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.
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