CN116763888B - 一种改善控制性超促排卵周期卵泡发育和卵子质量的中药组合物及其应用 - Google Patents
一种改善控制性超促排卵周期卵泡发育和卵子质量的中药组合物及其应用 Download PDFInfo
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Abstract
本发明涉及一种改善控制性超促排周期卵泡发育和卵子质量的中药组合物及其应用,其具有燮理阴阳、调和枢机、益气养血、补肾填精的作用,改善控制性超促排周期卵泡发育,提升卵子质量,改善妊娠结局,也可应用于治疗卵巢储备功能下降、卵巢早衰、早发性功能不全。
Description
技术领域
本发明涉及一种用于辅助生殖技术周期中的复方中药,具体涉及一种改善控制性超促排周期卵泡发育和卵子质量的中药组合物及其应用。
背景技术
近年来不孕症的发病率呈逐年上升趋势,世界范围内不孕不育率高达15%-20%[1],是世界性的生殖健康问题。自1978年第1个试管婴儿诞生以来,以体外受精-胚胎移植(in vitro fertilization-embryo transfer,IVF-ET)为代表的辅助生殖技术(assistedreproductive technology,ART)的迅猛发展为众多不孕患者及家庭带来曙光,而控制性超促排卵(controlled ovarian hyperstimulation,COH)是IVF-ET周期中的关键一环,因为获得足够数量并质量良好的胚胎是助孕成功的重要前提。然而,由于卵泡发育不同步,卵巢低反应、卵巢储备功能下降、早发性卵巢功能不全、高龄等问题,导致取卵失败、获卵数减少、卵子质量低、可移植胚胎数减少等问题,严重影响患者的妊娠结局,是当前生殖医学领域亟待解决的重要难题。
《灵枢·经脉》曰:“人始生,先成精”,先天之精禀受于父母,藏之于肾,主人体的生长发育与生殖,在女性生理中起着最重要的作用[2]。精气充足,则肾阴肾阳平衡协调;精气亏损,则肾之阴阳失调[3]。生理情况下,阴阳平衡,肾的精气充沛,通过天癸达于冲任使血海充盛,为卵子生发之本,卵细胞的生长、发育、成熟与肾精充盛及阳气生发密切相关,肾精不足、阴阳失衡是卵泡发育异常的基本病机[4-5]。控制性超促排卵具有异于生理周期的特征,需要在短期内募集多个卵母细胞,诱导多个卵泡同时发育。短时间内卵细胞大量的发育必然导致天癸大量泌至,耗损肾之阴阳,致使阴阳失衡,冲任失调,气血不充,卵泡缺少精血的滋养,使其生长缺乏物质基础或发育不能成熟[6]。若原有肾-天癸-冲任-胞宫轴失调,肾精不足,冲任不能相资,气血失和,阴阳失衡等病机因素,加之控制性超促排卵耗损太过,则卵泡发育不同步、或卵泡不能正常发育、卵子质量下降、取卵失败等。控制性超促排卵周期中,卵巢反应剧烈,肾气和天癸耗损严重。肾阴肾阳亏虚,肾阳虚则不能化气行水。阳虚血液运行不畅则脉络郁滞;若阳虚累及脾土,致脾阳失于温运则水湿运化失司,水湿内聚在内则成腹水、胸水,而外溢肌肤则为水肿,表现为卵巢过度刺激,严重影响患者的生命健康[6]。发明人运用燮理阴阳、调和枢机、益气养血、补肾填精中药可显著改善控制性超促排患者的获卵率及卵子质量,提高IVF患者的妊娠结局,降低卵巢过度刺激等并发症发生。
现有技术中,中国专利数据库公开了几种改善卵巢功能的中药复方,如CN105816660A公开了一种保养卵巢的膏滋及其制备方法,采用红枣、桑葚、当归、女贞子、益母草、旱莲草、杜仲、茯苓等制成,全方重在养血益肾,仅用滋补法。CN102258685B公开了治疗卵巢储备功能下降的复方中药及应用,采用熟地20-30、制首乌15-20、枸杞20-30、黄精20-30、淫羊藿10-15、补骨脂10-15、阿胶10-15、当归10-15、香附10-15、丹参10-20、红花3-6。其公开了卵巢储备功能下降病机属于中医肾精亏虚、肾阴不足,给予填精补肾、滋阴养血的治疗方法,从而改善卵巢储备功能。CN102846849B也公开了一种抗卵巢功能衰退的中药组合物及其应用,主要由菟丝子30-70%,枸杞子10-50%,桑椹4-20%,生地黄10-20%和红花1-10%组成,优选为由菟丝子30-55%,枸杞子17-38%,桑椹8-18%,生地黄13-19%和红花3-6%组成。该组方通过补肾抗衰、益精滋阴、养血调经进行治疗。但对于如何改善控制性超促排卵周期卵泡发育和卵子质量,目前的中药复方更关注填精补肾、滋阴养血,缺少对阴阳平衡的整体调节,因而导致临床治疗效果不佳,IVF患者并发症较多。
相关文献:
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[2]李文娜,陈璐,冯晓玲.补肾法辅治体外受精-胚胎移植的研究进展[J].中华中医药杂志,2019,34(02):692-696.
[3]胡海燕,孙玉华.中医药在体外受精—胚胎移植技术中的分期应用[J].中国中医药现代远程教育,2018,16(22):159-160.
[4]沈霞,邹奕洁,谈勇.滋阴补阳序贯法结合体外受精-胚胎移植治疗不孕症[J].吉林中医药,2012,32(12):1198-1200.
[5]连方,梁静雅.体外受精-胚胎移植中控制性超排卵后的中医证候分布[J].中医杂志,2012,53(06):485-487.
[6]连方,辛明蔚.体外授精-胚胎移植患者降调节后肾虚本质探讨[J].山东中医药大学学报,2008(02):109-110.
发明内容
有鉴于此,本发明的目的是提供一种改善控制性超促排卵周期卵泡发育和卵子质量的复方中药,具有燮理阴阳、调和枢机、益气养血、补肾填精的作用,应用于控制性超促排卵周期中,可提高促排周期获卵率,提升卵子质量,改善妊娠结局,降低促排副反应,也可应用于治疗卵巢储备功能下降、卵巢早衰、早发性卵巢功能不全,为安全有效的纯中药制剂。
本发明提供一种改善控制性超促排卵周期卵泡发育和卵子质量的中药组合物,所述中药组合物由下列重量份原料药制成,桂枝5-25份、白芍10-30份、柴胡5-25份、黄芪10-40份、鹿角霜15-25份、党参10-30份、茯苓10-30份、白术5-20份、菟丝子15-40份、肉苁蓉5-25份、熟地10-30份、枸杞子5-25份、山萸肉5-25份、当归5-25份、阿胶5-20份、知母5-25份、黄柏3-15份、香附5-25份、陈皮5-25份、薏米20-40份、藿香5-25份、山药10-30份、升麻5-25份,以及任选A药物,所述A药物选自下述重量份原料药:酸枣仁0-40份、栀子0-20份、五味子0-10份、生龙骨0-40份、女贞子0-20份、旱莲草0-20份中的一种或多种。
所述中药组合物优选由下列重量份原料药制成,桂枝10-20份、白芍10-20份、柴胡5-20份、黄芪15-35份、鹿角霜20-25份、党参15-25份、茯苓15-30份、白术5-20份、菟丝子15-40份、肉苁蓉5-25份、熟地10-30份、枸杞子10-20份、山萸肉10-20份、当归5-20份、阿胶5-20份、知母5-20份、黄柏3-10份、香附5-15份、陈皮5-10份、薏米20-35份、藿香5-20份、山药10-30份、升麻5-20份。
所述中药组合物优选由下列重量份原料药制成,桂枝10-15份、白芍10-15份、柴胡5-15份、黄芪20-35份、鹿角霜20-25份、党参15-20份、茯苓15-20份、白术5-15份、菟丝子20-30份、肉苁蓉10-25份、熟地15-30份、枸杞子10-15份、山萸肉10-15份、当归10-20份、阿胶5-15份、知母5-15份、黄柏3-9份、香附5-10份、陈皮5-10份、薏米20-35份、藿香5-15份、山药15-30份、升麻5-15份。
所述中药组合物优选由下列重量份原料药制成,桂枝10份、白芍15份、柴胡10份、黄芪20份、鹿角霜20份、党参10份、茯苓10份、白术10份、菟丝子20份、肉苁蓉10份、熟地20份、枸杞子10份、山萸肉10份、当归10份、阿胶10份、知母10份、黄柏5份、香附10份、陈皮10份、薏米20份、藿香10份、山药20份、升麻10份。
所述薏米为炒薏米,所述白术为炒白术,所述黄芪为生黄芪。
所述A药物选自酸枣仁20-40份和栀子5-20份,优选酸枣仁30份和栀子15份。
所述A药物选自五味子5-10份和生龙骨20-40份,优选五味子6份和生龙骨30份。
所述A药物选自女贞子5-20份和旱莲草5-20份,优选女贞子10-15份和旱莲草10-15份。
本发明中药组合物的君药由桂枝、白芍、柴胡组成。臣药由生黄芪、党参、茯苓、炒白术、鹿角霜、菟丝子、肉苁蓉、熟地、枸杞子、山药、山萸肉组成。佐药由升麻、当归、阿胶、知母、黄柏、香附、陈皮、薏米、藿香组成。本发明中药组合物可加入药学可接受的药物载体制成制剂,所述制剂选自汤剂、丸剂、膏剂、颗粒剂、片剂、胶囊剂、口服液中的一种。
本发明还提供上述中药组合物的制备方法,将各中药加水或C1-C4的醇溶液提取制得。所述醇为甲醇、乙醇、丙醇或丁醇中的一种,优选乙醇。
本发明还进一步提供中药组合物在制备改善控制性超促排卵周期卵泡发育和卵子质量药物的用途,尤其适用于卵巢功能下降患者在改善控制性超促排卵周期卵泡发育和卵子质量药物中的用途。优选上述中药组合物在制备改善性激素水平、提高卵巢原始卵泡数量、提高次级卵泡数量、提高窦卵泡数目或提升卵子质量、或改善双侧卵巢动脉血流的药物中的应用。
优选上述中药组合物在制备降低卵巢组织中EGF含量、血清FSH、LH含量的药物中的应用。
本发明针对控制性超促排卵时期特殊的病机特点,从阴阳失衡、枢机不利入手,充分考虑中药配伍原则。
君药:方中以桂枝、白芍、柴胡为君药。桂枝燮理阴阳、调和营卫、助阳化气;白芍滋阴柔肝、敛阴和营;柴胡和解少阳、疏肝解郁、升举阳气。桂枝主升阳宣发,白芍主收敛,桂枝辛甘化阳以助阳,白芍酸甘化阴以益阴,桂枝发散充卫气,白芍收敛益营阴,二者一散一收、一阴一阳,生中有敛,敛中有生。柴胡辅助桂枝升阳宣发,三药并用燮理阴阳、调和枢机、生发气血、转邪外达。阴阳调和则气血生化源泉不断,少阳枢机得利则气、血、津、液各行其道,五脏六腑各司其职。
臣药:生黄芪、党参、茯苓、炒白术共奏健脾益气之功,助气血生化,补养后天以助先天;臣药中鹿角霜、菟丝子、肉苁蓉益肾培元,补肾填精滋养先天;臣药中熟地、枸杞子、山药、山萸肉补肾益精、滋阴养血。
佐药:升麻佐柴胡、桂枝升阳之功;当归、阿胶养血活血,补养冲脉;知母、黄柏滋阴潜阳,滋肾坚阴,助白芍之收敛;香附、陈皮理气,防止诸药滋腻;炒薏米、藿香健脾化湿,芳香辟秽。
遵循“燮理阴阳、调和枢机”的原则,实现“阴阳平衡、枢机得利、气血精液充足、脏腑功能充盛”的治疗目的。本方配伍具有如下特点,①燮理阴阳,营卫同调,阴阳调和则气血生化源泉不断;②和解少阳,调畅枢机。《素问·阴阳离合论》记载:“太阳为开,阳明为合,少阳为枢。”少阳枢机得利则气血津液各行其道,五脏六腑各司其职。③补中兼疏,补而不滞,疏而不峻,彰显中庸之性、动态之妙。临床上本发明可改善控制性促排卵周期卵泡发育及卵子质量。
其中以桂枝、白芍、柴胡燮理阴阳、调和枢机、生发气血、转邪外达;生黄芪、党参、茯苓、炒白术共奏健脾益气之功,助气血生化,补养后天以助先天;鹿角霜、菟丝子、肉苁蓉益肾培元,补肾填精滋养先天;熟地、枸杞子、山药、山萸肉补肾益精、滋阴养血;升麻佐柴胡、桂枝升阳之功;当归、阿胶养血活血,补养冲脉;知母、黄柏滋阴潜阳,滋肾坚阴,助白芍之收敛;香附、陈皮理气,防止诸药滋腻;炒薏米、藿香健脾化湿,芳香辟秽。遵循“燮理阴阳、调和枢机”的原则,实现“阴阳平衡、枢机得利、气血精液充足、脏腑功能充盛”的治疗目的。全方燮理阴阳、调和枢机、益气养血、补肾填精,对改善控制性促排卵周期卵泡发育及卵子质量有良好的临床疗效。桂枝、白芍、柴胡为君药燮理阴阳、调和枢机、生发气血、转邪外达。桂枝燮理阴阳、调和营卫、助阳化气。桂枝辛、甘,温。归心、肺、膀胱经。辛可散,温可行,辛甘化阳、助阳化气、调和营卫。白芍滋阴柔肝、敛阴和营。《长沙药解》中认为白芍味酸、微苦,属阴,益阴敛营。桂枝和白芍同用助阳益阴以复营卫,待表阳恢复后,气化正常,阴生阳长,阴阳自和。柴胡和解少阳、疏肝解郁、升举阳气。《神农本草经》载:“柴胡味苦,平。治心腹,去肠胃中结气……推陈致新。久服轻身,明目益精”。《雷公炮制药性解》论道:“柴胡气味升阳,提下元之气上行,以泻三焦火”。
生黄芪、党参、茯苓、炒白术为臣药共奏健脾益气之功,助气血生化,补养后天以助先天。生黄芪为臣药善补脾胃之虚,正气虚损多为后天脾胃不足所致,脾在味为甘,黄芪性甘味温,为补气之长,在治疗肺脾肾虚损等相关疾病时多用。《药性论》言:“主虚喘,肾衰,耳聋……黄芪其补肾者,气为水也。”肾水为坎,一阴育于二阳中,肾脏元气充足,方可司气化、藏精等功能,黄芪为肾脏元气之药。黄芪补益后天,以滋先天,其升提之性有助肾气的固摄。党参、茯苓、炒白术取四君之法,有扶正培本之意。党参味甘,性平,归脾、肺经,具有补中益气、健脾益肺、养血生津的功效。白术味甘、苦,性温,入脾、胃经,为脾家要药。《本草通玄》中记述:“白术,补脾胃之药,更无出其右者”,白术健脾益气,脾气健运,水谷精微化源充足,气血运行充盈,滋润五脏六腑、四肢百骸、筋肉、皮毛,则肌肉发达,筋骨强壮,面色红润,可以延年。茯苓味淡而甘,性平,归肾、肺、心、脾经,善治脾虚、水肿。《本草纲目》认为茯苓有“补五劳七伤,开心益智,和中益气”的作用。《神农本草经》记载:“(茯苓)久服能延年、养身、安魂、不饥。”诸药同用则脾胃气足,中运健旺,血若波澜,气血生化不绝。
鹿角霜、菟丝子、肉苁蓉为臣药益肾培元,补肾填精滋养先天。鹿角霜为鹿角熬制鹿角胶后所剩下的骨渣,性温,味咸涩,入肾、肝、脾三经。补肾阳强筋骨之力尤强,血肉有情之物更是栽培精血之佳品。据《本草便读》所载:“鹿角胶、鹿角霜,性味功用与鹿茸相近,但少壮衰老不同,然总不外乎血肉有情之品,能温补督脉,添精益血。如精血不足,而可受腻补,则用胶;若仅阳虚而不受滋腻者,则用霜可也”。鹿角霜较鹿角而言补阳力偏弱,恰是取《黄帝内经》中“壮火食气,少火生气”之意,用鹿角霜温肾培精不易滋腻。虽然在控制性超促排卵过程中,阴液耗损严重,以恢复“阴”为重,多以滋阴益气养血,但施助肾阳,能助阴血化生。阴血足血海盛,肾阳鼓动阴血,则经血可调。因而本方在益气健脾的同时,重用鹿角霜以助肾阳鼓动阴血。菟丝子味辛、甘,性温,入肝、肾经,《神农本草经》言菟丝子“主续绝伤,补不足,益气力,肥健……久服明目。轻身延年。”其禀气中和,既可补阳,又可益阴,具有温而不燥,补而不滞的特点。现代药理学表明菟丝子具有改善生殖功能、延缓衰老、调节免疫功能等作用。菟丝子中起主要作用的化学物质是菟丝子黄酮,研究表明菟丝子黄酮有类雌激素的功能,通过调节下丘脑-垂体-性腺轴功能,对卵巢早衰大鼠的卵巢功能有明显的恢复作用,可提高大鼠的雌激素水平。肉苁蓉始载于《神农本草经》,被誉为“沙漠人参”,列属上品。其味甘、咸,性温,归肾、大肠经,中医认为其具有补肾阳、益精血、润肠通便之效。现代药理研究表明,肉苁蓉具有显著的抗氧化、延缓衰老等作用。
熟地、枸杞子、山药、山萸肉为臣药补肾益精、滋阴养血。熟地味甘,性微温,主归肝、肾经,乃补阴要药。陈士铎认为熟地乃“至阴之药”,至阴”即包涵血、津、液、精4个层面,其直接功效细化为益精、补血、生津、滋液,尤入肾中益精生髓而大补肾水之乏。由于本方中重用鹿角霜,助阳力大,易耗伤阴血,致冲任血海愈加不足,因而,本方采用至阴之药熟地以护阴阳平衡。枸杞子,气味甘寒,具有补肾益精的功效,最早见于《神农本草经》:“性寒。主五内邪气,热中,消渴,周痹。久服,坚筋骨,轻身不老。”山药其味甘,性平,入肺、脾、肾经,具有补脾养胃,生津益肺,补肾涩精之效。其首载于《神农本草经》,谓:“味甘温,补虚羸,除寒热邪气;补中,益气力,长肌肉;久服耳目聪明,轻身,不饥,延年”。山萸肉味酸、涩,微温,入肝、肾经。《本草纲目》载:”山茱萸,……有强阴益精、安五胎、通九窍、止小便淋沥之功;久服明目、强力长年”。《中医药大辞典》谓之“补肝肾,涩精气,固虚脱”。《本草正》云山茱萸“固阴补精,调经收血”。
升麻佐柴胡、桂枝升阳之功。《中国药典》记载:“升麻辛、微甘,性微寒。归肺、脾、胃、大肠经,功能发表透疹,清热解毒,升举阳气。”当归、阿胶养血活血,补养冲脉。当归性温味甘辛,归心、肝、脾经,主入血分,既能补血又能活血,补中有行。擅长补血调经、活血止痛,润肠通便,为补血之圣药。阿胶始载于《神农本草经》,属于胶类中药,具有补血滋阴、润燥、止血的功效。现代研究表明阿胶具有有抗氧化、抗疲劳、提高免疫力、促进造血、改善卵巢功能的作用。知母、黄柏滋阴潜阳,滋肾坚阴,助白芍之收敛。知母正名始载于东汉《神农本草经》,味苦,寒,具有清热、消肿、利水等功效。《东垣试效方》说:知母为“泻足阳明经火热圣药”。黄柏始载于东汉《神农本草经》,在《珍珠囊》中记载:“黄柏之用有六:渴膀胱龙火,一也;利小便结,二也;除下焦温肿,……五也;补紧不足,壮骨髓,六也”,说明了黄柏入肾经,具有泻肾中虚火而治虚热骨蒸之功效。清朝《本草备要》曰:“知母,泻火补水,润燥滑肠。辛苦寒滑。上清肺金而泻,下润肾燥而滋阴,入二经气分……黄柏入二经血分,故二药必相须而行”。香附、陈皮理气,防止诸药滋腻。香附味微苦甘、性辛。入肝、三焦经。《本草纲目》曰其入“手足厥阴、手少阳,兼行十二经,八脉气分”。又曰:“香附之气平而不寒,香而能窜,其味多辛;散,微苦能降,微甘能和。生则上行胸膈,外达皮肤;熟则下走肝肾,外彻腰足。”陈皮味苦、辛,性温,归肺、脾经,具有理气健脾、燥湿化痰的功效。炒薏米、藿香健脾化湿,芳香辟秽。炒薏苡仁甘、淡、凉,归脾、胃、肺经。具有利水消肿、健脾渗湿止泻的功效。藿香芳香醒脾,其性辛温,外可解表散邪,内可辟秽化湿,疏阳明经之秽浊之邪。
本发明还公开了本中药组合物可采取任何现有技术的方法,并添加任何其它成分,用于制备改善控制性超促排卵周期卵泡发育和卵子质量的药物。
本发明的有益效果:本发明为改善控制性超促排卵周期卵泡发育和卵子质量的复方中药,具有燮理阴阳、调和枢机、益气养血、补肾填精的作用,应用于控制性超促排卵周期中,可提高促排周期获卵率,提升卵子质量,改善妊娠结局,降低促排副反应,也可应用于治疗卵巢储备功能下降、卵巢早衰、早发性功能不全,为安全有效的纯中药制剂。
附图说明
图1各组小鼠子宫指数、卵巢指数比较;注:与对照组比较,aP<0.05,aaP<0.01;与模型组比较,bP<0.05,bbP<0.01;与中药低剂量组比较,cP<0.05。
图2光镜下小鼠动情周期各阶段阴道脱落细胞涂片(200X);注:P:动情前期;E:动情期;M:动情后期;D:间情期。
图3各组小鼠卵巢组织切片HE染色图(10×、30×、50×)。
图4各组小鼠卵巢各级卵泡图;注:与对照组比较,aP<0.05,aaP<0.01;与模型组比较,bP<0.05,bbP<0.01;与中药低剂量组比较,cP<0.05。
图5各组小鼠血清激素及细胞因子水平图;注:与对照组比较,aP<0.05,aaP<0.01;与模型组比较,bP<0.05,bbP<0.01;与中药低剂量组比较,cP<0.05,ccP<0.01;与中药中剂量组比较,dP<0.05。
图6各组小鼠卵巢组织EGF水平图;注:与对照组比较,aP<0.05;与模型组比较,bP<0.05;与中药低剂量组比较,cP<0.05。
实施例1
组方:桂枝10g、白芍15g、柴胡10g、生黄芪20g、鹿角霜20g、党参10g、茯苓10g、炒白术10g、菟丝子20g、肉苁蓉10g、熟地20g、山萸肉10g、枸杞子10g、当归10g、阿胶10g、知母10g、黄柏5g、升麻10g、香附10g、陈皮10g、炒薏米20g、藿香10g、山药20g。
制备方法:将鹿角霜加水先煎15分钟,然后加入桂枝、白芍、柴胡、生黄芪、党参、茯苓、炒白术、菟丝子、肉苁蓉、熟地、山萸肉、枸杞子、当归、知母、黄柏、升麻、香附、陈皮、炒薏米、山药继续煎煮30分钟,后下藿香再煎煮15分钟,过滤后收集滤液,将药渣继续加水煎煮40分钟,取滤液,合并两次滤液,将阿胶烊化后加入上述滤液,制得汤剂。
实施例2
组方:桂枝15g、白芍20g、柴胡15g、生黄芪25g、鹿角霜15g、党参10g、茯苓15g、炒白术20g、菟丝子30g、肉苁蓉10g、熟地25g、山萸肉15g、枸杞子10g、当归10g、阿胶15g、知母6g、黄柏6g、升麻15g、香附10g、陈皮10g、炒薏米20g、藿香6g、山药20g。
制备方法:将鹿角霜加水先煎15分钟,然后加入桂枝、白芍、柴胡、生黄芪、党参、茯苓、炒白术、菟丝子、肉苁蓉、熟地、山萸肉、枸杞子、当归、知母、黄柏、升麻、香附、陈皮、炒薏米、山药继续煎煮35分钟,后下藿香再煎煮15分钟,过滤后收集滤液,将药渣继续加水煎煮1小时,取滤液,合并两次滤液,将阿胶烊化后加入上述滤液浓缩,制得膏剂。
实施例3
组方:桂枝10g、白芍15g、柴胡10g、生黄芪15g、鹿角霜25g、党参15g、茯苓20g、炒白术10g、菟丝子30g、肉苁蓉15g、熟地20g、山萸肉20g、枸杞子15g、当归15g、阿胶9g、知母6g、黄柏6g、升麻10g、香附10g、陈皮10g、炒薏米30g、藿香10g、山药20g。
制备方法:将鹿角霜加水先煎15分钟,然后加入桂枝、白芍、柴胡、生黄芪、党参、茯苓、炒白术、菟丝子、肉苁蓉、熟地、山萸肉、枸杞子、当归、知母、黄柏、升麻、香附、陈皮、炒薏米、山药继续煎煮30分钟,后下藿香再煎煮15分钟,过滤后收集滤液,将药渣继续加水煎煮40分钟,取滤液,合并两次滤液,将阿胶烊化后加入上述滤液,浓缩、干燥后粉碎,加入糊精以及硬脂酸镁制成颗粒。
实施例4
组方:桂枝15g、白芍15g、柴胡10g、生黄芪20g、鹿角霜20g、党参15g、茯苓15g、炒白术10g、菟丝子30g、肉苁蓉10g、熟地20g、山萸肉15g、枸杞子15g、当归10g、阿胶9g、知母10g、黄柏6g、升麻10g、香附10g、陈皮10g、炒薏米30g、藿香10g、山药20g、酸枣仁30g、栀子10g。
制备方法:将鹿角霜加水先煎15分钟,然后加入桂枝、白芍、柴胡、生黄芪、党参、茯苓、炒白术、菟丝子、肉苁蓉、熟地、山萸肉、枸杞子、当归、知母、黄柏、升麻、香附、陈皮、炒薏米、山药、酸枣仁、栀子继续煎煮30分钟,后下藿香再煎煮15分钟,过滤后收集滤液,将药渣继续加水煎煮40分钟,取滤液,合并两次滤液,将阿胶烊化后加入上述滤液,制得汤剂。
实验例1:临床试验
以下是本发明中药组合物临床研究情况,表明本发明在卵巢储备功能下降治疗中的作用:
1.1一般资料
选取2021年9月至2022年12月就诊于天津中医药大学第一附属医院生殖中心符合纳排标准的行IVF助孕的卵巢储备功能下降(DOR)不孕症患者,治疗组33例,对照组30例。治疗组予以实施例1的中药组合物治疗,对照组安慰剂(颗粒剂)治疗,两组给药2月后予IVF-ET助孕治疗,控制性促排卵采用微刺激方案。
1.2诊断标准
以人类生殖和胚胎学协会(ESHRE)关于卵巢低反应的标准为基础。(1)基础窦卵泡数(basic antral follicle count,bAFC)≤5个(月经第2~5天);(2)抗苗勒氏管激素(AMH)<1.1ng/L;(3)月经周期第3天查血清FSH:10U/L<FSH<40U/L。符合上述其中1条,即可诊断为DOR。
1.3纳入标准:
(1)年龄20~40岁,有生育要求者。(2)符合DOR诊断标准和IVF/ICSI-ET适应证。(3)接受IVF-ET周期治疗,控制性促排卵方案为微刺激方案者;(4)研究对象配偶精液检查正常或经精液预洗后达到常规IVF或卵细胞浆内单精子注射(ICSI)标准,或研究者配偶无精子而采用供精助孕。
1.4排除标准:
(1)合并有其他内分泌疾病及自身免疫性疾病,如:多囊卵巢综合征、高泌乳素血症、高雄激素血症者、甲状腺功能异常、糖尿病;(2)合并有其他生殖系统疾病:如子宫内膜异位症、子宫内膜结核、宫腔粘连、子宫肌瘤、子宫畸形;(3)既往曾行卵巢手术者;(4)合并内科、外科、精神科严重原发性疾病;(5)男方或女方合并有遗传、获得性疾病或传染性疾病;(6)近三个月内服用过中药及激素类药物如避孕药、糖皮质激素等;(7)对研究方药中已知药物过敏者。
2治疗方法
治疗组予以实施例1的中药组合物治疗,对照组安慰剂(颗粒剂)治疗,两组治疗2月后予IVF-ET助孕治疗。进入促排卵周期后,于月经第2-3日晨起空腹抽取静脉血5ml,测量FSH、AMH、基础E2水平,采用微刺激方案进行控制性促排卵,并经阴道B超计数双侧卵巢内的基础AFC。经阴道B超定期监测卵泡生长情况。当双侧卵巢内至少有≥2个直径大于18mm的卵泡时,给予人绒毛膜促性腺激素(HCG)10000U。在注射HCG 36h左右取卵,根据男方精液情况,采用IVF或ICSI授精。
3疗效观察
3.1两组患者基线资料比较
两组患者在年龄、BMI、不孕时限、卵泡刺激素(FSH)、基础窦卵泡数(AFC)、基础雌二醇(E2)值、抗缪勒管激素(AMH)等方面差异均无统计学意义(P>0.05),具有可比性,详见表1。
表1两组患者的基线特征比较
3.2治疗后两组患者卵巢储备情况比较
治疗后治疗组与对照组比较,AFC数目、AMH均增高,差异具有统计学意义,FSH较对照组低,差异具有统计学意义。详见表2。
表2治疗后两组患者卵巢功能比较
3.3治疗后两组控制性促排卵周期情况比较
治疗后,两组予微刺激方案进行控制性促排卵,与对照组比较,治疗组获卵数、受精数及优质胚胎数均增多,差异具有统计学意义。详见表3。
表3治疗后两组患者控制性促排卵情况比较
3.4治疗后两组妊娠结局比较
治疗组与对照组比较,周期取消率降低,临床妊娠率升高,差异具有统计学意义。详见表4。
表4两组患者妊娠情况比较
3.5两组控制性促排卵副反应比较
对照组促排过程中有6例诉恶心,治疗组促排过程中有1例诉恶心;对照组促排过程中有4例诉腹胀腹痛,治疗组无腹胀腹痛;对照组3例发生轻度卵巢过度刺激,治疗组无卵巢过度刺激发生,药物显著降低促排过程中的副作用发生。
表5两组控制性促排卵副反应比较(例)
实验例2:动物实验
1、VCD诱导小鼠DOR模型的建立
腹腔注射具有的卵毒性化学物质4-乙烯基环己烯二环氧化物(4-vinylcyclohexene diepoxide,VCD)建立导小鼠DOR模型。除对照组外,其余各组(模型组、中药低剂量组、中药中剂量组、中药高剂量组)小鼠腹腔注射VCD,连续14天,每日一次,每次80mg/kg。同时对照组小鼠腹腔注射等量橄榄油,连续14天,每日一次。
2、动物分组及给药方案
将DOR模型组动物随机分为4组,每组10只。包括DOR模型组、中药低剂量组、中药中剂量组、中药高剂量组,同时随机取10只小鼠对照组。标记,称重并记录相关数据。中药低剂量组、中药中剂量组和中药高剂量组每日灌胃给药(实施例1的中药),剂量分别为14g/kg、28g/kg和56g/kg,每日一次,连续给药14天。对照组与模型组根据体重灌胃等量生理盐水,每日一次,连续14天。
3、取材方案
在给药期间,每日称取各组小鼠体重,并阴道涂片检测小鼠动情周期,于给药14天后,选取进入间情期小鼠取材,记录相关数据。称重后麻醉取血,收集血液后颈椎脱臼处死小鼠。小鼠血液4℃30min室温静置,3000rpm离心15min后收集上层血清,-80℃保存。同时解剖小鼠,收集其卵巢。
4、通过采取各组小鼠子宫及卵巢组织并计算其脏器指数(脏器湿重mg/体重g),用以评估其子宫、卵巢萎缩情况。结果显示:与对照组相比,模型组子宫指数、卵巢指数显著降低(P<0.05);而与模型组相比,中药低剂量、中剂量组高、剂量治疗组子宫指数虽有提升,但其差异不具有统计学意义(P>0.05);而中药高剂量治疗组相比于模型组、中药低剂量组,其卵巢指数显著提高(P<0.05)。如图1。
通过每日观察阴道涂片记录整理其动情周期,动情前期:视野内可见大量单个或成片的有核上皮细胞,及少量角化鳞状细胞和白细胞;动情期:涂片可见满视野角化鳞状上皮细胞,细胞内无细胞核,外形大而扁平,边缘不齐,可伴随的少量有核上皮细胞及白细胞;动情后期:视野内角化鳞状上皮细胞减少,同时少量有核上皮细胞及白细胞增多间情期:涂片内满布小而圆的白细胞。各组小鼠动情周期情况如图2所示。与对照组相比,模型组周期正常小鼠数量减少,周期混乱小鼠增加,其中大部分小鼠停经。与模型组相比,中药低、中、高剂量治疗的DOR模型小鼠,其周期正常数量增加,停经小鼠有所减少。
5、各组小鼠卵巢形态变化情况
通过对各组小鼠卵巢组织病理切片进行HE染色并统计其各级卵泡数量,具体结果如下:HE染色结果参见图3。对于原始卵泡各组卵泡数量差异具有统计学意义(p<0.01),与对照组相比,模型组、低剂量组、中剂量组小鼠卵巢原始卵泡数量明显减少(p<0.01);与模型组相比,高剂量组小鼠卵巢原始卵泡数量明显增加(p<0.01);与低剂量组相比,高剂量组小鼠卵巢原始卵泡数量明显增加(p<0.05)。对于初级卵泡各组卵泡数量差异无统计学意义(p>0.05)。对于次级卵泡,各组卵泡数量差异具有统计学意义(p<0.01),与模型组比较,高剂量组小鼠卵巢次级卵泡数量明显减少(p<0.05),低剂量组小鼠卵巢次级卵泡数量明显减少(p<0.01)。对于窦卵泡各组卵泡数量差异有统计学意义(p<0.01),与对照组比较,模型组小鼠卵巢窦卵泡数量明显减少(p<0.01);与模型组相比,高剂量组小鼠卵巢窦卵泡数量明显增加(p<0.01)。对于闭锁卵泡各组卵泡数量差异无统计学意义(p>0.05)。对于黄体各组黄体数量差异无统计学意义(p>0.05)。如图4。
6、各组小鼠血清激素及细胞因子水平变化情况
使用ELISA法检测对照组、模型组、中药低剂量组、中药中剂量组、中药高剂量组5组小鼠血清中FSH、LH、E2、INHB、AMH、EGF含量差异,结果如图5所示。小鼠血清INHB、AMH、E2,与对照组相比,模型组含量明显降低(P<0.05);与模型组相比,高中低剂量组含量显著提升(P<0.05)。小鼠血清FSH、LH,与对照组相比,模型组含量显著升高(P<0.01);与模型组相比,高中低剂量组含量显著降低(P<0.05)。小鼠血清EGF,与对照组相比,模型组含量显著升高(P<0.01);与模型组相比,低中高剂量组含量显著降低(P<0.05)。
7、各组小鼠卵巢组织EGF水平变化
使用ELISA法检测小鼠卵巢组织EGF的含量,结果如图6所示,经检测,对照组、模型组、中药低剂量组、中药中剂量、中药高剂量组5组小鼠卵巢组织EGF含量,差异均具有统计学意义(P<0.01)。与对照组相比,模型组小鼠卵巢组织中EGF含量显著升高(P<0.05);与模型组相比,中剂量组和高剂量组小鼠卵巢组织中EGF含量显著降低(P<0.05);与低剂量组相比,中剂量组和高剂量组小鼠卵巢组织中EGF含量显著降低(P<0.05)。
典型病例1:
患者兰某,女,35岁,因“IVF-ET失败3次”前来就诊。患者初婚3年,性生活规律,工具避孕1年,未避孕未孕2年余。2020年5月-9月于其他医院自然周期监测卵泡,有优势卵泡排出,未孕。2020年9月行左侧巧囊剥除术,术后因卵巢储备功能下降行IVF,2020年11月拮抗剂方案取卵11枚,配成2枚胚胎,ET后未孕。2021年7月拮抗剂方案取卵10枚,配成2枚胚胎,2021年9月FET后未孕。2022年4月,行PPOS-ICIS方案,取卵7枚,配成2枚胚胎,胚胎级别为7I、7II,FET后未孕。既往月经规律,27-28天一行,量少,色红,血块(+),痛经(+)。平素精神压力大,情绪急躁易怒,易口腔溃疡,排卵期水样白带,寐差,入睡困难,舌尖红,苔薄黄,脉弦数。西医诊断:反复种植失败。中医诊断:不孕症。根据其症状体征辨证属于脾肾阳虚、肝郁化火,患者拟调理后再行促排卵,中药治以燮理阴阳、调和枢机、疏肝清热,补脾益肾为主,方药组成:桂枝10g、白芍15g、柴胡10g、生黄芪20g、鹿角霜20g、党参10g、茯苓10g、炒白术10g、菟丝子20g、肉苁蓉10g、熟地20g、山萸肉10g、枸杞子10g、当归10g、阿胶10g、知母10g、黄柏5g、升麻10g、香附10g、陈皮10g、炒薏米20g、藿香10g、山药20g;寐差加酸枣仁30g、栀子10g。中药制膏方服用2月余。患者2022年9月取卵9枚,配成4枚(其中2枚囊胚,胚胎级别4AB、4BC;2枚冻胚,胚胎级别8I、8II)。患者获卵率及优胚率均较前改善,继续服用上述中药治疗2月余,结合患者病情变化辨证加减,患者2022年11月30日移植一枚囊胚,胚胎级别4AB。移植后两周随访患者已孕,HCG533.2mIU/mL,现孕8月余,孕期顺利。
典型病例2:
患者亢某,女,32岁,因“IVF-ET失败2次”前来就诊。患者初婚5年,性生活规律,未避孕未孕5年。患者2021年7月因不明原因不孕于其他医院行IVF,取卵10枚,配成4枚,胚胎级别分别为7I、7II、8I-、8II,分别于2021年8月与11月FET2枚,未孕。现拟调理后再行控制性促排卵。既往月经规律,2天/35天,量少,色红,痛经(+)伴随腰酸。现症:平素性情急躁易怒,饮食偏嗜辛辣,晨起乏力,畏寒肢冷,手脚冰凉,下肢明显。寐差失眠,便秘,质干呈球状,小便调。舌质胖,舌尖红,苔白,脉细弦,尺弱。LMP:2022年2月20日,AMH:4.26ng/ml。彩超示:子宫内膜欠均匀增厚,右卵巢囊性结构,巧囊可能,盆腔积液。【初步诊断】西医诊断:反复种植失败。中医诊断:不孕症。根据其症状体征辨证属于脾肾阳虚,肝肾阴虚。患者拟调理后再行控制性超促排卵,中药治以燮理阴阳、调和枢机、温补脾肾,滋肾柔肝为主,方药组成:桂枝10g、白芍15g、柴胡10g、生黄芪20g、鹿角霜20g、党参10g、茯苓10g、炒白术10g、菟丝子20g、肉苁蓉10g、熟地20g、山萸肉10g、枸杞子10g、当归10g、阿胶10g、知母10g、黄柏5g、升麻10g、香附10g、陈皮10g、炒薏米20g、藿香10g、山药20g;肝肾阴虚加女贞子15g、旱莲草15g。中药制膏方服用3月余。患者2022年7月取卵13枚,配成7枚(其中3枚囊胚,胚胎级别4AB、4BB、4BC;4枚冻胚,胚胎级别8I3枚、7I1枚)。患者取卵后继续中药治疗1月余,2022年9月移植一枚囊胚,2周后随访患者妊娠,2023年6月随访,患者顺产一健康男婴。
典型病例3:
张某,女,2018年2月就诊于我科。主诉:未避孕未孕10年,IVF-ET失败3次。患者2008年结婚,性生活规律,未避孕未孕。曾于外院查血清AMH及经阴道超声后提示“卵巢储备功能减退”,遂于2015年行辅助生殖技术,取卵7枚,成胚3枚,移植2枚鲜胚,孕50余天因胎停育行清宫术;2016年冻胚移植1枚,未孕。2018年1月自然周期取卵1枚,配成后移植未孕。月经周期近4年来逐渐缩短,23-25天一行,经量偏少,色黯红,无痛经。症见:面色晦暗,腰酸,时觉乏力心悸,眠差多梦,大便溏,小便调。舌质胖,有齿痕,质淡,舌尖红,苔少,脉沉,尺弱。LMP:2018年2月3日,于2月18日出现阴道褐色分泌物,量少,持续4天净。既往检查:性激素六项(D2):FSH:28mIU/mL,LH:6.36mIU/mL,E2:<20pg/mL;子宫输卵管造影结果提示:双侧输卵管通畅。就诊当日妇科双合诊及阴道分泌物未发现异常;经阴道超声:内膜:6.5mm/C型,右卵巢大小24mm×18mm,内可见1~2个AFC;左卵巢大小24mm×23mm,内可见2~3个AFC。【初步诊断】西医诊断:继发性不孕症;卵巢储备功能减退;中医诊断:不孕症(脾肾阳虚,心火亢盛)。【首诊医嘱】1.予中药治以燮理阴阳、健脾益气、清心养血、补肾填精,方药组成:桂枝10g、白芍15g、柴胡10g、生黄芪20g、鹿角霜20g、党参10g、茯苓10g、炒白术10g、菟丝子20g、肉苁蓉10g、熟地20g、山萸肉10g、枸杞子10g、当归10g、阿胶10g、知母10g、黄柏5g、升麻10g、香附10g、陈皮10g、炒薏米20g、藿香10g、山药20g。制膏方服用。一月后复诊:述腰酸乏力症状明显减轻,睡眠有所改善,仍多梦,心烦,晨起有时觉心慌,舌尖红,苔少,脉沉细。在原方基础上加入五味子6g,生龙骨30g。一月后三诊:心烦心悸症状缓解,睡眠改善,大便日一次,较前成形,舌红,苔薄,脉沉细。复查FSH:9.03mIU/mL,LH:4.51mIU/mL,E2:45pg/mL。原方继服三月后复诊:患者述近3个月未有明显不适,月经25天一行,量较前明显增多,色质正常。7月20日查:FSH:6mIU/mL,LH:5.36mIU/mL,E2:35pg/mL。后患者2月自行停止服用中药,无明显不适,月经基本正常,25天一行。于2月再次返诊,要求继续服用中药助孕,中药治疗原则同前。服药3月后返诊:停经28天,患者自测尿妊娠试纸,显示阳性,述近日乏力,腰骶下坠感,小腹隐痛,眠差多梦,醒后难以入睡,无阴道流血,二便调,舌红,苔薄白,脉沉细滑。查血HCG:378.0mIU/mL,P:29.6ng/mL,E2:179pg/mL。嘱动态观察血HCG水平,腹痛或阴道流血随诊。服药后再次返诊:腰酸腹痛等症状消失,2019年1月经阴道超声提示:宫内早孕,胎囊33mm×42mm×21mm,胎芽14mm,见胎心。2019年8月随访,患者足月顺产一女婴。
Claims (6)
1.一种改善控制性超促排卵周期卵泡发育和卵子质量的中药组合物,其特征在于,所述中药组合物由下列重量份原料药制成,桂枝5-25份、白芍10-30份、柴胡5-25份、黄芪10-40份、鹿角霜15-25份、党参10-30份、茯苓10-30份、白术5-20份、菟丝子15-40份、肉苁蓉5-25份、熟地10-30份、枸杞子5-25份、山萸肉5-25份、当归5-25份、阿胶5-20份、知母5-25份、黄柏3-15份、香附5-25份、陈皮5-25份、薏米20-40份、藿香5-25份、山药10-30份、升麻5-25份,酸枣仁20-40份和栀子5-20份。
2.根据权利要求1所述的中药组合物,其特征在于,酸枣仁30份和栀子15份。
3.根据权利要求1-2任意一项所述的中药组合物,其特征在于:所述中药组合物选自汤剂、丸剂、膏剂、颗粒剂、片剂、胶囊剂、口服液中的一种。
4.根据权利要求1-3任意一项所述的中药组合物的制备方法,其特征在于:将各中药加水或C1-C4的醇溶液提取制得。
5.根据权利要求4所述的制备方法,其特征在于:所述醇为甲醇、乙醇、丙醇或丁醇中的一种。
6.根据权利要求1-2任意一项所述的中药组合物在制备改善控制性超促排卵周期卵泡发育和卵子质量的药物中的用途。
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