Hélène Gelez PhD, Jonathan Greggain-Mohr, James G. Pfaus PhD, Kelly A. Allers PhD, François Giuliano MD, PhD
ONLINE: February 19, 2013 – The Journal of Sexual Medicine,
One of the most common sexual issues for women is a lack of desire. The study authors define hypoactive sexual desire disorder (HSDD) as a “persistent or recurrent deficiency or absence of sexual fantasies and desire for sexual activity that causes marked distress or interpersonal difficulty.”
Medical conditions, medications, and psychological factors can all contribute to HSDD. However, for premenopausal or naturally postmenopausal women, there are currently no approved pharmacologic treatments available.
The drug flibanserin is currently in clinical trials for the treatment of HSDD and is showing some encouraging results in premenopausal women, including improved sexual desire and an increase in the number of satisfying sexual events.
Flibanserin is a mixed 5-HT1A agonist/5-HT2A antagonist that was found to be ineffective as an antidepressant. In clinical trials, however, women’s scores on the Arizona Sexual Experiences Scale increased, leading researchers to consider its use for HSDD.
Studies of certain animals, such as rats, have shown that animal sexual behavior may predict human sexual behavior. For females, this includes solicitation, choosing or rejecting a male partner, copulatory contact rates, and copulatory responses.
Sexual responses in female rats include the following:
- Solicitation (moving the head a certain way and running so that a male will chase her)
- Partial solicitations (hops and darts to encourage a male to mount)
- Pacing behaviors (used to regulate timing between copulations)
- Rejection behaviors (such as defensive postures or fighting)
- Lordosis (raising the rump so that a male can penetrate)
Bi-level chambers can be used to observe these behaviors.
The current study aimed to investigate how acute and chronic doses of flibanserin affected sexual behavior in ovariectomized (OVX) female rats who have been primed with either a combination of estradiol benzoate (EB) and progesterone (P) [Experiment 1] or estradiol benzoate (EB) alone [Experiment 2].
Experiment 1 involved 52 female and 85 male Long-Evans rats.
For Experiment 2, 27 female and 30 male Long-Evans rats were used.
All rats in each experiment were sexually naïve. All females were ovariectomized and given a week of recovery time before the experiments began.
To become fully sexually receptive, female rats in Experiment 1 received subcutaneous injections of EB 48 hours and P 4 hours before each copulatory test.
Females in Experiment 2 were given subcutaneous injections of only EB 48 hours before each test.
Females in Experiment 1 were given flibanserin in the following doses:
- 0 mg/kg
- 5 mg/kg
- 15 mg/kg
- 45 mg/kg
Females in Experiment 2 were given flibanserin in these doses:
- 0 mg/kg
- 15 mg/kg
- 45 mg/kg
Females in both experiments were given flibanserin twice daily.
Before sexual interaction, both males and females were separately introduced to the bi-level chambers. When all rats were acclimatized, each rat participated in 10 pre-experimental training trials to gain sexual experience.
During this pre-experiment training period, all females were given EB and P. Once training was complete, they were randomly assigned to either Experiment 1 or Experiment 2. Females in Experiment 2, which used EB only, went through a two week washout period between training and the experiment to make sure there were no longer traces of the combined hormones used in training.
Females in Experiment 1 participated in five consecutive copulatory tests once every seven days (from Day 0 to Day 28).
Females in Experiment 2 had four consecutive tests every 7 days (from Day 0 to Day 21).
The last three training tests served as the baseline. These tests, along with all of the drug tests, were videotaped and analyzed using a computerized behavioral scoring system. In this way, sexual behaviors were categorized.
Experiment 1: Effects of Flibanserin in Females Primed with EB and P
Researchers analyzed appetitive behaviors (solicitations, hops and darts, and anogenital investigations), defensive behaviors, pacing (number of level changes in the chambers), lordosis, and male copulatory responses for the four experimental groups (based on flibanserin dose).
- Day 0: Acute flibanserin administration did not affect female appetitive behaviors, receptive behaviors, or pacing behaviors for any of the dosage groups. Females who received 45 mg/kg of flibanserin appeared sedated; only two females were active and sexually receptive.
- Day 7 (7 days of chronic treatment): There was no change in the females’ sexual behavior across dosage groups. Sedative effects were no longer observed; male copulatory behaviors were similar across groups.
- Day 14: Flibanserin had a “significant effect” on solicitations and genital investigations, especially for females who were given the 45 mg/kg dose.
- Day 21: A significant increase in female solicitations was still observed, especially in females who took the 15 mg/kg dose or the 45 mg/kg dose, when compared to those who took no flibanserin.
- Day 28: The trend for increased number of solicitations continued, but the difference did not reach statistical significance.
Experiment 2: Effects of Flibanserin in Females Primed with EB Alone
Females tested with EB alone also had delayed effects of flibanserin.
- Day 0: There were no observed solicitations, hops and darts, or lordosis events.
- Day 7: Again, females did not display solicitations, hops and darts, or lordosis. Without lordosis, males cannot copulate with females. However, males did try to mount the females and increased their genital investigations of females that took the high dose of flibanserin.
- Day 14: Observations were similar to those of Day 7. Males investigated genitals of females who took both doses of flibanserin.
- Day 21: Significant effects on solicitations, hops and darts, and female defensive responses were observed for both low and high doses of flibanserin. The high dose increased solicitations significantly over the low dose. The low dose increased hops and darts significantly over the high dose. It appeared that flibanserin reduced female defensive responses.
The researchers found that two weeks of chronic daily treatment with 45 mg/kg of flibanserin increased the number of solicitations, a behavior that reflects sexual motivation. Three weeks of chronic treatment increased some appetitive behaviors but not lordosis, no matter which hormonal regimen was used.
The results corroborate with previous data with respect to female humans and marmosets. The authors noted that effective flibanserin doses are higher in rats and marmosets than in humans. They explained that appetitive behaviors “are considered as analogous to sexual desire expression in humans” but there is no human equivalent of lordosis. Overall, they suggest that solicitation patterns can be used to “identify predicting compounds for HSDD.”
OVX rats primed with both EB and P showed more full solicitations than partial solicitations. Females who had been primed with EB only showed no appetitive behaviors and a low level of lordosis.
In Experiment 2, females primed with a “threshold” level of EB alone showed high rates of defensive responses. However, the high dose of flibanserin decreased these rates, suggesting that the drug may overcome sexual inhibition as well as increase solicitations.
The authors pointed out that females who were primed with EB and P displayed solicitations earlier than those who were primed with EB only. Future research may examine this.
Overall, the study results showed that “chronic flibanserin treatment facilitates female sexual motivation, regardless of their hormonal regimen (EB alone or E + P).” This suggests that flibanserin has effects even in females who show “a high baseline of sexual behavior” and that “flibanserin action does not depend on P but might require estradiol supplementation.”
Taken together, the results show that pre- and postmenopausal women with HSDD could benefit from flibanserin treatment.