Side effects of low-dose tamoxifen: results from a six-armed randomised controlled trial in healthy women

This was a six-arm, double-blind randomized controlled trial (KARISMA trial) that enrolled 1440 healthy women to compare the side effects of five daily tamoxifen doses (20 mg, 10 mg, 5 mg, 2.5 mg, 1 mg) versus placebo over 6 months. Participants completed a 48-item symptom questionnaire. The primary analysis found that five symptoms (hot flashes, night sweats, cold sweats, vaginal discharge, and muscle cramps) were significantly associated with tamoxifen exposure. A key secondary finding was that in premenopausal women, the mean change in severity of these five side effects was 34% lower in the low-dose group (2.5 and 5 mg) compared to the high-dose group (10 and 20 mg). No similar dose-dependent reduction was seen in postmenopausal women. The study's major limitations include its short 6-month duration, which does not reflect typical long-term therapy, and its population of Swedish women, which may limit generalizability. The findings suggest menopausal status influences tamoxifen side effects and support investigating lower doses to improve tolerability.