Neutral associations of testosterone, dihydrotestosterone and estradiol with fatal and non‐fatal cardiovascular events, and mortality in men aged 17–97 years

Chan, Yi X.; Knuiman, Matthew; Hung, Joseph; Divitini, Mark; Beilby, John; Handelsman, David J.; Beilin, Jonathan; McQuillan, Brendan; Yeap, Bu B.

doi:10.1111/cen.13089

Cited by 35 publications

(34 citation statements)

References 40 publications

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“…Previous epidemiological studies have assessed associations of either PA or hormone levels with outcomes related to cardiometabolic health, but not analysed for interactions between the two. Some studies have adjusted for PA when examining hormones vs cardiometabolic outcomes.…”

Section: Discussionmentioning

confidence: 99%

Greater physical activity and higher androgen concentrations are independently associated with lower cardiometabolic risk in men

Chasland

Knuiman

Divitini

et al. 2017

Clinical Endocrinology

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Context:Male ageing is associated with lower circulating testosterone (T) and increased incidence of cardiovascular disease (CVD). Whether physical activity (PA) interacts with hormones to modify CVD risk is unclear.Objective: We assessed whether PA and sex hormone concentrations were independently associated with measures of CVD risk.Participants: A total of 1649 men.Methods: Leisure, home, work and total PA were ascertained. At baseline, serum T, dihydrotestosterone (DHT) and oestradiol (E2) were assayed. Men were stratified into high PA+high hormone (H/H); low PA+high hormone (L/H); high PA+low hormone (H/L); and low PA+low hormone (L/L). Results: Mean age was 49.8 years at outset with 415 CVD events and 127 CVD deaths occurring during 20-year follow-up. Men with higher PA and higher T or DHT had lower odds of metabolic syndrome (eg leisure H/H vs L/L odds ratio [OR] 0.17 P<.001 for T, 0.26 P<.001 for DHT). Men with higher PA and E2 had lower risk of metabolic syndrome (eg leisure PA H/H vs L/L OR 0.51, P=.001). Men with higher leisure, work or total PA and higher DHT had the lowest risk of CVD death (eg leisure H/H hazard ratio [HR] 0.55 vs L/L, P=.033). Men with lower leisure, home or work PA and higher E2 were at greater risk of CVD death (eg leisure L/H HR 1.60 vs L/L, P=.039). Conclusions: Considering T, DHT and E2 in the context of PA better informs consideration of cardiovascular risk. A 2×2 factorial RCT assessing PA and androgens would illuminate the scope for preventing CVD in men. K E Y W O R D S cardiovascular disease, metabolic syndrome, physical activity, testosterone 1 | INTRODUCTION As men grow older, circulating testosterone (T) concentrations decrease 1 while incidence of cardiovascular disease (CVD) increases. 2 Overweight older men have lower T levels compared to normal-weight men of the same age, 3 and reduced T levels are associated with poorer health outcomes including higher rates of metabolic syndrome and allcause mortality. 4,5 This has raised the question of whether reduced circulating T might be a modifiable risk factor for cardiometabolic ill health in ageing men, with increasing interest and controversy regarding the possible role of pharmacological T treatment as a means of preserving vascular health. 6 | 467 CHASLAND et AL.Testosterone is the predominant androgen in men's circulation and drives the regulation of sexual development, virilization, bone mineral density and body composition. 7 It is converted by 5α-reductase into dihydrotestosterone (DHT), a more potent androgen, and by aromatase into oestradiol (E2), a ligand for oestrogen receptors. 8 Lower T and DHT and higher E2 have been associated with features of the metabolic syndrome. 9 Furthermore, higher T and DHT are independent predictors for reduced incidence of stroke 10 with higher DHT also associated with reduced ischaemic heart disease mortality. 11However, one randomized controlled trial (RCT) was terminated early due to excess cardiovascular events in a group of older men with limited mobility being treated wi...

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Section: Discussionmentioning

confidence: 99%

Greater physical activity and higher androgen concentrations are independently associated with lower cardiometabolic risk in men

Chasland

Knuiman

Divitini

et al. 2017

Clinical Endocrinology

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“…Other studies reported that either low oestradiol levels, or high oestradiol levels were associated with increased mortality. There are also studies showing no association between endogenous oestradiol and all‐cause mortality . Possible explanations for these inconsistencies might be differences in subjects’ characteristics, numbers of events and adjustment for different covariates.…”

Section: Discussionmentioning

confidence: 99%

“…There are also studies showing no association between endogenous oestradiol and all-cause mortality. [11][12][13][14] Possible explanations for these inconsistencies might be differences in subjects' characteristics, numbers of events and adjustment for different covariates. Negative results tended to be more frequently observed in studies based on middle-aged men 11,12,14 ; biological effects of oestradiol might be more prominent in older men, or low mortality rates in middle-aged men may have led to insufficient statistical power.…”

Section: Discussionmentioning

confidence: 99%

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Oestradiol level, oestrogen receptors, and mortality in elderly men: The three‐city cohort study

Laouali

Brailly-Tabard

Helmer

et al. 2018

Clinical Endocrinology

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“…For example, high levels of luteinizing hormone were positively associated with AAA outcomes [62]. Interestingly, lower testosterone levels have been linked to coronary artery disease and peripheral arterial disease in older men, but show litle association when grouped with younger men [63][64][65].…”

Section: Inluences Of Sex Hormones On Aaa Development and Progressionmentioning

confidence: 99%

Sexual Dimorphism of Abdominal Aortic Aneurysms

Alsiraj¹,

Thatcher²,

Cassis³

2017

Aortic Aneurysm

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Sex is the largest nonmodiiable risk factor for the development of abdominal aortic aneurysms (AAAs) in humans and experimental models. Data from several studies consistently demonstrate a higher AAA prevalence in males than in females, contributing to divergent recommendations for AAA screening in men and women. Despite a higher AAA prevalence in males, females have more rapid rates of aneurysm dilation, and aneurysms rupture at smaller sizes. Unfortunately, no therapies have been efective to retard aneurysm dilation in either sex. Results from experimental AAA models indicate a protective role for estrogen in AAA development and progression, while male testosterone has been demonstrated to markedly promote angiotensin II (AngII)-induced AAAs. Potential mechanisms implicated in sex hormone regulation of AAAs include regulation of inlammation, matrix metalloproteinases, aromatase activity, oxidative stress, stem cells, and transforming growth factor-beta. In addition to sex hormones, sex chromosomes have been implicated in diseases of the aorta. Turner's syndrome (monosomy X) patients have a high incidence of thoracic aortic rupture. Recent studies indicate a novel approach to deine the relative role of sex hormones versus sex chromosomes in experimental AAAs. Further studies are warranted to determine interactions between sex hormones and sex chromosomes in AAA development and progression.

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Neutral associations of testosterone, dihydrotestosterone and estradiol with fatal and non‐fatal cardiovascular events, and mortality in men aged 17–97 years

Abstract: In predominantly middle-aged men, T, DHT and E2 do not influence mortality or CVD outcomes. This neutral association of hormones with CVD contrasts with prior studies of older men.

Cited by 35 publications

References 40 publications

Greater physical activity and higher androgen concentrations are independently associated with lower cardiometabolic risk in men

Greater physical activity and higher androgen concentrations are independently associated with lower cardiometabolic risk in men

Oestradiol level, oestrogen receptors, and mortality in elderly men: The three‐city cohort study

Sexual Dimorphism of Abdominal Aortic Aneurysms

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