Hypogonadism (män) Kardiovaskulär risk Erythrocytosendokrindagarna.se/wp-content/uploads/2019/02/Hypogonadism_S_Arver.pdf · Hypogonadism* (män) Erytrocytos Kardiovaskulär risk

Hypogonadism* (män)Erytrocytos

Kardiovaskulär risk

Stefan ArverANOVA, Karolinska Univ Sjukhuset

Inst. F Medicin/Huddinge Karolinska Institutet

Endokrindagar i Umeå 2019 1

*Lågt Testosteron och symtom

2

(Brown-Séquard, C. The Lancet 1889; 134 (3438); 105-107)

”... for his work on sex hormones.”

The story about testosterone

Endokrindagar i Umeå 2019

• “From this report of the practical use of testosterone in clinical medicine it is obvious that the drug is a potent one, particularly in hypogonadism in males. In this condition, its effectiveness as substitution therapy is uniformly accepted.”

N. Engl. J. Med. 1940; 222:877-881.


The story about testosterone

4

(Lesser, M. N Engl J Med 1943; 228:185-188)


Testosterone in coronary heart disease

Mathur A et al. European Journal of Endocrinology 161 443–449

När Testosteron Kommer på agendan undrar man

Dina Associationer ?


Förklaring till att män dör tidigare än kvinnorÖkar risken för hjärtkärlsjukdomStyr mäns aggressivitet och gör män våldsammaÖkar sexdrift och potensHierarkin på jobbet styrs av testosteron

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. Published by Lippincott Williams & Wilkins, Inc.2

Testosteronanvändning i USA 2008-2016

Patterns of testosterone prescription overuse.Jasuja, Guneet; Bhasin, Shalender; Rose, Adam

Current Opinion in Endocrinology, Diabetes & Obesity. 24(3):240-245, June 2017.DOI: 10.1097/MED.0000000000000336

FIGURE 1 . Proportion of male Veterans receiving testosterone therapy, FY2008-16. FY: Fiscal Year Data source: VA Corporate Data Warehouse.


Low Testosterone and Increased Mortality (N >500)

Studies HR (95% CI) Nature Men, nFollow-Up,

yMortality

Shores, 2006 1.88 (1.34–2.63) Retrospective 858 8 All-cause

Laughlin, 2008 1.38 (1.02–1.85) Prospective 794 20 CVD

Khaw, 2007 2.29 (1.60–3.26) Prospective2314 of 11,606

10All-cause and

CVD

Haring, 2010 2.32 (1.38–3.89) Prospective 1954 7.2 All-cause

2.56 (1.15-6.52) CVD

Malkin, 2010 2.27 (1.45–3.60) Prospective 930 6.9

All-cause in men with coronary disease

Tivesten, 2009 1.65 (1.29–2.12) Prospective 3014 4.5 All-cause

Menke, 2010 1.43 (1.09–1.87) Prospective 1114 9 All-cause

Vikan, 2009 1.24 (1.01–1.54) Prospective 1568 11.2 All-cause

Corona, 2010 7.1 (1.8–28.6) Prospective 1687 4.3 CVD

HR=hazard ratio; CI=confidence interval.Lunch Seminarium Endokrin Huddinge

20170522

Mulller M et al. Circulation 2004; 109: 2074−2079.

Progression of mean IMT of common carotid artery after 4 years correlates with serum total and free

testosterone

Muller M et al Circulation 2004;109:2074

Epidemiologi och observation


JAMA. 2015 Aug 11;314(6):570-81. doi: 10.1001/jama.2015.8881.Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men With Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial. Basaria S et al

Intervention

https://www.ncbi.nlm.nih.gov/pubmed/26262795

Conclusion:High serum testosterone predicted a reduced 5-year risk of CV events in elderly men. (J Am Coll Cardiol 2011;58:1674–81) © 2011 by the American College of Cardiology Foundation

High Serum Testosterone Is Associated WithReduced Risk of Cardiovascular Events in Elderly MenThe MrOS (Osteoporotic Fractures in Men) Study in SwedenClaes Ohlsson, MD, PHD,* Elizabeth Barrett-Connor, MD,‡ Shalender Bhasin, MD, PHD,§Eric Orwoll, MD, PHD, Fernand Labrie, MD, PHD,¶ Magnus K. Karlsson, MD, PHD,#Östen Ljunggren, MD, PHD,** Liesbeth Vandenput, PHARMD, PHD,* Dan Mellström, MD, PHD,*Åsa Tivesten, MD, PHD†

Testosterone Therapy Pros and Cons ESSM 2014

Vigen R et al. J Am Med Assoc 310(17): 1829-1836 (2013)Endokrindagar i Umeå 2019 12

Proportion of All Events According to Kaplan-Meier Estimation with Treatment asTime-Varying Covariate (Stabilized Inverse Probability of Treatment Weighting*)

Data from: Vigen R et al. J Am Med Assoc 310(17): 1829-1836 (2013)

10.1

15.4

19.9

11.3

18.5

25.7

0

5

10

15

20

25

30

at 1 year at 2 years at 3 years

no TRT TRT

*age, race, comorbidities: (prior MI, congestive heart failure, diabetes, renal failure, depression, posttraumatic stress disorder, hyperlipidemia, peripheral vascular disease, chronic pulmonary disease, chronic obstructive pulmonary disease, obstructive sleep apnea, hypertension, cerebrovascular disease, overweight, dialysis, ever smoker, alcohol, anemia, blood loss anemia, coagulation disorder, complicated diabetes, uncomplicated diabetes, drug abuse, fluid electrolyte disorder, human immunodeficiency syndrome or AIDS, hypothyroidism, liver disease, lymphoma, metastatic cancer, neurological disorder, paralysis, peptic ulcer disease, psychoses, pulmonary circulatory disorder, renal failure, rheumatoid arthritis, nonmetastatic tumor, and weight loss), and procedures (prior revascularization, prior catheterization, prior percutaneouscoronary intervention [PCI], prior coronary artery bypass graft surgery, cardiac transplant, prior stress test, prior cardiac blood pool imaging, cardiac magnetic resonance imaging, cardiac computed tomography [CT], CT coronary angiography, prior myocardial perfusion imaging,,priortransthoracic echocardiogram, and prior transesophageal echocardiogram


Proportion of All Events (Composite of All-cause Mortality, Myocardial Infarctionand Stroke) in Hypogonadal Patients (%) with or without Testosterone ReplacementTherapy (TRT)

9.1

5.6

6.5

5.5

1.9

2.7

0

2

4

6

8

10

Death Myocardial infarction Stroke

no TRT TRT

Data from: Vigen R et al. J Am Med Assoc 310(17): 1829-1836 (2013)

21,2

10,1

0

5

10

15

20

25

all events


Testosterone, coronary artery disease and prognosis930 men with coronary heart disease followed for 7 years

5 februari 2019 15

Low testosterone levels are common in men with coronary artery disease and

low bioavailable but not total testosterone related to impaired vascular survival

(Malkin et al. Heart 2010; 96: 1821-1825)

Bio T >2.6

nmol/L

Bio T <2.6

nmol/L

Days

Va

scu

lar

su

rviv

al

5 februari 2019 16(Muraleedharan et al. European Journal of Endocrinology 2013: 169 725–733.)

Cu

mu

lative

su

rviv

al

Cu

mu

lative

su

rviv

al

TT>300 ng/dl

TT≤300 ng/dl

p=0.009

HR=2.0 (1.2-3.4)

Months of survival Months of survival

Low TT

treated

Low TT

untreated

Normal

TT

p=0.004

HR=2.3 (1.3-3.9)

▪ Low total testosterone (TT) associated with worse prognosis in men with T2DM.

▪ Long-term testosterone treatment assessed retrospectively was associated with

improved survival in men with low testosterone.

Testosterone treatment in T2DMCohort study (n=581) of men with T2DM followed for 6 years

LL: Lower limit; MH-OR: Mantel-Haenszel odds ratio; UL: Upper limit

Odds Ratio for Major Adverse Cardiovascular Events (MACE) in Subjects Treated

with Testosterone or Placebo MACE: cardiovascular death, non-fatal myocardial infarction, stroke, acute coronary syndromes, and/or heart failure

Corona G et al. Expert Opin Drug Saf, published online August 19, 2014

TRT Placebo

0.01 0.1 1 10 100

Odds ratio for MACE

Placebo TS

Source MH - OR LL #Events # Patients #Events # Patients

Copenhagen SG, 1986 (31) 1,97 0,08 48,82 0,68Hall et al., 1996 (34) 0,32 0,01 8,23 0,49Sih et al., 1997 (36) 0,88 0,05 15,33 0,93Snyder et al., 1999 (40) 2,04 0,18 23,17 0,57English et al., 2000 (42) 3,12 0,12 80,39 0,49Seidman et al., 2001 (47) 0,41 0,02 10,83 0,59Steidle et al., 2003 (52) 2,83 0,11 70,27 0,53Armory et al., 2004 (54) 3,13 0,12 80,68 0,49Kenn et al., 2004 (56) 0,23 0,01 7,05 0,40Svartberg et al., 2004 (60) 0,29 0,01 7,74 0,46Brockenbrough et al., 2006 (63) 3,75 0,36 39,59 0,27Malkin et al., 2006 (69) 2,17 0,19 25,01 0,53Nair et al., 2006 (72) 5,70 0,26 123,78 0,27Svartberg et al., 2008 (81) 3,16 0,12 82,64 0,49Chapman et al., 2009 (84) 1,00 0,05 20,83 1,00Legros et al., 2009 (85) 1,01 0,04 25,01 1,00Aversa et al., 2010 (89) 0,08 0,00 2,07 0,13Aversa et al., 2010 (90) 0,07 0,00 1,97 0,12Basaria et al., 2010 (11) 13,39 0,74 240,78 0,08Kalinchenko et al., 2010 (92) 0,21 0,01 5,15 0,34Srinivas- Shankar et al., 2010 (93) 1,01 0,14 7,31 0,99Ho et al., 2011 (95) 1,00 0,06 16,37 1,00Jones et al., 2011 (96) 0,51 0,05 5,75 0,59Kaufman et al. 2011 (97) 0,87 0,04 18,48 0,93Behre et al. 2012 (99) 2,95 0,12 72,91 0,51 Hildreth et al. 2013 (100) 0,15 0,02 1,53 0,11 Overall 1,01 0,57 1,77 0,96

1 134 0 870 35 1 351 17 1 152 54 1 541 25 0 250 13 1 171 106 0 991 24 0 240 6 1 50 15 1 143 19 1 212 37 1 392 30 0 321 19 0 191 6 1 61 237 0 790 40 1 100 42 1 106 106 0 1030 113 1 712 136 2 1381 60 1 601 108 2 1122 234 0 401 183 0 1791 96 3 47

31 1895 20 1341

UL p


Lunch Seminarium Endokrin Huddinge 20170522


There have been no RCTs that were large enough or long enough to determine the effects of T-replacement therapy on major adverse cardiovascular events (MACE). Additionally, there is no conclusive evidence that T supplementation is associated with increased cardiovascular risk in hypogonadal men.

” Endocrine Soc Guidlines 2018”

EMA and FDA recommendations for CV disease risk

EMA recommendations

• Inconsistent evidence for increased risk of CV disease following TRT1

FDA recommendations

• TRT labels must specify possible increased risk of stroke and heart attack associated with TRT2

CV, cardiovascular; EMA, European Medicines Agency; FDA, Food and Drug Administration; TRT, testosterone replacement therapy

1. EMA Press Release 2014. Accessed [March 2018] at: http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Testosterone_31/Recommendation_provided_

by_Pharmacovigilance_Risk_AssessmentCommittee/WC500175213.pdf; 2. FDA Drug Safety Communication 2014. Accessed [March 2018] at:

http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Testosterone_31/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500175213.pdf

21

Changes in

CV surrogate measures

with testosterone treatment

Myocardial perfusion:

↑ Perfusion of coronary

territories with no

stenosis

QT interval:

↓ QT-interval

Coronary artery

blood flow:

↑ Blood flow and

artery diameter

Hemodynamics:

↑ Cardiac output

Testosterone treatment in the cardiovascular system

(Jones et al. Asian J Andrology (2018) 20, 120–130; Kloner et al. J Am Coll Cardiol 2016;67:545–57)

Myocardial protection:

Decreased reperfusion

injury

Exercise-induced

ischemia:

↑ Time to 1 mm ST

depression


5 februari 2019

Anne Wang

22

0

200

400

600

800

1000

1200

Day 1 Discharge 3 months 12 months Controls

To

tal te

sto

ste

ron

e(n

g/d

l)

Time point

p<0.0001

p=0.05

p<0.01

Testosterone levels in patients after AMI

compared to controls at baseline

Study I: Dynamics of testosterone123 male patients with AMI and 124 matched healthy controls






Hematocrit

TestosteroneEstradiol

From: Androgen Receptor Gene CAG Repeat Length and Body Mass Index Modulate the Safety of Long-

Term Intramuscular Testosterone Undecanoate Therapy in Hypogonadal Men

J Clin Endocrinol Metab. 2007;92(10):3844-3853. doi:10.1210/jc.2007-0620

Effekt av androgen receptor polymorfism på erytropoes respons av T-behandling






Bachman et al J Gerontology A Biol Sci Med 2014 (6):725-735


Clinicians should evaluate men who develop erythrocytosis during T-replacement therapy and withhold T therapy until hematocrit has returned to the normal range and then resume T therapy at a lower dose. Using therapeutic phlebotomy to lower hematocrit is also effective in managing T treatment–induced erythrocytosis

” Endocrine Soc Guidlines 2018”

Documents

Hypogonadism (män) Kardiovaskulär risk Erythrocytosendokrindagarna.se/wp-content/uploads/2019/02/Hypogonadism_S_Arver.pdf · Hypogonadism* (män) Erytrocytos Kardiovaskulär risk