Subject(s)
HIV Infections , Neurosyphilis , Sexual and Gender Minorities , Syphilis , Homosexuality, Male , Humans , Male , Probenecid/therapeutic useSubject(s)
Neurosyphilis , Syphilis , Humans , Neurosyphilis/diagnosis , Syphilis/diagnosis , Syphilis SerodiagnosisABSTRACT
OBJECTIVES: Boceprevir is a first-generation direct-acting antiviral licensed for the treatment of hepatitis C infection. Sildenafil is an oral therapy for erectile dysfunction. As boceprevir is a potent inhibitor of CYP3A4, potential pharmacokinetic interactions may occur when it is coadministered with sildenafil. The aim of this study was to assess the pharmacokinetic profile of sildenafil and boceprevir when dosed separately and together in healthy volunteers. METHODS: Thirteen male subjects completed the following study procedures: phase 1 (Day 0), a single dose of 25 mg of sildenafil was administered; washout period (Days 1-9); phase 2 (Days 10-15), 800 mg of boceprevir three times a day was administered; and phase 3 (Day 16), 800 mg of boceprevir and 25 mg of sildenafil were administered. All drugs were administered in the fed state. Intensive pharmacokinetic sampling was undertaken on Days 0, 15 and 16. Differences in the pharmacokinetic parameters of sildenafil, N-desmethyl-sildenafil and boceprevir between phase 3 and the earlier phases were evaluated by changes in the geometric mean ratios (GMRs). RESULTS: All the drugs were well tolerated with no safety concerns arising. In the presence of boceprevir (phase 3 versus phase 1), the GMR for the plasma Cmax and the AUC24 for sildenafil increased by 1.9-fold (95% CI 1.5-2.4) and 2.7-fold (95% CI 2.1-3.4), respectively, whereas a reduction in the Cmax of N-desmethyl-sildenafil was observed (GMR 0.5, 95% CI 0.4-0.7). No significant changes in boceprevir exposure were observed between phases 3 and 2. CONCLUSIONS: Exposure of sildenafil is increased in the presence of boceprevir. A dose adjustment of sildenafil is therefore necessary. An initial dose of 25 mg of sildenafil is suggested.
Subject(s)
Antiviral Agents/pharmacokinetics , Proline/analogs & derivatives , Sildenafil Citrate/pharmacokinetics , Urological Agents/pharmacokinetics , Adolescent , Adult , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Drug Interactions , Healthy Volunteers , Humans , Male , Middle Aged , Plasma/chemistry , Proline/administration & dosage , Proline/adverse effects , Proline/pharmacokinetics , Sildenafil Citrate/administration & dosage , Sildenafil Citrate/adverse effects , Urological Agents/administration & dosage , Urological Agents/adverse effects , Young AdultABSTRACT
Distressing low sexual desire, termed Hypoactive Sexual Desire Disorder (HSDD), affects approximately 10% of women and 8% of men. In women, the 'top-down' theory of HSDD describes hyperactivity in higher-level cognitive brain regions, suppressing lower-level emotional/sexual brain areas. However, it is unknown how this neurofunctional disturbance compares to HSDD in men. To investigate this, we employed task-based functional MRI in 32 women and 32 men with HSDD to measure sexual-brain processing during sexual versus non-sexual videos, as well as psychometric questionnaires to assess sexual desire/arousal. We demonstrate that women had greater activation in higher-level and lower-level brain regions, compared to men. Indeed, women who had greater hypothalamic activation in response to sexual videos, reported higher psychometric scores in the evaluative (r = 0.55, P = 0.001), motivational (r = 0.56, P = 0.003), and physiological (r = 0.57, P = 0.0006) domains of sexual desire and arousal after watching the sexual videos in the scanner. By contrast, no similar correlations were observed in men. Taken together, this is the first direct comparison of the neural correlates of distressing low sexual desire between women and men. The data supports the 'top-down' theory of HSDD in women, whereas in men HSDD appears to be associated with different neurofunctional processes.
Subject(s)
Brain , Libido , Magnetic Resonance Imaging , Sexual Dysfunctions, Psychological , Humans , Female , Male , Adult , Brain/diagnostic imaging , Brain/physiology , Sexual Dysfunctions, Psychological/psychology , Sexual Dysfunctions, Psychological/physiopathology , Libido/physiology , Sex Characteristics , Young Adult , Sexual Behavior/psychology , Sexual Behavior/physiology , Brain Mapping , Surveys and Questionnaires , Middle AgedABSTRACT
INTRODUCTION: Persistent genital arousal disorder (PGAD) is a potentially debilitating disorder of unwanted genital sensation and arousal that is generally spontaneous and unrelenting. Since its first description in 2001, many potential etiologies and management strategies have been suggested. AIM: To review the literature on PGAD, identify possible causes of the disorder, and provide approaches to the assessment and treatment of the disorder based on the authors' experience and recent literature. METHODS: PubMed searches through July 2012 were conducted to identify articles relevant to persistent sexual arousal syndrome and PGAD. MAIN OUTCOME MEASURES: Expert opinion was based on review of the medical literature related to this subject matter. RESULTS: PGAD is characterized by persistent sensations of genital arousal in the absence of sexual stimulation or emotion, which are considered unwanted and cause the patient at least moderate distress. The proposed etiologies of PGAD are plentiful and may involve a range of psychologic, pharmacologic, neurologic, and vascular causes. PGAD has been associated with other conditions including overactive bladder and restless leg syndrome. Assessment should include a through history and physical exam and tailored radiologic studies. Treatment should be aimed at reversible causes, whether physiologic or pharmacologic. All patients should be considered for cognitive therapy including mindfullness meditation and acceptance therapy. CONCLUSIONS: PGAD likely represents a range of conditions manifesting in unwanted genital sensations. Successful treatment requires a multidisciplinary approach and consideration of all reversible causes as well as cognitive therapy.
Subject(s)
Sexual Dysfunctions, Psychological/diagnosis , Sexual Dysfunctions, Psychological/etiology , Adaptation, Psychological , Cognitive Behavioral Therapy , Combined Modality Therapy , Cooperative Behavior , Cross-Sectional Studies , Diagnosis, Differential , Female , Humans , Interdisciplinary Communication , Meditation , Risk Factors , Sexual Dysfunctions, Psychological/epidemiology , Sexual Dysfunctions, Psychological/therapyABSTRACT
Importance: The human physiological sexual response is crucial for reward, satisfaction, and reproduction. Disruption of the associated neurophysiological pathways predisposes to low sexual desire; the most prevalent psychological form is hypoactive sexual desire disorder (HSDD), which affects 8% of men but currently has no effective pharmacological treatment options. The reproductive neuropeptide kisspeptin offers a putative therapeutic target, owing to emerging understanding of its role in reproductive behavior. Objective: To determine the physiological, behavioral, neural, and hormonal effects of kisspeptin administration in men with HSDD. Design, Setting, and Participants: This double-blind, 2-way crossover, placebo-controlled randomized clinical trial was performed at a single academic research center in the UK. Eligible participants were right-handed heterosexual men with HSDD. Physiological, behavioral, functional magnetic resonance imaging (fMRI), and hormonal analyses were used to investigate the clinical and mechanistic effects of kisspeptin administration in response to visual sexual stimuli (short and long video tasks). The trial was conducted between January 11 and September 15, 2021, and data analysis was performed between October and November 2021. Interventions: Participants attended 2 study visits at least 7 days apart, in balanced random order, for intravenous infusion of kisspeptin-54 (1 nmol/kg/h) for 75 minutes or for administration of a rate-matched placebo. Main Outcomes and Measures: Changes in (1) brain activity on whole-brain analysis, as determined by fMRI blood oxygen level-dependent activity in response to visual sexual stimuli during kisspeptin administration compared with placebo, (2) physiological sexual arousal (penile tumescence), and (3) behavioral measures of sexual desire and arousal. Results: Of the 37 men randomized, 32 completed the trial. Participants had a mean (SD) age of 37.9 (8.6) years and a mean (SD) body mass index of 24.9 (5.4). On viewing sexual videos, kisspeptin significantly modulated brain activity in key structures of the sexual-processing network on whole-brain analysis compared with placebo (mean absolute change [Cohen d] = 0.81 [95% CI, 0.41-1.21]; P = .003). Furthermore, improvements in several secondary analyses were observed, including significant increases in penile tumescence in response to sexual stimuli (by up to 56% more than placebo; mean difference = 0.28 units [95% CI, 0.04-0.52 units]; P = .02) and behavioral measures of sexual desire-most notably, increased happiness about sex (mean difference = 0.63 points [95% CI, 0.10-1.15 points]; P = .02). Conclusions and Relevance: Collectively, this randomized clinical trial provides the first evidence to date showing that kisspeptin administration substantially modulates sexual brain processing in men with HSDD, with associated increases in penile tumescence and behavioral measures of sexual desire and arousal. These data suggest that kisspeptin has potential as the first pharmacological treatment for men with low sexual desire. Trial Registration: isrctn.org Identifier: ISRCTN17271094.
Subject(s)
Penile Erection , Sexual Dysfunctions, Psychological , Male , Humans , Adult , Kisspeptins/pharmacology , Kisspeptins/therapeutic use , Sexual Behavior , Sexual Dysfunctions, Psychological/drug therapy , Brain/diagnostic imagingABSTRACT
BACKGROUNDHypoactive sexual desire disorder (HSDD) is characterized by a persistent deficiency of sexual fantasies and desire for sexual activity, causing marked distress and interpersonal difficulty. It is the most prevalent female sexual health problem globally, affecting approximately 10% of women, but has limited treatment options. Melanocortin 4 receptor (MC4R) agonists have emerged as a promising therapy for women with HSDD, through unknown mechanisms. Studying the pathways involved is crucial for our understanding of normal and abnormal sexual behavior.METHODSUsing psychometric, functional neuroimaging, and hormonal analyses, we conducted a randomized, double-blinded, placebo-controlled, crossover clinical study to assess the effects of MC4R agonism compared with placebo on sexual brain processing in 31 premenopausal heterosexual women with HSDD.RESULTSMC4R agonism significantly increased sexual desire for up to 24 hours after administration compared with placebo. During functional neuroimaging, MC4R agonism enhanced cerebellar and supplementary motor area activity and deactivated the secondary somatosensory cortex, specifically in response to visual erotic stimuli, compared with placebo. In addition, MC4R agonism enhanced functional connectivity between the amygdala and the insula during visual erotic stimuli compared with placebo.CONCLUSIONThese data suggest that MC4R agonism enhanced sexual brain processing by reducing self-consciousness, increasing sexual imagery, and sensitizing women with HSDD to erotic stimuli. These findings provide mechanistic insight into the action of MC4R agonism in sexual behavior and are relevant to the ongoing development of HSDD therapies and MC4R agonist development more widely.TRIAL REGISTRATIONClinicalTrials.gov NCT04179734.FUNDINGThis is an investigator-sponsored study funded by AMAG Pharmaceuticals Inc., the Medical Research Council (MRC) (MR/T006242/1), and the National Institute for Health Research (NIHR) (CS-2018-18-ST2-002 and RP-2014-05-001).
Subject(s)
Receptor, Melanocortin, Type 4 , Sexual Dysfunctions, Psychological , Brain/diagnostic imaging , Female , Humans , Interleukin-1 Receptor-Like 1 Protein , Sexual Behavior , Sexual Dysfunctions, Psychological/drug therapyABSTRACT
Importance: Despite being the most common female sexual health complaint worldwide, current treatment options for hypoactive sexual desire disorder (HSDD) are limited in their safety and effectiveness. The hormone kisspeptin is a key endogenous activator of the reproductive hormonal axis with additional emerging roles in sexual and emotional behavior; however, its effects in women with HSDD are unknown. Objective: To test the hypothesis that kisspeptin enhances sexual and attraction brain processing in women with HSDD. Design, Setting, and Participants: This randomized clinical trial was double-masked and placebo controlled with a 2-way crossover. The trial was conducted in a university research setting in the UK from October 2020 to April 2021. Eligible participants were premenopausal women with HSDD. Functional neuroimaging, psychometric, and hormonal analyses were employed to investigate the effects of kisspeptin administration on brain processing, in response to erotic stimuli (erotic videos) and facial attraction (face images of varying attractiveness). Data were analyzed from May to December 2021. Interventions: A 75-minute intravenous infusion of kisspeptin-54 (1 nmol/kg/h) vs equivalent-rate placebo infusion. Main Outcomes and Measures: Blood oxygen level-dependent responses across the whole brain and regions of interest during kisspeptin vs placebo administration in response to erotic and facial attraction stimuli. Results: Of the 40 participants who were randomized, 32 women completed both kisspeptin and placebo visits, with a mean (SE) age of 29.2 (1.2) years. Kisspeptin administration resulted in modulations in sexual and facial attraction brain processing (deactivation of the left inferior frontal gyrus: Z max, 3.76; P = .01; activation of the right postcentral and supramarginal gyrus: Z max, 3.73; P < .001; deactivation of the right temporoparietal junction: Z max 4.08; P = .02). Furthermore, positive correlations were observed between kisspeptin-enhanced hippocampal activity in response to erotic videos, and baseline distress relating to sexual function (r = 0.469; P = .007). Kisspeptin's enhancement of posterior cingulate cortex activity in response to attractive male faces also correlated with reduced sexual aversion, providing additional functional significance (r = 0.476, P = .005). Kisspeptin was well-tolerated with no reported adverse effects. Conclusions and Relevance: These findings lay the foundations for clinical applications for kisspeptin in women with HSDD. Trial Registration: ISRCTN trial registry identifier: ISRCTN17271094.
Subject(s)
Libido , Sexual Dysfunctions, Psychological , Female , Male , Humans , Adult , Kisspeptins/pharmacology , Kisspeptins/therapeutic use , Phentolamine/pharmacology , Phentolamine/therapeutic use , Sexual Dysfunctions, Psychological/drug therapy , Hormones/pharmacology , Hormones/therapeutic useABSTRACT
OBJECTIVES: Until recently, PCR had been used to detect but not quantify Treponema pallidum. To understand infection kinetics of this uncultivable organism, a real-time PCR assay was developed to quantify 47 kDa membrane lipoprotein gene DNA (tpp47). METHODS: Assay specificity was determined against DNA from humans, skin organisms and sexually transmitted pathogens. tpp47 DNA (Nichols strain) was used to construct a standard curve for T pallidum quantification. Blood and ulcer samples were obtained from 99 patients being investigated or screened for syphilis and tpp47 was quantified. RESULTS: The assay was specific, not cross-reactive with other organisms tested and sensitive, with a detection limit of a single copy of tpp47 DNA. For ulcer samples, the assay was 100% sensitive and 97.14% specific. Sensitivity fell to 34.1% for blood samples but specificity remained high (100%). tpp47 DNA was more commonly detected, and at a higher copy number, in blood of patients with secondary infection (sensitivity 57.89%) compared with primary infection. Quantity of tpp47 DNA was higher in primary infection ulcers, especially in HIV-1-positive patients, than in ulcers persisting into secondary disease. CONCLUSIONS: Quantifying T pallidum provides insight into syphilis infection kinetics: Ulcers of primary disease in HIV-1-positive patients are perhaps more infectious and the presence and load of T pallidum bacteraemia is variable, with a peak in the secondary stage. Quantitative PCR has the potential to map T pallidum infection and to highlight the impact of HIV on syphilis.
Subject(s)
Carrier Proteins/analysis , DNA, Bacterial/analysis , Lipoproteins/analysis , Polymerase Chain Reaction/methods , Syphilis/diagnosis , Adult , Cross-Sectional Studies , Early Diagnosis , Female , HIV Infections/complications , HIV-1 , Humans , Male , Prospective Studies , Sensitivity and Specificity , Syphilis/complications , Treponema pallidum/genetics , Treponema pallidum/isolation & purificationABSTRACT
INTRODUCTION: We describe two men with marked symptoms following orgasm. In each case, the symptoms were consistent with those found in postorgasm illness syndrome (POIS). AIM: Further elucidation of the cause of the patients' symptoms. METHODS: Both cases were investigated for causes of POIS with biochemical, hormonal, neurological, autonomic, cardiological, and psychological workup. RESULTS: Extensive investigation did not reveal a major organic cause for these patients' symptoms. Detailed history revealed likely differing etiologies in each case. In one case, the symptom picture suggested cytokine release, and, in fact, the patient subjectively improved by 80% on taking nonsteroidal anti-inflammatory drugs just prior to and for a day or two after orgasm. The other case appeared to have an ethnic/cultural etiology that was associated with the "Dhat" syndrome. CONCLUSION: The apparent differing etiologies/clinical associations of these cases highlight the need for careful history, examination, and investigations in patients presenting with POIS. We recommend that each case needs individual consideration and investigation, and treatment needs to be tailored to the likely cause. It seems likely that POIS represents a spectrum of syndromes of differing etiologies. Further research into the neurobiochemical sequelae of orgasm will be useful in understanding the pathological processes in these cases.
Subject(s)
Ejaculation , Fatigue/etiology , Mental Fatigue/etiology , Myofascial Pain Syndromes/etiology , Orgasm , Somatoform Disorders/etiology , Adult , Diagnosis, Differential , Homosexuality, Male , Humans , Male , Middle Aged , Neurologic Examination , Neuropsychological Tests , SyndromeABSTRACT
INTRODUCTION: There is a need for state-of-the-art information in the area of sexually transmitted infections (STIs) in relation to sexual function. There are an estimated 60 million people living with and 340 million with treatable STIs. Surveys show sexual problems to be as high as 35% for men and 55% for women; however, there is little research directly assessing relationships between infection and sexual function. AIM: To show that STIs are associated with (and may cause) sexual dysfunction. Conversely, sexual dysfunction can increase patients' risk of STI acquisition. In men, erectile dysfunction (ED) associated with condom use may lead to unsafe sexual practices and, hence, STI acquisition. The role of various therapies including phosphodiesterase type 5 inhibitors in the treatment of ED in positive men taking social drugs will be explored. METHODS: To provide state-of-the-art knowledge concerning sexual function and STIs, representing the opinions of five experts from four countries developed in a consensus process and encompassing a detailed literature review over a 2-year period. MAIN OUTCOME MEASURE: Expert opinion was based on the grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate. RESULTS: This article highlights major factors causing the spread of STIs and suggests management interventions to prevent further spread of HIV/STIs, focusing on the juxtaposition between STIs and sexual functioning. Women's unique vulnerabilities to HIV/STIs (biological and physiological issues, gender-based violence, gender inequity) and their impact on women's sexual function are reviewed. Similarly, men's unique vulnerabilities to HIV/STIs including condom use, disclosure, voluntary counseling and testing, multiple concurrent sexual partners, and recreational drug use--particularly in homosexual men--are explored, as is the association of prostatitis and sexual function. Lastly, the article reviews the relationship between circumcision and sexual dysfunction. CONCLUSIONS: A multidimensional approach to achieve optimal treatment outcomes should be embraced.
Subject(s)
Sexual Dysfunction, Physiological/epidemiology , Sexually Transmitted Diseases/epidemiology , AIDS Dementia Complex/epidemiology , Antiretroviral Therapy, Highly Active , Bacterial Infections/complications , Bacterial Infections/drug therapy , Bacterial Infections/epidemiology , Ejaculation , Female , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/epidemiology , Humans , Hypogonadism/epidemiology , Libido , Male , Peripheral Nervous System Diseases/epidemiology , Sexually Transmitted Diseases/microbiologyABSTRACT
INTRODUCTION: The Sexual Interest and Desire Inventory-Female (SIDI-F) is a 13-item scale developed as a clinician-administered assessment tool to measure hypoactive sexual desire disorder (HSDD) severity in women. AIM: To estimate the reliability and validity of the SIDI-F as a measure of HSDD severity. METHODS: Women, aged 18-65 years, with primary HSDD, Female Sexual Arousal Disorder (FSAD), or no Female Sexual Dysfunction (no FSD) participated in two nontreatment studies (in North America and Europe). On days 0 and 28, subjects were assessed using the SIDI-F, Female Sexual Function Index (FSFI), Changes in Sexual Functioning Questionnaire-Female (CSFQ-F), Locke-Wallace Marital Adjustment Test (MAT) and the Female Sexual Distress Scale (FSDS). MAIN OUTCOME MEASURES: Discriminant validity, convergent validity, divergent validity, test-retest validity, and internal consistency of the SIDI-F. RESULTS: The North American study enrolled women with HSDD (N = 113), FSAD (N = 49) and no FSD (N = 61); the European study enrolled women with HSDD (N = 130) and no FSD (N = 124). In both studies, mean SIDI-F total score for women with HSDD was lower than for those with no FSD (P < 0.001, for all) demonstrating discriminant validity. Further, mean SIDI-F total score for women with HSDD was lower than for those with FSAD in the North American study (P < 0.001). Convergent validity with the FSFI and CSFQ-F and divergent validity with MAT were demonstrated. Test-retest reliability and internal consistency were high. CONCLUSIONS: The SIDI-F is a valid and reliable measure of HSDD severity in women.
Subject(s)
Sexual Dysfunctions, Psychological/epidemiology , Surveys and Questionnaires , Adolescent , Adult , Aged , Europe/epidemiology , Female , Humans , Middle Aged , North America/epidemiology , Prospective Studies , Reproducibility of Results , Severity of Illness Index , Young AdultABSTRACT
Little is known with certitude about the triggers of persistent genital arousal disorder (PGAD) in women, although there appears to be certain common features of the disorder. Women complain of unbidden feelings of genital arousal that are qualitatively different from sexual arousal that is preceded by sexual desire/and or subjective arousal. The majority of women find PGAD distressing and report only brief relief with orgasm. In this article, we describe five women who believe they developed PGAD either after withdrawing from selective serotonin reuptake inhibitor (SSRI) anti-depressants or while using them. We discuss these sexual symptoms in relation to what is already known about prolonged SSRI withdrawal syndromes and the possible etiologies of these conditions. While not a common cause of PGAD, it is possible that use of, and withdrawal from, pharmacological agents contributes to the development of PGAD.
Subject(s)
Antidepressive Agents, Second-Generation/adverse effects , Libido , Selective Serotonin Reuptake Inhibitors/adverse effects , Sexual Behavior , Sexual Dysfunction, Physiological/chemically induced , Adult , Antidepressive Agents, Second-Generation/administration & dosage , Depressive Disorder/drug therapy , Female , Humans , Libido/drug effects , Middle Aged , Selective Serotonin Reuptake Inhibitors/administration & dosage , Sexual Behavior/drug effects , Sexual Dysfunction, Physiological/psychology , Substance Withdrawal Syndrome/etiology , Women's HealthABSTRACT
There have been a number of case reports published recently describing women who complain of persistent genital arousal. Most of these papers do not report medical data or observations from genital examination. We report in such detail on six cases of persistent genital arousal disorder (PGAD) in women. We further advance the hypothesis that in many cases the objective genital component may be induced by a variety of psychophysiological and pathological factors such as anxiety, genital prolapses and dermatoses. Genital engorgement so produced may not be continuous but when present may be enhanced and perpetuated by both anxiety focussed on the genitals and masturbation used in an attempt to relieve the sensations. Premorbid affective psychological illness negatively colours the subjective perception of this genital engorgement, leading to either elicitation or maintenance of PGAD. We discuss this hypothesis in relation to our six cases.