The mechanism of action of estrogen in castration-resistant prostate cancer: clues from hormone levels.
BACKGROUND
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Aggarwal
Rahul
R
Urologic Oncology Program, Department of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94115, USA.
Weinberg
Vivian
V
Small
Eric J
EJ
Oh
William
W
Rushakoff
Robert
R
Ryan
Charles J
CJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000097:blood*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D004054:Diethylstilbestrol / Q000627:therapeutic use*; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use*; D004968:Estrogens, Non-Steroidal / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009919:Orchiectomy; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000601:surgery; D012189:Retrospective Studies
D000728:Androgens; D000972:Antineoplastic Agents, Phytogenic; D004365:Drugs, Chinese Herbal; D004968:Estrogens, Non-Steroidal; C114209:herbal preparation PC-SPES; D004054:Diethylstilbestrol; D017430:Prostate-Specific Antigen