated by perceived discrimination and humiliation. Moreover, gender diverse AMAB people sought a non-standard hormonal treatment more often than their binary counterpart. CLINICAL IMPLICATIONS: The present study highlights the importance for transgender health professionals, when planning gender-affirming hormonal treatments, to offer flexible interventions, tailored on the patient's needs and goals. STRENGTHS & LIMITATIONS: Strengths included exploring whether and how perceived discrimination may affect mental health in gender diverse people. Limitations included the enrolled sample of people referring to different gender clinics, which is not fully representative of the transgender population. CONCLUSION: This study highlights the importance of evaluating each individual's unique health care needs, exploring each single request and its underlying reasons. Romani A., Mazzoli F., Ristori J., et al. Psychological Wellbeing and Perceived Social Acceptance in Gender Diverse Individuals. J Sex Med 2021;18:1933-1944.

Does Gender-Affirming Hormonal Treatment Affect 30-Year Cardiovascular Risk in Transgender Persons? A Two-Year Prospective European Study (ENIGI).

BACKGROUND: Cardiovascular (CV) implications of long-term gender affirming hormonal treatment (GAHT) in transgender individuals still remain largely unknown. AIM: To evaluate changes in the 30-year Framingham cardiovascular disease (CVD) risk in a large cohort of transgender individuals after the start of GAHT. METHODS: In a multicenter prospective study, a consecutive series of 309 participants (165 transmen and 144 transwomen) was evaluated during a 2-year follow-up. Prospectively, after the start of GAHT a physical examination was performed and blood samples were drawn. CVD risk was calculated for each person, according to the Framingham 30-year CVD risk estimate. MAIN OUTCOME MEASURE: Changes in CV risk factors and 30-year Framingham CVD risk during GAHT. CLINICAL IMPLICATIONS: In transmen testosterone-induced lipid profile alterations may have a clinical relevance on the individual long-term CVD risk. STRENGTHS & LIMITATIONS: The strength of the present study is the possibility to predict long-term CV outcomes in transgender individuals receiving GAHT based on a short observation; whereas the main limitation is that CVD risk prospective changes mainly represent the expression of risk factors changes during GAHT. RESULTS: In transwomen a significant decrease in triglycerides, total cholesterol and LDL-cholesterol was observed during the 2-year follow-up (P < .05), whereas unfavorable lipid changes - such as increased total cholesterol, triglycerides, and LDL cholesterol levels and decreased HDL cholesterol levels (P < .05)- occurred after the start of GAHT in transmen. These changes in risk factors led to an increase in the risk of general and hard CVD events based on lipid profile over time in transmen (P = .001 and P = .005, respectively). No significant changes in general and hard CVD risk based on lipid profile were observed in transwomen over time. CONCLUSIONS: Our findings confirmed the unfavorable lipid changes in transmen after the start of GAHT even during a longer follow-up, empathizing the potential clinical impact of these modifications on individual long-term CVD risk. Cocchetti C, Castellini G, Iacuaniello D, et al. Does Gender-Affirming Hormonal Treatment Affect 30-Year Cardiovascular Risk in Transgender Persons? A Two-Year Prospective European Study (ENIGI). J Sex Med 2021;18:821-829.

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.

International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women.

BACKGROUND: The Global Consensus Position Statement on the Use of Testosterone Therapy for Women (Global Position Statement) recommended testosterone therapy for postmenopausal women with hypoactive sexual desire disorder (HSDD). AIM: To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with HSDD. METHODS: The International Society for the Study of Women's Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. Consensus was reached using a modified Delphi method. OUTCOMES: A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up. RESULTS: Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women's Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Current available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide an informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data. CLINICAL IMPLICATIONS: This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring. STRENGTHS & LIMITATIONS: This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging. CONCLUSION: Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need. Parish SJ, Simon JA, Davis SR, et al. International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women. J Sex Med 2021;18:849-867.

International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women.

AIM: To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with hypoactive sexual desire disorder (HSDD). METHODS: The International Society for the Study of Women's Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. Consensus was reached using a modified Delphi method. OUTCOMES: A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up. RESULTS: Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women's Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Current available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide an informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data. CLINICAL IMPLICATIONS: This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring. STRENGTHS AND LIMITATIONS: This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging. CONCLUSION: Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need.

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.

Ghrelin as a possible biomarker and maintaining factor in patients with eating disorders reporting childhood traumatic experiences.

OBJECTIVE: The recent conceptualization of ghrelin as a stress hormone suggested that its chronic alterations may have a role in maintaining overeating behaviors in subjects with eating disorders (EDs) reporting childhood traumatic experiences. The aim of this study was to investigate the alterations of ghrelin levels in patients with EDs, their associations with early trauma, binge and emotional eating, and possible moderation/mediation models. METHOD: Sixty-four patients with EDs and 42 healthy controls (HCs) had their plasma ghrelin levels measured and completed questionnaires evaluating general and ED-specific psychopathology, emotional eating, and childhood traumatic experiences. RESULTS: Participants with anorexia nervosa had higher ghrelin levels than HCs in body mass index (BMI)-adjusted comparisons. Moreover, patients reporting a history of childhood trauma had higher ghrelin levels. Childhood sexual abuse (CSA), BMI, and self-induced vomiting were independent predictors of ghrelin levels. Moderation analyses showed that ghrelin levels were associated with binge and emotional eating only for higher levels of childhood trauma. Elevated ghrelin was a significant mediator for the association of CSA with binge eating. CONCLUSIONS: These results support the hypothesis that chronic alterations in ghrelin levels following childhood traumatic experiences could represent a neurobiological maintaining factor of pathological overeating behaviors in EDs.

Predictors of Resumption of Menses in Anorexia Nervosa: A 4-Year Longitudinal Study.

OBJECTIVE: Amenorrhea is a disabling medical consequence of anorexia nervosa (AN); therefore, resumption of menses (ROM) represents an important goal in the treatment for these patients. The aim of the present study was to evaluate possible clinical, psychopathological, and biological predictors of ROM, including age, body mass index (BMI), AN subtype, childhood abuse, duration of illness, general and eating disorder (ED)-specific psychopathology, and sex hormones. METHODS: Fifty amenorrheic patients with AN were enrolled. Baseline clinical data and information on childhood abuse were collected. Questionnaires to evaluate general and ED-specific psychopathology were administered, and blood samples were drawn. All patients received treatment as usual and underwent regular follow-up visits for 4 years or until ROM. Time to ROM, BMI at last evaluation, and data regarding diagnostic crossover into bulimia nervosa were collected. RESULTS: Twenty-nine (58.0%) patients recovered menses. Diagnostic crossover was associated with a higher probability of ROM (odds ratio = 10.3, p = .030). Time-to-event analysis showed that a shorter duration of illness (χ(1) = 11.00, p = .001), binge-eating/purging subtype (χ(1) = 7.01, p = .008), and history of childhood abuse (χ(1) = 4.03, p = .045) were associated with an earlier ROM. Furthermore, higher baseline ED-specific psychopathology was associated with a reduced likelihood for ROM, whereas higher general psychopathology and follicle-stimulating hormone levels predicted an earlier ROM (all, p < .050). Age, BMI, luteinizing hormone, and estrogen hematic levels had no predictive value with respect to ROM. CONCLUSIONS: The present study provides data in support of an integrated model, emphasizing the importance of duration of illness, childhood abuse, and psychopathological characteristics of amenorrheic patients with AN in predicting ROM.

Male and female sexual dysfunction in diabetic subjects: Focus on new antihyperglycemic drugs.

The association between diabetes mellitus (and its micro- and macro-vascular complications) and erectile dysfunction is widely known and the presence of hypogonadism may further complicate sexual dysfunction and quality of life, given the association between hypogonadism and reduced libido, ejaculatory disorders, and depressive symptoms. However, the recent introduction of novel antidiabetic agents with a wide range of mechanism of action may have a significant impact both on male and female sexuality directly (by inducing side effects as urinary tract infections) and indirectly (improving metabolic status and reducing diabetes complications behind sexual dysfunctions). To date only few papers are reporting the sexual effects of these treatments and, often, these are not comparable in their results. Conversely, female sexual dysfunctions are somehow under-investigated. Data on prevalence is heterogeneous and specific pathogenic mechanisms, as well as the burden of psychological factors, are still heatedly debated. The aim of this narrative review is to summarize current knowledge and stressing out the need to diagnose male and female sexual dysfunctions also in light of the impact of treatments with novel antidiabetic agents. This would highlight the still unmet needs for sexual care in a diabetes care setting and could represent an incentive for future discussions, as well as a required theoretical starting point for studies on this subject.

Methodological Challenges in Studying Testosterone Therapies for Hypoactive Sexual Desire Disorder in Women.

INTRODUCTION: Testosterone has been studied for its benefits on sexual health for decades. The research regarding testosterone in women has produced evidence that this is a potential treatment for women suffering from female sexual dysfunction. There are several limitations of the testosterone trials that can affect their interpretation and challenges posed by some regulatory agencies that have prevented approval of any testosterone treatment for women in several countries. AIM: To summarize the challenges of testosterone trials in terms of study populations, patient-reported outcomes, validated instruments in research, confounders, and regulatory barriers. METHODS: A thorough review of published data on testosterone for the treatment of women's sexual health problems was undertaken. A detailed evaluation of the limitations of these trials was conducted and incorporated with the published evidence on the regulatory processes involved in moving testosterone from clinical research to drug approval. MAIN OUTCOME MEASURE: Main outcome measures are assessment of clinical trial populations, survey tools, confounders, and regulatory barriers. RESULTS: There is some heterogeneity of study populations included in testosterone trials in women. Similarly, there have been differences in instruments used to assess patient-reported outcomes and often minimal control for potential confounders. The regulatory agency had posed a challenge to approve any testosterone treatment for women based on unproven concerns and a lack of regulatory guidance for drug developers. CLINICAL IMPLICATIONS: There is strong evidence that shows testosterone is effective for treating sexual health concerns in the women included in clinical trials. STRENGTH & LIMITATIONS: Strengths include thorough review of published literature and trial design for sexual health concerns. Limitations include being restricted to English Language publications and not having access to unpublished clinical trial data. CONCLUSIONS: Testosterone trials in women have been limited by homogeneity in the study populations and outcomes measured. Drug development has been hampered by inconsistent regulatory barriers. Rowen TS, Davis SR, Parish S, et al. Methodological Challenges in Studying Testosterone Therapies for Hypoactive Sexual Desire Disorder in Women. J Sex Med 2020;17:585-594.