译者按

  1. 译文篇幅极长,总计约 2.5 万个汉字,请耐心阅读。
  2. 原文存在多处引用和拼写错误,此处予以更正,但为保持页面简洁,不会一一附注,敬请留意。

摘要

雌激素和孕酮是主要的女性激素。已知二者均在人生不同阶段中对乳房发育有重要作用。至少自 1960 年代起,就有将孕激素用于女性倾向跨性别者以促进乳房发育的猜测、实践和传言。已有少数几项研究评价了孕激素用于女性倾向跨性别者时的乳房发育情况;但对于其是否确有促进乳房发育的作用,现有证据质量不足,无法得出明确结论。与此类似,有关用于顺性别女孩的孕激素及乳房发育情况的研究亦较有限。无论如何,当下有多项研究正在评价孕激素在乳房发育中的作用。
一些间接性证据亦可能揭示了孕激素有促进乳房发育的潜在作用:其中包括人体或动物在正常青春期、月经周期和妊娠期间,体内孕酮和乳房发育的关系。现有证据总体上不足以支持孕酮在青春期对乳房增长有决定性作用;但在妊娠期间,孕酮确实对乳腺小叶发育有明确、关键作用,而当泌乳、哺乳中止以后,妊娠带来的乳房改变将会逆转。在月经周期的黄体期内,孕酮可能还会引起可逆的乳房增大。
有结果表明,孕激素在乳房中可能有抗雌激素作用;如在激素治疗开始时过早引入,其可能对乳房发育有不良影响。但是,尚需更多研究来评价这种可能性。无论如何,兴许可以建议在雌激素介导的乳房发育基本或全部完成之前,延迟引入孕激素。
可用于女性倾向跨性别者的孕激素治疗选项有:具备生物同质性的孕酮,和人工孕激素。但是,口服孕酮有明显的生物利用度问题,不足以达到理想的孕酮水平。孕酮等孕激素均各自和重大健康风险有关,这是将其用于女性倾向跨性别者时需要着重考虑的。
综上,基于现有认知,孕激素用于女性倾向跨性别者不见得一定会促进乳房发育并持续;还需更多研究及数据来得出明确结论。


前言

在女性倾向跨性别者当中,常见乳房发育状况(尺寸、形状)不及预期的情况;群体中存在对可促进乳房增长的医疗手段需求。人体有两类主要的女性激素,分别是雌激素孕激素。其中雌激素是女性化激素治疗中几乎最基本的用药,而孕激素仅有一部分女性倾向跨性别者在应用;这里主要应用的孕激素有生物同质性孕酮,以及醋酸甲羟孕酮(MPA,一种人工孕激素)、有强孕激素作用的抗雄激素药物醋酸环丙孕酮(CPA)。雌激素在女性中是引起女性化和乳房发育的主要介导物质;但是,孕激素在乳房中也发挥生理作用,而这种作用不一定是正向的。

在跨性别社群中,关于孕激素和乳房发育的话题多年来一直在讨论,且颇有争议(Coleman et al., 2012)。将孕激素用于女性倾向跨性别者以改善乳房发育的应用,至少可追溯到 1960 年代 Harry BenjaminChristian Hamburger 的研究(Benjamin, 1966; Benjamin, 1967; Hamburger & Benjamin, 1969; 维基百科)。已有观点肯定了孕激素在乳房发育中有潜在作用(例如 Bevan, 2012; Bellwether, 2019Bevan, 2019),同时也有观点否定之(例如 Curtis, 2009)。其中提到较多的是,对于顺性别女性和女性倾向跨性别者,孕激素有助于乳房发育,甚而对完成乳房发育是必要的;还有人声称在女性倾向跨性别者青春期乳房发育过程中,需要孕激素实现从 Tanner 四期到五期的跨越,并使乳房更丰满、更圆润(例如 Vorherr, 1974a; Basson & Prior, 1998; Kaiser & Ho, 2015; Prior, 2011; Prior, 2019a; Prior, 2020)。更有甚者,认为乳房没有孕激素就将一直保持尖锥形,形如早期 Tanner 阶段。
有些人则走向另一个极端:他们声称“在生理男性身上不存在有生理功能的孕酮受体位点”,同时女性在青春期时、直至乳房发育完成都不分泌孕酮(Barrett, 2009; Seal, 2017; Coxon & Seal, 2018; Price, McManus, & Barrett, 2019; Richards & Barrett, 2020))。结果,他们在其著述中反对将孕激素用于女性倾向跨性别者(Google 学术)
总而言之,关于孕激素用于女性倾向跨性别者的争议由来已久,正反观点都很突出(Sam, 2020)

本文旨在对现有的、讨论孕激素和乳房发育的直接或间接证据进行回顾,以便解读孕激素用于女性倾向跨性别者是否可促进乳房发育的问题。以现有认识看,孕激素在身体女性化过程中除了参与乳房发育,并没有其它作用(例如 Coleman et al., 2012; Gooren, 2016);鉴于此,本文将聚焦于讨论孕激素和乳房发育的关系,不会就整个女性化过程展开讨论。

孕激素治疗和人类乳房发育的关系

用于女性倾向跨性别者的孕激素治疗和乳房发育情况

迄今仅有少量研究就孕激素治疗用于女性倾向跨性别者时的乳房发育情况进行评价。有的研究运用生物同质的孕酮,有的则运用 MPA、CPA 等人工孕激素的一种。对现有的孕激素和女性倾向跨性别者乳房发育情况相关资料,本文亦作了一定回顾,参考论文有:Wierckx, Gooren, & T’Sjoen (2014)Reisman, Goldstein, & Safer (2019)Patel et al. (2020)Patel et al. (2022)Milionis, Ilias, & Koukkou (2022)Coleman et al. (2022);以及 Berliere et al. (2023)

Orentreich & Durr (1974) 是最早的有关女性倾向跨性别者乳房发育的研究之一。在总计 5 名女性倾向跨性别者的病例系列中,研究者运用雌激素和孕激素组合以及性腺切除,以促成女性化和乳房发育。其中所用雌激素有肌注戊酸雌二醇 30 mg/两周、口服结合雌激素 1.25–5.0 mg/天;所用孕激素有肌注“己酸甲羟孕酮 60 mg”每两周、口服醋酸甲羟孕酮 0–10 mg/天。己酸甲羟孕酮(MPC)从未被批量生产,故推测原文系笔误,实际应采用了 MPA 或己酸羟孕酮(OHPC)作为孕激素。
据论文作者报道,雌激素和孕激素治疗对女性倾向跨性别者引起了轻度至明显的乳房发育,效果与剂量没有强相关性;作者还提供了对乳房的临床检查照片。他们总结认为,研究中乳房发育情况和成年顺性别妇女的基本一致。
Orentreich 及其同行还讨论了乳腺小叶的成熟,这已知和孕激素相关;但他们表示了未进行组织学检查,还透露从顺性别妇女的资料可知,乳腺小叶发育的程度并非必然和临床上的乳房体积相关。
Orentreich 及同行的结果存在一些研究方法上的限制:包括缺乏客观衡量方法、缺乏仅接受雌激素的对照组样本规模较小(女性倾向跨性别者共计仅 5 人)等等;因此从评价孕激素在乳房发育中的作用这个角度来说,这项研究的价值较为有限。

Meyer et al. (1986) 就雌激素治疗中加用的孕激素对女性倾向跨性别者的乳房发育和其它临床特征之影响进行研究。其中,60 名女性倾向跨性别者有 15 人(25%)给予口服孕激素,多为 10 mg/天的 MPA,且持续了“至少一段较短的时间”——仅 8 人(13.3%)在整个治疗期内持续服用。在该研究早期的报告中提到,观察期内有 90% 的时间以 10 mg/天的剂量给药,其余时间则为 20 mg/天(Meyer et al., 1981)。在 10 mg/天剂量下,MPA 的孕激素效力大致与黄体期孕酮暴露所致效力相当(维基百科)。研究中以乳房半围来评价乳房发育状况(示意图)
结果表明,孕激素治疗未改变由雌激素促导的变化过程,包括实验室检验结果、激素水平,以及体重、乳房增长等体征。其中,激素水平未发生改变的结果与预期不符:在其它高质量研究中,MPA 对睾酮有明显抑制作用(例如 Jain, Kwan, & Forcier, 2019; 维基百科)
Meyer 及其同行总结认为,在雌激素之外加用孕激素应不会促进女性倾向跨性别者的乳房发育。但是,他们提到该研究中服用孕激素的个体数偏少,尚需进一步研究。

Prior et al. (1986)Prior, Vigna, & Watson (1989) 将雌激素、高剂量螺内酯(100–600 mg/天)和 MPA(10–20 mg/天,序贯或连续服用)用于从未进行激素治疗、或曾接受高剂量雌激素(和/或孕激素)但未合并螺内酯治疗的女性倾向跨性别者,并进行研究。
研究者报告称,依指定激素方案治疗 12 个月后,乳房体积和乳头发育均有所增长。至研究结束前,大多数个体的乳房组织达到 A 罩杯,直径约达 8–14 cm。影像记录也作为乳房发育情况之评价的一部分进行。尽管乳房发育被报道有所改善,但据研究者的自述,难以确认其是否可归因于螺内酯或 MPA。此外,对睾酮的抑制效果在研究开始前是不充分的,而后随研究指定的激素方案有所改善;无论 MPA 是否对乳房有直接的孕激素作用,该方案都可能促进了乳房发育。最后,不能排除研究前由雌激素诱导的乳房发育尚未停止,而后仅靠雌激素本身便足以继续促进乳房发育的可能性。
上述研究的第一作者 Jerilynn Prior 在其它著述中称,孕酮有促进乳房发育的作用,并引用上述研究以支持其论点(Prior, 2011; Prior, 2019a; Prior, 2019b; Prior, 2020)。然而,上面讨论的这些研究的局限性使得其论点缺乏足够根据。

Dittrich et al. (2005) 报告称,经口服戊酸雌二醇合并促性腺激素释放激素(GnRH)激动剂治疗二年后,女性倾向跨性别者有 5% 报告乳房达到 C 罩杯或更大,30% 报告有 B 罩杯,35% 报告有 A 罩杯,其余 30% 未达到 A 罩杯。但他们指出,有 70% 的个体对乳房发育情况不满意,有意接受隆胸手术
研究者声称,某些个体报告在研究开始前曾采用炔雌醇和 CPA 治疗,而研究所用配方所促成的乳房体积增长等女性化效果与其相似。论文未透露其它细节。这个说法和本文要讨论的有关,因为 CPA 在早期用于女性倾向跨性别者的剂量下有很强的孕激素作用(Aly, 2019)。但应当注意,该研究并未运用孕激素疗法本身或对其研究。此外,自发报告具有很大主观性,作为评价乳房发育和乳房体积的依据是欠妥的。因此,从理解孕激素和乳房发育关系的角度出发,这项研究结果价值如何是有待商榷的。

在乳房发育过程中,雌激素主要参与乳腺导管发育,而孕酮主要参与乳腺小叶/小泡的发育。Kanhai et al. (2000) 记录了雌激素和 100 mg/天 CPA(即超高剂量孕激素)用于 14 名女性倾向跨性别者所引起的乳腺组织学变化,以及非甾体抗雄激素制剂氟他胺比卡鲁胺)单药用于 2 名患前列腺癌的顺性别男性所引起的乳腺改变,并加以比较。这两种疗法均可阻断雄激素,使雌激素水平升高,且均已知有较高几率促导乳房发育或男性乳腺增生。然而,这二者有一点不同:非甾体抗雄制剂单药并不具备孕激素效力。
乳腺活体切片显示,在女性倾向跨性别者当中,乳腺小叶发育充分;而在男性前列腺癌患者中,仅观察到“中等程度”发育、即发育不充分的乳腺小叶。论文还指出,当女性倾向跨性别者接受性腺切除术,从而停用 CPA 之后,其乳腺小叶形成有退化倾向。研究者总结认为,有必要使乳房暴露于孕激素,以实现组织学意义上的完全发育;对于女性倾向跨性别者,如此可完全模拟成熟的女性乳腺组织形态。
该研究的结果虽引人注目,但其关注点局限于组织形态,并未真正提供任何关于乳房发育的外观资料。从这点来说,组织学上的差异可能不足以体现乳房体积或外形等性质的相对差异。因此,如要理解孕激素用于女性倾向跨性别者时是否可实实在在地促进乳房发育,则该研究的参考价值是有限的。

Seal 及同行开展了一项回顾性 图表调研,以评价面向女性倾向跨性别者的隆胸手术的临床预测因子(Seal et al., 2012)。其中,螺内酯的使用率在接受了隆胸手术的女性倾向跨性别者当中,要高于未接受手术者。对于醋酸环丙孕酮、5α-还原酶抑制剂、GnRH 类似物等其它特定的抗雄激素制剂,在接受手术者和未接受者之间,其使用率没有明显差别。
但是,其研究方法存在诸多局限性,包括:进行 30 余次未按多重比较修正t-检验,从而存在假阳性风险和 P 值篡改p-hacking)的嫌疑;诸抗雄制剂各自的样本规模较小;未实际对乳房或其体积进行物理测量,便以隆胸替代乳房发育过程;未就潜在干扰变量的控制进行相关性设计。综上,该研究没有表明各类抗雄制剂所引起的乳房发育效果有所差异,其结果须予以审慎看待。

Jain, Kwan, & Forcier (2019) 对经舌下含服的雌二醇和螺内酯(合并或不合并 MPA)用于 92 名女性倾向跨性别者的情况进行研究。其中,MPA 有两种给药方式:舌下含服 5–10 mg/天,或每三个月肌注 150 mg;接受 MPA 治疗者有 39 人,其中 26 人(67%)报告乳房发育有所增长。论文虽未提供其余细节,但可以认为其中对乳房发育的评价源自患者的主观口述。
Igo & Visram (2021) 对在女性倾向跨性别者的激素疗法中加用孕酮的情况进行研究。其中,孕酮以微粉化 100 mg 制剂(或为口服)的形式给药;如患者主动要求,或患者表示对当前女性化和/或乳房发育效果不满意,则给予孕酮。受试者共 190 人,其中 51 人(26.8%)接受孕酮治疗。孕酮的初次给药时间平均比雌二醇治疗开始时要晚 12.7 个月;对激素治疗的平均跟踪时长为 14.3 个月。在服用孕酮的个体中,仅 6 人(11.8%)报告孕酮对乳房发育有益。论文虽未提供其余细节,但和其它研究类似的是,其中对乳房发育效果的量化很可能也依赖于口述的自发报告。
综上,这两项研究显然均未对乳房发育进行任何客观评价,也未设置对照组以比较,故其结果的参考价值有限。

Nolan 及其同行则在一项前瞻性对照研究中,对正平稳接受激素治疗的女性倾向跨性别者加用了低剂量口服微粉化孕酮,并评价了该形式的孕酮对乳房发育的短期影响(Nolan et al., 2022a; Nolan et al., 2022b)。其中,23 名女性倾向跨性别者给予孕酮 100 mg/天,持续三个月;其结果与由 19 名女性倾向跨性别者构成的对照组进行比较。乳房发育效果通过患者自发报告的 Tanner 发育阶段进行评价,具体为患者从各个 Tanner 阶段的照片中选择一张上报。
治疗三个月后,两组报告的 Tanner 阶段的差异没有统计显著性(孕酮组平均值 3.5,95% 置信区间 3.2–3.7;对照组平均值 3.6,95% 置信区间 3.3–3.9;P = 0.42)。该研究存在一项局限性,即口服孕酮的生物利用度极低,在 100 mg/天剂量下,其仅可产生很低的孕酮水平,远低于黄体期正常范围(Aly, 2018a; 维基百科)。因此,在这项研究以及 Igo & Visram (2021) 等其他研究中,孕激素暴露很可能是不充分的。
除孕激素作用强度以外,该研究在方法上的重大局限性还有:研究时长非常短(仅三个月);研究依赖于有主观性的 Tanner 阶段自发报告,而非较客观的乳房外围测量。无论如何,该研究从质量而言仍高于前述研究,且将来还有继续研究并提供更长跟踪期之结果的可能性。

Bahr et al. (2024) 在其诊所内开展了一项回顾性图表调研,将 29 名曾服用孕激素的女性倾向跨性别者和 59 名未服用者的情况加以比较。其中运用的孕激素有:口服或直肠给药的孕酮,占比 93%;肌注 MPA,占比 7%。孕酮使用者中,有 25 人(93%)口服孕酮,另有 2 人(7%)以直肠给予孕酮胶囊。关于孕激素剂量,仅报道了 100 mg 孕酮胶囊的使用,其余未见报道。孕激素使用者有大部分(59%)于常规激素治疗开始后 1–6 个月起服用孕激素。
研究者发现,激素治疗六个月后,孕激素使用者所自行报告的乳房发育满意程度,相较未使用者有统计显著性地更高(满意程度分“满意”“一般”“不满意”三级,其中“满意”的比例:53.8% 对 19.6%,p = 0.004);治疗九个月后亦然(“满意”比例:71.4% 对 20.8%,p = 0.003)。
该研究的局限性有:缺乏对乳房发育的客观测量手段,研究本身具有回顾性性质,没有随机化分配治疗方案,等等。

前述研究之外,还有一批研究报告了雌激素和 CPA 用于女性倾向跨性别者时的乳房发育情况,其中大多采用较客观的物理测量手段(如乳房体积乳房—下胸围差乳房罩杯乳房半围等);但因缺乏对照组,没有将含孕激素的激素治疗和不含孕激素的治疗进行比较。此外,CPA 还有一点跟其它孕激素不同:其用于女性倾向跨性别者的剂量特别高(Aly, 2019),相比近似于生理性的孕激素暴露,这可能会导致不一致、甚至不充分的乳房发育结局。因此,本章节没有就此类研究展开讨论,而在其它章节展开(详见下文)。无论如何,这里简要概括这批研究的结果,即雌激素和 CPA 用于女性倾向跨性别者所引起的乳房发育大多不良;所载结局包括,乳房的 Tanner 分级均未达到完全成熟(2–4 级),罩杯较小,乳房体积较小,乳房尺寸较顺性别妇女更小等等。

由于方法上的局限性,前述研究的质量很不理想:例如,未设置对照组,未随机分配受试者,依赖于低可信度手段(如主观评价和自发报告)而非客观的物理测量手段(维基百科),治疗时长较短,样本规模较小,等等。这可能解释了以上研究的结论为何互相矛盾。
对于孕激素在女性倾向跨性别者中如何影响乳房发育,还需更多研究佐证;尤其需要开展随机对照试验(RCT),来比较含孕激素的女性化激素治疗和不含孕激素者引起的乳房发育情况,还要有客观的测量手段、有足够大的样本规模、有足够长的跟踪时长。另外诸如孕激素种类、给药途径、剂量、何时引入治疗等变量,也是值得探究的。一份有关用于女性倾向跨性别者的激素治疗、于 2014 年发表的评述,汇总了当时对孕激素和女性倾向跨性别者之乳房发育的研究情况,其结论至今依然成立(Wierckx, Gooren, & T’Sjoen, 2014)

我们对跨性别女性乳房发育的自然史,以及受不同跨性别激素疗法有何影响的认识严重不足,且证据质量欠佳。目前的证据未证实孕激素用于跨性别女性可促进乳房发育,也不能证实这个作用不存在。因此,我们目前无法得出任何明确结论;这也表明尚需更多研究以厘清这些问题。

与此类似,多份综述和指南均总结认为,没有可靠证据表明将孕激素加入到女性倾向跨性别者的激素治疗,对乳房发育有任何益处或不利(Wierckx, Gooren, & T’Sjoen, 2014; Reisman, Goldstein, & Safer, 2019; Patel et al., 2022; Milionis, Ilias, & Koukkou, 2022; Coleman et al., 2022; Berliere et al., 2023)

目前正在开展的研究

目前已有多项针对孕酮和其它孕激素用于女性倾向跨性别者的研究陆续开展。其中包括:

  1. 由 Sandeep Dhindsa 博士及其同行于美国密苏里州圣路易斯市开展的,有关在激素治疗中加用口服孕酮的一项随机对照试验(ClinicalTrials.gov; MediFind; ICH GCP)
  2. 由 Ada Cheung 及其同行于澳大利亚墨尔本开展的,有关口服孕酮用于激素治疗的一项前瞻性观察性研究和/或 RCT(University of Melbourne; University of Melbourne)
  3. 同样由 Ada Cheung 及其同行开展的,有关雌二醇—螺内酯复方和雌二醇—CPA 复方之对比的一项 RCT(ANZCTR; WHO ICTRP; Trans Health Research [传单] [海报]; University of Melbourne)(参见后记一);
  4. 由 Martin den Heijer 及其同行于荷兰阿姆斯特丹自由大学医学中心(VUMC)开展的,有关不同剂量的口服孕酮用于激素治疗的一项大型 RCT(Dijkman et al., 2023a; 汇总资料和链接; 资料单荷兰语原文; 资料单英译文)

但遗憾的是,以上研究所用孕酮均以口服给药,而此用途在生物利用度和效力上存在重大缺陷(Aly, 2018a; 维基百科)。不管怎样,据闻 VUMC 的研究者有意开展后续试验,对其它途径给药的孕酮进行研究(汇总资料和链接)。以上研究有望就孕激素是否对女性倾向跨性别者的乳房发育有临床收益的问题提供更多视角。

孕激素在顺性别女性中对乳房发育的作用

目前为止,能够就孕酮或其它孕激素对顺性别女性乳房发育之作用提供有用线索的研究基本为零。从零星的文献中,几乎只能找到几个简要的、互相矛盾的临床经验片段。有些讨论孕激素在因性腺发育不良引起青春期延迟或无青春期的顺性别女孩和妇女当中用于青春期的诱导,在此一一摘录:

笔者(…)对三名乳房发育不足、且有明显性腺发育不良征象的女性进行研究。
(…)
以 30 日为一个周期,每日给予 5 个国际单位的黄体素单药,未引起可测出的乳房改变。这与 Turner2、Corner3 动物模型以及其它模型实验的观察结果一致。但当对患者每日注射 1 个国际单位的孕酮、20,000–50,000 个国际单位的雌酮或苯甲酸雌二醇时,乳房增长速率高于雌激素单药治疗。黄体素和孕激素的合用引起了更实在的乳房增长,触诊时乳腺小叶清楚可辨;而雌激素单药引起的增长更缓和,乳腺组织边缘较难分辨。终止激素注射后,出现了乳房尺寸的快速衰减,但联合治疗组的衰减更慢。[MacBryde (1939)]

有专家认为,在雌激素治疗周期的后半段加用孕激素,可引起更佳的乳房发育(Capraro, 1971)。Shearman (1971) 在其病例中采用了连续治疗。但是 Huffman (1971) 认为加用孕激素没有任何收益。 [Dewhurst (1971a)]

孕酮对人类乳房的作用尚不明确。尽管多人声称其可引起乳腺发育,但相关证据薄弱(Benson et al 1959)。 [Shearman (1972a)]

虽然不少人服用雌激素单药,但每月加用一种孕激素并持续 6 天或 10 天时,有明显更好的月经周期调控作用,且可引起更好的乳房发育效果。 [Shearman (1972b)]

一些专家认为,在每个疗程的后半段给予孕激素,会引起更好的乳房增长效果。 [Capraro & Dewhurst (1975)]

有人推荐在每个雌激素治疗周期的最后一周加用孕激素,以使乳房发育得更圆润,不加用就会像许多此类患者一样长出圆锥形的乳房;但是,我们未能发现加用或不加用孕激素对乳房轮廓产生的任何差异。 [Davajan & Kletzky (1979)]

笔者相信,在激素治疗中,有必要加用孕激素来得到较好的乳房反应——尽管如笔者先前所述,孕激素在有子宫的情况下治疗一年之后是必需的。 [Dewhurst (1982)]

除了以上片段,Werner (1935)Geschickter (1945) 也评价了孕激素对顺性别女性乳房的作用。其中,Werner (1935) 尝试对 8 名经手术切除性腺的顺性别女性注射雌激素、孕酮和泌乳素(均为粗提取物),以诱导泌乳。他声称,在两名给予了孕酮的女性中观察到乳房尺寸有明显增长,且幅度较给予雌激素单药者要更大。他还声称,前者的乳房更为结实,乳腺组织“曲度更大且有结节”,乳头更突出。他在研究中未能成功诱导泌乳。激素系提取而来,故剂量不明,从实验目的看估计是超生理的、甚至接近于妊娠水平的剂量。Werner 的研究曾被 Nelson (1936) 简要讨论,在他处亦有引用。
Geschickter (1945) 则对两名女性中的一名给予孕酮并持续六周至两个月,另一名不给予,然后通过组织活检对小叶发育情况进行观察。然而,作者没有评价乳房外形的物理改变,故其结果的参考价值有限。

继上述报道和传言之后,关于孕激素对顺性别女孩乳房之作用的研究却屈指可数,这很令人意外。尽管有关孕激素和顺性别女性乳房增长的现有资料十分稀少,但总算有临床研究开始更深入地了解各类激素药品——包括孕激素——在正接受青春期诱导治疗的女孩的乳房发育上的作用(例如 Rodari et al., 2023);因此,将来的研究有望在这方面提供更多视角。

孕酮及其在人类乳房发育过程中的作用

青春期的孕酮和乳房发育

要回答孕酮在乳房发育过程中起何等作用,以及孕酮在女性化激素治疗中是否有助于乳房发育,不妨参考顺性别女性经历青春期时的正常生理状况。顺性别女孩的青春期通常于 11 周岁左右(8–13 周岁之间)开始,后于 15 周岁左右(12–19 周岁)结束,平均持续 3–4 年,但大部分女孩可能会经历 1.5–6 年左右(Schauffler, 1942; Marshall & Tanner, 1969; Marshall, 1978; Begley, Firth, & Hoult, 1980; Drife, 1986)。孕酮在青春期内不会产生,直至有排卵月经周期出现。初潮——即第一次月经和月经周期的开始——通常出现于 Tanner 四期、即 13 周岁左右,但也有相当一部分女孩在 Tanner 三期或五期经历初潮;Tanner 三、四、五期发生初潮的分别有 26%、62% 和 10% (Marshall & Tanner, 1969; Marshall, 1978; Drife, 1986; Hillard, 2007)。因此,孕酮的产生在整个青春期内是较晚出现的事件(Scott et al., 1950; Marshall, 1978; Begley, Firth, & Hoult, 1980; Drife, 1986);乳房发育的大部分时间处在初潮或孕酮开始分泌之前(Huffman, Dewhurst, & Capraro, 1981; Drife, 1982);更有甚者,在初潮之前便已达到 Tanner 五期,即乳房完全发育(Edmonds, 1989);这表明,在青春期,孕酮并非使乳房完成发育的必要条件。

在青春期,顺性别女孩的生殖轴尚未成熟(Rosenfield, 2013; Gunn et al., 2018; Carlson & Shaw, 2019; Sun et al., 2019);初潮后一至两年内,月经周期大多不伴随排卵(Döring, 1963 [表格]; Apter, 1980; Lemarchand-Béraud et al., 1982; Talbert et al., 1985; Venturoli et al., 1987; Rosenfield, 2013; Gunn et al., 2018; Carlson & Shaw, 2019)。不排卵的情况下,卵泡不会破裂形成黄体,从而不会出现孕酮分泌。在 Tanner 五期之前,有排卵的月经周期仅占半数左右(Talbert et al., 1985)。此外,初潮后一段时间里月经周期是偏长的(如 50 天;成人为 28 天),故每年经历的月经周期偏少(Rosenfield, 2013; Gunn et al., 2018; Carlson & Shaw, 2019)。相比成年人,已经历初潮的青年人在黄体期的孕酮水平更低,即使排卵后亦然(McArthur, 1966 [图例]; Lemarchand-Béraud et al., 1982; Apter et al., 1987; Venturoli et al., 1987; Venturoli et al., 1989; Sun et al., 2019)。从而,即使到青春期晚期,孕酮暴露仍是散发且有限的。还有,这种情况不仅发生于 Tanner 五期之前,还会在之后数年间发生。
初潮后,月经周期趋于成熟并持续排卵需六年以上的时间(Lemarchand-Béraud et al., 1982; Venturoli et al., 1987; Carlson & Shaw, 2019);此期间,有排卵的周期占比逐渐上升,直至接近 100%(Lemarchand-Béraud et al., 1982; Venturoli et al., 1987; Carlson & Shaw, 2019);在此之后,孕酮暴露方可完全达到成年水平(Lemarchand-Béraud et al., 1982; Venturoli et al., 1987)

提供了青春期不同发育阶段或年龄的孕酮水平的研究屈指可数(例如 Sizonenko, 1978 [图表]; Kühnel, 2000; Lee, 2001 [表格]; Aly, 2020a);他们复现了上述青春期内孕酮暴露有限的结果。
一项名曰“女孩的初例假”(A Girl’s First Period Study)的研究项目于 2022 年公开,旨在更精确地测量青春期和青年女孩的性激素水平,有望更好地揭示孕酮在青春期内所发挥的生理作用(Lucien et al., 2022)。研究者特意将孕酮在乳房发育中的作用作为研究目的的一部分:

初潮以前,包括在伴有一定程度的卵泡黄体化的较低水平的无排卵周期内、以及在早期未成熟的周期内,(孕酮)暴露处于较低水平;那么这种暴露对于青春期乳房的正常发育是否会发挥重要作用?这个问题之所以有重大的临床意义,是因为青春期激素替代治疗通常不包含低剂量孕酮——它采用的是规律性(staggered)的雌激素单药治疗,仅当治疗两年后或出现点状出血时方才加用成人剂量的外源性孕酮。27 这旨在避免出现乳腺管状化(tubular breasts),不过有限证据提示早期孕酮暴露和不理想的乳房发育有关。28

综上所述,孕酮分泌是在女性正常青春期当中较晚出现的事件;即使开始分泌,孕酮暴露也是散发且有限的,直至青春期结束之后很长一段时间均如此;还有,一部分女孩在孕酮分泌开始前便已完成乳房发育;加之乳房发育的多数时间都在孕酮产生之前便已完成,以上事实使得孕酮在女性青春期乳房发育过程中的作用受到了怀疑。然而,还需更多研究来探究这点。

从女性正常青春期启发,兴许可以建议:如对女性倾向跨性别者引入孕激素以图促进乳房发育,引入时机应延迟至激素治疗后的两、三年,这样可模拟青春期内孕激素的正常暴露。

妊娠期间的孕酮和乳房发育

妊娠期间,受卵巢高度刺激和胎盘形成影响,包括雌激素、孕酮、泌乳素等多种激素在内的激素状况有大幅改变(见表一)。和月经周期的激素水平相比,妊娠晚期的雌二醇水平升高 100 倍,孕酮水平升高 10–20 倍,泌乳素水平升高约 10 倍(见表一)。其它诸多激素水平在妊娠期间也有明显改变,例如:雌二醇以外的其它雌激素,雄激素促性腺激素人绒膜促性腺激素 *,即 hCG),人胎盘催乳素(hPL),松弛素促肾上腺皮质激素(ACTH),皮质醇醛固酮生长激素(GH),胰岛素样生长因子-1(IGF-1),等等(Goodman, 2009 [图片]; Mesiano, 2019)。它们各自由卵巢、胎盘、脑垂体腺等腺体分泌。随着妊娠期多种激素的改变,乳房出现了显著改变,为产后母亲的泌乳哺乳做准备。

* 原文为 human choronic gonadotropin,系笔误。“Choronic”应作“chorionic”。

表一: 正常妊娠期内雌二醇、孕酮和泌乳素等激素水平的改变,中位值(范围)

激素未妊娠时妊娠前期妊娠中期妊娠后期
雌二醇100 (~5–750) pg/mL1,000–5,000 pg/mL5,000–15,000 pg/mL10,000–40,000 pg/mL
孕酮8.9 (1.0–24) ng/mLa22 (5–75) ng/mLb35 (15–85) ng/mL102 (25–280) ng/mL
泌乳素13.0 (4.6–37) ng/mL16 (3.2–43) ng/mLb49 (13–166) ng/mL113 (13–318) ng/mL

注: a) 在月经周期的黄体期内的范围。 b) 格式已修复——译者注。 参考资料: 雌二醇(Aly, 2018b; 维基百科; 维基百科)∕孕酮(Kühnel, 2000; Aly, 2020a; 维基百科; 维基百科)∕泌乳素(Kühnel, 2000; 维基百科)

妊娠以前,在每个月经周期的黄体期时,乳房有相当微小却明显的小叶发育(Scott et al., 1950; Drife, 1984; Drife, 1989; Drife, 1990; Pocock, Richards, & Richards, 2013; Johnson & Cutler, 2016; Alekseev, 2021)
但是在妊娠期,乳房会经过明显得多的小叶发育,并完全成熟;这样就有了产后乳汁产生和分泌的条件。乳房尺寸会随妊娠进行而逐渐、大幅增加(Hytten, 1954a; Hytten, 1954b; Baird, Hytten, & Thomson, 1958; Hytten & Thomson, 1965; Hytten & Leitch, 1971a; Hytten & Leitch, 1971b; Hytten, 1976; Thoresen & Wesche, 1988; Cox et al., 1994; Whiteley, 1994; Cox et al., 1999; Cregan & Hartmann, 1999; Kent et al., 1999; Galbarczyk, 2011; Abduljalil et al., 2012; Bayer et al., 2014; Lawrence & Lawrence, 2015; Żelaźniewicz & Pawłowski, 2015; Dallman et al., 2017; Drąsutis, 2017; Żelaźniewicz & Pawłowski, 2019)
临床定量分析研究结果显示,自妊娠早期至妊娠晚期或产后早期,乳房体积平均增加约 100–300 mL(范围 -20 至 880 mL),重量平均增加约 200–400 g(Hytten & Thomson, 1965; Hytten & Thomson, 1968; Hytten & Leitch, 1971a; Hytten & Leitch, 1971b; Hytten, 1976; Thoresen & Wesche, 1988; Whiteley, 1994; Hartmann et al., 1996; Cox et al., 1999; Cregan & Hartmann, 1999; Kent et al., 1999; Wright, 2015; Bayer et al., 2014; Żelaźniewicz & Pawłowski, 2015; Drąsutis, 2017; Żelaźniewicz & Pawłowski, 2019)。据报道,某些妇女的乳房尺寸至多可增加两到三倍(Greydanus et al., 2010)。妊娠期乳房尺寸的增长在个体之间有显著不同(Hytten & Thomson, 1965; Hytten & Leitch, 1971a; Hassiotou & Geddes, 2013; Bayer et al., 2014)。乳房尺寸的增加与年龄成反比,即较年轻妇女的增加量要明显高于较年长者:例如 20 岁以下者增加 234–258 mL,而 30 岁以上者增加 79–131 mL([Hytten & Baird, 1958; Hytten & Leitch, 1971a [摘录]; Hytten, 1976)
除乳房总体尺寸以外,乳头和乳晕在妊娠期亦有所增大(Hytten & Baird, 1958; Hytten & Leitch, 1971a; Rohn, 1989; Cox et al., 1999; Hassiotou & Geddes, 2013; Thanaboonyawat et al., 2013; Park et al., 2014);色素沉积更多,从而变成深棕色乃至黑色(Dickson & Hewer, 1950; Thody & Smith, 1977; Wade, Wade, & Jones, 1978; Wong & Ellis, 1984; Elling & Powell, 1997; Muzaffar, Hussain, & Haroon, 1998; Muallem & Rubeiz, 2006; Nussbaum & Benedetto, 2006; Olanrewaju et al., 2017)
乳房会在妊娠第三、四个月以前具备泌乳能力(Walker, Baker, & Lamb, 2013; Pipkin, 2019; Pocock, Richards, & Richards, 2013; Wright, 2015; Lawrence & Lawrence, 2015);但是,这种能力的完全成熟至少要到妊娠第 6.5 个月左右才发生(Hassiotou & Geddes, 2013)。由若干妊娠期妇女照片组成的时间线,可直观地看到妊娠期乳房的变化(注意,工作时间不宜Reddit; 更多材料)

妊娠期间有多种激素水平会出现大幅改变,目前尚不清楚具体哪些激素推动了妊娠期乳房的改变(Hytten & Leitch, 1971a; Hytten, 1976)。不过,从动物研究可以推断,包括雌激素、孕酮、泌乳素、胎盘催乳素、糖皮质激素、生长激素在内的一系列激素均通过不同方式,在乳房成熟过程中发挥重要作用(Hytten & Leitch, 1971a; Hytten, 1976; Cox et al., 1999)。一项针对妊娠期乳房改变的临床定量分析研究显示,乳房体积和乳晕面积的增加与 hPL 水平呈正相关,而乳头尺寸的增加与泌乳素水平呈正相关(Cox et al., 1999)。孕酮和泌乳素被认为推动了妊娠期乳腺小叶的发育(Bässler, 1970; Lee & Ormandy, 2012; Obr & Edwards, 2012);动物研究显示,二者对于小叶正常增生过程是缺一不可的(Obr & Edwards, 2012; McNally & Stein, 2017; Hannan et al., 2023)。类似地,有病例报道显示有孤立性泌乳素缺乏的妇女出现无乳(Buhimschi, 2004),这说明泌乳素对于人体也不可或缺。相反的是,病例报道显示即使妊娠期间 hPL 水平极低,妇女仍可正常泌乳(Gaede, Trolle, & Pedersen, 1978; Hannan et al., 2023),这说明 hPL 可能不是必要的。

分娩、泌乳之后,乳房会经历“泌乳后退行”的过程,恢复到妊娠前的状态(Dickson & Hewer, 1950; Ingleby, Moore, & Gershon-Cohen, 1957; Harley, 1969; Gershon-Cohen, 1970; Petrakis, 1978; Huffman, Dewhurst, & Capraro, 1981; Drife, 1986; Caro, 1987; Tanos & Brisken, 2008; Radisky & Hartmann, 2009; Fridriksdottir, Petersen, & Rønnov-Jessen, 2011; Hassiotou & Geddes, 2013; Sun et al., 2018; Alex, Bhandary, & McGuire, 2020)。过程中,大量细胞死亡,随妊娠期发育的小叶以及其它乳房改变出现回退(Radisky & Hartmann, 2009; Alex, Bhandary, & McGuire, 2020)。临床定量分析研究显示,随着退行过程完成,乳房完全恢复到妊娠前的大小,甚而略小于之(Kent et al., 1999 [图片]; Jernström et al., 2005; Dorgan et al., 2013; Lim et al., 2018)。对于妊娠期乳房肥大,同样观察到了显著且完全(或接近完全)的乳房萎缩过程——不过常伴有需手术干预的乳房下垂、畸形(Moss, 1968; van der Meulen, 1974 [图片]; Swelstad et al., 2006; Naik et al., 2015)。产妇乳房萎缩后,其内科组织学检查结果和未曾生育者的乳房别无二致(Drife, 1986)。但是,产后乳房并非跟妊娠前的完全一致:前者在组织学层面上的复杂度更高(Dickson & Hewer, 1950; Gershon-Cohen, 1970; Hytten, 1976; Drife, 1986; Drife, 1989; Jeruss, 2006; Fridriksdottir, Petersen, & Rønnov-Jessen, 2011; Hassiotou & Geddes, 2013; Lewin, 2016; Sun et al., 2019);因皮肤和韧带受到拉伸,往往会更松弛、更柔软、更易下垂(Begley, Firth, & Hoult, 1980; Duncan, 2010; Rauh et al., 2013; Lewin, 2016);乳头和乳晕仍维持高度成熟和色素沉积(Dickson & Hewer, 1950; Hytten & Baird, 1958; Hytten, 1976; Nussbaum & Benedetto, 2006; Sanuki, Fukuma, & Uchida, 2009; Thanaboonyawat et al., 2013; Park et al., 2014)
主观感受方面,一部分妇女感觉到乳房在妊娠后变大,而另一部分感到乳房变小(Rauh et al., 2013; Lewin, 2016)。妊娠可使较小的乳房短暂增大(Capraro & Dewhurst, 1975; Petrakis, 1978; Huffman, Dewhurst, & Capraro, 1981);但也有人称,产后乳房的萎缩可能“令人烦躁”(Capraro & Dewhurst, 1975)。当再次妊娠时,乳房会和初次妊娠一样,经历一轮增大、缩小的循环(Hassiotou & Geddes, 2013)

综上所述,即使妊娠期间乳房受激素的极端刺激而出现大幅改变,这种改变基本上不会持续,且完全可逆;只有持续处于高度的激素暴露,这种改变方可维持下去。这其中就包括极高水平的孕酮暴露。从妊娠情况来看,可以认为一旦青春期乳房发育完成,无论暴露于孕激素还是其它已知作用于乳房的激素,乳房都不再永久地进一步增长。

乳腺结构和乳腺小叶容积

乳房主要由两类组织构成:一是上皮组织,包含导管小泡/小叶,是实际意义上的乳腺组织;二是间质组织,包括结缔组织脂肪组织。小泡/小叶发育是指小泡和小叶的增生和成熟,是上皮或腺体组织发育的一种形式。孕激素主要参与乳腺小泡/小叶的发育;这类发育主要发生于妊娠期间,为泌乳和哺乳所需。

研究发现,在未妊娠或泌乳的妇女中,上皮组织仅占乳房体积的 5–20% 左右,其余 80–95% 均由间质组织构成(Hutson, Cowen, & Bird, 1985; Drife, 1986; Bryant et al., 1998; Gertig et al., 1999; Howard & Gusterson, 2000; Cline & Wood, 2006; Lorincz & Sukumar, 2006; Wilson et al., 2006; Xu et al., 2010; Pandya & Moore, 2011; Hagisawa, Shimura, & Arisaka, 2012; Sandhu et al., 2016; Rosenfield, Cooke, & Radovick, 2021; 维基百科)。具体而言,一项大型研究结果显示,育龄妇女的乳房有约 10–20% 为上皮组织;脂肪组织约占 10–35%;结缔组织约占 60–80%(Hutson, Cowen, & Bird, 1985; Wilson et al., 2006)。但多项采用了乳腺 X 光成像的研究所报道的乳腺组织比例更高,介乎 35–48%,与前述矛盾(Klein et al., 1997; Jamal et al., 2004; Duncan, 2010)
此外,据其它研究发现,乳房中的脂肪占比平均为 26–48%(范围 2–78%)(Lejour, 1994; Lejour, 1997; Vandeweyer & Hertens, 2002)。类似地,在患有乳房肥大的妇女中,乳腺组织仅占乳房的一小部分(如 1–7%)(Bames, 1948; Cruz-Korchin et al., 2001)

妊娠和哺乳期间,乳房结构有大幅改变,上皮组织占比大幅增加(Ramsay et al., 2005; Bland, Copeland, & Klimberg, 2018)。实际上,有资料显示在妊娠和哺乳期间,乳房大部分由乳腺组织构成;一项研究中,乳腺组织构成了哺乳妇女乳房的 63%(范围 46–83%)(Ramsay et al., 2005)。这并非仅仅出于小泡/小叶发育和腺体增长的缘故;乳房脂肪组织显著(但可逆)的减少也是原因之一(Wang & Scherer, 2019; Alex, Bhandary, & McGuire, 2020)。 无论如何,在通常的生理条件和孕酮暴露下,乳腺小泡/小叶组织在乳房中的占比是很小的。于此相关,除了妊娠期水平的孕酮以外,由孕激素介导的乳腺小泡/小叶增长在乳房体积上的体现并不明确,尚且存疑(Orentreich & Durr, 1974; Wierkcx, Gooren, & T’Sjoen, 2014)

患有完全性雄激素不敏感综合征、从而缺乏孕酮的顺性别女性中的乳房发育情况

有观点认为,孕酮可帮助顺性别女性和女性倾向跨性别者的乳房从 Tanner 四期发展到五期,使乳房更为丰满(例如 Vorherr, 1974a; Prior, 2011; Prior, 2019a; Prior, 2020)。在跨性别网络社群中也有人认为,在患有“大自然的实验”:完全性雄激素不敏感综合征(CAIS)的顺性别女性中,因无孕酮分泌,其乳房发育停滞于 Tanner 四期,乳房“如圆锥形”。但事实上,当前尚无明确证据表明孕酮对于青春期乳房正常发育过程是必要的;尚无证据表明其对于达到 Tanner 五期和乳房的丰满是有益的;也缺乏其对乳房之圆润有益的证据。以上观点和海量文献和证据南辕北辙,其中也包括有关 CAIS 女性本身的文献。

CAIS 是指女性的核型为 46,XY(即遗传学上属于“男性”),且有睾丸,但由于编码雄激素受体的基因变异,其对雄激素完全脱敏,从而未能像男性一样发育。此类综合征还有两种不完全的形态,即部分性雄激素不敏感综合征(PAIS)、轻度雄激素不敏感综合征(MAIS)。CAIS 女性的激素由睾丸分泌,处于男性典型状态;其中有处于男性正常偏高水平的睾酮,处于女性正常偏低水平的雌二醇,以及极低的孕酮分泌和孕酮水平(维基百科; 表格)
从外表看,CAIS 女性并不像男性,而是彻彻底底的女性形态;其体型如正常女性,有阴道和乳房(维基百科; 照片)。其体内的睾酮无法促成男性化,而不受抑制的雌二醇则可促成完全女性化。CAIS 女性的生殖系统和发育高度不良的男性类同,其有睾丸而无卵巢、子宫、输卵管、宫颈,也没有前列腺或精囊。睾丸隐于体内,位于腹中、腹股沟或阴唇;因位置缘故,出现睾丸癌的风险更高,故大多于成年以前被手术摘除。阴道通常偏浅,内端闭合,这与子宫的缺失相关。CAIS 患者从行为、性别、性功能上均被认为是女性。

文献上,患有 CAIS 的女性之乳房发育情况被描述为“良好”“较佳”“正常”“完全”“发育状况较好”“丰满”“普遍高于平均水平”“很大”,甚至是“丰乳肥臀(voluptuous)”(Morris, 1953; Simmer, Pion, & Dignam, 1965; Hertz et al., 1966; Valentine, 1969; Adams et al., 1970; Polani, 1970; Weisberg, Malkasian, & Pratt, 1970; Dewhurst, 1971; Dewhurst, 1972; Perez-Palacios & Jaffe, 1972; Glenn, 1976; Dewhurst & Spence, 1977; Dewhurst, 1981; Rutgers & Scully, 1991; Patterson, McPhaul, & Hughes, 1994; Quigley et al., 1995; McPhaul, 2002; Galani et al., 2008; Oakes et al., 2008; Tiefenbacher & Daxenbichler, 2008; Barbieri, 2019)
妇科专家 John McLean Morris 曾于 1953 年回顾并总结当时关于 CAIS 女性的既有科学文献(共 82 个病例),将该症状描述为“有睾丸的女性化”(此名称现已弃用),他将这批女性的乳房描述为“不寻常的大”“体积很大”(Morris, 1953; Quigley et al., 1995)。另一作者还称,“在(‘男性’)有睾丸的女性化中观察到乳房发育得圆润透红(florid),这可能不以任何外部环境为转移”(Wilson, 1968)

尽管以上观点都称 CAIS 女性乳房大,但实际上,有的 CAIS 女性乳房偏大,有的则偏小。一项研究经测量发现,其乳房尺寸介乎 16×14 cm 至 41×31 cm;以面积计算,差异达接近六倍之多(Wisniewski et al., 2000)。还有,CAIS 女性和普通女性乳房的大小至今从未有直接比较。因此,目前尚无明确资料证明其乳房体积是否确实大于女性平均水平。
从 CAIS 女性观察到的乳房发育之差异,和在一般顺性别女性当中观察到的乳房体积之巨大差异是一致的。此相册收集了文献上公开的病例报告和综述所附 CAIS 女性及其乳房发育的照片;从中可以看出,CAIS 女性的乳房发育正常且往往较佳,但乳房体积和形状在不同个体间有较大差异,这和一般女性相似。

假定 CAIS 女性确实较一般女性有更佳的乳房发育和体积,那么原因可能在于其对雄激素不敏感,从而由雌激素介导的乳房发育不会被雄激素阻断(Wilson, 1968; Sobrinho, Kase, & Grunt, 1971; Andler & Zachmann, 1979; Zachmann et al., 1986; Patterson, McPhaul, & Hughes, 1994; Barbieri, 2019);理论上还有一种可能性,即在其乳房和其它组织中,因睾酮水平较高,经芳香化形成的雌二醇也会更多,从而使得更好的乳房发育成为可能(Ladjouze & Donaldson, 2019)
有意思的是,有学者的经验之谈称,(未接受性腺切除术的)CAIS 女性可在内源激素影响下自然地经历青春期,相比于青春期前即摘除性腺、需外源性雌激素治疗来诱导青春期的 CAIS 女性,前者的乳房发育情况要好上许多(Dewhurst, 1972; Glenn, 1976; Dewhurst, 1981; Reindollar & McDonough, 1985; Shearman, 1985; Laufer, Goldstein, & Hendren, 2005);相应地,已有经青春期诱导的 CAIS 女性因乳房发育不良,要求接受隆胸手术的报道(Dewhurst, 1981; Shearman, 1985)。有鉴于此,临床实践中常采用的一线方案是,推迟对 CAIS 女性行性腺切除术,直至青春期完全结束(Laufer, Goldstein, & Hendren, 2005)。不过,据一项临床研究报道,所有经历自发性的、或治疗诱导的青春期的 CAIS 女性均有良好的乳房发育,达 Tanner 五期(Cheikhelard et al., 2008)
在 CAIS 女性的青春期诱导过程中模拟青春期雌激素的暴露,可能是必要的:先引入较低的生理性雌二醇水平,此后数年间逐渐、缓慢增加(Dewhurst, 1981; Cheikhelard et al., 2008; Bertelloni et al., 2011)

Baron 对 41 名雄激素不敏感综合征(AIS)患者进行评价时发现,CAIS 女性中 97% 的乳房发育正常;“不完全的 AIS”(估计是 PAIS)患者中有 63% 的乳房发育正常(Baron, 1993; Baron, 1994a; Baron, 1994b)。更早前由 Christopher John Dewhurst 爵士开展并发表的一项研究显示,50 名 CAIS 女性被评价为“乳房发育完全”的占 76%,“乳房中等发育”的占 14%,“乳房轻度发育”的占 10%,“乳房未发育”的占 0%(Dewhurst, 1971b)。由以上大规模样本的结果可知,大多数、或几乎所有的个体均有正常或完全的乳房发育。之所以小部分 CAIS 女性乳房增长较小,可能是因为:某些个体的雌二醇水平较低、从而相对不足;接受试验时的年龄较小,乳房尚未完成发育;一般女性本就有一小部分的乳房发育不完全或较小;等等。

CAIS 女性的乳房从未被描述成“锥形”“尖状”或其它不规则形状。只有一种例外,就是其乳晕和乳头常被描述为“粉嫩(juvenile)”“如婴儿般白嫩(infantile)”“小”“白皙”“无色素沉积”(例如此照片(见于 Morris, 1953; Morris & Mahesh, 1963; Simmer, Pion, & Dignam, 1965; Dewhurst, 1967; Khoo & Mackay, 1972; Perez-Palacios & Jaffe, 1972; Dewhurst & Spence, 1977)。有观点认为,此现象与乳房尺寸或成熟度均无关(Khoo & Mackay, 1972)。其原因可能在于 CAIS 女性的雌二醇水平平均仅有 35 pg/mL 左右(维基百科; 表格),而雌激素可引导乳头、乳晕增大和色素沉积,且与浓度相关(Davis et al., 1945 [图片]; Kennedy & Nathanson, 1953)。孕激素的情况则相反:其尚未被认为和乳头或乳晕的色素沉积相关。因此,要让乳头、乳晕和成人一样完全成熟,可能需更高的雌激素水平。

CAIS 女性的乳房可像正常女性一样发育至 Tanner 五期,即完全成熟(Quigley, 1988; Quigley et al., 1995; Finkenzeller & Loveless, 2007; Cheikhelard et al., 2008; Ramos et al., 2018; Arya et al., 2021; Zhang et al., 2021)
妇科专家 Robert Rebar 曾在其数十年间的多份综述、图书章节等专著中称,CAIS 女性的乳房发育大多仅达到了 Tanner 三期(Kustin & Rebar, 1987; Rebar, 1988; Rebar, 1990; Simpson & Rebar, 1990; Rebar, 1993; Rebar, 1996; Wellons & Rebar, 2013; Wellons, Weeber, & Rebar, 2017);但是,他的看法跟其他学者的观点、研究和病例报告都截然相反。Rebar 在某图书的一章写道,CAIS 女性会经历乳房发育和女性化,且乳房有正常的导管和乳腺组织结构,但“乳晕白皙,发育不良(Tanner 三期)”(Rebar, 1993)。这表明他所指出的可能并非整个乳房的增长达到 Tanner 三期,而是乳头和乳晕的成熟度如此(Rebar, 1993)
除 CAIS 以外,患有 PAIS 的个体也往往有可观的乳房增长,与女性无异(例如 Saito et al., 2014; Lee et al., 2015);还有报道称 PAIS 女性接受雌激素治疗后,乳房同样发育至 Tanner 五期(Guaragna-Filho et al., 2023)

据称 CAIS 女性虽多有较大的乳房,但乳腺组织较小(相对于脂肪和结缔组织),乳腺小泡/小叶几乎未发育(Morris, 1953; Morris & Mahesh, 1963; Simmer, Pion, & Dignam, 1965; McMillan, 1966; Perez-Palacios & Jaffe, 1972; Dewhurst & Spence, 1977; Shapiro, 1982)。这与孕酮的缺乏有关,因为孕酮对于诱导乳腺小泡/小叶的增长至关重要。CAIS 女性的乳房在乳腺和小叶结构较小的情况下仍维持较大尺寸,也印证了乳房主要由间质脂肪组织和结缔组织构成这一事实。因此,正如上文所述,更高的乳腺或小泡/小叶组织占比不一定会使得乳房体积更大,这点在 CAIS 女性身上显而易见。

除了乳房发育正常乃至更佳,还需说明的是,CAIS 女性因有睾丸、从而没有来自性腺的大量孕酮分泌的缘故,孕酮水平极度偏低(维基百科; 表格; Barbieri, 2019)。综合 CAIS 女性乳房发育正常(且往往偏大)、乳房依 Tanner 分级达到完全成熟等事实来看,在青春期并不需要孕酮来实现正常、完全的乳房发育(Barbieri, 2019)。无论如何,必须再次提请留意:CAIS 女性乳房和普通女性的乳房之间至今从未经过直接比较。
还有,对 CAIS 女性乳房的量化研究十分稀少,我们对此的认识亦大多局限于口头上的临床经验和主观的乳房评价。这很大程度上要归咎于 CAIS 女性数目之稀少、获取足够样本以供研究的难度之大。除缺乏孕酮外,CAIS 女性跟普通女性还有其它诸多不同之处,例如:雌二醇循环水平相对较低,睾酮水平偏高(在乳房等组织内可经芳香化成为雌二醇),对雄激素不敏感,核型为 XY,等等。因此,这里讨论 CAIS 女性乳房发育的同时,也附上了一系列补充说明。

耐人寻味的是,尽管乳房发育良好,但 CAIS 女性从未有任何乳腺癌报告(Aly, 2020b; Aly, 2020c)。这可能和以下因素有关:缺乏孕酮、缺乏乳腺小泡/小叶的成熟,和/或缺少第二条 X 染色体(Aly, 2020b; Aly, 2020c)。这表明,乳腺癌并非乳房发育较佳的必然结局。

月经周期和伴随的周期性短暂性乳房增大

乳房尺寸随月经周期而发生波动,其中在黄体期有明显增大(Shuttleworth, 1938 [图片]; Ingleby, 1949; Scott et al., 1950; Milligan, Drife, & Short, 1975; Drife, 1982; Malini, Smith, & Goldzieher, 1985; Drife, 1989; Fowler et al., 1990; Graham et al., 1995; Jemström & Olsson, 1997; Hussain et al., 1999; Hussain, Brooks, & Percy, 2008; Wang et al., 2019; Rix et al., 2023)。此时女性会感到乳房发胀、刺痒、紧张等(Shuttleworth, 1938 [图片]; Milligan, Drife, & Short, 1975; Laessle et al., 1990; Jemström & Olsson, 1997)。据报道,乳房体积于黄体期平均增长约 75–100 mL;相对于平均体积,卵泡期和排卵时最低可缩小至 90%,而黄体期可增至 110%,二者间平均相差 15–20% 左右(Milligan, Drife, & Short, 1975; Malini et al., 1985; Drife, 1989; Fowler et al., 1990; Hussain et al., 1999; Hussain, Brooks, & Percy, 2008; Rix et al., 2023)。然而,近期研究采用更佳的测量手段测出的乳房改变幅度更小:卵泡期乳房体积距平减小 4–10%,黄体期距平增加 3–21%(Rix et al., 2023);同时,据称乳房体积平均增长的幅度(37 mL 或 35 g)相当于三分之一个罩杯,某些人的增幅可达一个罩杯(Rix et al., 2023)。个体间乳房体积变幅的差异极大:在整个月经周期,一些人的乳房没有改变,而最极端的案例可见 40–45% 的增幅(Ingleby, 1949; Malini, Smith, & Goldzieher, 1985; Fowler et al., 1990; Hussain et al., 1999; Hussain, Brooks, & Percy, 2008; Rix et al., 2023)

黄体期乳房的增大被认为归因于:乳腺和间质组织的短暂增长,导管和小泡内腔扩张,乳腺和间质组织内液体潴留,以及血管形成和血流量增加(Scott et al., 1950; Drife, 1989; Fowler et al., 1990; Hussain et al., 1999; Alekseev, 2021; Biswas et al., 2022)。但有研究表明,这种改变大多仅仅出于水含量波动的缘故,而乳腺体积的实际改变较小(Rix et al., 2023)。月经周期内的乳房改变被发现和黄体期雌二醇、孕酮水平的升高呈正相关(Jemström & Olsson, 1997; Clendenen et al., 2013; Rix et al., 2023)。还有,雌激素治疗被发现可增加乳房尺寸(过程可逆)(例如 Hartmann et al., 1998),且雌二醇水平与乳房紧张感呈正相关(例如 de Lignières & Mauvais-Jarvis, 1981 [图片]; Sitruk-Ware et al., 1984) 。雌二醇和孕酮均可以各自的方式增加水分潴留,介导乳腺增长和乳房改变(Rix et al., 2023)。因此,月经周期内的乳房改变被推测归因于雌二醇和孕酮水平的改变,但要注明的是孕酮被认为在黄体期推动了乳房体积的增加(Lawrence & Lawrence, 2015; Rix et al., 2023)。月经周期的乳房增大相对于雌二醇和孕酮水平达到峰值的时间有所延后,并非立即发生(Rix et al., 2023)

口服复方避孕药是一系列雌激素—孕激素复方产品,其和更年期雌激素—孕激素治疗均可短暂地引起乳房增大和乳房发胀感,类似于月经周期内黄体期的变化(Milligan, Drife, & Short, 1975; Dennerstein et al., 1980 [图片]; Malini, Smith, & Goldzieher, 1985; Jemström & Olsson, 1997; Jernström et al., 2005)。一项研究中,正服用口服避孕药的妇女出现了相对于未服用者/既往服用者约 100 mL(~30%)的乳房体积增长;据一些妇女的自发报告,其乳房增长最大达到一个罩杯(Jemström & Olsson, 1997)。然而,同一批研究者开展的、样本规模更大的另一项研究中,激素避孕药使用者(n=258)和未服用者(n=65)之间的乳房体积没有显著差别(Jernström et al., 2005)。还有一项研究测量了服用不同类型的雌激素—孕激素口服避孕药(其中孕激素成分均为炔诺酮,但剂量相差六倍,介乎 0.4–2.5 mg/天)的妇女和未服用者的乳房体积,未发现有显著差别;但是,其样本规模过小(每组 n=5 和 n=15),统计证据不足(Malini, Smith, & Goldzieher, 1985)

Engman et al. (2008) 开展了一项为期三个月的 RCT,其中评价了米非司酮(一种选择性孕酮受体调节剂,主要发挥抗孕激素作用)用于月经正常的未绝经顺性别女性时对其乳房的作用,并和安慰剂进行比较。结果是,米非司酮降低了 Ki-67 抗原系数(一种反映乳房细胞增殖的指标),也降低了乳房症状自评表(BSI)的主观得分:具体而言,BSI“乳房疼痛感”“乳房肿胀感”“对乳房体积增长的感觉”等小项以及总得分均有显著性地下降。但是,该研究没有采用客观的乳房体积测量手段。该研究有一项重大局限性:即米非司酮可抑制排卵,并改变雌二醇及其它激素的水平(Spitz et al., 1989; Spitz et al., 1994; Engman et al., 2008; Spitz, 2010)。因此,尚不清楚 Engman 及同行所观察到的结果是否可归因于对乳房孕酮受体的抑制作用,或是对下丘脑—垂体—性腺轴(HPG 轴)的干扰作用,例如雌二醇水平下降。

一份耐人寻味的案例报告记录了某患有 CAIS 的成年女性接受雌激素—孕激素联合治疗后,出现相对于雌激素单药治疗有显著性地更大的乳房体积增长(Dijkman et al., 2023b)。该女性初始时序贯口服雌二醇 2 mg/天、地屈孕酮 10 mg/天,自称治疗期间经历了乳房疼痛和乳房体积的波动,变幅约为一个罩杯;随后,她改用口服戊酸雌二醇 3 mg/天单药,乳房体积的波动中止。但是,其乳房总体积也缩小了,遂决定恢复雌激素—孕激素联合治疗。其医师以全身三维扫描的形式测量乳房体积;接受雌激素单药治疗时,左、右乳房体积分别为 758 mL、673 mL;接受雌激素—孕激素联合治疗时,则分别增长至 875 mL、784 mL,净增加值分别达 117 mL(+16%)和 111 mL(+17%)。此增幅几乎相当于一个罩杯的差异。研究者写道,雌二醇和孕酮均与乳房的周期性变化有关,并推断患者乳房的改变归因于体液潴留增加。综上,该案例报告表明了孕激素在某些女性中可引起快速、明显、可逆的乳房增大,类似于正常月经周期中的改变。

动物中孕酮和乳腺发育的关系

动物中的孕酮和青春期乳腺发育

雌性小鼠中,敲除 孕酮受体导致生育力完全丧失,卵巢、子宫、生殖行为功能重度受损(Lydon et al., 1995; Ismail et al., 2003)。但另一方面,被敲除孕酮受体的小鼠在青春期的乳腺导管发育正常,形态学上与正常小鼠别无二致(Soyal et al., 2002; Ismail et al., 2003; Fernandez-Valdivia et al., 2005)。而被敲除雌激素受体 α 的小鼠则有相反的表现,其青春期乳腺发育完全停止(Ismail et al., 2003; Fernandez-Valdivia et al., 2005; 维基百科; 维基百科)
然而,后续研究表明,雌性小鼠在无孕酮分泌、无孕酮受体或给予孕酮受体拮抗剂(米非司酮)的情况下,实际上出现了乳腺导管推迟发育的情况(Shi, Lydon, & Zhang, 2004)。换言之,孕酮在青春期可刺激并加速乳腺导管发育,从而在青春期乳腺早期发育当中具备明显的生理作用。孕酮对乳腺导管发育的刺激作用应是通过引诱乳腺导管和尾结表达双调蛋白而介导的(Kariagina et al., 2010; Aupperlee et al., 2013);双调蛋白作为表皮生长因子受体(EGFR)的激动剂,是青春期由雌激素引诱表达、介导乳腺发育的主要生长因子(Ciarloni, Mallepell, & Brisken, 2007; LaMarca & Rosen, 2007; McBryan et al., 2008)。无论如何,由于无孕酮参与的青春期乳腺导管发育只是被延迟、而会逐渐完成,故而有观点总结道,孕酮在小鼠的青春期乳腺发育过程中是可有可无的(Soyal et al., 2002; Ismail et al., 2003; Fernandez-Valdivia et al., 2005)

尽管孕酮在小鼠青春期乳腺的正常发育中并不是必需的,但有研究表明其可取代雌激素来介导发育过程中的导管发育。Ruan, Monaco, & Kleinberg, 2005 就各类含外源性雌二醇、孕酮、IFG-1 的组合用于摘除卵巢且敲除 IGF-1 的小鼠时的作用开展研究。其中,孕酮和 IGF-1 组合所诱导的导管发育占据了乳腺脂肪垫的 92%;雌二醇和 IGF-1 组合占据了 92%;雌二醇、孕酮和 IGF-1 组合占据了 96%;IGF-1 单药仅占据了 28%(Ruan, Monaco, & Kleinberg, 2005; Kleinberg & Ruan, 2008)。据称,孕酮和 IGF-1 所促成的树状导管络从解剖学形态上接近于青春期正常发育的乳腺(Ruan, Monaco, & Kleinberg, 2005)。然而,雌二醇/IGF-1 组合和孕酮/IGF-1 组合之间的乳腺发育有明显差别,其中前者对末端尾结形成、导管纹理的作用更大,也对小泡成熟有较弱作用;而后者对导管形成、扩张、分叉的作用更大(Ruan, Monaco, & Kleinberg, 2005; Kleinberg & Ruan, 2008)。孕酮受体拮抗剂米非司酮逆转了孕酮引起的乳腺发育作用(Ruan, Monaco, & Kleinberg, 2005)。只有雌二醇/孕酮/IGF-1 组合实现了近似于妊娠中期的乳腺发育,分泌小泡结构完全成熟(Ruan, Monaco, & Kleinberg, 2005; Kleinberg & Ruan, 2008)

除上述研究外,还有多项研究发现,小鼠于妊娠期给予外源性孕酮后,乳腺导管分叉有所增加(Atwood et al., 2000; Hovey et al., 2001; Satoh et al., 2007; Aupperlee et al., 2013)

这些采用外源性孕酮来诱发小鼠青春期乳腺发育的研究有一项局限性:即孕酮剂量以及其它合用的激素剂量(如雌二醇)足以促使乳腺增长至妊娠典型水平,乳腺小叶/小泡结构高度成熟(例如 Škarda, Fremrová, & Bezecný, 1989; Ruan, Monaco, & Kleinberg, 2005);在妊娠期间,激素水平远高于通常状态。因此,这些研究中的孕酮暴露可能超出了正常青春期的生理范围,其带来的效果不能反映青春期的状态。相应地,据 Škarda, Fremrová, & Bezecný, 1989 的发现,未经治疗、和以外源性雌激素治疗的正常雌性小鼠的乳腺面积分别达 26.4 mm2、25.3 mm2,而以外源性雌二醇及孕酮治疗的、和外源性孕酮单药治疗的正常雌性小鼠则分别有 43.5 mm2、64.6 mm2的乳腺面积;未治疗者未见有小泡结节,而经孕酮治疗者可见小泡成熟,且发育程度接近于妊娠、也高于未妊娠小鼠的生理状态(Škarda, Fremrová, & Bezecný, 1989)。无论如何,有一项研究尽管采用了很低的孕酮剂量——0.1 mg/天,是其它多数研究(1 mg/天)的十分之一——但仍明显诱导了小鼠乳腺导管的发育(Aupperlee et al., 2013; Berryhill, Trott, & Hovey, 2016)。因此,即使剂量较低,孕酮仍可诱导一定程度的小鼠乳腺导管增长。

尽管孕激素本身显然可取代雌激素暴露,诱导小鼠青春期乳腺的正常发育,但这是否对人类适用尚未可知。已知在人体缺少雌激素活性的情况下,孕激素本身一般不会引起乳房发育。例如,MPA、CPA 等孕激素曾被作为青春期阻断剂,以较高剂量用于男孩及女孩;其并未引起乳房发育,反而因抑制性腺功能而中断、逆转了乳房发育(Lyon, de Bruyn, & Grant, 1985; Fuqua & Eugster, 2022)。男孩中有因 CPA 引起乳房增生的报道,但占比很低,且完全可归因于孕激素活性以外的原因——例如 CPA 的抗雄激素作用和对 HPG 轴的干扰作用(Kauli et al., 1984; Laron & Kauli, 2000)。无独有偶,MPA、CPA 等孕激素曾用于男性以治疗前列腺症状和性欲障碍,并未普遍引起乳房增生;CPA 用于治疗前列腺癌时,男性乳腺增生的发生率很低(~10%),与经手术或药物去势者的发生率没有明显差别(Fourcade & McLeod, 2004; di Lorenzo et al., 2005)。这与雌激素和非甾体抗雄制剂引起的男性乳腺增生发生率(高达 70–80%)可谓天壤之别(Fourcade & McLeod, 2004; di Lorenzo et al., 2005; Deepinder & Braunstein, 2012)。物种间的差别可能是孕激素引起小鼠青春期乳腺发育、但没有引起人体乳房发育的原因所在。

动物中的孕酮和妊娠乳腺发育

和人体相似,在啮齿动物和灵长目动物等多种动物模型中,妊娠引起了雌激素、孕酮、泌乳素等多种激素水平的上升(Hasan, 1974; Cowie, Forsyth, & Hart, 1980; Pasqualini & Kincl, 1985; Günzel et al., 1987; Seibert & Günzel, 1994);同时,乳腺组织有大幅改变,其中小泡/小叶极大成熟,为泌乳和哺乳做准备(Cowie, Forsyth, & Hart, 1980; Richert et al., 2000; Cline & Wood, 2008; McNally & Stein, 2017)。动物中也观察到了乳房的永久性增大,主要归因于青春期脂肪组织的极大增加;动物外乳尽管亦有所增长(例如 Geschickter, 1945 [图片]),但仅在妊娠时才有大幅增大(Pawłowski & Żelaźniewicz, 2021)。猕猴模型中,乳腺组织在妊娠期间增长了约 10–20 倍(Cline & Wood, 2008)

对啮齿目等多种动物的未妊娠雌性成年个体给予一定量的外源性雌二醇和孕酮,引起了类似于妊娠期的乳腺发育(Nelson, 1936; Turner, 1939; Folley, 1940; Folley, 1947; Folley & Malpress, 1948; Folley, 1950; Folley, 1952; Folley, 1956; Lyons, 1958; Lyons, Li, & Johnson, 1958; Cowie & Folley, 1961; Jacbosohn, 1961; Cole & Hopkins, 1962; Lloyd & Leathem, 1964; Meites, 1966; Bässler, 1970; Ceriani, 1974; Vorherr, 1974b; Cowie, Forsyth, & Hart, 1980; Tucker, 2000; Kleinberg, 2006; Kleinberg & Ruan, 2008; Kleinberg et al., 2009; Kleinberg & Barcellos-Hoff, 2011);同时,由于雌激素和孕酮诱导了脑垂体腺产生和分泌泌乳素,故泌乳素水平也升至高位(Ceriani, 1974; Bethea, Kohama, & Pecins-Thompson, 1997; Camilletti et al., 2019)。尽管在多类物种中,雌二醇和孕酮各自均足以引起类似于妊娠的、完全的乳腺发育;但在恒河猴模型中,雌二醇、孕酮和胎盘催乳素组合所诱导的泌乳活动远远弱于经过正常妊娠者(Beck, 1972; Cowie, Forsyth, & Hart, 1980)。相应地,在灵长目动物中,可能还需胎盘催乳素和/或其它激素因子来实现类似妊娠的、完全的乳腺发育成熟(Beck, 1972; Cowie, Forsyth, & Hart, 1980)

已知在啮齿目、猴等动物中,乳腺在泌乳和哺乳结束后发生退行,恢复到妊娠前状态,这与人类相似(Richert et al., 2000; Cline & Wood, 2006; Cline & Wood, 2008; Fridriksdottir, Petersen, & Rønnov-Jessen, 2011; McNally & Stein, 2017)

治疗性假妊娠引起的乳房改变

治疗性/药理假妊娠是激素治疗的一种,即出于某些医疗目的而需要复现妊娠期激素状态(mileu)之时,对顺性别女性给予外源性激素;实际采用的激素有雌激素和孕激素,剂量非常高,而其它妊娠相关的激素并未被使用。该疗法最初于 1950 年代被发明,而现今医学上已很少使用(Kaiser, 1993)

治疗性假妊娠对乳房的作用及改变和妊娠相同,例如小泡/小叶的发育和乳房的显著增大(且可逆),故值得关注。Lauritzen 及同行于 1980 年代开展了一项研究,其中对顺性别女性采取治疗性假妊娠以治疗乳房发育不全(Lauritzen, 1980; Lauritzen, 1982; Lauritzen, 1989; Göretzlehner & Lauritzen, 1992);采用的雌激素为戊酸雌二醇,肌注 40 mg/周;采用的孕激素为己酸羟孕酮(OHPC),肌注 250–500 mg/周;治疗持续 4–5 个月。戊酸雌二醇剂量极高:据同一批作者于其它研究论文报道,该剂量使得雌二醇水平升至女性妊娠前期范围(约 3,000 pg/mL,或 11,000 pmol/L)(Ulrich, Pfeifer, & Lauritzen, 1994; Ulrich et al., 1995),相当于未妊娠时正常浓度的约 30 倍(Aly, 2018b)。OHPC 剂量也非常高:在每月 250–500 mg 的剂量下,孕激素暴露强度已相当于黄体期水平(维基百科),而研究中每周就注射等量的 OHPC,此时暴露强度相当于黄体期的约 4.5 倍、接近于妊娠前期或中期的孕酮水平(Aly, 2020d)。作者表示前期曾运用较低的、接近于 1950 年代主流的激素剂量,但未引起明显的乳房增长,故增加了剂量。研究中测量乳房改变的手段有:卷尺(水平、垂直贴附于乳房区域),照片,X 光和超声波成像,以及——后续加入的——用橡皮泥对乳房印模后测量模型容积。

Lauritzen 及其同行在四篇不同著述中都报道了这项研究的结果,不仅跟踪时长不同,且样本规模逐渐增加。第二次跟踪时,接受治疗者计 78 人,其中 29 人(37%)被报道小于 18 周岁;但在最后一次跟踪时,接受治疗者累计 221 人,年龄范围介乎 18–42 周岁。研究发现,治疗组有 65% 的乳房体积较基线增加了 10–30%;相应地,几乎所有受试女性均有乳房紧张感,但紧张感随时间推移而逐渐减弱;观察到罕见的、乳房相关的其余副作用,包括色素沉积和伸展疤痕等。至治疗结束时,泌乳素水平略微升至 14–28 pg/mL。乳房成像结果提示了乳腺密度加大。研究者认为,研究中的乳房体积增加是由脂肪组织增长、液体潴留、中等程度的乳腺组织增生所致。

治疗终止后,受试女性有 40% 的乳房体积出现逐渐的、部分程度的萎缩,结果仍大于基线 10–20%。但作者认为,通过给予适当剂量的雌激素—孕激素复方避孕药片、或对乳房给予外用雌激素和孕激素治疗,可减少乳房萎缩程度;还声称可再次利用治疗性假妊娠来增加乳房体积——上述受试女性的一部分在六个月后又接受了 1–2 次治疗性假妊娠。据称至第二次跟踪时,78 名受试者有 12 名(15%)曾接受多次治疗。
另外还有多名研究者报道,为增加乳房尺寸,对顺性别女性给予雌激素和/或孕激素治疗,治疗停止后乳房尺寸有明显或完全的萎缩(例如 Cernea, 1944; Müller, 1953; Anderson, 1962; Bruck & Müller, 1967; Keller, 1984; Kaiser & Leidenberger, 1991; Keller, 1995; Hartmann et al., 1998)

Lauritzen 及同行的研究结果鲜少通过正式途径发表:分散于未经同行评议的图书章节、会议纪要和医学杂志,从未发表于经同行评议的期刊文章上。与此对应地,对研究方法和结果的描述都比较粗略且不甚精确。研究方法上的问题还有:缺少对照组,缺少随机化,乳房测量手段的质量,等等。因此,研究结果的解读难度大,可信度堪忧。不管怎样,研究结果表明,高剂量雌激素—孕激素联合治疗通过给予妊娠早期水平的雌激素和孕激素暴露量,可引起乳房尺寸短期的明显增加,以及长期的小幅增加——如此结果与其他研究者的结果相矛盾,后者显示乳房的改变在治疗停止后便完全回退了。这也与关于妊娠妇女的结果大相径庭:当哺乳期结束后,其乳房便完全恢复至妊娠前大小,甚而略小于之。

由于 Lauritzen 及同行的研究中未设置仅给予雌激素或孕激素单药的对照组,故难以判断其中雌激素和孕激素各自的作用。已知雌激素和孕激素均与乳房增大有关,且很可能是引起乳房改变的原因所在;故此,尚不清楚孕激素暴露和雌激素暴露在乳房改变中孰重孰轻。

Lauritzen 及同行所观察到的乳房尺寸之增幅应当小于妊娠期间的改变;他们亦未提及妊娠相关的某些乳房改变,如乳头、乳晕色素沉积;其中原因尚不完全清楚。诸研究的受试群体并不一致,例如初始乳房尺寸和年龄等可能影响研究结果的因素;还有一点,研究中仅发现雌激素和孕激素水平升高,而其它妊娠激素中仅泌乳素水平有小幅升高,其余均未上升——这也可能影响研究结果。像 hPL 和 IGF-1 这样的妊娠激素,也是有可能参与妊娠期乳房发育的。最后一点,治疗仅持续了 4–5 个月,雌激素、孕激素暴露量仅相当于妊娠早期至中期水平——须知一次正常妊娠会持续 9 个月,直至分娩时仍持续有雌激素、孕酮水平的大幅上升。

需要注明,由于治疗性假妊娠所需的、高度超生理性的雌激素和孕激素水平可引起血栓和心血管疾病等重大并发症(Aly, 2020e),且乳房体积的增加在治疗后基本不能维持,故其不适用于、也不宜推荐用于女性倾向跨性别者。但不管怎样,我们讨论雌激素和孕激素对乳房增长的作用时,通过历史上治疗性假妊娠用于顺性别女性乳房以促进体积增长的研究结果,尚可获得一些理论上的见解。

孕激素早期暴露和乳房发育不理想的潜在关系

尽管有女性倾向跨性别者看中了孕激素促进乳房发育的潜力而寻求之,但文献上已有观点称,孕激素可能导致乳房发育不理想,亦可能抑制或削弱雌激素介导的乳房发育。资料分为以下几类:孕激素在乳房中表达抗雌激素作用的记载;动物模型给予高剂量孕激素后出现乳房发育不良的记载;以乳房发育可能不良为由,不推荐于女性青春期诱导过程中过早引入孕激素的相关临床出版物;临床上将孕激素用于顺性别女性以治疗乳房肥大的记载;顺性别女孩中因性发育障碍导致孕酮暴露量高、从而经雌激素诱导的乳房发育不良的记载;以及,女性倾向跨性别者经雌激素和 CPA(强效孕激素)治疗后,乳房发育大多不良的记载。至于孕激素是否可改善乳房发育这个问题,目前尚不清楚孕激素是否反过来使之恶化,或者在何等剂量、何时引入才有改善作用。不管怎样,以上话题将各自以一个章节加以讨论,以图面面俱到。

孕激素在乳房中表达的抗雌激素作用

已知孕激素在子宫、阴道和宫颈等组织内具有很强的抗雌激素作用(维基百科)。因为这点,孕激素被引入到更年期激素治疗,以预防子宫内膜增生子宫内膜癌——而不受控的雌激素治疗会有这方面的风险(维基百科)。在乳房,孕激素也会表达抗雌激素作用(Mauvais-Jarvis, Kuttenn, & Gompel, 1986a; Mauvais-Jarvis, Kuttenn, & Gompel, 1986b; Mauvais-Jarvis, Kuttenn, & Gompel, 1987; Mauvais-Jarvis et al., 1987; Kuttenn et al., 1994; Wren & Eden, 1996; Plu-Bureau, Touraine, & Mauvais-Jarvis, 1999; 维基百科)。其作用可能包括:

临床研究发现,将外用孕酮直接用于乳房,可抑制雌激素介导的乳腺细胞增生;但这可能是因为对乳房局部给予了超生理水平的孕酮(Barrat et al., 1990; Chang et al., 1995; Foidart et al., 1996; Spicer, Ursin, & Pike, 1996; Foidart et al., 1998; de Lignières, 2002; Gompel & Plu-Bureau, 2018; Trabert et al., 2020)。与此相关的是,孕激素被认为可有效治疗乳房疼痛乳腺结节乳腺纤维囊性病变等雌激素依赖性良性乳房疾病(Mauvais-Jarvis, Sitruk-Ware, & Kuttenn, 1981; Winkler et al., 2001; Schindler, 2011; 维基百科; 维基百科; 维基百科)。据报道,孕激素也抑制了高剂量雌激素治疗诱导的乳头和乳晕色素沉积作用(Crowley & Macdonald, 1965)。但和上述结果相反的是,在围绝经期的雌激素治疗中加入孕激素后,引起了乳腺癌风险的明显上升(Aly, 2020b; 维基百科)。无论如何,通过孕激素在乳房中的抗雌激素作用,孕激素是有可能限制雌激素介导的乳房发育的;但是,孕激素亦可能借此作用来同时诱导导管发育和小泡/小叶发育,这种发育不符合青春期的特征(Randolph, 2018)

动物研究中孕激素引起的乳腺增长不良

有动物研究运用了生物同质的孕酮、以及醋酸氯地孕酮(CMA,一种类似于 CPA 的人工孕激素),结果表明:两类孕激素在高剂量下明显阻滞了兔的乳腺发育,但在低剂量下没有阻滞作用(Lyons & McGinty, 1941; Beyer, Cruz, & Martinez-Manautou, 1970)。相关文献摘录及图片参见此页面
Lyons & McGinty, 1941 [图片] 曾发现,雌激素单剂诱导了乳腺导管发育,而雌激素—孕酮(0.25–1 mg/天)复方引起了导管发育和轻度至“中度(fair)”的小叶/小泡发育;相反的是,雌激素—孕酮(4–8 mg/天,相当于最佳剂量的 4–8 倍)之复方引起了乳腺发育不良,体现在导管发育被抑制、小泡/小叶发育较轻微,最高剂量下的乳腺尺寸远小于 ≤1 mg/天组别。他们总结称,高剂量孕酮可抑制乳腺发育,导致发育相对不良。虽然论文中以“国际单位”(IU)作为孕酮剂量的单位,但 Pfeiffer (1943) 的综述引用此文时,称 1 IU 孕酮相当于 1 mg;据此,本文改用毫克来表示剂量。
Beyer, Cruz, & Martinez-Manautou, 1970 [图片] 则发现,雌激素单药引起了较佳的导管发育、未引起小泡/小叶发育,乳腺平均面积 376 mm2;雌激素和 CMA 0.5 mg/天复方、雌激素和孕酮 2.5 mg/天复方均引起了理想的导管和小泡/小叶发育,乳腺平均面积分别为 765 mm2、688 mm2。相反的是,雌激素和 CMA 2.5 mg/天(五倍于最佳剂量)导致导管发育大幅减弱、乳腺尺寸减小,但小泡/小叶发育明显,乳腺平均面积 284 mm2。论文作者总结称,孕激素在中等剂量下刺激乳腺增生,但在大剂量下抑制乳腺增生。

尽管上述研究表明高剂量孕激素可能阻滞人体乳房发育,但尚不能盖棺定论。不同物种间经激素介导的乳腺发育可能不尽相同:即针对兔的研究结果可能无法推广到人类,甚至是亲缘关系更近的大鼠、豚鼠等其他物种(Bässler, 1970)。据笔者所知,迄今尚未有关于高剂量孕激素在其他动物(例如其它啮齿目物种或猴)身上阻滞乳腺发育的研究或报道。动物实验所用剂量是否必然和人体孕激素治疗相关也尚不清楚;这是因为,为了实现乳腺小泡/小叶的明显发育,需要使孕酮升至妊娠水平(远高于黄体期水平),而研究所用孕激素剂量比这还高一个数量级——如此暴露量放到人体身上也是极高的。但是,此等剂量仍可能和 CPA 作为抗雄激素制剂用于人类的情况相似,毕竟该用途下 CPA 剂量是相当高的(见下文)。在笔者印象中,尚无动物实验报道过非妊娠水平的孕酮对乳腺发育有任何阻滞作用或其它副作用;这表明孕激素只有在高剂量下才显现此类作用。最后还需说明,在以上动物实验中,雌激素和孕激素治疗是同时开始的,但在适当剂量下未能实现理想的、接近于妊娠状态的乳腺发育;这表明对于人体,早期或初始的孕激素暴露可能对乳房发育不利。但要重申,不同物种间可能存在差异,还需人体临床研究来验证这点。

临床文献上以乳房发育可能不良为由而不推荐过早引入孕激素的相关记载

已有儿内分泌科方面的多份临床著述警告称,顺性别女孩和/或女性倾向跨性别者过早暴露于孕激素(例如青春期诱导治疗),可能导致乳房发育不理想(Zacharin, 2000; Bondy et al., 2007; Colvin, Devineni, & Ashraf, 2014; Wierckx, Gooren, & T’Sjoen, 2014; Kaiser & Ho, 2015; Bauman, Novello, & Kreitzer, 2016; Gawlik et al., 2016; Randolph, 2018; Donaldson et al., 2019; Heath & Wynne, 2019a; Heath & Wynne, 2019b; Iwamoto et al., 2019; Crowley & Pitteloud, 2020; Naseem, Lokman, & Fitzgerald, 2021; Federici et al., 2022; Lucien et al., 2022; Rothman & Iwamoto, 2022)。以上信源的相关片段摘录可参见此页面。与此相关,对青春期推迟的女孩进行青春期诱导治疗时,孕激素仅当以雌激素治疗约 2–3 年之后才加入,此时一般认为乳房发育趋于完成。还有,对女性倾向跨性别青年进行青春期诱导治疗时,通常不会加入孕激素。尽管青春期诱导方面的文献记载和经过考验的临床实践已经汗牛充栋,但需要强调的是,其中有关过早引入孕激素可能会阻滞乳房发育的说法没有任何临床证据支持,形同空中楼阁;甚至连它们是否基于口头的临床经验、而非单纯臆想都不大清楚。由于近期有更多将孕激素用于顺性别女孩以诱导青春期的研究开展,相关资料的缺位在未来有望得到弥补(例如 Rodari et al., 2023)

Rodari 及其同行就青春期诱导治疗的优化开展了研究,其中对 49 名患有性腺发育不全的顺性别女孩给予雌激素治疗,并于后续引入孕激素治疗(例如 Rodari et al., 2022; Rodari, 2022; Rodari et al., 2023)。雌激素以透皮方式给予,剂量低,随时间逐渐增加,以模拟正常青春期内偏低、且逐渐上升的雌二醇水平;孕激素仅于月经出血发生后引入。治疗平均持续了 2.65 ± 1 年;初潮发生于治疗 2.3 ± 1 年后;引入孕激素时间的中位数为治疗后 2.22 年(IQR 1.56–2.87 年)。研究对象有 90% 的乳房发育至 Tanner 四期,但仅有 41% 发育至 Tanner 五期。乳房完全发育和雌二醇剂量的增加、以及在引入孕激素时的剂量呈强相关性。据研究者解释,提及后者是出于孕激素暴露妨碍乳房发育的可能性。他们不支持在乳房发育不完全的情况下引入孕激素治疗,并建议医师应在乳房发育完成之前略微降低雌二醇剂量、推迟引入孕激素,而非初潮后即引入孕激素。以上资料虽饶有趣味,但需要注意这仅仅探究了相关性,没有建立孕酮抑制乳房成熟的因果关系,且对此有很多解释都适用。

用于乳房肥大的孕激素治疗

有人认为,低孕酮水平可能是导致青春期乳房肥大的因素之一(Sun et al., 2018)。多份已发表的病例报告系列病例研究都有孕激素用于治疗青春期乳房肥大的记载(Sperling & Gold, 1973; Boyce, Hoffman, & Mathes, 1984; Ryan & Pernoll, 1985; Aritaki et al., 1992; Gliosci & Presutti, 1993; Sridhar & Jaya Sinha, 1995; Baker et al., 2001; Dancey et al., 2008; Bland, Howard, Romrell, 2009; Hoppe et al., 2011; Sun et al., 2018);其中,地屈孕酮、MPA 和 CPA 等孕激素被假定在乳房有抗雌激素作用,而被用以尝试阻止或减缓乳房增长。在这批数目有限的病例中,治疗有效性不尽相同。由于青春期乳房肥大可自愈(即乳房发育会逐渐自行停止),且研究方法存在局限性(例如受试者数目很少、缺乏未经治疗的对照组),故难以从这批报告得出可靠的结论。

近年有同一批研究者开展的多项研究,评价了不同种类的激素避孕药对顺性别青年女性所患有的乳房肥大的作用(Nuzzi et al., 2021; Nuzzi et al., 2022)。研究发现,孕激素单方避孕药的使用和经手术切除的乳房组织的增加相关,且有统计显著性(959.9 g/m2 对 735.9 g/m2 [+30%],p = 0.04);相对于接受手术、但不使用激素避孕药的个体,临床症状有所恶化(例如乳房疼痛;发生率 4.94,P = 0.005)(Nuzzi et al., 2021)。与此相反,雌激素—孕激素复方避孕药的使用和经手术切除的乳房组织的减少有关,且有统计显著性(639.5 g/m2 对 735.9 g/m2 [-13%],p = 0.003);但跟不使用激素者相比,临床症状没有任何差异(Nuzzi et al., 2022)。需要说明,孕激素单方避孕药可抑制 HPG 轴,从而降低雌二醇水平;而复方避孕药虽然也抑制 HPG 轴并减少雌二醇分泌,但同时补充的外源性雌激素弥补了雌激素信号的缺位;这种差异可能是二者对乳房肥大症状的影响截然相反的原因所在。尽管 Nuzzi 及同行的研究结果饶有趣味,但曾有一封寄给编者的信讨论其中一篇文章时,对研究方法和结果提出了质疑(Karp, 2022)

Santen et al. (2024) 在一项有关患青少年乳房肥大的顺性别女孩的系列病例研究中指出,乳房发育在开始后仅会持续几年,那么一定有某种停止信号被激活并阻止乳房进一步增长。他们猜测这种信号可能和细胞凋亡有关。他们还指出,在成年顺性别女性的月经周期内,乳腺细胞随卵泡期增生,随黄体期凋亡;同时推测在黄体期发生的细胞凋亡可能阻断了乳房进一步发育。考虑到孕酮于黄体期产生并可能介导所谓凋亡过程,这为孕激素治疗乳房肥大这一用途提供了支持。但是据研究者所述,尚无资料表明患青少年乳房肥大的顺性别女孩的乳房存在细胞凋亡。另外,作者的假设有一点需要反驳:对于从未进入月经周期、也不曾暴露于黄体期孕激素水平的人,经雌激素诱导的乳房增长会随时间逐渐减缓、以至停止,这和正常顺性别女孩一模一样。这类人有很多,包括 CAIS 女性、女性倾向跨性别者,以及患有前列腺癌、接受雌激素治疗的顺性别男性。

17α-羟化酶/17,20-裂解酶不足所致的乳房发育不良

已有 17α-羟化酶/17,20-裂解酶不足的女孩接受雌激素治疗后出现乳房发育不良的报告;在治疗以前暴露于较高孕酮水平被猜测是此状况的原因(Turan et al., 2009; Athanasoulia et al., 2013; Deeb et al., 2015; Çamtosun et al., 2017; Fernández-Cancio et al., 2017; Kardelen et al., 2018)。然而,这仅仅出于理论,目前尚无证据表明孕酮与乳房发育不良存在明确因果关系。

醋酸环丙孕酮用于女性倾向跨性别者时对乳房发育的影响

对于孕激素抑制乳房发育的可能性,作为抗雄激素制剂用于女性倾向跨性别者的 CPA 是尤其需要注意的。这是因为,CPA 不仅是一种抗雄激素制剂,还是一种强效孕激素;其为女性倾向跨性别者所用的剂量可导致非常高的孕激素暴露量(Aly, 2019)。在 2 mg/天剂量下,CPA 便足以产生和黄体期孕酮暴露量相当的孕激素效力(Aly, 2019; 维基百科);相比之下,用于女性倾向跨性别者的 CPA 剂量介于 10–100 mg/天之间(Aly, 2019)。即使以 12.5 mg/天计算,其孕激素效力也相当于黄体期孕酮暴露量的约 6.25 倍;25、50、100 mg/天则相当于后者的 12.5 倍、25 倍和 50 倍。这还没有考虑以下事实:孕酮仅于黄体期被分泌,而 CPA 每天都要服用。CPA 所带来的如此高的孕激素暴露相对于妊娠期间的水平有过之而无不及。直到近年,更低剂量的 CPA(如 ≤12.5 mg/天)才开始被运用于女性化激素治疗。

有研究报道,处于青春期的青年女性倾向跨性别者给予 GnRH 激动剂以阻断青春期、而后给予雌激素治疗后,其乳房发育情况以主观的临床体验或 Tanner 分级评价,结果较佳(de Vries et al., 2010; Hannema et al., 2017);不过研究中没有采取客观的乳房测量手段。
相反的是,另一批非对照性研究对成年女性倾向跨性别者给予了雌激素和 CPA,其报道后者乳房小幅发育,体现在 Tanner 分级为 2–4 期(发育不完全)、罩杯较小、体积较小等(Kanhai et al., 1999; Sosa et al., 2003; Sosa et al., 2004; Wierckx et al., 2014; Fisher et al., 2016; Tack et al., 2017; de Blok et al., 2018; Reisman, Goldstein, & Safer, 2019; Meyer et al., 2020; de Blok et al., 2021);还有报道称乳房尺寸小于顺性别女性(Asscheman & Gooren, 1992; Kanhai et al., 1999)。有一项研究以处于青春期后期的女性倾向跨性别者为对象,也报道了乳房发育不良(Tack et al., 2017);但作者也坦白,其运用的雌激素剂量可能过低,导致雌二醇水平不足,从而可能干扰了研究结果(Tack et al., 2017)。无论如何,可以认为运用雌激素和 CPA 的女性倾向跨性别者的乳房发育普遍不良。
与之相对,由雌激素和无孕激素效力的抗雄激素制剂(螺内酯、比卡鲁胺、GnRH 调节剂等)组成的其它激素治疗方案,迄今均未得到充分研究,故难以比较各方案之间有何效果上的不同。

一项高质量研究对 69 名成年女性倾向跨性别者给予雌激素和 CPA,治疗持续三年后,以三维全身扫描(Vectra XT)测量的乳房体积平均值为 100 mL,小于 A 罩杯(95% 置信区间:~75–125 mL;最大值 ~750 mL)(de Blok et al., 2021 [图片])。研究中乳房改变随时间逐渐放缓,提示乳房发育完成或近乎完成;大多数(71%)的受试者乳房小于 A 罩杯,但有小部分测得了 A 罩杯(9%)、B 罩杯(16%)、C 罩杯(3%)或 E 罩杯(1%)(de Blok et al., 2021 [图片])。作为对比,另一研究用不同的三维全身扫描仪(Artec Eva 3D)对 378 名顺性别女性进行扫描,测得乳房体积中位数 ~515 mL、平均值 ~650 mL(IQR ~310–850 mL;范围 ~50–3,100 mL)(Coltman, Steele, & McGhee, 2017)。据此,可以认为以雌激素和 CPA 治疗的成年女性倾向跨性别者的乳房会明显小于顺性别女性。但这里必须强调一点:以上数据来自不同的临床研究,不能直接比较。还需注明,不同研究所测得的乳房体积可能有较大差异,即使测量方法相似亦然(例如都采用核磁共振成像(例如 Sindi et al., 2019 [表格])。因此,为了公平对比,有必要开展进一步研究,用一致的测量手段对女性倾向跨性别者和顺性别女性的乳房体积进行直接比较。

抛开上述不谈,或许女性倾向跨性别者只是单纯地普遍有不良的乳房发育,这不一定与 CPA 或孕激素暴露有关。事实上,在近期开展的一项研究中,先接受青春期抑制治疗(估计采用 GnRH 激动剂)、后接受雌激素治疗的女性倾向跨性别者,也和成人一样有不良的乳房发育(Boogers et al., 2022; 参照前述 de Blok et al., 2021);其中以激素治疗 4.2 年后,以三维全身扫描的方式测得的乳房体积平均值为 114 mL(IQR 58–203 mL),小于 A 罩杯(Boogers et al., 2022)。研究者和前述对象为成年女性倾向跨性别者的高质量研究的开展者是同一群人,故两项研究可能都采用了一致的三维全身扫描方法(de Blok et al., 2021)

目前,对 CPA 和其它抗雄激素制剂用于女性倾向跨性别者后的乳房发育情况进行直接比较的研究资料还是空缺的;因此,不能肯定上述结果是否局限于 CPA,也不能肯定其是否适用于孕激素效力相对较弱的其它抗雄激素制剂。目前,Ada Cheung 及同行正于澳大利亚开展一项 RCT,将雌二醇—螺内酯复方、雌二醇—CPA 复方用于女性倾向跨性别者时的乳房发育情况进行对比;考虑到螺内酯有微弱的、不具备临床显著性的孕激素效力,该研究有望为这个问题提供更多见解(Aly, 2018b; 维基百科; 参见后记一)

有关用于女性倾向跨性别者的孕激素治疗及其乳房发育的一些补充看法

讨论孕激素和乳房发育的传言

有不少女性倾向跨性别者自发报道,在激素治疗中加入的孕激素改善了其乳房发育。同时其他一些人则自发报道,孕激素对乳房发育没有产生裨益。必须注意,一般而言,自发报告可信度不足,作为医学证据的强度是很低的;这是因为主观的观察和因果推论往往会出错。人们对事物的感知可能会有误,尤其是对于身体改变这样缓慢的过程;身体改变亦可能是巧合以及与人无关的干扰因素导致的,而不是某人自身的因果关系所致。对于孕激素和乳房发育这方面,潜在的干扰因素包括:(1) 乳房发育仍受雌激素本身介导而继续进行;(2) 孕激素引起乳房液体潴留、血流量增加、可逆的小泡/小叶发育,从而短暂引起乳房增大。以上因素可能造成误导,助推“孕激素改善乳房发育”这类自发报告的产生。为了准确地评价孕激素对乳房发育的作用,还需开展更多临床研究,其中设计要严谨、要有对照、要有可靠的客观测量手段、跟踪期要长,最后还要停用孕激素以便控制可逆结局。

口服孕酮的临床局限性

口服孕酮所引起的孕酮水平非常低,即使在高剂量下,其孕激素效力也很弱(Aly, 2018a; 维基百科)。较低的孕酮水平可能不足以在乳房等部位起到生理性的孕激素作用。特别地,口服孕酮还会引起较强的神经甾体作用:其被代谢为别孕烷醇酮等神经活性代谢物,而后者可产生形如酒精中枢神经抑制作用情绪波动等明显副作用(Aly, 2018b; 维基百科; 维基百科)。此类副作用和剂量正相关,剂量越高、副作用越强。为避免以上问题,可改用非口服途径的孕酮或人工孕激素,例如直肠栓剂或注射剂(Aly, 2018a; Aly, 2018b)

孕激素的耐受性和安全性

孕激素存在一系列耐受性安全性问题(Aly, 2018b);例如,情绪恶化乳腺癌血栓心血管疾病良性脑肿瘤(如泌乳素瘤脑膜瘤),以及伴有不良反应的脱靶效应(如雄激素活性糖皮质激素活性),等等(Aly, 2018b)。特别地,CPA 在高剂量下有明显的严重肝毒性风险(Aly, 2018b)。诸孕激素风险不一,取决于种类和剂量,但都已知有一定的风险,即使是生物同质的孕酮也不例外。正是因为孕激素的这些风险,以及缺乏孕激素是否有益于女性化、情绪和健康的证据,才有了对孕激素用于女性倾向跨性别者的疑虑和犹豫(Aly, 2018b)。不过,顺性别女性体内天然地会产生孕酮,而且孕激素的绝对风险是很低的(Aly, 2018b)。为尽量减小孕激素风险,可采取的办法有:在较短年限(个位数)以内服用;以可达到预期疗效的最低剂量服用;采用药理特性更温和的品种(Aly, 2018a; Aly, 2018b)

后记

后记一:Angus et al. (2023–2024)

上文曾报道 Ada Cheung 及同行正开展一项 RCT,其中将雌二醇—螺内酯复方、雌二醇—CPA 复方用于女性倾向跨性别者时的乳房发育情况进行对比;考虑到螺内酯有微弱的、不具备临床显著性的孕激素效力,该研究有望为这个问题提供更多见解。该研究现已被发表于两份会议纪要,而期刊文章已进入发表流程 *:

  • Angus, L. M., Leemaqz, S., Zajac, J. D., & Cheung, A. S. (November 2023). A randomised controlled trial of spironolactone versus cyproterone in trans people commencing estradiol. AusPATH 2023 Symposium. [URL] [PDF] [Trans Health Research 博客文章]
  • Angus, L. M., Leemaqz, S. Y., Zajac, J. D., & Cheung, A. S. (November 2023). The effect of cyproterone and spironolactone on breast development in transgender women: a randomised controlled trial. ESA/SRB/ENSA 2023 ASM 26-29 November, Brisbane, 54–55 (abstract no. 132). [URL] [PDF] [摘要全文] [Trans Health Research 博客文章]

* 译者注: 期刊文章现已在线公开,摘录如下:

  • Angus, L. M., Leemaqz, S. Y., Kasielska-Trojan, A. K., Mikołajczyk, M., Doery, J. C., Zajac, J. D., & Cheung, A. S. (2024). Effect of spironolactone and cyproterone acetate on breast growth in transgender people: a randomized clinical trial. The Journal of Clinical Endocrinology & Metabolism, dgae650. [DOI: 10.1210/clinem/dgae650]

为准确表述研究结果,以下数据以最终期刊文章为准,做了相应改动;在期刊文章中没有体现的数据未改动。

研究对象是 55 名女性倾向跨性别者,其中 27 人给予雌二醇和螺内酯 100 mg/天,28 人给予雌二醇和 CPA 12.5 mg/天;激素治疗——至少到最近一次跟踪为止——持续了六个月。对乳房发育的测量手段乳房—下胸围差(主要结局),以及乳房体积测算(次要结局)。

螺内酯组和 CPA 组的乳房—下胸围差(平均值 ± 标准差)分别为 8.2 ± 2.7 cm 和 9.2 ± 3.0 cm,差距无统计显著性(p = 0.6);经测算的乳房体积(平均值 ± 标准差)分别为 158.5 ± 110.0 mL190.2 ± 158.6 mL,差距无统计显著性(p = 0.3)。经测算的乳房体积在个体间有较大差异,介乎 20–788 mL 不等。研究结果还显示,CPA 引起的体脂肪增幅和女性型脂肪分布占比较螺内酯更大;雌二醇水平基本相当;总睾酮水平(平均值 ± 标准差),螺内酯组 4.15 ± 5.38 nmol/L(119.7 ± 155.2 ng/dL),CPA 组 1.48 ± 3.45 nmol/L(42.7 ± 99.5 ng/dL),二者差异 统计显著性(p = 0.07)。

研究者总结称,研究中螺内酯组和 CPA 组的乳房发育没有差异;建议在选择抗雄激素制剂时,尊重患者和医师意愿、并考虑相关副作用,实施一人一方;未来应开展进一步研究来优化女性倾向跨性别者的乳房发育。

研究中以在线免费工具 BreastIdea Volume Estimator 来计算乳房体积;仅需提交二维照片即可测算(Mikołajczyk, Kasielska-Trojan, & Antoszewski, 2019; Kasielska-Trojan, Mikołajczyk, & Antoszewski, 2020)。该工具已在顺性别女性和顺性别男性当中进行验证(Mikołajczyk, Kasielska-Trojan, & Antoszewski, 2019; Kasielska-Trojan, Mikołajczyk, & Antoszewski, 2020)。此外,Cheung、Angus 以及包括该工具的一部分开发者在内的其他同行曾共同开展一项研究,验证工具对顺性别男性和女性倾向跨性别者的有效性,成果于 2022 年发表于以下会议摘要:

  • Angus, L., Mikolajczyk, M., Cheung, A., Zajac, J., Antoszewski, B., & Kasielska-Trojan, A. (2022). Estimation of breast volume in transgender women using 2D photography: validation of the BreastIdea Volume Estimator in men and transgender women. ESA/SRB/APEG/NZSE ASM 2022, November 13-16, Christchurch, Abstracts and Programme, 127–127 (abstract no. 279). [URL] [PDF] [摘要全文]

BreastIdea 开发者开展的研究用该工具测算了顺性别女性乳房体积,其结果可与上述 Cheung、Angus 及同行针对女性倾向跨性别者的测算结果相互对比。BreastIdea 开发者报道的乳房体积(平均值 ± 标准差)是:乳房正常的顺性别女性(n=30)283 ± 144 mL,患有乳房肥大或巨乳症的顺性别女性(n=35)888 ± 277 mL(Kasielska-Trojan, Zawadzki, & Antoszewski, 2022);另一项研究报道,顺性别女性 272 ± 150 mL,范围 99–694 mL(Kasielska-Trojan, Mikołajczyk, & Antoszewski, 2020)

BreastIdea 这个乳房体积测算工具看似有趣且实用,实则有其局限性,例如其分辨率和精度均远逊于 Artec Eva 和 Vectra XT 等三维扫描仪(Mikołajczyk, Kasielska-Trojan, & Antoszewski, 2019)。Artec 和 Vectra 扫描仪已在其他研究中被用于测量女性倾向跨性别者经激素治疗后的乳房发育情况(de Blok et al., 2021; Boogers et al., 2022; Dijkman et al., 2023a; Dijkman et al., 2023b; Lopez et al., 2023)。精度问题或许正是 BreastIdea 所测得的顺性别女性、女性倾向跨性别者乳房体积和其它研究中以三维扫描仪测量的结果大相迥异的原因所在。
另一方面,乳房—下胸围差作为衡量女性倾向跨性别者乳房发育的指标也存在局限性:例如,其无法反映仍在持续增长的乳房体积(de Blok et al., 2021)

除了以上乳房测量手段以外,Lachlan Angus 及同行的 RCT 还存在以下局限性:跟踪时长仅有六个月;螺内酯和 CPA 组的睾酮水平不一致;样本规模有限。需要说明,螺内酯治疗组中的睾酮水平未得到完全抑制,而这部分剩余的睾酮可阻断雌激素介导的乳房发育,从而使发育效果减弱。有限的样本规模可能是导致两个治疗组之间乳房发育情况的数值差异不具备统计显著性的原因之一。无论如何,从 Angus 及同行的研究结果可以看出,至少在六个月的激素治疗中,相比于螺内酯,具有强孕激素效力的 CPA 既不会促进、也不会阻滞乳房发育。这项 RCT 将来貌似还会继续开展,跟踪期和激素治疗时长都有望得到延伸。

后记二:Flamant, Vervalcke, & T’Sjoen (2023) 以及 Yang et al. (2024)

就女性倾向跨性别者暴露于孕激素(具体而言是 CPA)是否影响乳房发育这个话题,近期开展的两项研究可提供更多见解:

  • Flamant, T., Vervalcke, J., & T’Sjoen, G. (November 2023). Dose Reduction of Cyproterone Acetate in Trans Women and the Effect on Patient-reported Outcomes: Results from the ENIGI Study. Endocrine Abstracts, 97 [Belgian Endocrine Society 2023], 5–5 (abstract no. 007). [URL] [PDF]
  • Yang, W., Hong, T., Chang, X., Han, M., Gao, H., Pan, B., Zhao, Z., & Liu, Y. (2024). The efficacy of and user satisfaction with different antiandrogens in Chinese transgender women. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2024.2323514]
    ——【译者注】 部分作者经查证分别为:洪天配(共同第一作者)、常旭、高洪伟、潘柏林、赵振民、刘烨

第一项,即 Flamant, Vervalcke, & T’Sjoen (2023) 的研究于比利时根特大学的诊所开展,将低剂量(10–12.5 mg/天)和高剂量(25–50 mg/天)的 CPA 用于 72 名女性倾向跨性别者,并比较其临床结局。两组的睾酮抑制效果一致。治疗一年后,两组之间以体象量表评价的乳房发育满意度的差异无统计显著性(p = 0.078);但是,P 值非常接近于 统计显著性阈值(0.05 以下——译者注)。论文没有显示哪一组的满意度得分更高。无论如何,据研究者称,低剂量 CPA 治疗组的乳房发育满意度并“不逊于”高剂量 CPA,换言之,可能高于后者。上述结果表明,高剂量 CPA 并不会比低剂量有更强的乳房发育阻滞作用,但孕激素活性依然极高。

另一项,即 Yang et al. (2024)回顾性研究于中国北京大学第三医院开展,其中比较了雌二醇—螺内酯复方(n=43)、雌二醇—CPA 复方(n=53)用于女性倾向跨性别者的临床结局。螺内酯组的睾酮水平远高于 CPA 组(374 ng/dL 对 20 ng/dL,或 13.0 nmol/L 对 0.7 nmol/L;P < 0.001);螺内酯组的跟踪期较 CPA 组偏短(中位数分别是 12 个月和 18 个月)。在以视觉模拟量表(VAS)评价的乳房发育满意度方面,螺内酯组、CPA 组的得分中位数分别是 6.0(IQR 4.0–7.0)和 6.0(IQR 4.0–7.0),差别无统计显著性。至于 VAS 其它项目的评价上,CPA 组在多个项目的得分都高于螺内酯组,包括面部女性化、睾丸萎缩、勃起减少等;CPA 组的综合满意度得分也更高。上述结果表明,螺内酯和 CPA 用于女性倾向跨性别者时,乳房发育情况相似,这与 Lachlan Angus 及同行的 RCT 结果一致;但在睾酮水平和其它临床结局上都存在差异。

Flamant, Vervalcke, & T’Sjoen (2023) 以及 Yang et al. (2024) 的研究都存在重大局限性:即采用主观的自评量表、而非客观的物理测量手段来评价乳房发育。

参考文献

  • Abduljalil, K., Furness, P., Johnson, T. N., Rostami-Hodjegan, A., & Soltani, H. (2012). Anatomical, Physiological and Metabolic Changes with Gestational Age during Normal Pregnancy. Clinical Pharmacokinetics, 51(6), 365–396. [DOI:10.2165/11597440-000000000-00000]
  • Adams, R. D., Kliman, B., Federman, D. D., Ulfelder, H. S., & Holmes, L. B. (1970). Syndromes of Testicular Feminization. Clinical Pediatrics, 9(3), 165–178. [DOI:10.1177/000992287000900312]
  • Alekseev, N. P. (2021). Origin and Development of the Mammary Glands. In Alekseev, N. P. Physiology of Human Female Lactation (pp. 11–66). Cham: Springer. [DOI:10.1007/978-3-030-66364-3_2]
  • Alex, A., Bhandary, E., & McGuire, K. P. (2020). Diseases of the Breast during Pregnancy and Lactation. In Alipour, S., & Omranipour, R. (Eds.). Diseases of the Breast during Pregnancy and Lactation (Advances in Experimental Medicine and Biology, Volume 1252). Cham: Springer International Publishing. [DOI:10.1007/978-3-030-41596-9]
  • Anderson, W. A. (1962). Experimental stimulation of breast development in the teen-age female. The Journal of the Medical Society of New Jersey, 59(10), 541–543. [Google 学术] [PubMed] [PDF]
  • Andler, W., & Zachmann, M. (1979). Spontaneous breast development in an adolescent girl with testicular feminization after castration in early childhood. The Journal of Pediatrics94(2), 304–305. [DOI:10.1016/s0022-3476(79)80852-5]
  • Apter, D. (1980). Serum steroids and pituitary hormones in female puberty: a partly longitudinal study. Clinical Endocrinology, 12(2), 107–120. [DOI:10.1111/j.1365-2265.1980.tb02125.x]
  • Angus, L. M., Leemaqz, S., Zajac, J. D., & Cheung, A. S. (November 2023). A randomised controlled trial of spironolactone versus cyproterone in trans people commencing estradiol. AusPATH 2023 Symposium. [URL] [PDF] [Trans Health Research 博客文章]
  • Angus, L. M., Leemaqz, S. Y., Zajac, J. D., & Cheung, A. S. (November 2023). The effect of cyproterone and spironolactone on breast development in transgender women: a randomised controlled trial. ESA/SRB/ENSA 2023 ASM 26-29 November, Brisbane, 54–55 (abstract no. 132). [URL] [PDF] [摘要全文] [Trans Health Research 博客文章]
  • Angus, L., Mikolajczyk, M., Cheung, A., Zajac, J., Antoszewski, B., & Kasielska-Trojan, A. (2022). Estimation of breast volume in transgender women using 2D photography: validation of the BreastIdea Volume Estimator in men and transgender women. ESA/SRB/APEG/NZSE ASM 2022, November 13-16, Christchurch, Abstracts and Programme, 127–127 (abstract no. 279). [URL] [PDF] [摘要全文]
  • Apter, D., Räisänen, I., Ylöstalo, P., & Vihko, R. (1987). Follicular growth in relation to serum hormonal patterns in adolescent compared with adult menstrual cycles. Fertility and Sterility, 47(1), 82–88. [DOI:10.1016/s0015-0282(16)49940-1]
  • Aritaki, S., Miyazawa, H., Ogihara, M., Ushio, M., & Izumizawa, A. (1992). An Endocrinological Study of Persistent Pubertal Macromastia. The Tohoku Journal of Experimental Medicine, 167(3), 189–196. [DOI:10.1620/tjem.167.189]
  • Arya, S., Barnabas, R., Lila, A. R., Sarathi, V., Memon, S. S., Bhandare, V. V., Thakkar, K., Patil, V., Shah, N. S., Kunwar, A., & Bandgar, T. (2021). Clinical, Hormonal, Genetic, and Molecular Characteristics in Androgen Insensitivity Syndrome in an Asian Indian Cohort from a Single Centre in Western India. Sexual Development15(4), 253–261. [DOI:10.1159/000517763]
  • Asscheman, H., & Gooren, L. J. (1992). Hormone Treatment in Transsexuals. In Bocking, W. O., Coleman, E. (Eds). Gender Dysphoria: Interdisciplinary Approaches in Clinical Management (pp. 39–54). Binghamton: Haworth Press. / Journal of Psychology & Human Sexuality, 5(4), 39–54. [Google 学术] [Google 阅读] [DOI:10.1300/J056v05n04_03]
  • Athanasoulia, A., Auer, M., Riepe, F., & Stalla, G. (2013). Rare Missense P450c17 (CYP17A1) Mutation in Exon 1 as a Cause of 46,XY Disorder of Sexual Development: Implications of Breast Tissue ‘Unresponsiveness’ despite Adequate Estradiol Substitution. Sexual Development, 7(4), 212–215. [DOI:10.1159/000348301]
  • Atwood, C., Hovey, R., Glover, J., Chepko, G., Ginsburg, E., Robison, W., & Vonderhaar, B. (2000). Progesterone induces side-branching of the ductal epithelium in the mammary glands of peripubertal mice. Journal of Endocrinology, 167(1), 39–52. [DOI:10.1677/joe.0.1670039]
  • Aupperlee, M. D., Leipprandt, J. R., Bennett, J. M., Schwartz, R. C., & Haslam, S. Z. (2013). Amphiregulin mediates progesterone-induced mammary ductal development during puberty. Breast Cancer Research, 15(3), R44. [DOI:10.1186/bcr3431]
  • Bahr, C., Ewald, J., Dragovich, R., & Gothard, M. D. (2024). Effects of progesterone on gender affirmation outcomes as part of feminizing hormone therapy. Journal of the American Pharmacists Association, 64(1), 268–272. [DOI:10.1016/j.japh.2023.08.001]
  • Baird, D., Hytten, F. E., & Thomson, A. M. (1958). Age and Human Reproduction. BJOG, 65(6), 865–876. [DOI:10.1111/j.1471-0528.1958.tb08582.x]
  • Baker, S. B., Burkey, B. A., Thornton, P., & LaRossa, D. (2001). Juvenile Gigantomastia: Presentation of Four Cases and Review of the Literature. Annals of Plastic Surgery, 46(5), 517–526. [DOI:10.1097/00000637-200105000-00011]
  • Bames, H. O. (1948). Reduction of massive breast hypertrophy. Plastic and Reconstructive Surgery, 3(5), 560–569. [DOI:10.1097/00006534-194809000-00006]
  • Barbieri, R. L. (2019). Breast. In Strauss, J. F., & Barbieri, R. L. (Eds.). Yen and Jaffe’s Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 8th Edition (pp. 248–255.e3). Philadelphia: Elsevier. [Google 阅读] [DOI:10.1016/B978-0-323-47912-7.00010-X]
  • Baron, J. (1993). Zespół braku wrazliwości na androgeny. Studium kliniczne i endokrynologiczne 40 osobników [Androgen insensitivity syndrome. Clinical and endocrinologic study of 40 cases]. Endokrynologia Polska44(2), 175–186. [Google 学术] [PubMed]
  • Baron, J. (1994). Klasyczne i niepełne zespoły braku wrazliwości na androgeny [Classical and incomplete androgen insensitivity syndromes]. Ginekologia Polska65(7), 377–386. [Google 学术] [PubMed]
  • Baron, J. (1994). Niepełny lub cześciowy zespół braku wrazliwości na androgeny [Partial androgen insensitivity syndrome]. Ginekologia Polska65(6), 319–325. [Google 学术] [PubMed]
  • Barrat, J., de Lignières, B., Marpeau, L., Larue, L., Fournier, S., Nahoul, K., Linares, G., Giorgi, H., & Contesso, G. (1990). Effet in vivo de l’administration locale de progestérone sur l’activité mitotique des galactophores humains. Résultat d’une étude pilote. [The in vivo effect of the local administration of progesterone on the mitotic activity of human ductal breast tissue. Results of a pilot study.] Journal de Gynecologie, Obstetrique et Biologie de la Reproduction, 19(3), 269–274. [Google 学术 1] [Google 学术 2] [PubMed]
  • Barrett, J. (2009). The clinical risks associated with the diagnosis and management of disorders of gender identity. Clinical Risk, 15(4), 131–134. [DOI:10.1258/cr.2008.080069]
  • Bässler, R. (1970). The Morphology of Hormone Induced Structural Changes in the Female Breast. In Altmann, H.-W., et al. (Eds.). Current Topics in Pathology: Ergebnisse der Pathology, Volume 53 (pp. 1–89). Heidelberg: Springer Berlin. [DOI:10.1007/978-3-662-30514-0_1] [PDF]
  • Basson, R., & Prior, J. C. (1998). Hormonal Therapy of Gender Dysphoria: The Male-to-Female Transsexual. In Denny, D. (Ed.). Concepts in Transgender Identity (Garland Gay and Lesbian Studies, Volume 11) (pp. 277–296). New York: Garland Publishing Inc. [Google 学术] [Google 阅读] [DOI:10.4324/9780203775134-19] [PDF]
  • Bauman, A., Novello, L., & Kreitzer, P. (2016). Endocrine Disorders and Delayed Puberty. In Appelbaum, H. (Ed.). Abnormal Female Puberty: A Clinical Casebook (pp. 87–107). Cham: Springer. [DOI:10.1007/978-3-319-27225-2_5]
  • Begley, D. J., Firth, J. A., & Hoult, J. R. (1980). The Breast and Lactation. In Begley, D. J., Firth, J. A., & Hoult, J. R. Human Reproduction and Developmental Biology (pp. 204–219). London: Macmillan Education UK. [DOI:10.1007/978-1-349-16260-4_14]
  • Bayer, C. M., Bani, M. R., Schneider, M., Dammer, U., Raabe, E., Haeberle, L., Faschingbauer, F., Schneeberger, S., Renner, S. P., Fischer, D., Schulz-Wendtland, R., Fasching, P. A., Beckmann, M. W., & Jud, S. M. (2014). Assessment of breast volume changes during human pregnancy using a three-dimensional surface assessment technique in the prospective CGATE study. European Journal of Cancer Prevention, 23(3), 151–157. [DOI:10.1097/cej.0b013e3283651ccb]
  • Beck, P. (1972). Lactogenic Activity of Human Chorionic Somatomammotropin in Rhesus Monkeys. Experimental Biology and Medicine, 140(1), 183–187. [DOI:10.3181/00379727-140-36422]
  • Begley, D. J., Firth, J. A., & Hoult, J. R. (1980). The Breast and Lactation. In Begley, D. J., Firth, J. A., & Hoult, J. R. Human Reproduction and Developmental Biology (pp. 204–219). London: Macmillan Education UK. [DOI:10.1007/978-1-349-16260-4_14]
  • Bellwether, C. J. (2020). Why Should a Transfeminine Person Consider Progesterone? Google Docs. [URL]
  • Benjamin, H. (1966). Nonsurgical Management of Transsexualism. In Benjamin, H. The Transsexual Phenomenon (pp. 86–99). New York: Julian Press. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [PDF]
  • Benjamin, H. (1967). Transvestism and Transsexualism in the male and female. Journal of Sex Research, 3(2), 107–127. [DOI:10.1080/00224496709550519]
  • Berliere, M., Coche, M., Lacroix, C., Riggi, J., Coyette, M., Coulie, J., Galant, C., Fellah, L., Leconte, I., Maiter, D., Duhoux, F. P., & François, A. (2022). Effects of Hormones on Breast Development and Breast Cancer Risk in Transgender Women. Cancers, 15(1), 245. [DOI:10.3390/cancers15010245]
  • Berryhill, G. E., Trott, J. F., & Hovey, R. C. (2016). Mammary gland development—It’s not just about estrogen. Journal of Dairy Science, 99(1), 875–883. [DOI:10.3168/jds.2015-10105]
  • Bertelloni, S., Dati, E., Baroncelli, G. I., & Hiort, O. (2011). Hormonal Management of Complete Androgen Insensitivity Syndrome from Adolescence Onward. Hormone Research in Paediatrics76(6), 428–433. [DOI:10.1159/000334162]
  • Bethea, C. L., Kohama, S. G., & Pecins-Thompson, M. (1997). Pituitary and Brain Actions of Estrogen and Progesterone in the Regulation of Primate Prolactin Secretion. In Pavlik, E. J. (Ed.). Estrogens, Progestins, and Their Antagonists: Functions and Mechanisms of Action (pp. 3–46). Boston: Birkhäuser. [DOI:10.1007/978-1-4612-2004-6_1]
  • Bevan, D. J. (2012). Progesterone for Breast Development? / Should Male-to-Female Transsexuals Take Progesterone as part of Hormone Therapy (HT) for Better Breast Development? Biopsychology of TSTG / Transgender Forum. [URL 1] [URL 2]
  • Bevan, D. J. (2019). Grow Your Own : Breast Development Update. Transgender Forum. [URL]
  • Beyer, C., Cruz, M. L., & Martinez-Manautou, J. (1970). Effect of Chlormadinone Acetate on Mammary Development and Lactation in the Rabbit. Endocrinology, 86(5), 1172–1174. [DOI:10.1210/endo-86-5-1172]
  • Biswas, S. K., Banerjee, S., Baker, G. W., Kuo, C., & Chowdhury, I. (2022). The Mammary Gland: Basic Structure and Molecular Signaling during Development. International Journal of Molecular Sciences, 23(7), 3883. [DOI:10.3390/ijms23073883]
  • Bland, K. I., Copeland, E. M., & Klimberg, V. S. (2018). Anatomy of the Breast, Axilla, Chest Wall, and Related Metastatic Sites. In Bland, K. I., Copeland, E. M., Klimberg, V. S., Gradishar, W. J., White, J., & Korourian, S. (Eds.). The Breast: Comprehensive Management of Benign and Malignant Diseases, 5th Edition (pp. 20–36.e2). Philadelphia: Elsevier. [DOI:10.1016/b978-0-323-35955-9.00002-7]
  • Bland, K. I., Harrison Howard, J., & Romrell, L. J. (2009). Congenital and Acquired Disturbances of Breast Development and Growth. In Bland, K. I., & Copeland, E. M. (Eds.). The Breast: Comprehensive Management of Benign and Malignant Diseases, 4th Edition (pp. 189–207). Philadelphia: Saunders/Elsevier. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat]
  • Bondy, C. A., & Turner Syndrome Consensus Study Group. (2007). Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. The Journal of Clinical Endocrinology & Metabolism, 92(1), 10–25. [DOI:10.1210/jc.2006-1374]
  • Boogers, L., Infirri, S. S., Bouchareb, A., de Blok, C., Liberton, N., van Trotsenburg, P., Dreijerink, K., den Heijer, M., Wiepjes, C., & Hannema, S. (2022). The effect of timing of puberty suppression on breast development in trans girls; a cross-sectional study. Hormone Research in Paediatrics, 95(Suppl 2) [60th Annual Meeting of the European Society for Paediatric Endocrinology (ESPE), Rome, Italy, September 15–17, 2022], 390–391 (abstract no. P1-379). [Google 学术] [DOI:10.1159/000525606] [URL] [PDF 1] [PDF 2]
  • Boyce, S. W., Hoffman, P. G., & Mathes, S. J. (1984). Recurrent Macromastia after Subcutaneous Mastectomy. Annals of Plastic Surgery, 13(6), 511–518. [DOI:10.1097/00000637-198412000-00008]
  • Bruck, H. G., & Müller, G. (1967). Zur Hormontherapie der Hypoplastischen Weiblichen Brust. [On Hormonal Therapy of the Hypoplastic Female Breast.] Ästhetische Medizin [Ästhetische Medizin : Kongreß-Organ der Deutschen Gesellschaft für die Ästhetische Medizin und ihre Grenzgebiete], 16(12), 365–366. [ISSN:0400-6755] [Google 学术] [PubMed] [WorldCat] [PDF] [英译文]
  • Bryant, R., Underwood, A., Robinson, A., Stephenson, T., & Underwood, J. (1998). Determination of breast tissue composition for improved accuracy in estimating radiation doses and risks in mammographic screening. The Breast, 7(2), 95–98. [DOI:10.1016/s0960-9776(98)90064-9]
  • Buhimschi, C. S. (2004). Endocrinology of lactation. Obstetrics and Gynecology Clinics of North America, 31(4), 963–979. [DOI:10.1016/j.ogc.2004.08.002]
  • Camilletti, M. A., Abeledo-Machado, A., Faraoni, E. Y., Thomas, P., & Díaz-Torga, G. (2019). New insights into progesterone actions on prolactin secretion and prolactinoma development. Steroids, 152, 108496. [DOI:10.1016/j.steroids.2019.108496]
  • Çamtosun, E., Şıklar, Z., Ceylaner, S., Kocaay, P., & Berberoğlu, M. (2017). Delayed Diagnosis of a 17-Hydroxylase/17,20-Lyase Deficient Patient Presenting as a 46,XY Female: A Low Normal Potassium Level Can Be an Alerting Diagnostic Sign. Journal of Clinical Research in Pediatric Endocrinology, 9(2), 163–167. [DOI:10.4274/jcrpe.3839]
  • Capraro, V. J., & Dewhurst, C. J. (1975). Breast Disorders in Childhood and Adolescence. Clinical Obstetrics and Gynecology, 18(2), 25–50. [DOI:10.1097/00003081-197506000-00003]
  • Carlson, L. J., & Shaw, N. D. (2019). Development of Ovulatory Menstrual Cycles in Adolescent Girls. Journal of Pediatric and Adolescent Gynecology, 32(3), 249–253. [DOI:10.1016/j.jpag.2019.02.119]
  • Caro, T. M. (1987). Human breasts: Unsupported hypotheses reviewed. Human Evolution, 2(3), 271–282. [DOI:10.1007/bf03016112]
  • Ceriani, R. L. (1974). Hormones and Other Factors Controlling Growth in the Mammary Gland: A Review. Journal of Investigative Dermatology, 63(1), 93–108. [DOI:10.1111/1523-1747.ep12678104]
  • Cernea, R. (1944). Lokale Hormonbehandlung bei Mammaatrophie und Unterentwicklung. [Local Hormone Treatment in Mammary Atrophy and Underdevelopment.] Medizinische Klinik, 40(11/12), 169–170. [Google 学术] [PDF] [英译文]
  • Chang, K., Lee, T. T., Linares-Cruz, G., Fournier, S., & de Ligniéres, B. (1995). Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertility and Sterility, 63(4), 785–791. [DOI:10.1016/s0015-0282(16)57482-2]
  • Cheikhelard, A., Morel, Y., Thibaud, E., Lortat-Jacob, S., Jaubert, F., Polak, M., & Nihoul-Fekete, C. (2008). Long-Term Followup and Comparison Between Genotype and Phenotype in 29 Cases of Complete Androgen Insensitivity Syndrome. Journal of Urology, 180(4), 1496–1501. [DOI:10.1016/j.juro.2008.06.045]
  • Ciarloni, L., Mallepell, S., & Brisken, C. (2007). Amphiregulin is an essential mediator of estrogen receptor α function in mammary gland development. Proceedings of the National Academy of Sciences, 104(13), 5455–5460. [DOI:10.1073/pnas.0611647104]
  • Clendenen, T. V., Kim, S., Moy, L., Wan, L., Rusinek, H., Stanczyk, F. Z., Pike, M. C., & Zeleniuch-Jacquotte, A. (2013). Magnetic Resonance Imaging (MRI) of hormone-induced breast changes in young premenopausal women. Magnetic Resonance Imaging, 31(1), 1–9. [DOI:10.1016/j.mri.2012.06.022]
  • Cline, J. M., & Wood, C. E. (2006). Hormonal Effects on the Mammary Gland of Postmenopausal Nonhuman Primates. Breast Disease, 24(1), 59–70. [DOI:10.3233/bd-2006-24105]
  • Cline, J. M., & Wood, C. E. (2008). The Mammary Glands of Macaques. Toxicologic Pathology, 36(7 Suppl), 130S–141S. [DOI:10.1177/0192623308327411]
  • Cole, R. D., & Hopkins, T. R. (1962). A Biochemical Test of Artificial Mammogenesis and Lactogenesis As Models of the Natural Processes. Endocrinology, 70(3), 375–380. [DOI:10.1210/endo-70-3-375]
  • Coleman, E., Bockting, W., Botzer, M., Cohen-Kettenis, P., DeCuypere, G., Feldman, J., Fraser, L., Green, J., Knudson, G., Meyer, W. J., Monstrey, S., Adler, R. K., Brown, G. R., Devor, A. H., Ehrbar, R., Ettner, R., Eyler, E., Garofalo, R., Karasic, D. H., Lev, A. I., Mayer, G., Meyer-Bahlburg, H., Hall, B. P., Pfaefflin, F., Rachlin, K., Robinson, B., Schechter, L. S., Tangpricha, V., van Trotsenburg, M., Vitale, A., Winter, S., Whittle, S., Wylie, K. R., & Zucker, K. (2012). [World Professional Association for Transgender Health (WPATH)] Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People, Version 7. International Journal of Transgenderism, 13(4), 165–232. [DOI:10.1080/15532739.2011.700873] [URL] [PDF]
  • Coleman, E., Radix, A. E., Bouman, W. P., Brown, G. R., de Vries, A. L., Deutsch, M. B., Ettner, R., Fraser, L., Goodman, M., Green, J., Hancock, A. B., Johnson, T. W., Karasic, D. H., Knudson, G. A., Leibowitz, S. F., Meyer-Bahlburg, H. F., Monstrey, S. J., Motmans, J., Nahata, L., … & Arcelus, J. (2022). [World Professional Association for Transgender Health (WPATH)] Standards of Care for the Health of Transgender and Gender Diverse People, Version 8. International Journal of Transgender Health, 23(Suppl 1), S1–S259. [DOI:10.1080/26895269.2022.2100644] [URL] [PDF]
  • Coltman, C. E., Steele, J. R., & McGhee, D. E. (2017). Breast volume is affected by body mass index but not age. Ergonomics, 60(11), 1576–1585. [DOI:10.1080/00140139.2017.1330968]
  • Colvin, C., Devineni, G., & Ashraf, A. P. (2014). Delayed Puberty. In Bandeira, F., Gharib, H., Golbert, A., Griz, L., & Faria, M. (Eds.). Endocrinology and Diabetes (pp. 203–217). New York: Springer. [DOI:10.1007/978-1-4614-8684-8_17]
  • Cowie, A. T., & Folley, S. J. (1961). The Mammary Gland and Lactation. In Young, W. C. (Ed.). Sex and Internal Secretions, 3rd Edition, Volume I (pp. 590–642). Baltimore: Williams & Wilkins. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [Archive.org]
  • Cowie, A. T., Forsyth, I. A., & Hart, I. C. (1980). Growth and Development of the Mammary Gland. In Cowie, A. T., Forsyth, I. A., & Hart, I. C. Hormonal Control of Lactation (Monographs on Endocrinology, Volume 15) (pp. 58–145). Berlin/Heidelberg: Springer Berlin Heidelberg. [DOI:10.1007/978-3-642-81389-4_3]
  • Cox, D. B., Kent, J. C., Casey, T. M., Owens, R. A., & Hartmann, P. E. (1999). Breast Growth and the Urinary Excretion of Lactose During Human Pregnancy and Early Lactation: Endocrine Relationships. Experimental Physiology, 84(2), 421–434. [DOI:10.1111/j.1469-445x.1999.01807.x]
  • Cox, C. B., Kent, J. C., Owens, R., & Hartmann, P. E. (1994). Mammary morphological and functional changes during pregnancy in women. In Thompson, J. (Ed.). Proceedings of the Twenty-Sixth Annual Conference, Hilton Hotel, Brisbane, 26–28 September, 1994 [The Australian Society for Reproductive Biology Inc., Twenty Sixth Annual Conference, The Hilton Hotel, Brisbane, September 26 - 28 1994, Programme and Miniposters of Papers] (pp. 47–47). Australia: Australian Society for Reproductive Biology. [Google 学术] [WorldCat] [URL] [PDF]
  • Coxon, J., & Seal, L. (2018). Hormone management of trans women. Trends in Urology & Men’s Health, 9(6), 10–14. [DOI:10.1002/tre.663]
  • Cregan, M. D., & Hartmann, P. E. (1999). Computerized Breast Measurement from Conception to Weaning: Clinical Implications. Journal of Human Lactation, 15(2), 89–96. [DOI:10.1177/089033449901500202]
  • Crowley, L. G., & Macdonald, I. (1965). Delalutin and estrogens for the treatment of advanced mammary carcinoma in the postmenopausal woman. Cancer, 18(4), 436–446. [DOI:10.1002/1097-0142(196504)18:4<436::aid-cncr2820180407>3.0.co;2-d]
  • Crowley, W. F., & Pitteloud, N. (2020). Approach to the patient with delayed puberty. UpToDate. [Google 学术] [URL]
  • Cruz-Korchin, N., Korchin, L., González-Keelan, C., Climent, C., & Morales, I. (2002). Macromastia. Plastic and Reconstructive Surgery, 109(1), 64–68. [DOI:10.1097/00006534-200201000-00011]
  • Curtis, R. J. (2009 July 10). The Lowdown on Progesterone. London: The London Gender Clinic. [Google 学术] [URL] [PDF]
  • Dallmann, A., Ince, I., Meyer, M., Willmann, S., Eissing, T., & Hempel, G. (2017). Gestation-Specific Changes in the Anatomy and Physiology of Healthy Pregnant Women: An Extended Repository of Model Parameters for Physiologically Based Pharmacokinetic Modeling in Pregnancy. Clinical Pharmacokinetics, 56(11), 1303–1330. [DOI:10.1007/s40262-017-0539-z]
  • Dancey, A., Khan, M., Dawson, J., & Peart, F. (2008). Gigantomastia – a classification and review of the literature. Journal of Plastic, Reconstructive & Aesthetic Surgery, 61(5), 493–502. [DOI:10.1016/j.bjps.2007.10.041]
  • Davajan, V., & Kletzky, O. A. (1979). Amenorrhea without Galactorrhea or Hirsutism. In Mishell, D. R., & Davajan, V. (Eds.). Reproductive Endocrinology, Infertility, and Contraception (pp. 219–248). Philadelphia: F. A. Davis Co. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [Archive.org]
  • Davis, M. E., Boynton, M. W., Ferguson, J. H., & Rothman, S. (1945). Studies on Pigmentation of Endocrine Origin. The Journal of Clinical Endocrinology & Metabolism, 5(3), 138–146. [DOI:10.1210/jcem-5-3-138]
  • de Blok, C. J., Dijkman, B. A., Wiepjes, C. M., Staphorsius, A. S., Timmermans, F. W., Smit, J. M., Dreijerink, K. M., & den Heijer, M. (2021). Sustained Breast Development and Breast Anthropometric Changes in 3 Years of Gender-Affirming Hormone Treatment. The Journal of Clinical Endocrinology & Metabolism, 106(2), e782–e790. [DOI:10.1210/clinem/dgaa841]
  • de Blok, C. J., Klaver, M., Wiepjes, C. M., Nota, N. M., Heijboer, A. C., Fisher, A. D., Schreiner, T., T’Sjoen, G., & den Heijer, M. (2017). Breast Development in Transwomen After 1 Year of Cross-Sex Hormone Therapy: Results of a Prospective Multicenter Study. The Journal of Clinical Endocrinology & Metabolism, 103(2), 532–538. [DOI:10.1210/jc.2017-01927]
  • de Lignières, B. (2002). Effects of progestogens on the postmenopausal breast. Climacteric, 5(3), 229–235. [DOI:10.1080/cmt.5.3.229.235]
  • de Lignières, B., & Mauvais-Jarvis, P. (1981). Hormonal Dependence of Benign Breast Disease, Gynecomastia and Breast Cancer. In Hollman, K. H., Brux, J., & Verley, J. M. (Eds.). New Frontiers in Mammary Pathology (pp. 287–308). Boston: Springer US. [DOI:10.1007/978-1-4757-0019-0_17]
  • de Vries, A. L., Steensma, T. D., Wagemaar, E. C. F., Doreleijers, T. A., & Cohen-Kettenis, P. T. (2010). Puberty suppression followed by cross-sex hormones and gender reassignment surgery: A prospective follow-up of gender dysphoric adolescents into adulthood. In de Vries, A. L. (Ed.). Gender Dysphoria in Adolescents: Mental Health and Treatment Evaluation (pp. 91–106). (Doctoral thesis, Vrije Universiteit Amsterdam.) [Google 学术] [URL] [PDF]
  • Deeb, A., Al Suwaidi, H., Attia, S., & Al Ameri, A. (2015). 17-hydroxylase/17,20-lyase deficiency due to a R96Q mutation causing hypertension and poor breast development. Endocrinology, Diabetes & Metabolism Case Reports, 2015(1), 15-0069. [DOI:10.1530/EDM-15-0069]
  • Deepinder, F., & Braunstein, G. D. (2012). Drug-induced gynecomastia: an evidence-based review. Expert Opinion on Drug Safety, 11(5), 779–795. [DOI:10.1517/14740338.2012.712109]
  • Dennerstein, L., Burrows, G. D., Hyman, G. J., & Sharpe, K. (1980). Some clinical effects of oestrogen-progestogen therapy in surgically castrated women. Maturitas2(1), 19–28. [DOI:10.1016/0378-5122(80)90056-0]
  • Dewhurst, C. J. (1967). The XY Female. BJOG74(3), 353–366. [DOI:10.1111/j.1471-0528.1967.tb03959.x]
  • Dewhurst, C. J. (1971). Sex Chromosome Abnormalities and the Gynaecologist. BJOG, 78(12), 1058–1076. [DOI:10.1111/j.1471-0528.1971.tb00227.x]
  • Dewhurst, C. (1971). The XY female. American Journal of Obstetrics and Gynecology, 109(5), 675–688. [DOI:10.1016/0002-9378(71)90753-8]
  • Dewhurst, C. (1972). Amenorrhoea and the Paediatrician. Pediatric Clinics of North America, 19(3), 605–618. [DOI:10.1016/s0031-3955(16)32741-9]
  • Dewhurst, C., & Spence, J. E. (1977). The XY female. British Journal of Hospital Medicine, 17(5), 498, 501–506. [Google 学术] [PubMed] [PDF]
  • Dewhurst, J. (1981). Breast Disorders in Children and Adolescents. Pediatric Clinics of North America, 28(2), 287–308. [DOI:10.1016/s0031-3955(16)33997-9]
  • Dewhurst, J. (1982). Breast Hypoplasia. In Bruni, V., Gasparri, F., Dewhurst, J., & Rey-Stocker, I. (Eds.). Pediatric and Adolescent Gynaecology [Proceedings of the IVth International Symposium, Florence, October 5-7, 1978] (pp. 205–212). Rome, Italy: Serono Symposia. [Google 学术] [Google 阅读] [WorldCat] [PDF]
  • Di Lorenzo, G., Autorino, R., Perdonà, S., & De Placido, S. (2005). Management of gynaecomastia in patients with prostate cancer: a systematic review. The Lancet Oncology, 6(12), 972–979. [DOI:10.1016/s1470-2045(05)70464-2]
  • Dickson, L. M., & Hewer, E. E. (1950). The structure of the breast. In Saner, F. D. (Ed.). The Breast: Structure, Function, Disease (pp. 1–52). Baltimore: William & Wilins. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [URL] [PDF]
  • Dijkman, B. A., Blok, C. J., Dreijerink, K. M., & den Heijer, M. (2023). Progestin-related breast volume changes in a woman with complete androgen insensitivity syndrome (CAIS). Endocrinology, Diabetes & Metabolism Case Reports, 2023(2), 22-0346. [DOI:10.1530/edm-22-0346]
  • Dijkman, B. A., Helder, D., Boogers, L. S., Gieles, N. C., van Heesewijk, J. O., Slaa, S. t., Liberton, N. P., Wiepjes, C. M., de Blok, C. J., den Heijer, M., & Dreijerink, K. M. (2023). Addition of progesterone to feminizing gender-affirming hormone therapy in transgender individuals for breast development: a randomized controlled trial. BMC Pharmacology and Toxicology, 24(1), 80. [DOI:10.1186/s40360-023-00724-4]
  • Dittrich, R., Binder, H., Cupisti, S., Hoffmann, I., Beckmann, M., & Mueller, A. (2005). Endocrine Treatment of Male-to-Female Transsexuals Using Gonadotropin-Releasing Hormone Agonist. Experimental and Clinical Endocrinology & Diabetes113(10), 586–592. [DOI:10.1055/s-2005-865900]
  • Donaldson, M., Kriström, B., Ankarberg-Lindgren, C., Verlinde, S., van Alfen-van der Velden, J., Gawlik, A., van Gelder, M., Sas, T., & (2019). Optimal Pubertal Induction in Girls with Turner Syndrome Using Either Oral or Transdermal Estradiol: A Proposed Modern Strategy. Hormone Research in Paediatrics, 91(3), 153–163. [DOI:10.1159/000500050]
  • Dorgan, J. F., Klifa, C., Deshmukh, S., Egleston, B. L., Shepherd, J. A., Kwiterovich, P. O., Van Horn, L., Snetselaar, L. G., Stevens, V. J., Robson, A. M., Lasser, N. L., & Hylton, N. M. (2013). Menstrual and reproductive characteristics and breast density in young women. Cancer Causes & Control, 24(11), 1973–1983. [DOI:10.1007/s10552-013-0273-2]
  • Döring, G. K. (1963). Über die relative Häufigkeit des anovulatorischen Cyclus im Leben der Frau. [On the relative frequency of the anovulatory cycle in women’s lives.] Archiv für Gynäkologie, 199(2), 115–123. [DOI:10.1007/bf00668062]
  • Drąsutis, J. (2017). Changes in breast morphological parameters, body size and shape, blood serum prolactin and lipids during pregnancy, multiple relationships of these indicators and morphological markers for health risk. (Doctoral dissertation, Vilniaus Universitetas.) [Google 学术] [URL]
  • Drife, J. O. (1982). The effects of parity and the menstrual cycle on the normal mammary gland and their possible relationship to malignant change. (Doctoral dissertation, University of Edinburgh). [Google 学术] [Google 阅读] [WorldCat] [URL] [PDF]
  • Drife, J. O. (1984). The pill and the breast. IPPF Medical Bulletin, 18(6), 1–2. [Google 学术] [PubMed]
  • Drife, J. O. (1986). Breast Development in Puberty. Annals of the New York Academy of Sciences, 464(1) [Endocrinology of the Breast: Basic and Clinical Aspects], 58–65. [DOI:10.1111/j.1749-6632.1986.tb15993.x]
  • Drife, J. O. (1989). Breast modifications during the menstrual cycle. Supplement to International Journal of Gynecology and Obstetrics1, 19–24. / International Journal of Gynecology and Obstetrics, 1989(Suppl 1), 19–24. [Google 学术] [PubMed] [Archive.org]
  • Drife, J. O. (1990). Premenopausal Hormone Therapy. In Drife, J. O., & Studd, J. W. W. (Eds.). HRT and Osteoporosis (pp. 351–362). London: Springer London. [DOI:10.1007/978-1-4471-1799-5_25]
  • Duncan, M. (2010). Sexual Selection and Human Breast Morphology. (Doctoral dissertation, Te Herenga Waka-Victoria University of Wellington.) [Google 学术] [URL]
  • Edmonds, D. K. (1989). Normal Puberty. In Edmonds, D. K. Dewhurst’s Practical Paediatric and Adolescent Gynaecology, 2nd Edition (pp. 56–62). London: Butterworths. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [URL] [Archive.org]
  • Elling, S. V., & Powell, F. C. (1997). Physiological changes in the skin during pregnancy. Clinics in Dermatology, 15(1), 35–43. [DOI:10.1016/s0738-081x(96)00108-3]
  • Engman, M., Skoog, L., Soderqvist, G., & Gemzell-Danielsson, K. (2008). The effect of mifepristone on breast cell proliferation in premenopausal women evaluated through fine needle aspiration cytology. Human Reproduction23(9), 2072–2079. [DOI:10.1093/humrep/den228]
  • Federici, S., Goggi, G., Quinton, R., Giovanelli, L., Persani, L., Cangiano, B., & Bonomi, M. (2021). New and Consolidated Therapeutic Options for Pubertal Induction in Hypogonadism: In-depth Review of the Literature. Endocrine Reviews, 43(5), 824–851. [DOI:10.1210/endrev/bnab043]
  • Fernández-Cancio, M., García-García, E., González-Cejudo, C., Martínez-Maestre, M., Mangas-Cruz, M., Guerra-Junior, G., Pandi de Mello, M., Arnhold, I. J., Nishi, M. Y., Bilharinho Mendonça, B., García-Arumí, E., Audí, L., Tizzano, E., & Carrascosa, A. (2017). Discordant Genotypic Sex and Phenotype Variations in Two Spanish Siblings with 17α-Hydroxylase/17,20-Lyase Deficiency Carrying the Most Prevalent Mutated CYP17A1 Alleles of Brazilian Patients. Sexual Development, 11(2), 70–77. [DOI:10.1159/000468160]
  • Fernandez-Valdivia, R., Mukherjee, A., Mulac-Jericevic, B., Conneely, O. M., DeMayo, F. J., Amato, P., & Lydon, J. P. (2005). Revealing Progesterone’s Role in Uterine and Mammary Gland Biology: Insights from the Mouse. Seminars in Reproductive Medicine, 23(1), 22–37. [DOI:10.1055/s-2005-864031]
  • Finkenzeller, D. A., & Loveless, M. B. (2007). Pediatric Gynecology. In Fortner, K. B., Szymanski, L. M., Fox, H. E., & Wallach, E. E. (Eds.). The Johns Hopkins Manual of Gynecology and Obstetrics, 3rd Edition (Spiral Manual Series) (pp. 363–379). Philadelphia: Lippincott Williams & Wilkins. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [Archive.org]
  • Fisher, A. D., Castellini, G., Ristori, J., Casale, H., Cassioli, E., Sensi, C., Fanni, E., Amato, A. M., Bettini, E., Mosconi, M., Dèttore, D., Ricca, V., & Maggi, M. (2016). Cross-Sex Hormone Treatment and Psychobiological Changes in Transsexual Persons: Two-Year Follow-Up Data. The Journal of Clinical Endocrinology & Metabolism, 101(11), 4260–4269. [DOI:10.1210/jc.2016-1276]
  • Flamant, T., Vervalcke, J., & T’Sjoen, G. (November 2023). Dose Reduction of Cyproterone Acetate in Trans Women and the Effect on Patient-reported Outcomes: Results from the ENIGI Study. Endocrine Abstracts, 97 [Belgian Endocrine Society 2023], 5–5 (abstract no. 007). [URL] [PDF]
    ——译者注:原文引用格式和排序有误,此处予以更正
  • Foidart, J. M., Colin, C., Denoo, X., Desreux, J., Fournier, S., & de Linières, B. (1996). Influence of percutaneous administration of estradiol and progesterone on the proliferation of human breast epithelial cells. In Calvo, F., Crépin, M., & Magdelenat, H. (Eds.). Breast Cancer. Advances in Biology and Therapuetics. John Libbey Eurotext, 329–334. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat]
  • Foidart, J., Colin, C., Denoo, X., Desreux, J., Béliard, A., Fournier, S., & de Lignières, B. (1998). Estradiol and Progesterone Regulate the Proliferation of Human Breast Epithelial Cells. Fertility and Sterility, 69(5), 963–969. [DOI:10.1016/s0015-0282(98)00042-9]
  • Folley, S. J. (1940). Lactation. Biological Reviews, 15(4), 421–458. [DOI:10.1111/j.1469-185x.1940.tb00947.x]
  • Folley, S. J. (1947). Endocrine Control of the Mammary Gland. British Medical Bulletin, 5(2–3), 130–134. [DOI:10.1093/oxfordjournals.bmb.a073121]
  • Folley, S. J. (1950). Lactational Physiology. In Bowes, K. (Ed.). Modern Trends in Obstetrics and Gynaecology (pp. 441–453). London: Butterworth. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [PDF]
  • Folley, S. J. (1952). Lactation. In Parkes, A. S. (Ed.). Marshall’s Physiology of Reproduction, 3rd Edition, Volume II (pp. 525–647). Longmans, Green & Co.: London. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [PDF]
  • Folley, S. J. (1956). Recent Studies on the Development of the Mammary Gland. In Folley, S. J. The Physiology and Biochemistry of Lactation, 1st Edition (pp. 1–22). Edinburgh: Oliver & Boyd. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat]
  • Folley, S. J., & Malpress, F. H. (1948). Hormonal Control of Mammary Growth. In Pincus, G., & Thimann, K. V. (Eds.). The Hormones: Physiology, Chemistry and Applications, Volume I (pp. 695–743). New York: Academic Press. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [PDF]
  • Fourcade, R., & McLeod, D. (2004). Tolerability of Antiandrogens in the Treatment of Prostate Cancer. UroOncology, 4(1), 5–13. [DOI:10.1080/1561095042000191655]
  • Fowler, P. A., Casey, C. E., Cameron, G. G., Foster, M. A., & Knight, C. H. (1990). Cyclic changes in composition and volume of the breast during the menstrual cycle, measured by magnetic resonance imaging. BJOG, 97(7), 595–602. [DOI:10.1111/j.1471-0528.1990.tb02546.x]
  • Fridriksdottir, A. J., Petersen, O. W., & Rnnov-Jessen, L. (2011). Mammary gland stem cells: current status and future challenges. The International Journal of Developmental Biology, 55(7–8–9), 719–729. [DOI:10.1387/ijdb.113373af]
  • Fuqua, J. S., & Eugster, E. A. (2022). History of Puberty: Normal and Precocious. Hormone Research in Paediatrics, 95(6), 568–578. [DOI:10.1159/000526464]
  • Gaede, P., Trolle, D., & Pedersen, H. (1978). Extremely low placental lactogen hormone (hpl) values in an otherwise uneventful pregnancy preceding delivery of a normal baby. Acta Obstetricia et Gynecologica Scandinavica, 57(3), 203–209. [DOI:10.3109/00016347809154883]
  • Galani, A., Kitsiou-Tzeli, S., Sofokleous, C., Kanavakis, E., & Kalpini-Mavrou, A. (2008). Androgen insensitivity syndrome: clinical features and molecular defects. Hormones, 7(3), 217–229. [DOI:10.14310/horm.2002.1201]
  • Galbarczyk, A. (2011). Unexpected changes in maternal breast size during pregnancy in relation to infant sex: An evolutionary interpretation. American Journal of Human Biology, 23(4), 560–562. [DOI:10.1002/ajhb.21177]
  • Gawlik, A., Hankus, M., Such, K., Drosdzol-Cop, A., Madej, P., Borkowska, M., Zachurzok, A., & Malecka-Tendera, E. (2016). Hypogonadism and Sex Steroid Replacement Therapy in Girls with Turner Syndrome. Journal of Pediatric and Adolescent Gynecology, 29(6), 542–550. [DOI:10.1016/j.jpag.2016.03.005]
  • Gershon-Cohen, J. (1970). The Normal Breast. In Gershon-Cohen, J. Atlas of Mammography (pp. 23–38). Berlin/Heidelberg: Springer. [DOI:10.1007/978-3-642-85678-5_4] [Google 阅读]
  • Gertig, D. M., Stillman, I. E., Byrne, C., Spiegelman, D., Schnitt, S. J., Connolly, J. L., Colditz, G. A., & Hunter, D. J. (1999). Association of age and reproductive factors with benign breast tissue composition. Cancer Epidemiology, Biomarkers & Prevention8(10), 873–879. [Google 学术] [PubMed] [URL]
  • Geschickter, C. F. (1945). Endocrine Physiology of the Breast. In Geschickter, C. F. Diseases of the Breast: Diagnosis, Pathology, Treatment, 2nd Edition (pp. 42–81). Philadelphia: J.B. Lippincott. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [PDF]
  • Glenn, J. F. (1976). Testicular feminization syndrome current clinical considerations. Urology, 7(6), 569–577. [DOI:10.1016/0090-4295(76)90079-0]
  • Gliosci, A., & Presutti, F. (1993). Virginal gigantomastia: Validity of combined surgical and hormonal treatments. Aesthetic Plastic Surgery, 17(1), 61–65. [DOI:10.1007/bf00455051]
  • Gompel, A., & Plu-Bureau, G. (2018). Progesterone, progestins and the breast in menopause treatment. Climacteric, 21(4), 326–332. [DOI:10.1080/13697137.2018.1476483]
  • Goodman, H. M. (2009). Hormonal Control of Pregnancy and Lactation. In Goodman, H. M. Basic Medical Endocrinology, 4th Edition (pp. 277–301). Amsterdam: Academic Press/Elsevier. [DOI:10.1016/b978-0-12-373975-9.00014-8]
  • Gooren, L. J. (2016). Hormone Treatment of Adult Transgender People. In Ettner, R., Monstrey, S., & Coleman, E. (Eds.). Principles of Transgender Medicine and Surgery, 2nd Edition (pp. 167–179). New York: Routledge. [Google 学术] [Google 阅读] [DOI:10.4324/9781315718972-11]
  • Gordon, C. M., & Laufer, M. R. (2005). The Physiology of Puberty. In Emans, S. J., Laufer, M. R., & Goldstein, D. P. (Eds.). Pediatric and Adolescent Gynecology, 5th Edition (pp. 120–155). Philadelphia: Lippincott Williams & Wilkins. [Google 学术] [[Google 阅读][GL05]] [OpenLibrary] [WorldCat] [Archive.org]
  • Göretzlehner, G. & Lauritzen, C. (1992). Hormontherapie bei Gynäkologischen Erkrankungen [Hormone Therapy for Gynecological Diseases]. In Göretzlehner, G. & Lauritzen, C. Praktische Hormontherapie in der Gynäkologie, 1. Auflage [Practical Hormone Therapy in Gynecology, 1st Edition] (pp. 245–299). Berlin/New York: de Gruyter. [DOI:10.1515/9783112417706-007] [Google 阅读] [PDF] [英译文]
  • Graham, J. D., & Clarke, C. L. (1997). Physiological Action of Progesterone in Target Tissues. Endocrine Reviews18(4), 502–519. [DOI:10.1210/edrv.18.4.0308]
  • Graham, S. J., Stanchev, P. L., Lloyd‐Smith, J. O., Bronskill, M. J., & Plewes, D. B. (1995). Changes in Fibroglandular Volume and Water Content of Breast Tissue During the Menstrual Cycle Observed by MR Imaging at 1.5 T. Journal of Magnetic Resonance Imaging, 5(6), 695–701. [DOI:10.1002/jmri.1880050613]
  • Greydanus, D. E., Omar, H. A., Matytsina, L. A., & Tsitsika, A. (2010). Breast Disorders in Children and Adolescents. In Omar, H. A., Greydanus, D. E., Tsitsika, A. K., Patel, D. R., & Merrick, J. (Eds.). Pediatric and Adolescent Sexuality and Gynecology: Principles for the Primary Care Clinician (pp. 245–316). Hauppauge: Nova Science Publishers. [Google 学术] [Google 阅读] [URL] [OpenLibrary] [WorldCat] [PDF]
  • Guaragna-Filho, G., Guerra-Junior, G., Tadokoro-Cuccaro, R., Hughes, I. A., Barros, B. A., Hiort, O., Balsamo, A., Guran, T., Holterhus, P. M., Hannema, S., Poyrazoglu, S., Darendeliler, F., Bryce, J., Ahmed, S. F., & Quigley, C. A. (2023). Pubertal and Gonadal Outcomes in 46,XY Individuals with Partial Androgen Insensitivity Syndrome Raised as Girls. Sexual Development17(1), 16–25. [DOI:10.1159/000526997]
  • Gunn, H. M., Tsai, M., McRae, A., & Steinbeck, K. S. (2018). Menstrual Patterns in the First Gynecological Year: A Systematic Review. Journal of Pediatric and Adolescent Gynecology, 31(6), 557–565.e6. [DOI:10.1016/j.jpag.2018.07.009]
  • Günzel, P., Hasan, S. H., Düsterberg, B., Hümpel, M., Putz, B., & Lehmann, M. (1987). Zur toxikologischen Prüfung von Steroidhormonen. [For the Toxicological Testing of Steroid Hormones.] In Burger, O. K., Grosdanoff, P., Henschler, D., Kraupp, O., & Schnieders, B. (Eds.). Aktuelle Probleme der Biomedizin (pp. 93–112). Berlin/New York: De Gruyter. [Google 学术] [Google 阅读] [DOI:10.1515/9783110898231-014]
  • Hagisawa, S., Shimura, N., & Arisaka, O. (2012). Effect of Excess Estrogen on Breast and External Genitalia Development in Growth Hormone Deficiency. Journal of Pediatric and Adolescent Gynecology, 25(3), e61–e63. [DOI:10.1016/j.jpag.2011.11.005]
  • Hamburger, C., & Benjamin, H. (1969). Endocrine Treatment of Male and Female Transsexualism / Appendix for the Practicing Physician: Suggestions and Guidelines for the Management of Transsexuals. In Green, R., & Money, J. (Eds.). Transsexualism and Sex Reassignment (pp. 291–307). Baltimore: John Hopkins University Press. [Google 学术] [Google 阅读] [PDF]
  • Hannan, F. M., Elajnaf, T., Vandenberg, L. N., Kennedy, S. H., & Thakker, R. V. (2022). Hormonal regulation of mammary gland development and lactation. Nature Reviews Endocrinology, 19(1), 46–61. [DOI:10.1038/s41574-022-00742-y]
  • Hannema, S. E., Schagen, S. E., Cohen-Kettenis, P. T., & Delemarre-van de Waal, H. A. (2017). Efficacy and Safety of Pubertal Induction Using 17β-Estradiol in Transgirls. The Journal of Clinical Endocrinology & Metabolism, 102(7), 2356–2363. [DOI:10.1210/jc.2017-00373]
  • Harley, J. M. G. (1969). The endocrine control of the breasts. The Practitioner, 203(1214), 153–157. [Google 学术] [Google 阅读] [PubMed] [DOI:10.5555/19700402477] [HathiTrust]
  • Hartmann, B. W., Laml, T., Albrecht, A. E., Huber, J. C., & Kirchengast, S. (1998). Hormonal Breast Augmentation: Prognostic Relevance of Insulin-Like Growth Factor-I. Gynecological Endocrinology, 12(2), 123–127. [DOI:10.3109/09513599809024960]
  • Hartmann, P. E., Owens, R. A., Cox, D. B., & Kent, J. C. (1996). Breast Development and Control of Milk Synthesis. Food and Nutrition Bulletin, 17(4), 1–12. [DOI:10.1177/156482659601700404]
  • Hasan, S. (1974). Steroid Hormone Levels During Pregnancy in Various Species. In Bernhard, S., & Raspé, G. (Ed.). Hormones and Embryonic Development (Advances in the Biosciences, Volume 13) (pp. 181–197). Oxford/New York: Pergamon Press. [Google 学术] [Google 阅读] [DOI:10.1016/b978-0-08-018239-1.50014-3] [OpenLibrary] [Archive.org]
  • Hassiotou, F., & Geddes, D. (2012). Anatomy of the human mammary gland: Current status of knowledge. Clinical Anatomy, 26(1), 29–48. [DOI:10.1002/ca.22165]
  • Heath, R. A., & Wynne, K. (2019). Children and Adolescents. In Heath, R. A., & Wynne, K. A Guide to Transgender Health: State-of-the-art Information for Gender-Affirming People and Their Supporters (pp. 87–106). Santa Barbara: Praeger/ABC-CLIO. [Google 阅读]
  • Heath, R. A., & Wynne, K. (2019). Hormone and Surgical Therapies for Adults. In Heath, R. A., & Wynne, K. A Guide to Transgender Health: State-of-the-art Information for Gender-Affirming People and Their Supporters (pp. 107–146). Santa Barbara: Praeger/ABC-CLIO. [Google 阅读]
  • Hertz, R., Odell, W. D., & Ross, G. T. (1966). Diagnostic Implications of Primary Amenorrhea: Combined Clinical Staff Conference at the National Institutes of Health. Annals of Internal Medicine, 65(4), 800–820. [DOI:10.7326/0003-4819-65-4-800]
  • Hillard, P. J. A. (2007). Benign Diseases of the Female Reproductive Tract. In Berek, J. S., & Novak, E. (Eds.). Berek & Novak’s Gynecology, 14th Edition (pp. 431–496). Philadelphia: Lippincott Williams and Wilkins, 431–496. [Google 学术] [OpenLibrary] [WorldCat] [Archive.org]
  • Hoppe, I. C., Patel, P. P., Singer-Granick, C. J., & Granick, M. S. (2011). Virginal Mammary Hypertrophy: A Meta-Analysis and Treatment Algorithm. Plastic and Reconstructive Surgery, 127(6), 2224–2231. [DOI:10.1097/prs.0b013e3182131bd1]
  • Hovey, R. C., Trott, J. F., Ginsburg, E., Goldhar, A., Sasaki, M. M., Fountain, S. J., Sundararajan, K., & Vonderhaar, B. K. (2001). Transcriptional and spatiotemporal regulation of prolactin receptor mRNA and cooperativity with progesterone receptor function during ductal branch growth in the mammary gland. Developmental Dynamics, 222(2), 192–205. [DOI:10.1002/dvdy.1179]
  • Howard, B. A., & Gusterson, B. A. (2000). Human Breast Development. Journal of Mammary Gland Biology and Neoplasia, 5(2), 119–137. [DOI:10.1023/a:1026487120779]
  • Huffman, J., Dewhurst, C. J., & Capraro, V. J. (1981). The Breast and its Disorders in Childhood and Adolescence. In Huffman, J., Dewhurst, J., & Capraro, V. The Gynecology of Childhood and Adolescence, 2nd Edition (pp. 542–559). Philadelphia: Saunders. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [Archive.org] [PDF]
  • Hussain, Z., Brooks, J., & Percy, D. (2008). Menstrual variation of breast volume and T2 relaxation times in cyclical mastalgia. Radiography, 14(1), 8–16. [DOI:10.1016/j.radi.2006.07.003]
  • Hussain, Z., Roberts, N., Whitehouse, G. H., García-Fiñana, M., & Percy, D. (1999). Estimation of breast volume and its variation during the menstrual cycle using MRI and stereology. The British Journal of Radiology, 72(855), 236–245. [DOI:10.1259/bjr.72.855.10396212]
  • Hutson, S. W., Cowen, P. N., & Bird, C. C. (1985). Morphometric studies of age related changes in normal human breast and their significance for evolution of mammary cancer. Journal of Clinical Pathology, 38(3), 281–287. [DOI:10.1136/jcp.38.3.281]
  • Hytten, F. E. (1954). Clinical and Chemical Studies in Human Lactation–VI. BMJ, 1(4867), 912–915. [DOI:10.1136/bmj.1.4867.912]
  • Hytten, F. E. (1954). Observations on Human Lactation. (Doctor’s thesis, University of Aberdeen.) [Google 学术] [Google 阅读] [URL] [WorldCat]
  • Hytten, F. E. (1976). The physiology of lactation. International Journal of Food Sciences and Nutrition, 30(4), 225–232. [DOI:10.3109/09637487609142745]
  • Hytten, F. E., & Baird, D. (1958). The Development of the Nipple in Pregnancy. The Lancet, 271(7032), 1201–1204. [DOI:10.1016/s0140-6736(58)91908-1]
  • Hytten, F. E., & Leitch, I. (1971). Preparations for Breast Feeding. In Hytten, F. E., & Leitch, I. The Physiology of Human Pregnancy, 2nd Edition (pp. 234–241). Oxford: Blackwell Scientific Publications. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [Archive.org]
  • Hytten, F. E., & Thomson, A. M. (1965). Pregnancy, childbirth and lactation. In Edholm, O. G., & Bacharach, A. L. (Eds.). The Physiology of Human Survival (pp. 327–350). London/New York: Academic Press. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [Archive.org]
  • Hytten, F. E., & Thomson, A. M. (1968). Maternal physiological adjustments. In Assali, N. S. (Ed.). The Maternal Organism, Volume I (Biology of Gestation) (pp. 449–479). New York: Academic Press. [Google 学术] [Google 阅读] [WorldCat]
  • Igo, J., & Visram, H. (2021). Progesterone Therapy Use and Safety in Male to Female Transgender Patients. Canadian Journal of Diabetes, 45(7 Suppl), S39–S39 (abstract no. 109). [DOI:10.1016/j.jcjd.2021.09.119] [URL] [PDF]
  • Ingleby, H. (1949). Changes in breast volume in a group of normal young women. Bulletin of the International Association of Medical Museums, 29, 87–92. [Google 学术] [Google 阅读] [HathiTrust]
  • Ingleby, H., Moore, L., & Gershon-Cohen, J. (1957). Gestational breast changes: x-ray studies of the human breast. Obstetrics & Gynecology, 10(2), 149–157. [Google 学术] [PubMed] [URL]
  • Ismail, P. M., Amato, P., Soyal, S. M., DeMayo, F. J., Conneely, O. M., O’Malley, B. W., & Lydon, J. P. (2003). Progesterone involvement in breast development and tumorigenesis—as revealed by progesterone receptor “knockout” and “knockin” mouse models. Steroids, 68(10–13), 779–787. [DOI:10.1016/s0039-128x(03)00133-8]
  • Iwamoto, S. J., Defreyne, J., Rothman, M. S., Van Schuylenbergh, J., Van de Bruaene, L., Motmans, J., & T’Sjoen, G. (2019). Health considerations for transgender women and remaining unknowns: a narrative review. Therapeutic Advances in Endocrinology and Metabolism, 10, 204201881987116. [DOI:10.1177/2042018819871166]
  • Jacobsohn, D. (1961). Hormonal Regulation of Mammary Gland Growth. In Kon, S. K., & Cowie, A. T. (Eds.). Milk: The Mammary Gland and Its Secretion, Volume 1 (pp. 127–160). New York: Academic Press. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [PDF]
  • Jain, J., Kwan, D., & Forcier, M. (2019). Medroxyprogesterone Acetate in Gender-Affirming Therapy for Transwomen: Results From a Retrospective Study. The Journal of Clinical Endocrinology & Metabolism104(11), 5148–5156. [DOI:10.1210/jc.2018-02253]
  • Jamal, N., Ng, K., McLean, D., Looi, L., & Moosa, F. (2004). Mammographic Breast Glandularity in Malaysian Women: Data Derived from Radiography. American Journal of Roentgenology, 182(3), 713–717. [DOI:10.2214/ajr.182.3.1820713]
  • Jemstrom, H., & Olsson, H. (1997). Breast Size in Relation to Endogenous Hormone Levels, Body Constitution, and Oral Contraceptive Use in Healthy Nulligravid Women Aged 19-25 Years. American Journal of Epidemiology, 145(7), 571–580. [DOI:10.1093/oxfordjournals.aje.a009153]
  • Jernström, H., Sandberg, T., Bågeman, E., Borg, Å., & Olsson, H. (2005). Insulin-like growth factor-1 (IGF1) genotype predicts breast volume after pregnancy and hormonal contraception and is associated with circulating IGF-1 levels: implications for risk of early-onset breast cancer in young women from hereditary breast cancer families. British Journal of Cancer, 92(5), 857–866. [DOI:10.1038/sj.bjc.6602389]
  • Jeruss, J. S. (2006). Molecular Basis of Breast Cancer. In Winchester, D. J., Winchester, D. P., Hudis, C. A., & Norton, L. (Eds.). Breast Cancer, 2nd Edition (pp. 83–95). Hamilton: B.C. Decker. [Google 学术] [Google 阅读] [WorldCat]
  • Johnson, M. C., & Cutler, M. L. (2016). Anatomy and Physiology of the Breast. In Jatoi, I., & Rody, A. (Eds.). Management of Breast Diseases (pp. 1–39). Cham: Springer. [DOI:10.1007/978-3-319-46356-8_1]
  • Kaiser, R. (1993). Gestagen-Östrogen-Kombinationen in der Gynäkologie. Zur Geschichte, Dosierung und Anwendung eines Hormonprinzips. [Gestagen-Oestrogen Combinations in Gynaecology. History, Dosage and Use of a Hormonal Principle.] Geburtshilfe und Frauenheilkunde, 53(7), 503–513. [Google 学术] [PubMed] [DOI:10.1055/s-2007-1022924]
  • Kaiser, R., & Leidenberger, F. (1991). Hormonbehandlung bei Benign Mammaerkrankungen: Mammahypoplasie. [Hormonal Treatment in Benign Breast Diseases: Breast Hypoplasia.] In Kaiser, R., & Leidenberger, F. Hormonbehandlung in der Gynäkologischen Praxis, 7. Auflage [Hormone Treatment in Gynecological Practice, 7th Edition] (pp. 138–138). Stuttgart: Georg Thieme Verlag. [Google 阅读] [OpenLibrary] [WorldCat] [PDF] [英译文]
  • Kaiser, U., & Ho, K. K. (2015). Pituitary Physiology and Diagnostic Evaluation. In Melmed, S., Polonsky, K. S., Larsen, P. R., Kronenberg, & H. M. (Eds.). Williams Textbook of Endocrinology, 13th Edition (pp. 176–231). Philadelphia: Elsevier. [DOI:10.1016/B978-0-323-29738-7.00008-3] [Google 阅读]
  • Kanhai, R. C., Hage, J. J., Asscheman, H., Mulder, W. J., & Hage, J. J. (1999). Augmentation Mammaplasty in Male-to-Female Transsexuals. Plastic and Reconstructive Surgery, 104(2), 542–549. [DOI:10.1097/00006534-199908000-00040]
  • Kanhai, R. C., Hage, J. J., van Diest, P. J., Bloemena, E., & Mulder, J. W. (2000). Short-Term and Long-Term Histologic Effects of Castration and Estrogen Treatment on Breast Tissue of 14 Male-to-Female Transsexuals in Comparison With Two Chemically Castrated Men. The American Journal of Surgical Pathology, 24(1), 74–80. [DOI:10.1097/00000478-200001000-00009]
  • Kardelen, A. D., Toksoy, G., Baş, F., Yavaş Abalı, Z., Gençay, G., Poyrazoğlu, Ş., Bundak, R., Altunoğlu, U., Avcı, Ş., Najaflı, A., Uyguner, O., Karaman, B., Başaran, S., & Darendeliler, F. (2018). A Rare Cause of Congenital Adrenal Hyperplasia: Clinical and Genetic Findings and Follow-up Characteristics of Six Patients with 17-Hydroxylase Deficiency Including Two Novel Mutations. Journal of Clinical Research in Pediatric Endocrinology, 10(3), 206–215. [DOI:10.4274/jcrpe.0032]
  • Kariagina, A., Xie, J., Leipprandt, J. R., & Haslam, S. Z. (2010). Amphiregulin Mediates Estrogen, Progesterone, and EGFR Signaling in the Normal Rat Mammary Gland and in Hormone-Dependent Rat Mammary Cancers. Hormones and Cancer, 1(5), 229–244. [DOI:10.1007/s12672-010-0048-0]
  • Karp, N. S. (2022). Discussion: The Impact of Combined Oral Contraceptives on Adolescents with Macromastia. Plastic & Reconstructive Surgery, 150(4), 739–740. [DOI:10.1097/prs.0000000000009514]
  • Kasielska-Trojan, A., Mikołajczyk, M., & Antoszewski, B. (2020). BreastIdea Volume Estimator: A New Tool for Breast Volume Estimation—Presentation and Validation for Women. Plastic & Reconstructive Surgery, 146(6), 744e–748e. [DOI:10.1097/prs.0000000000007373]
  • Kasielska-Trojan, A., Zawadzki, T., & Antoszewski, B. (2022). Breast Fluctuating Asymmetry in Women with Macromastia/Gigantomastia. International Journal of Environmental Research and Public Health, 19(24), 16895. [DOI:10.3390/ijerph192416895]
  • Kauli, R., Pertzelan, A., Ben‐Zeev, Z., Lewin, R. P., Kaufman, H., Schally, A. C., Schally, A. V., & Laron, Z. (1984). Treatment of precocious puberty with LHRH analogue in combination with cyproterone acetate—further experience. Clinical Endocrinology, 20(4), 377–387. [DOI:10.1111/j.1365-2265.1984.tb03433.x]
  • Keller, P. J. (1984). Diagnostik und Therapie wichtiger hormonaler Störungen: Mammahypoplasie. [Diagnosis and Treatment of Important Hormonal Disorders: Mammary Hypoplasia.] In Keller, P. J. Hormonale Störungen in der Gynäkologie: Diagnostik und Behandlung, 3. Auflage [Hormonal Disorders in Gynecology: Diagnosis and Treatment, 3rd Edition] (Kliniktaschenbücher) (pp. 133–134). Berlin/Heidelberg: Springer. [Google 阅读] [DOI:10.1007/978-3-662-00442-5_3]
  • Keller, P. J. (1995). Diagnostik und Therapie wichtiger Störungen: Mammahypoplasie. [Diagnosis and Treatment of Important Disorders: Mammary Hypoplasia.] In Keller, P. J. Hormon- und Fertilitätsstörungen in der Gynäkologie, 4. Auflage [Hormonal and Fertility Disorders in Gynecology, 4th Edition] (pp. 145–146). Berlin/Heidelberg: Springer. [Google 阅读] [DOI:10.1007/978-3-662-12026-2_3]
  • Kennedy, B. J. (1953). Effects of intensive sex steroid hormone therapy in advanced breast cancer. JAMA, 152(12), 1135–1141. [DOI:10.1001/jama.1953.63690120004013]
  • Kent, J. C., Mitoulas, L., Cox, D. B., Owens, R. A., & Hartmann, P. E. (1999). Breast Volume and Milk Production During Extended Lactation in Women. Experimental Physiology, 84(2), 435–447. [DOI:10.1111/j.1469-445x.1999.01808.x]
  • Khoo, S. K., & Mackay, E. V. (1972). Testicular Feminization: The Clinical Features, Endocrine Function and Gonadal Pathology in Six Patients. The Australian and New Zealand Journal of Obstetrics and Gynaecology, 12(1), 1–13. [DOI:10.1111/j.1479-828x.1972.tb00721.x]
  • Klein, R., Aichinger, H., Dierker, J., Jansen, J. T., Joite-Barfuß, S., Säbel, M., Schulz-Wendtland, R., & Zoetelief, J. (1997). Determination of average glandular dose with modern mammography units for two large groups of patients. Physics in Medicine and Biology, 42(4), 651–671. [DOI:10.1088/0031-9155/42/4/004]
  • Kleinberg, D. L. (2006). Endocrinology of lactation. In DeGroot, L. J., & Jameson, J. L. (Eds). Endocrinology, 5th Edition (pp. 3461–3473). Philadelphia: Elsevier Saunders. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [Archive.org]
  • Kleinberg, D. L., & Barcellos-Hoff, M. H. (2011). The Pivotal Role of Insulin-Like Growth Factor I in Normal Mammary Development. Endocrinology and Metabolism Clinics of North America, 40(3), 461–471. [DOI:10.1016/j.ecl.2011.06.001]
  • Kleinberg, D. L., & Ruan, W. (2008). IGF-I, GH, and Sex Steroid Effects in Normal Mammary Gland Development. Journal of Mammary Gland Biology and Neoplasia, 13(4), 353–360. [DOI:10.1007/s10911-008-9103-7]
  • Kleinberg, D. L., Wood, T. L., Furth, P. A., & Lee, A. V. (2008). Growth Hormone and Insulin-Like Growth Factor-I in the Transition from Normal Mammary Development to Preneoplastic Mammary Lesions. Endocrine Reviews, 30(1), 51–74. [DOI:10.1210/er.2008-0022]
  • Kühnel, W. (2000). IMMULITE® and IMMULITE® 2000 Reference Range Compendium, First English Edition. Los Angeles, California: Diagnostic Products Corporation. [Google 学术] [URL] [PDF 1] [PDF 2]
  • Kustin, J., & Rebar, R. W. (1987). Menstrual Disorders in the Adolescent Age Group. Primary Care: Clinics in Office Practice14(1), 139–166. [DOI:10.1016/s0095-4543(21)01004-6]
  • Kuttenn, F., Malet, C., & Leygue, E. (1994). Antiestrogen action of progestogens in human breast cells. In Berg, G., & Hammar, M. (Eds.). The Modern Management of the Menopause: A Perspective for the 21st Century [The Proceedings of the VII International Congress on the Menopause, Stockholm, Sweden 1993] (pp. 419–433). Canforth: Parthenon. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [Archive.org] [PDF]
  • Ladjouze, A., & Donaldson, M. (2019). Primary gonadal failure. Best Practice & Research Clinical Endocrinology & Metabolism33(3), 101295. [DOI:10.1016/j.beem.2019.101295]
  • Laessle, R. G., Tuschi, R. J., Schweiger, U., & Pirke, K. M. (1990). Mood changes and physical complaints during the normal menstrual cycle in healthy young women. Psychoneuroendocrinology, 15(2), 131–138. [DOI:10.1016/0306-4530(90)90021-z]
  • LaMarca, H. L., & Rosen, J. M. (2007). Estrogen regulation of mammary gland development and breast cancer: amphiregulin takes center stage. Breast Cancer Research, 9(4), 304. [DOI:10.1186/bcr1740]
  • Laron, Z., & Kauli, R. (2000). Experience with Cyproterone Acetate in the Treatment of Precocious Puberty. Journal of Pediatric Endocrinology and Metabolism, 13(Suppl 1), 805–810. [DOI:10.1515/jpem.2000.13.s1.805]
  • Laufer, M. R., Goldstein, D. P., & Hendren, W. H. (2005). Structural Abnormalities of the Female Reproductive Tract. In Emans, J. E., Laufer, M. R., & Goldstein, D. P. (Eds.). Pediatric and Adolescent Gynecology, 5th Edition (pp. 334–416). Philadelphia: Lippincott Williams and Wilkins. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [Archive.org]
  • Lauritzen, C. (1980 October 27). Hormonkur Kann Hypoplastischer Mamma Aufhelfen. [Hormone Therapy Can Help Hypoplastic Breasts.] Selecta: Medizin aktuell; das Magazin für ärztliche Fortbildung [Selecta: Medicine Currently; the Magazine for Medical Training], 22(43), 3798–3801. Planegg: Selecta-Verlag. [ISSN:0582-4877] [WorldCat] [PDF] [英译文]
  • Lauritzen, C. (1982). Treatment of mammary- and uterus hypoplasia by estrogen-progestagen pseudopregnancy. In Richter, K., Huber, A., Terruhn, V. (Eds.) 1. Europäisches Symposium für Kinder- und Jugendgynäkologie. München 19.-21.3.1981, Band 2 [First European Symposium on Pediatric and Adolescent Gynaecology. München, March 19–21, 1981, Volume 2] (pp. 487–489). Friedrichsdorf/Taunus: Milupa-Aktiengesellschaft, Wissenschaftliche Abteilung. [Google 学术] [PDF]
  • Lauritzen, C. (1989). Hormonelle Substitutionstherapie zur Brustvergrößerung. [Hormonal Substitution Therapy for Breast Enlargement.] In Beller, F. K. & Seitzer, D. (Eds.). 7. Siebte Wissenschaftliche Tagung der Deutschen Gesellschaft für Senologie, Münster, 25. - 27. September 1987: Ausgewählte Referate [7th Scientific Conference of the German Society for Senology, Münster, [Germany,] September 25–27, 1987: Selected Papers] (pp. 39–41). Mülheim, Germany: H.U.F. Verlag. [Google 学术] [WorldCat 1] [WorldCat 2] [WorldCat 3] [Cited By 1] [Cited By 2] [Cited By 3] [PDF] [英译文]
  • Lawrence, R. A., & Lawrence, R. M. (2015). Physiology of Lactation. In Lawrence, R. A., & Lawrence, R. M. Breastfeeding: A Guide for the Medical Profession, 8th Edition (pp. 56–90). Philadelphia: Elsevier. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [Archive.org]
  • Lee, H. J., & Ormandy, C. J. (2012). Interplay between progesterone and prolactin in mammary development and implications for breast cancer. Molecular and Cellular Endocrinology, 357(1–2), 101–107. [DOI:10.1016/j.mce.2011.09.020]
  • Lee, P. A. (2001). Physiology of Puberty. In Becker, K. L., Bilezikian, J. P., Bremner, W. J., Hung, W., Kahn, C. R., Loriaux, D. L., Nylén, E. S., Rebar, R. W., Robertson, G. L., Snider, R. H., Wartofsky, L. (Eds.). Principles and Practice of Endocrinology and Metabolism, 3rd Edition (pp. 885–893). Philadelphia: Lippincott Williams & Wilkins. [Google 学术] [Google 阅读] [Archive.org] [OpenLibrary] [WorldCat]
  • Lee, S. W., Kwak, D. S., Jung, I. S., Kwak, J. H., Park, J. H., Hong, S. M., Lee, C. B., Park, Y. S., Kim, D. S., Choi, W. H., & Ahn, Y. H. (2015). Partial Androgen Insensitivity Syndrome Presenting with Gynecomastia. Endocrinology and Metabolism, 30(2), 226–230. [DOI:10.3803/enm.2015.30.2.226]
  • Lejour, M. (1994). Vertical Mammaplasty and Liposuction of the Breast. Plastic and Reconstructive Surgery, 94(1), 100–114. [DOI:10.1097/00006534-199407000-00010]
  • Lejour, M. (1997). Evaluation of Fat in Breast Tissue Removed by Vertical Mammaplasty. Plastic and Reconstructive Surgery, 99(2), 386–393. [DOI:10.1097/00006534-199702000-00012]
  • Lemarchand-Béraud, T., Zufferey, M., Reymond, M., & Rey, I. (1982). Maturation of the Hypothalamo-Pituitary-Ovarian Axis in Adolescent Girls. The Journal of Clinical Endocrinology & Metabolism, 54(2), 241–246. [DOI:10.1210/jcem-54-2-241]
  • Lewin, R. (2016). Breast Hypertrophy and Outcome of Breast Reduction Surgery. (Doctoral thesis, University of Gothenburg. Sahlgrenska Academy.) [Google 学术] [URL]
  • Lim, L. Y., Ho, P. J., Liu, J., Chay, W. Y., Tan, M., Hartman, M., & Li, J. (2018). Determinants of breast size in Asian women. Scientific Reports, 8(1), 1201. [DOI:10.1038/s41598-018-19437-4]
  • Lloyd, C. W., & Leathem, J. H. (1964). Growth and development of the breast and lactation. In Lloyd, C. W. (Ed.). Human Reproduction and Sexual Behavior (pp. 117–134). Philadelphia: Lea & Febiger. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat]
  • Lopez, X., Panton, J., Nagarkar, P., Preston, S., Abramowitz, J., & Amirlak, B. (2023). Initial Assessment of VECTRA Three-Dimensional Imaging to Accurately Simulate Breast Volume Changes in Transfeminine Patients: A Mannequin Study. Aesthetic Surgery Journal Open Forum, 5, online ahead of print. [DOI:10.1093/asjof/ojad015]
  • Lorincz, A. M., & Sukumar, S. (2006). Molecular links between obesity and breast cancer. Endocrine-Related Cancer, 13(2), 279–292. [DOI:10.1677/erc.1.00729]
  • Lucien, J. N., Ortega, M. T., Calvert, M. E., Smith, C., White, X., Rogers, H., Mosley, B., Agrawal, R., Drude, A., McGee, C., George, M., Brown, A., Downey, K., Wild, C., Njunge, A., Kuzmiak, C. M., Zava, D., Zava, T., Pollard, J., Francis, J., Beery, B. L., Harlin, M., Gonzalez, G. R., & Shaw, N. D. (2022). The Launch of A Girl’s First Period Study: Demystifying Reproductive Hormone Profiles in Adolescent Girls. Journal of Pediatric and Adolescent Gynecology, 35(4), 420–425. [DOI:10.1016/j.jpag.2021.12.018]
  • Lydon, J. P., DeMayo, F. J., Funk, C. R., Mani, S. K., Hughes, A. R., Montgomery, C. A., Shyamala, G., Conneely, O. M., & O’Malley, B. W. (1995). Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities.. Genes & Development, 9(18), 2266–2278. [DOI:10.1101/gad.9.18.2266]
  • Lyon, A. J., De Bruyn, R., & Grant, D. B. (1985). Isosexual Precocious Puberty in Girls. Acta Paediatrica, 74(6), 950–955. [DOI:10.1111/j.1651-2227.1985.tb10063.x]
  • Lyons, W. R. (1958). Hormonal synergism in mammary growth. Proceedings of the Royal Society of London. Series B - Biological Sciences, 149(936), 303–325. [DOI:10.1098/rspb.1958.0071]
  • Lyons, W. R., & McGinty, D. A. (1941). Effects of estrone and progesterone on male rabbit mammary glands. I. Varying doses of progesterone. Proceedings of the Society for Experimental Biology and Medicine, 48(1), 83–86. [DOI:10.3181/00379727-48-13227]
  • Lyons, W. R., Li, C. H., & Johnson, R. E. (1958). The Hormonal Control of Mammary Growth and Lactation. In Pincus, G. (Ed.). Recent Progress in Hormone Research, Volume 14 [Proceedings of the Laurentian Hormone Conference 1957, Held at Mont Tremblant, Quebec] (pp. 219–254). New York/London: Academic Press. [Google 学术] [Google 阅读] [PubMed] [OpenLibrary] [WorldCat] [PDF]
  • MacBryde, C. M. (1939). The Production of Breast Growth in the Human Female. Journal of the American Medical Association, 112(11), 1045–1049. [DOI:10.1001/jama.1939.02800110025006]
  • Malet, C., Gompel, A., Yaneva, H., Cren, H., Fidji, N., Mowszowicz, I., Kuttenn, F., & Mauvais-Jarvis, P. (1991). Estradiol and Progesterone Receptors in Cultured Normal Human Breast Epithelial Cells and Fibroblasts: Immunocytochemical Studies. The Journal of Clinical Endocrinology & Metabolism, 73(1), 8–17. [DOI:10.1210/jcem-73-1-8]
  • Malini, S., Smith, E. O., & Goldzieher, J. W. (1985). Measurement of breast volume by ultrasound during normal menstrual cycles and with oral contraceptive use. Obstetrics and Gynecology, 66(4), 538–541. [Google 学术] [PubMed] [URL] [PDF]
  • Marshall, W. A. (1978). Puberty. In Falkner, F., & Tanner, J. M. (Eds.). Human Growth: Postnatal Growth (pp. 141–181). Boston: Springer US. [DOI:10.1007/978-1-4684-2622-9_6]
  • Marshall, W. A., & Tanner, J. M. (1969). Variations in pattern of pubertal changes in girls. Archives of Disease in Childhood, 44(235), 291–303. [DOI:10.1136/adc.44.235.291]
  • Mauvais-Jarvis, P., Sitruk-Ware, R., & Kuttenn, F. (1981). Benign Breast Disease. In McGuire, W. L. (Ed.). Breast Cancer 4: Advances in Research and Treatment (pp. 51–94). Boston: Springer US. [DOI:10.1007/978-1-4615-6571-0_3]
  • Mauvais-Jarvis, P., Kuttenn, F., & Gompel, A. (1986). Antiestrogen action of progesterone in breast tissue. Breast Cancer Research and Treatment, 8(3), 179–188. [DOI:10.1007/bf01807330]
  • Mauvais-Jarvis, P., Kuttenn, F., & Gompel, A. (1986). Estradiol/Progesterone Interaction in Normal and Pathologic Breast Cells. Annals of the New York Academy of Sciences, 464(1), 152–167. [DOI:10.1111/j.1749-6632.1986.tb16002.x]
  • Mauvais-Jarvis, P., Kuttenn, F., & Gompel, A. (1987). Antiestrogen Action of Progesterone in Breast Tissue. Hormone Research, 28(2–4), 212–218. [DOI:10.1159/000180946]
  • Mauvais-Jarvis, P., Kuttenn, F., Gompel, A., & Benotmane, A. (1987). Action anti-estrogène de la progestérone dans le sein. [Antiestrogen action of progesterone in the breast]. Pathologie-Biologie, 35(7), 1081–1086. [Google 学术 1] [Google 学术 2] [PubMed]
  • McArthur, J. W. (1966). The Reproductive Endocrinology of Adolescence. In Heald, F. P. (Ed.). Adolescent Gynecology (pp. 9–20). Baltimore: Williams & Wilkins. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat]
  • McBryan, J., Howlin, J., Napoletano, S., & Martin, F. (2008). Amphiregulin: Role in Mammary Gland Development and Breast Cancer. Journal of Mammary Gland Biology and Neoplasia, 13(2), 159–169. [DOI:10.1007/s10911-008-9075-7]
  • McDonough, P. G., Spicer, D. V., Ursin, G., & Pike, M. C. (1996). Progesterone Concentrations—Physiologic or Pharmacologic? Fertility and Sterility, 65(5), 1077–1078. [DOI:10.1016/s0015-0282(16)58295-8]
  • McMillan, M. (1966). Five cases of testicular feminisation including one with a teratoma of the testis. The Journal of Pathology and Bacteriology, 91(2), 417–427. [DOI:10.1002/path.1700910216]
  • McNally, S., & Stein, T. (2016). Overview of Mammary Gland Development: A Comparison of Mouse and Human. In Martin, F., Stein, T., & Howlin, J. (Eds.). Mammary Gland Development (Methods in Molecular Biology, Volume 1501) (pp. 1–17). New York: Springer New York. [DOI:10.1007/978-1-4939-6475-8_1]
  • McPhaul, M. J. (2002). Androgen receptor mutations and androgen insensitivity. Molecular and Cellular Endocrinology, 198(1–2), 61–67. [DOI:10.1016/s0303-7207(02)00369-6]
  • Meites, J. (1966). Control of mammary growth and lactation. In Martini, L., & Ganong, W. F. (Eds.). Neuroendocrinology, Volume I (pp. 669–707). New York: Academic Press. [Google 学术] [Google 阅读] [DOI:10.1016/B978-1-4832-3228-7.50023-2] [OpenLibrary] [WorldCat]
  • Mesiano, S. (2019). Endocrinology of Human Pregnancy and Fetal-Placental Neuroendocrine Development. In Strauss, J. F., & Barbieri, R. L. (Eds.). Yen and Jaffe’s Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 8th Edition (pp. 256–284.e9). Philadelphia: Elsevier. [Google 阅读] [DOI:10.1016/b978-0-323-47912-7.00011-1]
  • Meyer, G., Mayer, M., Mondorf, A., Flügel, A. K., Herrmann, E., & Bojunga, J. (2020). Safety and rapid efficacy of guideline-based gender-affirming hormone therapy: an analysis of 388 individuals diagnosed with gender dysphoria. European Journal of Endocrinology, 182(2), 149–156. [DOI:10.1530/eje-19-0463]
  • Meyer, W. J., Finkelstein, J. W., Stuart, C. A., Webb, A., Smith, E. R., Payer, A. F., & Walker, P. A. (1981). Physical and hormonal evaluation of transsexual patients during hormonal therapy. Archives of Sexual Behavior10(4), 347–356. [DOI:10.1007/bf01565538]
  • Meyer, W. J., Webb, A., Stuart, C. A., Finkelstein, J. W., Lawrence, B., & Walker, P. A. (1986). Physical and hormonal evaluation of transsexual patients: A longitudinal study. Archives of Sexual Behavior15(2), 121–138. [DOI:10.1007/bf01542220]
  • Mikołajczyk, M., Kasielska-Trojan, A., & Antoszewski, B. (2019). A New Tool for Breast Anthropometric Measurements: Presentation and Validation for Women and Men. Aesthetic Plastic Surgery, 43(5), 1160–1170. [DOI:10.1007/s00266-019-01467-6]
  • Milionis, C., Ilias, I., & Koukkou, E. (2022). Progesterone in gender-affirming therapy of trans women. World Journal of Biological Chemistry, 13(3), 66–71. [DOI:10.4331/wjbc.v13.i3.66]
  • Milligan, D., Drife, J. O., & Short, R. V. (1975). Changes in breast volume during normal menstrual cycle and after oral contraceptives. BMJ, 4(5995), 494–496. [DOI:10.1136/bmj.4.5995.494]
  • Morris, J. M. (1953). The syndrome of testicular feminization in male pseudohermaphrodites. American Journal of Obstetrics and Gynecology, 65(6), 1192–1211. [DOI:10.1016/0002-9378(53)90359-7]
  • Morris, J. M., & Mahesh, V. B. (1963). Further observations on the syndrome, “testicular feminization”. American Journal of Obstetrics and Gynecology87(6), 731–748. [Google 学术 1] [Google 学术 2] [PubMed] [PDF]
  • Moss, W. M. (1968). Gigantomastia With Pregnancy. Archives of Surgery, 96(1), 27–32. [DOI:10.1001/archsurg.1968.01330190029007]
  • Muallem, M. M., & Rubeiz, N. G. (2006). Physiological and biological skin changes in pregnancy. Clinics in Dermatology, 24(2), 80–83. [DOI:10.1016/j.clindermatol.2005.10.002]
  • Müller, C. (1953). Zur Hormonalen Kosmetik der Weiblichen Brust: Wirkung und Nebenwirkung Östrogenhaltiger Kosmetischer Präparate. [Hormonal Cosmetics of the Female Breast: Effects and Side Effects of Estrogen-Containing Cosmetic Preparations.] Schweizerische Medizinische Wochenschrift [Swiss Medical Weekly], 83(4), 81–84. [Google 学术 1] [Google 学术 2] [PubMed] [PDF] [英译文]
  • Muzaffar, F., Hussain, I., & Haroon, T. S. (1998). Physiologic skin changes during pregnancy: a study of 140 cases. International Journal of Dermatology, 37(6), 429–431. [DOI:10.1046/j.1365-4362.1998.00281.x]
  • Naik, M., Diwakar, R. K., Patre, S., & Singh, S. (2015). Gigantomastia: A Rare Complication In Pregnancy. Journal of Medical Science and Clinical Research, 3(7), 6873–6876. [Google 学术] [URL] [PDF]
  • Naseem, H., Lokman, M., & Fitzgerald, C. (2021). Management of congenital hypogonadotropic hypogonadism in females. Human Fertility, advance online publcation. [DOI:10.1080/14647273.2021.1998929]
  • Nelson, W. O. (1936). Endocrine Control of the Mammary Gland. Physiological Reviews, 16(3), 488–526. [DOI:10.1152/physrev.1936.16.3.488]
  • Nolan, B. J., Frydman, A. S., Leemaqz, S. Y., Carroll, M., Grossmann, M., Zajac, J. D., & Cheung, A. S. (2022). Effects Of Low-dose Oral Micronised Progesterone On Sleep, Psychological Distress And Breast Development In Transgender Individuals Undergoing Feminising Hormone Therapy: A Prospective Controlled Study. Journal of the Endocrine Society6(Suppl 1), A653–A654 (abstract no. LBODP089). [DOI:10.1210/jendso/bvac150.1351]
  • Nolan, B. J., Frydman, A. S., Leemaqz, S. Y., Carroll, M., Grossmann, M., Zajac, J. D., & Cheung, A. S. (2022). Effects of low-dose oral micronised progesterone on sleep, psychological distress, and breast development in transgender individuals undergoing feminising hormone therapy: a prospective controlled study. Endocrine Connections, 11(5), e220170. [DOI:10.1530/EC-22-0170]
  • Nussbaum, R., & Benedetto, A. V. (2006). Cosmetic aspects of pregnancy. Clinics in Dermatology, 24(2), 133–141. [DOI:10.1016/j.clindermatol.2005.10.007]
  • Nuzzi, L. C., Pramanick, T., Massey, G. G., Walsh, L. R., McNamara, C. T., Firriolo, J. M., DiVasta, A. D., & Labow, B. I. (2021). The Impact of Progestin-only Contraception on Adolescents with Macromastia. Plastic and Reconstructive Surgery - Global Open, 9(2), e3421. [DOI:10.1097/gox.0000000000003421]
  • Nuzzi, L. C., Pramanick, T., Massey, G. G., Walsh, L. R., McNamara, C. T., Firriolo, J. M., DiVasta, A. D., & Labow, B. I. (2022). The Impact of Combined Oral Contraceptives on Adolescents with Macromastia. Plastic and Reconstructive Surgery, 150(4), 731–738. [DOI:10.1097/prs.0000000000009513]
  • Oakes, M. B., Eyvazzadeh, A. D., Quint, E., & Smith, Y. R. (2008). Complete Androgen Insensitivity Syndrome—A Review. Journal of Pediatric and Adolescent Gynecology, 21(6), 305–310. [DOI:10.1016/j.jpag.2007.09.006]
  • Obr, A. E., & Edwards, D. P. (2012). The biology of progesterone receptor in the normal mammary gland and in breast cancer. Molecular and Cellular Endocrinology, 357(1–2), 4–17. [DOI:10.1016/j.mce.2011.10.030]
  • Olanrewaju, F., Onayemi, O., Olasode, O., Adeyemi, A., Oninla, A., Oripelaye, M., Ezejiofor, O., & Oke, O. (2017). Prevalence and Pattern of Pigmentary Changes among Primigravidae Attending a Tertiary Health Facility in South-Western Nigeria. British Journal of Medicine and Medical Research, 21(5), 1–9. [DOI:10.9734/bjmmr/2017/33382]
  • Orentreich, N., & Durr, N. P. (1974). Mammogenesis in Transsexuals. Journal of Investigative Dermatology, 63(1), 142–146. [DOI:10.1111/1523-1747.ep12678272]
  • Pandya, S., & Moore, R. G. (2011). Breast Development and Anatomy. Clinical Obstetrics & Gynecology54(1), 91–95. [DOI:10.1097/grf.0b013e318207ffe9]
  • Park, I. Y., Kim, M. R., Jo, H. H., Lee, M. K., & Kim, M. J. (2014). Association of the Nipple-Areola Complexes with Age, Parity, and Breastfeeding in Korean Premenopausal Women. Journal of Human Lactation, 30(4), 474–479. [DOI:10.1177/0890334414549049]
  • Pasqualini, J. R. (2007). Progestins and breast cancer. Gynecological Endocrinology, 23(Suppl 1), 32–41. [DOI:10.1080/09513590701585003]
  • Pasqualini, J. R. (2009). Breast cancer and steroid metabolizing enzymes: The role of progestogens. Maturitas, 65(Suppl 1), S17–S21. [DOI:10.1016/j.maturitas.2009.11.006]
  • Pasqualini, J. R., & Kincl, F. A. (1985). Hormone Production and Concentrations During Pregnancy in Humans and in Other Mammalian Species. In Pasqualini, J. R., & Kincl, F. A. Hormones and the Fetus, Volume I: Production, Concentration and Metabolism During Pregnancy (pp. 173–334). Oxford: Pergamon Press. [DOI:10.1016/b978-0-08-019708-1.50007-6]
  • Patel, H., Arruarana, V., Yao, L., Cui, X., & Ray, E. (2020). Effects of hormones and hormone therapy on breast tissue in transgender patients: a concise review. Endocrine, 68(1), 6–15. [DOI:10.1007/s12020-020-02197-5]
  • Patel, K. T., Adeel, S., Rodrigues Miragaya, J., & Tangpricha, V. (2022). Progestogen Use in Gender-Affirming Hormone Therapy: A Systematic Review. Endocrine Practice, 28(12), 1244–1252. [DOI:10.1016/j.eprac.2022.08.012]
  • Patterson, M. N., McPhaul, M. J., & Hughes, I. A. (1994). Androgen insensitivity syndrome. Baillière’s Clinical Endocrinology and Metabolism, 8(2), 379–404. [DOI:10.1016/s0950-351x(05)80258-7]
  • Pawłowski, B., & Żelaźniewicz, A. (2021). The evolution of perennially enlarged breasts in women: a critical review and a novel hypothesis. Biological Reviews, 96(6), 2794–2809. [DOI:10.1111/brv.12778]
  • Perez-Palacios, G., & Jaffe, R. B. (1972). The Syndrome of Testicular Feminization. Pediatric Clinics of North America, 19(3), 653–667. [DOI:10.1016/s0031-3955(16)32744-4]
  • Petrakis, N. (1978). Recurrent extreme breast involution following pregnancy and susceptibility to breast cancer: A hypothesis. Medical Hypotheses, 4(3), 268–272. [DOI:10.1016/0306-9877(78)90006-3]
  • Pfeiffer, C. A. (1943). Endocrinology of Reproduction. Annual Review of Physiology5(1), 413–452. [DOI:10.1146/annurev.ph.05.030143.002213]
  • Pipkin, F. B. (2019). Physiological Changes in Pregnancy. In Symonds, I. M., & Arulkumaran, S. (Eds.). Essential Obstetrics and Gynaecology, 6th Edition (pp. 22–40). Edinburgh: Elsevier. [Google 阅读] [OpenLibrary] [WorldCat]
  • Plu-Bureau, G., Touraine, P., & Mauvais-Jarvis, P. (1999). Interactions Between Estradiol and Progesterone in Normal Breast: Implications for Mammary Carcinogenesis. In Manni, A. (Ed.). Endocrinology of Breast Cancer (Contemporary Endocrinology, Volume 11) (pp. 21–37). Totowa, New Jersey: Humana Press. [DOI:10.1007/978-1-59259-699-7_2] [OpenLibrary] [Archive.org]
  • Pocock, G., Richards, C. D., & Richards, D. A. (2013). Fertilization, Pregnancy, and Lactation. In Pocock, G., Richards, C. D., & Richards, D. A. Human Physiology, 4th Edition (pp. 655–752). Oxford: Oxford University Press. [Google 学术] [Google 阅读]
  • Polani, P. E. (1970). Hormonal and clinical aspects of hermaphroditism and the testicular feminizing syndrome in man. Philosophical Transactions of the Royal Society of London. B, Biological Sciences, 259(828), 187–206. [DOI:10.1098/rstb.1970.0058]
  • Price, S., McManus, J., & Barrett, J. (2019). The transgender population: improving awareness for gynaecologists and their role in the provision of care. The Obstetrician & Gynaecologist, 21(1), 11–20. [DOI:10.1111/tog.12521]
  • Prior, J. C. (2011). Progesterone for Symptomatic Perimenopause Treatment - Progesterone politics, physiology and potential for perimenopause. Facts, Views & Vision in ObGyn, 3(2), 109–120. [PubMed] [PubMed Central] [PDF]
  • Prior, J. C. (2019). Progesterone Is Important for Transgender Women’s Therapy—Applying Evidence for the Benefits of Progesterone in Ciswomen. The Journal of Clinical Endocrinology & Metabolism, 104(4), 1181–1186. [DOI:10.1210/jc.2018-01777]
  • Prior, J. C. (2019). Response to Letter to the Editor: “Progesterone Is Important for Transgender Women’s Therapy—Applying Evidence for the Benefits of Progesterone in Ciswomen”. The Journal of Clinical Endocrinology & Metabolism, 104(8), 3129–3130. [DOI:10.1210/jc.2019-00524]
  • Prior, J. C. (2020). Women’s Reproductive System as Balanced Estradiol and Progesterone Actions—A revolutionary, paradigm-shifting concept in women’s health. Drug Discovery Today: Disease Models, 32(Part B), 31–40. [DOI:10.1016/j.ddmod.2020.11.005]
  • Prior, J. C., Vigna, Y. M., & Watson, D. (1989). Spironolactone with physiological female steroids for presurgical therapy of male-to-female transsexualism. Archives of Sexual Behavior, 18(1), 49–57. [DOI:10.1007/bf01579291]
  • Prior, J. C., Vigna, Y. M., Watson, D., Diewold, P., & Robinow, O. (1986). Spironolactone in the presurgical therapy of male to female transsexuals: Philosophy and experience of the Vancouver Gender Dysphoria Clinic. Journal of Sex Information & Education Council of Canada, 1(1), 1–7. [Google 学术] [PDF]
  • Quigley, C. A. (1998). The androgen receptor: Physiology and pathophysiology. In Nieschlag, E., & Behre, H. M. (Eds.). Testosterone: Action · Deficiency · Substitution, 2nd Edition (pp. 33–106). Berlin/Heidelberg: Springer. [DOI:10.1007/978-3-642-72185-4_2]
  • Quigley, C. A., Bellis, A. D., Marschke, K. B., El-Awady, M. K., Wilson, E. M., & French, F. S. (1995). Androgen Receptor Defects: Historical, Clinical, and Molecular Perspectives. Endocrine Reviews, 16(3), 271–321. [DOI:10.1210/edrv-16-3-271]
  • Radisky, D. C., & Hartmann, L. C. (2009). Mammary Involution and Breast Cancer Risk: Transgenic Models and Clinical Studies. Journal of Mammary Gland Biology and Neoplasia, 14(2), 181–191. [DOI:10.1007/s10911-009-9123-y]
  • Ramos, L., Chávez, B., Mares, L., Valdés, E., & Vilchis, F. (2018). Mutational analysis of the androgen receptor (NR3C4) gene in patients with 46,XY DSD. Gene, 641, 86–93. [DOI:10.1016/j.gene.2017.10.038]
  • Ramsay, D. T., Kent, J. C., Hartmann, R. A., & Hartmann, P. E. (2005). Anatomy of the lactating human breast redefined with ultrasound imaging. Journal of Anatomy, 206(6), 525–534. [DOI:10.1111/j.1469-7580.2005.00417.x]
  • Randolph, J. F. (2018). Gender-Affirming Hormone Therapy for Transgender Females. Clinical Obstetrics & Gynecology, 61(4), 705–721. [DOI:10.1097/grf.0000000000000396]
  • Rauh, C., Faschingbauer, F., Haeberle, L., Jud, S. M., Heusinger, K., Fasching, P. A., Goecke, T. W., Rajakaruna, N., Voigt, F., Bani, M. R., Lux, M. P., Renner, S. P., Loehberg, C. R., Hartmann, A., Schulz-Wendtland, R., Beckmann, M. W., & Bayer, C. M. (2013). Factors influencing breast changes after pregnancy. European Journal of Cancer Prevention, 22(3), 259–261. [DOI:10.1097/cej.0b013e328359cb81]
  • Rebar, R. W. (1988). The Ovaries. In Wyngaarden, J. B., & Smith, L. H. (Eds.). Cecil Textbook of Medicine, 18th Edition (pp. 1425–1446). Philadelphia: W. B. Saunders. [Google 阅读] [OpenLibrary] [WorldCat] [Archive.org]
  • Rebar, R. W. (1990). Disorders of Menstruation, Ovulation, and Sexual Response. In Becker, K. L., Bilezikian, J. P., Bremner, W. J., Hung, W., Kahn, C. R., Loriaux, D. L., Rebar, R. W., Robertson, G. L., & Wartofsky, L. (Eds.). Principles and Practice of Endocrinology and Metabolism, 1st Edition (pp. 798–814). Philadelphia: Lippincott. [Google 学术—3rd/2001 Edition] [Google 阅读—3rd/2001 Edition] [OpenLibrary] [WorldCat] [Archive.org]
  • Rebar, R. W. (1993). Normal and Abnormal Sexual Differentiation and Pubertal Development. In Moore, T. R., Reiter, R. C., Rebar, R. W., & Baker, W. (Eds.). Gynecology & Obstetrics: A Longitudinal Approach (pp. 97–133). New York: Churchill Livingstone. [Google 阅读] [OpenLibrary] [WorldCat] [Archive.org]
  • Rebar, R. W. (1996). Puberty. In Berek, J. S., Adashi, E. Y., & Hillard, P. A. (Eds.). Novak’s Gynecology, 12th Edition (pp. 771–807). Baltimore: Williams & Wilkins. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [Archive.org]
  • Reindollar, R. H., & McDonough, P. G. (1985). The Child with Ambiguous Genitalia. In Lavery, J. P., & Sanfilippo, J. S. (Eds.). Pediatric and Adolescent Obstetrics and Gynecology, 1st Edition (Clinical Perspective in Obstetrics and Gynecology) (pp. 38–60). New York: Springer. [DOI:10.1007/978-1-4612-5064-7_5]
  • Reisman, T., Goldstein, Z., & Safer, J. D. (2019). A Review of Breast Development in Cisgender Women and Implications for Transgender Women. Endocrine Practice, 25(12), 1338–1345. [DOI:10.4158/ep-2019-0183]
  • Richards, C., & Barrett, J. (2020). Physical Treatments for Trans People and Their Interactions with Psychiatric Treatments. In Richards, C., & Barrett, J. Trans and Non-binary Gender Healthcare for Psychiatrists, Psychologists, and Other Health Professionals (pp. 31–44). Cambridge: Cambridge University Press. [DOI:10.1017/9781108628419.003]
  • Richert, M. M., Schwertfeger, K. L., Ryder, J. W., & Anderson, S. M. (2000). An Atlas of Mouse Mammary Gland Development. Journal of Mammary Gland Biology and Neoplasia, 5(2), 227–241. [DOI:10.1023/a:1026499523505]
  • Rix, J., Mills, C., Ross, E., Allen, S., Lai, A., & Wakefield-Scurr, J. (2023). Breast volume fluctuations are associated with oestradiol and progesterone changes across the menstrual cycle. Research Square, preprint. [Google 学术] [DOI:10.21203/rs.3.rs-3753080/v1] [PDF]
  • Rodari, G. (2022). Pubertal induction in girls with hypogonadism: estrogen replacement therapy outcomes and optimization of progesterone introduction. (Doctoral thesis, Università degli Studi di Milano.) [URL]
  • Rodari, G., Federici, S., Cattoni, A., Todisco, T., Ubertini, G., Giacchetti, F., Profka, E., Dall’Antonia, A., Cangiano, B., Arosio, M., Bonomi, M., Cappa, M., & Giavoli, C. (2022). Pubertal induction in girls with hypogonadism: insight into estrogen replacement therapy outcomes and optimization of progesterone introduction. Endocrine Abstracts, 81 [24th European Congress of Endocrinology 2022 21–24 May 2022, Milan, Italy], 107–107 (abstract no. RC12.7). [DOI:10.1530/endoabs.81.rc12.7] [PDF]
  • Rodari, G., Federici, S., Todisco, T., Ubertini, G., Cattoni, A., Pagano, M., Giacchetti, F., Profka, E., Citterio, V., Messetti, D., Collini, V., Soranna, D., Carbone, E., Arosio, M., Mantovani, G., Persani, L., Cappa, M., Bonomi, M., & Giavoli, C. (2023). Towards an individualized management of pubertal induction in girls with hypogonadism: insight into the best replacement outcomes from a large multicentre registry. European Journal of Endocrinology, 188(6), 467–476. [DOI:10.1093/ejendo/lvad056]
  • Rohn, R. D. (1989). Nipple (papilla) development in girls: III. Journal of Adolescent Health Care, 10(1), 39–40. [DOI:10.1016/0197-0070(89)90045-4]
  • Rosenfield, R. L. (2013). Adolescent Anovulation: Maturational Mechanisms and Implications. The Journal of Clinical Endocrinology & Metabolism, 98(9), 3572–3583. [DOI:10.1210/jc.2013-1770]
  • Rosenfield, R. L., Cooke, D. W., & Radovick, S. (2021). Puberty in the Female and Its Disorders. In Sperling, M. A., Majzoub, J. A., Menon, R. K., & Stratakis, C. A. (Eds.). Sperling Pediatric Endocrinology, 5th Edition (pp. 528–626). Philadelphia: Elsevier. [DOI:10.1016/B978-0-323-62520-3.00016-6]
  • Rothman, M. S., & Iwamoto, S. J. (2022). Feminizing Gender-Affirming Hormone Therapy: Special Considerations for Older Adults. In Davis, T. F. (Ed.). A Case-Based Guide to Clinical Endocrinology (pp. 513–523). Cham: Springer International Publishing. [DOI:10.1007/978-3-030-84367-0_58]
  • Ruan, W., Monaco, M. E., & Kleinberg, D. L. (2005). Progesterone Stimulates Mammary Gland Ductal Morphogenesis by Synergizing with and Enhancing Insulin-Like Growth Factor-I Action. Endocrinology, 146(3), 1170–1178. [DOI:10.1210/en.2004-1360]
  • Rutgers, J. L., & Scully, R. E. (1991). The Androgen Insensitivity Syndrome (Testicular Feminization). International Journal of Gynecological Pathology, 10(2), 126–144. [DOI:10.1097/00004347-199104000-00002]
  • Ryan, R. F., & Pernoll, M. L. (1985). Virginal Hypertrophy. Plastic and Reconstructive Surgery, 75(5), 737–742. [DOI:10.1097/00006534-198505000-00024]
  • Saito, R., Yamamoto, Y., Goto, M., Araki, S., Kubo, K., Kawagoe, R., Kawada, Y., Kusuhara, K., Igarashi, M., & Fukami, M. (2014). Tamoxifen Treatment for Pubertal Gynecomastia in Two Siblings with Partial Androgen Insensitivity Syndrome. Hormone Research in Paediatrics, 81(3), 211–216. [DOI:10.1159/000356923]
  • Sandhu, R., Chollet-Hinton, L., Kirk, E. L., Midkiff, B., & Troester, M. A. (2016). Digital histologic analysis reveals morphometric patterns of age-related involution in breast epithelium and stroma. Human Pathology, 48, 60–68. [DOI:10.1016/j.humpath.2015.09.031]
  • Santen, R. J., Karaguzel, G., Livaoglu, M., Yue, W., Cline, J. M., Ratan, A., & Sasano, H. (2024). Role of ERα and aromatase in juvenile gigantomastia. The Journal of Clinical Endocrinology and Metabolism, online ahead of print. [DOI:10.1210/clinem/dgae019]
  • Sanuki, J., Fukuma, E., & Uchida, Y. (2008). Morphologic Study of Nipple-Areola Complex in 600 Breasts. Aesthetic Plastic Surgery, 33(3), 295–297. [DOI:10.1007/s00266-008-9194-y]
  • Satoh, K., Hovey, R. C., Malewski, T., Warri, A., Goldhar, A. S., Ginsburg, E., Saito, K., Lydon, J. P., & Vonderhaar, B. K. (2007). Progesterone enhances branching morphogenesis in the mouse mammary gland by increased expression of Msx2. Oncogene, 26(54), 7526–7534. [DOI:10.1038/sj.onc.1210555]
  • Schauffler, G. C. (1942). Disorders During Adolescence—The Onset of Menstruation. In Schauffler, G. C. Pediatric Gynecology; with Sections on Urology and Proctology, 1st Edition (pp. 169–211). Chicago: Year Book. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [URL]
  • Schindler, A. E. (2010). Dydrogesterone and other progestins in benign breast disease: an overview. Archives of Gynecology and Obstetrics, 283(2), 369–371. [DOI:10.1007/s00404-010-1456-7]
  • Scott, P. P., Greene, R., Lane-Roberts, C. S., & Swain, V. (1950). The Function of the Breast. In Saner, F. D. (Ed.). The Breast: Structure, Function, Disease (pp. 53–86). Baltimore: Williams and Wilkins. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [URL] [PDF]
  • Seal, L. (2017). Adult Endocrinology. In Richards, C., Bouman, W. P., & Barker, M.-J. (Eds.). Genderqueer and Non-Binary Genders (Critical and Applied Approaches in Sexuality, Gender and Identity) (pp. 183–223). London: Palgrave Macmillan UK. [DOI:10.1057/978-1-137-51053-2_10]
  • Seal, L. J., Franklin, S., Richards, C., Shishkareva, A., Sinclaire, C., & Barrett, J. (2012). Predictive Markers for Mammoplasty and a Comparison of Side Effect Profiles in Transwomen Taking Various Hormonal Regimens. The Journal of Clinical Endocrinology & Metabolism97(12), 4422–4428. [DOI:10.1210/jc.2012-2030]
  • Seibert, B., & Günzel, P. (1994). Animal toxicity studies performed for risk assessment of the once-a-month injectable contraceptive Mesigyna®. Contraception, 49(4), 303–333. [DOI:10.1016/0010-7824(94)90030-2]
  • Shapiro, L. R. (1982). Disorders of Female Sex Differentiation. In Blaustein, A. (Ed.). Pathology of the Female Genital Tract, 2nd Edition (pp. 479–510). New York: Springer New York. [DOI:10.1007/978-1-4757-1767-9_20]
  • Shearman, R. P. (1972). Ovarian Function and its Control. In Shearman, R. P. (Ed.). Human Reproductive Physiology, 1st Edition (pp. 45–90). Oxford: Blackwell Scientific Publications. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [Archive.org]
  • Shearman, R. P. (1972). Primary Ammenorhoea. In Dewhurst, C. J. (Ed.). Integrated Obstetrics and Gynaecology for Postgraduates, 1st Edition (pp. 55–62). Oxford: Blackwell Scientific Publications. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [Archive.org]
  • Shearman, R. P. (1985). Primary Amenorrhoea. In Shearman, R. P. (Ed.). Clinical Reproductive Endocrinology (481–492). Edinburgh: Churchill Livingstone. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [Archive.org]
  • Shi, H. Y., Lydon, J. P., & Zhang, M. (2004). Hormonal Defect in Maspin Heterozygous Mice Reveals a Role of Progesterone in Pubertal Ductal Development. Molecular Endocrinology, 18(9), 2196–2207. [DOI:10.1210/me.2004-0052]
  • Shuttleworth, F. K. (1938). The Adolescent Period: A Graphic and Pictorial Atlas (Monographs of the Society for Research in Child Development, Volume 3, Number 3 / Serial No. 16). Washington, D. C.: Society for Research in Child Development. [Google 学术] [Google 阅读] [DOI:10.2307/1165482]
  • Simmer, H. H., Pion, R. J., & Dignam, W. J. (1965). Testicular Feminization: Endocrine Function of Feminizing Testes, Comparison with Normal Testes. Springfield, Illinois: Thomas. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat]
  • Simpson, J. L., & Rebar, R. W. (1990). Normal and Abnormal Sexual Differentiation and Development. In Becker, K. L., Bilezikian, J. P., Bremner, W. J., Hung, W., Kahn, C. R., Loriaux, D. L., Rebar, R. W., Robertson, G. L., & Wartofsky, L. (Eds.). Principles and Practice of Endocrinology and Metabolism, 1st Edition (pp. 710–739). Philadelphia: Lippincott. [Google 学术] [Google 阅读—3rd/2001 Edition] [OpenLibrary] [WorldCat] [Archive.org]
  • Sindi, R., Sá Dos Reis, C., Bennett, C., Stevenson, G., & Sun, Z. (2019). Quantitative Measurements of Breast Density Using Magnetic Resonance Imaging: A Systematic Review and Meta-Analysis. Journal of Clinical Medicine, 8(5), 745. [DOI:10.3390/jcm8050745]
  • Sitruk-Ware, R., Basdevant, A., de Lignières, B., & Mauvais-Jarvis, P. (1984). Percutaneous oestrogen therapy. In van Herendael, H., van Herendael, B., Riphagen, F. E., Goessens, L., & van der Plas, H. (Eds.). The Climacteric: An Update: Proceedings of the fourth Jan Palfijn Symposium, European Conference on the Menopause, held in Antwerp, Belgium, on September 1–2, 1983, under the auspices of ‘De Vereniging voor Nederlandstalige gynecologen van België’ and ‘The International Menopause Society’ (pp. 127–139). Lancaster: MTP Press. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [DOI:10.1007/978-94-009-5608-7_14]
  • Sizonenko, P. C. (1978). Endocrinology in Preadolescents and Adolescents. American Journal of Diseases of Children132(7), 704–712. [DOI:10.1001/archpedi.1978.02120320064015]
  • Škarda, J., Fremrová, V., & Bezecný, I. (1989). Progesterone alone is responsible for stimulation of the growth of ducts and of mammary alveolar structures in mice. Endocrinologia Experimentalis, 23(1), 17–28. [Google 学术] [PubMed] [PDF]
  • Sobrinho, L. G., Kase, N., & Grunt, J. A. (1971). Spontaneous pubertal breast growth in a castrated patient with the syndrome of testicular feminization. The Yale Journal of Biology and Medicine44(2), 225–9. [Google 学术] [PubMed] [PubMed Central] [PDF]
  • Sosa, M., Jódar, E., Arbelo, E., Domínguez, C., Saavedra, P., Torres, A., Salido, E., de Tejada, M. J., & Hernández, D. (2003). Bone Mass, Bone Turnover, Vitamin D, and Estrogen Receptor Gene Polymorphisms in Male to Female Transsexuals. Journal of Clinical Densitometry, 6(3), 297–304. [DOI:10.1385/jcd:6:3:297]
  • Sosa, M., Jódar, E., Arbelo, E., Domı́nguez, C., Saavedra, P., Torres, A., Salido, E., Limiñana, J., Gómez de Tejada, M. J., & Hernández, D. (2004). Serum lipids and estrogen receptor gene polymorphisms in male-to-female transsexuals: effects of estrogen treatment. European Journal of Internal Medicine, 15(4), 231–237. [DOI:10.1016/j.ejim.2004.04.009]
  • Soyal, S., Ismail, P. M., Li, J., Mulac-Jericevic, B., Conneely, O. M., & Lydon, J. P. (2002). Progesterone receptors - animal models and cell signaling in breast cancer: Progesterone’s role in mammary gland development and tumorigenesis as disclosed by experimental mouse genetics. Breast Cancer Research, 4(5), 191. [DOI:10.1186/bcr451]
  • Sperling, R. L., & Gold, J. J. (1973). Use of an anti-estrogen after a reduction mammaplasty to prevent recurrence of virginal hypertrophy of breasts. Plastic and Reconstructive Surgery, 52(4), 439–442. [DOI:10.1097/00006534-197352040-00030]
  • Spitz, I. M., Shoupe, D., Sitruk-Ware, R., & Mishell, D. R. (1989). Response to the antiprogestagen RU 486 (mifepristone) during early pregnancy and the menstrual cycle in women. Journal of Reproduction and Fertility Supplement37, 253–260. [Google 学术] [PubMed]
  • Spitz, I., Croxatto, H., Lahteenmaki, P., Heikinheimo, O., & Bardin, C. (1994). Effect of mifepristone on inhibition of ovulation and induction of luteolysis. Human Reproduction9(Suppl 1), 69–76. [DOI:10.1093/humrep/9.suppl_1.69]
  • Spitz, I. M. (2010). Mifepristone: where do we come from and where are we going? Contraception82(5), 442–452. [DOI:10.1016/j.contraception.2009.12.012]
  • Sridhar, G. R., & Sinha, M. J. (1995). Macromastia in adolescent girls. Indian Pediatrics, 32(4), 496–499. [Google 学术] [PubMed] [PDF]
  • Sun, B. Z., Kangarloo, T., Adams, J. M., Sluss, P. M., Welt, C. K., Chandler, D. W., Zava, D. T., McGrath, J. A., Umbach, D. M., Hall, J. E., & Shaw, N. D. (2018). Healthy Post-Menarchal Adolescent Girls Demonstrate Multi-Level Reproductive Axis Immaturity. The Journal of Clinical Endocrinology & Metabolism, 104(2), 613–623. [DOI:10.1210/jc.2018-00595]
  • Sun, S. X., Bostanci, Z., Kass, R. B., Mancino, A. T., Rosenbloom, A. L., Klimberg, V. S., & Bland, K. I. (2018). Breast Physiology: Normal and Abnormal Development and Function. In Bland, K. I., Copeland, E. M., Klimberg, V. S., Gradishar, W. J., White, J., & Korourian, S. (Eds.). The Breast: Comprehensive Management of Benign and Malignant Diseases, 5th Edition (pp. 37–56.e6). Philadelphia: Elsevier. [DOI:10.1016/b978-0-323-35955-9.00003-9]
  • Swelstad, M. R., Swelstad, B. B., Rao, V. K., & Gutowski, K. A. (2006). Management of Gestational Gigantomastia. Plastic and Reconstructive Surgery, 118(4), 840–848. [DOI:10.1097/01.prs.0000232364.40958.47]
  • Tack, L. J., Heyse, R., Craen, M., Dhondt, K., Bossche, H. V., Laridaen, J., & Cools, M. (2017). Consecutive Cyproterone Acetate and Estradiol Treatment in Late-Pubertal Transgender Female Adolescents. The Journal of Sexual Medicine, 14(5), 747–757. [DOI:10.1016/j.jsxm.2017.03.251]
  • Talbert, L. M., Hammond, M. G., Groff, T., & Udry, J. R. (1985). Relationship of age and pubertal development to ovulation in adolescent girls. Obstetrics & Gynecology, 66(4), 542–544. [Google 学术] [URL]
  • Tanos, T., & Brisken, C. (2008). What Signals Operate in the Mammary Niche? Breast Disease, 29(1), 69–82. [DOI:10.3233/bd-2008-29108]
  • Thanaboonyawat, I., Chanprapaph, P., Lattalapkul, J., & Rongluen, S. (2013). Pilot Study of Normal Development of Nipples during Pregnancy. Journal of Human Lactation, 29(4), 480–483. [DOI:10.1177/0890334413493350]
  • Thody, A. J., & Smith, A. G. (1977). Hormones and Skin Pigmentation in the Mammal. International Journal of Dermatology, 16(8), 657–664. [DOI:10.1111/j.1365-4362.1977.tb01876.x]
  • Thoresen, M., & Wesche, J. (1988). Doppler measurements of changes in human mammary and uterine blood flow during pregnancy and lactation. Acta Obstetricia et Gynecologica Scandinavica, 67(8), 741–745. [DOI:10.3109/00016349809004301]
  • Tiefenbacher, K., & Daxenbichler, G. (2008). The Role of Androgens in Normal and Malignant Breast Tissue. Breast Care, 3(5), 325–331. [DOI:10.1159/000158055]
  • Trabert, B., Sherman, M. E., Kannan, N., & Stanczyk, F. Z. (2019). Progesterone and Breast Cancer. Endocrine Reviews, 41(2), 320–344. [DOI:10.1210/endrev/bnz001]
  • Tucker, H. (2000). Hormones, Mammary Growth, and Lactation: a 41-Year Perspective. Journal of Dairy Science, 83(4), 874–884. [DOI:10.3168/jds.s0022-0302(00)74951-4]
  • Turan, S., Bereket, A., Guran, T., Akcay, T., Papari-Zareei, M., & Auchus, R. J. (2009). Puberty in a case with novel 17-hydroxylase mutation and the putative role of estrogen in development of pubic hair. European Journal of Endocrinology, 160(2), 325–330. [DOI:10.1530/eje-08-0632]
  • Turner, C. W. (1939). The Mammary Glands. In Allen, E., Danforth, C. H., & Doisy, E. A. (Eds.). Sex and Internal Secretions: A Survey of Recent Research, 2nd Edition (pp. 740–803). Baltimore: Williams & Wilkins. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat]
  • Ulrich, U., Pfeifer, T., & Lauritzen, C. (1994). Rapid Increase in Lumbar Spine Bone Density in Osteopenic Women by High-Dose Intramuscular Estrogen-Progestogen Injections. Hormone and Metabolic Research, 26(9), 428–431. [DOI:10.1055/s-2007-1001723]
  • Ulrich, U., Pfeifer, T., Buck, G., Keckstein, J., & Lauritzen, C. (1995). High-dose estrogen-progestogen injections in gonadal dysgenesis, ovarian hypoplasia, and androgen insensitivity syndrome: Impact on bone density. Adolescent and Pediatric Gynecology, 8(1), 20–23. [DOI:10.1016/s0932-8610(12)80156-3]
  • Valentine, G. H. (1969). The Chromosome Disorders: An Introduction for Clinicians, 2nd Edition. London: W. Heinemann Medical Books. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat] [Archive.org]
  • van der Meulen, A. J. (1974). An unusual case of massive hypertrophy of the breasts. South African Medical Journal=Suid-Afrikaanse Tydskrif vir Geneeskunde48(34), 1465–1466. [Google 学术] [PubMed] [URL 1] [URL 2]
  • Vandeweyer, E., & Hertens, D. (2002). Quantification of glands and fat in breast tissue: An experimental determination. Annals of Anatomy - Anatomischer Anzeiger, 184(2), 181–184. [DOI:10.1016/s0940-9602(02)80016-4]
  • Venturoli, S., Porcu, E., Fabbri, R., Magrini, O., Paradisi, R., Pallotti, G., Gammi, L., & Flamigni, C. (1987). Postmenarchal evolution of endocrine pattern and ovarian aspects in adolescents with menstrual irregularities. Fertility and Sterility, 48(1), 78–85. [DOI:10.1016/s0015-0282(16)59294-2]
  • Venturoli, S., Fabbri, R., Porcu, E., Paradisi, R., Orsini, L. F., Brondelli, L., Ruggeri, S., & Flamigni, C. (1989). Endocrine and ovarian parameters at various frequencies of ovulation in adolescents. Archives of Gynecology and Obstetrics, 246(2), 107–114. [DOI:10.1007/bf00934127]
  • Vorherr, H. (1974). Development of the Female Breast. In Vorherr, H. The Breast: Morphology, Physiology, and Lactation (pp. 1–19). New York: Academic Press. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat]
  • Vorherr, H. (1974). Morphology of the Mature Female Breast. In Vorherr, H. The Breast: Morphology, Physiology, and Lactation (pp. 20–70). New York: Academic Press. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat]
  • Wade, T. R., Wade, S. L., & Jones, H. E. (1978). Skin changes and diseases associated with pregnancy. Obstetrics and Gynecology, 52(2), 233–242. [Google 学术] [PubMed] [URL]
  • Walker, M., Baker, G., & Lamb, M. (2013). Physiology of the Breast During Pregnancy and Lactation. In Mannel, R., Martens, P. J., & Walker, M. (Eds.). Core Curriculum for Lactation Consultant Practice, 3rd Edition (pp. 287–300). Burlington: Jones & Bartlett Learning. [Google 学术] [Google 阅读—2013/3rd Edition] [Google 阅读—2008/2nd Edition] [OpenLibrary] [WorldCat]
  • Wang, C., Luan, J., Cheng, H., Chen, L., Li, Z., Panayi, A. C., & Liu, C. (2018). Menstrual Cycle-Related Fluctuations in Breast Volume Measured Using Three-Dimensional Imaging: Implications for Volumetric Evaluation in Breast Augmentation. Aesthetic Plastic Surgery, 43(1), 1–6. [DOI:10.1007/s00266-018-1243-6]
  • Wang, Q. A., & Scherer, P. E. (2019). Remodeling of Murine Mammary Adipose Tissue during Pregnancy, Lactation, and Involution. Journal of Mammary Gland Biology and Neoplasia, 24(3), 207–212. [DOI:10.1007/s10911-019-09434-2]
  • Weisberg, M. G., Malkasian, G. D., & Pratt, J. H. (1970). Testicular feminization syndrome. American Journal of Obstetrics and Gynecology, 107(8), 1181–1187. [DOI:10.1016/s0002-9378(15)30367-7]
  • Wellons, M. F., & Rebar, R. W. (2013). Amenorrhea. In Falcone, T., & Hurd, W. W. (Eds.). Clinical Reproductive Medicine and Surgery: A Practical Guide, 2nd Edition (pp. 105–112). New York: Springer New York. [DOI:10.1007/978-1-4614-6837-0_7]
  • Wellons, M. F., Weeber, K. M., & Rebar, R. W. (2017). Amenorrhea. In Falcone, T., & Hurd, W. W. (Eds.). Clinical Reproductive Medicine and Surgery, 3rd Edition (pp. 109–122). Cham: Springer International Publishing. [DOI:10.1007/978-3-319-52210-4_6]
  • Werner, A. A. (1935). Experiment to produce lactation in castrate women. Endocrinology, 19(2), 144–150. [DOI:10.1210/endo-19-2-144]
  • Whiteley, S. (1994). Predictors of Milk Production in Lactating Women. (Master’s thesis, The Open University.) [Google 学术] [DOI:10.21954/ou.ro.0000fe02] [URL]
  • Wierckx, K., Gooren, L., & T’Sjoen, G. (2014). Clinical Review: Breast Development in Trans Women Receiving Cross-Sex Hormones. The Journal of Sexual Medicine, 11(5), 1240–1247. [DOI:10.1111/jsm.12487]
  • Wierckx, K., Van Caenegem, E., Schreiner, T., Haraldsen, I., Fisher, A., Toye, K., Kaufman, J. M., & T’Sjoen, G. (2014). Cross‐Sex Hormone Therapy in Trans Persons Is Safe and Effective at Short‐Time Follow‐Up: Results from the European Network for the Investigation of Gender Incongruence. The Journal of Sexual Medicine, 11(8), 1999–2011. [DOI:10.1111/jsm.12571]
  • Wilson, J. D. (1968 March 28). Medical Grand Rounds: Testicular Feminization. Parkland Memorial Hospital, UT Southwestern Medical Center. [Google 学术] [URL] [PDF]
  • Wilson, C. L., Sims, A. H., Howell, A., Miller, C. J., & Clarke, R. B. (2006). Effects of oestrogen on gene expression in epithelium and stroma of normal human breast tissue. Endocrine-Related Cancer, 13(2), 617–628. [DOI:10.1677/erc.1.01165]
  • Winkler, U. H., Schindler, A. E., Brinkmann, U. S., Ebert, C., & Oberhoff, C. (2001). Cyclic progestin therapy for the management of mastopathy and mastodynia. Gynecological Endocrinology, 15(Suppl 6), 37–43. [DOI:10.1080/gye.15.s6.37.43]
  • Wisniewski, A. B., Migeon, C. J., Meyer-Bahlburg, H. F., Gearhart, J. P., Berkovitz, G. D., Brown, T. R., & Money, J. (2000). Complete Androgen Insensitivity Syndrome: Long-Term Medical, Surgical, and Psychosexual Outcome. The Journal of Clinical Endocrinology & Metabolism, 85(8), 2664–2669. [DOI:10.1210/jcem.85.8.6742]
  • Wong, R. C., & Ellis, C. N. (1984). Physiologic skin changes in pregnancy. Journal of the American Academy of Dermatology, 10(6), 929–940. [DOI:10.1016/s0190-9622(84)80305-9]
  • Wren, B. G., & Eden, J. A. (1996). Do Progestogens Reduce The Risk of Breast Cancer? A Review of the Evidence. Menopause, 3(1), 4–12. [DOI:10.1097/00042192-199603010-00003]
  • Wright, E. M. (2015). Breastfeeding and the Mother–Newborn Dyad (pp. 1157–1182). In King, T. L., Brucker, M. C., Kriebs, J. M., Fahey, J. O., Gegor, C. L., & Varney, H. (Eds.). Varney’s Midwifery, 5th Edition. Burlington: Jones & Bartlett Learning. [Google 学术] [Google 阅读] [OpenLibrary] [WorldCat]
  • Xu, P., Ye, W., Zhong, S., Li, H., Feng, E., Lin, S. H., Kuo, C. T., Liu, J. Y., & Lin, Y. C. (2010). Leptin and zeranol up-regulate cyclin D1 expression in primary cultured normal human breast pre-adipocytes. Molecular Medicine Reports3(6), 983–990. [DOI:10.3892/mmr.2010.370]
  • Yang, W., Hong, T., Chang, X., Han, M., Gao, H., Pan, B., Zhao, Z., & Liu, Y. (2024). The efficacy of and user satisfaction with different antiandrogens in Chinese transgender women. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2024.2323514]
  • Zacharin, M. (2000). Use of androgens and oestrogens in adolescents - A review of hormone replacement treatment. Journal of Pediatric Endocrinology and Metabolism, 13(1), 3–12. [DOI:10.1515/JPEM.2000.13.1.3]
  • Zachmann, M., Prader, A., Sobel, E. H., Crigler, J. F., Ritzén, E. M., Atarés, M., & Ferrandez, A. (1986). Pubertal growth in patients with androgen insensitivity: Indirect evidence for the importance of estrogens in pubertal growth of girls. The Journal of Pediatrics108(5), 694–697. [DOI:10.1016/s0022-3476(86)81043-5]
  • Żelaźniewicz, A., & Pawłowski, B. (2015). Breast size and asymmetry during pregnancy in dependence of a fetus’s sex. American Journal of Human Biology, 27(5), 690–696. [DOI:10.1002/ajhb.22716]
  • Żelaźniewicz, A., & Pawłowski, B. (2018). Maternal breast volume in pregnancy and lactation capacity. American Journal of Physical Anthropology, 168(1), 180–189. [DOI:10.1002/ajpa.23734]
  • Zhang, D., Yao, F., Tian, T., Deng, S., Luo, M., & Tian, Q. (2021). Clinical characteristics and molecular genetics of complete androgen insensitivity syndrome patients: a series study of 30 cases from a Chinese tertiary medical center. Fertility and Sterility115(5), 1270–1279. [DOI:10.1016/j.fertnstert.2020.12.008]

译文修订记录

时间备注
2023 年 11 月 2 日初次翻译。
2025 年 4 月 8 日重新翻译了全文。

相关文章