Brain-Selective Estrogen Therapy Prevents Androgen Deprivation-Associated Hot Flushes in a Rat Model
| Autor: | Christina A. Stennett, Laszlo Prokai, Istvan Merchenthaler, Katalin Prokai-Tatrai, Min Zhan, Vien Nguyen, Malcolm V. Lane |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty androgen deprivation medicine.drug_class lcsh:Medicine lcsh:RS1-441 Pharmaceutical Science brain-selective estrogen prodrug male hot flush urologic and male genital diseases Article lcsh:Pharmacy and materia medica 03 medical and health sciences Prostate cancer chemistry.chemical_compound 0302 clinical medicine Oral administration Internal medicine Drug Discovery medicine Testosterone DHED thermoregulation business.industry rat model lcsh:R Androgen medicine.disease prostate cancer 030104 developmental biology Endocrinology Castration chemistry Estrogen Hypothalamus 030220 oncology & carcinogenesis Molecular Medicine business Hormone |
| Zdroj: | Pharmaceuticals Volume 13 Issue 6 Pharmaceuticals, Vol 13, Iss 119, p 119 (2020) |
| ISSN: | 1424-8247 |
| DOI: | 10.3390/ph13060119 |
| Popis: | 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 17&beta 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 10&beta 17&beta 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. |
| Databáze: | OpenAIRE |
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