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2024年5月8日，影响因子全球排名第一神刊、美国癌症学会官方期刊《临床医师癌症杂志》在线发表报道：绝经激素疗法与乳腺癌的关联仍然存在争议。 女性绝经前后，可以出现月经不调、阴道干涩、潮热盗汗、心慌失眠、情绪变化、骨质疏松、体重增加、新陈代谢减缓等症状体征，俗称更年期综合征，根源在于卵巢功能减退、雌激素缺乏。上个世纪40年代开始，绝经激素疗法（雌激素联合孕激素）被用于绝经前后女性缓解绝经症状，孕激素还可保护子宫内膜。 二十多年前，美国史诗级临床研究《女性健康倡议》发布的报告令临床医师感到震惊，该报告发现雌激素联合孕激素用于绝经女性，可增加乳腺癌风险以及冠心病、中风和总死亡风险，而并未改善生活质量。此后，一些研究者对这些发现提出质疑，《女性健康倡议》研究者自己也对首要结论进行复核。虽然如此，临床医师及其患者仍然采取“宁要更安全也不要后悔”的立场，并且经常决定不采用绝经激素疗法，无论可能出现什么症状。 例如，2023年4月《女性健康倡议》研究者在美国绝经学会官方期刊《绝经》发表研究，承认激素疗法能够带来巨大获益。不过，他们继续断言，联合激素疗法（雌激素联合孕激素）相关乳腺癌风险增加仍然是实际问题。 作为回应，该期刊发表述评，试图纠正乳腺癌与激素疗法的关联，无论单用雌激素还是雌激素联合孕激素，这是误解的重要根源。该述评作者之一、南加利福尼亚大学凯克医学院肿瘤内科医师阿夫鲁姆·布鲁明博士解释：根据《女性健康倡议》自己的数据，单用雌激素就可显著降低乳腺癌发病风险达23%和乳腺癌死亡风险达40%，对于子宫切除（没有必要用孕激素）女性而言至关重要；此外，《女性健康倡议》现在认可，如果在女性末次月经后10年内开始用药，可以显著降低冠心病风险、延长寿命，是最有效和最安全的绝经症状治疗方法，而且不增加中风风险，还可降低骨质疏松所致髋部骨折、结肠癌和糖尿病的风险；唯一的问题是联合激素疗法（雌激素联合孕激素）与乳腺癌风险的关联。 关键问题 《女性健康倡议》分析存在问题 布鲁明博士等人在述评中写道：联合激素疗法与乳腺癌风险增加的关联实际并无统计学意义。此外，即使接受《女性健康倡议》关于风险增加的说法是准确的，意味着每年每1000例被治疗女性可增加1例乳腺癌病例，但是乳腺癌致死风险并未增加。此外，他们认为《女性健康倡议》研究者关于乳腺癌发病率下降与激素疗法处方减少存在关联的断言并未得到任何数据支持，包括这实际上早于《女性健康倡议》结果发布。 布鲁明博士等人担心《女性健康倡议》研究者发表于2023年的文章将大量批评最小化并歪曲，以牺牲女性健康为代价，延长女性和医师深深的焦虑，并导致激素疗法利用不足。他们总结道：随着新一代女性思考激素疗法的获益和风险，对乳腺癌的恐惧成为女性健康选择的驱动因素，现在是诚实对待《女性健康倡议》这些发现的时候了。 纽约西奈山医院附属伊坎医学院内科学教授、跨性别医学和外科中心执行主任约书亚·塞弗博士称：该分析有争议，并未改变我们从《女性健康倡议》接受并相信的全部信息，但是很好地强调了相对于乳腺癌风险而言女性接受雌激素治疗的获益，这是多年来被掩盖的关键之处。 肿瘤外科医师观点 耶鲁大学外科乳腺外科肿瘤学助理教授、斯米洛肿瘤医院肿瘤遗传与预防部门高风险乳腺癌负责人埃莉·普鲁萨洛格鲁博士认为：该述评很重要，让我们重新考虑如果你为绝经女性处方或者考虑处方全身激素补充疗法的风险和获益是什么，该述评探讨了我们是否对有全身绝经症状女性治疗不足以及产生什么影响？这非常重要，因为我们有责任考虑数据实际上告诉我们的癌症风险；我对患者以及临床医师的建议是，对患者正在经历的症状、决策时考虑的乳腺癌风险因素进行详细沟通，例如家族史和个人史，然后进行权衡。很多时候，患者被医师明确告知激素疗法疗法不好，可增加乳腺癌风险，并未解释激素补充疗法的全部其他医学获益和生活质量因素，也未考虑特定激素配方带来的不同风险；肿瘤医师应该分别考虑激素疗法用于已患癌症和未患癌症的患者，将患者人群区分为未患癌症和已患癌症非常重要，我认为本文以及其他研究现有数据表明激素疗法并不像我们想象的那么糟糕；对于癌症患者而言，关于激素补充疗法风险的沟通内容完全不同。 塞弗博士相信：我们所知关于乳腺癌和外源性雌激素的关联，其实可能是乳腺癌和外源性孕激素的关联，只是大多数研究出于对癌症风险的担忧，而将这两种药物一起分析；有趣的是，雌激素联合孕激素治疗的女性乳腺癌风险可能并不更高，这与许多人的想法相反。可能令人难以置信，雌激素在某些情况下似乎可以预防乳腺癌，而孕激素可削弱或者完全逆转该获益，但这仍然是事实。这意味着也许我们应该鼓励没已经切除子宫而不需要服用孕激素的女性，在过了典型的绝经年龄后就可以服用雌激素，这对于跨性别女性和接受子宫切除术的顺性别女性而言都是如此。 布鲁明博士表示，他对其述评能否被采纳持现实态度，这篇论文本身应该引起相当大的争议，他认为文章的结论极好阐明了要点： 如果2002年《女性健康倡议》透明地报告了他们的乳腺癌发现，强调对不同研究方案进行校正后的乳腺癌风险缺乏统计学意义，并且随后迅速发表对不同研究方案进行校正后的基线乳腺癌风险因素分析，而且提醒公众其研究结果不适用于围绝经或绝经后早期开始接受激素治疗的女性，这样就不会产生太大争议，不会造成混淆，而且女性健康也不会在随后二十年受到如此严重的影响。 相关链接 CA Cancer J Clin. 2024 May-Jun;74(3):210-212. IF: 254.7The association between menopausal hormone therapy and breast cancer remains unsettled."Too often, we have patients who are told concretely—by their physicians—that HT therapy is bad—it increases your breast cancer risk; this doesn't account for all of the other medical benefits of HRT and quality-of-life factors that impact women during menopause." —Ellie Proussaloglou, MDIt has been more than 2 decades since the Women's Health Initiative (WHI) alarmed clinicians with a report that found that the combination of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA), when administered to postmenopausal women, increased breast cancer risk as well as the risks for coronary heart disease, stroke, and total mortality without improving quality of life. Since then, several researchers have questioned the findings, and the overarching conclusions have been revisited by WHI investigators themselves. Despite this, clinicians and their patients continue to take on a "safer rather than sorry" stance and often decide against taking the menopausal hormone therapy (HT), regardless of what symptoms may be present.For example, in a study appearing in the journal Menopause: The Journal of The Menopause Society in April 2023, WHI investigators conceded that HT yielded considerable benefits. However, they continued to assert that the associated increase in the risk of breast cancer with combined HT (CEE and MPA) remained a valid concern.In response, a review published in the journal sought to rectify the association between breast cancer and HT—both CEE alone and CEE in combination with MPA, a large source of the misinterpretation. One of the authors, Avrum Z. Bluming, MD, an oncologist at the Keck School of Medicine at the University of Southern California in Los Angeles, explains it this way: "According to WHI's own data, estrogen alone significantly decreases the risk of breast cancer development (by 23%) and the risk of breast cancer death (by 40%)—crucial information for women who have had hysterectomies." In addition, "when started within 10 years of a woman's final period (the 'window of opportunity'), the WHI now agrees," says Dr Bluming, that "it significantly decreases the risk for coronary heart disease, improves longevity, is the best and safest treatment for menopausal symptoms, and does not increase the risk of stroke. Further, it decreases the risk of osteoporotic hip fracture, colon cancer, and diabetes mellitus." The sole issue at play is the association between combined HT (CEE plus MPA) and the risk of breast cancer.- In a new perspective, authors argue that the association between combination hormone therapy (conjugated equine estrogen and medroxyprogesterone acetate) and an increased risk of breast cancer continues to be overstated and, at worst, is incorrect.
- Rather than adopting a unilateral opinion that it is universally contraindicated regardless of the symptoms that patients are experiencing, clinicians should consider specific patients and their medical histories when approaching conversations about hormone therapy.
Issues with the analysis from the WHIIn their review, Dr Bluming and his colleagues write that "the association between combined HT and an 'increased breast cancer risk' is actually not statistically significant. Further, even if one were to accept that the WHI's claims of an increased risk were accurate, that increase would amount to one additional case of breast cancer for every 1,000 women treated per year but no increase in the risk of dying from breast cancer." In addition, they argue that the assertion from WHI investigators that there is an association between the declining incidence of breast cancer and the reduction in HT prescriptions is not supported by several lines of data, including the fact that the decline in breast cancer incidence in the United States actually predated the release of the WHI's results.Dr Bluming and his colleagues are concerned that the WHI investigators' 2023 article, by minimizing and deflecting repeated substantive criticisms, prolongs the worry so deeply felt by women and physicians and the resulting underutilization of HT at the expense of women's health. "As a new generation of women ponders the benefits and risks of HT," they conclude, "with breast cancer fear as a driving factor in women's health choices, it is time to be honest about these findings from WHI.""This analysis is provocative," says Joshua D. Safer, MD, a professor of medicine at the Icahn School of Medicine at Mount Sinai in New York, New York. "It does not change all the messages we've received and believed from WHI, but it does a good job of highlighting that the women treated with estrogen had benefit with regard to breast cancer risk—a key point that has been buried for years."A cancer surgeon's perspective"I think this review is important in that it makes us reconsider what the risks and benefits are if you've prescribed—or are considered prescribing—systemic hormone replacement therapy for women with menopause," says Ellie Proussaloglou, MD, an assistant professor of surgery (breast surgical oncology) at Yale University in New Haven, Connecticut. "This review addresses whether we are undertreating women with systemic menopausal symptoms, and what's the impact of that? This is very important as we responsibly consider what the data actually tells us about cancer risk."The advice that I give to my patients, and the advice I give to clinicians I meet is to have a really nuanced conversation about the symptoms their patient is experiencing, what breast cancer risks are factoring into that decision making, such as family history and personal factors, and then to strike a balance," adds Dr Proussaloglou, who is also the physician lead for high-risk breast care in the Division of Cancer Genetics and Prevention at Smilow Cancer Hospital in New Haven, Connecticut. "Too often, we have patients who are told concretely—by their physicians—that HT therapy is bad—it increases your breast cancer risk; this doesn't account for all of the other medical benefits of HRT [hormone replacement therapy] and quality-of-life factors that impact women during menopause. It also doesn't account for differential risk from specific hormone formulations."Dr Proussaloglou says that oncologists should think about the use of HT separately for patients who have cancer and patients who have not had cancer. "It is important to distinguish patient groups into people who do not have cancer, for whom I think the existing data in this article and other research indicates that HT is not this terrible option that we thought, and those who do have cancer. Of course, for patients with cancer it's a different conversation regarding risks of hormone replacement.""A takeaway from this study is humility," says Dr Safer, who is also the executive director of the Mount Sinai Center for Transgender Medicine and Surgery. "Some of what we've believed we've known regarding the connection between breast cancer and exogenous estrogens may be a connection between breast cancer and exogenous progestogens instead. It's just that most studies examine both agents together due to concern for cancer risk with unopposed exogenous estrogens. It is interesting to consider that the breast cancer risk may not be higher for women who take estrogen/progestogen combination therapy—the opposite of what many have thought."Even if that were not true, it would be still true that estrogen seems to protect against breast cancer in some instances, while progestogens mitigate or completely reverse that benefit. That means perhaps we should be encouraging women who don't have a uterus, and therefore who can take estrogens without progestogens, to take estrogens as they pass typical menopause age. That could be true for both transgender women and for cisgender women who have had a hysterectomy."Dr Bluming says that he is realistic about how his and his colleagues' critique will be received. "This paper (itself) should generate considerable controversy." He believes that the takeaway message is best stated in the conclusion of the article:"If WHI had transparently reported their breast cancer findings in 2002, emphasizing, among other things, a lack of statistical significance in breast cancer risk in the per-protocol adjusted statistic; had quickly followed up by publishing a per-protocol analysis adjusting for baseline breast cancer risk factors; and had reminded the public that its findings did not apply to women initiating HT in perimenopause or early post-menopause, there would have been minimal controversy, no confusion, and women's health would not have suffered so dramatically over the ensuing decades."
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