Abstract
Hot flushes are common and troublesome symptoms of menopause. The neuropeptide calcitonin gene-related peptide (CGRP) is increased in plasma during hot flushes but it has not been clear if CGRP is causally involved in the mechanism underpinning the flushes. Here, we examined the effect of interventions with CGRP in a mouse model of hot flushes based on flush-like temperature increases triggered by forced physical activity in ovariectomized mice. Compared to normal mice, ovariectomized mice reacted with an exaggerated, flush-like, temperature increase after physical exercise. This increase was completely blocked by the non-peptide CGRP-antagonist MK-8825 (-0.41 degrees Celsius, 95% CI: -0,83 to 0,012, p < 0.0001) at a dose that had no obvious effects on locomotor activity (50 mg/kg). Further, the flush-like temperature increases were strongly attenuated in ovariectomized mice lacking αCGRP due to a genetic modification. Collectively, our findings suggest that CGRP is an important mediator of experimentally induced hot flushes and they identify CGRP antagonists as promising treatment candidates for women and possibly also men with hot flushes.
Highlights
Hot flushes are classic menopausal symptoms in women (Hammar et al, 1984; McKinlay et al, 1992) but are reported by men after castration therapy or with testicular insufficiency (Feldman et al, 1976; Karling et al, 1994), usually persisting over many years and impairing quality of life (Karling et al, 1994)
In order to study the role of calcitonin gene-related peptide (CGRP) in hot flushes, we used a previously described mouse model in which ovariectomized mice respond with abnormal increases in tail-skin temperature upon a short episode of exercise on a treadmill
Ovariectomized mice that were treated with the CGRP receptor antagonist MK-8825 at a dose of 50 mg/kg exhibited no increase in tail skin temperature (-0.41 ± 0.19◦C, n = 13) (p < 0.0001) (Figure 2B)
Summary
Hot flushes are classic menopausal symptoms in women (Hammar et al, 1984; McKinlay et al, 1992) but are reported by men after castration therapy or with testicular insufficiency (Feldman et al, 1976; Karling et al, 1994), usually persisting over many years and impairing quality of life (Karling et al, 1994). Reports during the early 2000s on increased risk of breast cancer and cardiovascular disease (Herrington et al, 2002; Rossouw et al, 2002; Beral, 2003) led to a substantial reduction in hormone therapy use. Despite the fact that later studies suggest that the risks are smaller in recently menopausal women than previously believed (Phillips and Langer, 2005; Rossouw et al, 2007) alternative treatments for menopausal symptoms are needed, especially for women with a history of breast cancer or thromboembolic disease. There are a few alternative pharmacological and non-pharmacological treatments, but none of these seem to be as effective as hormone therapy (Wyon et al, 2004; Albertazzi, 2007; Wong et al, 2009; Daley et al, 2011)
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