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DOI: 10.1148/radiol.2351040012
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(Radiology 2005;235:36-41.)
© RSNA, 2005

Breast Imaging

Hormone Replacement Therapy in Postmenopausal Women: Breast Tissue Perfusion Determined with MR Imaging—Initial Observations1

Jean-Paul Delille, MD, PhD, Priscilla J. Slanetz, MD, MPH, Eren D. Yeh, MD, Daniel B. Kopans, MD, Elkan F. Halpern, PhD and Leoncio Garrido, PhD

1 From the Division of Breast Imaging and NMR Center, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Mass (J.P.D., E.D.Y., D.B.K., E.F.H., L.G.), and the Department of Radiology, Caritas St Elizabeth’s Medical Center and Tufts University School of Medicine, 736 Cambridge St, Brighton, MA 02135 (P.J.S.). Received January 5, 2004; revision requested March 4; revision received June 25; accepted July 27. Supported by Société Française de Radiologie, Association pour la Recherche contre le Cancer, Institut National de la Santé et de la Recherche Médicale, and Massachusetts General Hospital NMR Center. P.J.S. supported in part by RSNA Research Fellow grant (1995–1997). Address correspondence to P.J.S. (e-mail: priscilla_slanetz@cchcs.org).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To use magnetic resonance (MR) imaging to evaluate tissue perfusion in the normal breast parenchyma of postmenopausal women with current or recent hormone replacement therapy (HRT).

MATERIALS AND METHODS: The study was approved by the institutional subcommittee on human studies, and informed consent was obtained from all patients prior to MR imaging. Sixty postmenopausal women (age range, 44–77 years) were grouped according to HRT received: estrogen replacement therapy (ERT) (n = 13), combined (estrogen and progesterone) replacement therapy (CRT) (n = 16), selective estrogen receptor modulator (SERM) therapy (n = 8), and no (hormone replacement) therapy (NT) (n = 23). MR imaging with a 1.5-T magnet was performed by using gradient-echo and dynamic contrast material–enhanced echo-planar pulse sequences before and after gadopentetate dimeglumine injection. Precontrast T1 relaxation times were measured, after which extraction-flow product (EFP) maps were calculated with a multicompartmental model. Analysis of variance was performed.

RESULTS: Age did not significantly differ between the groups (P > .3). Women receiving ERT or CRT at the time of MR imaging had higher EFP values (7.3 mL · 100 g–1 · min–1± 2.6 and 7.1 mL · 100 g–1 · min–1± 3.8, respectively) than did women receiving NT (4.4 mL · 100 g–1 · min–1± 2.1) (P = .012 and P = .008, respectively) or SERM therapy (3.9 mL · 100 g–1 · min–1± 1.1) (P = .015 and P = .013, respectively). Women who ended ERT or CRT 1–47 months before MR examination had lower EFP values than did women with current ERT or CRT and had higher EFP values than did women receiving NT or SERM therapy (6.2 mL · 100 g–1 · min–1± 2.4 and 5.9 mL · 100 g–1 · min–1± 3.8, respectively), but the observed differences were not significant (P > .1). Differences in T1 between all groups were not significant (P > .5).

CONCLUSION: Higher breast tissue perfusion is observed in postmenopausal women receiving HRT.

© RSNA, 2005


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Hormone replacement therapy (HRT) was introduced more than 2 decades ago to relieve symptoms of hot flashes, mood swings, weight gain, and insomnia experienced by most perimenopausal and postmenopausal women. Since then, many physicians have advocated the widespread use of HRT in peri- and postmenopausal women to provide additional health benefits—most notably, to reduce morbidity from osteoporosis (1–3)—while the expectation of a reduction in mortality from coronary disease (4,5) recently has been reconsidered (3,6,7) and the relative risk of breast cancer has been reported to be slightly increased with use of specific forms of HRT (3).

Previously published studies have shown detectable changes in breast tissue at mammography, Doppler ultrasonography (8,9), and magnetic resonance (MR) imaging in premenopausal women (10–15). It is likely that HRT produces pathophysiologic changes in the breast parenchyma in postmenopausal women. Breast tissue density has been reported to increase by 8.7%–35.6% in postmenopausal women who receive HRT (16–22). A pilot study demonstrated that changes in the ratio of total breast tissue to breast fat after HRT are detectable at MR imaging without contrast medium injection (23). MR imaging is now more frequently used to characterize breast lesions and to detect recurrence of breast cancers in difficult cases (24–27).

As MR signal enhancement depends on pathophysiologic changes in the tissue, intrinsic MR properties of the tissue, and the type of pulse sequence used, the assessment of MR signal changes that are associated with specific MR tissue properties (eg, T1) requires the measurement of these three parameters (28). Hulka et al (29) proposed that the effect of these parameters be determined by measuring the T1 of the breast parenchyma prior to the contrast medium injection and by using a physiologic model to estimate the uptake of gadolinium in tissue. This model allows calculation of the extraction-flow product (EFP), which represents the ratio of the volume of blood to the weight of tissue over time (calculated in milliliters per 100 grams per minute) and which depends on the blood flow, permeability, and surface area of the microvascular network. Thus, EFP may be used to quantify tissue perfusion. The increase in EFP caused by the leakage of gadolinium from capillaries in the presence of neovascularization has been shown to be useful for the characterization of breast lesions (29,30). The influence of estrogen on vascular permeability is known, and it is explained by a histamine-like effect that induces an increase in microvascular permeability, as well as vasodilatation (31). Thus, we hypothesized that EFP would be increased in postmenopausal women receiving HRT.

It is reasonable to assume that the observation of trophic changes in breast tissue as a result of action by HRT agents requires a higher level of metabolic activity, which in turn implies increased perfusion. Because trophic changes seen at mammography may still be visible on mammograms months after HRT is stopped, we expected to observe changes in breast tissue perfusion even if HRT had been discontinued at the time of MR examination. The purpose of our study, therefore, was to use MR imaging to evaluate breast tissue perfusion in the normal breast parenchyma of postmenopausal women with current or recent HRT.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
This study was focused on the contralateral normal breast in 60 consecutive postmenopausal women (mean age, 58 years ± 8.1; range, 44–77 years) who were enrolled in a protocol designed to correlate MR images of suspicious breast lesions with pathologic findings between March 1999 and May 2000. The research study, which involved MR imaging in both breasts, was approved by the Massachusetts General Hospital Subcommittee on Human Studies, and informed consent was obtained from patients before imaging was performed. The contralateral breast in each patient was examined with palpation and mammography prior to MR imaging. Medical history with regard to the breasts, medication history, and menopausal status were recorded on the basis of information reported by the patient at the time of breast MR examination. All 60 patients denied having undergone surgery, chemotherapy, or radiation therapy in the breast within 1 year prior to the study.

Of the 60 patients, 29 were currently receiving or had received HRT; 31 others were enrolled as a control group. Of those 31 patients, eight were receiving therapy with a selective estrogen receptor modulator (SERM); the other 23 denied use of HRT or SERM therapy and were designated as receiving no (hormone replacement) therapy (NT). In the SERM therapy group, five women received tamoxifen (Nolvadex; Zeneca Pharmaceuticals, Wilmington, Del), two received raloxifene (Evista; Eli Lily, Indianapolis, Ind), and one received tamoxifen and subsequently raloxifene. The doses of HRT agents varied but corresponded to the recommended standard ranges. Median duration of HRT was 60 months (range, 2–228 months) in 24 subjects and was undetermined in five women. Among the 29 women who received HRT, 13 reported use of conjugated estrogens (Premarin; Wyeth, Collegeville, Pa) or estradiol (Estrace; Warner Chilcott/Galen Holdings, Rockaway, NJ), and, therefore, these 13 were designated as the estrogen replacement therapy (ERT) group. Sixteen other women reported receiving either (a) conjugated estrogens or estradiol combined with either continuous or cyclic medroxyprogesterone acetate (Provera; Pfizer, Cambridge, Mass) or progesterone (Prometrium; Solvay Pharmaceuticals, Marietta, Ga) or (b) conjugated estrogens and medroxyprogesterone acetate (Prempro; Wyeth, Rockaway, NJ); these 16 women were designated as the combined (estrogen-progesterone) replacement therapy (CRT) group. To assess the possibility of a residual effect of previous HRT on breast tissue perfusion, women in the HRT group were stratified into two subgroups: those currently receiving HRT and those who had previously received HRT. Because there were no demonstrative data about the duration of any effect of interrupted HRT on breast tissue perfusion, we decided to include all women who had stopped HRT at the time of MR imaging, regardless of the length of the nontreatment interval prior to MR examination. Among the 13 subjects in the ERT group, seven who were receiving therapy at the time of MR examination were designated as the current-ERT subgroup, while six subjects who had stopped HRT within an interval ranging from 1 to 47 months prior to examination were designated as the previous-ERT subgroup. Among the 16 subjects in the CRT group, 10 who were receiving HRT at the time of MR examination were designated as the current-CRT subgroup, while six subjects who had stopped HRT within an interval ranging from 1 to 22 months prior to examination were designated as the previous-CRT subgroup.

MR Imaging
MR imaging of the breast was performed on a 1.5-T MR imager with a dedicated breast coil (Signa; GE Medical Systems, Milwaukee, Wis). An intravenous catheter was inserted in an antecubital vein before imaging and was connected to a power injector (Medrad, Pittsburgh, Pa) that contained gadopentetate dimeglumine (Magnevist; Berlex Laboratories, Wayne, NJ). Nonenhanced imaging was performed with a gradient-echo sequence (18/5 [repetition time msec/echo time msec]) for localization, followed by a transverse fast spin-echo acquisition (3500/17, 165). After manual shimming of the magnet to ensure maximal field homogeneity in the volume of interest, a three-dimensional spoiled gradient-echo sequence (23/6, flip angle of 30°, one signal acquired) was used to acquire high-spatial-resolution images. Fat suppression was performed by using a binomial water-selective excitation pulse to suppress signal from spins at 220 Hz from the resonance frequency. The matrix size was 512 x 256, and the field of view was 28–35 cm. Sixty sections with thicknesses of 2.0–2.7 mm were acquired to provide full coverage of the volume of interest, with voxel sizes ranging from 0.5 x 1.0 x 2.0 mm to 0.7 x 1.4 x 2.7 mm. For calculation of EFP, two different echo-planar spin-echo sequences were applied. First, prior to the administration of the contrast agent, the T1 of breast tissue was measured with an echo-planar inversion-recovery sequence (6000/30/50–1400 [repetition time msec/echo time msec/inversion time msec]) with one signal acquired and with inversion time increased nine times in increments of 150 msec. The matrix size was 128 x 128, and the field of view was 35–40 cm. Seventeen to 19 sections, with a section thickness of 5–7 mm and an intersection gap of 1.5 mm, were acquired. The voxel size ranged from 2.7 x 2.7 x 5.0 mm to 3.1 x 3.1 x 7.0 mm. Next, for dynamic monitoring of the contrast material uptake in tissue, MR data were acquired before, during, and after administration of a contrast agent (gadopentetate dimeglumine) by using a second echo-planar inversion-recovery sequence (8000/30/160). In this sequence, a fixed inversion time was used to minimize the contribution of fat to the total MR signal. The other parameters were the same as those used for T1 measurements. Twenty-six images were acquired at 8-second intervals during a total imaging time of 3 minutes 29 seconds. Five to seven images were acquired before administration of an intravenous bolus of gadopentetate dimeglumine at a dose of 0.1 mmol/kg and with an injection rate of 3.5 mL/sec, followed by 10 mL of saline solution. Immediately after MR data acquisition with this sequence, a second series of postcontrast high-spatial-resolution images were acquired by using a three-dimensional spoiled gradient-echo sequence with fat suppression and with the same parameters as were used for precontrast MR imaging. The three-dimensional spoiled gradient-echo acquisition started 4 minutes after the injection of contrast medium and lasted 4 minutes 24 seconds.

Image Analysis
The echo-planar inversion recovery data were used to calculate T1 maps on a pixel-by-pixel basis by using a standard three-parameter fitting procedure. These dynamic data indicated tissue signal intensity changes as a function of time, and these changes were converted into R1 relaxivity measurements by taking into consideration the previous T1 calculations. Then, tissue R1 relaxivity changes in each pixel were converted into time-concentration curves by using the r1 relaxivity of gadopentetate dimeglumine (4.5 sec–1 · mmol–1 · L–1 at 37°C). With use of a multicompartmental physiologic model of the tissue gadolinium uptake (32) and an average arterial input function weighted with the subject weight, maps of EFP were calculated from the tissue gadolinium concentration–time curves by using a linear fitting algorithm (29). Values of EFP that were measured in voxels with low signal-to-noise ratio or gadolinium uptake of less than 0.2 mmol · sec–1 were excluded from the final EFP maps.

All MR measurements were performed by the same operator (J.P.D., with 2 years of experience with breast MR imaging), who was blinded to treatment or absence of treatment. To limit possible bias in the reproducibility of measurements as a result of the variable repartitioning of fibroglandular tissue throughout the breast, measurements were performed in locations where breast tissue is usually constant and is more homogeneous so that there were fewer fatty areas to exclude. In our experience, that location corresponded to the level of the nipple; therefore, measurements were performed in two sections above the level of the nipple and in two sections below the level of the nipple. With the given section thicknesses and gap, measurements included breast tissue located at a distance of 11.5–15.5 mm from the nipple. Values for T1 relaxation time and EFP that were calculated on a pixel-by-pixel basis were averaged inside a region of interest (42.4 cm2± 23). That region of interest was drawn over all the fibroglandular tissue of the normal breast on the four sections selected, but it excluded any fatty areas macroscopically depicted, as well as any circumscribed areas of enhancement.

Statistical Analysis
All results were expressed as the mean ± standard deviation with 95% confidence intervals. Statistical analysis was performed (J.P.D.) with software (StatView, version 5.0; SAS Institute, Cary, NC). The means were compared by using one-way analysis of variance. Paired t tests of least squares means were performed only if the result of the analysis of variance was significant (P ≤ .05.).

To verify that there was no age-related bias between the groups, the ages of patients in the NT, SERM therapy, ERT, and CRT groups were compared.

The values of EFP and T1 were stratified as a function of the treatment groups defined previously and, within the HRT group, as a function of whether HRT had been discontinued or was current at the time of MR imaging. Thus, data for six groups were compared: NT, SERM therapy, current ERT, previous ERT, current CRT, and previous CRT.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
The mean age of all subjects was 58.0 years ± 8.1, with no significant difference in mean age between the NT (58.8 years ± 9.3), SERM therapy (55.0 years ± 6.5), ERT (60.6 years ± 8.8), and CRT (56.4 years ± 6.6) groups (F = 1.06; df = 3, 56; P > .3).

Analysis of variance showed a significant difference in the values of EFP among the NT, SERM therapy, current-ERT, previous-ERT, current-CRT, and previous-CRT groups (F = 2.97; df = 3, 56; P = .019). Women receiving ERT or CRT at the time of MR imaging had significantly higher EFP values (7.3 mL · 100 g–1 · min–1 ± 2.6 and 7.1 mL · 100 g–1 · min–1 ± 3.8, respectively) than did women from the NT group (4.4 mL · 100 g–1 · min–1 ± 2.1; P = .012 and .008, respectively) or women receiving SERM therapy (3.9 mL · 100 g–1 · min–1 ± 1.1; P = .015 and .013, respectively). The differences in EFP among the other treatment groups were not significant (Tables 1, 2; Fig 1).


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  		TABLE 1. EFP and T1 Measurements according to Treatment Group

 

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  		TABLE 2. Comparison of Mean EFP in All Treatment Groups

 


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  		Figure 1. Bar graphs show mean EFP measurements and standard deviations for all treatment groups. Significant differences were found between current ERT (ERT[+]) and NT (P = .012), current ERT and SERM therapy (P = .015), current CRT (CRT[+]) and NT (P = .008), and current CRT and SERM therapy (P = .013) groups. All other differences were not significant (CRT– = previous CRT, ERT– = previous ERT).

 
The results of analysis of variance showed no significant difference in T1 among the treatment groups (F = 0.867, P = .51) (Table 1, Fig 2).



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  		Figure 2. Bar graphs show mean T1 relaxation times (in milliseconds) and standard deviations for all treatment groups. Differences between groups were not significant (CRT[+] = current CRT, CRT[–] = previous CRT, ERT[+] = current ERT, ERT[–] = previous ERT).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
REFERENCES
 
Changes in breast tissue density detectable at mammography in postmenopausal women who have received or who are receiving HRT are well recognized (16,17,19). With findings in a pilot MR study having demonstrated an increased tissue-to-fat ratio in women who receive CRT (23), it is not surprising that alterations in tissue perfusion also might be seen at MR imaging. In this study, results of MR imaging of the breast and of EFP measurement confirmed that significant increases do occur in breast tissue perfusion in postmenopausal women receiving HRT. The change in tissue perfusion may affect the detection and characterization of lesions on MR images in these women, an effect that is of particular concern because the risk of breast cancer is increased in women receiving HRT (33–36). Use of HRT may increase overall mammographic breast density in as many as 30% of women and may place these women at higher risk for the subsequent development of breast cancer (37,38). In contrast, women receiving SERM therapy with an agent such as tamoxifen or raloxifene are not expected to exhibit increased tissue perfusion. In our study, women receiving SERM therapy had EFP and T1 values similar to those in women not receiving HRT.

Women in the NT and SERM therapy groups showed EFP values of 4.4 mL · 100 g–1 · min–1 ± 2.1 and 3.9 mL · 100 g–1 · min–1 ± 1.1, respectively. These values were lower than the lowest mean EFP values measured in premenopausal women during the proliferative phase of the menstrual cycle (5.5 mL · 100 g–1 · min–1 ± 2.9) (39). It is not surprising that breast tissue perfusion in menopausal women not receiving HRT and in those receiving SERM therapy is lower than that measured in premenopausal women during the hormonally and metabolically less active phase of the menstrual cycle (40).

Our results show evidence of higher EFP values for subjects currently receiving ERT or CRT at the time of MR examination than for the NT group (P = .012 and .008, respectively) and for those receiving SERM therapy (P = .015 and .013, respectively). Pathophysiologically, the increase in EFP may be explained by the histamine-like effect of estrogen, which induces vasodilatation and an increase in microvascular permeability (31), and by the mitogenic effect of progesterone (41), which may increase metabolic activity and result in an increase in perfusion. In our study, no significant difference in EFP was seen between women receiving CRT and those receiving ERT. This finding may be related to the fact that continuous therapy regimens were not distinguished from cyclic regimens in the CRT group, because of the small number of patients in that cohort. A prospective study might be the best method for assessing the optimal time to image patients with cyclic HRT regimens. In the absence of those data, however, it may be prudent to perform MR imaging in these patients during the postmenstrual phase of their artificial cycle, as is recommended for premenopausal women.

For women who stopped HRT before breast MR imaging, EFP values were lower than for women receiving current HRT, but the difference was not significant (P > .3). EFP values were higher for women who had received HRT than for those in the NT and SERM therapy groups, but the difference was not significant (P > .1). It is conceivable that women who stopped HRT a few weeks before their MR examination may still have evidenced a substantial hormonal effect at perfusion imaging, whereas women who stopped months or years before may have evidenced few or no remaining hormonal effects on breast tissue perfusion. Because the cohort of subjects was small, it was not possible to determine whether the interval between the end of HRT and MR examination (1–47 months) was related to the measured perfusion value. Thus, it is possible that the absence of significant differences between the current-HRT and previous-HRT groups and between the previous-HRT group and the SERM therapy and NT groups resulted from the heterogeneity in the intervals between the end of HRT and MR examination, which may have induced a lack of statistical power, considering the size of the population studied.

In this study, no relationship was shown between T1 and HRT. Our findings suggest that breast structural changes observed with mammography and MR imaging are related to the amount of fibroglandular tissue, rather than to the composition of that tissue, and that those changes do not affect T1 substantially. High intersubject variance in breast tissue T1 is well known (10,12,13), however, and it may account for the absence of visible effects.

The limitations of this study are mainly related to the heterogeneity of the treatment modalities, duration of hormone use, and length of time between the discontinuation of HRT and imaging. These limitations may account for some variability in our results, but they do not negate our observation of a significant increase in breast tissue perfusion in women with current HRT. In addition, this study relied on the patient’s report for HRT information. Clearly, the use of blood tests to measure the serum hormone levels in subjects would improve the accuracy of the information regarding HRT and would reveal the relationship between the MR signal and serum hormone levels. A prospective study with a greater number of subjects and homogeneous modalities of HRT and duration might be better for assessing the effects of continuous or cyclical administration of HRT, of duration of treatment, and of discontinuation of treatment on breast tissue perfusion.

In conclusion, the results of this study show a significant increase in breast tissue perfusion in postmenopausal women receiving HRT at the time of imaging. The observed variations in perfusion should be taken into account when breast MR imaging is performed, because they may affect patient care, particularly as the increased perfusion may complicate lesion detection and/or characterization, given the possibility of overlap between increased perfusion in breast parenchyma and low perfusion observed in some malignant tumors. MR imaging in postmenopausal women who receive cyclic HRT may be most prudently performed during the postmenstrual phase of their artificial cycle.


   ACKNOWLEDGMENTS
 
The authors thank Mary T. Foley, RT, and Terry Campbell, RT, for assistance with data acquisition, and Donna M. Burgess for assistance with clinical data collection.


   FOOTNOTES
 
Abbreviations: CRT = combined (estrogen-progesterone) replacement therapy, EFP = extraction-flow product, ERT = estrogen replacement therapy, HRT = hormone replacement therapy, NT = no (hormone replacement) therapy, SERM = selective estrogen receptor modulator

Author contributions: Guarantors of integrity of entire study, J.P.D., L.G., P.J.S.; study concepts, L.G., J.P.D., D.B.K., E.F.H., P.J.S.; study design, J.P.D., L.G., D.B.K., E.F.H.; literature research, J.P.D.; clinical studies, J.P.D., P.J.S., E.D.Y.; data acquisition, J.P.D.; data analysis/interpretation, J.P.D., P.J.S., E.D.Y.; statistical analysis, E.F.H.; manuscript preparation and editing, J.P.D., P.J.S.; manuscript definition of intellectual content, J.P.D., L.G., D.B.K.; manuscript revision/review, J.P.D., P.J.S., L.G., E.D.Y.; manuscript final version approval, all authors


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TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 

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