Abstract：
BACKGROUND: Olanzapine antagonizes dopamine receptors and is prescribed to treat multiple psychiatric conditions. The main side effect of concern for olanzapine is weight gain and metabolic syndrome. Olanzapine induces hyperprolactinemia, however its effect on the mammary gland is poorly documented.
METHODS: Rats received olanzapine by gavage or in drinking water at 1, 3, and 6 mg/kg/day for 5-40 days or 100 days, with and without coadministration of bromocriptine or aripiprazole and using once daily or continuous administration strategies. Histomorphology of the mammary gland, concentrations of prolactin, estradiol, progesterone, and olanzapine in serum, mammary gland and adipose tissue, and mRNA and protein expressions of prolactin receptors were analyzed.
RESULTS: In adult and prepubescent female rats and male rats, olanzapine induced significant development of mammary glands in dose- and time-dependent manners, with histopathological hyperplasia of mammary ducts and alveoli with lumen dilation and secretion, marked increase of mammary prolactin receptor expression, a marker of breast tissue, and with mild increase of circulating prolactin. This side effect can be reversed after medication withdrawal, but long-term olanzapine treatment for 100 days implicated tumorigenic potentials indicated by usual ductal epithelial hyperplasia. Olanzapine induced mammary development was prevented with the coaddition of the dopamine agonist bromocriptine or partial agonist aripiprazole, or by continuous administration of medication instead of a once daily regimen.
CONCLUSIONS: These results shed light on the previously overlooked effect of olanzapine on mammary development and present experimental evidence to support current clinical management strategies of antipsychotic induced side effects in the breast.
METHODS: Rats received olanzapine by gavage or in drinking water at 1, 3, and 6 mg/kg/day for 5-40 days or 100 days, with and without coadministration of bromocriptine or aripiprazole and using once daily or continuous administration strategies. Histomorphology of the mammary gland, concentrations of prolactin, estradiol, progesterone, and olanzapine in serum, mammary gland and adipose tissue, and mRNA and protein expressions of prolactin receptors were analyzed.
RESULTS: In adult and prepubescent female rats and male rats, olanzapine induced significant development of mammary glands in dose- and time-dependent manners, with histopathological hyperplasia of mammary ducts and alveoli with lumen dilation and secretion, marked increase of mammary prolactin receptor expression, a marker of breast tissue, and with mild increase of circulating prolactin. This side effect can be reversed after medication withdrawal, but long-term olanzapine treatment for 100 days implicated tumorigenic potentials indicated by usual ductal epithelial hyperplasia. Olanzapine induced mammary development was prevented with the coaddition of the dopamine agonist bromocriptine or partial agonist aripiprazole, or by continuous administration of medication instead of a once daily regimen.
CONCLUSIONS: These results shed light on the previously overlooked effect of olanzapine on mammary development and present experimental evidence to support current clinical management strategies of antipsychotic induced side effects in the breast.
摘要：
背景：奥氮平拮抗多巴胺受体，并用于治疗多种精神疾病。奥氮平的主要副作用是体重增加和代谢综合征。奥氮平诱导高催乳素血症，然而，它对乳腺的影响鲜有记载。
方法：大鼠以1、3和6mg/kg/天的剂量通过灌胃或饮用水接受奥氮平5-40天或100天，有或没有共同给药溴隐亭或阿立哌唑，并使用每日一次或连续给药策略。乳腺的组织形态学,催乳素的浓度，雌二醇,黄体酮,血清中的奥氮平,乳腺和脂肪组织，并分析催乳素受体的mRNA和蛋白表达。
结果：在成年和青春期前的雌性大鼠和雄性大鼠中，奥氮平以剂量和时间依赖性方式诱导乳腺的显着发育，乳腺导管和肺泡的组织病理学增生伴随管腔扩张和分泌，乳腺催乳素受体表达显著增加，乳房组织的标记，循环催乳素轻度增加。这种副作用可以在停药后逆转，但长期奥氮平治疗100天涉及常见的导管上皮增生的致瘤潜能。奥氮平诱导的乳腺发育与多巴胺激动剂溴隐亭或部分激动剂阿立哌唑的共同添加被阻止，或通过连续给药而不是每天一次的方案。
结论：这些结果揭示了奥氮平以前忽视的对乳腺发育的影响，并提供了实验证据支持当前抗精神病药物引起的乳腺副作用的临床管理策略。
方法：大鼠以1、3和6mg/kg/天的剂量通过灌胃或饮用水接受奥氮平5-40天或100天，有或没有共同给药溴隐亭或阿立哌唑，并使用每日一次或连续给药策略。乳腺的组织形态学,催乳素的浓度，雌二醇,黄体酮,血清中的奥氮平,乳腺和脂肪组织，并分析催乳素受体的mRNA和蛋白表达。
结果：在成年和青春期前的雌性大鼠和雄性大鼠中，奥氮平以剂量和时间依赖性方式诱导乳腺的显着发育，乳腺导管和肺泡的组织病理学增生伴随管腔扩张和分泌，乳腺催乳素受体表达显著增加，乳房组织的标记，循环催乳素轻度增加。这种副作用可以在停药后逆转，但长期奥氮平治疗100天涉及常见的导管上皮增生的致瘤潜能。奥氮平诱导的乳腺发育与多巴胺激动剂溴隐亭或部分激动剂阿立哌唑的共同添加被阻止，或通过连续给药而不是每天一次的方案。
结论：这些结果揭示了奥氮平以前忽视的对乳腺发育的影响，并提供了实验证据支持当前抗精神病药物引起的乳腺副作用的临床管理策略。
