Treatment of female sexual dysfunction : A personalized medicine approach

Abstract

n this thesis studies are presented which use a personalized medicine approach to investigate potential causal mechanisms, both biological and psychological, which might underlie sexual complaints such as low sexual desire, interest or arousal of women diagnosed with Female Sexual Interest/Arousal Disorder (FSIAD). The diagnosis FSIAD is described in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). An important criterion for diagnosing FSIAD is that sexual complaints of desire and arousal are accompanied by sexual dissatisfaction and personal distress. We hypothesized that these causal mechanisms are partly the result of differences in sensitivity of the brain to sexual stimuli. The degree of this sensitivity for sexual cues or stimuli is influenced by biological factors, including hormonal levels and genetic factors. The results of the different studies described in this thesis suggest that there are at least two different subtypes among women who are diagnosed with FSIAD; those who are low sensitive to sexual stimuli and those in which sexual stimuli elicit a dysfunctional activation of sexual inhibitory mechanisms. We hypothesized that women who are classified as low sensitive would benefit from an on-demand treatment of sublingual testosterone (0.5 mg) in combination with a PDE5-inhibitor (e.g., sildenafil (50 mg)) and that women with dysfunctional activation of sexual inhibitory mechanisms would benefit from the combination of sublingual testosterone (0.5 mg) and the 5-HT1A receptor agonist buspirone (10 mg). Besides the FSIAD population, these treatments could also be efficacious in another indication; women who developed sexual complaints as the result of the use of SSRI antidepressants.

On-demand sublingual testosterone administration forms the basis for the effect of our treatments for women diagnosed with FSIAD or SSRI-induced sexual dysfunction. After sublingual testosterone administration, plasma levels of total and free testosterone rapidly increases with a maximum plasma concentration after 15 minutes. In order to obtain a peak in plasma level of free testosterone, which is the biological active substance, the dosage of sublingual testosterone should be high enough to surpass the Sex Hormone Binding Globulin (SHBG) threshold. By surpassing the SHBG threshold, unbound free testosterone increases, which has repeatedly shown to result in behavioral effects approximately 4 hours later. This thesis describes the pharmacokinetics of 0.5 mg sublingual testosterone and the pharmacokinetic results of a new innovative combination tablet (a combination of 0.5 mg sublingual testosterone and 10 mg of the 5-HT1A receptor agonist buspirone hydrochloride). The pharmacodynamic effects are described in women with FSIAD and women with SSRI-induced sexual dysfunctioning. For the women with FSIAD the results show that the combination of testosterone and sildenafil significantly improved sexual functioning in the low sensitive women, while the combination of testosterone and buspirone improved sexual functioning in women with high inhibition. For the women who develop sexual complaints after the start of an SSRI the results of a preliminary study suggests that our treatments may be promising in certain subgroups with this indication, depending on genetics, SSRI dose, and psychological factors. In recent years, genetic polymorphisms are more and more studied and new polymorphisms are identified in a broad area of medicine. In a personalized medicine point of view, analysis of relevant polymorphisms might be an excellent method to identify individual differences in sensitivity for sexual stimuli and response of our pharmacological treatments.