Department of Psychological and Brain Sciences and Center for Neuroendocrine Studies, University of Massachusetts, Amherst, Massachusetts 01003 and
Department of Psychological and Brain Sciences and Center for Neuroendocrine Studies, University of Massachusetts, Amherst, Massachusetts 01003 and.
J Neurosci. 2019 Jan 30;39(5):918-928. doi: 10.1523/JNEUROSCI.0353-18.2018. Epub 2018 Dec 26.
Breast cancer patients using aromatase inhibitors (AIs) as an adjuvant therapy often report side effects, including hot flashes, mood changes, and cognitive impairment. Despite long-term use in humans, little is known about the effects of continuous AI administration on the brain and cognition. We used a primate model of human cognitive aging, the common marmoset, to examine the effects of a 4-week daily administration of the AI letrozole (20 μg, p.o.) on cognition, anxiety, thermoregulation, brain estrogen content, and hippocampal pyramidal cell physiology. Letrozole treatment was administered to both male and female marmosets and reduced peripheral levels of estradiol (E2), but unexpectedly increased E2 levels in the hippocampus. Spatial working memory and intrinsic excitability of hippocampal neurons were negatively affected by the treatment possibly due to increased hippocampal E2. While no changes in hypothalamic E2 were observed, thermoregulation was disrupted by letrozole in females only, indicating some impact on hypothalamic activity. These findings suggest adverse effects of AIs on the primate brain and call for new therapies that effectively prevent breast cancer recurrence while minimizing side effects that further compromise quality of life. Aromatase inhibitors (AIs) are used as an adjuvant therapy for estrogen-receptor-positive breast cancer and are associated with side effects, including hot flashes, depression/anxiety, and memory deficits severe enough for many women to discontinue this life-saving treatment. AIs are also used by men, yet sex differences in the reported side effects have not been systematically studied. We show that AI-treated male and female marmosets exhibit behavioral changes consistent with these CNS symptoms, as well as elevated hippocampal estradiol and compromised hippocampal physiology. These findings illustrate the need for (1) a greater understanding of the precise mechanisms by which AIs impact brain function and (2) the development of new treatment approaches for breast cancer patients that minimize adverse effects on the brain.
乳腺癌患者在接受芳香化酶抑制剂（AIs）作为辅助治疗时经常会出现副作用，包括热潮红、情绪变化和认知障碍。尽管在人类中长期使用，但对于连续使用 AI 对大脑和认知的影响知之甚少。我们使用人类认知衰老的灵长类动物模型——普通狨猴，来研究为期 4 周的 AI 来曲唑（20 μg，口服）的日常给药对认知、焦虑、体温调节、大脑雌激素含量和海马锥体神经元生理学的影响。来曲唑治疗应用于雄性和雌性狨猴，降低了外周雌二醇（E2）水平，但出乎意料的是，海马中的 E2 水平增加了。空间工作记忆和海马神经元的固有兴奋性受到该治疗的负面影响，可能是由于海马 E2 增加所致。虽然下丘脑的 E2 没有变化，但仅在雌性中观察到来曲唑扰乱了体温调节，表明对下丘脑活动有一定影响。这些发现表明 AI 对灵长类动物大脑有不良影响，并呼吁开发新的治疗方法，有效预防乳腺癌复发，同时最大限度地减少进一步降低生活质量的副作用。芳香化酶抑制剂（AIs）被用作雌激素受体阳性乳腺癌的辅助治疗药物，与副作用相关，包括热潮红、抑郁/焦虑和记忆力减退，严重到许多女性都停止了这种救命治疗。AIs 也被男性使用，但报告的副作用中的性别差异尚未得到系统研究。我们发现，接受 AI 治疗的雄性和雌性狨猴表现出与这些 CNS 症状一致的行为变化，以及海马中升高的雌二醇和受损的海马生理学。这些发现说明了（1）更深入了解 AI 影响大脑功能的确切机制的必要性，以及（2）为乳腺癌患者开发新的治疗方法的必要性，这些方法可以最大限度地减少对大脑的不良影响。
