The Mechanism of Action of Estrogen in Castration-Resistant Prostate Cancer: Clues From Hormone Levels

Urologic Oncology Program, Department of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94115, USA.
Clinical Genitourinary Cancer (Impact Factor: 2.32). 10/2009; 7(3):E71-6. DOI: 10.3816/CGC.2009.n.027
Source: PubMed


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.

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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 [22] [23]. 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) [24]. Several hormones, including the adrenal androgen DHEA, appeared to decline in patients with CRPC treated with oestrogen. "
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