Chinese Medicine Sequential Therapy Improves Pregnancy Outcomes after Surgery for Endometriosis-Associated Infertility: A Multicenter Randomized Double-blind Placebo Parallel Controlled Clinical Trial

Objective To evaluate the efficacy and safety of Chinese medicine (CM) improving pregnancy outcomes after surgery for endometriosis-associated infertility.

A multicenter, randomized, double-blind placebo parallel controlled clinical trial was designed. A total of 202 patients who had laparoscopy for endometriosis-associated infertility with qi stagnation and blood stasis syndrome were included and randomly divided into the CM treatment group and placebo control group at a ratio of 1:1 using a central block randomization from May 2014 to September 2017, 101 patients in each group. The two groups received continuous intervention at 1–5 days after surgery, for 6 menstrual cycles. Before ovulation, the CM group was treated Huoxue Xiaoyi Granule (活血消异颗粒); after ovulation, Bushen Zhuyun Granule (补肾助孕颗粒 was involved. The control group was treated with placebo. Transvaginal ultrasonography was performed every menstrual cycle during the treatment, and female hormone levels in the follicular and luteal phases were measured during the 1st, 3rd and 6th menstrual cycles. The analysis was continued until pregnancy. The primary outcomes were clinical pregnancy rate and pregnancy outcome, and the secondary outcomes were follicular development and endometrial receptivity. Safety evaluations were performed before and after treatment.

(1) Clinical pregnancy and live birth rates: the clinical pregnancy and live birth rates of the CM group were significantly higher than those of the placebo group [44.6% (45/101) vs. 29.7% (30/101), 34.7% (35/101) vs. 20.8% (21/101), both P<0.05]. (2) Follicle development: the incidence of dominant follicles, rate of cumulative cycle ovulation, and rate of cumulative cycle mature follicle ovulation were significantly higher in the CM group than those in the placebo group [93.8% (350/373) vs. 89.5% (341/381), 80.4% (275/342) vs. 69.1% (253/366), 65.8% (181/275) vs 56.1% (142/253), P<0.05 or P<0.01]). The incidence of cumulative cycle luteinized unruptured follicle syndrome was significantly lower in the CM group than in the placebo group [11.7% (40/342) vs. 17.8% (65/366), P<0.05). (3) Endometrial receptivity: after treatment, both endometrial types and endometrial blood flow types in the CM group were mainly types A and B, while those in the placebo group were mainly types B and C, with a significant difference between the two groups (both P0.05).

Strategies for activating blood circulation-regulating Gan (Liver)-tonifying Shen (Kidney) sequential therapy can effectively improve the clinical pregnancy rate and live birth rate of endometriosis-associated infertility with qi stagnation and blood stasis after laparoscopy, improve follicular development, promote ovulation, improve endometrial receptivity, while being a safe treatment option. (Trial registration No. NCT02676713) Similar content being viewed by others

Cooperative Group of Endometriosis, Obstetrics and Gynecology Branch, Chinese Medical Association. Guidelines for the diagnosis and treatment of endometriosis. Chin J Obstetr Gynecol (Chin) 2015;50:161–169. Fang MZ, Ding SG, Guo HF. Controlled study and analysis of the risk factors of infertile women with endometriosis. China Foreign Med Treat (Chin) 2014;4:4–6. Buyalos RP, Agarwal SK. Endometriosis-associated infertility. Curr Opin Obstet Gynecol 2000;12:377–381. Marcoux S, Maheux R, Bérubé S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N Engl J Med 1997;337:217–222. González-Comadran M, Schwarze JE, Zegers-Hochschild G, Souza MD, Garreras R, Checa MA. The impact of endometriosis on the outcome of assisted reproductive technology. Reprod Biol Endocrinol 2017;15:1–7. Luo LL, Xu H. GnRH agonist treatment on endometriosis-associated infertility after conservative surgery: a systematic review. Prog Obstet Gynecol (Chin) 2013;22:206–210. Collinet P, Fritel X, Revel-Delhom C, Ballester M, Bolze PA, Borghese B, et al. Management of endometriosis CNGOF/HAS clinical practice guidelines—short version. J Gynecol Obstet Hum Reprod 2018:47:265–274. Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D’Hooghe T, De Bie B, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod 2014;29:400–412. Zhang YZ, ed. Gynecology of traditional Chinese medicine. 2nd ed. Beijing: China Press of Traditional Chinese Medicine;2007:137. Zhao RH. Strategies for promoting blood circulation-regulating Gan (Liver)-tonifying Shen (Kidney) sequential therapy of endometriosis-associated infertility. Chin J Integr Med 2019;25:243–245. Zhang J, Zhao RH. Clinical observation on the treatment of infertility associated with endometriosis by Huoxue Bushen Cycle. Chin J Inf Chin Med (Chin) 2014;21:93–95. Zhao RH, Hao ZP, Zhang Y, Lian FM, Sun WW, Liu Y, et al. Controlling the recurrence of pelvic endometriosis after a conservative operation: comparison between Chinese herbal medicine and Western medicine. Chin J Integr Med 2013;19:820–825. Cao ZY, ed. Chinese gynecology and obstetrics. 2nd ed. Beijing: People’s Medical Publishing House;2004:1496. Rowe PJ, Comhaire FH, Hargreave TB, eds. World Henlth Orgnization manual for the standardized investigation and diagnosis of the infertile couple. New York: Cambridge University Press;2000:6. Gynecology and Obstetrics Branch, Chinese Medical Association. Clinical guidelines for diagnosis and treatment. Beijing: People’s Medical Publishing House;2007:127. Wang WJ, Li RQ, Fang TF, Huang LL, Ouyang NY, Wang LG, et al. Endometriosis fertility index score maybe more accurate for predicting the outcomes of in vitro fertilisation than r-AFS classification in women with endometriosis. Reprod Biol Endocrinol 2013;11:112–122. Zhu YJ. Pregnancy analysis of endometriosis with infertility. China Foreign Med Treat (Chin) 2011;30:51. Tang LR, Lu D, Duan AH. The analysis of expectant pregnant after treatment of endometriosis. Beijing Med J (Chin) 2011;33:306–309. Bi XY, Wang DD, Zhao RQ. Significance of basal sinus follicle count and basal follicle stimulating hormone/luteinizing hormone ratio in predicting ovarian responsiveness. Guide China Med (Chin) 2013;11:509–510. Luo LL, ed. Infertility and sterility. 1st ed. Beijing: People’s Medical Publishing House; 1998:310. Gonen Y, Casper RF. Prediction of implantation by the sonographic appearance of the endometrium during controlled ovarian stimulation for in vitro fertilization (IVF). J In Vitro Fert Embryo Transf 1990;7:146–152. Chien LW, Au HK, Chen PL, Xiao J, Tzeng CR, et al. Assessment of uterine receptivity by the endometrial-subendometrial blood flow distribution pattern in women undergoing in vitro fertilization-embryo transfer. Fertil Steril 2002;78:245–251. Bulletti C, Coccia ME, Battistoni S, Borini A. Endometriosis and infertility. J Assist Reprod Genet 2010;27:441–447. Vercellini P, Viganö P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol 2014;10:261–275. Rossi AC, Prefumo F. The effects of surgery for endometriosis on pregnancy outcomes following in vitro fertilization and embryo transfer: a systematic review and meta-analysis. Arch Gynecol Obstet 2016;294:647–655. Vercellini P, Parazzini F, Pietropaolo G, Cipriani S, Frattaruolo MP, Fedele L. Pregnancy outcome in women with peritoneal, ovarian and rectovaginal endometriosis: a retrospective cohort study. BJOG 2012;119:1538–1543. Sun WW, Chang H, Zhao RH. Effect of Huoxue Xiaoyi Prescription on fertility and early pregnancy toxicity of rats with endometriosis. Drug Evaluat Res (Chin) 2019;4:648–652. Dai ZQ, Zhao RH. ZHAO Rui-hua’s Experiences in the treatment of endometriosis-related infertility. World J Integr Tradit West Med (Chin) 2017;7:921–924. Cui YY, Sun WW, Zhao RH, Xu C, Wu TS. Effects of a Chinese traditional medicine, Huoxue Xiaoyi Fang, on embryo development after in vitro fertilization in mouse models of endometriosis. Chin J Comparat Med (Chin) 2015;25:31–36, 43, 85. Cui YY, Sun WW, Zhao RH, Xu C, Wu TS. Effects of Huoxue Xiaoyi Fang on embryo development after IVF-ET in endometriosis model mice. J Reproduct Med (Chin) 2016;25:166–171. Hu XW, Wang WP, Hong Y, Yang H, Qin L. Effects of Bushen Huoxue Decoction on FSH and its receptor mRNA expression in mice. Chin J Immunol (Chin) 2010;26:1003–1006. Author information Authors and Affiliations Contributions Zhao RH was responsible for the formulation of the clinical trial plan, case observation and paper writing; Lu D, Wu Y, Wang XY, Li WL, Zeng C, Meng QW, Zhou J, Shi Y, Liu Y, Sun WW, Han Q, Tang Y, and Shi G were responsible for the case observation and collection; and Lian FM was responsible for the statistical analysis of the data. Corresponding author Ethics declarations There is no conflict of interest. Additional information Supported by the Key Projects of the National Science and Technology Pillar Program during the 12th Five-Year Plan Period (No. 2014BAI10B08) Rights and permissions About this article Cite this article Zhao, Rh., Liu, Y., Lu, D. et al. Chinese Medicine Sequential Therapy Improves Pregnancy Outcomes after Surgery for Endometriosis-Associated Infertility: A Multicenter Randomized Double-blind Placebo Parallel Controlled Clinical Trial. Chin. J. Integr. Med. 26, 92–99 (2020). https://doi.org/10.1007/s11655-019-3208-2 Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s11655-019-3208-2