transfeminine-science/content/articles/bica-adoption.md

---
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: 2024-04-06
translated: 2024-10-18
translators:
  - Bersella AI
tags:
  - 比卡鲁胺
  - 抗雄激素制剂
  - 用药安全
trackHash: c17ddbc53fcd09bfbdc87887cbb4dd94e778dc48
keywords: [比卡鲁胺, 抗雄激素, 激素治疗, 安全性]
aliases: /articles/bica-adoption
---

## 译者按 {#notice}

1. **<u>⚠ 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。</u>**
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][wiki1]（Casodex 品牌）是一种[非甾体类抗雄制剂][wiki2]和[雄激素受体][wiki3]的[选择性拮抗剂][wiki4]；最初在 1995 年推出时，其用于顺性别男性治疗[前列腺癌][wiki5]。前列腺癌[由雄激素引起][wiki6]，因此可被抗雄制剂治疗。相比于[螺内酯][wiki7]（Aldactone 品牌）与[醋酸环丙孕酮][wiki8]（Androcur 品牌）等抗雄制剂，比卡鲁胺在[雄激素拮抗][wiki9] [效力][wiki10]、[临床疗效][wiki11]、[药理选择性][wiki12]和[耐受性][wiki13]等方面，具有显著优势。而相较早期的非甾体类抗雄制剂（如[氟他胺][wiki14]，Eulexin 品牌；[尼鲁米特][wiki15]，Anandron 品牌），比卡鲁胺则有更好的效力、[药代动力学][wiki16]特性以及耐受性，[安全性][wiki17]也大大提高。不过，直到最近，比卡鲁胺才被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][wiki18]（Zytiga 品牌，在 2011 年）、[恩杂鲁胺][wiki19]（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][wiki20-msc]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][wiki21] 率先在有关女性化激素治疗的文献中明确提及比卡鲁胺<sup>([Gooren, 2011][G11])</sup>。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][wiki22]《跨性别激素治疗指南》的编纂<sup>([Hembree et al., 2009][h09]; [Hembree et al., 2017][h17])</sup>。1980 年代末到 1990 年代初，在[阿姆斯特丹自由大学医学中心][wiki24]（VUMC）的[性别焦虑专家中心][wiki23]，Gooren 及其同行开展了有关[尼鲁米特][wiki15]（Anandron、Nilandron 品牌）作为抗雄制剂用于女性倾向跨性别者的研究<sup>([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][VK89]; [维基百科][wiki15-tht])</sup>。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][wiki25]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<sup>([Asscheman & Gooren, 1992][AG92]; [Gooren, 1999][G99])</sup>；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<sup>(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][H09]; [Moreno-Pérez et al., 2012][MP12])</sup>。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][wiki26]；部分人患有[多囊卵巢综合征][wiki27]（PCOS），其余则没有<sup>([Müderris, Bayram, & Güven, 1999][MBG99]; [Müderris et al., 2002][M02]; [Bahceci et al., 2004][B04]; [Müderris & Öner, 2009][MO09]; [Moretti et al., 2016][M16]; [Moretti et al., 2018][M18]; [维基百科][wiki28-shc])</sup>。\
比卡鲁胺还被研究了结合[阿那曲唑][wiki29]（Arimeidex 品牌；一种[芳香化酶抑制剂][wiki30]）用于顺性别男孩的[非促性腺激素相关性性早熟][wiki31]的治疗上<sup>([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][wiki28-mep])</sup>。此类[性早熟][wiki32]很罕见，此时[促性腺激素释放激素调节剂][wiki33]对其无效。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][wiki34-p2]临床试验，并提交了[新药申请][wiki35]，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<sup>([AstraZeneca, 2008][AZ08])</sup>。不过，尽管[在适应症之外][wiki36]，比卡鲁胺仍被用于该疗法；而在经[美国食品药品监管局][wiki37]（FDA）批准的 Casodex 药品说明书中，亦提及了比卡鲁胺的这项用途<sup>([FDA, 2017][FDA17])</sup>。

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][wiki1]的内容得到了大幅扩充；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讲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，并提倡本群体使用比卡鲁胺。\
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于女性倾向跨性别者的用途。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<sup>([Neyman, Fuqua, & Eugster, 2017][NFE17]; [Neyman, Fuqua, & Eugster, 2019][NFE19])</sup>。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][wiki38]用于跨性别女孩——其保险拒绝给付其[促性腺激素释放激素类似物][wiki39]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资料来源。虽然从各方面而言，其资料并不出色，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<sup>(例如 [Lenz et al., 2010][L10]; [Haddad & Eugster, 2012][HE12])</sup>。尽管资料有限，[Neyman, Fuqua 和 Eugster (2019)][NFE19] 的发现仍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（见下节）。事实上，现有跨性别激素治疗指南亦普遍未曾对此有所提及。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][wiki40]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][wiki41]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][wiki42]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][wiki43]（UCSF）编纂的跨性别护理指南警告称，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<sup>([Deutsch, 2016][D16])</sup>。\
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。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][wiki44]病例被公开发表<sup>([表格][table1])</sup>。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，已公开发表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 例脑膜炎病例被公开发表<sup>([表格][table2])</sup>；但法国政府在近期的一项大规模研究发现，仅在法国就有逾 500 例和持续服用 8 年以上的高剂量醋酸环丙孕酮相关的脑膜炎病例*进行了手术*<sup>([Aly, 2020][A20-CM])</sup>。\
与此对应，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[间质性肺炎][wiki45]病例，而已公开发表的只有 14 例<sup>([表格][table3])</sup>。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<sup>([Graham, Ahmad, & Piazza-Hepp, 2002][GAP02])</sup>。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（如 [Asa Radix][CL-AR] 和 [Zil Goldstein][CL-ZG]）所言，该病例是一名住在美国德克萨斯州的 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。\
还有一起未正式发表的病例，描述了一名年龄超 60 岁的跨性别者以比卡鲁胺治疗后发生肝衰竭，随后死亡<sup>([QueerDoc][QD])</sup>。

无论如何，以上有关跨性别者服用比卡鲁胺发生严重肝毒性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，在包含三次[三期][wiki34-p3] [随机对照试验][wiki50]、逾 8,000 名病人的[早期前列腺癌临床试验][wiki49]（EPC）中，跟踪三年后，[肝功能指标][wiki46]异常（即[肝转化酶][wiki47]的[验血][wiki48]结果偏高）的发生率在高剂量比卡鲁胺单药（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%<sup>([Anderson, 2003][A03]; [Iversen et al., 2004][I04]; [维基百科][wiki51-lt]; [维基百科][wiki49])</sup>。\
还有，在比卡鲁胺用于晚期前列腺癌的初步临床研发试验中，近 4,000 名男性无一出现严重肝毒性或肝衰竭<sup>([Blackledge, 1996][B96]; [Kolvenbag & Blackledge, 1996][KB96]; [McLeod, 1997][ML97]; [Anderson, 2003][A03]; [Iversen et al., 2004][I04]; [维基百科][wiki51-lt])</sup>；不过需要指出，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。\
在比卡鲁胺用于前列腺癌的主流临床试验中，这些男性每日服用 50–150 mg 的比卡鲁胺，其中约 0.5–1.5% 的人发生了肝功能病变，提示需要停药<sup>([Blackledge, 1996][B96]; [See et al., 2002][S02]; [维基百科][wiki51-lt])</sup>。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<sup>([Kolvenbag & Blackledge, 1996][KB96]; [Schellhammer et al., 1997][S97]; [Thole et al., 2004][T04]; [Manso et al., 2006][M06]; [表格][table4])</sup>；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，每个使用者都要注意监测肝功能。

## 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<sup>([Moretti et al., 2018][M18])</sup>。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<sup>([Fernandez-Nieto et al., 2019][FN19]; [Ismail et al., 2020][I20]; [Fernandez-Nieto et al., 2020][FN20]; [Moussa et al., 2021][M21])</sup>。这些有关脱发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。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》<sup>([Hembree et al., 2009][H09]; [Hembree et al., 2017][H17])</sup>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<sup>([Fishman, Paliou, Poretsky, & Hembree, 2019][FPPH19])</sup>。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。\
另一位跨性别医学领域的主要学者、美国内分泌学会版《指南》<sup>([Hembree et al., 2017][H17]; [Mitchell, 2020][M20])</sup>的联名作者：[Guy T’Sjoen][wiki52]，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<sup>([Iwamoto et al., 2019][I19])</sup>。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<sup>([Aly, 2020][A20-CM])</sup>。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<sup>([Randolph, 2018][R18])</sup>，不过此后他似乎改变了他的观点<sup>([Michigan Medicine, 2020][MM20])</sup>。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<sup>(例如 [Hamidi & Davidge-Pitts, 2019][HDP19]; [Cocchetti et al., 2020][C20])</sup>。

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][wiki53]、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。跨性别医学界当下做的还不够。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：Thompson 等人 (2021) 所作芬威健康《指南》 {#update-1-thompson-et-al-2021-fenway-health-guidelines}

2021 年 3 月，[芬威健康][wiki54]《跨性别健康临床实践指南》自 2015 年 10 月以来首次获得更新<sup>([Aly, 2020][A20-THG])</sup>：

- 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之。

### 后记二：Tomson 等人 (2021) 所作 SAHCS《指南》 {#update-2-tomson-et-al-2021-sahcs-guidelines}

2021 年 9 月，[南非洲艾滋病医师协会][SAHIV]（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：“损耗神经甾体的风险更低，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][wiki55]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<sup>([维基百科][wiki56-d])</sup>。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，这同样令人诧异。考虑到以上明显疏忽及其它因素，应当谨慎对待其推荐的理由。

### 后记三：Coleman 等人 (2022) 所作 WPATH SOC8《指南》 {#update-3-coleman-et-al-2022-wpath-soc8-guidelines}

2022 年 9 月，[世界跨性别人士健康专业协会][wpath]（WPATH）发布了《[跨性别及性别多元化人群健康护理标准][soc8]》第八版（SOC8）<sup>([Coleman et al., 2022][C22])</sup>。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<sup>(Neyman et al., 2019)</sup>。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<sup>(O’Bryant et al., 2008)</sup>。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）<sup>(Angus et al., 2021; Butler et al., 2017; Efstathiou et al., 2019; Tosun et al., 2019)</sup>。

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。

### 后记四：Jamie Reed 于 2023 年报告的比卡鲁胺所致肝毒性病例 {#update-4-jamie-reed-bicalutamide-liver-toxicity-case}

2023 年二月，曾述职于美国密苏里州[圣路易斯儿童医院][wiki57]附属[华盛顿大学跨性别中心][WUTC]的原个案经理 Jamie Reed，在保守派网络媒体《[自由报][wiki58]》上发表了一篇专栏文章《[我曾以为我在拯救跨性别儿童，但现在我要告发][R23]》。Reed 写道，她对青年跨性别者的医疗服务大失所望，并为此表达不满。不过，她简略提到一起传闻在该中心发生的、因比卡鲁胺引起肝毒性的女性倾向跨性别者病例。据称该病例年龄为 15 岁，接受该中心的联合创始人之一：[Christopher Lewis][WUSTL-profile] 博士开出的比卡鲁胺（作为青春期阻断剂）治疗；其随后出现肝毒性，停用了比卡鲁胺。其母亲在联系该中心时说：“你们该庆幸，我们不是那种讼棍。”此案例连同 Reed 的专栏文章，在福克斯新闻、《每日邮报》等保守派媒体当中被广泛传播<sup>([Google 搜索][google-search])</sup>。\
除了这篇专栏文章，Reed 还向密苏里州的共和党检察长 [Andrew Bailey][wiki59] 递交了一份经宣誓的证词，此后该检察长发起了对这家诊所的调查<sup>([密苏里州政府, 2023a][MG23])</sup>。该证词的部分内容如下：

> 该中心的其中一位医生：Chris Lewis 博士，向其病人开出一种叫比卡鲁胺的药物。这种药物可合法用于胰腺癌（*原文如此*）的治疗，但其有引起乳房发育的副作用，且对肝脏有毒性。尚无任何有关这种药物用于性别转变的临床研究，该药物也无任何公认的标准疗法。
>
> 考虑到上述风险及相关研究的缺失，其它性别转变中心不会使用比卡鲁胺。华盛顿大学附属的成人中心也不会使用。但儿童中心却使用了它。
>
> 据我所知，该中心至少有一名患者因发生肝脏损伤，被肾脏科建议停用比卡鲁胺。其家长通过在线自填病历（MyChart）向该中心报告此事。家长说道，尽管他们并非讼棍，但“这会给你们带来很大的公关麻烦”。

此前有关女性倾向跨性别者因比卡鲁胺引起肝毒性的报告，很多都未公开或未确认；而这是迄今资料最完善的一起相关病例。该病例未披露更多临床方面的细节，尚不清楚它（*比卡鲁胺*）是否引起了重度肝毒性、或仅仅是无症状的肝功能结果异常，或者某种介于二者之间的临床状况。无论如何，可以明确的是，对于比卡鲁胺用于女性化激素治疗的进一步普及，此事并不会起到积极作用。

在该诊所的调查开始之后，2023 年四月，密苏里州对面向跨性别青年及成人的性别肯定照护作出了大幅限制，其中部分措施不仅在美国已有施行，严苛程度亦是数一数二的<sup>([美联社, 2023a][BH23]; [密苏里州政府, 2023b][mo-704f2159])</sup>。比卡鲁胺及其肝毒性未得到进一步解释。该州对性别肯定照护的管制令于 2023 年 8 月 28 日起生效；不久后，华盛顿大学宣布将停止向跨性别青年开出青春期阻断剂和激素处方<sup>([美联社, 2023b][SB23])</sup>。

《纽约时报》同样在事后刊登了一篇文章，其中提供有关此病例的更多细节<sup>([Ghorayshi, 2023][G23] \[[摘要][G23-EXC]])</sup>。其提到，这名青年曾服用比卡鲁胺长达一年，且可以肯定发生了肝毒性。但是，青年其人有着复杂病史：包括免疫力下降、近期曾感染新冠病毒、曾服用另一种已知与肝毒性有关的药物等。因此，该病例的肝毒性不能完全归咎于比卡鲁胺，但同时也不能排除比卡鲁胺在其中的作用或因果关系。

#### Burgener 等人（2023、2024）后续研究的结果 {#subsequent-burgener-et-al-2023-2024-findings}

继上述病例之后，Lewis 及其同行继续为一项有关比卡鲁胺用于跨性别青年和年轻成人的研究发表会议纪要和预印本；其中他们声明，比卡鲁胺在该群体中并未使肝转化酶增加<sup>([Burgener et al., 2023][B23-PDF2]; [Burgener et al., 2024][B24])</sup>。然而，细看其数据会发现，比卡鲁胺相对其它抗雄制剂*确确实实* 引起了某些肝脏指标的有统计意义的上升——即[天门冬氨酸转氨酶][wiki60]（AST）升高的发生率（实验组、对照组达正常范围上限的分别占 10.7%、1.5%，*P* = 0.02）<sup>([Burgener et al., 2024][B24])</sup>。无独有偶，[谷丙转氨酶][wiki61]（ALT）升高的发生率亦有增长趋势，但不具统计意义（实验组、对照组达正常范围上限的分别占 16.7%、11.6%，*P* = 0.37）<sup>([Burgener et al., 2024][B24])</sup>。无论如何，在本研究中出现肝转化酶临床显著性上升（即三倍于正常范围上限）的发生率未见明显增加。

以针对男性前列腺癌患者的相关研究<sup>([维基百科][wiki51-lt])</sup>为基线来看，Lewis 及其同行的研究仅有 84 名女性倾向跨性别者作为受试者来评价肝功能改变，其样本规模是严重[不足][wiki62]的。据有关高剂量比卡鲁胺单药用于男性前列腺癌患者的研究：“[早期前列腺癌试验][wiki49]”之结果，比卡鲁胺引起肝转化酶上升的发生率相较安慰剂仅高出约 1.5%，即每 66 人多发生一例<sup>([维基百科][wiki51-lt])</sup>。基于[样本效力分析][clincalc-1f907031]，要确保统计学证据充分，且有机会实现统计显著性，则需要远大于此的样本规模。

综上，笔者关于比卡鲁胺用于女性倾向跨性别者不会引起肝酶升高的论断可能言之过早了。

Lewis 及其同行并未在论文中提及上述由 Jamie Reed 报告的跨性别青年肝毒性病例，亦未发布相关的病例报告；其论文内仅作了如下描述：

> 据一份 2024 年发表的病例报告所述，一名被给予比卡鲁胺 50 mg/天的跨性别女性青年因肝毒性而就医，肝毒性随比卡鲁胺的停用而缓解<sup>(Wilde et al., 2024)</sup>。这应该是迄今第一例记录在案的、发生于跨性别女性的比卡鲁胺所致肝毒性病例。

尽管病人凑巧也是 17 岁的女性倾向跨性别青年<sup>([Wilde et al., 2024][W24])</sup>，但从病史和该报告的作者/院校判断，此病例和 Lewis 博士所引用 Jamie Reed 的病例应该是两回事。

不过，Lewis 及其同行的论文中还有这么一个片段，似乎说的正是 Jamie Reed 的病例：

> 本研究中有一人在研究规定的跟踪期后停用了比卡鲁胺。此人在新冠流行期后出现 ALT、AST 超标两倍以上，并接受了全面肝脏病学检查。鉴于 ALT、AST 未曾出现超标三倍以上的情况，未建议停用比卡鲁胺；但最终经临床决策，决定终止用药，此后 ALT、AST 恢复正常。

另一项对 Lewis 及同行所著论文的顾虑，体现在以下段落：

> 用于前列腺癌的比卡鲁胺剂量高达 150 mg；相比之下，用于出生指派性别为男（AMAB）的女性倾向跨性别者之照护的剂量要小得多（25～50 mg/天）。

> 用于前列腺癌的比卡鲁胺剂量可高达 150 mg。尽管用于 AMAB 女性倾向跨性别者的剂量要小很多（约 25～50 mg/天），但出于对肝毒性的担忧，比卡鲁胺尚未被作为抗雄制剂的常规用药用于该群体。

事实上，比卡鲁胺最常见的用途，就是作为联合雄激素阻断疗法（合用手术或药物去势）的一部分用于前列腺癌治疗，剂量为 50 mg/天；而在不常用的单药疗法下，其剂量为 150 mg/天<sup>([维基百科][wiki1])</sup>。此外在美国，单药疗法未被批准，使用的剂量仅有 50 mg/天。现有男性前列腺癌患者中所报告的比卡鲁胺所致肝毒性病例当中，有一半服用了 50 mg/天，另一半则服用 80～150 mg/天<sup>([维基百科][table1])</sup>。有两例因比卡鲁胺所致肝毒性而死亡的病例，均曾服用 50 mg/天。尽管目前尚无证据表明比卡鲁胺的肝毒性在临床剂量范围内和剂量相关<sup>([维基百科][wiki51-lt])</sup>，但保险起见，为女性倾向跨性别者采取最低有效剂量的做法似乎是明智的。  
综上，和 Lewis 及同行的观点相反，比卡鲁胺在 50 mg/天的剂量下并不比治疗前列腺癌所用的要少，且明显仍保有一定的肝毒性潜力。

### 后记五：2022～2024 年间新发表的比卡鲁胺相关文献 {#update-5-new-bicalutamide-publications-in-2022-through-2024}

- Angus, L., Nolan, B., Zajac, J., & Cheung, A. (November 2022). Use of bicalutamide as an androgen receptor antagonist in transgender women. *ESA/SRB/APEG/NZSE ASM 2022, November 13-16, Christchurch, Abstracts and Programme*, 127–127 (abstract no. 280). \[[URL][A22]] \[[PDF][A22-PDF]] \[[摘要全文][A22-ABS]]
- Angus, L. M., Nolan, B. J., Zajac, J. D., & Cheung, A. S. (November 2023). Bicalutamide as an anti-androgen in trans people: a cross-sectional study. *AusPATH 2023 Symposium*. \[[URL][A23]] \[[PDF][A23-PDF]] \[[幻灯片][A23-PPT]] \[[跨性别健康研究小组博客文章][A23-THR]]
- Bambilla, A., Beal, C., & Vigil, P. (2023). Improving Access to Bicalutamide in Gender Affirming Medical Care. \[Unpubished/pending publication] \[[QueerCME 博客文章][BBV23]]
- Burgener, K., DeBosch, B., Lewis, C., Wallendorf, M., & Herrick, C. (May 2023). Assessment of Liver Function and Toxicity in Transgender Female Adolescents Prescribed Bicalutamide. *Hormone Research in Paediatrics*, *96*(Suppl 3 \[*Abstracts of the 2023 Pediatric Endocrine Society (PES) Annual Meeting’ to Hormone Research in Paediatrics*]), 377–378 (abstract no. 6232). \[DOI:[10.1159/000531602][B23]] \[[PDF][B23-PDF]]
- Gómez-Aguilar, F., Martínez-Sánchez, L., Arias-Constantí, V., Muñoz-Santanach, D., & Sarquella-Brugada, G. (2023). QT prolongation and Torsade de Pointes in a 13-year-old transgender adolescent in treatment with bicalutamide and tacrolimus. *Clinical Toxicology*, *61*(Suppl 1 \[*43rd International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT), 23–26 May 2023, Palma de Mallorca, Spain*]), 81–82 (abstract no. 170). \[DOI:[10.1080/15563650.2023.2192024][GA23]] \[[PDF][GA23-PDF]] \[[Reactions Weekly][GA23-RW]]
- Karakılıç Özturan, E., Öztürk, A. P., Baş, F., Erdoğdu, A. B., Kaptan, S., Kardelen Al, A. D., Poyrazoğlu, Ş., Yıldız, M., Direk, N., Yüksel, Ş., & Darendeliler, F. (2023). Endocrinological Approach to Adolescents with Gender Dysphoria: Experience of a Pediatric Endocrinology Department in a Tertiary Center in Turkey. *Journal of Clinical Research in Pediatric Endocrinology*, *15*(3), 276–284. \[DOI:[10.4274/jcrpe.galenos.2023.2023-1-13][KO23]]
- Vierregger, K., Tetzlaff, M., Zimmerman, B., Dunn, N., Finney, N., Lewis, K., Slomoff, R., & Strutner, S. (May 2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. *National Transgender Health Summit (NTHS) 2023 Symposium*. \[[会议日程 PDF][V23A-PDF]] \[[座谈会][V23A]] \[[座谈会摘要/意见书][V23A-NTHS]]
- Vierregger, K., Tetzlaf, M., Zimmerman, B., Dunn, N., Finney, N., Lewis, K., Slomoff, R., & Strutner, S. (November 2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. *USPATH Scientific Symposium, November 1-5, 2023, The Westin Westminster, Westminster, Colorado, Abstract Submissions*, 96–96 (abstract no. SAT-B2-T4). \[[座谈会日程][V23B-SS]] \[[PDF][V23B]] \[[摘要全文][V23B-ABS]]
- Warus, J., Rincon, M. G., Salvetti, B., & Olson-Kennedy, J. (November 2023). Safety of Bicalutamide as Anti-Androgenic Therapy in Gender Affirming Care for Adolescents and Young Adults: A Retrospective Chart Review. *USPATH Scientific Symposium, November 1-5, 2023, The Westin Westminster, Westminster, Colorado, Abstract Submissions*, 124–124 (abstract no. SUN-B1-T5). \[[座谈会日程][V23B-SS]] \[[PDF][W23]] \[[摘要全文][W23-ABS]]
- Wilde, B., Diamond, J. B., Laborda, T. J., Frank, L., O’Gorman, M. A., & Kocolas, I. (2023). Bicalutamide-Induced Hepatotoxicity in a Transgender Male-to-Female Adolescent. *Journal of Adolescent Health*, *74*(1), 202–204. \[DOI:[10.1016/j.jadohealth.2023.08.024][W24]]
- Burgener, K., DeBosch, B., Wang, J., Lewis, C., & Herrick, C. J. (2024). Bicalutamide does not raise transaminases in comparison to alternative anti-androgen regimens among transfeminine adolescents and young adults: a retrospective cohort study. *medRxiv*, preprint. \[DOI:[10.1101/2024.02.21.24302999v1][B24]] \[[PDF][B24-PDF]]
- Fuqua, J. S., Shi, E., & Eugster, E. A. (2024). A retrospective review of the use of bicalutamide in transfeminine youth; a single center experience. *International Journal of Transgender Health*, advance online publication. \[DOI:[10.1080/26895269.2023.2294321][FSE24]]
- Shumer, D., & Roberts, S. A. (2024). Placing a Report of Bicalutamide-Induced Hepatotoxicity in the Context of Current Standards of Care for Transgender Adolescents. *Journal of Adolescent Health*, *74*(1), 5–6. \[DOI:[10.1016/j.jadohealth.2023.10.010][SR24]]

### 后记六：Sam 本人的比卡鲁胺与肝、肺毒性分析结果 {#update-6-original-bicalutamide-liver-and-lung-toxicity-analysis-by-sam}

几年前的 2021 年，本站撰稿人 Sam 曾自发就已发表临床试验文献中比卡鲁胺所致肝、肺毒性发生率开展了一次分析；该项目未曾完成或对外界公开。但是，随着比卡鲁胺用于女性倾向跨性别者这一用途日益得到更多研究和认可，该项目的价值和相关性看来是蒸蒸日上了。因此，我们决定在这节篇幅发表 Sam 的分析成果。

Sam 的分析详情可见于[这份文档][S21]。研究方法方面，她检索了 [PubMed][pubmed1] 数据库中一切针对比卡鲁胺的临床研究，将相关结果整理到一张表格，随后从这些数据计算出重度肝毒性和肺毒性的发生率。临床试验中，不良事件依严重程度进行分级；其中**三级事件**指的是“严重”不良事件，**四级**即“可威胁生命的”，**五级**即“导致死亡的”<sup>([维基百科][wiki63])</sup>。

229 个检索结果中有 33 项试验被认为具有相关性而予以收录；其中大多数的试验对象是患前列腺癌的男性，但也有少量是以患癌症的妇女、患性早熟的男孩为对象的。在 7703 名可评价受试者中，Sam 发现有 2 例比卡鲁胺所致重度肝毒性、2 例重度肺毒性病例；二者的发生率均为 0.026%（95% 置信区间 0.003～0.094%），或大致每 3,846 人一例。结合二者来看，比卡鲁胺所致重度肝毒性、*或* 肺毒性的总发生率为 0.052%（95% 置信区间：0.014～0.133%），或大致每 1,923 人一例。观察到的一切毒性事件均被列为**三级**或**四级**不良事件。  
需要说明，比卡鲁胺相关临床试验一般都有完备的实验室监测和临床不良事件评价机制，并会在实验室结果出现不良改变时指令中止用药。

尽管 Sam 的分析中[置信区间][wiki64]（CI）大，从而估计值不甚精确，但基于高质量的临床资料可以得知，比卡鲁胺对女性倾向跨性别者具有潜在的、实质的重度毒性风险。还需说明，在这批研究中不会出现不良事件[漏报][wiki65]的问题——这在已发表[病例报告][wiki66]、[药物警戒数据库][wiki67]和某些类别的[观察性研究][wiki68]上时有发生。但是，Sam 的分析也有其局限性，包括：

1. 对于未给予比卡鲁胺治疗的对照组，未就毒性事件发生率进行分析；
1. 大多数受试者年龄较大且患有癌症，其结论是否能够推广到健康女性倾向跨性别者群体尚不完全清楚。

无论如何，当第一次接触到她的分析结果时，笔者对（毒性）事件发生率之高感到了惊诧；笔者相信其他人亦或如是。

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--------

## 译文修订记录 {#revision}

```csv
时间,备注
2022 年 11 月 14 日,首次翻译。
2023 年 3 月 28 日,第一次修订，增补“后记四”内容，更正若干不当叙述，补齐链接。
2024 年 10 月 18 日,第二次修订，增补后记四、五、六等新内容，更新链接。
```

[G11]: http://doi.org/10.1056/NEJMcp1008161
[H09]: https://doi.org/10.1210/jc.2009-0345
[H17]: https://doi.org/10.1210/jc.2017-01658
[V87a]: https://kinseyinstitute.org/pdf/HBIGDA_S10_1987OCR.pdf#page=55
[V87b]: https://doi.org/10.1002/pros.2990110403
[G87]: https://doi.org/10.1210/jcem-64-4-763
[J87]: https://kinseyinstitute.org/pdf/HBIGDA_S10_1987OCR.pdf#page=35
[R88]: https://doi.org/10.1016/0022-4731(88)90024-6
[AGP89]: https://doi.org/10.1111/j.1365-2230.1989.tb02585.x
[VK89]: https://doi.org/10.1007/BF01543196
[AG92]: https://doi.org/10.1300/J056v05n04_03
[G99]: http://web.archive.org/web/20070430161048/http://www.symposion.com/ijt/ijt990301.htm
[IT97]: https://books.google.com/books?id=IlPX6E5glDEC&pg=PA66
[LCR03]: https://doi.org/10.1046/j.1365-2265.2003.01821.x
[D06a]: https://doi.org/10.1300/J485v09n03_06
[D06b]: https://www.cpath.ca/wp-content/uploads/2009/12/guidelines-endocrine.pdf
[MP12]: https://doi.org/10.1016/j.endoen.2012.07.004
[MBG99]: https://doi.org/10.1093/humrep/14.Suppl_3.366-a
[M02]: https://doi.org/10.1080/gye.16.1.63.66
[B04]: https://doi.org/10.1159/000081973
[MO09]: https://www.turkiyeklinikleri.com/article/en-hirsutizm-tedavisinde-flutamid-ve-bikalutamid-kullanimi-55753.html
[M16]: https://web.archive.org/web/20221108144934/https://endo.confex.com/endo/2016endo/webprogram/Paper26631.html
[M18]: https://doi.org/10.1210/jc.2017-01186
[K06]: https://doi.org/10.1016/j.jpeds.2006.04.027
[L09]: https://doi.org/10.1159/000239668
[ML09]: https://doi.org/10.1515/JPEM.2009.22.12.1163
[S09]: https://doi.org/10.1159/000239668
[L10]: https://doi.org/10.1542/peds.2010-0596
[R10]: https://doi.org/10.1515/jpem.2010.161
[T12]: https://doi.org/10.1507/endocrj.ej11-0214
[O15]: https://doi.org/10.4274/jcrpe.2067
[K18]: https://doi.org/10.1007/s42000-018-0029-1
[AD19]: https://doi.org/10.1515/jpem-2018-0419
[NE19]: https://doi.org/10.4158/ACCR-2018-0246
[F20]: https://doi.org/10.1097/DBP.0000000000000865
[GDC21]: https://doi.org/10.4274/jcrpe.galenos.2020.2020.0067
[AZ08]: https://web.archive.org/web/20190730023433/https://www.fda.gov/media/75809/download
[FDA17]: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020498s028lbl.pdf
[NFE17]: https://files.transfemscience.org/pdfs/Neyman,%20Fuqua,%20&%20Eugster%20(2017)%20-%20Bicalutamide%20as%20an%20Androgen%20Blocker%20with%20Secondary%20Effect%20of%20Promoting%20Feminization%20in%20Male%20to%20Female%20(MTF)%20Transgender%20Adolescents.pdf#page=4
[NFE19]: https://doi.org/10.1016/j.jadohealth.2018.10.296
[HE12]: https://doi.org/10.1007/978-1-4419-1795-9_71
[faers]: https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard
[GAP02]: https://doi.org/10.1002/0470853093.ch17
[D16]: https://transcare.ucsf.edu/guidelines
[A20-CM]: https://transfemscience.org/articles/cpa-meningioma/
[A03]: https://doi.org/10.1046/j.1464-410X.2003.04026.x
[I04]: https://doi.org/10.1097/01.ju.0000139719.99825.54
[B96]: https://doi.org/10.1159/000473847
[KB96]: https://doi.org/10.1016/S0090-4295(96)80012-4
[ML97]: https://doi.org/10.1634/theoncologist.2-1-18
[S02]: https://doi.org/10.1016/S0022-5347(05)64652-6
[S97]: https://doi.org/10.1016/s0090-4295(97)00279-3
[T04]: https://doi.org/10.1159/000081585
[M06]: https://doi.org/10.1002/pds.1168
[FN19]: https://doi.org/10.1111/dth.13096
[I20]: https://doi.org/10.1016/j.jaad.2020.03.034
[FN20]: https://doi.org/10.1016/j.jaad.2020.04.054
[M21]: https://doi.org/10.1016/j.jaad.2021.10.048
[FPPH19]: https://doi.org/10.1007/978-3-030-05683-4_8
[M20]: https://doi.org/10.1016/S2213-8587(20)30192-3
[I19]: https://doi.org/10.1177%2F2042018819871166
[R18]: http://doi.org/10.1097/GRF.0000000000000396
[MM20]: http://www.med.umich.edu/1libr/ComprehensiveGenderServicesProgram/MMapproachFemGenderAffirmingHormones.pdf
[HDP19]: https://doi.org/10.1016/j.ecl.2019.02.001
[C20]: https://doi.org/10.3390/jcm9061609
[A20-THG]: https://transfemscience.org/articles/transfem-hormone-guidelines/
[T21]: https://www.lgbtqiahealtheducation.org/publication/medical-care-of-trans-and-gender-diverse-adults-2021/
[T21-PDF]: https://www.lgbtqiahealtheducation.org/wp-content/uploads/2021/07/Medical-Care-of-Trans-and-Gender-Diverse-Adults-Spring-2021.pdf
[SAHIV21]: https://doi.org/10.4102/sajhivmed.v22i1.1299
[SAHIV21-PDF]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517808/pdf/HIVMED-22-1299.pdf
[WPATH]: https://zh.wikipedia.org/wiki/%E4%B8%96%E7%95%8C%E8%B7%A8%E6%80%A7%E5%88%AB%E4%BA%BA%E5%A3%AB%E5%81%A5%E5%BA%B7%E4%B8%93%E4%B8%9A%E5%8D%8F%E4%BC%9A
[SOC8]: https://en.wikipedia.org/wiki/Standards_of_Care_for_the_Health_of_Transgender_and_Gender_Diverse_People
[C22]: https://doi.org/10.1080/26895269.2022.2100644
[R23]: https://www.thefp.com/p/i-thought-i-was-saving-trans-kids
[MG23]: https://web.archive.org/web/20230828192422/https://ago.mo.gov/home/news/2023/02/09/missouri-attorney-general-andrew-bailey-confirms-launch-of-multi-agency-investigation-into-st.-louis-transgender-center-for-harming-hundreds-of-children
[AG92-GS]: https://scholar.google.com/scholar?cluster=3926911364428297742
[AG92-GB]: https://books.google.com/books?id=fny-DwAAQBAJ&pg=PT38
[AZ08-FDA]: https://www.fda.gov/media/75809/
[AZ08-PDF]: https://www.fda.gov/media/75809/download
[MG23-PDF]: https://ago.mo.gov/docs/default-source/press-releases/2023-04-13---emergency-reg.pdf
[C22-WPATH]: https://www.wpath.org/publications/soc
[C22-PDF]: https://www.tandfonline.com/doi/pdf/10.1080/26895269.2022.2100644
[D06b-GS]: https://scholar.google.com/scholar?cluster=10288793516023166968
[D16-FHT]: https://transcare.ucsf.edu/guidelines/feminizing-hormone-therapy
[D16-PDF]: https://transcare.ucsf.edu/sites/transcare.ucsf.edu/files/Transgender-PGACG-6-17-16.pdf#page=26
[FDA17-FDA]: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020498
[G99-GS]: https://scholar.google.com/scholar?cluster=1501455977722930279
[G99-ALT]: http://www.tgmeds.org.uk/hormonal-sex-reassignment.html
[H17-PDF]: https://academic.oup.com/jcem/article-pdf/102/11/3869/21533864/jc.2017-01658.pdf
[IT97-GS]: https://scholar.google.com/scholar?cluster=5451071852495304201
[L09-GS]: https://scholar.google.com/scholar?cluster=5540864211259664143
[MM20-UMICH]: https://medicine.umich.edu/dept/obgyn/education/continuing-medical-education-cme/transgender-healthcare-curriculum
[M16-DOI]: https://doi.org/10.1093/edrv/37.supp.1
[MO09-ISSN]: https://portal.issn.org/resource/ISSN/1308-0954
[MO09-PDF]: https://files.transfemscience.org/pdfs/M%C3%BCderris%20&%20%C3%96ner%20%282009%29%20-%20Hirsutizm%20Tedavisinde%20Flutamid%20ve%20Bikalutamid%20Kullan%C4%B1m%C4%B1%20[Flutamide%20and%20Bicalutamide%20Treatment%20in%20Hirsutism].pdf
[MO09-ENG]: https://docs.google.com/document/d/1jwdHS1kUQk4pm4J1xVTtUehiFnrkIkpTMO1D1yI7fpI/view
[NFE17-DOI]: https://doi.org/10.1159/000481424
[R18-URL]: https://www.ingentaconnect.com/content/wk/cobg/2018/00000061/00000004/art00008
[S09-GS]: https://scholar.google.com/scholar?cluster=9944726539277415138
[G23]: https://www.nytimes.com/2023/08/23/health/transgender-youth-st-louis-jamie-reed.html
[G23-EXC]: https://archive.is/oqLqD
[B23-PDF2]: https://karger.com/hrp/article-pdf/96/Suppl.%203/1/4008437/000531602.pdf#page=377
[B24]: https://www.medrxiv.org/content/10.1101/2024.02.21.24302999v1
[W24]: https://doi.org/10.1016/j.jadohealth.2023.08.024
[A22]: https://esa-srb-apeg-nzse-2022.p.asnevents.com.au/days/2022-11-14/abstract/85266
[A22-PDF]: https://files.transfemscience.org/pdfs/Angus%20et%20al.%20%282022%29%20-%20Use%20of%20bicalutamide%20as%20an%20androgen%20receptor%20antagonist%20in%20transgender%20women%20%28ESA-SRB-APEG-NZSE%20ASM%202022,%20abstract%20no.%20280%29.pdf
[A22-ABS]: https://www.endocrinesociety.org.au/esa-srb-apeg-nzse-2022-program_abstracts.pdf#page=127
[A23]: https://ashm.eventsair.com/QuickEventWebsitePortal/auspath-conference-2023/aus24/Agenda/AgendaItemDetail?id=0c7c2d1d-21c4-4b21-920f-99446f96a548
[A23-PDF]: https://az659834.vo.msecnd.net/eventsairaueprod/production-ashm-public/071ac7b75cbe4d35a6fa168110ea3070
[A23-PPT]: https://files.transfemscience.org/pdfs/misc/Angus%20et%20al.%20AUSPATH%202023%20Bicalutamide%20Study%20Slides.pdf
[A23-THR]: https://www.transresearch.org.au/post/2023_auspath
[BBV23]: https://www.queercme.com/blog/bicalutamide-prescribing-in-gender-affirming-care
[B23]: https://doi.org/10.1159/000531602
[B23-PDF]: https://files.transfemscience.org/pdfs/Burgener%20et%20al.%20%282023%29%20-%20Assessment%20of%20Liver%20Function%20and%20Toxicity%20in%20Transgender%20Female%20Adolescents%20Prescribed%20Bicalutamide%20%28PES%202023,%20abstract%20ID%206232%29.pdf
[GA23]: https://doi.org/10.1080/15563650.2023.2192024
[GA23-PDF]: https://www.eapcct.org/publicfile.php?folder=congress&file=Abstracts_Mallorca23.pdf#page=81
[GA23-RW]: https://doi.org/10.1007/s40278-023-45800-4
[KO23]: https://doi.org/10.4274/jcrpe.galenos.2023.2023-1-13
[V23A-PDF]: https://web.archive.org/web/20240321010915/https://d1keuthy5s86c8.cloudfront.net/static/ems/upload/files/nyhs_202305_agenda_pdf_lbjyz.pdf
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[V23A-NTHS]: https://prevention.ucsf.edu/transhealth/education/nths
[V23B-SS]: https://www.wpath.org/media/cms/Upcoming%20Conferences/2023/Schedules/Final%20USPATH%202023%20Scientific%20Symposium%20Main%20Program%20-%20Full%20Schedule.pdf
[V23B]: https://files.transfemscience.org/pdfs/Vierregger%20et%20al.%20%282023%29%20-%20Bicalutamide%20Use%20as%20Antiandrogen%20in%20Trans%20Feminine%20Adults%20-%20A%20Safety%20Profile%20%28USPATH%202023,%20abstract%20no.%20SAT-B2-T4%29.pdf
[V23B-ABS]: https://files.transfemscience.org/pdfs/wpath-symposia-materials/USPATH%202023%20Symposium%20Abstracts.pdf#page=96
[W23]: https://files.transfemscience.org/pdfs/Warus%20et%20al.%20%282023%29%20-%20Safety%20of%20Bicalutamide%20as%20Anti-Androgenic%20Therapy%20in%20Gender%20Affirming%20Care%20for%20Adolescents%20and%20Young%20Adults_%20A%20Retrospective%20Chart%20Review%20%28USPATH%202023,%20abstract%20no.%20SUN-B1-T5%29.pdf
[W23-ABS]: https://files.transfemscience.org/pdfs/wpath-symposia-materials/USPATH%202023%20Symposium%20Abstracts.pdf#page=124
[B24-PDF]: https://www.medrxiv.org/content/medrxiv/early/2024/02/23/2024.02.21.24302999.full.pdf
[FSE24]: https://doi.org/10.1080/26895269.2023.2294321
[SR24]: https://doi.org/10.1016/j.jadohealth.2023.10.010
[S21]: https://files.transfemscience.org/pdfs/docs/Supplementary%20Material_%20Liver%20and%20Lung%20Toxicity%20with%20Bicalutamide%20in%20Clinical%20Trials.pdf
[BH23]: https://apnews.com/article/transgender-gender-affirming-care-restrictions-missouri-4def2189dac9979a00d298efb3baf12a
[SB23]: https://apnews.com/article/transgender-care-minors-missouri-b65a81c842c6add70529acec231858cd

[table1]: https://en.wikipedia.org/wiki/Template:Published_case_reports_of_bicalutamide-associated_liver_injury
[table2]: https://en.wikipedia.org/wiki/Template:Published_case_reports_of_cyproterone_acetate-associated_meningioma
[table3]: https://en.wikipedia.org/wiki/Template:Published_case_reports_of_bicalutamide-associated_lung_toxicity
[table4]: https://en.wikipedia.org/wiki/Template:Side_effects_of_combined_androgen_blockade_with_nonsteroidal_antiandrogens

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[wiki2]: https://en.wikipedia.org/wiki/Nonsteroidal_antiandrogen
[wiki3]: https://en.wikipedia.org/wiki/Androgen_receptor
[wiki4]: https://en.wikipedia.org/wiki/Receptor_antagonist
[wiki5]: https://en.wikipedia.org/wiki/Prostate_cancer
[wiki6]: https://en.wikipedia.org/wiki/Androgen-dependent_condition
[wiki7]: https://en.wikipedia.org/wiki/Spironolactone
[wiki8]: https://en.wikipedia.org/wiki/Cyproterone_acetate
[wiki9]: https://en.wikipedia.org/wiki/Antiandrogen
[wiki10]: https://en.wikipedia.org/wiki/Potency_(pharmacology)
[wiki11]: https://en.wikipedia.org/wiki/Clinical_effectiveness
[wiki12]: https://en.wikipedia.org/wiki/Binding_selectivity
[wiki13]: https://en.wikipedia.org/wiki/Tolerability
[wiki14]: https://en.wikipedia.org/wiki/Flutamide
[wiki15]: https://en.wikipedia.org/wiki/Nilutamide
[wiki15-tht]: https://en.wikipedia.org/wiki/Nilutamide#Transgender_hormone_therapy
[wiki16]: https://en.wikipedia.org/wiki/Pharmacokinetics
[wiki17]: https://en.wikipedia.org/wiki/Drug_safety
[wiki18]: https://en.wikipedia.org/wiki/Abiraterone_acetate
[wiki19]: https://en.wikipedia.org/wiki/Enzalutamide
[wiki20-msc]: https://en.wikipedia.org/wiki/Standard_of_care#Medical_standard_of_care
[wiki21]: https://en.wikipedia.org/wiki/Louis_Gooren
[wiki22]: https://en.wikipedia.org/wiki/Endocrine_Society
[wiki23]: https://en.wikipedia.org/wiki/Center_of_Expertise_on_Gender_Dysphoria
[wiki24]: https://en.wikipedia.org/wiki/VU_University_Medical_Center
[wiki25]: https://en.wikipedia.org/wiki/Off-target_activity
[wiki26]: https://en.wikipedia.org/wiki/Hirsutism
[wiki27]: https://en.wikipedia.org/wiki/Polycystic_ovary_syndrome
[wiki28-shc]: https://en.wikipedia.org/wiki/Medical_uses_of_bicalutamide#Medical_uses_of_bicalutamide#Skin_and_hair_conditions
[wiki28-mep]: https://en.wikipedia.org/wiki/Medical_uses_of_bicalutamide#Male_early_puberty
[wiki29]: https://en.wikipedia.org/wiki/Anastrozole
[wiki30]: https://en.wikipedia.org/wiki/Aromatase_inhibitor
[wiki31]: https://en.wikipedia.org/wiki/Familial_male-limited_precocious_puberty
[wiki32]: https://en.wikipedia.org/wiki/Precocious_puberty
[wiki33]: https://en.wikipedia.org/wiki/Gonadotropin-releasing_hormone_modulator
[wiki34-p2]: https://en.wikipedia.org/wiki/Phases_of_clinical_research#Phase_II
[wiki34-p3]: https://en.wikipedia.org/wiki/Phases_of_clinical_research#Phase_III
[wiki35]: https://en.wikipedia.org/wiki/New_Drug_Application
[wiki36]: https://en.wikipedia.org/wiki/Off-label_use
[wiki37]: https://en.wikipedia.org/wiki/Food_and_Drug_Administration
[wiki38]: https://en.wikipedia.org/wiki/Puberty_blocker
[wiki39]: https://en.wikipedia.org/wiki/Gonadotropin-releasing_hormone_analogue
[wiki40]: https://en.wikipedia.org/wiki/Self-medication
[wiki41]: https://en.wikipedia.org/wiki/Liver_failure
[wiki42]: https://en.wikipedia.org/wiki/Risk%E2%80%93benefit_ratio
[wiki43]: https://en.wikipedia.org/wiki/University_of_California,_San_Francisco
[wiki44]: https://en.wikipedia.org/wiki/Hepatotoxicity
[wiki45]: https://en.wikipedia.org/wiki/Interstitial_lung_disease
[wiki46]: https://en.wikipedia.org/wiki/Liver_function_tests
[wiki47]: https://en.wikipedia.org/wiki/Elevated_transaminases
[wiki48]: https://en.wikipedia.org/wiki/Blood_test
[wiki49]: https://en.wikipedia.org/wiki/Early_Prostate_Cancer_(clinical_programme)
[wiki50]: https://en.wikipedia.org/wiki/Randomized_controlled_trial
[wiki51-lt]: https://en.wikipedia.org/wiki/Side_effects_of_bicalutamide#Liver_toxicity
[wiki52]: https://nl.wikipedia.org/wiki/Guy_T'Sjoen
[wiki53]: https://en.wikipedia.org/wiki/Contraindication
[wiki54]: https://en.wikipedia.org/wiki/Fenway_Health
[wiki55]: https://en.wikipedia.org/wiki/5%CE%B1-Reductase_inhibitor
[wiki56-d]: https://en.wikipedia.org/wiki/Pharmacology_of_bicalutamide#Distribution
[wiki57]: https://en.wikipedia.org/wiki/St._Louis_Children%27s_Hospital
[wiki58]: https://en.wikipedia.org/wiki/The_Free_Press_(media_company)
[wiki59]: https://en.wikipedia.org/wiki/Andrew_Bailey_(politician)
[wiki60]: https://en.wikipedia.org/wiki/Aspartate_transaminase
[wiki61]: https://en.wikipedia.org/wiki/Alanine_transaminase
[wiki62]: https://en.wikipedia.org/wiki/Power_of_a_test
[wiki63]: https://en.wikipedia.org/wiki/Common_Terminology_Criteria_for_Adverse_Events
[wiki64]: https://en.wikipedia.org/wiki/Confidence_interval
[wiki65]: https://en.wikipedia.org/wiki/Under-reporting
[wiki66]: https://en.wikipedia.org/wiki/Case_report
[wiki67]: https://en.wikipedia.org/wiki/Pharmacovigilance
[wiki68]: https://en.wikipedia.org/wiki/Observational_study

[CL-AR]: https://web.archive.org/web/20230321104049/https://callen-lorde.org/providers/asa-radix/
[CL-ZG]: https://web.archive.org/web/20221208035109/https://callen-lorde.org/providers/zil-goldstein/
[QD]: https://queerdoc.com/how-do-you-know-which-t-blocker-to-take-what-is-going-on-with-bica/
[WUTC]: https://physicians.wustl.edu/specialties/lgbtq-health/washington-university-transgender-center/
[SAHIV]: https://sahivsoc.org/

[WUSTL-profile]: https://profiles.wustl.edu/en/persons/christopher-lewis
[google-search]: https://www.google.com/search?q=%22jamie+reed%22+bicalutamide+transgender+OR+trans+OR+gender-affirming&tbs=cdr%3A1%2Ccd_min%3A2%2F9%2F2023%2Ccd_max%3A2%2F28%2F2023
[clincalc-1f907031]: https://clincalc.com/stats/samplesize.aspx
[pdf-6a22ac1a]: https://files.transfemscience.org/pdfs/translations/M%C3%BCderris%20&%20%C3%96ner%20%282009%29%20-%20Hirsutizm%20Tedavisinde%20Flutamid%20ve%20Bikalutamid%20Kullan%C4%B1m%C4%B1.pdf
[mo-704f2159]: https://ago.mo.gov/home/news/2023/04/13/missouri-attorney-general-andrew-bailey-promulgates-emergency-regulation-targeting-gender-transition-procedures-for-minors
[pubmed1]: https://pubmed.ncbi.nlm.nih.gov/