Clinical trial NCT06523530: Effect of a GnRH Analog on Hepatic Steatosis
Official title: Effect of the Pharmacological Cessation of Menstruation with a GnRH Analog on Hepatic Steatosis in Women with Endometriosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Metabolic Dysfunction-Associated Steatotic Liver Disease
Nonalcoholic Fatty Liver
Endometriosis
Keywords: endometriosis
goserelin acetate
hepatic fibrosis
MASLD
MASH
metabolic dysfunction-associated steatotic liver disease
metabolic dysfunction-associated steatohepatitis
NAFLD
NASH
nonalcoholic fatty liver disease
nonalcoholic steatohepatitis
treatment
menopause
Lead sponsor: Aristotle University Of Thessaloniki
Sponsor class: OTHER
Collaborators: name: 424 General Military Hospital
First posted: 2024-07-26
Enrollment: 62
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter, interventional, open label, non-randomized, parallel group
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Hepatic steatosis
timeFrame: 6 months
measure: Hepatic fibrosis
timeFrame: 6 months
Secondary outcomes:
measure: Liver function tests I - ALT and AST
timeFrame: 6 months
measure: Liver function tests II - γGT
timeFrame: 6 months
measure: Insulin resistance
timeFrame: 6 months
measure: Lipid profile
timeFrame: 6 months
measure: Non-invasive hepatic steatosis index I - Fatty Liver Index (FLI)
timeFrame: 6 months
measure: Non-invasive hepatic steatosis index II - Hepatic Steatosis Index (HSI)
timeFrame: 6 months
measure: Non-invasive hepatic steatosis index III - Triglyceride/Glucose Index (TyG)
timeFrame: 6 months
measure: Non-invasive hepatic steatosis index IV - Tyg-BMI
timeFrame: 6 months
measure: Non-invasive hepatic steatosis indices V - NAFLD test
timeFrame: 6 months
measure: Non-invasive hepatic steatosis index VI - Metabolic Score for Insulin Resistance (MetS-IR)
timeFrame: 6 months
measure: Non-invasive hepatic steatosis index VII - Lipid Accumulation Product index (LAP)
timeFrame: 6 months
measure: Non-invasive hepatic steatosis index VIII - Liver Fat Score (LFS)
timeFrame: 6 months
measure: Non-invasive hepatic fibrosis index I - NAFLD fibrosis score (NFS)
timeFrame: 6 months
measure: Non-invasive hepatic fibrosis index II - Fibrosis-4 index (FIB-4)
timeFrame: 6 months
measure: Non-invasive hepatic fibrosis index III - AST-to-Platelet Ratio Index (APRI)
timeFrame: 6 months
measure: Non-invasive hepatic fibrosis index IV - Metabolic dysfunction-Associated Fibrosis Score (MAF-5)
timeFrame: 6 months
measure: Adiponectin
timeFrame: 6 months
measure: Leptin
timeFrame: 6 months
measure: Tumor Necrosis Factor-α (TNF-α)
timeFrame: 6 months
measure: Sex hormones I - Estradiol
timeFrame: 6 months
measure: Sex hormones II - Testosterone
timeFrame: 6 months
measure: Sex hormones III - Sex Hormone Binding Globulin (SHBG)
timeFrame: 6 months
Other outcomes:
Locations:
city: Thessaloniki
country: Greece
facility: 424 General Military Hospital
city: Thessaloníki
country: Greece
facility: 1st Department of Obstetrics and Gynecology, School of Medicine, Aristotle University of Thessaloniki
Study officials:
affiliation: School of Medicine, Aristotle University of Thessaloniki
name: Dimitrios A Anastasilakis, MD, PhDc
role: STUDY_DIRECTOR
affiliation: 424 General Military Hospital, Thessaloniki, Greece
name: Athina I Gkiomisi, MD, PhD
role: STUDY_DIRECTOR
affiliation: School of Medicine, Aristotle University of Thessaloniki
name: Dimitrios G Goulis, MD, PhD
role: STUDY_DIRECTOR
affiliation: School of Medicine, Aristotle University of Thessaloniki
name: Angelos Daniilidis, MD, PhD
role: STUDY_DIRECTOR
affiliation: 424 General Military Hospital, Thessaloniki, Greece
name: Athanasios A Anastasilakis, MD, PhD
role: STUDY_DIRECTOR
affiliation: "G. Gennimatas" General Hospital, Thessaloniki, Greece
name: Chrysi Nalmpantidou, MD
role: STUDY_DIRECTOR
affiliation: School of Medicine, Aristotle University of Thessaloniki
name: Stergios A Polyzos, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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