药学学报

Main component	Pharmacological effect	Ref.
Estrone	Reversible conversion to estradiol; promotes uterine development and alleviates perimenopausal syndrome	[20]
Equilin	Prevents Alzheimer's disease and promotes cortical neuron growth	[21]
17α-Dihydro equilin	Avoids first-pass effect of CE; anti-atherosclerotic	[22]
17α-Estradiol	Weak estrogenic activity; anti-aging; alleviates perimenopausal syndrome	[23]
△^{8, 9}Dehydro estrone	Treats vasomotor symptoms, maintains bone mass; effectively protects neurons	[24, 25]
Equilenin	Treats vasomotor symptoms and maintains bone mass	[26]
17β-Dihydro equilin	Treats vasomotor symptoms	[27]
17α-Dihydro equilenin	Prevents atherosclerosis	[26]
17β-Estradiol	Aalleviates perimenopausal syndrome, maintains bone mass; prevents Alzheimer's disease	[28]
17β-Dihydro equilenin	Cardiovascular protective effects	[29]

Main component	Pharmacological effect	Ref.
Estrone	Reversible conversion to estradiol; promotes uterine development and alleviates perimenopausal syndrome	[20]
Equilin	Prevents Alzheimer's disease and promotes cortical neuron growth	[21]
17α-Dihydro equilin	Avoids first-pass effect of CE; anti-atherosclerotic	[22]
17α-Estradiol	Weak estrogenic activity; anti-aging; alleviates perimenopausal syndrome	[23]
△^{8, 9}Dehydro estrone	Treats vasomotor symptoms, maintains bone mass; effectively protects neurons	[24, 25]
Equilenin	Treats vasomotor symptoms and maintains bone mass	[26]
17β-Dihydro equilin	Treats vasomotor symptoms	[27]
17α-Dihydro equilenin	Prevents atherosclerosis	[26]
17β-Estradiol	Aalleviates perimenopausal syndrome, maintains bone mass; prevents Alzheimer's disease	[28]
17β-Dihydro equilenin	Cardiovascular protective effects	[29]

Dosage form	Product name	Main formulation	Source	Specification	Route of administration	Advantage	Disadvantage	Indication	Manufacturer	Ref.
Tablet	Premarin	CE, calcium phosphate, calcium sulfate, etc.	Pregnant mare urine	0.3 mg·g^-1 0.625 mg·g^-1	Oral	Convenient to use	May cause gastrointestinal discomfort, first-pass effect, low bioavailability	Long-term treatment of systemic symptoms	Pfizer	[18]
	Honglilai	CE, calcium phosphate, calcium sulfate, etc.	Pregnant mare urine	0.3 mg·g^-1 0.625 mg·g^-1					Xinjiang Xinzhiyuan Biopharmaceutical Co., Ltd.	[35]
	Cenestin	CE-A, ethyl cellulose, hypromellose, etc.	Soybean, yam, etc.	Discontinued					Pfizer	[30]
	Enjuvia	CE-B, silica, hypromellose, etc.	Synthetic	Discontinued					Teva Pharmaceutical Industries Ltd.	[33]
Creams	Premarin	CE, cetearyl alcohol, cetyl esters, etc.	Pregnant mare urine	14 g/tube 0.625 mg·g^-1	Vaginal	Local action, avoids first-pass effect	Inconvenient application, requires frequent use	Treatment of local symptoms	Pfizer	[38]
	Honglilai	CE, stearic acid, cetyl alcohol, etc.	Pregnant mare urine	14 g/tube 0.625 mg·g^-1					Xinjiang Xinzhiyuan Biopharmaceutical Co., Ltd.	[37]
Injection	Premarin	CE, lactose, sodium citrate, dimethicone, etc.	Pregnant mare urine	25 mg/vial	Intravenous or intramuscular	Rapid onset, precise dosing	Requires medical personnel for administration	Treatment of abnormal uterine bleeding due to hormonal imbalance	Pfizer	[39]
Soft capsule	/	CE, gelatin, glycerin, water, etc.	Pregnant mare urine	/	Vaginal	Accurate local dosing	Issues with patient compliance and drug stability	Treatment of local symptoms	/	[40]
Liposomal thermosensitive gel	/	CE, soybean phospholipid, cholesterol, etc.	Pregnant mare urine	/	Vaginal	Good biocompatibility, avoids first-pass effect	release Characteristics may be affected by body Temperature and pH changes	Treatment of local symptoms	/	[45]

Dosage form	Product name	Main formulation	Source	Specification	Route of administration	Advantage	Disadvantage	Indication	Manufacturer	Ref.
Tablet	Premarin	CE, calcium phosphate, calcium sulfate, etc.	Pregnant mare urine	0.3 mg·g^-1 0.625 mg·g^-1	Oral	Convenient to use	May cause gastrointestinal discomfort, first-pass effect, low bioavailability	Long-term treatment of systemic symptoms	Pfizer	[18]
	Honglilai	CE, calcium phosphate, calcium sulfate, etc.	Pregnant mare urine	0.3 mg·g^-1 0.625 mg·g^-1					Xinjiang Xinzhiyuan Biopharmaceutical Co., Ltd.	[35]
	Cenestin	CE-A, ethyl cellulose, hypromellose, etc.	Soybean, yam, etc.	Discontinued					Pfizer	[30]
	Enjuvia	CE-B, silica, hypromellose, etc.	Synthetic	Discontinued					Teva Pharmaceutical Industries Ltd.	[33]
Creams	Premarin	CE, cetearyl alcohol, cetyl esters, etc.	Pregnant mare urine	14 g/tube 0.625 mg·g^-1	Vaginal	Local action, avoids first-pass effect	Inconvenient application, requires frequent use	Treatment of local symptoms	Pfizer	[38]
	Honglilai	CE, stearic acid, cetyl alcohol, etc.	Pregnant mare urine	14 g/tube 0.625 mg·g^-1					Xinjiang Xinzhiyuan Biopharmaceutical Co., Ltd.	[37]
Injection	Premarin	CE, lactose, sodium citrate, dimethicone, etc.	Pregnant mare urine	25 mg/vial	Intravenous or intramuscular	Rapid onset, precise dosing	Requires medical personnel for administration	Treatment of abnormal uterine bleeding due to hormonal imbalance	Pfizer	[39]
Soft capsule	/	CE, gelatin, glycerin, water, etc.	Pregnant mare urine	/	Vaginal	Accurate local dosing	Issues with patient compliance and drug stability	Treatment of local symptoms	/	[40]
Liposomal thermosensitive gel	/	CE, soybean phospholipid, cholesterol, etc.	Pregnant mare urine	/	Vaginal	Good biocompatibility, avoids first-pass effect	release Characteristics may be affected by body Temperature and pH changes	Treatment of local symptoms	/	[45]

结合雌激素的剂型发展及临床应用现状

PDF下载

伍思怡 ¹^,² , 李佳奇 ³ , 董健 ¹^,² , 叶军 ⁴ , 宁美英 ¹^,^*

药学学报 | 综述 2025,60(4): 949-958

收起

药学学报 | 综述 2025, 60(4): 949-958

结合雌激素的剂型发展及临床应用现状

全屏

伍思怡¹^,², 李佳奇³, 董健¹^,², 叶军⁴, 宁美英¹^,^*

作者信息

¹ 国家卫生健康委科学技术研究所, 北京 100081

² 中国医学科学院、北京协和医学院, 北京 100073

³ 河南工业大学, 河南郑州 450001

⁴ 中国医学科学院、北京协和医学院药物研究所, 北京 100050

通讯作者:

宁美英，E-mail: mayning999@126.com

Current status of dosage forms and clinical use of conjugated estrogens

Si-yi WU¹^,², Jia-qi LI³, Jian DONG¹^,², Jun YE⁴, Mei-ying NING¹^,^*

Affiliations

¹National Research Institute for Family Planning, Beijing 100081, China

²Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100073, China

³Henan University of Technology, Zhengzhou 450001, China

⁴Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

出版时间: 2025-04-12 doi: 10.16438/j.0513-4870.2025-0015

文章导航

摘要

收起

结合雌激素(conjugated estrogens, CE) 广泛应用于绝经激素治疗, 能有效缓解绝经及其相关症状(如血管舒缩症状、神经精神症状、泌尿生殖道萎缩症状等), 且是预防绝经后骨质疏松症的有效方法。本文综述了CE的不同剂型(片剂、乳膏和注射剂) 的特点、药理作用及其在临床中的应用。CE片剂通过全身治疗作用有效调节体温中枢, 减轻潮热和盗汗, 促进骨形成, 增加骨密度; CE乳膏用于局部治疗, 改善更年期泌尿生殖系统综合征; CE注射剂用于治疗无器官病理的因激素失衡而引起的异常子宫出血, 但仅适合短期使用, 可以快速而暂时地增加雌激素水平。此外, CE在代谢方面具有重要作用, 能够提高胰岛素的清除率和敏感性, 并对神经系统和心血管系统有潜在的保护作用, 显示出广泛的治疗潜力。本文通过探讨CE的制剂和应用, 为药物剂型的设计和开发提供新思路。

关键词

结合雌激素 / 激素替代疗法 / 剂型 / 更年期综合征 / 泌尿生殖系统综合征

Abstract

收起

Conjugated estrogens (CE) are widely used in menopausal hormone therapy (MHT) for the relief of menopause-related symptoms (e.g., vasodilatory symptoms, neuropsychiatric symptoms, genitourinary atrophy symptoms, etc.) and the prevention of postmenopausal osteoporosis. This article reviews the characteristics, pharmacological effects, and practical applications of different dosage forms of CE (tablets, creams, and injections) in clinical practice. It has been shown that tablet CE effectively regulates the body's temperature center through systemic treatment, reduces hot flashes and night sweats, promotes bone formation, and increases bone density. Cream CE is used for local treatment to improve the genitourinary syndrome of menopause (GSM). Injectable CE is used for the treatment of abnormal uterine bleeding caused by hormonal imbalance without organ pathology. CE administered intravenously is indicated only for short-term use to rapidly and temporarily increase estrogen levels. Additionally, CE plays an important role in metabolism by improving insulin clearance and sensitivity and potentially protecting the nervous and cardiovascular systems, demonstrating a wide range of therapeutic potential. This paper provides new ideas for the design and development of drug dosage forms by exploring the formulation and application of CE.

Key words

conjugated estrogen / hormone replacement therapy / dosage form / menopausal syndrome / genitourinary syndrome of menopause

引用本文

伍思怡, 李佳奇, 董健, 叶军, 宁美英. 结合雌激素的剂型发展及临床应用现状. 药学学报, 2025 , 60 (4) : 949 -958 . DOI: 10.16438/j.0513-4870.2025-0015

Si-yi WU, Jia-qi LI, Jian DONG, Jun YE, Mei-ying NING. Current status of dosage forms and clinical use of conjugated estrogens[J]. Acta Pharmaceutica Sinica, 2025 , 60 (4) : 949 -958 . DOI: 10.16438/j.0513-4870.2025-0015

正文

收起

女性在绝经后面临多年的雌激素缺乏症状, 结合雌激素(conjugated estrogens, CE) 作为绝经激素治疗(menopausal hormone therapy, MHT) 的药物之一, 主要用于缓解潮热、夜汗、阴道干燥和性欲下降等症状^[1-3]。国内外近几十年来不断研讨和实践后, MHT已日趋成熟。目前的证据表明, MHT是唯一能够一揽子解决由于绝经后雌激素缺乏所带来的各种相关问题的方案, MHT的本质就是弥补增龄引起的卵巢功能衰竭而采取的一项治疗措施^[4]。在医生指导下应用MHT既可以缓解绝经相关症状, 也能在一定程度上延缓或避免中老年慢性代谢性疾病的发生, 改善和提高中老年女性的生命质量。CE的发现和应用是医学史上的重要里程碑。CE治疗始于19世纪末, 当时研究表明牛卵巢组织注射能有效逆转绝经期症状^[5]。第一种激素替代疗法产品Emmenin于1933年在Ayerst公司生产并销售, progynon也是倍美力(Premarin) 的前身, 它们都含有与倍美力相似的多组分结合雌激素, 但由于为人类来源, 生产成本高昂, 1941年被倍美力取代^{[6, 7]}。

CE的作用机制复杂, 主要通过与特定的雌激素受体(estrogen receptors, ERs) 结合来实现其广泛的生理和病理调节作用^[8-14]。这些受体包括核受体雌激素受体α (estrogen receptor α, ERα) 和雌激素受体β (estrogen receptor β, ERβ), 以及膜受体G蛋白偶联雌激素受体1 (G protein-coupled estrogen receptor 1, GPER1), 它们在女性生理病理过程中扮演着关键角色, 在癌症、心血管疾病、骨质疏松症、神经退行性疾病、肝损伤和肺癌等常见疾病中起调节作用。CE主要用于缓解绝经后女性的症状, 如潮热、夜汗、阴道干燥和性欲下降等。近年来CE在治疗骨质疏松症、心血管疾病、和神经系统疾病方面也显示出潜力^[15-17]。本文旨在总结CE的制剂与应用, 随着对CE的深入研究, 助力未来研发出更多创新的剂型以及更多维的临床应用场景, 为女性提供更安全、更有效的治疗选择。

1 CE的剂型

收起

目前CE的递送形式有口服给药、经阴道给药、静脉或肌肉注射(图 1)。

1.1 片剂

片剂是一种固体剂型, 由药物成分与适宜的辅料混合后, 通过压制工艺制成圆形或其他形状的片状制剂。CE的片剂因其良好的水溶性, 口服后能有效通过胃肠道吸收。1942年FDA批准了CE制剂倍美力的上市, 成为MHT的先驱^[18]。2009年国内新疆新姿源生物制药有限公司成功从孕马尿中提取CE, 孕马尿中提取的天然CE由多种雌激素组成, 多达230种化合物, 主要成分包括雌酮硫酸钠和马烯雌酮硫酸钠等, 还可能含有少量具有性激素活性的甾体类激素^[19], 这些成分共同赋予了CE独特的治疗潜力, 不同成分的主要药理作用如表 1所示^[20-29]。

除天然CE外, 1999年FDA批准的新型植物性雌激素——结合雌激素A (synthetic conjugate estrogens A, SCE-A) 片剂Cenestin上市(目前已停产), 用于治疗与绝经相关的血管舒缩症状和外阴及阴道萎缩症状。另外, 2004年结合雌激素B (synthetic conjugate estrogens B, SCE-B) 片剂Enjuvua被批准上市, 目前已停产, 用于治疗更年期症状, 如潮热、阴道干燥、灼热和刺激, 其他用途包括预防绝经后妇女的骨质疏松症, 以及在卵巢功能衰竭或其他导致体内缺乏天然雌激素的疾病中替代雌激素^[30-32]。Cenestin由9种不同的植物雌激素组成, 为山药、大豆等植物提取并修饰; Enjuvia片剂的主要成分有10种, 为化学合成的混合药物, 其中9种成分与Cenestin相同, 另外添加了Δ^{8, 9}-脱氢硫酸雌酮^{[33, 34]} (图 2)。

目前市场上主要使用两种天然孕马尿来源的CE片剂: 倍美力和红丽来, 在临床上用于预防和治疗由雌激素缺乏引起的更年期症状, 以及绝经后妇女的骨质疏松症、冠心病, 并可能有助于预防阿尔茨海默症。倍美力采用羟丙甲纤维素凝胶骨架技术, 实现了药物的缓释效果。红丽来则采用湿法制粒压制片芯, 并外加控释膜, 达到与倍美力相似的体外释放特性, 膜控缓释技术在制备工艺上更为复杂, 对生产条件有更高要求。Li等^[35]评估了国产仿制药红丽来与原研药倍美力释放曲线, 结果表明具有高度相似性。此外, 一种新的粉末直接压片法^[36]已被开发用于CE片剂的生产, 此方法在稳定性和可靠性方面展现出优势, 并具有工业化生产的潜力。然而, CE片剂在给药过程中的首过效应可能降低药物的生物利用度, 并可能引起恶心、呕吐、乳房触痛、腹痛等不良反应。此外, 与其他药物的相互作用可能影响CE片剂的疗效。因此，在临床应用中需要严格的药物监测, 并根据患者的具体情况制定个体化的治疗计划, 避免影响疗效或增加不良反应的风险。

1.2 乳膏

CE乳膏剂是半固体制剂, 由药物成分在乳状基质中均匀分散或溶解而成。该基质是水相和油相在乳化剂作用下形成的混合物, 能在黏膜表面形成保护层, 发挥屏障作用。目前市场上的CE乳膏也主要是红丽来和倍美力, 均采用阴道给药的方式。红丽来乳膏的pH值设定为5, 其辅料包括硬脂酸、十六醇等, 旨在提供稳定的乳膏形态和适宜阴道健康的pH环境。而倍美力的基质则是鲸蜡酯蜡、鲸蜡醇等成分^[37]。

Yang等^[38]报道在中国开展的为期3周的多中心、随机对照试验中, 480名绝经后妇女被随机分配接受红丽来或倍美力阴道乳膏治疗, 研究主要疗效指标是阴道细胞成熟指数(vaginal maturation index, VMI)、阴道症状评分和阴道健康评分。结果显示, 阴道症状评分两组间无显著差异, 红丽来组的不良事件发生率较低, 在50~59岁年龄组中, 红丽来组的VMI低于倍美力组; 在60岁以上女性中, 两种乳膏在治疗绝经期泌尿生殖综合征(genitourinary syndrome of menopause, GSM) 方面具有可比的疗效。CE乳膏的阴道给药方式, 不仅能有效缓解外阴、阴道的局部症状和性功能, 还避免了口服给药可能引起的肝脏首过效应及其他不良反应, 提高治疗的针对性和依从性。CE乳膏的剂型开发应继续关注提高疗效和安全性, 同时探索新的药物载体和给药技术, 以进一步提高患者的生活质量。可以研究乳膏的新型缓释系统, 以实现更持久的治疗效果和更好的患者体验; 同时, 深入研究乳膏剂中活性成分的释放动力学和组织渗透性, 将有助于优化药物的剂量和给药频率。

1.3 注射剂

注射剂是一种将药物成分与适宜溶剂或分散介质混合后制成的无菌制剂。市售的倍美力注射剂, 每瓶含有25 mg的CE, 以冷冻干燥粉饼形式存在。辅料处方包括乳糖、枸橼酸钠和二甲基硅油。使用前, 需调节pH值至7.3, 以确保药物的稳定性和生物相容性。临床上, 该注射剂通过静脉或肌肉注射, 用于治疗无器官病理的因激素失衡而引起的异常子宫出血^[39]。CE注射仅适合短期使用进而快速且短暂地增加雌激素水平, 优点在于药效迅速、剂量精确, 避免了肝脏的首过效应, 减少了药物在吸收过程中的损失, 提高了生物利用度。另外, CE注射剂适应症范围窄, 只能用于功能性子宫出血, 且不能长期应用, 因此在临床治疗中具有很大的局限性。

未来的研究方向可以包括对CE注射剂的配方优化, 以减少不良反应并提高患者接受度。例如, 使用生物可降解的载体材料, 或者开发长效制剂以减少注射频率、拓展适应症。考虑到患者对治疗便利性的需求, 研究者可以探索新型给药系统, 如皮下植入剂或微针技术, 这些给药系统可能提供更为便捷的雌激素替代治疗方案。

1.4 阴道软胶囊剂

尽管目前市场上尚无CE阴道软胶囊剂获批上市, 但相关研究已日趋成熟。Zhao等^[40-42]对此类剂型进行了深入研究, 旨在解决由雌激素不足引起的GSM相关症状。研究团队采用单因素实验和正交实验方法, 确定最佳配方, 还关注了胶囊内容物的稳定性和流动性, 确保其适合工业生产。通过小鼠和家兔动物实验进一步评估了阴道给药后的安全性和局部耐受性, 证实CE阴道软胶囊无局部毒性, 对月经周期和出血风险无明显影响, 全身反应优于口服给药。确立的质量标准与参比制剂对比, 验证了质量控制方法的准确性和可靠性, 为新型阴道软胶囊的开发提供了坚实的基础^[43]。

CE阴道软胶囊剂的研究展示了一种新兴的局部雌激素替代疗法, 为绝经后妇女提供了一种潜在的新治疗选择。与传统口服或注射给药方式相比, 阴道软胶囊剂提供了一种更为便捷的局部靶向治疗方案, 有望减少全身性不良反应, 提高患者的依从性和治疗满意度。

1.5 脂质体温敏凝胶

脂质体温敏凝胶融合了脂质体与温敏材料的优势。通常, 脂质体温敏凝胶由低温到高温会从固态或半固态转变为液态^[44], 而Wang等^[45]采用逆向蒸发法和冷溶法制备的CE脂质体温敏凝胶可以实现在给药前保持液态, 而在体温环境下, 其迅速转变为半固态或固态, 进而与阴道黏膜紧密结合。药效学研究以卵巢切除大鼠为模型, 证实该凝胶在体温下能够快速相变, 显著延长药物在阴道内的滞留时间^[46]。CE脂质体温敏凝胶对卵巢切除大鼠的阴道黏膜具有增厚效果, 血清雌二醇水平得到提高, 同时对子宫影响不显著。药效结果证实了CE脂质体温敏凝胶潜在的治疗效果和良好的使用安全性, 这些研究为开发新型阴道给药系统提供了理论和实验支持。脂质体温敏凝胶可以实现小剂量给药的长时程作用, 减少药物漏出, 提高了患者舒适性的同时可以减少给药剂量, 减少全身暴露引起的不良反应。随着材料科学和纳米技术的发展, 未来的研究可以进一步改进凝胶体系的物理化学特性, 如增强其黏附性、稳定性和响应性, 以实现更为精准的药物递送。同时, 智能响应性材料的开发, 如pH或酶敏感的凝胶, 可能为女性生殖健康相关疾病的治疗提供更为先进的解决方案。

2 CE的临床应用

收起

CE在临床上广泛应用于治疗绝经相关疾病, 如图 3所示。CE通过调节体温中枢, 减轻潮热和盗汗等更年期症状, 同时促进骨形成和抑制骨吸收, 增加骨密度, 降低骨折风险。CE还能够改善GSM, 通过局部作用于泌尿生殖道, 缓解阴道干涩和尿路感染等症状。此外, 有研究表明CE在代谢方面也有重要作用, 能够调节血脂和血糖水平, 可能有助于降低心血管疾病和糖尿病的风险。CE除了单独使用外, 与一些别的药物如巴多昔芬(bazedoxifene, BZA)、甲硝唑、孕酮等联合使用在某些症状下能产生更好的治疗效果和更小的不良反应^[47]。

2.1 血管舒缩症状

口服CE以及口服和透皮17β-雌二醇是减少更年期潮热最常用的雌激素制剂。雌激素-孕激素疗法(estrogen-progestin therapy, EPT) 是一种传统方法, 用于缓解有子宫功能的女性更年期引起的血管舒缩症状, 如潮热和盗汗。然而, EPT可能存在安全性和耐受性问题, 如乳房刺激和不规则阴道出血^[13]。作为EPT的替代方案, 组织选择性雌激素复合物(tissue-selective estrogen complexes, TSEC), 例如BZA和CE的组合, 提供了一种新的治疗方式。CE/BZA已于2013年10月3日获得美国食品和药物管理局批准第一个完成临床开发的TSEC药物。辉瑞公司通过一系列Ⅲ期临床试验验证了BZA/CE的疗效和安全性^[48], 结果显示, CE/BZA在缓解潮热、阴道萎缩等更年期症状以及提高骨密度方面, 与EPT同样有效, 且具有更好的安全性和耐受性, 不刺激子宫内膜和乳腺组织, 为绝经后妇女提供了一种安全有效的治疗选择。CE在缓解更年期血管舒缩症状方面表现出显著的疗效, 尤其是在使用TSEC时, 进一步提升了治疗的安全性和耐受性。基于TSEC可以开发更多的雌激素复合治疗药物方案, 扩大治疗选择的范围。

2.2 骨质疏松症的预防与治疗

雌激素能够减少抑制成骨细胞功能的细胞因子TNF-α的产生, 此外, TNF-α和IL-6均能刺激破骨细胞的生成。绝经后雌激素水平降低会增加破骨细胞活性, 最终导致骨质疏松症^[49]。CE常用于治疗绝经后妇女骨质疏松症, 通过增加骨密度降低骨折风险^[50]。然而, 单独使用雌激素可能增加子宫内膜癌和乳腺癌的风险。BZA作为一种选择性雌激素受体调节剂, 在某些组织中发挥类似雌激素的作用, 而在其他组织中则具有抗雌激素的效应。研究表明, CE/BZA组合能够显著增加腰椎和髋部的骨密度^[51], 并对子宫内膜和乳腺组织无刺激性。同时CE/BZA方案显著提高骨密度, 减少椎骨骨折风险以及改善绝经症状^[52]。此外, CE/BZA组合在治疗绝经后手部骨关节炎患者具有良好的前景, 虽然仍需更多长期研究和临床数据以确定其安全性和效果。Lane等^[53]研究SCE-A对去卵巢大鼠骨小梁结构和强度的影响, 证实低剂量和高剂量的SCE-A均能维持雌激素缺乏时胫骨近端的骨小梁骨量和结构。50名早期绝经后妇女中进行的双盲、安慰剂对照研究^[54], 结果显示, SCE-A治疗组骨形成标志物的下降延迟, SCE-A显着减少了骨吸收, 被证明可有效预防绝经后骨质流失。性类固醇主要通过减少破骨细胞骨吸收从而抑制骨重塑的速度, 并维持吸收和形成之间的平衡。女性雌激素的突然下降会导致骨重塑率的短暂增加, 并加速松质骨量的年龄依赖性下降^{[55, 56]}。基于雌激素缺乏在女性骨质疏松症的发展中起着重要作用, CE在更年期女性骨质疏松方面的效用有很大的应用潜力。

2.3 泌尿生殖系统问题

绝经后女性雌激素水平下降, 导致阴道壁萎缩和黏膜变薄, 增加阴道感染的风险。CE软膏通过维持局部药物的高浓度改善阴道环境, 可以恢复阴道中乳酸菌优势, 增加阴道上皮细胞成熟度, 减轻阴道干涩和瘙痒, 从而恢复阴道健康^[57-59]。CE阴道给药对改善GSM症状具有显著疗效和良好安全性。还有报道表明阴道补充CE有助于减轻阴道脱垂修复术后萎缩相关症状^[60]。研究表明, 联合使用CE和甲硝唑阴道凝胶^[61]或者甲硝唑栓^[62]治疗老年性阴道炎, 疗效显著高于单一治疗。局部治疗方法为GSM问题提供了一种非侵入性的治疗选择, 尤其适合那些对全身荷尔蒙治疗存在顾虑的患者。此外, CE与其他药物的联合使用策略能够针对不同的病理机制, 提高治疗效果, 减少可能的不良反应。通过不断的创新和研究, 有望为这些患者提供更为安全、有效、个性化的治疗选择, 改善她们的生活质量。

2.4 代谢影响

CE对绝经后妇女的代谢影响是多方面的, 其通过不同机制发挥作用的证据提示了其在代谢性疾病预防和治疗中的潜在应用价值。葡萄糖稳态受ERα和ERβ调节, 雌激素是葡萄糖稳态的重要调节因子, 有充分的报道观察到雌激素诱导的PKB (protein kinase B) 和AMP活化蛋白激酶(adenosine 5′-monophosphate-activated protein kinase, AMPK) 激活与促进p38 MAPK的磷酸化等^{[63, 64]}, 静脉注射CE能显著提高胰岛素的清除率和作用^[65], 表现为血清胰岛素水平降低和葡萄糖清除率提高。此外, CE/BZA口服复方制剂对肥胖绝经后妇女的胰岛素敏感性、能量代谢和血清代谢组有积极影响^[66]。CE/BZA增加了高密度脂蛋白胆固醇水平^[67], 并对胰岛β细胞功能和胰岛素分泌产生有益影响^[68], 对胰岛素敏感性无显著改善, 可能对绝经后妇女的代谢健康和糖尿病风险具有积极影响。考虑到肥胖和代谢综合征在绝经后妇女中的高发性, 未来的研究应进一步探索CE在代谢调节中的作用机制, 特别是其对胰岛素信号通路、脂肪代谢和能量平衡的具体影响, 为绝经后妇女的健康管理提供新的视角。

2.5 其他健康效应

CE在其他健康效应方面也显示出复杂影响。有研究数据表明, CE和微粉化黄体酮联用能够显著改善更年期失眠症状^[69]。CE/BZA组合可能为子宫内膜异位症提供一种有效替代治疗方案^[70]。有一些研究报道了CE的心脏保护特性, 可能来源于对低密度脂蛋白的抗氧化作用^{[71, 72]}。此外, CE可能影响血液丢失和凝血过程, 减少心脏手术后的失血量^[73]。CE对神经系统有一定保护作用, ERα和ERβ有助于神经保护并增加原代海马神经元中的Bcl-2表达^{[74, 75]}。CE减少脊髓损伤后的神经变性^[76], 并且具有抗阿尔茨海默症等神经退行性疾病中的潜在获益^{[74, 77-79]}。雌激素影响许多免疫和炎症状况, 包括自身免疫性疾病, 调节的免疫基因编码MHC I类和II类(RT1-Aw2、Cd74)、Fcγ受体(Fcgr2a、Fcgr2b) 和补体蛋白(C3、C4b)^[3]。近来还有报道在动物实验中, 雌激素治疗可以抑制炎症反应, 降低病毒滴度, 因此有报道其为一种理想的预防和治疗新冠病毒的方法^[80], CE的多方面健康效应突显了其在医学应用中的多样性和复杂性。

3 总结

收起

目前市场上的CE主要有片剂、乳膏和注射剂3种剂型, 各具特点并针对不同的治疗需求, 也有各团队致力于新剂型新适应症的研发(表 2)。口服片剂适用于长期激素替代疗法, 以缓解由绝经后雌激素缺乏引起的多种症状; 乳膏剂型则专注于局部治疗, 如阴道和外阴萎缩, 通过阴道给药减少全身性不良反应; 注射剂适用于异常子宫出血的急救。

市场上亦有其他雌激素递送方式, 如透皮贴剂、栓剂和阴道环等^[81]。2001年, 美国FDA批准了含乙炔雌二醇和甲基孕酮的Ortho Evra透皮贴剂。微针技术作为经皮给药系统的研究热点, 通过在皮肤上创造微米级通道, 实现大分子药物的无痛递送。此外, ovesterin等雌激素栓剂产品, 以及NuvaRing、Estring等阴道环, 为绝经后妇女提供了多样化的治疗选择。

以CE为代表药物的雌、孕激素用于绝经激素治疗, 其安全问题一直是医学研究的重点。在妇女健康倡议(Women's Health Initiative, WHI) 的随机对照试验中^[82], 对27 347名绝经后妇女进行了长达18年的跟踪研究, CE治疗与安慰剂相比, 在全因死亡率、心血管或癌症死亡率方面没有显著差异, 表明这种治疗在长期内对绝经后妇女的死亡率风险没有负面影响, 并且绝经后使用CE预防冠心病与MHT开始的年龄有关, 60岁之前是窗口期, 获益最大。WHI另一项长达20年的跟踪研究显示^[7], 单独使用CE能显著降低乳腺癌发病率, 停止使用CE后该影响仍持续超过10年。CE的疗效和安全性已得到广泛研究, TSECs如CE/BZA的开发, 标志着治疗方案向个体化和风险最小化方向发展, 旨在平衡疗效与安全性。Shi等^[83]进行了一项药代动力学研究, 发现在接受0.625毫克CE治疗的健康中国绝经后妇女中, 与北美妇女相比, 中国妇女体内的雌酮和赤霉素暴露量更高。未来的研究将继续优化雌激素替代疗法, 满足不同患者的特定需求, 确保更安全有效的治疗策略, 改善绝经后妇女的生活质量。

在安全性与疗效的双重考量下, CE需要在药物设计、制剂工艺和临床应用策略上进行综合优化。这包括对特殊患者群体(如肝功能不全患者) 的剂型调整, 以及对新剂型(如经皮给药系统) 的探索, 以实现对绝经后妇女更全面、更精准的治疗。

已上市的剂型和临床数据为CE新剂型的设计和评估提供了宝贵的参考, 包括疗效评估、安全性监测和患者选择标准。CE的剂型研发应继续探索新的药物递送系统, 以提高疗效、减少不良反应, 并满足不同患者的治疗偏好。期望未来CE新剂型能通过临床评估, 为绝经后妇女带来更安全、有效、便捷的治疗选择。随着个性化医疗的发展, 研究将更加关注患者的个体差异, 如基因多态性、生活习惯和疾病史, 以实现精准治疗。

此外, 随着生物技术的不断进步, 未来的CE剂型可能将结合智能递药系统, 如响应体内环境变化的可控释放技术, 进一步提高治疗的安全性和有效性。同时, 深入研究CE的分子机制和长期影响, 将有助于优化治疗方案, 实现对绝经后妇女症状的更好管理。

CE的临床应用前景广阔, CE的多效性强调了对其作用机制的深入研究的必要性, 以及在不同医学领域中探索其应用潜力的重要性。期待CE能够为多种疾病提供更有效、更安全的治疗选择, 从而提高患者的生活质量。未来的研究应聚焦于CE的分子机制、长期影响及个体化治疗方案的开发, 以实现精准医疗和最大化治疗效果, 为绝经后妇女的健康和福祉提供更有力的支持。

基金

收起

国家重点研发计划(2023YFC2706100)
国家自然科学基金资助项目(82304393)
国家卫生健康委科学技术研究所中央级公益性科研院所基本科研业务费专项资金(2022GJZ04)

参考文献

收起

文献

收起

参考文献引证文献

排序方式：

Menopause Subgroup, Chinese Society of Obstetrics and Gynecology. The 2023 Chinese menopause symptom management and menopausal hormone therapy guidelines [J]. Chin J Obstet Gynecol (中华妇产科杂志), 2023, 58: 4-21.

The NAMS 2020 GSM Position Statement Editorial Panel. The 2020 genitourinary syndrome of menopause position statement of The North American Menopause Society [J]. Menopause (New York, NY), 2020, 27: 976-992.

Nelson HD. Commonly used types of postmenopausal estrogen for treatment of hot flashes: scientific review [J]. JAMA, 2004, 291: 1610-1620.

D'Alonzo M, Bounous VE, Villa M, et al. Current evidence of the oncological benefit-risk profile of hormone replacement therapy [J]. Medicina (Kaunas), 2019, 55: 573.

Kopera H. The dawn of hormone replacement therapy [J]. Maturitas, 1991, 13: 187-188.

Kohn GE, Rodriguez KM, Hotaling J, et al. The history of estrogen therapy [J]. Sex Med Rev, 2019, 7: 416-421.

Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women's Health Initiative randomized clinical trials [J]. JAMA, 2020, 324: 369-380.

Chen P, Li B, Ou-Yang L. Role of estrogen receptors in health and disease [J]. Front Endocrinol (Lausanne), 2022, 13: 839005.

Li J, Yu J, Zou H, et al. Estrogen receptor-mediated health benefits of phytochemicals: a review [J]. Food Funct, 2023, 14: 10681-10699.

Shanle EK, Xu W. Selectively targeting estrogen receptors for cancer treatment [J]. Adv Drug Deliv Rev, 2010, 62: 1265-1276.

Deschamps AM, Murphy E, Sun J. Estrogen receptor activation and cardioprotection in ischemia reperfusion injury [J]. Trends Cardiovasc Med, 2010, 20: 73-78.

Barros RP, Machado UF, Gustafsson JA. Estrogen receptors: new players in diabetes mellitus [J]. Trends Mol Med, 2006, 12: 425-431.

Sárvári M, Hrabovszky E, Kalló I, et al. Gene expression profiling identifies key estradiol targets in the frontal cortex of the rat [J]. Endocrinology, 2010, 151: 1161-1176.

Zhao L, Brinton RD. Estrogen receptor alpha and beta differentially regulate intracellular Ca²⁺ dynamics leading to ERK phosphorylation and estrogen neuroprotection in hippocampal neurons [J]. Brain Res, 2007, 1172: 48-59.

Arao Y, Korach KS. The physiological role of estrogen receptor functional domains [J]. Essays Biochem, 2021, 65: 867-875.

Yoon BK. The impacts of menopausal hormone therapy on longer-term health consequences of ovarian hormone deficiency [J]. Climacteric, 2023, 26: 193-197.

Shufelt CL, Manson JE. Menopausal hormone therapy and cardiovascular disease: the role of formulation, dose, and route of delivery [J]. J Clin Endocrinol Metab, 2021, 106: 1245-1254.

Stefanick ML. Estrogens and progestins: background and history, trends in use, and guidelines and regimens approved by the US Food and Drug Administration [J]. Am J Med, 2005, 118 (Suppl 12B): 64-73.

Zhang LL, Zhao WJ, Wu XP, et al. Research status of steroid components and their activities in pregnant mare urine [J]. Nat Prod Res Dev (天然产物研究与开发), 2003, 15: 354-358.

Bózsity N, Nagy V, Szabó J, et al. Synthesis of estrone heterodimers and evaluation of their in vitro antiproliferative activity [J]. Int J Mol Sci, 2024, 25: 4274.

Ito F, Mori T, Tarumi Y, et al. Equilin in conjugated equine estrogen increases monocyte-endothelial adhesion via NF-κB signaling [J]. PLoS One, 2019, 14: e0211462.

Fitzsimmons J, Mulla W. The 17-alpha hydroxyprogesterone chronicle [J]. Am J Obstet Gynecol, 2022, 227: 356.

Harrison DE, Strong R, Reifsnyder P, et al. 17-α-Estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex [J]. Aging Cell, 2021, 20: e13328.

Zhao L, Brinton RD. Select estrogens within the complex formulation of conjugated equine estrogens (Premarin) are protective against neurodegenerative insults: implications for a composition of estrogen therapy to promote neuronal function and prevent Alzheimer's disease [J]. BMC Neurosci, 2006, 7: 24.

Baracat E, Haidar M, Lopez FJ, et al. Estrogen activity and novel tissue selectivity of delta8, 9-dehydroestrone sulfate in postmenopausal women [J]. J Clin Endocrinol Metab, 1999, 84: 2020-2027.

Spink DC, Zhang F, Hussain MM, et al. Metabolism of equilenin in MCF-7 and MDA-MB-231 human breast cancer cells [J]. Chem Res Toxicol, 2001, 14: 572-581.

Gherezghiher TB, Michalsen B, Chandrasena RE, et al. The naphthol selective estrogen receptor modulator (SERM), LY2066948, is oxidized to an o-quinone analogous to the naphthol equine estrogen, equilenin [J]. Chem Biol Interact, 2012, 196: 1-10.

Dubey RK, Jackson EK. Cardiovascular protective effects of 17beta-estradiol metabolites [J]. J Appl Physiol (1985), 2001, 91: 1868-1883.

Schulz K, Oberdieck U, Weitschies W. Separation of delta6- and delta9, 11-estradiol: analytical method development, validation and practical application [J]. Pharmazie, 2013, 68: 311-316.

Liu JH, Reape KZ, Hait HI. Synthetic conjugated estrogens-B and postmenopausal nocturnal vasomotor symptoms: a randomized controlled trial [J]. Obstet Gynecol, 2012, 119: 78-84.

Simon JA, Reape KZ, Wininger S, et al. Randomized, multicenter, double-blind, placebo-controlled trial to evaluate the efficacy and safety of synthetic conjugated estrogens B for the treatment of vulvovaginal atrophy in healthy postmenopausal women [J]. Fertil Steril, 2008, 90: 1132-1138.

Marx P, Schade G, Wilbourn S, et al. Low-dose (0.3 mg) synthetic conjugated estrogens A is effective for managing atrophic vaginitis [J]. Maturitas, 2004, 47: 47-54.

Booyens RM, Engelbrecht AM, Strauss L, et al. To clot, or not to clot: the dilemma of hormone treatment options for menopause [J]. Thromb Res, 2022, 218: 99-111.

Jing Y. Synthesis of Estrone and Estrogen Derivatives (雌酚酮及雌激素衍生物的合成研究) [D]. Shanghai: Shanghai Normal University, 2010.

Li XR, Liang LW, Shan Y, et al. Release similarity evaluation of generic and original low-dose conjugated estrogen sustained-release tablets [J]. Chin J Pharm (中国医药工业杂志), 2020, 51: 1558-1563.

Liu YX, Li PP, Xie XY, et al. Development of conjugated estrogen sustained-release tablets by direct powder compression and similarity evaluation with reference preparations [J]. Chin Pharm J (中国药学杂志), 2023, 58: 807-817.

Yang T. Study on Content Determination Methods and Excipient Interactions of Conjugated Estrogen Cream (结合雌激素乳膏含量测定方法及原辅料相互作用研究) [D]. Urumqi: Xinjiang Medical University, 2022.

Yang M, Lin S, Zheng S, et al. A multicenter, randomized, open, controlled trial to evaluate the efficacy of honglilai vaginal cream and premarin vaginal cream for genitourinary syndrome of menopause in different subgroups of Chinese postmenopausal women [J]. Gynecol Endocrinol, 2022, 38: 861-867.

Yang DZ, Zhou LX, Xie MQ, et al. Clinical study of conjugated estrogen in the treatment of dysfunctional uterine bleeding [J]. Chin J Clin Obstet Gynecol (中国妇产科临床), 2001, 2: 331-333, 368.

Zhao FC, Shao XX, Gao XL. Screening of capsule shell formulation for conjugated estrogen vaginal soft capsules [J]. China Pharm (中国药房), 2006, 17: 1611-1613.

Zhao FC, Zhang CX, Gao XL. Screening of capsule content formulation for conjugated estrogen vaginal soft capsules [J]. Chin J New Drugs (中国新药杂志), 2010, 19: 417-421, 438.

Zhao FC, Gao XL, Ran XJ, et al. Preliminary pharmacodynamics and local toxicity study of conjugated estrogen vaginal soft capsules [J]. Northwest Pharm J (西北药学杂志), 2006, 21: 256-258.

Zhao FC, Li L, Gao XL. Quality study of conjugated estrogen vaginal soft capsules [J]. Chin J Mod Appl Pharm (中国现代应用药学), 2009, 26: 951-954.

Ta TRC, Porter TM. Thermosensitive liposomes for localized delivery and triggered release of chemotherapy [J]. J Control Release, 2013, 169: 112-125.

Wang XY, Yan SJ, Niu RH, et al. Preparation and properties of conjugated estrogen vaginal thermosensitive liposomal gel [J]. Chin J Mod Appl Pharm (中国现代应用药学), 2022, 39: 1059-1066.

Wang XY. Study on Conjugated Estrogen Thermosensitive Liposomal Gel (结合雌激素脂质体温敏凝胶的研究) [D]. Urumqi: Xinjiang Medical University, 2022.

Komm BS, Mirkin S, Jenkins SN. Development of conjugated estrogens/bazedoxifene, the first tissue selective estrogen complex (TSEC) for management of menopausal hot flashes and postmenopausal bone loss [J]. Steroids, 2014, 90: 71-81.

Mirkin S, Komm BS. Tissue-selective estrogen complexes for postmenopausal women [J]. Maturitas, 2013, 76: 213-220.

Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial [J]. JAMA, 2003, 290: 1729-1738.

Luengratsameerung S, PanyakhamLerd K, Treratanachat S, et al. Systemic effects of conjugated equine estrogen vaginal cream on bone turnover markers in postmenopausal women [J]. Climacteric, 2013, 16: 133-140.

Lewiecki EM. Bazedoxifene and bazedoxifene combined with conjugated estrogens for the management of postmenopausal osteoporosis [J]. Expert Opin Investig Drugs, 2007, 16: 1663-1672.

Sharifi M, Lewiecki EM. Conjugated estrogens combined with bazedoxifene: the first approved tissue selective estrogen complex therapy [J]. Expert Rev Clin Pharmacol, 2014, 7: 281-291.

Lane NE, Kumer JL, Majumdar S, et al. The effects of synthetic conjugated estrogens, a (cenestin) on trabecular bone structure and strength in the ovariectomized rat model [J]. Osteoporosis Int, 2002, 13: 816-823.

Garnero P, Stevens RE, Ayres SA, et al. Short-term effects of new synthetic conjugated estrogens on biochemical markers of bone turnover [J]. J Clin Pharmacol, 2002, 42: 290-296.

Almeida M, Laurent MR, Dubois V, et al. Estrogens and androgens in skeletal physiology and pathophysiology [J]. Physiol Rev, 2017, 97: 135-187.

Khosla S, Monroe DG. Regulation of bone metabolism by sex steroids [J]. Cold Spring Harb Perspect Med, 2018, 8: a031211.

Maloney C, Oliver ML. Effect of local conjugated estrogens on vaginal pH in elderly women [J]. J Am Med Dir Assoc, 2001, 2: 51-55.

Crandall CJ, Mehta JM, Manson JE. Management of menopausal symptoms: a review [J]. JAMA 2023, 329: 405-420.

Liu HH, Liu W, Wang GC, et al. Efficacy and safety analysis of long-term use of estrogen with different administration methods for genitourinary syndrome of menopause [J]. China Med Pharm (中国医药科学), 2024, 14: 132-135, 144.

Rahn DD, Richter HE, Sung VW, et al. Perioperative vaginal estrogen as adjunct to native tissue vaginal apical prolapse repair: a randomized clinical trial [J]. JAMA 2023, 330: 615-625.

Wu SS, Yang L, Wang J, et al. Clinical efficacy of conjugated estrogen cream combined with metronidazole vaginal gel in the treatment of senile vaginitis [J]. Chin J Clin Ration Drug Use (临床合理用药), 2022, 15: 112-114.

Xie XY. Clinical efficacy of conjugated estrogen ointment combined with compound metronidazole suppository in the treatment of senile vaginitis [J]. J Women Child Health (妇儿健康导刊), 2024, 3: 25-28.

Mauvais-Jarvis F, Clegg DJ, Hevener AL. The role of estrogens in control of energy balance and glucose homeostasis [J]. Endocr Rev, 2013, 34: 309-338.

Xu Z, Yu Z, Chen M, et al. Mechanisms of estrogen deficiency-induced osteoporosis based on transcriptome and DNA methylation [J]. Front Cell Dev Biol, 2022, 10: 1011725.

Van Pelt RE, Gozansky WS, Schwartz RS, et al. Intravenous estrogens increase insulin clearance and action in postmenopausal women [J]. Am J Physiol Endocrinol Metab, 2003, 285: E311-317.

Hugenschmidt CE, Duran T, Espeland MA. Interactions between estradiol, diabetes, and brain aging and the risk for cognitive impairment [J]. Climacteric, 2021, 24: 359-365.

Marlatt KL, Lovre D, Beyl RA, et al. Effect of conjugated estrogens and bazedoxifene on glucose, energy and lipid metabolism in obese postmenopausal women [J]. Eur J Endocrinol, 2020, 183: 439-452.

Lovre D, Peacock E, Katalenich B, et al. Conjugated estrogens and bazedoxifene improve β cell function in obese menopausal women [J]. J Endocr Soc, 2019, 3: 1583-1594.

Montplaisir J, Lorrain J, Denesle R, et al. Sleep in menopause: differential effects of two forms of hormone replacement therapy [J]. Menopause (New York, NY), 2001, 8: 10-16.

Flores VA, Stachenfeld NS, Taylor HS. Bazedoxifene-conjugated estrogens for treating endometriosis [J]. Obstet Gynecol, 2018, 132: 475-477.

Wilcox JG, Hwang J, Hodis HN, et al. Cardioprotective effects of individual conjugated equine estrogens through their possible modulation of insulin resistance and oxidation of low-density lipoprotein [J]. Fertil Steril, 1997, 67: 57-62.

Bhavnani BR, Cecutti A, Gerulath A, et al. Comparison of the antioxidant effects of equine estrogens, red wine components, vitamin E, and probucol on low-density lipoprotein oxidation in postmenopausal women [J]. Menopause (New York, NY), 2018, 25: 1214-1223.

Hull RW, Hasbargen JA, Fall S, et al. Conjugated estrogens reduce endothelial prostacyclin production and fail to reduce postbypass blood loss [J]. Chest, 1991, 99: 1116-1119.

Berco M, Bhavnani BR. Differential neuroprotective effects of equine estrogens against oxidized low density lipoprotein-induced neuronal cell death [J]. Gynecol Obstet Invest, 2001, 8: 245-254.

Spence RD, Voskuhl RR. Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration [J]. Front Neuroendocrinol, 2012, 33: 105-115.

Haque A, Das A, Samantaray S, et al. Premarin reduces neurodegeneration and promotes improvement of function in an animal model of spinal cord injury [J]. Int J Mol Sci, 2022, 23: 2384.

Bhavnani BR. Estrogens and menopause: pharmacology of conjugated equine estrogens and their potential role in the prevention of neurodegenerative diseases such as Alzheimer's [J]. J Steroid Biochem Mol Biol, 2003, 85: 473-482.

Bhavnani BR, Berco M, Binkley J. Equine estrogens differentially prevent neuronal cell death induced by glutamate [J]. J Soc Gynecol Investig, 2003, 10: 302-308.

Stute P, Wienges J, Koller AS, et al. Cognitive health after menopause: does menopausal hormone therapy affect it? [J]. Best Pract Res Clin Endocrinol Metab, 2021, 35: 101565.

Suba Z. Prevention and therapy of COVID-19 via exogenous estrogen treatment for both male and female patients [J]. J Pharm Pharm Sci, 2020, 23: 75-85.

Stumpf PG. Pharmacokinetics of estrogen [J]. Obstet Gynecol, 1990, 75: 9S-17S.

Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women's Health Initiative randomized trials [J]. JAMA, 2017, 318: 927-938.

Shi M, Yin L, Sun Y, et al. Pharmacokinetic study of conjugated equine estrogens in healthy Chinese postmenopausal women using a Parallel two-column LC-MS/MS method [J]. Clin Pharmacokinet, 2022, 61: 1571-1583.

2025年第60卷第4期

PDF下载

198

引用本文

BibTeX

文章信息

doi: 10.16438/j.0513-4870.2025-0015

接收时间：2025-01-06
首发时间：2025-10-29
出版时间：2025-04-12

补充材料

相关文章

文章信息

作者

出版历史

收稿日期：2025-01-06
修回日期：2025-03-05

基金

国家重点研发计划(2023YFC2706100)

国家自然科学基金资助项目(82304393)

国家卫生健康委科学技术研究所中央级公益性科研院所基本科研业务费专项资金(2022GJZ04)

作者信息

¹ 国家卫生健康委科学技术研究所, 北京 100081

² 中国医学科学院、北京协和医学院, 北京 100073

³ 河南工业大学, 河南郑州 450001

⁴ 中国医学科学院、北京协和医学院药物研究所, 北京 100050

通讯作者:

宁美英，E-mail: mayning999@126.com

参考文献

分享链接

https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2025-0015

分享至

全文二维码

扫描看全文

引用本文

BibTeX

本文的引用情况

2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

关闭全屏

BibTeX
EndNote
RefWorks
TxT

Main component	Pharmacological effect	Ref.
Estrone	Reversible conversion to estradiol; promotes uterine development and alleviates perimenopausal syndrome	[20]
Equilin	Prevents Alzheimer's disease and promotes cortical neuron growth	[21]
17α-Dihydro equilin	Avoids first-pass effect of CE; anti-atherosclerotic	[22]
17α-Estradiol	Weak estrogenic activity; anti-aging; alleviates perimenopausal syndrome	[23]
△^{8, 9}Dehydro estrone	Treats vasomotor symptoms, maintains bone mass; effectively protects neurons	[24, 25]
Equilenin	Treats vasomotor symptoms and maintains bone mass	[26]
17β-Dihydro equilin	Treats vasomotor symptoms	[27]
17α-Dihydro equilenin	Prevents atherosclerosis	[26]
17β-Estradiol	Aalleviates perimenopausal syndrome, maintains bone mass; prevents Alzheimer's disease	[28]
17β-Dihydro equilenin	Cardiovascular protective effects	[29]

Main component

Structural formula

Pharmacological effect

Ref.

Estrone

Reversible conversion to estradiol; promotes uterine development and alleviates perimenopausal syndrome

[20]

Equilin

Prevents Alzheimer's disease and promotes cortical neuron growth

[21]

17α-Dihydro equilin

Avoids first-pass effect of CE; anti-atherosclerotic

[22]

17α-Estradiol

Weak estrogenic activity; anti-aging; alleviates perimenopausal syndrome

[23]

△^{8, 9}Dehydro estrone

Treats vasomotor symptoms, maintains bone mass; effectively protects neurons

[24, 25]

Equilenin

Treats vasomotor symptoms and maintains bone mass

[26]

17β-Dihydro equilin

Treats vasomotor symptoms

[27]

17α-Dihydro equilenin

Prevents atherosclerosis

[26]

17β-Estradiol

Aalleviates perimenopausal syndrome, maintains bone mass; prevents Alzheimer's disease

[28]

17β-Dihydro equilenin

Cardiovascular protective effects

[29]

Dosage form	Product name	Main formulation	Source	Specification	Route of administration	Advantage	Disadvantage	Indication	Manufacturer	Ref.
Tablet	Premarin	CE, calcium phosphate, calcium sulfate, etc.	Pregnant mare urine	0.3 mg·g^-1 0.625 mg·g^-1	Oral	Convenient to use	May cause gastrointestinal discomfort, first-pass effect, low bioavailability	Long-term treatment of systemic symptoms	Pfizer	[18]
	Honglilai	CE, calcium phosphate, calcium sulfate, etc.	Pregnant mare urine	0.3 mg·g^-1 0.625 mg·g^-1					Xinjiang Xinzhiyuan Biopharmaceutical Co., Ltd.	[35]
	Cenestin	CE-A, ethyl cellulose, hypromellose, etc.	Soybean, yam, etc.	Discontinued					Pfizer	[30]
	Enjuvia	CE-B, silica, hypromellose, etc.	Synthetic	Discontinued					Teva Pharmaceutical Industries Ltd.	[33]
Creams	Premarin	CE, cetearyl alcohol, cetyl esters, etc.	Pregnant mare urine	14 g/tube 0.625 mg·g^-1	Vaginal	Local action, avoids first-pass effect	Inconvenient application, requires frequent use	Treatment of local symptoms	Pfizer	[38]
	Honglilai	CE, stearic acid, cetyl alcohol, etc.	Pregnant mare urine	14 g/tube 0.625 mg·g^-1					Xinjiang Xinzhiyuan Biopharmaceutical Co., Ltd.	[37]
Injection	Premarin	CE, lactose, sodium citrate, dimethicone, etc.	Pregnant mare urine	25 mg/vial	Intravenous or intramuscular	Rapid onset, precise dosing	Requires medical personnel for administration	Treatment of abnormal uterine bleeding due to hormonal imbalance	Pfizer	[39]
Soft capsule	/	CE, gelatin, glycerin, water, etc.	Pregnant mare urine	/	Vaginal	Accurate local dosing	Issues with patient compliance and drug stability	Treatment of local symptoms	/	[40]
Liposomal thermosensitive gel	/	CE, soybean phospholipid, cholesterol, etc.	Pregnant mare urine	/	Vaginal	Good biocompatibility, avoids first-pass effect	release Characteristics may be affected by body Temperature and pH changes	Treatment of local symptoms	/	[45]

Dosage form

Product name

Main
formulation

Source

Specification

Route of administration

Advantage

Disadvantage

Indication

Manufacturer

Ref.

Tablet

Premarin

CE, calcium phosphate, calcium sulfate, etc.

Pregnant mare urine

0.3 mg·g^-1
0.625 mg·g^-1

Oral

Convenient to use

May cause gastrointestinal discomfort, first-pass effect, low bioavailability

Long-term treatment of systemic symptoms

Pfizer

[18]

Honglilai

CE, calcium phosphate, calcium sulfate, etc.

Pregnant mare urine

0.3 mg·g^-1
0.625 mg·g^-1

Xinjiang Xinzhiyuan Biopharmaceutical Co., Ltd.

[35]

Cenestin

CE-A, ethyl cellulose, hypromellose, etc.

Soybean, yam, etc.

Discontinued

Pfizer

[30]

Enjuvia

CE-B, silica, hypromellose, etc.

Synthetic

Discontinued

Teva Pharmaceutical Industries Ltd.

[33]

Creams

Premarin

CE, cetearyl alcohol, cetyl esters, etc.

Pregnant mare urine

14 g/tube
0.625 mg·g^-1

Vaginal

Local action, avoids first-pass effect

Inconvenient application, requires frequent use

Treatment of local symptoms

Pfizer

[38]

Honglilai

CE, stearic acid, cetyl alcohol, etc.

Pregnant mare urine

14 g/tube
0.625 mg·g^-1

Xinjiang Xinzhiyuan Biopharmaceutical Co., Ltd.

[37]

Injection

Premarin

CE, lactose, sodium citrate, dimethicone, etc.

Pregnant mare urine

25 mg/vial

Intravenous or intramuscular

Rapid onset, precise dosing

Requires medical personnel for administration

Treatment of abnormal uterine bleeding due to hormonal imbalance

Pfizer

[39]

Soft capsule

CE, gelatin, glycerin, water, etc.

Pregnant mare urine

Vaginal

Accurate local dosing

Issues with patient compliance and drug stability

Treatment of local symptoms

[40]

Liposomal thermosensitive gel

CE, soybean phospholipid, cholesterol, etc.

Pregnant mare urine

Vaginal

Good biocompatibility, avoids first-pass effect

release Characteristics may be affected by body Temperature and pH changes

Treatment of local symptoms

[45]