譯者按

  1. 長文注意:本譯文共計約 1.6 萬個漢字。
  2. 本文有關於手術前後是否應暫停激素治療的敘述,詳見“對血栓的預防”最後一段。
  3. 為便於閱讀及理解,本文對原文個別敘述略有改動(調整排版,或以斜體 標記)。
  4. 因譯者能力所限,部分術語之翻譯或有紕漏,煩請指正。

摘要

雌激素可透過啟用肝臟雌激素受體、調節各類血清凝血因子的分泌,而增強凝血功能。在雌激素暴露量足夠高的情況下,其會引起血栓風險以及與凝血功能有關的心血管併發症(如心肌梗塞和卒中)之風險的升高。
不過,依雌激素種類、途徑與劑量的不同,風險升高的幅度各異。由於非生物同質性雌激素(如炔雌醇)對肝臟代謝的抗性更強,故其在肝臟的表達強度更大,從而無疑會比具有生物同質性的雌二醇更能引起血栓風險升高;另外,口服雌二醇會經過肝臟的首渡效應,其在肝臟的表達強度也高於非口服途徑。
在非口服途徑下,生理水平的雌二醇應僅有微弱、以至沒有血栓風險;而口服雌二醇的風險顯著更大,且在高劑量下,會有類似於現代避孕藥所提供劑量下的炔雌醇的風險。此外,高劑量的非口服雌二醇應當也有不小的血栓與心血管疾病風險,不過該風險應小於含炔雌醇的避孕藥。
每單位人口的血栓風險絕對值雖低,但會隨時間累加。另外,其它風險因素也會明顯助長風險率,包括:年齡、運動量少、與孕激素合用、原因多不明的血栓形成異常等。
對於女性傾向跨性別者,出於血栓風險更高的考慮,最好應避免使用口服雌二醇與劑量過高的非口服雌二醇——尤其是有相關風險因素者。無論如何,為女性傾向跨性別者作出治療建議時,不僅要考慮安全性,還應考慮有效性、開銷、便利性等其它因素,以及其它替代治療選項。

前言

雌激素會增強凝血功能並引起血栓(一種心血管疾病)之風險的升高。人體內的血管分為動脈靜脈,其中動脈將血液從心臟帶離,而靜脈將血液送回心臟;血栓也主要分為兩種:靜脈血栓或栓塞(VTE)、以及動脈血栓。VTE 還分兩種亞型:發生於腿部和骨盆的深靜脈血栓(DVT),以及肺血栓(PE)——這種血栓會轉移至肺動脈並阻塞之。而動脈血栓會導致心肌梗塞(MI;也稱心臟病發作)或腦卒中(CVA;俗稱中風)。
血栓是很嚴重的健康問題,其會引起嚴重併發症乃至死亡。而雌激素在暴露量足夠高、從而增強凝血功能的情況下,也有可能引起靜脈與動脈血栓、以及上述一系列風險的升高。出於此類潛在健康後果的考慮,血栓風險會成為其使用當中的一項限制因素。

雌激素是雌激素受體(ER)的選擇性 促效劑。透過啟用 ER,其被認為會增強凝血功能,並引起血栓風險升高。不過,依雌激素型別、途徑與劑量的不同,其對凝血功能與血栓風險的影響各異。此外,其它因素已知也會影響該風險——包括與孕激素合用,以及一系列激素無關的因素。
本文旨在對以下方面進行評述:雌激素與血栓風險的關係;雌激素與凝血功能與血栓風險之增長背後的機制;以及為何不同雌激素引起的風險不一。
此外,較高的雌激素水平有助於女性傾向跨性別者抑制睪酮分泌、但可能使得血栓風險升高,故需要就此分析其利弊

雌激素與孕激素引起的血栓風險

臨床上應用的雌激素種類有很多。其中包括:

雌二醇可經口服或非口服形式(如透皮貼片)用藥,而非生物同質性雌激素常用於口服。為此,下表列出了以上雌激素在綜合雌激素效力上大致等同的劑量。

【表一】 諸雌激素在綜合雌激素效力上大致或估計等同的劑量(Aly, 2020; Kuhl, 2005; 表格1; 表格2; 表格3)

雌激素型別、途徑極低劑量(1)低劑量(1)中等劑量(2)高劑量
口服雌二醇1 mg/天2 mg/天4 mg/天8 mg/天
透皮雌二醇(3)25 μg/天50 μg/天100 μg/天200 μg/天
口服結合雌激素0.625 mg/天1.25 mg/天2.5 mg/天5 mg/天
口服炔雌醇7.5 μg/天15 μg/天30 μg/天60 μg/天
口服己烯雌酚0.375 mg/天0.75 mg/天1.5 mg/天3 mg/天
等效雌二醇水平約 25 pg/mL約 50 pg/mL約 100 pg/mL約 200 pg/mL

(1) 用於更年期激素替代治療。
(2) 與絕經前婦女在整個月經週期的正常平均/綜合雌激素暴露量相當(Aly, 2018)
(3) 指透皮貼片。

1960 到 1970 年代,雌激素首度被確認與血栓及心血管併發症相關。在臨床試驗和研究中,以下均被發現會引起上述風險的顯著或大幅升高:

男性前列腺癌患者使用 DES 引起的心血管問題相當之大,在整體死亡率上,這實際抵消了其抑制前列腺癌所帶來的益處。這些研究的發現給人們敲響了警鐘,也引起了對雌激素安全性的擔憂;此後,雌激素劑量得以減少。其中,用於治療前列腺癌的 DES 劑量降至 1–3 mg/天,而避孕藥內含的 EE 劑量降至 20–35 μg/天。其它療法所用雌激素的劑量也有所降低,例如更年期激素治療。
調低劑量雖不能根除用藥風險,但有助於降低之。

在美國“婦女健康倡議”(WHI)隨機對照試驗當中,單用低劑量口服 CEE(0.625 mg/天)會引起些微的血栓風險上升(Anderson et al., 2004; Curb et al., 2006; Prentice & Anderson, 2008; Prentice, 2014; 表格)。此外,當與低劑量醋酸甲羥孕酮(MPA;2.5 mg/天)合用時,該風險還會有顯著增長(Rossouw et al., 2002; Cushman et al., 2004; Prentice & Anderson, 2008; Prentice, 2014; 表格)
另一項大型隨機對照試驗:心臟與雌激素/合成孕酮補充治療研究(HERS)也發現,合用低劑量 CEE 與低劑量 MPA 時會引起血栓風險的升高(Hulley et al., 1998; Grady et al., 2000)。除 MPA 以外,其它孕激素在與口服雌激素合用時,也會進一步增大由後者引起的血栓風險(Rovinski et al., 2018; Scarabin, 2018; Oliver-Williams et al., 2019; Vinogradova, Coupland, & Hippisley-Cox, 2019; 表格)
一些大型觀察性研究發現,類似於 CEE,低劑量口服雌二醇(通常不大於 2 mg/天)也與血栓風險的升高有關,增幅取決於劑量(Olié, Canonico, & Scarabin, 2010; Renoux, Dell’Aniello, & Suissa, 2010; Vinogradova, Coupland, & Hippisley-Cox, 2019; Konkle & Sood, 2019; 表格)。不過,口服雌二醇或酯化雌激素的風險應小於口服 CEE(Smith et al., 2004; Smith et al., 2014; Vinogradova, Coupland, & Hippisley-Cox, 2019; 表格)。(酯化雌激素是一種與 CEE 類似的製劑,但馬雌激素含量更少。)
另一方面,還有一項大型觀察性研究發現,口服雌二醇與口服 CEE 在與孕激素合用時,二者引起的血栓風險增幅相當(Roach et al., 2013)。孕激素與口服雌二醇合用時,也會進一步增大由後者引起的血栓風險,這跟與口服 CEE 合用時類似(Vinogradova, Coupland, & Hippisley-Cox, 2019; 表格)

透皮雌二醇的情況與口服雌激素相反:已知其在低至中等劑量(50–100 μg/天)之下,並未引起凝血功能的增強,也未引起血栓及其關聯的心血管併發症之風險的上升(Canonico et al., 2008; Hemelaar et al., 2008; Olié, Canonico, & Scarabin, 2010; Renoux, Dell’Aniello, & Suissa, 2010; Mohammed et al., 2015; Stuenkel et al., 2015; Bezwada, Shaikh, & Misra, 2017; Rovinski et al., 2018; Scarabin, 2018; Konkle & Sood, 2019; Oliver-Williams et al., 2019; Vinogradova, Coupland, & Hippisley-Cox, 2019; Abou-Ismail, Sridhar, & Nayak, 2020; 表格)
類似地,更年期、雌激素與靜脈事件(MEVE)研究專案發現,當用於有血栓史的婦女時,口服雌二醇可引起血栓風險的大幅上升;而透皮雌二醇(平均劑量 50 μg/天)並未引起該風險的上升(Olié et al., 2011)
然而,有幾項關於透皮雌二醇與心血管風險的例外;例如,一項觀察性研究發現,較高劑量(大於 50 μg/天)的透皮雌二醇用於更年期婦女時,會引起腦卒中風險的增長(Renoux et al., 2010; Oliver-Williams et al., 2019);還有一些研究發現,口服和透皮雌二醇對女性傾向跨性別者的凝血功能的影響差異很小以至無差異(Lim et al., 2020; Scheres et al., 2021)
在有關更年期所用劑量下的透皮雌二醇與孕激素合用時是否與更高的血栓風險有關的問題上,現有研究的結論五花八門;有的未發現任何差異,有的則發現風險有所上升(Rovinski et al., 2018; Scarabin, 2018; Vinogradova, Coupland, & Hippisley-Cox, 2019)。已有人表示,這應該與所用孕激素型別有關(Scarabin, 2018)

關於口服或透皮雌二醇在高於更年期激素療法所用的劑量下對血栓風險的影響,至今仍鮮有高質量臨床資料發表。無論如何,用於女性化激素療法的口服雌二醇(如 2–8 mg/天;通常還與抗雄性素製劑、孕激素等其它藥品合用)所引起的血栓風險已得到較有限的評估。此類研究所披露的血栓風險增幅,要高於更年期激素療法所用較低劑量下的口服雌二醇(Wierckx et al., 2013; Weinand & Safer, 2015; Arnold et al., 2016; Getahun et al., 2018; Irwig, 2018; Connelly et al., 2019; Connors & Middeldorp, 2019; Goldstein et al., 2019; Iwamoto et al., 2019; Khan et al., 2019; Konkle & Sood, 2019; Quinton, 2019; Swee, Javaid, & Quinton, 2019; Abou-Ismail, Sridhar, & Nayak, 2020)

儘管 WHI 已披露口服 CEE 單藥治療與血栓風險的相關性,但對於口服或透皮雌二醇單藥治療與血栓風險的關係,目前尚無任何隨機對照試驗能夠給出具備統計學意義的結論。由於血栓很罕見,只有大規模、且高支出的試驗專案方可呈現這類資料,但至今沒有任何這樣的研究進行過。同樣地,對於含 EE 的避孕藥與血栓風險之升高的關係,至今亦無任何隨機對照試驗進行過(Moores, Bilello, & Murin, 2004)
無論如何,在其它情況下,雌激素已被明確表明與此相關;該結論也可類推至口服雌二醇。
另外,有一項隨機對照試驗:雌激素及靜脈血栓影響試驗(EVTET),在曾有血栓史的已絕經婦女當中分別使用低劑量口服雌二醇(2 mg/天)合併醋酸炔諾酮(NETA;一種孕激素)、以及安慰劑;其發現,該激素配方引起了凝血功能與血栓發生率的顯著升高——試驗組、對照組發生率分別為 10.7% 和 2.3%(統計學 P 值:0.04)(Høibraaten et al., 2000; Høibraaten et al., 2001)

絕經前婦女體內的雌二醇水平應與血栓風險無關(Holmegard et al., 2014)。這裡要指出一項事實:更年期婦女使用 100 μg/天的透皮雌二醇貼片,並未引起更大的血栓風險;因為此劑量平均可達到 100 pg/mL 的雌二醇水平,這與絕經前婦女正常月經週期內的綜合平均水平相當(Aly, 2018; 維基百科)
當異常激素狀態(如妊娠與服用避孕藥)得到控制之後,無論是女性還是男性(男性的雌二醇水平通常很低),都會有相近的血栓發生率(Moores, Bilello, & Murin, 2004; Rosendaal, 2005; Montagnana et al., 2010; Roach et al., 2013)。不過有意思的是,男性復發血栓的機率總是高於女性(Roach et al., 2013)
上述發現表明,絕經前婦女生理水平下的雌二醇與孕酮,應不會使凝血功能或血栓風險明顯升高。不過,現有資料五花八門,有的研究指出生理範圍內的雌二醇、孕酮水平其實會影響到絕經前、圍絕經期婦女的凝血功能(Chaireti et al., 2013)以及血栓風險(Simon et al., 2006; Canonico et al., 2014; Scheres et al., 2019)

現代複方避孕藥含有中等劑量的 EE(20–35 μg/天)和一種生理劑量的孕激素。其可將血栓風險提高數倍之多(Konkle & Sood, 2019; Vinogradova, Coupland, & Hippisley-Cox, 2015; 表格)。此外,其還會將心肌梗塞與腦卒中風險提高約 1.5–2 倍(Lidegaard, 2014; Konkle & Sood, 2019)。不過,避孕藥並未引起整體死亡率的升高——至少對服用該藥的較年輕婦女而言(Hannaford et al., 2010)
依據關於更年期激素治療的研究,此類避孕藥中的孕激素會助長由 EE 引起的血栓風險。早年使用的避孕藥(含高劑量 EE,即 50–100 μg/天)所引起的血栓風險,可達現代避孕藥的兩倍之高(Gerstman et al., 1991; PCASRM, 2017; 表格)
而非口服形式的含 EE 避孕製劑(如透皮避孕貼片和陰道避孕環等)所引起的血栓風險,和口服避孕藥相似;這與口服和透皮雌二醇之間的風險有別的情況截然相反(Plu-Bureau et al., 2013; PCASRM, 2017; Konkle & Sood, 2019; Abou-Ismail, Sridhar, & Nayak, 2020)。因此,根據現有資料,EE 的給藥途徑並不會改變血栓風險,這與雌二醇不同。

用於乳癌或前列腺癌患者的高劑量雌激素療法(如口服人工雌激素 DES 和 EE),已知也會引起血栓及心血管併發症風險的劇烈升高(Phillips et al., 2014; Turo et al., 2014; Coelingh-Bennink et al., 2017)。另外,以大劑量用於治療前列腺癌(如口服 140–1,400 mg/天)、且引起妊娠時雌二醇水平的一種雌二醇酯磷酸雌莫司汀(EMP),已知也有此現象(Kitamura, 2001 [圖表]; Ravery et al., 2011)
不過在 1980 年代,有研究發現,高劑量非口服雌二醇所引起的心血管風險,並不等同於高劑量口服人工雌激素或 EMP 的風險(von Schoultz et al., 1989; Ockrim & Abel, 2009);其中包括針對聚磷酸雌二醇(PEP;一種注射用長效雌二醇前體)、以及高劑量雌二醇透皮凝膠的研究(von Schoultz et al., 1989; Aly, 2019)
然而,後續規模更大、質量更佳的研究發現,儘管 PEP 引起的心血管風險遠低於高劑量人工雌激素,但仍有所增長(Hedlung et al., 2008; Ockrim & Abel, 2009; Hedlund et al., 2011; Sam, 2020);其中,在雌二醇水平大致達 300–500 pg/mL 之範圍內的情況下,血栓風險會增長約兩倍(Sam, 2020)
而迄今採用高劑量雌二醇透皮貼片的研究,則未發現心血管併發症有大幅增長(Langley et al., 2013; Sam, 2020)。不過,這些研究仍較缺乏統計學意義支撐,從而使其解釋不大有力。無論如何,高劑量透皮貼片在使雌二醇水平達到 350–500 pg/mL 的情況下,所引起的凝血功能之增強已測得與 PEP 相似(Bland et al., 2005; Mikkola et al., 1999)
目前在英國有兩項正評估高劑量雌二醇透皮貼片用於前列腺癌的大規模臨床研究:前列腺癌透皮激素療法研究(PATCH)與晚期、轉移性前列腺癌系統性治療用藥有效性評估研究(STAMPEDE),其未來有望提供更多關於該雌二醇形式與血栓、心血管風險的資料(Gilbert et al., 2018; Singla, Ghandour, & Raj, 2019)

還需留意注射用短效雌二醇酯(如戊酸雌二醇,EV;環戊丙酸雌二醇,EC)的情況:其常為女性傾向跨性別者所用,且常用劑量可引起較高雌二醇水平。和高劑量雌二醇透皮貼片的情況類似,目前鮮少或尚未有關於這類注射劑與血栓風險的高質量資料。
Pyra 及其同行發現,EV 注射劑用於女性傾向跨性別者時,可將血栓風險提高約 2 倍,但結果置信區間極大,並不具備統計學意義(Pyra et al., 2020)。實驗群體所用劑量並未提供;但對於實際患靜脈血栓的人群,所用 EV 劑量範圍據稱為每週一次 4–20 mg、以及每兩週一次 10–40 mg(Pyra et al., 2020)
其它研究也對此有所評估,並發現高劑量 EV 注射劑(每兩週一次 10–40 mg)用於男性前列腺癌患者時,會引起凝血功能的增強(Kohli & McClellan, 2001; Kohli et al., 2004; Kohli, 2005)
還有,用於絕經前婦女的、含 5 mg 的 EV 和一種孕激素的注射用複方避孕藥(每月一次),已知也會引起凝血功能增強(Meng et al., 1990; d’Arcangues et al., 2003)
對於短效雌二醇注射劑所引起的雌二醇水平尖峰,是否會對凝血功能及血栓風險有害,目前尚不明確(Hembree et al., 2017)。不過,鑑於短效睪酮酯注射劑所引起的紅血球增多症風險要高於其它非口服睪酮(Ohlander, Varghese, & Pastuszak, 2018),可以間接推論,以上觀點可能屬實。與此對應,有一項研究發現,使用相同劑量的注射用複方避孕藥時,含 EV 者會引起凝血功能增強,含 EC 者卻不會(EC 作用時間更長、且有更穩定的雌二醇水平)(d’Arcangues et al., 2003)

與雌激素相似,諸如他莫昔芬雷洛昔芬選擇性雌激素受體調節劑(SERM),也會使血栓風險升高(Park & Jordan, 2002; Fabian & Kimler, 2005)
該風險增幅可達數倍,接近於中等劑量口服雌二醇或 CEE 的預估風險(Deitcher & Gomes, 2004; Iqbal et al., 2012; Konkle & Sood, 2019)

妊娠期間,體內雌二醇與孕酮會激增至極高水平(圖表)。其中,雌二醇水平在妊娠期間會逐漸升高,在妊娠前期、中期和後期結束時平均分別達 2,000 pg/mL、10,000 pg/mL 和 20,000 pg/mL 左右(Kerlan et al., 1994 [圖表]; Schock et al., 2016)。凝血功能在妊娠期間大幅增強,血栓風險也隨之劇烈升高(Heit et al., 2000; Abdul Sultan et al., 2015; Heit, Spencer, & White, 2016; 表格)。妊娠期間的雌二醇與孕酮水平與凝血功能之增強高度相關(Bagot et al., 2019)
由現代避孕藥引起的血栓風險,總和上和妊娠相近(Heit, Spencer, & White, 2016);而早年曾用的含高劑量 EE 的避孕藥、以及用於乳癌與前列腺癌的高劑量口服人工雌激素治療所引起的風險增長,則與妊娠後期相似。
另外,在刺激絕經前婦女排卵以進行體外受精的過程中,其體內雌二醇也會升至相當高的水平;已知這也與凝血功能及血栓風險之升高有關(Westerlund et al., 2012; Rova, Passmark, & Lindqvist, 2012; Kasum et al., 2014)

由於存在心血管健康風險更高等諸多疑慮,DES 事實上已被棄用;而 EE 也不再用於除避孕以外的一切用途。之所以 EE 還用於避孕,是因為其對子宮的代謝作用有抗性,其控制月經出血的能力亦優於口服雌二醇(Stanczyk, Archer, & Bhavnani, 2013)。至於 CEE,儘管醫學上仍較多用於順性別婦女的激素治療,但也正逐漸為雌二醇所取代。
此外,透皮雌二醇也大有取代口服雌二醇用於更年期激素治療之勢。
目前主流的跨性別激素治療指南(另見 Aly, 2020)不建議將 EE 與 CEE 用於女性傾向跨性別者,因為其風險更大、且血清雌激素水平無法準確監測(Coleman et al., 2012; Deutsch, 2016; Hembree et al., 2017)。如今雌二醇是女性傾向跨性別者使用的幾乎唯一一種雌激素。
除雌激素型別外,這些指南還建議年齡高於 40–45 歲、或者有血栓風險的女性傾向跨性別者應以透皮雌二醇取代口服使用(Deutsch, 2016; Iwamoto et al., 2019; Glintborg et al., 2021)
現有關於更年期激素治療的指南,同樣建議有較高血栓風險的順性別婦女使用透皮雌二醇、而非口服(例如 Stuenkel et al., 2015)

如上文所述,孕激素會助長口服雌激素引起的血栓風險。但與此相反的是,關於非口服雌二醇與孕激素合用的研究結果眾說紛紜——有的發現風險升高了,有的則未發現額外的風險(Rovinski et al., 2018; Scarabin, 2018; Vinogradova, Coupland, & Hippisley-Cox, 2019)
孕激素本身通常不會增強凝血功能(Kuhl, 1996; Schindler, 2003; Wiegratz & Kuhl, 2006; Sitruk-Ware & Nath, 2011; Sitruk-Ware & Nath, 2013; Skouby & Sidelmann, 2018)、也不會提高血栓風險(Blanco-Molina et al., 2012; Mantha et al., 2012; Tepper et al., 2016; Rott, 2019)。不過有一項特例:避孕劑量下的 MPA 積存注射劑可將血栓風險提高數倍(van Hylckama Vlieg, Helmerhorst, & Rosendaal, 2010; DeLoughery, 2011; Blanco-Molina et al., 2012; Gourdy et al., 2012; Mantha et al., 2012; Rott, 2019; Tepper et al., 2019)。其原因尚不明確,不過可能與該注射劑引起的較高 MPA 水平峰值(Mantha et al., 2012)、或者 MPA 的弱糖皮質素活性有關(Kuhl & Stevenson, 2006; Sitruk-Ware & Nath, 2011)
除生理劑量的 MPA 單藥之外,高劑量 MPA、醋酸甲地孕酮(MGA)和醋酸環丙孕酮(CPA)已知會引起凝血功能與血栓風險升高(Schröder & Radlmaier, 2002; Schindler, 2003; Seaman et al., 2007; Garcia et al., 2013; Taylor & Pendleton, 2016)
然而,有一項小型研究將醋酸氯地孕酮(CMA)用於曾有血栓史的婦女,發現 CMA 的情況並非同樣如此(Conard et al., 2004)
如將 CPA 與雌激素一併用於女性傾向跨性別者,其也會引起血栓風險增長(Patel et al., 2022)
口服孕酮的情況與合成孕酮製劑相反:在雌激素治療中加入口服孕酮,並不會進一步提高血栓風險(Scarabin, 2018; Oliver-Williams et al., 2019; Kaemmle et al., 2022)。不過這也許只是出於口服孕酮僅可產生很低的孕酮水平、且孕激素效力很弱的事實罷了(Aly, 2018)。非口服、效力完全的孕酮的情況尚未得到足夠研究,故其風險如何仍未可知(Aly, 2018)

值得一提的是,歷史上曾由荷蘭阿姆斯特丹自由大學醫學中心(VUMC)的性別焦慮專家中心(CEGD)在 1980 年代進行的一項研究中,在血栓風險上,服用高劑量 EE 與 CPA 的女性傾向跨性別者比一般人群預期值高了 45 倍之多(Asscheman, Gooren, & Eklund, 1989; Asscheman et al., 2014);而其它風險也一併升高,甚至死亡率也更高了(Asscheman, Gooren, & Eklund, 1989; Gooren & T’Sjoen, 2018)
CEGD 後來針對女性傾向跨性別者進行的一項研究,確認了 EE 會極大增強凝血功能,但口服或透皮雌二醇僅些微增強之(Toorians et al., 2003)。當 CEGD 決定以生理劑量的口服或透皮雌二醇(還常與 CPA 合併)取代高劑量 EE 用於女性傾向跨性別者之後,該風險得到顯著降低(van Kesteren et al., 1997; Asscheman et al., 2011; Asscheman et al., 2014)
這些發現對促進在女性化激素治療當中以雌二醇取代 EE 的過程至關重要;其也無疑極大增長了對高劑量雌激素用於女性傾向跨性別者的顧忌。

綜上所述,已知各類雌激素均會提高血栓風險、或與之存在關聯——取決於劑量。上述發現表明,只要暴露量足夠大,雌激素無疑都會引起凝血功能和血栓風險升高。然而,相比於雌二醇,非生物同質性的人工雌激素皆會有更高血栓風險;而口服雌二醇的風險亦高於非口服。
事實上,在婦女生理水平下的雌二醇,或低至中等劑量下的透皮雌二醇,皆應不會有明顯的血栓風險。儘管如此,只要暴露量足夠高,非口服雌二醇同樣可引起一定的血栓風險升高。
孕激素在與雌激素合用時,應會助長由後者引起的血栓風險,在高劑量下尤其明顯。

不同激素暴露量引起的風險

下表顯示了不同型別、途徑、劑量下的雌激素,以及 SERM、妊娠和高劑量 CPA 所引起的相對風險率。其中可見風險更高的情況:

  1. 口服雌二醇之於非口服雌二醇;
  2. 非生物同質性雌激素之於雌二醇;
  3. 高雌激素劑量、水平之於低雌激素劑量、水平。

【表二】 不同激素暴露量所引起的血栓相對風險率(另見 Machin & Ragni, 2020)

雌激素血栓風險率資料來源
口服雌二醇 ≤1 mg/天1.2 倍Vinogradova et al. (2019) [表格]
口服雌二醇 >1 mg/天(1)1.4 倍Vinogradova et al. (2019) [表格]
口服雌二醇約 1 mg/天(1)合併孕激素(2)1.4–1.8 倍Vinogradova et al. (2019) [表格]
透皮雌二醇 ≤50 μg/天0.9 倍Vinogradova et al. (2019) [表格]
透皮雌二醇 >50 μg/天(1)1.1 倍Vinogradova et al. (2019) [表格]
口服 CEE ≤0.625 mg/天1.4 倍Vinogradova et al. (2019) [表格]
口服 CEE >0.625 mg/天(1)1.7 倍Vinogradova et al. (2019) [表格]
口服 CEE 約 0.625 mg/天(1)合併孕激素(2)1.5–2.4 倍Vinogradova et al. (2019) [表格]
現代避孕藥(EE 與孕激素)(3)4.2 倍Heit, Spencer, & White (2016)
早期避孕藥(高劑量 EE 與孕激素)(3)4–10 倍(4)Tchaikovski, Tans, & Rosing (2006);
PCASRM (2017) [表格]
高劑量聚磷酸雌二醇注射劑(5)2.1 倍Sam (2020)
高劑量口服 DESEEEMP5.7–10 倍Seaman et al. (2007);
Ravery et al. (2011);
Klil-Drori et al. (2015)
SERM(他莫昔芬、雷洛昔芬)約 1.5–3 倍Deitcher & Gomes (2004);
Iqbal et al.(2012);
Konkle & Sood (2019)
妊娠(整體風險)(6)4.0 倍Heit, Spencer, & White (2016)
妊娠(後期)5.1–7.1 倍Abdul Sultan et al. (2015) [表格]
單用高劑量 CPA3–5 倍Seaman et al. (2007)

(1) 在用於更年期激素替代的通常劑量下(不會很高;應不高於所示劑量的兩倍)。
(2) 以下其中一種:醋酸甲羥孕酮、炔諾酮炔諾孕酮屈螺酮
(3) 現代避孕藥含有 20–35 μg/天的炔雌醇,而早期避孕藥(1960–1970 年代所用)則含有 50–150 μg/天。
(4) 該風險率可達現代避孕藥的約兩倍之高。
(5) 來自本站未正式發表的原創研究/分析文章,結果勉強具備統計學意義(95% 可信區間:0.99–4.22)。
(6) 不包括產後時期。如一併計入,則妊娠引起的血栓風險率為 5–10 倍(McLintock, 2014)

需要指出,上表所列各值幾乎來自諸觀察性研究的相關量,而非隨機對照試驗。因此,其成因大多尚未最終確立。此外,由於 95% 可信區間很大,以上各值多僅代表粗略的平均值。因此,以上估計值的準確性在某些情況下可能較差。
還需指出,因定義及方法的差異,不同研究對血栓風險的量化可能有別(其成因包括取樣誤差、對混雜變數的控制手段、以及殘餘混雜因子的影響等)。

雌激素對凝血功能的增強之機理

雌激素受體(ER)在肝臟內表達,而雌激素透過啟用受體而在肝臟發揮效力(Eisenfeld & Aten, 1979; Eisenfeld & Aten, 1987; Sahlin & von Schoultz, 1999; Grossmann et al., 2019)。雌激素被認為可透過啟用肝臟內的 ER、調節多種凝血因子(包括促凝因子抗凝因子)在肝臟的產生,而引起血栓風險的升高(Kuhl, 2005; Tchaikovski & Rosing, 2010; DeLoughery, 2011; Konkle & Sood, 2019)
大多數凝血因子及其抑制劑由肝臟合成(Mammen, 1992; Amitrano et al., 2002; Peck-Radosavljevic, 2007);隨後被分泌至血液,進入體內迴圈,間接發揮效力。
雌激素可影響以下凝血因子的血清水平(Hemelaar et al., 2008; Doxufils, Morimont, & Bouvy, 2020)

淨凝血活性標誌物(如凝血酵素原片段 1.2D-二聚體凝血酵素—抗凝血酵素複合物等)以及全身凝血功能測定(如基於凝血酵素生成潛力活性 C 蛋白抗性試驗)的評估顯示,由雌激素引起的血清因子水平變動,會導致整體促凝作用的加強(口服避孕藥與凝血功能研究小組, 1999; Kohli, 2006; Hemelaar et al., 2008; Douxfils et al., 2020; Douxfils, Morimont, & Bouvy, 2020)
大多數由雌激素引起的凝血因子水平之變動相對較小,且通常仍維持於正常範圍內。不過,放到一起的話,它們對全身凝血功能與血栓風險的增長作用會更大(Douxfils et al., 2020; Douxfils, Morimont, & Bouvy, 2020; Reda et al., 2020)

除凝血因子外,雌激素還調節多種肝臟產物的合成(Kuhl, 1999; Kuhl, 2005; 表格)。其中包括:

與雌激素引起凝血功能與血栓風險升高背後的機理一樣,不同型別及途徑的雌激素在對雌激素敏感的肝臟產物上的影響,和對血栓風險的影響完全一致。也就是說,不同雌激素在肝臟和在體內其它部位的效力差別,是有所不同的。
非生物同質性的人工雌激素對肝臟合成的影響,要高於雌二醇;而口服雌二醇的影響要高於非口服途徑(如透皮和肌肉注射)。這可能解釋了為何這些雌激素對凝血功能與血栓風險的影響不一。
下表顯示了不同雌激素暴露量對肝臟的效力;其中測定的是 SHBG 水平,其為受雌激素調節的肝臟產物當中最敏感、且特徵明顯的一種。

【表三】 不同雌激素暴露量所引起的 SHBG 水平相對增長率(另見 Aly, 2020):

雌激素SHBG 增幅資料來源
雌二醇貼片 50 μg/天1.1 倍Kuhl (2005)
雌二醇貼片 100 μg/天1.2 倍Shifren et al. (2008)
口服雌二醇 1 mg/天1.6 倍Kuhl (1998)
口服雌二醇 2 mg/天2.2 倍Kuhl (1998)
口服雌二醇 4 mg/天1.9–3.2 倍Fåhraeus & Larsson-Cohn (1982);
Gibney et al. (2005);
Ropponen et al. (2005)
口服 EV 6 mg/天(1)
(等效雌二醇約 4.5 mg/天)
2.5–3.0 倍Dittrich et al. (2005);
Mueller et al. (2005);
Mueller et al. (2006)
口服 CEE 0.625 mg/天1.8 倍Kuhl (1998)
口服 CEE 1.25 mg/天2.2 倍Kuhl (1998)
口服 EE 5 μg/天2.0 倍Kuhl (1999)
口服 EE 10 μg/天3.0 倍Kuhl (1998)
口服 EE 20 μg/天3.4 倍Kuhl (1998)
口服 EE 50 μg/天4.0 倍Kuhl (1997)
現代避孕藥(含 EE 與孕激素)(2)約 3.0–4.0 倍Odlind et al. (2002)
早期避孕藥(含高劑量 EE 與孕激素)(2)約 5–10 倍Hammond (2017)
雌二醇貼片 200 μg/天約 1.5 倍Smith et al. (2019)
雌二醇貼片 300 μg/天約 1.7 倍Smith et al. (2019)
雌二醇貼片 600 μg/天約 2.3 倍Bland et al. (2005)
高劑量雌二醇注射劑(3)1.7–3.2 倍Stege et al. (1988);
Kronawitter et al. (2009) 表格;
Mueller et al. (2011);
Nelson et al. (2016)
高劑量口服 DESEEEMP約 5–10 倍von Schoultz et al. (1989)
妊娠約 5–10 倍Hammond (2017)

(1) 戊酸雌二醇所含雌二醇佔其質量的約 75%。因此,6 mg/天的戊酸雌二醇大致等效於 4.5 mg/天的雌二醇。
(2) 現代避孕藥含有 20–35 μg/天的炔雌醇,而早期避孕藥(1960–1970 年代所用)則含有 50–150 μg/天。
(3) 注射 320 mg/月的 PEP(雌二醇水平約 700 pg/mL)、100 mg/月的十一酸雌二醇(雌二醇水平約 500–600 pg/mL)或 10 mg/十天的 EV(雌二醇水平峰值約 500–1200 pg/mL;圖表

雌激素治療所引起的 SHBG 水平升高,與凝血功能及血栓風險的上升有相互聯絡,故可視作此類效應的一種可靠的替代指標(Odlind et al., 2002; van Rooijen et al., 2004; van Vliet et al., 2005; Tchaikovski & Rosing, 2010; Raps et al., 2012; Stegeman et al., 2013; Hugon-Rodin et al., 2017; Eilertsen et al., 2019)
某些情況下,SHBG 水平的增幅甚至還與血栓風險之增幅非常接近;例如,服用現代避孕藥(皆提高約 4 倍)、服用高劑量口服人工雌激素以及妊娠後期(皆提高約 5–10 倍)。
儘管目前有關特定雌激素途徑或劑量的血栓風險資料還較缺乏以至不存在(例如高劑量口服雌二醇、或者高劑量雌二醇酯注射劑);但藉由觀察 SHBG 水平的變動,可以粗略推斷對肝臟總的影響、凝血系統變化的幅度,以及血栓風險。
不過需要注意,孕激素在與雌激素合用時,會助長後者的血栓風險,同時不一定會影響 SHBG 水平、反而可能降低之(如伴有雄激素活性)(Kuhl, 2005; Vinogradova, Coupland, & Hippisley-Cox, 2019)

生理水平下的雌二醇應對肝臟合成具有相對微弱的影響(Eisenfeld & Aten, 1979; Lax, 1987; Kuhl, 2005);這與其在婦女當中僅有些微、以至沒有血栓風險的認識相一致。目前認為,在正常生理條件下,雌二醇應僅在相當高的水平下——即懷孕期間——才會明顯影響肝臟合成。妊娠期間肝臟產物的變化可能會起到重要的生物作用(Eisenfeld & Aten, 1979);凝血功能被認為是其中之一,因為凝血功能可減少分娩時的失血,從而有助於 (產婦) 存活。
相反的是,除妊娠之外,凝血功能的增強並不會帶來任何明顯益處。

口服雌二醇與肝臟首渡效應

口服藥品需首先從肝門靜脈經過肝臟,即首渡效應;而非口服 途徑的藥品不會先經過肝臟(Pond & Tozer, 1984; Back & Rogers, 1987)。因此,口服雌二醇會受肝臟首渡效應影響,但非口服(如透皮、注射)形式的雌二醇則不會(Kuhl, 1998; Kuhl, 2005)
首渡效應會導致雌二醇在肝臟的暴露量、以及其對肝臟蛋白合成的雌激素作用畸高(Kuhl, 2005)。類似地,口服雌二醇對肝臟凝血因子合成的雌激素作用同樣畸高(Kuhl, 1998; Kuhl, 2005)。據估計,受首渡效應影響,口服雌二醇對肝臟的雌激素作用強度是非口服雌二醇的 4–5 倍(Kuhl, 2005)
從觀察性研究已發現透皮雌二醇的血栓風險較口服更低;由於大多數非口服途徑可避免肝臟首渡效應,這點應相當符合生物學邏輯(Baber et al., 2016)

figure 1

【圖一】 口服雌激素經肝臟首渡效應引起凝血功能增強的示意圖(Scarabin et al., 2020)。縮寫:

另見活性 C 蛋白抗性(APCR)。

儘管口服雌二醇因首渡效應而具有更高的引起血栓之可能,但只要血清雌二醇水平足夠高,無論何種途徑的雌二醇,都會擴散至肝臟併發揮效力。因此,非口服途徑(或自身分泌)引起的高雌二醇水平也會像口服一樣,引起凝血功能與血栓風險的升高。這點可從雌激素效力極高的一些情況明確證實,例如妊娠及刺激排卵以供體外受精的情況——此時雌二醇水平升至極高,會顯著影響肝臟蛋白的合成。

非生物同質性雌激素與肝臟代謝抗性

諸如 EEDESCEE 等非生物同質性雌激素,對肝臟蛋白的合成以及血栓風險之影響,不僅大於口服雌二醇,也高於非口服雌二醇(Kuhl, 1998; Kuhl, 2005; Phillips et al., 2014; Turo et al., 2014; 表格)。這是因為,雌二醇會被肝臟劇烈代謝並失活,而非生物同質性雌激素在分子結構上有別於雌二醇,使得其對肝臟代謝的抗性遠高於之(Kuhl, 1998; Kuhl, 2005; Connors & Middeldorp, 2019; Swee, Javaid, & Quinton, 2019)

EE 為例:其口服生物利用度約為 45%,而口服雌二醇僅有約 5%(Kuhl, 2005; Stanczyk, Archer, & Bhavnani, 2013)。此外,EE 的血漿清除半衰期長達 5–30 小時,而雌二醇僅有不足 1 小時(White et al., 1998; Kuhl, 2005; Stanczyk, Archer, & Bhavnani, 2013)。還有其它一系列差別;從總和雌激素效力來看,同質量下 EE 之效力相當於雌二醇的約 120 倍(Kuhl, 2005; 表格)。因此,臨床上 EE 的劑量以微克計,而口服雌二醇的劑量要以毫克計、且高出 100 倍以上。
從 EE 與雌二醇在藥代動力學上的差別可以反映出 EE 對肝臟代謝的高度抗性(Kuhl, 2005)。之所以 EE(也稱 17α-乙炔雌二醇)具備對肝臟代謝的抗性,是因為其在碳 17α 點位上比雌二醇多出了一個乙炔基團(Kuhl, 2005);這種分子修飾導致了位阻效應,即其阻止了 17β-羥類固醇脫氫酵素(17β-HSD)、以及硫酸基轉移酵素葡萄糖醛酸基轉移酵素結合酵素作用於碳 17β 點位上的羥基團,從而阻止對 EE 的代謝。其中,17β-HSD 通常將雌二醇轉化為效力較弱的雌酮,而結合酵素會將雌二醇轉化為無活性的 17β-硫酸或葡萄糖醛酸雌激素結合物(如硫酸雌酮(Kuhl, 2005)
事實上,類似於“乙炔雌酮”的代謝物是完全不存在的;因為其需要在第 17 碳原子上以兩個分子鍵與氧原子結合 為酮基團——而結合點位只有 17α 與 17β,前者在 EE 分子內已由乙炔基團佔有。因此,EE 不像雌二醇那樣會在肝臟內代謝成效力較弱或無活性的物質(如雌酮與硫酸雌酮),以防止啟用肝臟受體、增強凝血功能;其也因此與更高的血栓風險有關(Kuhl, 2005; Russell et al., 2017)

figure 2

【圖二】 幾種雌激素的化學結構,分別為雌二醇、炔雌醇、雌酮與己烯雌酚。甾體雌激素(雌二醇、炔雌醇與雌酮)的第 17 碳原子位於其結構式的右上角。

由於 EE 對肝臟代謝與失活機制有明顯抗性,故可在肝臟內維持很長時間;其裂解之前往往會多次迴圈經過肝臟。此外,相比於等效劑量的口服雌二醇,EE 對肝臟蛋白合成作用的畸高程度要高出好幾倍(Kuhl, 2005; 表格)。因此,EE 不僅在總和效力上比口服雌二醇高約 120 倍,更是在對肝臟的效力上高出約 350–1,500 倍(von Schoultz et al., 1989; Kuhl, 2005)。即使非常小的劑量下(1 μg/天),EE 仍會對肝臟代謝造成影響(Speroff et al., 1996; Trémollieres, 2012)
還有,無論是經口服、還是經透皮或陰道給藥,EE 皆會對肝臟與血栓風險產生相似的影響;該事實表明,EE 無需經過口服的首渡效應便可影響血栓風險,這點與口服雌二醇不同(Plu-Bureau et al., 2013; PCASRM, 2017; Konkle & Sood, 2019)。EE 的代謝抗性很高,這意味著無論何種途徑,都對肝臟有顯著影響。
EE 在肝臟的超強效力,使得其對凝血功能與血栓風險的影響遠甚於等效劑量下的雌二醇。

CEE 對肝臟蛋白合成作用的畸高程度,也高於口服雌二醇數倍,但低於 EE(Kuhl, 2005; 表格)。這可能與其含有的馬雌激素有關;馬雌激素並不為人體接受,也對人肝臟代謝存在抗性。
另一方面,DES 對肝臟的雌激素作用則更甚於 EE(Kuhl, 2005; 表格)。之所以 DES 對肝臟合成的影響畸高程度還高於 EE 或 CEE,可能是因為 DES 是一種非甾體類雌激素,在結構上相較甾體雌激素精簡了許多。這點應該有一定關係,因為 DES 不像甾體雌激素對肝臟甾體代謝酵素有不同程度的敏感性(Kuhl, 2005),其對 17β-HSD 無親和性,故其羥基團也不會被氧化,成為形如雌酮的酮基代謝物;這點和 EE 類似(Jensen et al., 2010)
由於具有高於雌二醇的肝臟代謝抗性,在等效劑量下,CEE 及非甾體類雌激素 DES 等也與 EE 一樣,對凝血功能與血栓風險具有更大影響(不過影響程度不一)。

如將口服非生物同質性雌激素與透皮(而非口服)雌二醇作比較,其對受雌激素調節的肝臟蛋白合成之影響就猶如天壤之別了。只需簡略計算,便很快得知為何此類雌激素在高劑量下會有類似於妊娠的、對肝臟蛋白及血栓風險的影響。下表顯示了經粗略估算的、不同雌激素對肝臟的相對作用強度。

【表四】 雌激素對肝臟的雌激素效力及總和/全身雌激素效力之比值,由特定肝臟產物(如 SHBG)粗略估算而來(Kuhl, 2005; 表格)

雌激素相比口服雌二醇的肝臟效力相比透皮雌二醇的肝臟效力
透皮雌二醇約 0.25 倍(1)1.0 倍(1)
口服雌二醇1.0 倍約 4.0 倍
口服結合雌激素1.3–4.5 倍約 5.2–18 倍
口服炔雌醇2.9–5.0 倍約 12–20 倍
口服己烯雌酚5.7–7.5 倍約 23–30 倍

(1) 資料來源自一項研究的發現:在可達到同等雌二醇水平的劑量下,口服雌二醇對 SHBG 水平的影響相當於透皮雌二醇的 4 倍(Nachtigall et al., 2000)

由雌激素引起的肝臟蛋白合成之變化,並非與劑量或對肝臟相對效力呈線性關係。其中,SHBG 及其它肝臟產物的水平會隨雌激素劑量上升,並逐漸達到飽和——也即,高劑量的影響並沒有低劑量下那麼大(Kuhl, 1990; Kuhl, 1999)。例如,口服 EE 在 5 μg/天、10 μg/天、20 μg/天與 50 μg/天的劑量下,引起 SHBG 水平上升的幅度分別為 2.0 倍、3.0 倍、3.4 倍和 4.0 倍(Kuhl, 1998; Kuhl, 1999)。此類發現應歸因於高雌激素濃度對肝臟 ER 的競爭性結合、啟用趨於飽和(Kuhl, 1990)
有一點可以印證之:儘管口服 EE 對肝臟的效力遠甚於口服雌二醇,但後者可能會意外地很快“後來居上”,超過 EE 及其它非生物同質性雌激素。相應地,已知口服雌二醇在 1 mg/天、2 mg/天與 4 mg/天劑量下,引起的 SHBG 水平增幅分別為 1.6 倍、2.2 倍和 1.9–3.2 倍(Fåhraeus & Larsson-Cohn, 1982; Kuhl, 1998; Gibney et al., 2005; Ropponen et al., 2005)
因此,儘管口服 EE 對肝臟的效力應有口服雌二醇的約 3–5 倍,但在總和雌激素效力接近於 EE 的劑量下,口服雌二醇也足以引起較大的 SHBG 水平增長,增幅僅僅略低於 EE。

選擇性雌激素受體調節劑及其代謝抗性

SERM 是雌激素受體(ER)的部分促效劑,包括他莫昔芬、雷洛昔芬等。這與雌激素不同——像雌二醇、CEE、EE 和 DES 之類都是 ER 的完全促效劑
與 DES 等非甾體類雌激素類似,臨床上使用的 SERM 均屬於非甾體類物質,對肝臟代謝有高度抗性。事實上,像他莫昔芬與氯米芬等特定型別的 SERM,在分子結構上與 DES 很接近,也是 DES 的衍生物。
SERM 在不同組織內有不同的雌激素調節作用;其在骨骼等一些組織會發揮雌激素效力,而在乳房等其它組織發揮抗雌激素效力(Lain, 2019; 表格)。儘管不同 SERM 對特定組織(如子宮)的效力各異,但其皆在肝臟表達雌激素效力;因此,SERM 也會像雌激素一樣提高血栓風險(Park & Jordan, 2002; Fabian & Kimler, 2005)。與非生物同質性雌激素類似,SERM 引起血栓風險的增幅也高於口服雌二醇,其原因亦可歸於對肝臟更高的代謝抗性、以及更強的雌激素效力。
醫學上使用的 SERM 可分為多種結構型別;例如他莫昔芬屬於三苯乙烯類,而雷洛昔芬屬於苯並噻吩類。不同結構型別的 SERM 之間只有一項共同點:就是其與 ER 的互動機制相似。

figure 3

【圖三】 部分 SERM 的化學結構。其在結構上均屬於非甾體類物質,其中包括他莫昔芬(三苯乙烯類)與雷洛昔芬(苯並噻吩類)。

雌激素與 SERM 對雌激素受體的啟用:凝血功能增強的緣由

來自臨床前基因研究的發現,直接證明了血栓風險之升高源自 ER 的啟用。有一項重要的動物實驗研究,對小鼠服用 EE 後的促凝及抗凝生物標記的變化進行了測定;其發現 EE 引起了多種凝血因子水平的變化(Cleuren et al., 2010)
研究者還評估了服用雌二醇的情況,也發現了類似變化(Cleuren et al., 2010)
如將 EE 與一種選擇性 ER 完全拮抗劑:氟維司群合用,則後者會完全中和由 EE 引起的凝血變化(Cleuren et al., 2010)
此外,在已敲除雌激素受體 α 的小鼠中使用 EE,則未對凝血因子產生影響(Cleuren et al., 2010)
上述發現與對人及小鼠的全基因組關聯分析所發現的一致——即雌激素響應元件(ERE)在涉及凝血通路的大量基因當中廣泛存在(Cleuren et al., 2010; Stanczyk, Mathews, & Cortessis, 2017)(ERE 是一段位於基因轉錄起點的 DNA 序列,受 ER 調控而與轉錄因子結合,從而起到調控這些基因的作用。)

以上發現恰恰表明,之所以雌激素會引起凝血功能與血栓風險升高,就是因為 ER 的啟用。其也印證了一項事實:各類選擇性 ER 促效劑無論在化學結構上有多大差別,皆會引起血栓風險;其也間接證明了某些非 ER 引起的效應並非凝血功能增強的起因(例如雌酮作為弱雌激素活性的代謝物,會在一定程度上與雌二醇共同引起血栓風險Bagot et al., 2010)。
因此,凝血功能與血栓風險的升高可視為雌激素與 SERM 的共同作用——在肝臟暴露量足夠高的情況下。不過,不同型別的 ER 促效劑對肝臟代謝的敏感度不同,從而對凝血功能具有不同的影響。
雌二醇對肝臟代謝缺乏抗性,也會在肝臟內大量失活,因此其引起凝血功能與血栓風險升高所需的劑量(尤其是非口服雌二醇),要高於非生物同質性雌激素。故此,如用於雌激素治療,雌二醇(尤其非口服途徑)會比其它雌激素更安全。

血栓絕對發生率與風險因素

對婦女而言,雌激素、孕激素暴露量狀態(例如極高的激素攝入,或者妊娠),無疑是公認的血栓風險因素。不過,在無相關風險因素的年輕健康人群當中,即使因激素引起血栓風險的極大提升,也極少出現血栓病例(Rosendaal, 2005)
非妊娠期婦女的年化 VTE 絕對發生率,為每萬人 1–5 例(即年均 0.01–0.05%)(PCASRM, 2017; Konkle & Sood, 2019)。而當婦女服用含 EE 的避孕藥時,儘管其 VTE 風險平均會提高約 4 倍,但年化 VTE 發生率僅有每萬人 3–9 例(即年均 0.03–0.09%)(Konkle & Sood, 2019)。類似地,婦女妊娠期間,儘管雌二醇與孕酮水平變得極高,VTE 風險也升高達 7 倍(Abdul Sultan et al., 2015),但血栓絕對發生率僅有每年每萬人約 5–20 例(即年均 0.05–0.2%)(PCASRM, 2017; Konkle & Sood, 2019)

【表五】 絕經前婦女在不同雌激素暴露量下的 VTE 絕對發生率(Gerstman et al., 1991; Konkle & Sood, 2019; Douxfils, Morimont, & Bouvy, 2020)

組別/療法年均發生率
非妊娠期婦女每萬人 1–5 例(0.01–0.05%)
各年齡段(Rabe et al., 2011)
不足 19 歲: 每萬人 1–2 例;
20–29 歲: 每萬人 2–3 例;
30–39 歲: 每萬人 3–4 例;
40–49 歲: 每萬人 5–7 例;
15–49 歲平均: 每萬人約 3–4 例
現代避孕藥(EE 劑量小於 50 μg/天)每萬人 3–12 例(0.03–0.09%)
早期避孕藥(EE 劑量大於 50 μg/天)每萬人約 10 例(0.1%)
妊娠每萬人 5–20 例(0.05–0.2%)
產後時段每萬人 40–65 例(0.4–0.65%)

無論如何,高雌激素暴露量引起的 VTE 及心血管風險,會隨時間及人口規模累積。據估計,歐洲每年會發生 22,000 例由避孕藥引起的 VTE 病例(Morimont, Dogné, & Douxfils, 2020);在美國,每年有 300–400 名年輕健康婦女會死於由避孕藥引起的血栓(Keenan, Kerr, & Duane, 2019)
需要指出,相比於含有 EE,如避孕藥改為含有雌二醇或雌四醇,應會顯著減小促凝作用、降低血栓風險;如果這點得到進一步確認,將有望大幅減少血栓病例(Stanczyk, Archer, & Bhavnani, 2013; Dinger, Minh, & Heinemann, 2016; Grandi, Facchinetti, & Bitzer, 2017; Fruzzetti & Cagnacci, 2018; Grandi et al., 2019; Grandi et al., 2020; Douxfils, Morimont, & Bouvy, 2020; Reda et al., 2020; Morimont et al., 2021; Grandi, Facchinetti, Bitzer, 2022)

已知除雌激素與孕激素暴露量之外,也有一系列引起血栓風險的其它因素,其會與時間和人口規模一道明顯助推風險率(Heit et al., 2000; Rosendaal, 2005)。其中,年齡是已知最主要的風險因素之一(Rosendaal, 2005; Montagnana et al., 2010)。年齡也是最特別的一項因素,因為每個人都會逐漸與此相關。血栓風險率在 15 歲以下的人群中僅有年均不足 0.005% 到 0.01%;而到了 80 歲以上,該風險率升至年均約 0.5–1.0%,增長一百倍左右(Rosendaal, 2005; Montagnana et al., 2010; Rabe et al., 2011)
下圖將年齡對血栓風險的影響視覺化展現。

figure 4

【圖四】 在不同年齡段,每十萬名男性(黑色柱)及女性(灰色柱)首次發生 VTE 的年均風險率(Oger, 2000; Rosendaal, 2005; Rosendaal, 2016)

引起血栓及心血管問題的其它已知風險因素包括(Baron et al., 1998; Heit et al., 2000; Rosendaal, 2005; Lijfering, Rosendaal, & Cannegieter, 2010; Timp et al., 2013)

  • 運動量少(例如由床上休息、長途旅行等引起);
  • 肥胖;
  • 吸菸;
  • 凝血指標異常
  • 癌症;
  • 外科手術;
  • 艾滋病;
  • 等等。

除年齡之外,運動量少也是最主要的血栓風險因素之一,也會助推許多其它因素引起的風險(Oger, 2000; Rosendaal, 2005; Rosendaal, 2016)
吸菸本身並不大會引起 VTE 風險的增長(Lijfering, Rosendaal, & Cannegieter, 2010);但如同時服用含 EE 的避孕藥,也會一併提高 VTE 風險(Pomp, Rosendaal, & Doggen, 2008),同時還大幅提高心肌梗塞風險——例如,老菸民患心梗的風險會提高 20 倍(Kuhl, 1999)
下表顯示了一些已知風險因素對 VTE 的影響:

【表六】 除激素過量以外的其它 VTE 風險因素,以及 VTE 風險相對增幅(Baron et al., 1998; Heit et al., 2000; Rosendaal, 2005; Lijfering, Rosendaal, & Cannegieter, 2010; Timp et al., 2013)

風險因素相對風險率
年齡1 倍到無窮大
癌症2–20 倍(1)
艾滋病3–10 倍
體重過大、肥胖2–3 倍
外科手術、創傷、無法行動5–50 倍
在家臥床不動9 倍
乘坐飛機1.5–3 倍
吸菸0.8–1.5 倍(2)
靜脈曲張1–4 倍
妊娠4 倍
產後15–20 倍

(1) 視型別與階段而不同(Baron et al., 1998; Timp et al., 2013)。據一項研究的發現,乳癌與前列腺癌分別使 VTE 風險增至一般人群的 1.8 倍與 4.2 倍(Baron et al., 1998)
(2) 吸菸本身不大會引起 VTE 風險的增長(Lijfering, Rosendaal, & Cannegieter, 2010; Rabe et al., 2011)

遺傳性與獲得性易栓症,在人群中佔比不小,且會導致血栓風險大幅增長(Lijfering, Rosendaal, & Cannegieter, 2010)。其也很少被人察覺(Morimont, Dogné, & Douxfils, 2020)。這是因為,對遺傳性易栓症的篩查多基於家族病史,在識別有相關異常的人群時,這不僅難以感知,且很難作出預警(Morimont, Dogné, & Douxfils, 2020)。故此,許多人正處在高血栓風險而不自知。
下表顯示了一系列凝血指標異常的流行率,以及其對血栓風險的影響。

【表七】 凝血指標異常的流行率,及 VTE 相對風險率(Martinelli, Passamonti, & Bucciarelli, 2014; Mannucci & Franchini, 2015; 另見 Walker, 2009; Konkle & Sood, 2019)

易栓症型別一般人群流行率VTE 患者流行率VTE 首次發病
風險率
VTE 復發
風險率
抗凝血酵素缺陷0.02–0.2%1%50 倍2.5 倍
C 蛋白缺陷0.2–0.4%3%15 倍2.5 倍
S 蛋白缺陷0.03–0.1%2%10 倍2.5 倍
凝血因子 V 的 Leiden 突變(雜合型)5%20%7 倍1.5 倍
凝血因子 V 的 Leiden 突變(純合型)0.02%1.5%80 倍-
凝血酵素原 G20210A 突變(雜合型)2%6%3–4 倍1.5 倍
凝血酵素原 G20210A 突變(純合型)0.02%小於 1%30 倍-
非 O 型血人群55–57%75%2 倍2 倍
抗磷脂抗體1–2%5–15%11 倍不明
高同型半胱氨酸血癥5%10–15%1.5 倍不明

血栓被視為一種多成因的疾病(Rosendaal, 2005)。當多種風險因素並存時,激素暴露量對血栓及心血管併發症風險的影響是最大的。在最極端的情況之一下——即年齡高、又有癌症、同時還在服用高劑量人工雌激素(如 DES)——,血栓發生率可達 15–28%,而心血管併發症的總和發生率可達 35%(Phillips et al., 2014; Sciarria et al., 2014; Turo et al., 2014)
上述不良反應讓這些人群的發病率和死亡率都有很大增加。不過,絕大多數人遠未達到如此高的風險。就像妊娠期婦女在其雌二醇與孕酮水平已極高的同時,仍僅有微小的血栓問題,是因為年齡所致;又如,老年癌症患者接受高劑量人工雌激素治療,卻有很高的死亡風險,這也是年齡作梗。

由 VUMC 進行的研究發現,女性傾向跨性別者使用高劑量 EECPA 長達 5–10 年之後,其血栓發生率增長了 20–45 倍;VUMC 於 1989 年的報告和 1997 年的跟蹤報告指出的血栓絕對發生率,分別為 6.3% 和 5.5%(每年每萬人 142 例和 58 例)(Asscheman, Gooren, & Eklund, 1989; van Kesteren et al., 1997; Asscheman et al., 2014; Goldstein et al., 2019; Min & Hopkins, 2021)
而年齡低於 40 歲和高於 40 歲的人群之絕對發生率,則為 2.1% 和 12%;這與目前關於年齡對血栓風險之影響的認識相吻合(Asscheman, Gooren, & Eklund, 1989; Asscheman et al., 2014)。有約 70% 的病例除年齡以外無任何已知的血栓風險因素(Asscheman, Gooren, & Eklund, 1989; Asscheman et al., 2014)。當以低至中等劑量的透皮雌二醇取代 EE 用於已超過 40 歲的人群之後,其血栓發生率顯著降低了(該群體內僅出現一例血栓病例)(van Kesteren et al., 1997; Asscheman et al., 2014; Min & Hopkins, 2021)
2013 年,由比利時根特大學附屬醫院進行的一項研究發現,治療時長平均達 7.7 年(範圍從 3 個月到 35 年不等)的女性傾向跨性別者群體的血栓發生率為 5.1%;其用藥主要為雌二醇(口服或透皮)、合併或不合並 CPA(Wierckx et al., 2013) Min & Hopkins, 2021)。患血栓的人群多有諸如高年齡、吸菸、因手術失去行動能力或處於高凝狀態等風險因素(Wierckx et al., 2013) Min & Hopkins, 2021)
除(激素)累計暴露時間之外,以上研究還揭示了多種風險因素並存會對血栓風險有何等影響;這些因素包括雌激素型別、途徑和劑量,孕激素暴露量,以及年齡,等等。

對女性傾向跨性別者的治療意義

非生物同質性雌激素(如 EECEE)因有更高的血栓和心血管健康風險,如今已幾乎不再為女性傾向跨性別者所用;取而代之的是口服與非口服形式的雌二醇。目前通行的跨性別臨床指南一般都推薦,無論使用口服、還是非口服途徑的雌二醇,皆應將雌二醇水平維持在非妊娠期婦女的正常生理範圍內,即 100–200 pg/mL 左右(Aly, 2018)
已知高於此範圍的雌二醇水平並不會在女性化或乳房發育等方面具備更好的療效(Nolan & Cheung, 2020)。不過,當雌二醇水平處於較高的 200–500 pg/mL 範圍內時,其還可有效抑制睪酮——如先前女性化效果不夠充分,如此或可起到間接促進作用(Aly, 2018)
如使用雌二醇酯注射劑,在現有跨性別臨床指南所推薦的劑量下,其引起的雌二醇水平可達到以至大幅超出其推薦要維持的生理水平之上限:200 pg/mL(Aly, 2021)

基於現有研究的結果(例如低劑量下或同等 SHBG 增幅下的血栓風險),高劑量口服雌二醇(如 8 mg/天)在血栓風險上的表現若與含較少 EE 的避孕藥別無二致,也不會令人意外。與孕激素(如 CPA)合用時,風險還會變得更高。由於口服雌二醇相比非口服途徑具有更大、且不必要的風險,故最好避免用於女性傾向跨性別者——尤其是有血栓相關風險因素者(如年齡已過 40 歲),以及與孕激素合用者。不過,口服雌二醇具有便利性較好、開銷較少等顯著優點;女性傾向跨性別者及其醫師(在用藥選擇上)也會將其納入考慮。
非口服雌二醇的情況與口服相反:在維持生理範圍(即 100–200 pg/mL)的雌二醇水平的同時,其僅會有微弱、以至不會有血栓風險。因此,生理水平下的非口服雌二醇可安全用於女性傾向跨性別者。

而某些非口服雌二醇會引起超生理的水平;據估計,300–500 pg/mL 左右的雌二醇水平可將血栓水平升至 2 倍(Sam, 2020),而這仍低於由正廣泛使用的含 EE 避孕藥引起的平均 4 倍之多的風險增長。鑑於如此高的雌二醇水平有助於抑制睪酮分泌,且此類避孕藥在全球正廣泛為順性別婦女所用,可以認為,高劑量(合理範圍內)的非口服雌二醇所引起的血栓風險率在女性傾向跨性別者當中應該足可容忍(Haupt et al., 2020);尤其是將高劑量非口服雌二醇單藥治療與雌二醇、抗雄製劑聯合治療(如雌二醇合併蘇拉通、CPA 或可蘇多等——皆有各自的風險及缺點)進行比較之後,更會凸顯前者的優越性。
無論如何,與口服雌二醇的理由類似,使用非口服雌二醇時,最好也應避免引起較高的雌二醇水平,因為其也會表現出更大的風險;尤其是對於有血栓相關風險因素者(如年齡較高)。此外,使用超高劑量、且已超過抑制睪酮所需的非口服雌二醇,是很難站得住腳的;因為其會徒增不必要的風險,亦無任何額外益處。

對血栓的預防

預防血栓的最好方式,是避免引來任何風險。從這點而言,如果可行、且希望選用更安全的治療方案,則可推薦避免使用口服雌二醇、過高劑量的非口服雌二醇,以及孕激素。此外,對於有相關風險因素者(如年齡超 40 歲)、凝血指標異常者、以及有久坐習慣者,則更提倡避免使用以上方案。
積極運動(如步行健身)、戒菸減肥等,皆有助於減小血栓風險(Hibbs, 2008)

某些抗凝血藥品及抗血小板藥品可用於高風險人群,避免其發生血栓。例如:

已知阿司匹林可有效預防血栓(Mekaj, Daci, & Mekaj, 2015; Matharu et al., 2020),也有人建議將其用於正接受激素治療的女性傾向跨性別者(Feldman & Goldberg, 2006; Deutsch, 2016)。不過,關於預防由激素治療引起的血栓之證據仍較有限,且存在爭議(Grady et al., 2000; Cushman et al., 2004);不建議將阿司匹林用於女性傾向跨性別者以預防血栓的也大有人在(Shatzel, Connelly, & DeLoughery, 2017)
已知利伐沙班不僅可完全中和由更年期口服激素治療引起的血栓風險,且遊刃有餘(Blondon, 2020)
無論如何,目前尚無任何抗凝藥品被批准或支援用於預防激素療法引起的血栓風險。有鑑於此,現有臨床指南表示,目前已有證據尚不足以為這方面的抉擇提供指引(例如 McLintock, 2014)
還需注意,抗凝藥品也有各自的副作用及風險,應當謹慎使用。

在跨性別社群當中,有人推薦將蘆丁用於預防血栓,且聲稱有臨床前研究支援(Jasuja et al., 2012; Choi et al., 2015)。(蘆丁是一種天然的黃酮苷,見於多種植物與食物,並以草本保健品的形式在售。)
不過,目前尚無任何臨床證據對此用法或其效力予以支援(Martinez-Zapata et al., 2016; Morling et al., 2018);其有效劑量範圍也尚未得到研究確立。
此外,已知蘆丁等黃酮苷在體內會有諸多不良性質(例如生物利用度很低、代謝率高、半衰期短),因此其生物活性很弱、且療效不佳,使得其用處有限(Ma et al., 2014; Higdon et al., 2016; Cassidy & Minihane, 2017; Zhao, Yang, & Xie, 2019; Zhang et al., 2021)
最後,蘆丁的耐受性及安全性尚未得到評估。出於上述原因,目前不應建議女性傾向跨性別者為降低血栓風險而服用蘆丁。

手術前暫停雌激素的服用曾被認為理論上有助於減小術後恢復期的血栓風險,也曾被建議、指示用於即將接受手術的女性傾向跨性別者(例如 Asscheman et al., 2014)。然而,目前關於此法尚缺乏有力的證據支援;仍需更多研究來確認其是否真的會有益處(Boskey, Taghinia, & Ganor, 2019; Nolan & Cheung, 2020; Haveles et al., 2021; Hontscharuk et al., 2021; Kozato et al., 2021; Nolan et al., 2021; Zucker, Reisman, & Safer, 2021)
近期進行的研究並未發現女性傾向跨性別者術前停用激素會使血栓風險降低;但其統計學證據不足,尚需更大規模的研究以佐證之(Blasdel et al., 2021)
暫停服用激素對某些女性傾向跨性別者而言會很痛苦,為此要相應做出權衡。有一種辦法可作為替代,就是短期使用生理劑量的透皮雌二醇;其不會引起血栓風險,應更為安全。

後記

後記一:Langley 等人 (2021) 所做 PATCH 研究的結果

2021 年二月,一篇有關前列腺癌透皮激素治療(PATCH)試驗引起的長期心血管後果的報告被公開發表(Langley et al., 2021; PDF 文件; 補充附錄)。PATCH 是一項大型隨機對照試驗,其將高劑量雌二醇透皮貼片和 GnRH 促效劑用於治療男性前列腺癌的情況進行對比;目前正進行二期三期試驗(Langley et al., 2021)。其中所用雌二醇貼片的劑量,為每日 3–4 片 100 μg;品牌來自 FemSeven 或 Progynova TS(Langley et al., 2021)
據該報告所述,有 1,694 名男性參與試驗並被隨機分配,其中 790 人服用 GnRH 促效劑,904 人使用雌二醇貼片(Langley et al., 2021)

在上述雌二醇劑量下,雌二醇水平中值約達 215 pg/mL(5%–95% 大致範圍:100–550 pg/mL)(Langley et al., 2021)。有 93% 的雌二醇貼片組男性的睪酮水平被抑制到已去勢範圍內(小於 50 ng/dL),這與 GnRH 促效劑組的抑制率相當一致(約 93%)(Langley et al., 2021)。然而,該報告雖有睪酮抑制率,卻未提供實際睪酮水平,因此這兩組之間無法進行比較(Langley et al., 2021)
在平均約 4 年的跟蹤時長之後,雌二醇組與 GnRH 促效劑組的多項心血管後果並無明顯差異;其中包括 VTE血栓栓塞性卒中及其它動脈栓塞事件(Langley et al., 2021)。此結果與早前有關 PEP 用於前列腺癌的臨床研究結果截然相反;後者發現心血管發病率與 VTE 風險皆有所上升,但其中雌二醇水平明顯高於 PATCH 試驗(Ockrim & Abel, 2009; Sam, 2020)
PATCH 的研究者從其大有前景的用藥安全性資料出發,表示治療前列腺癌時應重新考慮採用透皮雌激素(Langley et al., 2021)

上述發現令人安心,其表明將雌二醇水平控制在有限的較高範圍(像 200–300 pg/mL 這樣)時,其對女性傾向跨性別者的血栓及心血管風險應該也足夠安全。
然而應當指出,這項試驗當中的樣本規模儘管大於早前的同類臨床研究,但仍不足以對血栓風險進行評估;血栓發生率極低,需要很大的樣本規模方可完全量化之。例如,有的研究對更年期及已絕經婦女的血栓風險進行了精確評估,而其受試者規模多達數萬人。因此,儘管從該試驗可知風險率並未顯著上升,但也不能排除有小幅上升的可能。
還應指出,該研究所用劑量引起的較強睪酮抑制效力,並不代表女性傾向跨性別者也會有;因為該研究的受試者大多已步入老年,且睪酮水平會隨年齡增長而降低。

後記二:Totaro 等人 (2021) 與 Kotamarti 等人 (2021) 所作論文

2021 年十一月,一篇有關女性化激素療法引起的血栓風險的系統性評述薈萃分析迴歸分析論文被公開發表:

  • Totaro, M., Palazzi, S., Castellini, C., Parisi, A., D’Amato, F., Tienforti, D., Baroni, M. G., Francavilla, S., & Barbonetti, A. (2021).
    Risk of Venous Thromboembolism in Transgender People Undergoing Hormone Feminizing Therapy: A Prevalence Meta-Analysis and Meta-Regression Study. [一項流行率薈萃分析兼迴歸分析研究:關於正接受女性化激素治療的跨性別者的靜脈血栓風險]
    Frontiers in Endocrinology, 12, 741866. [DOI:10.3389/fendo.2021.741866]

該專案是迄今同類研究當中規模最大的一個。該薈萃分析囊括了來自 18 項研究的總計 11,542 名正接受激素治療的女性傾向跨性別者。其中,VTE 的總流行率為 2%(95% 可信區間:1–3%)。然而,不同研究之間存在很大的差異。
該薈萃分析發現,高年齡與更長的激素治療年限,皆與 VTE 流行率高度正相關。年齡達 37.5 歲及以上的人群當中,VTE 流行率為 3%(95% 可信區間:0–5%);但當年齡小於 37.5 歲時,VTE 流行率則為 0%(95% 可信區間:0–2%)。
激素治療年限達 4.4 年及以上的人群當中,VTE 流行率為 1%(95% 可信區間:0–3%);而不足 4.4 年者則為 0%(95% 可信區間:0–3%)。
這個 0% 估計值並不意味著其完全沒有 VTE 風險,但可以認為此風險率足夠低,以至於這次薈萃分析的樣本規模還不足以探測並量化之。

該薈萃分析存在一項侷限性:其聲稱,由於資料不足,其未能也無法基於雌激素型別(如雌二醇、CEE 與 EE 的比較)與途徑(如口服雌激素,或者口服、透皮雌二醇的比較)進行亞組分析
然而,有另一項近期的薈萃分析,不僅也做了 Totaro 等人 (2021) 的大部分工作,而且確實進行了對諸雌激素型別及途徑的亞組分析;其論文於 2021 年七月公開發表:

  • Kotamarti, V. S., Greige, N., Heiman, A. J., Patel, A., & Ricci, J. A. (2021).
    Risk for Venous Thromboembolism in Transgender Patients Undergoing Cross-Sex Hormone Treatment: A Systematic Review. [一次系統性評述:關於正接受跨性別激素治療的跨性別者的靜脈血栓風險]
    The Journal of Sexual Medicine, 18(7), 1280–1291. [DOI:10.1016/j.jsxm.2021.04.006]

以下是他們關於對諸雌激素型別及途徑的亞組分析的敘述:

由於已有人報告不同雌激素配方具有不同的 VTE 發生率,故在此對口服或透皮給藥途徑、或者特定雌激素劑型在 VTE 發生率上的差異進行了分析。考慮到有多項研究所報告的受試者的用藥包含多種雌激素製劑、或者未披露其型別,故本文無法進行進一步的統計分析。

在出生指派性別為男的人群當中,雌激素的給藥途徑應該 (對血栓發生率) 起到一定作用:(口服)雌二醇的 VTE 發生率,為每年每萬人 34.0 例(來自 7 項研究);透皮雌激素的 VTE 發生率,則為每年每萬人 11.2 例(來自 3 項研究)。
此外,不同雌激素劑型也應有不同的 VTE 發生率。
炔雌醇也與 VTE 發生率的升高有關,為每年每萬人 293.1 例(來自 3 項研究);其次是結合馬雌激素,發生率為每年每萬人 49.0 例(來自 1 項研究);最後是戊酸雌二醇,發生率為每年每萬人 31.5 例(來自 4 項研究)。

由於所引用研究的資料質量參差不齊,尚不清楚以上計算值的準確度如何。而且,抗雄性素製劑(如 CPA)這個因素並未得到控制,據本文所述,其有可能會對 VTE 風險產生額外影響。無論如何,以上數值很有參考意義,也與不同雌激素型別及途徑在 VTE 風險上的不同之處相吻合。

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譯文修訂歷史

時間備註
2022 年 12 月 12 日首次翻譯。
2023 年 4 月 3 日第一次修訂,增補“參考文獻”,更新個別敘述。
2023 年 6 月 29 日更正“己烯雌酚”譯名。

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