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

Istvan Merchenthaler, Malcolm Lane, Gauri Sabnis, Angela Brodie, Vien Nguyen, Laszlo Prokai, Katalin Prokai-Tatrai

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

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.

Original languageEnglish
Article number30721
JournalScientific Reports
Volume6
DOIs
StatePublished - 1 Aug 2016

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Prodrugs
Estradiol
Estrogens
Skin Temperature
Brain
Uterus
Tail
Therapeutics
Circadian Rhythm
Heterografts
Morphine
Oral Administration
Breast
Breast Neoplasms

Cite this

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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.",
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Treatment with an orally bioavailable prodrug of 17β-estradiol alleviates hot flushes without hormonal effects in the periphery. / Merchenthaler, Istvan; Lane, Malcolm; Sabnis, Gauri; Brodie, Angela; Nguyen, Vien; Prokai, Laszlo; Prokai-Tatrai, Katalin.

In: Scientific Reports, Vol. 6, 30721, 01.08.2016.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Merchenthaler, Istvan

AU - Lane, Malcolm

AU - Sabnis, Gauri

AU - Brodie, Angela

AU - Nguyen, Vien

AU - Prokai, Laszlo

AU - Prokai-Tatrai, Katalin

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