《中国绝经管理与绝经激素治疗指南（2018）》在临床的实践

        随着全球人口老龄化,绝经问题越来越受到重视。中国的绝经事业相对于全球而言起步较晚。2000年中华医学会妇产科学分会绝经学组（以下简称“绝经学组”）在北京成立,标志着中国的绝经事业正式起步。众所周知,2002年妇女健康倡议（WHI）雌激素加孕激素分支的结果在JAMA杂志上的发表,令绝经激素治疗领域从高峰瞬间跌入低谷［1］。从那时起至今的10余年中,绝经领域取得了很大进展。为应对日新月异的变化,绝经学组在2003年、2006年、2009年、2012年分别制定或修订了相应的中国绝经指南,而最新一版--《中国绝经管理与绝经激素治疗指南（2018）》［2-3］是在2012年版［4］的基础上时隔6年再一次修订,间隔时间相对较长,反映本领域进入了一个比较稳定的阶段。 浏览更多请关注本刊微信公众号及当期杂志。     

《中国绝经管理与绝经激素治疗指南（2018）》在临床的实践

随着全球人口老龄化,绝经问题越来越受到重视。中国的绝经事业相对于全球而言起步较晚。2000年中华医学会妇产科学分会绝经学组（以下简称“绝经学组”）在北京成立,标志着中国的绝经事业正式起步。众所周知,2002年妇女健康倡议（WHI）雌激素加孕激素分支的结果在JAMA杂志上的发表,令绝经激素治疗领域从高峰瞬间跌入低谷［1］。从那时起至今的10余年中,绝经领域取得了很大进展。为应对日新月异的变化,绝经学组在2003年、2006年、2009年、2012年分别制定或修订了相应的中国绝经指南,而最新一版——《中国绝经管理与绝经激素治疗指南（2018）》［2-3］是在2012年版［4］的基础上时隔6年再一次修订,间隔时间相对较长,反映本领域进入了一个比较稳定的阶段。 浏览更多请关注本刊微信公众号及当期杂志。     

激素补充治疗与安慰剂治疗6个月的心血管效应：与绝经年限相关的差异

为评估妇女健康研究（WHI）之后个体化激素替代治疗（HRT）的效果，观察按绝经年限分组的妇女使用HRT和安慰剂对心血管和神经内分泌的影响。     

近3年国内外绝经激素治疗相关指南简介及比较

        女性绝经在整个生物界中是很特殊的情况,在身体的其他器官系统功能正常时卵巢功能就已衰退,而其他动物以及男性的性腺衰退几乎与其他器官衰退同步。女性的平均绝经年龄在50岁左右,此时距离其他系统的衰竭、生命的终止还有很长的时间。目前,妇女平均寿命80岁左右,意味着妇女一生中超过1/3的时间将在绝经后度过。绝经对女性影响重大：很多女性会经历潮热、出汗、骨关节肌肉疼、失眠、情绪障碍等症状的困扰,严重影响生活质量;很多老年退行性疾病如心血管疾病、骨质疏松和脑血管疾病等是从围绝经期开始萌芽、起病。因此,绝经相关问题正越来越受到重视。
        绝经激素治疗（MHT）是以雌激素补充为核心的一种疗法,是针对引起绝经相关问题的根本原因--雌激素缺乏的治疗,因此可以称之为针对病因的治疗。该疗法可以降低60岁以下妇女全因病死率39%[1]。这是改变生活方式、饮食结构或任何一种单一治疗方法都不可能达到的效果。MHT从诞生之日起因其良好疗效,迅速得到大家的认可;但又正因为对其疗效的过分推崇,导致某种程度上的不恰当应用,积累问题到一定程度后又会陷入低谷。迄今为止MHT已经历了数次大起大落。最近一次大的风波是源于2002年7月妇女健康启动（WHI）研究的第1批数据公布[2]。当时研究者的初步结论是该疗法不能预防心血管疾病,同时出于对乳腺癌风险方面的考虑,研究被提前终止。此后MHT进入一个“严冬”。经过10余年的反思、总结和新的证据积累[3-5],近几年在整个国际范围内绝经相关研究发展非常迅速。
        自2012年以来,绝经相关的各重要学术组织相继颁布了关于MHT的指南性文件,其中影响较大的有：2012年北美绝经协会（the North American Menopause Society,NAMS）发表的《NAMS 2012激素治疗的立场声明》[6]、2013年国际绝经学会（International Menopause Society,IMS）制定的《国际绝经学会对绝经激素治疗及中年女性健康预防策略的2013版最新建议》[7]、2013年由IMS牵头完成的《绝经激素治疗的全球共识声明》[8]、2013年英国绝经学会制订的《英国绝经学会和妇女健康委员会对激素补充治疗的2013年声明》[9],当然还有我们中国自己的指南,是由中华医学会妇产科学分会绝经学组制订的《绝经期管理与激素补充治疗临床应用指南（2012版）》[10]。这些指南基本原则一致,但又各有特色。考虑到《全球共识》是全世界主要学术团体均认可的,故首先介绍,然后再将依次介绍其他指南。另需说明的是,各指南所用名词并不完全一致,从激素治疗（hormone therapy,HT)、激素替代治疗（hormone replacement therapy,HRT)到绝经激素治疗（menopausal hormone therapy,MHT）均有应用,故在本文中,HT、HRT、MHT具有同样的含义,本文尊重各指南成文时所采用的名词。以笔者的个人观点,MHT应是最恰当的说法,从趋势上看也是如此。     

绝经激素治疗与乳腺癌风险

众所周知,乳腺癌是激素依赖性肿瘤,也是全球范围内女性患病率最高的恶性肿瘤。绝经虽然是一种人体自然现象,但也会引起很多病理性结果,严重影响女性的生活质量,增加各种慢性病发生的风险。绝经激素治疗（MHT）是治疗更年期症状最有效的方法,但很多女性最恐惧激素与乳腺癌风险。关于激素与乳腺癌的关系近几十年来争议不断,最初的妇女健康倡议（WHI）结果于2002年发表后,报告了乳腺癌的总体风险增加;最近研究表明：除了阴道雌激素外,每一种MHT都与额外的乳腺癌风险相关,且这种风险随着应用时间的增加而稳步升高;与雌激素相比,雌激素-孕激素的风险更大。文章主要讨论MHT与乳腺癌风险。     

绝经激素治疗与乳腺癌风险

众所周知,乳腺癌是激素依赖性肿瘤,也是全球范围内女性患病率最高的恶性肿瘤。绝经虽然是一种人体自然现象,但也会引起很多病理性结果,严重影响女性的生活质量,增加各种慢性病发生的风险。绝经激素治疗（MHT）是治疗更年期症状最有效的方法,但很多女性最恐惧激素与乳腺癌风险。关于激素与乳腺癌的关系近几十年来争议不断,最初的妇女健康倡议（WHI）结果于2002年发表后,报告了乳腺癌的总体风险增加;最近研究表明：除了阴道雌激素外,每一种MHT都与额外的乳腺癌风险相关,且这种风险随着应用时间的增加而稳步升高;与雌激素相比,雌激素-孕激素的风险更大。文章主要讨论MHT与乳腺癌风险。     

怎样做到正确应用绝经后激素治疗

针对绝经相关的临床问题,给予绝经后妇女以单一雌激素或与孕激素联合的治疗方法在既往的英文文献中常统称之为HRT(hormone replacement therapy),国内的中译名有激素替代治疗和激素补充治疗。自2002年7月以后,特别是随着美国WHI临床试验结果的陆续发表,不少国家或     

女性围绝经期激素治疗国内外近期临床应用进展

观察性研究提示激素疗法（hormone therapy，HT）具有心脏保护作用，为验证这一结果的正确性，进行了几项大规模多中心的随机对照临床试验（RCT）。这些RCT包括，心脏和雌、孕激素补充治疗研究：Ⅰ期和Ⅱ期（HERSⅠ，HERSⅡ）及妇女健康基础干预研究：雌、孕激素（WHI EPT）和单雌激素（WHI ET），与其他RCT不同的是，他们不是以中间指标，而是以疾病作为研究的终点。在这些RCT研究中，     

绝经后激素治疗适应证

伴随绝经过程及绝经后内分泌事件对妇女健康产生的不良影响,出现了一些临床问题需要激素治疗来纠正。激素治疗纠正这些健康问题是效价比最佳的措施。目前激素治疗主要有三大适应证:缓解绝经相关症状、治疗泌尿生殖道萎缩相关疾病、预防和治疗骨质疏松症。     

绝经后妇女雌激素替代治疗

绝经后妇女雌激素替代治疗程国钧，刘建立妇女生命的１／３以上的时间是在绝经后渡过的。绝经后雌激素（Ｅ）缺乏可以引起一系列疾病，影响老年妇女的生活质量。自５０年代以来，国外对激素替代治疗（ＨＲＴ）进行了大量研究。目前，ＨＲＴ在许多国家已十分流行，不仅用于...     

CEU:Managing menopausal symptoms after the women's health initiative

Until the results of the Women's Health Initiative (WHI) were released in July 2002, hormone replacement therapy (HRT) had been thought to be the most effective way to manage unwanted menopausal symptoms and to prevent long-term health problems associated with aging. The results of the WHI, showing that HRT is less beneficial and associated with more risks than previously thought, has complicated the management of unwanted menopausal symptoms. This article discusses the effectiveness of HRT and other modalities used to relieve menopausal symptoms and discusses how to choose an HRT product to match specific menopausal complaints and provide maximum safety.     

Hormone therapy in the WHI era

The announcement in July 2002 in the media of the results of the combined continuous hormone treatment arm of the Women's Health Initiative (WHI) had a profound effect on perceptions about hormone therapy among the lay public and the medical profession. Careful scrutiny of the announcement and the subsequent publications leads to the conclusion that the widespread fear of hormone therapy that was generated was not supported by the facts. WHI was not designed to be, nor can it be, interpreted as a randomised controlled trial of menopausal hormone therapy--rather, it was a trial of chronic disease prevention, particularly aimed at the possible cardiovascular benefits of a specific combination hormone therapy in postmenopausal women. The results, which were consistent with existing data, did not and do not warrant any major change in the previously established guidelines for the use of hormone therapy. Tibolone has emerged as an alternative treatment for menopausal symptoms, but its long-term benefits and risks have yet to be documented.     

Hormones down under: hormone therapy use after the Women's Health Initiative

AIMS: The primary objective was to describe the usage pattern of hormone therapy (HT) in a sample of urban Australian women in 2001 and to assess the characteristics of users vs. non-users. The second objective was to determine whether there had been any change in usage since the publication of the results of the combined oestrogen plus progestagen arm of the Women's Health Initiative (WHI) in 2002. METHODS: A cohort of 374 postmenopausal women aged 50-80 years participated in this substudy of the LAW (Longitudinal Assessment of Ageing in Women) project: a 5-year multidisciplinary, observational study. Participants completed an annual medical assessment including details of the use of HT and the reasons for use, as well as demographic and psychosocial data. RESULTS: In December 2001, 30.8% of the participants were using HT, whereas 55.4% were ever users. The management of vasomotor symptoms and mood disturbance were the primary reasons for use. Of those who had been using HT in December 2001 (24.4%) women ceased using HT in the 3 months following publication of the WHI results. The percentage of women using HT in December 2003 (13.9%) was less than half of that of December 2001. CONCLUSION: The rate of HT use and the reasons for use, in 2001 in Brisbane was similar to that of other Australian regions. Usage of HT decreased since the publication of the WHI results in 2002 which may reflect changing attitudes by patients and practitioners regarding HT.     

Androgen Replacement Therapy and Women’s Health

Although androgen replacement has been in use for several decades for various gynaecological disorders, it has had few adherents in women’s health because of misconceptions that it is unphysiobgical and a male hormone. The potential role of androgens in the pharmacological management of menopausal hormone deficiency states remains to be firmly defined, but there has recently been renewed interest in the addition of low-dose androgen to the traditional estrogen replacement therapy. This is a welcome development because not all menopausal symptoms are adequately controlled with estrogen or estrogen/progestin therapy. Weight gain, increase in body hair and slight enlargement of the clitoris constitute the most important side effects experienced by androgen users. The purpose of this review is to discuss the role of androgens as an adjuvant to estrogen/progestin replacement therapy with the hope that the clinician will evaluate its incorporation into menopausal women’s health care.     

Revised key messages for hormone replacement therapy from the New Zealand Guidelines Group

The publication of the Women's Health Initiative Study in 2002 has led to changes in the advice for women considering hormone replacement therapy (HRT) use. Along with other organisations worldwide, the New Zealand Guidelines Group (NZGG) revised their key messages for the appropriate prescribing of HRT. Long-term HRT use was not recommended, nor was the use of HRT for the prevention of coronary heart disease and stroke. While acknowledging the effectiveness of HRT for relief of menopausal symptoms, the group felt that women needed to be informed of the potential risks. Methodological criticisms of Women's Health Initiative (WHI) are discussed along with suggestions of how the study findings may be used for individual decision-making. In addition to presenting the new advice from the NZGG, the present paper compares these findings with other international bodies and seeks to present some consensus that may help decision-making for women who are symptomatic at menopause.     

Current opinions and understandings of menopausal women about hormone replacement therapy (HRT)-the University of Florida experience

OBJECTIVE: This study was designed to assess the opinions and understanding of patients about hormone replacement therapy (HRT) since the release of the Women's Health Initiative (WHI) HRT trial data, which was widely publicized in the lay press. METHODS: All patients between the ages of 45 and 65 years seen in the last 3 years in the University of Florida Women's Clinics were mailed a survey asking about their attitudes and perceptions of HRT. RESULTS: A total of 6468 surveys were mailed with the return of 1076 completed surveys (16.6%); 78% of the respondents were menopausal and 65% had taken HRT. Of the women taking HRT, 70% stated it was for symptom relief and 30% for long-term benefits, including protection from heart disease (10%), Alzheimer's (4%), and osteoporosis (16%). Attitude changes about HRT since the release of WHI results were reported in 42% of respondents. Women currently on HRT had a more positive view of therapy (88%) compared with respondents overall (58%). Despite a great deal of media attention given to the topic of HRT, many women dramatically overestimated the risks of HRT, with 31% believing HRT increases the risk of heart disease 10% to 30% per year and 53% believing HRT increases the risk of breast cancer 10% to 30% per year. Despite this overestimation of risks, only 35% of respondents would not recommend HRT to a friend. CONCLUSION: This study suggests that WHI results did not impact attitudes about HRT in the majority of women taking HRT, as they were usually on therapy for relief of menopausal symptoms. However, there is a great need for consumer education about the attributable risks of HRT, approximately 1 per 1000 per year for heart disease, stroke, DVT, and breast cancer, so they can better weigh the benefits of HRT versus the risks.     

A critique of the Women's Health Initiative hormone therapy study

OBJECTIVE: This review critiques The Women's Health Initiative (WHI) study, focusing on aspects of the study design contributing to the adverse events resulting in the study's discontinuation. CONCLUSION(S): Two aspects of the design contributed to the adverse events: [1] The decision to administer continuous combined conjugated equine estrogen (CEE)/medroxyprogesterone acetate (MPA) or E alone as a standard regimen to a population with little previous hormonal treatment, ranging in age from 50-79 years, who, because of their age, were predisposed to coronary and cerebral atherosclerosis. [2] Selection of an untested regimen of continuous combined CEE plus MPA, which we hypothesize, negated the protective effect of E on the cardiovascular and cerebrovascular systems. Multiple observational studies that preceded the WHI study concluded that the use of E alone and E plus cyclic (not daily) progestin combination treatments initiated in early menopause had beneficial effects. The therapeutic regimens resulted in prevention of atherosclerosis and reductions in coronary artery disease mortality. It is our conclusion that the WHI hormonal replacement study had major design flaws that led to adverse conclusions about the positive effects of hormone therapy. An alternative hormonal regimen is proposed that, on the basis of data supporting its beneficial cardiovascular effects, when initiated appropriately in a population of younger, more recently menopausal women, has promise to yield a more favorable risk/benefit outcome.     

Effect of the WHI study on the attitude of Israeli gynecologists to hormonal therapy during menopause

OBJECTIVE: To evaluate the attitude of Israeli gynecologists to the use of hormonal therapy (HT) during menopause consequent to the recent publication of the Women's Health Initiative (WHI) study. DESIGN: Gynecologists present at the annual convention of the Israeli Society of Obstetrics and Gynecology in the community were asked to complete a 5-item questionnaire on their opinions regarding hormone therapy (HT) use in light of the WHI study. RESULTS: Ninety-five percent of the physicians believed that HT is still a legitimate treatment modality during menopause, although almost 40% would now limit it to the management of climacteric symptoms. As a result of the WHI study, 65% of the physicians recommended cessation of HT use in up to 30% of their treated postmenopausal patients. The responders estimated that about 40% of their patients using HT ceased treatment on their own initiative following publication of the WHI study. CONCLUSIONS: Both physicians and patients were clearly influenced by the WHI study. Today, HT is being reserved by most gynecologists in Israel for the treatment of menopausal symptoms and is not being used as a preventive measure against future complications of heart disease and osteoporosis.     

The randomized world is not without its imperfections: reflections on the Women's Health Initiative Study

In May 2002, the Women's Heath Initiative (WHI) clinical trial, designed to clarify the risks and benefits of combination hormone replacement therapy, came to a premature halt. An interim safety review after an average follow-up of 5.2 years found that a combination of estrogen and progestin often prescribed to postmenopausal women increased the risk of invasive breast cancer, heart disease, stroke, and pulmonary embolism. The combination hormone therapy reduced bone fractures and colorectal cancer, but not enough to outweigh the other risks. The WHI trial presents a challenge for patients, physicians, and epidemiologists, since many observational studies have shown cardiovascular benefits of long-term hormone replacement therapy (HRT). At the same time, a companion paper in the same journal reported an epidemiologic study with a 13.4-year mean follow-up suggesting that estrogen replacement therapy, when used alone for 10 years or more, increases the risk of ovarian cancer. The medical community is still recovering from these twin shocks and trying to digest the results of both of these studies. The WHI study calls into question the long-term use of HRT in healthy women. The benefit of the temporary use of estrogen in controlling disruptive symptoms of the menopause is not being contested. Absent from many news releases are the hedging and equivocation typical of other reported clinical trials. There are still some "hanging chads" out there, and this commentary is designed to examine the uncertainties that remain after the WHI report. It is also intended to suggest development of alternative strategies to control symptoms of the menopausal transition that will reduce risks of HRT. The evidence from the WHI study will need to be incorporated into medical decision making, but clinical decisions, like most human decisions, are complex and in the final analysis must be based on information from many sources.     

Hormone replacement therapy: time to move on?

The risks and benefits of hormone replacement therapy (HRT) need to be put in perspective. In the analysis of clinical trials, emphasis is often placed on relative risks, statistical significance and 95% confidence intervals, whereas, from a clinical perspective, more may be gained from a consideration of the absolute and attributable risks of therapy. The Council for International Organizations of Medical Sciences recommended that the frequency of adverse events be categorized as "rare" if less than 1/1000 but more than 1/10,000, and as "very rare" if less than 1/10,000. In the analyses of the Women's Health Initiative (WHI), the attributable risks were "appreciable" (i.e. more than 1/1000) only in women aged over 70 years, with the exception of the risks of venous thromboembolism and stroke. The women in the WHI trial do not represent the relatively younger, healthy, postmenopausal women most commonly prescribed HRT, who are probably at much lower risk. Moreover, the WHI trial did not take into account the benefit of relief of menopausal symptoms, which is, for many women, paramount and outweighs the "rare" long-term risks. Age may be a useful guide to risks and some simple guidelines for management, based on age, are suggested. Many women have been denied or have discontinued HRT because of the fear of risks, which may not have been put in perspective or fully understood. The care of postmenopausal women is not static, and sufficient has now been learned to enable each menopausal woman, with the help of her medical adviser, to come to a balanced and reasonable decision.