Sexual Performance Anxiety.

INTRODUCTION: Sexual performance anxiety (SPA) is one of the most prevalent sexual complaints; yet, no diagnosis is recognized for either gender. Thus, research into treatment has been minimal. AIM: Review the prevalence of SPA and its relation to sexual dysfunctions and anxiety disorders. Compare SPA to (non-sexual) performance anxiety and social anxiety (PA/SA). Apply pharmacologic principles to the known properties of drugs and phytotherapies to hypothesize treatments for SPA. METHODS: Review SPA and PA/SA through PubMed searches for relevant literature from 2000 to 2018. MAIN OUTCOME MEASURE: Prevalence was estimated using population-representative surveys. For treatment results, controlled clinical trial results were prioritized over open-label trial results. RESULTS: SPA affects 9-25% of men and contributes to premature ejaculation and psychogenic erectile dysfunction (ED). SPA affects 6-16% of women and severely inhibits sexual desire. Cognitive behavior therapy and mindfulness meditation training have been proven effective for PA/SA and are recommended for SPA, but controlled studies are lacking. Phosphodiesterase type 5 inhibitors are effective for psychogenic ED and premature ejaculation, both of which include SPA as a major element. Drugs proven for PA/SA have adverse sexual and sedative effects, but serotonergic anxiolytics with prosexual effects (buspirone ± testosterone, trazodone ± bupropion) may have potential, and sage, passionflower, l-theanine, and bitter orange are anxiolytic. Nitric oxide boosters (l-citrulline, l-arginine, Panax ginseng) have the potential for increasing genital tumescence and lubrication, and plant-based alpha-adrenergic antagonists may aid sexual arousal (yohimbine/yohimbe, Citrus aurantium/p-synephrine). CONCLUSION: SPA causes or maintains most common sexual dysfunction. No treatments are well proven, although cognitive behavior therapy, mindfulness meditation training, and serotonergic anxiolytics (buspirone, trazodone, gepirone) have potential, and phosphodiesterase type 5 inhibitors are effective for psychogenic ED and premature ejaculation. Several phytotherapies also appear to have potential. Pyke RE. Sexual Performance Anxiety. J Sex Med 2020;8:183-190.

Lumping, Splitting, and Treating: Therapies Are Needed for Women With Overlapping Sexual Dysfunctions.

INTRODUCTION: Phase-specific diagnoses, such as hypoactive sexual desire disorder, are the norm in sexual medicine. Epidemiologic surveys and clinical trials show the value of this structure for understanding and treating premenopausal sexual dysfunction; however, postmenopausal women have sexual dysfunction in >1 phase, for example, in desire and arousal. OBJECTIVE: To evaluate the evidence for mixed or global sexual dysfunction in women, identify associated comorbidities, and determine the best available treatment. METHODS: Literature review of epidemiologic surveys and clinical trials to quantitate overlap in sexual dysfunction and render conclusions about treatments. MAIN OUTCOME MEASURES: The main outcome measures were the Changes in Sexual Functioning Questionnaire and the Female Sexual Function Index. RESULTS: Overlap of sexual dysfunction in women is low to moderate before menopause, but it is high after menopause. Data suggest that clinical trials of postmenopausal women diagnosed with hypoactive sexual desire disorder actually entered patients with mixed or global sexual dysfunction and that benefits were pan-phasic rather than concentrated on desire. Whether local/vaginal products for the genitourinary syndrome of menopause impact all phases of sexual dysfunction is under study. Women treated for breast or gynecologic cancer or taking antidepressants also have global sexual dysfunction. Treatment options are limited but support mindfulness-based cognitive behavioral therapy and others. Other strategies include adding or switching to a serotonin 1A receptor agonist (eg, buspirone, flibanserin), a serotonin 2A receptor antagonist (eg, flibanserin, trazodone), or a norepinephrine-dopamine reuptake inhibitor (eg, bupropion). Elimination of hormonal contraception in premenopausal women and adding hormonal therapies in postmenopausal women may be necessary. CONCLUSIONS: Practitioners should be alert to overlap of sexual dysfunction in women. Focusing diagnostics and treatment on individual phases of sexual function is appropriate in premenopausal patients, but global sexual dysfunction is more likely in women taking antidepressants or cancer chemotherapy or during and after the menopausal transition. More safe, broadly effective treatments for mixed sexual dysfunction are needed for these populations of women. Pyke RE, Clayton AH. Lumping, Splitting, and Treating: Therapies Are Needed for Women With Overlapping Sexual Dysfunctions. Sex Med Rev 2019;7:551-558.

Toward a Scientific Nutritional Supplement Combination for Prostatism and Erectile Dysfunction I: From Known Pharmacology to Clinical Testing.

Prostatism and erectile dysfunction (ED) are highly prevalent and closely comorbid. Prescription treatments are limitingly expensive but robust in mechanisms of action (MoA). Nutritional supplements (NS) are low-cost but inadequately supported by evidence. Do any NS use robust MoA? Could their efficacy be amplified via dosing, concentration of active principles, and/or use in combination? The goal is to develop an effective NS for prostatism and ED using the MoA of prescription treatments. Literature reviews were conducted on dietary supplements for prostatism or ED and MoA of relevant drugs. The most promising NS employing these MoA were chosen. A pilot study of a prototype combination was conducted. A protocol was created for an adequate dose-response trial to test the NS combination in men with ED and prostatism. The main measures were response rates, International Prostate Symptom Score, and International Index of Erectile Function. For drugs, the MoAs best proven for prostatism and ED were nitric oxide augmentation, mild androgen inhibition, and anti-inflammatory effects. The following NS best simulate these MoA and are best supported for efficacy; for prostatism: beta sitosterol; for ED: panax ginseng, arginine, and citrulline. Pilot clinical data provided support. A plan for a formal dose-response clinical trial was approved by a central institutional review board. NS using effective MoA might suffice for prostatism and ED. Pilot testing of a combination NS with the best-supported MoA supported further development. A dose-response trial should be conducted using adequate doses of L-citrulline, beta-sitosterol, ginseng, and vitamin D3.

Exo-Clinical Trials of Nutritional Supplements for Sexual Dysfunction: Precedents, Principles, and Protocols.

INTRODUCTION: Care-seeking for sexual dysfunction is limited by embarrassment, efficacy/safety concerns, and cost. Nutritional supplements (NSs) are low-cost but unproven. AIM: To provide hypotheses on whether effective NS combinations for sexual dysfunction can be created following known pharmacology principles and tested with sufficient rigor in Internet-based "exo-clinical" trials (XCTs). METHODS: PubMed and Google searches were conducted to review the feasibility of XCTs of NS combinations for sexual dysfunction. Findings were synthesized into recommendations for XCTs to treat the most common sexual problems. MAIN OUTCOME MEASURE: The hierarchy of references used for making recommendations was controlled clinical trials over uncontrolled trials. The frequency of sexual dysfunction was determined in population-representative national surveys. RESULTS: XCTs of cognitive behavioral therapy show conclusive efficacy for anxiety and depression. 5 small XCTs showed efficacy for female sexual dysfunction and erectile dysfunction (ED), and 2 XCTs of NS for other medical problems substantiated feasibility. To test the feasibility of XCTs for the most common forms of sexual dysfunction-ED, hypoactive sexual desire disorder (HSDD), and sexual performance anxiety-protocol outlines were generated for frugal XCTs; the total estimated subject time burden is ≤1 hour. CONCLUSION: An XCT is a cost-effective method of evaluating new treatments, including sexual dysfunction and common mental disorders, if compliance is maintained by regular outreach while minimizing the time burden on subjects and handling consent and privacy issues appropriately. NS combinations might expand the opportunities for relief of sexual dysfunction if formulated with pharmacologically active doses of NS with already supported efficacy and safety. The feasibility of XCTs of NS combinations for sexual dysfunction might be tested most productively in men with ED, in women with HSDD, and in men and women with sexual performance anxiety. Pyke RE. Exo-Clinical Trials of Nutritional Supplements for Sexual Dysfunction: Precedents, Principles, and Protocols. Sex Med Rev 2019;7:251-258.

Effect Size in Efficacy Trials of Women With Decreased Sexual Desire.

BACKGROUND: Regarding hypoactive sexual desire disorder (HSDD) in women, some reviewers judge the effect size small for medications vs placebo, but substantial for cognitive behavior therapy (CBT) or mindfulness meditation training (MMT) vs wait list. However, we lack comparisons of the effect sizes for the active intervention itself, for the control treatment, and for the differential between the two. AIM: For efficacy trials of HSDD in women, compare effect sizes for medications (testosterone/testosterone transdermal system, flibanserin, and bremelanotide) and placebo vs effect sizes for psychotherapy and wait-list control. METHODS: We conducted a literature search for mean changes and SD on main measures of sexual desire and associated distress in trials of medications, CBT, or MMT. Effect size was used as it measures the magnitude of the intervention without confounding by sample size. OUTCOMES: Cohen d was used to determine effect sizes. RESULTS: For medications, mean (SD) effect size was 1.0 (0.34); for CBT and MMT, 1.0 (0.36); for placebo, 0.55 (0.16); and for wait list, 0.05 (0.26). CLINICAL TRANSLATION: Recommendations of psychotherapy over medication for treatment of HSDD are premature and not supported by data on effect sizes. Active participation in treatment conveys considerable non-specific benefits. Caregivers should attend to biological and psychosocial elements, and patient preference, to optimize response. CONCLUSIONS: Few clinical trials of psychotherapies were substantial in size or utilized adequate control paradigms. Medications and psychotherapies had similar, large effect sizes. Effect size of placebo was moderate. Effect size of wait-list control was very small, about one quarter that of placebo. Thus, a substantial non-specific therapeutic effect is associated with receiving placebo plus active care and evaluation. The difference in effect size between placebo and wait-list controls distorts the value of the subtraction of effect of the control paradigms to estimate intervention effectiveness. Pyke RE, Clayton AH. Effect Size in Efficacy Trials of Women With Decreased Sexual Desire. Sex Med Rev 2018;6:358-366.

Psychological Treatment Trials for Hypoactive Sexual Desire Disorder: A Sexual Medicine Critique and Perspective.

INTRODUCTION: Publications claim efficacy for treatment of hypoactive sexual desire disorder (HSDD) in women with cognitive behavior therapy (CBT) and mindfulness meditation training (MMT). However, no review has evaluated the evidence for these therapies from the rigorous perspective of sexual medicine. AIMS: The aim of this study was to evaluate the published controlled trials of CBT and MMT for disorders of sexual desire from the perspective of sexual medicine standards of control paradigms, risk/benefit ratios, and clinical significance. METHODS: MEDLINE was reviewed from the last 10 years. Evaluated study quality via 10 metrics and efficacy as mean change, and proportion of responders and remitters. RESULTS: Three controlled trials support CBT and two controlled trials support MMT. The reports of the trials each lacked several scientific requirements: a hierarchy of endpoints with a planned primary endpoint, sufficient information on the intervention to reproduce it, randomization, adequate control, accepted measures of benefits and harms, compliance data, and/or outcomes of clinical relevance. CONCLUSIONS: Psychological treatments for HSDD are not yet supported by adequate clinical trials. The current scientific and regulatory standards for drug treatment trials should also be applicable to psychological treatment trials.