Abstract In the absence of contraindications, short-term HRT is appropriate for those peri- and postmenopausal women who have moderate to severe vasomotor symptoms associated with estrogen deficiency. Based on the current information, it appears that rather than the dose of the progestin, the duration of progestin is the most important aspect in the prevention of endometrial cancer. The clinician should increase the duration of the progestin in women on HRT to at least 12 14 days in a calendar month or cycle. In fact, ERT should not be used in women with a uterus. Currently available data suggest that long-term users of HRT may have a slightly increased risk for ovarian cancer compared to women who have never used estrogen. The risk might particularly involve the endometrioid type of ovarian cancer. There is clear and consistent evidence that use of E +P increases a woman's risk of breast cancer. Alternatively, current evidence suggests that use of unopposed E is not as strongly associated with breast cancer risk. Further studies are needed though to examine how different HRT regimens, doses, and methods of delivery are related to breast cancer risk, and how HRT impacts the risks of different types of breast cancer. It is still a controversial issue whether patients with a history of gynecologic malignancies can be safely prescribed HRT. There are no data to suggest that HRT is contraindicated in women who have been treated for cervical or ovarian cancer. HRT did not appear to increase the rate of death among endometrial cancer survivors. However, as available data does not yet allow drawing absolute conclusions as to the safety of HRT use, it is necessary to inform patients about the potential risks and alternative therapies. The possibility that estrogen can stimulate or anticipate proliferation of micrometastatic foci is all but a theory, above all in the case of receptor positive tumors. Despite these doubts, the available data on selected groups of patients are all favorable and point to the possibility of treating good risk women and women with hormone receptor negative tumors without any increase of the risk of recurrence or death. Randomized clinical trials are needed to obtain definite results, but this will take a very long time and a large number of subjects. In the meantime, it is necessary to provide relief to patients who complain of menopause symptoms, both by offering them the several alternatives of proven effectiveness to HRT already available, and by giving them no-biased information. -49S -
Luncheon seminar 1. 서론. 1980,. 1998 Heart and Estrogen/progestin Replacement Study (HERS) 1 2002 Women's Health Initiative (WHI) study 2 - (estrogen plus progestin trial),, (global index) (Table 1). WHI study 5.2, - (Data and Safty Monitoring Board, DSBM). WHI study (estrogen-alone trial) 1. estrogen arm estrogen-progestin arm,. WHI study 60 50, (conjugated equine estrogen 0.625 mg, medroxyprogesterone acetate 2.5 mg),.... (Hormone replacement therapy, HRT). 2. 자궁내막암 (Endometrial Cancer) (estrogen-alone replacement therapy, ERT). unopposed estrogen 1 15 20%. unopposed estrogen (relative risk, RR) 2.8 (95% CI, 2.4 3.2) -50S -
, ERT 5., case-controlled study conjugated equine estrogen (CEE) 0.3 mg (RR) 5.4 (95% CI, 2.3 13.0), 3 estrogen (estriol) 5 (RR, 3.0; 95% CI, 2.0 4.4). Nelson 29 observational study unopposed estrogen meta-analysis. 4 (ERT) (RR, 2.3; 95% CI, 2.1 2.5)(Table 2). unopposed estrogen 5. Nelson 7 meta-analysis - (estrogen and progestin combined therapy, EPT) (RR, 0.8; 95% CI, 0.6 1.2), 4 WHI HERS EPT. 1,2 (sequential combined HRT, SC-HRT) 5 (RR, 1.2; 95% CI, 1.0 1.5), 5 10 3.7 (95% CI, 1.7 8.2) 2.9 (95% CI, 1.8 9.6) (Table 3). 5,6 10. (continuous combined HRT, CC-HRT), 1.4, 1.07, 0.2 (Table 3). 5-7 Archer HRT HRT 5 10 1.8, CC-HRT SC-HRT 10. 8. (Million women study) HRT CC-HRT (RR, 0.71; 95% CI, 0.56 0.90), SC-HRT, ERT (RR, 1.45; 95% CI, 1.02 2.06). 9 ERT. 10 5 12 14. CC-HRT.. -51S -
Luncheon seminar Unopposed estrogen. ERT EPT. Creasman 221 stage I,,,. 10. Lee ERT 44. 11,. HRT 34% 2 HRT regimen 34%. Chapman 1984 1994 stage I-II 123. 62 ERT, 61 ERT. 12 52%,. Suriano 130 matched control study. 13 83 (p 0.006), ERT. leiomyosarcoma endometrial stromal sarcoma HRT. 14,15 American College of Obstetricians and Gynaecologists, HRT,. 16 3. 난소암 (Ovarian Cancer)... HRT. case-control study (Table 4). Riman case-control study HRT ERT, SC- HRT, CC-HRT, serous mucinous borderline tumor (epithelial ovarian cancer, EOC). 17 ERT -52S -
(RR, 1.4; 95% CI, 1.0 2.0) SC-HRT(RR, 1.5; 95% CI, 1.2 2.0) EOC CC-HRT EOC, ever-use unopposed estrogen serous borderline tumor (odds ratio 2.1, 95% CI 1.1 4.0). body mass index (BMI) BMI 25 3 (odds ratio 3.4, 95% CI 1.4 8.4) BMI 26. Lacey ERT 10 estrogen-progestin. 18 endometrioid type HRT (Table 5). Anderson 10 42 placebo 15 (RR, 1.58; 95% CI, 0.77 3.24). 19 WHI. HRT... HRT. Guidozzi randomized controlled trial HRT. 20 130 ERT ERT 32, 41,. ERT. 2 meta-analysis HRT (RR, 1.1; 95% CI, 0.9 1.3), 21 (RR, 1.15; 95% CI,1.05 1.27). 22 meta-analysis estrogen 10 1.27 (CI 95%, 1.00 1.61). estrogen. 4. 자궁경부암 (Cervical Cancer) hormone receptor. HRT. 15%.. Lacey case-control study HRT 2.1 (95% CI, 0.95 4.6) 0.85 (95% CI, 0.34 2.1). 23 2.7 (95% CI, 1.1 6.8) -53S -
Luncheon seminar 0.86 (95% CI, 0.26 2.8), 1.1 (95% CI, 0.26 5.0) (Table 6). HPV 2.0 (95% CI, 0.39 10.7).. Ploch 120 stage I II HRT 5. 24 5. 외음부암 (Vulvar Cancer). estrogen, progesterone, androgen receptor HPV progesterone.. case-control study 1.2 (95% CI, 0.7 2.1), 1.2 (95% CI, 0.6 2.3).. 25 HRT 1.2 (95% CI, 0.7 1.8). HRT. 6. 유방암 (Breast cancer) 1997 51 case-controlled, cohort study collaborative group HRT (current user) 1 4 1 (RR) 1.023 (95% CI, 1.011 1.036), 5 1.35 (95% CI, 1.21 1.49). 1 1.028 (95% CI, 1.021 1.034). 5 5, (body mass index) (Table 7). 26 Nelson ERT current user meta-analysis (RRs: 1.21 1.40) Estrogen ever user (RRs, 0.85 1.14), 4 (RRs, 1.23 1.35) (Table 2). (Million Women Study) 50 64 108 HRT. 27 HRT (current users) (RR, 1.66; 95% CI, 1.58 1.75), EPT (RR, 2.0; 95% CI, 1.88 2.12) ERT (RR, 1.30; 95% CI, 1.21 1.40).,, -54S -
. 10 ERT 1,000 5, EPT 19., 2.1. WHI study estrogen plus progestin trial (CEE 0.625mg, medroxyprogesterone acetate 2.5 mg) 5.2 26% (38 vs 30 per 10,000 person-years) (RR) 1.26 (95% CI: 1.00 1.59), (Figure 1). 2 HERS-II estrogen progestin 6.8 1.27 (95% CI: 0.84 1.94) 25% WHI. 28 WHI study estrogen-alone trial 0.77 (95% CI; 0.59 1.01) 23% (Figure 2). 29, observational study. 30 ( ). meta-analysis. 5 cohort study (RRs, 0.5 1.0). 5, 5 2 good-quality (Table 2).,.... HRT. HRT receptor,, HRT. HRT, HRT, receptor. O Meara 174 HRT (RR, 0.50; 95% CI, 0.30 0.85) (RR, 0.48; 95% CI, 0.29 0.78), HRT type (oral or vaginal). 31 11 214 52 HRT 4.2%, 5.4%. 32 HRT. vasomotor. -55S -
Luncheon seminar 20 30%. megestrol acetate, Selective Serotonine Re-uptake Inhibitor venlafaxine fluoxetine. diphosphonates, raloxifen, statin. tibolone estrogen, progestin, androgen vasomotor. 7. 결론 HRT vasomotor.. ERT. SC-HRT 10 5 12 14. CC-HRT. HRT HRT.,.. HRT., HRT. HRT,. estrogen. HRT.. estrogen receptor, 1st stage. receptor.. HRT. References 1. Hulley S, Grady D, Bush T, et al, for the Heart and Estrogen/progestin Replacement Study Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 2 80: 605-13. 2. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002; 288: 321-33. -56S -
3. Cushing KL, Weiss NS, Voigt LF, McKnight B, Beresford SA. Risk of endometrial cancer in relation to use of low-dose, unopposed estrogens. Obstet Gynecol 1998; 91: 35-9. 4. Nelson HD, Humphrey LL, Nygren P, et al. Postmenopausal hormone replacement therapy. (scientific review) JAMA 2002; 288: 872-81.(Level III) 5. Beresford SA, Weiss NS, Voigt LF, McKnight B. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestogen therapy in postmenopausal women. Lancet 1997; 349: 458-61. 6. Weiderpass E, Adami HO, Baron JA, et al. Risk of endometrial cancer following estrogen replacement with and without progestins. J Natl Cancer Inst 1999; 91: 1131-7. 7. Pike MC, Peters RK, Cozen W, et al. Estrogen-progestin replacement therapy and endometrial cancer. J Natl Cancer Inst 1997; 89: 1110-6. 8. Archer DF. The effect of the duration of progestin use on the occurrence of endometrial cancer in postmenopausal women. Menopause 2001; 8: 245-51. 9. Million Women Study Collaborators. Lancet 2005; 365: 1543-51. 10. Creasman WT, Henderson D, Hinshaw W, Clarke-Pearson DL. Estrogen replacement therapy in the patient treated for endometrial cancer. Obstet Gynecol 1986; 67: 326-30. 11. Lee RB, Burke T. W, Park RC. Estrogen replacement therapy following treatment for stage I endometrial carcinoma. Gynecol Oncol 1990; 36: 189-91. 12. Chapman JA, DiSaia PJ, Osann K, Roth PD, Gillotte DL, Berman ML. Estrogen replacement in surgical stage I and II endometrial cancer survivors. Am J Obstet Gynecol 1996; 175: 1195-200. 13. Suriano KA, McHale M, McLaren CE, Li KT, Re A, DiSaia PJ. Estrogen replacement therapy in endometrial cancer patients: a matched control study. Obstet Gynecol 2001; 97: 555-60 14. Spano JP, Soria JC, Kambouchner M, et al. Long-term survival of patients given hormonal therapy for metastatic endometrial stromal sarcoma. Med Oncol 2003; 20: 87-93. 15. Ursic-Vrscaj M. Hormone replacement therapy after uterine leiomyosarcoma treatment. Case reports. Eur J Gynaecol Oncol 1999; 20: 379-82. 16. ACOG committee opinion. Hormone replacement therapy in women treated for endometrial cancer. Number 234, May 2000 (replaces number 126, August 1993). Int J Gynaecol Obstet 2001; 73: 283-4. 17. Riman T, Dickman PW, Nilsson S, et al. Hormone replacement therapy and the risk of invasive epithelial ovarian cancer in Swedish women. J Natl Cancer Inst 2002; 94: 497-504. (Level II-2) 18. Lacey JV JR, Mink PJ, Lubin JH, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 2002; 288: 334-41. (Level II-2) 19. Anderson GL, Judd HL, Kaunitz AM, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA 2003; 290: 1739-48. 20. Guidozzi F, Daponte A. Estrogen replacement therapy for ovarian carcinoma survivors: A randomized controlled trial. Cancer. 1999; 15: 86: 1013-8. (Level I) 21. Coughlin SS, Giustozzi A, Smith SJ, Lee NC. A metaanalysis of estrogen replacement therapy and risk of epibreak thelial ovarian cancer. J Clin Epidemiol 2000; 53: 367-75. 22. Garg PP, Kerlikowscke K, Subac L, Grady D. Hormone replacement therapy and the risk of epithelial ovarian carcinoma: a meta-analysis. Obst Gynecol 1998; 92: 472-9. 23. Lacey JV, Brinton LA, Barnes WA, et al. Use of hormone replacement therapy and adenocarcinomas and squamous cell carcinomas of the uterine cervix. Gynecol Oncol 2000; 77: 149-54. 24. Ploch E. Hormonal replacement therapy in patients after cervical cancer treatment. Gynecol Oncol 1997; 26: 169-77. 25. Sherman KJ, Daling JR, McKnight B, Chu J. Hormonal factors in vulvar cancer. A case-control study. J Reprod Med 1994; 39: 857-61. 26. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative re-analysis of data from 51 epidemiologic studies o f 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997; 350: 1047-59. (Level II-2) -57S -
Luncheon seminar 27. Breast cancer and hormone-replacement therapy in the Million Women Study Million Women Study Collaborators. Lancet 2003; 362: 419-27. 28. Hulley S, Furberg C, Barrett-Connor E, Cauley D, Haskell W, Knopp R, Lowery M, et al. Noncardiovascular disease outcomes during 6.8 years of hormone therapy. Heart and estrogen/progestin replacement study follow-up (HERS II) JAMA 2002; 288: 58. 29. Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy: The Women's Health Initiative Randomized Controlled Trial 30. The Women's Health Initiative Steering Committee JAMA. 2004; 291: 1701-12. 31. Ross R, Paganini-Hill A, Wan P, et al. Effect of hormone replacement therapy on breast cancer risk: estrogen vs estrogen plus progestin. J Natl Cancer Inst 2000; 92: 328-32. (Level II-2) 32. O'Meara ES, Rossing MA, Daling JR, Elmore JG, Barlow WE, Weiss NS. Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality. J Nat Cancer Inst 2001; 93: 754-62. 33. Col NF, Hirota LK, Orr RK, Erban JK, Wong JB, Lau J. Hormone replacement therapy after breast cancer: a systematic review and quantitative assessment of risk. J Clin Oncol 2001; 19: 2357-63. 34. Purdie DM, Bain CJ, Siskind V, et al. Hormone replacement therapy and risk of epithelial ovarian cancer. Br J Cancer 1999; 81: 559-63. 35. Persson I, Yuen J, Bergkvist L, Schairer C. Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy- long-term follow-up of a Swedish cohort. Int J Cancer 1996; 67: 327-32. 36. Rodriguez C, Patel AV, Calle EE, Jacob EJ, Thun MJ. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA 2001; 285: 1460-5. 37. Risch HA. Estrogen replacement therapy and risk of epithelial ovarian cancer. Gynecol Oncol 1996; 63: 254-7. 38. Weiss NS, Lyon JL, Krishnamurty S, Dietert S, Liff JM, Daling JR. Noncontraceptive estrogen use and the occurrence of ovarian cancer. J Natl Cancer Inst 1982; 68: 95-8. -58S -
대한부인종양 콜포스코피학회제 20 차학술대회 이선경 : : : Tel: 02) 958-8327 Fax: 02) 965-1359 E-mail: leeobgy@yahoo.co.kr 1991.11~1992. 10 Vanderbilt University Gynecologic Oncology, Special Fellowship 1998~2004 유희석 : : : 442-721 5 Tel: 031) 219-5252 Fax: 031) 219-5245 E-mail: hsryu@ajou.ac.kr Ohio State University, Gynecologic Oncology Division, James Cancer Center 류기성 : : : 62 Tel: 02) 3779-2045 Fax: 02) 3779-1930 E-mail: ryuks@catholic.ac.kr