Reappraising 21 years of the WHI study: Putting the findings in context for clinical practice.

Menopausal hormone treatment (MHT) is recommended for the management of menopause symptoms. The Women's Health Initiative (WHI) placebo-controlled randomised study examined the effects of continuous combined or estrogen-only MHT on the risk of non-communicable diseases (NCDs) in post-menopausal women. The study was terminated prematurely after an interim analysis showed an increased risk of breast cancer diagnosis, which led to a rapid decrease in MHT use worldwide. Subsequently, limitations of the study design and its interpretation in the context of other clinical studies has contributed to a more nuanced appreciation of the risk-benefit profile of differing MHT regimens regarding risk associated with the class of progestogen prescribed, its pattern of prescription, duration of use and timing of initiation related to menopause onset. This review provides a contextual interpretation of the WHI placebo-controlled study and evaluates the impact of bioidentical MHT, with a focus on combined therapies containing micronised progesterone, on the risk of chronic NCDs in post-menopausal women.

The British menopause society consensus statement on the management of estrogen deficiency symptoms, arthralgia and menopause diagnosis in women with treated for early breast cancer.

This guidance document by the British Menopause Society provides an overview of the management of women experiencing estrogen deficiency symptoms and arthralgia following a breast cancer diagnosis. It is now recommended breast cancer patients are referred to health care professionals with an expertise in menopause for management of such symptoms, which in turn often involves liaison with patients' breast cancer teams.1 However, as many women initially present to primary health care professionals for advice, this statement is aimed to support the latter in such consultations by providing information about symptom aetiology, current management strategies and controversies and identifying useful practice points. This is an updated version of the 2018 consensus statement prepared by Miss Jo Marsden Consultant Breast Surgeon, King's College Hospital, London, (retired), Mr Mike Marsh, Consultant Gynae-endocrinologist, King's College Hospital, London, Dr Anne Rigg, Consultant Medical Oncologist, Guy's and St Thomas' Hospital, London.

Cancer-related fatigue and functional impairment - Towards an understanding of cognitive and behavioural factors.

OBJECTIVE: Fatigue is a highly prevalent and debilitating problem in women with breast cancer. This study investigated the cognitive, behavioural, interpersonal and affective responses associated with fatigue and functional impairment for women with breast cancer undergoing chemotherapy. A nested prospective study examined factors predictive of cancer-related fatigue after three cycles of chemotherapy. METHOD: 159 women with breast cancer who were about to begin or undergoing chemotherapy completed a range of measures. Correlational and multiple regression analyses explored associations between fatigue severity, functioning and a range of psychological, behavioural, demographic and clinical variables. Forty-two patients were followed-up prospectively to examine the relationship between psychosocial variables, fatigue and functioning after three cycles of chemotherapy. RESULTS: A range of cognitive, behavioural and affective variables were associated with increased fatigue severity and poorer functioning. Key cognitive and behavioural correlates included, all-or-nothing behaviour, avoidance behaviour, cancer-related catastrophising and critical/punishing responses from others. For the women in the nested prospective study, fatigue significantly increased after three cycles of chemotherapy. Increased fatigue was predicted by increased anxiety before starting chemotherapy. CONCLUSIONS: Behavioural factors and cancer-specific cognitions make important contributions to cancer-related fatigue and associated impairments. Such factors are potentially amenable to change within the context of cognitive behavioural therapy.

British Menopause Society consensus statement: The risks and benefits of HRT before and after a breast cancer diagnosis.

In women at population risk of breast cancer (i.e. most), short-term exposure to hormone replacement therapy (i.e. up to five years' use) for symptom relief exceeds its potential harms, including the associated, increased risk of breast cancer diagnosis. Many women and health care professionals, however, consider this to be unacceptably high, although the degree of risk conferred appears equivalent to, or less than that of, other lifestyle risk factors for this condition. In contrast, it is recommended that symptomatic women at high baseline risk due to a family history or a biopsy-confirmed high-risk benign breast condition and those with previous breast cancer should be managed initially with lifestyle changes and non-hormonal alternatives. In a minority, whose symptoms are refractory, hormone replacement therapy and or topical estrogen can be considered but prescription should only take place after a discussion between the patient, her primary health care and breast specialist teams.

British Menopause Society consensus statement on the management of estrogen deficiency symptoms, arthralgia and menopause diagnosis in women treated for early breast cancer.

This guidance document by the British Menopause Society provides an overview of the management of women experiencing estrogen deficiency symptoms and arthralgia following a breast cancer diagnosis. It is now recommended that breast cancer patients are referred to health care professionals with an expertise in menopause for the management of such symptoms, which in turn often involves liaison with patients' breast cancer teams. However, as many women initially present to primary health care professionals for advice, this statement is aimed to support the latter in such consultations by providing information about symptom aetiology, current management strategies and controversies and identifying useful practice points.

Hormonal contraception and breast cancer, what more do we need to know?

Most women use hormonal contraception for more than 30 years and for many, this may involve exposure in their older reproductive years when baseline breast cancer risk rises steeply. Overall, the risk of breast cancer diagnosis with exposure to hormonal contraception is very small and outweighed by its contraceptive benefits but despite this, there are still outstanding questions for all methods used in clinical practice due to paucity of available evidence, lack of which should not be taken to imply safety. This is exemplified by the following assumptions: the progestogen-only pill and long-acting reversible contraceptives are 'breast-safe' options in peri-menopausal women, use of the levonorgestrel intrauterine system for the management of endometrial pathology in breast cancer survivors is less likely to promote disease recurrence and the benefit all hormonal contraceptive methods confer in reducing unplanned pregnancy in women at high familial risk outweigh the risk of breast cancer diagnosis. There is no data on risk with the concurrent prescription of hormone replacement therapy in women exhibiting climacteric symptoms who are still menstruating. Advice of GPs and Community Sexual & Reproductive Health specialists will inevitably be sought about some or all these issues and in the absence of conclusive evidence from clinical studies, caution should be applied and women counselled appropriately.

The menopause specialist and breast cancer survivorship.

Due to improvement in survival rates, breast cancer is the most prevalent female malignancy in Europe and hence the management of breast cancer survivorship is garnering significant attention. Most of the health issues associated with treatment result from iatrogenic estrogen deficiency and recognition of this in the recent National Institute for Health and Care Excellence (NICE) menopause guidance has resulted in the recommendation for referral of breast cancer patients to menopause specialists for appropriate counselling about and management of early menopause, estrogen deficiency symptoms and lifestyle risk modification. The latter has significant implications for both all-cause and breast cancer-specific mortality. Extending the role of health professionals with an interest in menopause to provide such service for breast cancer patients is necessary as this is not within the remit or expertise of specialist breast cancer teams; however it will in turn, require menopause specialists to expand and regularly update their knowledge of breast cancer and its treatment.

Postmenopausal hormone therapy: an Endocrine Society scientific statement.

OBJECTIVE: Our objective was to provide a scholarly review of the published literature on menopausal hormonal therapy (MHT), make scientifically valid assessments of the available data, and grade the level of evidence available for each clinically important endpoint. PARTICIPANTS IN DEVELOPMENT OF SCIENTIFIC STATEMENT: The 12-member Scientific Statement Task Force of The Endocrine Society selected the leader of the statement development group (R.J.S.) and suggested experts with expertise in specific areas. In conjunction with the Task Force, lead authors (n = 25) and peer reviewers (n = 14) for each specific topic were selected. All discussions regarding content and grading of evidence occurred via teleconference or electronic and written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement. EVIDENCE: Each expert conducted extensive literature searches of case control, cohort, and randomized controlled trials as well as meta-analyses, Cochrane reviews, and Position Statements from other professional societies in order to compile and evaluate available evidence. No unpublished data were used to draw conclusions from the evidence. CONSENSUS PROCESS: A consensus was reached after several iterations. Each topic was considered separately, and a consensus was achieved as to content to be included and conclusions reached between the primary author and the peer reviewer specific to that topic. In a separate iteration, the quality of evidence was judged using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system in common use by The Endocrine Society for preparing clinical guidelines. The final iteration involved responses to four levels of additional review: 1) general comments offered by each of the 25 authors; 2) comments of the individual Task Force members; 3) critiques by the reviewers of the Journal of Clinical Endocrinology & Metabolism; and 4) suggestions offered by the Council and members of The Endocrine Society. The lead author compiled each individual topic into a coherent document and finalized the content for the final Statement. The writing process was analogous to preparation of a multiauthored textbook with input from individual authors and the textbook editors. CONCLUSIONS: The major conclusions related to the overall benefits and risks of MHT expressed as the number of women per 1000 taking MHT for 5 yr who would experience benefit or harm. Primary areas of benefit included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. Risks included venothrombotic episodes, stroke, and cholecystitis. In the subgroup of women starting MHT between ages 50 and 59 or less than 10 yr after onset of menopause, congruent trends suggested additional benefit including reduction of overall mortality and coronary artery disease. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Beneficial effects on colorectal and endometrial cancer and harmful effects on ovarian cancer occurred but affected only a small number of women. Data from the various Women's Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause. At the present time, assessments of benefit and risk in these younger women are based on lower levels of evidence.

Polyarteritis nodosa of the breast: presentation and management.

Polyarteritis nodosa (PAN) of the breast is a rare condition where literature review identified eleven patients so far. The clinical presentation ranged from localized disease involving the breast parenchyma and skin only to breast manifestations as part of systemic PAN. The diagnosis of PAN could be challenging as it can mimic breast cancer, inflammatory carcinomatosis or breast infection including mastitis and necrotizing fasciitis. The key importance is accurate diagnosis to avoid unnecessary other treatment modalities and the timely recognition of PAN in cases of localized forms. The authors present three new cases which represent the full range of the clinical spectrum and their management.

Cancer issues.

The potential for hormone therapy to cause cancer is the greatest fear for postmenopausal women considering hormone replacement therapy (HRT). Breast cancer is the most common female malignancy, for which HRT is one of many modifiable risk factors, often attracting disproportionate attention. Randomized controlled trials have confirmed that in postmenopausal women aged 50-59 years taking combined oestrogen and progestogen HRT over 5 years, there will be three extra cases of breast cancer per 1000 women. With the use of unopposed conjugated equine oestrogens, there would be four fewer cases over the same time. Women can be advised that the risk of breast cancer is not significantly increased with up to 3 years of combined HRT and up to 5 years of unopposed oestrogen. Unopposed oestrogen increases the risk of endometrial hyperplasia and carcinoma significantly, and this is dose and duration dependent. The addition of progestogen prevents the proliferative effect of oestrogen on the endometrium, and may even reduce the risk of endometrial cancer compared with non-users if given continuously. The use of combined oral contraception in premenopausal women also reduces the risk of endometrial cancer but increases the risk of cervical carcinoma significantly. HRT does not influence the risk of cervical cancer. Epithelial ovarian cancer risk may be slightly increased with long-term use of unopposed oestrogen, is not altered by the addition of progestogen, and is reduced significantly in users of combined oral contraception. The mechanism for these effects is not understood. Colorectal cancer and possibly lung and gastric cancers are reduced by the use of HRT. Apart from a slight increased risk of gallbladder disease and carcinoma with HRT, there are no data linking oestrogen or progestogen with any other malignancies.

Non-estrogen-based treatments for menopausal symptoms.

The British Menopause Society Council is committed to provide up-to-date authoritative reviews to aid health professionals to inform and advise women about key issues in postreproductive health. This guidance refers to non-estrogen-based treatments for menopausal symptoms, such as hot flushes, symptoms of urogenital atrophy and lack of sexual desire. Treatment of choice should be based on up to-date information and targeted to individual women's needs. Non-hormonal strategies may be useful for women with estrogen-dependent disease such as breast cancer.

Management of premature menopause.

There has been some confusion among women and health professionals since the publication of the Women's Health Initiative and Million Women studies about the management of premature ovarian failure (POF). Both studies were undertaken in women aged 50 and over, and cannot be extrapolated to their younger counterparts, who would normally be producing their endogenous estrogen, since they have functioning ovaries. Estrogen-based replacement therapy is the main stay of treatment for women with POF and is recommended at least until the average age of natural menopause (52 years in the UK). This view is endorsed by regulatory bodies such as the Committee on Safety of Medicines (now the Commission on Human Medicines) in the UK. No evidence shows that estrogen replacement increases the risk of breast cancer to a level greater than that found in normally menstruating women, and women with POF do not need to start mammographic screening early unless other risk factors are present, such as family history.

Is there a role for hormone replacement therapy after breast cancer?

Breast cancer is the most common female malignancy in the UK, with an overall lifetime risk of 1 in 9. Despite the high incidence, breast cancer mortality is decreasing. Approximately 40,000 women were diagnosed with breast cancer in England and Wales in 2000 but the majority will have normal or near-normal life expectancy. One of the main contributory factors to this marked improvement in survival over the last 20 years in women of all ages has been the more widespread use of systemic therapy in early-stage disease. For women with hormone-sensitive cancer, this involves adjuvant endocrine therapy that reduces estrogen synthesis (i.e. ovarian suppression in premenopausal women or aromatase inhibitors in postmenopausal women) or estrogen activity (the anti-estrogen tamoxifen, irrespective of menopausal status). Many women experience health and quality-of-life problems related to estrogen deficiency as a result, the commonest being vasomotor symptoms and vaginal dryness. This article summarizes and interprets key recent papers on the use of hormone replacement therapy (HRT) and selective serotonin reuptake inhibitors in breast cancer survivors. HRT may be safe in women with receptor-negative disease or receptor-positive cancers in the presence of tamoxifen. However, there is a dearth of useful alternatives.