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

Overview

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.

Interventions

• 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)

Primary outcome measures

• Recruitment into an experimental medicine study investigating the impact of HRT on MASLD [Time frame: 7 months]

Secondary outcome measures (10)

• Acceptability of experimental protocols in experimental medicine study investigating the impact of HRT on MASLD [Time frame: 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 [Time frame: From enrollment to the end of the study after completing 12 weeks of intervention]
• Fatty acid esterification into triglyceride [Time frame: Performed at baseline and after 12 weeks of intervention]
• Hepatic lipid content [Time frame: At baseline and after 12 weeks of intervention]
• Whole body fatty acid oxidation [Time frame: At baseline and after 12 weeks of intervention]
• Fasting and postprandial plasma intrahepatic fatty acid synthesis. [Time frame: At baseline and after 12 weeks of intervention]
• Liver profile blood tests and circulating lipid profiles [Time frame: At baseline and after 12 weeks of intervention]
• Interstitial levels of metabolites in adipose tissue [Time frame: At baseline and after 12 weeks of intervention]
• Adipose tissue transcriptomic profile [Time frame: At baseline and after 12 weeks of intervention]
• Total and regional lean and fat tissue distribution [Time frame: At baseline and after 12 weeks of intervention]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United Kingdom · 1 center

• Oxford Centre for Diabetes Endocrinology and Metabolism (OCDEM), Churchill Hospital — Oxford

Identifiers

NCT: NCT06704516 · 345429

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗