李華萍，郭 禎，殷志強(qiáng)，鄧克紅，張保華，徐文怡

1.上海市浦南醫(yī)院婦產(chǎn)科，上海 200125；

2.江西省南昌市第三醫(yī)院乳腺科，江西 南昌 330009；

3.上海交通大學(xué)附屬仁濟(jì)醫(yī)院乳腺科，上海 200001；

4.鄭州大學(xué)第二附屬醫(yī)院婦產(chǎn)科，河南 鄭州 450014

抗米勒管激素用于年輕乳腺癌患者卵巢功能抑制個(gè)體化治療的評(píng)價(jià)

李華萍1，郭 禎2，殷志強(qiáng)3，鄧克紅4，張保華1，徐文怡1

1.上海市浦南醫(yī)院婦產(chǎn)科，上海 200125；

2.江西省南昌市第三醫(yī)院乳腺科，江西 南昌 330009；

3.上海交通大學(xué)附屬仁濟(jì)醫(yī)院乳腺科，上海 200001；

4.鄭州大學(xué)第二附屬醫(yī)院婦產(chǎn)科，河南 鄭州 450014

背景與目的：年輕乳腺癌患者應(yīng)用促黃體生成素釋放激素類似物戈舍瑞林治療沒有個(gè)體化用藥方案，并缺乏臨床可用的指導(dǎo)依據(jù)。該研究皆在探討抗米勒管激素(anti-Müllerian hormone，AMH)在年輕乳腺癌患者卵巢功能抑制個(gè)體化治療的評(píng)價(jià)作用。方法：選取2012年5月—2014年1月在上海交通大學(xué)附屬仁濟(jì)醫(yī)院因雌激素受體(estrogen receptor，ER)和孕激素受體(progesterone receptor，PR)陽(yáng)性的乳腺癌41例患者，術(shù)前隨機(jī)分為戈舍瑞林6個(gè)療程+化療組(簡(jiǎn)稱戈舍瑞林組)20例，化療組21例，30例同年齡組健康婦女為正常對(duì)照組，隨訪(17.4±6.2)個(gè)月。觀察兩組治療后的停經(jīng)時(shí)間與復(fù)潮時(shí)間，于術(shù)前1個(gè)月、戈舍瑞林組或化療組術(shù)后月經(jīng)復(fù)潮后3、6個(gè)月檢測(cè)AMH、促卵泡激素(follicle-stimulating hormone，F(xiàn)SH)和E2水平。正常對(duì)照組在相應(yīng)時(shí)間段內(nèi)檢測(cè)AMH、FSH和E2水平。結(jié)果：3組患者的術(shù)前臨床資料及術(shù)前FSH、E2水平差異均無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)，乳腺癌患者術(shù)前AMH水平較正常對(duì)照組降低，差異有統(tǒng)計(jì)學(xué)意義(P=0.04)；戈舍瑞林組較化療組停經(jīng)時(shí)間更短，差異有統(tǒng)計(jì)學(xué)意義(P=0.00)；戈舍瑞林組較化療組復(fù)潮時(shí)間更短，差異有統(tǒng)計(jì)學(xué)意義(P=0.00)；與正常對(duì)照組及術(shù)前比較，戈舍瑞林組及化療組FSH、E2水平在5個(gè)測(cè)定時(shí)間的差異均無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)；戈舍瑞林組及化療組在5個(gè)測(cè)定時(shí)間的AMH水平均顯著降低，差異均有統(tǒng)計(jì)學(xué)意義(P=0.00)，兩組在復(fù)潮后3、6個(gè)月AMH水平逐漸上升，差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)；與化療組相比，戈舍瑞林組的AMH水平下降明顯，戈舍瑞林組的AMH水平在復(fù)潮6個(gè)月后比化療組升高，差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)。結(jié)論：年輕乳腺患者在卵巢功能抑制治療+化療過(guò)程中，AMH較其他評(píng)價(jià)卵巢儲(chǔ)備的指標(biāo)明顯下降，在其他指標(biāo)恢復(fù)術(shù)前水平后仍提示卵巢受損，提示AMH可以作為評(píng)價(jià)年輕乳腺癌患者卵巢功能的指標(biāo)，亦有可能成為戈舍瑞林個(gè)體化治療的評(píng)價(jià)指標(biāo)。

抗米勒管激素；戈舍瑞林；年輕乳腺癌患者；卵巢功能抑制

根據(jù)美國(guó)癌癥研究所1975—2006年的流行病學(xué)統(tǒng)計(jì)，約2%的乳腺癌患者發(fā)生在20～34歲，約11%的患者發(fā)生在35～44歲［1］，研究表明化療可導(dǎo)致年輕乳腺癌患者卵巢儲(chǔ)備下降及卵巢早衰［2-6］。年輕乳腺癌患者推薦年卵巢功能抑制治療(ovarian function suppression，OFS)已達(dá)成國(guó)際共識(shí)，即應(yīng)用一種促黃體激素釋放激素類似物戈舍瑞林治療，可有效保護(hù)年輕患者的卵巢功能，不影響化療效果［7］，戈舍瑞林治療建立在個(gè)體化治療上［8］。但目前對(duì)年輕乳腺癌患者戈舍瑞林治療沒有個(gè)體化用藥方案，并缺乏臨床可用的指導(dǎo)依據(jù)。血清抗米勒管激素(anti-Müllerian hormone，AMH)水平與卵巢卵泡數(shù)具有相關(guān)性，近年來(lái)成為優(yōu)于年齡、促卵泡激素(follicle-stimulating hormone，F(xiàn)SH)和抑制素B等反映卵巢儲(chǔ)備的良好指標(biāo)［9-11］。本文研究雌激素受體(estrogen receptor，ER)和孕激素受體(progesterone receptor，PR)陽(yáng)性的年輕乳腺癌患者術(shù)后應(yīng)用戈舍瑞林+化療或化療，探討AMH在年輕乳腺癌戈舍瑞林個(gè)體化用藥方案的評(píng)價(jià)作用。

1 資料和方法

1.1 資料

1.1.1 患者分組

選取2012年5月—2014年1月在上海交通大學(xué)附屬仁濟(jì)醫(yī)院因ER和PR陽(yáng)性的乳腺癌將行手術(shù)治療的58例患者，隨機(jī)分為戈舍瑞林6個(gè)療程+化療組(以下簡(jiǎn)稱戈舍瑞林組)、化療組，隨訪(17.4±6.2)個(gè)月，因失訪剔除17例。選取同年齡組健康婦女為正常對(duì)照組。患者入選標(biāo)準(zhǔn)：① 年齡30～40歲；② 無(wú)內(nèi)分泌疾病、卵巢囊腫病史，無(wú)子宮卵巢手術(shù)史；③ 無(wú)激素服用史，無(wú)內(nèi)外科合并癥；④ 經(jīng)病理或細(xì)胞學(xué)診斷為乳腺癌，ER和(或)PR陽(yáng)性；⑤已行乳腺癌手術(shù)切除；⑥ 既往未行化療，Karnofsky評(píng)分≥80，目前病情需要；⑦ 無(wú)化療禁忌證，化療方案均為TAC(多西他賽75 mg/m2+多柔比星350 mg/m2+環(huán)磷酰胺500 mg/m2，第1天，每3周1次，共6次)；⑧ 患者知情同意，主觀上有強(qiáng)烈的維持正常月經(jīng)或生育要求；⑨ 化療結(jié)束后繼續(xù)口服他莫昔芬治療。正常對(duì)照組入選標(biāo)準(zhǔn)：①年齡30～40歲；②無(wú)內(nèi)分泌疾病、卵巢囊腫病史、無(wú)子宮卵巢手術(shù)史；③無(wú)激素服用史，無(wú)內(nèi)外科合并癥。具體情況見表1?；颊呔炇鹬橥鈺?，經(jīng)上海市浦南醫(yī)院倫理委員會(huì)批準(zhǔn)。

表1 戈舍瑞林組、化療組與正常對(duì)照組的臨床情況Tab. 1 The clinical situation of goserelin group, chemotherapy group and normal control group

1.1.2 實(shí)驗(yàn)材料

AMH ELISA試劑盒購(gòu)自德國(guó)貝-克曼二代公司，F(xiàn)SH、E2化學(xué)發(fā)光試劑盒及酶標(biāo)儀購(gòu)自德國(guó)西門子公司。所有激素測(cè)定均由上海達(dá)安公司完成。

1.2 方法

1.2.1 術(shù)前觀察指標(biāo)

正常對(duì)照組月經(jīng)第2～5天上午抽肘靜脈血，患者術(shù)前1個(gè)月月經(jīng)第2～5天上午抽肘靜脈血，采用化學(xué)發(fā)光法檢測(cè)FSH和E2水平，ELISA法檢測(cè)AMH水平。

1.2.2 手術(shù)和用藥方法

戈舍瑞林組20例和化療組21例，手術(shù)均由同一組醫(yī)師完成。戈舍瑞林組：化療前應(yīng)用1次戈舍瑞林3.6 mg，化療中每28 d應(yīng)用1次戈舍瑞林3.6 mg，一共應(yīng)用6次，化療方案為TAC，化療結(jié)束后停用戈舍瑞林?；熃M：常規(guī)化療，化療方案同上。

1.2.3 術(shù)后觀察指標(biāo)及隨訪

患者均完成手術(shù)，術(shù)后戈舍瑞林組在注射戈舍瑞林3、6針后，如月經(jīng)規(guī)律在月經(jīng)第2～5天上午抽血查AMH、FSH和E2，如停經(jīng)在戈舍瑞林注射后2天內(nèi)上午抽血查AMH、FSH和E2；停戈舍瑞林月經(jīng)復(fù)潮后3、6個(gè)月隨診1次，在月經(jīng)第2天上午抽血查AMH、FSH和E2；化療組術(shù)后在化療3、6次后，如月經(jīng)規(guī)律在月經(jīng)第2天上午抽血查AMH、FSH和E2，如停經(jīng)在化療結(jié)束后2天內(nèi)上午抽血查AMH、FSH和E2；正常對(duì)照組在同時(shí)期內(nèi)月經(jīng)第2～5天上午抽血查AMH、FSH和E2。

1.3 統(tǒng)計(jì)學(xué)處理

采用SPSS 10.0軟件進(jìn)行統(tǒng)計(jì)學(xué)分析，計(jì)量資料采用χ±s表示，假設(shè)檢驗(yàn)均為雙側(cè)檢驗(yàn)。各組比較采用重復(fù)測(cè)量數(shù)據(jù)方差分析，各組間比較采用單因素方差分析、秩和檢驗(yàn)；計(jì)數(shù)資料比較采用χ2檢驗(yàn)。P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

2 結(jié) 果

2.1 兩組治療后閉經(jīng)情況及月經(jīng)恢復(fù)時(shí)間

戈舍瑞林組使用戈舍瑞林后的閉經(jīng)時(shí)間顯著低于化療組，療程結(jié)束后月經(jīng)規(guī)律率高于化療組，復(fù)潮時(shí)間顯著低于化療組。戈舍瑞林組在應(yīng)用戈舍瑞林治療(2.20±0.62)個(gè)療程后閉經(jīng)，化療組在應(yīng)用化療(4.14±0.91)個(gè)療程后閉經(jīng)，差異有統(tǒng)計(jì)學(xué)意義(U=12.50，P=0.00)。兩組月經(jīng)復(fù)潮率均為100%，戈舍瑞林組在結(jié)束治療后(68.05±13.18)個(gè)月復(fù)潮，化療組在結(jié)束治療后(91.43±21.45)個(gè)月復(fù)潮，差異有統(tǒng)計(jì)學(xué)意義(U=68.00，P=0.00)；戈舍瑞林組月經(jīng)不規(guī)律5例，化療組月經(jīng)不規(guī)律7例，差異無(wú)統(tǒng)計(jì)學(xué)意義(χ2=0.51，P=0.29，表2)。

2.2 激素水平

戈舍瑞林組及化療組術(shù)前AMH水平均低于正常對(duì)照組，戈舍瑞林組在應(yīng)用戈舍瑞林+化療6次后AMH水平顯著低于化療組及正常對(duì)照組，戈舍瑞林組在停用戈舍瑞林+化療月經(jīng)復(fù)潮3個(gè)月后AMH水平逐漸恢復(fù)，6個(gè)月后AMH水平顯著高于化療組。

3組術(shù)前E2和FSH水平差異均無(wú)統(tǒng)計(jì)學(xué)意義(F=2.29和1.94，P=0.11和0.13)；兩組在應(yīng)用戈舍瑞林+化療或化療6次、月經(jīng)復(fù)潮6個(gè)月后不同的測(cè)量時(shí)間差異均有統(tǒng)計(jì)學(xué)意義(P均=0.00)，戈舍瑞林組與化療組在兩個(gè)測(cè)量時(shí)間的E2和FSH水平上差異均無(wú)統(tǒng)計(jì)學(xué)意義(P=0.34和0.08)。戈舍瑞林組和化療組術(shù)前AMH水平低于正常對(duì)照組，差異有統(tǒng)計(jì)學(xué)意義(F=4.32，P=0.04)。3組的AMH測(cè)量時(shí)間和分組差異均有統(tǒng)計(jì)學(xué)意義(F=52.89和24.76，P均=0.00)，兩兩比較，5個(gè)測(cè)定時(shí)間差異均有統(tǒng)計(jì)學(xué)意義(P均=0.00)；戈舍瑞林組及化療組在3、6個(gè)療程后AMH水平低于正常對(duì)照組及術(shù)前，差異均有統(tǒng)計(jì)學(xué)意義(P均=0.00)，兩兩比較，戈舍瑞林組與化療組在6個(gè)療程后AMH水平的差異有統(tǒng)計(jì)學(xué)意義(P=0.03)，兩組在復(fù)潮6個(gè)月后AMH水平的差異均有統(tǒng)計(jì)學(xué)意義(P=0.01，表3)。

表2 戈舍瑞林組和化療組患者的閉經(jīng)情況及恢復(fù)月經(jīng)時(shí)間Tab. 2 The amenorrhea and menstrual recovery time of goserelin group and chemotherapy group

表3 戈舍瑞林組、化療組與正常對(duì)照組患者的激素水平Tab. 3 The hormone levels of goserelin group, chemotherapy group and normal control group(χ±s)

3 討 論

越來(lái)越多的年輕乳腺癌患者在考慮癌癥治療、保留生育能力及生存質(zhì)量的問題，針對(duì)年輕乳腺癌患者戈舍瑞林治療的個(gè)體化在臨床工作中顯得尤為重要。去年國(guó)際乳腺癌聯(lián)盟建議年輕乳腺癌患者卵巢功能抑制治療5年［8］。一項(xiàng)回顧性的戈舍瑞林用于絕經(jīng)前乳腺癌患者治療的成本效益分析表明，接受戈舍瑞林治療較長(zhǎng)之間的患者生存期較長(zhǎng)［(122.5±6.3)個(gè)月 vs (112.2±6.7)個(gè)月］，比化療獲得更好生存率及生存質(zhì)量，并且有更好的成本效益［12］。關(guān)于放化療后保留生育功能的癌癥患者在輔助生殖技術(shù)結(jié)局中的研究表明，激素受體陽(yáng)性的乳腺癌患者，接受卵細(xì)胞體外成熟后體外受精-胚胎移植獲卵數(shù)及AMH水平均較低，差異有統(tǒng)計(jì)學(xué)意義(P=0.000 7)［9］。

生育期女性的AMH主要由次級(jí)卵泡、竇前和竇狀卵泡顆粒細(xì)胞產(chǎn)生［13］，卵泡發(fā)育到4～6 mm后分泌AMH，到竇前及小竇卵泡期達(dá)到高峰，隨著卵泡發(fā)育其表達(dá)水平逐漸降低［14］，AMH水平與卵巢卵泡數(shù)目具有相關(guān)性。AMH在正常周期女性血中波動(dòng)很小，不受周期影響［15-16］。近年AMH成為優(yōu)于年齡、FSH和抑制素B等反映卵巢儲(chǔ)備的良好指標(biāo)。有學(xué)者對(duì)147例生育期的晚期乳腺癌患者臨床研究表明，AMH、FSH和抑制素B能夠預(yù)測(cè)卵巢儲(chǔ)備功能的下降，AMH能更早、更準(zhǔn)確地反映卵巢儲(chǔ)備功能的下降，不受外源激素的影響［4］，并且成為評(píng)價(jià)乳腺癌患者卵巢儲(chǔ)備的指標(biāo)［17-18］。Su等［19］研究表明，在均衡了年齡、身體質(zhì)量指數(shù)、妊娠、種族、月經(jīng)模式和吸煙等因素，年輕乳腺癌患者的平均血清AMH水平和健康對(duì)照組差異無(wú)統(tǒng)計(jì)學(xué)意義(0.85 ng/mL vs 0.76 ng/mL，P=0.06)。本研究比較了年輕乳腺癌患者接受戈舍瑞林+化療或化療及正常生育期婦女的5個(gè)不同時(shí)間段AMH、E2和FSH的血清水平，以及戈舍瑞林+化療或化療后閉經(jīng)情況及月經(jīng)恢復(fù)時(shí)間。結(jié)果表明，兩組年輕乳腺癌患者術(shù)前AMH水平均低于正常對(duì)照組(P均<0.05)，與Su等［19］的研究結(jié)果不同，可能與樣本量較小有關(guān)。戈舍瑞林組在應(yīng)用戈舍瑞林+化療6次后AMH水平顯著低于化療組及正常對(duì)照組(P<0.05)，戈舍瑞林組在停用戈舍瑞林+化療月經(jīng)復(fù)潮3個(gè)月后AMH水平逐漸恢復(fù)(P<0.05)，6個(gè)月后AMH水平顯著高于化療組(P<0.05)。兩組應(yīng)用戈舍瑞林+化療或化療6個(gè)療程、月經(jīng)復(fù)潮6個(gè)月后戈舍瑞林組與化療組在2個(gè)測(cè)量時(shí)間FSH、E2水平上差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。戈舍瑞林組使用戈舍瑞林后的閉經(jīng)時(shí)間顯著低于化療組，療程結(jié)束后月經(jīng)規(guī)律率高于化療組，復(fù)潮時(shí)間顯著低于化療組。本研究結(jié)果表明，戈舍瑞林可以保護(hù)年青乳腺腺癌患者的卵巢功能，AMH可以作為評(píng)價(jià)年輕卵巢癌患者的卵巢功能的指標(biāo)，亦有可能成為OFS個(gè)體化治療的評(píng)價(jià)指標(biāo)。

年輕乳腺癌患者在考慮保留生育能力和提高生活質(zhì)量方面的目的不同，未生育年輕乳腺癌患者在完成乳腺癌常規(guī)治療后，應(yīng)用戈舍瑞林和內(nèi)分泌治療多久可以妊娠，已生育的年輕乳腺癌患者如何能在生存期內(nèi)有較高的生存質(zhì)量，目前在臨床工作中缺乏可用的評(píng)價(jià)指標(biāo)，而且個(gè)體化治療已迫在眉睫。本研究將繼續(xù)擴(kuò)大樣本量，加長(zhǎng)隨訪時(shí)間，將會(huì)得到一個(gè)更科學(xué)的結(jié)論。

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Anti-Müllerian hormone as a new marker of the individualized ovarian function suppression treatment in the young breast cancer patients

LI Huaping1, GUO Zhen2, YIN Zhiqiang3, DENG Kehong4, ZHANG Baohua1, XU Wenyi1(1.Department of Obstetrics and Gynecology, the Punan Hospital of Shanghai, Shanghai 200315, China; 2.Department of Breast, the Nanchang Third Hospital of Jiangxi Province, Nanchang 330009, Jiangxi Province, China; 3.Department of Breast, the Renji Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200001, China; 4.Department of Gynecology and Obstetrics, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, Henan Province, China)

YIN Zhiqiang E-mail: zdlhp@126.com

Background and purpose:The young breast cancer patients were treated with goserelin without individualized regimen, and lack of available clinical marker. The aim of this study was to investigate the role of anti-Müllerian hormone (AMH) in evaluation of individualized treatment of ovarian function suppression in the young breastcancer patients.Methods:Forty-one young patients with estrogen receptor (ER) and progesterone receptor (PR) positive breast cancer from May 2012 to Jan. 2014 were randomly divided into 2 groups to undergo radical resection of breast cancer. According to postoperative treatment, one group was treated with goserelin + chemotherapy (n=20), and the other group received chemotherapy alone (n=21). Thirty female patients in the same age group were selected as normal control group. The time of menopause and menstrual recovery after the goserelin + chemotherapy or chemotherapy alone were observed in 2 groups. In early follicular phase (day 3-5) of the cycle preceding the operation and 3, 6 courses after the goserelin + chemotherapy treatment or chemotherapy treatment, serum levels of AMH, FSH and E2were measured in 2 groups. Accordingly, serum levels of AMH, FSH and E2were evaluated as well in normal control group.Results:There were no significant differences in preoperative general conditions and preoperative serum FSH and E2levels among the 3 groups (P>0.05). Compared with normal control group, the preoperative serum AMH levels of young breast cancer patients were decreased significantly (P=0.04). The menopause time and menstrual recovery time in 2 chemotherapy groups were significantly shorter than that in normal control group (P=0.00). Compared with normal control group and preoperative measurement, the differences in serum FSH and E2levels were not statistically significant in goserelin + chemotherapy group or chemotherapy alone group (P<0.05). The serum AMH levels measured at different time points of the goserelin + chemotherapy group and chemotherapy alone group were decreased significantly (P<0.05). Compared with the chemotherapy group, the serum AMH levels of the goserelin + chemotherapy group after 6 courses were significantly decreased, and then significantly increased 6 months after menstrual recovery (P<0.05).Conclusion:This study demonstrated that the serum AMH levels were obviously decreased after the ovarian function suppression treatment and increased after the menstrual recovery compared with evaluation of other ovarian reserve index. The serum AMH level could suggest ovarian reserve damage even after ovarian function has recovered to the noticeable level. Thus, AMH could be used clinically to evaluate the ovarian reserve of breast cancer patients as a potential marker for the individualized ovarian function suppression treatment in young breast cancer patients.

Anti-Müllerian hormone; Goserelin; Young breast cancer patients; Ovarian function suppression

10.3969/j.issn.1007-3969.2015.12.011

R737.9

A

1007-3639(2015)12-0983-06

2015-05-11

2015-06-29）

上海市浦東新區(qū)青年醫(yī)學(xué)人才項(xiàng)目(PWRq2012-31)；上海市衛(wèi)計(jì)委課題(201440468)。

殷志強(qiáng) E-mail：zdlhp@126.com