COmmencing Menopausal HOrmone Replacement Therapy and the Effect on Metabolic-dysfunction Associated Steatotic Liver Disease: a Pilot Mechanistic Study (COHORT: pilot)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease worldwide, currently affecting approximately 1-in-4 people globally. The prevalence is expected to rise further, driven at least partly by the epidemic of obesity and diabetes. MASLD is a condition of fat build-up in the liver that can progress to liver scarring which is associated with higher chances of death. Women are more than twice as likely to develop MASLD after menopause compared to before menopause, and previous research has shown that this may be caused by a lack of oestrogen. A lack of oestrogen is also believed to lead to harmful changes in adipose (body fat), which has an important role in the development of MASLD. Oestrogen contained in hormone replacement therapy (HRT) is an effective treatment for hot flushes and other problems in menopause. The popularity of HRT has increased dramatically in the United Kingdom in recent years, however the exact way in which it affects adipose and MASLD is unclear. The investigators will study how HRT affects the processes that drive MASLD in 10 women before and after using the treatment. This is a small-scale pilot study to understand feasibility of recruitment and test the procedures for a future, larger-scale studies.

The investigators will recruit women who are about to begin HRT for the first time and perform the same tests for each participant before starting HRT, and after using HRT for 12-weeks. The participants will undergo meal testing including non-radioactive, stable isotopes, and blood and breath samples will be collected to measure fat processing. The total fat content of the liver will be measured using magnetic resonance imaging (MRI) scans. Adipose samples will be collected, fat metabolites will be measured and the distribution of fat around the body will be assessed using a dual energy x-ray absorptiometry (DEXA) scan. To find out how HRT affects these processes, the results from before and after using HRT will be compared. Understanding how HRT affects adipose and the liver may help reduce the development of MASLD in women after the menopause and improve their health and survival.

Study Overview

• Status: Recruiting
• Conditions: Menopause; Metabolic Dysfunction Associated Steatotic Liver Disease
• Intervention / Treatment: Drug: Menopausal hormone therapy

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Jiawen Dong, MB BChir, MRCP; Phone Number: +441865 857300; Email: jiawen.dong@ocdem.ox.ac.uk

Study Locations

• United Kingdom
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 7LE
      • Recruiting
      • Oxford Centre for Diabetes Endocrinology and Metabolism (OCDEM), Churchill Hospital
      • Contact: Jiawen Dong, MB BChir, MRCP; Phone Number: +441865 857300; Email: jiawen.dong@ocdem.ox.ac.uk
      • Contact: Jeremy Tomlinson, MB BCh, PhD, FRCP
      • Contact: Jiawen Dong, MB BChir, MRCP

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Potential participant is willing and able to give informed consent for participation in the trial
• In the Investigator's opinion, is able and willing to comply with all trial requirements
• Female, aged 18 years and above
• Body mass index 18 to 45 kg/m2

• Postmenopausal status:

  • For women ≥ 40 defined clinically (amenorrhoea for ≥ 1 year) or biochemically (FSH >30IU/L on 2 occasions 4-6 weeks apart).
  • For women < 40 defined as a combination of oligomenorrhoea/amenorrhoea for ≥ 4 months and FSH >30IU/L on 2 occasions 4-6 weeks apart
  • Women who have undergone bilateral oophorectomy (no additional testing is required)
• Low oestradiol levels
• No exposure to systemic oestrogen-based HRT within the previous 3 months
• Willing to allow his or her General Practitioner and consultant, if appropriate, to be notified of participation in the trial.

Exclusion Criteria:

• Potential participant with known chronic liver disease, with the exception of MASLD
• The use of drugs which, in the opinion of the investigator, will significantly impact on hepatic lipid content or metabolism. This applies to drugs currently being used or used in the past, within a timeframe where the investigator believes it may impact hepatic lipid content or metabolism.
• Potential participant with any other medical explanation for amenorrhoea, apart from menopause
• History of harmful alcohol consumption (>35 units/week) or alcohol misuse disorder
• Potential participants with contraindication to MRI
• Scheduled elective surgery or other procedures requiring general anaesthesia during the trial.
• Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial.
• Potential participant with life expectancy of less than 6 months.
• Potential participants who have participated in another research trial involving an investigational product in the past 12 weeks.
• Potential participants without a sufficient understanding of written or verbal English to participate in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hormone Replacement Therapy; Participants starting any brand, composition, route and dose of oestrogen-based systemic hormone replacement therapy, will be included in this group.	Drug: Menopausal hormone therapy; Any brand, composition, route and dose of systemic menopausal hormone therapy containing oestrogen. Brands of HRT include oestrogel, Evorel, Lenzetto, Estradot, Progynova (this list is not exhaustive)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recruitment into an experimental medicine study investigating the impact of HRT on MASLD	Number of participants who are screened and recruited into the study	7 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acceptability of experimental protocols in experimental medicine study investigating the impact of HRT on MASLD	Feedback from questionnaire completed by study participants	From enrollment to the end of the study after completing 12 weeks of intervention
Participant retention in an experimental medicine study investigating the impact of HRT on MASLD	Number of participants who complete the study (per protocol)	From enrollment to the end of the study after completing 12 weeks of intervention
Fatty acid esterification into triglyceride	Measurement of 13C-palmitate incorporation into very low density lipoprotein triglyceride (VLDL-TG)	Performed at baseline and after 12 weeks of intervention
Hepatic lipid content	Measurement of intrahepatic triglyceride content by magnetic resonance imaging / spectroscopy	At baseline and after 12 weeks of intervention
Whole body fatty acid oxidation	Measurement of incorporation of 13C into breath CO2 using GC-C-IRMS.	At baseline and after 12 weeks of intervention
Fasting and postprandial plasma intrahepatic fatty acid synthesis.	Change in hepatic fatty acid synthesis as measured by incorporation of 2H2 palmitate (via 2H2O) into VLDL-TG	At baseline and after 12 weeks of intervention
Liver profile blood tests and circulating lipid profiles	Routine laboratory biochemistry	At baseline and after 12 weeks of intervention
Interstitial levels of metabolites in adipose tissue	Change in adipose tissue metabolite profile	At baseline and after 12 weeks of intervention
Adipose tissue transcriptomic profile	Change in adipose tissue transcriptomic profile in abdominal subcutaneous and gluteal depots	At baseline and after 12 weeks of intervention
Total and regional lean and fat tissue distribution	Total and regional lean and fat mass on Dual energy X-ray absorptiometry (DXA) scan	At baseline and after 12 weeks of intervention

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adipose tissue steroid profile	Adipose tissue steroid profile	At baseline and after 12 weeks of intervention

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: Oxford University Hospitals NHS Trust

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2025
• Primary Completion (Estimated): August 5, 2025
• Study Completion (Estimated): January 1, 2026

Study Registration Dates

• First Submitted: October 29, 2024
• First Submitted That Met QC Criteria: November 22, 2024
• First Posted (Actual): November 26, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 10, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: estrogen; NAFLD; liver; steatosis; hormone; replacement; fat; adipose; MASLD; MASH; oestrogen
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormones
• Other Study ID Numbers: 345429

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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