Mammographic Changes in Postmenopausal W omen :

Transcription

1 J Korean adiol Soc 199?; 36: 1 08? Mammographic Changes in Postmenopausal W omen : Comparative Effects between Continuous Combined Hormone and Single Estrogen eplacement Therapy 1 Sug Oh, M.D., Jong-Tae Choi, M.D., Kyoon Soon Jung, M.D.2, Seung Hye JungM.D. 2 Purpose : As the use of hormone replacement therapy for the menopausal women increases, some caution is advised, since there is an increased risk ofbreast cancer. Accordingly, the importance of regular mammography has been addressed. This cross-sectional study analyzed the effects of different hormone therapies on mammographic density. Materials and Methods: Sixty-seven postemenopausal women who had completed one year ofhormone therapy and had undergone follow-up mammography, were divided into two groups: Group 1 : continuous conjugated equine estrogen, O. 625mg, plus continuous medroxyprogesterone acetate, 2.5mg (n=48), Group II : continuous conjugated equine estrogen mg (n = 19). The mammograms were read by two radiologists. es비 ts : With regard to the radiologists involved, interobserver reliability (kappa) was 0.70 and intrao bserver reliability (kappa) was 0.51 and Before hormone therapy, factors related to decreased mammographic density were age and number of full term pregnancies (p < 0.05). After one year ofhormone therapy, body fat showed a significant increase (p < 0.05), but in spite of this, increased mammographic density induced by hormone therapy remained significantly high (p < 0.05). Compared with Group II, Group 1 showed a significant increase in mammographic density (p < 0.05). In Group 1, mammographic density increased from P2 to DY pattern in two cases, but there was no such change in Group II. Conclusion : The increase of mammographic density seen in Group II was much more significant statistically than that seen in Group 1. The mammograms ofwomen who have undergone continuous combined hormone therapy should therefore be interpreted very cautiously. Index Words : Breast, parenchymal pattern Breast radiography Increasing numbers of postmenopausal women are undergoing hormone replacement therapy (HT) for a variety ofreasons : to relieve menopausal symptoms, to prevent menopause- induced osteoporosis, and for the beneficial effects on the prevention and prognosis of cardiovascular disease (1, 2). Even though the risk of breast cancer is a matter of controversy, some prospec- tive studies have indicated a gradually-increasing risk of this after long term estrogen use (3, 4); in a significant percentage ofwomen undergoing HT, increased breast density on mammography has also been reported (5, 6). There are many factors affecting breast density; we analyzed the differing effects of different HT regimens in postmenopausal women. IDepartmentofFamily Medicine, Jeil Women s Hospital, Seoul, Korea ' Department of adiology, Jeil Women s Hospital, Seoul, Korea eceived December 23, 1996; Accepted April3, 1997 Address reprint requests to : Sug Oh, M.D., Department of Family Medicine, Yongdong Jeil Women s Hospital, # , Daechi-dong, Kangnam-Ku, Seoul, Korea. Tel Fax Subjects and Methods Subjects Among 1934 women who visited Yongdong Jeil

2 Sug Oh. et' a/: Mammographic Changes in Postmenopausal Women Women s hospital for their first general examination, 67 postmenopausal women who had fulfilled the following criteria were selected : 1) last menstrual period at least one year previously; 2) FSH) 4O m1u and last menstrual period at least 6 months previously; 3) no previous history of hormone replacement therapy ; 4) successful follow-up of second mammography one year after baseline mammography. These 67 women were treated for 12 months with one of two regimens : Group 1 : 48 women who received 0.625mg/day conjugated equine estrogen (CEE) (Premarin, Wyeth-Ayerst Laboratories, adnor, PA) plus 2.5mg/day medroxyprogesterone acetate (Provera, Upjohn Co., Kalamaz- 00, MI) for 30 consecutive days, Group II : 19 women who received CEE, 0.625mg/day, for 30 consecutive days. Mammography Baseline craniocaudal and mediolateral oblique mammograms were obtained with a Senographe 600T (G.E., Milwaukee, U.S. A.), using the maximum tolerated compression. All subjects underwent a follow-up mammogram, using the same equipment, one year after their first visit. All mammograms were obtained by the same radiologic technologist, who maintained strict quality control, and were evaluated by two board certified radiologists. Mammographic density was assessed according to the Wolfe classification (7, 8) : Nl, breasts composed primarily of fat; Pl, prominent ducts in the subareolar area involving approximately one-third of the breast; P2, prominent ducts involving the major portion of the breast; DY, a considerable amount of collagen or dysplasia, with or without identified ducts. Data Analysis An estimation of the reliability ofthe two radiologists used kappa statistics (9) to compare interobserver consistency, and 3-month interval readings ofthe same 40 films to determine intraobserver reproducibility. To assess the factors that have been shown to influence the appearance of the breast on mammograms before hormone replacement treatment (10-12), simple correlation and multiple regression analysis were perfor med. These factors include interval since last men strual period, age at menarche, number of children, weight, body fat, and lactation. Comparisons of those factors before and after hormone therapy were performed using student s t-test for paired quantitative data. After adjustment for those factors which significantly changed after treatment, differences in mammographic changes between the two regimens were compared by ANOV A. We used the Statistical Package for Social Sciences for Windows TM(SPSS Inc, Chicago, 1L, U.S.A.) for calculation; the minimum level of statistical significance for all analyses was p (0.05. esults eliability of Mammographic eadings between two adio/ogists 1nterobserver reliability (kappa) was 0.70 while intraobserver reliability (kappa) was 0.51 and 0.67 General Characteristics of Study Population (Tab/e 1) Mean age of the study population was 58 :t 7.8 years, and median ages of menarche and menopause were 16 and 49 years, respectively. As older women disliked bleeding during hormone therapy, we had, for them, preferred to prescribe a continuous combined regimen. Table 1 clearly shows that those women who underwent this regimen were older and had a much higher body fat component than those whose therapy involved only estrogen (p (0.05). Factors influencing Mammographic Density before Hormone eplacement Therapy (HT) (Tab/e2) As women aged, they had less dense breast (p = O. 002) and the more children they had, the less dense were their breasts (p=o.ooi); tall women had denser breasts (p=o.027). Age of menarche and menopause, smoking history, body weight, body fat, body mass index (BM1), and lactation were not statistically significant factors influencing mammographic change Table 1. Comparison of Demographic & Anthropometric Characteristics of Two Groups Group I Group n n mean (SD) n mean (SD) Age (years) (7.1)* (6.2) Pregnancy No (1.7)* 정 (0.8) Menarche (years) (1. 9) (1. 8) Menopause (years) (4.3) (4.9) Weight (kg) (7.9) (5.7) Height (cm) (5.1) (4.3) Body fat (%) (4.7)* (4.4) BMI (kg/cm 2 ) (3.2) (2.0) * p < 0.05 vs. Group II Group 1 : continuous conjugated equine estrogen 0.625mg plus continuous medroxyprogesterone acetate 2.5mg Group II : continuous conjugated estrogen 0.625mg

3 J Körean adi 이 S 1997; 36: When age was controlled by using multiple regression analysis, these factors lost their statistical significances. Mammographic Change after Hormone eplacement Therapy (HT) After hormone therapy, increased mammographic density was noted in both groups; it was seen in 30 of 67 postmenopausal women (44.8 %) who had undergone HT. The mammographs of the 48 women who had undergone continuous combined HT showed significantly increased dens띠1 in 27 cases (56.3 %) ; this was seen in only 3 of 19 (15.8 %) who underwent single estrogen replacement therapy (ET) (p < 0.05) (Fig 1, 2) (Tabel 3). Because hormone therapy changes some anthropometric components, we analyzed factors inf1uencing mammographic change after HT. Only hormone therapy itself had a significant impact on mammographic change (p = O.OOI) (Table 4). In women who had undergone continuous combined HT, two cases showed the DY pattern, which changed from P2, while there was no such change in the single ET group. Discussion Previously little kaown effects of HT, such as dementia and cardiovascular protection have recently came to light, and this has increased demand upon this treatment. With increasing numbers ofwomen undergoing HT, physicians are very concerned about the possible risk of breast cancer and advocate regular mammography. Mammographic change associated with HT has been reported in many studies (6, 13-15), including ours, in which 44.8 % (30/67) of postmenopausal women showed increased density, a figure much higher than that ofstomper et al. (14), who reported that 24 % (12/50) of postmenopausal women undergoing HT showed mammographic change, or of Berkowitz et al. (15) whose data showed that change Table 2. Correlation of Mammographic Density with Demographic & Anthropometric Variables before Hormone eplacement Therapy (HT) Significant (p < 0.05) Age (yeras) r = p = n=67 Height(cm) r = p = n= 65 Pregnancy number r = p = n=65 BMI = Body Mass Index Not Significant Menarche (years) Menopause (years) Smoking Weight(kg) Body fat(%) BMI (kg /cm 2 ) Lactation A B c D Fig. 1. Significant mammographic change of 54 year old woman (A, 8) and 67 year old woman (C, D) before (A, C) and after (8, D) continuous combined hormone replacement therapy

4 Sug Oh. et a/: Mammographic Changes in Postmenopausal Women had occurred in 17 % of women. Both these studies showed that treatment with both estrogen and progesterone more often led to mammographic change than treatment with estrogen alone. This latter increases the mitogenic activity of epithelial cells, which leads to duct growth; connective tissue surrounding the ducts is also very sensitive to the action of estrogen. Whether progesterone causes increased or Table 3. Mammographic Density before & after Hormone eplacement Therapy (HT) between Two Gro 때 S before HT after HT M N m N *Group 1 (n=48) mη깅7 5 애깅2 Group n (n=19) * p < 0.05 vs. Group n Group 1 : continuous conjugated equine estrogen 0.625mg plus continuous medroxyprogesterone acetate 2. 5mg Group n : continuous conjugated estrogen 0.625mg 1ι NS 1i 1i n? 1i decreased or has no effect on mitotic activity and proliferation of breast epithelial cells, continues to be very controversial. Progesterone acts in synergism with estrogen on the distal portion of the ducts, favoring differentiation into acini, and promotes the growth of lobuloalveolar structures. It can reduce estrogen induced proliferation and converts the proliferative effect of estrogen on the ductal cells into cellular differ entiation (16; 17). As ductal, periductal connective, and lobular tissue proliferates in response to a combination of estrogen and progesterone, the greatest increase in mammographic breast density would be expected in women being treated with combination Table 4. Correlation of Mammographic Changes with Anthropometric Changes after Hormone eplacement Therapy (HT) B 뼈T G v nu B o B h -M 빼때안뺑t 서매oe-s 삐%써파싸-= -m -빡CJ m r= p=o.ool n=67 NS NS BMI = Body Mass lndex A 8 C D Fig. 2. No significant mammographic change of 50 year old woman (A, 8), and 55 year old woman (C, D) before (A, C) and after (8, D) singe estrogen replacement therapy

5 J Korean adiol Soc 1997; 36: therapy (5). There has, however, been no report describing the likely effect of different drug combination on mammographic change. Our study showed that the continuous combined regimen we used resulted in significantly increased mammographic density after one year s treatment; we observed that mammographic density after 50 years of age, or after menopause decreased, and breast parenchyma became less dense (7, 8, 12). Boyd et a1. (18) reported the relationship between mammographic density and hist이 ogic risk factor for breast cancer, and Wolfe (7, 8) and Saftla (19) reported an increased risk of breast cancer in women with mammographically dense breasts. According to Saftla s retrospective review of cases detected during the fifth year of the Breast Cancer Detection Demonstration 안이 ects ' (19), high risk patterns were particularly significant in women with a positive family history of breast cancer ; in those with P2 or DY patterns, the likelihood ofbreast cancer was 7.37 times higher than in those with an N1 pattern. In women with no family history, the corresponding odds ratio was In our study, two cases who had undergone the continuous combined HT showed a DY pattern after one year' s treatment, while there was no such change in the single ET group. This implies that in the continuous combined HT group, we should be alert to the risk of increased risk of breast cancer. Most postmenopausal women who underwent continuous combined therapy complained of more frequent mastalgia (data not shown) than those whose regimen was different. Plu-Bureau et a1. (20) asserted that mastalgia is an easy and early marker of breast susceptibility to estrogen, and reported that it was associated with the occurrence of breast cancer. Beca use of breast tenderness, adequate breast compression could not be performed, resulting in an apparent increase in density and a decreased sensitivity ofmammograms. In women under 50, breast density had a greater inf1uence on mammographic sensitivity than was the case in women aged 50 or over (12); in women with primarily fatty breasts, sensitivity was higher. Irrespective of the cause of increased density, improved quality and increased sensitivity are very important for reliable mammographic interpretation. Our study showed that mammographic density increased significantly as a result of continuous combined HT; this treatment could thus lead to decreased m know whether increased density would disappear after a couple ofyears under the combined regimen. To be aware of further mammographic change, which might occur after the first year of treatment, a longer follow-up period is therefore needed; longitudinal observation to assess the relative risk of eventual breast cancer with the use of the continuous combined regimen is also required. In conclusion, this regimen, with estrogen and progesterone, led to a significant increase in mammographic density, compared to that seen after single estrogen therapy. To determine whether this increase remains or disappears - in other words, to determine its clinical significance - a longer follow-up period is required; after resolving such factors as mastalgia and mammographic sensitivity, further studies are therefore needed. Dense mammograms should also be interpreted more carefully. eferences 1. European Menopause Society. European consensus development conference on menopause. Human eproduction 1996; Harlap S. The benefits and risks of hormone replacement ther apy: an epidemiologic overview. Am J Obstet Gynecol 1992; Bergkvist I, Adami H, Persson I, Hoover, Scharer C. The risk of breast cancer after estrogen and estrogen-progestin replace ment. N Engl J Med 1989; 321 : Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995; 33 2: Cylark D, Wong CH. Mammographic changes in postmenopausal women undergoing hormonal replacemcnt therapy. AJ 1993; 161: Mcnicholas MMJ, Heneghan JP, Milner MH, et al. Pain and increased mammographic density in women receiving hormone replacement therapy. AJ 1994; 163: Wolfe JN. isk for breast cancer development determined by mammographic parenchymal pattern. Cancer 1976; 37: Wolfe JN. Breast patterns as an index of risk for developing breast cancer. AJ 1976 ; osner B. Fundamentals of Biostatistics. 2nd ed. Boston Duxbury Press, 1990; Buchanan JB, Weisberg BF, Sandoz JP, Gray LA, Bland KI. Selected prognostic variables for mammographic parenchymal variables. Cancer 1981; 47: Leinster SJ, Whitehouse GH. The mammographic breast pattern and oral contraception. Br J adiol 1986; 59: Kerlikowske K. Grady D, et al. Effect of age, breast density, and family history on the sensitivity of first screening mammography. JAMA 1996; 276: Peck D, Lowman M. Estrogen and the postmenopausal breast: mammographic considerations. JAMA 1978; 240: Stomper Pc. VonVoorhis BJ, avnikar VA. Meyer JE. Mammograhic changes associated with postmenopausal hor

6 Sug Oh. et a/: Mammographic Changes in PostmenopausalWomen mone replacement therapy : a longitudinal study. adiology 1990 ; gesterone on human breast epitheli 꾀 cell cycje in vivo. Fertil and 174: Steri11995; 63: Berkowitz JE, Gatewood OMB, Goldblum LE, Gayler BW. Hor- 18. Boyd NF, Jensen HM, Cooke G, Han HL. elationship between monal replacement therapy: mammographic manifestations. mammographic and hisologic risk factor for breast cancer. J Natl adiology 1990; 174: Cancer Inst 1992 ; 84: Kuttenn F, Fournier S, Sitruk-W are, Martin P, Mauvais-Jarvis P. 19. Saftla AF, Szklo M. Mammographic parenchymal patterns and Progesterone deficiency in benign breast disease. In: Angeli A, breast cancer risk. Epidemiol ev 1987; 9: Bradlow ML, Dogliotti L, eds. Endocrinology of cystic breast disease. 20. Plu-Bureau G, Thalabard JC, Sitruk-Ware, Asselain B, New York: aven, 1983; Mauvais-Jarvis P. Cyclical mastalgia as a marker of breast cancer 17. Chang KJ, Lee TTY, Linares-Cruz G, Fournier S, Lignieres B. susceptibility: result of a case-control study among French Influences of percutaneous administration of estradiol and pro- women. Br J Câncer 1992 ; 65 : 대한빙사선의학회지 1997; 36: 폐경여성에서지속적병합요법과에스트로젠단독요법간의 유방음영변화의비교 1 l 영동제일병원가정의학과 2 영동제일병원방사선과오석 최종태 정균순2 정숭혜 2 목 적 : 폐경여성에서심혈관계질환, 골다공증의예방및갱년기에나타나는여러증상을예방하고치료하 기위해호르몬제제들을사용하고있다. 호르몬제의사용에따른유방암의위험도에대한논란이많은바호르 몬사용시유방촬영은필수적인검사가되었다. 따라서저자들은지속적인에스트로젠요볍과지속적인에스트 로젠과프로제스테론의병합요법간의유방실질음영의변화를살펴보고이에대한임상적의미를고찰하였다. 대상및방법 : 결합에스트로젠 (CEE 0.625mg, Premarin) 과 MPA 2. 5mg 을연속적으로투여한 48명과 CEE 0.625mg 을연속적으로단독투여한 19 명, 총 67 명을대상으로치료전유방촬영소견과치료 l 년후소견을비교 분석하였다. 결 과 : 유방촬영의판독은 2 명의방사선과전문의가하였으며, interobserver reliabili ty 는 0.70 (kappa), intraobserver reliabili ty는 kappa값이각각 0.51, 0.67이였다. 치료시작전유방음영의감소소견과관련된요인 들은임신회수 연령의증가였다 (p<0.05 ). 호르몬투여 1 년후투여전에비해체지방의유의한증가를보였다 (p<0.05). 체지방의증가를조절한후에도호르몬투여에따른유방음영의증가된소견은변하지않았다 (p<o. 05). 에스트로젠단독투여군에비해병합투여군에서는유방음영의유의한증가를보였다 (p<0.05). 에스트로젠 단독투여군에서는 P2 에서 DY 로의음영증가는없었으나병합투여군의경우, 2 명에서 DY 로증가된소견을보 였다. 결론 : 호르몬제제에따른유방음영의증가는지속적병합투여군에서통계학적으로유의한증가를보였다. 따라서지속적인호르몬투여여성에서유방촬영판독시이러한사항을고려해야하겠으며병합투여군에서 DY 로음영증가를보인여성의경우유방암위험도에대해재평가하고, 호르몬요볍이지속적으로필요한경우철 저한유방검사와자가진찰이필요하다고생각된다