Abstract
Synthetic estrogens are used in the clinic to alleviate debilitating neurological symptoms associated with androgen deprivation therapy (ADT), an effective treatment improving survival in prostate cancer patients when administered timely in the course of the cancer. However, this therapy to relieve the symptoms, most commonly hot flushes, causes feminizations that significantly diminishes patients’ compliance because of physical and psychological discomfort. Because only estrogens can provide adequate therapy of hot flushes based on current clinical practices, there is an unmet medical need for an effective, side effect-free and, consequently, compliance-gaining intervention to alleviate these vasomotor symptoms distressing prostate cancer patients on ADT. The goal with our experiments was to show that treatment with 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED, a brain-selective bioprecursor prodrug of 17β-estradiol (E2) will ease ADT-associated hot flushes without feminizing side-effects.
To evaluate the effect of DHED on hot flushes the pharmacological rat hot flush model was used. Orchiectomized (ORDX) rats were treated orally with three different doses (10, 30, and 100 µg/kg) of DHED or ethynyl estradiol (EE, 200 µg/kg) for ten days. They were addicted to morphine and the tail skin temperature (TST) of saline-treated rats raised by 4.4±0.5 °C when morphine effect was withdrawn with naloxone injection. DHED and EE treatments significantly lowered such TST rise from 4.4 °C to 2.9 ±0.5°C and 1.8 ±0.5°C, respectively.
The conversion of DHED to E2 in the brain was confirmed by measuring the effect of DHED-derived E2 on the expression of progesterone receptors (PR) in the preoptic area of the hypothalamus with in situ hybridization histochemistry. Both DHED and EE treatment stimulated PR expression compared to saline-treatment in ORDX rats.
In our previous studies, we have shown the lack of conversion of DHED to E2 in the periphery in ovariectomized female rats; i.e., DHED treatment did not have uterotrophic, mammotrophic activities and did not stimulate galanin expression in the anterior pituitary. In these studies, the lack of conversion of DHED to E2 was also confirmed in male rats by measuring the expression of galanin, a highly estrogen-regulated gene, in the pituitary with quantitative RT-PCR. Contrary to EE, DHED treatment did not stimulate galanin expression in this estrogen target.
These observations support subsequent translational research focusing on DHED’s therapeutic use to remedy hot flushes and potentially other neurological symptoms in prostate cancer patients undergoing ADT to manage their malignancy. An estrogen therapy with the brain-selective DHED would provide a safe approach to prevent these neurological symptoms without causing peripheral estrogenic side effects such as gynecomastia or deep vein thrombosis.
Side Effects and Complications of Androgen Deprivation in Prostate Cancer Patients
