Effects of Intravenous Administration of High Dose-Diethylstilbestrol Diphosphate on Serum Hormonal Levels in Patients with Hormone-Refractory Prostate Cancer.

Abstract

Abstaract.The objective of this study was to elucidate the mechanism underlying the further suppression of serum testosterone (T) by diethylstilbestrol diphosphate (DES-DP) in patients with prostate cancer refractory to hormonal treatment.These patients received an LHRH agonist with or without a non-steroidal androgen-receptor blocker or a gestagen before DES-DP.We measured serum levels of total and free T, dihydrotestosterone (DHT), estradiol (E2), dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), androstenedione, cortisol, aldosterone before and during intravenous administration of high doses of DES-DP (500 or 1000 mg/day).DES-DP administration suppressed the serum levels of FSH (p=0.04) and total T (p=0.02), and eliminated free T (p =0.04) and E2 (p = 0.04) from serum, while reducing serum DHEA-S to approximately two-thirds of the pretreatment level (p=0.03).In contrast, serum levels of SHBG (p=0.02) and cortisol (p=0.02) were markedly increased after DES-DP administration.The latter had no significant effect on serum levels of LH, DHT, ACTH, 17a-hydroxypregnenolone, 17a-hydroxyprogesterone, DHEA, androstenedione, or aldosterone. The results suggest that the potent suppression of circulating total T by DES-DP is caused, in part, by the inhibitory effect of DES-DP on serum DHEA-S level. In most patients, high-dose DES-DP treatment completely suppressed the serum level of free T, while possibly elevating serum SHBG and decreasing serum total T. The mechanisms that maintain the serum level of serum DHT during DES-DP treatment require further elucidation.

A Phase II Multicenter, Randomized, Double-Blind, Safety Trial Assessing the Pharmacokinetics, Pharmacodynamics, and Efficacy of Oral 2-Methoxyestradiol Capsules in Hormone-Refractory Prostate Cancer

“…However, there is evidence that SHBG may mediate the activity of certain agents that induce tumor regressions in patients with prostate cancer. Diethylstilbestrol diphosphate, an estrogen prodrug, is one such agent (26). It is also possible that 2ME 2 may exert some of its effects through SHBG in addition to its effects on death receptor 5 (13).…”

Pretreatment Serum Level of Testosterone as a Prognostic Factor in Japanese Men with Hormonally Treated Stage D2 Prostate Cancer.

“…About 70-80% of prostate cancer patients initially respond to endocrine therapy, but more than half of them gradually develop resistance [23]. Once the disease progresses during endocrine therapy, the mean survival is only approximately 6-12 months [24][25][26] . If it were possible to identify those patients whose tumor cells are primarily androgen-insensitive, an alternative treatment might be initiated.…”

Diethylstilbestrol decreased adrenal cholesterol and corticosterone in rats

“…However, the serum ACTH levels and pituitary Pomc mRNA were not increased by DES treatment in this study. It has been reported that DES-diphosphate (500 or 1000 mg/day for 2-5 weeks) suppressed the serum level of testosterone for the treatment of prostate cancer patients without significant effect on serum levels of ACTH (Kitahara et al 1999). Recently another factor for adrenal development has been reported.…”

“…DES has been extensively used as a treatment for prostate cancer in humans. Higher doses of DES-diphosphate (500-1000 mg/day for 2-5 weeks) were found to suppress the serum level of testosterone for the treatment of prostate cancer patients (Kitahara et al 1999). DES, a synthetic non-steroidal oestrogen, binds to ERs and exhibits strong oestrogenic toxicities, including adverse reproductive effects on male animals (Hillered & Ernster 1983, Dean et al 1997.…”