title: Endpoints of drug discovery for menopausal vasomotor symptoms:  interpretation of data from a proxy of disease.
abstract: 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.
authors.affiliation: Toxicology, Global Early Development, Bayer HealthCare, Wuppertal, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Prelle
authors.forename: Bernd-Wolfgang
authors.initials: BW
authors.lastname: Igl
authors.forename: Maik
authors.initials: M
authors.lastname: Obendorf
authors.forename: Dorothee
authors.initials: D
authors.lastname: Girbig
authors.forename: Tanja
authors.initials: T
authors.lastname: Lehmann
authors.forename: Vladimir K
authors.initials: VK
authors.lastname: Patchev
mesh_terms: D000081:Acetamides / Q000008:administration & dosage; D000588:Amines / Q000008:administration & dosage; D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage; D003511:Cyclohexanols / Q000008:administration & dosage; D004195:Disease Models, Animal; D053207:Diurnal Enuresis; D055808:Drug Discovery / Q000379:methods*; D004958:Estradiol / Q000008:administration & dosage; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage; D000077206:Gabapentin; D019584:Hot Flashes / Q000188:drug therapy*; D006993:Hypnotics and Sedatives / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage; D012881:Skin Temperature / Q000187:drug effects; D000069470:Venlafaxine Hydrochloride; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D003511:Cyclohexanols; D004958:Estradiol; D005473:Fluoxetine; D000077206:Gabapentin; D006993:Hypnotics and Sedatives; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride; D005680:gamma-Aminobutyric Acid; C084711:agomelatine; D009281:Naphthalenes