Estrogens vs Testosterone for cardiovascular health and longevity

Estrogens vs Testosterone for cardiovascular health and longevity Panagiota Pietri, MD, PhD, FESC Director of Hypertension Unit Athens Medical Center Athens, Greece

Women vs Men Is there a difference in survival? In 1900, life expectancy was, approximately, 48 years for women and 46 years for men. Today, it is 83.5 years for women and 79.5 years for men.

Women vs Men Is there a difference in survival? Blue zone IKARIA Panagiotakos D, et al. Cardiology Res Pract 2011

Women vs Men Cardiovascular disease mortality: Is there a difference between the two genders? Previous data Current knowledge

Women vs Men Death rates by sex Hazzard W, Trans Am Clin Climatol Assoc 1990;101:168-188

Women vs Men Cardiovascular disease mortality: Is there a difference between the two genders? Previous data Current knowledge

Women vs Men 2010.Deaths by cause, Europe MEN European Cardiovascular Disease Statistic 2012 edition

Women vs Men 2010 Deaths by cause, Europe WOMEN European Cardiovascular Disease Statistic 2012 edition

Women vs Men The role of sex hormones on cardiovascular system: Females-estrogens Males-testosterone

Estrogens and cardiovascular health Potential beneficial effects of estrogens on cardiovascular system Vasodilatation (via VSMC relaxation or NO synthase activation) Improvement of aortic elasticity Inhibition of renin-angiotensin-aldosterone system Upregulation of AT2 receptors Natriuresis Increase insulin secretion Increase insulin sensitivity Pietri P, Vlachopoulos C. Chapter 20, In book: Hypertension and Cardiovascular Disease, Springer 2016

Estrogens and coronary vasodilatation 7 men, 9 women with CAD. Intracoronary administration of pharmacological dose of 17β-estradiol, 20 minutes after Infusion of acetylcholine. In both women and men, acetylcholine caused vasoconstriction of atherosclerotic coronary arteries. This was rapidly reversed by estrogen in women but not in men. Collins P, et al. Circulation 1995;92:24-30

Estrogens and aortic elasticity 20 postmenopausal women Group 1: without CAD Group 2: with CAD Intravenous administration of 10 μg of 17β-estradiol increased aortic distensibility in both groups. Stefanadis C, et al. Am J Physiol 1999;276:H658-H662

Estrogens and renin-angiotensin system Women Men (n=342) No ERT (n=239) ERT (n=107) Renin (mu/l) 20.5±1.5 16.6±0.9 12.0±0.7 Renin activity 2.74±0.03 2.57±0.04 2.34±0.05 Renin levels (and activity) were lower in women with ERT compared to women without ERT or men. Renin suppression was seen with either oral or transdermal ERT. ERT, estrogen replacement therapy Schunkert H, et al. Circulation 1997;95:39-45

Menopausal status and insulin metabolism 66 premenopausal women 92 postmenopausal women Premenopausal women Postmenopausal women Premenopausal women Postmenopausal women After IV GTT: No difference in insulin and glucose levels between the 2 groups However, postmenopausal women produced 50% less insulin and eliminated it more slowly-thus compensating for reduced secretion and maintaining insulin at premenopausal levels. Walton C, et al. Eur J Clin Invest 1993;23:466-473

Menopause: Opposite results Menopause Low-grade inflammation Endothelial dysfunction Aortic stiffness Insulin resistance RAAS activation Coexisting factors that increase CAD risk Age Smoking Coronary Artery Disease Risk Pietri P, Vlachopoulos C. Chapter 20, In book: Hypertension and Cardiovascular Disease, Springer 2016

Hormone replacement therapy and CV risk Contradictory Results

Hormone replacement therapy and CV risk 16,608 postmenopausal women (50-79) 1006 postmenopausal women (45-48) FU = 5 years FU = 10 years Combined HRT was associated Combined HRT reduced the risk of with increased risk of CHD (HR=1.24) mortality, heart failure or myocardial infarction (HR=0.48) Manson J, et al. N Engl J Med 2003;349:523-534 Schierbeck L, et al. BMJ 2012;345:e6409

Hormone replacement therapy and CV risk Diamanti-Kandarakis E, et al. Eur J Endocrinol 2017;176:R283-R308

Women vs Men The role of sex hormones on cardiovascular system: Females-estrogens Males-testosterone

Testosterone and cardiovascular risk No effect 1,009 white men (40-79 years) FU: 12 years CONCLUSION: No sex hormone measured (testosterone, androstenedione, estrone or estradiol) was significantly associated with known cardiovascular disease at baseline or with subsequent cardiovascular mortality. Barrett-Connor E, Knaw KT. Circulation 1988;78:539-545

Barrett-Connor E, Knaw KT. Circulation 1988;78:539-545

Testosterone and cardiovascular risk Inverse relationship Multivariate-adjusted survival by quartile group of endogenous testosterone concentrations 2314 men (42-78 years old) FU: 1993-2003 The highest quartile of testosterone was associated with lower risk of cardiovascular and total mortality (25-30% lower risk for total mortality) Highest quartile Lowest quartile Khaw KT, et al. Circulation 2007;116:2694-2701

Testosterone and cardiovascular risk Inverse relationship 2416 men (69-81 years) FU: 5 years Men in the highest quartile (Q4) of testosterone ( 550 ng/dl), had a lower risk of CV events compared to men in the 3 lower quartiles (HR:0.71, 95% CI:0.53-0.95) Ohlsson C, et al. J Am Coll Cardiol 2011;58:1674-1681

Low testosterone and cardiovascular risk Adverse effects of low testosterone on cardiovascular system: Endothelial dysfunction Low-grade inflammation Insulin resistance Metabolic syndrome Abnormal lipid profile High central (aortic) blood pressure Aortic stiffness and LV hypertrophy

Low testosterone, erectile dysfunction and cardiovascular disease Endothelial dysfunction and inflammation are the common denominators between ED and CVD. Low androgen levels may mediate this relationship. Gandaglia G, et al. Eur Urol 2014;65:968-978

Erectile dysfunction and CV disease Erectile dysfunction is associated with increased CV events and mortality 14 studies 92,757 men FU = 6 years Vlachopoulos C, et al. Circ Cardiovasc Outcomes 2013;6:99-109

Low testosterone, insulin resistance and metabolic syndrome Testosterone was inversely associated with abnormal waist circumference, hs-crp, insulin and HDL-cholesterol. Habitual physical activity seems to be related with higher serum testosterone levels and improved insulin resistance in elderly diabetic individuals. Chrysohoou et al. The Review of DIABETIC STUDIES 2013

Low testosterone and central blood pressure Inverse association of total testosterone with central SBP (upper panel) and central PP (lower panel) in hypertensive men. The association was independent of age, BMI, smoking, total cholesterol, glucose, statin use. Total testosterone 10 9 8 7 6 5 4 3 2 1 0 r= -0.23, p=0.03 80 90 100 110 120 130 140 150 160 170 Central SBP Total testosterone 10 9 8 7 6 5 4 3 2 1 0 r=-0.30, p=0.01 20 30 40 50 60 70 80 Central PP Pietri P, et al. J Hypertens 2015;33 Suppl1:e67

Low testosterone and arterial stiffness Inverse association of total testosterone with PWV Atherosclerosis 2014;233:278-283 455 males without CVD 57% hypertensives In the category of high mean BP, males with total testosterone (TT) deficiency had significantly higher PWV compared to males with TT concentration within normal limits. On the contrary, in lower pressure categories, PWV did not differ between males with low and males with normal TT levels.

Low testosterone and LV hypertrophy Atherosclerosis 2016;250:57-62 134 middle-aged hypertensive patients 60 age-matched controls TT was significantly and inversely related to left ventricular mass (LVM) after adjustment for several confounders.

Testosterone Replacement Therapy and CV risk Contradictory Results

Testosterone Replacement and CV risk Vigen R, et al. JAMA 2013;310:1829-1836 8709 men with low TT (<300 ng/dl), 80% had CAD 1223 started testosterone At 3 years FU, testosterone therapy was associated with increased risk of adverse events (total mortality, MI, stroke) Sharma R, et al. Eur Heart J 2015; 83010 men with low TT, median age = 66 years Gp1: TRT with resulting normalization of TT - Gp2: TRT without normalization of TT Gp3: no TRT treatment At 6 years FU, all-cause mortality (HR:0.53), risk of MI (HR:0.82) and stroke (HR:0.70) were significantly lower in Gp1 vs Gp2.

CONCLUSIONS The endogenous sex hormones (estrogens-testosterone) exert favorable effects on cardiovascular system. The decline of sex hormones with advancing age (menopause-andropause) is associated with increased risk of cardiovascular morbidity and mortality. Despite the beneficial role of endogenous sex hormones on cardiovascular system, their use as hormone replacement therapy, give contradictory results. Prospective, well designed, studies are needed to establish the definite role of hormone replacement therapy (especially testosterone) on cardiovascular risk.

Estrogens vs Testosterone for cardiovascular health and longevity