Different effects of menopausal hormone therapy on non-alcoholic fatty liver disease based on the route of estrogen administration

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The study included 368 postmenopausal women who received MHT for 12 months. Patients were divided into transdermal (n = 75) and oral (n = 293) groups based on the estrogen route. Changes in the prevalence of NAFLD were compared between the two groups before and after 12 months of MHT. In addition, differences in the progression of NAFLD after MHT based on the dose of estrogen and type of progestogen were evaluated in the oral group. After MHT, the prevalence of NAFLD decreased from 24–17.3% in the transdermal group but increased from 25.3–29.4% in the oral group. Little or no change was found in clinical characteristics and laboratory tests in the transdermal group during MHT. However, serum levels of total cholesterol and low-density lipoprotein cholesterol decreased and triglycerides and high-density lipoprotein cholesterol increased significantly in the oral group. Furthermore, changes in the prevalence of NAFLD were not significantly different based on the dose of estrogen or type of progestogen. Our findings indicate that transdermal estrogen can be beneficial in terms of NAFLD progression. Health sciences/Endocrinology Health sciences/Gastroenterology Health sciences/Health care Non-alcoholic fatty liver disease prevalence menopausal hormone therapy route of estrogen administration Figures Figure 1 Figure 2 Introduction Non-alcoholic fatty liver disease (NAFLD) is characterized by extensive accumulation of fat and triglycerides in the liver and not caused by excessive alcohol or drug use 1 , 2 . NAFLD is the most common chronic liver disease, and the prevalence in postmenopausal women is greater than 20% worldwide 3 – 5 . Although the prevalence of NAFLD differs based on age, sex, menopausal status, region, time, diagnostic tool, and definition, the incidence of NAFLD continues to increase. Furthermore, NAFLD can progress to more serious conditions such as cirrhosis and hepatocellular carcinoma; however, an established treatment does not exist. Therefore, NAFLD has clinical importance and should be further investigated. NAFLD occurs less frequently in premenopausal women than in men or postmenopausal women 6 , 7 , indicating that estrogen plays a protective role against the progression of NAFLD. Estrogen inhibits proliferation of stellate cells and fibrogenesis in the liver 8 and reduces hepatic fibrosis 9 . In addition, estrogen depletion can lead to visceral fat accumulation, weight gain as well as elevated triglycerides and cholesterol 10 , 11 , which are associated with NAFLD progression. In aromatase-deficient knockout mice, supplementation of estrogen restored gene expression and β-oxidation and prevented steatosis similar to in wild-type mice 12 . Furthermore, the incidence of NAFLD was lower 13 and the progression of liver fibrosis was prevented 14 in menopausal hormone therapy (MHT) patients. Because hepatic effects differ based on the route of estrogen administration, the effects of MHT on NAFLD can also differ between transdermal and oral MHT treatment. Transdermal MHT bypasses the first-pass metabolism of the liver and thus has less influence on lipid metabolism, especially triglycerides, an important factor associated with NAFLD 15 , 16 . However, the effects of MHT on the prevalence of NAFLD based on the route of estrogen administration have not been evaluated to date. In the present study, the effects on NAFLD were compared between transdermal and oral MHT treatment for 12 months in postmenopausal women. Materials And Methods Study subjects All consecutive postmenopausal women who received MHT at the Menopause Clinic in Samsung Medical Center (Seoul, Korea) to relieve menopausal symptoms and who had a routine checkup in the health promotion center from January 2016 to December 2020 were considered for this retrospective cohort study. The MHT consisted of estrogen and progestogen for women with a uterus but only estrogen for women without a uterus. The inclusion criteria for the study were as follows: postmenopausal women 45–60 years of age, regardless of type of menopause (natural or induced), postmenopausal women who used the same MHT regimen for at least 12 months and had undergone a general health screening including abdominal ultrasonography before and after MHT. Women were excluded for the following reasons: (1) use of tibolone for MHT; (2) changed the MHT regimen within 12 months; (3) had any other liver disease; (4) had positive serology for hepatitis B or C; (5) consumed more than 10 grams of alcohol per day; (6) used any drugs that can significantly affect hepatic metabolism; (7) used any drugs that can affect body weight. Finally, 368 women were included in this study for analyses and divided into two groups based on the route of estrogen administration: transdermal MHT (n = 75) and oral MHT (n = 293). The Institutional Review Board of Samsung Medical Center approved the study protocol and informed consent was waived because the medical records were retrospectively reviewed. All methods were performed in accordance with relevant guidelines and regulations. Definitions Menopause was defined as at least 12 months of consecutive amenorrhea or elevated serum follicle-stimulating hormone level > 20 IU/L. NAFLD was defined based on hepatic steatosis from abdominal ultrasound. Ultrasound was evaluated by experienced doctors. Fatty liver evaluation criteria included liver parenchyma echogenicity compared with kidney, deep attenuation, and vascular structures 32 . Radiologists classified ultrasonography findings into four categories 33 , 34 : normal, mild (normal visualization of the diaphragm and intrahepatic vessel borders and a diffuse slight increase in echogenicity in the hepatic parenchyma), moderate (slightly impaired visualization of the diaphragm and intrahepatic vessel borders and diffuse increase in echogenicity), or severe (poor or no visualization of the diaphragm and intrahepatic vessel borders and significant increase in echogenicity). Progression of NAFLD was defined as newly diagnosed NAFLD after MHT in women with no NAFLD at baseline or exacerbation of pre-existing NAFLD after MHT. For oral MHT, a low estrogen dose was defined as ≤ 1 mg of 17β-estradiol or conjugated estrogen < 0.625 mg 35 and a standard estrogen dose as 2 mg of 17β-estradiol or 0.625 mg of conjugated estrogen. Transdermal MHT was used with an equivalent dose of a standard oral MHT. Natural progestogen included only micronized progesterone, and synthetic progestogens included dydrogesterone, cyproterone acetate, drospirenone, and norethisterone acetate. Measurements Baseline clinical characteristics including age, age at menarche, age at menopause, parity, and smoking history were obtained from medical records. History and medication for hypertension, diabetes mellitus, and dyslipidemia were also evaluated. Before and after MHT, height and weight were measured to one decimal place, and body mass index was calculated by dividing weight by the square of height. Waist circumference was measured at the thickest part of the abdomen. Blood pressure was measured with a standard mercury sphygmomanometer after rest. Using standard methods for each biochemical parameter, laboratory tests were performed in the morning after overnight fasting before and after MHT. The reference ranges of the laboratory tests were as follows: aspartate aminotransferase (0–32 U/L), alanine aminotransferase (0–33 U/L), alkaline phosphatase (35–104 U/L), gamma-glutamyl transferase (6–42 U/L), total bilirubin (0–1.2 mg/dL), fibrinogen (182–380 mg/dL), total cholesterol (0–200 mg/dL), triglycerides (0–149 mg/dL), high-density lipoprotein cholesterol (50–200 mg/dL), low-density lipoprotein cholesterol (0–129 mg/dL), fasting blood glucose (74–109 mg/dL), insulin (2.6–24.9 µIU/mL), hemoglobin A1c (4.0–6.0%), uric acid (2.4–5.7 mg/dL), and C-reactive protein (0–0.5 mg/dL). Insulin resistance was evaluated with the homeostasis model assessment of insulin resistance (HOMA-IR) using the following equation: insulin resistance = fasting blood insulin (µU/mL) × fasting blood glucose (mg/dL)/405. Abdominal ultrasound was performed on the liver, gallbladder, pancreas, and kidney by experienced radiologists using a Philips Ultrasonography (Bothell, WA, USA) 4-MHz probe. Statistical analysis All statistical analyses were performed using SPSS version 27 (SPSS Inc, Chicago, IL, USA). Data are presented as the mean ± standard deviation or percentage. The assumption of normality was evaluated before statistical analysis. Clinical characteristics and laboratory results were compared between transdermal and oral MHT groups using t -test for continuous variables and chi-square test for categorical variables. Changes in the clinical characteristics and laboratory results before and after MHT were assessed using paired t -test within each treatment. In addition, progression of NAFLD based on ultrasonography was compared using the chi-square test based on the route of estrogen administration as well as the dose of estrogen and type of progestogen in the oral MHT group. The results were considered statistically significant when P -values were < 0.05. Results Table 1 shows the comparisons of baseline characteristics between the transdermal and oral MHT groups. The mean age was 54.3 years in the transdermal MHT group and 53.7 years in the oral MHT group. Age, reproductive or menstrual history, body mass index, blood pressure, and history of chronic medical diseases did not differ between the two groups before starting MHT. Table 1 Baseline clinical characteristics of patients Transdermal MHT (n = 75) Oral MHT (n = 293) P -value Age (years) 54.3 ± 3.4 53.7 ± 3.4 0.201 Parity (n) 1.8 ± 0.8 1.8 ± 0.7 0.738 Age at menarche (years) 13.6 ± 1.4 13.7 ± 1.5 0.680 Age at menopause (years) 49.2 ± 3.4 49.4 ± 3.7 0.794 Years since menopause 5.1 ± 4.1 4.4 ± 4.1 0.202 Body mass index (kg/m 2 ) 22.5 ± 3.0 22.2 ± 2.8 0.475 Waist circumference (cm) 74.2 ± 7.2 74.5 ± 7.1 0.778 Systolic blood pressure (mmHg) 114.8 ± 14.6 112.6 ± 14.8 0.303 Diastolic blood pressure (mmHg) 70.3 ± 10.0 68.9 ± 10.8 0.366 Hypertension (%) 12.0 7.8 0.255 Diabetes mellitus (%) 4.0 2.7 0.703 Dyslipidemia (%) 24.0 15.0 0.064 Current smoking (%) 2.7 2.4 1.000 Data are presented as mean ± standard deviation or percent. P -value based on t test or chi-square test, as indicated. MHT, menopausal hormone therapy The prevalence of NAFLD before and after MHT based on the route of estrogen administration is shown in Fig. 1 . Among 368 postmenopausal women, 24.7% (24.0% in the transdermal MHT group and 25.3% in the oral MHT group) had pre-existing NAFLD before MHT; however, a difference was not found in the prevalence based on the route of estrogen administration. After 12 months of MHT, the prevalence of NAFLD was 17.3% in the transdermal MHT group and 29.4% in the oral MHT group with statistically significant difference ( P = 0.036). In addition, when the progression of NAFLD after MHT (newly diagnosed NAFLD or worsened pre-existing NAFLD) was compared based on the route of estrogen administration, the proportion of progression was significantly lower in the transdermal MHT group than in the oral MHT group (2.7% vs. 11.3%, P = 0.024; Fig. 2 ). In addition, progression after MHT was more prominent in women with pre-existing NAFLD (16.2%) than without NAFLD (9.6%) in the oral MHT group but did not reach statistical significance (data not shown). Tables 2 and 3 show the changes in clinical characteristics and laboratory results during 12 months of MHT. In the transdermal MHT group, significant changes were not found in most variables during MHT, except a decrease of diastolic blood pressure. However, in the oral MHT group, serum levels of total cholesterol and low-density lipoprotein cholesterol decreased, and triglycerides and high-density lipoprotein cholesterol significantly increased after MHT. In addition, serum fibrinogen level was significantly increased after MHT in the oral MHT group. Table 2 Changes in clinical characteristics after 12 months of MHT Transdermal MHT (n = 75) Oral MHT (n = 293) before after before after Body mass index (kg/m 2 ) 22.5 ± 3.0 22.5 ± 2.9 22.2 ± 2.8 22.1 ± 2.5 Waist circumference (cm) 74.2 ± 7.2 74.4 ± 7.1 74.5 ± 7.1 74.2 ± 7.2 Systolic blood pressure (mmHg) 114.8 ± 14.6 112.2 ± 13.8 112.6 ± 14.8 113.1 ± 15.3 Diastolic blood pressure (mmHg) 70.3 ± 10.0 67.6 ± 9.4 * 68.9 ± 10.8 68.5 ± 11.4 Data are presented as mean ± standard deviation * P < 0.05 based on paired t -test within each treatment MHT, menopausal hormone therapy Table 3 Changes in laboratory results after 12 months of MHT Transdermal MHT (n = 75) Oral MHT (n = 293) before after before after AST 20.9 ± 6.7 20.8 ± 5.3 22.1 ± 8.7 22.2 ± 7.8 ALT 19.0 ± 8.6 17.6 ± 6.7 19.0 ± 10.9 18.2 ± 9.4 ALP 55.0 ± 17.2 54.3 ± 16.4 53.8 ± 16.2 49.7 ± 12.1 *,† ɣ-GT 24.5 ± 23.6 24.3 ± 23.8 18.8 ± 18.7 18.5 ± 17.2 Total bilirubin 0.7 ± 0.3 0.7 ± 0.3 0.6 ± 0.2 0.6 ± 0.3 Fibrinogen 282.9 ± 68.6 286.2 ± 55.8 278.0 ± 68.6 288.0 ± 51.6 * Total cholesterol 194.0 ± 31.6 192.3 ± 32.0 202.3 ± 45.7 195.4 ± 31.7 * Triglycerides 107.4 ± 62.1 104.6 ± 51.1 104.4 ± 59.2 118.4 ± 98.1 * HDL-C 57.9 ± 10.0 65.4 ± 16.6 59.9 ± 9.8 70.5 ± 16.1 *,† LDL-C 116.0 ± 29.3 116.0 ± 32.0 119.7 ± 33.3 114.6 ± 28.8 * FBS 91.3 ± 13.5 90.8 ± 15.1 89.2 ± 10.3 88.7 ± 9.1 Insulin 6.1 ± 2.3 5.5 ± 3.7 5.5 ± 3.1 5.3 ± 3.4 HbA1c 5.6 ± 0.5 5.6 ± 0.6 5.4 ± 0.5 5.5 ± 0.5 HOMA-IR 1.4 ± 0.6 1.3 ± 1.0 1.3 ± 0.8 1.2 ± 0.8 eGFR 89.8 ± 16.1 85.2 ± 13.9 87.2 ± 13.4 86.6 ± 14.0 Uric acid 4.3 ± 0.8 4.2 ± 0.9 4.3 ± 0.9 4.3 ± 0.8 CRP 0.08 ± 0.09 0.11 ± 0.24 0.10 ± 0.14 0.12 ± 0.01 Data are presented as mean ± standard deviation * P < 0.05 based on paired t -test, within each treatment; † P < 0.05 based on t -test between the two treatments MHT, menopausal hormone therapy; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; ɣ-GT, gamma-glutamyltransferase; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; FBS, fasting blood sugar; HbA1c, hemoglobin A1c; HOMA-IR, homeostatic model assessment for insulin resistance; eGFR, estimated glomerular filtration rate; CRP, C-reactive protein In addition, when the oral MHT group was divided into subgroups based on the dose of estrogen and type of progestogen, difference was not found in the progression of NAFLD between low-dose and standard-dose MHT (7.1% [6/85] vs. 13.0% [27/208]) or between natural progesterone and synthetic progestogen (14.5% [11/76] vs. 9.9% [18/181]); data not shown). Discussion In this retrospective cohort study, the effects of 12 months of MHT on the prevalence of NAFLD were compared based on the route of estrogen administration. Results showed transdermal estrogen can be more beneficial than oral estrogen for preventing the development or progression of NAFLD in postmenopausal women. Estrogen affects the development or progression of NAFLD in various ways. Estrogen exerts anti-steatotic effect in hepatocytes and an anti-inflammatory effect in Kupffer cells. Estrogen also shows anti-fibrotic effects in hepatic stellate cells 17 , 18 . Overall, experimental data regarding the effects of estrogen on the liver are favorable toward inhibiting the development or progression of NAFLD. In addition to the direct effects of estrogen on the cells in the liver, estrogen has beneficial effects on lipid metabolism 19 , 20 . By improving dyslipidemia, which plays an important role in the pathogenesis of NAFLD, estrogen can indirectly contribute to preventing the development or progression of NAFLD. However, the significance of MHT on NAFLD has not been confirmed in human studies. Clinical studies for evaluating the effects of MHT on NAFLD diagnosed using sonography or liver biopsy remain limited and controversial, and most were cross-sectional studies. In a cross-sectional study including postmenopausal women in Brazil, the prevalence of NAFLD diagnosed with ultrasound was lower in women who received MHT than in women who did not (26.4% vs. 39.9%) 21 . However, in a 1-year study in Japanese women without pre-existing NAFLD, difference was not found in the development of NAFLD between women who received MHT (5.3%) and women who did not receive MHT (6.1%) 22 . In addition, MHT tended to be associated with higher risk of lobular inflammation (odds ratio = 1.61, 95% confidence interval = 1.00–2.59) after adjustment for confounding factors from a cross-sectional study in the United States 23 . To the best of our knowledge, this is the first clinical study in which the different effects of MHT on NAFLD were assessed based on the route of estrogen administration. Although transdermal estrogen was predicted to show different effects compared with oral estrogen due to the first-pass effects with oral MHT 24 , the effects of MHT on NAFLD based on the route of estrogen administration have not been compared to date. In the present study, the prevalence of NALFD was significantly lower in the transdermal MHT group than in the oral MHT group after 12 months of MHT, and the change in the prevalence of NAFLD was opposite between the treatment groups (from 24.0–17.3% in the transdermal MHT group and from 25.3–29.4% in the oral MHT group). Because little or no changes were observed in the clinical characteristics, including weight and waist circumference, as well as in laboratory results, including insulin resistance, in the transdermal MHT group, the difference in the prevalence of NAFLD based on the route of estrogen administration may be explained by the change in lipid profile after oral MHT. Consistent with previous studies 19 , 20 , triglycerides significantly increased after oral MHT, which was different from other favorable changes observed in total, high- and low-density lipoprotein cholesterol. Because high triglyceride level is strongly associated with NAFLD 16 , 25 , 26 , transdermal MHT, which has a neutral effect on triglycerides, resulted in the favorable effects on NAFLD compared with oral MHT in the present study. Because moderate-to-severe vasomotor symptoms are associated with higher prevalence of NAFLD after adjustments 27 , transdermal MHT should be considered for postmenopausal women with pre-existing NAFLD or with higher risk of developing NAFLD. In addition, the effects of oral MHT on the progression of NAFLD were evaluated based on the dose of estrogen and type of progestogen for the first time. Although the effects of estrogen on the liver and lipid profile are dose-dependent 19 , 20 and progestogens can affect lipids, these issues have rarely been investigated. In the present study, the dose of oral estrogen did not affect the progression of NAFLD, although progression of NAFLD was apparently more prevalent with a low dose than a standard dose. The lowest effective dose of estrogen is recommended for oral MHT, especially in women with pre-existing liver disease such as NAFLD and other chronic liver diseases, or those with risk factors associated with liver disease. However, in healthy postmenopausal women, who are the most likely to receive MHT, a standard dose of oral estrogen does not appear to negatively affect the liver in terms of NAFLD and can be used to relieve severe symptoms based on the results of this study. However, progesterone has been suggested to influence carbohydrate, lipid, and protein metabolism and cause severe lobular inflammation in the liver 23 , 28 . In previous studies, co-administration of progestogen during MHT was shown to reduce the favorable effects of oral estrogen on lipids, although the net effect remained beneficial 19 , 20 . However, clinical data to prove the effect of progestogens on NAFLD remain limited 29 . In the present study, progression of NAFLD did not differ based on the addition of progestogen or type of progestogen. However, despite the absence of a difference, due to the different clinical profiles between natural and synthetic progestogens on other organs (e.g., risk of breast cancer), natural progesterone is preferred, especially when a higher dose is needed. Micronized progesterone and dydrogesterone, which have little or no effect on the lipid profile, may be preferred for women with dyslipidemia in need of a progestogen 30 . More clinical studies in which the focus is on NAFLD are warranted in the future to determine a conclusion regarding the associations between dose of estrogen or use of progestogen and NAFLD. The present study had several limitations. First, due to the retrospective study design, bias may have existed. Randomized controlled studies are warranted to confirm the superiority of transdermal estrogen to oral estrogen in terms of NAFLD progression. Second, the number of women receiving transdermal estrogen was smaller than women receiving oral estrogen. However, all consecutive postmenopausal women who met the criteria during the study period were included for analyses, and a lower prevalence of women receiving transdermal estrogen may reflect the real word in which transdermal MHT is less common 31 . In addition, diet and exercise, which are considered preventive and therapeutic measures for NAFLD, were not evaluated, although lifestyle modification was routinely recommended for all women. However, younger postmenopausal women (mean age 54 years) who received MHT and routine annual checkups in the health promotion center likely maintained a similar lifestyle during the study period as evidenced by unchanged body mass index and waist circumference after 12 months of MHT in both groups. In conclusion, the results showed that transdermal MHT is more beneficial than oral MHT in terms of preventing the development and progression of NAFLD. The findings can help healthcare providers and patients in decision-making regarding choosing the best MHT option, especially in postmenopausal women who already have pre-existing NAFLD or who are at high risk of developing NAFLD. Declarations Author’s contribution SE Kim: data analysis and interpretation, manuscript writing; JS Min: data collection and management; S Lee: data collection and management; DY Lee: project development, data analysis, manuscript writing; DS Choi: manuscript writing All authors have reviewed the paper and approved the final version. Competing interests: The authors declare no competing interests. Data availability: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Source of funding : None References EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 64 , 1388–1402, doi: 10.1016/j.jhep.2015.11.004 (2016). 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Clin Liver Dis 11 , 37–54, viii, doi: 10.1016/j.cld.2007.02.014 (2007). Mazhar, S. M., Shiehmorteza, M. & Sirlin, C. B. Noninvasive assessment of hepatic steatosis. Clin Gastroenterol Hepatol 7 , 135–140, doi: 10.1016/j.cgh.2008.11.023 (2009). Kim, S. M., Kim, S. E., Lee, D. Y. & Choi, D. Serum estradiol level according to dose and formulation of oral estrogens in postmenopausal women. Sci Rep 11 , 3585, doi: 10.1038/s41598-021-81201-y (2021). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 19 Sep, 2023 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Major revision 22 Aug, 2023 Reviews received at journal 18 Aug, 2023 Reviewers agreed at journal 16 Aug, 2023 Reviews received at journal 07 Aug, 2023 Reviewers agreed at journal 28 Jul, 2023 Reviewers invited by journal 11 Jul, 2023 Editor assigned by journal 20 May, 2023 Editor invited by journal 15 Feb, 2023 Submission checks completed at journal 15 Feb, 2023 First submitted to journal 05 Feb, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-2553520","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":176326281,"identity":"5cb9ddef-44f3-4563-9558-b4259310b9c2","order_by":0,"name":"Sung Eun Kim","email":"","orcid":"","institution":"Samsung Medical Center, Sungkyunkwan University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sung","middleName":"Eun","lastName":"Kim","suffix":""},{"id":176326282,"identity":"283281f8-53e1-4de4-bfd6-0fd28158fa63","order_by":1,"name":"Ji-Song Min","email":"","orcid":"","institution":"Samsung Medical Center, Sungkyunkwan University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ji-Song","middleName":"","lastName":"Min","suffix":""},{"id":176326283,"identity":"748d315f-8b50-4cda-acad-77c1834be46f","order_by":2,"name":"Saemi Lee","email":"","orcid":"","institution":"Samsung Medical Center, Sungkyunkwan University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Saemi","middleName":"","lastName":"Lee","suffix":""},{"id":176326284,"identity":"25d60f79-58db-421f-9c2f-91ea3cb18b21","order_by":3,"name":"Dong-Yun Lee","email":"data:image/png;base64,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","orcid":"","institution":"Samsung Medical Center, Sungkyunkwan University School of Medicine","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Dong-Yun","middleName":"","lastName":"Lee","suffix":""},{"id":176326285,"identity":"ddc84d3a-c430-4688-899d-f83ce6e8c296","order_by":4,"name":"DooSeok Choi","email":"","orcid":"","institution":"Samsung Medical Center, Sungkyunkwan University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"DooSeok","middleName":"","lastName":"Choi","suffix":""}],"badges":[],"createdAt":"2023-02-05 20:14:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2553520/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2553520/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-023-42788-6","type":"published","date":"2023-09-19T15:00:31+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":33106208,"identity":"fb696707-a56a-44cd-97b9-1081a2d53fe4","added_by":"auto","created_at":"2023-02-17 22:07:21","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":40874,"visible":true,"origin":"","legend":"\u003cp\u003eThe prevalence of non-alcoholic fatty liver disease (NAFLD) before and after menopausal hormone therapy (MHT) based on the route of estrogen administration. \u003cem\u003eP\u003c/em\u003e-value based on chi-square test. NS, non-significant\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-2553520/v1/87c6e64cfcbd82c4203ddf1f.png"},{"id":33106209,"identity":"b0a6639a-5cbd-40b8-9504-c1e35cc11043","added_by":"auto","created_at":"2023-02-17 22:07:21","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":19889,"visible":true,"origin":"","legend":"\u003cp\u003eThe proportion of progression (newly diagnosed or worsened severity) in non-alcoholic fatty liver disease (NAFLD) after menopausal hormone therapy (MHT) based on route of estrogen administration. \u003cem\u003eP\u003c/em\u003e-value based on chi-square test.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-2553520/v1/41b70201f689e6d249c5dca1.png"},{"id":43640310,"identity":"67d6cced-c36e-4104-938b-4739cf17c0bc","added_by":"auto","created_at":"2023-09-25 15:04:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":424457,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2553520/v1/a8ffc00c-3ba9-4cd8-b6fd-13b33221cd94.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Different effects of menopausal hormone therapy on non-alcoholic fatty liver disease based on the route of estrogen administration","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNon-alcoholic fatty liver disease (NAFLD) is characterized by extensive accumulation of fat and triglycerides in the liver and not caused by excessive alcohol or drug use \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. NAFLD is the most common chronic liver disease, and the prevalence in postmenopausal women is greater than 20% worldwide \u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Although the prevalence of NAFLD differs based on age, sex, menopausal status, region, time, diagnostic tool, and definition, the incidence of NAFLD continues to increase. Furthermore, NAFLD can progress to more serious conditions such as cirrhosis and hepatocellular carcinoma; however, an established treatment does not exist. Therefore, NAFLD has clinical importance and should be further investigated.\u003c/p\u003e \u003cp\u003eNAFLD occurs less frequently in premenopausal women than in men or postmenopausal women \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, indicating that estrogen plays a protective role against the progression of NAFLD. Estrogen inhibits proliferation of stellate cells and fibrogenesis in the liver \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e and reduces hepatic fibrosis \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. In addition, estrogen depletion can lead to visceral fat accumulation, weight gain as well as elevated triglycerides and cholesterol \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, which are associated with NAFLD progression. In aromatase-deficient knockout mice, supplementation of estrogen restored gene expression and β-oxidation and prevented steatosis similar to in wild-type mice \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Furthermore, the incidence of NAFLD was lower \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e and the progression of liver fibrosis was prevented \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e in menopausal hormone therapy (MHT) patients.\u003c/p\u003e \u003cp\u003eBecause hepatic effects differ based on the route of estrogen administration, the effects of MHT on NAFLD can also differ between transdermal and oral MHT treatment. Transdermal MHT bypasses the first-pass metabolism of the liver and thus has less influence on lipid metabolism, especially triglycerides, an important factor associated with NAFLD \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. However, the effects of MHT on the prevalence of NAFLD based on the route of estrogen administration have not been evaluated to date.\u003c/p\u003e \u003cp\u003eIn the present study, the effects on NAFLD were compared between transdermal and oral MHT treatment for 12 months in postmenopausal women.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy subjects\u003c/h2\u003e \u003cp\u003eAll consecutive postmenopausal women who received MHT at the Menopause Clinic in Samsung Medical Center (Seoul, Korea) to relieve menopausal symptoms and who had a routine checkup in the health promotion center from January 2016 to December 2020 were considered for this retrospective cohort study. The MHT consisted of estrogen and progestogen for women with a uterus but only estrogen for women without a uterus.\u003c/p\u003e \u003cp\u003eThe inclusion criteria for the study were as follows: postmenopausal women 45\u0026ndash;60 years of age, regardless of type of menopause (natural or induced), postmenopausal women who used the same MHT regimen for at least 12 months and had undergone a general health screening including abdominal ultrasonography before and after MHT. Women were excluded for the following reasons: (1) use of tibolone for MHT; (2) changed the MHT regimen within 12 months; (3) had any other liver disease; (4) had positive serology for hepatitis B or C; (5) consumed more than 10 grams of alcohol per day; (6) used any drugs that can significantly affect hepatic metabolism; (7) used any drugs that can affect body weight.\u003c/p\u003e \u003cp\u003eFinally, 368 women were included in this study for analyses and divided into two groups based on the route of estrogen administration: transdermal MHT (n\u0026thinsp;=\u0026thinsp;75) and oral MHT (n\u0026thinsp;=\u0026thinsp;293). The Institutional Review Board of Samsung Medical Center approved the study protocol and informed consent was waived because the medical records were retrospectively reviewed. All methods were performed in accordance with relevant guidelines and regulations.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDefinitions\u003c/h2\u003e \u003cp\u003eMenopause was defined as at least 12 months of consecutive amenorrhea or elevated serum follicle-stimulating hormone level\u0026thinsp;\u0026gt;\u0026thinsp;20 IU/L.\u003c/p\u003e \u003cp\u003eNAFLD was defined based on hepatic steatosis from abdominal ultrasound. Ultrasound was evaluated by experienced doctors. Fatty liver evaluation criteria included liver parenchyma echogenicity compared with kidney, deep attenuation, and vascular structures \u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Radiologists classified ultrasonography findings into four categories \u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e: normal, mild (normal visualization of the diaphragm and intrahepatic vessel borders and a diffuse slight increase in echogenicity in the hepatic parenchyma), moderate (slightly impaired visualization of the diaphragm and intrahepatic vessel borders and diffuse increase in echogenicity), or severe (poor or no visualization of the diaphragm and intrahepatic vessel borders and significant increase in echogenicity). Progression of NAFLD was defined as newly diagnosed NAFLD after MHT in women with no NAFLD at baseline or exacerbation of pre-existing NAFLD after MHT.\u003c/p\u003e \u003cp\u003eFor oral MHT, a low estrogen dose was defined as \u0026le;\u0026thinsp;1 mg of 17β-estradiol or conjugated estrogen\u0026thinsp;\u0026lt;\u0026thinsp;0.625 mg \u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e and a standard estrogen dose as 2 mg of 17β-estradiol or 0.625 mg of conjugated estrogen. Transdermal MHT was used with an equivalent dose of a standard oral MHT. Natural progestogen included only micronized progesterone, and synthetic progestogens included dydrogesterone, cyproterone acetate, drospirenone, and norethisterone acetate.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eMeasurements\u003c/h2\u003e \u003cp\u003eBaseline clinical characteristics including age, age at menarche, age at menopause, parity, and smoking history were obtained from medical records. History and medication for hypertension, diabetes mellitus, and dyslipidemia were also evaluated. Before and after MHT, height and weight were measured to one decimal place, and body mass index was calculated by dividing weight by the square of height. Waist circumference was measured at the thickest part of the abdomen. Blood pressure was measured with a standard mercury sphygmomanometer after rest.\u003c/p\u003e \u003cp\u003eUsing standard methods for each biochemical parameter, laboratory tests were performed in the morning after overnight fasting before and after MHT. The reference ranges of the laboratory tests were as follows: aspartate aminotransferase (0\u0026ndash;32 U/L), alanine aminotransferase (0\u0026ndash;33 U/L), alkaline phosphatase (35\u0026ndash;104 U/L), gamma-glutamyl transferase (6\u0026ndash;42 U/L), total bilirubin (0\u0026ndash;1.2 mg/dL), fibrinogen (182\u0026ndash;380 mg/dL), total cholesterol (0\u0026ndash;200 mg/dL), triglycerides (0\u0026ndash;149 mg/dL), high-density lipoprotein cholesterol (50\u0026ndash;200 mg/dL), low-density lipoprotein cholesterol (0\u0026ndash;129 mg/dL), fasting blood glucose (74\u0026ndash;109 mg/dL), insulin (2.6\u0026ndash;24.9 \u0026micro;IU/mL), hemoglobin A1c (4.0\u0026ndash;6.0%), uric acid (2.4\u0026ndash;5.7 mg/dL), and C-reactive protein (0\u0026ndash;0.5 mg/dL). Insulin resistance was evaluated with the homeostasis model assessment of insulin resistance (HOMA-IR) using the following equation: insulin resistance\u0026thinsp;=\u0026thinsp;fasting blood insulin (\u0026micro;U/mL) \u0026times; fasting blood glucose (mg/dL)/405.\u003c/p\u003e \u003cp\u003eAbdominal ultrasound was performed on the liver, gallbladder, pancreas, and kidney by experienced radiologists using a Philips Ultrasonography (Bothell, WA, USA) 4-MHz probe.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll statistical analyses were performed using SPSS version 27 (SPSS Inc, Chicago, IL, USA). Data are presented as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or percentage. The assumption of normality was evaluated before statistical analysis. Clinical characteristics and laboratory results were compared between transdermal and oral MHT groups using \u003cem\u003et\u003c/em\u003e-test for continuous variables and chi-square test for categorical variables. Changes in the clinical characteristics and laboratory results before and after MHT were assessed using paired \u003cem\u003et\u003c/em\u003e-test within each treatment. In addition, progression of NAFLD based on ultrasonography was compared using the chi-square test based on the route of estrogen administration as well as the dose of estrogen and type of progestogen in the oral MHT group. The results were considered statistically significant when \u003cem\u003eP\u003c/em\u003e-values were \u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the comparisons of baseline characteristics between the transdermal and oral MHT groups. The mean age was 54.3 years in the transdermal MHT group and 53.7 years in the oral MHT group. Age, reproductive or menstrual history, body mass index, blood pressure, and history of chronic medical diseases did not differ between the two groups before starting MHT.\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\u003eBaseline clinical characteristics of patients\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\u003eTransdermal MHT (n\u0026thinsp;=\u0026thinsp;75)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOral MHT (n\u0026thinsp;=\u0026thinsp;293)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.201\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParity (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.738\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at menarche (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.680\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at menopause (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.794\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYears since menopause\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.202\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.475\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWaist circumference (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74.5\u0026thinsp;\u0026plusmn;\u0026thinsp;7.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.778\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystolic blood pressure (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e114.8\u0026thinsp;\u0026plusmn;\u0026thinsp;14.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e112.6\u0026thinsp;\u0026plusmn;\u0026thinsp;14.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.303\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiastolic blood pressure (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70.3\u0026thinsp;\u0026plusmn;\u0026thinsp;10.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68.9\u0026thinsp;\u0026plusmn;\u0026thinsp;10.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.366\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.255\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes mellitus (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.703\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDyslipidemia (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.064\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent smoking (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or percent. \u003cem\u003eP\u003c/em\u003e-value based on \u003cem\u003et\u003c/em\u003e test or chi-square test, as indicated.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eMHT, menopausal hormone therapy\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe prevalence of NAFLD before and after MHT based on the route of estrogen administration is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Among 368 postmenopausal women, 24.7% (24.0% in the transdermal MHT group and 25.3% in the oral MHT group) had pre-existing NAFLD before MHT; however, a difference was not found in the prevalence based on the route of estrogen administration. After 12 months of MHT, the prevalence of NAFLD was 17.3% in the transdermal MHT group and 29.4% in the oral MHT group with statistically significant difference (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.036). In addition, when the progression of NAFLD after MHT (newly diagnosed NAFLD or worsened pre-existing NAFLD) was compared based on the route of estrogen administration, the proportion of progression was significantly lower in the transdermal MHT group than in the oral MHT group (2.7% vs. 11.3%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In addition, progression after MHT was more prominent in women with pre-existing NAFLD (16.2%) than without NAFLD (9.6%) in the oral MHT group but did not reach statistical significance (data not shown).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e show the changes in clinical characteristics and laboratory results during 12 months of MHT. In the transdermal MHT group, significant changes were not found in most variables during MHT, except a decrease of diastolic blood pressure. However, in the oral MHT group, serum levels of total cholesterol and low-density lipoprotein cholesterol decreased, and triglycerides and high-density lipoprotein cholesterol significantly increased after MHT. In addition, serum fibrinogen level was significantly increased after MHT in the oral MHT group.\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\u003eChanges in clinical characteristics after 12 months of MHT\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eTransdermal MHT (n\u0026thinsp;=\u0026thinsp;75)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eOral MHT (n\u0026thinsp;=\u0026thinsp;293)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ebefore\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eafter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ebefore\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eafter\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e22.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWaist circumference (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74.4\u0026thinsp;\u0026plusmn;\u0026thinsp;7.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e74.5\u0026thinsp;\u0026plusmn;\u0026thinsp;7.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e74.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystolic blood pressure (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e114.8\u0026thinsp;\u0026plusmn;\u0026thinsp;14.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e112.2\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e112.6\u0026thinsp;\u0026plusmn;\u0026thinsp;14.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e113.1\u0026thinsp;\u0026plusmn;\u0026thinsp;15.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiastolic blood pressure (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70.3\u0026thinsp;\u0026plusmn;\u0026thinsp;10.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.4\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e68.9\u0026thinsp;\u0026plusmn;\u0026thinsp;10.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e68.5\u0026thinsp;\u0026plusmn;\u0026thinsp;11.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e*\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 based on paired \u003cem\u003et\u003c/em\u003e-test within each treatment\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eMHT, menopausal hormone therapy\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=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChanges in laboratory results after 12 months of MHT\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eTransdermal MHT (n\u0026thinsp;=\u0026thinsp;75)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eOral MHT (n\u0026thinsp;=\u0026thinsp;293)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ebefore\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eafter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ebefore\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eafter\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20.9\u0026thinsp;\u0026plusmn;\u0026thinsp;6.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20.8\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e22.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19.0\u0026thinsp;\u0026plusmn;\u0026thinsp;8.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.6\u0026thinsp;\u0026plusmn;\u0026thinsp;6.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19.0\u0026thinsp;\u0026plusmn;\u0026thinsp;10.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e18.2\u0026thinsp;\u0026plusmn;\u0026thinsp;9.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55.0\u0026thinsp;\u0026plusmn;\u0026thinsp;17.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54.3\u0026thinsp;\u0026plusmn;\u0026thinsp;16.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e53.8\u0026thinsp;\u0026plusmn;\u0026thinsp;16.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e49.7\u0026thinsp;\u0026plusmn;\u0026thinsp;12.1\u003csup\u003e*,\u0026dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eɣ-GT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.5\u0026thinsp;\u0026plusmn;\u0026thinsp;23.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.3\u0026thinsp;\u0026plusmn;\u0026thinsp;23.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18.8\u0026thinsp;\u0026plusmn;\u0026thinsp;18.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e18.5\u0026thinsp;\u0026plusmn;\u0026thinsp;17.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal bilirubin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFibrinogen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e282.9\u0026thinsp;\u0026plusmn;\u0026thinsp;68.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e286.2\u0026thinsp;\u0026plusmn;\u0026thinsp;55.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e278.0\u0026thinsp;\u0026plusmn;\u0026thinsp;68.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e288.0\u0026thinsp;\u0026plusmn;\u0026thinsp;51.6\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal cholesterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e194.0\u0026thinsp;\u0026plusmn;\u0026thinsp;31.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e192.3\u0026thinsp;\u0026plusmn;\u0026thinsp;32.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e202.3\u0026thinsp;\u0026plusmn;\u0026thinsp;45.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e195.4\u0026thinsp;\u0026plusmn;\u0026thinsp;31.7\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriglycerides\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e107.4\u0026thinsp;\u0026plusmn;\u0026thinsp;62.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e104.6\u0026thinsp;\u0026plusmn;\u0026thinsp;51.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e104.4\u0026thinsp;\u0026plusmn;\u0026thinsp;59.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e118.4\u0026thinsp;\u0026plusmn;\u0026thinsp;98.1\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHDL-C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57.9\u0026thinsp;\u0026plusmn;\u0026thinsp;10.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.4\u0026thinsp;\u0026plusmn;\u0026thinsp;16.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e59.9\u0026thinsp;\u0026plusmn;\u0026thinsp;9.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e70.5\u0026thinsp;\u0026plusmn;\u0026thinsp;16.1\u003csup\u003e*,\u0026dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDL-C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e116.0\u0026thinsp;\u0026plusmn;\u0026thinsp;29.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e116.0\u0026thinsp;\u0026plusmn;\u0026thinsp;32.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e119.7\u0026thinsp;\u0026plusmn;\u0026thinsp;33.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e114.6\u0026thinsp;\u0026plusmn;\u0026thinsp;28.8\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFBS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e91.3\u0026thinsp;\u0026plusmn;\u0026thinsp;13.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90.8\u0026thinsp;\u0026plusmn;\u0026thinsp;15.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e89.2\u0026thinsp;\u0026plusmn;\u0026thinsp;10.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e88.7\u0026thinsp;\u0026plusmn;\u0026thinsp;9.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInsulin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHbA1c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHOMA-IR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e89.8\u0026thinsp;\u0026plusmn;\u0026thinsp;16.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e85.2\u0026thinsp;\u0026plusmn;\u0026thinsp;13.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e87.2\u0026thinsp;\u0026plusmn;\u0026thinsp;13.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e86.6\u0026thinsp;\u0026plusmn;\u0026thinsp;14.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUric acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e*\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 based on paired \u003cem\u003et\u003c/em\u003e-test, within each treatment; \u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 based on \u003cem\u003et\u003c/em\u003e-test between the two treatments\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eMHT, menopausal hormone therapy; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; ɣ-GT, gamma-glutamyltransferase; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; FBS, fasting blood sugar; HbA1c, hemoglobin A1c; HOMA-IR, homeostatic model assessment for insulin resistance; eGFR, estimated glomerular filtration rate; CRP, C-reactive protein\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn addition, when the oral MHT group was divided into subgroups based on the dose of estrogen and type of progestogen, difference was not found in the progression of NAFLD between low-dose and standard-dose MHT (7.1% [6/85] vs. 13.0% [27/208]) or between natural progesterone and synthetic progestogen (14.5% [11/76] vs. 9.9% [18/181]); data not shown).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this retrospective cohort study, the effects of 12 months of MHT on the prevalence of NAFLD were compared based on the route of estrogen administration. Results showed transdermal estrogen can be more beneficial than oral estrogen for preventing the development or progression of NAFLD in postmenopausal women.\u003c/p\u003e \u003cp\u003eEstrogen affects the development or progression of NAFLD in various ways. Estrogen exerts anti-steatotic effect in hepatocytes and an anti-inflammatory effect in Kupffer cells. Estrogen also shows anti-fibrotic effects in hepatic stellate cells \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Overall, experimental data regarding the effects of estrogen on the liver are favorable toward inhibiting the development or progression of NAFLD. In addition to the direct effects of estrogen on the cells in the liver, estrogen has beneficial effects on lipid metabolism \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. By improving dyslipidemia, which plays an important role in the pathogenesis of NAFLD, estrogen can indirectly contribute to preventing the development or progression of NAFLD. However, the significance of MHT on NAFLD has not been confirmed in human studies. Clinical studies for evaluating the effects of MHT on NAFLD diagnosed using sonography or liver biopsy remain limited and controversial, and most were cross-sectional studies. In a cross-sectional study including postmenopausal women in Brazil, the prevalence of NAFLD diagnosed with ultrasound was lower in women who received MHT than in women who did not (26.4% vs. 39.9%) \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. However, in a 1-year study in Japanese women without pre-existing NAFLD, difference was not found in the development of NAFLD between women who received MHT (5.3%) and women who did not receive MHT (6.1%) \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. In addition, MHT tended to be associated with higher risk of lobular inflammation (odds ratio\u0026thinsp;=\u0026thinsp;1.61, 95% confidence interval\u0026thinsp;=\u0026thinsp;1.00\u0026ndash;2.59) after adjustment for confounding factors from a cross-sectional study in the United States \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, this is the first clinical study in which the different effects of MHT on NAFLD were assessed based on the route of estrogen administration. Although transdermal estrogen was predicted to show different effects compared with oral estrogen due to the first-pass effects with oral MHT \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e, the effects of MHT on NAFLD based on the route of estrogen administration have not been compared to date. In the present study, the prevalence of NALFD was significantly lower in the transdermal MHT group than in the oral MHT group after 12 months of MHT, and the change in the prevalence of NAFLD was opposite between the treatment groups (from 24.0\u0026ndash;17.3% in the transdermal MHT group and from 25.3\u0026ndash;29.4% in the oral MHT group). Because little or no changes were observed in the clinical characteristics, including weight and waist circumference, as well as in laboratory results, including insulin resistance, in the transdermal MHT group, the difference in the prevalence of NAFLD based on the route of estrogen administration may be explained by the change in lipid profile after oral MHT. Consistent with previous studies \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, triglycerides significantly increased after oral MHT, which was different from other favorable changes observed in total, high- and low-density lipoprotein cholesterol. Because high triglyceride level is strongly associated with NAFLD \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e, transdermal MHT, which has a neutral effect on triglycerides, resulted in the favorable effects on NAFLD compared with oral MHT in the present study. Because moderate-to-severe vasomotor symptoms are associated with higher prevalence of NAFLD after adjustments \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e, transdermal MHT should be considered for postmenopausal women with pre-existing NAFLD or with higher risk of developing NAFLD.\u003c/p\u003e \u003cp\u003eIn addition, the effects of oral MHT on the progression of NAFLD were evaluated based on the dose of estrogen and type of progestogen for the first time. Although the effects of estrogen on the liver and lipid profile are dose-dependent \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e and progestogens can affect lipids, these issues have rarely been investigated. In the present study, the dose of oral estrogen did not affect the progression of NAFLD, although progression of NAFLD was apparently more prevalent with a low dose than a standard dose. The lowest effective dose of estrogen is recommended for oral MHT, especially in women with pre-existing liver disease such as NAFLD and other chronic liver diseases, or those with risk factors associated with liver disease. However, in healthy postmenopausal women, who are the most likely to receive MHT, a standard dose of oral estrogen does not appear to negatively affect the liver in terms of NAFLD and can be used to relieve severe symptoms based on the results of this study. However, progesterone has been suggested to influence carbohydrate, lipid, and protein metabolism and cause severe lobular inflammation in the liver \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. In previous studies, co-administration of progestogen during MHT was shown to reduce the favorable effects of oral estrogen on lipids, although the net effect remained beneficial \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. However, clinical data to prove the effect of progestogens on NAFLD remain limited \u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. In the present study, progression of NAFLD did not differ based on the addition of progestogen or type of progestogen. However, despite the absence of a difference, due to the different clinical profiles between natural and synthetic progestogens on other organs (e.g., risk of breast cancer), natural progesterone is preferred, especially when a higher dose is needed. Micronized progesterone and dydrogesterone, which have little or no effect on the lipid profile, may be preferred for women with dyslipidemia in need of a progestogen \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. More clinical studies in which the focus is on NAFLD are warranted in the future to determine a conclusion regarding the associations between dose of estrogen or use of progestogen and NAFLD.\u003c/p\u003e \u003cp\u003eThe present study had several limitations. First, due to the retrospective study design, bias may have existed. Randomized controlled studies are warranted to confirm the superiority of transdermal estrogen to oral estrogen in terms of NAFLD progression. Second, the number of women receiving transdermal estrogen was smaller than women receiving oral estrogen. However, all consecutive postmenopausal women who met the criteria during the study period were included for analyses, and a lower prevalence of women receiving transdermal estrogen may reflect the real word in which transdermal MHT is less common \u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. In addition, diet and exercise, which are considered preventive and therapeutic measures for NAFLD, were not evaluated, although lifestyle modification was routinely recommended for all women. However, younger postmenopausal women (mean age 54 years) who received MHT and routine annual checkups in the health promotion center likely maintained a similar lifestyle during the study period as evidenced by unchanged body mass index and waist circumference after 12 months of MHT in both groups.\u003c/p\u003e \u003cp\u003e In conclusion, the results showed that transdermal MHT is more beneficial than oral MHT in terms of preventing the development and progression of NAFLD. The findings can help healthcare providers and patients in decision-making regarding choosing the best MHT option, especially in postmenopausal women who already have pre-existing NAFLD or who are at high risk of developing NAFLD.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSE Kim: data analysis and interpretation, manuscript writing; JS Min: data collection and management; S Lee: data collection and management; DY Lee: project development, data analysis, manuscript writing; DS Choi: manuscript writing\u003c/p\u003e\n\u003cp\u003eAll authors have reviewed the paper and approved the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests: \u003c/strong\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability: \u003c/strong\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSource of funding\u003c/strong\u003e: None\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. 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Sci Rep \u003cb\u003e11\u003c/b\u003e, 3585, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41598-021-81201-y\u003c/span\u003e\u003cspan address=\"10.1038/s41598-021-81201-y\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\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":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Non-alcoholic fatty liver disease, prevalence, menopausal hormone therapy, route of estrogen administration","lastPublishedDoi":"10.21203/rs.3.rs-2553520/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2553520/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe effects of menopausal hormone therapy (MHT) on non-alcoholic fatty liver disease (NAFLD) were compared based on the route of estrogen administration. The study included 368 postmenopausal women who received MHT for 12 months. Patients were divided into transdermal (n\u0026thinsp;=\u0026thinsp;75) and oral (n\u0026thinsp;=\u0026thinsp;293) groups based on the estrogen route. Changes in the prevalence of NAFLD were compared between the two groups before and after 12 months of MHT. In addition, differences in the progression of NAFLD after MHT based on the dose of estrogen and type of progestogen were evaluated in the oral group. After MHT, the prevalence of NAFLD decreased from 24\u0026ndash;17.3% in the transdermal group but increased from 25.3\u0026ndash;29.4% in the oral group. Little or no change was found in clinical characteristics and laboratory tests in the transdermal group during MHT. However, serum levels of total cholesterol and low-density lipoprotein cholesterol decreased and triglycerides and high-density lipoprotein cholesterol increased significantly in the oral group. Furthermore, changes in the prevalence of NAFLD were not significantly different based on the dose of estrogen or type of progestogen. Our findings indicate that transdermal estrogen can be beneficial in terms of NAFLD progression.\u003c/p\u003e","manuscriptTitle":"Different effects of menopausal hormone therapy on non-alcoholic fatty liver disease based on the route of estrogen administration","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-02-17 22:07:16","doi":"10.21203/rs.3.rs-2553520/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-08-22T06:06:33+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-08-18T07:38:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"27f77268-962a-4d30-9a1d-590dd7685e07","date":"2023-08-16T15:58:51+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-08-07T11:10:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"853d1822-1411-4ad1-9308-136860291f95_SNPRID","date":"2023-07-28T18:25:48+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-07-12T02:46:54+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-05-20T11:39:57+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2023-02-15T12:38:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-02-15T12:32:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2023-02-05T20:12:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"dbd2d820-fb2b-44d8-a83f-daecc63b40be","owner":[],"postedDate":"February 17th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":19239850,"name":"Health sciences/Endocrinology"},{"id":19239851,"name":"Health sciences/Gastroenterology"},{"id":19239852,"name":"Health sciences/Health care"}],"tags":[],"updatedAt":"2023-09-25T15:02:24+00:00","versionOfRecord":{"articleIdentity":"rs-2553520","link":"https://doi.org/10.1038/s41598-023-42788-6","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2023-09-19 15:00:31","publishedOnDateReadable":"September 19th, 2023"},"versionCreatedAt":"2023-02-17 22:07:16","video":"","vorDoi":"10.1038/s41598-023-42788-6","vorDoiUrl":"https://doi.org/10.1038/s41598-023-42788-6","workflowStages":[]},"version":"v1","identity":"rs-2553520","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2553520","identity":"rs-2553520","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}