Treatment with an orally bioavailable prodrug of 17beta-estradiol alleviates hot flushes without hormonal effects in the periphery

dc.creatorMerchenthaler, Istvan
dc.creatorLane, Malcolm
dc.creatorSabnis, Gauri
dc.creatorBrodie, Angela
dc.creatorNguyen, Vien
dc.creatorProkai, Laszlo
dc.creatorProkai-Tatrai, Katalin
dc.creator.orcid0000-0002-4559-3458 (Prokai, Laszlo)
dc.creator.orcid0000-0001-5595-1346 (Prokai-Tatrai, Katalin)
dc.description.abstractEstrogen 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 10beta,17beta-dihydroxyestra-1,4-dien-3-one (DHED), a novel brain-targeting bioprecursor prodrug of the main human estrogen, 17beta-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 17beta-estradiol therapy to relieve hot flushes without undesirable peripheral side-effects.
dc.description.sponsorshipThe project was supported in part by the National Institutes of Health (grant numbers AG031535 to I.M. and L.P., and AG050900 to I.M.) and the Robert A. Welch Foundation (endowment BK-0031; L.P.).
dc.identifier.citationMerchenthaler, I., Lane, M., Sabnis, G., Brodie, A., Nguyen, V., Prokai, L., & Prokai-Tatrai, K. (2016). Treatment with an orally bioavailable prodrug of 17[beta]-estradiol alleviates hot flushes without hormonal effects in the periphery. Scientific reports, 6, 30721.
dc.publisherSpringer Nature
dc.rights.holder© The Author(s) 2016
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.sourceScientific Reports
dc.subject.meshAdministration, Oral
dc.subject.meshEstradiol / administration & dosage
dc.subject.meshEstrogens / administration & dosage
dc.subject.meshHot Flashes / drug therapy
dc.subject.meshProdrugs / administration & dosage
dc.subject.meshTreatment Outcome
dc.titleTreatment with an orally bioavailable prodrug of 17beta-estradiol alleviates hot flushes without hormonal effects in the periphery


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