今日の臨床サポート

ホルモン補充療法

著者: 安井敏之 徳島大学医歯薬学研究部 生殖・更年期医療学分野

監修: 小林裕明 鹿児島大学大学院医歯学総合研究科生殖病態生理学

著者校正/監修レビュー済:2021/01/13
参考ガイドライン:
  1. 日本産科婦人科学会日本産婦人科医会:産婦人科診療ガイドライン 婦人科外来編2020
  1. 日本産科婦人科学会日本女性医学学会:ホルモン補充療法ガイドライン2017年度版
患者向け説明資料

概要・推奨   

  1. マイナートラブルとして、出血、乳房痛、乳房緊満感について説明する。
  1. HRT(ホルモン補充療法)により増加する可能性のある疾患として、冠動脈疾患、脳卒中、静脈血栓塞栓症、乳がん、卵巣癌について説明する。
  1. 慎重投与ないしは条件付きで投与が可能な症例については、ホルモン補充療法ガイドライン2017年度版を参照しながら説明する。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となり
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
安井敏之 : 特に申告事項無し[2021年]
監修:小林裕明 : 講演料(中外製薬株式会社,アストラゼネカ株式会社),奨学(奨励)寄付など(中外製薬株式会社)[2021年]

改訂のポイント:
  1. 上記ガイドラインに基づいて確認を行い修正した。

まとめ・診察

薬物療法のまとめ  
  1. ホルモン補充療法(hormone replacement therapy、HRT)とは、エストロゲン欠乏に伴う症状の治療や予防を目的に考案された療法で、閉経移行期以降の女性にエストロゲン製剤を投与する治療の総称をさす。子宮がある女性では、子宮内膜癌の発生を増加させないために黄体ホルモン製剤を併用する。エストロゲンには女性の生殖機能を維持する以外に多くの生理機能を有しており、閉経後などの卵巣機能の低下した女性では、エストロゲン欠落症状やエストロゲンの欠乏に起因する機能障害は程度の差こそあれ必発である。したがって、HRTを閉経後女性のヘルスケアに対して用いることは、目的に合致し、かつ有効な手段になりうることは疑うことのない事実である。HRTは欧米では1970年代の中頃から使用され始め、20世紀の後半には閉経後女性の健康維持や改善に有効かつ有用な療法として高い期待が寄せられていた。
  1. 2002年のWomen’s Health Initiative(WHI)の中間報告以降、HRTの有する副作用のみに関心が寄せられ、HRTの普及は後退を余儀なくされた。
  1. しかし、その後のサブ解析やメタアナリシスにより、HRTは ①患者の年齢、②閉経後年数、③投与ルート、④薬剤の種類、⑤薬剤の量、⑥投与方法、⑦投与期間によって、WHI(2002)の報告とは異なる結果が出てきた。ここ数年の風潮として、WHI試験で後退したHRTの有用性を見直す機運が世界的に叫ばれるようになり[1][2]、HRTは冬の時代を抜けて、新しいステージに入ったといえる。さらに2017年春には、WHI研究中間報告の内情を暴露するような総説も発表され[1][2]、HRTは「2002年の振り出しに戻った」と考えられている。HRTは薬物療法の1つの選択肢であることに今も昔も変わりはない。HRTを選択するに当たっては、一人一人の女性について、そのリスクとベネフィットを慎重に判断することが重要である。
 
  1. WHIの報告(2002)
  1. Framingham Studyによれば、心血管疾患の発生は男女とも経年的に増加する。
  1. 50歳以前では男性が女性の3~4倍高率であるが、それ以降女性の頻度が急激に増加し、70歳代ではほとんど差がなくなる[3]
  1. 女性における発生頻度の急激な増加は加齢よりも閉経(低エストロゲン)によるところが大きく、HRTは脂質代謝改善作用をはじめ多くの抗動脈硬化作用を有し、心血管疾患リスクを低下させると信じられてきた。
  1. ところが、2002年に報告されたWomen’s Health Initiative (WHI) の中間報告によりこの考え方には変化が生じてきた。
  1. WHIとは、閉経後の女性における疾患の発症予防対策を総合的に評価することを目的に、米国の50~79歳(平均年齢63.6歳)の健康な一般女性を対象とした大規模前向き臨床試験である。
  1. そのうち、2002年に報告されたものはEPTのデータであり、EPT(エストロゲン・黄体ホルモン併用療法)では冠動脈疾患(CHD)、浸潤性乳癌、脳卒中、肺塞栓症のリスクを有意に増加させることが判明した。(Women’s Health Initiative (WHI, 2002) の結果 ―HRTに関するnon-adjusting results―:<図表>
  1. その結果、HRTはCHDの一次予防を目的として開始すべきではなく、これのみを主たる目的でHRTを行っている場合には継続すべきではないとの結論が下された。
  1. 一方で、WHIの報告は当初から対象年齢が高いという欠点が指摘されていた。さらに、8,500人の女性のうち50%が、以前に喫煙や現在の喫煙歴のある対象であった。これは、わが国の女性とは明らかに背景因子の異なる集団と言える。
  1. また、米国のデータをそのまま日本人に当てはめてよいかも疑問視されていたが、その後の検討により、HRTの効果や有害事象は患者の年齢、閉経後期間、薬剤の投与ルート、薬剤の量、薬剤の種類によって異なることが報告されるようになってきた。
  1. 特に閉経後のHRTが心・血管系へ及ぼす有害事象は、閉経後早期に開始すればそれほど大きな問題になることはないことも判明してきた。
  1. 2017年春には、WHI研究中間報告の内情を暴露するような総説も発表された[1]。ここ数年の風潮として、WHI試験で後退したHRTの有用性を見直す機運が世界的に叫ばれるようになり、HRTは冬の時代を抜けて、新しいステージに入ったと言える[4]
  1. WHI研究の見直しもこれまでに繰り返し行われてきたが、研究開始約18年間の経過についてまとめたMansonsらの論文[5]では、50~59歳でHRTを開始した女性の全般的な死亡ハザード比が、介入期間中に0.69、経過観察中に0.89と低下することが改めて示された。
  1. 追記:HRTを行うには最適の年齢がある。これを「The window of opportunity」という。
 
Women’s Health Initiative (WHI, 2002) の結果 ―HRTに関するnon-adjusting results―

HRTにより心筋梗塞、脳卒中、脳梗塞、乳癌の発生は増加する。しかし、骨粗鬆症による大腿骨頚部骨折、結腸・大腸癌の発症を防止する効果がある。
 
参考文献:
Rossouw JE, Anderson GL, Prentice RL, et al; Risk and benefit of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288: 321-33  PMID:12117397

出典

img1:  堂地勉先生ご提供
 
 
薬剤投与前、フォローアップ時の問診のポイント  
  1. 毎回、更年期症状の有無の変化やマイナートラブル(出血の状態、乳房腫脹の有無、血栓症の有無など)を含む症状について問診する。10日間以上の長期あるいは平常の月経より多量の出血がある場合には、子宮内膜の検査(子宮内膜細胞診または組織診)を行う。

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文献 

著者: R D Langer
雑誌名: Climacteric. 2017 Apr;20(2):91-96. doi: 10.1080/13697137.2017.1280251. Epub 2017 Mar 10.
Abstract/Text Prior to the unexpected early termination of the Women's Health Initiative (WHI) trial of continuous conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA), the prevailing view was that hormone replacement therapy (HRT) was a low-risk intervention with immediate value for symptom relief in recently menopausal women, and that it probably conferred long-term protection against the major chronic diseases that affect women after menopause. Rather than replicating prior studies, the WHI was designed to test whether the beneficial associations consistently seen in women starting HRT near menopause would be found in women well beyond menopause. Views of the benefits and risks of HRT changed dramatically in 2002 with the unexpected early termination of the CEE + MPA trial and the alarming initial WHI report. HRT use plummeted world-wide, driven by fear of breast cancer and skepticism about cardiovascular benefits. Stunningly, the contrasting findings of the WHI trial of CEE alone reported 2 years later - suggesting prevention of coronary heart disease in women who began HRT at age <60 years, and a reduction in breast cancer overall - were largely ignored. Key lessons from the WHI are that the effects of HRT on most organ systems vary by age and time since last physiologic exposure to hormones and that there are differences between regimens. In the years since the first WHI report, we have learned much about the characteristics of women who are likely to benefit from HRT. The range of HRT regimens has also increased. Not all women have indications for HRT, but for those who do and who initiate within 10 years of menopause, benefits are both short-term (vasomotor, dyspareunia), and long-term (bone health, coronary risk reduction). Critically, the 'facts' that most women and clinicians consider in making the decision to use, or not use, HRT are frequently wrong or incorrectly applied.

PMID 28281363  Climacteric. 2017 Apr;20(2):91-96. doi: 10.1080/1369713・・・
著者: JoAnn E Manson, Aaron K Aragaki, Jacques E Rossouw, Garnet L Anderson, Ross L Prentice, Andrea Z LaCroix, Rowan T Chlebowski, Barbara V Howard, Cynthia A Thomson, Karen L Margolis, Cora E Lewis, Marcia L Stefanick, Rebecca D Jackson, Karen C Johnson, Lisa W Martin, Sally A Shumaker, Mark A Espeland, Jean Wactawski-Wende, WHI Investigators
雑誌名: JAMA. 2017 Sep 12;318(10):927-938. doi: 10.1001/jama.2017.11217.
Abstract/Text Importance: Health outcomes from the Women's Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality.
Objective: To examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women's Health Initiative hormone therapy trials.
Design, Setting, and Participants: Observational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014.
Interventions: Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years (median) or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years (median).
Main Outcomes and Measures: All-cause mortality (primary outcome) and cause-specific mortality (cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization.
Results: Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7489 deaths occurred (1088 deaths during the intervention phase and 6401 deaths during postintervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96-1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88-1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95% CI, 0.92-1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95-1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88-1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials.
Conclusions and Relevance: Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years.
Trial Registration: clinicaltrials.gov Identifier: NCT00000611.

PMID 28898378  JAMA. 2017 Sep 12;318(10):927-938. doi: 10.1001/jama.20・・・
著者: W B Kannel, M C Hjortland, P M McNamara, T Gordon
雑誌名: Ann Intern Med. 1976 Oct;85(4):447-52.
Abstract/Text The relation of menopause to cardiovascular disease incidence was examined in women less than 55 years old from the cohort of 2873 women in the initial Framingham examination. Although the number of person-years of experience during the 20 years of observation was nearly the same for premenopausal and postmenopausal status, there were only 20 cardiovascular events among the premenopausal women in this age group whereas 70 events occurred among the postmenopausal women of the same age. In each specific age group studied incidence rates were lower in premenopausal than postmenopausal women. This was also true for coronary heart disease. Contrast for "hard" diagnoses of cardiovascular disease (excluding diagnoses of angina pectoris and intermittent claudication) was in the same direction. Although cholesterol and hemoglobin did rise somewhat more steeply in women undergoing the menopause, this greater incidence of cardiovascular disease in postmenopausal women could not be explained by the influence of the menopause on the usual cardiovascular risk factors.

PMID 970770  Ann Intern Med. 1976 Oct;85(4):447-52.
著者: Henry M P Boardman, Louise Hartley, Anne Eisinga, Caroline Main, Marta Roqué i Figuls, Xavier Bonfill Cosp, Rafael Gabriel Sanchez, Beatrice Knight
雑誌名: Cochrane Database Syst Rev. 2015 Mar 10;(3):CD002229. doi: 10.1002/14651858.CD002229.pub4. Epub 2015 Mar 10.
Abstract/Text BACKGROUND: Evidence from systematic reviews of observational studies suggests that hormone therapy may have beneficial effects in reducing the incidence of cardiovascular disease events in post-menopausal women, however the results of randomised controlled trials (RCTs) have had mixed results. This is an updated version of a Cochrane review published in 2013.
OBJECTIVES: To assess the effects of hormone therapy for the prevention of cardiovascular disease in post-menopausal women, and whether there are differential effects between use in primary or secondary prevention. Secondary aims were to undertake exploratory analyses to (i) assess the impact of time since menopause that treatment was commenced (≥ 10 years versus < 10 years), and where these data were not available, use age of trial participants at baseline as a proxy (≥ 60 years of age versus < 60 years of age); and (ii) assess the effects of length of time on treatment.
SEARCH METHODS: We searched the following databases on 25 February 2014: Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE and LILACS. We also searched research and trials registers, and conducted reference checking of relevant studies and related systematic reviews to identify additional studies.
SELECTION CRITERIA: RCTs of women comparing orally administered hormone therapy with placebo or a no treatment control, with a minimum of six months follow-up.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for each outcome. We combined results using random effects meta-analyses, and undertook further analyses to assess the effects of treatment as primary or secondary prevention, and whether treatment was commenced more than or less than 10 years after menopause.
MAIN RESULTS: We identified six new trials through this update. Therefore the review includes 19 trials with a total of 40,410 post-menopausal women. On the whole, study quality was good and generally at low risk of bias; the findings are dominated by the three largest trials. We found high quality evidence that hormone therapy in both primary and secondary prevention conferred no protective effects for all-cause mortality, cardiovascular death, non-fatal myocardial infarction, angina, or revascularisation. However, there was an increased risk of stroke in those in the hormone therapy arm for combined primary and secondary prevention (RR 1.24, 95% CI 1.10 to 1.41). Venous thromboembolic events were increased (RR 1.92, 95% CI 1.36 to 2.69), as were pulmonary emboli (RR 1.81, 95% CI 1.32 to 2.48) on hormone therapy relative to placebo.The absolute risk increase for stroke was 6 per 1000 women (number needed to treat for an additional harmful outcome (NNTH) = 165; mean length of follow-up: 4.21 years (range: 2.0 to 7.1)); for venous thromboembolism 8 per 1000 women (NNTH = 118; mean length of follow-up: 5.95 years (range: 1.0 to 7.1)); and for pulmonary embolism 4 per 1000 (NNTH = 242; mean length of follow-up: 3.13 years (range: 1.0 to 7.1)).We performed subgroup analyses according to when treatment was started in relation to the menopause. Those who started hormone therapy less than 10 years after the menopause had lower mortality (RR 0.70, 95% CI 0.52 to 0.95, moderate quality evidence) and coronary heart disease (composite of death from cardiovascular causes and non-fatal myocardial infarction) (RR 0.52, 95% CI 0.29 to 0.96; moderate quality evidence), though they were still at increased risk of venous thromboembolism (RR 1.74, 95% CI 1.11 to 2.73, high quality evidence) compared to placebo or no treatment. There was no strong evidence of effect on risk of stroke in this group. In those who started treatment more than 10 years after the menopause there was high quality evidence that it had little effect on death or coronary heart disease between groups but there was an increased risk of stroke (RR 1.21, 95% CI 1.06 to 1.38, high quality evidence) and venous thromboembolism (RR 1.96, 95% CI 1.37 to 2.80, high quality evidence).
AUTHORS' CONCLUSIONS: Our review findings provide strong evidence that treatment with hormone therapy in post-menopausal women overall, for either primary or secondary prevention of cardiovascular disease events has little if any benefit and causes an increase in the risk of stroke and venous thromboembolic events.

PMID 25754617  Cochrane Database Syst Rev. 2015 Mar 10;(3):CD002229. d・・・
著者: Martina Dören, Jan-Ake Nilsson, Olof Johnell
雑誌名: Hum Reprod. 2003 Aug;18(8):1737-46.
Abstract/Text BACKGROUND: Long-term post-menopausal hormone therapy (pHT) was often regarded as first-line therapy to prevent fractures in post-menopausal women, a recommendation under scrutiny given the benefit-risk profile of the Women's Health Initiative results of the estrogen-progestin combination. Apart from controlled clinical studies providing data with fractures as an end point, measures of lumbar and hip bone mineral density (BMD) may be used to assess bone-related effects of pHT. The objective of this study was to conduct a systematic review of 2-year trials, published between 1990 and December 2002, and assessing changes in BMD by any estrogen including ethinyl estradiol, any estrogen plus any progestin, or tibolone.
METHODS: We searched MEDLINE, EMBASE and systematic reviews. Thirty-nine randomized, prospective, controlled 2-year trials were analysed in pre-specified groups according to the profile of the compounds.
RESULTS: Virtually all pHT regimens at least maintain BMD at the lumbar spine and the hip compared with baseline; there is no apparent difference between the various estrogenic compounds. Tibolone, a synthetic progestin, appears to be as effective as any estrogen. Most trials were conducted in early post-menopausal women, fewer in women with hysterectomy and/or bilateral oophorectomy.
CONCLUSIONS: The size of impact on BMD does not appear to differ between tibolone and any estrogen compound studied.

PMID 12871893  Hum Reprod. 2003 Aug;18(8):1737-46.
著者: Amos Pines, David W Sturdee, Martin Birkhäuser, International Menopause Society
雑誌名: Climacteric. 2006 Apr;9(2):75-6.
Abstract/Text
PMID 16715592  Climacteric. 2006 Apr;9(2):75-6.
著者: Deborah Grady, David Herrington, Vera Bittner, Roger Blumenthal, Michael Davidson, Mark Hlatky, Judith Hsia, Stephen Hulley, Alan Herd, Steven Khan, L Kristin Newby, David Waters, Eric Vittinghoff, Nanette Wenger, HERS Research Group
雑誌名: JAMA. 2002 Jul 3;288(1):49-57.
Abstract/Text CONTEXT: The Heart and Estrogen/progestin Replacement Study (HERS) found no overall reduction in risk of coronary heart disease (CHD) events among postmenopausal women with CHD. However, in the hormone group, findings did suggest a higher risk of CHD events during the first year, and a decreased risk during years 3 to 5.
OBJECTIVE: To determine if the risk reduction observed in the later years of HERS persisted and resulted in an overall reduced risk of CHD events with additional years of follow-up.
DESIGN AND SETTING: Randomized, blinded, placebo-controlled trial of 4.1 years' duration (HERS) and subsequent unblinded follow-up for 2.7 years (HERS II) conducted at outpatient and community settings at 20 US clinical centers.
PARTICIPANTS: A total of 2763 postmenopausal women with CHD and average age of 67 years at enrollment in HERS; 2321 women (93% of those surviving) consented to follow-up in HERS II.
INTERVENTION: Participants were randomly assigned to receive 0.625 mg/d of conjugated estrogens and 2.5 mg of medroxyprogesterone acetate (n = 1380), or placebo (n = 1383) during HERS; open-label hormone therapy was prescribed at personal physicians' discretion during HERS II. The proportions with at least 80% adherence to hormones declined from 81% (year 1) to 45% (year 6) in the hormone group, and increased from 0% (year 1) to 8% (year 6) in the placebo group.
MAIN OUTCOME MEASURES: The primary outcome was nonfatal myocardial infarction and CHD death. Secondary cardiovascular events were coronary revascularization, hospitalization for unstable angina or congestive heart failure, nonfatal ventricular arrhythmia, sudden death, stroke or transient ischemic attack, and peripheral arterial disease.
RESULTS: There were no significant decreases in rates of primary CHD events or secondary cardiovascular events among women assigned to the hormone group compared with the placebo group in HERS, HERS II, or overall. The unadjusted relative hazard (RH) for CHD events in HERS was 0.99 (95% confidence interval [CI], 0.81-1.22); HERS II, 1.00 (95% CI, 0.77-1.29); and overall, 0.99 (0.84-1.17). The overall RHs were similar after adjustment for potential confounders and differential use of statins between treatment groups (RH, 0.97; 95% CI, 0.82-1.14), and in analyses restricted to women who were adherent to randomized treatment assignment (RH, 0.96; 95% CI, 0.77-1.19).
CONCLUSIONS: Lower rates of CHD events among women in the hormone group in the final years of HERS did not persist during additional years of follow-up. After 6.8 years, hormone therapy did not reduce risk of cardiovascular events in women with CHD. Postmenopausal hormone therapy should not be used to reduce risk for CHD events in women with CHD.

PMID 12090862  JAMA. 2002 Jul 3;288(1):49-57.
著者: Jacques E Rossouw, Ross L Prentice, JoAnn E Manson, Lieling Wu, David Barad, Vanessa M Barnabei, Marcia Ko, Andrea Z LaCroix, Karen L Margolis, Marcia L Stefanick
雑誌名: JAMA. 2007 Apr 4;297(13):1465-77. doi: 10.1001/jama.297.13.1465.
Abstract/Text CONTEXT: The timing of initiation of hormone therapy may influence its effect on cardiovascular disease.
OBJECTIVE: To explore whether the effects of hormone therapy on risk of cardiovascular disease vary by age or years since menopause began.
DESIGN, SETTING, AND PARTICIPANTS: Secondary analysis of the Women's Health Initiative (WHI) randomized controlled trials of hormone therapy in which 10,739 postmenopausal women who had undergone a hysterectomy were randomized to conjugated equine estrogens (CEE) or placebo and 16,608 postmenopausal women who had not had a hysterectomy were randomized to CEE plus medroxyprogesterone acetate (CEE + MPA) or placebo. Women aged 50 to 79 years were recruited to the study from 40 US clinical centers between September 1993 and October 1998.
MAIN OUTCOME MEASURES: Statistical test for trend of the effect of hormone therapy on coronary heart disease (CHD) and stroke across categories of age and years since menopause in the combined trials.
RESULTS: In the combined trials, there were 396 cases of CHD and 327 cases of stroke in the hormone therapy group vs 370 [corrected] cases of CHD and 239 cases of stroke in the placebo group. For women with less than 10 years since menopause began, the hazard ratio (HR) for CHD was 0.76 (95% confidence interval [CI], 0.50-1.16); 10 to 19 years, 1.10 (95% CI, 0.84-1.45); and 20 or more years, 1.28 (95% CI, 1.03-1.58) (P for trend = .02). The estimated absolute excess risk for CHD for women within 10 years of menopause was -6 per 10,000 person-years; for women 10 to 19 years since menopause began, 4 per 10,000 person-years; and for women 20 or more years from menopause onset, 17 per 10,000 person-years. For the age group of 50 to 59 years, the HR for CHD was 0.93 (95% CI, 0.65-1.33) and the absolute excess risk was -2 per 10,000 person-years; 60 to 69 years, 0.98 (95% CI, 0.79-1.21) and -1 per 10,000 person-years; and 70 to 79 years, 1.26 (95% CI, 1.00-1.59) and 19 per 10,000 person-years (P for trend = .16). Hormone therapy increased the risk of stroke (HR, 1.32; 95% CI, 1.12-1.56). Risk did not vary significantly by age or time since menopause. There was a nonsignificant tendency for the effects of hormone therapy on total mortality to be more favorable in younger than older women (HR of 0.70 for 50-59 years; 1.05 for 60-69 years, and 1.14 for 70-79 years; P for trend = .06).
CONCLUSIONS: Women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause, but this trend test did not meet our criterion for statistical significance. A similar nonsignificant trend was observed for total mortality but the risk of stroke was elevated regardless of years since menopause. These data should be considered in regard to the short-term treatment of menopausal symptoms.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.

PMID 17405972  JAMA. 2007 Apr 4;297(13):1465-77. doi: 10.1001/jama.297・・・
著者: H N Hodis, W J Mack
雑誌名: Climacteric. 2009;12 Suppl 1:71-5.
Abstract/Text The discordance in coronary heart disease (CHD) outcome between randomized, controlled trials and observational studies of hormone replacement therapy (HRT) is likely the result of the dissimilar cohorts studied. This observation led to the formation of the timing hypothesis that benefits and risks of HRT depend upon age of HRT initiation and/or time of HRT initiation in relation to menopause. This hypothesis has been supported with data from large, randomized, controlled trials that have studied HRT and selective estrogen receptor modulators (SERMs) in the prevention of CHD. Initiation of HRT in women <60 years of age and/or within 10 years of menopause reduces both CHD and total mortality; SERMs have been shown to reduce CHD in women <60 years. What has become clear from the cumulated literature is that in young postmenopausal women who initiate HRT in close proximity to menopause, the adverse effects of HRT are rare and no greater than those of other commonly used pharmacological agents and that the primary prevention benefits for CHD are at least equivalent to those of other commonly used therapies. Additionally, the literature indicates that the duration of HRT confers greater CHD benefit especially in women <60 years who initiate therapy. The cumulated literature dispels misperceptions concerning HRT and CHD.

PMID 19811246  Climacteric. 2009;12 Suppl 1:71-5.
著者: Judith Hsia, Robert D Langer, Joann E Manson, Lewis Kuller, Karen C Johnson, Susan L Hendrix, Mary Pettinger, Susan R Heckbert, Nancy Greep, Sybil Crawford, Charles B Eaton, John B Kostis, Pat Caralis, Ross Prentice, Women's Health Initiative Investigators
雑誌名: Arch Intern Med. 2006 Feb 13;166(3):357-65. doi: 10.1001/archinte.166.3.357.
Abstract/Text BACKGROUND: In recent randomized trials, conjugated equine estrogens (CEE) with continuous medroxyprogesterone acetate provided no protection against coronary heart disease in postmenopausal women and may have increased cardiac risk. These trials did not address the role of unopposed estrogen for coronary protection.
METHODS: A total of 10 739 women aged 50 to 79 years at baseline (mean age, 63.6 years) who had previously undergone hysterectomy were randomized to receive CEE, 0.625 mg/d, or placebo at 40 US clinical centers beginning in 1993. The trial was terminated early after 6.8 years of follow-up (planned duration, 8.5 years). This report includes final, centrally adjudicated results for the primary efficacy outcome (myocardial infarction or coronary death), secondary coronary outcomes, and subgroup analyses.
RESULTS: During the active intervention period, 201 coronary events were confirmed among women assigned to receive CEE compared with 217 events among women assigned to receive placebo (hazard ratio, 0.95; nominal 95% confidence interval, 0.79-1.16). Among women aged 50 to 59 years at baseline, the hazard ratio for the primary outcome was 0.63 (nominal 95% confidence interval, 0.36-1.08). In that age group, coronary revascularization was less frequent among women assigned to receive CEE (hazard ratio, 0.55; nominal 95% confidence interval, 0.35-0.86), as were several composite outcomes, which included the primary outcome and coronary revascularization (hazard ratio, 0.66; nominal 95% confidence interval, 0.44-0.97).
CONCLUSIONS: Conjugated equine estrogens provided no overall protection against myocardial infarction or coronary death in generally healthy postmenopausal women during a 7-year period of use. There was a suggestion of lower coronary heart disease risk with CEE among women 50 to 59 years of age at baseline.

PMID 16476878  Arch Intern Med. 2006 Feb 13;166(3):357-65. doi: 10.100・・・
著者: Mary Cushman, Lewis H Kuller, Ross Prentice, Rebecca J Rodabough, Bruce M Psaty, Randall S Stafford, Steven Sidney, Frits R Rosendaal, Women's Health Initiative Investigators
雑誌名: JAMA. 2004 Oct 6;292(13):1573-80. doi: 10.1001/jama.292.13.1573.
Abstract/Text CONTEXT: Postmenopausal hormone therapy increases the risk of venous thrombosis. It is not known whether other factors influencing thrombosis add to this risk.
OBJECTIVE: To report final data on incidence of venous thrombosis in the Women's Health Initiative Estrogen Plus Progestin clinical trial and the association of hormone therapy with venous thrombosis in the setting of other thrombosis risk factors.
DESIGN, SETTING, AND PARTICIPANTS: Double-blind randomized controlled trial of 16,608 postmenopausal women between the ages of 50 and 79 years, who were enrolled in 1993 through 1998 at 40 US clinical centers with 5.6 years of follow up; and a nested case-control study. Baseline gene variants related to thrombosis risk were measured in the first 147 women who developed thrombosis and in 513 controls.
INTERVENTION: Random assignment to 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate, or placebo.
MAIN OUTCOME MEASURES: Centrally validated deep vein thrombosis and pulmonary embolus.
RESULTS: Venous thrombosis occurred in 167 women taking estrogen plus progestin (3.5 per 1000 person-years) and in 76 taking placebo (1.7 per 1000 person-years); hazard ratio (HR), 2.06 (95% confidence interval [CI], 1.57-2.70). Compared with women between the ages of 50 and 59 years who were taking placebo, the risk associated with hormone therapy was higher with age: HR of 4.28 (95% CI, 2.38-7.72) for women aged 60 to 69 years and 7.46 (95% CI, 4.32-14.38) for women aged 70 to 79 years. Compared with women who were of normal weight and taking placebo, the risk associated with taking estrogen plus progestin was increased among overweight and obese women: HR of 3.80 (95% CI, 2.08-6.94) and 5.61 (95% CI, 3.12-10.11), respectively. Factor V Leiden enhanced the hormone-associated risk of thrombosis with a 6.69-fold increased risk compared with women in the placebo group without the mutation (95% CI, 3.09-14.49). Other genetic variants (prothrombin 20210A, methylenetetrahydrofolate reductase C677T, factor XIII Val34Leu, PAI-1 4G/5G, and factor V HR2) did not modify the association of hormone therapy with venous thrombosis.
CONCLUSIONS: Estrogen plus progestin was associated with doubling the risk of venous thrombosis. Estrogen plus progestin therapy increased the risks associated with age, overweight or obesity, and factor V Leiden.

PMID 15467059  JAMA. 2004 Oct 6;292(13):1573-80. doi: 10.1001/jama.292・・・
著者: Céline Straczek, Emmanuel Oger, Marianne Beau Yon de Jonage-Canonico, Geneviève Plu-Bureau, Jacqueline Conard, Guy Meyer, Martine Alhenc-Gelas, Hervé Lévesque, Nathalie Trillot, Marie-Thérèse Barrellier, Denis Wahl, Joseph Emmerich, Pierre-Yves Scarabin, Estrogen and Thromboembolism Risk (ESTHER) Study Group
雑誌名: Circulation. 2005 Nov 29;112(22):3495-500. doi: 10.1161/CIRCULATIONAHA.105.565556. Epub 2005 Nov 21.
Abstract/Text BACKGROUND: Oral estrogen increases the risk of venous thromboembolism (VTE) in postmenopausal women, particularly in those with a prothrombotic mutation. Transdermal estrogen may be safe with respect to VTE. We investigated the impact of the route of estrogen administration on the association between a prothrombotic mutation (factor V Leiden or prothrombin G20210A mutation) and VTE risk.
METHODS AND RESULTS: We performed a multicenter case-control study of VTE among postmenopausal women who were enrolled in 1999 through 2004 at 7 clinical centers in France. We recruited 235 consecutive patients with a first documented episode of idiopathic VTE and 554 controls. Factor V Leiden was associated with a 3.4-fold-increased risk of VTE (95% confidence interval [CI], 2.0 to 5.8), and a prothrombin mutation was associated with a 4.8-fold-increased risk of VTE (95% CI, 2.5 to 9.4). Oral but not transdermal estrogen was associated with an increased risk of VTE (odds ratio [OR], 4.3; 95% CI, 2.6 to 7.2; and OR, 1.2; 95% CI, 0.8 to 1.7, respectively). After adjustment for potential confounding factors, the combination of either factor V Leiden or prothrombin G20210A mutation and oral estrogen gave a 25-fold-increased risk of VTE compared with nonusers without mutation (95% CI, 6.9 to 95.0). However, the risk for women with prothrombotic mutation using transdermal estrogen was similar to that of women with a mutation who were not using estrogen (OR, 4.4; 95% CI, 2.0 to 9.9; and OR, 4.1; 95% CI, 2.3 to 7.4, respectively).
CONCLUSIONS: In contrast to oral estrogen, transdermal estrogen does not confer additional risk on women who carry a prothrombotic mutation. The safety of transdermal estrogen has to be confirmed in randomized trials.

PMID 16301339  Circulation. 2005 Nov 29;112(22):3495-500. doi: 10.1161・・・
著者: M Canonico, E Oger, J Conard, G Meyer, H Lévesque, N Trillot, M T Barrellier, D Wahl, J Emmerich, P Y Scarabin, EStrogen and THromboEmbolism Risk (ESTHER) Study Group
雑誌名: J Thromb Haemost. 2006 Jun;4(6):1259-65. doi: 10.1111/j.1538-7836.2006.01933.x.
Abstract/Text BACKGROUND: Oral estrogen use and elevated body mass index (BMI) increase the risk of venous thromboembolism (VTE). Recent data suggest that transdermal estrogen might be safe with respect to thrombotic risk. However, the impact of transdermal estrogen on the association between overweight (25 kg m(-2) < BMI < or = 30 kg m(-2)) or obesity (BMI >30 kg m(-2)) and VTE risk has not been investigated.
METHODS: We carried a multicenter case-control study of VTE among postmenopausal women aged 45-70 years, between 1999 and 2005, in France. Case population consisted of women with a first documented idiopathic VTE. We recruited 191 hospital cases matched with 416 hospital controls and 62 outpatient cases matched with 181 community controls.
RESULTS: The odds ratio (OR) for VTE was 2.5 [95% confidence interval (CI):1.7-3.7] for overweight and 3.9 (95% CI: 2.2-6.9) for obesity. Oral, not transdermal, estrogen was associated with an increased VTE risk (OR = 4.5; 95% CI: 2.6-7.7 and OR = 1.1; 95% CI: 0.7-1.7, respectively). Compared with non-users with normal weight, the combination of oral estrogen use and overweight or obesity further enhanced VTE risk (OR = 10.2; 95% CI: 3.5-30.2 and OR = 20.6; 95% CI: 4.8-88.1, respectively). However, transdermal users with increased BMI had similar risk as non-users with increased BMI (OR = 2.9; 95% CI: 1.5-5.8 and OR = 2.7; 95% CI: 1.7-4.5 respectively for overweight; OR = 5.4; 95% CI: 2.1-14.1 and OR = 4.0; 95% CI: 2.1-7.8 respectively for obesity).
CONCLUSIONS: In contrast to oral estrogen, transdermal estrogen does not confer an additional risk of idiopathic VTE in women with increased BMI. The safety of transdermal estrogen on thrombotic risk has to be confirmed.

PMID 16706969  J Thromb Haemost. 2006 Jun;4(6):1259-65. doi: 10.1111/j・・・
著者: The NAMS 2017 Hormone Therapy Position Statement Advisory Panel
雑誌名: Menopause. 2017 Jul;24(7):728-753. doi: 10.1097/GME.0000000000000921.
Abstract/Text The 2017 Hormone Therapy Position Statement of The North American Menopause Society (NAMS) updates the 2012 Hormone Therapy Position Statement of The North American Menopause Society and identifies future research needs. An Advisory Panel of clinicians and researchers expert in the field of women's health and menopause was recruited by NAMS to review the 2012 Position Statement, evaluate new literature, assess the evidence, and reach consensus on recommendations, using the level of evidence to identify the strength of recommendations and the quality of the evidence. The Panel's recommendations were reviewed and approved by the NAMS Board of Trustees.Hormone therapy (HT) remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause (GSM) and has been shown to prevent bone loss and fracture. The risks of HT differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used. Treatment should be individualized to identify the most appropriate HT type, dose, formulation, route of administration, and duration of use, using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of the benefits and risks of continuing or discontinuing HT.For women aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is most favorable for treatment of bothersome VMS and for those at elevated risk for bone loss or fracture. For women who initiate HT more than 10 or 20 years from menopause onset or are aged 60 years or older, the benefit-risk ratio appears less favorable because of the greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia. Longer durations of therapy should be for documented indications such as persistent VMS or bone loss, with shared decision making and periodic reevaluation. For bothersome GSM symptoms not relieved with over-the-counter therapies and without indications for use of systemic HT, low-dose vaginal estrogen therapy or other therapies are recommended.This NAMS position statement has been endorsed by Academy of Women's Health, American Association of Clinical Endocrinologists, American Association of Nurse Practitioners, American Medical Women's Association, American Society for Reproductive Medicine, Asociación Mexicana para el Estudio del Climaterio, Association of Reproductive Health Professionals, Australasian Menopause Society, Chinese Menopause Society, Colegio Mexicano de Especialistas en Ginecologia y Obstetricia, Czech Menopause and Andropause Society, Dominican Menopause Society, European Menopause and Andropause Society, German Menopause Society, Groupe d'études de la ménopause et du vieillissement Hormonal, HealthyWomen, Indian Menopause Society, International Menopause Society, International Osteoporosis Foundation, International Society for the Study of Women's Sexual Health, Israeli Menopause Society, Japan Society of Menopause and Women's Health, Korean Society of Menopause, Menopause Research Society of Singapore, National Association of Nurse Practitioners in Women's Health, SOBRAC and FEBRASGO, SIGMA Canadian Menopause Society, Società Italiana della Menopausa, Society of Obstetricians and Gynaecologists of Canada, South African Menopause Society, Taiwanese Menopause Society, and the Thai Menopause Society. The American College of Obstetricians and Gynecologists supports the value of this clinical document as an educational tool, June 2017. The British Menopause Society supports this Position Statement.

PMID 28650869  Menopause. 2017 Jul;24(7):728-753. doi: 10.1097/GME.000・・・
著者: Christel Renoux, Sophie Dell'aniello, Edeltraut Garbe, Samy Suissa
雑誌名: BMJ. 2010 Jun 3;340:c2519. Epub 2010 Jun 3.
Abstract/Text OBJECTIVES: To determine the risk of stroke associated with oral and transdermal routes of administration of hormone replacement therapy.
DESIGN: Population based nested case-control study. Setting About 400 general practices in the United Kingdom contributing to the General Practice Research Database. Participants Cohort of all women in the database aged 50-79 years between 1 January 1987 and 31 October 2006 who were members of a practice that fulfilled predefined quality criteria and without a diagnosis of stroke before cohort entry. For each case of stroke occurring during follow-up, up to four controls were selected from among the cohort members in the risk sets defined by the case. Exposure to hormone replacement therapy (HRT) was categorised into oestrogens only, oestrogens plus progestogen, progestogen only, and tibolone. Oestrogens were further subdivided according to the route of administration (oral v transdermal) and dose (high v low). Main outcome measures Rate ratio of stroke associated with current use of oral and transdermal HRT compared with no use. Current use was considered as a prescription whose duration included the index date.
RESULTS: There were 15,710 cases of stroke matched to 59 958 controls. The rate of stroke in the cohort was 2.85 per 1000 per year. The adjusted rate ratio of stroke associated with current use of transdermal HRT was 0.95 (95% CI 0.75 to 1.20) relative to no use. The risk of stroke was not increased with use of low oestrogen dose patches (rate ratio 0.81(0.62 to 1.05)) compared with no use, whereas the risk was increased with high dose patches (rate ratio 1.89 (1.15 to 3.11)). Current users of oral HRT had a higher rate of stroke than non-users (rate ratio 1.28 (1.15 to 1.42)) with both low dose and high dose.
CONCLUSIONS: The use of transdermal HRT containing low doses of oestrogen does not seem to increase the risk of stroke. The presence of residual confounding, however, cannot be entirely excluded in the interpretation of this finding.

PMID 20525678  BMJ. 2010 Jun 3;340:c2519. Epub 2010 Jun 3.
著者: Rowan T Chlebowski, Garnet L Anderson, Margery Gass, Dorothy S Lane, Aaron K Aragaki, Lewis H Kuller, JoAnn E Manson, Marcia L Stefanick, Judith Ockene, Gloria E Sarto, Karen C Johnson, Jean Wactawski-Wende, Peter M Ravdin, Robert Schenken, Susan L Hendrix, Aleksandar Rajkovic, Thomas E Rohan, Shagufta Yasmeen, Ross L Prentice, WHI Investigators
雑誌名: JAMA. 2010 Oct 20;304(15):1684-92. doi: 10.1001/jama.2010.1500.
Abstract/Text CONTEXT: In the Women's Health Initiative randomized, placebo-controlled trial of estrogen plus progestin, after a mean intervention time of 5.6 (SD, 1.3) years (range, 3.7-8.6 years) and a mean follow-up of 7.9 (SD, 1.4) years, breast cancer incidence was increased among women who received combined hormone therapy. Breast cancer mortality among participants in the trial has not been previously reported.
OBJECTIVE: To determine the effects of therapy with estrogen plus progestin on cumulative breast cancer incidence and mortality after a total mean follow-up of 11.0 (SD, 2.7) years, through August 14, 2009.
DESIGN, SETTING, AND PARTICIPANTS: A total of 16,608 postmenopausal women aged 50 to 79 years with no prior hysterectomy from 40 US clinical centers were randomly assigned to receive combined conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo pill. After the original trial completion date (March 31, 2005), reconsent was required for continued follow-up for breast cancer incidence and was obtained from 12,788 (83%) of the surviving participants.
MAIN OUTCOME MEASURES: Invasive breast cancer incidence and breast cancer mortality.
RESULTS: In intention-to-treat analyses including all randomized participants and censoring those not consenting to additional follow-up on March 31, 2005, estrogen plus progestin was associated with more invasive breast cancers compared with placebo (385 cases [0.42% per year] vs 293 cases [0.34% per year]; hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.07-1.46; P = .004). Breast cancers in the estrogen-plus-progestin group were similar in histology and grade to breast cancers in the placebo group but were more likely to be node-positive (81 [23.7%] vs 43 [16.2%], respectively; HR, 1.78; 95% CI, 1.23-2.58; P = .03). There were more deaths directly attributed to breast cancer (25 deaths [0.03% per year] vs 12 deaths [0.01% per year]; HR, 1.96; 95% CI, 1.00-4.04; P = .049) as well as more deaths from all causes occurring after a breast cancer diagnosis (51 deaths [0.05% per year] vs 31 deaths [0.03% per year]; HR, 1.57; 95% CI, 1.01-2.48; P = .045) among women who received estrogen plus progestin compared with women in the placebo group.
CONCLUSIONS: Estrogen plus progestin was associated with greater breast cancer incidence, and the cancers are more commonly node-positive. Breast cancer mortality also appears to be increased with combined use of estrogen plus progestin.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.

PMID 20959578  JAMA. 2010 Oct 20;304(15):1684-92. doi: 10.1001/jama.20・・・
著者: John A Eden
雑誌名: Gynecol Endocrinol. 2011 Mar;27(3):170-5. doi: 10.3109/09513590.2010.488778. Epub 2010 May 26.
Abstract/Text There seems to be irrefutable evidence that oestrogen is involved in the pathogenesis of breast cancer. The disease mostly affects women and the epidemiology of breast cancer relates to reproductive markers such as pregnancy, age at menarche and age of menopause. Most breast cancers elaborate oestrogen receptors (ER) and in such cases endocrine therapies such as tamoxifen and aromatase-inhibitors (AIs) are effective adjuvant treatments. However, high-quality randomised controlled trials (RCTs) (such as the WHI study) have shown that oestrogen-only hormone therapy (ET) does not increase breast cancer risk at all. This would seem to be a remarkable paradox. There appears to be at least two reasons for this apparent contradiction. First, it has been known for two decades that the breast itself produces oestrogens locally and the microenvironment around a breast cancer is more important that the impact of systemic-oestrogens. Second, breast cancer stem cells (breast CSC) have been identified and it seems likely that these long-lived, multipotential cells are responsible for the genesis of many breast cancers, as well as their malignant behaviour. Breast CSC usually do not contain sex-hormone receptors, but their offspring often elaborate ER and progesterone receptor (PR). Thus, it appears unlikely that oestrogen per se initiates breast cancer, but rather might stimulate an existing tumour.

PMID 20500114  Gynecol Endocrinol. 2011 Mar;27(3):170-5. doi: 10.3109/・・・
著者: J Geisler, I H Omsjø, S I Helle, D Ekse, T Silsand, P E Lønning
雑誌名: J Endocrinol. 1999 Aug;162(2):265-70.
Abstract/Text The aim of this study was to determine the impact of the administration route and cigarette smoking on plasma oestrogen levels during oral and parenteral oestrogen replacement therapy (ERT). Fourteen healthy postmenopausal women (six smokers and eight non-smokers) were recruited for a prospective, randomised, crossover study at a private outpatient medical centre in Oslo, Norway. All patients were randomised to receive cyclic therapy with oestradiol and norethisterone orally or by the transdermal route each for a 6-month period. Plasma levels of oestrone (Oe(1)), oestradiol (Oe(2)) and oestrone sulphate (Oe(1)S) were determined using highly sensitive RIA methods before and during hormone replacement therapy given by the oral and transdermal route. Comparing smokers and non-smokers, plasma levels of Oe(1), Oe(2) and Oe(1)S were all found to be 40-70% lower in smokers compared with non-smokers when ERT was given orally (Oe(1)S, P<0.05; Oe(1) and Oe(2), P<0.01 for both). Oe(2) given orally caused a higher Oe(1)S/Oe(2) ratio but also a higher Oe(1)/Oe(2) ratio compared with parenteral therapy in smokers (40.2 versus 7(.)0, P<0.01; and 3.2 versus 0.8, P<0.05 respectively). No significant differences in these parameters in the different test-situations were seen in non-smokers. Except for a lower level of Oe(1)S in smokers (non-significant), no difference in plasma oestrogen levels between smokers and non-smokers was observed during parenteral therapy. In conclusion, cigarette smoking has been shown to have major impact on plasma oestrogen levels during oral but not during parenteral Oe(2) replacement.

PMID 10425465  J Endocrinol. 1999 Aug;162(2):265-70.
著者: Gerardo Heiss, Robert Wallace, Garnet L Anderson, Aaron Aragaki, Shirley A A Beresford, Robert Brzyski, Rowan T Chlebowski, Margery Gass, Andrea LaCroix, JoAnn E Manson, Ross L Prentice, Jacques Rossouw, Marcia L Stefanick, WHI Investigators
雑誌名: JAMA. 2008 Mar 5;299(9):1036-45. doi: 10.1001/jama.299.9.1036.
Abstract/Text CONTEXT: The Women's Health Initiative (WHI) trial of estrogen plus progestin vs placebo was stopped early, after a mean 5.6 years of follow-up, because the overall health risks of hormone therapy exceeded its benefits.
OBJECTIVE: To report health outcomes at 3 years (mean 2.4 years of follow-up) after the intervention was stopped.
DESIGN, SETTING, AND PARTICIPANTS: The intervention phase was a double-blind, placebo-controlled, randomized trial of conjugated equine estrogens (CEE) 0.625 mg daily plus medroxyprogesterone acetate (MPA) 2.5 mg daily, in 16,608 women aged 50 through 79 years, recruited by 40 centers from 1993 to 1998. The postintervention phase commenced July 8, 2002, and included 15 730 women.
MAIN OUTCOME MEASURES: Semi-annual monitoring and outcomes ascertainment continued per trial protocol. The primary end points were coronary heart disease and invasive breast cancer. A global index summarizing the balance of risks and benefits included the 2 primary end points plus stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.
RESULTS: The risk of cardiovascular events after the intervention was comparable by initial randomized assignments, 1.97% (annualized rate) in the CEE plus MPA (343 events) and 1.91% in the placebo group (323 events). A greater risk of malignancies occurred in the CEE plus MPA than in the placebo group (1.56% [n = 281] vs 1.26% [n = 218]; hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.04-1.48). More breast cancers were diagnosed in women who had been randomly assigned to receive CEE plus MPA vs placebo (0.42% [n = 79] vs 0.33% [n = 60]; HR, 1.27; 95% CI, 0.91-1.78) with a modest trend toward a lower HR during the follow-up after the intervention. All-cause mortality was somewhat higher in the CEE plus MPA than in the placebo group (1.20% [n = 233] vs 1.06% [n = 196]; HR, 1.15; 95% CI, 0.95-1.39). The global index of risks and benefits was unchanged from randomization through March 31, 2005 (HR, 1.12; 95% CI, 1.03-1.21), indicating that the risks of CEE plus MPA exceed the benefits for chronic disease prevention.
CONCLUSIONS: The increased cardiovascular risks in the women assigned to CEE plus MPA during the intervention period were not observed after the intervention. A greater risk of fatal and nonfatal malignancies occurred after the intervention in the CEE plus MPA group and the global risk index was 12% higher in women randomly assigned to receive CEE plus MPA compared with placebo.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.

PMID 18319414  JAMA. 2008 Mar 5;299(9):1036-45. doi: 10.1001/jama.299.・・・
著者: T J de Villiers, A Pines, N Panay, M Gambacciani, D F Archer, R J Baber, S R Davis, A A Gompel, V W Henderson, R Langer, R A Lobo, G Plu-Bureau, D W Sturdee, International Menopause Society
雑誌名: Climacteric. 2013 Jun;16(3):316-37. doi: 10.3109/13697137.2013.795683.
Abstract/Text
PMID 23672656  Climacteric. 2013 Jun;16(3):316-37. doi: 10.3109/136971・・・
著者: Celeste Leigh Pearce, Karine Chung, Malcolm C Pike, Anna H Wu
雑誌名: Cancer. 2009 Feb 1;115(3):531-9. doi: 10.1002/cncr.23956.
Abstract/Text BACKGROUND: It has become increasingly clear that use of menopausal hormone therapy (HT) is associated with an increased risk of ovarian cancer; however, the effects by type of formulation and duration of use are less clear. A systematic review of the HT and ovarian cancer literature was conducted to identify population-based case-control studies, cohort studies, and randomized trials that examined effects by formulation of HT (estrogen-alone [ET] and estrogen plus progestin [EPT]) and duration of use.
METHODS: Pub-Med (www.pubmed.gov) was used to identify relevant publications through December 2007; 14 studies were identified. The authors abstracted relative risks (RRs) and 95% confidence intervals (CIs) in relation to duration of HT use (ET and EPT separately). The authors used the risk estimates per year of HT use if these were provided; otherwise, they calculated a duration-response for a log-linear model of the duration of HT use against risk.
RESULTS: Ovarian cancer risk was increased among ET users (RR per 5 years of use, RR(5) = 1.22; 95% CI, 1.18-1.27; P < .0001), and a lower but still statistically significant increased risk was seen with EPT use (RR(5) = 1.10; 95% CI, 1.04-1.16; P = .001). The increased risk in ET users was statistically significantly higher than the increased risk in EPT users (P = .004).
CONCLUSIONS: ET use increases risk of ovarian cancer in a duration-dependent manner, and it appears that the addition of progestins blocks this effect, at least to some extent. Whether the effect of estrogens would be completely blocked if progestins were given every day is unclear.

(c) 2008 American Cancer Society.
PMID 19127543  Cancer. 2009 Feb 1;115(3):531-9. doi: 10.1002/cncr.2395・・・
著者: Lina Steinrud Mørch, Ellen Løkkegaard, Anne Helms Andreasen, Susanne Krüger-Kjaer, Ojvind Lidegaard
雑誌名: JAMA. 2009 Jul 15;302(3):298-305. doi: 10.1001/jama.2009.1052.
Abstract/Text CONTEXT: Studies have suggested an increased risk of ovarian cancer among women taking postmenopausal hormone therapy. Data are sparse on the differential effects of formulations, regimens, and routes of administration.
OBJECTIVE: To assess risk of ovarian cancer in perimenopausal and postmenopausal women receiving different hormone therapies.
DESIGN AND SETTING: Nationwide prospective cohort study including all Danish women aged 50 through 79 years from 1995 through 2005 through individual linkage to Danish national registers. Redeemed prescription data from the National Register of Medicinal Product Statistics provided individually updated exposure information. The National Cancer Register and Pathology Register provided ovarian cancer incidence data. Information on confounding factors and effect modifiers was from other national registers. Poisson regression analyses with 5-year age bands included hormone exposures as time-dependent covariates.
PARTICIPANTS: A total of 909,946 women without hormone-sensitive cancer or bilateral oophorectomy.
MAIN OUTCOME MEASURE: Ovarian cancer.
RESULTS: In an average of 8.0 years of follow-up (7.3 million women-years), 3068 incident ovarian cancers, of which 2681 were epithelial cancers, were detected. Compared with women who never took hormone therapy, current users of hormones had incidence rate ratios for all ovarian cancers of 1.38 (95% confidence interval [CI], 1.26-1.51) and 1.44 (95% CI, 1.30-1.58) for epithelial ovarian cancer. The risk declined with years since last use: 0 to 2 years, 1.22 (95% CI, 1.02-1.46); more than 2 to 4 years, 0.98 (95% CI, 0.75-1.28); more than 4 to 6 years, 0.72 (95% CI, 0.50-1.05), and more than 6 years, 0.63 (95% CI, 0.41-0.96). For current users the risk of ovarian cancer did not differ significantly with different hormone therapies or duration of use. The incidence rates in current and never users of hormones were 0.52 and 0.40 per 1000 years, respectively, ie, an absolute risk increase of 0.12 (95% CI, 0.01-0.17) per 1000 years. This approximates 1 extra ovarian cancer for roughly 8300 women taking hormone therapy each year.
CONCLUSION: Regardless of the duration of use, the formulation, estrogen dose, regimen, progestin type, and route of administration, hormone therapy was associated with an increased risk of ovarian cancer.

PMID 19602689  JAMA. 2009 Jul 15;302(3):298-305. doi: 10.1001/jama.200・・・
著者: Alice W Lee, Roberta B Ness, Lynda D Roman, Kathryn L Terry, Joellen M Schildkraut, Jenny Chang-Claude, Jennifer A Doherty, Usha Menon, Daniel W Cramer, Simon A Gayther, Harvey Risch, Aleksandra Gentry-Maharaj, Marc T Goodman, Francesmary Modugno, Ursula Eilber, Kirsten B Moysich, Andrew Berchuck, Mary Anne Rossing, Allan Jensen, Kristine G Wicklund, Kara L Cushing-Haugen, Estrid Hogdall, Anja Rudolph, Pamela J Thompson, Lynne R Wilkens, Susanne K Kjaer, Michael E Carney, Daniel O Stram, Susan J Ramus, Anna H Wu, Malcolm C Pike, Celeste Leigh Pearce, Ovarian Cancer Association Consortium
雑誌名: Obstet Gynecol. 2016 May;127(5):828-36. doi: 10.1097/AOG.0000000000001387.
Abstract/Text OBJECTIVE: To describe the association between postmenopausal estrogen-only therapy use and risk of ovarian carcinoma, specifically with regard to disease histotype and duration and timing of use.
METHODS: We conducted a pooled analysis of 906 women with ovarian carcinoma and 1,220 women in a control group; all 2,126 women included reported having had a hysterectomy. Ten population-based case-control studies participating in the Ovarian Cancer Association Consortium, an international consortium whose goal is to combine data from many studies with similar methods so reliable assessments of risk factors can be determined, were included. Self-reported questionnaire data from each study were harmonized and conditional logistic regression was used to examine estrogen-only therapy's histotype-specific and duration and recency of use associations.
RESULTS: Forty-three and a half percent of the women in the control group reported previous use of estrogen-only therapy. Compared with them, current or recent estrogen-only therapy use was associated with an increased risk for the serous (51.4%, odds ratio [OR] 1.63, 95% confidence interval [CI] 1.27-2.09) and endometrioid (48.6%, OR 2.00, 95% CI 1.17-3.41) histotypes. In addition, statistically significant trends in risk according to duration of use were seen among current or recent postmenopausal estrogen-only therapy users for both ovarian carcinoma histotypes (Ptrend<.001 for serous and endometrioid). Compared with women in the control group, current or recent users for 10 years or more had increased risks of serous ovarian carcinoma (36.8%, OR 1.73, 95% CI 1.26-2.38) and endometrioid ovarian carcinoma (34.9%, OR 4.03, 95% CI 1.91-8.49).
CONCLUSION: We found evidence of an increased risk of serous and endometrioid ovarian carcinoma associated with postmenopausal estrogen-only therapy use, particularly of long duration. These findings emphasize that risk may be associated with extended estrogen-only therapy use.

PMID 27054934  Obstet Gynecol. 2016 May;127(5):828-36. doi: 10.1097/AO・・・
著者: R J Baber, N Panay, A Fenton, IMS Writing Group
雑誌名: Climacteric. 2016 Apr;19(2):109-50. doi: 10.3109/13697137.2015.1129166. Epub 2016 Feb 12.
Abstract/Text The International Menopause Society (IMS) has produced these new 2016 recommendations on women's midlife health and menopause hormone therapy (MHT) to help guide health-care professionals in optimizing their management of women in the menopause transition and beyond. The term MHT has been used to cover therapies including estrogens, progestogens and combined regimens. For the first time, the 2016 IMS recommendations now include grades of recommendations, levels of evidence and 'good practice points', in addition to section-specific references. Where possible, the recommendations are based on and linked to the evidence that supports them, unless good-quality evidence is absent. Particular attention has been paid to published evidence from 2013 onwards, the last time the IMS recommendations were updated. Databases have been extensively searched for relevant publications using key terms specific to each specialist area within menopause physiology and medicine. Information has also been drawn from international consensus statements published by bodies such as the IMS, the European Menopause and Andropause Society and the North American Menopause Society. The recommendations have been produced by experts derived mainly from the IMS, with the assistance of key collaborators where deemed advantageous. In preparing these international recommendations, experts have taken into account geographical variations in medical care, prevalence of diseases, and country-specific attitudes of the public, medical community and health authorities towards menopause management. The variation in availability and licensing of MHT and other products has also been considered.

PMID 26872610  Climacteric. 2016 Apr;19(2):109-50. doi: 10.3109/136971・・・
著者: Cynthia A Stuenkel, Susan R Davis, Anne Gompel, Mary Ann Lumsden, M Hassan Murad, JoAnn V Pinkerton, Richard J Santen
雑誌名: J Clin Endocrinol Metab. 2015 Nov;100(11):3975-4011. doi: 10.1210/jc.2015-2236. Epub 2015 Oct 7.
Abstract/Text OBJECTIVE: The objective of this document is to generate a practice guideline for the management and treatment of symptoms of the menopause.
PARTICIPANTS: The Treatment of Symptoms of the Menopause Task Force included six experts, a methodologist, and a medical writer, all appointed by The Endocrine Society.
EVIDENCE: The Task Force developed this evidenced-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned three systematic reviews of published data and considered several other existing meta-analyses and trials.
CONSENSUS PROCESS: Multiple e-mail communications, conference calls, and one face-to-face meeting determined consensus. Committees of The Endocrine Society, representatives from endorsing societies, and members of The Endocrine Society reviewed and commented on the drafts of the guidelines. The Australasian Menopause Society, the British Menopause Society, European Menopause and Andropause Society, the European Society of Endocrinology, and the International Menopause Society (co-sponsors of the guideline) reviewed and commented on the draft.
CONCLUSIONS: Menopausal hormone therapy (MHT) is the most effective treatment for vasomotor symptoms and other symptoms of the climacteric. Benefits may exceed risks for the majority of symptomatic postmenopausal women who are under age 60 or under 10 years since the onset of menopause. Health care professionals should individualize therapy based on clinical factors and patient preference. They should screen women before initiating MHT for cardiovascular and breast cancer risk and recommend the most appropriate therapy depending on risk/benefit considerations. Current evidence does not justify the use of MHT to prevent coronary heart disease, breast cancer, or dementia. Other options are available for those with vasomotor symptoms who prefer not to use MHT or who have contraindications because these patients should not use MHT. Low-dose vaginal estrogen and ospemifene provide effective therapy for the genitourinary syndrome of menopause, and vaginal moisturizers and lubricants are available for those not choosing hormonal therapy. All postmenopausal women should embrace appropriate lifestyle measures.

PMID 26444994  J Clin Endocrinol Metab. 2015 Nov;100(11):3975-4011. do・・・

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