Labrie C, Cusan L, Plante M, Lapointe S, Labrie F
Medical Research Council Group in Molecular Endocrinology, Laval University Medical Center, Quebec, Canada.
J Steroid Biochem. 1987 Oct;28(4):379-84. doi: 10.1016/0022-4731(87)91054-5.
In order to assess the androgenic activity of synthetic "progestins" currently used as "antiandrogens" for the treatment of prostate cancer in men, the effect of a series of these compounds has been measured following 14 days of treatment of adult castrated rats on specific and sensitive parameters of androgenic activity, namely ventral prostate weight and prostatic ornithine decarboxylase (ODC) activity. Medroxyprogesterone acetate (MPA) is almost equipotent with 5 alpha-dihydrotestosterone (DHT), a 49% increase in prostatic weight being observed at the low dose of 0.15 mg, twice daily (P less than 0.01). Megestrol acetate (Megace), chlormadinone acetate (CMA) and spironolactone were less potent but caused a 36-59% increase in prostatic weight at the highest dose used, namely 10 mg. At the 5 mg dose, cyproterone acetate (CPA) caused a 75% increase in prostatic weight. The androgenic activity of the compounds is even more clearly illustrated by their marked stimulatory effect on prostatic ornithine decarboxylase (ODC) activity. MPA, at the low dose of 0.15 mg, caused a 20-fold increase (relative to the effect of placebo) in the activity of the enzyme while the same dose of DHT caused a 15-fold stimulation of enzymatic activity. At the 10 mg dose, megestrol acetate, CMA and spironolactone caused 13.1, 11.8 and 8.6-fold stimulations of ODC activity, respectively. Flutamide, on the other hand, had no stimulatory effect on either ventral prostate weight or prostatic ODC activity. In agreement with glucocorticoid activity, MPA, megestrol acetate and CMA caused a marked inhibition (45-64%) of adrenal weight. The present data show that MPA is a highly potent androgen while megestrol acetate, CMA, CPA and spironolactone have lower but significant androgenic activity on all the parameters measured. It should be added that MPA, megestrol acetate and CMA are completely devoid of antiandrogenic activity while spironolactone shows weak antiandrogen action and CPA is a mixed agonist-antagonist. Flutamide, the compound used as reference, is the only compound devoid of any androgenic action and is thus acting as a pure antiandrogen on both ventral prostate weight and prostatic ODC activity. The present data have major implications for the choice of drug to be used for the treatment of androgen-sensitive diseases, especially prostate cancer. As shown by the present data, the synthetic "progestins" so-far available all possess variable levels of androgenic activity and are thus not recommended for the treatment of prostate cancer.
为了评估目前用作“抗雄激素”治疗男性前列腺癌的合成“孕激素”的雄激素活性，在成年去势大鼠接受14天治疗后，针对雄激素活性的特定敏感参数，即腹侧前列腺重量和前列腺鸟氨酸脱羧酶（ODC）活性，测定了一系列这些化合物的作用。醋酸甲羟孕酮（MPA）几乎与5α-二氢睾酮（DHT）等效，每日两次给予低剂量0.15mg时，前列腺重量增加49%（P<0.01）。醋酸甲地孕酮（Megace）、醋酸氯地孕酮（CMA）和螺内酯的效力较低，但在所用最高剂量即10mg时，前列腺重量增加36%-59%。在5mg剂量时，醋酸环丙孕酮（CPA）使前列腺重量增加75%。这些化合物对前列腺鸟氨酸脱羧酶（ODC）活性的显著刺激作用更清楚地说明了它们的雄激素活性。MPA在低剂量0.15mg时，使该酶的活性增加了20倍（相对于安慰剂的作用），而相同剂量的DHT使酶活性增加了15倍。在10mg剂量时，醋酸甲地孕酮、CMA和螺内酯分别使ODC活性增加了13.1、11.8和8.6倍。另一方面，氟他胺对腹侧前列腺重量或前列腺ODC活性均无刺激作用。与糖皮质激素活性一致，MPA、醋酸甲地孕酮和CMA使肾上腺重量显著降低（45%-64%）。目前的数据表明，MPA是一种高效雄激素，而醋酸甲地孕酮、CMA、CPA和螺内酯在所有测量参数上具有较低但显著的雄激素活性。应该补充的是，MPA、醋酸甲地孕酮和CMA完全没有抗雄激素活性，而螺内酯显示出弱抗雄激素作用，CPA是一种混合激动剂-拮抗剂。用作对照的化合物氟他胺是唯一没有任何雄激素作用的化合物，因此在腹侧前列腺重量和前列腺ODC活性方面均作为纯抗雄激素起作用。目前的数据对用于治疗雄激素敏感性疾病尤其是前列腺癌的药物选择具有重要意义。如目前数据所示，目前可用的合成“孕激素”均具有不同程度的雄激素活性，因此不推荐用于治疗前列腺癌。
