acm Advances in Clinical Medicine 2161-8712 2161-8720 beplay体育官网网页版等您来挑战! 10.12677/acm.2024.1472085 acm-91874 Articles 医药卫生 青春期前男性乳腺发育症病因及影响因素研究进展
The Causes and Influencing Factors of Prepubertal Gynecomastia
1 梁丽俊 2 宁夏医科大学第一临床学院,宁夏 银川 宁夏医科大学总医院儿科,宁夏 银川 02 07 2024 14 07 825 832 17 6 :2024 11 6 :2024 11 7 :2024 Copyright © 2024 beplay安卓登录 All rights reserved. 2024 This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/ 青少年时期发生的男性乳腺发育症往往被认为是生理性或特发性表现,未受到足够的重视。实际上青春期前男性乳腺发育症在很多情况下有明确的基础病因,但由于往往被认为是生理性或特发性表现延迟诊断延误病情,造成儿童不可逆的生长发育障碍和严重心理问题。因此,本文综述了国内外的相关研究,探讨青春期前男性乳腺发育症不同病因的特征和可能影响青春期男性乳房发育的因素,希望引起儿科医生的重视,并联合多学科多领域协作,共同促进儿童健康成长。
Gynecomastia in adolescence is often considered to be physiological or idiopathic and has not received enough attention. In fact, in many cases, prepubertal gynecomastia has a clear cause. However, due to often being considered to be physiological or idiopathic, it causes delayed diagnosis and delayed disease, resulting in irreversible growth and development disorders and serious psychological problems in children. Therefore, this article reviews the domestic and foreign research, discusses the characteristics of different causes of prepubertal gynecomastia and the influencing factors that may affect pubertal gynecomastia, hoping to attract the attention of pediatricians and to join forces with other disciplines to jointly promote the healthy growth of children.
青春期前,男性乳腺发育症,病因,影响因素
Prepubertal
Gynecomastia Causes Influence Factor
1. 引言

男性乳腺发育症(gynecomastia, GYN)目前被认为是男性乳腺疾病中发病率最高的疾病,在婴儿期、青春期、老年期三个时期的GYN被认为是生理性表现,其中青春期GYN是一种常见的情况。大约50%的青春期中期男孩会受到影响,超过90%的患者在24个月内自发缓解 [1] 。与青春期GYN不同,青春期前男性乳腺发育症(prepubertal gynecomastia, PPGM)却很少见,国内外PPGM病例也很少报道,但只要是青春期前发现的男性乳腺增生就怀疑很有可能存在比较复杂的原发性病因、特殊的接触性和其他未知的病理性因素。并不能简单的认为PPGM都是特发性的 [2]

2. 青春期前男性乳腺发育症的概念及危害 2.1. 概念

青春期前男性乳腺发育症PPGM,指男性乳腺增生乳房体积增大且没有其他第二性特征的表现,增生乳腺组织可为单侧或双侧,伴或不伴有乳晕下触及可推动肿块。不同于青春期的生理性GYN,PPGM被认为在多数情况下是罕见的病理性表现 [1] 。需要长期的临床评估和随访,详细询问特殊物品的接触史、家族史,和全面的辅助检查排除可能的病理因素。

PPGM的机制可以概括为:1) 由于内源性过量雌激素产生或全身暴露于外源性雌激素而导致雌激素水平升高;2) 雌激素/雄激素平衡向有利于雌激素水平的方向转变;3) 由于局部应用含雌激素的产品而导致局部旁分泌和自分泌雌激素效应;4) 乳腺组织雌激素敏感性增加;5) 乳腺组织原发肿瘤性病变 [3]

PPGM的全面检查应包括性激素(雌二醇、FSH、LH、雄烯二酮、17-OH-孕酮、雌酮、睾酮、泌乳素水平);甲状腺功能fT3、fT4、TSH、抗甲状腺球蛋白、抗甲状腺过氧化物酶);肝功能;肾功能;肿瘤标志物(甲胎蛋白、β-HCG、Ca125);乳腺超声检查、睾丸超声检查、上下腹超声检查等 [4]

2.2. 危害

乳腺增生肥大,可作为其他严重内分泌或肿瘤疾病的首发表现,如睾丸支持细胞瘤、芳香化酶过度综合征等,除了会导致GYN外,还可导致患儿线性生长、骨龄成熟等更严重的内分泌系统紊乱表现 [5] 。并且GYN被认为是男性乳腺癌的已知危险因素 [5] 。有研究表明病理原因所导致的青少年GYN患者往往在乳房出现后18个月以上才被诊断出来 [6] 。所以对PPGM进行早期全面的评估和病因检查是有必要的,以免遗漏病理和延迟诊断延误病情。

PPGM对青少年的心理影响是不可估量的,青少年时期被认为是发展自尊的最关键的时期。当男性乳房发育增大发生在与身心发展和自尊建立有关的年龄,可能会导致焦虑,与同龄人的差异感,以及限制社会交往和参与运动,特别是团体运动,Zdravka P. Todorova等 [7] 的研究中84名青少年患者(53.5%)承认由于乳房增大产生心理负担(感到羞耻、困窘、幸福感降低、焦虑),12.1%的GYN患者因其进行过心理咨询,8.2%的GYN患者在团体运动中停止运动,2.5%的GYN患者更换了衣服 [6] 。有研究提出GYN可能引起精神病理,认为GYN是一种精神内分泌疾病。

3. 青春期前男性乳腺发育症的病因

导致青春期前乳腺增大最常见的病理原因包括药物、性早熟、甲状腺功能异常、高芳香化酶综合征以及睾丸、肾上腺、乳腺和人绒毛膜促性腺激素分泌肿瘤 [2] 。其他如:间接接触雌激素、乳腺组织雌激素受体过度表达、先天性睾丸发育不全、雄激素不敏感综合征、肯尼迪症、Prader-Willi综合症、病毒性睾丸炎、肾上腺疾病、甲亢、性激素结合球蛋白-SHBG增加、肝病等均有可能是PPGM的病因。

3.1. 睾丸支持细胞瘤(Sertoli Cell Tumor, SCT)

SCT是一种少见的肿瘤,约占睾丸肿瘤的0.4%~1.5%,分为四种组织学形式:大细胞钙化的SCT、小管内的大细胞透明SCT、硬化SCT和其他未特指的肿瘤 [8] 。芳香化酶是雌激素合成并将雄激素转化为雌激素的关键 [9] 。Sertoli细胞增生可导致的芳香化酶活性增加,导致雄烯二酮向雌酮的转化增加,从而导致青春期前男性乳腺增生肥大、睾丸增大和线性生长、骨龄成熟和等表现。

Peutz-雅格斯综合征(Peutz-Jeghers syndrome, PJS)和Carney综合征(Carney complex, CNC)都是罕见的遗传性综合征 [10] [11] 。而在John C Thomas等 [12] 的研究中青春期前睾丸肿瘤登记处报告的43例间质瘤患者,有10名男孩有SCT,其中40%的SCTs是PJS和CNC的一部分。

Hale Tuhan等 [13] 报道了一例8岁半的患者,以双侧乳房发育为主诉,在两年的随访中实验室检查未发现内分泌异常,但发现双侧乳房发育进展,睾丸体积增大,骨龄提前,生长速度加快,最后在睾丸活检后才明确诊断为小管内的大细胞透明SCT。Fatma Dursun等 [14] 人报道了一例4岁男孩因双侧乳房肿大被转诊至儿科内分泌,后续检查中发现乳房发育表现为Tanner 2期,腋毛和阴毛缺失,阴茎伸展长度6 × 1.5 cm,右侧睾丸2 mL,左侧睾丸5 mL,阴囊超声显示左侧睾丸内有囊性成分的8 × 12 mm实性病灶,激素水平均在正常范围内。进行了左睾丸切除术,乳腺发育症于术后3个月末消退。Beeling Armijo等 [15] 人报道了一例4岁的男孩发现GYN,嘴唇伴有斑点。该患者的碱性磷酸酶被报告显著升高,无触及阴囊肿物或疼痛。由于保守的方法GYN没有变化,以及他骨龄的加速、雌二醇的激增,且由于肿瘤的双侧弥漫性,缺乏任何离散的病灶,最后患者接受了双侧根治性睾丸切除术。Masako Izawa等 [16] 人报道了一例具有Sertoli细胞肿瘤的雄激素不敏感综合征患者。患者在8岁时出现乳房增大和生长加速,同时伴有血清雌二醇水平升高和血清促性腺激素水平降低,并在10岁时接受了性腺切除术,组织学显示右侧性腺中存在非恶性Sertoli细胞肿瘤。

3.2. 先天性睾丸发育不全(Klinefelter Syndrome, KS)

KS是男性最常见的染色体畸变,大约每600例新生儿中就有1例发生,研究表明,KS的诊断率只有25%,只有10%的患者在青春期前确诊 [17] 。有研究表明大多数KS患者(83.7%)表现为典型的47,XXY核型,7.1%表现为47,XXY/46,XY嵌合体,半数小于18岁的患儿表现为轻度神经发育障碍,最常见的临床表现是青春期前患者的隐睾,以及青春期患者的小睾丸、隐睾和GYN [17] 。患有KS的患者经常有发育缺陷、语言问题和社交困难,并存在一系列合并症,使发病率和死亡率增加40% [18] 。其中有研究表明KS中GYN的发生率约为40%,且GYN是由于睾酮/雌二醇比值降低引起的 [19]

Eda Celebi Bitkin等 [20] 的研究中,研究分析43名GYN患者。36例(83.7%)为PPGM,7例(16.2%)为病理性GYN,病理性乳腺发育症患者中3例为PPGM,其中2例为KS。

3.3. 芳香化酶过度综合征(Aromatase Excess Syndrome, AES)

AES是一种罕见的遗传性常染色体显性遗传病,由编码芳香化酶AES的CYP19A1基因突变引起,表现为雌激素生成增加和睾酮(T)水平降低。AEX的临床表现包括青春期前或青春期的GYN、性腺功能失调、骨龄提前和成年身高降低 [21]

Gerhard Binder等 [22] 人回顾性收集7例AEXS患儿均出现青春期前男性乳腺发育,中位年龄9.0岁。Kotb Abbass Metwalley等 [23] 报道了一例以青春期前男性乳腺发育为表现的AEXS,并且患有NF1,骨龄提前了3年。谭新睿等 [24] 报道了一例8岁患者,由于GYN就诊,体格检查显示Tanner III期男性乳腺发育,没有阴毛,呈现高大的身材并发现有明显的骨龄提前,经过8个月的积极治疗,他的身高从137.7 cm增加到144 cm,没有明显的骨龄进展,但他的乳房发育仍处于Tanner III期。

3.4. 神经纤维瘤病1型(Neurofibromatosis Type 1, NF1)

NF1是一种常染色体显性遗传病,大多数NF1患儿的乳腺发育症是由于乳腺区域的假血管基质增生、脂肪瘤或神经纤维瘤样增生或神经及其支持基质的错构瘤样病变 [23]

Reinhard E. Friedrich等 [25] 报道了一例16个月大的男孩表现为单侧乳腺发育症的NF1儿童,并回顾分析了17篇文献报道中的27例患者,其中至少有18名年龄在10岁或10岁以下,分析所述GYN是NF1表型的特征,NF1中腺体肥大和神经纤维瘤均可引起乳腺肿大,从而使乳腺发育上升为人体生理表现,通常与内分泌学功能失调无关。

3.5. 药物

药物对GYN的影响主要是通过影响其内分泌紊乱,根据机制不同可分为:雌激素增多(雌二醇、己烯雌酚、氯米芬、香豆素类)或活性增强(孕激素、洋地黄、苯妥英钠),雄激素减少(酮康唑、烷化剂、西咪替丁、奥美拉唑)或活性减弱(螺内酯、雷尼替丁),改变雄激素芳香化(异烟肼、乙胺丁醇)等 [26] 。其中Bonnie He等 [27] 人的大型回顾性队列研究的结果表明,在使用PPI的男性患者中GYN的风险增加。有研究表明长期使用唑类药物与肝毒性和激素相关效应有关,包括男性乳腺发育、肾上腺皮质功能不全等副反应 [28] 。有研究表明抗雄激素、5-a还原酶抑制剂和螺内酯与发展 GYN 的风险增加有关 [29] [30] [31] 。他汀类药物的使用被认为与GYN的风险增加有关 [32]

目前还没有针对药物引起PPGM的系统性病因研究,只有少数的病例被报道。Sarah Wing Yiu Poon 等 [33] 报道了一例11岁的青春期前男孩,他在异烟肼治疗四个月后在出现了左乳房肿胀疼痛感,查体:左侧乳头乳晕复合体周围有一1.5 cm × 1 cm的实性腺体组织,右侧乳头乳晕复合体周围有一0.5 × 0.5 cm的腺体组织,停用异烟肼8周后乳房肿胀消退。Eda Celebi Bitkin等 [22] 报道了1例患有充血性心力衰竭的患儿在使用螺内酯三个月后出现双侧乳房发育,停药后乳房发育消退。

3.6. 其他

乳腺组织雌激素受体过度表达可能会导致PPGM。有研究证明在缺乏内源性雌激素生成的芳香化酶KO小鼠和缺乏功能性ER a (estrogen receptor, ER a)的ER a敲除小鼠中,均表现出乳腺发育受损 [34] 。提示ER a在乳腺发育的过程中起着重要的作用。有研究表明患有特发性GYN的男性存在ER和PR (progestogen receptor, PR)的原发性过度表达 [35] 。Wang C等 [36] 报道的1例单侧乳房组织肿大11岁患儿,血清雌激素和雌激素/睾酮水平在正常范围内,但ER a (强阳性,70%)和PR (强阳性,80%),提示局部雌激素和孕激素的敏感性增加,推测单侧乳腺组织上ER a的过度表达可能是GYN的原因之一。

间接暴露于过量的局部雌激素可能会引起青春期前儿童的乳房发育、生长的快速变化和骨龄提前,Joao Correia De Pinho等 [37] 报道了三例因间接接触雌激素产品引起的PPGM,同时引起了骨龄提前,在停用含有雌激素的软膏后乳腺发育均自行缓解,并在之后的随访中未复发。

4. 青春期前男性乳腺发育症的影响因素 4.1. 肥胖

儿童青少年超重和肥胖在GYN的发生发展中起重要作用 [38] 。芳香化发生在脂肪组织中,是男性体内E2的主要来源 [39] 。脂肪组织中芳香化酶的产生和活性增加是导致肥胖GYN的主要因素 [22] 。有研究表明当前中国大约一半的成年人和五分之一的儿童存在超重或肥胖,使中国成为世界上超重或肥胖人数最多的国家 [40] 。随着近些年中国社会经济的发展、人们的生活水平提高,以及疫情影响下儿童肥胖患者的门诊数量在不断增加,也提示应该更加重视开展青少年儿童肥胖对于是否能引起PPGM等相关性研究调查。

Zdravka P. Todorova等 [6] 人的回顾分析157名转诊到内分泌科诊断患有GYN的男孩和青少年中,有76.43 %的人被诊断为肥胖,3.18 %的人超重。

4.2. 精油

日常生活中许多商品含有精油成分,包括食品调味品、肥皂、乳液、洗发水、发型产品、古龙水和洗衣粉 [41] 。内分泌干扰物(Endocrine Disrupting Chemicals, EDC)是一种外源性物质或化学物质的混合物,已知EDC会干扰荷尔蒙的合成、代谢、运输和降解 [42] 。有研究表明,薰衣草精油和茶树精油及其成分中含有EDCs,并且精油可作为雌激素受体α (ERα)的激动剂和雄激素受体(AR)的拮抗剂,从而对青春期前儿童的乳房生长有促进作用 [43] [44]

Alejandro Diaz等 [45] 报道了三例9岁患儿接触有精油成分的产品导致PPGM的病例,并在停止使用产品后进行了为期4个月的后续评估,显示患儿GYN都完全缓解。同时有研究指出,由于系统性综述报告纳入、人口数据、临床数据和因果关系的可能性被认为是不够的,并不能证明精油能够导致GYN [46] 。需要进一步全面的流行性调查来证明精油和PPGM的关系。

4.3. 其他

Wafaa Laimon等 [2] 报道了一例10岁的孩子由于长期使用优势左臂携带西瓜,反复的压力和摩擦而导致的单侧GYN。Maria Chiara Pellegrin等 [47] 报道了一例11岁的男孩,由于受到学校同学的骚扰欺凌,反复的左侧乳头挤压引起的左侧乳房胀痛。提示摩擦和压力刺激乳房可能会引起PPGM。

5. 结语

PPGM的诊断应包括对可能的病理疾病的检查和详细的询问病史及家族史,不能认为是围青春期发生的生理性或特发性的GYN而保守观察治疗,以免遗漏病理因素引起的PPGM,延迟诊断延误病情,造成儿童不可逆的生长发育障碍和严重心理问题,需要引起儿科医生的重视,并联合多学科多领域协作,共同促进儿童健康成长。肥胖、精油和摩擦刺激等可能引起PPGM的影响因素在生活中很常见,中国是全球超重和肥胖人数最多的国家并且随着社会经济的发展有逐年上升的趋势,肥胖已成为严重的公共卫生问题,需要进一步前瞻性的研究分析PPGM与其可能的影响因素之间的关系。

NOTES

*通讯作者。

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