Originally used primarily for the treatment of menopausal symptoms, prescriptions for menopausal hormone therapy (MHT) rose sharply from the late 1980s onwards following the publication of several epidemiologic studies showing that use of MHT was associated with a lower risk of osteoporosis and coronary heart disease. These studies also showed an increased risk of venous thrombo-embolism, and with prolonged use also of breast cancer, in addition to a previously demonstrated risk of endometrial cancer. Whereas the increased risk of endometrial cancer could be abolished by the addition of a progestin to estrogen, breast cancer risk appeared to be further increased by progestin. Nonetheless, towards the turn of the new century the consensus opinion of most professional societies was that the benefits of MHT outweighed the risks, and MHT was widely recommended for all post-menopausal women and in particular for women at high risk of coronary heart disease. The perceived favorable risk-benefit ratio depended heavily on the assumption that MHT would reduce the risk of coronary heart disease, a major affliction of women in the postmenopausal and older age groups. The findings from the first large-scale randomized controlled clinical trials caused a reevaluation of this favorable paradigm for MHT. In 1998 the Heart and Estrogen-Progestin Replacement Study (HERS) showed that MHT did not in fact reduce risk of recurrent myocardial infarction.1 Subsequently, in 2002 and 2004 the Women’s Health Initiative (WHI) primary prevention trials showed that neither estrogen plus progestin nor estrogen alone reduced risk of coronary heart disease—in fact the risk was increased compared to placebo in the first several years.2,3 In addition the combination of estrogen plus progestin increased the risk of stroke, venous thromboembolism, and breast cancer; these risks were not offset by the benefits for fractures and colorectal cancer. Similarly, estrogen alone increased the risks of stroke and venous thrombombolism (but not of breast cancer) and reduced the risk of fracture; again with no overall benefit. As a result of these findings, most professional societies no longer recommend MHT for either primary or secondary prevention of coronary heart disease, and MHT is now a second-line drug for the prevention of osteoporosis. Prescriptions for MHT dropped precipitously around the world and appear to be decreasing further over time. Within the WHI cohort breast cancer has decreased after stopping estrogen plus progestin, and in the US population the national decrease in hormone use has been accompanied by reduced rates of breast cancer and coronary heart disease. The observational studies clearly overestimated the coronary heart disease benefits of MHT, and over time the reasons for this have become clearer. Within the WHI program the results of the (initially more favorable) observational study could be reconciled with those of the trials by taking into account age, risk factors, and most importantly the differences in duration of therapy.4 Duration of therapy is critical, because in general clinical trials are of shorter duration but capture all initial events, while observational studies have longer periods of exposure but often are poor at capturing initial events; since most coronary heart disease risk occurs in the first two years after initiation observational studies may overestimate benefit. Joint analyses of the WHI observational study and clinical trial data showed no overall effect on coronary heart disease, albeit with significantly increased initial risk and no significant benefit with prolonged therapy. Re-analysis of the Nurses’ Health Study (NHS) observational data using a methodology similar to that of a clinical trial, and which (unlike all previous analyses) includes coronary heart disease events in the first two years after starting MHT, yielded results very similar to those of the WHI trial of estrogen plus progestin: no benefit overall, increased initial risk, and no significant benefit with prolonged therapy.5 Thus, data from an observational study whose findings were key to creating the enthusiasm for MHT can no longer be regarded as being supportive of a role for MHT in the prevention of coronary heart disease. The major remaining reason for prescribing MHT is for the relief of vasomotor symptoms; but even here caution is warranted. Older women and especially those with vasomotor symptoms appear to be at higher risk of coronary heart disease if given MHT, but this is not a major concern because only a small proportion of older women have persistent severe symptoms and MHT should rarely if ever be prescribed to older women.6 On the other hand, re-analyses of both the WHI and NHS data suggest that MHT does not affect the overall risk of coronary heart disease in younger women.5,6 However, there is a trend towards increased risk of coronary heart disease in the first two years after initiation which does not differ significantly from the initially increased risk in older women, and even with prolonged therapy there is no significant benefit. Furthermore, both WHI and NHS have found that the increased risk of stroke is not modified by age. The risk of venous thrombo-embolism due to MHT is also not modified by age. More disturbing is the finding from the joint WHI observational and clinical trial data that women who initiate estrogen plus progestin close to the menopause, and who continue it for a long period of time, are at higher risk for breast cancer.4 These new insights should be considered when prescribing MHT to younger women. While they might expect relief of vasomotor symptoms, they should be counseled that there is small chance of coronary heart disease, stroke, or venous thrombo-embolism even with short-term therapy. They should not expect long-term benefit for coronary heart disease; rather, they should be cautioned that long-term use carries with it an increased risk of breast cancer.

中文翻译：

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在后妇女健康倡议时代为 50 多岁的妇女开出绝经后激素疗法

最初主要用于治疗更年期症状的更年期激素疗法 (MHT) 的处方从 1980 年代后期开始急剧增加，因为多项流行病学研究表明使用 MHT 与骨质疏松症和冠心病的风险降低有关。这些研究还表明，除了先前证明的子宫内膜癌风险外，静脉血栓栓塞的风险也会增加，长期使用还会增加乳腺癌的风险。虽然在雌激素中添加孕激素可以消除子宫内膜癌风险的增加，但孕激素似乎会进一步增加患乳腺癌的风险。尽管如此，在新世纪之交，大多数专业协会的共识是 MHT 的好处大于风险，MHT 被广泛推荐给所有绝经后女性，尤其是冠心病高危女性。认为有利的风险收益比在很大程度上取决于 MHT 会降低冠心病风险的假设，冠心病是绝经后和老年女性的主要痛苦。第一次大规模随机对照临床试验的结果引起了对 MHT 的这种有利范式的重新评估。1998 年的心脏和雌激素-孕激素替代研究 (HERS) 表明，MHT 实际上并没有降低复发性心肌梗塞的风险。 1 随后，2002 年和 2004 年，妇女健康倡议 (WHI) 一级预防试验表明，雌激素加孕激素或单独使用雌激素都不能降低患冠心病的风险——事实上，在最初几年，与安慰剂相比，风险增加了。2,3 此外雌激素加孕激素的组合增加了中风、静脉血栓栓塞和乳腺癌的风险；这些风险并没有被骨折和结直肠癌的益处所抵消。同样，单独使用雌激素会增加中风和静脉血栓栓塞（但不会发生乳腺癌）的风险并降低骨折风险；再次没有整体利益。由于这些发现，大多数专业协会不再推荐 MHT 用于冠心病的一级或二级预防，而MHT现在是预防骨质疏松症的二线药物。MHT 的处方在世界范围内急剧下降，并且随着时间的推移似乎进一步减少。在 WHI 队列中，停止使用雌激素和孕激素后，乳腺癌的发病率有所下降，而在美国人口中，全国激素使用的减少伴随着乳腺癌和冠心病发病率的降低。观察性研究显然高估了 MHT 对冠心病的益处，随着时间的推移，其原因变得更加清晰。在 WHI 计划中，通过考虑年龄、风险因素以及最重要的治疗持续时间的差异，可以将（最初更有利的）观察性研究的结果与试验结果进行协调。4 治疗持续时间至关重要，因为一般而言，临床试验持续时间较短，但捕获所有初始事件，而观察性研究的暴露时间较长，但在捕获初始事件方面往往较差；因为大多数冠心病风险发生在开始观察性研究后的前两年，可能会高估获益。WHI 观察性研究和临床试验数据的联合分析显示，对冠心病没有总体影响，尽管初始风险显着增加，并且长期治疗没有显着益处。使用类似于临床试验的方法重新分析护士健康研究 (NHS) 的观察数据，并且（与之前的所有分析不同）包括开始 MHT 后前两年的冠心病事件，产生的结果与雌激素加孕激素的 WHI 试验的结果非常相似：总体上没有益处，初始风险增加，延长治疗没有显着益处。 5 因此，来自一项观察性研究的数据，其结果是激发人们对 MHT 的热情的关键不再被视为支持 MHT 在预防冠心病中的作用。处方 MHT 的主要剩余原因是为了缓解血管舒缩症状；但即使在这里也需要谨慎。如果给予 MHT，老年女性，尤其是有血管舒缩症状的女性，患冠心病的风险似乎更高，但这并不是主要问题，因为只有一小部分老年女性有持续的严重症状，而且 MHT 很少被处方用于治疗老年妇女。 6 另一方面，对 WHI 和 NHS 数据的重新分析表明，MHT 不会影响年轻女性患冠心病的总体风险。 5,6 然而，在开始后的前两年，冠心病的风险有增加的趋势这与老年女性最初增加的风险没有显着差异，即使延长治疗时间也没有显着益处。此外，WHI 和 NHS 都发现中风风险的增加不受年龄影响。MHT 引起的静脉血栓栓塞风险也不受年龄影响。更令人不安的是，WHI 联合观察和临床试验数据发现，在接近更年期时开始使用雌激素和孕激素，并持续很长一段时间的女性患乳腺癌的风险更高。4 在为年轻女性开 MHT 处方时，应考虑这些新见解。虽然他们可能期望血管舒缩症状得到缓解，但应告知他们即使进行短期治疗，冠心病、中风或静脉血栓栓塞的几率也很小。他们不应期望对冠心病有长期益处；相反，应提醒他们长期使用会增加患乳腺癌的风险。