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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.)

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., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2013 International Society for Sexual Medicine.)

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

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.)

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

Introduction: Hypoactive sexual desire disorder (HSDD) is a common problem in women and may have a negative impact on quality of life. A recent clinical study shows an increase in sexual drive of HSDD women after cotreatment of testosterone and vardenafil (phosphodiesterase type 5 inhibitor)., Aim: In this study, we investigated the effect of testosterone and vardenafil on sexual activity in female rats., Main Outcome Measures:   Proceptive (darts and hops), receptive (lordosis), and paced-mating (percentages after exits and contact-return latencies) behaviors were quantified., Methods: Ovariectomized female rats, sub-primed with only estradiol and fully primed with estradiol and progesterone, were tested in a paced-mating sex test and sexual behaviors were quantified. The sub-primed rats are thought to model HSDD. The effect of testosterone (100 and 300 µg, subcutaneous [SC]) and vardenafil (10 mg/kg, per os [PO]) alone and testosterone (300 µg, SC) in combination with vardenafil (3 and 10 mg/kg, PO) were tested. We also studied the effects of testosterone (300 µg, SC) + intracerebroventricular (ICV) injections of vardenafil (25 and 50 µg) on sexual activity., Results: No effect of testosterone and vardenafil alone was found, but cotreatment of testosterone and vardenafil (PO) caused a significant increase in proceptive and receptive behavior in the sub-primed female rats. Testosterone and vardenafil did not affect fully primed females. ICV administration of vardenafil combined with systemic testosterone, on the other hand, had no effect on sexual activity in both sub-primed and fully primed female rats., Conclusions: We conclude that cotreatment of subcutaneous testosterone and oral vardenafil increase sexual activity in sub-primed female rats. Our data supports the human finding that combination treatment of testosterone and vardenafil could be used as a new treatment for women with HSDD., (© 2011 International Society for Sexual Medicine.)

Introduction: Selective serotonin reuptake inhibitors (SSRIs) cause sexual dysfunctions in humans. However, because SSRIs are used to treat depression, it is unclear whether the problems are caused by the drug, by the depression itself, or an interaction between both., Aim: The present study investigated the effects of chronic paroxetine treatment on sexual behavior in female rats. Furthermore, we tested whether 5-hydroxytryptamine (5-HT)₁(A) receptors were desensitized in these females., Methods: Ovariectomized female rats, either sub-primed with estradiol or fully primed with estradiol and progesterone, were tested in a paced mating test. Proceptive (darting and hopping), receptive (lordosis), and paced mating-related (percentages of exits and contact-return latencies) behaviors were quantified during the course of 56 days of chronic paroxetine treatment (10 mg/kg and 20 mg/kg per day). The 5-HT₁(A) /5-HT₇ receptor agonist (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide ((±)8-OH-DPAT) alone and in combination with the selective 5-HT₁(A) receptor antagonist WAY-100635 was administered to study putative 5-HT₁(A) desensitization in the same females., Main Outcome Measures: Proceptive, receptive, and paced mating behaviors were quantified., Results: Acute and chronic paroxetine treatment did not change proceptive and receptive behaviors in both sub-primed and fully primed female rats. In all groups, (±)8-OH-DPAT showed a clear dose-dependent inhibition of sexual behaviors in vehicle-treated females and a right-shifted dose-response effect in the paroxetine-treated rats. WAY-100635 attenuated the inhibiting effect of the 5-HT₁(A) receptor agonist in all females. These data suggest 5-HT₁(A) receptor desensitization after chronic paroxetine treatment., Conclusions: Chronic paroxetine treatment does not cause sexual side effects in sub- or fully hormonally primed female rats. Furthermore, chronic treatment causes adaptive changes in the serotonin system such as desensitization of 5-HT₁(A) receptors, which may counteract the inhibiting effects of increased extracellular serotonin levels in the chronic paroxetine-treated rats., (© 2011 International Society for Sexual Medicine.)

Introduction: Serotonin (5-HT) is an important neurotransmitter for sexual behaviors. Heterozygous (+/-) serotonin transporter (SERT) rats and SERT knockout rats (-/-) have serotonergic disturbances with significant elevations of basal extracellular 5-HT levels., Aim: To investigate the putative role of the SERT in male sexual behavior., Methods: After extensive sexual training, the effects of the 5-HT(1A/7) receptor agonist ± 8-OH-DPAT, the 5-HT(1A) receptor antagonist WAY100 635 and a combination of both on sexual behaviors of SERT(-/-) and SERT(+/-) knockout and wildtype (SERT(+/+) ) male Wistar rats were examined., Main Outcome Measures: Male rat sexual behaviors of mounts, intromissions, and ejaculations., Results: SERT(-/-) had lower basal ejaculation frequencies than SERT(+/-) and SERT(+/+) animals. ± 8-OH-DPAT enhanced sexual performance in all three genotypes to the same extent. WAY100635 dose-dependently inhibited sexual behavior in all three genotypes with significant dose to genotype interactions. WAY100635 exerted the strongest effects in SERT(-/-) animals. The combination of a dose range of ± 8-OH-DPAT and a selected dose of WAY100635 revealed only partial antagonism by ± 8-OH-DPAT of the sexual inhibitory effects of WAY100635., Conclusions: Absence of the serotonin transporter reduces basal ejaculatory performance in male rats. Pharmacological experiments suggest that separate pools of 5-HT(1A) receptors regulate different aspects of sexual performance in male rats. 5-HT(7) receptors may play a minor role in the partial recovery of sexual behavior after combination of ± 8-OH-DPAT and WAY100635. The SERT(-/-) rat may be a model for chronic SSRI treatment, delayed ejaculation, anorgasmia, and/or low libido., (© 2010 International Society for Sexual Medicine.)

Introduction: Female sexual dysfunction (FSD) affects 33-48% of women. Female rats with low sexual activity might model FSD., Aim: In this study, we have investigated whether in a population of normal female rats, subpopulations of rats exist with different levels of sexual behavior., Methods: Sexually experienced, intact, estradiol-primed female rats were placed in an empty compartment adjacent to a compartment with a male. The females were allowed, during 30 minutes, to switch between the compartments via a hole through which only the females could pass (paced mating). Next, we investigated the acute effects on female sexual behavior of apomorphine, a D(1) - and D(2) -type dopamine receptor agonist, (+/-)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (± 8-OH-DPAT), a 5-HT1A receptor agonist, and paroxetine, a selective serotonin reuptake inhibitor., Main Outcome Measures: Time spent in compartments, proceptive behaviors, contact-return latencies, and percentages of exits were quantified., Results: Based on their behavior in the paced mating sex test, estradiol-primed, intact female rats can be divided into three groups: those that mostly avoid the male, a large middle group, and those that mostly approach the male. The avoiders also showed significantly less proceptive behavior than the male approachers. The sexual behavior of the females was relatively stable over time, suggesting the existence of different endophenotypes in female rats. Apomorphine and ± 8-OH-DPAT had an inhibiting effect on sexual behavior, but only females dosed with apomorphine showed a different response in avoiders and approachers, more inhibiting effect in avoiders than approachers. Paroxetine had no effect on proceptive behavior., Discussion: The stable, male-avoiding behavior of some females might correspond to the characteristics of women with FSD. Therefore, these avoiders are a promising new model for FSD, specifically for sexual desire and/or arousal disorders. Furthermore, the apomorphine data suggest that differences in the dopamine system may (partly) underlie the differences in sexual behaviors between avoiders and approachers., (© 2010 International Society for Sexual Medicine.)

Introduction: Serotonin plays a key role in sexual behavior. In serotonin transporter (SERT) knockout rats (-/-), basal extracellular 5-HT levels are considerably increased, indicating a serotonergic disturbance. Heterozygous SERT(+/-) rats express 50% of SERT in comparison to wild-type rats and may therefore model the s/s phenotype of the human SERT promoter (5-HTTLPR) polymorphism., Aim: In the present study, we used both homozygote and heterozygote SERT knockout and wild-type rats (+/+) to study the putative role of the SERT in female sexual behavior., Methods: Female rats were brought into estrous by hormonal injections before a paced mating sex test. The effects of the 5-HT(1A)/5-HT(7) receptor agonist (+/-)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (+/-8-OH-DPAT) (0.03-1 mg/kg s.c.) and the 5-HT(1A) receptor antagonist WAY-100635 (0.1-1-mg/kg i.p.) on sexual behaviors of the females were tested separately and in a selected combination of both in all three genotypes., Main Outcome Measures: Proceptive (darting and hopping) and receptive (lordosis) behaviors were quantified., Results: Basal proceptive and receptive sexual activities were not different between SERT+/+, +/- and -/- female rats. The dose-effect curve after +/-8-OH-DPAT for these activities was clearly shifted to the right in SERT-/- animals compared to other genotypes. WAY-100635 alone had no effect on sexual behavior in any genotype, but was able to antagonize the +/-8-OH-DPAT-induced decrease in sexual activities indicating the involvement of the 5-HT(1A) receptor., Conclusions: The absence (-/-) or reduced (+/-) expression of SERT does not affect basal sexual activity in female rats in a paced mating situation. The data indicate a desensitized 5-HT1A receptor in the SERT-/-, but not in the SERT+/- females. Under normal basal conditions, desensitized 5-HT1A receptors apparently do not play a role in female sexual behavior of the SERT-/-. However, upon activation of the 5-HT1A receptor in "normal" females (SERT+/+ and SERT+/-), a hyposexual behavior is induced.

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.

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.

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.

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.

Introduction: Lifelong premature ejaculation (LPE) is characterized by persistent intravaginal ejaculation latency times (IELTs) of less than 1 minute, and has been postulated as a neurobiological dysfunction with genetic vulnerability for the short IELTs, related to disturbances of central serotonin (5-hydroxytryptamine [5-HT]) neurotransmission and 5-HT receptor functioning., Aim: To investigate the relationship between 5-HT transporter gene-linked polymorphism (5-HTTLPR) and short IELTs in men with lifelong PE., Methods: A prospective study was conducted in 89 Dutch Caucasian men with lifelong PE. IELT during coitus was assessed by stopwatch over a 1-month period. Controls consisted of 92 Dutch Caucasian men. All men with LPE were genotyped for a 5-HTT-promoter polymorphism. Allele frequencies and genotypes of short (S) and long (L) variants of 5-HTTLPR polymorphism were compared between patients and controls. Association between LL, SL, and SS genotypes, and the natural logarithm of the IELT in men with LPE was investigated., Main Outcome Measures: IELT measured by stopwatch, 5-HTTLPR polymorphism., Results: In men with lifelong PE, the geometric mean, median, and natural mean IELTs were 21, 26, and 32 seconds, respectively. There were no significant differences in the 5-HTT polymorphism alleles and genotypes between 89 Dutch Caucasian men with LPE (S 47%, L 53%/LL 29%, SL 48%, SS 22%) and 92 Dutch Caucasian controls (S 48%, L 52%/LL 29%, SL 45%, SS 26%). In men with lifelong PE there was a statistically significant difference between LL, SL, and SS genotypes in their geometric mean IELT (P < or = 0.027); the LL genotypes had significantly shorter IELTs than the SS and SL genotypes., Conclusions: The 5-HTTLPR polymorphism is associated with significant effects on the latency to ejaculate in men with lifelong PE. Men with SS and SL genotypes have 100% and 90% longer ejaculation time, respectively than men with LL genotypes.

Introduction: The intravaginal ejaculation latency time (IELT) behaves in a skewed manner and needs the appropriate statistics for correct interpretation of treatment results., Aims: To explain the rightful use of geometrical mean IELT values and the fold increase of the geometric mean IELT because of the positively skewed IELT distribution., Methods: Linking theoretical arguments to the outcome of several selective serotonin reuptake inhibitor and modern antidepressant study results., Main Outcome Measures: Geometric mean IELT and fold increase of geometrical mean IELT., Results: Log-transforming each separate IELT measurement of each individual man is the basis for the calculation of the geometric mean IELT. A drug-induced positively skewed IELT distribution necessitates the calculation of the geometric mean IELTs at baseline and during drug treatment. In a positively skewed IELT distribution, the use of the "arithmetic" mean IELT risks an overestimation of the drug-induced ejaculation delay as the mean IELT is always higher than the geometric mean IELT. Strong ejaculation-delaying drugs give rise to a strong positively skewed IELT distribution, whereas weak ejaculation-delaying drugs give rise to (much) less skewed IELT distributions. Ejaculation delay is expressed in fold increase of the geometric mean IELT., Conclusions: Drug-induced ejaculatory performance discloses a positively skewed IELT distribution, requiring the use of the geometric mean IELT and the fold increase of the geometric mean IELT.

Introduction: Whether men with lifelong premature ejaculation (PE) prefer on-demand drug treatment to delay ejaculation time to daily drug treatment, has never been studied as a separate study question., Aim: To study how men with lifelong PE feel about the use of serotonergic antidepressants, and which option they would prefer for themselves: either a daily drug, a drug to be used on demand, or a topical anesthetic cream to be applied on demand., Main Outcome Measures: Treatment preference was determined by questionnaire., Methods: An observational questionnaire survey in a clinical sample. Preferences of different treatment strategies were queried before and after standard efficacy and safety information., Results: A consecutive group of 88 men with lifelong PE who decided for themselves to be seen for rapid ejaculation was studied. The age was 37 +/- 11 years (mean +/- SD), range 18-64 years. None of these men was ever treated for PE and 21% used medication that did not affect sexual performance. Of them, 71 (81%) preferred a drug for daily use, 14 (16%) a drug on demand, while three men preferred topical anesthetic cream. Those men who initially preferred daily treatment did not change their view after standard information about efficacy and side effects, while 9 of 17 men who initially preferred on-demand drug treatment had switched their preferences to daily oral drug usage. Around 60% of men did not care about the nature of the drug, i.e., an antidepressant. The most frequently reported argument to prefer daily drug treatment was that this strategy would have the least effects toward the spontaneity of having sex., Conclusion: As opposed to agents that must be taken 4-6 hours prior to coitus and with the methods used here, this group of Dutch men with lifelong PE favor uninterrupted daily drug treatment to delay ejaculation mainly because daily treatment guarantees no interference with the spontaneity of having sex.

Introduction: Selective serotonin reuptake inhibitors (SSRIs) differ in the severity of induced ejaculation delay. Various studies indicate that oxytocin is involved in sexual behavior., Aim: To review and evaluate the involvement of oxytocin in SSRI-induced ejaculation delay., Main Outcome Measures: Oxytocine release, 5-hydroxytryptamine (5-HT) neurotransmission, and desensitization of 5-HT(1A) receptors., Methods: A review and critical analysis of animal studies investigating the interaction of serotonergic and oxytocinergic neurotransmission in relation to the ejaculation process., Results: Although acute treatment with the SSRIs fluoxetine and paroxetine immediately causes increased serotonin levels, delayed ejaculation does not occur. The increased serotonin levels induce oxytocin release via activation of 5-HT(1A) receptors, and this might compensate for the inhibitory actions of serotonin on sexual behavior. Chronic treatment with fluoxetine and paroxetine desensitizes 5-HT(1A) receptors on oxytocin neurons, and that might in part determine the onset of delayed ejaculation. Desensitization of 5-HT(1A) receptors is less strong following chronic treatment with the SSRIs fluvoxamine or citalopram, which may attenuate the degree of delayed ejaculation., Conclusions: Preliminary data suggest that the severity of chronic SSRI treatment-induced delayed ejaculation and the differences between the various SSRIs in inducing ejaculation delay is related to gradual desensitization of 5-HT(1A) receptors on oxytocin neurons.

Introduction: Apart from the involvement of central serotonergic neurotransmission on lifelong premature ejaculation, interference of thyroid function has been speculated., Aim: To study thyroid function in a large group of men with lifelong premature ejaculation (LPE)., Methods: Lifelong premature ejaculation was defined as an intravaginal ejaculation latency time (IELT) of less than 1 minute. Any consecutive man with LPE and no erectile dysfunction assessed by medical history and the International Index of Erectile Function (IIEF-5) was eligible for the study. Apart from the assessment of thyroid-stimulating hormone (TSH) also free thyroxin (f T4) was determined in case of a TSH of <0.3 mU/L or TSH of >4.0 mU/L (being the lower and upper limits of normal values, respectively). Blood samples were drawn throughout the day within office hours., Main Outcome Measures: Thyroid-stimulating hormone and f T4., Results: Included were 620 men; age (mean+/-SD) was 39.9+/-9.4 years (range 19-65). TSH concentrations from morning, early and late afternoon samples did not differ. The geometrical mean TSH concentration was 0.85 mU/L (95% confidence intervals: 0.82-0.90) with a coefficient of variation of 57.9%. Fourteen men had a TSH of <0.3 mU/L (2.2%), while five men (0.8%) of >4.0 mU/L. All men with an abnormal TSH had a normal f T4 (between 10 and 20 pmol/L). No relationship was found between age and TSH concentrations., Conclusion: Thyroid-stimulating hormone distribution was analyzed in a cohort of Dutch men with lifelong premature ejaculation and no erectile dysfunction. According to statistical analysis, there appeared to be no interaction between this ejaculatory complaint and the prevalence of thyroidal dysfunction. However, further studies are needed to gain more insight into the role of thyroid dysfunction and regulation of ejaculation time.

Introduction: Consensus on a definition of premature ejaculation has not yet been reached because of debates based on subjective authority opinions and nonstandardized assessment methods to measure ejaculation time and ejaculation control., Aim: To provide a definition for lifelong premature ejaculation that is based on epidemiological evidence including the neurobiological and psychological approach., Methods: We used the 0.5 and 2.5 percentiles as accepted standards of disease definition in a skewed distribution. We applied these percentiles in a stopwatch-determined intravaginal ejaculation latency time (IELT) distribution of 491 nonselected men from five different countries. The practical consequences of 0.5% and 2.5% cutoff points for disease definition were taken into consideration by reviewing current knowledge of feelings of control and satisfaction in relation to ejaculatory performance of the general male population., Main Outcome Measures: Literature arguments to be used in a proposed consensus on a definition of premature ejaculation., Results: The stopwatch-determined IELT distribution is positively skewed. The 0.5 percentile equates to an IELT of 0.9 minute and the 2.5 percentile an IELT of 1.3 minutes. However, there are no available data in the literature on feelings of control or satisfaction in relation to ejaculatory latency time in the general male population. Random male cohort studies are needed to end all speculation on this subject. Exact stopwatch time assessment of IELT in a multinational study led us to propose that all men with an IELT of less than 1 minute (belonging to the 0.5 percentile) have "definite" premature ejaculation, while men with IELTs between 1 and 1.5 minutes (between 0.5 and 2.5 percentile) have "probable" premature ejaculation. Severity of premature ejaculation (nonsymptomatic, mild, moderate, severe) should be defined in terms of associated psychological problems., Conclusion: We define lifelong premature ejaculation as a neurobiological dysfunction with an unacceptable increase of risk to develop sexual and psychological problems anywhere in a lifetime. By defining premature ejaculation from an authority-defined disorder into a dysfunction based on epidemiological evidence it is possible to establish consensus based on epidemiological evidence. Additional epidemiological stopwatch studies are needed for a final decision of IELT values at both percentile cutoff points.

Introduction: Recently, the idea has emerged that on-demand use of serotonin reuptake inhibitors (SSRIs), particularly short half-life, should be equally effective in delaying ejaculation as daily SSRI treatment of premature ejaculation., Aim: To provide evidence that SSRI-induced ejaculation delay is mainly dependent on pharmacodynamic properties of the drug and hardly on pharmacokinetic factors, and that combined SSRI administration with specific 5-hydroxytryptamine (5-HT) receptor antagonism leads acutely to stronger ejaculation delay than acute SSRI monoadministration., Methods: We performed a detailed analysis of serotonin neurotransmission and reviewed animal studies with 5-HT(1A) receptor antagonists. In addition, we critically reviewed existing on-demand SSRI treatments publications and the current debate on a definition of premature ejaculation., Main Outcome Measures: Intravaginal ejaculation latency time (IELT)., Results: Acute SSRI administration leads to only a mild or no increase of 5-HT neurotransmission and concomitant stimulation of postsynaptic 5-HT receptors. Existing on-demand SSRI treatment studies suffer from methodological insufficiencies, and the reported high-fold increases of ejaculation time contradict with neuropharmacological insights from serotonin metabolism. Animal studies show that SSRI coadministration with 5-HT(1A) receptor antagonists significantly increases the ejaculation time acutely compared to acute SSRI monoadministration., Conclusion: On-demand SSRI treatment has less ejaculation-delaying effects than daily SSRI treatment. SSRIs with a short half-life are likely leading to much less ejaculation delay than current registered SSRIs. Combined use of SSRIs with 5-HT(1A) receptor antagonists increases the likelihood of clinically relevant ejaculation delay after on-demand treatment. On-demand SSRIs with short half-life that insufficiently delay ejaculation in men with IELTs less than 1 minute should be called ejaculation-delaying drugs rather than drugs against premature ejaculation.