Effects of a short-term suspension of hormone replacement therapy on mammographic density

Transcription

1 FERTILITY AND STERILITY VOL. 76, NO. 3, SEPTEMBER 2001 Copyright 2001 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. Effects of a short-term suspension of hormone replacement therapy on mammographic density Nicola Colacurci, M.D., a Felice Fornaro, M.D., a Pasquale De Franciscis, M.D., a Daniela Mele, M.D., a Mario Palermo, M.D., b and Walter del Vecchio, M.D. b Institute of Gynecology and Obstetrics, School of Medicine, and Second University of Naples, Naples, Italy Objective: To evaluate the effects of hormone replacement therapy (HRT) and of a short-term suspension of HRT on mammographic density. Design: Prospective clinical study. Setting: Outpatient menopausal clinic of the Second University of Naples. Patient(s): Ninety-seven healthy postmenopausal women. Intervention(s): Thirty-nine menopausal women with intact uterus (group A) were treated with continuous transdermal E 2 plus acetate nomegestrolo sequentially added, 37 women in surgical menopause (group B) were treated with transdermal E 2 continuously administered, and 21 menopausal women did not receive any medication (group C). At the entry and after 12 months, a mammography was performed without suspension of HRT (group A1: 19 women; group B1: 19 women) or after a short-term suspension (group A2: 20 women; group B2: 18 women). Main Outcome Measure(s): Mammographic density evaluated according to a quantitative method. Result(s): At the second mammography, seven patients in group A1, four patients in group B1, and one patient in both groups A2 and B2 showed an increase in mammographic density, whereas no mammographic density increase was observed in patients in group C. A statistically significant difference in the mammographic density increase was found between group A1 and group A2; no difference was found between group B1 and B2. Conclusion(s): Suspension of HRT for about 3 weeks may reverse mammographic density increase associated with its use. (Fertil Steril 2001;76: by American Society for Reproductive Medicine.) Key Words: Breast, hormone replacement therapy, mammography, postmenopause Received December 29, 2000; revised and accepted March 27, Reprint requests: Nicola Colacurci, M.D., Via Manzoni 88, Naples, Italy (FAX: ; colacurci@ hotmail.com). a Outpatient Menopausal Clinic, Institute of Gynecology and Obstetrics. b Institute of Radiology, Second University of Naples /01/$20.00 PII S (01) Hormone replacement therapy (HRT) is widely recognized as an effective treatment for climacteric symptoms and as a preventive measure of cardiovascular disease and osteoporosis in postmenopausal women (1 3), but despite the numerous benefits of HRT, the compliance is still low (4). The fear of breast cancer is one of the main reasons that women are reluctant to begin HRT and are unwilling to continue it for the long term (5). Actually, there is much interest concerning the link between the use of HRT and breast carcinoma because an increased risk of this neoplasia has been reported with long-term HRT treatment (6). Mammographic screening is able to reduce breast cancer mortality (7), but the accuracy of screening mammography also depends on mammographic density (8, 9). The aim of our study was to investigate the effects of HRT and of a short-term suspension of HRT on mammographic density in postmenopausal women. MATERIALS AND METHODS Ninety-seven healthy postmenopausal women (mean age SD: years; range, years) were selected as eligible for the present study from January 1997 to December 1998 at the Outpatient Menopause Clinic of the Second University of Naples. The procedures used were in accordance with the guidelines of the Helsinki Declaration on human experimentation. All the patients signed written informed consent before they were enrolled. Inclusion criteria were as follows: 451

2 TABLE 1 Clinical characteristics of the study groups at baseline. Parameter Group A1 (n 19) Group A2 (n 20) Group B1 (n 19) Group B2 (n 18) Group C (n 21) Age (y) Age at menarche (y) Parity Age of first pregnancy (y) Age of menopause (y) Years since menopause FSH (miu/ml) E 2 (pg/ml) Body mass index (kg/m 2 ) Note: Values are means SD. menopausal status confirmed by serum FSH level of 30 miu/ml and E 2 level of 20 pg/ml, amenorrhea lasting between 12 and 60 months, no contraindication for the use of HRT, previous nonuse of oral contraceptives or of HRT, lack of benign mastopathies and of familiarity for breast cancer, and body mass index of 28. The study was designed to do the following: perform a baseline mammography at enrollment (T0); administer estroprogestogenic replacement therapy on continuous sequential regimen in women with uterus (group A) and continuous estrogen replacement therapy (ERT) in women without uterus (group B); and perform a control mammography after 12 months (T1) without discontinuing hormone replacement therapy or after a suspension of at least 14 days. Therefore, groups A and B were randomly assigned to two subgroups according to the time when the second mammography was performed: during HRT/ERT (groups A1 and B1) or during a free-hrt interval (groups A2 and B2). The study groups were as follows. Group A1 included 19 patients treated with continuous transdermal 17beta-E 2 (0.05 mg/d) plus acetate nomegestrolo (5 mg/d) added sequentially from day 17 to day 28 of each 28-day cycle. Group A2 included 20 patients treated with continuous transdermal 17beta-E 2 (0.05 mg/d) plus acetate nomegestrolo (5 mg/d) added sequentially from day 17 to day 28 of each 28-day cycle. Group B1 included 19 patients treated with transdermal 17beta-E 2 (0.05 mg/d) administered continuously. Group B2 included 18 patients treated with transdermal 17beta-E 2 (0.05 mg/d) administered continuously. Group C included 21 patients (16 in natural menopause and 5 in surgical menopause) not receiving any medication; they represented the control group. Screening consisted of performing two-view mammography; the films were always read independently by the same radiologists (M.P. and W.d.V.). In group A, the mammography was performed between the 3rd and the 10th day after the assumption of the last progestinic tablet. Mammographic density was evaluated according to the quantitative method proposed by Wolfe et al. in 1987 (10): the percentage of the total parenchymal area of each mamma covered with dense tissue was calculated by means of a computerized planimetric program. Three parenchymal patterns were considered: type 1, in which 25% of mammary gland is covered by dense tissue; type 2, in which from 25% to 75% of dense tissue is found in mammary gland; and type 3, in which 75% of mammary parenchyma is covered by dense tissue. All data are presented as mean standard deviation. Analysis of variance was performed to compare basal clinical characteristics between the study groups, and Fisher s exact test was performed to compare frequencies (Stat for Windows, Release 4.5, Stat Soft Inc., 1993; Epi Info 6, Version 6.04, 1996, CDC-Atlanta, WHO-Geneve). Statistical significance was set at P.05. RESULTS There were no statistically significant differences (P.05) between the study groups in the clinical characteristics at baseline (Table 1), and even the mammographic tests at time of recruitment revealed similar characteristics (Fig. 1). Before the second mammographic test, the patients from groups A2 and B2 discontinued HRT for a period of days and days, respectively, without significant differences; the duration of HRT was months in group A1, months in group A2, months in group B1, and months in group B2. At the second mammography, 7 of 19 patients included in group A1 showed an increase in mammographic density: in fact, between the first and the second mammography, there were five changes from type 1 to type 2 mammographic 452 Colacurci et al. HRT suspension and mammographic density Vol. 76, No. 3, September 2001

3 FIGURE 1 Changes of mammographic density patterns between the first (T0) and the second examination (T1). Open square, 25%; gray square, 25% 75%; filled square, 75%. pattern, one case of change from type 2 to type 3, and one case of change from type 1 to type 3. In group A2, we found one case of increased mammographic density, with a change in mammographic pattern type from 1 to 2. As regards the patients in surgical menopause treated with ERT, we observed an increase of mammographic density in 4 of 19 patients in the group B1 (with a change from type 2 to type 3 mammographic pattern in one case and from type 1 to type 2 in three cases); in group B2, one case of increase in mammographic density (shift from type 2 to type 3) was found. No variation of density was observed at the second mammographic test in the control group (Fig. 1). The mammographic density increase that occurred in group A1 was statistically significant (P.05) when compared with either that in group A2 or in the control group; we showed that a statistically significant difference between the mammographic density increase occurred in group B1 and the control group; and no statistically significant difference (P.05) was found in mammographic density increase between group B1 and group B2 (Fig. 2). DISCUSSION The findings of our study confirm that HRT may cause a mammographic density increase, as previously reported by other authors: Berkowitz et al. (11) showed an increased mammographic density in 5 of 30 women on HRT, McNicholas et al. (12) noted an increase in mammographic density with respect to basal mammography in 27% of the patients undergoing HRT, whereas Laya et al. (13) found an increased mammographic density in 30 of 41 women (73%) recruited in their study. In a previous study (14), we observed that in postmenopausal women, 12 months of sequential HRT may be associated with an increase in mammographic density, whereas tibolone does not seem to affect normostructured breast. Some studies have reported that the use of HRT may be associated with a reduction in specificity and sensitivity of screening mammography (15 18). Laya et al. (15) showed a decrease in mammographic specificity in patients using HRT at the time of the test (82% as compared with 86% in nontreated women). Kavanagh et al. (18) found a lower sensitivity of screening mammography in HRT users (64.8%) compared with nonusers (74.7%), after adjusting for age, symptomatic status, and family history. It has been suggested that the effects of HRT should be reversible because the specificity and sensitivity for former users were identical to those for women who had never used HRT (19). Harvey et al. (20) noted that 74% of women who had a new or enlarging, circumscribed mass or a developing breast density while on HRT experienced an interval decrease or resolution of the mammographic abnormality after a brief period (2 weeks) of hormone cessation. Therefore, they affirmed that short-term HRT cessation could avoid unnecessary biopsy and improve mammographic specificity. This retrospective study suggests that mammographic changes induced by hormonal replacement may be rapidly reversible. FERTILITY & STERILITY 453

4 FIGURE 2 Mammographic density increase at the second mammography. a P.05. b P.05. Our study investigates prospectively the effects of HRT and of a short-term suspension of HRT on mammographic density in postmenopausal women. At the second mammography, we showed in all treated groups an increased density that was statistically significant in women who did not discontinue both HRT and ERT when compared with the control group. As regards hormone treatment suspension, we noted a significantly lower increase of mammographic density in women discontinuing HRT (group A2) compared with the women not discontinuing (group A1), whereas we did not find any statistically significant difference in the mammographic density increase among patients taking ERT whether they suspended treatment (group B2) or not (group B1); nevertheless, we showed that mammographic density increase was less in group B2 than in group B1 (Fig. 2). We found that HRT suspension before mammographic tests in groups A2 and B2 led to a reduced frequency of mammographic density increase caused by hormonal therapy. Because high mammographic density is associated with a reduction in the sensitivity of screening mammography (8, 9), the results of our study entitle us to believe that a short-term cessation of HRT may be useful in enhancing mammographic sensitivity. Furthermore, the utility of HRT suspension appeared more evident with estrogen-progestogenic therapy than with the estrogen-only treatment. The different incidence of mammographic density increase between HRT and ERT observed in our study confirms that mammographic changes are different according to the regimen adopted, as previously reported (21 24). We showed that the sequential addition of acetate nomegestrolo led to a greater mammographic density increase than only E 2 did. Lundstrom et al. (23) found an increase in mammographic density to be much more common among women receiving estrogen in continuous combination with progestogen (52%) than among those receiving estrogen in cyclic combination with progestogen (13%) and estrogen-only (18%) treatment. It has been reported that postmenopausal HRT with estrogen plus progestin is associated with a greater breast epithelial cell proliferation and breast epithelial cell density than estrogen alone or no HRT (25); furthermore, stromal edema is also greatest in the luteal phase of the menstrual cycle (26), indicating the progesterone effect; therefore, a replacement therapy including a progestin should lead to more evident mammographic changes. In conclusion, the results of our preliminary study suggest that a short-term suspension of HRT before mammographic screening may reverse mammographic density increases associated with its use. In this light, we believe that the cessation of the replacement therapy for a brief period may be useful for enhancing the sensitivity of the mammographic test, especially when a progestin is added to the estrogen. However, further studies are necessary to establish whether time length of HRT influences this utility. References 1. Campbell S, Whitehead M. Oestrogen therapy and the menopausal syndrome. Clin Obstet Gynaecol 1977;4: Stampfer MJ, Colditz GA, Willet WC, Manson JE, Rosner B, Speizar FE, et al. Postmenopausal estrogen therapy and cardiovascular disease. N Engl J Med 1991;325: Ettinger B, Genant HK, Cann CE. Long-term estrogen replacement therapy prevents bone loss and fractures. Ann Intern Med 1985;102: Mattson LA. What do women want? Br J Obstet Gynaecol 1996;103: Okon MA, Lee S, Li TC. A study to examine women s knowledge, 454 Colacurci et al. HRT suspension and mammographic density Vol. 76, No. 3, September 2001

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