Menopause increases the risk of metabolic dysfunction-associated steatotic liver disease (MASLD), possibly owing to the abrupt lack of estrogen. Gonadotropin-releasing hormone (GnRH) treatment in endometriosis is regarded as a model of pharmaceutical menopause. Thus, the effect of goserelin acetate, a GnRH analog that results in transient menopause, on hepatic steatosis and fibrosis will be evaluated in this study.
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), which until recently was known as nonalcoholic fatty liver disease (NAFLD), has risen to 30% of the global adult general population, whereas the pharmaceutical interventions against it remain limited. Owing to the epidemiologic and pathophysiologic association of MASLD with obesity, type 2 diabetes mellitus, dyslipidemia and arterial hypertension, the diagnostic criteria for MASLD are similar to those of the metabolic syndrome. Menopause has been associated with higher MASLD prevalence, with the lack of estrogen being a very plausible pathogenetic contributor to this liver disease. Other pathogenetic contributors of MASLD, including abdominal obesity, increase in insulin resistance (IR) and dysmetabolism of carbohydrates and lipids, are aggravated after menopause, thus adversely contributing to the pathogenesis of MASLD. Regarding the effect of the lack of estrogen on the liver, most to date data are derived from experimental studies, largely showing a favoring effect on MASLD. Epidemiological studies have also shown menopause as an associate of MASLD. However, existing clinical studies are mostly observational, thereby not being able to show a causative association between menopause and MASLD. Gonadotropin-releasing hormone (GnRH) treatment in disorders such as endometriosis can be regarded as a model of pharmaceutical menopause. More specifically, GnRH analogs, like goserelin acetate, lead to pharmaceutical menopause by suppressing the axis hypothalamus-pituitary-ovaries, thus, causing an iatrogenic, reversible ovarian cessation, which lasts as long as the use of GnRH. The adverse effects of GnRH are generally mild and reversible after their discontinuation. This is a prospective, interventional non-randomized study, which aims to evaluate the effect of goserelin acetate on hepatic steatosis in women with histologically confirmed endometriosis compared with women with endometriosis that will not receive pharmacological treatment post-surgically.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
62
3.6 mg (1ml) administered subcutaneously once every month for 6 months (totally 6 injections)
1st Department of Obstetrics and Gynecology, School of Medicine, Aristotle University of Thessaloniki
Thessaloniki, Greece
RECRUITING424 General Military Hospital
Thessaloniki, Greece
RECRUITINGHepatic steatosis
Ultrasound-Guided Attenuation Parameter (UGAP) measured on an ultrasound machine GE Logiq E10s. Between-within group interactions in UGAP UGAP is a non-invasive index based on the attenuation quantification of the ultrasound beam through the hepatic parenchyma, thus used for hepatic steatosis quantification. Cut-off values of ≥ 0.53 dB/cm/MHz, ≥ 0.60 dB/cm/MHz, and ≥ 0.65 dB/cm/MHz have been proposed for the diagnosis of steatosis grade S1, S2, and S3, respectively
Time frame: 6 months
Hepatic fibrosis
Liver stiffness (LS) measured with 2D Shear Wave Elastography (2D SWE) on an ultrasound machine GE Logiq E10s. Between-within group interactions in LS 2D SWE is a non-invasive tool measuring the hepatic parenchyma stiffness, thus indirectly suggesting fibrosis stage (F). Cut-offs values of \<8.27 kPa, 8.27-9.39 kPa, 9.40-11.88 kPa and ≥11.88 kPa have been proposed for F0-F1, F2, F3, and F4, respectively.
Time frame: 6 months
Liver function tests I - ALT and AST
Between-within group interactions will be performed for each of the following parameters: Alanine aminotransferase (ALT; IU/l), aspartate aminotransferase (AST; IU/l); ALT to AST ratio will be calculated
Time frame: 6 months
Liver function tests II - γGT
Between-within group interactions will be performed for: γ-glutamyltransferase (GGT; IU/l)
Time frame: 6 months
Insulin resistance
Between-within group interactions will be performed for Homeostasis Model Assessment - Insulin Resistance (HOMA-IR), which is calculated by the formula: fasting glucose (mg/dl) × insulin (mU/l)/405, and is an index of insulin resistance; higher score indicates greater insulin resistance.
Time frame: 6 months
Lipid profile
Between-within group interactions will be performed for each of the following parameters: Total cholesterol (TC; mg/dL) Triglycerides (TG; mg/dL) High-density lipoprotein cholesterol (HDL-C; mg/dL) 4. Low-density lipoprotein cholesterol (LDL-C) LDL-C (mg/dL) is calculated by the formula: TC (mg/dl) - HDL-C (mg/dl) - TG (mg/dl)/5.
Time frame: 6 months
Non-invasive hepatic steatosis index I - Fatty Liver Index (FLI)
FLI is calculated by the formula \[(e0.953 × Loge (TG, mg/dL) + 0.139×BMI (kg/m2) + 0.718× Loge (GGT, U/L) + 0.053 × waist circumference (cm) -15.745) / (1 + e0.953 × Loge (TG, mg/dL) + 0.139×BMI (kg/m2) + 0.718×Loge (GGT, U/L) + 0.053 × waist circumference (cm) -15.745)\] × 100. Between-within group interactions will be performed.
Time frame: 6 months
Non-invasive hepatic steatosis index II - Hepatic Steatosis Index (HSI)
HSI is calculated by the formula: 8 \* ALT (U/L) / AST (U/L) + BMI (kg/m2) + 2 \[if type 2 diabetes melitus (T2DM)\] + 2 (if female). Between-within group interactions will be performed.
Time frame: 6 months
Non-invasive hepatic steatosis index III - Triglyceride/Glucose Index (TyG)
TyG is calculated by the formula: Ln\[TG (mg/dL) \* Glu (mg/dL) / 2\]. Between-within group interactions will be performed.
Time frame: 6 months
Non-invasive hepatic steatosis index IV - Tyg-BMI
Tyg-BMI is calculated by the formula: TyG \* BMI (kg/m2). Between-within group interactions will be performed.
Time frame: 6 months
Non-invasive hepatic steatosis indices V - NAFLD test
NAFLD test is calculated by the formula: -0.695 + 0.031 \* BMI (kg/m2) + 0.003 \* TC (mg/dL) + 0.014 \* ALT (U/L) + 0.025 \* C-reactive protein (CRP) (mg/dL). Between-within group interactions will be performed.
Time frame: 6 months
Non-invasive hepatic steatosis index VI - Metabolic Score for Insulin Resistance (MetS-IR)
MetS-IR is calculated by the formula: Ln\[2 \* Glu (mg/dL) + TG (mg/dL)\] \* BMI (kg/m2) / Ln\[HDL-C (mg/dL)\]. Between-within group interactions will be performed.
Time frame: 6 months
Non-invasive hepatic steatosis index VII - Lipid Accumulation Product index (LAP)
LAP is calculated by the formula: \[WC (cm) - 58\] \* \[TG (mg/dL) / 88.57\]. Between-within group interactions will be performed.
Time frame: 6 months
Non-invasive hepatic steatosis index VIII - Liver Fat Score (LFS)
LFS is calculated by the formula: -2.89 + 1.18 (if metabolic syndrome) + 0.45 \* 2 (if T2DM) + 0.15 \* insulin (mU/L) + 0.04 \* AST (U/L) - 0.94 \* AST (U/L) / ALT (U/L). Between-within group interactions will be performed.
Time frame: 6 months
Non-invasive hepatic fibrosis index I - NAFLD fibrosis score (NFS)
NFS is calculated by the formula: -1.675 + 0.037 \* age (years) + 0.094 \* BMI (kg/m2) + 1.13 (if impaired fasting glucose or T2DM) + 0.99 \* AST (U/L) / ALT (U/L) - 0.013 \* platelet count \[\*10(9)/L\] - 0.66 \* albumin (g/dL). Between-within group interactions will be performed.
Time frame: 6 months
Non-invasive hepatic fibrosis index II - Fibrosis-4 index (FIB-4)
FIB-4 is calculated by the formula: age (years) \* AST (U/L) / {platelet count \[\*10(9)/L\] \* √ALT (U/L)}. Between-within group interactions will be performed.
Time frame: 6 months
Non-invasive hepatic fibrosis index III - AST-to-Platelet Ratio Index (APRI)
APRI is calculated by the formula: AST (U/L) / upper limit of normal \* 100 / platelet count \[\*10(9)/L\]. Between-within group interactions will be performed.
Time frame: 6 months
Non-invasive hepatic fibrosis index IV - Metabolic dysfunction-Associated Fibrosis Score (MAF-5)
MAF-5 is calculated by the formula: -11.3674 + 0.0282 \* WC (cm) - 0.1761 \* BMI (kg/m2) + 0.0019 \* WC (cm) \* BMI (kg/m2) + 2.0762 (if T2DM) + 2.9207 \* Ln\[AST (U/L)\] - 0.0059 \* platelet count \[\*10(9)/L\]. Between-within group interactions will be performed.
Time frame: 6 months
Adiponectin
Adiponectin is measured in μg/mL. Between-within group interactions will be performed.
Time frame: 6 months
Leptin
Leptin is measured in ng/mL. Between-within group interactions will be performed.
Time frame: 6 months
Tumor Necrosis Factor-α (TNF-α)
TNF-a is measured in pg/mL. Between-within group interactions will be performed.
Time frame: 6 months
Sex hormones I - Estradiol
Estradiol is measured in pg/mL. Between-within group interactions will be performed.
Time frame: 6 months
Sex hormones II - Testosterone
Testosterone is measured in ng/mL. Between-within group interactions will be performed.
Time frame: 6 months
Sex hormones III - Sex Hormone Binding Globulin (SHBG)
SHBG is measured in nmol/L. Between-within group interactions will be performed.
Time frame: 6 months
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