ESTEEM - Evaluating the clinical and cost-effectivenesS of TEstosteronE to improve Menopause-related quality of life

Research question: Is testosterone an effective and safe treatment for menopausal symptoms, beyond altered sexual function, when added to standard hormone replacement therapy (HRT) treatment?

Background: The menopause affects 51% of the population and is associated with multiple symptoms, which can negatively affect quality of life for some women. HRT is prescribed to relieve these symptoms by replacing the oestrogen the body loses during the menopause. The role of testosterone in HRT to manage symptoms, other than altered sexual function, is not clearly understood and poorly evidenced to date.

There is no licensed testosterone for use in women available within the NHS. As a result, prescribing practices and access to ‘unlicensed’ testosterone across the UK are variable although demand for testosterone as part of HRT has increased. Aims and objectives Primary:

· To investigate whether testosterone is effective in reducing menopause symptoms beyond altered sexual function, using the Menopause-Specific Quality of Life Intervention questionnaire Scale (MENQOL-I). Secondary: · Establish the cost-effectiveness of testosterone based on a primary outcome of Quality Adjusted Life Years.

· Assess safety profile and potential harms of testosterone treatment. · Gain patient consent and link data to allow long-term monitoring of health outcomes using routinely collected data. · Confirm feasibility of adequate and equitable trial recruitment, retention and data quality in an internal pilot.

· Explore barriers/facilitators amongst service providers and women to future prescribing and uptake of testosterone.

· Work with lay research partners to design, deliver and report a trial to meet needs of all women who may experience menopausal symptoms.

Methods: Multi-centre double-blind parallel arm randomised controlled trial to compare outcomes for women aged >45-years with menopausal symptoms despite standard HRT, allocated at random to receive testosterone gel or matched placebo. 416 women will be recruited via NHS organisations and by self-referral, promoted via social media and community groups. Following eligibility screening, electronic consent will be taken, including agreement for long-term follow-up.

Baseline and follow-up data will be collected using electronic case report forms (eCRF) using a trial app or by phone if preferred. The primary outcome of MENQOL-I will be at 6 months, and secondary outcomes at 3, 6 and 12 months, all analysed based on intention to treat. A health economic evaluation will assess relative costs and benefits of adding testosterone to standard HRT.

Lay research partners and community groups will inform study design and conduct, and alongside a qualitative process evaluation will inform recruitment/retention and dissemination strategies.

Timelines for delivery: Complete milestones (by month): set up (8), pilot (14), assess progression criteria (17), main recruitment (32), follow-up (44), analysis/report (51).

Anticipated impact and dissemination: The trial will provide clarity to policy, practice and patients about efficacy and safety of testosterone when added to standard HRT, beyond altered sexual function. We will disseminate via academic pathways (eg journals), key training organisations and professional networks (e.g. RCOG, RCGP, FSRH) and NICE to update current guidance on Menopause management.

We will co-develop summaries with PPI partners to feedback to trial participants, patient groups, and broader public.