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腎病癌癥手術史睪丸固定術腹膜后或盆腔手術疝修補術輸精管切除術膀胱頸或前列腺手術?    性激素暴露藥物（內分泌調節(jié)劑、抗高血壓藥，抗生素、抗精神病藥）環(huán)境（殺蟲劑、重金屬）化療或放療生活方式（肥胖、吸煙、吸煙、娛樂性毒品，合成代謝類固醇）家族史不孕囊性纖維化雄激素受體缺乏癥男性不育癥的成功診斷可能具有挑戰(zhàn)性，因為受孕過程涉及多個器官，需要對兩個人進行評估。評估不孕癥的第一步是獲得完整的病史(專題2)。不孕癥可分為原發(fā)性不孕癥(即無生育史)或繼發(fā)性不孕癥(即既往有生育史，目前不育) [1]。雖然這種區(qū)分可以縮小鑒別診斷，但被歸類為原發(fā)性或繼發(fā)性不孕癥的男性應該以同樣的方式進行評估[50]。各種兒童疾病(如隱睪癥、青春期后腮腺炎、睪丸扭轉或創(chuàng)傷)可導致睪丸萎縮或精液質量下降[51-53]。男性泌尿生殖道感染(前列腺炎、尿道炎、附睪炎和睪丸炎)可能導致男性不育[30]。在一項對4000多名不育癥男性的研究中，男性泌尿生殖道感染的患病率高達35%[54]。一項對1689名男性的橫斷面研究顯示，20%的原發(fā)不育癥男性有無癥狀的精液感染，這與精子密度受損有關[55]。前列腺炎是由大腸桿菌引起的一種常見的泌尿生殖系統(tǒng)疾病，它可以對精子的各種參數(shù)產(chǎn)生有害影響[56]。在35歲以下的性活躍男性中，沙眼衣原體和淋球菌是引起附睪炎的最常見病原體。大腸桿菌是35歲以上男性不育癥的主要病原體。雖然不建議對急性附睪炎或前列腺炎患者進行精液分析，但慢性附睪炎或前列腺炎患者可能出現(xiàn)白細胞精子癥(＞1×10?白細胞/毫升)，這是一種炎癥標志[30]，可以通過精液中的過氧化物酶檢測來確認[57]。  生活方式因素，如吸煙、飲酒、娛樂性吸毒（如可卡因、阿片類毒品、大麻和合成代謝類固醇）以及肥胖也與男性不育相關[40-42]。一項涉及20項研究中5865名男性的大型薈萃分析顯示，中度和重度吸煙者的精液質量惡化[40]。同樣，一項對15項橫斷面研究的薈萃分析揭示了飲酒與精子參數(shù)之間的負相關[41]。大麻是最常用的娛樂藥物，通過抑制下丘腦-垂體-性腺軸、精子產(chǎn)生和精子功能，對男性生育能力產(chǎn)生負面影響[58]。隨著全球肥胖率的持續(xù)上升，肥胖和男性不育之間的關系已經(jīng)得到了廣泛的研究[12]。肥胖引起的內分泌改變導致睪酮外周轉化為雌激素，這與精子濃度降低有關[59]。在肥胖癥的亞群中，代謝性不健康肥胖(即伴有代謝異常，如糖尿病、高血壓、血脂異常、胰島素抵抗)被認為是勃起功能障礙的危險因素，而男性勃起功能障礙和代謝性健康肥胖癥(即沒有代謝和心血管疾病的證據(jù))的組合代表著未來不良代謝后果的早期標志[60]。  夫婦的性行為，包括性交的時間、勃起和射精功能，都應該進行評估。應使用排卵跟蹤方法，以確保夫婦有效地計時性交。建議在排卵前后每48小時進行一次性交，以最大限度地增加受精的機會[61]。影響不孕不育男性的最常見的性功能障礙是性欲低下和性滿足缺失(快感、積極感覺和性高潮) [62]。六分之一的不育癥患者有勃起功能障礙或早泄，或兩者同時存在[63]。數(shù)據(jù)摘自世衛(wèi)組織手冊。ND=未定義。*可能基于麥克勞德的研究73?？捎丝诘?平均值。?任意值。§值未定義，但嚴格的標準和體外受精數(shù)據(jù)建議截止值為14%。表：1980年至2010年世界衛(wèi)生組織《檢驗實驗室手冊》前五版精液參數(shù)正常值的演變情況，以及處理人類精液和精子-宮頸粘液的相互作用。性功能障礙和男性不育的心理影響可能是成功生育的重要障礙，應該在臨床評估中進行篩查。此外，許多夫婦使用陰道潤滑劑，但這些潤滑劑可能會殺死精子[64.65]。植物油、生蛋清和有利于生育的潤滑劑(如美國華盛頓州斯波坎市的Pre-Seed、ING Fertility)的殺精效果最小，但夫婦仍應意識到適量使用這些潤滑劑[66-68]。精液分析世界衛(wèi)生組織建議將常規(guī)精液分析作為評估男性生育潛力的第一步。世界衛(wèi)組織《人類精液和精子-宮頸粘液相互作用檢驗和處理實驗室手冊》自1980[69-72]年出版，最新的手冊于2010年出版[57]。精液參數(shù)的推薦臨界值多年來發(fā)生了巨大變化(表)，但與精液質量相關的命名法仍未改變(專題3)。世界衛(wèi)生組織手冊最新版本[57]中描述的參考下限是通過對來自世界各地的1953名有生育能力的男子精液參數(shù)的統(tǒng)計分析得出的[54]。然而，這些參考限值被批評為沒有考慮女性因素，個體間存在高度生物學差異，以及缺乏具有代表性的種族群體的數(shù)據(jù)[75-77]。因此，標準的精液分析在確定男性生育潛力或預測生殖成功方面的準確性有限。事實上，精液樣本使用世界衛(wèi)生組織2010年參考值來解釋精液分析被認為是正常的，如果使用1999年的手冊就會被認為是異常的[78]。Ombelet和他的同事使用受試者操作特性曲線分析來確定單個精子參數(shù)和組合精子參數(shù)的診斷潛力和臨界值[79]。他們的前瞻性研究顯示，單個精子參數(shù)對于區(qū)分生育能力強的男性和低生育能力的男性幾乎沒有臨床價值，并表明使用多種精子參數(shù)組合來預測男性的生育狀況是很重要的[79]。標準精液分析的另一個問題是，并不是所有的實驗室都嚴格遵守世界衛(wèi)組織的手冊方法。在美國，只有不到60%的實驗室符合世界衛(wèi)生組織的手冊指南，在英國，只有不到5%的實驗室符合世界衛(wèi)生組織的手冊指南[80-81]。至關重要的是，所有實驗室都要嚴格遵守世界衛(wèi)生組織手冊指南，以提供可靠和可比較的結果。已經(jīng)引進了幾個半自動和全自動計算機輔助精子分析系統(tǒng)。盡管計算機輔助精子分析系統(tǒng)在準確評估精子形態(tài)方面存在缺陷[82.83]，但在許多嚴格遵守質量控制協(xié)議以準確量化精液參數(shù)的男科學和體外受精診所中，計算機輔助精子分析系統(tǒng)被廣泛使用[84]。系統(tǒng)比如臺中市邦瑞生物公司，臺灣）采用人工智能簡化精液分析。Agarwal和他的同事對精液分析的前瞻性研究結果表明[85]，該設備是一種可靠的診斷工具，提供了世界衛(wèi)生組織第五版指南定義的臨床可接受的結果。在家收集精液樣本是精液分析的另一個進步[86]。支持在家中測試精子的技術為那些在陌生環(huán)境中提供精液樣本感到不舒服的男性提供了一個潛在的解決方案[87.88]。家庭精子檢測系統(tǒng)主要是基于抗體反應，微流體學，或智能手機技術。這些測定精子濃度的儀器的準確度在95%到98%之間，這使得它們成為一種實用和經(jīng)濟的方法來進行男性不育的初步篩查[89]。體格檢查體格檢查是評估男性不育癥的一個關鍵部分，應該包括身體狀況、第二性征和生殖器的評估?；加袃确置诩膊〉幕颊?例如，低血清睪酮、Klinefelter綜合征、高催乳素血癥)?？赡軙霈F(xiàn)生殖腺發(fā)育不全的特征、體毛減少(與Tanner V期相比)、肥胖或女性乳房發(fā)育癥[90.91]。生殖器檢查應該從陰莖開始，仔細評估陰莖彎曲、斑塊、尿道外翻或尿道下裂，所有這些都會損害精液在陰道穹窿的沉積。應該檢查睪丸的存在、大小和一致性。睪丸大小應使用Prader睪丸計或卡尺(正常體積為20毫升或4×3厘米)進行評估[92]。當患者的身體習性或陰囊解剖(鞘膜積水、附睪擴張或腹股溝睪丸)可能使Prader睪丸儀測量睪丸不可靠時，陰囊超聲檢查是有用的[93]。應該排除睪丸腫塊，因為有不育癥的男性患睪丸腫瘤的風險更高[94]。應該觸診附睪，以評估是否有可能提示遠端梗阻的增大。附睪發(fā)育不良伴有單側或雙側未觸及的輸精管，與血管發(fā)育不全相一致，也可能與遺傳或腎臟異常有關。精索應該在仰臥和站立位置進行評估，以便發(fā)現(xiàn)精索靜脈曲張。精索靜脈曲張按大小分級：1級僅通過Valsalva動作可觸及，2級可在沒有Valsalva動作的情況下觸及，3級靜脈曲張可見[95]。雖然不育的年輕男性不常規(guī)進行直腸指檢，但射精量低的男性可以進行直腸指診。應該評估前列腺的大小和一致性。中線囊腫或突出的精囊可能表明射精管阻塞[92]。生殖內分泌評估專題4：男性不育患者內分泌激素評估的臨床解釋性腺功能減退癥卵泡刺激素、黃體生成素和睪酮濃度降低睪丸功能衰竭（少弱精子癥或非梗阻性無精子癥）卵泡刺激素和黃體生成素濃度升高，睪酮濃度降低或正常無定論：精子發(fā)生正常或有缺陷精子發(fā)生正常濃度的促卵泡激素，黃體生成激素和睪酮高催乳素血癥催乳素濃度升高，睪酮濃度正常或降低生殖內分泌激素評估是治療男性不育的重要工具。許多臨床醫(yī)生認為激素評估是對每一位男性不育患者進行常規(guī)檢查的一部分[96]，盡管國際社會建議限制對特定的患者群體使用激素，包括精子濃度低于10×10?/mL或性功能受損的男性，或者懷疑有內分泌疾病的患者[49.50]。推薦的基礎激素評估應包括卵泡刺激素和總睪酮的分析(專題4)。如果發(fā)現(xiàn)總睪酮濃度較低，建議進行更徹底的內分泌評估。這一過程包括復查總睪酮和增加黃體生成素測定以鑒別原發(fā)性和繼發(fā)性性腺功能減退。在這種情況下，催乳素分析也被推薦[49.50]。ASRM指南用于男性不育癥激素評估的有效性在預測性腺功能減退方面受到了挑戰(zhàn)[97]。Ventimiglia及其同事[97]的一項回顧性研究顯示，該指南的預測價值較低，總體準確率為58%，敏感度為75%，特異度為39%。對于睪酮濃度的下限沒有普遍的共識。ASRM采用小于300 ng/dL作為診斷性腺功能減退的臨界值，EAU建議230 ng/dL(8nmol/L) [98.99]為診斷性腺功能減退的臨界值。在性激素結合球蛋白升高的情況下(例如，75歲以上的男性、甲狀腺疾病或糖尿病)，僅測量總睪酮濃度是不夠的。在這種情況下，建議測量游離睪酮。盡管反向平衡透析是測量游離睪酮的黃金標準，但它價格昂貴，技術上具有挑戰(zhàn)性。使用計算出的游離睪酮來評估男性性腺功能減退可能是一種更準確的臨床評估方法[99.100]。雖然催乳素在女性生育中的作用已經(jīng)確定，但它在男性不育癥中的作用尚不清楚，盡管輕度升高并不重要。嚴重的高催乳素血癥可能與總睪酮濃度降低有關，從而影響精子發(fā)生和男性的性功能[101]。高催乳素血癥在40%的病例中是由催乳素瘤引起的[102]。卵泡刺激素通常與精子發(fā)生呈負相關，因此在精原細胞缺失或減少的病例中回看到卵泡刺激素會升高[103.104]。然而，在某些精母細胞或精子細胞水平的生精停止病例中，卵泡刺激素、黃體生成素和睪酮的濃度可能是正常的，這限制了內分泌評估在非梗阻性無精子癥患者中的預測價值。基因檢測約15%的男性不育與遺傳異常有關[105]。最近對男性不育基因的系統(tǒng)回顧和臨床有效性評估顯示，總共有78個基因與92個男性不育表型有關[106]。已經(jīng)發(fā)現(xiàn)了幾個與精子發(fā)生有關的基因和基因突變[26.107]。有遺傳異常的男性通常表現(xiàn)為精子發(fā)生缺陷，導致嚴重的少精子癥或無精子癥，并增加非整倍體[108]。胚胎中的基因突變可能會導致反復的胞漿內單精子注射失敗，反復流產(chǎn)，或者父系遺傳缺陷的垂直傳遞。因此，在卵泡胞漿內單精子注射之前，識別基因缺陷對于診斷和正確的咨詢至關重要?；蛉毕莸拇怪眰鞑タ梢酝ㄟ^植入前的基因檢測和移植基因健康的胚胎來預防[109]?；驒z測對于預測取精成功也很重要[109]。核型分析(也稱為染色體分析)是檢測染色體數(shù)目缺陷或結構缺陷。核型異常是最常見的遺傳缺陷類型，在無精子癥中患病率為12-15%，在嚴重少精子癥中為5%，在正常精液中不到1%[110-112]。最常見的核型缺陷是Klinefelter綜合征(又稱47，XXY)，其次是易位、倒位和缺失。不同的專業(yè)協(xié)會一致建議對無精子癥或嚴重少精子癥(精子數(shù)＜5×10?/mL)的男性進行核型分析[113-115]。然而，EAU將他們的指南建議擴展到包括精子數(shù)低于10×10~6/ml的男性[30.35]。EAU還建議，如果有反復自然流產(chǎn)、畸形或智力殘疾的家族病史[30.35]，無論精子濃度如何，都要進行核型分析[30]。這一建議[35]在對1168名男性的隊列研究中得到了回顧性驗證，研究發(fā)現(xiàn)，建議的閾值具有中等的敏感性(80%)，但特異性(37%)和區(qū)分度(59%)較低[116]。因此，主要根據(jù)精子計數(shù)的EAU指南的使用可能導致不必要的核型分析，核型分析是一項昂貴而費力的檢測。Y染色體微缺失分析適用于精子數(shù)低于5×10?/ml的無精子癥或少精子癥患者[117]。Kohn和他的同事的薈萃分析顯示，大多數(shù)Y染色體微缺失發(fā)生在精子數(shù)量低于1×10?/mL[118]的男性中。最新的EAU指南建議，如果精子濃度低于5×10?/mL，則進行Y染色體微缺失檢測，并強制對精子濃度低于1×10?/ml的Y染色體微缺失進行檢測[30]。Y染色體微缺失會影響Y染色體長臂上的無精癥因子a、b或c。雖然無精子癥c因子缺失的男性可以從睪丸中提取精子，但a或b因子缺失的無精子癥患者預后非常差，在這種情況下不建議提取精子。重要的是，Y染色體微缺失可能會遺傳給男性后代，因此建議在胞漿內精子注射之對夫婦進行專業(yè)的咨詢[119.120]。大多數(shù)囊性纖維化患者先天性雙側輸精管缺失，大約三分之二患有這種疾病的男性有CFTR突變，沒有任何其他囊性纖維化表現(xiàn)[121.122]。對于輸精管結構異常的男性，建議對雙方進行CFTR突變檢測，其中包含最少的公共點突變和5T等位基因[30]。影像檢查在某些情況下，對男性不育癥的全面評估常需要涉及影像學方法。陰囊超聲檢查因其無創(chuàng)性、安全性和低成本而成為首選的影像檢查手段。它提供了有關睪丸大小和體積、睪丸回聲的詳細信息，血流、精索靜脈曲張和附睪解剖。陰囊超聲檢查不適用于亞臨床精索靜脈曲張的診斷，體檢結果正常的男性可以避免[123]超聲檢查。懷疑近端生殖道梗阻的患者(根據(jù)病史、體檢和精液分析)需要經(jīng)直腸超聲檢查精囊擴張、前列腺中線囊腫和射精管擴張[93.124]。經(jīng)直腸超聲可以與精囊抽吸結合使用，以更準確地診斷射精管梗阻[124]。如果需要對泌尿生殖道進行更詳細的成像，可以做MRI。對于不育、性腺功能低下和催乳素升高的男性，頭顱MRI可以診斷出垂體病變(最常見的是催乳素瘤)，催乳素瘤是高催乳素血癥和性腺功能低下的潛在原因[125]。輸精管造影術是一種侵入性成像手段[126]，用于確定輸精管或射精管的通暢性或梗阻情況，通常僅作為最終重建手術的一部分進行。在許多情況下，僅憑體檢就能讓男性不育專家作出診斷，但上述影像學方法可用于未確診病例，或在重建顯微外科手術中使用[92]。精子功能檢測專題5：精子DNA片段測試的臨床適應癥臨床精索靜脈曲張對于常規(guī)精液參數(shù)正常的2級或3級精索靜脈曲張患者，建議進行精子DNA片段檢測建議對1級患者進行精子DNA碎片檢測對于精液常規(guī)參數(shù)有臨界值或異常的1級精索靜脈曲張患者，建議進行精子DNA片段檢測不明原因不孕或宮內受精失敗或反復妊娠損失對于不孕和反復妊娠丟失的夫婦，或在子宮內授精之前，應進行精子DNA碎片檢測早期體外受精或卵胞漿內單精子注射可能是不孕癥和復發(fā)性流產(chǎn)或宮內受精失敗夫婦的另一種治療方法體外受精失敗，或卵胞漿內精子注射失敗，或兩者都有精子DNA碎片測試適用于反復失敗的輔助生殖患者對于少精子癥、精子DNA碎片化程度高和反復發(fā)生體外受精失敗的男性，使用睪丸精子而不是射精精子可能是有益的。臨界異常（或正常）精液參數(shù)與危險因素精子DNA片段化檢測應提供給生活方式可改變的男性不育危險因素患者地評傳統(tǒng)的精液參數(shù)不能檢測出與精子功能相關的缺陷[127]，所以精子功能測試已經(jīng)被開發(fā)出來以加強精液分析(圖1)。在體外受精和卵胞漿內單精子注射出現(xiàn)后，精子功能測試的臨床重要性開始顯現(xiàn)[129-131]。在傳統(tǒng)的體外受精中，精子-透明帶相互作用缺陷是受精失敗的主要原因。然而，在當前的胞漿內單精子注射時代，半透明帶或頂體功能檢測不再用于臨床實踐，因為胞質內單精子注射繞過了精子的穿透能力。因此，人們更加重視用精子DNA片段化檢測來評估精子染色質的質量[132-134]。精子DNA片段分析可能比傳統(tǒng)的精液參數(shù)更全面地評估總體生育狀況[135]。圖1：男性不育的實驗室評估標準精液分析包括宏觀和微觀參數(shù)分析。先進的精子功能測試包括使用不同的技術測定活性氧、精子DNA碎片、頂體反應和MMP。FITC-PSA=異硫氰酸熒光素標記的豌豆凝集素.MiOXSYS=男性不孕癥氧化系統(tǒng)。MMP=線粒體膜potential.ORP=氧化-還原潛力。ROS=活性氧。SCD=精子染色質分散試驗。精子染色質結構分析。末端脫氧核苷酸轉移酶介導的dUTP缺口末端標記。改編自阿加瓦爾及其同事【128】，經(jīng)韓國性醫(yī)學和男科學會許可。目前，末端脫氧核苷酸轉移酶介導的dUTP缺口末端標記法、精子染色質結構分析，精子染色質分散分析是目前最常用的精子DNA片段分析方法之一[136]。盡管檢測方案和截止值大大提高了精子DNA片段檢測的精確度，減少了變話，但缺乏嚴格的標準化和明確的閾值，這一方法的廣泛應用受到了阻礙[137]。因此，盡管新出現(xiàn)的證據(jù)支持精子DNA碎片化在生殖結果中的作用(無論是自然的還是通過輔助生殖技術) [49]， AUA或ASRM不推薦常規(guī)使用精子DNA片段檢測[30.49.50]。2017年，一份關于臨床實踐指南的出版物綜合了關于精子DNA片段測試的現(xiàn)有數(shù)據(jù)，并在四種具體的臨床情況下[138](專題5)提出了建議。EAU指南建議對反復妊娠丟失的夫婦或不明原因不育癥的男性進行精子DNA片段檢測[30]。精子染色質結構分析顯示，DNA碎片指數(shù)超過30%與自然受孕或宮內受精妊娠的發(fā)生率較低有關[138]?？紤]到精子DNA碎片和活性氧之間的密切和潛在的因果關系，測量精液氧化應激可能是評估精子功能的另一種手段。過量的活性氧物種，如果不被抗氧化劑平衡，會導致氧化應激，導致蛋白質、脂質和DNA損傷[139.140]。用化學發(fā)光法或熒光法直接測定精液中的活性氧對男性生育潛力的評估有一定的預測價值[141-143]，其臨界值為每毫升小于102.2RLU/s/10?精子，以區(qū)分有生育能力的男性和不育的男性[144]。精液氧化還原電位是一個新的概念，用來測量精液樣本中的整體氧化應激，這是一個快速而簡單的試驗[145]。在一項多中心研究中報告了氧化還原電位測定的潛在臨床價值，該研究確定了每毫升1.34 mV/10?精子的臨界值，以區(qū)分精液參數(shù)正常和異常的男性[146]。雖然精液氧化應激可以通過各種檢測方法來確定，但EAU指南建議，活性氧的常規(guī)檢測應保持實驗性，直到這些測試在隨機對照試驗（RCTs）中得到驗證[30]。管理無精癥無精子癥的原因可分為睪丸前、睪丸或睪丸后。無精子癥的睪丸前病因包括涉及下丘腦-垂體-性腺軸的內分泌異常。雖然先天性和獲得性性腺激素低減是罕見的，但它是為數(shù)不多的男性不育的醫(yī)學原因之一。常見的顯著原因包括Kallmann綜合征和外源性雄激素過多。在無精子癥男性的激素評估過程中，促性腺激素減退癥的特征是血清卵泡刺激素和睪酮濃度低。臨床上常用人絨毛膜促性腺激素與更年期促性腺激素合用，分別替代黃體生成素和促卵泡激素，誘導性腺功能減退癥患者生育。據(jù)報道，16-57%患有先天性性腺機能減退癥的男性在治療后成功懷孕[147]。一旦排除了青春期前的原因，無精子癥男性被歸類為梗阻性無精子癥或非梗阻性無精子癥(圖2)。睪丸活檢不再被推薦用于診斷。一般情況下，卵泡刺激素的臨界值為7.6mIU/mL，睪丸長軸為4.6 cm，用于區(qū)分梗阻性無精子癥和非梗阻性無精子癥[148]。梗阻性無精子癥患者有幾種選擇，包括取附睪或睪丸精子進行胞漿內單精子注射或手術重建[149]。原發(fā)性睪丸功能衰竭導致的生精功能障礙是非梗阻性無精子癥最常見的原因。雖然從梗阻性無精子癥患者中成功獲取睪丸精子的可能性很高，但非梗阻性無精子癥患者的成功率要低得多[150-152]。盡管非梗阻性無精子癥患者的精子產(chǎn)量往往不足以達到射精，但睪丸活檢發(fā)現(xiàn)異質性斑塊狀生精，且60%的非梗阻性無精子癥患者睪丸內可見精子，這為非梗阻性無精子癥的治療提供了取精的理論基礎[150-151]。雖然睪丸精子抽吸術可以使用麻醉部位經(jīng)皮進行，但精子回收率低導致該手術不常見，除非與睪丸定位結合使用[153]。根據(jù)對15個病例對照研究數(shù)據(jù)的薈萃分析，顯微切割睪丸精子提取可能比傳統(tǒng)睪丸精子提?。ㄊ中g取精52%對35%）更有效[154]。重要的是，顯微切割睪丸精子提取術可獲得大量的精子，睪丸組織切除較少，并發(fā)癥發(fā)生率最低[151.154]。然而，隨后的薈萃分析顯示，在非梗阻性無精子癥患者中，顯微切割和常規(guī)睪丸精子提取在取精或活產(chǎn)結局方面沒有差異[152]。在Klinefelter綜合征患者中也發(fā)現(xiàn)了類似的結果，他們在常規(guī)或睪丸顯微切割取精后比較了手術取精和活產(chǎn)結局[155]。需要進一步設計良好的隨機對照試驗來闡明哪種技術更有效。在指導患者使用某種特定的精子提取技術之前，應該考慮幾個變量(例如，手術技巧、睪丸組織學、費用和并發(fā)癥風險)，因為沒有明確的建議使用哪種技術[30]。精索靜脈曲張修補術在非梗阻性無精子癥患者中的作用一直存在相當大的爭論，因為手術取精率和胞漿內單精子注射的結果尚未確定[156]。盡管生殖醫(yī)學取得了進展，但在約50%的非梗阻性無精子癥男性中，取精不成功，這使得這些男性只能選擇捐贈者精子受精或領養(yǎng)。圖2：無精子癥的分類FSH--促卵泡激素。ICSI卵胞漿內單精子注射。精索靜脈曲張精索靜脈曲張是盤狀神經(jīng)叢靜脈擴張，從睪丸排出血液，在15%的健康男性和25%精液分析異常的男性中存在[30]。精索靜脈曲張影響睪丸功能的機制可能是多因素的，但最普遍接受的理論包括盤狀神經(jīng)叢中的靜脈血液相對停滯，這會提高睪丸溫度，導致活性氧水平升高[157]。精索靜脈曲張修補術的適應證和手術方式一直存在爭議。在臨床精索靜脈曲張和精液分析異常的男性中，精索靜脈曲張修補術可以顯著改善精液參數(shù)[30.33.158]。目前的指南不建議精液分析正常的不育癥患者或亞臨床精索靜脈曲張患者行精索靜脈曲張切除術。然而，精索靜脈曲張修補術推薦給有臨床精索靜脈曲張、精液參數(shù)異常和原因不明的不育癥的男性，其女性伴侶的激素水平健康且卵子計數(shù)良好[30]。一項系統(tǒng)的回顧和薈萃分析得出結論，即使精液參數(shù)沒有改善，精索靜脈曲張修補術可以改善輔助生殖技術手術后的活產(chǎn)結局[159]。手術修復是精索靜脈曲張的主要治療方法，經(jīng)皮放射栓塞術是可行的替代方法[160]。精索靜脈曲張切除術可以通過后腹膜、腹腔鏡或機器人輔助的腹腔鏡、顯微外科腹股溝或腹股溝下入路完成[161]。不同手術方式的成功率沒有顯著差異，但顯微外科腹股溝下精索靜脈曲張切除術被認為是金標準，因為與其他手術方式相比，精索靜脈曲張復發(fā)(0.4%)或術后鞘膜積液(0.44%)的風險較低[30.32]。精索靜脈曲張切除術可以改善精液參數(shù)，減少氧化應激，可能使夫婦免于進行昂貴的輔助生殖技術程序[32]。特發(fā)性男性不育在患有特發(fā)性不育的男性中，盡管完成了診斷調查，但仍無法確定精液參數(shù)改變的原因[35]。目前對特發(fā)性男性不育的治療包括輔助生殖技術或經(jīng)驗性藥物治療，其中包括改善生活方式和激素或非激素治療。改變生活方式(如減肥、體力活動和戒煙)是重要的非侵入性措施[30]，并與改善精子參數(shù)有關[162-165]。經(jīng)驗性激素藥物治療的主要是選擇性雌激素受體調節(jié)劑和芳香化酶抑制劑。選擇性雌激素受體調節(jié)劑（特別是克羅米酚檸檬酸鹽）已被用于實驗室外改善精液參數(shù)，但很少有高質量的隨機對照試驗證明其有效性[166.167]。外源性睪酮不應用于治療男性不育，因為它會抑制精子生成[168]。80%的男性不育癥患者精液氧化還原電位升高支持了氧化應激作為男性不育原因的作用[37]。氧化應激可能是可逆的，這為治療提供了機會。因此，口服抗氧化劑是最常用的經(jīng)驗性藥物治療。盡管文獻中的研究存在異質性，但一項系統(tǒng)的綜述表明，抗氧化療法在改善男性不育癥患者精液參數(shù)和減輕氧化應激方面的效果[169]。2019年Cochrane的一篇綜述對6264名接受抗氧化劑聯(lián)合治療的不育癥男性的61項隨機對照試驗進行了薈萃分析，報告了低質量的證據(jù)表明，補充抗氧化劑可以改善臨床妊娠和活產(chǎn)的比例[170]。這項審查承認了重要的局限性，包括低質量的隨機對照試驗，由于隨機方法報告不當，存在嚴重的偏差風險，未能報告臨床結果（如活產(chǎn)、臨床妊娠）、高損耗率以及由于事件數(shù)量少和總樣本量少而導致的不精確性[170]。因此，在推薦最佳抗氧化劑方案之前，進一步的大規(guī)模隨機對照試驗報告臨床相關結果是必要的。輔助生殖技術的作用輔助生殖技術的使用大大提高了不孕不育夫婦生育親生子女的能力。在宮內受精中，在排卵期間，逐漸活動的精子從精液中分離出來，直接受精到宮腔內。對于更嚴重的男性因素不育癥，可以使用常規(guī)的體外受精或胞漿內單精子注射。盡管這些技術取得了成功，但一些夫婦的結局仍然不佳，這可能是由于卵子或精子的質量不佳，或者兩者都有。Lee和他的同事表明，使用嚴重少弱精子癥和非梗阻性無精子癥男性的精子進行胞質內單精子注射周期，在胚胎植入和臨床妊娠方面比正常精子癥男性的結局更差[171]。這一發(fā)現(xiàn)表明了父親貢獻的重要性，以及在胞漿內單精子注射之前選擇最好的精子的必要性。對不孕不育夫婦的最佳管理應該包括糾正精子缺陷，即使是對接受輔助生殖技術的夫婦也是如此。使用睪丸來源的精子越來越重要，因為與射出的精子相比，睪丸精子的精子DNA碎片較少[172]。因此，睪丸精子提取-胞漿內單精子注射可用于非無精子癥，精子DNA碎片化升高且之前胞漿內單精子注射周期失敗的男性。然而，還需要更多的證據(jù)來支持這一常規(guī)臨床實踐。未來的治療方法和挑戰(zhàn)現(xiàn)代組學技術的進步促進了在基因、分子和細胞水平上診斷和治療男性不育。 下一代測序技術，如疾病靶向測序、全外顯子組和基因組測序，以及精子的表觀遺傳學分析，是基因測試中有前途的技術[173]。下一代測序技術已經(jīng)能夠識別與男性不育相關的新候選基因，如無精癥[174]、少精子癥[175]和特發(fā)性男性不育[107]。關于小RNA和microRNA在表觀遺傳調控中的作用[176]以及它們參與精子發(fā)生和附睪精子成熟的發(fā)現(xiàn)，擴大了目前對這些過程的理解[177-180]。精漿代謝指紋分析是另一個很有前途的研究領域[181]，尤其是在特發(fā)性男性不育的病例中。2019年發(fā)表的一項研究發(fā)現(xiàn)，在精子正常的不育男性中，活性氧引起的精子DNA表觀遺傳改變和精子代謝譜與精液質量相關[182]。男性生殖蛋白質組學研究的轉變揭示了幾種蛋白質作為生物標志物與男性不育的各種原因有關，如氧化應激介導的精子功能障礙[183.184]、精索靜脈曲張[176.185.186]、弱精子癥[187.188]、球精子癥[189.190]和睪丸癌[191.192]。一個主要的問題是需要確定一個獨特的生物標志物與特定的條件。從戰(zhàn)略上講，通過開發(fā)一種對特定男性不育疾病具有高特異性的蛋白質生物標志物面板，可以實現(xiàn)正確的診斷。此外，在臨床應用組學研究結果之前，確定合適的組學數(shù)據(jù)的適用性或它們與適當?shù)呐R床驗證相結合是至關重要的[193]。未來男性不育的診斷和治療正在走向男性學與人工智能的融合，使用密集的機器學習。正在開發(fā)算法來預測哪些男性是無精子癥，可能需要進行基因調查、精子檢測，以及輔助生殖技術和體外受精胚胎選擇的選擇[194]。人工智能在男科和輔助生殖技術中的使用仍處于早期階段，并伴隨著倫理問題，因此有必要進行進一步的全面和廣泛的研究[195.196]。  在過去的十年里，在男性生殖方面的研究已經(jīng)看到了使用干細胞的下一代療法的重大進展。利用胚胎干細胞、誘導多能干細胞和膠質母細胞瘤干細胞建立了不同的體外方法和器官模型[197]。方和他的同事強調了人類誘導的多能干細胞在男性不育治療中的可能性[198]。人類誘導的多能干細胞可用于重建精子發(fā)生，并在CRISPR-Cas9基因編輯技術中用于糾正遺傳性疾病。此外，人類誘導的多能干細胞源性外顯體可能對接受化療或放療的患者恢復生精功能具有治療意義[198]。精原干細胞具有相似的再生和自我更新特性，為男性不育的治療開辟了新的前景[199.200]。對于接受過性腺毒性治療的兒科患者，自體冷凍精原組織移植被認為是保存生育能力的新策略[201]。然而，在干細胞治療用于男性不育的管理和治療之前，必須克服一些障礙，包括倫理問題和在干細胞體外培養(yǎng)過程中向后代傳播遺傳損傷的風險。ContributorsAll authors wrote this Seminar and read and approved the final manuscript.Declarationof interests We declare no competing interests.AcknowledgmentsWe thank Joseph Terry and Mary Reagan, Center for Medical Art and Photography,Cleveland Clinic, for their assistance in preparing the figures.參考文獻1.       Zegers-Hochschild F, Adamson GD, Dyer S,et al. 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