Effect of a GnRH Analog on Hepatic Steatosis

Phase 4

Recruiting

• Conditions: Metabolic Dysfunction-Associated Steatotic Liver Disease; Nonalcoholic Fatty Liver; Endometriosis
• Interventions: Drug: Goserelin Acetate 3.6 mg inj, implant

• Registration Number: NCT06523530
• Lead Sponsor: Aristotle University Of Thessaloniki

Brief Summary

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.

Detailed Description

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 Timeline

• Study First Submitted: 2024-07-10
• Study First Submitted QC: 2024-07-21
• Study First Posted: 2024-07-26
• Study Start: 2024-11-26
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-10
• Last Update Posted: 2024-12-13
• Primary Completion: 2026-10
• Study Completion: 2027-04

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Female
• Target Recruitment: 62

Inclusion Criteria

• women of reproductive age
• diagnosis of endometriosis. The disease is suspected by patient's individual history (chronic pelvic pain, dyspareunia or/and dysmenorrhea) and the ultrasonographic imaging (chocolate cysts). The diagnosis is confirmed histologically, after laparoscopic surgical treatment and biopsy sampling, which will be interpreted by an independent blinded pathologist.
• use of contraceptives, which is the first line treatment, is contraindicated or the patient does not consent to receive contraceptives, due to personal preferences.
• written informed consent to participate to the study

Exclusion Criteria

• mean ethanol consumption >10 g/day
• history of other chronic liver disease (e.g., viral hepatitis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis and overlap syndromes, drug-induced liver injury, hemochromatosis, Wilson's disease, α1-antitrypsin deficiency)
• liver cirrhosis
• any malignancy
• chronic kidney disease
• uncontrolled hypothyroidism or hyperthyroidism
• severe sexual hormone disorders (congenital adrenaline hyperplasia, Down syndrome, Turner syndrome).
• use of the following medications within a 12-month period before baseline, which are associated with drug-induced liver injury (DILI): interferon, tamoxifen, amiodarone, aloperidin, glucocorticoids, hormone replacement therapy, contraceptives, anabolic steroids, any medication against tuberculosis, epilepsy or viruses, methotrexate, parenteral nutrition
• use of the following medications within a 12-month period before baseline, which are probably associated with improvement in hepatic steatosis: vitamin E, pioglitazone, insulin, glucagon-like peptide-1 receptor agonists (GLP-1RAs), sodium- glucose co-transporter-2 inhibitors (SGLT-2i), orlistat, ursodeoxycholic acid
• use of any GnRH agonist or antagonist within a 12-month period before baseline

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Goserelin	Goserelin Acetate 3.6 mg inj, implant	31 women with histologically confirmed endometriosis will receive goserelin acetate post-surgically.

Primary Outcome Measures

Name	Time	Method
Hepatic fibrosis	6 months	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.
Hepatic steatosis	6 months	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

Secondary Outcome Measures

Name	Time	Method
Lipid profile	6 months	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.
Non-invasive hepatic steatosis index I - Fatty Liver Index (FLI)	6 months	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.
Non-invasive hepatic steatosis index II - Hepatic Steatosis Index (HSI)	6 months	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.
Liver function tests I - ALT and AST	6 months	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
Insulin resistance	6 months	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.
Non-invasive hepatic fibrosis index IV - Metabolic dysfunction-Associated Fibrosis Score (MAF-5)	6 months	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.
Sex hormones III - Sex Hormone Binding Globulin (SHBG)	6 months	SHBG is measured in nmol/L.; Between-within group interactions will be performed.
Non-invasive hepatic steatosis indices V - NAFLD test	6 months	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.
Non-invasive hepatic steatosis index VI - Metabolic Score for Insulin Resistance (MetS-IR)	6 months	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.
Non-invasive hepatic steatosis index VIII - Liver Fat Score (LFS)	6 months	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.
Non-invasive hepatic fibrosis index II - Fibrosis-4 index (FIB-4)	6 months	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.
Non-invasive hepatic fibrosis index III - AST-to-Platelet Ratio Index (APRI)	6 months	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.
Liver function tests II - γGT	6 months	Between-within group interactions will be performed for: γ-glutamyltransferase (GGT; IU/l)
Non-invasive hepatic steatosis index IV - Tyg-BMI	6 months	Tyg-BMI is calculated by the formula: TyG \* BMI (kg/m2).; Between-within group interactions will be performed.
Non-invasive hepatic steatosis index III - Triglyceride/Glucose Index (TyG)	6 months	TyG is calculated by the formula: Ln\[TG (mg/dL) \* Glu (mg/dL) / 2\].; Between-within group interactions will be performed.
Adiponectin	6 months	Adiponectin is measured in μg/mL.; Between-within group interactions will be performed.
Tumor Necrosis Factor-α (TNF-α)	6 months	TNF-a is measured in pg/mL.; Between-within group interactions will be performed.
Non-invasive hepatic steatosis index VII - Lipid Accumulation Product index (LAP)	6 months	LAP is calculated by the formula: \[WC (cm) - 58\] \* \[TG (mg/dL) / 88.57\].; Between-within group interactions will be performed.
Non-invasive hepatic fibrosis index I - NAFLD fibrosis score (NFS)	6 months	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.
Leptin	6 months	Leptin is measured in ng/mL.; Between-within group interactions will be performed.
Sex hormones I - Estradiol	6 months	Estradiol is measured in pg/mL.; Between-within group interactions will be performed.
Sex hormones II - Testosterone	6 months	Testosterone is measured in ng/mL.; Between-within group interactions will be performed.

Trial Locations

Locations (2)

424 General Military Hospital; 🇬🇷 Thessaloniki, Greece

1st Department of Obstetrics and Gynecology, School of Medicine, Aristotle University of Thessaloniki; 🇬🇷 Thessaloníki, Greece