Elsevier

Maturitas

Volume 64, Issue 2, 20 October 2009, Pages 104-108
Maturitas

Review
Calcitonin gene-related peptide, adrenomedullin and flushing

https://doi.org/10.1016/j.maturitas.2009.08.011Get rights and content

Abstract

Administration of calcitonin gene-related peptide (CGRP) or adrenomedullin (AM) can cause facial flushing, suggesting that the peptides may be important in hot flushes experienced particularly by post-menopausal women. Five studies have measured plasma CGRP concentrations in post-menopausal women who suffer from flushes; all demonstrated elevations of between 170% and 320% over control. Three of the studies showed a temporal relationship between flushes and CGRP elevation. A further study has shown that CGRP is elevated in the urine of women who suffer from flushes. Only a single study has investigated flushes in pre-menopausal women; no elevation of CGRP was observed. Flushes are also experienced by men undergoing androgen deprivation therapy. Whilst one study failed to find any increase in CGRP in the urine of these individuals, a small study has identified an increase in plasma CGRP. No studies have investigated plasma AM or the related peptide, intermedin/AM2. Overall, there is good evidence to show that flushes in post-menopausal women are accompanied by an increase in CGRP. CGRP could act centrally on the thermoregulatory centre of the hypothalamus as well as peripherally to cause vasodilation and sweating. However, it remains to be demonstrated that the elevated CGRP causes flushes. Recently developed CGRP antagonists provide an opportunity to test this hypothesis. If they are successful, they may represent a useful alternative to oestrogen replacement therapy.

Introduction

Both calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) are extremely potent vasodilators. They are related peptides, belonging to the calcitonin peptide family. When administered to humans CGRP can cause facial flushing [1]. This has lead to the suggestion that these peptides may have a role in abnormal flushing seen particularly in post-menopausal women and so blocking their actions may be a novel way of alleviating this condition. Whilst flushing is currently treated with oestrogen replacement, this is not suitable for all individuals [2]. This review considers the evidence that implicates CGRP and AM in flushing and evaluates their potential as relevant drug targets.

Section snippets

Hot flushes

Hot flushes are commonly reported by women at the time of the menopause. Whilst their frequency normally declines with time, they can persist for many years in a minority of individuals. They are characterised by increases in cutaneous blood flow coupled by elevation of temperature, which can lead to sweating. Although the temperature rise is most marked in the extremities, the flushing characteristically occurs in the region of the face, neck and upper part of the torso. The sensation of

CGRP

CGRP is a 37 amino acid neuropeptide, found predominantly in sensory C and Aδ nerve fibres. It is a potent dilator of the microvasculature (21) and plays an important role in neurogenic vasodilation in the skin [5]. Accordingly, one of the most obvious effects of exogenously administered human α-CGRP is a potent vasodilatory action in the skin. This effect has been reported following intradermal, subcutaneous and intravenous/intra-arterial routes of administration [6], [7], [8]. For example,

AM, intermedin and flushing

As a potent vasodilator, there is at least a superficial case for considering whether AM might have a role in flushing. Administration of AM to humans can certainly cause flushing [34] and its levels are reported to increase in adipose tissue in post-menopausal women [15]. Since intermedin/AM2, a close relative of AM can activate CGRP and AM receptors, it is logical also to include it in the debate. What is currently lacking is any data indicating what happens to serum levels of these peptides

Treating flushing by targeting CGRP and AM

Both AM and CGRP have their own specific receptors, although there is also cross-reactivity of the peptides at each other's receptors [35]. For CGRP, it is likely to be acting at its cognate receptor. For AM, given the lack of information relating to any potential role for AM in flushing it is also not possible to speculate about which receptor it may be acting through and therefore which receptor it may be most useful to target. There are a number of non-peptide CGRP receptor antagonists in

Concluding remarks

There is evidence from several studies for an association between CGRP and flushes in post-menopausal women. A link between AM and this condition has yet to be reported. Further research is needed to prove a causal relationship and to establish any role with flushes in men. The use of the recently available CGRP antagonists in a clinical study might provide the data needed to confirm a role for this peptide in flushing. If this is the case, CGRP antagonists will represent a useful alternative

Contributors

David Poyner; commissioned to write the review, collected data and contributed to writing.

Debbie Hay; collected data and contributed to writing.

Competing interests and funding source

David Poyner; undertook the writing of this article as part of his normal duties as an employee of Aston University. The university took no role in any part of this work. There are no competing interests.

Debbie Hay; undertook the writing of this article as part of her normal duties as an employee of Auckland University. The university took no role in any part of this work. There are no competing interests.

Provenance

Commissioned and externally peer reviewed.

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