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.