Outline. Classic Androgen deficiency. Cardiovascular Risk and Testosterone Fact vs Fiction. Professor Robert I McLachlan AM, FRACP, PhD

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1 Health Ed Brisbane Saturday 27 th October 2018 Cardiovascular Risk and Testosterone Fact vs Fiction Professor Robert I McLachlan AM, FRACP, PhD Hudson Institute of Medical Research, Monash University Department of Endocrinology, Monash Health Director, Andrology Australia Consultant Andrologist, Monash IVF Group 1. Background: organic vs late onset hypogonadism Height loss Spinal fractures Osteoporosis Preservation of scalp hair Muscle Wasting Weakness Gynecomastia Loss of body hair Central Adiposity Courtesy of H. Newnham, Melbourne Eugonadism Organic Hypogonadism* Fatigue, Low libido, Erectile dysfunction Infertility, Small testes disease of hypothalamicpituitary-testicular axis Diabetes Classic Testosterone Deficiency Defined testicular or hypothalamo-pituitary disease Can occur at all ages Testis failure - 95% Pituitary failure - 5% Testosterone replacement is marvellous Restores all the things testosterone does Classic Androgen deficiency Primary (high LH) impaired testis function Secondary (low LH) hypothalamo-pituitary 1

2 Classic Androgen deficiency Primary (high LH) impaired testis function Klinefelter s syndrome Infertile men Testicular damage vascular, cancer Rx Secondary (low LH) hypothalamo-pituitary Prolactinoma Iron deposition Kallmann s syndrome Klinefelter s Syndrome 47XXY Commonest chromosomal disorder 1:600 males Commonest cause of undiagnosed androgen deficiency Almost all androgen deficient as adults: benefit from TRT Only 25-50% Klinefelter s are diagnosed in their lifetime Bojesen JCEM 2003; Herlihy MJA 2011 Detection strategies a major challenge Reject your stereotypical images of KS Classical KS in textbooks gynecomastia Profound learning difficulties narrow shoulders reduced body hair Classical KS in textbooks gynecomastia <50% Profound learning difficulties Not always!! narrow shoulders may appear entirely normal and reduced adequately body hair virilised when clothed abdominal obesity small testes horizontal pubic hairline abdominal obesity small testes horizontal pubic hairline varicose veins From: Nieschlag and Behre, 2007 varicose veins From: Nieschlag and Behre, 2007 Classical KS in textbooks gynecomastia Profound learning difficulties narrow shoulders reduced body hair The testis is the most accessible endocrine organ abdominal obesity ~12,000 missed KS males in horizontal USA pubic hairline small testesr volume Failure to systemically examine male genitalia : flaw in education & practice From: Nieschlag and Behre, 2007 varicose Klinefelter s veins syndrome: The most overlooked cause of androgen deficiency. St John B & McLachlan RI Endocrinology Today 2015; 4(1): 8-14 Physical examination is pivotal Courtesy of M Zitzmann, Munster 2

3 Testosterone replacement in men with organic hypogonadism has marked benefits* Sexual Function Energy Late Onset Hypogonadism Testosterone Levels Decline Gradually During Male Aging Aging and Hypogonadism have Overlapping Features +40% +20% Hemoglobin Bone Density Serum Testosterone 3.5 nmol/l Serum Testosterone 25 nmol/l Think of hypogonadism: e.g. unexplained psychosexual complaints, osteoporosis, anemia, sarcopenia +2g/dl Muscle Mass +3kg +7.5% Fat Mass -2kg *except fertility Grossmann et al, JCEM 2008 Central Adiposity, Muscle Wasting, Osteoporosis 1. Is low testosterone causally related to the aging phenotype? 2. Is testosterone therapy in aging men beneficial or harmful? Largest Testosterone RCT: 790 men randomized for 12 months Snyder NEJM 2016 Controversy: androgens in health & aging Low testosterone levels are common Is this a pathological states in which androgen Rx is effective and safe? Age-related... or Late onset hypogonadism (LOH) Andropause Low T Obesity-related HH Massive increase in testosterone prescribing USA - 9 fold over Andropause hypothesis Age Barometer of Health hypothesis WHY? Recognition of real entity T 1 2 Disease or Wishful thinking + marketing (direct to consumer) 1 Symptoms 2 Courtesy D Handelsman 3

4 European Male Aging Study (EMAS) Relationship between Age and Testosterone in 3220 Men ng/ml >60% population Wu FCW et al. J Clin Endocrin Metab 93(7): (2008) European Male Aging Study (EMAS) Relationship between Age and Testosterone in 3220 Men ng/ml 5.8 Healthy Man Study Sartorius G et al Clin Endocrinol 2012 ;77:755 Serum T BMI <25 BMI BMI 30 Serum T did not vary with age Wu FCW et al. J Clin Endocrin Metab 93(7): (2008) Successful weight loss combined with optimization of comorbidities can be sufficient to Improve symptoms Normalize testosterone levels and Reduce cardiovascular risk in men with Late Onset Hypogonadism Lose weight testosterone rises 30% 9nM 10% 3nM >60% population 4

5 Symptomatic diabetic with low serum T, normal LH and replete with co-morbibities, CV risk Age Barometer of Health hypothesis Lifestyle Diet Exercise Medical diabetes, hypertension, cholesterol Psychosexual issues Judicious use of PDE5 inhibitors T A Symptoms Disease B Age Barometer of Health hypothesis Risks and benefits of TRT in middle aged and older men with low T and co-morbidities Placebo-controlled RCT data is limited T Disease Testosterone Trials: 7 coordinated trials of T treatment in elderly men Cauley JA et al J Gerontol A Biol Sci Med Sci Sep;70(9):1105? Testosterone as adjunct in management A Symptoms B Snyder PJ et al. Clin Trials. 2014;11:362 Abd alamira M et al Coron Artery Dis ; 27: 95 Snyder PJ et al; N Engl J Med. 2016;374:611 Resnick SM et al JAMA 2017 ;317:717 Snyder PJ et al JAMA Intern Med ;177:471 Budoff MJ et al JAMA ;317:708 T Trial population Men > 65 years Serum total T <9.5nM One or more symptoms potentially related to low testosterone 5

6 What to do know about the impacts of testosterone on such men? Outcomes of T Trial in Aging (co-morbid) Men Physical Function Trial Sexual Function Trial Vitality Trial Cognitive Function Trial Anemia Trial Cardiovascular Trial Bone Trial USA T Trials placebo controlled RCT ~800 men Snyder P Clin Trials 2014, 11:362 Sexual Function - Modest & transient benefits in some aspects ED: PDE5 inhibitors are more effective. Cognition and memory - not improved Vitality and fatigue - in the vitality trial sub study -no benefits Physical function - some benefits in some testing procedures Testosterone target range 18-27nM ng/dl Bone - density improved: not compared to established therapies Medication Adherence to Topical Testosterone Therapy: Schoenfeld MJ et al J Sex Med 2013;10: ,435 hypogonadal men Persistence = time to last script OR gap of >30 days OR to at 12 months. 6 months, 34.7% 12 months, 15.4%. Over time, dose escalation ~ 50% of men resumed therapy 1. Background: organic vs late onset hypogonadism Conclusions. High discontinuation rates irrespective of age, diagnosis, and index dose. Testosterone and CV Risk Current data inconclusive, confusing & contradictory due to inherent limitations of existing studies Lack of adequately designed and powered randomized controlled clinical trials with cardiovascular events as the primary outcome 1. Background: organic vs late onset hypogonadism 6

7 Survival (%) In Men with Type 2 Diabetes Low Testosterone is Common and Associated with an Adverse Cardiovascular Risk Profile Percentage of Diabetic Men with Low* Testosterone Melbourne Cohort (n=580) Diabetic Men with Low Testosterone have Increased Obesity Insulin Resistance HOMA-IR Dr. Aye Tint Low Testosterone Independently Predicts Mortality in Men with Type 2 Diabetes Melbourne Cohort: 572 men with T2D: Age 66 y, BMI 29.2 kg/m 2, Total T 10.5 nmol/l, HbA1c 7.3% >230 pmol/l > pmol/l Dr. Emily Gianatti % Dyslipidemia Inflammation Free Testosterone (normal range > 230 pmol/l) <160 pmol/l p<0.001* * Cardiovascular mortality p=0.001 *Relative to reference ranges based on healthy young men Grossmann et al, JCEM 93:1834, Observation Time (years) Numbers at risk *independent of age, BMI, micro- and macro-vascular disease, duration of T2DM, hemoglobin, CRP, renal function, HOMA-IR Tint et al, Eur J Endocrinol 2016 Meta-Analysis of Epidemiological Studies: Low serum testosterone predicts increased mortality 16,184 community-dwelling men (US, Europe) mean age 61 years, 9.7 years follow-up All-Cause Mortality Cardiovascular Mortality Observational studies-by design-can never prove causality 1.35 ( ) 1.25 ( ) No effect Mortality Decreased Increased between study heterogeneity suggests that low testosterone may be a marker of poor health Araujo et al, JCEM 2011 Non-causation: low T and poor health share common risk factors Causation: low T poor health Reverse causation: poor health low T + earlier death Inconclusive Cardiac Effects of T Treatment in Retrospective Database Analyses T treatment associated with increased, decreased or unchanged risk 1. Background: organic vs late onset hypogonadism Shores AJA

8 Inconclusive Cardiac Effects of T Treatment in Retrospective Database Analyses T treatment associated with increased, decreased or unchanged risk Inadequate outcome validation Limitations incomplete covariate ascertainment confounding due to lack of randomisation: e.g. preferential treatment of healthier men? indication for T treatment dose and duration?hypogonadal symptoms 1. Background: organic vs late onset hypogonadism Baseline and on treatment T levels Inconclusive Cardiac Effects of T Treatment in Meta-Analyses of RCTs in Older Men TOM trial: RCT older men with preexisting cardiovascular Disease N = 209; age 74 y Increased Risk of CVS events with Testosterone n=23 Testosterone n=5 Placebo Xu Haddad Calof Albert Corona Men (n) Treated Untreated CV events (n) Treated Untreated Odds ratio (95 CI%) Increased Risk in the first 12 months of T treatment Fernandez- 715 Bassels Small number and broad array of cardiovascular-related events* RCT not powered to evaluate cardiovascular events *including oedema, blood pressure increase, arrhythmia, self reported chest pain & syncope Basaria et al, NEJM 2010 Limitations of RCTs: low number of events, CVD events heterogeneous, RCTs small, short-term, not designed or powered for CVD outcomes, heterogenous populations/ inclusion criteria 1 BMC Med 2013; 2 Mayo Clin Proc 2007; 3 J Geront A Biol Sci Med Sci 2005; 4 Clin Endo 2016; 5 Expert Opin Drug Safety 2014; 6 JCEM 2010 Testosterone Treatment: Risks? No definitive outcome data regarding long-term CV events Non-randomized studies (epidemiologic, prescription database) -Subject to confounding, bias and reverse causality Labeling change to inform of possible increased risk of heart attacks and strokes with testosterone therapy Labeling change to clarify that testosterone therapy approved only for medical disorders of the HPT* axis Benefit and safety not established for the treatment of low testosterone levels due to aging see also ESA Position statement Yeap et al MJA 2016 PBS testosterone prescribing criteria (updated 2015) *hypothalamic-pituitary-testicular Existing RCTs: Underpowered, short-term, CVD events not pre-specified Need > 10,000 men No evidence for risk if testosterone 1) for approved indications (organic hypogonadism)* 2) contraindications observed* 3) treatment monitored in line with guideline recommendations* Possibly increased CVS risk: Older men (>65 years) within the first few months after testosterone initiation, especially if pre-existing cardiovascular disease *Yeap et al, MJA

9 Testosterone Treatment: Risks? No definitive outcome data regarding long-term CV events Non-randomized studies (epidemiologic, prescription database) -Subject to confounding, bias and reverse causality Existing RCTs: Underpowered, short-term, CVD events not pre-specified Need > 10,000 men No evidence for risk if testosterone 1) for approved indications (organic hypogonadism)* 2) contraindications observed* 3) treatment monitored in line with guideline recommendations* Possibly increased CVS risk: Older men (>65 years) within the first few months after testosterone initiation, especially if pre-existing cardiovascular disease 1. Background: organic vs late onset hypogonadism *Yeap et al, MJA 2016 Testosterone Treatment and Vascular Risk: Clinical Implications No evidence that testosterone replacement in men with organic^ hypogonadism is harmful: testosterone maintain virilisation and optimal health*. ^established organic hypothalamic-pituitary-testicular axis pathology *unless fertility desired Vascular risk an important factor in decision making in men without organic hypogonadism # : especially if pre-existing CV disease or risk of venous thromboembolism # Routine T treatment in Late Onset Hypogonadism not recommended by Australian Guidelines (Yeap et al MJA 2016) or by the US Federal Drug Administration (FDA) Testosterone Treatment: Benefits in older men with low T Concern Testosterone effect 1 st line therapy Sexual Modest increase in overall function, if TT<9.5-12nmol/L 1,2. Libido > erectile function. Muscle kg increase in mass 4 Modest performance rise in some RCTs 5,6 PDE5 inhibitor No added benefit of T 3 Exercise Fat 1.6 to 2.0 kg decrease 7 Weight loss Glucose Modest fall in insulin resistance. No fall HbA1c8 Lifestyle, antidiabetic medications Bone 2-7% increase in BMD lumbar spine 9 Anti-resorptives Mood/ Cognition No consistent effects 1,10 e.g. Counseling, antidepressants Not powered for clinically important health outcomes: mortality, quality of life, physical function, falls or fractures 1 Isidori Clin Endo 2005a; 2 Snyder NEJM 2016; 3 Spitzer Ann Int Med 2012; 4 Bhasin NCPEM 2006; 5 Basaria NEJM 2010; 6 Srinivas-Shankar JCEM Isidori Clin Endo 2005b; 8 Grossmann Clin Endo 2015; 9 Snyder JAMA Int Med 2017; 10 Snyder NEJM 2016 Take Home Messages (1) Organic Hypogonadism Underdiagnosed and undertreated Benefits of testosterone replacement clearly outweigh cardiovascular (and other) risks Think of hypogonadism: e.g. unexplained psychosexual complaints, osteoporosis, anemia, sarcopenia Take Home Messages (2) Older men Late Onset Hypogonadism = Chronic disease-associated low testoterone In older men, low T is often a marker of poor health holistic focus on lifestyle and optimization of comorbidities Long term risks of T treatment are unknown: some evidence for increased CV risks, esp. with pre-existing CVD Benefits of T treatment are relatively modest: the benefit : risk profile is overall unconvincing Current Australian guidelines* recommend against T treatment (more research) * Yeap et al, MJA

10 15 August, 2016; part 2; 5 Sept, 2016 Men with organic hypogonadism^ should be identified and given testosterone replacement*, but further research is needed to clarify whether there is a role for testosterone in other settings (such as late onset hypogonadism ) ^medical disease of the hypothalamic-pituitary-testicular axis such as pituitary tumor, Klinefelter s ect. *unless fertility is desired Health professionals Resources Clinical Summary Guides on male reproductive health Patient resources Orchidometer Position statements and guidelines Support Accredited online education (GPs, Nurses & other HPs) A&TSI health education (GPs, Nurses, AHWs) Speakers for health professional events Activities Presenting and attending professional conferences Future doctors Andrology training Clinical summary guides 10