Study Participants
The participants were recruited from 9 NHS hospitals across the UK via
menopause, oncology or research clinics. Women also attended for
screening by direct self-referral following advertisements placed within
the participating hospitals, and local general practitioners’ surgeries,
pharmacies and libraries. Women were eligible for enrolment in the study
if they were 40 to 70 years of age, with normal baseline serum folate
level (3.1 to 20.0µg/L), postmenopausal (either healthy, or breast or
endometrial cancer survivors with iatrogenic onset of menopause) and
experiencing ≥50 hot flushes per week as quantified from daily Sloan
Diary24 recordings for 7 days prior to randomisation
(Supplementary Document 1, p 48). Menopausal status was defined as
cessation of menstruation for 12 months or 6 weeks after surgical
removal of ovaries. All participants provided written informed consent.
Participants were excluded from randomisation in the following
circumstances: (1) Baseline serum folic acid level above the normal
laboratory range, (2) Intestinal malabsorption e.g. celiac or Crohn’s
disease, (3) Chronic renal impairment, (4) Chronic conditions mimicking
climacteric presentation e.g. poorly controlled hypertension,
hyperglycaemia or thyroid instability, (5) Pernicious anaemia due to
vitamin B12 deficiency, (6) Alcohol consumption > 14 units
per week, (7) Pheochromocytoma or carcinoid syndrome, (8) Allergy to
folic acid, (9) Participation in another clinical trial within 4 weeks
prior to enrolment, and/or (10) Taking prohibited medications
unless the participant was willing
and it was safe to discontinue. In such cases, wash out periods were
allowed before randomisation and were estimated based on the drug
specifications published on MHRA website25(Supplementary Document 1, p22).