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

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    Author
    Merchenthaler, Istvan
    Lane, Malcolm
    Stennett, Christina
    Zhan, Min
    Nguyen, Vien
    Prokai-Tatrai, Katalin
    Prokai, Laszlo
    Date
    2020-06-10
    Journal
    Pharmaceuticals
    Publisher
    MDPI AG
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.3390/ph13060119
    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.
    Keyword
    DHED
    androgen deprivation
    brain-selective estrogen prodrug
    male hot flush
    prostate cancer
    rat model
    thermoregulation
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/13738
    ae974a485f413a2113503eed53cd6c53
    10.3390/ph13060119
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