A study to evaluate the different levels of attention and valence direction for erotic stimuli, in relation to genital and subjective sexual arousal in healthy female subjects and healthy female subjects with Female Sexual Dysfunction. |
|- candidate number||2648|
|- NTR Number||NTR1009|
|- Date ISRCTN created||23-aug-2007|
|- date ISRCTN requested||13-aug-2007|
|- Date Registered NTR||2-jul-2007|
|- Secondary IDs||EB069(VAL) |
|- Public Title||A study to evaluate the different levels of attention and valence direction for erotic stimuli, in relation to genital and subjective sexual arousal in healthy female subjects and healthy female subjects with Female Sexual Dysfunction. |
|- Scientific Title||A double blind randomized placebo-controlled cross-over study to validate the distinction between women with different levels of attention and valence direction for erotic stimuli, in relation to genital and subjective sexual arousal in healthy female subjects and healthy female subjects with Female Sexual Dysfunction. |
|- hypothesis||In the present placebo controlled study we will investigate the influence of valence on attention when viewing visual erotic stimuli. Especially when under the treatment condition of testosterone with sildenafil. In addition, we will investigate the effects of testosterone in combination with sildenafil on vaginal and subjective sexual arousal induced by visual erotic stimuli in females with FSD and control subjects, for individual motivational and emotional differences (valence). In earlier study's we've found a distinction between groups that differ in colour naming of erotic words compared to neutral words. These two groups also differed in their benefit from testosterone combined with sildenafil.
We expect that for some women this treatment, testosterone with sildenafil will work adequately. For the other group, we expect that negative sexual experiences and personality differences and therefor the negative/defensive motivational neural circuit is responsible for the more difuse reaction to the treatment of testosterone and sildenafil, in women with FSD.|
|- Healt Condition(s) or Problem(s) studied||Female sexual dysfunction (FSD), Hypoactive sexual desire disorder, Female sexual arousal disorder, |
|- Inclusion criteria||40 Subjects must meet the following criteria:|
1. Subjects must have a heterosexual orientation;
2. Subjects must be between 21 and 65 years of age;
3. Subjects with normal sexual functioning;
4. Subjects must have signed the Informed Consent Form;
5. Inclusion will be following the selection criteria including, but not limited to, a physical examination, gynecological examination, medical history, vital signs, pregnancy test and ECG.
80 Subjects must meet the following criteria:
1. Subjects must have a heterosexual orientation;
2. Subjects must be between 21 and 65 years of age;
3. Subjects must have experienced low sexual arousal and/or low sexual desire for at least six months prior to study entry according to DSM IV criteria. The diagnosis will be made by an experienced psychologist/sexologist;
4. Subjects must have signed the Informed Consent Form;
5. Inclusion will be following the selection criteria including, but not limited to, a physical examination, gynecological examination, medical history, vital signs, pregnancy test and ECG, and by the scoring on the strooptask during familiarization trial.
|- Exclusion criteria||Subjects will not be eligible for inclusion if one of the following criteria applies: |
1. Use of oral contraception containing anti-androgens (Like Diane 35 or Minerva);
2. Use of oral contraception containing 50 μg estrogen or more;
3. Pregnancy, or intention to become pregnant during this study (Note: a serum or urine pregnancy test will be performed in all women prior to the administration of study medications);
4. A pelvic inflammatory disease or an untreated vaginal infection at screening;
5. Lactating or subjects who have given birth in the previous 6 months;
6. Previous prolapse and incontinence surgery affecting the vaginal wall;
7. Women with other unexplained gynecological complaints, such as abnormal uterine bleeding patterns;
8. History of endocrinological treatment or current endocrinological treatment (with the exception of the use oral contraceptives and of fertility-promoting treatment);
9. History of neurological treatment or current neurological treatment;
10. History of serious psychiatric treatment or current psychiatric treatment;
11. Any underlying cardiovascular condition including unstable angina pectoris, that would preclude sexual activity;
12. History of myocardial infarction, stroke or life-threatening arrhythmia within the prior 6 months;
13. Uncontrolled atrial fibrillation/flutter at screening (ventricular response rate > 100 bpm), or other significant abnormality observed on ECG;
14. Systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg. For subjects with age > 60 years and without diabetic mellitus, familiar hypercholesterolemia or cardiovascular disease: Systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 90 mmHg (According to the CBO-guideline hypertension (CBO.2000a));
15. Subjects who are taking strong CYP3A4-inhibitors: ritonavir (HIV-proteaseremmer), ketoconazol en itraconazol;
16. Subjects who are taking less strong CYP3A4-inhibitors: claritromycine, erytromycine en saquinavir;
17. Subjects who are taking CYP3A4-inducers: carbamazepine, fenytoÔne, fenobarbital, st Johns Wort, rifampicine;
18. Severe chronic or acute liver disease, history of moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment;
19. Use of medicinal herb as Ginkgo Biloba and nutrition containing grapefruit;
20. Subjects who are taking nitrates or nitric oxide donors;
21. A substance abuse disorder that in the opinion of the investigator is likely to affect the subject's ability to complete the study or precludes the subjectís participation in the study; mild or moderately alcohol drinking behavior is allowed, only 12 hours before the experimental days is alcohol drinking not allowed. Three weeks before the start of the experimental day is the taking of any recreational drug not allowed. Smoking is allowed;
22. Use of any treatment for FSD within the 7 days before visit 1 or during the study, including oral medications or constrictive devices;
23. Subjects who are illiterate, unwilling or unable to understand and complete the questionnaires;
24. Any other clinically significant abnormality or condition which in the opinion of investigator would interfere with the participantís ability to provide informed consent, comply with study instructions, possibly confound interpretation of study results, or endanger the participant if she took part in the trial;
25. Moderate and severe hearing impairment;
26. Subjects who are colour blinded;
27. Subjects who are having botoxģ (or other equivalents of botox, like dysport) in the facial area within 6 months before the first experimental day.
|- mec approval received||yes|
|- multicenter trial||no|
|- Type||2 or more arms, randomized|
|- planned startdate ||21-jun-1978|
|- planned closingdate||1-nov-2007|
|- Target number of participants||120|
|- Interventions||Testosterone, administered as a solution sublingually (0.5 mg) and sildenafil, type 5 phosphodiesterase (PDE5) inhibitor, administered as an encapsulated tablet orally (50 mg).|
Treatment A: 0.5 mg testosterone + sildenafil 50 mg.
Treatment P: Placebo testosterone + Placebo sildenafil.
The two treatments (A and P) will be randomized across the 120 subjects.
Two different drug combinations will be given on separate days: (day 1) placebo, (day 2) sildenafil plus testosterone.
Drug administration will be divided into 2 parts. Testosterone will be administered first. Two hours after testosterone administration, sildenafil (Viagra) will be administered.
Testosterone will have a behavioral effect, increasing sexual desire and arousal, after 4 hours of intake.
Sildenafil will have a physical effect, increasing bloodflow to the genitals, after 1 hour of intake. It's duration is about 6 hours.
Two separate experimental days are separated by a three- to ten day period.
|- Primary outcome||1. Evaluation of the womenís judgment of valence (negative or positive) for erotic stimuli under placebo condition and the condition of 0.5 mg sublingual testosterone combined with sildenafil (50 mg) and the influence of positive and/or negative valence on attention for erotic
cues, in healthy female subjects with and without Female Sexual Dysfunction.
Data for analysis:
a. Attention for erotic stimuli (strooptask: speedrate). A masked version of the Emotional Stroop Task comparing colour-naming latencies on neutral and erotic words will be used. The word is presented before and after the erotic film excerpts in the attention condition for about 24 ms and then masked by randomly cut, reassembled signs in the same colour (red, green, yellow or blue). The colour of the mask has to be assigned, and subjects are asked to verbally name the colours as quickly as possible. The stimuli are presented in the centre of the screen. An extra set of stimuli will be prepared for practice-trials. A trial consists of a fixation point, which will be shown for 750 ms, followed by the target stimulus (the coloured neutral or erotic word and mask). Vocal responses will be recorded and will terminate the trials. The order of these 2 blocks will be randomly assigned. Attention will be measured on both the experimental days in the morning (pre-dose) and in the afternoon (post-dose).
b. Vaginal Pulse Amplitude (VPA)
A vaginal photoplethysmograph will be used to measure Vaginal Pulse Amplitude (VPA) (the AC component of the signal), which is a reliable index for genital vasocongestion. Changes in the amplitude of the signal reflect changes in vaginal vasocongestion. The vaginal photoplethysmograph (VP) is a clean tampon shaped device, which contains an infrared light-emitting diode (LED) as a light source and a photosensitive light detector (photodiode). It measures the blood volume in the tissue surrounding the plethysmograph. The light emitted by the LED is reflected by the blood vessels in the tissue. This light is measured by the photodiode. The output signal of the photodiode varies with changes in the amount of blood in the vessels.
VPA will be measured on both the experimental days in the morning (pre-dose) and in the afternoon (post-dose).
c. Valence for erotic stimuli
Perceived emotional valence of erotic stimuli will be measured and compared to neutral, pleasant and unpleasant stimuli. Facial expressions reveal emotions with corresponding appetitive and defensive motivational circuits. The amygdala projects to the facial motor nucleus, which reflects the chosen motivational circuit; appetitive or defensive. Therefore, electromyographic (EMG) activity will be measured over the corrugator, zygomatic major and orbicularis oculi muscles. Activation of the zygomatic muscle reveals a smile, but coactivation of the zygomatic and orbicularis mirrors a major smile. Activation of the corrugator muscle alone is correlated with viewing unpleasant events. More specifically, coactivation of the corrugator and orbicularis oculi reflects the emotion of repulsion and aversion. While viewing IAPS pictures (8 pictures for each domain; pleasant, neutral, unpleasant and erotic) and an additional category of sexually explicit pictures (depicting vaginal coitus), activation of the three muscles will be measured 2 seconds before picture onset and for 6 seconds during picture presentation.
The activation of the orbicularis oculi muscle is also a component of the startle reflex. When viewing the pictures, half of all pictures will be accompanied by a startle stimulus. The acoustic startle stimulus consists of a 50-ms burst of white noise, presented at 95dB. The startle stimuli will be presented through earplugs, between 3 and 5 seconds following picture onset. Prior to the first block, six startle sounds will be presented to allow habituation of the startle reflex.
After the presentation of the pictures subjects are instructed to give a subjective rating of the emotional pictures by finger pointing at a touch screen. Each emotional picture will be followed by a picture of five figures with expressions ranging from happy (smiling) to unhappy (frowning). Subjects are instructed to rate on a 9-point scale how their feeling towards the preceding picture was reflected by one of the figures. The same was done for arousal, with excited, wide-eyed figures to sleepy, relaxed figures.
Valence be measured on both the experimental days in the morning (pre-dose) and in the afternoon (post-dose).
|- Secondary outcome||1. To evaluate the correlation between subjective ratings of sexual functioning and physiological sexual responses.|
2. To evaluate the changes in differences in direction of valence when viewing visual erotic stimuli under the placebo condition and the condition with testosterone combined with sildenafil.
3. To evaluate the individual differences in attention in relation to positive and/or negative valence induced by visual erotic stimuli.
4. To evaluate the influence of personality traits on the differences in vaginal & subjective sexual arousal, EMG, valence direction and startle reflex.
5. Subjective ratings of sexual functioning.
6. Startle reflex;
7. EMG activation;
8. Personality traits;
9. Negative sexual experiences will be assesed with a questionnaire and in the clinical interview, both during screening.
|- Trial web site||http://www.emotionalbrain.nl|
|- status||inclusion stopped: follow-up|
|- CONTACT FOR PUBLIC QUERIES|| D. Ham, van|
|- CONTACT for SCIENTIFIC QUERIES|| D. Ham, van|
|- Sponsor/Initiator ||Emotional Brain BV|
(Source(s) of Monetary or Material Support)
|Emotional Brain BV|
|- Publications||in submission|
|- Brief summary||It has been frequently shown that an increase in subjective sexual arousal is accompanied by an increase in positive affect (both alterations can be the result of an increase in dopaminergic activity in the brain). Motivational stances towards emotional relevant cues have abundantly been demonstrated using the Emotional Stroop Task. Performance, in terms of slowing down or speeding up in colour naming, depends on the motivational state of the subject and the emotional content of the word. |
Orienting attention towards the genitals has been hypothesized to induce an increase in peripheral responding. However, there is also evidence that attention directed at alterations in genital arousal can induce inhibition of the VPA response to erotic visual stimuli in women with FSD under certain circumstances, namely when these women had been administered testosterone and a PDE5 inhibitor (sildenafil). In the same line, there is evidence that in sexual dysfunction, attentional withdrawal of the genitals can have a positive influence. Attention directed at sexual stimuli can thus have a positive but also a negative influence on sexual arousal. In an earlier study, we found differences in genital and subjective arousal under the treatment condition of testosterone combined with vardenafil. Here we saw two distinctive groups that differ in colour naming of erotic words compared to neutral words. The first group slowed down in colour naming and the second group speeded up. Thereby, the first group showed a higher VPA respons and a higher subjective arousal and desire when viewing visual erotic stimuli, under the condition of testosterone combined with vardenafil. In contrast, the second group showed a lower VPA respons and a lower subjective arousal and desire when viewing visual erotic stimuli, under the treatment condition testosterone combined with vardenafil. These differences between women may be due to emotional values for erotic stimuli. When stimuli are seen as threatening a defensive reaction is likely, for protection of the self. This may be the same for women who experience erotic stimuli as threatening, probably arising from negative sexual events.
In the present placebo controlled study we will investigate the influence of valence on attention when viewing visual erotic stimuli. Especially when under the treatment condition of testosterone with sildenafil. In addition, we will investigate the effects of testosterone in combination with sildenafil on vaginal and subjective sexual arousal induced by visual erotic stimuli in females with FSD and control subjects, for individual motivational and emotional differences.
|- Main changes (audit trail)|
|- RECORD||2-jul-2007 - 13-jan-2010|
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