CN113456801A - 人绒毛膜促性腺激素在制备早发性卵巢功能不全患者的助孕药物中的应用 - Google Patents
人绒毛膜促性腺激素在制备早发性卵巢功能不全患者的助孕药物中的应用 Download PDFInfo
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Abstract
本发明涉及制药技术领域，特别是涉及人绒毛膜促性腺激素在制备早发性卵巢功能不全患者的助孕药物中的应用。发明利用人绒毛膜促性腺激素制备的药物，通过将患者的FSH降到＜15mIU/ml，LH降到＜10mIU/ml，再一次性给患者肌肉注射HCG 10000U，可通过体内激活休眠卵泡，从而使POI患者获得带有自己遗传基因的后代，且具有经济、方便、无痛苦的优势。
Description
技术领域
本发明涉及制药技术领域，特别是涉及人绒毛膜促性腺激素在制备早发性卵巢功能不全患者的助孕药物中的应用。
背景技术
早发性卵巢功能不全(premature ovarian insufficiency，POI)是指女性在40岁之前卵巢活动衰退的临床综合征，以月经紊乱(如停经或稀发月经)伴有高促性腺激素和低雌激素为特征。POI患者的特点：卵巢卵泡耗竭缺乏生长卵泡、残留极少休眠卵泡(＜1000个)，常规促排卵药物治疗无效。POI的病因主要是性染色体及常染色体基因缺陷、自身免疫功能紊乱、感染或医源性因素等均可导致POI发生。然而，接近50％的POI病因不明确。供卵是目前最有效的治疗，但是患者无法获得带有自己遗传基因的后代。
现有一些体外激活POI患者休眠卵泡的助孕方法，如：原始卵泡体外激活(IVA)后自体移植、卵巢注射富含血小板的血浆(PRP)或干细胞、卵巢移植或线粒体替代疗法等，费用昂贵且治疗效果不确定。目前，国内外尚无体内激活休眠卵泡的研究报道。
发明内容
为了解决上述问题，本发明提供了人绒毛膜促性腺激素在制备早发性卵巢功能不全患者的助孕药物中的应用。本发明利用人绒毛膜促性腺激素制备的药物，可通过体内激活休眠卵泡，从而使POI患者获得带有自己遗传基因的后代，且具有经济、方便、无痛苦的优势。
为了实现上述目的，本发明提供如下技术方案：
本发明提供了人绒毛膜促性腺激素在制备早发性卵巢功能不全患者的助孕药物中的应用。
本发明还提供了一种早发性卵巢功能不全患者的助孕药物，所述药物包括独立包装的人绒毛膜促性腺激素。
优选的，所述药物还包括独立包装的雌激素制剂和孕激素制剂。
优选的，所述雌激素制剂包括戊酸雌二醇制剂；
所述孕激素制剂包括醋酸甲羟孕酮制剂。
优选的，所述戊酸雌二醇制剂包括补佳乐。
优选的，所述醋酸甲羟孕酮制剂包括安宫黄体酮片。
有益效果：
本发明提供了人绒毛膜促性腺激素在制备早发性卵巢功能不全患者的助孕药物中的应用。本发明利用人绒毛膜促性腺激素制备的药物，通过雌激素和/或孕激素将患者的FSH降到＜15mIU/ml，LH降到＜10mIU/ml，再一次性给患者肌肉注射HCG 10000U，可通过体内激活休眠卵泡，从而使POI患者获得带有自己遗传基因的后代，且具有经济、方便、无痛苦的优势。
附图说明
图1为实施例2中取卵后胚胎培养的阶段图，其中A为D1胚胎，B为D2胚胎，C为D3胚胎；
图2为实施例2中D5囊胚图
图3为实施例2中出生三天后的男婴图；
图4为实施例3中取卵后胚胎培养的阶段图，其中A为D1胚胎，B为D2胚胎，C为D3胚胎；
图5为实施例3中D5囊胚图；
图6为移植后28天，B超提示的宫内单活胎图。
具体实施方式
本发明提供了人绒毛膜促性腺激素在制备早发性卵巢功能不全患者的助孕药物中的应用。
本发明还提供了一种早发性卵巢功能不全患者的助孕药物，所述药物包括独立包装的人绒毛膜促性腺激素。
在本发明中，所述药物优选还包括独立包装的雌激素制剂和孕激素制剂；所述雌激素制剂优选包括戊酸雌二醇制剂；所述戊酸雌二醇制剂优选包括补佳乐；所述孕激素制剂优选包括醋酸甲羟孕酮制剂；所述醋酸甲羟孕酮制剂优选包括安宫黄体酮片。本发明对所述雌激素和孕激素的来源没有特殊要求，采用本领域技术人员所熟知的市售商品即可。
本发明利用人绒毛膜促性腺激素制备的药物，通过雌激素和孕激素将患者的FSH降到＜15mIU/ml，LH降到＜10mIU/ml，再一次性给患者肌肉注射HCG 10000U，通过注射适宜的HCG后可以增加卵泡的募集，并促进FSH诱导芳香化酶活性的提高，从而使血清中雌二醇(E2)总水平增加，进一步促进卵泡数量的募集和小卵泡的发育成熟；另外，注射适宜的HCG，可以使HCG与壁层颗粒细胞中的LH受体(LHR)结合快速诱导类表皮生长因子(EGF)表达，通过自分泌和旁分泌作用激活颗粒细胞与卵丘细胞中EGF受体(EGFR)，进而激活促进细胞增殖和分化的关键因子-丝裂原活化蛋白激酶(MAPK)，刺激颗粒细胞增殖、诱导卵丘扩张和卵母细胞成熟；同时注射适宜的HCG后可以使促黄体生成素(LH)激增，高LH增加卵源性生长因子GDF-9和骨形态发生蛋白15(BMP-15)分泌，进一步促进卵丘扩张和卵母细胞成熟；另外，激增的GDF-9还可显著增强FSH诱导的窦前卵泡体外生长，通过上述调控从而激活体内休眠卵泡(停滞于次级卵泡到成熟卵泡阶段的休眠卵泡)，进而使POI患者获得带有自己遗传基因的后代，且具有经济、方便、无痛苦的优势。
本发明优选还提供了一种早发性卵巢功能不全患者的助孕方法，包括：
通过雌激素和孕激素将患者的FSH降到＜15mIU/ml，LH降到＜10mIU/ml，再一次性给入患者人绒毛膜促性腺激素10000U。
在本发明中，所述给入的方式优选包括肌肉注射。本发明对所述注射的方式没有特殊要求，采用本领域技术人员所熟知的注射方式即可。
为了进一步说明本发明，下面结合实施例对本发明提供的人绒毛膜促性腺激素在制备早发性卵巢功能不全患者的助孕药物中的应用进行详细地描述，但不能将它们理解为对本发明保护范围的限定。
实施例1
一种早发性卵巢功能不全患者的助孕药物，所述药物由以下独立包装的制剂组成：补佳乐、安宫黄体酮片和人绒毛膜促性腺激素。
实施例2
付某，31岁，0-0-0-0，不避孕未孕1年。自23岁开始出现稀发月经，月经周期40～180天，同时伴有潮热、失眠、性交困难等症状，一直间断激素替代治疗维持正常月经。2017年4月20日外院内分泌检测：FSH 95.65mIU/ml，E212 pg/ml，LH 29.75mIU/ml。2018年3月结婚后开始备孕，每月口服芬吗通维持月经，每周或每两周B超监测卵泡，连续1年B超均提示双卵巢萎缩无卵泡。
2019年6月11日初诊。初诊当日B超：子宫大小38*42*40mm，肌层回声均匀；左卵巢12*7mm，卵巢实性，未见卵泡；右卵巢12*9mm，卵巢实性，未见卵泡。FSH 32.2mIU/ml，E250pg/ml，LH 21.91mIU/ml；AMH：＜0.01ng/ml；女方染色体核型46，XX。
治疗过程：雌激素+孕激素(每天早晚两次口服补佳乐，每次2mg+每天一次口服8mg安宫黄体酮)治疗3个月，B超监测双卵巢未发现卵泡。当患者FSH12.69mIU/ml，E297 pg/ml，LH 6.89mIU/ml时，一次性给予HCG 10000U，继续接受上述雌激素+孕激素的治疗方案，并每周一次B超监测卵泡。HCG处理后第43天，左卵巢发现1枚18.5mm的卵泡(当日激素:E2261pg/ml，FSH 4.36mIU/ml，LH 4.44mIU/ml)，立即注射曲谱瑞林0.2mg+HCG 5000U扳机，隔天取得1枚成熟卵子，培养获得1枚优胚(8CI)(图1中的C)，行冷冻保存。取卵后继续接受上述雌激素+孕激素的治疗方案，观察44天后未发现双卵巢卵泡。随后患者又注射了1次HCG10000U，但是连续观察7个月未发现卵泡。患者随后进行冻融胚胎移植助孕，并要求将胚胎解冻后继续养囊，培养2天后得到3BB囊胚1枚(图2)，移植后妊娠。2021年4月21日足月剖宫产一健康男婴(3.65kg)(出生三天后的男婴见图3)。
实施例3
卢某，31岁，1-0-0-1，不避孕未孕7年。患者7年前与现夫顺产1孩，此后未避孕一直未孕。26岁时出现月经周期提前，近2年月经周期紊乱，需要黄体酮撤退出血，1年前开始出现潮热、失眠症状，间断服用芬吗通维持月经。连续1年B超监测未见窦卵泡。2019年4月bFSH32.26mIU/ml；2019年7月bFSH 52.67mIU/ml；2020年4月FSH 64.83mIU/ml、AMH 0.01ng/ml。
2020年5月15日初诊。初诊当日B超提示双侧卵巢萎缩(Lov 12*9；Rov 12*10)，回声偏实，双卵巢无卵泡。染色体核型46，XX。FSH 36.36mIU/ml，E2105 pg/ml，LH 22.23mIU/ml。
治疗过程：雌激素+孕激素(每天早晚两次口服补佳乐，每次2mg+每天一次口服8mg安宫黄体酮)治疗3个月，B超监测双卵巢未发现卵泡。当患者FSH 13.60mIU/ml，E295 pg/ml，LH 7.33mIU/ml时，一次性给予HCG 10000U，继续接受上述雌激素+孕激素的治疗方案，并每周一次B超监测卵泡。HCG处理后第76天，左卵巢发现1枚9.5mm的卵泡(当日激素:E2107.4 pg/ml，FSH 12.98mIU/ml，LH 6.91mIU/ml)，间隔2天卵泡发育到13.5mm(当日激素:E2128.64pg/ml，FSH 9.11mIU/ml，LH 6.19mIU/ml)，间隔2天卵泡发育到15.5mm(当日激素:E2169.58 pg/ml，FSH 8.43mIU/ml，LH 5.98mIU/ml)，次日卵泡发育到17.5mm(当日激素:E2191 pg/ml，FSH 7.82mIU/ml，LH 6.27mIU/ml)，次日卵泡发育到19.0mm(当日激素:E2219pg/ml，FSH 6.32mIU/ml，LH 5.79mIU/ml)，立即注射曲谱瑞林0.2mg+HCG 5000U扳机，隔天取得1枚成熟卵子，培养获得1枚优胚(8CI)(图4中的C)，行冷冻保存。取卵后继续接受接受上述雌激素+孕激素的治疗方案，观察5个月后未发现双卵巢卵泡。患者随后进行冻融胚胎移植助孕，并要求将胚胎解冻后继续养囊，培养2天后得到3BB囊胚1枚(图5)，移植后第11天血HCG 220mIU/ml，第14天血HCG 820mIU/ml，E2437.5pg/ml，P 20.82ng/ml。移植后28天，B超提示宫内单活胎(图6)。
综上所述，本发明利用人绒毛膜促性腺激素制备的药物，可通过体内激活休眠卵泡，从而使POI患者获得带有自己遗传基因的后代，且具有经济、方便、无痛苦的优势。
虽然本发明已以较佳的实施例公开如上，但其并非用以限定本发明，任何熟悉此技术的人，在不脱离本发明的精神和范围内，都可以做各种改动和修饰，因此本发明的保护范围应该以权利要求书所界定的为准。
Claims (6)
1.人绒毛膜促性腺激素在制备早发性卵巢功能不全患者的助孕药物中的应用。
2.一种早发性卵巢功能不全患者的助孕药物，其特征在于，所述药物包括独立包装的人绒毛膜促性腺激素。
3.根据权利要求2所述的药物，其特征在于，所述药物还包括独立包装的雌激素制剂和孕激素制剂。
4.根据权利要求3所述的药物，其特征在于，所述雌激素制剂包括戊酸雌二醇制剂；
所述孕激素制剂包括醋酸甲羟孕酮制剂。
5.根据权利要求4所述的药物，其特征在于，所述戊酸雌二醇制剂包括补佳乐。
6.根据权利要求4所述的药物，其特征在于，所述醋酸甲羟孕酮制剂包括安宫黄体酮片。
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