Kim van Rooij

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.

Pharmacokinetics of three doses of sublingual testosterone in healthy premenopausal women

CONTEXT Sublingual testosterone is a single-dose treatment often used in studies regarding social, cognitive and sexual behavior. It is hypothesized that an increase in the ratio of free to total testosterone (free fraction) is indirectly, via genomic effects, responsible for the behavioral effects after sublingual testosterone administration. OBJECTIVE To characterize the pharmacokinetics of three doses sublingual testosterone in premenopausal women. Also, to investigate the SHBG saturation threshold influencing the free level and free fraction of testosterone. DESIGN We conducted an investigator-blind, randomized, cross-over placebo controlled study. SETTING This study was undertaken at the research and development department of a scientific company for research regarding female sexual dysfunction. PARTICIPANTS 16 healthy premenopausal women (mean age 27.3±5.3 years). INTERVENTIONS Sublingual testosterone solution; 0.25, 0.50 and 0.75 mg. MAIN OUTCOMES MEASURE The pharmacokinetics of three single doses sublingual testosterone solution; the influence of SHBG levels on free and total levels of testosterone. RESULTS After sublingual testosterone administration, serum free and total testosterone levels peaked at 15 min and reached baseline levels within 150 min. The AUCs and C(max) of free and total testosterone differed significantly between the three doses (p<0.0001) and increased dose-dependently. A dose-dependent increase in free fraction of testosterone was found in women with low SHBG levels, but not in women with high SHBG levels. CONCLUSIONS The three doses sublingual testosterone are rapidly absorbed and quickly metabolized in premenopausal women. These data demonstrate the influence of SHBG levels on the treatment induced alterations in plasma free testosterone.

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.

Two novel combined drug treatments for women with hypoactive sexual desire disorder

Low sexual desire is the most common sexual complaint in women. As a result, many women suffer from sexual dissatisfaction which often negatively interferes with their quality of life. These complaints have been classified as the condition Hypoactive Sexual Desire Disorder (HSDD), and have recently been merged with the condition Female Sexual Arousal Disorder (FSAD) into the diagnosis Female Sexual Interest/Arousal Disorder (FSIAD) in the DSM-5. To date, no drug treatment approved by the U.S. Food & Drug Administration (FDA)/European Medicines Agency (EMA) is available to treat women with HSDD/FSIAD. As a result, there is an unmet need for a drug treatment for HSDD/FSIAD. In our search for an adequate treatment we followed a different approach compared to other pharmaceutical companies. Based on a personalized sexual medicine approach we proposed that different mechanisms cause low sexual desire in women, namely an insensitive system for sexual cues or dysfunctional activation of sexual inhibitory mechanisms. Subsequently we developed two new on-demand drug treatments for women with HSDD/FSIAD based on these different causal mechanisms. One treatment (testosterone combined with a phosphodiesterase type 5 inhibitor) has been developed for women with HSDD/FSIAD due to a relatively insensitive system for sexual cues, while the second treatment (testosterone combined with a 5-HT₁A receptor agonist) has been developed for women with HSDD/FSIAD due to dysfunctional activation of sexual inhibitory mechanisms.

Efficacy of testosterone combined with a PDE5 inhibitor and testosterone combined with a serotonin 1A receptor agonist in women with SSRI-induced sexual dysfunction. A preliminary study

Selective serotonin reuptake inhibitors (SSRIs) are known to cause sexual dysfunction, such as decreased sexual motivation, desire, arousal, and orgasm difficulties. These SSRI-induced sexual complaints have a high prevalence rate, while there is no approved pharmacological treatment for SSRI-induced sexual dysfunction. It is hypothesized that a polymorphisms in the androgen receptor gene, encoded by the nucleotides cysteine, adenine, and guanine (CAG), influence the effect of testosterone on sexual functioning. In an explorative, randomized, double-blind, placebo-controlled, crossover study we investigated the possible effects of sublingual testosterone combined with a serotonin (5-HT)1A receptor agonist, and of sublingual testosterone combined with a phosphodiesterase type 5 inhibitor (PDE5-i) on sexual functioning in women with SSRI-induced sexual dysfunction. Furthermore, we did an exploratory analysis to assess if the CAG polymorphism influences this effect. 21 pre- and postmenopausal women with SSRI-induced sexual dysfunction participated and underwent the following interventions: a combination of testosterone (0.5 mg) sublingually and the PDE5-i sildenafil (50 mg) and a combination of testosterone (0.5 mg) sublingually and the 5-HT1A receptor agonist buspirone (10 mg). The results show that women who use a low dose of SSRI and have relatively long CAG repeats report a marked improvement in sexual function in response to both treatments compared to placebo. This explorative study and preliminary results indicate that in women with SSRI-induced sexual dysfunction, a combination of testosterone sublingually and a PDE5-i or testosterone sublingually and a 5-HT1A receptor agonist might be promising treatments for certain subgroups of women with this condition.

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.

Een vernieuwende farmacotherapeutische behandeling voor vrouwen met hypoactive sexual desire disorder

SamenvattingVerminderd seksueel verlangen is de meest voorkomende seksuele klacht bij vrouwen. Dit kan seksuele ontevredenheid veroorzaken, wat een negatieve invloed kan hebben op de kwaliteit van leven. Deze klachten zijn in de DSM-IV geclassificeerd als de diagnose Hypoactive Sexual Desire Disorder (HSDD) en sinds kort ondergebracht in de nieuwe diagnose Female Sexual Interest/Arousal Disorder (FSIAD) in de DSM-5. Op dit moment is er nog geen goedgekeurde medicamenteuze behandeling beschikbaar voor vrouwen met HSDD (FSIAD) terwijl er wel grote behoefte aan is. In onze zoektocht naar adequate medische behandelingsmogelijkheden hebben wij een andere wetenschappelijke aanpak gevolgd dan de grote farmaceutische bedrijven. Op basis van een personalized sexual medicine approach hebben we eerst vastgesteld dat er tussen vrouwen verschillen bestaan in oorzakelijke mechanismen die ten grondslag kunnen liggen aan de seksuele klachten. Dit leidde tot twee onderscheidende mechanismen: een ongevoelig systeem voor seksuele stimuli en een overactief seksueel remsysteem. Gebaseerd op deze onderliggende oorzaken van HSDD zijn twee nieuwe on-demand medicamenteuze behandelingen ontwikkeld. De ene behandeling (testosteron gecombineerd met een fosfodiësterase-type-5-remmer) is ontwikkeld voor vrouwen die lijden aan HSDD als gevolg van een relatief ongevoelig systeem voor seksuele prikkels, terwijl de andere behandeling (testosteron gecombineerd met een 5-HT1A -receptoragonist) is ontwikkeld voor vrouwen die lijden aan HSDD als gevolg van overmatige activatie van het seksuele remsysteem.