17β-estradiol (E2)-containing hormone therapy is a safe, effective way to alleviate unwanted menopause symptoms. Preclinical research has focused upon the role of E2 in learning and memory using a surgically menopausal rodent model whereby the ovaries are removed. Given that most women retain their reproductive tract and undergo a natural menopause transition, it is necessary to understand how exogenous E2 impacts a structurally intact, but follicle-deplete, system. In the current study, 8 month old female rats were administered the ovatoxin 4-vinylcyclohexene diepoxide (VCD), which accelerates ovarian follicular depletion, to model the human menopause transition. After follicular depletion, at 11 months old, rats were administered Vehicle or tonic E2 treatment for 12 days prior to behavioral evaluation on spatial working and reference memory tasks. Results demonstrated that E2 had both enhancing and impairing effects on taxed working memory depending upon the learning or retention phases of the water radial-arm maze, with no impact on reference memory. Relationships between memory scores and circulating estrogen levels were specific to follicle-depleted rats without E2 treatment. Collectively, findings demonstrate the complexity of E2 administration in a follicle-depleted background, with cognitive effects specific to working memory; furthermore, E2 administration altered circulating hormonal milieu and relationships between hormone profiles and memory. In sum, menopausal etiology impacts the parameters of E2 effects on cognition, complementing prior work with other estrogen compounds. Deciphering estrogenic actions in a system wherein the reproductive tract remains intact with follicle-depleted ovaries, thus modeling the majority or menopausal women, is critical for translational perspectives.

含 17β-雌二醇 (E2) 的激素疗法是缓解不良更年期症状的安全有效方法。临床前研究重点关注 E2 在学习和记忆中的作用，使用手术切除卵巢的绝经啮齿动物模型。鉴于大多数女性保留生殖道并经历自然的更年期过渡，因此有必要了解外源 E2 如何影响结构完整但卵泡耗尽的系统。在当前的研究中，8 个月大的雌性大鼠被注射了卵毒素 4-乙烯基环己烯二环氧化物 (VCD)，它会加速卵巢卵泡的耗竭，以模拟人类更年期过渡。毛囊耗竭后，在 11 个月大时，对大鼠进行媒介物或补品 E2 治疗 12 天，然后对空间工作和参考记忆任务进行行为评估。结果表明，E2 对繁重的工作记忆有增强和减弱的作用，具体取决于水径向臂迷宫的学习或保留阶段，但对参考记忆没有影响。记忆评分和循环雌激素水平之间的关系对于未经 E2 治疗的卵泡耗竭大鼠来说是特有的。总的来说，研究结果证明了在卵泡耗尽背景下 E2 给药的复杂性，以及特定于工作记忆的认知效应；此外，E2 给药改变了循环激素环境以及激素分布和记忆之间的关系。总之，更年期病因影响 E2 对认知的影响参数，补充了之前其他雌激素化合物的研究。破译系统中的雌激素作用，其中生殖道保持完整且卵巢已耗尽，从而模拟大多数或更年期妇女，这对于转化观点至关重要。