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Associations of cognition and incident dementia with sex hormone concentrations in men: individual participant data meta-analyses (127609)

Ross J Marriott 1 , Kevin Murray 1 , Leen Antonio 2 , Shalendar Bhasin 3 , Adrian S Dobs 4 , Leon Flicker 5 6 , David J Handelsman 7 , Graeme J Hankey 5 8 , Robin Wilkening 9 10 , Alvin M Matsumoto 11 12 , Claes Ohlsson 13 , Eric S Orwoll 14 , Dirk Vanderschueren 2 , Hubert Vesper 15 , Gary A Wittert 16 , Frederick C W Wu 17 , Bu B Yeap 5 18
  1. School of Population and Global Health, University of Western Australia, Perth, Western Australia, Australia
  2. Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium
  3. Brigham and Women's Hospital, Harvard Medical School, Boston, USA
  4. School of Medicine, Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University, Baltimore, Maryland, USA
  5. Medical School, University of Western Australia, Perth, Western Australia, Australia
  6. Western Australian Centre for Healthy Aging, University of Western Australia, Perth, WA, Australia
  7. ANZAC Research Institute, University of Sydney, Sydney, NSW, Australia
  8. Perron Institute for Neurological and Translational Science, Perth, WA, Australia
  9. School of Public Health and Preventative Medicine, Monash University, Melbourne, Vic, Australia
  10. Faculty of Applied Public Health, European University of Applied Sciences, Rostock, Germany
  11. Department of Medicine, University of Washington School of Medicine, Seattle, USA
  12. Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, USA
  13. Centre for Bone and Arthritis Research at the Sahlgrenska Academy, Institute of Medicine, University of Gothenburg, Goteborg, Sweden
  14. Oregon Health and Science University, Portland, USA
  15. National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, USA
  16. Freemasons Centre for Men's Health, School of Medicine, University of Adelaide, Adelaide, SA, Australia
  17. Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, University of Manchester, Manchester, United Kingdom
  18. Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, WA, Australia

Background

Previous cohort studies have associated lower testosterone concentrations with poorer cognitive function, and higher dementia risk, with clinical trials of testosterone providing inconclusive results.

 

Aims

To clarify whether endogenous concentrations of testosterone, and of other sex hormones, were associated with cognition and incident dementia in men.

 

Methods

A systematic review was conducted, identifying suitable studies from which individual participant data (IPD) were requested (PROSPERO registration: CRD42019139668). Eligible studies were prospective cohort studies measuring testosterone using mass spectrometry, with at least five years of follow-up data. IPD meta-analysis (IPDMA) models were fitted. Datasets that included both the outcome (baseline cognitive function or time to dementia diagnosis) and exposure (total testosterone [T] or sex hormone-binding globulin [SHBG] concentration) were analysed.

 

Results

The cross-sectional analysis included 8,848 men, median age 74 years, from 6 cohorts; the longitudinal analysis had median 12.7 years and total 122,493 participant-years of follow-up. Harmonised z-scores of global cognition were not associated with T (estimated mean difference [MD] at medians of quintile 1 [Q1] vs Q5, 7.8 vs 22.6 nmol/L; MD, 0.04, 95% CI, -0.05 to 0.14) or with SHBG (26.5 [Q1] vs. 76.9 [Q5] nmol/L; MD, 0.08 [CI, -0.01 to 0.18]). Incident dementia was not associated with T (adjusted hazard ratio, HR for Q1 vs Q5, 0.97, [CI 0.76 to 1.23]) but men with lower SHBG had an estimated lower risk of incident dementia, relative to men with reference level SHBG (Q1 vs Q5; adjusted HR, 0.80 [CI 0.67 to 0.96]). The maximum of relative heterogeneity estimates was an I2 of 5.0, CI 0.0 to 53.6.

 

Conclusions

Constraining study eligibility to those that assayed testosterone using mass spectrometry facilitated analyses of high-quality datasets, using multivariable non-linear models. Lower SHBG is a biomarker for reduced risk of incident dementia in men, warranting further studies to explore potential mechanisms.