Jeroen Gerritsen

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 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 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.

Cannabinoid modulations of resting state eeg theta 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 Δ9-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.

ORIGINAL RESEARCH—ANATOMY/PHYSIOLOGY: 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 institutes 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 participants 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.

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.

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 womens 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 womens physiological sexual arousal.

Response to “Toward Personalized Sexual Medicine: Where is the Evidence?”

The authors of the letter “Toward Personalized Sexual Medicine: Where is the Evidence?” raise several concerns regarding the validity of the theoretical claims and findings described in our three “Toward Personalized Sexual Medicine” articles discussing two potential on-demand drug combinations for hypoactive sexual desire disorder (HSDD) ( J Sex Med 2013;10:791–809, 810–23, 824–37). It goes without saying that we appreciate critical review of our articles, but we believe that we can easily address the authors’ questions to the reader’s satisfaction. Empirical science consists of theoretical assumptions concerning cause-and-effect relationships, which are not directly observable. In other words, science is engaged with abstractions of the world. Based on such assumptions, predictions with observable consequences are made, which are tested against the empirical reality. If the results are consistent with what has been predicted, they can be regarded as (provisional) confirmation of the underlying theoretical assumptions (it is very unlikely that we will ever directly “see” the real truth). If the prediction does not come about (i.e., the empirical reality is recalcitrant), then doubts can be raised about the theoretical background (but this need not always be true). In the empirical sciences, we see scientists reporting correlations they have observed between variables. Such reports are descriptions of what the scientists have seen, not explanations in terms of the underlying mechanisms linking cause with effect. Such explanations are, strictly speaking, not part of science (although they can serve a hypothesis-forming function and, in this way, provide a gateway to the wonderful world of science).

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.