Influence of different HRT regimens on mammographic density

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1 Maturitas 50 (2005) Influence of different HRT regimens on mammographic density Hans Junkermann a,, Thomas von Holst b, Eva Lang c, Viatcheslav Rakov c a Ruprecht-Karls-Universität Heidelberg, Universitäts-Frauenklinik, Abteilung für Gynäkologische Radiologie, Heidelberg, Germany b Ruprecht-Karls-Universität Heidelberg, Abteilung für Gynäkologie, Heidelberg, Germany c Novo Nordisk, RE A/S, Zurich, Switzerland Received 7 November 2003; received in revised form 18 March 2004; accepted 27 April 2004 Abstract Objectives: A prospective, randomized, open-label study was conducted to evaluate effects on mammographic density in postmenopausal and late perimenopausal women receiving continuous combined or sequential combined hormone replacement therapy (HRT). Methods: The subjects were randomized to treatment with low-dose continuous combined HRT containing 1 mg 17 -estradiol plus 0.5 mg norethisterone acetate (Activelle ) or a sequential combined HRT regimen consisting of mg conjugated equine estrogens for 28 days plus 5 mg medrogestone for 14 days (Presomen ). Mammograms were obtained at baseline and after 9 cycles (each 28 days) of treatment. Results: The majority of women (approximately two-thirds in each treatment group) had no changes in mammographic breast density between baseline and the final study visit. There were no marked differences between treatment groups. Approximately 20% of women in both groups had a slight increase in mammographic density. Only 10 14% of women in both groups had a pronounced increase in mammographic density. The analyses of the degree of change showed no remarkable differences between treatments. Conclusion: These results indicate that the increase in mammographic density with a low-dose continuous combined HRT regimen is no greater than that with a sequential combined HRT regimen. The type of progestogen does not have an impact on the extent of mammographic density changes Elsevier Ireland Ltd. All rights reserved. Keywords: Breast cancer; Estradiol; Hormone replacement therapy; Mammographic density; Mammography; Norethisterone acetate 1. Introduction Screening mammography significantly reduces the rate of mortality from breast cancer in women 50 years of age and older [1,2]. HRT may increase the mammographic density of breast tissue and impair the ability to detect early signs of breast cancer [3 5]. The Corresponding author. Tel.: ; fax: address: hansjunkermann@aol.com (H. Junkermann). appearance of hormonally induced densities may also mimic that of breast disease, leading to diagnostic uncertainty and the need for additional mammographic assessments [5,6]. In women who are not taking hormones, radiographically dense breasts are associated with an increased risk of malignant breast tumors [7,8]. Conversely, no link has been established between hormonally related increases in breast density and an elevated risk of breast cancer [7,9 11]. Radiographic density related to HRT is nonetheless a matter of potential concern due to the risk of decreased sen /$ see front matter 2004 Elsevier Ireland Ltd. All rights reserved. doi: /j.maturitas

2 106 H. Junkermann et al. / Maturitas 50 (2005) sitivity and specificity of mammography and the loss of a degree of diagnostic confidence [5,6,10,12 14]. Some analyses have suggested that mammographic density is influenced more by continuous combined HRT regimens than by sequential combined regimens, and less so by unopposed estrogen [4,15 18]. Observers have also suggested that mammographic changes vary with the type of progestogen [4,15,19,20]. To shed more light on these issues, effects on radiographic breast density were compared as part of a prospective, randomized, open-label, multicenter study in which late perimenopausal and postmenopausal women received either a low-dose continuous combined HRT regimen containing 1 mg 17 -estradiol (E 2 ) and 0.5 mg norethisterone acetate (NETA) (Activelle, Novo Nordisk) or a sequential combined regimen containing mg conjugated equine estrogens (CEE) and 5 mg medrogestone (MG) (Presomen Comp, Solvay). The primary objective of the trial was to compare bleeding profiles with the two treatments. These results have been reported elsewhere [21]. Because the protocol called for all participants to undergo blinded mammographic assessments, the investigation also provided a valuable opportunity to examine changes in breast density with the two types of HRT regimens. Mammographic density was thereby designated as a secondary parameter. 2. Subjects and methods 2.1. Subjects Women were considered eligible for the study if they were younger than 65 years old, had an intact uterus and a normal endometrium (endometrial thickness <5 mm (double layer) on transvaginal ultrasound), and experienced their last natural menstrual cycle at least 6 months before baseline screening. The women were also required to present with menopausal symptoms (e.g., hot flushes and sweating) that would benefit from HRT. Exclusion criteria included an abnormal mammogram, known or suspected breast cancer or a history of this disease, known or suspected estrogen-dependent neoplasia (e.g., endometrial cancer), hepatic or renal impairment, type 1 or 2 diabetes mellitus; presence or history of deep venous thrombosis or thromboembolic disorders, known or suspected pregnancy or lactation, and known contraindications to estrogen treatment. Women were also excluded from the study if they had used any exogenous sex steroid hormones within the preceding 6 months Study protocol Following baseline assessment, eligible women were randomized to 9 cycles of treatment (each 28 days) with either continuous combined HRT (1 mg E 2 /0.5 mg NETA) or sequential combined HRT (0.625 mg CEE/5 mg MG). All subjects gave written informed consent of their willingness to participate in the trial. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki, and permission was secured from all local institutional review boards or independent ethics committees. Mammography was performed at baseline (screening visit (1) unless the results of a bilateral mammogram obtained within the previous 6 months were available. Mammography was repeated at the final visit (after 9 treatment cycles) or at the time of patient withdrawal from the study in cases of premature discontinuation, provided at least 7 cycles of study treatment had been taken. Mediolateral or oblique and craniocaudal images of both breasts were obtained. The density of breast parenchyma in the baseline mammograms (taken at visit 1 or within 6 months before screenings) was compared with that in the mammograms taken at the final visit. The mammograms for each subject were visually compared in pairs by one radiologist who was blinded to the timing of the mammograms (i.e., which images were taken before or after study treatment) and to the type of HRT the patient received. Each pair of mammograms was judged according to whether there was no detectable change or a slight or marked change in breast density. The treatment effect was categorized as marked lower density, mild lower density, no difference, mild higher density, and marked higher density. Statistical analyses were performed using the Wilcoxon test and Fisher s exact test. 3. Results A total of 513 postmenopausal or late perimenopausal women were enrolled in the study at 35

3 H. Junkermann et al. / Maturitas 50 (2005) centers in Germany and Austria. Of this group, 446 fulfilled all requirements and were randomized to the two treatment arms (223 in each group). A total of 82 subjects (16.0%) discontinued treatment prematurely: 23 subjects (10.3%) in the 1 mg E 2 /0.5 mg NETA group and 51 subjects (22.9%) in the mg CEE/5 mg MG group. The most common reason for withdrawal from the study was the occurrence of adverse events, which accounted for treatment discontinuations in 13 subjects (5.8%) in the 1 mg E 2 /0.5 mg NETA group and 20 subjects (9.0%) in the mg CEE/5 mg MG group. The intent-to-treat population for the mammographic analysis included patients with mammograms before and at the end of treatment: 167 subjects in the 1 mg E 2 /0.5 mg NETA group (mean age, 54.9 years; range, years) and 139 subjects in the mg CEE/5 mg MG group (mean age, 54.5 years; range, years). A total of 159 subjects in the 1mg E 2 /0.5 mg NETA group (mean age, 54.9 years; range, years) and 132 subjects in the mg CEE/5 mg MG group (mean age, 54.6 years; range, years) were included in the per-protocol population (women who did not miss more than 5 days of trial medication during any 1 month and not more than 20% of trial medication over the entire treatment period, and who completed the study). The demographic and screening characteristics of the two treatment groups did not differ markedly. Table 1 summarizes the results of the comparison of mammographic density from baseline to final visit in the per-protocol population. There were no notable differences between the treatment groups. The majority of women, comprising approximately two-thirds of each treatment group, had no change in mammographic breast density between baseline and final study visit. Overall, approximately one-third of women in each group had some degree of increase in breast den- Table 1 Change in mammographic density from baseline to final visit with 1 mg E 2 /0.5 mg NETA and mg CEE/5 mg MG (per-protocol population) View 1 mg E 2 /0.5 mg NETA mg CEE/5 mg MG n % n % Oblique or mediolateral, right breast Markedly lower Slightly lower No difference Slightly higher Markedly higher Craniocaudal, right breast Markedly lower Slightly lower No difference Slightly higher Markedly higher Oblique or mediolateral, left breast Markedly lower Slightly lower No difference Slightly higher Markedly higher Craniocaudal, left breast Markedly lower Slightly lower No difference Slightly higher Markedly higher

4 108 H. Junkermann et al. / Maturitas 50 (2005) Table 2 Comparison of continuous combined HRT (1 mg E 2 /0.5 mg NETA) vs. sequential combined HRT (0.625 mg CEE/5 mg MG) for dichotomized variable of higher mammographic breast density vs. not higher density for each mammographic view Fig. 1. Percentage of postmenopausal and late perimenopausal women with any increase in breast density after receiving continuous combined HRT (1 mg E 2 /0.5 mg NETA) or sequential combined HRT (0.625 mg CEE/5 mg MG) for 9 months. Robl/ml = right oblique/mediolateral; Lobl/ml = left oblique/mediolateral; Rcc = right craniocaudal; Lcc = left craniocaudal. sity (Fig. 1). Approximately 20% of subjects in each group had a slightly higher density. A pronounced increase in density was observed in only 10 14% of women in both groups, again with no remarkable difference between the two HRT regimens (Fig. 2). An evaluation of the incidence of mammography density at the final visit compared to baseline with regard to the dichotomized variable higher density versus not higher density likewise revealed no substantial differences between treatment groups (Table 2). Fig. 2. Percentage of postmenopausal and late perimenopausal women with a pronounced increase in breast density after receiving continuous combined HRT (1 mg E 2 /0.5 mg NETA) or sequential combined HRT (0.625 mg CEE and 5 mg MG) for 9 months. Robl/ml = right oblique/mediolateral; Lobl/ml = left oblique/mediolateral; Rcc = right craniocaudal; Lcc = left craniocaudal. View P-value (Fisher s exact test) a Oblique or mediolateral, right breast Craniocaudal, right breast Oblique or mediolateral, left breast Craniocaudal, left breast a For dichotomized variable of higher mammographic breast density vs. not higher density with 1 mg E 2 /0.5 mg NETA vs mg CEE/5 mg MG. Abnormal mammographic findings were reported in three subjects at the final visit. One subject treated with 1 mg E 2 /0.5 mg NETA was reported to have onset of fibrocystic/adenomatous structures, and one subject in each treatment group was reported to have fibroadenomas. There were no reports of breast cancer in this study. 4. Discussion Continuous combined HRT with 2 mg E 2 or 0.6 mg CEE has previously been shown to have a stronger impact on mammographic breast density compared to sequential HRT or unopposed estrogens. Therefore, it is important to look for the hormone dose in continuous combined preparations, which can minimize side effects without compromising efficacy of treatment. The results of this study demonstrate that the incidence and extent of changes in mammographic breast density are no different with a low-dose continuous combined HRT regimen (1 mg E 2 /0.5 mg NETA) than with a sequential combined regimen (0.6 mg CEE/5 mg MG) in postmenopausal and late perimenopausal women. In contrast to these findings, some prior reports suggested that increases in mammographic breast density were related to the HRT application scheme, with greater effects associated with continuous combined regimens [4,15 17]. A 1998 consensus document concluded that the incidence of increased mammographic density was as much as twice as high with continuous combined HRT (up to 30%) compared with cyclic combined HRT (up to 15%) [18]. In a more recent

5 H. Junkermann et al. / Maturitas 50 (2005) report on 175 consecutive women participating in a population-based screening program, increased radiographic breast density was identified in 52% of subjects who received continuous combined HRT with 2mgE 2 /1 mg NETA, as opposed to only 13% of those who received cyclic-sequential HRT (either 2 mg E 2 valerate for 11 days followed by 2 mg E 2 valerate plus 250 g levonorgestrel for 10 days, or 2 mg E 2 for 12 days followed by 2 mg E 2 plus 1 mg NETA for 10 days, followed by 1 mg E 2 for 6 days) [15]. The rate in women using estrogen alone (2 mg E 2 valerate or mg CEE) was 18%. These findings contrast with those of the present study. The lack of a more pronounced effect with continuous combined HRT as opposed to the sequential combined HRT regimen in our study may be related to the fact that the continuous regimen incorporated a lower dose of E 2 (1 mg) than that used in previous studies (2 mg) and a lower dose of NETA (0.5 mg) as well. More recently, an analysis of data from 571 participants in the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial found that the percent change in mammographic breast density did not vary by application scheme in women receiving continuous HRT with CEE 0.625/medroxyprogesterone acetate (MPA) 2.5 mg, cyclic HRT with daily CEE mg plus MPA 10 mg on days 1 through 12, or daily CEE plus micronized progesterone [7]. The question of the role of different progestogens has been discussed in the literature. A recent 12-month study of 121 women found that breast density increased in 31.4% of those receiving E 2 /NETA compared with 11.8% of those receiving CEE.MPA [19]. However, this study investigated high-dose combinations (2 mg E 2 /1 mg NETA and mg CEE/5 mg MPA). Overall, clinical studies have not been able to demonstrate that different progestogens have divergent effects on breast density [11]. The present study likewise found that the occurrence and extent of mammographic changes did not vary by the type of progestogen (NETA or MG). One reason for the attention given to HRT-induced increases in breast density is the possibility that such changes might undermine the utility of mammographic screening and require patients to undergo additional assessments. Although some investigators have described reductions in mammographic sensitivity, [5,6,10,12 14] recent retrospective and prospective studies from Massachusetts General Hospital concluded that recall rates for repeat evaluations were essentially the same in hormone users and nonusers [22]. An additional reason for the attention given to HRT-related mammographic changes is the fact that higher endogenous (naturally occurring) density is associated, in a graded fashion, with a higher risk of breast cancer [8,23]. Importantly, however, no link has been established between HRT-related changes in breast density and changes in the risk of breast cancer, stage of cancer at diagnosis, or associated mortality [7,9,10]. Another key consideration is that HRT-related increases in mammographic density are transient and reverse within weeks of the discontinuation of therapy [9,11,24,25]. Investigators have suggested that the increase in breast density seen with HRT may be morphologically different from that associated with an increased risk of breast cancer in untreated women [9]. Based on the data from some clinical studies the changes that occur in response to HRT could represent a combination of edema and vasodilatation, rather than epithelial proliferation [9]. But further investigations of this issue are needed. A major concern of postmenopausal women who have an intact uterus is the possibility of withdrawal bleeding with sequential combined HRT. Studies have found that fewer than 10% of postmenopausal women have little or no objection to monthly withdrawal bleeding with HRT [26]. Continuous combined HRT is the preferred treatment option for women who do not accept withdrawal bleeding because it typically produces a state of amenorrhea (although sporadic bleeding episodes may occur, particularly during the initial months of therapy) [27,28]. The primary analysis from the present trial showed that the incidence of irregular bleeding episodes was significantly reduced with the low-dose continuous combined regimen (1 mg E 2 /0.5 mg NETA) compared to the sequential combined regimen (0.625 mg CEE/5 mg MG): 12.2% versus 25.8%, respectively (P = ) [21]. Continuous combined therapy is the preferred regimen for postmenopausal women, and the observed improvement in irregular bleeding suggests that it may also be a useful option for late perimenopausal women. The lack of a difference in mammographic density between the continuous combined and sequential combined HRT regimens is therefore of substantial interest regarding safety concerns with

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