The formula is an eleven-herb decoction whose largest components are processed Rehmanniae radix praeparata and Atractylodes macrocephala, each weighing 30 grams in the standard prescription, followed by Rhizoma dioscoreae and Angelicae sinensis radix at 15 grams apiece. Smaller quantities of Paeoniae radix alba, Ziziphi spinosae semen, Glehniae radix, Moutan cortex, Eucommiae cortex, Radix bupleuri and Panax ginseng complete the prescription. Clinically, the decoction is used to tonify the kidney, regulate liver function, nourish blood and normalize menstruation. Earlier clinical work indicated that the formula increases the number of antral follicles, retrieved oocytes, mature oocytes and high-quality embryos, thereby improving in vitro fertilization outcomes in older patients. Network pharmacology analyses had pointed toward oxidative stress and angiogenesis as likely targets, but the precise molecular mechanism remained unresolved.

To test the formula systematically, the researchers established a diminished ovarian reserve model in female ICR mice using a single intraperitoneal injection of cyclophosphamide, a chemotherapy drug that depletes the ovarian follicle pool. Seventy-two mice with regular estrous cycles were divided into six groups: an untreated control, a disease model group, three Yijing Decoction dose groups receiving 0.9, 1.8 or 3.6 grams per kilogram by oral gavage, and a comparison group receiving estradiol valerate. Treatment continued for eight weeks. The team then evaluated ovarian index, estrous cycle regularity, serum levels of follicle-stimulating hormone, luteinizing hormone, estradiol, anti-Müllerian hormone and inhibin B, and histological follicle counts across all developmental stages.

The results showed a coherent pattern of restoration. Mice in the model group lost body weight, showed a profound reduction in ovarian index and developed persistent estrous cycle irregularities dominated by prolonged inter-estrous intervals. Serum follicle-stimulating hormone and luteinizing hormone surged, while estradiol, anti-Müllerian hormone and inhibin B plummeted. Histology revealed significant losses of primordial, primary and mature follicles alongside elevated numbers of atretic follicles and corpora lutea. High-dose Yijing Decoction reversed most of these changes: primordial and mature follicle counts recovered, atretic follicles declined, anti-Müllerian hormone and inhibin B rose, and estrous cyclicity normalized. The estradiol valerate comparison group produced broadly similar improvements, providing a pharmacological benchmark for the herbal intervention.

The most striking findings concerned the oocytes themselves. At the metaphase I stage, oocytes from diseased mice were fewer in number, morphologically aberrant and increasingly fragmented. Their meiotic spindles, the barrel-shaped microtubule structures that orchestrate chromosome segregation, were severely disorganized. Spindle assembly is extraordinarily energy-dependent, and consistent with this, intracellular ATP levels in the diseased oocytes were dramatically lower than in controls. After treatment with medium-dose or high-dose Yijing Decoction, the majority of oocytes regained a typical bipolar barrel-shaped spindle, and ATP levels were significantly restored. High-dose treatment also significantly increased the number of ovulated oocytes.

To explain this bioenergetic rescue, the researchers turned to glycolysis, the metabolic pathway that converts glucose and pyruvate into modest amounts of ATP and, ultimately, lactate. During normal oocyte maturation, glycolysis is transcriptionally suppressed because its ATP yield per mole of substrate is low; instead, mitochondrial oxidative phosphorylation dominates energy production. Immunofluorescence microscopy revealed that oocytes from diseased mice expressed abnormally high levels of the glucose transporters GLUT1 and GLUT4 and of lactate dehydrogenase A, the enzyme that converts pyruvate to lactate. Pyruvate uptake and lactate production, quantified using fluorescence-based assay kits in 150 to 200 oocytes per group, were both significantly elevated, indicating hyperactive glycolytic flux. Yijing Decoction treatment downregulated the glycolytic proteins, reduced pyruvate uptake and decreased lactate production, effectively steering metabolism back toward mitochondrial ATP generation.

The mechanistic thread connecting these observations is the SIRT3/HIF-1α/PDK1 signaling axis. SIRT3 is an NAD+-dependent mitochondrial deacetylase that negatively regulates glycolysis by promoting the degradation of hypoxia-inducible factor-1α, a master transcriptional activator of glycolytic genes. When SIRT3 falls, HIF-1α accumulates and drives expression of pyruvate dehydrogenase kinase 1, an enzyme that phosphorylates and inhibits the pyruvate dehydrogenase complex. This blocks the conversion of pyruvate to acetyl-CoA, diverts glycolytic flux toward lactate and starves the mitochondria of substrate. In the diseased oocytes, SIRT3 was significantly downregulated while HIF-1α and PDK1 were markedly upregulated. Yijing Decoction partially restored this expression pattern, upregulating SIRT3 while suppressing HIF-1α and PDK1.

Supporting evidence from independent studies reinforces the plausibility of this axis. Metabolomic analysis of human oocytes has shown that aging is accompanied by increased pyruvate and lactate levels and impaired mitochondrial metabolism, particularly at the metaphase I stage. Patients with diminished ovarian reserve exhibit disturbances in glucose metabolism and lactate-related pathways in ovarian granulosa cells. Experimental overexpression of SIRT3 has been shown to improve oocyte developmental competence, and SIRT3 mRNA levels are significantly lower in granulosa cells from older pregnant women relative to younger women with normal ovarian reserve. Culture media engineered to maintain low lactate levels suppress reactive oxygen species accumulation and enhance metabolic efficiency in oocytes, and faster meiotic resumption correlates with lower glycolytic flux.

The authors acknowledge important limitations. Rescue experiments using SIRT3-knockout mice or pharmacological inhibitors of pathway components were not performed, so direct causal evidence linking the formula’s effects to the SIRT3/HIF-1α/PDK1 axis remains lacking. The scarcity of oocytes prevented validation by RT-qPCR and Western blot. Food consumption was not systematically quantified, leaving unclear whether body weight changes reflected altered intake. Functional endpoints such as polar body extrusion and fertilization rates were not assessed, and the study evaluated the decoction as an integral multi-component formula rather than identifying individual bioactive constituents, although prior chemical characterization identified blood-absorbed compounds with reported ovarian-protective activities, including paeoniflorin, ginsenoside Rg1, naringin and hesperidin.

Nevertheless, the findings open a genuinely novel dimension in reproductive biology: the idea that a traditional herbal formula may protect the oocyte by correcting a metabolic imbalance rather than by simply supplementing hormones. If future work confirms that modulating lactate metabolism through the SIRT3/HIF-1α/PDK1 axis can improve oocyte quality in women with diminished ovarian reserve, the implications for fertility treatment could be substantial. The study provides new insights into the association between lactate metabolism-related mechanisms and the protective effects of Yijing Decoction, and the authors call for further investigation integrating rescue experiments, molecular validation and bioactivity-guided chemical study to establish the active chemical basis and confirm the therapeutic relevance of this ancient prescription in modern reproductive medicine.

Subject of Research: Yijing Decoction improves oocyte quality and inhibits lactate accumulation in mice with diminished ovarian reserve

Article Title: Yijing Decoction improves oocyte quality and inhibits lactate accumulation in mice with diminished ovarian reserve

Article References: Yang, J., Chu, M., Zhang, H., Meng, W., Zhang, C., Han, Y., Zeng, G., Zhou, Q., Zhang, X., Zhang, F., & Yan, Y. (2026). Yijing Decoction improves oocyte quality and inhibits lactate accumulation in mice with diminished ovarian reserve. Frontiers in Molecular Biosciences, 13, Article 1946851. https://doi.org/10.3389/fmolb.2026.1946851

Image Credits: AI Generated

DOI: 10.3389/fmolb.2026.1946851

Keywords: Yijing, Decoction, improves, oocyte, quality, inhibits, lactate, accumulation, mice, diminished, ovarian, reserve