The evolution of the human menopause.

The females of most species die soon after ceasing to reproduce, their purpose in life being to ensure survival of their kin. Human females may live more than one-third of their lives after they cease to reproduce, a property shared by few species, one of which is Orca whales. Orcas have been extensively studied because families live together in stable units or pods and individual whales have distinctive markings, enabling them to be identified. The females survive long after the menopause, one possible reason for this being that the older females provide a survival advantage since they are seen to lead the pods more often than younger females or males, thus providing a survival advantage in times of food shortage. The female lifespan is increasing in most countries worldwide, principally due to decreased infection and maternal mortality. Women are now more active through middle and into older age. Whatever sort of life they wish to lead, women need to be as fit as possible to facilitate healthy aging. Chronic diseases that affect millions of women are cardiovascular disease, osteoporosis, cancer, and dementia. The incidence of all these is increased by obesity, the prevention of which is a major challenge in our society. Hormone therapy may have a place for some women but for many others taking control of their health by lifestyle intervention is a major contributor to disease prevention. It is our duty as doctors to encourage this at every opportunity to help all women live a fruitful and healthy old age.

The neurokinin B pathway in the treatment of menopausal hot flushes.

Hot flushes remain a debilitating aspect of menopause, disrupting daytime activities and sleep, and may last for years. Estrogen replacement is an effective treatment, but takes time to become maximally effective and is contraindicated in a significant proportion of women, most notably after breast cancer. Effective, non-hormonal therapies are therefore required. Recent years have seen substantial increases in understanding of the role of novel neuropeptides and tachykinins in hypothalamic function, particularly in the regulation of the reproductive axis through control of gonadotropin releasing hormone secretion, but with links to the control of vasomotor function. Neurokinin B, often co-expressed with kisspeptin in hypothalamic neurons, appears to be a key factor in the control of both systems. Several neurokinin B antagonists have been developed; data are emerging as to their effectiveness in the treatment of menopausal hot flushes. While data remain limited, these agents appear to have a remarkably fast onset of action, with the first 1 or 2 days of administration, and with a dramatic effect on both daytime flushes and night sleep disturbance. If safety and long-term function can be confirmed, these novel agents will be an important advance in therapy.

The menopausal hot flush: a review.

The hot flush is the most characteristic and often the most distressing symptom of the menopause. It is a unique feature and yet the mechanism and health implications are still not fully understood. This review summarizes some of the current thoughts on factors contributing to flushing, the physiological, vascular and neuroendocrine changes associated with flushing and the possible cardiovascular and other health implications for women experiencing hot flushes. Therapy is not discussed.

Non-hormonal management of vasomotor symptoms.

Vasomotor symptoms are the most common indication for the prescription of hormone replacement therapy since it is effective in over 80% of cases. In 1995, 37% of American women took hormone replacement therapy, principally for this purpose. However, following the publication of results from the Women's Health Initiative, as many as half of these women in the US and in the UK and New Zealand discontinued hormone therapy. Discontinuation of estrogen is often accompanied by a return of vasomotor symptoms; however, only a small number (18%) of women report restarting hormone therapy. Alternatives are available, but limited knowledge on etiology 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.

Hot flushes, vascular reactivity and the role of the α-adrenergic system.

ABSTRACT Background Seventy percent of postmenopausal women suffer from hot flushes but the pathophysiology is poorly understood. Proposed mechanisms include altered peripheral vascular reactivity and a narrowed thermoneutral zone. A trigger has not yet been identified; however, the α-adrenergic system, and specifically noradrenaline, has been implicated. Aim To assess the role of the α-adrenergic system by studying the effect of clonidine (α-adrenergic agonist) on flushes and cutaneous microvascular perfusion. Methods Thirty-two postmenopausal women with severe flushing and 14 non-flushing postmenopausal women were recruited. Cutaneous microvascular perfusion was measured using laser Doppler imaging and endothelial function was assessed by iontophoresis (administration of vasoactive agents through the skin by an electric current) of acetylcholine (ACh - endothelium-dependent) and sodium nitroprusside (SNP - endothelium-independent). In a double-blind, longitudinal, cross-over study, clonidine (an α-adrenergic agonist) was compared to placebo in its ability to modulate this response in the flushing group of women. Results The response of the subcutaneous vessels was greater in women who flushed than those who did not (ACh, p < 0.001 and SNP, p = 0.001). However, even though the intensity and number of flushes were decreased by clonidine, there was no difference compared to placebo (p = 0.21) and this 'placebo effect' was also noted in perfusion responses (ACh, p = 0.98; SNP, p = 0.50). Conclusion There was a significant 'placebo effect' for both clinical response and the reactivity of the subcutaneous vessels, making conclusions regarding the role of the α-adrenergic nervous system in hot flushing difficult to determine at a peripheral level. The mechanism for the change in vascular reactivity remains unclear.

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

BACKGROUND: Seventy per cent of postmenopausal women suffer from hot flushes causing significant morbidity in 25%. Oestrogen replacement provides symptom relief, but its use has declined following safety issues and there is, as yet, no good alternative. Pathophysiology is poorly understood, but one proposed mechanism is altered peripheral vascular reactivity. It has recently been suggested that the presence of flushing may be a marker of underlying cardiovascular risk. AIM: To measure (i) peripheral vascular reactivity in subcutaneous vessels (ii) routine and novel cardiovascular risk factors in postmenopausal women who flush, and compare results to a matched group of women who do not flush. METHODS: Thirty-two postmenopausal women with at least 20 flushes/week and 14 nonflushing postmenopausal women were recruited. Cutaneous microvascular perfusion was measured using laser Doppler imaging, and endothelial function was assessed by iontophoresis (administration of vasoactive agents through the skin by an electric current) of acetylcholine [Ach] (endothelial-dependent) and sodium nitroprusside [SNP] (endothelial independent). Blood samples for risk factors were taken following vascular assessment. RESULTS: Both study groups were well matched demographically. The response of the subcutaneous vessels was greater in women who flushed than those who did not, following administration of both the endothelium-dependent and independent vasodilators, (ACh, P ≤ 0·001, SNP, P = 0·001, 2-way anova). By contrast, levels of High Density Lipoprotein (HDL)-cholesterol and ApoA1 were significantly lower in the flushing women compared with the control women (P = 0·02 and 0·002, respectively), and levels of inter-cellular adhesion molecule-1 (ICAM-1) were higher (P = 0·03), findings robust to adjustment for confounders, suggesting an adverse cardiovascular risk profile. CONCLUSION: These results confirm a better vascular response in women but paradoxically, such women appear to have worse (not better) cardiovascular disease risk factors in particular lower HDL-cholesterol but also higher non-HDL-c to HDL-c ratio and increased ICAM-1. Further studies are needed to assess vascular risk factors in women who flush.