호르몬요법의최신지견 ET / EPT / Tibolone 박형무 중앙대학교의과대학산부인과학교실
한국여성 평균수명 83.8 세 평균폐경연령 49.7 세 년도 총수 여성수 ( 백만 ) 50 세이상 % 2010 25.0 7.4 29.5 2020 25.9 9.7 37.5 2030 26.3 11.3 43.2 통계청 2010
consequences of menopause years -2 1 5 7 10 20 effect of menopause vasomotor psychological Sx UG atrophy skin age osteoporosis CHD Alzheimer s disease incidence (%) 60-75 20-30 25-35 increasing with age increasing with age
classification of ER- active agents natural synthetic steroidal E 1-4 / Equilin EE 2 non-steroidal phytoestrogen DES / SERM
적응증 호르몬제제도약제이다. 명확한적응증하에투여 FDA indication 1. Tx of moderate to severe vasomotor Sx 2. Tx of mod - severe Sx of genital atrophy 국소적요법고려 3. Px of PMO 비에스트로겐제제고려치료의적응증삭제 (1999 년 ) 4. Sexuality & QOL 향상 (IMS) 5. 당뇨병예방 ( Endocrine Society 2010 )
WHI - HT trial F/U : 8.5 yrs EPT 16,608 ( 55 % ) CEE 0.625 mg + MPA 2.5 mg/d ET 10,739 ( 45 % ) CEE 0.625 mg/d F/U : 5.2 yrs F/U : 6.8 yrs EPT HR / 만인년 HR / 만인년 CHD 1.29 +7 (30) Breast Ca. 1.26 +8 (30) Stroke 1.41 +8 (21) 1.39 +12 (32) VTE 2.11 +18 (16) Hip Fx 0.66-5 (15) 0.61-6 (17) Colorectal Ca. 0.63-6 (16) Dementia * 2.05 +23 (22) ET ( ) absolute risk in control
WHI 의문제점 고령의무증상여성 평균나이 63.2 세 단일형태 / 용량 / 투여경로와방법 type dose route regimen CEE 0.625mg + MPA 2.5mg oral continuous combined 높은탈락율 (42%) / 비맹검 (41%)
WHI 연구에의한호르몬요법의최종손익 감소증가영향없음 E + P 복합요법 골절 직장대장암 유방암뇌졸중정맥혈전색전증 관상동맥질환 자궁내막암 사망 치매 E 단독요법골절뇌졸중
Use of HT in Korea 600 500 400-41% - 25% 300 200 100 0 2002 2003 2004 2005 2006 2007 2008 2009 2010 년도 2002 2003 2004 2005 2006 2007 2008 2009 2010 ET/ EPT 377 억 -33-41 -44-51 -51-49 -41-39 (230 억 ) Tibolone 134억 -6-25 -13-5 +2 +2 +8 +13 (151억) total 511억 -24-41 -40-44 -41-39 -30-25 (381억)
치료용량 high standard low ultra-low CEE mg 1.25 0.625 0.3 /0.45 Micronized 17β-E 2 mg 4.0 2.0 1.0 0.5 E 2 valerate mg 2.0 1.0 Transdermal 17β-E 2 µg 100 50 25 14 super ultra-low dose E 2 0.25mg increase in BMΔ no effect for VMS
치료용량과기간 최소유효용량의사용 / shortest duration necessary ( FDA, NAMS ) 폐경이행기나초기폐경기에시작하는것이가장효과적 유익성 > 위험성을초과시지속 조기폐경여성 적어도정상폐경연령까지사용지속 일반적으로사용되는용량보다고용량을고려 VMS 의재발율 : WHI D/C of EPT ( 5.7 yrs use ) 21.2 % / 55.5 % ( Sx at baseline ) SSRI / SNRI / gabapentine
HRT 1 cyclic sequential 25 13 1 continuous sequential 30 14 1 continuous combined 30 1 cyclic combined 25 1 intermittent combined 30 1 4 6 10 12 16 18 22 24 28 30 1 long cycle 30 8 21 30
progestogen 의부가적투여 일차적적응증 : 에스트로겐으로부터자궁내막을보호 지속적 / 주기적으로시행 장주기요법 ( long-cycle regimen ) 자궁내장치저용량 / 초저용량에스트로겐단독요법안전성에대한자료가불충분
골다공증 폐경후골소실예방 / 골절률감소 골절의위험성이있는 60 세이전폐경여성의일차치료로권고 단지골절예방목적으로 60 세이상여성에서 HT 는권고되지않음 골밀도보호효과는호르몬치료를중단시사라진다.
HRT & CVD findings of observational study estrogen users : 30-50% lower risk of CHD similar benefit in E/P users stronger protection in women with CHD HERS(98) / PHASE (02) / ESPRIT (02)
WHI : CHD risk WHI-EPT (2002) : 1.29 ( 1.02-1.63 ) HR 95% CI total 1.07 0.92-1.23 ET 0.95 0.78-1.16 EPT 1.23 0.99-1.53 CHD 위험성 : 유의한영향없음 Rossuw JE JAMA 2007;297:1465
WHI : Risk of CHD by age & YSM <10 10~19 20 P for trend total 0.76 (0.50-1.16) 1.10 (0.84-1.45) 1.28 (1.03-1.58).02 만명당 -6 +4 +17 50-59 60-69 70-79 P for trend total 0.93 (0.65-1.33) 0.98 (0.79-1.21) 1.26 (1.00-1.59).16 만명당 -2-1 +19 CHD risk : only in older women Rossuw JE JAMA 2007;297:1465
WHI - Coronary Artery Calcium study PMWs 50-59 yrs in ET 7.4yrs of TX effect on atherosclerotic calcification (plaque burden) Lower mean CAC score ET PBO P value 83.1 123.1 0.02 1.25 1 0.75 0.5 High levels of CAC : 30-60% lower 0.67 0.25 0.43 0.39 <10 10-100 100-300 >300 Women age 50-59 treated with estrogen had less atherosclerosis. Manson JE. NEJM 2007;356:2591-2602
CHD associated with HT : a meta-analysis 23 trials Younger : 폐경후 10 년이하 / 60 세이하 younger 0.68 (CI, 0.48 0.96) older 1.03 (CI, 0.91 1.16) 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 Odds ratio for CHD Salpeter. J Gen Intern Med 2006;21:363
심혈관질환 폐경후 10 년이내 60 세이하에서호르몬요법을시작 : 보호효과 Kronos Early Estrogen Prevention Study (KEEPS) Early versus Late Interventional Trial with Estradiol (ELITE) 젊고건강한폐경여성은 CV risk 증가없이 HRT 시작할수있다. 호르몬요법이일차적 / 이차적심혈관계예방을위해권고되지는않는다.
timing of HT initiation : observational vs clinical trials
WHI : risk of Stroke all Ischemic Hemorrhagic EPT 1.31 (1.02-1.68) 1.44 (1.09-1.90) 0.82 (0.43-1.56) ET 1.37 (1.09-1.73) 1.55 (1.19-2.01) 0.64 (0.35-1.18) 용량감소를권고 Ischemic stroke : EPT 79.8 % ET 80.3 % Wassertheil-Smoller JAMA 2003;289:2673 Hendrix Circulation 2006;113:2425
risk of VTE in WHI - EPT 50-59 60-69 70-79 AGE PBO EPT PBO EPT PBO EPT absolute risk 8 +11 (19) 19 +16 (35) 27 +35 (62) HR 1.00 2.27 2.31 4.28 3.37 7.46 < 25 25-30 30 BMI PBO EPT PBO EPT PBO EPT absolute risk 9 +7 (16) 15 +20 (35) 25 +26 (51) HR 1.0 1.78 1.63 3.80 2.87 5.61 Greater risk with increasing age & weight 경피요법을권장 Cushman JAMA 2004:292:1573
WHI : risk of breast cancer WHI 기간 ( 년 ) RR 95% CI EPT 5.6 1.24 1.01-1.54 ET 6.8 0.77 0.59-1.01 EPT > ET 사용기간에비례하여위험성이증가실제적유방암위험성증가는적다 EPT : 만명 / 년간 8명증가 ( 0.1 % )
role of progestogen French E3N cohort study 80377 PMW F/U : 8.1 yrs HT RR 95% CI ET alone oral TD/PC 1.32 0.76-2.29 1.28 0.98-1.69 E T + progesterone 1.00 0.83-1.22 DDG 1.16 0.94-1.43 other progestogen 1.69 1.50-1.91 Breast Cancer Res Treat 2007;
NHS : Unopposed ET & breast cancer risk Women 50 years or older duration, y cases risk never 270 1.00 current < 5 114 0.99 ( 0.79-1.24 ) 5-9.9 148 0.97 ( 0.71-1.07 ) 10-14.9 191 1.05 ( 0.87-1.29 ) 15-19.9 190 1.19 ( 0.96-1.48 ) 20 145 1.41 ( 1.13-1.76 ) P value for trend < 0.001 Wendy, Arch Intern Med. 2006;166:1027
Role of HT on BC risk Increase in BC from HT effect on occult undiagnosed BC : promotional effect on pre-existing lesions (promotor) de novo development of new cancer (-) Gap time hypothesis WHI : 5 yrs E3N : 3 yrs
유방암 EPT 5년이하의치료에서는유의한증가없음 5년후부터는위험성이소폭증가비만이나음주로인한위험성과유사함 ET 7 년이하로시행시증가하지않음 위험성의비유의한감소 15 20 년이상사용시위험성증가 ( NHS )
대장암 대장직장암의위험성을감소 대장암을예방하기위하여권고되지는않는다.
WHI Memory Study (WHIMS) PMW 65yrs global cognitive decline increased risk for dementia EPT 4.2yrs ET 5.4yrs MCI 1.07 (0.74-1.55) 1.34 (0.95-1.89) dementia 2.05 (1.21-3.84) 1.49 (0.83-2.66) US FDA : boxed warning (2004 Feb 10) risks of probable dementia in PMW > 65yrs for 4yrs of Tx
Cache County Study : Risk of AD mean age : 74 yrs No HT Use HT Use Past < 3 yrs 3 10 >10 0.58 0.37 0.17 Current < 3 3 10 > 10 0.55 0.01 0.1 1 10 relative hazard (95%) JAMA 2002;288:2123-9
Relative risk Multi-Institutional Research in Alzheimer Genetic Epidemiology (MIRAGE) Study 426 cases, 545 controls Protective effect : only in the youngest age tertile 1.00 0.50 0.86 0.97 0.35* 0.10 HT used during early PM may reduce AD risk Never 50 63 64 71 72 99 yrs Henderson. J Neurol Neurosurg Psychiatry 2005;76:103
인지기능과치매 폐경초기에시행시알쯔하이머치매의위험성을감소 인지기능장애나알쯔하이머치매, 혹은다른형태의치매 예방이나치료를위해처방되지는않는다.
Tibolone selective tissue estrogenic activity regulator (STEAR) Synthetic steroid Bone / Vagina enzyme activity Breast Endometrium Androgen receptor Brain / Liver
HT market in Korea 2010 Tibolone ET + EPT 40% 60 % 381억원 Korea IMS Data 2010
Tibolone LIFT (LT Intervention on Fxs with Tibolone) 4538 PMW 60-85yr 1.25mg/d 34Ms Tx HR 95 % CI Vx Fx 0.55 0.41-0.74 non -Vx Fx 0.74 0.58-0.93 Breast cancer 0.32 0.13-0.80 Colon cancer 0.31 0.10-0.96 Stroke 2.19 1.14-4.23 CHD 1.37 0.77-2.45 VTE 0.57 0.19-1.69 Cummings NEJM 2008;359:697 LIBERATE breast cancer recurrence 1.40 (95% CI 1.14-1.70) IMS 2008
Use of tibolone in Asian postmenopausal women
Individualization of therapy is the key