슬라이드 1

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1 호르몬요법의최신지견 ET / EPT / Tibolone 박형무 중앙대학교의과대학산부인과학교실

2 한국여성 평균수명 83.8 세 평균폐경연령 49.7 세 년도 총수 여성수 ( 백만 ) 50 세이상 % 통계청 2010

3 consequences of menopause years effect of menopause vasomotor psychological Sx UG atrophy skin age osteoporosis CHD Alzheimer s disease incidence (%) increasing with age increasing with age

4 classification of ER- active agents natural synthetic steroidal E 1-4 / Equilin EE 2 non-steroidal phytoestrogen DES / SERM

5 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 )

6 WHI - HT trial F/U : 8.5 yrs EPT 16,608 ( 55 % ) CEE mg + MPA 2.5 mg/d ET 10,739 ( 45 % ) CEE mg/d F/U : 5.2 yrs F/U : 6.8 yrs EPT HR / 만인년 HR / 만인년 CHD (30) Breast Ca (30) Stroke (21) (32) VTE (16) Hip Fx (15) (17) Colorectal Ca (16) Dementia * (22) ET ( ) absolute risk in control

7 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%)

8 WHI 연구에의한호르몬요법의최종손익 감소증가영향없음 E + P 복합요법 골절 직장대장암 유방암뇌졸중정맥혈전색전증 관상동맥질환 자궁내막암 사망 치매 E 단독요법골절뇌졸중

9 Use of HT in Korea % - 25% 년도 ET/ EPT 377 억 (230 억 ) Tibolone 134억 (151억) total 511억 (381억)

10 치료용량 high standard low ultra-low CEE mg /0.45 Micronized 17β-E 2 mg E 2 valerate mg Transdermal 17β-E 2 µg super ultra-low dose E mg increase in BMΔ no effect for VMS

11 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

12 HRT 1 cyclic sequential continuous sequential continuous combined 30 1 cyclic combined 25 1 intermittent combined long cycle

13 progestogen 의부가적투여 일차적적응증 : 에스트로겐으로부터자궁내막을보호 지속적 / 주기적으로시행 장주기요법 ( long-cycle regimen ) 자궁내장치저용량 / 초저용량에스트로겐단독요법안전성에대한자료가불충분

14 골다공증 폐경후골소실예방 / 골절률감소 골절의위험성이있는 60 세이전폐경여성의일차치료로권고 단지골절예방목적으로 60 세이상여성에서 HT 는권고되지않음 골밀도보호효과는호르몬치료를중단시사라진다.

15 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)

16 WHI : CHD risk WHI-EPT (2002) : 1.29 ( ) HR 95% CI total ET EPT CHD 위험성 : 유의한영향없음 Rossuw JE JAMA 2007;297:1465

17 WHI : Risk of CHD by age & YSM <10 10~19 20 P for trend total 0.76 ( ) 1.10 ( ) 1.28 ( ).02 만명당 P for trend total 0.93 ( ) 0.98 ( ) 1.26 ( ).16 만명당 CHD risk : only in older women Rossuw JE JAMA 2007;297:1465

18 WHI - Coronary Artery Calcium study PMWs yrs in ET 7.4yrs of TX effect on atherosclerotic calcification (plaque burden) Lower mean CAC score ET PBO P value High levels of CAC : 30-60% lower < >300 Women age treated with estrogen had less atherosclerosis. Manson JE. NEJM 2007;356:

19 CHD associated with HT : a meta-analysis 23 trials Younger : 폐경후 10 년이하 / 60 세이하 younger 0.68 (CI, ) older 1.03 (CI, ) Odds ratio for CHD Salpeter. J Gen Intern Med 2006;21:363

20 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.

21 timing of HT initiation : observational vs clinical trials

22 WHI : risk of Stroke all Ischemic Hemorrhagic EPT 1.31 ( ) 1.44 ( ) 0.82 ( ) ET 1.37 ( ) 1.55 ( ) 0.64 ( ) 용량감소를권고 Ischemic stroke : EPT 79.8 % ET 80.3 % Wassertheil-Smoller JAMA 2003;289:2673 Hendrix Circulation 2006;113:2425

23 risk of VTE in WHI - EPT AGE PBO EPT PBO EPT PBO EPT absolute risk (19) (35) (62) HR < BMI PBO EPT PBO EPT PBO EPT absolute risk 9 +7 (16) (35) (51) HR Greater risk with increasing age & weight 경피요법을권장 Cushman JAMA 2004:292:1573

24 WHI : risk of breast cancer WHI 기간 ( 년 ) RR 95% CI EPT ET EPT > ET 사용기간에비례하여위험성이증가실제적유방암위험성증가는적다 EPT : 만명 / 년간 8명증가 ( 0.1 % )

25 role of progestogen French E3N cohort study PMW F/U : 8.1 yrs HT RR 95% CI ET alone oral TD/PC E T + progesterone DDG other progestogen Breast Cancer Res Treat 2007;

26 NHS : Unopposed ET & breast cancer risk Women 50 years or older duration, y cases risk never current < ( ) ( ) ( ) ( ) ( ) P value for trend < Wendy, Arch Intern Med. 2006;166:1027

27 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

28 유방암 EPT 5년이하의치료에서는유의한증가없음 5년후부터는위험성이소폭증가비만이나음주로인한위험성과유사함 ET 7 년이하로시행시증가하지않음 위험성의비유의한감소 년이상사용시위험성증가 ( NHS )

29 대장암 대장직장암의위험성을감소 대장암을예방하기위하여권고되지는않는다.

30 WHI Memory Study (WHIMS) PMW 65yrs global cognitive decline increased risk for dementia EPT 4.2yrs ET 5.4yrs MCI 1.07 ( ) 1.34 ( ) dementia 2.05 ( ) 1.49 ( ) US FDA : boxed warning (2004 Feb 10) risks of probable dementia in PMW > 65yrs for 4yrs of Tx

31 Cache County Study : Risk of AD mean age : 74 yrs No HT Use HT Use Past < 3 yrs 3 10 > Current < > relative hazard (95%) JAMA 2002;288:2123-9

32 Relative risk Multi-Institutional Research in Alzheimer Genetic Epidemiology (MIRAGE) Study 426 cases, 545 controls Protective effect : only in the youngest age tertile * 0.10 HT used during early PM may reduce AD risk Never yrs Henderson. J Neurol Neurosurg Psychiatry 2005;76:103

33 인지기능과치매 폐경초기에시행시알쯔하이머치매의위험성을감소 인지기능장애나알쯔하이머치매, 혹은다른형태의치매 예방이나치료를위해처방되지는않는다.

34 Tibolone selective tissue estrogenic activity regulator (STEAR) Synthetic steroid Bone / Vagina enzyme activity Breast Endometrium Androgen receptor Brain / Liver

35 HT market in Korea 2010 Tibolone ET + EPT 40% 60 % 381억원 Korea IMS Data 2010

36 Tibolone LIFT (LT Intervention on Fxs with Tibolone) 4538 PMW 60-85yr 1.25mg/d 34Ms Tx HR 95 % CI Vx Fx non -Vx Fx Breast cancer Colon cancer Stroke CHD VTE Cummings NEJM 2008;359:697 LIBERATE breast cancer recurrence 1.40 (95% CI ) IMS 2008

37 Use of tibolone in Asian postmenopausal women

38 Individualization of therapy is the key

Treatment and Role of Hormaonal Replaement Therapy

Treatment and Role of Hormaonal Replaement Therapy Treatment and Role of Hormone Replacement Therapy Chung-Ang University Hospital Chee Jeong Kim 7.2 5.3 6.4 5.6 7.3 5.5 1 1 2 3 4 10 11 7 34 49 122 123 1.0 - - 10. 2001 1998 1998 Improvement of postmenopausal