抗缪勒管激素用于戈舍瑞林在年轻乳腺癌患者化疗期间保护卵巢储备功能的评价

Anti-Müllerian hormone as a new marker of the ovarian reserve function preservation by goserelin during (neo) adjuvant chemotherapy for young breast cancer patients

目的:监测反映卵巢储备功能的最佳生化指标——抗缪勒管激素(anti-Müllerian hormone,AMH)在化疗前和化疗结束后1年内的动态变化,评价促性腺激素释放激素激动剂(gonadotropin-releasing hormone agonist, GnRHa)戈舍瑞林在年轻乳腺癌患者化疗期间保护卵巢储备功能的效果。方法:选择2015年12月至2017年6月在北京大学人民医院乳腺外科就诊的年龄≤45岁Ⅰ~Ⅲ期乳腺癌患者101位,根据患者意愿,无干预分至化疗联合戈舍瑞林组(戈舍瑞林组)和单纯化疗组(化疗组)。在化疗开始前、化疗期间、化疗结束后半年、化疗结束后1年,连续监测两组患者的血清AMH和月经状态。首要研究终点是化疗结束后1年AMH低水平(<0.4 μg /L),次要研究终点是闭经(入组后停经时间超过12个月)。结果: 51位患者选择单纯化疗,50位患者选择化疗联合戈舍瑞林保护卵巢功能。临床病理基线资料显示,未婚未育、生育意愿强烈、成功保乳、激素受体阴性、处于疾病Ⅰ期或Ⅱ期的乳腺癌患者更多地在化疗前选用戈舍瑞林保护卵巢功能。化疗结束后1年,化疗组患者AMH低水平率显著高于戈舍瑞林组患者(74.5% vs. 38.0%, P <0.001),闭经率也与AMH低水平率相一致(56.9% vs. 24.0%, P =0.001),并且戈舍瑞林组的患者更多在化疗结束后6个月内恢复月经(78.9% vs .54.5%), AMH升至0.4 μg /L以上(71.0% vs .53.8%)。亚组分析中,无论年龄分组、化疗方案分组或化疗后是否口服他莫昔芬分组,戈舍瑞林组患者的血清AMH值和月经均恢复得更多。在化疗结束后1年,化疗组月经恢复的22人中有8人( 36.4%),戈舍瑞林组月经恢复的38人中有7人(18.4%)AMH仍处于低水平。此外,对化疗组20位患者和戈舍瑞林组21位患者在化疗过程中动态监测AMH和月经状态,化疗组患者的AMH均值在化疗开始后快速下降,在第3周期化疗前降至极低水平,此时70%的患者还未停经;戈舍瑞林组患者在第3周期化疗前全部停经,但AMH均值未降至低水平。结论:由于选择联合治疗的患者其血清AMH值在化疗结束后更多、更早地恢复,故对戈舍瑞林保护年轻乳腺癌患者卵巢储备功能的有效性提供了证据。相比月经状态,AMH更能精准地用于临床评价化疗前后年轻乳腺癌患者的卵巢储备功能。

Objective: To observe the dynamic change of anti-Müllerian hormone (AMH) in 1 year after chemotherapy which is the best biochemical marker of ovarian reserve in reproductive medicine setting and to evaluate the effect of gonadotropin-releasing hormone agonist (GnRHa)goserelin to prevent ovarian reserve function during (neo)adjuvant chemotherapy for young breast cancer patients. Methods: Between December 2015 and June 2017, 101 breast cancer patients of age ≤ 45 years with stagesⅠtoⅢ had been enrolled. The patients were assigned without interference to receive either (neo)adjuvant chemotherapy with goserelin (goserelin group) or without goserelin (chemotherapy group) as their own selection. AMH and menstrual status were evaluated before, during and 0.5 year, 1 year after chemotherapy. Primary end point was the incidence of low AMH value (<0.4 μg/L) at the end of 1 year. Secondary end point was the incidence of amenorrhea(the absence of menses in the preceding 12 months after assignment). Results: In the study, 51 patients chose to join the chemotherapy group, while the other 50 patients selected goserelin to preserve their ovarian reserve function. More unmarried or childless, hormone receptors negative,receiving breast conservation therapy patients with earlier stage selected goserelin before chemotherapy. The incidence of low AMH value was significantly higher in chemotherapy group than in goserelin group (74.5% vs . 38.0%, P <0.001) in 1 year after chemotherapy. The incidence of amenorrhea was consistent with AMH (56.9% vs. 24.0%, P =0.001). And more patients’ menstruation (78.9% vs. 54.5%) and AMH value (71.0% vs . 53.8%) recovered in goserelin group within 6 months after chemotherapy. In sub-group analysis, AMH and menstruation seemingly recovered more in goserelin group independent of age, chemotherapy regimen and use of tamoxifen. Especially, AMH value of 36.4%(8/22) patients in chemotherapy group and 18.4%(7/38) patients in goserelin group still maintained low level (<0.4 μg /L) although their menstruation had recovered 1 year after chemotherapy. In addition, 41 patients (20 patients in chemotherapy group, 21 patients in goserelin group) could be evaluated for the dynamic change of AMH and menstrual status during chemotherapy. The mean level of AMH in chemotherapy group declined rapidly to very low level before the 3rd cycle, while 70% of the patients kept presence of menstruation. At the same time, the mean level of AMH in goserelin group was still above 0.4 μg /L, but all of the patients had menopause. Conclusion: Our study has offered evidence that Goserelin with chemotherapy could protect against ovarian reserve failure for young breast cancer patients, now that more patients’ AMH value recovered earlier who had selected co-treatment. AMH may be a more precise marker than menstrual status to clinically evaluate ovarian reserve function pre-, during and post- chemotherapy.