Effects of long-term testosterone administration on cognition in older men with low or low-to-normal testosterone concentrations: a prespecified secondary analysis of data from the randomised, double-blind, placebo-controlled TEAAM trial
Effects of long-term testosterone administration on cognition in older men with low or low-to-normal testosterone concentrations: a prespecified secondary analysis of data from the randomised, double-blind, placebo-controlled TEAAM trial
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DOI：
10.1016/s2213-8587(16)30102-4
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发表时间：
2016-08-01
影响因子：
44.5
通讯作者：
Basaria, Shehzad
中科院分区：
文献类型：
--
作者：
Huang, Grace;Wharton, Whitney;Basaria, Shehzad
睾酮对老年男性认知功能的影响尚不完全清楚。我们的目的是确定长期睾酮给药对睾酮浓度低或低至正常水平的老年男性认知功能多个领域的影响。方法在美国波士顿、凤凰城和洛杉矶的三个医疗中心进行随机、双盲、安慰剂对照、平行组的TEAAM试验。年龄在60岁及以上的男性，睾酮浓度低或低于正常水平（3.47-13.9 nmol/L，或75岁的游离睾酮），研究地点。调整睾酮剂量达到17.3-31.2 nmol/L。参与者和所有研究人员对治疗分配不知情。通过在基线和第6、18和36个月使用标准化测试评估认知功能的多个领域作为预先指定的次要结局。我们通过意向治疗（有认知功能基线评估的男性）和每个方案（仅限于完成研究药物并有基线和36个月认知功能评估的参与者）进行了分析。TEAAM试验已在ClinicalTrials.gov注册，注册号为NCT00287586。在2004年9月1日至2009年2月12日期间，我们随机分配308名参与者接受睾酮治疗（n=156）或安慰剂治疗（n=152）。280名男性进行了基线认知评估（每组n=140）。睾酮组平均随访时间为29.0个月（SD 11.5），安慰剂组平均随访时间为31.1个月（SD 9.5）。最后一位参与者于2012年5月11日完成研究。睾酮组血清总睾酮平均浓度从10.6 nmol/L （SD 2.2）增加到19.7 nmol/L(9.2)，游离睾酮浓度从222 pmol/L（62）增加到364 pmol/L（222）。在安慰剂组，基线时血清总睾酮平均浓度为10.7 nmol/L (SD 2.3)，干预后为11.1 nmol/L(3.2)，游离睾酮浓度分别为210 pmol/L（61）和172 pmol/L（49）。我们在视觉空间能力（平均差异：复杂图形测试-0.51,95% CI -2.0至1.0），音位或类别语言流畅性(音位流畅性测试0.90,-1.3至3.1；分类流畅性测试1.1,-0.3至2.6)，言语记忆（段落回忆测试0.29,-1.2至1.8），手灵巧性（槽形Pegboard测试4.2,-1.3至9.7），以及注意或执行功能（Stroop干扰测试-2.6,-7.4至2.3）在调整年龄，教育程度和基线认知功能后。在意向治疗和按方案治疗的人群中（每组n=86），认知功能评分的变化与总睾酮或游离睾酮或雌二醇浓度的变化没有显著相关性。对于睾酮浓度较低或低于正常水平的老年男性，给予36个月的睾酮治疗并没有改善认知功能。未来需要进行长期试验来研究睾酮替代对认知受损患者（如阿尔茨海默病患者）的疗效。
Background The effects of testosterone on cognitive function in older men are incompletely understood. We aimed to establish the effects of long-term testosterone administration on multiple domains of cognitive function in older men with low or low-to-normal testosterone concentrations.Methods We did the randomised, double-blind, placebo-controlled, parallel-group TEAAM trial at three medical centres in Boston, Phoenix, and Los Angeles, USA. Men aged 60 years and older with low or low-to-normal testosterone concentrations (3.47-13.9 nmol/L, or free testosterone 75 years) and study site. The testosterone dose was adjusted to achieve concentrations of 17.3-31.2 nmol/L. Participants and all study personnel were masked to treatment allocation. Multiple domains of cognitive function were assessed as prespecified secondary outcomes by use of standardised tests at baseline and months 6, 18, and 36. We did analyses by intention to treat (in men who had baseline assessments of cognitive function) and per protocol (restricted to participants who completed the study drug and had both baseline and 36 month assessments of cognitive function). The TEAAM trial is registered with ClinicalTrials.gov, number NCT00287586.Findings Between Sept 1, 2004, and Feb 12, 2009, we randomly assigned 308 participants to receive either testosterone (n=156) or placebo (n=152). 280 men had baseline cognitive assessments (n=140 per group). Mean follow-up time was 29.0 months (SD 11.5) in the testosterone group and 31.1 months (9.5) in the placebo group. The last participant completed the study on May 11, 2012. In the testosterone group, mean concentrations of serum total testosterone increased from 10.6 nmol/L (SD 2.2) to 19.7 nmol/L (9.2) and free testosterone concentrations increased from 222 pmol/L (62) to 364 pmol/L (222). In the placebo group, mean concentrations of serum total testosterone were 10.7 nmol/L (SD 2.3) at baseline and 11.1 nmol/L (3.2) post-intervention and free testosterone concentrations were 210 pmol/L (61) and 172 pmol/L (49), respectively. We recorded no between-group differences in changes in visuospatial ability (mean difference: Complex Figure Test -0.51, 95% CI -2.0 to 1.0), phonemic or category verbal fluency (phonemic fluency test 0.90, -1.3 to 3.1; categorical fluency test 1.1, -0.3 to 2.6), verbal memory (paragraph recall test 0.29, -1.2 to 1.8), manual dexterity (Grooved Pegboard Test 4.2, -1.3 to 9.7), and attention or executive function (Stroop Interference Test -2.6, -7.4 to 2.3) after adjustment for age, education, and baseline cognitive function. In both the intention-to-treat and per-protocol (n=86 per group) populations, changes in cognitive function scores were not related significantly to changes in total or free testosterone, or oestradiol concentrations.Interpretation Testosterone administration for 36 months in older men with low or low-to-normal testosterone concentrations did not improve cognitive function. Future long-term trials are needed to investigate the efficacy of testosterone replacement in patients with impaired cognition, such as people with Alzheimer's disease.