Introduction
Hot flushes, the most characteristic menopausal symptom, are experienced by up to 75% of menopausal women, and in half of them symptoms are severe enough to seek medical advice.1 They are associated with oestrogen deprivation; therefore, hormone replacement therapy (HRT) is the first treatment option.2 However, the perception of the risks and benefits of HRT has changed since the publication of Women’s Health Initiative Trial in 2002,3 and many women are seeking alternatives because of the concerns over increased risks particularly breast cancer.4, 5 The use of HRT in breast cancer survivors is not recommended because of the potential stimulation of residual cancer and the induction of new hormone-sensitive disease.6,7 Furthermore, the improved longevity of breast cancer survivors, the increased use of aromatase inhibitors over tamoxifen, leading to profound oestrogen deprivation8, and the limited success shown by the currently used non-hormonal alternatives9 made it imperative to find a therapy that is effective and safe.
Hot flushes are possibly triggered within the hypothalamus by increased central noradrenergic activity leading to disturbances in the thermoregulatory centre,10, 11 and/or activation of oestrogen withdrawal induced up-regulated 5-HT2Areceptors by mild internal or external stimuli resulting in a hyperthermic response.12Oestrogen replacement was shown to ameliorate hot flushes by interacting with monoamine neurotransmitters in the brain; noradrenaline and serotonin (5-hydroxytryptamine; 5-HT). It was found to significantly decrease plasma noradrenaline, increase plasma serotonin13 and augment serotonergic activity14 in postmenopausal women.
Folic acid is involved - via donation of a methyl group - in the monoamine neurotransmitters synthesis.15 Studies reported that it reduced noradrenaline secretion16, 17and increased serotonin activity.16, 18 Folic acid administered to mice produced an antidepressant-like effect mediated by an interaction with the noradrenergic receptors (α1 and α2) and serotonergic receptors (5-HT1Aand 5-HT2A/2C).16 Four small studies19-22 reported that folic acid ameliorates hot flushes in postmenopausal women; however, they had substantial methodologic flaws.
We hypothesised that folic acid supplementation ameliorates hot flushes by the same mechanism as oestrogen replacement i.e. by interacting with monoamine neurotransmitters in the brain. It lowers noradrenaline and increases serotonin activities.23 This randomised controlled trial (RCT) was designed to assess the efficacy of folic acid supplementation versus placebo to symptomatic postmenopausal women in terms of amelioration of hot flushes as the primary outcome measure, and to assess the efficacy on other menopausal symptoms and Quality of life (QoL) as secondary outcome measures.