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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. [ABSTRACT FROM AUTHOR]

A response from the authors of the articles related to the use of personalized medicine for the treatment of sexual disorders in women.

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. [ABSTRACT FROM AUTHOR]

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. Suschinsky KD, Shelley AJ, Gerritsen J, Tuiten A, and Chivers ML. The clitoral photoplethysmograph: A pilot study examining discriminant and convergent validity. J Sex Med 2015;12:2324-2338. [ABSTRACT FROM AUTHOR]

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. Bloemers J, Scholte HS, van Rooij K, Goldstein I, Gerritsen J, Olivier B, and Tuiten A. Reduced gray matter volume and increased white matter fractional anisotropy in women with hypoactive sexual desire disorder. J Sex Med 2014;11:753-767. [ABSTRACT FROM AUTHOR]

ABSTRACT 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 1A 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. Poels S, Bloemers J, van Rooij K, Goldstein I, Gerritsen J, van Ham D, van Mameren F, Chivers M, Everaerd W, Koppeschaar H, Olivier B, and Tuiten A. 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. J Sex Med 2013;10:810-823. [ABSTRACT FROM AUTHOR]

ABSTRACT 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-HT1A receptor agonist (5-HT1Ara) 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-HT1Ara might enhance sexual responsiveness, particularly in women exhibiting sexual inhibition. Aim. To investigate if treatment with a single dosage of T+5-HT1Ara 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-HT1Ara relative to placebo and relative to T+PDE5i. Conclusions. The present study demonstrated that on-demand T+5-HT1Ara is a potentially promising treatment for women with HSDD, particularly for those women who are prone to sexual inhibition. van Rooij K, Poels S, Bloemers J, Goldstein I, Gerritsen J, van Ham D, van Mameren F, Chivers M, Everaerd W, Koppeschaar H, Olivier B, and Tuiten A. 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. J Sex Med 2013;10:824-837. [ABSTRACT FROM AUTHOR]

ABSTRACT 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-hydroxytryptamine1A receptor agonist (5-HT1Ara) will reduce the sexual-stimulation-induced PFC-mediated sexual inhibition during a short period after administration. Consequently, treatment with T+5-HT1Ara 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. Bloemers J, van Rooij K, Poels S, Goldstein I, Everaerd W, Koppeschaar H, Chivers M, Gerritsen J, van Ham D, Olivier B, and Tuiten A. 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. J Sex Med 2013;10:791-809. [ABSTRACT FROM AUTHOR]

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. Bloemers J, Gerritsen J, Bults R, Koppeschaar H, Everaerd W, Olivier B, and Tuiten A. Induction of sexual arousal in women under conditions of institutional and ambulatory laboratory circumstances: A comparative study. J Sex Med 2010;7:1160–1176. [ABSTRACT FROM AUTHOR]

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. Gerritsen J, van der Made F, Bloemers J, van Ham D, Kleiverda G, Everaerd W, Olivier B, Levin R, and Tuiten A. The clitoral photoplethysmograph: A new way of assessing genital arousal in women. J Sex Med 2009;6:1678–1687. [ABSTRACT FROM AUTHOR]

Introduction. Women with female sexual dysfunction have a reduced sensitivity to sexual stimuli. Activation of central mechanisms may open a window for phosphodiesterase type 5 inhibitors (PDE5) to be effective; as a consequence, the combination of testosterone and a PDE5 inhibitor will restore sexual function. Aim. To demonstrate that the combination of testosterone and vardenafil will increase the sensitivity for sexual stimuli and will improve the desire and arousal components of the sexual response. Methods. In a double-blind randomly assigned placebo-controlled crossover design, 28 women with desire and/or arousal disorder underwent four different drug treatments on four separate experimental days. A masked version of the emotional Stroop task with sexual and nonsexual words was used to measure sensitivity for sexual content. Neutral and erotic film fragments were used to determine genital–physiological and subjective reactions. Main Outcome Measures. A masked version of the emotional Stroop task, vaginal pulse amplitude. For subjective measurement, responses were collected continuously with a lever and two self-report measures were used. Results. In two subgroups, which were differentiated on the basis of their initial preconscious attentional bias for sexual cues, a different sexual response profile was found. In an initially low-attention group, preconscious attentional bias for sexual cues increased under the testosterone condition. In these women, the combination of testosterone and vardenafil caused an improvement in genital response and subjective indices of sexual functioning. In the group that had initially a high attention for sexual cues, preconscious attentional bias for sexual cues decreased under the condition of testosterone. In these women, the combination of testosterone and vardenafil had no effect on any of the indices of their sexual functioning. Conclusion. In women suffering from low sexual desire—associated with low attention for sexual cues—the combination of testosterone and vardenafil may be a promising new treatment. van der Made F, Bloemers J, Yassem WE, Kleiverda G, Everaerd W, van Ham D, Olivier B, Koppeschaar H, and Tuiten A. The influence of testosterone combined with a PDE5-inhibitor on cognitive, affective, and physiological sexual functioning in women suffering from sexual dysfunction. J Sex Med 2009;6:777–790. [ABSTRACT FROM AUTHOR]

Introduction. Female sexual dysfunction (FSD) may be associated with reduced central sensitivity for sexual cues. A single dose of testosterone might induce an increase in sensitivity for sexual stimuli, which in turn allows a PDE5 inhibitor to be effective in boosting the physiological sexual response. Negative sexual experience—like childhood sexual abuse (CSA)—might be an important intervening factor in these drugs-induced alterations. Aim. To investigate if the combination of testosterone and vardenafil causes an increase in sensitivity for sexual cues and an increase in physiological sexual responding in women suffering from hypoactive sexual desire disorder (HSDD). Methods. Thirteen women with HSDD underwent four different drug treatments: (i) placebo; (ii) vardenafil; (iii) testosterone; and (iv) combination of testosterone and vardenafil. During each treatment, they performed an emotional Stroop task and watched neutral and erotic film clips. Main Outcome Measures. A masked version of the emotional Stroop task, and the vaginal pulse amplitude (VPA). Results. We found different effects in women who had reported CSA (N = 5) compared with those who had not (N = 8). In women without CSA, testosterone induced an increase in their originally low levels of preconscious attention for sexual cues, while women with CSA showed a decrease in their originally high levels of attention. In these groups, we also found different effects of the combination of testosterone and vardenafil on the VPA: women without CSA revealed a statistically significant increase in their VPA during treatment with the combination of testosterone and vardenafil as compared with placebo. Women with CSA, however, showed no alterations in their physiological sexual responding during this combined drug treatment. Conclusion. In women without CSA, testosterone appears to activate central sexual mechanisms resulting in higher VPA under the combination of testosterone and vardenafil. This effect did not occur in women with CSA. van der Made F, Bloemers J, van Ham D, El Yassem W, Kleiverda G, Everaerd W, Olivier B, and Tuiten A. Childhood sexual abuse, selective attention for sexual cues and the effects of testosterone with or without vardenafil on physiological sexual arousal in women with sexual dysfunction: A pilot study. J Sex Med 2009;6:429–439. [ABSTRACT FROM AUTHOR]

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 AUC 0-last was 1.2753 (0.9706-1.6755); for AUC 0-14h , it was 1.7521 (1.0819-2.8374); and for C max , 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 AUC 0-last was 0.8437 (0.6738-1.0564); for AUC 0-10h , it was 1.0847 (0.7648-1.5383); and for C max , it was 1.0083 (0.6638-1.5318). Only the GMRs were contained within bounds. No differences were observed between plasma testosterone C max and T max 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., (Copyright © 2019 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

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., (© 2012 International Society for Sexual Medicine.)