Title: FOlic Acid Supplementation in the management of Menopausal symptoms in cancer survivors and health postmenopausal women (FOAM Trial)
Funder: Department of Health and Social Care

Abstract: Background Hot flushes, the most characteristic menopausal symptom, are experienced by ~75% of menopausal women, in half of these symptoms are severe enough to seek medical advice (Freedman, 2005). Hot flushes are associated with oestrogen deprivation; therefore, HRT is the first treatment option (Berendsen, 2002). However, an increasing number of women are seeking alternatives for HRT because of concerns over increased breast cancer risk (Rossouw, 2002). Treatment of breast and endometrial cancers frequently results in the loss of ovarian function and menopausal symptoms. Symptoms of iatrogenic menopause are significantly more intense than those of natural menopause due to sudden onset, younger age, the physical and psychological impacts such as body image concerns and sexual dysfunction (Singh, 2010), and the increased use of aromatase inhibitors. The use of HRT in these patients is not recommended because of the potential stimulation of residual cancer (Biglia, 2006), and the non-hormonal alternatives showed a limited success (Nelson, 2006). This makes it imperative to find a therapy that is effective and safe. Oestrogen replacement was shown to ameliorate hot flushes by interacting with monoamine neurotransmitters in the brain; noradrenaline and serotonin (Freedman, 2005). Interestingly, animal studies reported that folic acid, like oestrogen, reduced noradrenaline secretion and increased serotonin activity (Brocardo, 2008). A recent small non-randomized study in healthy menopausal Egyptian women showed that folic acid 5 mg supplementation not only significantly improved hot flushes but also lowered the plasma levels of MHPG, the end metabolite of brain noradrenaline (Gaweesh, 2010). Although these results are encouraging, there are limitations with this study; particularly the lack of randomisation and being underpowered. The hypotheses to be tested: Folic acid supplementation objectively ameliorates hot flushes in postmenopausal women, both healthy women and breast and endometrial cancer survivors who experience early onset of symptoms due to treatment. Folic acid ameliorates hot flushes by lowering noradrenaline and increasing serotonin activities. Aims Primary objective: 1. To assess the efficacy of folic acid supplementation in terms of relief of the number and severity of vasomotor symptoms as compared to placebo. Secondary objectives: 1. To assess the effect of folic acid supplementation on the blood level of serotonin and noradrenaline. 2. To measure the correlation between clinical improvement, serum folate levels and blood levels of serotonin and noradrenaline. 3. To study the efficacy of folic acid supplementation in terms of other menopausal symptoms as compared to placebo. 4. To explore the effect of folic acid in various prognostic subgroups: Healthy women v cancer survivors Body Mass Index (BMI): &le;30 v >30 Plan of investigation FOAM is a multi-centre, phase III, double-blind, randomised placebo-controlled, trial in which 144 postmenopausal women will be randomised on 1:1 basis between folic acid (5mg) tablets or placebo tablets daily for 12 weeks. Postmenopausal women, both healthy and cancer (breast and endometrial) survivors, who fulfill all inclusion criteria and do not meet any of the exclusion criteria, will be recruited from 4 Trusts in England. All analyses will be carried out on an intention to treat basis. The Cancer Research UK Clinical Trials Unit (CRCTU), Birmingham will coordinate the study. Potential benefits to patients and the NHS If folic acid is demonstrated to be effective, this will be a turning point in the clinical practice in the NHS and worldwide since folic acid represents a cheap, safe, well-tolerated alternative to the conventional HRT particularly in cancer survivors who may be having more intense symptoms and certainly cannot take HRT. The intake of 5 mg of folic acid daily is the standard therapeutic dose widely used and is rarely cause any side effects (Butterworth, 1989).

Lay abstract: Hot flushes are experienced by ~75% of menopausal women, and in half of them symptoms are severe enough to seek medical advice. They are associated with oestrogen deprivation; therefore, hormone replacement therapy (HRT) is the first treatment option. However, its use is associated with concerns over increased risks of breast cancer. Treatment of breast and womb cancers frequently results in the loss of ovarian function. Symptoms of artificial menopause are significantly more intense than those of natural menopause due to sudden onset, younger age, the physical and psychological impacts such as body image concerns and sexual dysfunction, and the increased use of a group of medications called aromatase inhibitors. This makes it imperative to find a therapy that is effective and safe. The use of HRT in breast and womb cancer survivors is not welcomed because of the potential stimulation of residual cancer and non-hormonal alternatives show limited success. It was observed in animal studies that folic acid (a member of vitamin B family) administration may have a similar effect to oestrogen and ameliorate hot flushes by interacting with brain chemicals; reducing noradrenaline secretion and increasing serotonin activity. Interestingly, a small non-randomised Egyptian study showed that daily folic acid supplementation not only improved hot flushes in postmenopausal women but also reduced noradrenaline metabolite. These findings need to be confirmed in a larger better designed trial. This randomised controlled trial is designed to determine whether folic acid (5mg) supplementation improves the frequency and severity of hot flushes in postmenopausal women, either healthy women or breast and endometrial cancer patients who experience early onset of symptoms due to their treatment. We also intend to explore the mechanism of action of folic acid. If demonstrated to be effective, folic acid would represent a cheap, safe and easily deliverable alternative to the conventional HRT.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;CANCER AND NEOPLASMS