A biological condition gradient for coral reefs in the US Caribbean Territories: Part I. Coral narrative rules.

As coral reef condition and sustainability continue to decline worldwide, losses of critical habitat and their ecosystem services have generated an urgency to understand and communicate reef response to management actions, environmental contamination, and natural disasters. Increasingly, coral reef protection and restoration programs emphasize the need for robust assessment tools for protecting high-quality waters and establishing conservation goals. Of equal importance is the need to communicate assessment results to stakeholders, beneficiaries, and the public so that environmental consequences of decisions are understood. The Biological Condition (BCG) model provides a structure to evaluate the condition of a coral reef in increments of change along a gradient of human disturbance. Communication of incremental change, regardless of direction, is important for decision makers and the public to better understand what is gained or lost depending on what actions are taken. We developed a narrative (qualitative) Biological Condition Gradient (BCG) from the consensus of a diverse expert panel to provide a framework for coral reefs in US Caribbean Territories. The model uses narrative descriptions of biological attributes for benthic organisms to evaluate reefs relative to undisturbed or minimally disturbed conditions. Using expert elicitation, narrative decision rules were proposed and deliberated to discriminate among six levels of change along a gradient of increasing anthropogenic stress. Narrative rules for each of the BCG levels are presented to facilitate the evaluation of benthic communities in coral reefs and provide specific narrative features to detect changes in coral reef condition and biological integrity. The BCG model can be used in the absence of numeric, or quantitative metrics, to evaluate actions that may encroach on coral reef ecosystems, manage endangered species habitat, and develop and implement management plans for marine protected areas, watersheds, and coastal zones. The narrative BCG model is a defensible model and communication tool that translates scientific results so the nontechnical person can understand and support both regulatory and non-regulatory water quality and natural resource programs.

Development of a reef fish biological condition gradient model with quantitative decision rules for the protection and restoration of coral reef ecosystems.

Coral reef ecosystems are declining due to multiple interacting stressors. A bioassessment framework focused on stressor-response associations was developed to help organize and communicate complex ecological information to support coral reef conservation. This study applied the Biological Condition Gradient (BCG), initially developed for freshwater ecosystems, to fish assemblages of U.S. Caribbean coral reef ecosystems. The reef fish BCG describes how biological conditions changed incrementally along a gradient of increasing anthropogenic stress. Coupled with physical and chemical water quality data, the BGC forms a scientifically defensible basis to prioritize, protect and restore water bodies containing coral reefs. Through an iterative process, scientists from across the U.S. Caribbean used fishery-independent survey data and expert knowledge to develop quantitative decision rules to describe six levels of coral reef ecosystem condition. The resultant reef fish BCG provides an effective tool for identifying healthy and degraded coral reef ecosystems and has potential for global application.

The Effect of Food on the Pharmacokinetics of Buspirone After Single Administration of a Sublingual Testosterone and Oral Buspirone Combination Tablet in Healthy Female Subjects.

INTRODUCTION: A new combination tablet containing sublingual testosterone and oral buspirone (T+B) was developed to benefit a subgroup of women suffering from female sexual interest/arousal disorder, caused by dysfunctionally overactive sexual inhibition. AIM: The aim of this study was to compare the effect of food intake on the pharmacokinetics of buspirone, administered as a dual-route, dual-release combination tablet containing 0.5 mg testosterone (T) and 10 mg buspirone (B). METHODS: 19 healthy women took T+B under fed and fasted conditions during 2 overnight visits. The blood was sampled over a 24-hour period to determine the pharmacokinetics of buspirone and its active metabolite 1-(2-pyrimidinyl)piperazine (1-PP). Total testosterone levels were also assessed, at 5 time points and for quality control purposes only, as sublingual testosterone uptake is not expected to be influenced by prior food intake. MAIN OUTCOME MEASURE: PK profiles of buspirone and 1-PP. RESULTS: For buspirone, the 90% confidence intervals (CIs) of the observed fed/fasted ratios for the plasma area under the curve (AUC)0-last, AUC0-inf, and Cmax after administration of T+B were not contained within the prespecified bounds of 80% and 125%, except for the lower bound of AUC0-inf. However, the 90% CIs of the observed fed/fasted ratios for the plasma AUC0-last, AUC0-inf, and Cmax of 1-PP were contained within the prespecified bounds, with the exception of the upper bound for Cmax. The mean AUCs and Cmax for 1-PP did not differ between fed and fasted conditions. CONCLUSIONS: Administration of T+B after high-caloric food intake increased the bioavailability of buspirone but did not result in differences in Tmax when compared with fasted conditions. Both in fed and fasted conditions, T+B was generally well tolerated and safe. Exposure of 1-PP in fed and fasted conditions was comparable in both conditions. These results demonstrate that T+B can safely and effectively be used in both fed and fasted states. Gerritsen J, Bloemers J, van Rooij K, et al. The Effect of Food on the Pharmacokinetics of Buspirone After Single Administration of a Sublingual Testosterone and Oral Buspirone Combination Tablet in Healthy Female Subjects. J Sex Med 2020;8:186-194.

Effects of extreme high flow events on macroinvertebrate communities in Vermont streams.

Heavy precipitation events and subsequent high flows are occurring with greater frequency and intensity, which could have substantial implications for biomonitoring programs that typically evaluate changes in biological condition due to stressors at local and watershed scales. In this study we evaluated response and recovery of macroinvertebrate communities at nine reference quality streams located in multiple watersheds throughout Vermont to flooding from Tropical Storm (TS) Irene in 2011. At each site, the Vermont Department of Environmental Conservation (VT DEC) had collected macroinvertebrate data on an annual basis from 2009-2013. We compared the data collected in the days and weeks following TS Irene (2011) to samples collected for 2 years prior to the event (2009-2010) and 2 years after (2012-2013). While most metrics used in Vermont's biocriteria did not demonstrate a response to TS Irene, density showed a significant reduction in 2011 (across sites, percent change ranged from -24 to -91%; mean -66%). The percent change in density at each site was significantly correlated with the amount of localized rainfall during the storm (r s = -0.79, p = .02) and was most evident at small to medium-sized, high gradient streams. Reduced density caused several of these sites to fail to meet minimum criteria for biological integrity, though densities rebounded the following year. While the quick recovery indicated resiliency at these reference streams, the timing and magnitude of flood events may decrease the ability of biomonitoring programs to accurately evaluate the effect of watershed stressors.

The Effect of Food on the Pharmacokinetics of Sildenafil after Single Administration of a Sublingual Testosterone and Oral Sildenafil Combination Tablet in Healthy Female Subjects.

INTRODUCTION: Female sexual interest/arousal disorder (FSIAD) affects many women worldwide, but pharmacological treatment options are scarce. A new medicine being developed for FSIAD is an on-demand, dual-route, dual-release drug combination product containing 0.5 mg testosterone (T) and 50 mg sildenafil (S), referred to here as T+S. AIM: The aim of this study was to compare the effect of a fed and a fasted state on the pharmacokinetics of sildenafil following administration of T+S. METHODS: Eighteen healthy women were administered T+S under fed and fasted conditions during 2 separate overnight visits in this randomized, open-label, balanced, 2-period, 2-treatment, 2-sequence crossover study. MAIN OUTCOME MEASURES: The pharmacokinetics of sildenafil and its active metabolite N-desmethyl sildenafil were determined over a 24-hour period. Total testosterone was assessed only at a limited number of time points for quality purposes, as sublingual uptake is not expected to be affected by food intake. RESULTS: The observed geometric mean ratios (GMRs) and 90% confidence intervals of sildenafil were not all contained within the prespecified bounds (0.80, 1.25). The GMR (90% CI) for plasma AUC0-last was 1.2753 (0.9706-1.6755); for AUC0-14h, it was 1.7521 (1.0819-2.8374); and for Cmax, it was 1.5591 (0.8634-2.8153). Only lower limits of the CIs fell within the bounds. For N-desmethyl sildenafil, the GMR (90% CI) for AUC0-last was 0.8437 (0.6738-1.0564); for AUC0-10h, it was 1.0847 (0.7648-1.5383); and for Cmax, it was 1.0083 (0.6638-1.5318). Only the GMRs were contained within bounds. No differences were observed between plasma testosterone Cmax and Tmax under fed and fasted conditions, which is in line with expectations for a sublingual administration. CLINICAL IMPLICATIONS: The T+S combination tablet ruptures too late when taken in a fasted state and should therefore not be taken on an empty stomach. STRENGTHS & LIMITATIONS: This is a well-controlled study that provides important insights into the performance characteristics of the delayed-release coating of the combination tablet. The higher variability of the pharmacokinetic parameters in the fasted state was caused by severely delayed rupture in one-third of the women. A reason for this is proposed but the present data do not explain this phenomenon. CONCLUSION: The pharmacokinetics of sildenafil from this modified-release tablet are more robust under fed conditions as compared to the artificial fasted condition where no food is consumed 10 hours prior to and 4 hours after dosing. The dosing situation under the tested fasting condition does not represent the expected common use of this product. Patients should, however, be instructed not to take the tablet on an empty stomach. Bloemers J, Gerritsen J, van Rooij K, et al. The Effect of Food on the Pharmacokinetics of Sildenafil After Single Administration of a Sublingual Testosterone and Oral Sildenafil Combination Tablet in Healthy Female Subjects. J Sex Med 2019; 19:1433-1443.

Genotype scores predict drug efficacy in subtypes of female sexual interest/arousal disorder: A double-blind, randomized, placebo-controlled cross-over trial.

Attempts to develop a drug treatment for female sexual interest/arousal disorder have so far been guided by the principle of 'one size fits all', and have failed to acknowledge the complexity of female sexuality. Guided by personalized medicine, we designed two on-demand drugs targeting two distinct hypothesized causal mechanisms for this sexual disorder. The objective of this study was to design and test a novel procedure, based on genotyping, that predicts which of the two on-demand drugs will yield a positive treatment response. In a double-blind, randomized, placebo-controlled cross-over experiment, 139 women with female sexual interest/arousal disorder received three different on-demand drug-combination treatments during three 2-week periods: testosterone 0.5 mg + sildenafil 50 mg, testosterone 0.5 mg + buspirone 10 mg, and matching placebo. The primary endpoint was change in satisfactory sexual events. Subjects' genetic profile was assessed using a microarray chip that measures 300,000 single-nucleotide polymorphisms. A preselection of single-nucleotide polymorphisms associated with genes that are shown to be involved in sexual behaviour were combined into a Phenotype Prediction Score. The Phenotype Prediction Score demarcation formula was developed and subsequently validated on separate data sets. Prediction of drug-responders with the Phenotype Prediction Score demarcation formula gave large effect sizes (d = 0.66 through 1.06) in the true drug-responders, and medium effect sizes (d = 0.51 and d = 0.47) in all patients (including identified double, and non-responders). Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the Phenotype Prediction Score demarcation formula were all between 0.78 and 0.79, and thus sufficient. The resulting Phenotype Prediction Score was validated and shown to effectively and reliably predict which women would benefit from which on-demand drug, and could therefore also be useful in clinical practice, as a companion diagnostic establishing the way to a true personalized medicine approach.

Psychometric Properties of the Sexual Event Diary in a Sample of Dutch Women With Female Sexual Interest/Arousal Disorder.

BACKGROUND: Efficacy of on-demand drugs for women with hypoactive sexual desire disorder or female sexual interest/arousal disorder (FSIAD) should be assessed using a validated instrument that assesses the discrete sexual events during which the on-demand drug is taken, because this type of assessment is more proximate to an on-demand drug's efficacy compared to instruments that assess sexual function over longer periods of time. AIM: The aim of this study was to assess the psychometric properties of the Dutch translation of the previously validated 11-item Sexual Event Diary (SED) for measuring sexual satisfaction and sexual functioning during discrete sexual events. METHODS: Psychometric assessment was performed on data of 1,840 SEDs from 139 women with hypoactive sexual desire disorder/FSIAD, collected during a randomized clinical cross-over trial conducted in the Netherlands. OUTCOMES: Item scores of the SED at the event level, and at subject level, summarized item scores during the placebo run-in period (PRI) and active treatment period, and score changes from PRI to active treatment period. RESULTS: Reliability and convergent validity were confirmed. All item scores showed the ability to discriminate between known groups. Larger mean score changes from PRI were observed in groups with known benefit from the medication, as compared to those with no benefit. Guyatt effect sizes ranged from 0.51-1.02, thereby demonstrating ability to detect change. CLINICAL TRANSLATION: The Dutch version of the SED is an excellent instrument for assessing female sexual functioning and sexual satisfaction during discrete sexual events and for assessing these concepts over longer periods of time. CONCLUSIONS: Data were collected in a randomized, well-controlled trial. The large number of data points gave high statistical power, and the results confirmed previous findings. However, care is needed when generalizing the SED's validity to other areas of research, eg, recreational drug use and sexual risky behaviors, since the current validation study has not used such data. Consistent with the US-English version, the Dutch version of the SED is a reliable, valid, and responsive instrument, and suitable for use in evaluating effects of on-demand drugs in women with FSIAD. van Nes Y, Bloemers J, Kessels R, et al. Psychometric Properties of the Sexual Event Diary in a Sample of Dutch Women With Female Sexual Interest/Arousal Disorder. J Sex Med 2018;15:722-731.

Efficacy and Safety of On-Demand Use of 2 Treatments Designed for Different Etiologies of Female Sexual Interest/Arousal Disorder: 3 Randomized Clinical Trials.

BACKGROUND: In women, low sexual desire and/or sexual arousal can lead to sexual dissatisfaction and emotional distress, collectively defined as female sexual interest/arousal disorder (FSIAD). Few pharmaceutical treatment options are currently available. AIM: To investigate the efficacy and safety of 2 novel on-demand pharmacologic treatments that have been designed to treat 2 FSIAD subgroups (women with low sensitivity for sexual cues and women with dysfunctional over-activation of sexual inhibition) using a personalized medicine approach using an allocation formula based on genetic, hormonal, and psychological variables developed to predict drug efficacy in the subgroups. METHODS: 497 women (21-70 years old) with FSIAD were randomized to 1 of 12 8-week treatment regimens in 3 double-blinded, randomized, placebo-controlled, dose-finding studies conducted at 16 research sites in the United States. Efficacy and safety of the following on-demand treatments was tested: placebo, testosterone (T; 0.5 mg), sildenafil (S; 50 mg), buspirone (B; 10 mg) and combination therapies (T 0.25 mg + S 25 mg, T 0.25 mg + S 50 mg, T 0.5 mg + S 25 mg, T 0.5 mg + S 50 mg, and T 0.25 mg + B 5 mg, T 0.25 mg + B 10 mg, T 0.5 mg + B 5 mg, T 0.5 mg + B 10 mg). OUTCOMES: The primary efficacy measure was the change in satisfying sexual events (SSEs) from the 4-week baseline to the 4-week average of the 8-week active treatment period after medication intake. For the primary end points, the combination treatments were compared with placebo and the respective monotherapies on this measure. RESULTS: In women with low sensitivity for sexual cues, 0.5 mg T + 50 mg S increased the number of SSEs from baseline compared with placebo (difference in change [Δ] = 1.70, 95% CI = 0.57-2.84, P = .004) and monotherapies (S: Δ = 1.95, 95% CI = 0.44-3.45, P = .012; T: Δ = 1.69, 95% CI = 0.58-2.80, P = .003). In women with overactive inhibition, 0.5 mg T + 10 mg B increased the number of SSEs from baseline compared with placebo (Δ = 0.99, 95% CI = 0.17-1.82, P = .019) and monotherapies (B: Δ = 1.52, 95% CI = 0.57-2.46, P = .002; T: Δ = 0.98, 95% CI = 0.17-1.78, P = .018). Secondary end points followed this pattern of results. The most common drug-related side effects were flushing (T + S treatment, 3%; T + B treatment, 2%), headache (placebo treatment, 2%; T + S treatment, 9%), dizziness (T + B treatment, 3%), and nausea (T + S treatment, 3%; T + B treatment, 2%). CLINICAL IMPLICATIONS: T + S and T + B are promising treatments for women with FSIAD. STRENGTHS AND LIMITATIONS: The data were collected in 3 well-designed randomized clinical trials that tested multiple doses in a substantial number of women. The influence of T + S and T + B on distress and the potentially sustained improvements after medication cessation were not investigated. CONCLUSIONS: T + S and T + B are well tolerated and safe and significantly increase the number of SSEs in different FSIAD subgroups. Tuiten A, van Rooij K, Bloemers J, et al. Efficacy and Safety of On-Demand Use of 2 Treatments Designed for Different Etiologies of Female Sexual Interest/Arousal Disorder: 3 Randomized Clinical Trials. J Sex Med 2018;15:201-216.

The Sexual Event Diary (SED): Development and Validation of a Standardized Questionnaire for Assessing Female Sexual Functioning During Discrete Sexual Events.

BACKGROUND: The efficacy of on-demand drugs for hypoactive sexual desire disorder (HSDD) or female sexual interest/arousal disorder (FSIAD) should be assessed using a validated instrument that assesses the discrete sexual events during which the on-demand drug is taken. AIM: To develop and validate an event log for measuring sexual satisfaction and sexual functioning of discrete sexual events. METHODS: Psychometric assessment was carried out on data of 10,959 Sexual Event Diaries (SEDs) collected during three clinical trials in a total of 421 women with HSDD. Cognitive debriefing interviews were held with 16 women with HSDD. OUTCOMES: Item scores of the SED at the event level and at the subject level, summarized item scores of women during the baseline establishment and active treatment periods, and score changes in women from baseline establishment to active treatment. RESULTS: Several items of the initial 16-item SED items showed weak validity. The 16-item SED was refined to the 11-item SED. The reliability, content, and convergent validity of the 11-item SED were confirmed. For most 11-item SED item scores, the ability to discriminate between known groups was confirmed. Larger mean score changes from the baseline establishment period were found in those with than in those without known benefit from the medication, and Guyatt effect sizes ranged from 0.73 to 1.58, thereby demonstrating the ability to detect change. CLINICAL TRANSLATION: The SED is a good tool for assessing sexual function during a discrete sexual event and for assessing the sexual function of women over longer periods. STRENGTHS AND LIMITATIONS: The validation of the SED was performed on data from nearly 11,000 sexual events, gathered as part of a drug development program for HSDD and FSIAD. This amount of data provides very robust results when related to drug use for HSDD and FSIAD, but caution is advised when generalizing the validity of the SED directly to other areas of research (eg, recreational drug use and sexual risky behaviors), because such data were not used in this validation. CONCLUSIONS: The 11-item SED is a reliable, valid, and responsive instrument and suitable for use in evaluating the effects of on-demand drugs in women with HSDD or FSIAD. van Nes Y, Bloemers J, van der Heijden PGM, et al. The Sexual Event Diary (SED): Development and Validation of a Standardized Questionnaire for Assessing Female Sexual Functioning During Discrete Sexual Events. J Sex Med 2017;14:1438-1450.

A diatom-based biological condition gradient (BCG) approach for assessing impairment and developing nutrient criteria for streams.

Over-enrichment leading to excess algal growth is a major problem in rivers and streams. Regulations to protect streams typically incorporate nutrient criteria, concentrations of phosphorus and nitrogen that should not be exceeded in order to protect biological communities. A major challenge has been to develop an approach for both categorizing streams based on their biological conditions and determining scientifically defensible nutrient criteria to protect the biotic integrity of streams in those categories. To address this challenge, we applied the Biological Condition Gradient (BCG) approach to stream diatom assemblages to develop a system for categorizing sites by level of impairment, and then examined the related nutrient concentrations to identify potential nutrient criteria. The six levels of the BCG represent a range of ecological conditions from natural (1) to highly disturbed (6). A group of diatom experts developed a set of rules and a model to assign sites to these levels based on their diatom assemblages. To identify potential numeric nutrient criteria, we explored the relation of assigned BCG levels to nutrient concentrations, other anthropogenic stressors, and possible confounding variables using data for stream sites in New Jersey (n=42) and in surrounding Mid-Atlantic states, USA (n=1443). In both data sets, BCG levels correlated most strongly with total phosphorus and the percentage of forest in the watershed, but were independent of pH. We applied Threshold Indicator Taxa Analysis (TITAN) to determine change-points in the diatom assemblages along the BCG gradient. In both data sets, statistically significant diatom changes occurred between BCG levels 3 and 4. Sites with BCG levels 1 to 3 were dominated by species that grow attached to surfaces, while sites with BCG scores of 4 and above were characterized by motile diatoms. The diatom change-point corresponded with a total phosphorus concentration of about 50µg/L.

The Clitoral Photoplethysmograph: A Pilot Study Examining Discriminant and Convergent Validity.

INTRODUCTION: The clitoral photoplethysmograph (CPP) is a relatively new device used to measure changes in clitoral blood volume (CBV); however, its construct validity has not yet been evaluated. AIM: To evaluate the discriminant and convergent validity of the CPP. For discriminant validity, CBV responses should differ between sexual and nonsexual emotional films if the CPP accurately assesses clitoral vasocongestion associated with sexual arousal; for convergent validity, CBV responses should significantly correlate with subjective reports of sexual arousal. METHODS: Twenty women (M age = 21.2 years, SD = 3.4) watched neutral, anxiety-inducing, exhilarating, and sexual (female-male sex) audiovisual stimuli while their genital responses were measured simultaneously using vaginal and clitoral photoplethysmographs and CPPs. Most of these participants continuously reported sexual arousal throughout each stimulus (n = 16), and all reported their sexual and nonsexual affect before and after each stimulus; subjective responses were recorded via button presses using a keypad. MAIN OUTCOME MEASURES: Vaginal pulse amplitude (VPA), CBV, and self-reported sexual arousal and nonsexual affect were used as main outcome measures. RESULTS: CBV demonstrated both discriminant and convergent validity. CBV responses were similar to VPA responses and self-reported sexual arousal; all responses differed significantly as a function of stimulus content, with the sexual stimulus eliciting greater relative changes than nonsexual stimuli. CBV, but not VPA, was significantly (negatively) correlated with continuous self-reported sexual arousal during the shorter sexual stimulus. CBV was significantly negatively correlated with VPA for the shorter sexual stimulus. CONCLUSION: CBV may be a valid measure of women's genital sexual arousal that provides complementary information to VPA and correlates with self-reported sexual arousal. Given our relatively small sample size, and that this is among the first research to use the CPP, the current findings must be replicated. More research using the CPP and other devices is required for a more comprehensive description of women's physiological sexual arousal.

Reduced gray matter volume and increased white matter fractional anisotropy in women with hypoactive sexual desire disorder.

INTRODUCTION: Models of hypoactive sexual desire disorder (HSDD) imply altered central processing of sexual stimuli. Imaging studies have identified areas which show altered processing as compared with controls, but to date, structural neuroanatomical differences have not been described. AIM: The aim of this study is to investigate differences in brain structure between women with HSDD and women with no history of sexual dysfunction, and to determine sexual behavioral correlates of identified structural deviations. METHODS: Sexual functioning and gray matter (GM) and white matter (WM) were assessed in 29 women with HSDD and 16 healthy control subjects of comparable age and socioeconomic status with no history of sexual dysfunction. MAIN OUTCOME MEASURES: WM properties were measured using diffusion-weighted imaging and analyzed using fractional anisotropy (FA). GM volume was measured using three-dimensional T1-weighted recordings and analyzed using voxel-based morphometry. Sexual functioning was measured using the Sexual Function Questionnaire. RESULTS: Women with HSDD, as compared with controls, had reduced GM volume in the right insula, bilateral anterior temporal cortices, left occipitotemporal cortex, anterior cingulate gyrus, and right dorsolateral prefrontal cortex. Also, increased WM FA was observed within, amongst others, the bilateral amygdalae. Sexual interest and arousal correlated mostly with GM volume in these regions, whereas orgasm function correlated mostly with WM FA. CONCLUSION: HSDD coincides with anatomical differences in the central nervous system, in both GM and WM. The findings suggest that decreased salience attribution to sexual stimuli, decreased perception of bodily responses and sexual emotional stimulus perception, and concomitant altered attentional mechanisms associated with sexual response induction.

Toward personalized sexual medicine (part 3): testosterone combined with a Serotonin1A receptor agonist increases sexual satisfaction in women with HSDD and FSAD, and dysfunctional activation of sexual inhibitory mechanisms.

INTRODUCTION: Among other causes, low sexual desire in women may result from dysfunctional activation of sexual inhibition mechanisms during exposure to sex. Administration of sublingual 0.5 mg testosterone (T) increases the sensitivity of the brain to sexual cues, which might amplify sexual inhibitory mechanisms further in women already prone to sexual inhibition. Sexual stimulation might elicit a prefrontal cortex (PFC)-mediated phasic increase in sexual inhibition, in which activity of 5-hydroxytryptamine (5-HT, serotonin) is involved. A single dose of 5-HT receptor agonist (5-HT(1A)ra) might reduce the sexual stimulation induced PFC-mediated sexual inhibition during a short period after administration. Consequently, treatment with a single dose of T+5-HT(1A)ra might enhance sexual responsiveness, particularly in women exhibiting sexual inhibition. AIM: To investigate if treatment with a single dosage of T+5-HT(1A)ra will produce improvement in sexual functioning in women with Hypoactive Sexual Desire Disorder (HSDD) as the result of dysfunctional high sexual inhibition. METHODS: Fifty-four women were divided on the basis of their excitatory or inhibitory responses during T+phosphodiesterase type 5 inhibitor (PDE5i) in low (N = 26) and high inhibitors (N = 28). Physiological and subjective indices of sexual functioning were measured in a participant-controlled ambulatory psychophysiological experiment at home (the first week of each drug treatment). In a bedroom experiment (the subsequent 3 weeks), sexual functioning was evaluated by event, week, and monthly diaries. MAIN OUTCOME MEASURES: Subjective: sexual satisfaction, experienced genital arousal, sexual desire. Physiological: vaginal pulse amplitude. RESULTS: Women with high inhibition show a marked improvement in sexual function in response to treatment with T+5-HT ra relative to placebo and relative to T+PDE5i. CONCLUSIONS: The present study demonstrated that on-demand T+5-HT ra is a potentially promising treatment for women with HSDD, particularly for those women who are prone to sexual inhibition.

Toward personalized sexual medicine (part 2): testosterone combined with a PDE5 inhibitor increases sexual satisfaction in women with HSDD and FSAD, and a low sensitive system for sexual cues.

INTRODUCTION: Low sexual desire in women may result from a relative insensitivity of the brain for sexual cues. Administration of sublingual 0.5 mg testosterone (T) increases the sensitivity of the brain to sexual cues. Sexual stimulation in the brain is necessary for phosphodiesterase type 5 inhibitor (PDE5i)-mediated increase in genital sexual response. Accordingly, a single dose of T+PDE5i might enhance sexual responsiveness, especially in women with low sensitivity for sexual cues. AIM: To assess the hypothesis that treatment with on-demand use of T+PDE5i improves sexual functioning, particularly in women who suffer from Hypoactive Sexual Desire Disorder (HSDD) as the result of a relative insensitivity for sexual cues. METHODS: In a randomized, double-blind, placebo-controlled, crossover design, 56 women with HSDD underwent three medication treatment regimes (placebo, T+PDE5i, and T with a serotonin receptor agonist; see also parts 1 and 3), which lasted 4 weeks each. In a participant-controlled ambulatory psychophysiological experiment at home (the first week of each drug treatment), physiological and subjective indices of sexual functioning were measured. In a bedroom experiment (the subsequent 3 weeks), sexual functioning was evaluated following each sexual event after the self-administration of study medication. Subjective evaluation of sexual functioning was also measured by weekly and monthly reports. MAIN OUTCOME MEASURES: Subjective: sexual satisfaction, experienced genital arousal, sexual desire. Physiological: vaginal pulse amplitude. Cognitive: preconscious attentional bias. RESULTS: T+PDE5i, as compared with placebo, significantly improved physiological and subjective measures of sexual functioning during ambulatory psychophysiological lab conditions at home and during the sexual events, in women with low sensitivity for sexual cues. CONCLUSIONS: The present study demonstrated that on-demand T+PDE5i is a potentially promising treatment for women with HSDD, particularly in women with low sensitivity for sexual cues.

Toward personalized sexual medicine (part 1): integrating the "dual control model" into differential drug treatments for hypoactive sexual desire disorder and female sexual arousal disorder.

In three related manuscripts we describe our drug development program for the treatment of Hypoactive Sexual Desire Disorder (HSDD). In this first theoretical article we will defend the hypothesis that different causal mechanisms are responsible for the emergence of HSDD: low sexual desire in women (with HSDD) could be due to either a relative insensitive brain system for sexual cues or to enhanced activity of sexual inhibitory mechanisms. This distinction in etiological background was taken into account when designing and developing new pharmacotherapies for this disorder. Irrespective of circulating plasma levels of testosterone, administration of sublingual 0.5 mg testosterone increases the sensitivity of the brain to sexual cues. The effects of an increase in sexual sensitivity of the brain depend on the motivational state of an individual. It might activate sexual excitatory mechanisms in low sensitive women, while it could evoke (or strengthen) sexual inhibitory mechanisms in women prone to sexual inhibition. Sexual stimulation in the brain is necessary for phosphodiesterase type 5 inhibitor (PDE5i)-mediated increase in genital sexual response. Accordingly, a single dose of T+PDE5i might enhance sexual responsiveness, especially in women with low sensitivity to sexual cues. In other women sexual stimulation might elicit a prefrontal cortex (PFC)-mediated phasic increase in sexual inhibition, in which activity of 5-hydroxytryptamine (5-HT, serotonin) is involved. We hypothesize that a single dose of 5-hydroxytryptamine receptor agonist (5-HT(1A)ra) will reduce the sexual-stimulation-induced PFC-mediated sexual inhibition during a short period after administration. Consequently, treatment with T+5-HT(1A)ra will be more effective, in particular in women exhibiting sexual inhibition. Based on the results of our efficacy studies described in parts 2 and 3 of the series, we conclude that tailoring on-demand therapeutics to different underlying etiologies might be a useful approach to treat common symptoms in subgroups of women with HSDD.

Induction of sexual arousal in women under conditions of institutional and ambulatory laboratory circumstances: a comparative study.

INTRODUCTION: Measuring under naturally occurring circumstances increases ecological validity. We developed an ambulatory psychophysiological laboratory that allows experiments to be performed at home. AIMS: To compare institutional laboratory task measures with ambulatory laboratory task measures. MAIN OUTCOME MEASURES: Vaginal pulse amplitude (VPA), clitoral blood volume (CBV), subjective report of sexual arousal, preconscious attentional bias for erotic stimuli, subjective reports about feeling at ease, tense, anxious or inhibited. METHODS: VPA and CBV were measured in eight women with hypoactive sexual desire disorder (HSDD) and eight healthy controls while exposed to neutral and erotic film clips both in the institute's laboratory and at home. Before and after film clip presentations, subjects performed an emotional Stroop task and completed two questionnaires. RESULTS: In healthy controls, genital measures of sexual arousal were significantly increased at home compared with the institutional laboratory, whereas no differences were observed between the institutional laboratory and the at home measurements in women with HSDD. The responses at home were significantly higher in healthy controls compared with women with HSDD. Subjective experience of genital responding increased at home for both groups of women. Concordance between subjective experience and genital sexual arousal was more pronounced in the institutional laboratory setting. Preconscious attentional bias was stronger in the institutional laboratory for both groups of women. Healthy controls felt more at ease and less inhibited at home while subjects with HSDD did not. CONCLUSIONS: The use of an ambulatory laboratory is a valuable tool allowing psychophysiological (sex) research under more natural circumstances (e.g., a participant's home). In this study, the increase in ecological validity resulted in a qualitative differentiation between the healthy controls and the women with HSDD in the home setting, which is not apparent in the artificial setting of the institutional laboratory.

Cannabinoid modulations of resting state EEG θ power and working memory are correlated in humans.

Object representations in working memory depend on neural firing that is phase-locked to oscillations in the theta band (4-8 Hz). Cannabis intake disrupts synchronicity of theta oscillations and interferes with memory performance. Sixteen participants smoked cigarettes containing 0.0, 29.3, 49.1, or 69.4 mg Delta(9)-tetrahydrocannabinol (THC) in a randomized crossover design and performed working memory and general attention tasks. Dose-dependent effects of THC were observed for resting state EEG theta and beta power, working memory (per-item search time), and attentional performance (percent errors and RT). The THC effects on EEG theta power and memory performance were correlated, whereas other EEG and behavioral effects were not. These findings confirm and extend previous results in rodents and humans, and corroborate a neurocomputational model that postulates that temporal aspects of information processing in working memory depend causally on nested oscillations in the theta and gamma (>30 Hz) bands.

The clitoral photoplethysmograph: a new way of assessing genital arousal in women.

INTRODUCTION: In the present study, we introduce clitoral photoplethysmography as an instrument to assess clitoral blood volume (CBV). In research on female sexual functioning, vaginal pulse amplitude (VPA), as measured using vaginal photoplethysmography, has been used extensively as a measure of vaginal vasocongestion. Measurement of clitoral blood flow has thus far been problematic, mainly because of methodological constraints. AIM: To demonstrate that CBV is a valuable, easy to use complementary measure for the female sexual response, offering additional information to the VPA. METHODS: Thirty women with and without female sexual dysfunction (FSD) watched neutral and erotic film clips. At the end of the erotic clip, the session was interrupted to induce inhibition of the sexual response. Another neutral clip followed the interruption. VPA and CBV were measured simultaneously, as well as skin conductance levels (SCLs), to assess the amount of sympathetic activity. MAIN OUTCOME MEASURES: VPA, CBV, SCL. RESULTS: For both FSD and non-FSD women, VPA and CBV increased when sexually explicit material was presented. Changes in skin conductance significantly predicted changes in CBV (b = -0.61, t[27] = -3.88, P < 0.001), but not in VPA. A large increase in sympathetic activity was accompanied by a large decrease in CBV. Furthermore, a large increase in CBV at the end of the erotic film clip presentation, as compared with the neutral clip, was accompanied by a relatively small increase in VPA (b = -0.39, t[29] = -2.25, P < 0.033). CONCLUSION: CBV is a valid and sensitive tool to measure the female genital response. In the present study, it was particularly useful in investigating sexual inhibition, when used in combination with SCL. Furthermore, high CBV appeared to inhibit VPA, suggesting that VPA reflects an automatic preparatory response rather than genital arousal per se.