{"paper_id":"65190aff-2bdf-4bf0-804a-9ec0072b0185","body_text":"Indian Journal of Pharmaceutical Sciences\n91\nResearch Paper\nSpecial Issue 4, 2024\n*Address for correspondence\nE-mail: thl9077@163.com\nDong et al.: Combination of Nei Yi Formula with Diphereline for Ovarian Endometriomas\nThis study mainly reports the efficacy of Nei Yi formula with diphereline in patients with ovarian endometriomas \nafter surgery and its influence on ovarian functioning. 115 ovarian endometriomas individuals treated in our \nhospital were selected from December 2019 to March 2023 and were grouped into a control group (n=55) \ntreated and research group (n=60). Control group was treated with diphereline while the research group was \ntreated with Nei Yi formula on the basis of the control group. The treatment efficacy was evaluated comparing \nthe symptom improvement of dysmenorrhea, breast tenderness, anal swelling and dyspareunia. Further, \nechocardiographic indices such as antral follicle count, resistance index of ovarian stromal flow, and ovarian \ncyst diameter were assessed. Additionally, ovarian functioning using serum estradiol, luteinizing hormone and \nfollicle stimulating hormone was compared. Similarly, inflammatory indices such as tumor necrosis factor-\nalpha and interleukin-10 were also evaluated for comparative analysis. The data revealed a statistically higher \noverall response rate of treatment in the research group vs. the control group. Besides, the research group \nexhibited markedly reduced symptom improvement scores, resistance index, ovarian cyst diameter, ovarian \nfunction indices and tumor necrosis factor-alpha after treatment, lower than the baseline and the control \ngroup; while antral follicle count and interleukin-10 increased significantly after treatment, higher than the \nbaseline and the control group. The above demonstrates the definite efficacy of Nei Yi formula with diphereline \nin the treatment of endometriomas patients after surgery, which can significantly ameliorate clinical symptoms \nand echocardiographic indices and facilitate the repair of ovarian function and the suppression of serum \ninflammation.\nKey words: Nei Yi formula, diphereline, ovarian endometriomas, postoperative effect, ovarian function\nEndometriosis is a common gynecological \ncondition which can affect 10 % of women at \nchildbearing age. It is pathologically characterized \nby the appearance of endometrial glands and \nstroma at extrauterine (ectopic) sites [1,2] . It \ncarries a high risk of recurrence, a long course \nof disease and can be clinically classified into \nperitoneal, ovarian and deep-infiltrating types [3,4] . \nAmong them, Ovarian Endometriomas (EMA) \nare the most common clinical manifestation of \nendometriosis, accounting for approximately 17 \n%-44 % of total cases which is carrying 35 % risk \nof developing benign ovarian cysts [5,6] . EMA not \nonly damages the adjacent ovarian cortical tissue, \nbut it also affects the normal functioning of the \novaries, causing excessive secretion of estrogen, \ndriving the occurrence of inflammatory reaction in \nthe body and further aggravating the condition [7,8] . \nUntil today, radical surgery has been the support of \ntreatment for EMA, but it may have varying degrees \nof negative effects on ovarian function, which \nis difficult to cure and is associated with a high \nrisk of postoperative recurrence [9,10] . Therefore, \nseeking an effective treatment strategy to improve \nthe postoperative outcome of EMA is beneficial \nto control the patients' disease, the improvement \nof ovarian function and the alleviation of clinical \nsymptoms.\nDiphereline which is a Gonadotropin Releasing \nhormone-agonist (GnRh-a) and estrogen \nsuppressor, can reduce ovarian hormone levels \nEfficacy of Nei Yi Formula with Diphereline for Ovarian \nEndometriomas after Surgery and its Influence on Ovarian \nFunction\nHUI JING DONG, XIAO CHAO SUN1, QIAN LIU2 AND HAO LIN TAN3*\nDepartment of Gynecology, Shijiazhuang Great Wall Hospital of Integrated Traditional Chinese and Western Medicine, \nShijiazhuang, Hebei Province 050000, 1Department of Tumor Radiotherapy, Traditional Chinese Hospital of Lu'an, Lu'an, \nAnhui Province 237005, 2Department of Oncology, Shaoxing City Keqiao District Hospital of Traditional Chinese Medicine, \nShaoxing, Zhejiang Province 312030, 3Department of Orthopedics, Hangzhou Fuyang Traditional Chinese Medicine Bone \nInjury Hospital, Hangzhou, Zhejiang Province 311400, China\n\nIndian Journal of Pharmaceutical Sciences\n92\nwww.ijpsonline.com\nSpecial Issue 4, 2024\nby inhibiting pituitary secretion of gonadotropin \nand strengthen the ectopic endometrial atrophy, \nthus playing a preventive role in postoperative \nrecurrence [11,12] . In addition, GnRh-a can be \nused in the treatment of adenomyosis to assist \nhigh-intensity focused ultrasound, reduce the \nvolume of uterine and adenomyotic lesions and \npromote symptomatic relief [13] . However, a rat \nmodel experiment of perimenopausal symptoms \nshows that GnRh-a intervention may cause \nperimenopausal symptoms, which may limit the \nuse and efficacy of this therapy [14] . In the theory \nof Traditional Chinese Medicine (TCM), EMA is \ndivided into “lump in the abdomen” and \"abdominal \npain during menstruation\", with qi-stagnation \nand blood stasis as its common syndrome type. \nIt is considered to be mainly related to liver-qi \ndepression and emotional distress, so its treatment \nis primarily based on promoting qi and blood \ncirculation, tonifying kidney and qi, clearing heat \nand promoting diuresis [15] . \nNei Yi formula is mainly composed of fructus \nmume, Lindera aggregata, Salvia miltiorrhiza,  \ncommon motherwort, peach kernel, oyster, \nEupolyphaga sinensis  (steleophaga), Rhizoma \nCorydalis , seaweed, Fritillary thunberg  bulb, \nhawthorn, Cattail pollen, Trogopterus  dung and \nLigusticum wallichii . This composition can be used \nfor the treatment of EMA and all the components \nplay an important role in promoting qi and blood \ncirculation [16] .\nThere are currently limited clinical studies on the \ntreatment of EMA with Nei Yi formula combined \nwith diphereline. This study mainly verifies the \nclinical advantages of this combination therapy \nin EMA treatment, aiming to provide new insights \ninto the clinical management of EMA.\nMATERIALS AND METHODS\nGeneral information:\n115 EMA patients who received treatment at \nour hospital between December 2019 and March \n2023 were selected and were divided into two \ngroups namely, control group (n=55) and research \ngroup (n=60). The control group was treated with \ndiphereline, while the research group was treated \nwith diphereline along with Nei Yi formula. No \nnotable inter-group difference was determined \nin general data (p>0.05). This study received \napproval from the ethics committee approval from \nour hospital and informed consent was obtained \nfrom each participant. \nInclusion criteria: \nAll the patients who met the EMA diagnostic \ncriteria according to the revised-American Fertility \nSociety (r-AFS) classification; patients with qi-\nstagnation and blood stasis syndrome; patients with \nvarying degrees of dysmenorrhea, dyspareunia, \npelvic pain and irregular menstruation; patients \nwithout echo mass in the uterine adnexa; patients \nwith high echoic spots inside and patients having \ntypical EMA signs diagnosed through Brightness \n(B) scan-ultrasonography were included in the \nstudy.\nExclusion criteria: \nPatients having previous history of abdominal \nsurgery and reproductive system surgery; patients \nwith sexually transmitted diseases or genitourinary \ninfections; patients with autoimmune disorders \nand deficiency or blood coagulation dysfunction; \npatients who were allergic to the drugs in this study \nand patients with mental illness and cognitive \nimpairment were excluded from the study.\nTreatment methods:\nThe control group was treated with diphereline. \nAll the patients were given 3.75 mg intramuscular \ninjection of diphereline on the 5 th d of menstruation, \nonce every 4 w. On this basis, the research group \nwas additionally treated with Nei Yi formula \nwhich included 15 g of common motherwort, 20 \ng of oyster, 10 g of Eupolyphaga sinensis , 20 g \nof peach kernels, 15 g of Rhizoma Corydalis , 15 \ng of seaweed, 25 g fructus mume , 15 g of Lindera \naggregata , 10 g of Fritillary thunberg , 15 g of \nhawthorn, 20 g of Salvia miltiorrhiza , 15 g of \nCattail pollen, 15 g of Trogopterus  dung and 15 g of \nLigusticum wallichii . The formula was decocted in \nwater to 200 ml for oral administration and single \ndose was given every. Patients were instructed to \ntake it twice (morning and evening) warmly on an \nempty stomach since the 5 th d of menstruation. This \ntreatment was discontinued during menstruation \nand resumed after menstruation. Both the groups \nwere treated continuously for 6 mo.\nDetection indicators:\nClinical effectiveness: It is evaluated by grades like \n\nwww.ijpsonline.com\nIndian Journal of Pharmaceutical Sciences\n93\nSpecial Issue 4, 2024\nmarked effectiveness, response and non-response. \nReduction of resolved clinical symptoms and \nsigns, disappearance of masses by ultrasonography \nand normal menstruation are considered as \nmarked response. Response corresponds to the \nimprovement of clinical symptoms and signs, \ndisappearance of masses shown by ultrasonography \nand normal menstruation. Similarly, non-response \nrefers to no improvement or aggravation of signs \nand symptoms, and appearance of new cysts \nindicated by ultrasonography. \nOverall Response Rate (ORR)=sum of marked \neffectiveness+effective cases/total number of \ncases×100\nSafety:  The improvement of major symptoms such \nas dysmenorrhea, breast tenderness, anal swelling, \ndyspareunia before and after treatment were \nevaluated according to the diagnostic efficacy \ncriteria of TCM diseases, with 1-4 points for \neach of the symptom. Higher scores suggest more \nserious symptoms.\nUltrasonographic indices: These indices include \nchanges in Antral Follicle Count (AFC), Resistance \nIndex (RI) of ovarian stromal flow and ovarian \ncyst diameter were determined by color Doppler \nultrasonography.\nOvarian function: Fasting peripheral venous blood \nwas collected before and after treatment for the \nquantification of serum Estradiol (E2), Luteinizing \nHormone (LH) and Follicle-Stimulating Hormone \n(FSH). Quantification process was carried out \nusing Enzyme-Linked Immunosorbent Assay \n(ELISA) technique.\nInflammatory indices: ELISA was performed to \ndetermine the levels of inflammatory indices such \nas Tumor Necrosis Factor-Alpha (TNF)-α and \nInterleukin (IL)-10.\nStatistical analysis:\nThis study employed GraphPad Prism version 7.0 \nfor statistical analysis and p<0.05 was considered \nas the statistically significant. The mean±standard \ndeviation (x±s) was used to statistically describe \nmeasured data. Independent sample t-tests and \npaired t-tests were employed for inter- and intra-\ngroup comparisons, respectively. Count data, \ndescribed as n (%), was compared between groups \nusing Chi-square (χ 2) test.\nRESULTS AND DISCUSSION\nClinical information of EMA patients in the two \ngroups was compared. Baseline characters such as \nage, disease course, cyst diameter, gravidity, r-AFS \nstaging, smoking history and alcohol abuse history \nwere compared where control and research groups \nshowed no evident differences (p>0.05) (Table 1).\nTreatment response among the EMA patients of \nthe two groups was compared. The ORRs of the \ncontrol and research groups was found to be 72.73 \n% and 91.67 %, respectively, suggesting better \ntherapeutic efficacy in the research group (p<0.05) \n(Table 2).\nFactors Control group (n=55) Research group (n=60) χ2/t p\nAge (y) 28.96±5.37 29.52±5.14 0.571 0.569\nDisease course (mo) 27.15±11.35 27.42±11.25 0.123 0.902\nCyst diameter (cm) 7.42±0.86 7.27±1.16 0.782 0.436\nGravidity (times) 1.44±0.50 1.57±0.59 1.269 0.207\nr-AFS staging (I-II/III-IV) 27/28 25/35 0.639 0.424\nHistory of smoking (yes/no) 15/40 22/38 1.160 0.281\nHistory of alcoholism (yes/no) 18/37 18/42 0.099 0.753\nTABLE 1: CLINICAL INFORMATION OF EMA PATIENTS IN TWO GROUPS\nFactors Control group (n=55) Research group (n=60) χ2 p\nMarked response 25 (45.45) 35 (58.33)\nResponse 15 (27.27) 20 (33.33)\nNon-response 15 (27.27) 5 (8.33)\nORR 40 (72.73) 55 (91.67) 7.165 0.007\nTABLE 2: CLINICAL EFFICACY OF EMA PATIENTS IN TWO GROUPS\n\nIndian Journal of Pharmaceutical Sciences\n94\nwww.ijpsonline.com\nSpecial Issue 4, 2024\nSymptom improvement in two groups of EMA \npatients was comparatively analyzed between the \ntwo groups. The improvement of clinical symptoms \nsuch as dysmenorrhea, breast tenderness, anal \nswelling and dyspareunia revealed no marked \ninter-group difference before treatment (p>0.05). \nAfter treatment, the clinical symptom scores \nreduced statistically in both the groups, with even \nlower scores in the research group (p<0.05) (fig. \n1).\nUltrasonographic indices of EMA patients in \ntwo groups were compared. After analyzing the \nultrasonographic indices such as AFC, RI and \novarian cyst diameter, it was found that there was \nno significant difference between the research and \nthe control groups before intervention (p>0.05). \nHowever, after treatment AFC of both groups \nincreased significantly, while RI and ovarian cyst \ndiameter decreased significantly. In comparison \nwith the control group, AFC was higher while \nRI and ovarian cyst diameter were lower in the \nresearch group (p<0.05) (fig. 2).\nOvarian functioning in the two groups of EMA \npatients was evaluated. The testing of ovarian \nfunction indices such as E2, LH and FSH \nrevealed no marked inter-group differences before \nintervention (p>0.05). Marked reduction in these \novarian function indices was observed in both the \ngroups after intervention, with lower levels in the \nresearch group than in the control group (p<0.05) \n(fig. 3).\nFurther, inflammation indices in the EMA patients \nof the two groups were compared. We assessed \nthe expression levels of inflammatory indices like \nTNF-α and IL-10 before and after the intervention; \nwe found no evident inter-group difference before \nintervention (p>0.05). However, after intervention, \nthe level of TNF-α in both the groups decreased \nwith a lower level in the research group vs. control \ngroup; while the post-interventional IL-10 level of \nboth groups increased, with an even higher level in \nthe research group (p<0.05) (fig. 4).\nFig. 1: Markedly reduced clinical efficacy in EMA patients of after treatment in research group vs. control group, (A):  \nDysmenorrhea score; (B): Breast tenderness score; (C): Anal swelling score after treatment and (D): Dyspareunia score\nNote: **p<0.01 and #p<0.05, in comparison with control group vs. research group respectively before treatment, ( \n  ): Control \ngroup and ( \n  ): Research group\nFig. 2: Ultrasonographic indices of EMA patients in research and control groups, (A): Increased AFC; (B): Decreased RI and  \n(C): Reduced ovarian cyst diameter\nNote: *p<0.05, **p<0.01 vs. and #p<0.05 respectively before treatment, ( \n  ): Control group and ( \n  ): Research group\n\nwww.ijpsonline.com\nIndian Journal of Pharmaceutical Sciences\n95\nSpecial Issue 4, 2024\nFig. 3: Reduced ovarian function of EMA patients in two groups, (A): E2 level; (B): LH level and (C): FSH level\nNote: **p<0.01 and #p<0.05, in comparison with control group vs. research group respectively before treatment, ( \n  ): Control \ngroup and ( \n  ): Research group\nFig. 4: Inflammation indices in two groups of EMA patients, (A): Decreased TNF-α level and (B): Elevated IL-10 level\nNote: **p<0.01 and #p<0.05, in comparison with control group vs. research group respectively before treatment, ( \n  ): Control \ngroup and ( \n  ): Research group\nwarmer to dispel cold and promote qi circulation \nhelping to relieve pain. Salvia miltiorrhiza  can \nhelp to reinforce the liver and kidney and promote \nblood circulation to restore menstrual flow while \ncommon motherwort can activate blood to dissolve \nstasis, clear away heat and toxic materials. \nSimilarly, peach kernel plays the role of promoting \nblood circulation and removing blood stasis and, \nEupolyphaga sinensis  is capable of dispelling \nstasis and eliminating addiction [19-22] . \nThe combination of the above mentioned Chinese \nherbal medicines and diphereline can play a \nsynergistic therapeutic effect on EMA patients \nto a certain extent. In the research of Gao et \nal.[23] , the intervention of Salvia miltiorrhiza -\ncontaining Chinese herbs combined with GnRh-a \nfor postoperative treatment of EMA helps to \nimprove the postoperative effect and reduce the \nrisk of postoperative recurrence, with significant \nAlthough EMA is a benign inflammatory \nreproductive disease, it can cause dysmenorrhea, \nchronic fatigue, low fertility, chronic pelvic pain \nand bladder symptoms such as ozostomia and \nabdominal distension, etc., in female patients, \nwhich negatively affects their normal life and \neven fertility [17,18] . Therefore, it is of great value \nto explore new effective treatment strategies for \nthe clinical treatment of EMA to relieve patients' \nsymptoms and facilitate their restoration of normal \nlife and fertility.\nIn this study, the ORR of the research group was \nfound to be markedly superior to that of the control \ngroup (91.67 % vs. 72.73 %), suggesting that Nei \nYi formula+diphereline has a better clinical effect \non EMA. This may be attributed to the effective \ningredients present in the Nei Yi formula. fructus \nmume  can strengthen vital meridian and relieve \npain, Lindera aggregata  can warm the middle \n\nIndian Journal of Pharmaceutical Sciences\n96\nwww.ijpsonline.com\nSpecial Issue 4, 2024\nsafety, similar to this study. Another study shows \nthat Chinese herbal compound prescription has \na significant effect on EMA-related infertility, \nwhich is conducive to improving the pregnancy \nrate while ensuring certain safety [24] . Subsequently, \nthe evaluation of clinical symptom relief revealed \nthat the scores of clinical symptoms such as \ndysmenorrhea, breast tenderness, anal swelling and \ndyspareunia reduced statistically in the research \ngroup and were lower when compared with the \ncontrol group, suggesting that the combination of \nNei Yi formula and diphereline can significantly \nalleviate the clinical symptoms of patients after \nEMA treatment with a relief effect superior to \ndiphereline intervention alone. \nFurthermore, the ultrasonographic indices such \nas AFC, RI and ovarian cyst diameter improved \nsignificantly in the research group after \nintervention, with higher AFC and lower RI and \novarian cyst diameter compared with the control \ngroup, indicating that the treatment of EMA \nwith Nei Yi formula combined with diphereline \ncan significantly increase the number of sinus \nfollicles, improve ovarian follicular atresia and \nmicrocirculation, which is of great help to the \nrestoration of ovarian function. The testing results \nof E2, LH and FSH showed obviously reduced \nindices after treatment in the research group were \nlower vs. the control group, suggesting that EMA \npatients can achieve significant inhibition of \nestrogen secretion and repair of ovarian reserve \nfunction after receiving the intervention of Nei \nYi formula with diphereline. After the detection \nof inflammatory indices such as TNF-α and IL-\n10, the research group was found to present \nmarkedly inhibited TNF-α and elevated IL-10 than \nthe control group, indicating the ability of Nei Yi \nformula with diphereline to validly alleviate the \ninflammatory microenvironment of EMA patients. \nIL-10 may mediate the pathogenesis of EMA and \ninhibit TNF-α by regulating the Nuclear Factor \nKappa B (NF-κB) and Mitogen-Activated Protein \nKinase (MAPK) pathway in endometrial cells, \nthus weakening the induction of IL-6 synthesis by \nTNF-α [25] . Yu et al. [26]  pointed out in their study \nthat the effect of Nei Yi formula on EMA can \nsignificantly reduce the weight of endometriosis \ntissue and the number of peritoneal macrophages, \nwhich may be related to its up-regulation of IL-\n10 level to inhibit inflammatory reaction and the \ngrowth of endometriosis tissue, similar to our \nresearch results.\nIn conclusion, the combination of Nei Yi formula \nand diphereline can significantly improve efficacy \nin post-surgical EMA patients, which can improve \nthe curative effect, relieve clinical symptoms, repair \novarian function and inhibit serum inflammatory \nreaction, providing new path and reference for \nefficacy optimization in EMA patients. \nAuthor's contributions:\nHuijing Dong and Xiaochao Sun contributed \nequally to this work and are the co-first authors. \nHuijing Dong and Xiaochao Sun designed \nthe research and wrote the first version of the \nmanuscript. Huijing Dong, Xiaochao Sun, Qian \nLiu and Haolin Tan contributed to conceiving the \nresearch and analyzing the data. Huijing Dong and \nXiaochao Sun conducted the analysis and provided \nguidance for the research. All the authors reviewed \nand approved the final manuscript.\nConflict of interests:\nThe authors declared no conflict of interests.\nREFERENCES\n1. Huhtinen K, Suvitie P, Hiissa J, Junnila J, Huvila J, Kujari \nH, et al.  Serum HE4 concentration differentiates malignant \novarian tumours from ovarian endometriotic cysts. Br J Cancer \n2009;100(8):1315-9. \n2. Koninckx PR, Ussia A, Adamyan L, Tahlak M, Keckstein J, \nWattiez A, et al. The epidemiology of endometriosis is poorly \nknown as the pathophysiology and diagnosis are unclear. Best \nPract Res Clin Obstet Gynaecol 2021;71:14-26. \n3. Zhang Y , Qu P. Factors associated with ovarian endometriosis \nmalignancy and its recurrence in Chinese women . J Obstet \nGynaecol 2019;39(8):1148-53. \n4. Guidozzi F. 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Zhongguo Zhong Xi \nYi Jie He Za Zhi 2000;20(8):603-5.\nThis is an open access article distributed under the terms of the Creative \nCommons Attribution-NonCommercial-ShareAlike 3.0 License, which  \nallows others to remix, tweak, and build upon the work non-commercially,  \nas long as the author is credited and the new creations are licensed under \nthe identical terms\nThis article was originally published in a special issue,  \n“Drug Discovery and Repositioning Studies in Biopharmaceutical \nSciences” Indian J Pharm Sci 2024:86(4) Spl Issue “91-97”","source_license":"CC0","license_restricted":false}