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NCT Number: NCT06704516

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

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.

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Key information

Conditions

Menopause Digestive System Diseases Fatty Liver Liver Diseases Metabolic Dysfunction Associated Steatotic Liver Disease Non-alcoholic Fatty Liver Disease Platelet Glycoprotein IV Deficiency

Age range

18 year and older

Sex eligibility

Female

Study type

Interventional

Phase

Phase 1

Primary location

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

Oxford, Oxfordshire, OX3 7LE, United Kingdom

Location status: Recruiting

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Menopausal hormone therapy

Drug

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 outcomes

  1. Recruitment into an experimental medicine study investigating the impact of HRT on MASLD

    Time frame: 7 months

    Number of participants who are screened and recruited into the study

Secondary outcomes

  1. 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

    Feedback from questionnaire completed by study participants

  2. 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

    Number of participants who complete the study (per protocol)

  3. Fatty acid esterification into triglyceride

    Time frame: Performed at baseline and after 12 weeks of intervention

    Measurement of 13C-palmitate incorporation into very low density lipoprotein triglyceride (VLDL-TG)

  4. Hepatic lipid content

    Time frame: At baseline and after 12 weeks of intervention

    Measurement of intrahepatic triglyceride content by magnetic resonance imaging / spectroscopy

  5. Whole body fatty acid oxidation

    Time frame: At baseline and after 12 weeks of intervention

    Measurement of incorporation of 13C into breath CO2 using GC-C-IRMS.

  6. Fasting and postprandial plasma intrahepatic fatty acid synthesis.

    Time frame: At baseline and after 12 weeks of intervention

    Change in hepatic fatty acid synthesis as measured by incorporation of 2H2 palmitate (via 2H2O) into VLDL-TG

  7. Liver profile blood tests and circulating lipid profiles

    Time frame: At baseline and after 12 weeks of intervention

    Routine laboratory biochemistry

  8. Interstitial levels of metabolites in adipose tissue

    Time frame: At baseline and after 12 weeks of intervention

    Change in adipose tissue metabolite profile

  9. Adipose tissue transcriptomic profile

    Time frame: At baseline and after 12 weeks of intervention

    Change in adipose tissue transcriptomic profile in abdominal subcutaneous and gluteal depots

  10. Total and regional lean and fat tissue distribution

    Time frame: At baseline and after 12 weeks of intervention

    Total and regional lean and fat mass on Dual energy X-ray absorptiometry (DXA) scan

Other outcomes

  1. Adipose tissue steroid profile

    Time frame: At baseline and after 12 weeks of intervention

    Adipose tissue steroid profile

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Sponsors and collaborators

Lead sponsor

University of Oxford

Other

Collaborators

  • Oxford University Hospitals NHS Trust

Registry information

Important dates

Study start
2025
Primary completion
2025
Study completion
2026
First posted
Nov 26, 2024
Registry last updated
Jan 13, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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