二仙汤加减联合芬吗通治疗对原发性卵巢功能不全患者生殖内分泌激素及卵巢体积的影响.pdf

Hainan Med J,Aug.2023,Vol.34,No.15海南医学2023年8月第34卷第15期二仙汤加减联合芬吗通治疗对原发性卵巢功能不全患者生殖内分泌激素及卵巢体积的影响魏少奔1，王宇慧2，武俊丽3，孙晓盈4，陈梦捷11.西安市中医医院妇科，陕西西安710026；2.南京市中医院妇科，江苏南京210001；3.西安市雁塔区中医医院妇科，陕西西安710000；4.渭南职业技术学院医学院，陕西渭南714000【摘要】目的探讨二仙汤加减联合芬吗通治疗对原发性卵巢功能不全(POI)患者生殖内分泌激素、卵巢体积的影响。方法选取2019年12月至2021年12月期间西安市中医医院妇科收治的122例POI患者为研究对象，按随机数表法分为研究组和对照组，每组61例，对照组患者采用芬吗通治疗，研究组患者采用二仙汤加减联合芬吗通治疗，两组均持续治疗3个周期，1个周期为28 d。比较两组患者治疗前后的血清促卵泡素(FSH)、雌二醇(E2)、促黄体生成素(LH)水平、子宫内膜厚度及绝经指数，并统计两组患者治疗后的不良反应发生情况。结果两组患者治疗后的FSH、LH和E2水平均得到不同程度改善，且研究组患者的FSH、LH水平分别为(12.074.42)U/L、(6.570.56)U/L，明显低于对照组的(19.353.98)U/L、(8.410.66)U/L，E2为(122.3412.34)pmol/L，明显高于对照组的(91.6513.75)pmol/L，差异均有统计学意义(P0.05)；两组患者治疗后的子宫内膜厚度均上升，绝经指数均下降，且研究组患者的子宫内膜厚度为(7.190.98)mm，明显厚于对照组的(6.110.81)mm，绝经指数为(9.191.24)分，明显低于对照组的(14.551.54)分，差异均有统计学意义(P0.05)。结论二仙汤加减联合芬吗通治疗POI可明显改善患者的卵巢体积和内分泌激素水平，且安全性高。【关键词】原发性卵巢功能不全；二仙汤加减；芬吗通；生殖内分泌激素；卵巢体积【中图分类号】R711.75【文献标识码】A【文章编号】10036350（2023）15217704Effect of modified Erxian Decoction combined with Femoston on the reproductive endocrine hormones andovarian volume in patients with primary ovarian insufficiency.WEI Shao-ben1,WANG Yu-hui2,WU Jun-li3,SUNXiao-ying4,CHEN Meng-jie1.1.Department of Gynecology,Xian Hospital of Traditional Chinese Medicine,Xian 710026,Shaanxi,CHINA;2.Department of Gynecology,Nanjing Hospital of Traditional Chinese Medicine,Nanjing 210001,Jiangsu,CHINA;3.Department of Gynecology,Yanta District Hospital of Traditional Chinese Medicine,Xian 710000,Shaanxi,CHINA;4.School of Medicine,Weinan Vocational and Technical College,Weinan 714000,Shaanxi,CHINA【Abstract】ObjectiveTo analyze the effect of modified Erxian decoction combined with Femoston on the re-productive endocrine hormones and ovarian volume in patients with primary ovarian insufficiency(POI).MethodsA 论著 doi:10.3969/j.issn.1003-6350.2023.15.011基金项目：江苏省南京市中医院科研基金(编号：YJJ201907)。第一作者：魏少奔(1985)，男，硕士，主治医师，主要研究方向：妇科疾病的诊治。通讯作者：陈梦捷(1987)，女，硕士，主治医师，主要研究方向：妇科疾病的诊治，E-mail：。880-884.13 Ren WW,Sun L.Study on the clinical effect of letrozole combinedwith metformin in the treatment of polycystic ovarian syndrome-as-sociated infertility J.Chin J Postgrad Med,2020,43(8):741-744.任玮玮,孙林.来曲唑联合二甲双胍治疗多囊卵巢综合征不孕症的临床疗效观察J.中国医师进修杂志,2020,43(8):741-744.14 Merviel P,James P,Boue S,et al.Impact of myo-inositol treatmentin women with polycystic ovary syndrome in assisted reproductivetechnologies J.Reprod Health,2021,18(1):13-23.15 Wang LX,Yin QQ,Wang CY,et al.Clinical efficacy of different dos-es of folic acid for treating obese patients with polycystic ovary syn-drome and its influence on their levels of inflammatory factors J.Chin J Fam Plan,2022,30(8):1730-1733.王丽先,尹倩倩,王彩研,等.不同剂量叶酸治疗肥胖型多囊卵巢综合征临床疗效及对患者炎性因子影响J.中国计划生育学杂志,2022,30(8):1730-1733.16 An XZ,Li XL.Effects of metformin combined with ethinylestradioland cyproterone on IGFB P-1,IL-18 and antioxidant indexes in pa-tients with polycystic ovary syndrome J.J Clin Res,2022,39(1):150-152.安旭琢,李晓莉.二甲双胍联合炔雌醇环丙孕酮片治疗多囊卵巢综合征患者对IGFB P-1、IL-18、抗氧化指标的影响J.医学临床研究,2022,39(1):150-152.17 Azizi Kutenaei M,Hosseini Teshnizi S,Ghaemmaghami P,et al.Theeffects of myo-inositol vs.metformin on the ovarian function in thepolycystic ovary syndrome:a systematic review and meta-analysisJ.Eur Rev Med Pharmacol Sci,2021,25(7):3105-3115.(收稿日期：2023-03-08)2177海南医学2023年8月第34卷第15期Hainan Med J,Aug.2023,Vol.34,No.15原发性卵巢功能不全(primary ovarian insufficien-cy，POI)属于中年女性临床上较为常见的妇科疾病，而POI的发病机制为患者机体内卵泡的数量骤减或功能失常，从而引发患者闭经、子宫肌瘤、子宫颈癌、卵巢肿瘤、更年期忧郁症、不孕等一系列并发症出现1。近年来，POI的临床发病率呈现出一定的升高趋势。有关文献资料表明，我国女性POI的发病率为1%3.8%，而国外女性人群的发病率为1%左右2。我国女性人群的这一问题显得更为严峻，POI已经成为威胁中年女性人群生活质量的重要原因之一3。激素替代疗法是西医治疗POI的主要方案，如口服芬吗通、雌二醇等，虽具有一定疗效，但该方法远期效果欠佳1。近年来，随着中医药在临床的广泛应用，中西医结合治疗POI临床疗效优于单纯西医治疗2。POI属于中医学中的“血枯”范畴，治疗原则以滋阴养血为主，其中二仙汤加减则符合该病治疗原则，方中仙茅、当归等多种药材具有养血补血、滋阴养肾等功效。本文旨在探讨二仙汤加减联合芬吗通对POI患者生殖内分泌激素、卵巢体积的影响，现将结果报道如下：1资料与方法1.1一般资料选取2019年12月至2021年12月期间西安市中医医院妇科收治的122例POI患者进行研究。纳入标准：(1)均符合POI临床诊断标准4；(2)30岁且0.05)，具有可比性。本研究经医院医学伦理委员会批准。1.2治疗方法1.2.1对照组该组患者服用芬吗通(荷兰苏威制药有限公司，国药注进：H20100159)治疗，治疗前2周，1 d/次，1次/片(白色片，内含雌二醇1 mg)；治疗34周，1 d/次，1次/片(灰色片，内含雌二醇1 mg和地屈孕酮10 mg)。以28 d为一个治疗周期，第29天开始下一个疗程，根据疗效及个体需要调整剂量，连续服用3个周期。1.2.2研究组该组患者在对照组治疗的基础上服用二仙汤治疗。二仙汤组方：黄柏、知母各4.5 g，巴戟天、仙灵脾、仙茅、当归各9 g，根据患者情况加减药材(肾亏或月经不调患者可加入9 g杜仲、益母草及桑寄生；阳虚患者可加入9 g枸杞子及6 g菊花)。上述药材均经医院药剂科制作后送至病房给予患者(煎煮500 mL，去渣取液约300 mL，早晚分两次服用，于月经干净后3 d开始服用)。28 d为一个周期，连续服用3个周期。1.3观察指标与检测(评价)方法(1)卵巢激素水平：分别于治疗前后月经周期抽取患者静脉血3 mL，及时送往离心(3 500 r/min，15 min)，取上清液，放置冰箱低温进行保存，使用西门子全自动电化学发光免疫分析仪检测血清促卵泡素(FSH)、雌二醇(E2)、促黄体生成素(LH)水平。(2)子宫内膜厚度、绝经指数：所有患者均于治疗前后月经中期使用飞利浦彩色多普勒超声诊断仪检测子宫内膜厚度；Kupperman绝经指数(KMI评分)采用Kupperman量表进行测评，量表包含失眠、烦躁、多汗、焦虑及眩晕等13项症状，最后评分=各项症状基础分程度评分，得分范围为048分，得分越高说明症状越严重4。(3)不良反应：治疗过程中观察两组患者的胃部不适、头晕及乳头胀痛等不良反应发生情况。1.4统计学方法应用SPSS21.0软件进行数据total of 122 patients with POI admitted to the Department of Gynecology,Xian Hospital of Traditional Chinese Medi-cine from December 2019 to December 2021 were selected and randomly divided into a study group(n=61,treated withmodified Erxian decoction combined with Femoston)and a control group(n=61,treated with Femoston).The treatmentlasted for 3 cycles,with 28 days as one cycle.The serum levels of follicle-stimulating hormone(FSH),estradiol(E2),lu-teinizing hormone(LH),endometrial thickness,and menopausal index before and after treatment were compared be-tween the two groups.The incidence of adverse reactions after treatment was calculated.ResultsAfter treatment,FSH,LH,and E2 levels were improved to varying degrees in the two groups.FSH and LH in the study group were significant-ly lower than those in the control group:(12.074.42)U/L vs(19.353.98)U/L,(6.570.56)U/L vs(8.410.66)U/L,andE2 in the study group were significantly higher:(122.3412.34)vs(91.6513.75),with statistically significant differenc-es(P0.05).Endometrial thickness increased and menopause index decreased significantly in the two groups after treat-ment;endometrial thickness in the study group were significantly thicker than that in the control group:(7.190.98)mmvs(6.110.81)mm,and menopause index in the study group were significantly lower:(9.191.24)points vs(14.551.54)points,with statistically significant differences(P0.05).ConclusionModified Erxian decoction combined with Femoston can signif-icantly improve the ovarian volume and endocrine hormone levels in POI patients,and has high safety.【Key words】Primary ovarian insufficiency;Modified Erxian Decoction;Femoston;Reproductive endocrine hor-mones;Ovary volume2178Hainan Med J,Aug.2023,Vol.34,No.15海南医学2023年8月第34卷第15期2.3两组患者的不良反应比较研究组患者的不良反应总发生率为13.11%，略低于对照组的18.03%，但差异无统计学意义(2=0.561，P=0.4530.05)，见表3。3讨论近年来，受环境因素改变、个人遗传因素以及生活工作压力等方面的多重影响，女性人群原发性卵巢功能不全的发病率呈现出了一定的升高趋势，并且患者人群特点呈现为年轻化。受此影响，女性患者的相关癌症发生率也呈现出高度相关性5。POI已经成为临床上威胁女性人群健康的重大问题之一。临床研究证实：POI的发生一方面与外界影响因素相关，另一方面与女性个体自身代谢免疫机制异常等有一定关联6。患者因机体原始卵泡数目的逐渐减少、卵泡功能的严重失常，导致患者卵巢功能紊乱，给患者生活、工作带来一定压力，对患者的家庭和谐幸福造成不利影响7。既往临床经验认为，治疗POI的临床有效方法主要有激素替代疗法、诱导排卵及免疫疗法等7。众多疗法均能发挥一定的临床效果，但存在一定差异。芬吗通属于雌孕激素中的一种复合制剂，临床研究发现：虽然该种药物能够对POI患者的病情进行有效的控制，但是众多临床经验显示单独使用雌孕激素治疗的POI患者，继发形成乳腺癌、子宫内膜癌的风险相对较高，严重威胁患者生命健康，临床治疗的耐受程度不理想，患者容易出现复发等情况8-9。鉴于此，我院在积极总结临床经验的基础上，采用了中药二仙汤加减联合西药芬吗通治疗的中西医结合治疗方法，并取得了较好的临床治疗效果。在祖国医学中并无“卵巢功能不全”病名，但目前依据临床基本特征，认为POI可属于中医中“血枯”、“血隔”及“不孕”等范畴，该病根本病因在于肾虚10。二仙汤属中医方剂名，其来源为 妇产科学11。二仙汤方中仙茅、巴戟天、仙灵脾具有温肾阳，补肾精之功效，黄柏、知母具有泻肾火之功能，当归可温润养血、调理冲任；诸药合用具有活血化瘀、疏肝解郁、益肾填精等功效12。从现代病理药理学研究角度分析：补肾药具有较好的的类雌激素作用，且对人体下丘脑垂体肾上腺轴系统的功能有一定的改善，进而提高患者机体抗氧化、防衰老的功能，保障患者机体各项组织的正常生长，与西药联合应用可以发挥两者的协调之功效，对于原发性卵巢功能不全有很好的治疗效果13。近年亦有研究分析补肾药中黄柏、当归、仙灵脾等药材都性温和，对机体无明显异常干扰，无不良反应的风险14-15。本研究结果显示，治疗后，研究组患者的FSH、LH和E2等卵巢激素指标和子宫内膜厚度以及绝经指数均优于对照组，并且研究组患者的不良反应总发生率与对照组比较差异无统计学意义，进一步证实了二仙汤加减联合芬吗通治疗的临床优势，且两者联合具表1两组患者治疗前后的卵巢激素水平比较(x-s)Table 1Comparison of ovarian hormone levels between the two groups before and after treatment(x-s)组别研究组对照组t值P值例数6161治疗前29.353.1528.413.071.6690.098治疗后12.074.42a19.353.98a9.5600.001治疗前10.311.1910.281.150.1420.8876治疗后6.570.56a8.410.66a16.6030.001FSH(U/L)LH(U/L)注：与同组治疗前后比较，aP0.05。Note:Compared with that in the same group before treatment,aP0.05.治疗前73.244.3573.414.440.2140.831治疗后122.3412.34a91.6513.75a12.9690.001E2(pmol/L)表2两组患者治疗前后的子宫内膜厚度和绝经指数比较(x-s)Table 2Comparison of endometrial thickness and menopausal indexbetween the two groups before and after treatment(x-s)组别研究组对照组t值P值例数6161治疗前4.270.514.290.480.2230.824治疗后7.190.98a6.110.81a6.6340.001治疗前20.154.3519.985.240.1950.846治疗后9.191.24a14.551.54a21.1730.001子宫内膜厚度(mm)绝经指数(分)注：与同组治疗前后比较，aP0.05。Note:Compared with that in the same group before treatment,aP0.05.表3两组患者的不良反应比较(例)Table 3Comparison of adverse reactions between the two groups(n)别组对照组研究组例数6161胃部不适43乳房不适53头晕22总不良反应(%)18.0313.11统计分析。计量资料符合正态分布，以均数标准差(x-s)表示，两两间比较采用t检验；计数资料比较采用2检验。以P0.05为差异具有统计学意义。2结果2.1两组患者治疗前后的卵巢激素水平比较治疗后，两组患者的FSH、LH和E2水平均得到不同程度改善，且研究组患者的FSH、LH水平明显低于对照组，E2 水平明显高于对照组，差异均有统计学意义(P0.05)，见表1。2.2两组患者治疗前后的子宫内膜厚度和绝经指数比较治疗后，两组患者的子宫内膜厚度均上升，绝经指数均显著下降，且研究组患者的子宫内膜厚度明显厚于对照组，绝经指数明显低于对照组，差异均有统计学意义(P0.05)，见表2。2179海南医学2023年8月第34卷第15期Hainan Med J,Aug.2023,Vol.34,No.15备一定安全性，与国内有关报道结果一致16。综上所述，二仙汤加减联合芬吗通治疗方法能够改善POI患者的卵巢体积和内分泌激素水平，具有良好的临床应用效果。本研究新颖之处在于采用中西医相结合方法应用于POI患者治疗中，采用卵巢激素水平、绝经指数等指标评价临床疗效，且对比了两者安全性。但本文不足之处在于观察时间较短，且未对治疗方案远期效果进行评价，今后还需进一步扩大样本，行多中心，且延长随访时间进行研究。参考文献1Zhu JY,Guo Z,Wang SS.Clinical effect of dipeptidyl peptidase 4inhibitor on newly diagnosed PCOS patients and its effect on bloodlipid metabolism J Chin J Fam Plan,2019,27(5):599-603.朱军义,郭哲,王双双.二肽基肽酶4抑制剂治疗初诊PCOS患者临床效果及对血脂代谢影响J.中国计划生育学杂志,2019,27(5):599-603.2Xu KY,Sun ZG,Yang Y,et al.Research progress on etiology ofprimary ovarian insufficiency J.Chinese Journal of Birth Health&Heredity,2018,26(3):6-8.徐凯月,孙振高,杨毅,等.原发性卵巢功能不全的病因学研究进展J.中国优生与遗传杂志,2018,26(3):6-8.3Li L,Sun B,Sun YP.Research progress on the mechanism ofmesenchymal stem cell derived exosomes in the treatment of primaryovarian insufficiency J.Chinese Journal of Reproduction andContraception,2021,41(12):1091-1095.李璐,孙博,孙莹璞.间充质干细胞来源外泌体治疗原发性卵巢功能不全机制研究进展J.中华生殖与避孕杂志,2021,41(12):1091-1095.4Chen ZJ,Tian QJ,Qiao J,etc Chinese expert consensus on clinicaldiagnosis and treatment of premature ovarian insufficiency J.ChinJ Obstet Gynecol,2017,52(9):577-581.陈子江,田秦杰,乔杰,等.早发性卵巢功能不全的临床诊疗中国专家共识J.中华妇产科杂志,2017,52(9):577-581.5 Wang H,Chen D.Effect of Erxian Decoction plus Fenmatong on re-productive endocrine hormones and ovarian volume in patients withprimary ovarian insufficiency J.Journal of clinical rational druguse,2020,13(16):70-71.王皓,陈丹.二仙汤加减联合芬吗通治疗对原发性卵巢功能不全患者生殖内分泌激素及卵巢体积的影响J.临床合理用药杂志,2020,13(16):70-71.6 Ming ZS,Chen XY.Research progress on the mechanism of tradition-al Chinese medicine in the treatment of primary ovarian insufficiencyJ.Chinese Journal of Integrated Traditional and Western Medicine,2017,37(11):1405-1408.明章书,陈晓勇.中医药治疗原发性卵巢功能不全作用机制研究进展J.中国中西医结合杂志,2017,37(11):1405-1408.7Li XL,Tang H,Li L.Clinical effect of Guishen Pill plus Fenmatongon infertility patients with low ovarian reserve function and its influ-ence on sex hormone level J.Clinical Misdiagnosis&Mistherapy,2019,32(5):54-58.李晓林,汤华,李丽.归肾丸加减联合芬吗通治疗卵巢储备功能低下性不孕患者临床效果及对性激素水平影响J.临床误诊误治,2019,32(5):54-58.8 Hu YM.Application of Kuntai combined with Fenmatong in infertili-ty patients with early ovarian failure J.Chinese Medicine ModernDistance Education of China,2018,16(18):107-109.胡艳梅.坤泰联合芬吗通在早发性卵巢功能不全不孕患者中的应用J.中国中医药现代远程教育,2018,16(18):107-109.9Li X.Observation on therapeutic effect of Erxian decoction on earlyovarian insufficiency of spleen kidney yang deficiency type J.ActaChinese Medicine,2018,33(7):1340-1344.李潇.二仙汤加减治疗脾肾阳虚型早发性卵巢功能不全疗效观察J.中医学报,2018,33(7):1340-1344.10 Ming ZS,Wu XH,Wang Q,et al.Effect of Jiawei Guilu Erxian De-coction on the expression of miR-190 in the ovary of mice with pri-mary ovarian insufficiency J.China Journal of Traditional ChineseMedicine and Pharmacy,2019,34(11):5410-5414.明章书,吴小华,王巧,等.加味龟鹿二仙汤对原发性卵巢功能不全小鼠卵巢miR-190表达的影响J.中华中医药杂志,2019,34(11):5410-5414.11 Tang HX,Zhou L,Chen XL,et al.Effect and mechanism of BushenHuoxue Decoction combined with Fenmaotong in the treatment of ear-ly onset ovarian insufficiency(kidney deficiency and blood stasis type)J.Journal of Chinese Medicinal Materials,201,44(12):2955-2959.汤海霞,周丽,陈晓玲,等.补肾活血汤联合芬吗通治疗早发性卵巢功能不全(肾虚血瘀型)的疗效及作用机制J.中药材,2021,44(12):2955-2959.12 Chen CY,Hu F.The effect of neuromuscular stimulation combinedwith fentanyl on endometrial morphology and local blood flow in pa-tients with thin endometrium infertility J.Maternal and ChildHealth Care of China,2023,38(5):852-855.陈彩艳,胡芳.神经肌肉刺激联合芬吗通对薄型子宫内膜型不孕患者子宫内膜形态及局部血运的影响J.中国妇幼保健,2023,38(5):852-855.13 Zheng HJ,Pan H,Zhang H.The effect of Gegenheisu decoction com-bined with Fenmutong on traditional Chinese medicine syndromescore,endometrial classification,and pregnancy status in patientswith thin endometrium infertility J.The Chinese Journal of HumanSexuality,2022,31(6):129-133.郑慧君,潘鸿,张虹.葛根黑苏汤结合芬吗通对薄型子宫内膜不孕症患者中医证候积分、子宫内膜分型与妊娠情况的影响J.中国性科学,2022,31(6):129-133.14 Zhou JY,Wang X.Clinical observation on the treatment of early-onsetovarian dysfunction in liver depression and kidney deficiency syn-drome with the method of tonifying the kidney and soothing the liverJ.Information on Traditional Chinese Medicine,2022,39(12):56-61.周珈夷,王昕.补肾疏肝法治疗肝郁肾虚证早发性卵巢功能不全的临床观察J.中医药信息,2022,39(12):56-61.15 Yuan WH,Ma JQ.Comparative study on the effects of Yousimingand Fenmutong on postoperative endometrial repair in patients withmissed abortion undergoing curettage J.Journal of Hunan NormalUniversity(Medical Sciences),2022,19(1):170-172.袁伟华,马俊勤.优思明、芬吗通对稽留流产清宫患者术后子宫内膜修复的影响对比研究J.湖南师范大学学报(医学版),2022,19(1):170-172.16 Shen XP,Yang ML.Clinical observation on the treatment of meno-pausal syndrome of kidney deficiency and liver depression type withmodified Zishui Qinggan Yin combined with estradiol/estradiol de-droprogesterone J.Beijing J Trad Chin Med,2021,40(4):365-369.沈喜萍,杨明丽.滋水清肝饮加减联合雌二醇/雌二醇地屈孕酮治疗肾虚肝郁型绝经综合征的临床观察J.北京中医药,2021,40(4):365-369.(收稿日期：2022-11-17)2180