The Mechanism of Action of Estrogen in Castration-Resistant Prostate Cancer: Clues From Hormone Levels
ABSTRACT Estrogen therapy plays a role in the management of castration-resistant prostate cancer (CRPC), although the mechanism of action is not fully known. This current analysis reports the relationship of change in adrenal androgen levels and prostate-specific antigen (PSA) response in patients with CRPC treated with estrogen therapy.
Hormone levels were measured for patients with CRPC treated in a multicenter phase II trial of 2 estrogen-containing compounds, the herbal supplement PC-SPES and diethylstilbestrol (DES), with known efficacy in CRPC. Patients with castrate levels of testosterone were randomized to initially receive either PC-SPES 960 mg t.i.d. or DES 3 mg/day. Levels of testosterone, dihydrotestosterone (DHT), estradiol, estrone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEA-S), and androstenedione were obtained at baseline and at 12-week intervals until disease progression. Hormone levels were obtained for 38 patients, 20 treated with PC-SPES and 18 treated with DES.
Significant declines between baseline and 12 weeks of treatment were observed in levels of serum testosterone (P < .001), estrone (P = .02), and DHEA (P < .001). The percent changes at 12 weeks in these hormone levels were inversely proportional to baseline values as measured by Spearman's rank correlation (testosterone: -0.41, P = .01; estrone: -0.64, P = .0001; DHEA: -0.39, P = .02). Levels of SHBG increased in almost all of the patients (97%), with a median percent increase of > 5-fold (P < .0001). Of the 38 evaluable patients, 15 (39% [95% CI, 24%-57%]) experienced a > 50% decline in PSA level. There was no significant difference between treatment groups or between responders and nonresponders in baseline distributions for any of the hormones. At follow-up, 73% of the responders had a decline in the level of DHEA-S compared with 41% of the nonresponders, resulting in a difference in the distribution of the percent change between the subsets (Mann-Whitney test: P = .03). Conversely, 64% of the responders compared with 30% of the nonresponders experienced an increase in DHT, with differing distributions of percent change (P = .02).
Androgens decline in response to estrogen therapy. A decline in DHEA-S and a rise in DHT are both associated with a decline in PSA while patients receive estrogen therapy.
- SourceAvailable from: Rafal Turo
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- "Preclinical studies have shown that the mechanism of reducing serum levels of DHEA-S and testosterone by DES in patients with androgenindependent disease is likely to be mediated through inhibition of 17,20-lyase/17-hydroxylase and 3-hydro- xysteroid dehydrogenase activity in the adrenal gland or other steroidogenic tissues  . A recently performed phase II trial assessed 38 patients for hormone level changes in CRPC after treatment with DES and an oestrogen-containing herbal compound (PC-SPES) . Several hormones, including the adrenal androgen DHEA, appeared to decline in patients with CRPC treated with oestrogen. "
ABSTRACT: Abstract The aim of this review was to discuss the most recent data from current trials of diethylstilboestrol (DES) to identify its present role in advanced prostate cancer treatment as new hormonal therapies emerge. The most relevant clinical studies using DES in castration-refractory prostate cancer (CRPC) were identified from the literature. The safety, efficacy, outcomes and mechanisms of action are summarized. In the age of chemotherapy this review highlights the efficacy of oestrogen therapy in CRPC. The optimal point in the therapeutic pathway at which DES should be prescribed remains to be established.Scandinavian Journal of Urology and Nephrology 11/2013; DOI:10.3109/21681805.2013.861508 · 1.06 Impact Factor
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ABSTRACT: The robot navigation using visual landmark approach is described. The landmarks are not preselected or otherwise defined a priori, but rather, they are extracted automatically during a learning phase. To facilitate this, a saliency map is constructed which highlights potential landmarks. This is used in conjunction with a qualitative segregation of the workspace, to further delineate the search areas for environment landmarks. For the sake of robustness, no semantic information is attached to the landmarks; they are stored as raw patterns along with information readily available from the workspace segregation, that facilitates their accurate rate recognition at a later, navigation session. During such a session, similar steps with the learning phase are employed to locate landmarks. The stored information is used to transform a previously leaned landmark pattern, according to the current position of the observer, achieving thus accurate landmark recognition. Results obtained from our approach demonstrate its validity and applicability in indoor workspacesIntelligent Robots and Systems, 1997. IROS '97., Proceedings of the 1997 IEEE/RSJ International Conference on; 10/1997
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ABSTRACT: Benign prostatic hyperplasia (BPH) is associated with the proliferation of prostate tissue and an increase in smooth muscle tone. However, the way in which the hormonal environment affects cell proliferation and prostatic interstitial cells (PIC) responsible for the maintenance of the smooth muscle tone is not clear. The present study investigated the effect of estrogen supplementation on cell proliferation, androgen/estrogen ratio, and expression and/or distribution of PIC. Male Sprague-Dawley rats were anesthetized with isoflurane/oxygen breathing mixture and subcutaneously implanted with silastic capsules. These capsules were either empty or filled with a 10 or 20 mg of crystalline estrogen. Estrogen exerted a potent effect on ventral prostate weight, which was manifested as a significant decrease between controls and the E(10)- and E(20)-treated rats. Active cell proliferation detected as Ki67-positive nuclei was observed in the stromal and epithelial cells of the ventral prostatic lobes from estrogen-treated rats and controls. Estrogen supplementation caused a significant and dose-dependent increase in prostatic estradiol and 5alpha-dihydrotestosterone (DHT) concentration but the ratios of either DHT/E(2) or E(2)/DHT were not significantly affected. PIC were observed in the region between the fibromuscular stroma and the glandular epithelium in all three experimental groups. E(20)-treated rats showed a higher expression of PIC than controls and E(10)-treated rats. The present study provides novel information regarding the synergistic role of estrogens and androgens in the prostate: estrogen may prevent prostatic hyperplasia via mechanisms other than affecting cell proliferation or DHT/estrogen ratio.The Prostate 10/2010; 70(14):1555-62. DOI:10.1002/pros.21191 · 3.57 Impact Factor