Safety and feasibility of estrogen receptor-β targeted phytoSERM formulation for menopausal symptoms: Phase 1b/2a randomized clinical trial

Objective: PhytoSERM is a formulation of genistein, daidzein, and S-equol that has an 83-fold selective affinity for estrogen receptor-β (ERβ); and may enhance neuron function and estrogenic mechanisms in the brain without having peripheral estrogenic activity. Methods: We conducted an overarching, two-stage, dose-ranging, double-blinded, randomized, placebo-controlled trial of 12 weeks duration comparing 50 and 100mg/d of phytoSERM with placebo for noncognitively impaired, perimenopausal women aged 45 to 60, with intact uteri and ovaries, with at least one cognitive complaint, and one vasomotor-related symptom. Primary objectives were to assess safety and tolerability of a 50 and 100mg daily dose; and, secondly, to evaluate potential indicators of efficacy on cognition and vasomotor symptoms over 4 and 12 weeks, and using an embedded, 4-week, 2-period, placebo-controlled crossover trial for a subset of participants. Results: Seventy-one women were randomized to treatment; 70 were evaluated at 4 weeks; 12 were entered into the crossover study; 5 did not complete 12 weeks. Reasons for discontinuation were withdrawal of consent (n = 1) and lost to follow-up (n = 4). Adverse events occurred in 16.7% (n = 4) placebo, 39.1% (n = 9) 50mg/d, and 29.2% (n = 7) 100mg/d treated participants; 85% were mild and none was severe. Vaginal bleeding occurred in 0, placebo; 1, 50mg; and 3, 100mg/d participants. Conclusions: The phytoSERM formulation was well tolerated at 50 and 100mg daily doses. Based on safety outcomes, vaginal bleeding at the 100mg dose, and vasomotor symptoms and cognitive outcomes at 12 weeks, a daily dose of 50mg was considered preferable for a phase 2 efficacy trial.