The Effect of Hormone Therapy on Physiological Uptake of the Endometrium on [18F]F-FDG PET in Postmenopausal Women

The Effect of Hormone Therapy on Physiological Uptake of the Endometrium on [18F]F-FDG PET in Postmenopausal Women | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Effect of Hormone Therapy on Physiological Uptake of the Endometrium on [ 18 F]F-FDG PET in Postmenopausal Women Ryusuke Nakamoto, Masahiro Yakami, Tomomi Watanabe Nobashi, Hiroyoshi Isoda, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4247381/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Objective The effects of hormonal therapy, estrogen-based hormone replacement therapy (HRT), and anti-tumor hormone therapy, such as tamoxifen, on the physiological uptake of the endometrium on 2-deoxy-2[ 18 F]fluoro-D-glucose ([ 18 F]F-FDG) positron emission tomography (PET) in postmenopausal women have not been determined. We explored the effect of hormone therapy, particularly HRT, on physiological uptake in the endometrium of postmenopausal women. Materials and Methods Postmenopausal women receiving hormone therapy who underwent cancer screening using PET/computed tomography (CT) between June 2016 and April 2023 were included in the hormone therapy group (n = 21). Postmenopausal women with no history of hormone therapy were included in the control group (n = 49). First, the physiological endometrial uptake at menopausal age and at least 1 year thereafter was compared quantitatively (SUVmax) and qualitatively (4-point scale) in the control group, to assess when the endometrium ceased to show significant physiological [ 18 F]F-FDG uptake after menopause. Endometrial uptake was compared between the hormone therapy and control groups. The association between HRT duration (months) and endometrial uptake (SUVmax) was evaluated. Endometrial thickness, measured using transvaginal ultrasonography, was also compared between the two groups. Results Endometrial uptake was significantly reduced both qualitatively and quantitatively ( P < 0.05) at least 1 year after menopause in control patients, by which time most women (93.9%) no longer had significant endometrial uptake. The hormone therapy group (n = 21) showed higher FDG uptake in the endometrium compared to the control group (median SUVmax: 2.3 vs 1.9, P = 0.0011), as well as a higher visual score ( P < 0.0001). HRT duration did not correlate with endometrial uptake ( P = 0.097). Endometrial thickness in the hormone therapy group was significantly thicker than in the control group (median: 3.9 mm vs 1.8 mm, P = 0.002). Conclusion Hormone therapy may affect physiological uptake in the endometrium in postmenopausal women. PET PET/CT hormone replacement therapy estrogen endometrium endometrial physiologic uptake [18F]F-FDG menopause postmenopausal women Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Hormone replacement therapy (HRT), i.e., estrogen with or without progestin, is used for perimenopausal women to prevent and treat the symptoms and physical changes caused by estrogen deficiency, vasomotor symptoms, urogenital system atrophy, postmenopausal osteopenia, and osteoporosis [ 1 – 3 ]. The popularity of postmenopausal HRT of the 1990s [ 4 ] declined after the Women's Health Initiative (WHI) reported in 2002 that the disadvantages of HRT outweighed its benefits [ 5 ]. Nevertheless, HRT is still widely used for women with menopausal symptoms in some countries and regions [ 6 – 8 ]. Postmenopausal women treated with HRT have been reported to have significantly increased endometrial thickness, as measured using transvaginal ultrasonography (TVUS), as compared to controls [ 9 ]. In contrast, a previous study reported that hormonal therapies, including HRT and anti-tumor hormone therapy (AHT), such as tamoxifen, which is prescribed to breast cancer patients, were not associated with differences in physiologic endometrial uptake on 2-deoxy-2[ 18 F]fluoro-D-glucose ([ 18 F]F-FDG) positron-emission tomography (PET) in postmenopausal patients [ 10 ]. However, because of the limited number of patients receiving hormone therapy in that previous study (n = 11), the impact of hormone therapy on physiological uptake in the endometrium requires further investigation. This study therefore aimed to explore the effects of hormone therapy, particularly HRT, on physiological uptake in the endometrium of postmenopausal women. Materials and Methods Subjects Postmenopausal women aged 45 years and older who underwent cancer screening, including PET/computed tomography (CT) and pelvic magnetic resonance imaging (MRI) at our institution between June 2016 and April 2023, were retrospectively selected from our institutional database. All women had completed questionnaires regarding menopause, menstrual cycle status, gynecological history, and hormone therapy (HRT or AHT) at the time of the visit. Menopausal status was confirmed by questionnaire results and/or blood tests (estradiol 40 mIU/ml). Women with suspected gynecologic malignancy at the time of cancer screening by PET/CT and/or pelvic MRI at our institution, women with a history of gynecological malignancy, women with an implanted intrauterine device, and women who had undergone hysterectomy were excluded. The participants were further divided into two groups according to whether they received hormone therapy. Women who received HRT or AHT were assigned to the hormone therapy group. Women with no history of hormone therapy, who underwent PET/CT at the age of menopause and at least 1 year thereafter, were defined as the control group. The subject selection process is illustrated in Fig. 1 . This single-center retrospective study was approved by the institutional review board (R4126). All the participants provided written informed consent for data use. PET/CT imaging All subjects fasted for 5 h or more before the administration of [ 18 F]F-FDG. Intravenous injection of [ 18 F]F-FDG (3.5 MBq/kg of weight) was followed by whole-body PET/CT approximately 60 min later using a combined PET/CT scanner (Biograph mCT Flow64-4R; Siemens Medical Solutions USA, Inc., Knoxville, TN, USA). Low-dose CT was performed before the PET scan from the vertex of the skull to the mid-thigh. PET data were acquired at speed of 1.3 mm/s for the head, 0.9 mm/s for the trunk, and 1.3 mm/s from the bladder to the mid-thigh, using continuous table motion mode. All PET data were attenuation-corrected using CT data and reconstructed using a 3-dimensional ordered-subsets expectation-maximization algorithm (21 subsets, 2 iterations, a matrix size of 200 × 200, a voxel size of 4.07 × 4.07 × 3 mm, and postfiltering at 5 mm in full-width at half-maximum). Evaluation of endometrial uptake and endometrial thickness with TVUS The uterus was identified on CT images of a PET/CT scan. Referring also to pelvic MRI images taken on the same day as the PET/CT, a board-certified nuclear medicine physician (R.N.) measured the maximum standardized uptake value (SUVmax) of the endometrium, setting the spherical volume-of-interest on the PET images of each case so that it did not protrude from the endometrium. In addition to quantitative evaluation, two board-certified nuclear medicine physicians (R.N. and T.N.) evaluated the endometrial uptake on PET images of each case by consensus using a visual score based on a 4-point grading scale (1: Difficult to distinguish the endometrium from the myometrium; 2: Somewhat possible to distinguish between the endometrium and the myometrium; 3: Easily recognizable endometrial uptake; and 4: Marked endometrial uptake). Endometrial thickness measured by TVUS was compared between the hormone therapy and control groups. First, to ascertain the timing of the disappearance of significant physiological uptake in the endometrium after menopause, physiological uptake of the endometrium on PET/CT images taken at menopausal age and at least 1 year later in the control group was quantitatively (SUVmax) and qualitatively (visual score) compared. Next, the endometrial uptake on PET images was compared between the hormone therapy and control groups, at a time-point at least 1 year past the age of menopause. Additionally, the correlation between HRT duration (months) and endometrial uptake (SUVmax) was evaluated in the hormone therapy group. Finally, the correlation between endometrial thickness and endometrial uptake (SUVmax) was evaluated in all patients. Statistical analysis Data are shown as means ± standard deviation or median and interquartile range. Endometrial uptake at menopausal age and at least 1 year later in the control group was compared using the Wilcoxon matched-pair signed-rank test. Values were compared between the hormone therapy and control groups using the Wilcoxon signed-rank test. The association between the duration of HRT (months) and endometrial uptake (SUVmax) in the hormone therapy group, as well as the association between endometrial thickness and endometrial uptake (SUVmax) in all subjects, were analyzed by Spearman rank correlation coefficient (ρ). Statistical analyses were performed using MedCalc® Statistical Software version 22.019 (MedCalc Software Ltd, Ostend, Belgium; https://www.medcalc.org ; 2024). Two tailed P values < 0.05 were considered significant. Results In the control group (n = 49), the quantitative value of endometrial uptake was significantly higher at menopausal age than that at least 1 year after menopausal age (median SUVmax: 2.0 vs. 1.9, P = 0.037) (Fig. 2 ). In terms of visual assessment of endometrial uptake at menopausal age, 12 of 49 women (24.5%) had a visual score of 2 or higher, with higher visual endometrial uptake than myometrial uptake (6, 4, and 2 women with visual scores of 2, 3, and 4, respectively). On the other hand, at least 1 year after menopause, except for three women (6.1%) with a visual score of 2, the remaining 46 women had a visual score of 1, indicating difficulty in distinguishing between endometrial and myometrial uptake. Age at the time of PET/CT imaging or age at menopause did not differ significantly between women in the hormone therapy and control groups (Table 1 ). The hormone therapy group (n = 21) had a higher [ 18 F]F-FDG uptake in the endometrium than did the control group (median SUVmax: 2.3 vs. 1.9, P = 0.001 ) and a higher visual score (median visual score: 2 vs. 1, P < 0.001) (Table 1 ). Women in the HRT group (n = 14) had higher [ 18 F]F-FDG uptake in the endometrium than did those in the AHT group (n = 7) (median SUVmax: 2.45 vs. 1.9; P = 0.036), with a significantly higher visual score (median: 3 vs. 1, P = 0.023) (Table 2 ). Table 1 Comparison of endometrial uptake in women between hormone therapy group and control group HT (n = 21) Control (n = 49) P Age, median (IQR) 55 (52.8–57) 54 (52–55.3) 0.14 Age at menopause, median (IQR) 52 (50–53) 52 (50–54) 0.35 SUVmax, median (IQR) 2.3 (1.9–3.03) 1.9 (1.8–2.1) 0.0011* Visual score, median (IQR) 2 (1–3.3) 1 (1–1) < 0.0001* HT, hormone therapy group; Control, control group; IQR, interquartile range * statistically significant at P < 0.05 level Table 2 Comparison of endometrial uptake in women on hormone replacement therapy and on antitumor hormone therapy HRT (n = 14) AHT (n = 7) P Age, median (IQR) 55.5 (54–57) 54 (49.5–58.5) 0.74 Age at menopause, median (IQR) 52 (50–53) 51.5 (45–54) 0.81 SUVmax, median (IQR) 2.45 (2.1–4.1) 1.9 (1.8–2.38) 0.036* Visual score, median (IQR) 3 (1–4) 1 (1–1.8) 0.023* Duration, median (IQR) 28.5 (14–48) 48 (36–81) 0.040* HRT, hormone replacement therapy; AHT, antitumor hormone therapy; IQR, interquartile range * statistically significant at P < 0.05 level Of the 14 women receiving HRT, four were on estrogen alone and the remaining 10 were on combined estrogen and progestin therapy. No correlation was found between duration of HRT and endometrial uptake (ρ = 0.46, P = 0.097) (Fig. 3 ). TVUS was performed a median of 22 days (15.5–30) after PET/CT imaging. Endometrial thickness, as measured by TVUS, in the hormone therapy group (n = 20) was significantly thicker than that in the control group (n = 45) (median: 3.9 mm vs. 1.8 mm, P = 0.002) (Fig. 4 ). No significant correlation was found between endometrial thickness and endometrial uptake in the subjects who underwent TVUS (n = 65) (ρ = 0.22, P = 0.073). Figure 5 shows a representative case of a postmenopausal woman who underwent HRT and showed increased [ 18 F]F-FDG uptake in the endometrium on PET/CT. This woman had a thickened endometrium on TVUS; however, subsequent histological examinations showed no abnormalities. Figure 6 shows another representative case of a postmenopausal woman on long-term HRT (> 60 months) who was found to have cancer in the right breast on PET/CT. Interestingly, both postmenopausal women on HRT (Figs. 5 and 6 ) had somewhat prominent physiological uptake in the bilateral mammary glands, comparable to that in premenopausal women. Discussion In the previous study by Lerman et al., the effect of hormone therapy (HRT or AHT) on physiological [ 18 F]F-FDG uptake in the endometrium of postmenopausal women was unclear, perhaps because of the small sample size (n = 11), which necessitated further investigation [ 10 ]. Our study showed that hormone therapy may affect physiological endometrial uptake in postmenopausal women, with higher [ 18 F]F-FDG uptake in the endometrium of the hormone therapy group than in the control group, which has not been reported previously. In general, physiological endometrial [ 18 F]F-FDG uptake is minimal in postmenopausal women; therefore, an increase in endometrial uptake in this demographic typically warrants the suspicion of malignancy, such as endometrial carcinoma [ 11 ]. Increased [ 18 F]F-FDG uptake in the endometrium of postmenopausal women may also occur under benign conditions of inflammation caused by intrauterine devices [ 12 ] [ 13 ]. The results of this study indicated that hormone therapy may also increase physiological (non-malignant) endometrial [ 18 F]F-FDG uptake in postmenopausal women. Therefore, if the pattern of [ 18 F]F-FDG uptake is diffuse along the endometrium rather than localized in postmenopausal women receiving hormone therapy, nuclear medicine physicians should suspect that the increased endometrial uptake reflects non-neoplastic rather than neoplastic changes. However, since estrogen-only HRT (without progestin) and AHT, such as tamoxifen are risk factors for the development of uterine cancer [ 14 ] [ 15 ], it is important for nuclear medicine physicians to note increased endometrial uptake in postmenopausal women as a possible abnormal finding in their report, to avoid failing to detect uterine cancer, even if the finding is subsequently found to be non-neoplastic on pathology evaluation. In the control group, noticeable endometrial [ 18 F]F-FDG uptake was observed in some women at menopausal age (6 women with a visual score of 3 or higher). However, at least one year later, physiological [ 18 F]F-FDG uptake in the endometrium and myometrium was no longer distinguishable in the vast majority of cases (visual score of 1 in 46 of 49 cases) (Fig. 2 ). This result supports the concept that, in the first few years after menopause, during which the endometrium enters a quiescent state, physiological [ 18 F]F-FDG uptake is still observed in the endometrium [ 10 , 16 ]. Based on these results, we compared [ 18 F]F-FDG uptake in the endometrium between the control and hormone therapy groups using PET/CT data taken at least 1 year after menopause, when physiological uptake in the endometrium was considered minimal. Glucose transporter 1 (GLUT1) is highly expressed in human endometrial stromal cells (hESCs), whereas the expression of other GLUTs is either very low or undetectable [ 17 , 18 ]. As GLUT1 expression and glucose transport in the endometrium vary throughout the menstrual cycle in premenopausal women, [ 18 F]F-FDG uptake in the endometrium fluctuates in accordance with these changes [ 19 ]. Physiological [ 18 F]F-FDG uptake in the endometrium of premenopausal women shows two peaks in the menstrual cycle: during the menstrual (days 0–4 of the menstrual cycle) and the ovulatory phases (around day 14), when [ 18 F]F-FDG uptake is higher than that during the proliferative (days 7–13) and secretory (days 15–28) phases [ 10 , 20 ]. Increased endometrial [ 18 F]F-FDG uptake during the menstrual phase may reflect augmented expression of GLUT1, to facilitate glucose uptake, which is essential for hESC decidualization [ 17 , 18 , 21 ]. A previous study reported minimal endometrial uptake in women, even of reproductive age, with primary amenorrhea, which also suggested a strong association between [ 18 F]F-FDG uptake in the endometrium and menstruation [ 10 ]. The reason for the higher uptake in the endometrium of postmenopausal women receiving HRT in this study is not clear, but may involve the following: Estrogen upregulates GLUT1 expression in the endometrium [ 19 ]. In addition, combination therapy with estrogen and progestin administered cyclically to postmenopausal women can cause menstrual-like bleeding patterns, which may have affected endometrial [ 18 F]F-FDG uptake in postmenopausal women in a similar way to the increased physiological uptake during menstruation in premenopausal women. However, a retrospective review of the questionnaires completed by participants did not reveal whether postmenopausal women receiving HRT in this study had menstrual-like bleeding. The finding that not all women in the hormone therapy group showed strong endometrial uptake may be due to individual differences in sensitivity to hormone therapy, as menstrual bleeding also does not occur in all women receiving HRT, and/or because the interval between the last day of hormone therapy and the date of PET/CT imaging varied among subjects. TVUS measurements showed that endometrial thickness was significantly greater in the hormone therapy group than in the control group. Both HRT and AHT are known to be associated with a higher prevalence of histopathological changes in the endometrium such as thickening, glandular hyperplasia, and polyps (and even cystic atrophy in AHTs) [ 22 ]. The results of this study were consistent with a previous report [ 9 ]. Although the details are unknown because most women did not subsequently undergo histological examination of their endometrial tissue, it is possible that some women in the hormone therapy group had endometrial hyperplasia or polyps, which may have contributed to the increased endometrial [ 18 F]F-FDG uptake. However, the fact that endometrial [ 18 F]F-FDG uptake was greater during the menstrual phase, when the endometrium is shed, than during the proliferative or secretory phases, when the endometrium thickens, and the lack of correlation between endometrial thickness and endometrial uptake in this study ( P < 0.05), suggests that the higher endometrial [ 18 F]F-FDG uptake in the hormone therapy group cannot be explained solely in terms of endometrial thickness. The rationale for selecting subjects aged 45 years and older for this study is that the average age of menopause for Japanese women is approximately 50 years [ 23 ], and 5 years before and after menopause is defined as "menopause". HRT is used primarily to treat symptoms associated with estrogen deficiency during this period. A small increase in the risk of breast cancer with low-dose estrogen/progestin preparations has been previously reported [ 5 ]. In this study, we encountered one such case in which a woman who had undergone long-term HRT (> 60 months) and was diagnosed with breast cancer on PET/CT screening (Fig. 6 ). However, a causal relationship between HRT and the development of breast cancer remains unclear. Interestingly, both postmenopausal women on HRT (Figs. 5 and 6 ) had somewhat prominent physiological uptake in the mammary glands. A previous study of 36 women known to be menopausal found that premenopausal women had higher glucose metabolic activity (SUV) in breast tissue than did postmenopausal women not receiving HRT [ 24 ]. The authors noted that postmenopausal women receiving HRT showed glucose metabolic activity comparable to that of premenopausal women, suggesting that HRT normalizes glucose metabolism in the breast tissue of postmenopausal women. The limitations of this study were as follows: First, this was a retrospective study. Second, endometrial pathology in women receiving hormone therapy was not available, making it difficult to explain the reason for the increased physiological uptake in the endometrium associated with hormone therapy. Third, the number of participants in the hormone therapy group was small (HRT: n = 14; AHT: n = 7). This may be due to the lower rate of HRT use (approximately 2% [ 25 ]) among Japanese women with menopausal symptoms compared with other countries (13.2% in Finland, 5.3% in Sweden, and 9.7% in Belgium in 2013 [ 8 ]; 11.8% in Australia in 2010 [ 7 ]). Conclusion This study revealed that hormone therapy may affect physiological [ 18 F]F-FDG uptake in the endometrium in postmenopausal women on PET/CT. The interim Women’s Health Initiative report of 2002 showed that HRT was associated with the risk of cardiovascular disease and breast cancer [ 5 ]. Immediately thereafter, the Japan Society for Menopause and Women's Health published its opinion stating that the WHI study population (with an average starting age of 63 years for HRT, and a high proportion of individuals who were obese, smoked, and had hypertension) did not correspond to the Japanese perimenopausal female population. Nevertheless, HRT has not become popular in Japan, due to the widespread concerns about HRT use among Japanese women. However, PET/CT cancer screening is very popular in Japan, and thus, if HRT use becomes more widespread in future, postmenopausal women undergoing HRT may also undergo PET/CT. Therefore, understanding the possible effects of HRT on [ 18 F]F-FDG PET is important for accurate image interpretation. Declarations Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Author Contributions R.N.: writing the manuscript, data acquisition, data analysis M.Y.: data acquisition T.N.: data analysis H.I.: supervision of the clinical study Y.N.: supervision of the clinical study All authors: revision of the manuscript, approval of final version of submitted manuscript Conflict of Interest Ryusuke Nakamoto receives grants from Midtown Clinic Medical Corporation and Kyoto ProMed Co., Ltd. during the conduct of the study, and grants from Novartis AG outside the submitted work. Masahiro Yakami, Tomomi W Nobashi, and Hiroyoshi Isoda receive grants from Midtown Clinic Medical Corporation and Kyoto ProMed Co., Ltd. during the conduct of the study. Yuji Nakamoto receives grants from Novartis AG and Canon Medical Systems Corporation outside the submitted work. Data Availability declaration The data that support the findings of this study are available on request from the corresponding author, R.N.. The data are not publicly available due to their containing information that could compromise the privacy of research participants. Funding information This study was funded by Midtown Clinic Medical Corporation and Kyoto ProMed Co., Ltd.. References Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD. Postmenopausal hormone replacement therapy: scientific review. JAMA. 2002;288:872–81. 10.1001/jama.288.7.872 . Keating NL, Cleary PD, Rossi AS, Zaslavsky AM, Ayanian JZ. Use of hormone replacement therapy by postmenopausal women in the United States. Ann Intern Med. 1999;130:545–53. 10.7326/0003-4819-130-7-199904060-00002 . Lee SR, Cho MK, Cho YJ, Chun S, Hong S-H, Hwang KR, et al. The 2020 menopausal hormone therapy guidelines. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4247381","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":290541762,"identity":"ee59d77f-e2db-465d-bd41-b96fa6edc295","order_by":0,"name":"Ryusuke Nakamoto","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCklEQVRIiWNgGAWjYBACNjBiSJCTYOAB0geQpBgb8GsxhmvhIaSFAaolcQaGFlyAT7r52YMPFWnpM2fkHnvAcOawnD17A5sEQ40dA/Ns7NawyRwzN5xxJid3tkReugHDjcPGPDwHgFqOJTMwzjmAXYtEgpk0b1tF7jyJHDMJhg+HE3sk8r9JMLAdYGCckYBDS/o3kJZ0OYSWBKAt//BpyQHZkpMgDdZyA6qFsQ2vlnKgX9IMZ/a8MTdIOJNuzHPmALNFYl8yDy6/yM9I3wYMsWR5ieM5Zg8+HLOWY29vYLzx4ZudnCGOEEOxkSGBoRnCBDqJx3AGQR3gOK1DcoAEYS2jYBSMglEwIgAA63tWhBm6rgcAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-4950-6654","institution":"Kyoto University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Ryusuke","middleName":"","lastName":"Nakamoto","suffix":""},{"id":290541763,"identity":"79e024cd-a93f-4ed9-88b3-44e7472815fd","order_by":1,"name":"Masahiro Yakami","email":"","orcid":"","institution":"Kyoto University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Masahiro","middleName":"","lastName":"Yakami","suffix":""},{"id":290541764,"identity":"7df138e1-79ca-4612-9d54-26d0e3a78a49","order_by":2,"name":"Tomomi Watanabe Nobashi","email":"","orcid":"","institution":"Kyoto University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tomomi","middleName":"Watanabe","lastName":"Nobashi","suffix":""},{"id":290541765,"identity":"a78a4038-ab39-4535-b4c9-c4e8cec1aaab","order_by":3,"name":"Hiroyoshi Isoda","email":"","orcid":"","institution":"Kyoto University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hiroyoshi","middleName":"","lastName":"Isoda","suffix":""},{"id":290541766,"identity":"744db8d6-10d2-4f88-be2c-2ba960b068c9","order_by":4,"name":"Yuji Nakamoto","email":"","orcid":"","institution":"Kyoto University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuji","middleName":"","lastName":"Nakamoto","suffix":""}],"badges":[],"createdAt":"2024-04-10 12:29:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4247381/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4247381/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55003614,"identity":"89795c34-7097-4eaa-b8ff-b7a158dcdf20","added_by":"auto","created_at":"2024-04-19 18:42:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":370291,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of recruitment process for participants in the study.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-4247381/v1/70bf114104e5ff287f5a048e.png"},{"id":55003618,"identity":"9a4ea6ea-5377-49d7-9c67-875e3bde0801","added_by":"auto","created_at":"2024-04-19 18:42:56","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":651735,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in [18F]F-FDG uptake in the endometrium of women at menopausal age and at least 1 year thereafter in the control group.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-4247381/v1/d9bab7bdd50ca0791a3cc1e0.png"},{"id":55003612,"identity":"05e8e0fb-b193-4b38-b4e4-764404824fcd","added_by":"auto","created_at":"2024-04-19 18:42:56","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":216549,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation between [18F]F-FDG uptake in the endometrium (SUVmax) and duration of hormone replacement therapy.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-4247381/v1/21b79886c9a8709e271212f8.png"},{"id":55005600,"identity":"cbf98ebc-c37d-41af-8513-f582597080ac","added_by":"auto","created_at":"2024-04-19 18:50:56","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":283826,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of endometrial thickness between hormone therapy group (HT) and control group (Control) measured by transvaginal ultrasound.\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-4247381/v1/7cc62d8cfac9f4c30462a7cc.png"},{"id":55003615,"identity":"d02c223a-b05b-4ab7-9777-caf9630fcb45","added_by":"auto","created_at":"2024-04-19 18:42:56","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":864916,"visible":true,"origin":"","legend":"\u003cp\u003eA 56-year-old postmenopausal woman on hormone replacement therapy (HRT) shows increased [18F]F-FDG uptake in the endometrium on positron emission tomography/computed tomography (PET/CT) (SUVmax = 4.1) (A, B, arrows). The woman has a thickened endometrium (12 mm) on transvaginal ultrasound (TVUS) (C). Subsequent endometrial histology showed no abnormalities, but HRT was discontinued. One year later, the woman again underwent PET/CT for cancer screening (D-F), which showed decreased endometrial uptake (SUVmax = 1.9) (E, arrow). In addition, endometrial thickness on TVUS normalized (2.8 mm) (F). Interestingly, physiological uptake in bilateral mammary tissue after discontinuation of HRT (D) was also decreased as compared with that during HRT 1 year earlier (A).\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-4247381/v1/7061078870d7d579a089cec7.png"},{"id":55003616,"identity":"a6b3f027-fe3f-4125-92e6-ac07e63a1ae0","added_by":"auto","created_at":"2024-04-19 18:42:56","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":706648,"visible":true,"origin":"","legend":"\u003cp\u003eA 57-year-old postmenopausal woman on long-term (\u0026gt; 60 months) hormone replacement therapy (HRT) underwent positron emission tomography/computed tomography (PET/CT) for cancer screening (A-D) and was found to have cancer in the right breast (A, D, arrows). Her endometrial uptake on PET/CT was not markedly high (B, C, SUVmax = 2.1). The mass-like uptake, suspicious of breast cancer, was more clearly seen on a dedicated breast PET scan performed on the same day (E, arrow). This postmenopausal woman also had slightly prominent [18F]F-FDG uptake in the bilateral mammary gland tissues (A), similar to the postmenopausal woman on HRT shown in Figure 5.\u003c/p\u003e","description":"","filename":"FIg6.png","url":"https://assets-eu.researchsquare.com/files/rs-4247381/v1/748432f00f152de05651c210.png"},{"id":55006862,"identity":"9bb8bad7-5682-4478-8fb0-98e2b034ac77","added_by":"auto","created_at":"2024-04-19 18:58:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2136684,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4247381/v1/a419b76e-d2a7-42f1-8716-d14a737753eb.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eThe Effect of Hormone Therapy on Physiological Uptake of the Endometrium on [\u003csup\u003e18\u003c/sup\u003eF]F-FDG PET in Postmenopausal Women\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHormone replacement therapy (HRT), i.e., estrogen with or without progestin, is used for perimenopausal women to prevent and treat the symptoms and physical changes caused by estrogen deficiency, vasomotor symptoms, urogenital system atrophy, postmenopausal osteopenia, and osteoporosis [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The popularity of postmenopausal HRT of the 1990s [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] declined after the Women's Health Initiative (WHI) reported in 2002 that the disadvantages of HRT outweighed its benefits [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Nevertheless, HRT is still widely used for women with menopausal symptoms in some countries and regions [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePostmenopausal women treated with HRT have been reported to have significantly increased endometrial thickness, as measured using transvaginal ultrasonography (TVUS), as compared to controls [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In contrast, a previous study reported that hormonal therapies, including HRT and anti-tumor hormone therapy (AHT), such as tamoxifen, which is prescribed to breast cancer patients, were not associated with differences in physiologic endometrial uptake on 2-deoxy-2[\u003csup\u003e18\u003c/sup\u003eF]fluoro-D-glucose ([\u003csup\u003e18\u003c/sup\u003eF]F-FDG) positron-emission tomography (PET) in postmenopausal patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, because of the limited number of patients receiving hormone therapy in that previous study (n\u0026thinsp;=\u0026thinsp;11), the impact of hormone therapy on physiological uptake in the endometrium requires further investigation.\u003c/p\u003e \u003cp\u003eThis study therefore aimed to explore the effects of hormone therapy, particularly HRT, on physiological uptake in the endometrium of postmenopausal women.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSubjects\u003c/h2\u003e \u003cp\u003ePostmenopausal women aged 45 years and older who underwent cancer screening, including PET/computed tomography (CT) and pelvic magnetic resonance imaging (MRI) at our institution between June 2016 and April 2023, were retrospectively selected from our institutional database. All women had completed questionnaires regarding menopause, menstrual cycle status, gynecological history, and hormone therapy (HRT or AHT) at the time of the visit. Menopausal status was confirmed by questionnaire results and/or blood tests (estradiol\u0026thinsp;\u0026lt;\u0026thinsp;5 pg/ml, follicle stimulating hormone\u0026thinsp;\u0026gt;\u0026thinsp;40 mIU/ml). Women with suspected gynecologic malignancy at the time of cancer screening by PET/CT and/or pelvic MRI at our institution, women with a history of gynecological malignancy, women with an implanted intrauterine device, and women who had undergone hysterectomy were excluded. The participants were further divided into two groups according to whether they received hormone therapy. Women who received HRT or AHT were assigned to the hormone therapy group. Women with no history of hormone therapy, who underwent PET/CT at the age of menopause and at least 1 year thereafter, were defined as the control group. The subject selection process is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThis single-center retrospective study was approved by the institutional review board (R4126). All the participants provided written informed consent for data use.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePET/CT imaging\u003c/h2\u003e \u003cp\u003eAll subjects fasted for 5 h or more before the administration of [\u003csup\u003e18\u003c/sup\u003eF]F-FDG. Intravenous injection of [\u003csup\u003e18\u003c/sup\u003eF]F-FDG (3.5 MBq/kg of weight) was followed by whole-body PET/CT approximately 60 min later using a combined PET/CT scanner (Biograph mCT Flow64-4R; Siemens Medical Solutions USA, Inc., Knoxville, TN, USA). Low-dose CT was performed before the PET scan from the vertex of the skull to the mid-thigh. PET data were acquired at speed of 1.3 mm/s for the head, 0.9 mm/s for the trunk, and 1.3 mm/s from the bladder to the mid-thigh, using continuous table motion mode. All PET data were attenuation-corrected using CT data and reconstructed using a 3-dimensional ordered-subsets expectation-maximization algorithm (21 subsets, 2 iterations, a matrix size of 200 \u0026times; 200, a voxel size of 4.07 \u0026times; 4.07 \u0026times; 3 mm, and postfiltering at 5 mm in full-width at half-maximum).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eEvaluation of endometrial uptake and endometrial thickness with TVUS\u003c/h2\u003e \u003cp\u003eThe uterus was identified on CT images of a PET/CT scan. Referring also to pelvic MRI images taken on the same day as the PET/CT, a board-certified nuclear medicine physician (R.N.) measured the maximum standardized uptake value (SUVmax) of the endometrium, setting the spherical volume-of-interest on the PET images of each case so that it did not protrude from the endometrium. In addition to quantitative evaluation, two board-certified nuclear medicine physicians (R.N. and T.N.) evaluated the endometrial uptake on PET images of each case by consensus using a visual score based on a 4-point grading scale (1: Difficult to distinguish the endometrium from the myometrium; 2: Somewhat possible to distinguish between the endometrium and the myometrium; 3: Easily recognizable endometrial uptake; and 4: Marked endometrial uptake). Endometrial thickness measured by TVUS was compared between the hormone therapy and control groups.\u003c/p\u003e \u003cp\u003eFirst, to ascertain the timing of the disappearance of significant physiological uptake in the endometrium after menopause, physiological uptake of the endometrium on PET/CT images taken at menopausal age and at least 1 year later in the control group was quantitatively (SUVmax) and qualitatively (visual score) compared. Next, the endometrial uptake on PET images was compared between the hormone therapy and control groups, at a time-point at least 1 year past the age of menopause. Additionally, the correlation between HRT duration (months) and endometrial uptake (SUVmax) was evaluated in the hormone therapy group. Finally, the correlation between endometrial thickness and endometrial uptake (SUVmax) was evaluated in all patients.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eData are shown as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median and interquartile range. Endometrial uptake at menopausal age and at least 1 year later in the control group was compared using the Wilcoxon matched-pair signed-rank test. Values were compared between the hormone therapy and control groups using the Wilcoxon signed-rank test. The association between the duration of HRT (months) and endometrial uptake (SUVmax) in the hormone therapy group, as well as the association between endometrial thickness and endometrial uptake (SUVmax) in all subjects, were analyzed by Spearman rank correlation coefficient (ρ). Statistical analyses were performed using MedCalc\u0026reg; Statistical Software version 22.019 (MedCalc Software Ltd, Ostend, Belgium; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.medcalc.org\u003c/span\u003e\u003cspan address=\"https://www.medcalc.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e; 2024). Two tailed \u003cem\u003eP\u003c/em\u003e values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eIn the control group (n\u0026thinsp;=\u0026thinsp;49), the quantitative value of endometrial uptake was significantly higher at menopausal age than that at least 1 year after menopausal age (median SUVmax: 2.0 vs. 1.9, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.037) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In terms of visual assessment of endometrial uptake at menopausal age, 12 of 49 women (24.5%) had a visual score of 2 or higher, with higher visual endometrial uptake than myometrial uptake (6, 4, and 2 women with visual scores of 2, 3, and 4, respectively). On the other hand, at least 1 year after menopause, except for three women (6.1%) with a visual score of 2, the remaining 46 women had a visual score of 1, indicating difficulty in distinguishing between endometrial and myometrial uptake. Age at the time of PET/CT imaging or age at menopause did not differ significantly between women in the hormone therapy and control groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The hormone therapy group (n\u0026thinsp;=\u0026thinsp;21) had a higher [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake in the endometrium than did the control group (median SUVmax: 2.3 vs. 1.9, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001 ) and a higher visual score (median visual score: 2 vs. 1, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Women in the HRT group (n\u0026thinsp;=\u0026thinsp;14) had higher [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake in the endometrium than did those in the AHT group (n\u0026thinsp;=\u0026thinsp;7) (median SUVmax: 2.45 vs. 1.9; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.036), with a significantly higher visual score (median: 3 vs. 1, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of endometrial uptake in women between hormone therapy group and control group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHT (n\u0026thinsp;=\u0026thinsp;21)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl (n\u0026thinsp;=\u0026thinsp;49)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55 (52.8\u0026ndash;57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 (52\u0026ndash;55.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at menopause, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52 (50\u0026ndash;53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52 (50\u0026ndash;54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSUVmax, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.3 (1.9\u0026ndash;3.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.9 (1.8\u0026ndash;2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0011*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisual score, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1\u0026ndash;3.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1\u0026ndash;1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eHT, hormone therapy group; Control, control group; IQR, interquartile range\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e* statistically significant at \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 level\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of endometrial uptake in women on hormone replacement therapy and on antitumor hormone therapy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHRT (n\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAHT (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55.5 (54\u0026ndash;57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 (49.5\u0026ndash;58.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at menopause, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52 (50\u0026ndash;53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51.5 (45\u0026ndash;54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSUVmax, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.45 (2.1\u0026ndash;4.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.9 (1.8\u0026ndash;2.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.036*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisual score, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (1\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1\u0026ndash;1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.023*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28.5 (14\u0026ndash;48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (36\u0026ndash;81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.040*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eHRT, hormone replacement therapy; AHT, antitumor hormone therapy; IQR, interquartile range\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e* statistically significant at \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 level\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOf the 14 women receiving HRT, four were on estrogen alone and the remaining 10 were on combined estrogen and progestin therapy. No correlation was found between duration of HRT and endometrial uptake (ρ\u0026thinsp;=\u0026thinsp;0.46, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.097) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTVUS was performed a median of 22 days (15.5\u0026ndash;30) after PET/CT imaging. Endometrial thickness, as measured by TVUS, in the hormone therapy group (n\u0026thinsp;=\u0026thinsp;20) was significantly thicker than that in the control group (n\u0026thinsp;=\u0026thinsp;45) (median: 3.9 mm vs. 1.8 mm, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). No significant correlation was found between endometrial thickness and endometrial uptake in the subjects who underwent TVUS (n\u0026thinsp;=\u0026thinsp;65) (ρ\u0026thinsp;=\u0026thinsp;0.22, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.073).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e shows a representative case of a postmenopausal woman who underwent HRT and showed increased [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake in the endometrium on PET/CT. This woman had a thickened endometrium on TVUS; however, subsequent histological examinations showed no abnormalities. Figure\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e shows another representative case of a postmenopausal woman on long-term HRT (\u0026gt;\u0026thinsp;60 months) who was found to have cancer in the right breast on PET/CT. Interestingly, both postmenopausal women on HRT (Figs.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e and \u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e) had somewhat prominent physiological uptake in the bilateral mammary glands, comparable to that in premenopausal women.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the previous study by Lerman et al., the effect of hormone therapy (HRT or AHT) on physiological [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake in the endometrium of postmenopausal women was unclear, perhaps because of the small sample size (n\u0026thinsp;=\u0026thinsp;11), which necessitated further investigation [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Our study showed that hormone therapy may affect physiological endometrial uptake in postmenopausal women, with higher [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake in the endometrium of the hormone therapy group than in the control group, which has not been reported previously.\u003c/p\u003e \u003cp\u003eIn general, physiological endometrial [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake is minimal in postmenopausal women; therefore, an increase in endometrial uptake in this demographic typically warrants the suspicion of malignancy, such as endometrial carcinoma [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Increased [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake in the endometrium of postmenopausal women may also occur under benign conditions of inflammation caused by intrauterine devices [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The results of this study indicated that hormone therapy may also increase physiological (non-malignant) endometrial [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake in postmenopausal women. Therefore, if the pattern of [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake is diffuse along the endometrium rather than localized in postmenopausal women receiving hormone therapy, nuclear medicine physicians should suspect that the increased endometrial uptake reflects non-neoplastic rather than neoplastic changes. However, since estrogen-only HRT (without progestin) and AHT, such as tamoxifen are risk factors for the development of uterine cancer [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], it is important for nuclear medicine physicians to note increased endometrial uptake in postmenopausal women as a possible abnormal finding in their report, to avoid failing to detect uterine cancer, even if the finding is subsequently found to be non-neoplastic on pathology evaluation.\u003c/p\u003e \u003cp\u003eIn the control group, noticeable endometrial [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake was observed in some women at menopausal age (6 women with a visual score of 3 or higher). However, at least one year later, physiological [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake in the endometrium and myometrium was no longer distinguishable in the vast majority of cases (visual score of 1 in 46 of 49 cases) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This result supports the concept that, in the first few years after menopause, during which the endometrium enters a quiescent state, physiological [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake is still observed in the endometrium [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Based on these results, we compared [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake in the endometrium between the control and hormone therapy groups using PET/CT data taken at least 1 year after menopause, when physiological uptake in the endometrium was considered minimal.\u003c/p\u003e \u003cp\u003eGlucose transporter 1 (GLUT1) is highly expressed in human endometrial stromal cells (hESCs), whereas the expression of other GLUTs is either very low or undetectable [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. As GLUT1 expression and glucose transport in the endometrium vary throughout the menstrual cycle in premenopausal women, [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake in the endometrium fluctuates in accordance with these changes [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Physiological [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake in the endometrium of premenopausal women shows two peaks in the menstrual cycle: during the menstrual (days 0\u0026ndash;4 of the menstrual cycle) and the ovulatory phases (around day 14), when [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake is higher than that during the proliferative (days 7\u0026ndash;13) and secretory (days 15\u0026ndash;28) phases [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Increased endometrial [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake during the menstrual phase may reflect augmented expression of GLUT1, to facilitate glucose uptake, which is essential for hESC decidualization [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. A previous study reported minimal endometrial uptake in women, even of reproductive age, with primary amenorrhea, which also suggested a strong association between [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake in the endometrium and menstruation [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe reason for the higher uptake in the endometrium of postmenopausal women receiving HRT in this study is not clear, but may involve the following: Estrogen upregulates GLUT1 expression in the endometrium [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In addition, combination therapy with estrogen and progestin administered cyclically to postmenopausal women can cause menstrual-like bleeding patterns, which may have affected endometrial [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake in postmenopausal women in a similar way to the increased physiological uptake during menstruation in premenopausal women. However, a retrospective review of the questionnaires completed by participants did not reveal whether postmenopausal women receiving HRT in this study had menstrual-like bleeding. The finding that not all women in the hormone therapy group showed strong endometrial uptake may be due to individual differences in sensitivity to hormone therapy, as menstrual bleeding also does not occur in all women receiving HRT, and/or because the interval between the last day of hormone therapy and the date of PET/CT imaging varied among subjects.\u003c/p\u003e \u003cp\u003eTVUS measurements showed that endometrial thickness was significantly greater in the hormone therapy group than in the control group. Both HRT and AHT are known to be associated with a higher prevalence of histopathological changes in the endometrium such as thickening, glandular hyperplasia, and polyps (and even cystic atrophy in AHTs) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The results of this study were consistent with a previous report [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Although the details are unknown because most women did not subsequently undergo histological examination of their endometrial tissue, it is possible that some women in the hormone therapy group had endometrial hyperplasia or polyps, which may have contributed to the increased endometrial [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake. However, the fact that endometrial [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake was greater during the menstrual phase, when the endometrium is shed, than during the proliferative or secretory phases, when the endometrium thickens, and the lack of correlation between endometrial thickness and endometrial uptake in this study (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), suggests that the higher endometrial [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake in the hormone therapy group cannot be explained solely in terms of endometrial thickness.\u003c/p\u003e \u003cp\u003eThe rationale for selecting subjects aged 45 years and older for this study is that the average age of menopause for Japanese women is approximately 50 years [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], and 5 years before and after menopause is defined as \"menopause\". HRT is used primarily to treat symptoms associated with estrogen deficiency during this period.\u003c/p\u003e \u003cp\u003eA small increase in the risk of breast cancer with low-dose estrogen/progestin preparations has been previously reported [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In this study, we encountered one such case in which a woman who had undergone long-term HRT (\u0026gt;\u0026thinsp;60 months) and was diagnosed with breast cancer on PET/CT screening (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). However, a causal relationship between HRT and the development of breast cancer remains unclear. Interestingly, both postmenopausal women on HRT (Figs.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e and \u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e) had somewhat prominent physiological uptake in the mammary glands. A previous study of 36 women known to be menopausal found that premenopausal women had higher glucose metabolic activity (SUV) in breast tissue than did postmenopausal women not receiving HRT [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The authors noted that postmenopausal women receiving HRT showed glucose metabolic activity comparable to that of premenopausal women, suggesting that HRT normalizes glucose metabolism in the breast tissue of postmenopausal women.\u003c/p\u003e \u003cp\u003eThe limitations of this study were as follows: First, this was a retrospective study. Second, endometrial pathology in women receiving hormone therapy was not available, making it difficult to explain the reason for the increased physiological uptake in the endometrium associated with hormone therapy. Third, the number of participants in the hormone therapy group was small (HRT: n\u0026thinsp;=\u0026thinsp;14; AHT: n\u0026thinsp;=\u0026thinsp;7). This may be due to the lower rate of HRT use (approximately 2% [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]) among Japanese women with menopausal symptoms compared with other countries (13.2% in Finland, 5.3% in Sweden, and 9.7% in Belgium in 2013 [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]; 11.8% in Australia in 2010 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study revealed that hormone therapy may affect physiological [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake in the endometrium in postmenopausal women on PET/CT.\u003c/p\u003e \u003cp\u003eThe interim Women\u0026rsquo;s Health Initiative report of 2002 showed that HRT was associated with the risk of cardiovascular disease and breast cancer [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Immediately thereafter, the Japan Society for Menopause and Women's Health published its opinion stating that the WHI study population (with an average starting age of 63 years for HRT, and a high proportion of individuals who were obese, smoked, and had hypertension) did not correspond to the Japanese perimenopausal female population. Nevertheless, HRT has not become popular in Japan, due to the widespread concerns about HRT use among Japanese women. However, PET/CT cancer screening is very popular in Japan, and thus, if HRT use becomes more widespread in future, postmenopausal women undergoing HRT may also undergo PET/CT. Therefore, understanding the possible effects of HRT on [\u003csup\u003e18\u003c/sup\u003eF]F-FDG PET is important for accurate image interpretation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eR.N.: writing the manuscript, data acquisition, data analysis\u003c/p\u003e\n\u003cp\u003eM.Y.: data acquisition\u003c/p\u003e\n\u003cp\u003eT.N.: data analysis\u003c/p\u003e\n\u003cp\u003eH.I.: supervision of the clinical study\u003c/p\u003e\n\u003cp\u003eY.N.: supervision of the clinical study\u003c/p\u003e\n\u003cp\u003eAll authors: revision of the manuscript, approval of final version of submitted manuscript\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRyusuke Nakamoto receives grants from Midtown Clinic Medical Corporation and\u0026nbsp;Kyoto ProMed Co., Ltd. during the conduct of the study, and grants from\u0026nbsp;Novartis AG outside the submitted work.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMasahiro Yakami,\u0026nbsp;Tomomi W Nobashi, and Hiroyoshi Isoda receive grants from Midtown Clinic Medical Corporation and\u0026nbsp;Kyoto ProMed Co., Ltd. during the conduct of the study.\u003c/p\u003e\n\u003cp\u003eYuji Nakamoto receives grants from Novartis AG and Canon Medical Systems Corporation outside the submitted work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available on request from the corresponding author, R.N.. The data are not publicly available due to their containing information that could compromise the privacy of research participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by Midtown Clinic Medical Corporation and Kyoto ProMed Co., Ltd..\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD. Postmenopausal hormone replacement therapy: scientific review. JAMA. 2002;288:872\u0026ndash;81. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jama.288.7.872\u003c/span\u003e\u003cspan address=\"10.1001/jama.288.7.872\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKeating NL, Cleary PD, Rossi AS, Zaslavsky AM, Ayanian JZ. 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Maturitas. 1996;25:201\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s0378-5122(96)01067-5\u003c/span\u003e\u003cspan address=\"10.1016/s0378-5122(96)01067-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-nuclear-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anme","sideBox":"Learn more about [Annals of Nuclear Medicine](http://link.springer.com/journal/12149)","snPcode":"12149","submissionUrl":"https://www.editorialmanager.com/anme/default2.aspx","title":"Annals of Nuclear Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"PET, PET/CT, hormone replacement therapy, estrogen, endometrium, endometrial, physiologic uptake, [18F]F-FDG, menopause, postmenopausal women","lastPublishedDoi":"10.21203/rs.3.rs-4247381/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4247381/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThe effects of hormonal therapy, estrogen-based hormone replacement therapy (HRT), and anti-tumor hormone therapy, such as tamoxifen, on the physiological uptake of the endometrium on 2-deoxy-2[\u003csup\u003e18\u003c/sup\u003eF]fluoro-D-glucose ([\u003csup\u003e18\u003c/sup\u003eF]F-FDG) positron emission tomography (PET) in postmenopausal women have not been determined. We explored the effect of hormone therapy, particularly HRT, on physiological uptake in the endometrium of postmenopausal women.\u003c/p\u003e\u003ch2\u003eMaterials and Methods\u003c/h2\u003e \u003cp\u003ePostmenopausal women receiving hormone therapy who underwent cancer screening using PET/computed tomography (CT) between June 2016 and April 2023 were included in the hormone therapy group (n\u0026thinsp;=\u0026thinsp;21). Postmenopausal women with no history of hormone therapy were included in the control group (n\u0026thinsp;=\u0026thinsp;49). First, the physiological endometrial uptake at menopausal age and at least 1 year thereafter was compared quantitatively (SUVmax) and qualitatively (4-point scale) in the control group, to assess when the endometrium ceased to show significant physiological [\u003csup\u003e18\u003c/sup\u003eF]F-FDG uptake after menopause. Endometrial uptake was compared between the hormone therapy and control groups. The association between HRT duration (months) and endometrial uptake (SUVmax) was evaluated. Endometrial thickness, measured using transvaginal ultrasonography, was also compared between the two groups.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eEndometrial uptake was significantly reduced both qualitatively and quantitatively (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) at least 1 year after menopause in control patients, by which time most women (93.9%) no longer had significant endometrial uptake. The hormone therapy group (n\u0026thinsp;=\u0026thinsp;21) showed higher FDG uptake in the endometrium compared to the control group (median SUVmax: 2.3 vs 1.9, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0011), as well as a higher visual score (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). HRT duration did not correlate with endometrial uptake (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.097). Endometrial thickness in the hormone therapy group was significantly thicker than in the control group (median: 3.9 mm vs 1.8 mm, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eHormone therapy may affect physiological uptake in the endometrium in postmenopausal women.\u003c/p\u003e","manuscriptTitle":"The Effect of Hormone Therapy on Physiological Uptake of the Endometrium on [18F]F-FDG PET in Postmenopausal Women","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-19 18:42:51","doi":"10.21203/rs.3.rs-4247381/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-04-15T07:44:21+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-12T13:16:07+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-11T00:01:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Nuclear Medicine","date":"2024-04-10T08:28:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-nuclear-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anme","sideBox":"Learn more about [Annals of Nuclear Medicine](http://link.springer.com/journal/12149)","snPcode":"12149","submissionUrl":"https://www.editorialmanager.com/anme/default2.aspx","title":"Annals of Nuclear Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"2dfe6c1a-de7f-4b51-a75c-bd881ccdbba6","owner":[],"postedDate":"April 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-05-09T02:47:13+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-19 18:42:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4247381","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4247381","identity":"rs-4247381","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}