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

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. 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 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.

Reduced Gray Matter Volume and Increased White Matter Fractional Anisotropy in Women with Hypoactive Sexual Desire Disorder

“…According to this subdivision, HSDD can be caused by low sensitivity to sexual cues or by overactivation of sexual inhibitory systems. The overinhibitors, however, possess normal sexual cue sensitivity which does not seem to be the case with the present subset [59]. Possibly, these inhibitors were underrepresented in the present subset, or the decreased GM volume may not reflect The present study could not determine whether the observed GM volume and WM FA differences cause or are caused by sexual dysfunction.…”

“…If sexual responses are less frequent or weaker in HSDD (e.g., because of decreased sexual cue sensitivity), self-regulation of sexual behavior (e.g., inhibiting sexual responses in inappropriate situations) may be less developed because the need for or strength of such regulation is lower. Conversely, there is also evidence that a subset of subjects with HSDD may overinhibit their sexual responses via the DLPFC [59]. According to this subdivision, HSDD can be caused by low sensitivity to sexual cues or by overactivation of sexual inhibitory systems.…”

Gender-Specificity of Solitary and Dyadic Sexual Desire among Gynephilic and Androphilic Women and Men

“…The implications of such a study would be important in elucidating the factors underlying low sexual desire—especially among women—to determine whether these women are similarly less responsive to sexual cues, that is, that they experience low state sexual desire (see Bloemers et al. [85]).…”

Single dose sublingual testosterone and oral sildenafil vs. a dual route/dual release fixed dose combination tablet: a pharmacokinetic comparison

“…The two mechanisms are based on the idea postulated in the dual control model of sexual response [7,8] that sexual dysfunctions are caused and sustained by dysfunction in one of two separate but interacting systems, the sexual excitation and the sexual inhibition system. There is cognitive [9,10], psychophysiological [9][10][11][12][13], subjective [10][11][12], neuroanatomical [14,15] and pharmacological [9][10][11][12]15] evidence that shows that there are indeed women whose HSDD/FSIAD is caused by either a decreased propensity for sexual excitation or an increased propensity to inhibit their sexual response. The combination of testosterone and sildenafil is an ondemand (i.e.…”