Stronger Suppression of Serum Testosterone and FSH Levels by a Synthetic Estrogen than by Castration or an LH-RH Agonist.

Kitahara, Satoshi; Yoshida, Keisuke; Ishizaka, Kazuhiro; Kageyama, Yukio; Kawakami, Satoru; Tsujii, Toshihiko; Oshima, Hiroyuki

doi:10.1507/endocrj.44.527

Cited by 25 publications

(17 citation statements)

References 15 publications

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“…Previous studies have suggested several possibilities that may account for its antitumor effect. Suppression of the hypothalamic-testicular axis, thus reducing serum testosterone to castrate levels (1), and suppression of adrenal androgens such as dehydroandrostendione and dehydroepiandrosterone sulfate (14) are possible mechanism of action. In addition to these hormonally mediated effects, DES may interfere with the cell cycle and induce apoptosis of androgen-dependent and -independent prostate cancer cell lines (23).…”

Section: Discussionmentioning

confidence: 99%

“…In the last few years, the number of medicines approved for the treatment of CRPC has increased dramatically, and includes the hormonal agents abiraterone (14) and MDV3100 (enzalutamide), the cytotoxic agent cabazitaxel (28), an adoptive cellular immunotherapy Sipuleucel-T (29) and alpharadine, a bone-targeted radionuclide Radium-223 (30). In addition, promising early clinical data in CRPC have been obtained with cabozantinib, a tyrosine kinase inhibitor.…”

Section: Discussionmentioning

confidence: 99%

“…DES has been shown to have a high affinity for binding to androgen receptors, which play a significant role as growth-drivers of prostate cancer (13). Other suggested mechanisms include inhibition of the secretion of gonadotropins and a sharp reduction in free testosterone levels (14). DES also increases the production of sex hormonebinding globulin (SHBG) and prolactin, thus, decreasing the amount of bio-available testosterone (6,15).…”

Section: Introductionmentioning

confidence: 99%

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Diethylstilbestrol for the treatment of patients with castration-resistant prostate cancer: Retrospective analysis of a single institution experience

et al. 2013

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Abstract. The aim of the present retrospective study was to evaluate the efficacy and safety of diethylstilbestrol (DES) as treatment for patients with castration-resistant prostate cancer (CRPC) and to identify predicting factors of response to DES. Patients treated with DES during the castration-resistant phase following the failure of prior treatment with LH-RH analogs during the castration-sensitive phase were retrieved from a prostate cancer database of our institution. Patients were treated with a daily dose of DES of 1-4 mg (mean, 2.6 mg) and anticoagulants for thromboembolic prophylaxis until disease progression. We analyzed their medical records, biochemical prostate-specific antigen (PSA) response and time to disease progression (TDP). Disease response and progression were identified according to the PCWG2 criteria. Patient data were examined using Kaplan-Meier survival analysis and statistical correlation tests with intra-patient comparison of the LH-RH and DES treatment phases. Fortythree DES-treated CRPC patients were found in our database through July 2011. The median age was 66 years. Sixty-three percent of the patients achieved a ≥50% decline in their serum PSA levels during DES therapy. Median TDP was 20.4 months for LH-RH analog treatment in the castration-sensitive phase, and 7.1 months for DES treatment in the castration-resistant phase. Durable responses (>1 year) were observed in 31% of the patients. Median overall survival was 57 months from the start of the DES therapy. There was no significant correlation between the TDP under LH-RH analogs and under DES therapy among the 38 patients eligible for correlation analysis. However, the magnitudes of serum PSA responses under DES and LH-RH analogs were significantly correlated with each other, and with the TDP under DES therapy. There were no treatment-related deaths. Four patients (9%) developed thromboembolic complications while under treatment, some of which appeared to be related to a discontinuation of thromboprophylaxis. In conclusion, DES confers substantial clinical benefit in the treatment of CRPC, with a relatively good safety profile when administered with thromboprophylaxis. The use of DES may be effective in CRPC, irrespective of the length of the hormone-sensitive period with LH-RH treatment. The magnitude of PSA response to previous treatment with LH-RH analogs, as well as to DES, was predictive of the duration of response to DES.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Diethylstilbestrol for the treatment of patients with castration-resistant prostate cancer: Retrospective analysis of a single institution experience

et al. 2013

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“…The effect is significantly stronger than that of surgical castration or of the administration of an LH-RH agonist [7]. We presume a potent suppressive effect on serum T might be one of the mechanisms of DES-DP action in patients with hormone-refractory prostate cancers.…”

Section: Approximatelymentioning

confidence: 79%

“…Serum levels of steroids before and during diethylstilbestrol diphosphate treatment in patients with hormone-refractory prostate cancer level, although serum levels of T are suppressed more strongly by DES-DP than by an LH-RH agonist or by bilateral orchiectomy or by combined androgen blockade with an LH-RH agonist and an androgen receptor blocker [7]. The detectable T in serum of the patients treated by an LH-RH agonist, with or without one of the anti-androgens, or surgical castration must originate from serum adrenal androgens.…”

Section: Discussionmentioning

confidence: 93%

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

et al. 1999

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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.

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Phase II study of transdermal estradiol in androgen‐independent prostate carcinoma

Bland

Garzotto

DeLoughery

et al. 2005

Cancer

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BACKGROUND Oral estrogen therapy has activity in patients with hormone‐naive and androgen‐independent prostate carcinoma (AIPC), but its utility is limited by the associated risk of thromboembolic toxicity. Parenteral administration may be safer as it avoids “first pass” liver exposure to estrogen. The authors tested the safety and efficacy of transdermal estradiol (TDE), as well as the effect of therapy on hot flashes, sex hormones, the procoagulant cascade, and bone turnover in patients with AIPC. METHODS Patients with prostate carcinoma progressing after primary hormonal therapy received TDE 0.6 mg per 24 hours (administered as six 0.1 mg per 24‐hour patches replaced every 7 days). Serum prostate‐specific antigen (PSA) and hormone levels, coagulation factors, markers of bone turnover, bone density measurements, and a hot flash diary were collected at regular intervals. RESULTS Three of 24 patients (12.5%; 95% confidence interval [CI], 0–26%) had a confirmed PSA reduction > 50%. The Kaplan–Meier estimate of median time to disease progression was 12 weeks (95% CI, 4.6–19.4 weeks). Toxicity was modest and no thromboembolic complications occurred. The mean (±95% CI) serum estradiol level increased from 17.2 pg.mL (range, 14.8–19.6 pg/mL) to 460.7 pg/mL (range, 334.6–586.7 pg/mL). The total testosterone level remained stable in the anorchid range during treatment, but the free testosterone level decreased as a result of increased sex hormone binding globulin. No change in factor VIII activity, F 1.2, or resistance to activated protein C was observed, whereas a modest decrease in the protein S level was observed. CONCLUSIONS In patients with APIC, TDE was well tolerated and produced a modest response rate, but was not associated with thromboembolic complications or clinically important changes in several coagulation factors. Cancer 2005. © 2005 American Cancer Society.

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Stronger Suppression of Serum Testosterone and FSH Levels by a Synthetic Estrogen than by Castration or an LH-RH Agonist.

Cited by 25 publications

References 15 publications

Diethylstilbestrol for the treatment of patients with castration-resistant prostate cancer: Retrospective analysis of a single institution experience

Diethylstilbestrol for the treatment of patients with castration-resistant prostate cancer: Retrospective analysis of a single institution experience

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

Phase II study of transdermal estradiol in androgen‐independent prostate carcinoma

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