Project 1 - Effects of Bilateral Oophorectomy on Physical and Cognitive Aging

项目1：总结/摘要Michelle M. Mielke博士 子宫切除术是第二个最常见的主要外科手术中进行的妇女生活在 美国剖腹产后。在接受子宫切除术的妇女中，23%的年龄在40-44岁之间， 45%的45-49岁的患者同时接受双侧输卵管卵巢切除术（BSO），以防止卵巢癌的发生。 癌尽管绝经前BSO与卵巢和乳腺癌风险显著降低相关， 癌症，人们越来越担心BSO可能会产生有害的长期影响， 癌症保护所带来的好处。卵巢既是内分泌器官，又是生殖器官。他们 在绝经前分泌激素（主要是雌激素，孕酮和睾酮）和绝经后（主要是 睾酮、雄烯二酮和脱氢表雄酮）。因此，卵巢功能下降，尤其是 由于卵巢切除而引起的卵巢功能障碍可能会影响整个生命周期的多个系统。在更年期之前， 卵巢切除会引起严重的内分泌紊乱预防性BSO的做法正在减少。 然而，鉴于大量妇女因 绝经前BSO在过去的几十年里，迫切需要了解对长期的影响， 身体和认知功能。此外，阐明潜在的生物学机制可能有助于延缓 或预防绝经前BSO随年龄增长而产生的潜在负面后果。总体目标 项目1的目的是更好地了解长期的功能和认知影响以及潜在的 绝经前突然内分泌功能障碍的潜在机制。最近的研究 提示绝经前BSO可能与加速老化有关。然而，底层 除了DNA甲基化之外，还没有研究过生物学机制。此外，尚不清楚 绝经前BSO引起的内分泌紊乱是否对所有身体和 认知功能，或者身体或认知功能的特定领域是否比其他领域受到更多影响。 我们假设绝经前BSO引起的突然和显著的内分泌干扰， 有助于加速衰老，如身体和认知功能的更大下降， 与参照相比，衰老相关分泌表型（SASP）蛋白的血浆水平更高。 为了检验这些假设，我们将利用一个已建立的和特征良好的基于人群的队列， 有和没有绝经前BSO的妇女，现在仅通过罗切斯特被动随访 流行病学项目医疗记录连接系统。我们将招募250名女性， 250名绝经前无BSO的妇女，手术后或索引日期的中位数为22年。我们将 广泛描述他们的身体和认知功能，并收集血液样本以测量SASP 蛋白质，一种新的衰老标志物。研究在过去几十年中接受BSO的女性提供了一个独特的 自然实验，了解内分泌功能在调节衰老速度中的作用。

PROJECT 1: SUMMARY/ABSTRACT Michelle M. Mielke, Ph.D. Hysterectomy is the second most common major surgical procedure performed among women living in the United States after cesarean section. Among women who undergo hysterectomy, 23% aged 40-44 years and 45% aged 45-49 years undergo bilateral salpingo-oophorectomy (BSO) at the same time to prevent ovarian cancer. Although premenopausal BSO is associated with a significant reduced risk of ovarian and breast cancer, there is increasing concern that BSO may have harmful long-term effects which can negate some of the benefits conferred by protection from cancer. Ovaries are both endocrine and reproductive organs. They secrete hormones before menopause (primarily estrogen, progesterone, and testosterone) and after (primarily testosterone, androstenedione, and dehydroepiandrosterone). Thus, reduced ovarian function, especially as caused by the removal of ovaries, can impact multiple systems throughout the lifespan. Prior to menopause, ovarian removal causes significant endocrine disruption. The practice of prophylactic BSO is now declining. However, given the large number of women who have undergone abrupt endocrine disruption by premenopausal BSO over the past decades, there is an urgent need to understand the impact on long-term physical and cognitive function. In addition, elucidating the underlying biological mechanisms may help to delay or prevent the potential negative consequences of premenopausal BSO as these women age. The overall aim of Project 1 is to better understand the long-term functional and cognitive effects and the potential underlying mechanisms resulting from abrupt premenopausal endocrine dysfunction. Recent studies suggest that premenopausal BSO may be associated with accelerated aging. However, the underlying biological mechanisms have not been examined, other than DNA methylation. In addition, it is not clear whether the endocrine disruption that results from premenopausal BSO has a global effect on all physical and cognitive functions, or whether specific domains of physical or cognitive function are more affected than others. We hypothesize that the abrupt and significant endocrine disruption caused by premenopausal BSO will contribute to accelerated aging, as measured by a greater decline in physical and cognitive function and by higher plasma levels of senescence associated secretory phenotype (SASP) proteins compared to referents. To test these hypotheses, we will utilize an established and well-characterized population-based cohort of women with and without premenopausal BSO, who are now only passively followed through the Rochester Epidemiology Project medical-records linkage system. We will recruit, for an in-person study, 250 women with and 250 women without premenopausal BSO a median of 22 years after their surgery or index date. We will extensively characterize their physical and cognitive function and collect blood samples to measure SASP proteins, a novel marker of aging. Studying women who underwent BSO in the past decades provides a unique natural experiment to understand the effects of endocrine function in regulating the pace of aging.