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).