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

Authors
  • Merchenthaler, Istvan1, 2
  • Lane, Malcolm1
  • Stennett, Christina1
  • Zhan, Min1
  • Nguyen, Vien3, 4
  • Prokai-Tatrai, Katalin3, 4
  • Prokai, Laszlo3, 4
  • 1 Department of Epidemiology and Public Health, University of Maryland, Baltimore, MD 21201, USA.
  • 2 Department of Anatomy and Neurobiology, University of Maryland, Baltimore, MD 21201, USA.
  • 3 Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
  • 4 AgyPharma LLC, Mansfield, TX 76063, USA.
Type
Published Article
Journal
Pharmaceuticals
Publisher
MDPI AG
Publication Date
Jun 10, 2020
Volume
13
Issue
6
Identifiers
DOI: 10.3390/ph13060119
PMID: 32531919
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Hot 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 17β-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 10β, 17β-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.

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