男性生物利用睾酮：病理生理学、性欲的临床重要性、心血管影响以及使用睾酮和hCG的恢复疗法

基于证据的预防实践临床综述

摘要

男性雄激素状态的临床评估早已超越了单纯的血清总测量值。 睾酮. 总浓度通常具有误导性，因为大部分循环中的睾酮都与血浆结合 蛋白质 具有广泛不同的亲和力，其中性激素结合球蛋白（SHBG）作为决定输送至组织的激素实际数量的主要调节因子。本综述总结了对 生物利用 testosterone, 涵盖区室化的生物化学、与年龄相关的衰退机制、SHBG的调节（包括在临床升高时将其降低的实用策略）、产生可靠测量结果的分析方法，以及性欲减退作为真实雄激素缺乏的最具特异性的临床信号的临床重要性。详细探讨了低生物利用度睾酮对心血管的影响，包括以下研究结果 TRAVERSE 试验 以及2025年FDA说明书更新。治疗部分探讨了睾酮替代疗法以及人绒毛膜促性腺激素（hCG）的适当使用，后者可维持睾丸内睾酮的产生和精子发生。其目的是建立一个连贯的、当代的临床框架，供临床医生在实践中应用于男性患者，而不会将生化波动与疾病混为一谈。.

1. 引言

越来越多的证据重新塑造了临床医生对睾酮的认识。这种激素对组织的作用并不与其在血液中的总浓度成正比，而是与游离部分成正比，再加上在毛细血管通过期间从白蛋白释放的松散结合部分。紧密结合球蛋白的那部分在实际应用中具有生物惰性。这就是所谓的 游离激素假说, ，尽管自最初提出以来经过了不断完善，但其核心观点依然成立：生物可用睾酮（游离和白蛋白结合部分的综合）是更具生物学意义的变量。.^1-4

临床后果是，如果两个男性的 SHBG 浓度不同，即使他们的总睾酮浓度相同，其雄激素生理状态也可能截然不同。SHBG 本身受肝脏过程的调节，这些过程对……作出反应 胰岛素, ，甲状腺激素、性类固醇、炎性细胞因子、营养状况和衰老。因此，诸如 肥胖, ，2型 糖尿病, ，甲状腺功能亢进、肝功能障碍以及衰老过程会使总睾酮与该激素在组织中的实际活性脱节。.^5-7

本综述围绕临床医生在实践中需要解答的问题展开：为什么睾酮水平随年龄下降，为什么SHBG会上升，症状方面什么最重要（其中性欲是最具诊断价值的指标），实验室应如何检测这些分析物，心血管文献现在对内源性睾酮和替代疗法有何见解，以及应如何使用睾酮和hCG来安全地恢复生理机能。.

2. 循环睾酮的分隔

2.1 结合分数及其生物学后果

在一个健康的性腺功能正常的男性中，大约 44% 至 65% 的总睾酮与 SHBG 结合，30% 至 50% 与白蛋白疏松结合，1% 至 4% 以游离激素形式循环。.^1,2,3 SHBG是一种大约95 kDa的糖蛋白同源二聚体，主要由肝脏产生。它对睾酮的缔合常数约为每摩尔1 × 10⁹，足以使SHBG结合的部分在毛细血管床的短暂穿梭过程中实际上无法被利用。.¹ 相比之下，白蛋白含量丰富，但与睾酮的结合亲和力要低得多，约为每摩尔 3 × 10⁴。.^2,3 白蛋白结合的解离速度足够快，以至于白蛋白结合部分在转运过程中可以释放到组织中，这就是为什么游离部分和白蛋白结合部分的加和被称为生物利用睾酮。.^2,4

游离激素假说认为，只有未结合的分子才能扩散穿过细胞膜并作用于细胞内雄激素受体。.⁴ 最近使用高灵敏度检测方法的体内数据完善了这一认知，表明 SHBG 和白蛋白的解离动力学使得游离库之外的某些生物利用度成为可能，特别是在毛细血管转运缓慢的组织中。.² 实际结论没有改变：单凭总睾酮可能会产生误导，而临床上有意义的暴露量更接近生物利用部分。.

表1. 成年男性血浆睾酮组分

分数	结合伴侣	亲和力 (Ka, M⁻¹)	占总 T 的份额	临床相关性
免费	无	不适用	1–4%	自由扩散通过细胞膜；活性分数
白蛋白结合	白蛋白	约 3 × 10⁴	30–50%	疏松结合；在毛细血管通过期间释放并促进向组织的递送
结合SHBG的	性激素结合球蛋白	~1 × 10⁹	44–65%	结合紧密；在正常条件下具有生物惰性
生物利用度的	游离 + 白蛋白结合	混合	~30–54%	组织水平雄激素暴露的最佳指标

2.2 为什么总睾酮是不够的

由于结合球蛋白（SHBG）结合部分和白蛋白结合部分受质量作用平衡的控制，SHBG浓度的变化会改变结合态与游离态之间的分配 游离睾酮 即使睾丸的产生量没有变化。SHBG（性激素结合球蛋白）的加倍——这在从青年期过渡到古稀之年的过程中并不少见——可以使总睾丸激素恢复正常，而生物利用的睾丸激素却大幅下降。.^2,9,13 这是总睾酮水平看起来正常的年长男性会出现具有临床意义的雄激素缺乏症状的主要原因。.

3. 为什么睾酮水平会随年龄增长而下降

男性与年龄相关的雄激素水平下降现在已有充分的文献记录。 巴尔的摩老龄化纵向研究 对健康男性进行了数十年的追踪研究，结果显示，在三十岁之后，总睾酮水平每年下降约1%至2%，而游离睾酮和生物有效睾酮的下降幅度更为明显，每年约为2%至3%，这是因为性激素结合球蛋白（SHBG）同步上升。.⁹ 马萨诸塞州男性老龄化研究在一个基于社区的队列中证实了相似的发展轨迹。.¹⁰ 欧洲男性衰老研究（EMAS）进一步表明，在垂体功能正常的男性中，这种下降反映了睾丸机制和中枢机制的混合作用。.^11,15

3.1 下降机制

多种途径同时起作用，这就是为什么该综合征 迟发性性腺功能减退症 是异质的。.

睾丸老化. 莱迪希细胞数量下降，幸存的 间质细胞 类固醇生成能力降低。线粒体功能障碍、脂褐素蓄积以及StAR介导的受损 胆固醇 运输都会导致每个细胞的睾酮产量降低。.¹³

下丘脑-垂体脉冲分泌丧失. GnRH脉冲的频率变低、幅度减小，LH脉冲也随之减少，且驱动睾酮分泌所需的LH幅度更难以稳定达到。Veldhuis及其同事的研究表明，这种规律性脉冲分泌的丧失本身就是男性生殖衰老的一个独立组成部分。.¹⁴

身体成分转变. 内脏脂肪在中年时期会增加，即使在体重保持稳定的男性中也是如此。脂肪组织会分泌炎症细胞因子，从而抑制促性腺激素释放激素（GnRH）和垂体促性腺激素的分泌；脂肪组织还含有芳香化酶，能将睾酮转化为雌二醇。其结果是在原发性睾丸老化之上叠加了功能性继发性性腺功能减退症。.^20,21,22

SHBG升高。. 在大多数男性中，肝脏SHBG的合成量在三十岁之后每年大约增加百分之一。.^2,9 由于 SHBG 会结合睾酮，因此在老年男性中，相同的总睾酮水平会产生较低的生物利用度分数。 Travison 的标准化研究建立了考虑这一生理特征的年龄分层参考范围。.¹²

长期趋势. Travison及其同事的研究表明，近几十年来，美国男性的群体总体睾酮水平跨出生队列呈下降趋势，且与年龄无关，这表明除了固有的衰老过程之外，环境因素（很可能包括肥胖流行、内分泌干扰物以及体力活动的变化）也起到了促进作用。.¹⁶

3.2 衰老对症状的影响

EMAS 证实，在老年男性中，仅有一组狭窄的症状能够可靠地反映雄激素状态。三种性症状（晨勃不佳、性欲低下和勃起功能障碍）连同低于约 11 nmol/L (320 ng/dL) 的总睾酮以及低于 220 pmol/L (64 pg/mL) 的游离睾酮，共同界定了迟发性性腺功能减退症最具特异性的表型。.¹¹ 通常归因于低睾酮的其他症状，包括疲劳、情绪低落和体力下降，在老年男性中很常见，但与雄激素水平的关系较弱。.

4. 性激素结合球蛋白（SHBG）：调节机制及其重要性

SHBG 作为雄激素的主要关卡，其功能是 雌激素 生物利用度。其肝脏合成受HNF-4α调节，并接受来自胰岛素、甲状腺激素、性类固醇、炎性细胞因子和营养感受器的允许性或抑制性输入。.^1,5,6,17 重要的是，低SHBG现在被认为是一个独立的 生物标志物 的 胰岛素抵抗 并且伴发2型糖尿病，而高SHBG则是肝脏和代谢状态的标志物，这会改变对任何总睾酮数值的解读。.^18,19

4.1 升高 SHBG 的情况

衰 aging 是 SHBG 升高最常见的原因，表现为上述稳步上升的趋势。甲状腺功能亢进通过刺激 HNF-4α 和 HNF-1α 来提高 SHBG 水平。.¹⁷ 雌激素暴露（内源性、口服避孕药或雌激素替代疗法）会显著诱导肝脏 SHBG 的合成，这是口服雌激素（而非透皮雌激素）降低女性游离睾酮的机制之一。.⁶ 由于肝细胞代谢改变和清除率降低，肝硬化常会升高SHBG（考虑到其肝脏合成功能受损，这种升高有时甚至是矛盾的）。.²⁴ 神经性厌食症、严重的卡路里限制和慢性蛋白质缺乏会升高SHBG。几种抗惊厥药（苯妥英钠、卡马西平）和某些抗HIV药物通过肝酶效应诱导SHBG产生。.⁶

4.2 降低 SHBG 的条件

高胰岛素血症是现代人群中导致低SHBG（性激素结合球蛋白）的最具临床意义的单一原因。塞尔瓦（Selva）及其同事证明，单糖（特别是果糖和 葡萄糖通过下调 HNF-4α 抑制肝脏 SHBG 转录，并以肝脏脂质新生作为直接介质。.⁵ 这解释了为什么低 SHBG 会如此稳定地伴随 代谢综合征, ，肥胖和2型糖尿病，以及为什么SHBG现在被用作代谢研究中的生物标志物。.^18,19,40 其他抑制剂包括甲状腺功能减退症、外源性雄激素（包括超生理剂量的睾酮、合成代谢类固醇和达那唑）、糖皮质激素过多、生长激素或IGF-1过多，以及具有雄激素活性的孕激素。.⁶

表 2. 肝脏 SHBG 合的主要调节因子

升高SHBG	降低 SHBG
老化（从三十多岁起稳步上升）	高胰岛素血症与胰岛素抵抗
甲状腺功能亢进症	肥胖症，尤其是内脏脂肪过多
口服雌激素暴露（口服避孕药、妊娠）	2型糖尿病
肝硬化	甲状腺功能减退症
热量限制与神经性厌食症	外源性雄激素与合成代谢类固醇
HIV感染（多因素）	糖皮质激素过多（库欣综合征）
抗惊厥药（苯妥英钠、卡马西平）	肢端肥大症（GH/IGF-1过量）
慢性 炎症 （可变效应）	肾病综合征（尿蛋白丢失）

4.3 通过非药物手段降低临床升高的 SHBG

当SHBG在临床相关的情况下升高时（常见于体型相对瘦削的老年男性、亚临床甲状腺功能亢进症，或因任何原因服用口服雌激素的男性），首要任务是处理潜在的诱因。尽管许多策略的证据基础主要是观察性的而非随机对照的，但以下策略具有最强的机制支持。.

力量训练 以及充足的膳食蛋白质。. 运动诱发的 瘦体重, ，特别是通过力量训练，与SHBG的适度降低相关，这可能是通过改善 胰岛素敏感性 在肌肉层面。充足的蛋白质摄入（活跃老年男性的摄入量为每公斤体重 1.2 至 1.6 克）有助于增加肌肉质量，并限制本身会升高 SHBG 的分解代谢状态。.^20,21

碳水化合物 质量与 血糖负荷. 饮食干预对SHBG的影响取决于哪种驱动因素占主导地位，必须针对不同的患者表型进行分别考量。在伴有SHBG偏低的胰岛素抵抗男性中，改善胰岛素敏感性（通过减少精制糖、果糖甜味饮料和高血糖负荷食物）往往会使SHBG回升至正常水平。在因热量限制导致SHBG偏高的营养不良或能量缺乏男性中，充足的热量补充往往会降低SHBG。对于因甲状腺疾病、口服雌激素、抗惊厥药或肝脏疾病导致SHBG偏高的男性，单纯的饮食干预是不够的；适当的干预措施应针对潜在的驱动因素。.^5,18

治疗亚临床甲状腺功能亢进症. 当促甲状腺激素（TSH）被抑制且性激素结合球蛋白（SHBG）升高时，纠正甲状腺异常通常会在几个月内使SHBG恢复正常。.¹⁷

减少或替换口服雌激素。. 出于任何原因服用口服雌激素的患者都可以转换为经皮雌激素，这可以绕过肝脏首过效应，并使SHBG产生很小的变化。.⁶

正在核对药物。. 如果确诊性腺功能减退且SHBG是主要诱因，则可能需要更换抗惊厥药和某些抗逆转录病毒药物。.⁶

治疗肝病. 在慢性肝病男性患者中，SHBG（性激素结合球蛋白）出现反常升高，对肝脏病变的治疗（酒精 戒除，丙型肝炎抗病毒治疗，或 减肥 （针对肝脂肪变性）是适当的干预措施。.²⁴

充足的热量摄入。. 营养不良时，SHBG（性激素结合球蛋白）会急剧上升。处于负能量平衡状态的运动员和老年男性可能会出现高 SHBG，通过补充热量可以使其恢复正常。.^6,15

有时推荐补充硼、锌和镁来调节SHBG。临床证据有限且前后矛盾，这些都不能替代解决上述上游驱动因素的作用。.

5. 使总睾酮与生物利用睾酮脱钩的条件

5.1 肥胖与功能性继发性性腺功能减退症

肥胖，特别是内脏性肥胖，会产生一种被称为男性肥胖相关性继发性性腺功能减退症（MOSH）的模式。.²² 该模式的特征是总睾酮偏低，而黄体生成素（LH）和卵泡刺激素（FSH）处于不恰当的正常或偏低水平，这表明存在中枢性病因。三种机制同时发挥作用：高胰岛素血症抑制肝脏产生SHBG（性激素结合球蛋白），从而在不一定降低游离睾酮的情况下降低总睾酮；内脏脂肪组织分泌 白介素-6, ，TNF-α和瘦素以抑制下丘脑GnRH的模式分泌；并且脂肪芳香化酶将睾酮转化为雌二醇，为下丘脑提供额外的负反馈。.^20,22,23 在患有糖尿病性肥胖的男性中，横断面研究显示，超过 30% 的人符合性腺功能减退症的生化标准。.²³

至关重要的是，体重减轻和胰岛素敏感性的改善通常可以部分或全部扭转这一局面。减重手术可以使肥胖性腺功能减退男性的睾酮水平恢复正常，甚至5%至10%的适度减重也能提高总睾酮和游离睾酮水平。.^20,21,22

5.2 代谢功能障碍相关性脂肪性肝病 (MASLD)

肝脂肪变性是肝脏胰岛素抵抗的表型表现，与低SHBG和低总睾酮密切相关。.^19,40 游离睾酮或生物利用睾酮对于这些患者是更有意义的测量指标。脂肪性肝炎的存在增加了第二层复杂性，因为向纤维化和肝硬化的进展可能会反常地升高性激素结合球蛋白（SHBG）。.²⁴

5.3 肝硬化

晚期肝硬化会导致复杂的内分泌紊乱。尽管在许多其他方面的肝脏合成功能有所下降，性激素结合球蛋白（SHBG）仍会上升；白蛋白下降；雌二醇清除率降低。总睾酮可能看起来被欺骗性地维持，而游离睾酮已经崩溃。.²⁴ 在该人群中，生物利用度测量是必须的，否则会漏诊。.

5.4 肾病综合征

大量蛋白尿可导致 SHBG 和白蛋白随尿液丢失，从而使两者均降低。总睾酮因结合运载能力减弱而下降；游离睾酮最初可能通过 HPG 轴的代偿得以维持，但慢性的分解代谢应激以及细胞因子对莱迪希细胞的直接作用最终会损害其生成。.²⁵

5.5 甲状腺功能亢进症与甲状腺功能减退症

甲状腺功能亢进症通过诱导HNF-1α和HNF-4α升高SHBG，从而提高总睾酮水平，但对生物利用度睾酮的影响较小。.¹⁷ 甲状腺功能减退症则会产生相反的模式。在对任何患者的总睾酮进行临床解释时，都应了解其甲状腺状态。.

6. 生物利用度睾酮的心血管影响

睾酮状态与心血管的相关性是该领域在过去二十年中变化最大的部分。早期文献认为睾酮对心血管无影响或具有危害性；目前的证据支持一种更为细致的观点：生理水平的生物利用睾酮与良好的心血管表型相关，而过低和超生理水平则具有风险。.

6.1 睾酮的血管生物学

睾酮具有直接的血管作用。它促进内皮 一氧化氮 合成酶活性，该活性支持内皮依赖性血管舒张。它调节血管平滑肌钙通道活性，有助于冠状动脉和外周血管舒张。它影响血管壁的炎症基调，在许多队列研究中，低睾酮与升高的CRP和IL-6相关。.^34,50,56 在心肌细胞水平上，雄激素受体是有表达的，并且生理性雄激素支持对正常的心肌能量代谢似乎具有许可作用。.

睾酮还与 脂蛋白 系统产生具有临床相关性的 ASCVD 风险影响。超生理剂量的睾酮，包括大多数合成代谢类固醇滥用模式，会降低 高密度脂蛋白 并且可以升高含载脂蛋白B的脂蛋白。相比之下，生理性替代通常会产生微小的降低 总胆固醇 以及 载脂蛋白B 并且对高密度脂蛋白（HDL）有适度的降低作用，对胰岛素敏感性产生中性或有利的影响，且 内脏脂肪.^49,50,56 对...的影响 斑块 从恢复正常生理机能（而非超生理暴露）的角度来看生物学，才是预防所关乎的变量。.

6.2 内源性睾酮与心血管结局

大 前瞻性队列 通常发现内源性睾酮低与心血管疾病增加以及 全因死亡率 在男性中。由耶普（Yeap）及其同事进行的汇总分析结合了11个前瞻性队列和24,000多名男性，该分析报告称，总睾酮处于最低五分位数的男性发生心血管事件的风险更高，且极低的游离睾酮（约低于184 pmol/L或53 pg/mL）带来的风险最大。.³⁴ A 元分析 由科罗娜（Corona）及其同事发现内源性睾酮与心血管事件之间存在类似的负相关关系。.³⁵ 孟德尔随机化 分析得出了更多样化的结果，但总体而言并不支持生理性睾酮对心血管结局具有因果有害作用，且一些分析表明在分布的最低端存在保护性关联。.⁵⁵

SHBG本身似乎是一个独立的 心血管和代谢生物标志物。低 SHBG 能够预测 2 型糖尿病的发生，,¹⁸ 并且在一些队列研究中，老年男性体内非常高的 SHBG 与死亡率相关，尽管由于以下原因，其解读变得复杂： 反向因果关系 （虚弱和营养不良会升高SHBG水平。）.^19,58

6.3 睾酮替代治疗与心血管风险：TRAVERSE 研究之后的当前证据

在2013年和2014年，两项广受关注的研究（Vigen等人在退伍军人事务部系统中进行的研究，以及Finkle等人在索赔数据库中进行的研究）报告了睾酮替代疗法（TRT）与心血管事件之间的关联。这两项研究都存在严重的方法学局限性，包括对睾酮监测的记录不完整、随访时间短以及选择性偏差。随后的分析对这两项研究的方法学提出了质疑。.^54,54b 尽管如此，美国食品药品监督管理局（FDA）于2015年添加了关于潜在心血管风险的黑框警告（注：class label在这里通常指这类药物通用的警示标签），这减少了处方量。.

自此以后，在定义更明确的人群中进行的多次观察性研究报告了中性或有益的相关性。Sharma 及其同事在一项包含 83,000 多名男性的退伍军人事务部（VA）队列研究中发现，通过睾酮替代疗法（TRT）使睾酮水平恢复正常与以下疾病的发病率降低相关： 心肌梗死, 中风, ，与水平保持低下或未经治疗的男性相比，全因死亡率也较低。.³⁷ Cheetham及其同事在凯撒医疗（Kaiser Permanente）的数据中报告称，接受睾酮替代疗法（TRT）的男性的心血管事件风险降低了33%。.³⁸ 安德森及其同事在山间医疗系统（Intermountain Healthcare）的研究中也报道了中性或有利的心血管结局。.³⁹

迄今为止最大规模的心血管安全性试验是TRAVERSE（Lincoff等人，《新英格兰医学杂志》，2023年），这是一项随机、安慰剂对照、非劣效性试验，涉及约5,200名年龄在45至80岁之间、患有性腺功能减退症且伴有既往 心血管疾病 或具有高心血管风险。在平均 22 个月的随访中，包含心血管死亡、非致死性心肌梗死和非致死性卒中的主要复合终点事件在睾酮组中占 7.0%，在 安慰剂 group, meeting the prespecified criterion for non-inferiority (风险比 0.96; 95% CI 0.78 to 1.17).³⁶ Atrial fibrillation, acute kidney injury, and pulmonary embolism were modestly more common in the testosterone group, consistent with the known biology of testosterone-induced erythrocytosis; these are the principal residual safety signals requiring monitoring. TRAVERSE was a non-inferiority trial of moderate follow-up duration and does not establish long-term cardiovascular benefit or fully address plaque biology, 血压, or broader off-label use.

In 2025, the FDA issued class-wide labeling changes for testosterone products. The updated labels incorporated the TRAVERSE findings and removed boxed-warning language concerning increased risk of major adverse cardiovascular outcomes. The revised labels added or strengthened warnings regarding blood pressure elevation and retained existing limitations of use for age-related hypogonadism in the absence of documented biochemical deficiency. Clinicians should consult the current prescribing information for the specific formulation being used.

6.4 Testosterone and coronary plaque

The Testosterone Trials cardiovascular substudy (Budoff et al., JAMA, 2017) reported that men receiving testosterone gel for one year had a greater increase in non-calcified coronary 斑块体积 开启 冠状动脉CT血管造影 than placebo recipients.⁴⁸ The trial was not powered for clinical events, the increment in 非钙化斑块 was modest, and the longer-term clinical implication remains uncertain. Read alongside TRAVERSE, the most reasonable interpretation is that physiologic restoration has not been shown to increase clinical cardiovascular events at moderate follow-up duration, while plaque-imaging endpoints show signals that warrant continued surveillance.

6.5 Erythrocytosis and thrombotic risk

The most consistently reproducible adverse cardiovascular signal of TRT is erythrocytosis. Testosterone stimulates erythropoiesis through both direct bone marrow effects and increased erythropoietin production, with the magnitude of effect depending on formulation. Injectable esters at peak produce the largest increments; transdermal preparations the smallest. A 红细胞压积 above 54 percent is generally considered an indication to reduce dose, change formulation, or temporarily withhold therapy, and to assess for 混杂因素 such as obstructive 睡眠呼吸暂停 and dehydration.^7,54

6.6 Synthesis for the cardiovascular practitioner

Endogenous testosterone in the low end of the physiologic range is associated with increased cardiovascular risk, almost certainly representing a combination of true biological vulnerability and 混杂的 by adverse metabolic phenotype. Restoration of testosterone to the physiologic range in symptomatic hypogonadal men, monitored appropriately, has not been shown to increase 主要不良心血管事件 at the follow-up durations studied. Erythrocytosis must be monitored. Intensive management of conventional cardiovascular 风险因素 (ApoB lowering, blood pressure control, 血糖控制, 吸烟 cessation, and physical activity) remains the primary cardiovascular intervention. Testosterone replacement is an adjunct that addresses one specific deficiency rather than a cardiovascular therapeutic in its own right.

7. Sexual Desire: The Most Diagnostically Useful Symptom of Testosterone Deficiency

Of all the symptoms attributed to low testosterone, reduced sexual desire is the one most reliably and specifically tied to androgen status. This is not a small detail; it is the most useful diagnostic anchor a clinician has when sorting through the nonspecific complaints that often accompany aging and metabolic disease. It is important to note that the Endocrine Society recommends diagnosing hypogonadism only in men who have symptoms consistent with testosterone deficiency and unequivocally and consistently low testosterone concentrations confirmed on at least two separate morning measurements; symptom status alone is not sufficient.⁷

7.1 Why reduced sexual desire is the most diagnostically useful symptom

Travison and colleagues, analyzing the Massachusetts Male Aging Study, demonstrated a graded relationship between bioavailable testosterone and libido that holds across the physiological range, while the relationship between testosterone and erectile function is much less consistent.²⁹ EMAS independently identified three sexual symptoms (poor morning erection, low sexual desire, and erectile dysfunction) as the only symptoms that tracked low testosterone with reasonable specificity once age was accounted for.¹¹ Of the three, low desire is the most specific to androgen status; erectile dysfunction is heavily contaminated by vascular, neurogenic, and pharmacologic causes, and morning erections are a sensitive but less specific indicator.

In randomized testosterone-replacement trials, the most consistent and largest effect size is on sexual desire. The Testosterone Trial Sexual Function Substudy (Cunningham et al., 2016) showed that of the three primary sexual outcomes, the gain in desire scores was both the most consistent across men and the most clinically meaningful.³⁰ Meta-analyses of TRT effects on sexual function similarly show that libido is the dominant signal, with smaller and more variable effects on erectile function.³²

7.2 What patients describe and what to ask

Men with androgen-deficient libido describe a fundamental drop in the spontaneous interest that previously initiated sexual thought and behavior. They notice they no longer think about sex unprompted, they no longer find ordinary stimuli erotically salient, and they often describe the change as a loss of an internal drive rather than a loss of capability. Men can usually report whether their libido has changed compared to their own past baseline, which is more diagnostically informative than population-referenced thresholds.

Loss of nocturnal and early-morning erections is closely related and often co-reported. The clinical interview should ask about both desire and morning erections explicitly. Asking only about erectile function elicits answers that conflate vascular, neurologic, pharmacologic, and androgen contributions; asking specifically about desire and morning erections separates these.

7.3 What sexual symptoms do not predict

Erectile dysfunction without low desire is rarely resolved by testosterone replacement alone. In men with isolated erectile dysfunction and unequivocally normal bioavailable testosterone, the differential diagnosis is dominated by vascular disease (often the first manifestation of generalized 动脉粥样硬化), neurogenic causes, 抗高血压的 medications, antidepressants, and psychological factors. Treating these patients with testosterone is rarely effective and exposes them to the side effects of replacement without the corresponding benefit.^32,33

8. Other Manifestations of Androgen Deficiency

Beyond sexual symptoms, the syndrome of testosterone deficiency includes physical, metabolic, and psychological features. None is as specific as low libido, but in the right clinical context they corroborate the diagnosis.

8.1 Body composition and metabolism

Hypogonadal men accumulate visceral adipose tissue and lose lean muscle mass, with a corresponding decline in strength.^20,21,49,60 This is partly a direct consequence of the loss of androgen signaling at muscle and adipose tissue, and partly a consequence of the metabolic syndrome environment in which obesity-induced hypogonadism develops.⁵⁹ Long-term replacement studies in obese hypogonadal men have demonstrated meaningful reductions in 腰围, body weight, and HbA1c; these effects are often more modest than those achieved with intensive lifestyle intervention but appear additive to them.⁴⁹

8.2 Bone

Testosterone, in part through aromatization to estradiol, supports bone mineral density in men. The Testosterone Trial bone substudy demonstrated significant gains in volumetric bone density and estimated bone strength in older men with low testosterone after one year of replacement.⁴⁶

8.3 Anemia

Mild anemia is common in untreated hypogonadism. The Testosterone Trial anemia substudy showed correction of anemia in a meaningful proportion of treated men, including some without an identifiable alternative cause.⁴⁷

8.4 Mood, motivation, and cognition

Low mood, irritability, and reduced sense of vigor are reported by many hypogonadal men and tend to improve modestly with replacement, although these symptoms have many other causes and should not by themselves drive a diagnosis.^7,33 Cognitive effects of replacement in older men with mild memory complaints have been small and inconsistent in randomized trials.⁵⁷

9. Measurement: Methods That Work and Methods That Mislead

9.1 Total testosterone

The Endocrine Society and the CDC Hormone Standardization Program have for over a decade recommended LC-MS/MS as the reference method for total testosterone measurement, particularly at the lower concentrations that matter for diagnosis. Older platform immunoassays are reliable in the mid-to-high adult male range but have substantial error at low concentrations and are not recommended in women.^26,27

Pre-analytic variables matter. Total testosterone has a pronounced morning peak and a reduced afternoon trough, with the diurnal amplitude attenuated in older men. Samples should be drawn between 7 and 10 am, fasting, and on at least two separate occasions before a diagnosis of hypogonadism is confirmed. Acute illness, recent strenuous exercise, and recent caloric restriction can transiently lower testosterone and should be considered before interpreting an isolated low value.

9.2 Free testosterone: methods, ranked

Direct analog immunoassays for free testosterone are unreliable and are explicitly not recommended by the major endocrine and andrology societies.^26,27 They can produce values that vary several-fold from the true free fraction, with errors largest in the populations where the measurement matters most (men with abnormal SHBG).

Equilibrium dialysis followed by LC-MS/MS is the reference method. The serum sample is dialyzed across a semi-permeable membrane against buffer; only the unbound hormone crosses; the dialysate testosterone is then measured by mass spectrometry. This is the gold standard but is labor-intensive and not widely available.^3,28

Calculated free testosterone using the Vermeulen formula has shown excellent agreement with equilibrium dialysis (correlation coefficient r ≈ 0.99 in well-conducted comparisons), provided that total testosterone and SHBG are measured by accurate platforms.^3,28 The calculation is the practical method most clinicians should use; the more recent Goldman et al. multistep allosteric model improves accuracy at the extremes of SHBG but is not yet routinely available.²

Table 3. Methods for measuring or estimating free testosterone

方法	Accuracy	Practical use	Limitation
Direct analog immunoassay	Poor	Not recommended	Substantially inaccurate at low and high SHBG; errors largest in the populations where measurement matters most
Equilibrium dialysis + LC-MS/MS	参考标准	Research and diagnostically difficult cases	Labor-intensive, slow, expensive, and not widely available in routine clinical laboratories
Vermeulen calculated free T	High (r ≈ 0.99 vs equilibrium dialysis)	Routine clinical use	Dependent on quality of total testosterone and SHBG inputs; less accurate at extremes of SHBG
Goldman multistep allosteric model	Highest at extremes of SHBG	Selected difficult cases	Not yet broadly implemented in routine clinical laboratory systems

10. Restoring Bioavailable Testosterone: Pharmacology

10.1 Therapeutic targets

The aim of replacement is to restore symptoms (with sexual desire as the primary endpoint) while keeping biochemistry within the physiologic range for healthy young men. The Endocrine Society guideline targets a mid-normal total testosterone, typically 400 to 700 ng/dL (14 to 24 nmol/L), with corresponding free testosterone in the mid-normal range.⁷ In men with elevated SHBG, total testosterone targets must be interpreted with care; bioavailable testosterone, not total, should drive titration in this group.

10.2 Formulations

Topical gels and solutions deliver steady serum levels approximating the physiologic diurnal rhythm. They are first-line in many guidelines for that reason, with the trade-offs of daily application, modest skin reactions, and the small but real risk of interpersonal transfer.⁷

Intramuscular esters (testosterone cypionate or enanthate) are inexpensive and effective. The classic regimen of 100 to 200 mg every 1 to 2 weeks produces large peaks and troughs; many practitioners now favor smaller, more frequent injections (for instance, 50 to 80 mg twice weekly, often subcutaneously) to flatten the pharmacokinetic profile and reduce hematocrit excursions.^7,8

Long-acting testosterone undecanoate, given by deep intramuscular injection every 10 to 14 weeks after a loading phase, produces stable levels and is widely used outside the United States. The US formulation requires in-office observation due to the historically rare risk of pulmonary oil microembolism.⁵¹

Subcutaneous testosterone pellets, implanted every 3 to 6 months, provide stable levels for men who prefer infrequent dosing.⁸

Oral testosterone undecanoate (absorbed via the lymphatic route in current US formulations) and intranasal testosterone gel are additional options, each with specific monitoring considerations.

10.3 Dosing in high versus low SHBG

In men with high SHBG (often older, lean, with subclinical hyperthyroidism, or on anticonvulsants) higher doses may be needed to achieve a satisfactory bioavailable level, and the total testosterone may need to run in the high-normal range. In men with low SHBG (typically obese or insulin-resistant) standard doses may produce excessive free testosterone if titrated to total testosterone alone, leading to acne, irritability, and accelerated erythrocytosis. Calculated bioavailable testosterone should drive titration in both populations.

11. Human Chorionic Gonadotropin: Mechanism and Clinical Use

Human chorionic gonadotropin (hCG) acts as an analog of luteinizing hormone, binding the LH receptor on Leydig cells and stimulating intratesticular testosterone production directly. Because exogenous testosterone suppresses pituitary LH and FSH and shuts down endogenous Leydig cell stimulation (with the consequence that intratesticular testosterone falls and spermatogenesis is suppressed), hCG plays two important clinical roles: as monotherapy in selected men, and as an adjunct to testosterone replacement when fertility preservation matters.

11.1 The intratesticular testosterone problem

Spermatogenesis requires intratesticular testosterone concentrations roughly 50 to 100 times higher than circulating testosterone. Exogenous testosterone, by suppressing LH, removes the stimulus for intratesticular testosterone production. Coviello and colleagues demonstrated that low-dose hCG (250 IU subcutaneously every other day) administered concomitantly with exogenous testosterone preserves intratesticular testosterone within the normal range, while testosterone alone reduces it by more than 90 percent.⁴¹

Hsieh and colleagues subsequently showed that men receiving testosterone replacement with concomitant low-dose hCG (typically 500 IU three times weekly) maintained semen parameters across treatment, while those without hCG developed expected oligospermia or azoospermia.⁴² Ramasamy and others have summarized the practical implementation of fertility-preserving combination therapy.⁴³

11.2 hCG monotherapy

In younger hypogonadal men with secondary or mixed hypogonadism who wish to maintain fertility, hCG monotherapy is a reasonable first choice. Typical dosing begins at 1,000 to 1,500 IU subcutaneously two to three times per week, titrated against total testosterone, free testosterone, and estradiol response. Many men achieve mid-normal total testosterone on monotherapy. Estradiol may rise more than with testosterone replacement (because testicular aromatization is preserved), and selective use of an aromatase inhibitor is occasionally warranted; this should not be reflexive.^41,43,44

Use of hCG in this setting is generally off-label in most jurisdictions and should be individualized, ideally with reproductive-urology involvement when fertility is an active goal. Evidence supporting hCG protocols derives primarily from mechanistic studies and small observational or prospective trials rather than large 随机对照试验.

11.3 hCG adjunctive to testosterone replacement

In men on testosterone replacement who wish to preserve fertility, or who experience uncomfortable testicular atrophy, low-dose hCG (typically 500 IU two or three times weekly) is added to the testosterone regimen. This dose preserves intratesticular testosterone and spermatogenesis without producing excessive total testosterone or estradiol elevations.^41,42,43 As with monotherapy, this combination use is generally off-label and the supporting evidence is largely observational.

11.4 Restart protocols after testosterone withdrawal

Men who have used exogenous testosterone (whether prescribed or as part of anabolic-androgen use) and who wish to recover endogenous function and fertility are candidates for restart protocols. The components typically include hCG to drive Leydig cell recovery, a selective estrogen receptor modulator (clomiphene or tamoxifen) to disinhibit pituitary gonadotropin secretion, and in some cases recombinant FSH if spermatogenesis fails to recover. Wenker and colleagues reported encouraging recovery rates with such combinations in men attempting to resume fertility after exogenous androgen exposure.^44,45

11.5 Practical considerations

hCG is administered by subcutaneous injection. Side effects are usually mild and include local injection-site reactions, mild gynecomastia (when estradiol rises), and acne. Cost has historically been variable, and compounded formulations are available in some jurisdictions, where quality control is a legitimate clinical concern.

12. Monitoring of Therapy

Initiation and titration require systematic surveillance. The following framework is consistent with the Endocrine Society and AUA guidelines, modified by the cardiovascular evidence reviewed above.^7,8

Baseline. Total testosterone (LC-MS/MS or validated platform assay), SHBG, calculated free or bioavailable testosterone (Vermeulen), albumin if the calculation is to be performed, LH and FSH (to distinguish primary from secondary hypogonadism), prolactin (in selected cases), TSH, complete blood count (with attention to hematocrit), comprehensive metabolic panel, fasting lipid panel including ApoB where available, PSA in men over 40, and digital rectal examination per AUA guidance.

Three months. Symptom review (with sexual desire as the primary endpoint), repeat total testosterone (timed correctly for the formulation: trough for intramuscular esters, 2 to 8 hours post-application for gels), CBC, and PSA where appropriate. Hematocrit above 54 percent triggers dose reduction or formulation change.

Six and twelve months. Same panel, plus reassessment of body composition and waist circumference, lipid response, and glycemic indices in men with metabolic disease.

Annual thereafter. Symptom review, total and free testosterone, hematocrit, PSA in men over 40, and comprehensive cardiovascular risk reassessment. PSA increases of more than 1.4 ng/mL within 12 months, or a confirmed PSA above 4.0 ng/mL, warrant urological evaluation.^7,8,53

13. Safety: What to Watch and What Has Been Resolved

13.1 Prostate

Modern data do not support the older notion that physiological testosterone replacement causes prostate cancer in men with normal baseline prostate health. The saturation model proposed by Morgentaler and colleagues, in which androgen receptor signaling is saturated within the physiological range, fits the available data better than the linear stimulation model implicit in older recommendations.^52,53 This does not mean replacement is safe in untreated prostate cancer; it means that uncomplicated benign prostatic hyperplasia and a stable PSA do not contraindicate replacement when symptomatic hypogonadism is documented.

13.2 Erythrocytosis

Discussed in Section 6.5. Erythrocytosis is the most common dose-limiting laboratory abnormality of TRT. Coexisting obstructive sleep apnea should be sought in men with persistent erythrocytosis on appropriate doses.

13.3 Fertility

Exogenous testosterone reliably suppresses spermatogenesis. Men of reproductive age must be counseled in advance, and hCG-based combination therapy should be offered to those who wish to preserve fertility.^41,42,43,45

13.4 Cardiovascular

Discussed in detail in Section 6. The TRAVERSE trial provides Level 1 evidence that physiological replacement in symptomatic hypogonadal men, including those with elevated cardiovascular risk, has not been shown to increase major adverse cardiovascular events at the follow-up durations studied.³⁶ The 2025 FDA labeling update reflects this evidence. Erythrocytosis, atrial fibrillation, blood pressure, and venous thromboembolism remain monitorable signals.

13.5 Other considerations

Acne, mild gynecomastia (when estradiol rises), and edema are dose-related and usually manageable. Sleep apnea may worsen at high doses. Mood changes (typically improvement, occasionally irritability at supraphysiologic levels) should be tracked alongside laboratory parameters.

14. Conclusions

The diagnosis of testosterone deficiency in men is fundamentally a problem of identifying tissue-level androgen exposure, not of measuring a number on a laboratory report. Total testosterone is a screening tool, useful in young men with healthy SHBG biology, frequently misleading in older men or in any patient with metabolic disease. Bioavailable testosterone, calculated reliably from a high-quality total testosterone measurement and a measured SHBG, is the variable that matters.

SHBG itself deserves more clinical attention than it usually receives. It rises with age, with hyperthyroidism, with estrogen exposure, with caloric restriction, and with hepatic dysfunction. It falls with hyperinsulinemia, obesity, and anabolic steroid use. The principal non-pharmacologic levers for lowering clinically elevated SHBG are improving insulin sensitivity, addressing thyroid abnormalities, transitioning oral estrogens to transdermal where indicated, ensuring adequate caloric and protein intake, and treating any underlying hepatic process.

Clinically, sexual desire is the single most diagnostically useful symptom of androgen deficiency, provided it is accompanied by biochemical confirmation of consistently low testosterone on at least two morning measurements. A man with low desire and morning-erection loss in the context of confirmed low bioavailable testosterone is the patient most likely to benefit from replacement; a man with isolated erectile dysfunction and normal bioavailable testosterone is the patient least likely to benefit and most likely to need cardiovascular evaluation instead.

The cardiovascular dimension has come into focus over the last decade. Low endogenous testosterone correlates with increased cardiovascular and total mortality. Restoration to the physiologic range, monitored for erythrocytosis and blood pressure, has not been shown to increase major adverse cardiovascular events in the largest available randomized trial (TRAVERSE), and may in selected populations be associated with risk reduction in observational data. The 2025 FDA labeling update reflects this evolving evidence. Replacement therapy is not a substitute for ApoB lowering and lifestyle intervention; it is an adjunct that addresses one specific contributor to cardiovascular and metabolic risk in men who have a true deficiency.

Therapeutic restoration is achieved with testosterone preparations chosen to match the patient’s lifestyle and pharmacokinetic needs. In men of reproductive age, in men who object to testicular atrophy, or in men whose hypogonadism is secondary and who wish to maintain fertility, hCG (alone or in combination with testosterone) is the more appropriate strategy. The clinician’s task is to match the physiology to the patient and to monitor diligently.

Acknowledgments

The author acknowledges the use of an AI language model (Claude, Anthropic) in the drafting, structural organization, and editorial revision of this manuscript. All scientific content, clinical interpretations, literature citations, and the underlying research synthesis represent the work and judgment of the author. All cited sources were independently identified and verified by the author. The AI was used as a writing and editing tool; it did not contribute to the intellectual or scientific substance of the review. This disclosure is made in accordance with emerging editorial standards for AI-assisted manuscript preparation.

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