title: Treatment with an orally bioavailable prodrug of 17β-estradiol alleviates hot flushes without hormonal effects in the periphery.
abstract: Estrogen deprivation has a profound effect on the female brain. One of the most obvious examples of this condition is hot flushes. Although estrogens relieve these typical climacteric symptoms, many women do not want to take them owing to unwanted side-effects impacting, for example, the uterus, breast and blood. Therefore, there is a need for developing safer estrogen therapies. We show here that treatment with 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), a novel brain-targeting bioprecursor prodrug of the main human estrogen, 17β-estradiol, alleviates hot flushes in rat models of thermoregulatory dysfunction of the brain. Oral administration of DHED elicits a significant reduction of tail skin temperature (TST) rise representing hot flushes in the morphine-dependent ovariectomized rat model and results in the restoration of estrogen deprivation-induced loss of diurnal rhythm in TST. These beneficial effects occur without detrimental peripheral hormonal exposure; thus, the treatment avoids potentially harmful stimulation of estrogen-sensitive peripheral organs, including the uterus and the anterior pituitary, or the proliferation of MCF-7a breast cancer cell xenografts. Our promising preclinical assessments warrant further considerations of DHED for the development of a brain-selective 17β-estradiol therapy to relieve hot flushes without undesirable peripheral side-effects.
authors.affiliation: Department of Epidemiology &Public Health and Anatomy &Neurobiology, University of Maryland, Baltimore, MD 21154, USA.
authors.forename: Istvan
authors.initials: I
authors.lastname: Merchenthaler
authors.affiliation: Department of Epidemiology &Public Health and Anatomy &Neurobiology, University of Maryland, Baltimore, MD 21154, USA.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Lane
authors.affiliation: Department of Pharmacology, University of Maryland, Baltimore, MD 21154, USA.
authors.forename: Gauri
authors.initials: G
authors.lastname: Sabnis
authors.affiliation: Department of Pharmacology, University of Maryland, Baltimore, MD 21154, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Brodie
authors.affiliation: Center for Neuroscience Discovery, Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Vien
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: Center for Neuroscience Discovery, Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Prokai
authors.affiliation: Center for Neuroscience Discovery, Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Katalin
authors.initials: K
authors.lastname: Prokai-Tatrai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004958:Estradiol / Q000008:administration & dosage*; D004967:Estrogens / Q000008:administration & dosage*; D019584:Hot Flashes / Q000188:drug therapy*; D011355:Prodrugs / Q000008:administration & dosage*; D051381:Rats; D016896:Treatment Outcome
chemical_list: D004967:Estrogens; D011355:Prodrugs; D004958:Estradiol