Associations between blood sex steroid concentrations and risk of major adverse cardiovascular events in healthy older women in Australia: a prospective cohort substudy of the ASPREE trial.
Associations between blood sex steroid concentrations and risk of major adverse cardiovascular events in healthy older women in Australia: a prospective cohort substudy of the ASPREE trial.
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DOI：
10.1016/s2666-7568(22)00001-0
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发表时间：
2022-03
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影响因子：
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通讯作者：
Davis SR
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作者：
Islam RM;Bell RJ;Handelsman DJ;McNeil JJ;Nelson MR;Reid CM;Tonkin AM;Wolfe RS;Woods RL;Davis SR
妇女血液中的睾酮浓度在生育年龄期间下降，在第七个十年达到最低点，之后浓度增加，并在第八个十年初期恢复到生育年龄妇女的水平。我们的目的是确定血液中睾酮浓度与健康老年女性主要不良心血管事件（MACE）和全因死亡率风险之间的关系。SHOW是ASPREE纵向随机试验的一项前瞻性队列子研究。符合条件的参与者是来自澳大利亚的年龄至少70岁的女性，认知功能未受损，既往无MACE，预期寿命至少5年。接受激素或类固醇治疗的参与者不符合入选条件。我们用液相色谱-串联质谱法测定血清性类固醇浓度，用免疫法测定SHBG浓度。我们用四个四分位数比较了低浓度和高浓度的性激素。主要终点是主要不良心脏事件风险和全因死亡率，使用考克斯比例风险回归评估其与性类固醇浓度的相关性，其中包括年龄、体重指数、吸烟状况、饮酒、糖尿病、高血压、血脂异常、肾功能受损以及ASPREE试验中的治疗分配（阿司匹林与安慰剂）。ASPREE在ClinicalTrials.gov注册，NCT 01038583。在2010年3月10日至2014年12月31日期间招募的9180名女性中，6358名参与者在基线时提供了足够的生物样本库样本，5535名参与者被纳入最终分析。入组时的中位年龄为74.0岁（IQR 71.7 - 77.7）。在中位随访4.4年（24553人-年）期间，144名（2.6%）女性发生首次MACE（发生率为5.9/1000人-年）。在平均4.6年的随访期间（3.8 - 5.6），200名妇女死亡（每1000人-年7.9人）。在完全校正的模型中，较高浓度的睾酮与较低的MACE发生率相关（四分位数4与四分位数1：风险比0.57 [95% CI 0.36 - 0.91]; p= 0.02），较高浓度的DHEA也是如此（四分位数4与四分位数1：0.61 [0.38 - 0.97]; p= 0.04）。对于雌酮，与四分位数1相比，仅在四分位数2中观察到MACE风险较低（0.55 [0.33 - 0.92]; p= 0.02）。在完全校正的模型中，SHBG和MACE之间，或任何激素或SHBG和全因死亡率之间没有相关性。在老年女性中，睾酮和DHEA的血液浓度高于最低四分位数与首次MACE的风险降低相关。考虑到DHEA的生理效应是通过其类固醇代谢产物介导的，如果要复制目前的研究结果，则需要进行研究睾酮治疗对老年女性缺血性心血管疾病事件的一级预防的试验。澳大利亚国家健康和医学研究理事会、美国国家老龄问题研究所、维多利亚州癌症机构、英联邦科学和工业研究组织和莫纳什大学。
Blood testosterone concentrations in women decline during the reproductive years and reach a nadir in the seventh decade, after which concentrations increase and are restored to those of reproductive-aged women early in the eighth decade. We aimed to establish the association between the concentration of testosterone in the blood and risk of major adverse cardiovascular events (MACE) and all-cause mortality in healthy older women. SHOW was a prospective cohort substudy of the longitudinal randomised ASPREE trial. Eligible participants were women aged at least 70 years from Australia with unimpaired cognition, no previous MACE, and a life expectancy of at least 5 years. Participants who were receiving hormonal or steroid therapy were ineligible for inclusion. We measured serum concentrations of sex steroids with liquid chromatography–tandem mass spectrometry and of SHBG with immunoassay. We compared lower concentrations of sex hormones with higher concentrations using four quartiles. Primary endpoints were risk of MACE and all-cause mortality, the associations of which with sex steroid concentrations were assessed using Cox proportional hazards regression that included age, body-mass index, smoking status, alcohol consumption, diabetes, hypertension, dyslipidaemia, impaired renal function, and treatment allocation in the ASPREE trial (aspirin vs placebo). ASPREE is registered with ClinicalTrials.gov, NCT01038583. Of the 9180 women recruited to the ASPREE trial between March 10, 2010, and Dec 31 2014, 6358 participants provided sufficient biobank samples at baseline and 5535 were included in the final analysis. Median age at entry was 74·0 years (IQR 71·7–77·7). During a median 4·4 years of follow-up (24 553 person-years), 144 (2·6%) women had a first MACE (incidence 5·9 per 1000 person-years). During a median 4·6 years of follow-up (3·8–5·6), 200 women died (7·9 per 1000 person-years). In the fully adjusted models, higher concentrations of testosterone were associated with a lower incidence of MACE (quartile 4 vs quartile 1: hazard ratio 0·57 [95% CI 0·36–0·91]; p=0·02), as were higher concentrations of DHEA (quartile 4 vs quartile 1: 0·61 [0·38–0·97]; p=0·04). For oestrone, a lower risk of MACE was seen for concentrations in quartile 2 only, compared with quartile 1 (0·55 [0·33–0·92]; p=0·02). In fully adjusted models, no association was seen between SHBG and MACE, or between any hormone or SHBG and all-cause mortality. Blood concentrations of testosterone and DHEA above the lowest quartile in older women were associated with a reduced risk of a first-ever MACE. Given that the physiological effects of DHEA are mediated through its steroid metabolites, if the current findings were to be replicated, trials investigating testosterone therapy for the primary prevention of ischaemic cardiovascular disease events in older women would be warranted. The National Health and Medical Research Council of Australia, US National Institute on Aging, the Victorian Cancer Agency, the Commonwealth Scientific and Industrial Research Organisation, and Monash University.