女性倾向跨性别者科学:关于孕激素在乳房发育过程中有何潜在作用及影响的随笔

原名:Considerations in Understanding the Possible Role and Influence of Progestogens in Terms of Breast Development
原作者:Aly
译者:Bersella AI
原文首次发表于:2020 年 2 月 14 日
原文修订于:2023 年 5 月 15 日
翻译于:2023 年 11 月 2 日
原文出处:https://transfemscience.org/articles/progestogens-breast-dev/
译文存档:https://tfsci.mtf.wiki/zh-cn/articles/progestogens-breast-dev/
关键词:孕激素, 醋酸环丙孕酮, 醋酸甲羟孕酮, 黄体酮, 乳房发育

译者按

  1. 孕激素是会促进、还是会抑制乳房发育?过早暴露于孕激素会导致乳房发育不良吗?本文尝试梳理孕激素的作用,提供建设性见解。
  2. 特别提示:本系列译文优先于 Project Trans 旗下平台发表或修订,在 Limonnur 可能会延后数日更新,也可能不会同步。不便之处,敬请谅解。

现有关于女性倾向跨性别者采用孕激素治疗后的乳房发育情况的研究汇总

截至撰稿时,仅有少数几项研究就孕激素——具备生物同质性孕酮,或形如醋酸甲羟孕酮(MPA)、醋酸环丙孕酮(CPA)的人工孕激素制剂——用于女性倾向跨性别者时对乳房发育的影响进行探讨。有的论文就孕激素用于女性倾向跨性别者时的乳房发育情况作了一定回顾,其中包括 Wierckx, Gooren, & T’Sjoen (2014) 以及 Reisman, Goldstein, & Safer (2019)

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,且要持续“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 对睾酮明显有抑制作用(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,即直径约达 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。而据研究者的自述,尽管乳房发育有所改善,但难以确认是否可归因于螺内酯或 MPA。此外,研究开始前对睾酮的抑制效果是不充分的,而后随研究指定的激素配方有所改善;无论 MPA 是否对乳房有直接的孕激素作用,该配方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 在其它著述中声称,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,如本文和他处所述,上述研究所存在的局限性使得其论点缺乏足够根据(Aly, 2019)

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。考虑到 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,这个说法并非空穴来风。但应当注意,该研究并未应用孕激素本身或对其研究。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,这项研究结果对于理解孕激素和乳房发育(之关系)的价值是存疑的。

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,以及非甾体类抗雄激素制剂(氟他胺或比卡鲁胺)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房增生。然而,这二者有一点不同:非甾体类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”发育、即发育不充分的乳腺小叶。该论文还指出,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行倾向。研究者总结认为,有必要使乳房暴露于孕激素,以达到组织学意义上的完全发育;对女性倾向跨性别者而言亦然,其乳腺组织需暴露于孕激素以便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。有鉴于此,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。

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口述,主观因素较大。
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 及其同行则对正平稳接受激素治疗的女性倾向跨性别者加用低剂量口服微粉化孕酮,并就该形式的孕酮对乳房发育的短期影响进行研究(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 阶段无统计意义的差异(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, 2018)。因此,在这项研究以及 Igo & Visram (2021) 的研究中,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。

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外围测量手段(如乳房体积乳房—胸部高差、乳房罩杯和乳房半围等);但因缺乏各组之间的比较,故本章节不作赘述。([下文]({{< ref “#breast-development-with-cyproterone-acetate-in-transfeminine-people” >}})对其作了简要探讨。)无论如何,从这批研究的结果可以发现,女性倾向跨性别者的乳房发育大多不良,这令人遗憾。

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)以评价乳房发育情况,治疗时长过短,样本规模过小,等等。由此,以上研究中互相矛盾的结论或许都有了解释。
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。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(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。

所幸,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进行。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进行的,有关口服孕酮用于激素治疗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进行的,有关口服孕酮用于激素治疗的多项前瞻性 观察性研究以及一项随机对照试验(University of Melbourne; University of Melbourne)
  3. 由 Ada Cheung 及其同行于澳大利亚墨尔本进行的,有关雌二醇—螺内酯复方和雌二醇—CPA 复方之对比的一项随机对照试验(ANZCTR; WHO ICTRP; Trans Health Research [传单] [海报]; University of Melbourne)
  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)进行的,有关不同剂量的口服孕酮用于激素治疗的一项大型随机对照试验(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很大问题(Aly, 2018)。不过,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)

女性正常青春期内的孕酮及其在乳房发育过程中的作用

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。顺性别女孩平均会经历 3~4 年的青春期,但大部分女孩可能会经历 2~6 年。在有排卵月经周期开始前,孕酮一般维持于低位。初潮——即第一次月经和月经周期的开始——通常出现于 Tanner 四期,但也有相当一部分女孩在 Tanner 三期或五期(乳房发育完成时)经历初潮(Marshall & Tanner, 1969; Marshall, 1978; Hillard, 2007)。因此,相当一部分女孩在经历初潮或孕酮开始分泌之前便已达到 Tanner 五期(乳房发育完成);这表明对一部分女孩而言,孕酮并非使乳房达到 Tanner 五期的必要条件。整个乳房发育过程平均持续约 3.5 年,其中 Tanner 四期平均持续 2.5 年。综上,在女性正常青春期当中,孕酮分泌是相对较晚的事件之一(Marshall, 1978; Begley, Firth, & Hoult, 1980; Drife, 1986)

在青春期,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,月经周期大多无排卵(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(格氏囊)不会破裂形成黄体,从而不会开始孕酮的分泌。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)。有多项研究提供了青春期不同发育阶段或年龄的孕酮水平,显示出在此期间的孕酮暴露之低(例如 Sizonenko, 1978 [图表]; Lee, 2001 [表格]; Aly, 2020)

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,并一直持续到青春期结束之后;一部分女孩在孕酮分泌开始前便已完成乳房发育。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。

动物中孕酮和乳腺发育的关系

动物青春期乳腺发育

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)。但截然不同的是,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并无实际差异(Ismail et al., 2003)。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; 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)。然而,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,故而有观点认为,孕酮在小鼠的青春期乳腺发育过程中是可有可无的(Ismail et al., 2003)

* 译者注:原文为 rice(大米),或为笔误。

乳腺结构和乳腺小叶容积

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。乳房主要由两种组织构成:一是上皮组织,包含导管和小叶/小泡等,是实际意义上的乳腺组织;二是间质组织,包括结缔组织、脂肪组织等。小泡/小叶发育则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。
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)。具体而言,一项研究结果显示,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)。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)
但在妊娠和泌乳期间,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泌乳期间,乳房大部分由乳腺组织构成;一项针对泌乳妇女的研究中,乳腺组织构成了其乳房的 63%(范围 46~83%)(Ramsay et al., 2005)
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。同时,由孕激素介导的乳腺小叶增长对于乳房体积的重要性并不明确,尚且存疑(Wierkcx, Gooren, & T’Sjoen, 2014)

完全性雄激素不敏感综合征、孕酮和乳房发育的关系

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 Prior, 2011; Prior, 2019a; Prior, 2020)。在跨性别网络社群中也有人认为,对于患有完全性雄激素不敏感综合征(CAIS)的顺性别女性,因无孕酮分泌,其乳房发育停滞于 Tanner 四期,乳房“如锥形”。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,也无证据表明其对于达到 Tanner 五期和乳房的丰满是有益的。另外,以上观点和多份文献和证据南辕北辙,其中也包括 CAIS 女性本身。

CAIS 是指妇女的核型为 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。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、但足够多的雌二醇,以及极低的孕酮分泌和孕酮水平。
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女性化。CAIS 女性的生殖系统和发育不良的男性类同,其有睾丸而无卵巢、子宫和输卵管。其阴道通常偏浅,内端闭合,无宫颈,这与子宫的缺失相关。

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“丰满撩人(voluptuous)”(Morris, 1953; Hertz et al., 1966; Valentine, 1969; Adams et al., 1970; Polani, 1970; Weisberg, Malkasian, & Pratt, 1970; Dewhurst, 1971; Perez-Palacios & Jaffe, 1972; Glenn, 1976; Dewhurst & Spence, 1977; 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, 2017)
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)并将该症状描述为“有睾丸的女性化”(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)。在他著名的 1953 年评述中还提到,她们的乳房“和正常女性一致,大多趋于过度发育”(Morris, 1953)。但实际上,有的 CAIS 女性乳房偏大,有的则偏小(Wisniewski et al., 2000);我们尚无明确资料证明其乳房体积是否确实大于平均水平。
从 CAIS 女性观察到的乳房发育之差异,和在一般原生妇女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评述所附 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。

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/乳头常被描述为“稚嫩(juvenile)”——或相对“小”“颜色浅”(例如此照片(见于 Morris, 1953; Morris & Mahesh, 1963; Khoo & Mackay, 1972; Perez-Palacios & Jaffe, 1972; Dewhurst & Spence, 1977; 等等)。这可能是因为 CAIS 女性的雌二醇水平平均仅有 35 pg/mL 左右(表格),而雌激素可引导乳头、乳晕增大和色素沉积,且与剂量相关(Davis et al., 1945; Kennedy & Nathanson, 1953)。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。

此外,CAIS 女性的乳房并非仅可发育到 Tanner 四期;其会像正常女性一样达到 Tanner 五期(Quigley, 1988; Quigley et al., 1995; Fortner, 2007; Cheikhelard et al., 2008; Ramos et al., 2018)。以下为相关文献的摘录(Quigley et al., 1995)

患有完全性[雄激素不敏感综合征(AIS)]的个体在青春期有较佳的女性化效果,乳房发育正常或偏大,面色光滑、无痤疮。乳房和身形的女性化是在无雄激素抑制的情况下,对雌激素反馈的结果(雌激素主要源自睾丸,少量源自外周雄激素的芳香化)。……
在所有类型的 AIS 中,均可见乳房发育,程度介于轻度男性乳房增生和完全的 Tanner 五期女性乳房之间,且 AIS 程度越高,乳房发育越趋于明显。

这里“程度更高的 AIS”是指 CAIS,即此类综合征的完全形态,和不完全(部分轻度表征)的雄激素不敏感综合征(AIS)相对(Quigley, 1988)。这是一种谱系疾病,只有“程度最高”的 CAIS 患者会对雄激素经受体介导的作用完全不敏感,也只有她们会有完全女性化的身体。不过,即使是部分性雄激素不敏感综合征(PAIS)也会让患者有相当程度的乳房发育(例如 Saito et al., 2014; Lee et al., 2015)

如上文所述,之所以提及 CAIS 女性,是因为其睾丸不能分泌孕酮,从而使得孕酮水平非常低、以至可忽略不计(<2 ng/mL)(表格; Barbieri, 2017)。CAIS 女性相关的证据表明,——当下这可能是现有证据中最有说服力的一种——要达到正常或完全的乳房发育效果,是无需孕酮参与的(Barbieri, 2017)

作为大自然的一次基因实验,雄激素不敏感综合征 为雌激素和雄激素对于乳房增长之调节的重大相互作用提供了一种临床参考。38 遗传学男性(46,XY)在雄激素受体(AR)突变导致雄激素不敏感的情况下,体内 AR 无一可正常工作;尽管睾丸可产生睾酮,但其靶组织无法对较高水平的循环雄激素做出响应。此类综合征患者的循环雌二醇浓度约为 50 pg/mL,相当于女性卵泡早期的水平。 雄激素不敏感个体的乳房体积通常高于平均水平。 这表明,在雄激素完全失去抑制作用的情况下,中等水平的雌二醇足以引起明显的乳房增长。在无 AR 的个体中,孕酮水平处于低位;这表明乳房体积并不一定依赖于孕酮的刺激作用。

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)。这可能与孕酮的缺乏有关,因为孕酮会参与乳腺小泡/小叶的发育成熟。值得一提的是,一般妇女群体中的乳房大部分由间质脂肪和结缔组织构成(约 80~90%),而非乳腺组织(10~20%)(维基百科);此外,当乳腺小泡/小叶发育时(例如妊娠期间),其会取代间质组织(Alex, Bhandary, & McGuire, 2020)。因此,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。
还有,尽管乳房发育良好,但 CAIS 女性从未有任何乳腺癌报告(Aly, 2020a; Aly, 2020b)。这可能和以下因素有关:1) 缺乏孕酮;2) 乳腺小泡/小叶未发育成熟;3) 缺少第二条 X 染色体(Aly, 2020a; Aly, 2020b)

孕激素早期暴露和乳房发育不理想的潜在关系

已有文献指出,孕激素早期、过早暴露可能导致乳房发育不理想。动物研究发现,在高剂量下,孕酮、醋酸氯地孕酮(一种和 CPA 有高度联系的人工孕激素)等孕激素的早期/过早暴露会使得兔的乳房发育不理想,但低剂量下则不然(Lyons & McGinty, 1941; Beyer, Cruz, & Martinez-Manautou, 1970)
除动物研究外,已有多份临床著述警告称,顺性别女孩和女性倾向跨性别者早期/过早暴露于孕激素,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可于此处查阅。与此相关,对青春期推迟的女孩进行青春期诱导治疗时,孕激素仅当在以雌激素治疗约 2~3 年之后才加入,此时一般认为乳房发育趋于完成。

然而,不同物种的乳腺发育和对激素的反馈是有差异的;对于诸临床著述的观点,尚无任何实打实的数据或证据可以证实。因此,尚不清楚人类早期暴露于孕激素是否会导致乳房发育不理想。另外,即使这是真的,所需孕激素暴露量之多少也不清楚。不过,有多个研究领域是和这个问题相关的,包括:孕激素在乳房中表达的抗雌激素作用;临床研究中,雌激素和 CPA(一种强效孕激素)用于女性倾向跨性别者时对乳房发育之影响;病例报告中,孕激素用于治疗顺性别妇女乳房肥大;理论上,缺乏 17α-羟化酶/17,20-裂解酶的顺性别女孩乳房发育不良可能和较高的孕酮暴露有关;等等。下面会对此做详细讨论。

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,孕激素似乎也有抗雌激素作用(Mauvais-Jarvis, Kuttenn, & Gompel, 1986; 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)。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。

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,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)。在有关雌激素和 CPA 用于女性倾向跨性别者的研究中,乳房发育往往不甚理想(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; de Blok et al., 2020; Meyer et al., 2020)。然而,女性倾向跨性别者或许只是普遍有不良的乳房发育,而不一定与 CPA 或孕激素暴露有关。事实上,在一项研究中,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)
有一项关于雌二醇—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的研究,目前正在澳大利亚进行;其有望为这个问题提供更多见解(ANZCTR)

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录(Sperling & Gold, 1973; Boyce, Hoffman, & Mathes, 1984; Ryan & Pernoll, 1985; 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,地屈孕酮和 MPA 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,故难以从这批报告得出可靠的结论。

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;同时,高孕酮水平的早期暴露被猜测是仅次于此状况的原因(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。

另见

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2023 年 11 月 2 日 初次翻译。
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