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

Date

2020-06-10

Authors

Merchenthaler, Istvan
Stennett, Christina
Zhan, Min
Nguyen, Vien
Prokai-Tatrai, Katalin
Prokai, Laszlo

ORCID

0000-0002-4559-3458 (Prokai, Laszlo)
0000-0001-5595-1346 (Prokai-Tatrai, Katalin)

Journal Title

Journal ISSN

Volume Title

Publisher

MDPI

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 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.

Description

Keywords

Dhed, androgen deprivation, brain-selective estrogen prodrug, male hot flush, prostate cancer, rat model, thermoregulation

Citation

Merchenthaler, 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

Rights

© 2020 by the authors.

License

Attribution 4.0 International (CC BY 4.0)