Effect of gonadotropin releasing hormone agonist on menstrual cycle of premenopausal breast cancer patients during chemotherapy: a meta-analysis

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doi:10.3877/cma.j.issn.1674-0807.2018.05.005

Abstract:

Objective

To investigate whether the gonadotropin releasing hormone agonist (GnRHa) combined with chemotherapy can improve the menstrual cycle and protect ovarian function in premenopausal breast cancer patients.

Methods

The databases including Embase, PubMed, MEDLINE, China National Knowledge Infrastructure(CNKI), VIP, Wanfang network were searched to collect randomized controlled clinical trials on the effect of GnRHa on ovarian function of premenopausal breast cancer patients during chemotherapy until December 2016. Two researchers independently completed literature retrieval and data extraction, and evaluated the quality of the included studies using the Jadad evaluation scale. The odds ratio (OR) and 95% confidence interval (CI) were used as effect quantities, and the corresponding effect model was adopted for a meta-analysis using RevMan 5.0 software.

Results

Six randomized controlled trials were included, involving 714 patients. The rate of spontaneous menstrual resuscitation in patients receiving chemotherapy combined with GnRHa was significantly higher than that in patients receiving chemotherapy alone (OR=2.42, 95%CI: 1.16-5.05, P=0.02). Sensitivity analysis showed a stable result(OR=1.76, 95%CI: 1.21-2.56, P<0.01). There was no significant correlation between menstrual regurgitation rate and patient age (for patients < 40 years: OR=1.71, 95%CI: 0.70-4.15, P=0.24; for patients≥40 years: OR=1.27, 95%CI: 0.48-3.34, P=0.63). Menstrual regurgitation rate presented a significant difference between patients receiving tamoxifen combined with GnRHa and patients receiving no tamoxifen. (OR=3.39, 95%CI: 1.73-6.65, P<0.01). Anthracycline-based chemotherapy combined with GnRHa was significantly correlated with menstrual regurgitation rate (OR=2.49, 95%CI: 1.06-5.89, P=0.04). There was no significant difference in the incidence of adverse reactions such as hot flashes, vaginal dryness, mood change and decreased sexual desire between combination therapy group and chemotherapy group (OR=1.87, 95%CI: 1.00-3.51, P=0.05; OR=1.20, 95%CI: 0.66-2.20, P=0.55; OR=1.51, 95%CI: 0.56-4.07, P=0.41; OR=1.21, 95%CI: 0.64-2.32, P=0.56).

Conclusion

GnRHa combined with chemotherapy can improve menstrual regurgitation in premenopausal breast cancer patients during chemotherapy.

Key words: Breast neoplasms, Chemotherapy, adjuvant, Menstruation, Gonadotropin-releasing hormone

Chunhuai Liao, Jianlun Liu. Effect of gonadotropin releasing hormone agonist on menstrual cycle of premenopausal breast cancer patients during chemotherapy: a meta-analysis[J]. Chinese Journal of Breast Disease(Electronic Edition), 2018, 12(05): 282-289.

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研究者	入组时间	方法	患者	干预情况	结果	随访(月)
Del Mastro等^[2]	2003～2008年	公开的多中心随机对照	Ⅰ～Ⅲ期乳腺癌；年龄18～45岁；绝经前女性	手术：不详。化疗：6个周期的CMF±他莫昔芬。放射治疗：不详。GnRHa：曲普瑞林每28 d 3.75 mg直到化疗结束；对照组未使用促性腺激素释放激素类似物	更年期提前的定义：化疗结束1年后月经功能未恢复，FSH及E₂维持在绝经期水平。结果：化疗引起更年期提前	12
Munster等^[3]	2003～2007年	随机双盲安慰剂对照	Ⅰ～Ⅲ期乳腺癌；年龄<45岁；绝经前女性	手术：不详。化疗：AC (4个周期)或FEC/FAC(6个周期)±他莫昔芬。放射治疗：不详。GnRHa：化疗期间曲普瑞林每28 d 3.75 mg；对照组未使用促性腺激素释放激素类似物	保持或不间断月经的定义：21～35 d的规律月经周期，经期至少2 d的出血。月经恢复要求在6个月内至少3次月经并且FSH<40 mU/ml。结果：自然月经的恢复	>24
Badawy等^[4]	不详	随机对照	早期乳腺癌；年龄18～40岁；绝经前女性	手术：改良根治术或保留乳房手术加腋窝淋巴结清扫。化疗：6个周期FAC。放射治疗：无。GnRHa：戈舍瑞林每28 d 3.6 mg，连续6个月；对照组未使用促性腺激素释放激素类似物	卵巢早衰的定义：排卵及月经早期停止，血清FSH水平不升高(高促性腺激素水平导致停经)。结果：自然月经和自然排卵的发生	8
Sverrisdottir等^[5]	1990～1994年	多中心随机对照	早期乳腺癌；绝经前女性	手术：保留乳房手术。化疗：6个周期CMF方案±他莫昔芬。保留乳房患者和≥4枚淋巴结阳性者接受放射治疗。GnRHa：戈舍瑞林每28 d 3.6 mg，连续2年；对照组未使用促性腺激素释放激素类似物±他莫昔芬	卵巢早衰的定义：月经停止。结果：自然月经的发生	>24
Moore等^[6]	2004～2011年	公开的多中心随机对照	原发性激素不敏感Ⅰ～ⅢA期乳腺癌；年龄18～49岁；绝经前女性	手术：不详。化疗：<40岁使用蒽环类为基础化疗3～4个周期，约3个月；40～49岁使用非蒽环类为基础化疗6～8个周期，大约6个月；HER-2过表达者使用曲妥珠单克隆抗体。放射治疗：不详。GnRHa：戈舍瑞林每28 d 3.6 mg，连续2年；对照组未使用促性腺激素释放激素类似物	卵巢早衰的定义：月经停止连续6个月及2年内FSH维持在绝经后水平。结果：防止卵巢功能衰竭，降低早期绝经的风险并提高生育率	24
Elgindy等^[7]	2009～2011年	随机公开安慰剂对照	原发性激素不敏感型Ⅰ～Ⅲa期乳腺癌；年龄18～40岁；绝经前女性	手术：不详。GnRHa：西曲瑞克0.25 mg/d，直到E₂<50 pg/ml，曲普瑞林每28 d 3.75 mg；对照组未使用促性腺激素释放激素类似物	卵巢早衰的定义：月经停止。结果：自然月经的发生	18

研究者	入组时间	方法	患者	干预情况	结果	随访(月)
Del Mastro等^[2]	2003～2008年	公开的多中心随机对照	Ⅰ～Ⅲ期乳腺癌；年龄18～45岁；绝经前女性	手术：不详。化疗：6个周期的CMF±他莫昔芬。放射治疗：不详。GnRHa：曲普瑞林每28 d 3.75 mg直到化疗结束；对照组未使用促性腺激素释放激素类似物	更年期提前的定义：化疗结束1年后月经功能未恢复，FSH及E₂维持在绝经期水平。结果：化疗引起更年期提前	12
Munster等^[3]	2003～2007年	随机双盲安慰剂对照	Ⅰ～Ⅲ期乳腺癌；年龄<45岁；绝经前女性	手术：不详。化疗：AC (4个周期)或FEC/FAC(6个周期)±他莫昔芬。放射治疗：不详。GnRHa：化疗期间曲普瑞林每28 d 3.75 mg；对照组未使用促性腺激素释放激素类似物	保持或不间断月经的定义：21～35 d的规律月经周期，经期至少2 d的出血。月经恢复要求在6个月内至少3次月经并且FSH<40 mU/ml。结果：自然月经的恢复	>24
Badawy等^[4]	不详	随机对照	早期乳腺癌；年龄18～40岁；绝经前女性	手术：改良根治术或保留乳房手术加腋窝淋巴结清扫。化疗：6个周期FAC。放射治疗：无。GnRHa：戈舍瑞林每28 d 3.6 mg，连续6个月；对照组未使用促性腺激素释放激素类似物	卵巢早衰的定义：排卵及月经早期停止，血清FSH水平不升高(高促性腺激素水平导致停经)。结果：自然月经和自然排卵的发生	8
Sverrisdottir等^[5]	1990～1994年	多中心随机对照	早期乳腺癌；绝经前女性	手术：保留乳房手术。化疗：6个周期CMF方案±他莫昔芬。保留乳房患者和≥4枚淋巴结阳性者接受放射治疗。GnRHa：戈舍瑞林每28 d 3.6 mg，连续2年；对照组未使用促性腺激素释放激素类似物±他莫昔芬	卵巢早衰的定义：月经停止。结果：自然月经的发生	>24
Moore等^[6]	2004～2011年	公开的多中心随机对照	原发性激素不敏感Ⅰ～ⅢA期乳腺癌；年龄18～49岁；绝经前女性	手术：不详。化疗：<40岁使用蒽环类为基础化疗3～4个周期，约3个月；40～49岁使用非蒽环类为基础化疗6～8个周期，大约6个月；HER-2过表达者使用曲妥珠单克隆抗体。放射治疗：不详。GnRHa：戈舍瑞林每28 d 3.6 mg，连续2年；对照组未使用促性腺激素释放激素类似物	卵巢早衰的定义：月经停止连续6个月及2年内FSH维持在绝经后水平。结果：防止卵巢功能衰竭，降低早期绝经的风险并提高生育率	24
Elgindy等^[7]	2009～2011年	随机公开安慰剂对照	原发性激素不敏感型Ⅰ～Ⅲa期乳腺癌；年龄18～40岁；绝经前女性	手术：不详。GnRHa：西曲瑞克0.25 mg/d，直到E₂<50 pg/ml，曲普瑞林每28 d 3.75 mg；对照组未使用促性腺激素释放激素类似物	卵巢早衰的定义：月经停止。结果：自然月经的发生	18

Del Mastro等^[2]

Munster等^[3]

Badawy等^[4]

Sverrisdottir等^[5]

Moore等^[6]

Elgindy等^[7]