Is integrative therapy of traditional Chinese medicine and progesterone capsule more effective than monotherapies in oligomenorrhea and hypomenorrhea? Evidence based on a multi-center randomized controlled trial and metabolomic profile.

BACKGROUND AND OBJECTIVES

Oligomenorrhea and hypomenorrhea were common conditions in outpatient visit which affected child-bearing aged women, and the conventional progesterone treatment has been related to several side effect and contradiction, and this study aimed to evaluate the effectiveness and safety of traditional Chinese medicine (TCM), progesterone capsules, and their combination in treating oligomenorrhea and hypomenorrhea both clinical and metabolomic approach.

METHODS

A prospective, randomized, multi-center trial has been conducted, and a total of 239 oligomenorrhea and hypomenorrhea were randomly assigned to receive TCM, progesterone capsules (PG), or the combined Chinese and Western medicine (COM) and treated from 3 months, respectively. Scores were recorded at 1 and 3 month of treatment, while the seral samples for sex hormone and safety parameters were taken before and after management, with adverse events recorded. A post-hoc metabolomic research was further conducted, in which a total of 84 patients' blood sample collected before and after 3-month treatment were screened liquid chromatography-tandem mass spectrometry (LC-MS) and the results were analyzed with machine learning models to identify the differential metabolites, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database and Interactive pathways explore (iPath) database were applied to unveil the potential pathway involved in the treatment.

RESULTS

A total of 220 participants completed the trial treatment, with dropout rate of 11.6%. The Traditional Chinese Medicine Syndrome Scale (TCMSS) scores of each group were significantly lower than those before treatment after 1 month of treatment and after 3 months of treatment. After 3 months of treatment, the COM group had the highest total effective rate (61.54%). The pictorial blood loss assessment chart (PBAC) scores in the TCM group were significantly higher than those before treatment after 1 month of treatment and 3 months after treatment, whereas no difference before and after treatment was observed within PG group. In COM group, the score after 3 months of treatment was significantly higher than that before treatment. In the post-hoc study with metabolomic approach with KEGG pathway enrichment and topological analyses, glycerophospholipid (GPL) metabolism were found significantly altered in all 3 groups. while TCM could potentially improve the clinical symptom tryptophan metabolism.

CONCLUSION

From the perspective of TCMSS scores, the effect of COM group is more significant. In terms of PBAC scores, sex hormone level, endometrium and the improvement of ovarian function in patients with low ovarian function, the TCM group had a better response. In a comprehensive evaluation, the regimen of TCM alone or COM can significantly improve menstrual flow and treat oligomenorrhea and hypomenorrhea patients. With KEGG pathway enrichment and topological analyses, GPL metabolism were found significantly altered in all 3 groups, and TCM could potentially improve the clinical symptom tryptophan metabolism. Whereas unique pathways influenced under combo treatment suggested a synergetic effect of combination TCM with western medicine in management of oligomenorrhea and hypomenorrhea.