Research article
In vivo imaging of estrogen receptor concentration in the endometrium and myometrium using FES PET — influence of menstrual cycle and endogenous estrogen level

https://doi.org/10.1016/j.nucmedbio.2006.12.003Get rights and content

Abstract

Purpose

The goals of this study were to measure estrogen receptor (ER) concentration in the endometrium and myometrium using 16α-[18F]fluoro-17β-estradiol (FES) positron emission tomography (PET) and to investigate the relationship between changes in these parameters with the menstrual cycle and endogenous estrogen levels.

Methods

Sixteen female healthy volunteers were included in this study. After blood sampling to measure endogenous estrogen level, FES PET image was acquired 60 min postinjection of FES. After whole-body imaging of FES PET, averaged standardized uptake values (SUVs) in the endometrium and myometrium were measured, and the relationship between FES uptake and menstrual cycle or endogenous estrogen level was evaluated.

Results

Endometrial SUV was significantly higher in the proliferative phase than in the secretory phase (6.03±1.05 vs. 3.97±1.29, P=.022). In contrast, there was no significant difference in myometrial SUV when the proliferative and secretory phases were compared (P=.23). Further, there was no correlation between SUV and endogenous estrogen level in the proliferative phase.

Conclusions

The change of ER concentration relative to menstrual cycle as characterized by FES PET was consistent with those from previous reports that used an immunohistochemical technique. These data suggest that FES PET is a feasible, noninvasive method for characterizing changes in ER concentration.

Introduction

16α-[18F]fluoro-17β-estradiol (FES) is a radiopharmaceutical that binds to the estrogen receptor (ER) and expresses the existence of ER [1]. FES can help characterize the diagnosis and efficacy of hormonal therapy in patients with ER-positive breast cancer [2], [3], [4], [5], [6]. Indeed, Mintun et al. [2] reported that in vivo uptake of FES in primary breast carcinoma correlates with in vitro measurements of ER concentration and thereby represents a noninvasive quantitative measurement of ER in breast carcinoma. Although several studies reported the expression of ER in many organs other than breast using immunohistochemistry [7], such findings are yet to be confirmed in human studies, even in normal ER-rich tissue like the endometrium or myometrium. Because FES is expected to be a good tracer to reveal the change of ER concentration in normal tissue as well as in disease, normal control data should be required. In immunohistochemical studies, the relationships between the level of ER and menstrual cycle in the endometrium and myometrium are reported as follows [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. In the endometrium, the level of ER increases from the early to the late proliferative phase and decreases in the secretory phase. In the myometrium, the cyclical change of ER varies in different layers. The inner part of the myometrium (stratum subvasculare) adjacent to the endometrium shows the same behavior as the endometrium does. On the other hand, the outer part of the myometrium (stratum vasculare and supravasculare) shows the constant ER expression through the entire menstrual cycle. It is well known that the endogenous estrogen level alters during menstrual cycle, which has two peaks in the late proliferative and midsecretory phase, and thus, the effect of estrogen level on FES uptake should also be studied before clinical application. Therefore, the goals of this study were to measure ER concentration in the endometrium and myometrium using FES positron emission tomography (PET) and to investigate the relationship between changes in these parameters with the menstrual cycle and the endogenous estrogen level in healthy volunteers.

Section snippets

Subjects

Sixteen female normal volunteers were included in this study. Participants' age ranged from 21 to 28 years old (23.6±2.2 years; mean±S.D.). Medical interviews, which encompass previous malignancy and gynecological surgery, menstrual state and cycle and the last menstrual period, were conducted in all subjects. Written informed consent was obtained from all subjects participating in this study, which was approved by the Institutional Review Board of University of Fukui Hospital.

Synthesis of FES

FES synthesis was

Results

Characteristics of the subjects and a summary of the results are shown in Table 1.

One subject had an irregular menstrual cycle and was excluded from the analysis regarding the relationship between FES uptake and menstrual cycle. Based on the menstrual cycle classification mentioned in the Data analysis section, six subjects were classified as being in the proliferative phase and seven were classified as being in the secretory phase. Two subjects were in the menstrual phase and were also

Discussion

Physiological FES uptake in the endometrium is affected by the menstrual cycle secondary to changes in endogenous estrogen level in healthy women. However, the present study demonstrated that endometrial SUV was not directly correlated with plasma E2 level or FES uptake in the myometrium. Yoo et al. [19] reported that FES preferentially binds the ERα subtype with 6.3-fold higher affinity than that for ERβ. Further, the uterus is one of the target organs of E2 and expresses both ERα and ERβ. ERα

Conclusion

The change of ER concentration relative to menstrual cycle as characterized by FES was consistent with those from previous reports that used an immunohistochemical technique. Further, these data suggest that FES PET is a feasible, noninvasive method for characterizing changes in ER concentration.

Acknowledgments

The authors thank Miyuki Tamaru, Mika Ito and other staff members of the Biological Imaging Research Center, University of Fukui, for technical and clinical support. This study was partly funded by the Research and Development Project Aimed at Economic Revitalization (Leading Project) from MEXT Japan and by the 21st Century COE Program (Medical Science) from the Japan Society for the Promotion of Science.

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