A double blind, randomized, cross-over placebo controlled study to investigate the efficacy of sublingual testosterone solution on physiological and subjective arousal in healthy, sexually dysfunctional premenopausal women.

An important aspect of sexual motivation is physiological sexual responding.
Measured as an increase in vaginal vasocongestion and clitoral blood volume
(Gerritsen et al.,2009) elicited by sexual stimuli, this responding is
considered to be preparatory for copulatory behavior (Tuiten et al., 1996). In
hypogonadotropic, hypogonadal females we found that substitution with
testosterone undecanoate 40 mg orally per day during an 8-week period enhanced
vaginal responsiveness (Tuiten et al., 1996). This effect was not found in
another group of hypogonadotropic hypogonadal patients (unpublished data). In
both studies subjects received testosterone each morning, but patients in the
first experiment were tested in the afternoon and patients in the second
experiment in the morning. The different outcomes on physiological responding
between these experiments may be caused by a time dependent effect of
testosterone on vaginal arousal. Further, we examined whether administration of
a single dose of 0.5 mg testosterone sublingually, as compared with placebo,
increases vasocongestion during presentation of visual erotic stimuli (Tuiten
et al., 2000). On treatment days we exposed eight sexually functional women
with intervals of an hour and a half, to six erotic films depicting
intercourse. After 0.5 mg testosterone administration, plasma levels of
testosterone peaked in the first post dose plasma sample 15 minutes and then
fell, reaching baseline levels after 2-3 hours. About three to four and a half
hours after this testosterone peak, we found a striking increase in vaginal
responsiveness when the subjects were exposed to the visual sexual stimuli.
These findings demonstrate a time lag in the effect of sublingually
administered testosterone on genital arousal in sexually functional women. This
study was replicated 2 years later with the same results (Tuiten et al., 2002).
In these previous two studies only sexually functional women participated. For
women with Female Sexual Dysfunction, sublingual testosterone alone is not
sufficient (van der Made et al, 2009a). This study showed a slightly increase
in VPA for testosterone alone, although not significant. But the condition
sublingual testosterone combined with vardenafil (a PDE-5 inhibitor) showed a
strong, significant, increase in VPA, as compared to placebo, vardenafil and
testosterone alone. The same results, a slight increase with testosterone alone
and a high increase with testosterone combined with vardenafil, were found in a
second study with sexually dysfunctional women (van der Made et al, 2009b).

The results of the above mentioned studies demonstrate that testosterone is
involved in female sexual motivation in a time dependent fashion, and that this
pharmacodynamic effect on sexual functioning is higher when combined with a
PDE-5 inhibitor.

This research proposal describes a pharmacodynamic study of which the main goal
is to confirm the lack of effect of testosterone sublingual alone in
premenopausal sexually dysfunctional healthy women using physiological and
subjective measures of sexual arousal at four different time points.

Primary objectives:
To confirm the lack of effect of 0.5 mg sublingual testosterone on
physiological and subjective measures of sexual arousal in women with HSDD.

Secondary objective:
To confirm the lack of effect of 0.5 mg sublingual testosterone on
physiological and subjective measures of sexual arousal at three post dose time
points.

This is a single-center, double-blind, randomized, cross-over placebo
controlled study with one (1) dose of testosterone administered sublingually
and placebo.
A total of 16 subjects receive each medication condition once in random order,
so that 8 subjects will start at the 0.5 mg dose and 8 on placebo. Wash-out
between treatments will be at least 48 hours. Baseline pharmacodynamic
assessments will be performed each experimental day before each dosing.
Pharmacodynamic (physiological and subjective measures of sexual arousal)
assessments will be performed at pre-determined time points. Subjects visit the
site a total of four times: one day screening (V0), two experimental days (V1 &
V2) and one follow up visit (V3). During all visits the subject*s health will
be monitored.

HIV, hepatitis and pregnancy are determined during screening (pregnancy at
eacht visit). A positive result on each of these 3 may have a negative impact
on the subjects. Subjects are warned of this risk beforehand. Blood drawing may
give rise to hematomas. Testosterone administration as used in the present
study may give rise to mild decreases in blood pressure.