Effect of a GnRH Analog on Hepatic Steatosis (EndomMASLD)

Effect of the Pharmacological Cessation of Menstruation With a GnRH Analog on Hepatic Steatosis in Women With Endometriosis

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.

Study Overview

• Status: Recruiting
• Conditions: Endometriosis; Nonalcoholic Fatty Liver; Metabolic Dysfunction-Associated Steatotic Liver Disease
• Intervention / Treatment: Drug: Goserelin Acetate 3.6 mg inj, implant

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 Type: Interventional
• Enrollment (Estimated): 62
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Stergios A Polyzos, MD, PhD; Phone Number: +30 2310999316; Email: spolyzos@auth.gr
• Study Contact Backup: Name: Dimitrios A Anastasilakis, MD, PhDc; Phone Number: +30 6932238231; Email: dimitanast@auth.gr

Study Locations

• Greece
  • Thessaloniki, Greece, 56429
    • Recruiting
    • 424 General Military Hospital
    • Contact: Dimitrios A Anastasilakis, MD, PhDc; Phone Number: +30 6932238231; Email: dimitanast@auth.gr
    • Contact: Athanasios D Anastasilakis, MD, PhD; Phone Number: +30 2310839900; Email: a.anastasilakis@gmail.com
    • Principal Investigator: Athanasios D Anastasilakis, MD, PhD
    • Sub-Investigator: Dimitrios A Anastasilakis, MD, PhDc
    • Principal Investigator: Athina I Gκiomisi, MD, PhD
  • Thessaloniki, Greece, 56403
    • Recruiting
    • 1st Department of Obstetrics and Gynecology, School of Medicine, Aristotle University of Thessaloniki
    • Contact: Dimitrios G Goulis, MD, PhD; Phone Number: +30 2310233468; Email: dgg@auth.gr
    • Contact: Angelos Daniilidis, MD, PhD; Phone Number: +30 2310992843; Email: angedan@auth.gr
    • Principal Investigator: Dimitrios G Goulis, MD, PhD
    • Principal Investigator: Angelos Daniilidis, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Goserelin; 31 women with histologically confirmed endometriosis will receive goserelin acetate post-surgically.	Drug: Goserelin Acetate 3.6 mg inj, implant; 3.6 mg (1ml) administered subcutaneously once every month for 6 months (totally 6 injections); Other Names: Zoladex
No Intervention: Control; 31 women with histologically confirmed endometriosis will not receive pharmacological treatment post-surgically.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hepatic 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	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.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	6 months
Adiponectin	Adiponectin is measured in μg/mL. Between-within group interactions will be performed.	6 months
Leptin	Leptin is measured in ng/mL. Between-within group interactions will be performed.	6 months
Tumor Necrosis Factor-α (TNF-α)	TNF-a is measured in pg/mL. Between-within group interactions will be performed.	6 months
Sex hormones I - Estradiol	Estradiol is measured in pg/mL. Between-within group interactions will be performed.	6 months
Sex hormones II - Testosterone	Testosterone is measured in ng/mL. Between-within group interactions will be performed.	6 months
Sex hormones III - Sex Hormone Binding Globulin (SHBG)	SHBG is measured in nmol/L. Between-within group interactions will be performed.	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	6 months
Liver function tests II - γGT	Between-within group interactions will be performed for: γ-glutamyltransferase (GGT; IU/l)	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.	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.	6 months

Collaborators and Investigators

• Sponsor: Aristotle University Of Thessaloniki
• Collaborators: 424 General Military Hospital
• Investigators: Study Director: Dimitrios G Goulis, MD, PhD, School of Medicine, Aristotle University of Thessaloniki; Principal Investigator: Stergios A Polyzos, MD, PhD, School of Medicine, Aristotle University of Thessaloniki; Study Director: Dimitrios A Anastasilakis, MD, PhDc, School of Medicine, Aristotle University of Thessaloniki; Study Director: Athina I Gkiomisi, MD, PhD, 424 General Military Hospital, Thessaloniki, Greece; Study Director: Angelos Daniilidis, MD, PhD, School of Medicine, Aristotle University of Thessaloniki; Study Director: Athanasios A Anastasilakis, MD, PhD, 424 General Military Hospital, Thessaloniki, Greece; Study Director: Chrysi Nalmpantidou, MD, "G. Gennimatas" General Hospital, Thessaloniki, Greece

Publications and helpful links

General Publications

• Alberti KG, Zimmet P, Shaw J. Metabolic syndrome--a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med. 2006 May;23(5):469-80. doi: 10.1111/j.1464-5491.2006.01858.x.
• Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, Romero D, Abdelmalek MF, Anstee QM, Arab JP, Arrese M, Bataller R, Beuers U, Boursier J, Bugianesi E, Byrne CD, Castro Narro GE, Chowdhury A, Cortez-Pinto H, Cryer DR, Cusi K, El-Kassas M, Klein S, Eskridge W, Fan J, Gawrieh S, Guy CD, Harrison SA, Kim SU, Koot BG, Korenjak M, Kowdley KV, Lacaille F, Loomba R, Mitchell-Thain R, Morgan TR, Powell EE, Roden M, Romero-Gomez M, Silva M, Singh SP, Sookoian SC, Spearman CW, Tiniakos D, Valenti L, Vos MB, Wong VW, Xanthakos S, Yilmaz Y, Younossi Z, Hobbs A, Villota-Rivas M, Newsome PN; NAFLD Nomenclature consensus group. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023 Dec 1;78(6):1966-1986. doi: 10.1097/HEP.0000000000000520. Epub 2023 Jun 24.
• Henry L, Paik J, Younossi ZM. Review article: the epidemiologic burden of non-alcoholic fatty liver disease across the world. Aliment Pharmacol Ther. 2022 Sep;56(6):942-956. doi: 10.1111/apt.17158. Epub 2022 Jul 26.
• Polyzos SA, Lambrinoudaki I, Goulis DG. Menopausal hormone therapy in women with dyslipidemia and nonalcoholic fatty liver disease. Hormones (Athens). 2022 Sep;21(3):375-381. doi: 10.1007/s42000-022-00369-8. Epub 2022 May 9.
• Polyzos SA, Goulis DG. Menopause and metabolic dysfunction-associated steatotic liver disease. Maturitas. 2024 Aug;186:108024. doi: 10.1016/j.maturitas.2024.108024. Epub 2024 May 14.
• Palmisano BT, Zhu L, Stafford JM. Role of Estrogens in the Regulation of Liver Lipid Metabolism. Adv Exp Med Biol. 2017;1043:227-256. doi: 10.1007/978-3-319-70178-3_12.
• Venetsanaki V, Polyzos SA. Menopause and Non-Alcoholic Fatty Liver Disease: A Review Focusing on Therapeutic Perspectives. Curr Vasc Pharmacol. 2019;17(6):546-555. doi: 10.2174/1570161116666180711121949.
• Takaesu Y, Nishi H, Kojima J, Sasaki T, Nagamitsu Y, Kato R, Isaka K. Dienogest compared with gonadotropin-releasing hormone agonist after conservative surgery for endometriosis. J Obstet Gynaecol Res. 2016 Sep;42(9):1152-8. doi: 10.1111/jog.13023. Epub 2016 May 26.
• Ferrero S, Evangelisti G, Barra F. Current and emerging treatment options for endometriosis. Expert Opin Pharmacother. 2018 Jul;19(10):1109-1125. doi: 10.1080/14656566.2018.1494154. Epub 2018 Jul 5.
• DiVasta AD, Laufer MR. The use of gonadotropin releasing hormone analogues in adolescent and young patients with endometriosis. Curr Opin Obstet Gynecol. 2013 Aug;25(4):287-92. doi: 10.1097/GCO.0b013e32836343eb.
• Polyzos SA, Kang ES, Boutari C, Rhee EJ, Mantzoros CS. Current and emerging pharmacological options for the treatment of nonalcoholic steatohepatitis. Metabolism. 2020 Oct;111S:154203. doi: 10.1016/j.metabol.2020.154203. Epub 2020 Mar 6.
• Polyzos SA, Kountouras J, Tsatsoulis A, Zafeiriadou E, Katsiki E, Patsiaoura K, Zavos C, Anastasiadou VV, Slavakis A. Sex steroids and sex hormone-binding globulin in postmenopausal women with nonalcoholic fatty liver disease. Hormones (Athens). 2013 Jul-Sep;12(3):405-16. doi: 10.1007/BF03401306.
• Pafili K, Paschou SA, Armeni E, Polyzos SA, Goulis DG, Lambrinoudaki I. Non-alcoholic fatty liver disease through the female lifespan: the role of sex hormones. J Endocrinol Invest. 2022 Sep;45(9):1609-1623. doi: 10.1007/s40618-022-01766-x. Epub 2022 Mar 18.

Study record dates

Study Major Dates

• Study Start (Actual): November 26, 2024
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): October 1, 2027

Study Registration Dates

• First Submitted: July 10, 2024
• First Submitted That Met QC Criteria: July 21, 2024
• First Posted (Actual): July 26, 2024

Study Record Updates

• Last Update Posted (Actual): February 3, 2026
• Last Update Submitted That Met QC Criteria: February 1, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: treatment; menopause; NAFLD; NASH; endometriosis; hepatic fibrosis; nonalcoholic steatohepatitis; nonalcoholic fatty liver disease; goserelin acetate; MASLD; MASH; metabolic dysfunction-associated steatotic liver disease; metabolic dysfunction-associated steatohepatitis
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Pathologic Processes; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Digestive System Diseases; Genital Diseases, Female; Liver Diseases; Fibrosis; Fatty Liver; Pathological Conditions, Signs and Symptoms; Non-alcoholic Fatty Liver Disease; Liver Cirrhosis; Endometriosis; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Pharmaceutical Preparations; Dosage Forms; Gonadotropin-Releasing Hormone; Delayed-Action Preparations; Goserelin; Drug Implants
• Other Study ID Numbers: 5221

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD will be available to other researchers upon reasonable request
• IPD Sharing Time Frame: 12 months after the publication of the study.
• IPD Sharing Access Criteria: Yet unknown
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes