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.