Brain-Selective Estrogen Therapy Prevents Androgen Deprivation-Associated Hot Flushes in a Rat Model

dc.creatorMerchenthaler, Istvan
dc.creatorLane, Malcolm
dc.creatorStennett, Christina
dc.creatorZhan, Min
dc.creatorNguyen, Vien
dc.creatorProkai-Tatrai, Katalin
dc.creatorProkai, Laszlo
dc.creator.orcid0000-0002-4559-3458 (Prokai, Laszlo)
dc.creator.orcid0000-0001-5595-1346 (Prokai-Tatrai, Katalin)
dc.date.accessioned2022-11-15T22:34:39Z
dc.date.available2022-11-15T22:34:39Z
dc.date.issued2020-06-10
dc.description.abstractHot flushes are best-known for affecting menopausal women, but men who undergo life-saving castration due to androgen-sensitive prostate cancer also suffer from these vasomotor symptoms. Estrogen deficiency in these patients is a direct consequence of androgen deprivation, because estrogens (notably 17beta-estradiol, E2) are produced from testosterone. Although estrogens alleviate hot flushes in these patients, they also cause adverse systemic side effects. Because only estrogens can provide mitigation of hot flushes on the basis of current clinical practices, there is an unmet need for an effective and safe pharmacotherapeutic intervention that would also greatly enhance patient adherence. To this end, we evaluated treatment of orchidectomized (ORDX) rats with 10beta, 17beta-dihydroxyestra-1,4-dien-3-one (DHED), a brain-selective bioprecursor prodrug of E2. A pilot pharmacokinetic study using oral administration of DHED to these animals revealed the formation of E2 in the brain without the appearance of the hormone in the circulation. Therefore, DHED treatment alleviated androgen deprivation-associated hot flushes without peripheral impact in the ORDX rat model. Concomitantly, we showed that DHED-derived E2 induced progesterone receptor gene expression in the hypothalamus without stimulating galanin expression in the anterior pituitary, further indicating the lack of systemic estrogen exposure upon oral treatment with DHED.
dc.description.sponsorshipThis project was supported in part by the National Institutes of Health, grant numbers CA215550 (L.P. and I.M.) and CA195910 (V.N.), and by The Welch Foundation (endowment BK-0031, L.P.).
dc.identifier.citationMerchenthaler, I., Lane, M., Stennett, C., Zhan, M., Nguyen, V., Prokai-Tatrai, K., & Prokai, L. (2020). Brain-Selective Estrogen Therapy Prevents Androgen Deprivation-Associated Hot Flushes in a Rat Model. Pharmaceuticals (Basel, Switzerland), 13(6), 119. https://doi.org/10.3390/ph13060119
dc.identifier.issn1424-8247
dc.identifier.issue6
dc.identifier.urihttps://hdl.handle.net/20.500.12503/31931
dc.identifier.volume13
dc.publisherMDPI
dc.relation.urihttps://doi.org/10.3390/ph13060119
dc.rights.holder© 2020 by the authors.
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourcePharmaceuticals
dc.subjectDhed
dc.subjectandrogen deprivation
dc.subjectbrain-selective estrogen prodrug
dc.subjectmale hot flush
dc.subjectprostate cancer
dc.subjectrat model
dc.subjectthermoregulation
dc.titleBrain-Selective Estrogen Therapy Prevents Androgen Deprivation-Associated Hot Flushes in a Rat Model
dc.typeArticle
dc.type.materialtext

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