Recommendations for research
The Guideline Development Group has made the following recommendations for research. The full set of research recommendations is detailed in the full guideline.
What is the safety and effectiveness of alternatives to systemic hormone replacement therapy (HRT) as treatments for menopausal symptoms in women who have had treatment for breast cancer?
Women with a history of breast cancer are rarely offered hormonal treatment for menopausal symptoms but the available alternatives are less effective. There is limited evidence from randomised controlled trials on the safety and effectiveness of options such as non-hormonal treatments, ospemifene, conjugated equine estrogen/bazedoxifene (CEE/BZA) or local vaginal oestrogen for menopausal symptoms in women who have had treatment for breast cancer. There is insufficient evidence on the efficacy and safety of non-pharmaceutical treatments in women with breast cancer and other hormone-sensitive conditions. Randomised controlled trials or large cohort studies are needed to understand the effects of these treatments in women with breast cancer, and to investigate if there is a difference in breast cancer recurrence, mortality and tumour aggression with different types of treatment.
What is the difference in the risk of breast cancer in menopausal women on HRT with progesterone, progestogen or selective oestrogen receptor modulators?
Fear of breast cancer deters many women from taking HRT, even in the presence of debilitating menopausal symptoms. There is a lack of evidence from randomised controlled trials directly comparing the risk of breast cancer in menopausal women on HRT with progesterone, progestogen or selective oestrogen receptor modulators. There is a need for a national registry of women with breast cancer.
Optimising the risk–benefit profile of HRT will potentially reduce morbidity and mortality from breast cancer in women who need HRT over the long term because of continuing menopausal symptoms.
How does the preparation of HRT affect the risk of venous thromboembolism (VTE)?
An increase in the risk of VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) is a significant side effect of HRT, particularly because PEs can be fatal. This risk appears to be greater with oral than transdermal HRT. DVT risk increases with age and BMI, among other risk factors.
The progestogen component of HRT may also influence the risk of a DVT, which may be greater with androgenic synthetic progestogens than natural progesterone (but findings from observational studies need confirmation). Most women in the UK take oral HRT comprising oestrogen combined with a synthetic progestogen, and the use of progesterone is less common.
Randomised controlled trials are needed to compare oral with transdermal HRT, and HRT containing different types of progestogens. These trials should measure coagulation factors and the incidence of VTE in women at increased risk of VTE for whom transdermal oestrogen is indicated.
What are the effects of early HRT use on the risk of dementia?
Concern about the prospect of dementia in older age is increasing and any beneficial effect on the future risk of dementia will be important to women who are considering using HRT. There is a need for good-quality observational studies controlling for the effect of important confounders on how early HRT use affects dementia risk in women with early natural menopause, including women with premature ovarian insufficiency.
What are the main clinical manifestations of premature ovarian insufficiency and the short- and long-term impact of the most common therapeutic interventions?
Women with premature ovarian insufficiency can experience the effects of menopause for most of their adult life. This can lead to reduced quality of life and an increased risk of osteoporosis, cardiovascular disease and possibly dementia. There is uncertainty about the diagnosis, time course and management of premature ovarian insufficiency. For example, it is possible that different interventions produce different outcomes in terms of quality of life, and bone, cardiovascular and brain protection. Combined oral contraceptives are often prescribed when this might not be the best treatment in terms of quality of life and preservation of bone density and cardiovascular health. Short- and long-term outcomes of HRT versus combined hormonal contraceptives in women with premature ovarian insufficiency therefore need to be investigated.
Development of a collaborative premature ovarian insufficiency registry would allow the collection of high-quality demographic, biobank (genomic) and clinical data in order to clarify:
the diagnosis and presentation of premature ovarian insufficiency
the impact of therapeutic interventions such as combined hormonal contraceptives, HRT and androgens
the long-term impact of premature ovarian insufficiency on bone density and fracture, and cardiovascular and cognitive health
the long-term risk of cancer, which can be determined by linking with relevant cancer and mortality registries.