臺中榮民總醫院婦產部生殖醫學科陳明哲醫師

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(1)Review and Update on Hormone Therapy. 臺中榮民總醫院婦產部生殖醫學科陳明哲醫師.

(2) Menopause Terminology. FS 2001;76:874.

(3) Age of perimenopause. Maturita 1992;14:103. Mean. Median. Onset of perimenopause (y). 45.5. 47.5. Duration (y). 6.3. 3.8. Postmenopausal age (y). 51.8. 51.3.

(4) Factors that accelerate ovarian aging  Smoking  Chemotherapy  Radiation  Inborn. error of metabolism  Subtle genetic abnormalities  Autoimmune disorders  Pelvic surgery  COH? ART?.

(5) Is this women perimenopausal?. JAMA 2003;289:895. Definition of perimenopause (45 ~ 55 y/o) - amenorrhea for 3 to 11 months or irregular periods - ill-defined and poorly studied Age  Self-assessment of going through transition  Symptoms of hot flashes, night sweats, vaginal dryness  High FSH  Low inhibin B level Conclusion: no one symptoms or test is accurate enough by itself; diagnose perimenopause based upon menstrual history and age .

(6) Perimenopause: clinical manifestation  Irregular. uterine bleeding  Vasomotor symptoms  Sleep disturbances  Mood disorders  Genitourinary effects  Thyroid dysfunction  Changes in sexual function NAMS consensus opinion Menopause 2000;7:5.

(7) Uterine (endometrial) bleeding  Evaluate. - Pregnancy - Pelvic pathology myoma, adenomyosis, endometriosis, endometrial polyp, PCOD, CA, IUD - Thyroid disorder hypothyroid - Bleeding disorder thrombocytopathies, Von Willebrand’s disease, SLE, Chronic liver disease  Treatment options - Cyclical progestin therapy - NSAIDs at onset of menses - Low-dose oral contraceptives.

(8) Menopause health issues Vasomotor symptoms - up to 85% of women entering menopause - more than half of women report moderate to severe symptoms - hot flushes may continue years after menopause  Vulvar and vaginal atrophy - genitourinary atrophy is the most consistent and inevitable consequence of estrogen deficiency - atrophy and thinning of vagina mucosa can lead to vaginitis, dyspareunia, vaginismus and loss of sexual interest - left untreated, vaginal atrophy progressively worsen .

(9) Menopause health issues Postmenopausal bone loss - up to 20% of a women’s expected lifetime bone loss can occur in the years immediately following menopause - currently, about 30 million US women have osteoporosis or low bone mass  ET/EPT is an option for osteoporosis prevention - the only therapy that alleviates menopausal symptoms and concomitantly prevents osteoporosis - patients initiate therapy for menopausal symptom relief will also receive protection against early menopausal bone loss - patients initiate therapy for osteoporosis prevention should only be considered for women at significant risk and after non-estrogen therapies have been carefully considered .

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(12) 婦女有更年期症狀的平均年數 1- 5年 56% 5年以上 26%. 沒有症狀或有症狀但不超過一年 18%. 參考資料：Mckinlay and Jetterys Br J. Med 1974:28:108-115.

(13) 骨質疏鬆症危險因子  東方人  瘦削的人  不太運動的人  過度運動的人  未曾生育的人  長期使用類固醇者  腎功能不良者  服抗癲癇藥者.  家族史〈老年骨折或. 彎腰駝背〉  過早停經  抽煙、喝酒、嗜咖啡、飲食缺乏鈣質者  新陳代謝疾病〈泌乳素、副甲狀腺、甲狀腺機能亢進〉.

(14) 荷爾蒙療法藥物使用方法  雌激素：周期型或持續型療法  黃體素：順序型或合併型療法  是否仍有子宮？  五十歲以上之更年期婦女建議使用持續型之合併型療法，以最小有效劑量適期補充。.

(15) 「荷爾蒙療法」的意義、目的治療性－迅速減輕甚至完全緩解更年期症狀如、改善生活品質：熱潮紅、盜汗、失眠、心悸陰道乾澀、泌尿道萎縮、性交疼痛預防性－預防骨質疏鬆症、心臟血管疾病? 、老年失智症?、泌尿生殖器脫出附帶好處：延年益壽?.

(16) 荷爾蒙療法能預防骨質的流失，愈早補充效果愈好.

(17) 停經後婦女髖部骨折的發生率.

(18) 骨質疏鬆症如何治療？  荷爾蒙治療：雌激素、雄激素、黃體素、. 生長激素、降鈣激素  非荷爾蒙藥物治療：雙磷化合物〈福善美〉、氟化物(?)  生物物理刺激：負重、運動、電刺激  營養支持：鈣質(?)、維生素D  陽光.

(19) 荷爾蒙療法對骨質疏鬆症有幫助嗎？內科學年鑑1995年  9704名婦女，65歲以上  橈尺骨骨折相對危險性：0.39-0.29  股骨頸骨折相對危險性：0.60-0.29  對75歲以上婦女股骨頸骨折最具保護效果  停經五年內開始使用並持續使用者骨折相對危險性最低  黃體素並不會抵銷骨質保護之效果.

(20) 要多少藥荷爾蒙藥量才夠保護骨質？最小有效劑量：  共軛女性素〈普力馬林〉每日0.625毫克 ??  雌二醇霜劑每日1.5毫克  雌二醇錠劑每日2.0毫克〈益斯得〉  乙缺雌二醇每日20微克.

(21) 子宮出血 荷爾蒙療法，只要子宮還在，就有出. 血的可能。 持續性療法者，在使用初期可能會有 3-6個月點狀或不規則出血，但會隨使用時間延長而獲得改善。 週期性療法者，可產生類似月經的規則性出血。.

(22) 雌激素併服黃體素之荷爾蒙療法與子宮內膜癌之關係雌激素若與黃體素合併使用，不會增加子宮內膜癌發生率. 發生率 / 1000病患未服用. 只服用雌激素. 雌激素併服黃體素. Nachtigall et al, 1979. 1.2. --. 0. Hammond et al, 1979. 0.5. 6.5. 0. Gambrell, 1987. 2.5. 3.9. 0.5. Persson et al., 1989. 1.4. 1.8. 0.9.

(23) 荷爾蒙療法與子宮內膜  單獨使用雌激素補充治療，只適用於已切. 除子宮之患者。  合併使用黃體素，目的即在保護子宮內膜。  子宮內膜增生機率：使用Provera 10毫克零天 - 30% 七天 - 4% 十天 - 2% 十二天 - 0%.

(24) 荷爾蒙療法真的具有延年益壽之效果嗎？〈除改善生活品質外〉荷爾蒙補充治療對疾病死亡率之影響  急性心肌梗塞之相對危險性：0.60  其它心臟疾病之相對危險性：0.68  阻塞性中風之相對危險性：0.63  所有癌症之相對危險性：0.82  WHI study 死亡之相對危險性:0.98!.

(25) 荷爾蒙療法對心臟血管疾病有多大的幫助？新英格蘭雜誌 1996年  59337名婦女追蹤16年  荷爾蒙補充治療對發生嚴重冠狀動脈心臟病之相對危險性：0.39〈混合女性素及黃體素〉至0.60〈單獨使用女性素〉  荷爾蒙補充治療對發生中風之相對危險性：1.09〈混合女性素及黃體素〉至1.27 〈單獨使用女性素〉.

(26) 荷爾蒙療法對心臟血管疾病有多大的幫助？  8882名加州退休婦女〈平均年齡73歲〉追. 蹤六年 - 因腦中風死亡之相對危險性： 0.53  Henderson 1991：0.3  Falkeborn 1993：0.61-0.72  Boysen 1988：0.8.

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(28) 爭議引爆點：婦女健康關懷研究美國內科醫學會雜誌 JAMA 2002年7月  16608名停經婦女  使用合併連續型荷爾蒙補充  5.2年後之相對風險每萬人增加風險心臟病：1.29 + 7 人 (30->37) 中風：1.41 + 8 人 (21->29) 乳癌：1.26 + 8 人 (30->38) 血栓：2.11 + 18 人(16->34).

(29) 爭議引爆點：婦女健康關懷研究  5.2年後之相對風險. 每萬人增加風險直腸癌：0.63 - 6 人 (16->10) 髖部骨折：1.41 - 5 人 (15->10) 更年期症狀之舒緩：未列入評估  研究對象：高抽煙比率 50.4% - 50% . Financial Disclosures:.

(30) 乳癌的危險因子資料來源:New England Journal of Medicine , 2001 , 344: 276-285 ¦] ¤l §C ¦M ÀI ş °ª ¦M IÀ ş ¬Û ¹ï ¦M ÀI ©Ê Ê © §O. k̈ © Ê. ¤k © Ê. 150.0. ªì ģ ¦~ Ä Ö (·³ ). >14. <12. 1.5. ²Ä ¤@ ¦¸ ¥ Í ²£ ¦~ Ä Ö (·³ ). <20. >30. 1.9-3.5. ý ¥ Á À¥ ¤ (¤ë ). >16. 0. 1.37. ¦Û µ M °± ģ ¦~ Ä Ö (·³ ). <45. >55. 2.0. »Û ¿E À̄ Ȩ́ R ¥ À ø ªk. ¤£ ´¿ ± µ ü̈. Ø« ¥ e Ï̈ ¥ Î ¤. 1.2-1.4. °± ģ « á Å é « ¬ ªÎ D « ü ¼ Æ. <22.9. >30.7. 1.6. Å̈ À ù ® a ± Ú¥ v. S̈ ¦³. ¦³. 2.6.

(31) 女性癌症年齡別發生率.

(32) 荷爾蒙療法與乳房新英格蘭雜誌 1995年  使用雌激素者，發生乳癌之相對危險性為 1.32  使用雌激素暨黃體素者，發生乳癌之相對危險性為1.41  前曾使用或正在使用荷爾蒙，若其補充治療在5年以內者，發生乳癌之相對危險性與未使用荷爾蒙者相當。  有家族史之荷爾蒙治療者，乳癌發生機率之相對危險性與無家族史者相當。.

(33) 荷爾蒙療法與乳房  歐美停經後婦女，50-70歲  未用荷爾蒙者，乳癌之累積發生率. 45/1000  使用荷爾蒙5年者，乳癌之累積發生率 47/1000  使用荷爾蒙10年者，乳癌之累積發生率 51/1000  使用荷爾蒙15年者，乳癌之累積發生率 57/1000.

(34) 荷爾蒙療法與乳房內科醫學檔案雜誌 1991年  使用共軛雌激素0.625毫克，發生乳癌之相對危險性為1.08〈0.96-1.2〉  使用共軛雌激素1.25毫克，發生乳癌之相對危險性為2.0以下  對過去有良性乳房疾病者，發生乳癌之相對危險性為1.16〈0.89-1.5〉.

(35) 荷爾蒙療法與乳癌的臨床報告  荷爾蒙療法對乳癌確診後之復發率及死亡率的影響. 乳癌復發率 (1000 person-years). 乳癌死亡率 (1000 person-years). 總死亡率 (1000 person-years). 接受 HRT. 未接受 HRT. 17. 30. 5. 15. 16. 30. 相對危險性 (RR) 0.5. ( 降低 50% 危險性 ). 0.34. ( 降低 66% 危險性 ). 0.48. ( 降低 52% 危險性 ). 資料來源：Journal of the National Cancer Institute, Vol. 93, No. 10, 754-761, May 16, 2001.

(36) 荷爾蒙療法與乳癌的共識  EPT短期使用沒有乳癌增加的危險. (少於五. 年).  EPT使用五年以上，乳癌會小幅增加(0.1%) (by WHI).  Estrogen 為一 Promoter，但不是乳癌的 Initiator.  使用EPT的乳癌婦女，預後較好..

(37) 荷爾蒙療法之適應症  中度至重度之更年期症狀  骨質疏鬆症.  減低冠心病之危險性及死亡率?  萎縮性陰道炎  萎縮性尿道炎  女性生殖腺官能不足〈早發性停經〉.

(38) 荷爾蒙療法之副作用  突破性出血或停藥性出血  乳房漲痛或觸痛.  陰道分泌物增加與刺  腹部漲氣感  暫時性之腸胃不適  經前症狀  頭痛〈不常〉  水腫〈不常〉  體重增加〈輕微〉. 激不適感.

(39) 荷爾蒙療法之禁忌症絕對禁忌 子宮內膜癌 乳癌 急性肝炎 急性血管栓塞 未診明病因之陰道出血.

(40) 荷爾蒙療法如何開始？  最後一次月經何時來？  出現何種停經症狀？  現有之其它疾病史，乳癌家族史  乳房觸診，骨盆腔內診  子宮頸抹片檢查  婦科超音波，子宮內膜評估  血液檢查  骨質密度檢查  乳房X光造影術.

(41) 更年期治療藥品成份： 雌激素. –Conjugated Estrogen (Premarin) –Estradiol. 黃體素. –MedoxyProgesterone Acetate(MPA) –Norethisterone Acetate (NETA) –Cyproterone Acetate.

(42) 常見的更年期治療藥品-持續治療劑型商品名. 藥廠. Premelle 2.5. 惠氏. Premarin 0.625mg. MPA. 2.5mg. Premelle 5. 惠氏. Premarin 0.625mg. MPA. 5mg. 諾和諾德. Estradiol 2mg. NETA. 1mg. 健喬. Estradiol 2mg. NETA. 1mg. 諾和諾德. Estradiol 1mg. NETA. 0.5mg. 健喬. Estradiol 1mg. NETA. 0.5mg. Kliogest Covina Activelle Halvina. 雌激素. 黃體素.

(43) 常見的更年期治療藥品-週期治療劑型商品名. 藥廠. Premelle Cycle. 惠氏. Divina. ORION. Trisequens. 諾和諾德. Sevina. 健喬. Climen. 先靈. 雌激素/黃體素 Premarin 0.625mg 14’s Premarin 0.625mg + MPA 5mg 14’s Estradiol 2mg 11’s Estradiol 2mg + MPA 10mg 20’s Estradiol 2mg 12’s Estradiol 2mg + NETA 1mg 10’s Estrodiol 2mg 6’s Estradiol 2mg 12’s Estradiol 2mg + NETA 1mg 10’s Estrodiol 2mg 6’s Estradiol 2mg 11’s Estradiol 2mg + Cyproterone 1mg 10’s.

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(45) Patient Management Considerations  Appropriate. use of ET/HT  Patient barriers to ET/HT  Importance of individualizing therapy Characteristics of estrogens Characterisitics of progestins Effects of progestin Use of low-dose therapy  Other therapeutic options  Patient counseling strategies.

(46) Reasons Women Gave for Initiating or Continuing HT. Newton KM et al. J Women’s Health. 1997;6:459-65.

(47) Indications for ET/HT  The. treatment of moderate-to-severe vasomotor symptoms associated with menopause  The treatment of vulvar and vaginal atrophy  The prevention of postmenopausal osteoporosis.

(48) Consensus on Terminology  Recommended. terminologies: ET for estrogen only EPT for estrogen and progestogen HT for hormone therapy CS-EPT for continuous-sequential EPT CC-EPT for continuous combined EPT NAMS, IMS.

(49) Recent Studies Cause Controversies on HRT HERS WHI Million Women Study.

(50) WHI and HERS Randomized,. blinded placebo. controlled Postmenopausal women (n) Ages (mean,yr) Drugs* Coronary. heart disease (CHD) Duration of trial (yr). WHI Y. HERS Y. 16,508 2,763 63.2( 67(5550-79) 79) CEE+ CEE+PT PT N Y 5.2 4.1. *CEE+PT: oral, 0.625mg/d CEE + 2.5mg/d MPA.

(51) Effects on the Risk of CHD ?  WHI. (EPT).  HERS. Significant increased risk RR 1.29 (CI 1.02-1.63) AR 0.37% vs 0.30% Nonsignificant decreased risk RR 0.99 (CI 0.84-1.17) AR 3.66% vs 3.68%.

(52) Effects on the Risk of Stroke ?  WHI. Significant increased risk RR 1.41 (CI 1.07-1.85) AR 0.29% vs 0.21%.  HERS. Nonsignificant increased risk RR 1.09 (CI 0.88-1.35) AR 2.12% vs 1.95%.

(53) Effects on the Risk of Venous Thromboembolism !  WHI. Significant increased risk RR 2.11 (CI 1.58-2.82) AR 0.34% vs 0.16%.  HERS. Significant increased risk RR 2.08 (CI 1.28-3.40) AR 0.59% vs 0.28%.

(54) Effects on the Risk of Breast Cancer !  WHI. Nonsignificant increased risk RR 1.26 (CI 1.00-1.59) AR 0.38% vs 0.30%.  HERS. Nonsignificant increased risk RR 1.27 (CI 0.84-1.94) AR 0.59% vs 0.47%.

(55) Effects on the Risk of Colorectal Cancer ?  WHI. Significant decreased risk RR 0.63 (CI 0.43-0.92) AR 0.10% vs 0.16%.  HERS. Nonsignificant decreased risk RR 0.81 (CI 0.46-1.45) AR 0.25% vs 0.31%.

(56) Effects on the Risk of Osteoporotic Fracture ?  WHI. Significant decreased risk RR 0.76 (CI 0.69-0.85) AR 1.47% vs 1.91%.  HERS. Nonsignificant increased risk RR 1.04 (CI 0.87-1.25) AR 2.97% vs 2.84%.

(57) WHI Results: Overall Relative and Attributable Risk Women 50 to 79 Years of Age at Baseline. Event. Overall HR. 95% CI Attributable Risk per Benefit per 10000 women/Y 10000 women/Y. CHD Breast CA Stroke VTE PE Colorectal CA Hip fracture Total fracture. 1.24 1.24 1.31 2.11 2.13 0.63 0.66 0.76. Nominal 1.00-1.54 1.01-1.54 1.02-1.68 1.58-2.82 1.19-3.25 0.43-0.92 0.45-0.98 0.69-0.85. Adjusted 0.97-1.60 0.97-1.59 0.93-1.04 1.26-3.55 0.99-1.56 0.32-1.24 0.33-1.33 0.63-0.92. 6 8 7 18 8 6 5 44. JAMA 2002;288:321-333; NEJM 2003;349:523-34; JAMA 2003;289:2673-84; JAMA 2003;289:3243-53.

(58) WHI Results: Effect of CEE/MPA on CHD Risk by Age & Years Since Menopause.

(59) Cumulative Hazard for Invasive breast Cancer. WHI Results: Effect of HT on Risk of Invasive Breast Cancer. 0.02. Time (years).

(60) WHI Results: Effect of CEE/MPA on Risk of Colorectal Cancer. JAMA 2002;288:321-333.

(61) WHI Results: Cancer Outcomes. JAMA 2002;288:321-333.

(62) WHI HT Summary  Results. from WHI indicate that CEE 0.625mg/d plus MPA 2.5mg/d should not be initiated or continued for the primary prevention of CHD.  Risks. for cardiovascular disease (CVD) and breast cancer must be weighed against the benefit for fracture and colon cancer.

(63) WHI Study Clinical implications Estrogen with or without progestin:  Are the only FDA approved treatments for the relief of moderate to severe postmenopausal symptoms (i.e. hot flushes, night sweatings or vaginal dryness) and the concomitant prevention of postmenopausal osteoporosis  Should be prescribed at the lowest effective dose and for the shortest duration consistent with treatment goals and risk for the individual women.

(64) Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women.

(65) JAMA 2003; 289:2651.

(66)  Average. duration of follow-up = 6.8 years  Regimens: Conjugated estrogens (CE) 0.625mg (n=5310) or placebo (n=5429)  Primary efficacy outcome: coronary heart disease (nonfatal myocardial infarction or CHD death)  Primary safety outcome*: invasive breast cancer. JAMA 2004;291:1701-1712.

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(69) WHI ET Results Incidence of Events per 10,000 women/year CE Placebo Health event Absolute risk Absolute risk __________________________________________________ CHD 49 54 Stroke* 44 32 Breast CA 26 33 VTE 28 21 Colorectal CA 17 16 Hip fracture* 11 17 ___________________________________________________ • P < 0.05 • JAMA 2004; 291:1701.

(70) The ET arm of WHI  Terminated. early due to that all possible results of the trial have already been obtained  Risk of stroke was increased, 12 additional cases per 10,000 women per year (39% higher)  CHD was neither increased nor decreased  Breast cancer was decreased, 7 fewer cases per 10,000 women year (23% lower)  Osteoporotic fracture was decreased, 56 fewer cases per 10,000 women year, including 6 fewer cases of hip fracture and 6 fewer cases of vertebral fracture (30-39% lower) JAMA 2004;291:1701-1712.

(71) WHI ET study : Conclusions In the WHI ET study, CE was associated with :  No. effect on CHD at all  An increased risk of stroke  A decreased risk of hip fracture  Fewer breast cancers but the differences were not statistically significant  No effect on total mortality.

(72) WHI Recommendation on HT/ET  Risks. overweigh benefits. (?)  Do not use HT for prevention of CHD.  EPT may increase the risk of breast cancer.  EPT may increase the risk of thromboembolism.  EPT may decrease colorectal cancer.  EPT and ET both decrease osteoporotic fractures.  ET may increase the risk of stroke.  ET dose not increase the risk of CHD.  ET may decrease the risk of breast cancer..

(73) ACOG Advisory Women who have been taking HT for a number of years should not panic, but discuss their individual situation with their physician.  With respect to women’s short-term use of HT for relief of menopause symptoms, it may be reasonable for women to continue use for this purpose, since the benefits are likely to outweigh the risks.  Regarding a women’s short-term use of HT for relief of menopausal symptoms, ACOG continues to recommend that this be a personal individualized decision made after consultations between a woman and her physician-taking into account a woman’s individual benefits and risks from such use  press release 07-09-02 .

(74) Million Women Study  1,084,110. UK women  Aged 50-64 years  Recruited between 1996 and 2001  Information about the use of HRT  Followed up for invasive breast cancer incidence (at 2.6years) and death (at 4.1 years) The Lancet 2003;362:419-427.

(75) Million Women Study  550,172. (50%) had used HRT  9,364 incident invasive breast cancer  637 breast cancer deaths  Current users vs Never users Incident 1.66 (95% CI 1.58-1.75) Fatal 1.22 (1.00-1.48)  Past users: Incident 1.01(0.94-1.09) Fatal 1.05(0.82-1.34).

(76) Million Women Study.



(79) Million Women Study: Result  Increase. in the risk of breast cancer become apparent within 1-2 years of treatment, irrespective of the type of HRT.  The risk begins to decline when HRT is stopped and by 5 years reaches the same level as never users..

(80) Committee on Safety of Medicine and its Expert Working Group  Short. term use of HT for the relief of symptoms, the benefits overweigh the risk.  Longer term use of HT, women must be made aware of the possible risks.  Each decision to start HT should be made on an individual basis and should be regularly reappraised (at least once a year).  For combined EPT the benefits of lower risk of endometrial cancer should be weighed against the increased risk of breast cancer. The risk of endometrial cancer with Tibolone is unknown.

(81) Committee on Safety of Medicine and its Expert Working Group  The. results of the Million Women Study do not necessitate any urgent changes to women’s treatment.  Women who wish to stop or change their HT should discuss with their doctor.  It is important for all women to be “breast aware” and to attend for breast screening from the age of 50 years..

(82) Review of Observational Studies Published From 1975 To 2000. Breast CA Risk Estimates Obstet Gynecol 2001;98:498-508.

(83) Collaborative Group Reanalysis  52,705. women with breast cancer  108,411 women without breast cancer  51 studies, 21 countries  Main analysis based on • 53,865 postmenopausal women with known age at menopause • 17,830 (33%) HT users • 17,949 cases/35,916 controls The Lancet 1997;350:1047-59.

(84) Collaborative Group Reanalysis HT use. RR. Ever use. 1.14*. Current use. 1.21*. Past use. 1.07. * P<0.01. The Lancet 1997;350:1047-59.

(85) Breast Cancer Risks  Increased. risk for invasive but not in situ breast. cancer suggest that EPT does not increase the risk of new breast cancer but rather accelerates. the development of ones already present.  WHI. study demonstrated that short term use of. estrogen is not associated with any increased risk of breast cancer. ASRM.

(86) Effect of ET/HT on Breast Cancer Recurrence and Mortality. J Natl Cancer Inst 2001;93:754-62.

(87) Preventing Bone loss in early postmenopausal women  Bone. loss is most rapid in the years immediately following menopause.  HT. is the only therapy that has been demonstrated to prevent fractures in women whose risk for osteoporosis is unknown.

(88) Change in spine and femoral neck BMD versus years since menopause Bone 2002; 30:637.

(89) Effect of delayed initiation of ET on bone loss.

(90) Who should be considered for prevention or treatment?  Postmenopasual. women with T score below -2.0 with no risk factors.  Postmenopasal. women with T score below 1.5 with one or more risk factors.

(91) Patient Barriers to initiating ET/HT  Concerns. about the long-term safety of HT.  HT-related.  Weight. vaginal bleeding. gain with HT.

(92) Women’s perception of their greatest health problem  Breast. cancer 34%  Cancers 27%  Other problems 16%  Don’t know 16%  Cardiovascular disease 7%.

(93) Cause of death among women  Heart. disease 34%  Breast cancer 4%  Other cancers 15%  Cardiovascular disease 10%  Diabetes 3%  Chronic lower respiratory disease 6%  Other 28%.

(94) Absolute Risk of Breast Cancer after 5 years of HT . . . . WHI: Hazard risk of 1.26 (26% increased risk) 2.8 per 100 women at baseline to become 3.5 per 100 women user after 5 years of HT use (US) BREAST CANCER in Taiwan Incidence: The age-standardized incidence rate was 25.1 per 100,000 person-years. The age-specific incidence rates peaked at ages 4549 (122.44 per 100T) years. The increase in breast cancer incidence rates was most striking among younger birth cohorts. 2.5 (12.2) per 10000 women to become 3.2 (15.4) per 10000 women user (increase 0.032/100).

(95) 台灣地區女性乳癌年齡標準化發生率之長期趨勢，1979-2000年 #REF!. 女性. 45.0. 每十萬人口年齡標準化發生率. 40.0 35.0 30.0 25.0 20.0 15.0 10.0 5.0 0.0 1979. 1980. 1981. 1982. 1983. 1984. 1985. 1986. 1987. 1988. 1989. 1990. 1991. 1992. 1993. 1994. 發生年代. 台灣地區女性乳癌年齡標準化發生率之長期趨勢，1979-2000年. 1995. 1996. 1997. 1998. 1999. 2000.

(96) Managing patients’ Breast Health Concerns  More. than 80% breast cancers occur in women who have never used HT  If women who have used HT develop breast cancer: - smaller size tumor - better differentiated  BRCA1. patients who have been oophorectomized and are receiving HT have no increased risk of breast cancer compared with those not receiving HT  Mortality curves for women who have taken HT after diagnosis of breast cancer show an overall survival benefit.

(97)

(98) HT-related breakthrough bleeding  All. available continuous-combined HT regimens are associated with breakthrough bleeding  Definitions and indices used to report bleeding pattern vary - Most postmenopausal women will experience amenorrhea within 1 year of initiating therapy - Women who are postmenopausal > 3 years may experience less bleeding than recently menopausal women.  Managing. patient expectations about breakthrough bleeding is critical.

(99) Standard & low-dose HT and breakthrough bleeding.

(100) Standard & low-dose HT and breakthrough bleeding  WHI. study: 40% of the women used EPT had vaginal bleeding  HOPE study: - Low-dose HT had better no bleeding rates, particularly during cycle 1-3 (15-20% improvement) - no bleeding rates by cycle 13 were 95% in CEE 0.3/MPA 1.5 and 90% in CEE 0.45/MPA 1.5 compared to 87% in standard dose group.

(101) Patient Concerns Regarding Weight and ET/HT JECM 1997;82-1549 . . Changes commonly observed at menopause - weight gain - increased central adiposity ET/HT is associated with - Lower BW and BMI compared with nonuser - Less visceral adipose tissue - similar weight increase to that observed with placebo.

(102) Patient Concerns Regarding Weight and ET/HT JCEM 1997; 82:1549.

(103) Individualizing patient management with ET/HT  Type. of estrogen/progestin  Dose of estrogen/progestin  Type of regimen (cyclic vs continuous)  Metabolic profile of hormonal combination  Flexibility of treatment  Experience with therapy  Patient satisfaction with therapy.

(104)

(105)

(106) Metabolic effects of oral estrogen plus progestin regimens % change from baseline after 12 months therapy. Regimen. Total-C. LDL-C. HDL-C. TG. CEE/MPA 0.625/2.5 CEE/MPA 0.45/1.5 EE/NETA 0.05/1 E2/NETA 1/0.5 E2/NGT 1/0.09. -2.2. -9.3. 11.2. 32.8. -2.6. -6.7. 9.7. 24.8. -7.0. -7.5. -6.7. 12.1. -10.5. -10.8. -12.4. 2.2. -1.9. 1.2. 9.7. 9.4.

(107) Doses of Progestins used in continous combined HT MPA NETA Medroxyprogest Norethindrone erone acetate acetate. NGT Noregestimate. Doses used in combined HT products. 2.5~5.0 mg/d With 0.625 mg/d CEE). 0.09 mg/d (with 1mg/d E2). Lowest dose approved for use in HT. 2.5 mg/d. 0.5-1.0 mg/d (with 5 ug/d EE or 1 mg/d E2) 0.5 mg/d. Minimum dose shown to be effective for endometrial protection. 2.5 mg/d. 0.1 mg/d. 0.09 mg/d. 0.09 mg/d.

(108) Endometrial response to sequential versus continuous HT BJOG 2000; 107:1392  In. an open-label, prospective study, 1312 women taking sequential HT (with at least 10 days progestin) and 921 not taking HT were given contnous combined HT for 9 months (Kliogest)  At baseline, sequential HT was associated with complex hyperplasia (5.5%) and atypical hyperplasia (0.7%)  After continous combined HT, not associated with increased risk of hyperplasia and converted the endometrium to normal in those with complex hyperplasia arising during sequential HT.

(109) Oral Contraceptive (OC) use in perimenopause A safe, appropriate option for symptomatics  Benefits:. - Resolve irregular bleeding - Improve vasomotor symptoms Menopause 1997; 4:139 - Enhance MBD, prevent fracture Maturita 1994; 19:125  Concerns: - OCs and cancer - Cardiovascular safety - When to stop OCs continue until mid 50s ? When probability of menopause is high.

(110) Perimenopause Reduced hip fracture risk with OCs Lancet 1999; 353:1481.

(111) OCs and cancer prevention Endometrial cancer - 50% protection with several years of use; 75% after 12 years - protection persists ~ 20 years after OC discontinuation  Ovarian cancer - 40% protection with 4 years of use; 80% after 10-12 years - protection persists ~ 30 years after OC discontinuation  Colorectal cancer - Meta analysis: ~ 20% protection - No dose (duration of use) reponse noted .

(112) OCs and Breast Cancer Risk  Ever. user of OCs not associated with increased risk of breast cancer (odds ratio 0.9)  Risk not increased with - duration of use - age of first use - estrogen dose, progestin type - family history of breast cancer.

(113) Vascular contraindications to OCs in perimenopausal women  History. of DVT or Pulmonary embolism  Cerebraovascular or coronary artery disease  Cigarette smoking  Diabetes  Hypertention  Migraine headache  Obesity (?)  Lipid disorders(?).

(114) The role of low-dose ET/EPT  Prescribe. the lowest effective hormone dose - NAMS report Menopause 2003; 10:6-12  In a survey, the following postmenopausal women expressed interest in a low-dose product - 77% of current ET/EPT users - 84% of women who report moderate to severe symptom.

(115) Women’s HOPE Study. FS 2001;75:1065.

(116)

(117) Long-cycle, Low-dose HT using esterified estrogens OG 2001;98:205.

(118) Standard & Low-dose CEE/MPA Therapy on BMD JAMA 2002;287:2668.

(119) Low-dose HT and lipid level.

(120) Low-dose HT and lipid level  Low-dose. HT as well as standard dose regimen has favorable effects on the overall lipid profile, decreasing total and LDL-C, and increasing HDL-C  The addition of MPA to CEE decrease the effect of CEE alone on HDL-C but not on LDL-C.  Oral estrogen elevated TG levels, as does CEE/MPA..

(121) Low-dose HT and lipid level  CEE. 0.625 mg/d: increased TG, decreased LDL, no change in LDL-derived TBARS and lag time indicate enhance the oxidative susceptibility of LDL  CEE 0.3125 mg/d: no change in TG and LDL, decreased LDL-derived TBARS, prolonged LDL lag time, indicate decrease the oxidative stress of LDL -> cardioprotective TBARS thiobarbituric acid reactive substance.

(122) Low-dose HT and Hemostatic factors  Oral. E2 2mg/d may have adverse procoagulant effect.  Oral. E2 1,g/d alone or combined with gestodene 25 ug/d may cause increase in fibrinolysis and small decrease in procoagulant variables AJOG:2003;189:1221.

(123) Low-dose HT and Cardiac Health  Given. the positive effects of HT on lipid profiles, one would expect HT to be associated with a decreased risk of CHD  The results of WHI and HERS study in older women have shown an increased CHD risk in the first year of HT.  Low-dose HT could be antioxidative and antocoagulant, thus might decrease risk of CHD  HT is presently not indicated for the prevention and treatment of heart disease.

(124) Low-dose HT and Breast Health  Breast. pain was less frequent among women taking lower doses of CEE with MPA compared with those taking standard dose CEE/MPA.  No. dose effect on breast pain was observed with use of CEE alone, although breast pain was less commonly reported in these women compared with those taking CEE/MPA FS 2001;75:1065.

(125) Low-dose Hormone Therapy  There. is the potential of fewer side effects, less bleeding and comparable efficacy with the use of lower estrogen and progestin doses..  Clinician. may discuss with their patients about this issue to help them making decisions about HT..

(126) Who will benefit from low-dose HT?  Women. with vasomotor symptoms  Women with vaginal atrophy  Women with bone loss  Women on higher doses presently.

(127) Who will not benefit from low-dose HT?  Patients. with : - Recent surgical menopause, still having menses prior to operation - Premature ovarian failure - Autoimmune disorders - Chemotherapy - Genetic issues - Unknown causes.

(128) 荷爾蒙替代療法： Livial® (tibolone) 利飛亞錠  Tibolone. 在子宮內膜細胞中被代謝成 D4Tibolone 代謝物具有下列特性: –黃體素接受器與雄性素接受器的親和力 –在子宮內膜組織中的黃體素/雄性素作用  沒有子宮內膜刺激性 –不出血比率高 (在3個月內90%婦女不會有再出血的現象) –不須再吃黃體素.

(129)

(130) 荷爾蒙替代療法：植物擬動情激素  異烷酮類〈大豆異黃酮素〉Isoflavones.  天然成份不等於安全  北美停經學會雜誌2000：共識意見. 對減緩燥熱：研究結果仍未一致對乳房：尚未有足夠資訊對其他婦女癌症：尚未有足夠資訊對骨質密度：尚未有足夠資訊要建議增加異黃酮之攝取尚有待進一步之臨床試驗.

(131) Topical Vaginal Cream. 衛生署核可的適應症 Vaginal Cream的適應症 : 萎縮性陰道炎 (Atrophic Vaginitis) 更年期性外陰萎縮 (Kraurosis Vulvae).

(132) Estradiol administered vaginally treats UG symptoms MP 2002;9:179.

(133) Counseling Topics for Patients Considering ET/HT  Review. the risks and benefits of ET/HT  Discuss the probability of early bleeding while receiving continuous-combined HT  Review other potential side effects  Provide information about ET/HT and breast health  Emphasize that ET/HT use does not cause weigh gain  Obtain informed consent.

(134) Counseling Topics for Patients Who Decline or Discontinue ET/HT  Asympomtatic. obese women may still require progestational therapy  Urogenital atrophy will develop  Need to increase surveillance for osteoporosis and/or consider alternative osteoporosis regimens  Hot flushes and night sweats may return after discontinuation.

(135) Counseling Women About ET/HT  Document. reasons for considering ET/HT (eg, use quality-of-life questionnaire)  Review annually indications for ET/HT  Explain benefits of short-term ET/HT use will often outweigh risks  Emphasize that risks attributable to HT in the WHI were low ACOG News Release. http://www.acog.org/from_home/publications/press_releases/nr07-09-02.cfm.

(136) Counseling on Duration of ET/HT Use Individualized therapy  Consider. continuing therapy (possibly lower dose) if initial indication was vasomotor symptoms  Excess cardiovascular events occurred in the first 2 years in women (average age, 63 years) in the WHI trial  Breast cancer risk was not increased with <5 years of HT use in the WHI trial ☆After 5 years, HT was associated with a slight increased risk (<0.1 % per year)  VTE risk continues for duration of therapy  Bone protection is afforded by continuing therapy.

(137) EPT and ET of WHI Study  The. WHI results indicate that estrogen alone does have advantages over estrogen plus progestin for treatment of postmenopausal women  EPT and ET both increase the risk of stroke  ET, not like EPT, does not increase the risk of CHD and decreases the risk of breast cancer  Reconsideration of appropriate use of progestin is needed.

(138) Ratinale for HT for Perimenopausal Women  Even. if hazard ratios are similar in women of all ages, the absolute risks for many diseases approximately doubles with each decade of age. Thus, women in their 50s have about half the risk of women in their 60s and one quarter the risk of women in their 70s.  This means that HT can be used more favorably in 50- to 59-year-old women for treatment of menopausal symptoms..

(139) Recommendations for Clinical Practice (NAMS 2003)  Treatment. of menopause symptoms remains the primary indication for EPT and ET.  EPT should not be used for prevention of CHD.  HT should be limited to the shortest duration consistent with treatment goals, benefits, and risks for the individual woman.  Lower-than-standard doses of EPT and ET should be considered.  Vaginal ET can be used for urogenital atrophy.  Individual risks and benefits should be considered before starting HT..

(140) 荷爾蒙療法的共識 治療更年期症狀仍是EPT及ET的主要適應症.. EPT不能被用來預防CHD. HT須短期使用，並與治療目標、利益、婦女. 個別化風險配合. 低劑量的EPT及ET應被考慮使用. 陰道軟膏使用在泌尿生殖道萎縮. 使用HT之前必須個別化評估其風險及利益..

(141) 臺灣更年期醫學會對WHI之看法總結  WHI. 研究之美國的研究, 其人種與生活習慣與我國不盡相同 , 不一定能完全引用於國人.  此單項研究結果未必足以推翻以前的研究結果而說荷爾蒙療法一定有問題.  WHI 研究有 Risk - Breast Cancer, CVD.  WHI研究有 Benefit - Hip Fracture, Colorectal Cancer.  WHI 未將更年期症狀與萎縮性陰道炎/尿道炎列入效益評估.  HRT 是緩解更年期症狀與萎縮性陰道炎/尿道炎與預防骨質疏鬆症最有效的方法, 應列入效益評估, 再作成結論.  HRT短期使用( < 4 年)利大於弊.  HRT使用四年以上需請醫師評估症狀需求, 骨質狀態與相關危險因子後再做決定, 並做定期檢查..

(142) 臺灣更年期醫學會對WHI之看法總結  婦女應在醫師處方下服用荷爾蒙，由婦產. 科醫師評估處方才能保障用藥安全。  此研究提醒醫師未來使用荷爾蒙療法時需更加謹慎。  研究負責人強調，這種危險相當小，婦女無須驚慌，還建議婦女不要隨意停藥，宜請教醫師。.

(143) 我們應該如何給婦女建議我們對荷爾蒙療法的建議乃參考以下機構 1.美國預防醫療小組(USPSTF) 2.美國婦產科醫學會 3.北美更年期醫學會 4.行政院衛生署國民健康局 5.臺灣更年期醫學會.

(144) 我們應該如何給婦女建議一. 使用荷爾蒙療法的主要適應症為治療更年期症候群使用期間越短越好，使用劑量越低越好。二. 荷爾蒙療法不應用於(初級或次級)預防心臟血管疾病三. 雖然美國食品藥物管理局核可荷爾蒙療法用於預防骨鬆症，且 WHI 也證實荷爾蒙療法可減少骨鬆引起的骨折。但荷爾蒙療法可能增加心臟血管疾病與乳癌，要用於預防骨鬆症應小心的做個別考量.要預防骨鬆症，美國預防醫學小組與美國婦產科醫學會不建議用荷爾蒙療法，可考慮其他方式來預防。在國內，荷爾蒙療法為健保局有幾付的唯一 ( 預防 ) 骨鬆症之藥物，其他藥物則只有在已發生骨鬆症骨折後才有給付使用.未有骨折的婦女，如要使用其他藥物預防骨鬆症, 必須自費。.

(145) 我們應該如何給婦女建議四.已切除子宮 , 單獨使用雌激素的婦女可繼續使用荷爾蒙療法 . 五.少數可考慮長期使用荷爾蒙療法的症狀如下： (一)更年期症狀嚴重的婦女，經說明利弊後，仍覺得荷爾蒙療法對她來說好處多餘壞處者。 (二)有更年期症狀且有骨鬆症之風險之婦女。 (三)有骨鬆症之風險而又無法接受其他骨鬆症治療方式婦女。.

(146) 我們應該如何給婦女建議六.荷爾蒙療法有利有弊，每個婦女的需求（是否有更年期症狀）,期望與危險因子（是否有心臟病、乳癌、靜脈栓塞、大腸直腸癌、骨鬆症的危險因子）都不同。需要作個別的考量，無一體適用的答案。停經婦女應與醫師商量，了解荷爾蒙療法對她的利弊後，再決定是否要使用。七.使用荷爾蒙療法的婦女應於一段時間後（不超過半年）再做整體評估。看是否需要改變治療方式，針對停經婦女的需求。醫師也應與她討論荷爾蒙之外的其他處置方式。.

(147) NAMS 北美更年期學會雌激素與黃體素於更年期及停經後婦女之應用: 2003年九月北美更年期學會之立場聲明.

(148) 臨床實務建議 : 有共識的部分  治療中度至重度更年期症狀(例如血管舒縮症狀. ，以及因此而造成之睡眠中斷)，仍是全身性作用之ET/EPT製劑的主要適應症。  治療中度至重度外陰及陰道萎縮症狀，如陰道乾澀，性交疼痛及萎縮性陰道炎皆為政府核准之所有全身性及局部性作用ET/EPT製劑的適應症; 當僅有上述症狀時，通常建議採用局部作用之ET製劑。  黃體素在主要更年期相關適應症中的用途為保護子宮內膜不受未經拮抗之ET 的影響。對沒有子宮之婦女，則不需處方黃體素。.

(149) 臨床實務建議 : 有共識的部分  有些子宮完整的婦女在選用EPT之後，可能會因. 黃體素的成分而發生不良的副作用。  所有EPT皆不可用於冠心病或中風的初級預防或次級預防。  ET對CHD及中風的作用，目前尚未明瞭。X  使用ET及EPT (影響程度更大) 超過5年之後，發生乳癌的危險性便會開始升高。黃體素似乎會明顯促進這種不良的作用。X  在降低停經後發生骨質疏鬆性骨折的危險性方面，EPT的療效已經獲得明確的證實。.

(150) 臨床實務建議 : 有共識的部分  不可建議在65歲之後開始使用EPT作為失智症的. 初級預防療法，因為對此族群而言，它會升高在後續5年間發生失智症的危險性。HT在阿滋海默症所造成之失智症的次級預防(即症狀治療)方面似乎並不具直接的效益或傷害。  HT對停經期間且有症狀之婦女發生乳癌及骨質疏鬆性骨折之危險性的影響，尚未在隨機性的臨床試驗中獲得確立。  早發性停經與早發性卵巢衰竭都會導致骨質疏鬆症與CHD提早發生，但在ET或EPT是否可降低這些疾病的發生率或死亡率方面，目前並無確切的數據資料。其危險效益比在較年輕的婦女中可能較為有利。.

(151) 臨床實務建議 : 有共識的部分  使用ET及EPT時，應限制採取符合個別婦女. 之治療目標、效益及風險的最短療期。  應考慮使用劑量較標準為低的ET與EPT 。許多研究已經證實，其緩解血管舒縮症狀與外陰陰道症狀的效果以及保存骨質密度的作用和標準劑量幾乎相等。  非經口投予的EP/EPT可能有利也有弊，但其長期使用時的效益風險比，目前仍未獲得證實。.

(152) 臨床實務建議 : 有共識的部分  如果婦女充分瞭解治療的風險，並接受嚴密的臨床監督. ，那麼在下列情況下是可以延長ET或EPT的使用期間的： –用於治療停用HT的嘗試失敗之後自認為症狀緩解的效益明顯超越治療風險的婦女。此時應嘗試緩慢降低劑量，進而停用HT。 –用於治療出現中至重度停經症狀，並有發生骨質疏鬆性骨折之高危險的婦女。此時應嘗試緩慢降低劑量，或停用HT，並改用其它的保骨療法。 –應用於不適用其它療法的高危險婦女，藉以預防骨質疏鬆症。  在考慮採用任何的治療方式(包括HT)之前，所有的婦女. 都應接受完整的健康評估，包括廣泛的病史評估和體檢.

(153) 臨床實務建議 : 有共識的部分 顧問小組認為，截至目前為止，文獻. 上所見的和ET/EPT有關的絕對風險都很低。對每一位考慮採用任何EPT或ET 療法的婦女而言，一份針對個人的風險說明是不可或缺的。應該要讓婦女瞭解目前已知的危險性。.

(154) 因證據不足或證據衝突而未能達成共識的部分  關於“短期”與“長期”的HT，目前可接. 受的定義為何？  HT是否伴有提早發生CHD的危險性？  用以緩解症狀的HT處方應持續多久？.  採用哪一種方式來停用HT最好？.

(155) 因證據不足或證據衝突而未能達成共識的部分  是否可能對所有的雌激素與黃體素系列產. 品做出一體適用的結論？  和連續使用雌激素合併間續使用黃體素的. 療法(CS-EPT)相比較，連續混合使用的 EPT療法(CC-EPT)是否具有不同的作用？  HT是否能夠增進生活品質(QOL)？.

(156) 臺灣更年期醫學會荷爾蒙治療指引 2004-06-15 荷爾蒙治療仍是緩解婦女更年期症狀（如熱潮紅、盜汗、心悸、失眠、陰道萎縮乾澀、尿道萎縮等）最有效的方法。如僅為治療局部性症狀，如陰道萎縮、性交困難、萎縮性尿道炎，建議使用局部性雌激素療法。  在使用荷爾蒙治療之前及長期使用荷爾蒙時，所有的婦女都應接受完整的健康及風險評估。  荷爾蒙治療超過五年以上，發生乳癌危險性便會少許升高。但乳癌風險升高的現象，並不具統計學上的意義。  根據WHI研究報告顯示，子宮切除之停經婦女使用雌激素，會增加中風之危險，減少股骨骨折之危險。但使用雌激素6.8年以內乳癌的發生率減少，同時不會影響冠心病發生率。  對停經並保有子宮的婦女，可以使用其他藥物或方法降低心血管疾病，建議不要為了預防心血管疾病而處方荷爾蒙療法。 .

(157) 臺灣更年期醫學會荷爾蒙治療指引 2004-06-15 醫師應提供專業諮詢，告知婦女荷爾蒙療法的好處與可能帶來的風險，以決定是否需使用。  黃體素在主要更年期相關適應症中的用途為保護子宮內膜不受未經拮抗之雌激素的影響，對所有正在使用雌激素療法且子宮完整的婦女，建議醫師處方適當的黃體素，對無子宮的婦女則不應處方黃體素。但黃體素似乎會明顯促進乳癌及冠心病之不良作用。  在降低停經後發生骨質疏鬆性骨折的危險性方面及降低大腸癌的危險性方面，荷爾蒙治療的療效已經獲得明確的證實。停經婦女應做一次DEXA（Spine）之骨密度測定，若確定為骨質疏鬆症，則建議使用荷爾蒙治療五年以上。  荷爾蒙治療在停經初期（3年以內）就開始使用，則其效益高且風險低。使用時應考慮劑量較標準量為低的荷爾蒙療法。  針劑荷爾蒙療法，因其長期使用之療效及危險性仍未確定，不建議使用。 .

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