Higher-Than-Replacement Testosterone Plus Finasteride Treatment After SCI

说明： 医学研究所指出，应该进行短期、小规模的随机临床试验(RCT)，以确定睾酮替代疗法(TRT)在性腺功能低下男性临床人群中作为增强肌肉力量和减少残疾的一种策略的有效性。患有脊髓损伤(SCI)的男性经历了很高的性腺功能减退症，这会影响到损伤后发生的神经、肌肉、骨骼和身体成分缺陷。在这方面，一项单一的回顾分析报告说，TRT改善了性腺功能低下的不完全脊髓损伤男性的运动功能。然而，只有一项小型前瞻性(开放标签)临床试验评估了TRT在男性脊髓损伤患者中的安全性/有效性。这项研究报告说，小剂量的TRT改善了运动性完全性脊髓损伤患者的下肢瘦体重，降低了心源性猝死的风险，表明即使在没有自主肌肉活动的情况下，睾酮(T)也能安全地改善瘦体重。然而，在这项研究中，身体成分和骨密度(BMD)没有改变，因为这些缺陷只对高于替代T的反应，尽管TRT有潜在的好处，但临床上对这种治疗的安全性存在担忧，荟萃分析证实，红细胞压积增加(很少是有害的)和前列腺增大是唯一的健康风险。有趣的是，T的5�-还原为双氢睾酮(DHT)可以调节前列腺增大，但这种转换并不是TRT的益处所必需的。作为证据，药理学上的5�还原酶抑制(通过非那雄胺)在接受高于替代T治疗的神经健康的性腺功能低下的男性中可以消融前列腺增大，而不会抑制这种治疗的实质性肌肉骨骼和脂肪分解益处。然而，这种新的联合疗法在慢性运动不完全性脊髓损伤患者中的安全性和有效性仍有待确定。对于这项双盲安慰剂对照RCT，患有慢性运动不全脊髓损伤(AIS C/D)的18岁性腺功能减退男性和GT；出现步行功能障碍(10m步行试验0.20m/S-0.80m/S)的性腺功能低下男性和GT；将接受略高于替代T的T(125 mg/周，I.M.)。加非那雄胺(5毫克/天，P.O.)在FDA批准的剂量或载体/安慰剂中使用12个月。我们将通过DXA评估骨密度和身体成分，通过MRI评估大腿肌肉横截面积(CSA)，通过测力测量最大膝关节伸肌(KE)扭矩，通过抽动内插法激活KE肌肉，骨周转和代谢健康的循环标志物，以及安全措施，包括前列腺健康、红细胞压积和其他与TRT相关的潜在健康风险。我们的主要假设是，略高于替代T加非那雄胺将安全地1)通过抗吸收作用在该人群中再生骨密度，2)增强肌肉CSA和改善神经肌肉力量产生，3)改善身体成分。为了验证这些假说，将评估以下具体目标：目的1：评估稍高于替代治疗12个月的T加非那雄胺对性腺功能低下的运动性不全脊髓损伤患者的骨矿特性和骨转换的影响。目的：确定稍高于替代剂量的T加非那雄胺对性腺功能低下的运动不全男性脊髓损伤患者肌肉完整性和神经肌力产生的影响。探索性目标3：研究略高于替换性T加非那雄胺对运动性不全脊髓损伤患者的身体成分和代谢综合征的病理生理学的影响。这项建议将提供有史以来第一个前瞻性的临床证据，评估高于替代治疗的T加非那雄胺能否安全地再生患有运动性不全脊髓损伤的性腺功能低下的男性患者的肌肉骨骼完整性，增强神经肌肉功能，改善身体组成和代谢健康。这些发现将使患有肌肉骨骼损伤的退伍军人受益，并可能为退伍军人提供一种能够改善这一人群肌肉骨骼和新陈代谢健康的新的成本效益疗法。

DESCRIPTION: The Institute of Medicine has indicated that short-term, small scale randomized clinical trials (RCTs) should be conducted to establish the efficacy of testosterone replacement therapy (TRT) as a strategy to enhance muscular strength and reduce disability in clinical populations of hypogonadal men. Men with spinal cord injury (SCI) experience a high prevalence of hypogonadism which influences the neural, muscular, skeletal, and body composition deficits that occur after injury. In this regard, a single retrospective analysis has reported that TRT improved motor function in hypogonadal men with incomplete SCI. However, only one small prospective (open label) clinical trial has evaluated the safety/efficacy of TRT in men with SCI. This study reported that low- dose TRT improved lower extremity lean mass and reduced risk of sudden cardiac death in men with motor complete SCI, demonstrating that testosterone (T) safely improves lean mass even in the absence of voluntary muscle activity. However, body composition and bone mineral density (BMD) were unaltered in this study because these deficits respond only to higher-than-replacement T. Despite the potential benefits of TRT, clinical concern exists regarding the safety of this therapy, with increased hematocrit (which is rarely detrimental) and prostate enlargement being the only health risks proven by meta-analysis. Interestingly, the 5�-reduction of T to dihydrotestosterone (DHT) mediates prostate enlargement, but this conversion is not required for the benefits of TRT. As evidence pharmacologic 5�-reductase inhibition (via finasteride) ablates prostate enlargement in neurologically healthy hypogonadal men receiving higher-than-replacement T, without inhibiting the substantial musculoskeletal and lipolytic benefits of this treatment. However, the safety and efficacy of this novel combination therapy remains to be determined in men with chronic motor incomplete SCI. For this double-blind placebo-controlled RCT, hypogonadal men >18 years of age with chronic motor incomplete SCI (AIS C/D) who present with ambulatory dysfunction (0.20m/s - 0.80m/s on 10m walk test) will receive slightly higher-than-replacement T (125mg/week, i.m.) plus finasteride (5mg/day, p.o.) in FDA approved doses or vehicle/placebo for 12 months. We will assess: BMD and body composition via DXA, thigh muscle cross-sectional area (CSA) via MRI, maximal knee extensor (KE) torque via dynamometry, KE muscle activation via twitch interpolation, circulating markers of bone turnover and metabolic health, and safety measures including prostate health, hematocrit, and other putative health risks associated with TRT. Our primary hypotheses are that slightly higher-than-replacement T plus finasteride will safely 1) regenerate BMD in this population via antiresorptive actions, 2) enhance muscle CSA and improve neuromuscular force production, and 3) improve body composition. In order to test these hypotheses, the following Specific Aims will be evaluated: AIM 1: Evaluate the effects of 12 months of slightly higher-than-replacement T plus finasteride on bone mineral characteristics and bone turnover in hypogonadal men with motor incomplete SCI. AIM 2: Determine the effects of slightly higher-than-replacement T plus finasteride on the recovery of muscle integrity and neuromuscular force production in hypogonadal men with motor incomplete SCI. Exploratory AIM 3: Examine the effects of slightly higher-than-replacement T plus finasteride on body composition and the pathophysiology underlying metabolic syndrome in men with motor incomplete SCI. This proposal will provide the first-ever prospective clinical evidence evaluating whether higher-than- replacement T plus finasteride safely regenerates musculoskeletal integrity, enhances neuromuscular function, and improves body composition and metabolic health in hypogonadal men with motor incomplete SCI. These findings will benefit Veterans with SCI who experience musculoskeletal impairments and may provide the VA with a novel cost-effective therapy able to improve musculoskeletal and metabolic health in this population.