Dans la troisième partie de notre travail, nous montrons qu’indépendamment du statut œstrogénique, l’inhibition de la PDE-5 par le sildénafil augmente la lubrification vaginale et pour la première fois que cet effet est indépendant de la voie de l’isoforme neuronale de la NOS et est plus prononcé chez l’animal ovariectomisé.
L’abolition de toute lubrification vaginale après stimulation cervico-vaginale en présence d’un puissant inhibiteur non spécifique des NOS (L-MMA) confirme le rôle central du NO. En revanche, la persistance de lubrification en présence d’un puissant inhibiteur sélectif de la nNOS (7-NI) montre que cet effet passe soit par la eNOS soit par la iNOS.
Les souris ovariectomisées ont une diminution de la lubrification vaginale par comparaison aux souris ayant eu une simulation d’ovariectomie. Cependant, en prenant en compte la présence d’une atrophie marquée comme mis en évidence par histomorphométrie, l’augmentation de la lubrification par gramme de vagin est trois fois supérieure après ovariectomie par rapport aux souris ayant eu une simulation d’ovariectomie.
Alors que la plupart des études rapportées à ce jour évaluant la fonction sexuelle utilisent des méthodes invasives telles que la stimulation des nerfs pelviens, nous avons développé ici un modèle de stimulation cervico-vaginale. Ce dernier permettra de réaliser des études
longitudinales évaluant différents modulateurs pharmacologiques chez de petits animaux tels que des souris transgéniques par exemple.
La facilitation de la lubrification vaginale par les IPDE-5 indépendamment du statut œstrogénique indique qu’ils pourraient constituer un traitement des dysfonctions sexuelles féminines à type de sécheresse vaginale ou de dyspareunie et ce quel que soit la période de la vie génitale féminine. Des essais évaluant l’effet des IPDE-5 sur la lubrification vaginale et sur le traitement des conséquences de l’atrophie vulvo-vaginale après la ménopause devront être mis en place. De même, l’administration locale de NO pourrait être envisagé au travers de microparticules ou de gels libérant du NO (449) (450).
Enfin comme les eNOS et iNOS sont sous contrôle des œstrogènes (451, 452), la réponse la plus logique dans le traitement de l’inconfort vaginal post-ménopausique serait le traitement hormonal substitutif. Cependant les controverses actuelles concernant ce dernier en limitent aujourd’hui l’utilisation. Une nouvelle voie serait l’emploi soit de SERM tels qu’un SERM de troisième génération comme le lasoxifène soit de l’œstrogène fœtal naturel, l’estetrol. Une évaluation préclinique sur le modèle de stimulation cervico-vaginale développé permettra de déterminer leur impact sur la lubrification vaginale.
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