Objective: Estrogen supplementation is considered a reliable therapeutic approach to symptoms of vasomotor dysregulation (hot flashes) associated with the menopausal transition and sex hormone deprivation. Implication of changes in central neurotransmission in the pathogenesis of hot flashes has prompted the off-label use of serotonergic and γ-aminobutyric acid-ergic drugs as a therapeutic alternative, claiming similarity of outcomes to those of estrogen treatment.
Methods: Using telemetric recordings in a rat model of estrogen deficit–induced vasomotor dysregulation, we compared the long- and short-term effects of estrogen supplementation and treatment with neuropharmaceuticals (venlafaxine, desvenlafaxine, fluoxetine, agomelatine, gabapentin) on endpoints of thermoregulation.
Results: Among the tested drugs, only fluoxetine was capable to emulate the restorative action of estradiol on the diurnal oscillations in skin temperature and control of heat dissipation. Unlike estradiol, several of the tested compounds produced marked transient decreases in skin temperature within the first 2 hours of application while being unable to restore physiological diurnal patterns of thermoregulation.
Conclusions: Our findings suggest that in this animal model of impaired thermoregulation, neuropharmaceuticals may simulate therapeutic effects by eliciting immediate but transient hypothermia, which is not associated with the recovery of physiological control of heat dissipation. Therefore, short-term monitoring of drug actions in this disease model may considerably bias readouts of drug discovery for menopausal vasomotor symptoms.
From the 1Toxicology, Global Early Development, Bayer HealthCare, Wuppertal, Germany; 2Statistics, Global Drug Discovery, Bayer HealthCare, Berlin, Germany; 3Target Discovery, Global Drug Discovery, Bayer HealthCare, Berlin, Germany; and 4TRG Women’s Healthcare, Global Drug Discovery, Bayer HealthCare, Berlin, Germany.
Received September 30, 2011; revised and accepted December 6, 2011.
K.P. and B.-W.I. contributed equally to this work.
Financial disclosure/conflicts of interest: These studies were conducted as a part of the duties of the authors as employees of Bayer HealthCare.
Address correspondence to: Vladimir K. Patchev, MD, PhD, TRG Women’s Healthcare, Global Drug Discovery, Bayer HealthCare, Müllerstr. 178, 13353 Berlin, Germany. E-mail: Vladimir.Patchev@Bayer.com