Managing menopause after cancer.

Globally, 9 million women are diagnosed with cancer each year. Breast cancer is the most commonly diagnosed cancer worldwide, followed by colorectal cancer in high-income countries and cervical cancer in low-income countries. Survival from cancer is improving and more women are experiencing long-term effects of cancer treatment, such as premature ovarian insufficiency or early menopause. Managing menopausal symptoms after cancer can be challenging, and more severe than at natural menopause. Menopausal symptoms can extend beyond hot flushes and night sweats (vasomotor symptoms). Treatment-induced symptoms might include sexual dysfunction and impairment of sleep, mood, and quality of life. In the long term, premature ovarian insufficiency might increase the risk of chronic conditions such as osteoporosis and cardiovascular disease. Diagnosing menopause after cancer can be challenging as menopausal symptoms can overlap with other common symptoms in patients with cancer, such as fatigue and sexual dysfunction. Menopausal hormone therapy is an effective treatment for vasomotor symptoms and seems to be safe for many patients with cancer. When hormone therapy is contraindicated or avoided, emerging evidence supports the efficacy of non-pharmacological and non-hormonal treatments, although most evidence is based on women older than 50 years with breast cancer. Vaginal oestrogen seems safe for most patients with genitourinary symptoms, but there are few non-hormonal options. Many patients have inadequate centralised care for managing menopausal symptoms after cancer treatment, and more information is needed about cost-effective and patient-focused models of care for this growing population.

Elinzanetant: a phase III therapy for postmenopausal patients with vasomotor symptoms.

INTRODUCTION: Menopausal vasomotor symptoms (VMS) are experienced by most women and are often debilitating and can last for years. While hormone replacement therapy is effective, it carries risks that have impacted its wider use, and it can be contraindicated. There is a large unmet need for a safe, effective non-hormonal therapy. AREAS COVERED: The importance of the neurokinin (NK) system in the hypothalamic regulation of the vasomotor center has become clear. NK antagonists, previously developed for other indications, have therefore been investigated for the treatment of VMS. Elinzanetant is a potent antagonist at both NK1 (endogenous ligand Substance P) and NK3 (neurokinin B) receptors, whereas other related drugs in development are selective NK3 antagonists. Elinzanetant has been investigated in 2 Phase II trials for menopausal VMS, demonstrating rapid onset and dose-dependant efficacy for the relief of VMS and improvement in quality of life for up to 12 weeks. Phase III trials are underway in women both with physiological menopause and after treatment for breast cancer. EXPERT OPINION: Elinzanetant is a very promising non-hormonal approach to a highly prevalent symptom constellation, with rapid onset and high efficacy. Wider indications are being explored in current Phase III trials.

Managing vulvovaginal atrophy after breast cancer.

Cancer treatment may result in loss of ovarian function through surgical removal of the ovaries, chemotherapy or radiation. While menopausal symptoms, such as hot flushes, night sweats, sleep disturbance, memory concerns and mood issues can be extremely bothersome to some women going through menopause naturally, women who undergo an induced menopause usually experience more sudden and severe symptoms. Pain and vaginal dryness can occur whether a woman has a sexual partner or not. In women with breast cancer, the aetiology of impaired sexual functioning, and lowered sexual desire, is often multifactorial, and may be related to physical and/or psychological reasons. Pain and vaginal dryness in women without a history of breast cancer can usually be safely treated with vaginal estrogens, in the form of a cream, pessary or ring, and simple lubricants or vaginal moisturisers. Safe usage of vaginal estrogen replacement therapy in breast cancer patients has not been studied within randomised clinical trials of long duration; the guidelines below reflect a clinical consensus.

Oestrogen replacement in postmenopausal women.

Menopausal symptoms can disrupt a woman's personal and social life. Vasomotor symptoms (hot flushes and night sweats) are the most common symptoms and can be treated very effectively with oestrogen-based hormone therapy. The decision to use oestrogen (often simply termed hormone therapy or hormone replacement therapy or HT) therapy involves balancing the potential benefits against the potential risks. Most agree that short-term oestrogen therapy, using the lowest effective dose, is a reasonable option for recently menopausal women with moderate-to-severe symptoms who are in good cardiovascular health (Martin and Manson. 2008. J. Clin. Endocrinol. Metab. 93, 4567-75). Whilst effective and safe in most instances, HT is not suitable for all women or for all menopause-related symptoms when alternatives are available. The role of HRT in chronic disease prevention is also discussed.

Vascular function and cardiovascular risk factors in women with severe flushing.

Cardiovascular disease is the leading cause of death in women of postmenopausal age worldwide. It is a relatively rare occurrence before the menopause and the increase in incidence coincides with the most common symptom associated with menopausal transition, hot flushing. Interest in cardiovascular disease post-menopause has largely focused on the effect of hormone therapy on risk of coronary events and stroke, with vasomotor symptoms considered merely a nuisance symptom, but recent work suggests that the presence of flushing may be a marker of underlying cardiovascular disease.

Sex hormone replacement in ovarian failure - new treatment concepts.

Premature ovarian failure is associated with decreased bone mass and fractures, and an increased risk of premature death from cardiovascular disease. There is also fertility compromise associated not only with the loss of ovarian function but, in those with pre-pubertal POF, inadequate uterine morphology. A wide variety of hormone replacement regimes are reported, but there is no clear evidence of best practice. Hormone replacement therapy (HRT) and the combined oral contraceptive pill (COCP) will suppress menopausal symptoms; however neither is designed to achieve physiological replacement of oestrogen and progesterone. There is evidence that physiological sex steroid replacement is superior to standard hormone replacement, in improving uterine volume as well as an improved blood pressure profile and bone mineral density. Sex steroid replacement therapy is long-term in these women, and therefore it is essential that the risk benefit ratio is optimal to maximise longer term health.

Venlafaxine alters microvascular perfusion, [¹²³I]-beta-CIT binding and BDI scores in flushing postmenopausal women.

BACKGROUND: Although 70% of postmenopausal women suffer from hot flashes the pathophysiology is poorly understood. The serotonin and noradrenaline reuptake inhibitor (SNRI) venlafaxine provides relief of flushing although the mechanism is unknown and could involve a central effect and/or a peripheral effect. Using single photon emission computed tomography (SPECT) we studied the central serotonin transporter (SERT) in vivo using [(123)I]-beta-carbomethoxy-3-ß-(4-iodophenyl)tropane (beta-CIT) and, as previous studies have shown that reactivity of the skin blood vessels is enhanced in those who flush, we examined cutaneous microvascular perfusion. METHODS: Cutaneous microvascular perfusion was assessed in 31 postmenopausal women, with flushing, using laser Doppler imaging with iontophoresis (LDI+ION), before and after 8 weeks of treatment with venlafaxine. A sub-group of 14 of these women also had SPECT imaging at both time points to evaluate the availability of SERT in the brain. Flush frequency and score was recorded, and Beck Depression Inventory (BDI) II scores were assessed before and after treatment. RESULTS: Following treatment with venlafaxine, there was a significant reduction in the [(123)I]-beta-CIT binding ratio, BDI scores, flushing and endothelial dependent perfusion response. [(123)I]-Beta-CIT reduction was associated with BDI reduction (r(2)=0.54; F=8.8; p=0.004), but not flushing reduction or perfusion reduction. CONCLUSIONS: Venlafaxine resulted in a decrease in BDI II scores with an associated reduction in [(123)I]-beta-CIT binding in a group of non-depressed women. It also improved flush frequency and severity which may be as a result of decreases seen in enhanced cutaneous microvascular perfusion.

Hot flushes: are there effective alternatives to estrogen?

Hot flushes are the most common indication for the prescription of hormone replacement therapy (HRT) since it is effective in over 80% of cases. In 1995, 37% of American women took HRT, principally for this purpose. However, over the last five years, publications such as those from the Women's Health Initiative (WHI) have caused concern among women since they perceive that the risks outweigh the benefits. Following this publication, half of the women taking HRT in the UK, USA and New Zealand discontinued HRT. With the discontinuation of estrogen many women re-developed hot flushes; however only a small number (18%) of women report restarting hormone therapy. The majority of these (76%) for the recurrence of severe hot flushes or night sweats. Alternatives are available, but limited knowledge on aetiology and mechanisms of hot flushing represents a major obstacle for the development of new, targeted, non-hormonal treatments, and no current alternatives are as effective as estrogen.