Endocrine profile of the VCD-induced perimenopausal model rat

During the transition to menopause, women experience a variety of physical and psychological symptoms that are directly or indirectly linked to changes in hormone secretion. Establishing animal models with intact ovaries is essential for understanding these interactions and finding new therapeutic targets. In this study, we assessed the endocrine profile, as well as the estrous cycle, in the 4-vinylcyclohexene diepoxide (VCD)-induced follicular depletion rat model in 10-day intervals over 1 month to accurately establish the best period for studies of the transition period. Twenty-eight-day-old female rats were injected daily with VCD or oil s.c. for 15 days and euthanized in the diestrus phase approximately 70, 80, 90 and 100 days after the onset of treatment. The percentage of rats showing irregular cycles and the plasma level of FSH increased only in the 100-day VCD group. Plasma anti-Müllerian hormone (AMH) and progesterone were lower in all VCD groups compared to control groups, while estradiol remained unchanged or higher. As in control groups, dihydrotestosterone (DHT) progressively decreased in the 70-90-day VCD groups; however, it was followed by a sharp increase only in the 100-day VCD group. No changes were found in plasma corticosterone, prolactin, thyroid hormones or luteinizing hormone. Based on the estrous cycle and endocrine profile, we conclude that 1) the time window from 70 to 100 days is suitable to study a perimenopause-like state in this model, and 2) regular cycles with low progesterone and AMH and normal FSH can be used as markers of the early/mid-transition period, whereas irregular cycles associated with higher FSH and DHT can be used as markers of the late transition period to estropause.在向绝经过渡期的过程中，女性会出现多种与激素分泌变化直接或间接相关的躯体与心理症状。构建卵巢完整的动物模型，对于阐明这类相互作用并发掘全新治疗靶点至关重要。本研究以4-乙烯基环己烯二环氧化物（4-vinylcyclohexene diepoxide, VCD）诱导的卵泡耗竭大鼠模型为对象，在1个月内以10天为间隔开展检测，对其内分泌特征与动情周期进行评估，以期精准确定绝经过渡期相关研究的最佳周期。将28日龄雌性大鼠每日皮下注射VCD或空白油溶剂，持续15天，并分别于治疗开始后约70、80、90及100天的动情间期处死动物。仅在治疗后100天的VCD处理组中，大鼠出现周期异常的比例及血浆卵泡刺激素（Follicle-Stimulating Hormone, FSH）水平均显著升高。与对照组相比，所有VCD处理组的血浆抗缪勒管激素（anti-Müllerian hormone, AMH）与孕酮水平均有所降低，而雌二醇水平则保持不变或升高。与对照组一致，70~90天的VCD处理组大鼠的血浆双氢睾酮（dihydrotestosterone, DHT）水平呈进行性下降，但在100天的VCD处理组中，该水平随后出现大幅升高。血浆皮质酮、催乳素、甲状腺激素及黄体生成素（luteinizing hormone, LH）水平未出现显著变化。基于动情周期与内分泌特征，本研究得出以下结论：1）该模型中，70~100天的时间窗口适用于模拟围绝经期样状态；2）伴随孕酮与抗缪勒管激素水平降低、卵泡刺激素水平正常的规则动情周期，可作为绝经过渡早/中期的标志物；而伴随卵泡刺激素与双氢睾酮水平升高的异常动情周期，则可作为向绝经期过渡的晚期阶段标志物。