The hot flush: symptom of menopause or sign of disease?

Knowledge of post-reproductive life dates to ancient Egypt and Greece¹; however, an understanding of what caused it, its consequences and how to treat them were not formed until the 20th century advances in endocrinology². Menopause is still a retrospective diagnosis, defined as the permanent absence of menstruation after more than 12 months' amenorrhea, but, for many women, it is the onset of hot flushes (or hot flashes) and other symptoms that herald the beginning of ‘the change’.

In this issue of Climacteric, Sturdee and colleagues³ provide a comprehensive review of the hot flush including physical and cognitive aspects, physiological changes and associated pathophysiology. Vasomotor symptoms (VMS), including the hot flush, are amongst the commonest symptoms of the menopause transition. The prevalence of hot flushes varies between countries, between regions and between women. For individual women, the bother caused by a hot flush depends on many external factors including cultural attitudes, family and social networks, general health and well-being, social status and a societal understanding of the menopause. Hot flushes are a heat dissipation response characterized by flushing and sweating, probably triggered by a narrowing of the thermoneutral zone in the hypothalamus and an increased central secretion of noradrenaline. The neuroendocrine changes associated with a hot flush may have significance far beyond the immediate distress and discomfort experienced at the time.

Treatments for hot flushes are innumerable. Almost every imaginable extract of human or animal tissue has been tried as well as alcohol, herbs and grains, phytoestrogens, acupuncture and heavy metals including lead, mostly with limited benefit and sometimes with harm. Hot flushes subside with time, although not as quickly as we once thought⁴, and the placebo response in randomized, clinical trials is generally high, requiring any active comparator to have a high rate of response to demonstrate statistically significant benefit. To date, the most effective treatment for VMS has been estrogen replacement therapy, combined with progestogen when endometrial protection is required⁵. Now, new non-hormonal options are under investigation including modulation of transmission via the kisspeptin–neurokinin B–dynorphin signaling system with neurokinin B receptor antagonists⁶. These compounds, or others like them, may at last provide an effective alternative for women unable or unwilling to use hormonal interventions to alleviate their symptoms.

The hot flush may have more serious connotations. A review article by Biglia and colleagues⁷ raises the question of whether vasomotor symptoms are a marker of chronic disease, by pointing to a growing body of evidence linking hot flushes to a range of chronic postmenopausal conditions including cardiovascular disease, osteoporosis and cognitive decline.

A longitudinal study of over 11 000 women followed for 14 years⁸ reported an increased risk of coronary heart disease for women with hot flushes or night sweats which persisted after correction for other risk factors. Possible mechanisms to explain this include reports linking vasomotor symptoms with adverse lipid profiles, a rise in systolic blood pressure, increased insulin resistance and inflammatory markers. Results from the Study of Women Across the Nation, a multiethnic US study, have linked a higher frequency of hot flushes with both a rise in blood pressure and, in younger women, a worsening of endothelial function⁹.

Similar links are seen between hot flushes and other diseases of aging. For example, US researchers¹⁰ found that lower bone density and a higher rate of bone turnover during the menopause transition were linked to the presence of vasomotor symptoms. Australian researchers found moderate to severe vasomotor symptoms were associated with moderate to severe depressive symptoms¹¹.

Perhaps then, vasomotor symptoms, the classical symptom of the menopause, should also be regarded as a warning of other chronic disease. The midlife women’s health check is an opportunity for a discussion of healthy lifestyle measures such as regular exercise, normalization of weight, cessation of smoking and a healthy diet. It should also be a time for a thorough general health check and for appropriate screening tests to minimize the risk of diseases of aging.

Should we also seek out the troublesome hot flush and, if found, institute primary prevention? Should that be hormonal or is there another option? Too often this question has been ignored because of concerns regarding inappropriate use of menopausal hormone therapy (MHT). Early observational studies suggested long-term health benefits for users of MHT but the Women’s Health Initiative (WHI) randomized, clinical trial initially found the opposite. Subsequent re-analysis of WHI data with age stratification¹², newer randomized, clinical trials, observational studies and meta-analyses have consistently shown reductions in coronary heart disease, reduced risk of fracture and improved quality of life when MHT is initiated close to the menopause at a time when menopausal symptoms are at their peak. Other than lifestyle modification, there are no other validated primary prevention strategies for women under age 60 or within 10 years of their last period.

There is still a strong push against MHT for primary prevention. The American College of Physicians has warned against using MHT for primary prevention of fracture because of so-called high-quality evidence linking MHT to cerebral vascular attack and coronary heart disease¹³. A draft document from the US Preventive Services Task Force warns against the use of MHT for primary prevention, although these conclusions seem reliant upon old randomized, clinical trial data not focused on the cohort of women who seek treatment and are usually close to their last menstrual period.

Long-term follow-up of WHI data¹² found no increased risk of adverse health outcomes during the intervention phase of the trial for women aged 50–59 using either conjugated estrogens alone or in combination with a progestogen.

A Cochrane systematic review of hormone therapy for prevention of heart disease in postmenopausal women¹⁴ also warned against the use of MHT for primary prevention; however, when the authors confined their analysis to women aged 50–59 or within 10 years of their last period, they found lower mortality (relative risk 0.70, 95% confidence interval 0.52–0.95) and lower coronary heart disease risk using a composite of death from cardiovascular disease and non-fatal myocardial infarction (relative risk 0.52, 95% confidence interval 0.29–0.96). Stroke risk was not increased although the risk for venous thromboembolism was, as expected with oral therapy.

The hot flush, much maligned over time, may be more than a symptom. It may be a marker of risk of chronic disease. Perhaps we should pay more attention to the flush, particularly to those women most affected, and look again at a role for newer, lower-dose, hormone therapy as well as other interventions for appropriate primary prevention of disease in midlife.