Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Hum Reprod Update. 2019 Mar 1;25(2):257-271. doi: 10.1093/humupd/dmy039.
The effect of postmenopausal hormone therapy (HT) on cardiovascular disease (CVD) risk remains controversial.
We aimed to systematically review the evidence regarding the role of dose, route of hormone administration, timing of initiation and duration of HT on cardiovascular risk among postmenopausal women.
The electronic databases Medline Ovid, Web of Science and Cochrane Central were systematically searched to identify studies published before 30 January 2018. Reference lists, using Elsevier's Scopus, of the included studies were searched for further identification of relevant studies. Clinical trials and observational studies that assessed clinical and subclinical cardiovascular outcomes in relation to dose, route of administration, duration of use, or timing of HT initiation among postmenopausal women were included. Data were extracted by independent reviewers using a pre-designed data collection form. The Cochrane Collaboration's tool and the Newcastle-Ottawa Scale were used by two independent investigators to assess the risk of bias in RCTs and in prospective observational studies, respectively.
In total, 33 unique studies (6 trials and 27 prospective observational studies) were identified, including a total of 2 588 327 women. The synthesis of the existing knowledge on this topic was challenging due to inconsistent findings between some studies, caused by substantial diversity in scientific rigor and quality across the available literature. Overall, the evidence did not support the concerns that oral or transdermal HT increases heart disease risk. Contrary, observational data showed that a beneficial cardioprotective effect can be observed even with use of low doses of oral HT (effect of 0.3 mg/day of oral conjugated equine estrogen was similar to that seen with the standard dose of 0.625 mg/day), but clinical trials to support a cardioprotective benefit of HT in primary prevention have not been identified. Furthermore, the current data suggested that oral and transdermal HT, in dose-dependent manner and irrespective of HT formulation, may increase thromboembolic risk, as well as risk of stroke. However, transdermal estrogen with <50 μg/day of estrogen combined with micronized progesterone appears to be the safer choice with respect to thrombotic and stroke risk. Also, vaginal HT administration may play a role in myocardial infarction and stroke risk prevention, but this is based on limited evidence and requires further investigation. The timing of HT initiation and duration may be important factors to consider when prescribing HT especially in women with adverse cardiometabolic profile and pre-existing conditions such as coronary/carotid atherosclerosis, which are at risk of developing, and thus progressing to CVD. The quality of evidence was generally low or moderate and the findings were based mostly on observational data.
Use of low-dose oral and transdermal HT appears to be safe with regard to CVD risk in women in menopausal transition and within the first years (e.g. 10 years) after menopause onset. In women with increased baseline thromboembolic risk, alternative non-hormonal medications are suggested as first-line treatment and transdermal estradiol alone or with micronized progesterone only should be considered when these options are not effective. When HT is initiated >10 years since the menopause onset (>60 years old), due to greater absolute risks of coronary heart disease, stroke and venous thromboembolism, HT should be used for the shortest time possible and in lowest possible dose and preferably transdermal administration should be recommended. However, an individualized treatment approach including baseline CVD risk assessment should be applied when prescribing HT. The majority of studies included in the current review are from North American and European populations, which might limit the generalizability of the findings of this review to the other populations. Finally, the quality of evidence included in this review was generally low or moderate, highlighting a need for more rigorous research to help us better understand HT and cardiovascular health.
绝经后激素治疗（HT）对心血管疾病（CVD）风险的影响仍存在争议。
我们旨在系统地回顾有关剂量、激素给药途径、起始时间和 HT 持续时间对绝经后女性心血管风险的作用的证据。
系统检索了 Medline Ovid、Web of Science 和 Cochrane 中心电子数据库，以查找截至 2018 年 1 月 30 日发表的研究。使用爱思唯尔的 Scopus 搜索纳入研究的参考文献列表，以进一步确定相关研究。纳入了评估剂量、给药途径、使用持续时间或 HT 起始时间与临床和亚临床心血管结局之间关系的临床试验和观察性研究。独立审查员使用预先设计的数据收集表提取数据。两名独立调查员使用 Cochrane 协作工具和纽卡斯尔-渥太华量表分别评估 RCT 和前瞻性观察性研究的偏倚风险。
共确定了 33 项独特的研究（6 项试验和 27 项前瞻性观察性研究），共纳入 2588327 名女性。由于可用文献的科学严谨性和质量存在很大差异，导致一些研究之间的结果不一致，因此对这一主题的现有知识进行综合具有挑战性。总的来说，现有的证据并不支持口服或经皮 HT 会增加心脏病风险的担忧。相反，观察性数据表明，即使使用低剂量的口服 HT（0.3 毫克/天的口服结合马雌激素的效果与 0.625 毫克/天的标准剂量相似），也可以观察到有益的心脏保护作用，但尚未发现支持 HT 在一级预防中具有心脏保护作用的临床试验。此外，目前的数据表明，口服和经皮 HT 以剂量依赖的方式，并且与 HT 制剂无关，可能会增加血栓栓塞风险以及中风风险。然而，与血栓形成和中风风险相比，每天<50μg 的经皮雌激素与米诺孕素联合使用似乎是更安全的选择。此外，阴道 HT 给药可能在预防心肌梗死和中风风险方面发挥作用，但这基于有限的证据，需要进一步研究。HT 起始时间和持续时间可能是在开处方 HT 时需要考虑的重要因素，尤其是对于有不良代谢特征和预先存在的心血管疾病（如冠状动脉/颈动脉动脉粥样硬化）的女性，这些女性有发展和进展为 CVD 的风险。证据质量普遍较低或中等，研究结果主要基于观察性数据。
在绝经过渡和绝经后最初几年（例如 10 年），使用低剂量口服和经皮 HT 似乎对女性 CVD 风险是安全的。对于基线血栓栓塞风险增加的女性，建议首选非激素药物作为一线治疗，当这些选择无效时，应考虑单独使用经皮雌二醇或仅与米诺孕素联合使用。当 HT 在绝经后 10 年（>60 岁）开始时，由于冠心病、中风和静脉血栓栓塞的绝对风险增加，HT 的使用时间应尽可能短，剂量应尽可能低，最好推荐经皮给药。然而，在开处方 HT 时，应采用个体化的治疗方法，包括基线 CVD 风险评估。当前综述中纳入的大多数研究都来自北美和欧洲人群，这可能限制了本综述结果对其他人群的普遍性。最后，纳入本综述的证据质量普遍较低或中等，这突出表明需要进行更严格的研究，以帮助我们更好地了解 HT 和心血管健康。
