UNLABELLED: Menopausal symptoms, including hot flashes, metabolic changes, and osteoporosis, significantly impact postmenopausal women. Given concerns about hormone replacement therapy, S-equol, a metabolite of the soybean isoflavone daidzein, has emerged as a potential alternative. This study explored the efficacy of S-equol-containing-supplement (SE5-OH), a fermented soy germ containing S-equol, on menopausal symptoms and osteoporosis in 6-month-old and 8-week-old ovariectomized (OVX) rat models. SE5-OH did not affect uterine weight or endometrial thickness but significantly reduced body weight in 8-week-old OVX rats (p <
0.01). SE5-OH also decreased estrogen receptor upregulation in the liver and hypothalamus. In the hypothalamus, SE5-OH downregulated calcitonin gene-related peptide levels, which are linked to hot flashes and osteoporosis (p <
0.05). Additionally, SE5-OH stabilized the bone-formation marker RANKL/OPG, tended to increase estrogen receptor levels in tibial bone tissue and increased serum bone-turnover biomarkers. In conclusion, SE5-OH may alleviate postmenopausal symptoms, including hot flashes, lipid metabolism changes, and osteoporosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10068-024-01768-w.