Patient-reported outcomes for menopause management intervention

The Society for Endocrinology is developing a real-world data register in women’s health. Using the society's extensive networks and expertise, a steering group will be brought together to identify missing and underreported outcomes for patients in this area. Connections with industry, patient support groups, and health care professionals will be used to support the patients. 

Most women worldwide experience menopausal symptoms during the menopause transition or post-menopause. Vasomotor symptoms are most pronounced during the first four to seven years but can persist for more than a decade, and genitourinary symptoms tend to be progressive. Although the hallmark symptoms are hot flashes, night sweats, disrupted sleep, and genitourinary discomfort, other common symptoms and conditions are mood fluctuations, cognitive changes, low sexual desire, bone loss, increase in abdominal fat, and adverse changes in metabolic health. These symptoms and signs can occur in any combination or sequence, and the link to menopause may even be elusive. Oestrogen based hormonal therapies are the most effective treatments for many of the symptoms and, in the absence of contraindications to treatment, are considered to have a favourable benefit: risk ratio for women below age 60 and within 10 years of the onset of menopause. 

However, research evidence for the efficacy and safety of hormone-based menopause treatments have historically been limited to selected groups of women: women with a history of severe obesity, uncontrolled blood pressure, cardiovascular disease, and any recent cancer diagnosis being excluded from clinical trials. Furthermore, the majority of research has included a predominance of white, middle-class women. There is sparse evidence for efficacy and safety in women from ethnic minority backgrounds and those experiencing socioeconomic adversity. 

A survey in 2022 by the Fawcett Society found that 46% of women who started on hormone replacement therapy (HRT) or menopausal hormone therapy said their menopause symptoms had not resolved. There is emerging evidence of unconventional dosing regimens for HRT being used due to lack of symptom resolution. Testosterone use with HRT has also increased since the licensing in Australia of a female testosterone product in 2020. However, there is a lack of post-marketing surveillance data on testosterone use in modern cohorts. 

Non-hormonal treatment options for menopause are offered second-line for women who choose not to take HRT, develop side effects with it or for whom it is not safe, such as oestrogen receptor positive cancer, which frequently occurs in peri-post menopausal women.

Furthermore, breast cancer treatments, chemotherapy for other cancers or induction of medical menopause as a treatment for gynaecological conditions such as fibroids or endometriosis frequently induce menopause in younger pre-menopausal women. However, there are no robust outcome data reporting tolerability and efficacy of treatments or menopause-related patient outcomes for such women outside clinical trials.   

There is, therefore, a clear unmet need to assess outcomes for efficacy and safety of menopause treatments in modern cohorts of women in the menopause transition. Collection of real-world data is crucial, particularly with respect to women commencing menopause treatments which may not be represented in historical or recent clinical trials.

Area 1 

Menopause symptom management, including HRT doses & regimens with focus on metabolic disease including diabetes, non-diabetic hyperglycaemia and Turner Syndrome.

Metabolic conditions, particularly Type 2 diabetes (T2D) are highly prevalent globally and are associated with worse microvascular and macrovascular outcomes. Metabolic changes during menopause include increase in central adiposity, reduce insulin secretion, insulin resistance and decrease in energy expenditure which are all associated with increased risk of developing T2D. Early onset of menopause has also been shown to be associated with increased risk of T2D.

Hormone replacement therapy has a favourable effect on glucose metabolism both in people with and without diabetes. Some studies have suggested that HRT may delay onset of T2D although the precise mechanisms of this are unknown. HRT also has beneficial effects on glucose metabolism. The beneficial effects could potentially be through oestrogens leading to improved insulin secretion and insulin sensitivity. Whether HRT leads to better outcomes in people with diabetes is not known.

The association of menopause with prediabetes are not known but may have the same pathophysiological effects as those with diabetes with increased risk of development of T2D. Associations of HRT in people with prediabetes are also lacking.

Turner Syndrome is the commonest X chromosome abnormality and affects 1/2500 live births. It is associated with primary ovarian insufficiency as well as other associated comorbidities which are commoner than in the background female population, including metabolic risk (diabetes mellitus, MASLD), hypertension and increased mortality compared to the background female population from vascular disease (CVA and ischaemic heart disease) as well as increased fracture risk and reduced bone density. Some studies demonstrate a beneficial effect of HRT on these parameters,  but whether transdermal or oral HRT is beneficial, and whether satisfactory HRT can reduce these risks is largely unknown.

Area 2

Menopause symptom management including HRT doses & regimens with focus on oncology and surgical outcomes.

Women with a history of breast cancer have particular challenges around menopause management.  Menopausal symptoms are a common side effect of endocrine therapies, used to reduce the risk of breast cancer recurrence and improve survival and are taken for up to ten years after diagnosis. Endocrine therapies owe their effect to either stopping oestrogen signalling (e.g. tamoxifen) or by lowering oestrogen production (e.g. letrozole).  Chemotherapy in pre-menopausal women causes premature ovarian insufficiency with some evidence that treatment-induced menopause may be associated with more severe symptoms that a natural menopause. Finally, women on HRT at diagnosis of a breast cancer are advised to discontinue.

Although there are effective non-hormonal interventions to manage menopausal symptoms after a diagnosis of breast cancer women may struggle to access sufficient support from health care providers, compounded by the move away from specialist follow-up. This has the potential to not only adversely impact on women’s quality of life but may lead to women discontinuing their endocrine therapy with a consequent higher risk of breast cancer recurrence.

HRT remains unlicensed for use after a history of breast cancer with two randomised studies to date stopping early due to concerns about higher recurrence rates in the interventional arm. Despite these concerns some women with a history are choosing to take HRT as means to manage their symptoms.

Area 3

Hormone Implants and Transdermal Testosterone.

Testosterone prescribing in post-menopausal women has increased in recent years and although there is evidence from clinical trials for its effectiveness in improving libido and treatment for hypoactive sexual desire disorder (HSDD), randomised clinical trials have not demonstrated benefit from testosterone therapy on mood, cognition, energy or musculoskeletal health. Short term data on cardiovascular and breast outcomes are reassuring but more long-term outcome data are required. Adverse effects are rare if serum testosterone concentrations are maintained within the physiological range but there have been reports of excess hair growth, voice deepening and weight gain.

As the demand for testosterone prescribing has increased among postmenopausal women and there is not a licenced product available in this country, there is an unmet need to provide evidence to women and prescribers on the safety and efficacy of testosterone products. Collection of real-world data will provide a very useful resource to then form the basis of clinical trials.

Hormone implant use has been in practice for decades and is available for both oestrogen and testosterone replacement. Published evidence appears to support the safety and efficacy of these products, but data are sparse.  More real-world evidence is required to ensure there is standardised practice regarding oestrogen and testosterone implant use and to ensure that patient satisfaction and adverse events are recorded. Subcutaneous hormone treatment avoids the first pass effect through the liver and is thought to have a similar risk/benefit profile to transdermal hormonal therapy, but this should be further evaluated.

Area 4

Long-term GnRH agonist and antagonist use for chronic gynaecological conditions

Chronic pelvic pain (CPP) and heavy menstrual bleeding (HMB) are common debilitating symptoms and affect 1in 4 and 1 in 3 women (and those assigned female at birth) respectively. CPP is commonly associated with endometriosis, and for women with HMB may be due to structural causes (e.g., fibroids, adenomyosis) or non-structural causes (e.g., ovulatory or endometrial disorders). For both symptoms, hormonal treatment is the mainstay of medical treatment but first-line treatment is often either ineffective or has unacceptable side-effects.

GnRH agonists, and the new class GnRH receptor antagonists, are used as second line medical treatments. They render the user in a reversible menopausal state and may bring about reduction in pain, control of bleeding and shrinkage of endometriosis/fibroids. They are licenced for six months of use in isolation, or for two years if used in conjunction with add-back HRT. However, they are often used ‘off-label’ for longer-term use, both with and without addback HRT. The scope and duration of off-label use is unknown.

A hypoestrogenic state has potential for impact on cardiovascular and bone health. This is best exemplified by those undergoing a surgical menopause under the age of 45, who have a 31% increase in all-cause mortality within the next 20 years, predominantly due excess cardiac deaths. Osteoporosis is a source of significant morbidity, frailty and loss of independence in later life. The Women’s Health Plan and Strategy highlight the impact of these conditions – nearly 1:10 deaths in women in Scotland are caused by ischaemic heart disease, death from stroke is more common for women than men, and there are currently 300,00 people living with osteoporosis in Scotland.

There is no recommendation in national or international guidelines about how and when to monitor those on long-term GnRH agonists/receptor antagonists. Anecdotally, there is significant variation in surveillance for osteoporosis by DEXA scan, and no formal monitoring by gynaecologists for cardiovascular disease in the context of off-label use. This is in direct contradiction to the Women’s Health Plan principle of aiming reduce inequalities in health outcomes for women's general health, including work on cardiac disease.

• Annice Mukherjee, Consultant Endocrinologist
• Paula Briggs, Consultant Reproductive Health
• Lynne Robinson, Consultant Gynaecologist
• Jennifer Tamblyn, Clinical Lecturer on Obstetrics and Gynaecology
• Joyce Harper, Prof Reproductive Science
• Nick Panay, Prof Reproductive Medicine
• Paul Simpson, Consultant Gynaecologist
• Anne Armstrong, Consultant Oncologist Breast
• Carlo Palmieri, Prof Oncologist Breast
• Richard Simcock, Prof Oncologist Breast
• David Rook, SRH trainee ST5
• Mike Savvas, Consultant Gynaecologist
• Vikram Talauliker, Consultant Gynaecologist
• Gail Allsopp, General Practitioner
• Maxine Whelan, Research Scientists
• Ketan Dhatariya, Prof Endocrinologist
• Kamlesh Khunti, Professor of Primary Care, DUK, University of Leicester
• Rebecca Reynold, Prof Endocrinology and Diabetes
• Helen Turner, Consultant Endocrinologist
• Liz O’Riordan, Consultant Breast Surgeon
• Punith Kempagowda, Consultant Endocrinologist
• Aled Rees, Prof Endocrinologist
• Niamh Martin, Consultant Endocrinologist
• Ali Abarra, Consultant Endocrinologist
• Channa Jayasena, Consultant Endocrinologist
• Gayathri Delanerolle, Research Scientist
• Rebecca Bowen, Prof Oncologist Breast
• Victoria Corkhill, Consultant Obstetrician and Gynaecologist
• Steven Parks, Diabetes UK
• Anna Morris, Diabetes UK
• Mick O'Reilly, Consultant Endocrinologist
• Jackie Maybin, Consultant Obstetrics and Gynaecology
• Andrew Horne, Professor of Gynaecology and Reproductive Sciences
• Rowena Sharma, Consultant Obstetrics and Gynaecology
• Stuart Ralston, Consultant Endocrinology
• Any Tatham GP, Menopause Specialist

• Liverpool Women’s NHS Foundation Trust
• Birmingham Women’s Hospital
• Institute for Women's Health University College London
• The Christie NHS Foundation Trust
• The Clatterbridge Cancer Centre NHS Foundation Trust
• King's College Hospital London
• University College London Hospital NHS trust
• Norfolk and Norwich University Hospitals NHS Foundation Trust
• NHS Lothian
• Oxford University Hospitals NHS Trust
• Queen Elizabeth Hospital Birmingham
• Imperial College Healthcare NHS Trust
• Southern Health NHS Foundation Trust
• Royal United Hospitals Bath NHS Foundation Trust
• Manchester Foundation NHS Trust
• Beaumont Hospital Dublin
• Aneurin Bevan University Hospital Board
• St George’s Healthcare NHS Trust
• Salford NHS Trust
• Manchester Spire Hospital

Primary Objectives: Quality of life difference for women who are taking and not taking HRT across the cohort of patients

Outcome measures: Analysis on the Eq5D data to assess quality of life

Time point (s): Questionnaire to be asked once every 6 months or triggered when a new symptom or treatment is logged.

Secondary objectives: Quality of life differences for women who are taking and not taking HRT between each of the 4 areas

Outcome measures: Analysis on the Eq5D data to assess quality of life

Time point(s): Questionnaire to be asked once every 6 months or triggered when a new symptom or treatment is logged

General Objectives from the whole dataset

The overall endpoints of this study are to determine

1. General Disease Characteristics

a.1 All-cause mortality

1. 2 Patient-reported outcomes

a.3 Social Factors including economic/smoking/alcohol/ employment status,

1. 4 Blood pressure, BMI considerations during menopause
2. 5 Comorbidities including Cancer diagnosis, Diabetes, CVD, hypertension, hyperlipidaemia, MASLD

a.6 Current and historic medications and medical history (including obstetrics and gynaecology history

a.7 Health inequalities in prescribed therapies for age, ethnicity and socio-economic status

a.8 Primary care investigations, including, where available, biochemical profile, full blood count, HbA1C, thyroid function, LFTs/U&E/Bone

a.9 Investigations relevant to primary diagnosis (including menopause related investigations; LH/FSH/Oestradiol/testosterone/SHBG, ultrasound scans)

1. Area 1 Menopause symptom management, including HRT doses & regimens with focus on metabolic disease, including Diabetes, non-diabetic hypoglycaemia and Turner Syndrome;

B 1. Patient data collection will include vasomotor severity and frequency, treatment impact on quality of life outcomes, and collection around diabetes diagnosis, treatment, and medication.

B 2. Clinical and patient data collection on menopause symptoms & HRT use in women with diabetes (dose and regimen).

B 3. Clinical and patient data collection on use and doses/regimens of HRT to manage menopause symptoms in women with diabetes (efficacy & side effects).

B 4. Use of HRT and menopause symptoms on patients with Turner Syndrome

B 5. Diabetes micro/macrovascular complications

C Area 2 Menopause symptom management including HRT doses & regimens with focus on oncology and surgical outcomes;

C 1. Data collection of menopause symptoms & management in women undergoing treatment for breast cancer

C 2. Data collection on systemic HRT use in women with a history of breast cancer (dose and regimen).

C 3. Data collection on vaginal oestrogen use in women with a history of breast cancer.

C 4. Data collection on incidence of new breast cancer episodes in women treated with HRT (dose and regimen).

C 5. Cancer treatments/recurrences/adjuvant therapy

C 6. Endometrial cancer/hyperplasia incidence

C 7. Primary & secondary breast cancer incidence

D Area 3 Hormone Implant and Transdermal Testosterone Management;

D 1. Data collection of menopausal symptoms before and during transdermal testosterone treatment including libido, vaginal dryness, mood, cognition, musculoskeletal symptoms.

D 2. Data collection on evidence of safety and adverse effects of transdermal testosterone therapy in post-menopausal women.

D 3. Data collection on symptom control and patient satisfaction of transdermal testosterone therapy in post-menopausal women, unwanted side effects and evidence of clinical practice

D 4. Data collection of menopausal symptoms before and during subcutaneous hormone implant therapy including libido, vaginal dryness, mood, cognition, musculoskeletal symptoms.

D 5. Data collection on evidence of safety and adverse effects of subcutaneous hormone implant therapy in post-menopausal women

D 6. Data collection on symptom control and patient satisfaction of subcutaneous hormone implant therapy in postmenopausal women, unwanted side effects and evidence of clinical practice

D 7. Symptom scoring, compliance to medication, mental health assessment,

D 8. Side effects: Subcutaneous hormone implant (oestrogen and testosterone) and transdermal testosterone use: Tachyphylaxis, Tiredness, hair growth/loss, acne, mood changes, vasomotor symptom control, clitoral enlargement, sleep related symptoms, voice changes, weight gain

D 9. Subcutaneous hormone implant therapy: Frequency of serum hormone level monitoring, dose prescribed, frequency of implants, progestogen type and dose used if not hysterectomized. Cardiovascular outcomes and biomarkers, breast cancer incidence, endometrial cancer/hyperplasia incidence, thrombosis, Blood pressure, BMI, liver function, bone density, fracture incidence, side effect profile

D 10. Transdermal testosterone use: Frequency of serum hormone level monitoring, dose prescribed, progestogen type and dose used if not hysterectomized. Cardiovascular outcomes and biomarkers, breast cancer incidence, endometrial cancer/hyperplasia incidence, thrombosis, blood pressure, BMI, liver function, bone density, fracture incidence, side effect profile

Section E Area 4 Long-term GnRH agonist and antagonist use for chronic gynaecological conditions

E 1. Indication for treatment

E 2. Duration of treatment

E 3. Use of add-back HRT

E 4. Use and frequency of DEXA scanning

E 5. Long term fracture and cardiovascular outcomes

E 6. Impact on symptoms (including but not limited to Chronic Pelvic Pain, Bleeding, Pre-Menopausal Symptoms).

The ability to use the patient app to reinforce conversations with their clinicians about their health in consultation visits. 

The ability to track their own health and medications through the app and learn more about themselves and their health in this manner.  

Safety Reporting in the Data Register: 

Regarding safety reporting; the clinical portal and the patient app will have the ability to tag a national yellow card adverse event reporting completion of any adverse drug related events at any time during the project. There will be a notification upon completion by the clinician or patient to prompt the clinician to report these to the drug company per normal protocols.  

https://www.gov.uk/guidance/the-yellow-card-scheme-guidance-for-healthcare-professionals  

October 2024 – October 2026

Data is made available to researchers, patient support groups, pharmaceutical or medical device companies, and other health care professionals via the data access request form in line with the data access policy of the Society for Endocrinology.

You can find more information about governance here. 

• Astellas Pharmaceuticals has provided funding for this project via sponsorship. The project has been developed independently of Astellas.
• Bayer Pharmaceuticals has provided funding for this project via sponsorship. The project has been developed independently of Bayer.
• Besins Healthcare has provided funding for this project via sponsorship. The project has been developed independently of Besins Healthcare.
• Lawley Pharmaceuticals has provided funding for this project via sponsorship. The project has been developed independently of Lawley Pharmaceuticals.

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Most women worldwide experience menopausal symptoms during the menopause transition or post menopause. Vasomotor symptoms are most pronounced during the first four to seven years but can persist for more than a decade, and genitourinary symptoms tend to be progressive. Although the hallmark symptoms are hot flashes, night sweats, disrupted sleep, and genitourinary discomfort, other common symptoms and conditions are mood fluctuations, cognitive changes, low sexual desire, bone loss, increase in abdominal fat, and adverse changes in metabolic health. These symptoms and signs can occur in any combination or sequence, and the link to menopause may even be elusive. Estrogen based hormonal therapies are the most effective treatments for many of the symptoms and, in the absence of contraindications to treatment, are considered to have a favourable benefit: risk ratio for women below age 60 and within 10 years of the onset of menopause.  

However, research evidence for efficacy and safety of hormone-based menopause treatments have historically been limited to selected groups of women; women with a history of severe obesity, uncontrolled blood pressure, active vascular disease, and any recent cancer diagnosis being excluded from clinical trials. Furthermore, the majority of research has included a predominance of white Caucasian, middle class women. There is sparse evidence for efficacy and safety in women from BAME backgrounds and those experiencing socioeconomic adversity.  

A survey in 2022 by the Fawcett Society found that 46% of women started on hormone replacement therapy (HRT) said their menopause symptoms had not resolved. There is emerging evidence of unconventional dosing regimens for HRT being used due to lack of symptom resolution. Testosterone use with HRT has also increased since the licensing in Australia of a female testosterone product in 2020. However, there is a lack of post-marketing surveillance data on testosterone use in modern cohorts.  

Non-hormonal treatment options for menopause are offered second-line for women who choose not to take HRT, develop side effects with it or for whom it is not safe, such as estrogen receptor positive cancer, which frequently occurs in peri- post menopausel women. Furthermore breast cancer treatments and chemotherapy for other cancers frequently induce menopause in younger pre-menopausal women. However, there are no robust outcome data reporting tolerability and efficacy of treatments or menpause related patient outcomes for such women outside clinical trials.    

There is therefore a clear unmet need to assess outcomes for efficacy and safety of menopause treatments in modern cohorts of women in the menopause transition. Collection of real word data is crucial particularly with respect to women commencing on menopause treatments who may not be represented in historic, or recent clinical trials.