This study analyzed CGRD medical records of newly diagnosed uterine leiomyoma patients presenting within the Chang Gun hospital system between 2005 and 2014. We found that patients in the 30–44-year age group comprised the main treatment group (49.1%). This finding confirms the results of a nationwide population-based study in Taiwan conducted in 2002–2010.(21) However, in the CGRD study, the second most common group were patients between 13 and 29 years of age, who were thus considerably younger than in Yen et al.’s study (among patients 45–55 years of age). We also found a declining trend in the number of outpatient visits per patient in the CGRD study (with groupings ranging from 1–5 visits to > 40 visits), compared to the bimodal distribution in Yen et al.’s NHIRD study (> 40 or 1–5 visits). The CGRD encompasses hospital data, whereas the NHIRD data mainly includes local clinics (89.7% in Yen et al.’s study). This difference may imply that younger patients tend to seek medical treatment in hospitals rather than in local clinics, whereas, for long-term treatment (i.e., > 40 visits), patients tend to visit local clinics rather than hospitals due to medical accessibility. It is convenient for patients to visit local clinics if frequent outpatient follow-ups are needed.
Chang Gung has seven main branches of hospitals in Taiwan; the Linkou Chang Gung Hospital is the largest branch. From the study, we found that most patients visited the Linkou, Taipei, and Kaohsiung branches of the Chang Gung hospital system. The urban population densities of the neighborhoods for these three branches are the highest in Taiwan; thus, our finding is consistent with our previous findings on the average population densities of these cities (i.e., New Taipei City, 1,947/km2; Taipei City, 9818/km2; Taoyuan City, 1819/km2; Kaohsiung City, 940/km2; the average population density of Taiwan is 282/km2). The number of CHMs per prescription shown in Fig. 2 revealed that the most common number of formula/medicinal herbs combinations in a prescription was seven combined medicines. This finding is similar to a previous study on CHM treatment of endometriosis in the NHIRD.
In traditional Chinese theory, uterine myoma is classified as an abdominal mass disease with the etiologies of blood stasis, qi stagnation, qi and blood insufficiency, and cold-dampness stagnation. These TCM etiologies and related TCM patterns are commonly described in Chinese publications presenting TCM clinical studies. The corresponding methods of TCM treatment for uterine myoma were invigorating blood circulation and eliminating stasis, dispersing liver and regulating qi, supply qi and blood, and warming meridian to expel cold-dampness. Most of the top 10 formulas and medicinal herbs are shown in Tables 2 and 3 and have these treatment effects. These TCM etiologies and Zheng descriptions are very different from current WM clinical manifestation descriptions and translations are needed for communication. For example, qi stagnation and blood stasis may relate to the clinical manifestations of heavy menstrual flow, blood clots, uterine myoma masses, and dysmenorrhea. The traditional herbal formula Gui-Zi-Fu-Ling-Wan can invigorate blood, eliminate blood stasis, and reduce fixed abdominal myoma masses, and can thus be widely used in treating uterine fibroids.
Tables 2 and 3 present the top 10 prescribed formulas and medicines. The most frequent formula for uterine myoma treatment in the CGRD was Jia-Wei-Xiao-Yao-San; this formula was the second most frequently prescribed formula in the NHIRD. The treatment effect of Jia-Wei-Xiao-Yao-San is dispersing liver and regulating qi. This medicine is used for qi stagnation Zheng of myoma patients. The second most frequently prescribed formula in our study was Zou-Gui-Wan, though it was not one of the top 10 formulas in Yen et al.’s NHIRD study. Zou-Gui-Wan, the effect of which is to nourish yin and tonify the kidneys, is not commonly used for the treatment of uterine myoma but is frequently prescribed for infertility. This may imply that, in the Chang Gung hospitals, Zou-Gui-Wan is prescribed among women of reproductive age with uterine myoma complicated with infertility or recurrent abortions. This is consistent with the fact that the myoma patients in our CGRD study were younger than in Yen et al.’s NHIRD study. The third most frequently prescribed formula in our study was Gui-Zhi-Fu-Lin-Wan, the effect of which was to invigorate blood circulation and eliminating stasis. This was the most frequently prescribed formula in Yen et al.’s study. When combined with Western medical treatment, Gui-Zhi-Fu-Lin-Wan has synergistic efficacy for the treatment of myoma. Gui-Zhi-Fu-Lin-Wan is also prescribed in endometriosis, and it was the most frequently prescribed formula for endometriosis in Tsai et al.’s NHIRD study in Taiwan.
The most frequently prescribed single herb for the treatment of myoma in the CGRD study was Xian-fu (Rhizoma Cyperi), with the treatment effect of dispersing liver and regulating qi. It was the third most frequently prescribed single herb in Yen et al.’s study. Xian-fu has been found to have antioxidant, anti-inflammatory, and potentially neural protective effects. The second most frequently prescribed single herb in our study was Yan-Hu-Suo (Rhizoma Corydalis), which was the fifth most frequently prescribed single herb in Yen et al.’s study. Yan-Hu-Suo has an analgesic effect and may be used to treat dysmenorrhea in myoma patients. The compound L-tetrahydropalmatine, which is extracted from Yan-Hu-Suo, has good anesthetic and analgesic effects.[27, 28] This may imply that the myoma patients in the CGRD study had more pain than those in the NHIRD study, and this may be the reason that Yan-Hu-Suo was prescribed more frequently. The third most frequently prescribed single herb in our study was Dan-Shen, which was the sixth most commonly prescribed single herb in Yen et al.’s study. Yi-Mu-Cao (Herba Leonuri) was the fourth most commonly prescribed single herb in both our study and Yen et al.’s study. Yi-Mu-Cao, also termed the Chinese Motherwort, has treatment effects of invigorating blood circulation and eliminating blood stasis, and inducing diuresis for removing edema; it is most commonly prescribed for dysmenorrhea, postpartum abdominal pain, and hypermenorrhagia. A recent study of the unique alkaloid, leonurine, found in Yi-Mu-Cao, showed that it has antioxidant, anti-apoptotic, and anti-inflammatory effects and may improve micro-circulation. Thus, treatment effects of Yi-Mu-Cao may include invigorating blood circulation and eliminating blood stasis in ischemic heart disease and cardiac fibrosis. These findings may provide scientific evidence informing TCM treatment logic. Taken together, it appears that the patients in our study complained most about anxiety and infertility problems, and thus Jia-Wei-Xiao-Yao-San, Xiang-Fu, and Zou-Gui-Wan were prescribed frequently. The patients in our study also expressed more pain symptomology, so that herbs with analgesic effects (i.e., Yan-Hu-Suo, and Yi-Mu-Cao) were more commonly prescribed. The effects discussed above may account for the differences observed between our study and that of Yen et al.
ARM can help discover frequent prescription combinations of formulas and single herbs, which may help uncover hidden treatment theories and inform medical education and medical decision-making. The confidence between the decoction pieces of Chuan-Xoing, Dang-Gui, Shu-Di-Huang, and Bai-Sao was much higher (> 90%) than that of other herbal powders, which implies that these four decoction medicines were frequently prescribed as a group. In TCM clinical practice, these four decoctions form the Si-Wu-Tang formula, whose function is to tonify blood and promote menstruation. In TCM clinical practice, the Si-Wu-Tang decoction may treat menorrhagia and hypermenorrhea of myoma patients with anemia symptoms. In phenylhydrazine-induced hemolytic anemia in rats, extracts of Si-Wu-Tang exhibited hemopoietic effects, which may provide evidence for TCM clinical practice.
The other medicine combinations with high confidence are common TCM herbal treatments for pain in gynecologic disease. For example, in Table 4, the confidence levels of combination values for Yan-Hu-Suo/Xiang-Fu as well as Wu-Lin-Zhi/Pu-Huang were > 40%. These two combinations may have synergistic effects for promoting qi to activate blood and analgesia and can thus be used in treating dysmenorrhea or benign gynecology tumors (i.e., myoma, endometrioma, adenomyosis). In addition, the combination of Yan-Hu-Suo/Xiang-Fu has high support and confidence, implying that this herbal pair is frequently used to treat myoma. The combination of Zou-Gui-Wan and Xiang-Fu can have synergistic effects for treating infertility. Combining Nu-Zhen-Zi with Han-Lian-Cao forms a new combination, termed Er-Zhi-Wan. Its function is to tonify the liver and kidney yin and it may be prescribed for hypermenorrhagia in chronic anemia patients. The support of each herbal pair showed the prevalence of the combination in treating myoma. TCM herbal pairs may exhibit synergistic effects, such as those of the common herbal pair Radix notoginseng and Radix Salivae Miltiorrhizae, which are used in TCM for invigorating blood circulation and eliminating stasis. The biological basis of this combination includes a complex network of activities involving apoptosis, superoxide dismutase, intercellular adhesion molecule-1, etc.
SNA can help visualize and clarify treatment logic and medical decision-making. Results of SNA may determine physicians’ general treatment logic and medication prescription tendency. For example, SNA can help visualize the core combination of medicines for the treatment of uterine fibroids (i.e., Xiang-Fu/Dan-Shen/Jia-Wei-Xiao-Yao-San/Yan-Hu-Suo/Zuo-Gui-Wan). This may help educate TCM physicians, especially younger TCM physicians, in TCM clinical reasoning for treating uterine fibroids and may shorten and simplify physician training and continuing medical education.
Another clinical reasoning example may be deduced from the iron supplement data. Menorrhagia and hypermenorrhea among myoma patients may lead to iron deficiency anemia[9, 32]; thus, iron supplementation is frequently necessary for these patients. Because the iron supplements were prescribed during WM outpatient visits, they can only be analyzed in the WM-only group or the combined therapy group. As seen in Table 5, the ratio of patients receiving iron supplementation was similar in the WM-only (6.5%) and combined therapy groups (6.7%). However, the WM OPD visit number and PLB001M/PLB012M pills prescribed per patient were statistically significantly higher in the combined therapy group. This may imply that these patients searched for combined therapies due to severe anemia related to uterine fibroids and thus visited WM physicians more frequently to receive iron supplements. This may be consistent with the finding that the Si-Wu-Tang cluster seen in the SNA analysis of our study is frequently prescribed to treat severe anemia. A previous study  demonstrated that Chinese medicine may reduce conventional WM medicine consumption and annual medical costs in treating uterine fibroids owing to its low cost. TCM may thus be employed in future combined therapies in the Chang Gung Memorial Hospitals.
Despite our findings and the substantial strengths of this study, the present study has some limitations. First, although our study used the same ICD-9 codes as the Yen et al. NHIRD study, the patient medical record time span in Yen et al.’s NHIRD study (2002–2010) differed from ours (2005–2014). Thus, these studies need to be compared with caution. Only 6 years of data were matched (2005–2014), i.e., data in CGRD were also included in NHIRD. Second, although imaging findings and laboratory data could be obtained from the CGRD, we could not analyze these findings because the data fluctuated with the menstruation cycle. Similarly, manual extraction of myoma size data from the ultrasound reports is challenging, costly, and beyond the scope of the current study. Thus, treatment efficacy for reducing myoma size could not be evaluated.