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

项目1：摘要/摘要米歇尔·M·米尔克博士。 子宫切除术是居住在美国的妇女中第二常见的主要外科手术。 美国剖腹产术后。在接受子宫切除术的女性中，23%的年龄在40-44岁和 45%的45-49岁的人同时接受双侧输卵管卵巢切除术(BSO)以预防卵巢 癌症。尽管绝经前BSO与卵巢和乳房风险显著降低有关 癌症，人们越来越担心BSO可能会有有害的长期影响，这可能会否定一些 预防癌症所带来的好处。卵巢既是内分泌器官，又是生殖器官。他们 绝经前和绝经后分泌激素(主要是雌激素、黄体酮和睾酮) 睾酮、雄烯二酮和脱氢表雄酮)。因此，卵巢功能减退，尤其是在 由卵巢切除引起的，可在整个生命周期内影响多个系统。在绝经前， 摘除卵巢会造成严重的内分泌紊乱。预防性BSO的做法现在正在下降。 然而，鉴于大量女性因以下原因突然内分泌中断 绝经前BSO几十年来，迫切需要了解其对远期的影响 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迟 或者随着这些女性年龄的增长，防止绝经前BSO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。最新研究 提示绝经前BSO可能与加速衰老有关。然而，潜在的 除了DNA甲基化之外，还没有研究过生物机制。此外，目前还不清楚 绝经前BSO引起的内分泌紊乱是否对所有生理和 认知功能，或者是身体或认知功能的特定领域受到的影响比其他领域更大。 我们假设绝经前BSO引起的突然而显著的内分泌紊乱将 导致加速衰老，通过身体和认知功能的更大下降和通过 与参照者相比，血浆衰老相关分泌表型(SASP)蛋白水平更高。 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 有绝经前BSO和没有绝经前BSO的女性，现在只有被动地通过罗切斯特进行跟踪 流行病学项目病案联动系统。我们将招募250名女性进行面对面研究 以及250名没有绝经前BSO的妇女，她们手术后或索引日期后的中位数为22年。我们会 广泛鉴定他们的身体和认知功能，并采集血液样本以测量SASP 蛋白质，一种新的衰老标志。研究过去几十年中接受BSO的女性提供了一种独特的 通过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.