Wilson M E, Mook D, Graves F, Felger J, Bielsky I F, Wallen K
Division of Psychobiology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Endocrine. 2003 Dec;22(3):305-15. doi: 10.1385/ENDO:22:3:305.
The selective estrogen receptor modulator, tamoxifen, effectively slows the progression of estrogen-positive breast cancer and reduces the possibility of this cancer developing in women at high risk. Despite the widespread acceptance of tamoxifen as a therapeutic agent for this disease, its effects on other estrogen-dependent pathways, particularly on neural circuits regulating brain function and peripheral hormone secretion, are poorly understood. The present study, using previously ovariectomized rhesus monkeys, examined the effects of tamoxifen, in both the presence and absence of estradiol replacement, on the reproductive and hypo-thalamic-pituitary-adrenal (HPA) axes. In Experiment 1, monkeys randomly assigned to three groups (n = 8 each) were treated with placebo and either two doses of estradiol, two doses of tamoxifen alone, or two doses of tamoxifen plus high-dose estradiol to assess the effects on negative feedback suppression of luteinizing hormone (LH). Both doses of tamoxifen effectively antagonized the negative feedback efficacy of estradiol on LH secretion. In contrast, neither the low- or high-dose tamoxifen alone had any effect on LH secretion, as concentrations during tamoxifen treatments were indistinguishable from those during placebo. In Experiment 2, females were randomly assigned to one of four treatment groups (placebo, n = 6; estradiol, n = 5; tamoxifen only, n = 5; or tamoxifen plus estradiol, n = 6) to assess the effects on glucocorticoid negative feedback and pituitary and adrenal responsiveness to exogenous corticotropin- releasing hormone (CRH). Tamoxifen also antagonized the facilitating effects of estradiol on basal and CRH-induced ACTH and cortisol secretion. However, this antagonism produced basal and CRH-stimulated cortisol and ACTH concentrations that were lower than placebo-treated females. Interestingly, tamoxifen in the absence of estradiol produced a similar diminution in ACTH and cortisol response. These data suggest that, in the presence of estradiol, tamoxifen not only antagonized estrogenic facilitation of HPA responsivity but also actually attenuated the response compared with the placebo-treatment condition. Taken together, these data indicate that tamoxifen acts as an estrogen antagonist on the neural circuits controlling the neuroendocrine regulation of the hypothalamic-pituitary-ovarian and adrenal axes in ovariectomized macaque females.
选择性雌激素受体调节剂他莫昔芬能有效减缓雌激素阳性乳腺癌的进展，并降低高危女性患这种癌症的可能性。尽管他莫昔芬作为这种疾病的治疗药物已被广泛接受，但其对其他雌激素依赖途径的影响，尤其是对调节脑功能和外周激素分泌的神经回路的影响，却知之甚少。本研究使用先前已切除卵巢的恒河猴，研究了在有和没有雌二醇替代的情况下，他莫昔芬对生殖轴和下丘脑 - 垂体 - 肾上腺（HPA）轴的影响。在实验1中，将猴子随机分为三组（每组n = 8），分别用安慰剂以及两种剂量的雌二醇、两种剂量的他莫昔芬单独处理，或两种剂量的他莫昔芬加高剂量雌二醇处理，以评估对促黄体生成素（LH）负反馈抑制的影响。两种剂量的他莫昔芬均有效拮抗了雌二醇对LH分泌的负反馈作用。相比之下，单独使用低剂量或高剂量他莫昔芬对LH分泌均无任何影响，因为他莫昔芬治疗期间的浓度与安慰剂期间的浓度无差异。在实验2中，雌性猴子被随机分配到四个治疗组之一（安慰剂组，n = 6；雌二醇组，n = 5；仅他莫昔芬组，n = 5；或他莫昔芬加雌二醇组，n = 6），以评估对糖皮质激素负反馈以及垂体和肾上腺对外源性促肾上腺皮质激素释放激素（CRH）反应性的影响。他莫昔芬还拮抗了雌二醇对基础和CRH诱导促肾上腺皮质激素（ACTH）和皮质醇分泌的促进作用。然而，这种拮抗作用导致基础和CRH刺激的皮质醇和ACTH浓度低于安慰剂处理的雌性猴子。有趣的是，在没有雌二醇的情况下，他莫昔芬也使ACTH和皮质醇反应出现类似的降低。这些数据表明，在有雌二醇存在的情况下，他莫昔芬不仅拮抗了雌激素对HPA反应性的促进作用，而且与安慰剂处理条件相比，实际上还减弱了反应。综上所述，这些数据表明，他莫昔芬在切除卵巢的猕猴雌性中，对控制下丘脑 - 垂体 - 卵巢和肾上腺轴神经内分泌调节的神经回路起雌激素拮抗剂的作用。
