A single blind, randomized, cross-over placebo controlled dose finding study to investigate the pharmacokinetic profile of 3 doses of sublingual testosterone solution and their effect on physiological and subjective arousal in healthy, sexually functional 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another group of hypogonadotropic hypogonadal patients (unpublished data).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 a study investigating the pharmacokinetics of aerosol delivery of 0.1, 0.2
and 0.3 mg testosterone it was shown that plasma levels of testosterone peaked
at 3 minutes after drug delivery (Davison et al., 2005). The route of
administration in this study differs from our sublingual method, but it gives
reason to assume that the peak in plasma testosterone concentration as found in
our own study, may have fallen well before the first post dose measurement
point (15 minutes).

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 motivation does not coincide with the timing
of the pharmacokinetics of testosterone administration (as was already
concluded by Tuiten et al., 2000).

This research proposal describes a pharmacokinetic-pharmacodynamic study of
which the main goal is to establish the lowest effective dose of testosterone
sublingual in premenopausal sexually healthy women using physiological and
subjective measures of sexual arousal. Also, it is directed at evaluating and
comparing the pharmacokinetics of testosterone and its metabolites following
administration of three single doses of testosterone sublingual (0.25, 0.50 and
0.75 mg).

Primary objectives:
To establish the lowest effective dose using physiological and subjective
measures of sexual arousal.
To evaluate and compare the pharmacokinetics of testosterone and its
metabolites following administration of three (3) doses (0.25, 0.50 & 0.75 mg)
of testosterone sublingual.

Secondary objective:
To investigate the effect of three (3) different doses (0.25, 0.50 & 0.75 mg)
of testosterone sublingual on the duration of increased physiological and
subjective measures of sexual arousal.

This is a single-center, single-blind, randomized, cross-over placebo
controlled dose-finding study with three (3) doses of testosterone administered
sublingually and placebo.
A total of 16 subjects receive each investigational drug dose once in random
order, so that 4 subjects will start at the 0.25mg dose, 4 at the 0.5mg dose, 4
at the 0.75mg dose and 4 on placebo. Wash-out between treatments will be at
least 48 hours. Baseline assessments will be performed each experimental day
before each dosing. Pharmacokinetic and pharmacodynamic (physiological and
subjective measures of sexual arousal) assessments will be performed at
pre-determined time points. Subjects visit the site a total of 6 times: 1 day
screening (V0), 4 experimental days and 1 follow up visit. 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.