Tokishakuyakusan Ameliorates Age-Related Pregnancy Loss by Modulating Endocrine, Inflammatory, and Placental Factors in an Advanced Maternal Age Rat Model.

ETHNOPHARMACOLOGICAL RELEVANCE: Tokishakuyakusan is a traditional Japanese Kampo medicine widely prescribed for gynecological disorders, including reproductive dysfunction. AIM OF THE STUDY: Using an advanced maternal age (AMA) rat model, we investigated the effects of tokishakuyakusan on pregnancy loss and the mechanisms involved, including endocrine, inflammatory, and placentation-related factors. MATERIALS AND METHODS: Aged (36-week-old) female Wistar-Imamichi rats served as the AMA model and were compared with young (12-week-old) controls. Before mating, AMA rats were fed either a diet containing 3% tokishakuyakusan or a control diet for 4 weeks. Pregnancy outcomes were assessed on gestational day 19, and plasma and placental samples were collected. RESULTS: AMA rats showed a reduced live fetus rate, an increased post-implantation loss rate, fetal growth restriction, and reduced placental efficiency, together with lower plasma progesterone (P4) levels, elevated inflammatory cytokines and chemokines, lower placental fms-like tyrosine kinase-1 (Flt1/Flt-1) and placental growth factor (Pgf/PlGF) mRNA expression, and higher circulating soluble Flt-1 (sFlt-1). Placental Flt1 expression and circulating sFlt-1 levels correlated significantly with the post-implantation loss rate, indicating an association between impaired PlGF-Flt-1 signaling and pregnancy loss. Tokishakuyakusan increased the live-fetus rate, reduced the post-implantation loss rate, improved placental efficiency, increased plasma P4 levels, suppressed inflammatory mediators, increased placental Flt1 expression, and reduced circulating sFlt-1 levels. CONCLUSIONS: AMA-related pregnancy loss is associated with endocrine imbalance, inflammation, and placental dysfunction. Tokishakuyakusan ameliorated these changes and may offer a therapeutic strategy for age-related pregnancy loss.