TY - JOUR
T1 - Treatment with an orally bioavailable prodrug of 17β-estradiol alleviates hot flushes without hormonal effects in the periphery
AU - Merchenthaler, Istvan
AU - Lane, Malcolm
AU - Sabnis, Gauri
AU - Brodie, Angela
AU - Nguyen, Vien
AU - Prokai, Laszlo
AU - Prokai-Tatrai, Katalin
N1 - Funding Information:
The 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.). The authors are grateful to Dr. Min Zhan for helping with the statistical analysis, Dr. Jessica Mong and Shaun Viechweg for their support in the telemetric tail skin temperature measurements, and Dr. Szabolcs Szarka for contributing to the drug distribution studies.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84982733919&partnerID=8YFLogxK
U2 - 10.1038/srep30721
DO - 10.1038/srep30721
M3 - Article
C2 - 27477453
AN - SCOPUS:84982733919
SN - 2045-2322
VL - 6
JO - Scientific Reports
JF - Scientific Reports
M1 - 30721
ER -