醋酸甲地孕酮联合盐酸二甲双胍作为早期子宫内膜样腺癌和子宫内膜非典型增生患者保留生育功能治疗：一项前瞻性研究

doi:10.12122/j.issn.1673-4254.2024.11.01

南方医科大学学报 ›› 2024, Vol. 44 ›› Issue (11): 2055-2062.doi: 10.12122/j.issn.1673-4254.2024.11.01

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醋酸甲地孕酮联合盐酸二甲双胍作为早期子宫内膜样腺癌和子宫内膜非典型增生患者保留生育功能治疗：一项前瞻性研究

王圆圆¹^,²(), 来天娇², 褚丹霞², 白晶², 严淑萍², 秦海霞¹, 郭瑞霞²()

^1.新乡医学院第一附属医院妇科一病区，河南卫辉 453100
^2.郑州大学第一附属医院妇科一病区，河南郑州 450052

收稿日期:2024-05-09 接受日期:2024-10-29 出版日期:2024-11-20 发布日期:2024-11-29
通讯作者: 郭瑞霞 E-mail:wyy15973143013@163.com;grxcdxzzu@163.com
作者简介:王圆圆，主治医师，硕士研究生，E-mail： wyy15973143013@163.com
基金资助:
国家自然科学基金(31670844);中原英才千人计划项目(ZYQR200810107);河南省科技创新计划杰出人才项目(2018JR0004)

Megestrol acetate plus metformin for fertility-sparing treatment of atypical endometrial hyperplasia and early-stage endometrial adenocarcinoma: a prospective study

Yuanyuan WANG¹^,²(), Tianjiao LAI², Danxia CHU², Jing BAI², Shuping YAN², Haixia QIN¹, Ruixia GUO²()

^1.Department of Gynecology, First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, China
^2.Department of Gynecology, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China

Received:2024-05-09 Accepted:2024-10-29 Online:2024-11-20 Published:2024-11-29
Contact: Ruixia GUO E-mail:wyy15973143013@163.com;grxcdxzzu@163.com
Supported by:
Supported by National Natural Science Program of China(31670844);Central Plains Thousand Talents Program(ZYQR200810107);Outstanding Talents of Science and Technology Innovation Program of Henan Province(2018JR0004)

摘要/Abstract

摘要：

目的评估在子宫内膜不典型增生（AEH）或早期1级子宫内膜样腺癌（G1 EAC）患者中，使用醋酸甲地孕酮（MA）联合二甲双胍作为保留生育功能治疗的疗效和复发率，分析治疗后子宫内膜中IGFBP-rP1、p-AMPK和p-Akt的表达变化。方法前瞻性招募60名年龄在20~42岁之间的AEH和/或病灶局限于子宫内膜的1级EAC患者。患者被随机分为MA组（n=30）和MA加二甲双胍组（n=30）。对照组患者接受MA（口服160 mg，2次/d）治疗，联合组患者在口服MA治疗的基础上加用二甲双胍（口服850 mg，2次/d），治疗持续至少6个月，必要时可延长至12个月以达到完全缓解（CR），并每3个月进行一次随访宫腔镜检查和刮宫术。对于达到CR的患者，通过免疫组织化学方法检测子宫内膜组织中IGFBP-rP1、p-Akt和p-AMPK的表达。结果共有58名患者完成了治疗。在治疗第9个月时，联合治疗组中23例（76.7%）患者达到了CR；对照组中20例（71.4%）患者达到了CR，另外两例患者在将治疗改为二甲双胍联合MA治疗后也达到了CR。联合治疗组的复发率为22.7%，对照组为30.0%。对照组10名患者（35.7%）体质量增加5.7±6.1 kg，而在联合组患者体质量变化没有统计学意义。与对照组相比，联合治疗组子宫内膜组织中IGFBP-rP1和p-AMPK表达增加， p-Akt表达降低。结论 MA和二甲双胍联合治疗可作为1级IA期EAC和AEH的保留生育功能治疗的有效方法，二甲双胍辅助治疗可以控制由MA引起的体质量增加，增加子宫内膜组织中IGFBP-rP1和p-AMPK的表达，同时抑制p-Akt的表达。该疗法在早期EAC和AEH治疗中的作用值得进一步研究。

关键词: 子宫内膜样腺癌, 盐酸二甲双胍, 子宫内膜非典型增生, 保留生育功能治疗, 醋酸甲地孕酮, 胰岛素样生长因子结合蛋白相关蛋白1

Abstract:

Objective To evaluate the efficacy of medroxyprogesterone acetate (MA) plus metformin as the primary fertility-sparing treatment for atypical endometrial hyperplasia (AEH) and early-stage grade 1 endometrial adenocarcinoma (G1 EAC) and the recurrence rate after treatment. Methods Sixty patients (aged 20-42 years) with AEH and/or grade 1 EAC limited to the endometrium were enrolled prospectively and randomized into two groups (n=30) to receive oral MA treatment at the daily dose of 160 mg (control) or MA plus oral metformin (850 mg, twice a day) for at least 6 months. The treatment could extend to 12 months until a complete response (CR) was achieved, and follow-up hysteroscopy and curettage were performed every 3 months. For all the patients who achieved CR, endometrial expressions of IGFBP-rP1, p-Akt and p-AMPK were detected immunohistochemically. Results A total of 58 patients completed the treatment. After 9 months of treatment, 23 (76.7%) patients in the combined treatment group and 20 (71.4%) in the control group achieved CR; two patients in the control group achieved CR after converting to the combined treatment. The recurrence rate did not differ significantly between the control group and combined treatment group (30.0% vs 22.7%, P>0.05). Ten (35.7%) patients in the control group experienced significant weight gain of 5.7±6.1 kg, while none of the patients receiving the combined treatment exhibited significant body weight changes. Compared with the control group, the patients receiving the combined treatment showed enhanced endometrial expressions of IGFBP-rP1 and p-AMPK with lowered p-Akt expression. Conclusion Metformin combined with MA may provide an effective option for fertility-sparing treatment of AEH and grade 1 stage IA EAC, and the clinical benefits of metformin for controlling MA-induced weight gain and promoting endometrial expressions of IGFBP-rP1 and p-AMPK while inhibiting p-Akt expression warrants further study.

Key words: endormetrial adenocarcinoma, metformin, atypical endometrial hyperplasia, fertility-sparing treatment, megestrol acetate, insulin-like growth factor binding protein-related protein 1

王圆圆, 来天娇, 褚丹霞, 白晶, 严淑萍, 秦海霞, 郭瑞霞. 醋酸甲地孕酮联合盐酸二甲双胍作为早期子宫内膜样腺癌和子宫内膜非典型增生患者保留生育功能治疗：一项前瞻性研究[J]. 南方医科大学学报, 2024, 44(11): 2055-2062.

Yuanyuan WANG, Tianjiao LAI, Danxia CHU, Jing BAI, Shuping YAN, Haixia QIN, Ruixia GUO. Megestrol acetate plus metformin for fertility-sparing treatment of atypical endometrial hyperplasia and early-stage endometrial adenocarcinoma: a prospective study[J]. Journal of Southern Medical University, 2024, 44(11): 2055-2062.

图/表 7

Tab.1 Response distribution in the control and combined treatment groups after 6 months of treatment ［n （%）］

Group	n	CR	PR	SD	PD	Response rate
Met+MA	30	21 （70.0%）	4 （13.3%）	4 （13.3%）	1 （3.3%）	83.3%
MA	28	17 （60.7%）	6 （21.4%）	4 （14.3%）	1 （3.6%）	82.1%
χ²	1.070*
P	0.889

Tab.2 Response distribution in the two groups after 9 months of treatment ［n （%）］

Group	n	CR	PR	SD	PD	Response rate
Met+MA	32*	26 (81.3%)	3 (9.4%)	2 (3.1%)	1 (3.1%)	90.7%
MA	26	20 (76.9%)	3 (11.5%)	1 (3.8%)	2 (7.7%)	88.4%
χ²	0.163
P	0.983

Tab.3 Mean PR and CR time of the patients in the two groups （month）

Group	CR patients (n)	PR time	CR time	Total time
Met+MA	26	3.59±1.26	4.78±2.26	7.83±2.03
MA	20	3.98±1.36	5.49±2.08	8.49±2.11
t		1.049	1.419	1.384
P		0.288	0.163	0.172

Fig.1 Immunohistochemical staining for IGFBP-rP1 in endometrial tissues of the patients in MA and combined treatment groups. A, B: Negative IGFBP-rP1 expression in MA group both before treatment (A) and after CR (B). C, D: In the combined treatment group, IGFBP-rP1 was negative before treatment (C) but positive after CR (D).

Tab.4 Endometrial IGFBP-rP1， p-Akt and p-AMPK positivity in the two groups after treatment ［n （%）］

Group	n	IGFBP-rP1		p-Akt		p-AMPK
Group	n	Negative	Positive	Negative	Positive	Negative	Positive
MA	20	20 (100.0%)	0 (0%)	4 (20.0%)	16 (80%)	16 (80.0%)	4 (20%)
Met+MA	26	23 (88.5%)	3 (11.5%)	17 (65.4%)	9 (34.6%)	14 (53.8%)	12 (46.2%)
χ²		3.584		9.385		3.409
P		0.058		0.002		0.065

Fig.2 Immunohistochemical staining for p-Akt in endometrial tissues of the patients in MA and combined treatment groups. The endometrial tissue was positive for p-Akt in MA group before treatment (A) and remained positive after treatment (B); in the combined treatment group, p-Akt was positive before treatment (C) but became negative after treatment (D).

Fig.3 Immunohistochemical staining for endometrial p-AMPK expressions in MA and combined treatment groups. The expression of p-Akt was negative in MA group before treatment (A) and remained so after treatment (B); in the combined treatment group, p-Akt was negative before treatment (C) but became positive after treatment (D).

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醋酸甲地孕酮联合盐酸二甲双胍作为早期子宫内膜样腺癌和子宫内膜非典型增生患者保留生育功能治疗：一项前瞻性研究

Megestrol acetate plus metformin for fertility-sparing treatment of atypical endometrial hyperplasia and early-stage endometrial adenocarcinoma: a prospective study

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