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

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...

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Bibliographic Details
Published in:Pharmaceuticals (Basel, Switzerland) Switzerland), 2020-06, Vol.13 (6), p.119
Main Authors: Merchenthaler, Istvan, Lane, Malcolm, Stennett, Christina, Zhan, Min, Nguyen, Vien, Prokai-Tatrai, Katalin, Prokai, Laszlo
Format: Article
Language:English
Subjects:
androgen deprivation
Androgens
Animals
Brain
brain-selective estrogen prodrug
Cancer therapies
DHED
Drug dosages
Drug withdrawal
Enzymes
Estrogens
Gene expression
Heat
Hypothalamus
male hot flush
Males
Morphine
Prostate cancer
rat model
Rodents
Skin
Womens health
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Summary: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, E ) 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 E . A pilot pharmacokinetic study using oral administration of DHED to these animals revealed the formation of E 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 E 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.
ISSN:1424-8247
1424-8247
DOI:10.3390/ph13060119