Interpretation:
It was plausible to hypothesise that folic acid ameliorates hot flushes in postmenopausal women. Tetrahydrofolates; the metabolically active and tissue-usable forms of folic acid, are essential for the biosynthesis of the monoamine neurotransmitters serotonin and noradrenaline. 5-methyltetrahydrofolate, participates in re-methylation of the amino acid metabolite homocysteine, creating methionine. The downstream metabolite of methionine; S-adenosylmethionine must be present as a methyl donor for both the serotonin and catecholamine pathways to function properly. Without the participation of 5-methyltetrahydrofolate in this process, S-adenosylmethionine and neurotransmitter levels decrease in the cerebrospinal fluid. 5-methyltetrahydrofolate was also found to stabilise and enhance production of tetrahydrobiopterin, which is an essential nutrient cofactor in the biosynthesis of serotonin and noradrenaline.15, 31-34 In addition, 5-methyltetrahydrofolate was shown to cause a significant reduction in the noradrenaline secretion to only 12.9% of control release, probably by duplicating the rate limiting behaviour of a synthetic pteridine cofactor “DL,2-amino4-hydroxy-6,7,dimethyltetrahydropteridine”.17Moreover, folate deficiency was associated with decreased serotonin activity,35 and supplementation with folic acid increased CSF levels of 5-HIAA in folate deficient patients with depression.18 Interestingly, it was found that the regional distribution of 5-methyltetrahydrofolate in the brain was similar to that of serotonin.36
Four small studies suggested that folic acid supplementation significantly ameliorated hot flushes in postmenopausal women. The first study, including two groups (n =23 each) of postmenopausal women, reported significant improvement of hot flushes and lowering in plasma levels of 3-methoxy 4-hydroxy phenyl glycol (MHPG, the end metabolite of brain noradrenaline) with daily folic acid 5 mg supplementation for 4 weeks when compared with placebo. There was also significant negative correlation between improvement in hot flushes and the plasma level of MHPG.19 The second study, including two groups (n =20 each) of postmenopausal women, demonstrated an average of 57% reduction in the frequency in hot flushes with daily folic acid 5 mg supplementation for 4 weeks when compared with no treatment.20 The third study, including 2 groups (n =35 each) of postmenopausal women, revealed significant improvement in severity, duration, and frequency of hot flushes with daily folic acid 1 mg supplementation for 4 weeks as well as with placebo tablets. However; there was more improvement in the folic acid group.21 The fourth study included 3 groups (n =40 each) of postmenopausal women taking daily supplementation of folic acid 1 mg, omega-3 1000 mg, or placebo tablets for 12 weeks. There was statistically significant improvement in severity, duration, and frequency of hot flushes in the folic acid group when compared with placebo.22Nonetheless, all these studies had serious methodologic flaws. First, they were underpowered with small number of participants. Second, folic acid supplementation was given for a short duration of 4 weeks raising the suspicion of placebo effect. Third, the bias in allocation and assessment cannot be excluded given the poor reporting of the methods. None of the studies specified the method of concealment of study-group assignments. In one study, placebo was not used for comparison. In all studies, women were allocated (by alternation) into the groups. Fourth, two studies used a small dose of 1 mg of folic acid and reported positive results. Last, no validated method to assess the frequency and intensity of the flushes was used, and the improvement was subjectively described by women based on their overall feelings.