Testosterone deficiency: A determinant of aortic stiffness in men

doi:10.1016/j.atherosclerosis.2013.12.010

Atherosclerosis

Volume 233, Issue 1, March 2014, Pages 278-283

https://doi.org/10.1016/j.atherosclerosis.2013.12.010 Get rights and content

Highlights

•
We assessed the association between testosterone and arterial stiffness in men without cardiovascular disease.
•
We investigated the influence of androgen level on the age- and blood-pressure related increase in aortic stiffness.
•
Testosterone concentration is a potent independent determinant of aortic stiffness.
•
Younger patients with testosterone deficiency have higher vascular age.
•
The effect of testosterone deficiency on aortic stiffness is more prominent in subjects with higher blood pressure levels.

Abstract

Objective

Low testosterone levels and increased aortic stiffness are predictors of cardiovascular events. The influence of androgen level on the age- and blood pressure-related increase in aortic stiffness is unknown.

Methods

From January 2007 to June 2011 we enrolled 455 consecutive men with no evidence of cardiovascular disease from a large cohort followed in our Department for arterial function studies. Their total testosterone (TT) levels were measured and carotid-femoral pulse wave velocity (PWVc-f) was measured as an index of aortic stiffness.

Results

In multivariable analysis, PWVc-f values were inversely correlated to TT after adjustment for confounders (β = −0.365, P < 0.001). In younger age categories (<50 yrs and 50–59 yrs), patients with testosterone deficiency (TD) had higher blood pressure-adjusted PWVc-f (P < 0.001 and P = 0.005, respectively) compared to subjects with normal TT, indicating an “aging effect” of 10 years, whereas in older age categories such a difference was not observed. Furthermore, in men with a higher mean pressure (102–108 mmHg and >108 mmHg), patients with TD had higher age-adjusted PWVc-f (P < 0.001) compared to subjects with normal TT, indicating a synergistic unfavorable effect of testosterone deficiency and blood pressure on aortic stiffness.

Conclusions

TT levels are independently associated with aortic stiffening. The effect of low testosterone concentration on aortic stiffness is more prominent in young men and in subjects with higher blood pressure levels. These findings identify testosterone as a marker of arterial damage with special emphasis on young and hypertensive individuals and support its role as predictor of events.

Introduction

Increasing attention is focused on the adverse effects of testosterone deficiency on cardiovascular (CV) health. Men with lower testosterone levels tend to have higher incidence of cardiovascular risk factors and coronary artery disease [1], [2]. As we and others have shown, testosterone deficiency has emerged as an important predictor of future cardiovascular events and all-cause mortality both in the general population and in patients with disease states [3], [4], [5]. On the other hand, the levels of testosterone undergo age-related decline [6], while there is also evidence suggesting that risk factors such as hypertension may hasten the age-related fall in testosterone levels [7].

Carotid-femoral (aortic) pulse wave velocity (PWVc-f) is the gold-standard index for assessment of aortic stiffness [8]. Its implementation in clinical practice is based on its reliability, ease of use [9], and predictive value for future CV events and all-cause mortality independent of classic CV risk factors [10], [11] both in the general population [12] and in patients with disease states [13], [14]. It has been included as a recommended test in the recent European Society of Cardiology/European Society of Hypertension guidelines for the management of arterial hypertension [15]. Aortic PWV is strongly dependent on age and blood pressure (BP) [8], [16].

Low testosterone has been associated both through causal and associative relationships with functional and structural changes in the properties of the arterial wall. Studies that investigated the association between testosterone and arterial elastic properties involved diverse populations, such as either elderly [17] or young [18] subjects, as well as patients with diabetes [19], prostate cancer [17], [20] or hemodialysis [21]. In the present study, we sought to investigate whether testosterone levels are associated with aortic stiffness in a population with a broad range of age and risk factors without overt cardiovascular disease. We also assessed the influence of androgen level on the age- and blood-pressure related increase in aortic stiffness.

Section snippets

Study population

From January 2007 to June 2011 we enrolled consecutive men from a large cohort followed in our Department for arterial function studies. All participants were screened for sociodemographic data and risk factors for cardiovascular disease and comprehensively evaluated using medical history, physical examination and electrocardiogram. In the present study, patients with a history of coronary artery disease, stroke or peripheral artery disease and subjects with untreated sleep apnea, chronic

Population characteristics

The baseline clinical characteristics of the 455 participants are given in Table 1. One-hundred and nine (24%) patients had biochemical TD, while 23 of those (5%) had TT levels below 2.5 ng/ml (severe TD). Compared to patients with normal TT levels, subjects with TD were older (P < 0.001) and had higher BMI (P < 0.05), waist circumference (P < 0.05), systolic pressure (P < 0.01), pulse pressure (P < 0.001), fasting blood glucose (P < 0.001), C-reactive protein (P < 0.01) and a higher prevalence

Discussion

Our study is the first, to the best of our knowledge, to demonstrate the association between testosterone levels and arterial stiffness over a broad range of men without manifest cardiovascular disease. Specifically, testosterone concentration is a potent independent determinant of PWVc-f, while the effect of testosterone deficiency on aortic stiffness is more prominent in young men and in subjects with higher BP levels. Our observations highlight the role of testosterone as a marker of

Conclusion

In conclusion, this is the first study to demonstrate that testosterone is independently associated with aortic stiffness over a broad range of individuals without manifest cardiovascular/atherosclerotic disease. Our results highlight the important role of testosterone deficiency as a marker of vascular damage with special emphasis on young and hypertensive individuals. Further investigations are warranted to determine possible causal relationships and to define whether low testosterone should

Conflict of interest

The authors declare no conflict of interest.

References (45)

M. Kaushik et al.
Cardiovascular disease and androgens: a review
Int J Cardiol
(2010)
R. Fogari et al.
Sexual activity and plasma testosterone levels in hypertensive males
Am J Hypertens
(2002)
C. Vlachopoulos et al.
Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis
J Am Coll Cardiol
(2010)
M. Fukui et al.
Relationship between low serum endogenous androgen concentrations and arterial stiffness in men with type 2 diabetes mellitus
Metab Clin Exp
(2007)
C. Wang et al.
Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations
Eur Urol
(2009)
A.M. Traish et al.
Testosterone deficiency
Am J Med
(2011)
J.F. Price et al.
Steroid sex hormones and peripheral arterial disease in the Edinburgh Artery Study
Steroids
(1997)
A. Nehra et al.
The Princeton III consensus recommendations for the management of erectile dysfunction and cardiovascular disease
Mayo Clin Proc
(2012)
M. Miner et al.
Prognostic utility of erectile dysfunction for cardiovascular disease in younger men and those with diabetes
Am Heart J
(2012)
M.R. Nelson et al.
Noninvasive measurement of central vascular pressures with arterial tonometry: clinical revival of the pulse pressure waveform?
Mayo Clin Proc
(2010)

M.M. Miner

Men's health in primary care: an emerging paradigm of sexual function and cardiometabolic risk

Urol Clin North Am

(2012)

J. Buvat et al.

Testosterone deficiency in men: systematic review and standard operating procedures for diagnosis and treatment

J Sex Med

(2013)

D.M. Kelly et al.

Testosterone: a vascular hormone in health and disease

J Endocrinol

(2013)

J.B. Ruige et al.

Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis

Heart

(2011)

G. Corona et al.

Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study

Eur J Endocrinol

(2011)

C. Vlachopoulos et al.

Plasma total testosterone and incident cardiovascular events in hypertensive patients

Am J Hypertens

(2013)

H.A. Feldman et al.

Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study

J Clin Endocrinol Metab

(2002)

M.F. O'Rourke et al.

McDonald's blood flow in arteries: theoretical, experimental and clinical principles

(2011)

S. Laurent et al.

Expert consensus document on arterial stiffness: methodological issues and clinical applications

Eur Heart J

(2006)

C. Vlachopoulos et al.

Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a systematic review and meta-analysis

Eur Heart J

(2010)

G.F. Mitchell et al.

Arterial stiffness and cardiovascular events: the Framingham Heart Study

Circulation

(2010)

S. Laurent et al.

Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients

Hypertension

(2001)

Cited by (67)

Age-related decrease in serum dihydrotestosterone concentration is accompanied by impaired vascular status
2023, Experimental Gerontology
The effect of androgens on the cardiovascular system in humans is ambiguous. Moreover, still little is known about the effects of the most potent androgen, dihydrotestosterone, on arterial stiffness and endothelial function. The aim of this study was to evaluate whether age-dependent alterations in serum concentration of dihydrotestosterone and its circulating metabolite are accompanied by changes in endothelial function and arterial stiffness.
In 12 young and 11 older men, basal serum concentrations of testosterone, dehydroepiandrosterone sulfate (DHAE-S), androstenedione (AE), dihydrotestosterone (DHT) and androstanediol glucuronide (ADG) were analyzed in relation to vascular status including cIMT — carotid intima media thickness, cAI — central augmentation index, crPWV — carotid radial pulse wave velocity, SI — stiffness index, endothelial and inflammatory markers.
Although concentration of testosterone was not different between young and older group, it was demonstrated that DHT, DHEA-S, AE and ADG were significantly lower in older men in comparison to young men (p < 0.01). Interestingly the most surprising difference was found for DHT concentration, that was as much as 61 % lower in aged men that displayed significantly higher values of cIMT, AI, crPWV and SI (p < 10⁻⁴), suggestive of arterial stiffness. Furthermore, DHT was negatively correlated to all arterial wall parameters (cAI, crPWV, SI and cIMT), c-reactive protein (CRP) and hyaluronic acid (HA) concentration, as well as positively correlated to markers of endothelial function (MNA and 6-keto-PGF_1α) in all studied individuals (n = 23).
We have shown that ageing leads to a significant decrease in DHT concentration that is accompanied by impaired arterial wall characteristics and worsened endothelial function. Therefore more attention should be paid to the DHT, DHEA-S and ADG concentrations as a biomarkers for vascular dysfunction in ageing men.
Cadmium exposure is associated with testosterone levels in men: A cross-sectional study from the China National Human Biomonitoring
2022, Chemosphere
Citation Excerpt :
Our study observed positive and significant associations between Cd exposure and both serum testosterone and T/E2, which may have important implications for improving male health and reducing the burden of sex hormone-related disease. Because serum testosterone and T/E2 are frequently used as biomarkers of risk for many clinical outcomes (Corona et al., 2011; Münzker et al., 2015; Svartberg et al., 2004; Vlachopoulos et al., 2014), the ability of sex hormones to correctly identify patient risk of adverse clinical outcomes may be impaired by exposure to Cd. Further work is needed to reduce Cd exposure in men in order to reduce the incidence of clinical sex hormone-related diseases and promote health.
Sex hormone disorders can cause adverse health consequences. While experimental data suggests that cadmium (Cd) disrupts the endocrine system, little is known about the link between Cd exposure and sex hormones in men.
We measured blood cadmium (B-Cd), urine cadmium (U-Cd), serum testosterone and serum estradiol in men aged ≥18 years old participating in the China National Human Biomonitoring program, from 2017 to 2018. Urine cadmium adjusted for creatinine (Ucr-Cd) and the serum testosterone to serum estradiol ratio (T/E₂) were calculated. The association of Cd exposure to serum testosterone and T/E₂ in men was analyzed with multiple linear regression models.
Among Chinese men ≥18 years old, the weighted geometric mean (95% CI) of B-Cd and Ucr-Cd levels were 1.23 (1.12-1.35) μg/L and 0.53 (0.47-0.59) μg/g, respectively. The geometric means (95% CI) of serum testosterone and T/E₂ were 18.56 (17.92-19.22) nmol/L and 143.86 (137.24-150.80). After adjusting for all covariates, each doubling of B-Cd level was associated with a 5.04% increase in serum testosterone levels (β = 0.071; 95%CI: 0.057-0.086) and a 4.03% increase in T/E₂ (β = 0.057; 95%CI: 0.040-0.075); similar findings were found in Ucr-Cd.
In Chinese men, Cd may be an endocrine disruptor, which is positively associated with serum testosterone and T/E₂.
Autonomic and neuroendocrine modulation of arterial stiffness and hemodynamics
2022, Textbook of Arterial Stiffness and Pulsatile Hemodynamics in Health and Disease
The autonomic nervous system is essential to maintaining tonic and reflex cardiovascular control through the regulation of neural outflow to the heart and circulation. Autonomic modulation of arterial stiffness and hemodynamics can occur reflexively in response to alterations in stroke volume, heart rate, and the mechanical properties of conduit and resistance vessels. Whether acute or chronic increases in sympathetic activity can affect arterial stiffness and pulse wave characteristics independent of changes in distending pressure remains an important physiological question. In this chapter, we discuss the controversies stimulated by human cross-sectional data and recent evidence supporting the concept that acute increases in muscle sympathetic nerve firing can increase central and peripheral arterial stiffness. The moderating effects of neuroendocrine factors on arterial stiffness, including the influence of sex hormones on the relationship between sympathetic outflow and pulse wave characteristics, also will be reviewed.
Sex Differences in the Relationship Between Arterial Stiffness and Cognitive Function in Older Adults
2022, Journal of Stroke and Cerebrovascular Diseases
To examine potential sex differences in the relationship between arterial stiffness and global cognitive function and executive functions.
Baseline data from 80 older adults were included from two randomized controlled trials (NCT02669394 and NCT02737878). Arterial stiffness was measured by carotid-femoral pulse wave velocity (cf-PWV). Cognitive function assessment included global cognition (Mini-Mental State Examination [MMSE]) and executive functions (set shifting [Trail Making Test Part B minus A], inhibition [Stroop Test], and working memory [Verbal Digit Span Backwards Test]). Separate statistical models were constructed to assess the effect of cf-PWV on each cognitive outcome for females and males. Each statistical model controlled for Framingham cardiovascular disease risk score and education.
Higher cf-PWV was associated with impaired MMSE performance in males (β = -0.48; p = 0.018), but not females (p ≥ 0.389). For executive processes, higher cf-PWV was associated with impaired Trail Making Test Part B minus A (β = 0.56; p = 0.005) and Stroop Test (β = 0.59; p = 0.004) in males, but not in females (ps ≥ 0.108). cf-PWV was not significantly associated with Verbal Digit Span Forward minus Backward Test in males or females (ps ≥ 0.108).
Arterial stiffness is more strongly associated with cognitive impairment in males than females. These results further elucidate the interplay between vascular health and cognitive function by providing support for sex-specific mechanisms.
Low Serum-Free Testosterone Concentration in Chinese Male Patients with Uncomplicated Acute Type B Aortic Dissection
2021, Annals of Vascular Surgery
Citation Excerpt :
Vascular stiffness is an important manifestation of vascular aging. Subjects with lower testosterone manifest similar vascular stiffness as subjects with normal testosterone levels but 1 decade older.31 A stiff aorta increases left ventricular afterload and disturbs myocardial blood flow.
Although aortic dissection occurs predominantly in men, its association with androgens is unknown. The aim of this study was to evaluate the androgen levels in Chinese male patients with uncomplicated, acute type B aortic dissection.
Cross-sectional study.
A total of 192 age-matched male patients with uncomplicated, acute type B aortic dissection or essential hypertension were recruited between 2016 and 2018. The demographic and clinical data were analyzed.
Male patients with uncomplicated, acute type B aortic dissection had lower serum total testosterone and free testosterone than male patients with essential hypertension (7.6 ± 3.7 nmol/L vs. 10.9 ± 3.8 nmol/L, P < 0.001; 36.0 ± 19.8 pmol/L vs. 56.4 ± 19.2 pmol/L, P < 0.001). Lower free testosterone level was significantly associated with uncomplicated, acute type B aortic dissection (univariate odds ratio 0.948, P < 0.001; multivariate odds ratio = 0.966, P = 0.002). No statistical difference was observed for free testosterone between younger patient groups (aged < 51 years; aged 51–60 years) and older patient groups (aged 61–70 years; aged >70 years) with uncomplicated, acute type B aortic dissection (33.7 ± 19.8 pmol/L vs. 38.5 ± 19.8 pmol/L, P = 0.239).
Lower free testosterone was independently associated with uncomplicated, acute type B aortic dissection in the Chinese male population with hypertension. Additional studies are needed to clarify whether earlier onset in Chinese patients with aortic dissection is associated with androgen deficiency.
Sex Differences in Children and Young Adults With Bicuspid Aortic Valve Disease in First Two Decades of Life
2021, Mayo Clinic Proceedings
Citation Excerpt :
Various population-based studies on testosterone have also demonstrated a protective effect on the aorta by decreasing aortic stiffness.32 In addition, a testosterone deficiency state can lead to higher arterial stiffness in men,33 and in men with acquired hypogonadism, replacement of testosterone can lead to a rapid improvement in arterial stiffness.34 The effects of various hormones on the aortic wall stiffness are shown in Figure 7.
To elucidate sex differences in valve morphology, disease phenotype, progression, and outcomes among children and young adults with bicuspid aortic valve (BAV).
This is a retrospective cohort study examining all children and young adults (aged ≤22 years) with isolated BAV diagnosed, by excluding patients with concomitant congenital heart defects or genetic syndromes, from January 1, 1990, through December 1, 2016, at Mayo Clinic in Rochester, Minnesota.
Of 1010 patients with BAV, 558 had isolated BAV. Distributions of morphology were right-left in 65.8% (n=367), right-noncoronary in 34% (n=190), and left-noncoronary cusp fusion in 0.2% (n=1) of patients; with no sex differences. Male to female ratio was 3:1. At the first echocardiographic evaluation in the study, there were no sex differences in terms of frequency of aortic valve stenosis or regurgitation. However, males had significantly higher grades of aortic valve regurgitation at 17 years of age onward (P<.0001). Males had significantly larger mid-ascending aorta (P=.01) and sinus of Valsalva dimensions (z score; P=.0001) as compared with females, with a novel finding of peak aortic dimensions around 8 years of age. Males also had more than 2-fold higher risk for sinus of Valsalva dilation (z score >2) as compared with females (odds ratio, 2.3; 95% CI, 1.2 to 4.2; P=.01). There were no significant sex differences in the primary cardiac outcomes of interventions on aortic valve and/or aorta, aortic dissection, or death.
In children and young adults with BAV, males have a higher grade of aortic regurgitation in late adolescence, significantly larger aortic dimensions, different patterns of aortic growth, and more frequent sinus of Valsalva dilation as compared with females. Overall, the rate of primary cardiac events is lower in young patients, with no significant sex differences.

View all citing articles on Scopus

View full text

Testosterone deficiency: A determinant of aortic stiffness in men

Highlights

Abstract

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Study population

Population characteristics

Discussion

Conclusion

Conflict of interest

Int J Cardiol

Am J Hypertens

J Am Coll Cardiol

Metab Clin Exp

Eur Urol

Am J Med

Steroids

Mayo Clin Proc

Am Heart J

Mayo Clin Proc

Urol Clin North Am

J Sex Med

Testosterone: a vascular hormone in health and disease

J Endocrinol

Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis

Heart

Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study

Eur J Endocrinol

Plasma total testosterone and incident cardiovascular events in hypertensive patients

Am J Hypertens

Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study

J Clin Endocrinol Metab

McDonald's blood flow in arteries: theoretical, experimental and clinical principles

Expert consensus document on arterial stiffness: methodological issues and clinical applications

Eur Heart J

Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a systematic review and meta-analysis

Eur Heart J

Arterial stiffness and cardiovascular events: the Framingham Heart Study

Circulation

Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients

Hypertension