The Ovary Is Surprisingly Active After Menopause. Scientists Are Trying to Figure Out Why

绝经后卵巢的活跃程度令人惊讶，科学家们正试图找出原因

When Francesca Duncan decided to take a look at what was going on in postmenopausal ovaries, she assumed she wouldn’t find much of interest. In a woman’s reproductive years, the ovary is exceptionally dynamic, shifting form and function from day to day throughout her cycle. But after menopause, when egg supply has dwindled and hormone production has waned, the ovaries are often thought of as little more than empty sacks. 当弗朗西斯卡·邓肯（Francesca Duncan）决定研究绝经后卵巢的情况时，她以为自己不会发现什么有趣的东西。在女性的生育期，卵巢极其活跃，在整个月经周期中，其形态和功能每天都在发生变化。但在绝经后，当卵子供应减少、激素分泌减弱时，卵巢通常被认为不过是空囊而已。

“I assumed it was just sitting there inert,” says Duncan, a reproductive biologist at Northwestern University, who was only looking at postmenopausal ovaries as part of a project to map a cellular aging process called senescence throughout the body. “我原以为它只是静止在那里，”西北大学的生殖生物学家邓肯说。她研究绝经后卵巢最初只是为了绘制全身细胞衰老过程（即衰老现象）图谱项目的一部分。

Instead, Duncan found that aged ovaries were anything but stagnant. When looking at the protein composition of ovaries of postmenopausal women between the ages of 50 and 75 years old, her team found that the molecular signatures differed significantly across the decades. The oldest ovary looked nothing like a 60- or 70-year-old organ at the molecular level. She was shocked. “Clearly something is still happening,” says Duncan. 然而，邓肯发现衰老的卵巢绝非处于停滞状态。在观察 50 至 75 岁绝经后女性的卵巢蛋白质组成时，她的团队发现，不同年龄段的分子特征存在显著差异。从分子水平上看，最年长的卵巢与 60 或 70 岁的器官完全不同。她感到震惊。“显然，这里面依然在发生着什么，”邓肯说。

The question is: what? 问题是：到底发生了什么？

A new wave of discovery is forcing researchers to recast the ovary not as an egg factory with an expiration date, but as an organ that impacts a woman’s overall health and may shape the trajectory of aging long after the fertile years have passed. What they are only beginning to understand is whether changes to the ovary after menopause are harmful, protective, or some combination of the two, shifting over time. 新一轮的发现正迫使研究人员重新审视卵巢——它不再仅仅是一个有保质期的“卵子工厂”，而是一个影响女性整体健康，并可能在生育期结束后长期塑造衰老轨迹的器官。他们才刚刚开始了解，绝经后卵巢发生的变化究竟是有害的、保护性的，还是两者的某种结合，并随时间推移而发生转变。

This isn’t the first time the ovary’s role in maintaining health has been underestimated. For decades, surgeons removed healthy organs during hysterectomies, figuring they weren’t doing much besides posing cancer risks. But 20 years ago, evidence began accumulating that removing healthy ovaries actually harms a woman’s overall health, finding an increased risk of dementia, cardiovascular disease, and premature death. 这并不是卵巢在维持健康方面的作用第一次被低估。几十年来，外科医生在进行子宫切除术时会顺便切除健康的卵巢，认为它们除了带来癌症风险外别无他用。但 20 年前，越来越多的证据表明，切除健康的卵巢实际上会损害女性的整体健康，并发现这会增加患痴呆症、心血管疾病和过早死亡的风险。

Because the ovary has historically been understood primarily as a reproductive organ, though, research has largely ignored what might be happening once those functions decline. “We don’t even know much about what the premenopausal ovary is doing outside of fertility,” says Jennifer Garrison, an ovarian aging expert and founder of a women’s health biotech company currently in stealth mode. After menopause, the extent of what we know about the ovary basically boils down to “it’s important,” she adds. 然而，由于卵巢在历史上主要被理解为生殖器官，研究在很大程度上忽略了当这些功能衰退后会发生什么。“我们甚至对绝经前卵巢在生育功能之外的作用知之甚少，”卵巢衰老专家、一家目前处于隐身模式的女性健康生物技术公司创始人詹妮弗·加里森（Jennifer Garrison）说。她补充道，在绝经后，我们对卵巢的了解程度基本上只能归结为“它很重要”。

Biologists have known for decades, for instance, that after menopause, ovaries continue producing hormones, including testosterone and small amounts of estrogen. But arguments continue over the clinical significance of those hormones. And hormones are only part of a complex signaling system. 例如，生物学家几十年来一直知道，绝经后卵巢会继续产生激素，包括睾酮和少量的雌激素。但关于这些激素的临床意义，争论仍在继续。而且，激素只是复杂信号系统的一部分。

Generally, the hormones the ovary produces postmenopause are known to help maintain libido, bone, and muscle, among other things, although it’s not clear how much the relatively small amounts produced by the postmenopausal ovary contribute to those effects. Multiple studies demonstrate that women who undergo oophorectomies fare worse than those who do not, particularly when having their ovaries removed before going through menopause naturally. 通常，人们认为绝经后卵巢产生的激素有助于维持性欲、骨骼和肌肉等功能，尽管目前尚不清楚绝经后卵巢产生的相对较少的激素对这些影响有多大贡献。多项研究表明，接受卵巢切除术的女性比未接受该手术的女性状况更差，尤其是在自然绝经前就切除卵巢的情况下。

Recent brain-imaging work by Pauline Maki at the University of Illinois at Chicago shows that even low levels of estrogen circulating postmenopause may matter: Women with higher levels had better-functioning memory circuits when performing memory tasks. Where that estrogen comes from—and how much the ovary contributes—isn’t as clear. After menopause, evidence suggests the brain reorganizes, possibly to compensate for declining estrogen levels. Maki hypothesizes that ovarian signaling may contribute to that adaptation, and that hormone therapy could alter the relationship between the ovary, the body’s circulating estrogen, and the brain. 伊利诺伊大学芝加哥分校的宝琳·马基（Pauline Maki）最近的脑成像研究表明，即使是绝经后循环中低水平的雌激素也可能很重要：雌激素水平较高的女性在执行记忆任务时，其记忆回路的功能更好。这些雌激素来自何处，以及卵巢贡献了多少，尚不清楚。证据表明，绝经后大脑会进行重组，可能是为了补偿雌激素水平的下降。马基推测，卵巢信号可能有助于这种适应，而激素疗法可能会改变卵巢、体内循环雌激素与大脑之间的关系。

The significance of residual hormone production may decrease over time. Still, says Walter Rocca, a professor of epidemiology and neurology at the Mayo Clinic, that doesn’t mean the ovary has become unimportant. 残留激素产生的意义可能会随时间推移而降低。尽管如此，梅奥诊所的流行病学和神经学教授沃尔特·罗卡（Walter Rocca）表示，这并不意味着卵巢变得不重要了。

“I am convinced until proven otherwise that removing ovaries even after menopause is not advisable,” he says, with a caveat for women at an increased risk of ovarian cancer. “除非有相反的证据，否则我坚信即使在绝经后也不建议切除卵巢，”他说，但同时也提醒了那些卵巢癌风险较高的女性。

Just how long that importance persists after menopause is still an open question, says Stephanie Faubion, medical director of the Menopause Society. It’s also unclear, she says, how much the answer may vary from woman to woman. “We just have huge gaps,” she says. 更年期协会医学主任斯蒂芬妮·福比恩（Stephanie Faubion）表示，这种重要性在绝经后能持续多久仍是一个悬而未决的问题。她说，目前还不清楚这个答案在不同女性之间会有多大差异。“我们在这方面存在巨大的认知空白，”她说。

Duncan’s work suggests one reason the importance of the postmenopausal ovary may change over time. In analyzing human ovaries, the team found that protein patterns in older ovaries suggested that the ovary becomes a more inflammatory environment. To better understand what may be driving those changes, they looked more closely at the ovaries of mice. The research, published in June in the journal Molecular Human Reproduction, suggests that the ovary may eventually take on a completely new identity after menopause. 邓肯的研究提出了绝经后卵巢的重要性随时间推移而改变的一个原因。在分析人类卵巢时，研究小组发现，较年长卵巢中的蛋白质模式表明，卵巢变成了一个更具炎症性的环境。为了更好地了解是什么在驱动这些变化，他们更仔细地观察了小鼠的卵巢。这项发表在 6 月份《分子人类生殖》（Molecular Human Reproduction）杂志上的研究表明，绝经后卵巢最终可能会呈现出一种全新的身份。

The team compared the ovaries of two-month-old mice, reproductively old 18-month-old mice, and post-reproductive 24-month-old mice, and found that over time, the genes linked to inflammation and immune activity became far more active. The number of immune cells in the ovary also increased. While research on mice does not always translate to humans, it could help to explain the molecular changes Duncan observed in human ovaries. 研究小组比较了 2 个月大、处于生殖衰老期的 18 个月大以及绝经后的 24 个月大小鼠的卵巢，发现随着时间的推移，与炎症和免疫活动相关的基因变得活跃得多。卵巢中的免疫细胞数量也增加了。虽然小鼠研究的结果并不总是能直接转化为人类的情况，但这有助于解释邓肯在人类卵巢中观察到的分子变化。

“We think that a lot of those changes may make the ovary more prone to age-related diseases like ovarian cancer,” says Birgit Schilling, an aging researcher at the Buck Institute for Research on Aging who collaborated with Duncan on the human ovary work, which has been published as a preprint. After menopause, the risk of a host of conditions goes up, including stroke, heart disease, and osteoporosis. “我们认为，许多这些变化可能会使卵巢更容易患上卵巢癌等与年龄相关的疾病，”巴克衰老研究所的衰老研究员比尔吉特·席林（Birgit Schilling）说。她与邓肯合作完成了这项人类卵巢研究，该研究已作为预印本发表。绝经后，包括中风、心脏病和骨质疏松症在内的多种疾病风险都会上升。

Other organs undergo immune remodeling with time, but the ovary ages long before most other organs. Duncan’s work raises the… 随着时间的推移，其他器官也会经历免疫重塑，但卵巢的衰老远早于大多数其他器官。邓肯的研究提出了……