--- title: 比卡鲁胺在女性化激素治疗方面的使用状况，以及医学界对其的接受情况 linkTitle: 比卡鲁胺在女性化激素治疗上的使用与接受情况 description: 比卡鲁胺尚未得到充分研究，其安全性也令人堪忧，使用范围仍很有限。 author: Aly published: 2020-07-01 updated: 2022-11-08 translated: 2022-11-14 translators: - Bersella AI tags: - 比卡鲁胺 - 抗雄激素制剂 - 用药安全 trackHash: fdd701930bcb4e0f6f2c2ca8df31b80ae016e9a0 --- ## 译者按 {#notice} 1. **⚠ 免责声明：本文不构成任何医疗、处方建议。 如有医疗需要，应于专业医师指导下进行。** 1. 以下《指南》《跨性别……指南》等应当皆指代同一事物，原文如此。 1. 因译者能力所限，部分术语之翻译或有纰漏，烦请指正。 --- ## 摘要 {#abstract} > 比卡鲁胺是一种抗雄制剂，多年前其被推出时曾用于前列腺癌的治疗；但多年来，其因价格昂贵，未被推广至其它用途。不过，其价格已有所下降，现正广泛用于女性化激素治疗、以及其他群体（如顺性别妇女）由雄激素引起的症状的治疗上。\ > 比卡鲁胺存在一些风险，例如肝毒性等罕见的不良反应；这引起了对其安全性的担忧，从而限制了其在女性倾向跨性别者当中的使用。不过，在恰当的监测与临床管理下，这些风险相对较低——尽管仍很显著。最近，跨性别医学方面的一些著名学者，对比卡鲁胺在女性倾向跨性别者上的使用持开放态度，在其著述中亦对此做积极评价。\ > 比卡鲁胺也许会逐渐被认为在女性化激素治疗当中足够安全，就像螺内酯、醋酸环丙孕酮等风险很低的抗雄制剂一样；但是，在其被跨性别医学广泛接受前，可能还需更多的有关女性倾向跨性别者使用比卡鲁胺的研究与描述。 ## 女性倾向跨性别者使用比卡鲁胺的历史 {#history-of-bicalutamide-for-transfeminine-people} 比卡鲁胺（Casodex 品牌）是一种非甾体类抗雄制剂和选择性雄激素受体拮抗剂；最初在 1995 年推出时，其用于顺性别男性治疗前列腺癌。前列腺癌由雄激素引起，因此可被抗雄制剂治疗。相比于螺内酯（Aldactone 品牌）与醋酸环丙孕酮（Androcur 品牌）等抗雄制剂，在雄激素拮抗效力、临床疗效、药理选择性和可耐受度等方面，比卡鲁胺具有显著优势。而相较早期的非甾体类抗雄制剂（如氟他胺，Eulexin 品牌；尼鲁米特，Anandron 品牌），比卡鲁胺则有更好的效力、药代动力学特性以及可耐受度，安全性也大大提高。不过，直到最近，比卡鲁胺才作为抗雄制剂用于女性化激素治疗。\ 之所以多年来比卡鲁胺未被广泛用于女性倾向跨性别者，是因为比卡鲁胺曾受制药厂专利的保护，价格亦十分昂贵。不过，从 2007 至 2009 年开始出现的比卡鲁胺仿制品，改变了这一事实。此后，陆续推出的醋酸阿比特龙（Zytiga 品牌，在 2011 年）、恩杂鲁胺（Xtande 品牌，在 2012 年）等抗雄制剂具有更高效力，因而取代了比卡鲁胺，成为前列腺癌的标准治疗用药。新药的研发使得近十年内比卡鲁胺的价格大幅下降，而逐渐变得可以承受。 2015 年以前，只有极少的文献(见[相关文献一页][alyw19_lit])和一些网络传闻提到了女性倾向跨性别者使用比卡鲁胺。2011 年，Louis Gooren 率先在有关女性化激素治疗的文献中明确提及比卡鲁胺([Gooren, 2011][g11]; [Aly, 2019][alyw19_lit])。Gooren 其人是跨性别医学领域的主要资深学者之一，曾参与美国内分泌学会《跨性别激素治疗指南》的编纂([Hembree et al., 2009][h09]; [Hembree et al., 2017][h17])。1980 年代末到 1990 年代初，在阿姆斯特丹自由大学医学中心（VUMC）的性别焦虑专家中心，Gooren 及其同行开展了有关尼鲁米特（Anandron、Nilandron 品牌）作为抗雄制剂用于女性倾向跨性别者的研究([de Voogt et al., 1987a][v87a]; [de Voogt et al., 1987b][v87b]; [Gooren et al., 1987][g87]; [Johannes et al., 1987][j87]; [Rao et al., 1988][r88]; A[sscheman, Gooren, & Peereboom-Wynia, 1989][agp89]; [van Kemenade et al., 1989][k89]; [维基百科][wiki_nilu])。不过，他们后来似乎放弃了尼鲁米特的研究；这可能出于其肺毒性发生率高、以及其它因脱靶效应带来的副作用之缘故。尽管如此，从 1990 年代开始，Gooren 还是在其发表的资料中将氟他胺与尼鲁米特纳入到可用于女性化激素治疗的潜在选项当中([Asscheman & Gooren, 1992][ag92]; [Gooren, 1999][g99]; 见[相关文献][alyw19_lit])；也正因如此，氟他胺被一些《跨性别健康指南》及其它出版物收录了，不过评价并不大积极(例如 [Israel & Tarver, 1997][it97]; [Levy, Crown, & Reid, 2003][lcr03]; [Dahl et al., 2006a][d06a]; [Dahl et al., 2006b][d06b]; Hembree et al., 2009; [Moreno-Pérez et al., 2012][mp12])。作为一名对女性倾向跨性别者使用的非甾体类抗雄制剂感兴趣的学者，Gooren 本应对安全性远胜于氟他胺与尼鲁米特的比卡鲁胺引起注意；但是 Gooren 及其同行从未进行有关比卡鲁胺用于女性倾向跨性别者的研究，在其发表的资料中也仅仅简单提及了这项用途。其他学者亦皆如是。 除了用于女性倾向跨性别者和患有前列腺癌的男性之外，比卡鲁胺还被研究用于治疗其他人群中由雄激素引起的症状。例如，其被用于治疗顺性别妇女的多毛症；部分人患有多囊卵巢综合征，其余则没有([Müderris, Bayram, & Güven, 1999][mbg99]; [Müderris et al., 2002][m02]; [Bahceci et al., 2004][b04]; [Müderris & Öner, 2009][mo09], [PDF][mo09_pdf], [英语译文][mo09_eng]; [Moretti et al., 2016][m16]; [Moretti et al., 2018][m18]; [维基百科][wiki_use_bica_s])。\ 比卡鲁胺还被研究了结合阿那曲唑（Arimeidex 品牌；一种芳香化酶抑制剂）用于顺性别男孩的非促性腺激素相关性早熟的治疗上([Kreher et al., 2006][k06]; [Lewis et al., 2009][l09]; [Mitre & Lteif, 2009][ml09]; [Stenger et al., 2009][s09]; [Lenz et al., 2010][l10]; [Reiter et al., 2010][r10]; [Tessaris et al., 2012][t12]; [Özcabı et al., 2015][o15]; [Kor, 2018][k18]; [Arya & Davies, 2019][ad19]; [Nabhan & Eugster, 2019][ne19]; [Finkle et al., 2020][f20]; [Gurnurkar, DiLillo, & Carakushansky, 2021][gdc21]; [维基百科][wiki_use_bica_m])。此类性早熟很罕见，其中促性腺激素释放激素（GnRH）调节机制失去了作用。在美国，这种比卡鲁胺结合阿那曲唑的特定疗法已完成了二期临床试验，并提交了新药申请，但未获通过；原因是在主要疗效终点——限制身高上之效果的证据尚不充分([AstraZeneca, 2008][az08])。不过，尽管在适应症之外，比卡鲁胺仍被用于该疗法；而在经美国食品药品监管局（FDA）批准的 Casodex 药品标示中，亦提及了比卡鲁胺的这项用途([FDA, 2017][fda17])。 到了 2015 年中，比卡鲁胺在女性倾向跨性别者当中的使用和相关讨论稀少的事实，开始有了改变。维基百科上有关比卡鲁胺的内容，从最基本的页面逐步扩充了起来；现在有了更丰富的用药信息。此外，在网络圈子里，一些女性倾向跨性别者开始提倡本群体使用比卡鲁胺——例如正叙述其较之于现成选项的优势、以及其用于女性化激素治疗的优良潜力的笔者。\ 今后一段时间里，许多开明的医务工作者，都开始接纳比卡鲁胺用在女性倾向跨性别者上。其中，最早的一项对女性倾向跨性别者使用比卡鲁胺的临床研究，开始于 2013 年；其论文摘要于 2017 年发表，全文则于 2019 年发表([Neyman, Fuqua, & Eugster, 2017][nfe17]; [Neyman, Fuqua, & Eugster, 2019][nfe19])。该研究是一项规模较小的回顾性图表总结，针对的是比卡鲁胺作为二线青春期阻断剂用于跨性别女孩——其保险拒绝给付其 GnRH 类似物的费用。目前为止，该研究仍为在比卡鲁胺用于女性倾向跨性别者方面的唯一数据来源。虽然从各方面而言，其数据并不出色，但起码还算正规。该研究的发起者早前还发表了有关患有非促性腺激素相关性早熟的男孩们使用比卡鲁胺作为青春期阻断剂的论文(例如 [Lenz et al., 2010][l10]; [Haddad & Eugster, 2012][he12])。Neyman, Fuqua 和 Eugster (2019) 的发现——尽管资料有限——有助于让医务工作者和学者对比卡鲁胺在女性化激素治疗当中的应用产生浓厚的兴趣。 无论如何，在当下，比卡鲁胺尚未在女性倾向跨性别者当中被广泛采用；这是因为，比卡鲁胺成为女性化激素治疗的一种选项的时间还不太久，而且关于女性倾向跨性别者使用之的研究与描述还很稀缺，其安全性亦引起担忧。事实上，《跨性别激素治疗指南》亦普遍未曾对此有过提及。目前，比卡鲁胺的使用基本上局限于一些思想更灵活的医务工作者、以及自行安排跨性别激素治疗用药（DIY）的人群里。 ## 一些和比卡鲁胺有关的，限制了其使用率的担忧 {#concerns-about-bicalutamide-limiting-its-use} 目前为止，跨性别医学界并不大愿意认可比卡鲁胺在女性倾向跨性别者的使用。这是因为，关于女性倾向跨性别者使用之的研究与描述还很稀缺，尤其是在安全性方面。有一些担忧是和患有前列腺癌的男性当中由比卡鲁胺引起肝衰竭的罕见案例相关的。这些有关比卡鲁胺之肝毒性的已报告病例，一般发病很突然、且症状严重。对患有前列腺癌的男性而言，比卡鲁胺治疗其癌症的收益远大于概率极低的肝毒性之风险，因此这种风险足可容忍。不过，对一般既年轻而又健康的女性倾向跨性别者而言，比卡鲁胺并非用于治疗绝症；一旦因其患上肝衰竭而亡，那便得不偿失了。也正因如此，加州大学旧金山分校（UCSF）版《跨性别护理指南》警告，出于潜在肝脏风险的考虑，当下不应将比卡鲁胺用于女性倾向跨性别者([Deutsch, 2016][d16])。\ 除了风险以外，目前还缺少可供指导适合女性倾向跨性别者使用的比卡鲁胺剂量之数据([Aly, 2019][alyw19_dose])。目前普遍推荐使用的典型剂量，是 50 mg/天，但该剂量应该是缺少数据支持的情况下的主观臆断。 目前为止，已有 10 例和比卡鲁胺有关的严重肝毒性病例被报告([图表][table_2a])。这些病例皆为患有前列腺癌的男性，且皆在开始比卡鲁胺疗法的六个月内发病，其中两例随后死亡。尽管这些病例不多，看上去多少令人安心，但需要注意，已报告的不良反应病例数往往远低于其实际发生率。例如，对于醋酸环丙孕酮，迄今有大约 50 例脑膜炎病例被报告；但法国政府在近期的一项大规模研究发现，仅在法国就有超过 500 例和持续服用超过 8 年的高剂量醋酸环丙孕酮相关的脑膜炎病例*进行了手术*([Aly, 2020][alyw20_meni])。相应地，截至撰稿时，在美国 FDA 的国际 [MedWatch/FAERS 数据库][faers]当中，共有 40 例和比卡鲁胺相关的肝衰竭病例，其中 25 例死亡；还有 240 例与其相关的肺间质病变病例，而已报告的只有 14 例([表格][table_2b])。但据估计，该数据库也仅报告了不足 10% 的严重不良反应现象([Graham, Ahmad, & Piazza-Hepp, 2002][gap02])。因此，实际病例数可能远大于此。这些案例不过出于巧合：迄今尚未确认比卡鲁胺和肝毒性之间是否存在因果关系。尽管如此，它们还是引起了不小担忧。传闻还有一件和比卡鲁胺相关的女性倾向跨性别者死亡病例，尽管不曾公开发表，但已在跨性别医学界当中口口相传。根据在跨性别医学领域的几位可靠人士所言，该病例是一名住在德克萨斯州的 20 岁跨性别女孩，服用比卡鲁胺后出现急性肝衰竭，且事前无任何征兆。该病例促使一些关注比卡鲁胺的医务工作者和学者，对比卡鲁胺在女性倾向跨性别者激素治疗中的使用，作出了保留意见。 无论如何，这名女性倾向跨性别者的病例从未被公开发表、并确认属实。此外，和比卡鲁胺相关的肝毒性绝对发生率可能非常低。例如，在一次包含 4,000 名病人的三期随机对照试验中，肝功能检测结果异常（即血浆肝转化酶含量偏高）的发生率，在单服高剂量比卡鲁胺（150 mg/天）组别和安慰剂组别上分别仅有 3.4% 和 1.9% ——也即，比卡鲁胺在其中贡献了 1.5%([Anderson, 2003][a03]; [Iversen et al., 2004][i04])。还有，在一次严苛的将比卡鲁胺用于前列腺癌的临床试验中，超过 8,000 名男性无一出现严重肝毒性或肝衰竭([Blackledge, 1996][b96]; [Kolvenbag & Blackledge, 1996][kb96]; [McLeod, 1997][m97]; Anderson, 2003; Iversen et al., 2004)；不过，该试验对每名病人的肝功能皆做了细致监测，一旦检测到肝功能出现临床上足可引起担忧的异常情况，即要求其停止服用比卡鲁胺。该试验中，这些男性每日服用 50-150 mg 的比卡鲁胺，其中约 0.5-1.4% 的人产生了肝功能病变，随即停药(Blackledge, 1996; [See et al., 2002][s02])。故此，为避免出现严重肝毒性的可能，服用比卡鲁胺的人需要定期监测肝功能。 在肝毒性风险上，比卡鲁胺远低于其类似物氟他胺(Kolvenbag & Blackledge, 1996; [Schellhammer et al., 1997][s97]; [Thole et al., 2004][t04]; [Manso et al., 2006][m06]; [表格][table_2c])；不过，其仍保有微弱的肝毒性风险——还可能附带严重并发症。故此，有必要谨慎使用之，每个服用它的人都需要注意监测肝功能。 ## 近期进展及未来展望 {#recent-developments-and-the-future} 比卡鲁胺在顺性别妇女改善和雄激素相关的皮肤及体毛状况上的使用，正被逐渐接受并加以描述。例如，在意大利进行的、有关比卡鲁胺用于多毛症的一项严谨的三期随机对照试验，近期已被公开发表([Moretti et al., 2018][m18])。此外，一项有关比卡鲁胺用于顺性别妇女脱发的回顾性图表总结，业已于近期公开发表([Fernandez-Nieto et al., 2019][fn19]; [Ismail et al., 2020][i20]; [Fernandez-Nieto et al., 2020][fn20]; [Moussa et al., 2021][m21])。这些有关体毛的研究发现了使用比卡鲁胺后的较低、但显著的肝功能病变发生率。 一些跨性别医学研究者也对比卡鲁胺产生了兴趣([Aly, 2019][alyw19_lit])。其中可能尤其要关注的是，美国内分泌学会 2009、2017 年版《跨性别激素治疗指南》(Hembree et al., 2009; Hembree et al., 2017)的领衔作者：Wylie Hembree，在近期的评述中对比卡鲁胺用于女性倾向跨性别者做了积极评价([Fishman, Paliou, Poretsky, & Hembree, 2019][fpph19])。Hembree 及其同行提到了近期有关比卡鲁胺用于顺性别妇女多毛症的三期试验，以及有关比卡鲁胺作为青春期阻断剂用于跨性别女孩的研究，以支持将其用于女性倾向跨性别者的可能性。\ 另一位在跨性别医学领域的主要学者、美国内分泌学会版《指南》(Hembree et al., 2017; [Mitchell, 2020][m20])的联名作者：Guy T’Sjoen，在一篇与其同行创作的评述里，似乎也对比卡鲁胺持开放态度([Iwamoto et al., 2019][i19])。特别是在美国以外的学者，对比卡鲁胺的态度可能更开放，这归功于醋酸环丙孕酮——在美国以外使用最广泛的一种抗雄制剂——长期使用后引起的健康顾虑([Aly, 2020][alyw20_meni])。密歇根州立大学的学者：John Randolph，同样对比卡鲁胺作出了积极评价([Randolph, 2018][r18])，不过此后他似乎改变了他的观点([Michigan Medicine, 2020][mm20])。而另一方面，其他学者并不那么欢迎比卡鲁胺在女性倾向跨性别者当中的使用(例如 [Hamidi & Davidge-Pitts, 2019][hdp19]; [Cocchetti et al., 2020][c20])。 只要给以适当的健康监测，比卡鲁胺较低的风险应可为跨性别医学界所接受。这种情况就跟有极低的严重不良反应发生率的其它药品一样：诸如螺内酯（高钾血症），醋酸环丙孕酮（良性脑膜瘤、血栓、乳腺癌、肝毒性），等等。考虑到其风险，比卡鲁胺可能最终不会被推荐用于一线治疗。不过，如果其它抗雄制剂的可行性因为某些缘故（例如，未按预期起效、耐受度低、有禁忌症、无法获取等）而变得更低、以至不具备，那么比卡鲁胺可作为二线治疗的一种选项。跨性别医学界做的还不够。在比卡鲁胺可被女性倾向跨性别者广泛接纳、或者为《跨性别激素治疗指南》所广泛推荐之前，可能需要更多的相关进展才行——也即，对真正的女性倾向跨性别者使用比卡鲁胺进行研究并加以描述。 ## 后记 {#updates} ### 后记一 {#update-1} 2021 年 3 月，芬威健康版《跨性别健康临床实践指南》自 2015 年 10 月以来首次获得更新([Aly, 2020][aw20-guide])： - Thompson, J., Hopwood, R. A., deNormand, S., & Cavanaugh, T. (2021). Medical Care of Trans and Gender Diverse Adults. Boston: Fenway Health. [[网址][t21]] [[PDF文档][t21_pdf]] 之所以提及此次更新，是因为该《指南》将比卡鲁胺列为女性倾向跨性别者的抗雄制剂选项之一。尽管该《指南》出于有关比卡鲁胺用于女性倾向跨性别者的描述有限、以及其微弱的肝毒性风险之缘故，并未推荐其作为一线用药；但允许了在女性化激素治疗当中谨慎使用之： > （在性别肯定激素治疗中，）是可以使用比卡鲁胺的；不过当下只有极个别研究考察了其在此情况下之使用以及相关联的风险/收益。考虑到已有暴发性肝炎病例报告，当下的共识是：将其纳入性别肯定激素治疗方案应当非常谨慎；只有当其替代选项皆已尝试或提供，并且充分讨论了其潜在风险之后，方可予以纳入。 这是第一份允许使用比卡鲁胺的《跨性别护理指南》，也是第二份纳入了比卡鲁胺的《指南》——首次纳入的是 UCSF 版《指南》，但其并不允许女性倾向跨性别者使用它。 在他处亦提供了从芬威健康版《指南》节选的有关女性倾向跨性别者使用比卡鲁胺的内容——还包括了对其安全性之监测的建议([Aly, 2019][alyw19_lit_t])。 ### 后记二 {#update-2} 2021 年 9 月，南非洲艾滋病医师协会（SAHCS）首次发表了针对跨性别护理的《临床指南》： - Tomson, A., McLachlan, C., Wattrus, C., Adams, K., Addinall, R., Bothma, R., Jankelowitz, L., Kotze, E., Luvuno, Z., Madlala, N., Matyila, S., Padavatan, A., Pillay, M., Rakumakoe, M. D., Tomson-Myburgh, M., Venter, W., & de Vries, E. (2021). Southern African HIV Clinicians’ Society gender-affirming healthcare guideline for South Africa. Southern African Journal of HIV Medicine, 22(1), a1299. [DOI:[10.4102/sajhivmed.v22i1.1299][sahiv21]] [[PDF文档][SAHIV21_PDF]] 令人惊异的是，该《指南》不仅纳入了比卡鲁胺，而且其推荐作为抗雄制剂的程度更甚于螺内酯与醋酸环丙孕酮。对于原因，其写道：“损耗神经类固醇的风险更低，因其并不易穿过血脑屏障”。不过，此效应并非除 5α-还原酶抑制剂以外的抗雄制剂所引起的已知顾虑之一；而事实上，比卡鲁胺的确能够渗透到人体的神经中枢([维基百科][wiki_pc_bica_d])。此外，该《指南》并未提及和比卡鲁胺相关的肝毒性或肝转化酶监测，这同样令人惊异。考虑到以上疏忽及其它因素，应当对其之推荐作谨慎说明。 本站在他处亦提供了从该《指南》节选的有关女性倾向跨性别者使用比卡鲁胺的内容([Aly, 2019][alyw19_lit_sahiv])。 ### 后记三 {#update-3} 2022 年 9 月，[世界跨性别人士健康专业协会][wpath]（WPATH）发布了第八版《[跨性别及性别多元化人群健康护理标准][soc8]》（SOC8）([Coleman et al., 2022][c22])。该《标准》是现有最权威的跨性别护理指南之一，由健康护理专家担任顾问。此指南在以下两个片段中简要讨论了比卡鲁胺： > 比卡鲁胺是一种抗雄制剂，用于治疗前列腺癌。其竞争性结合于雄激素受体，从而阻止雄激素与受体结合。有关比卡鲁胺用于女性倾向跨性别群体的数据非常稀少，其安全性资料也很缺乏。有一项小型研究探索了将 50 mg/天的比卡鲁胺作为青春期阻断剂，用于 23 名无法获得 GnRH 类似物治疗的青少年女性倾向跨性别者(Neyman et al., 2019)。这 23 人均发生了乳房发育——这与接受比卡鲁胺治疗的前列腺癌患者的普遍现象一致。\ > 比卡鲁胺已被指出可引起罕见的暴发性肝中毒，并导致死亡(O’Bryant et al., 2008)。考虑到比卡鲁胺用于女性倾向跨性别者的情况尚未得到充分研究，我们并不推荐其用于常规治疗。 > 在药物的选择上，我们建议采用已被研究用于多名跨性别者的药物（如雌激素、醋酸环丙孕酮与 GnRH 激动剂），而非鲜少或从未经过有同行评议的科学研究的药物（如比卡鲁胺、直肠给药的孕酮等）(Angus et al., 2021; Butler et al., 2017; Efstathiou et al., 2019; Tosun et al., 2019)。 如上文所述，由于缺乏相关研究、且有潜在风险，《标准》并未建议将比卡鲁胺用于女性倾向跨性别者的常规治疗。本文也已提到，在比卡鲁胺得到主流《跨性别护理指南》的认可之前，可能还需要更多研究探索其用于女性倾向跨性别者的情况。 ## 参考文献 {#references} - Anderson, J. 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