AAS and Cardiovascular/Pulmonary Function

[Dr JIM]

The maximum attachment file size is 40 MB. But there seems to be a problem with larger uploads that I will look into.

Ok got cha.

IDK but it seems a 6 page narrative would be considerably less than 40MB.

FYI the original file did contain
one real time CT and ECHO
which I thought was the problem, but the server “error” msg persisted in spite of those
being deleted.

Jim

 

[Michael Scally MD]

Heidari A, Sabzi F, Faraji R. Spontaneous coronary artery dissection in anabolic steroid misuse. Annals of cardiac anaesthesia 2018;21:103-4. Spontaneous coronary artery dissection in anabolic steroid misuse Heidari A, Sabzi F, Faraji R - Ann Card Anaesth

A 27-year-old male professional bodybuilder presented with excruciating retrosternal chest pain, extending to his neck and shoulder. He gave a history of taking traditional medication (containing opium) for the pain that was self-prescribed but the pain did not subside with that treatment, and his general physician referred him for cardiac evaluation in the emergency department.

He gave a history of long-term anabolic steroid usage and multiple intramuscular injections of human growth hormone in the recent past. There was no history of early coronary artery disease or sudden death in the family.

On physical examination, he was well built and nourished with prominent muscles over pectoral girdle, hypertrophied pectoralis, biceps, triceps, rectus abdominis, and quadriceps muscles. In the electrocardiogram, Q waves and S-T elevation in lead V1–V6 were found. The creatine phosphokinase myocardial band and troponin levels were raised.

The patient was referred to the coronary care unit and was treated with intravenous trinitroglycerin, aspirin, clopidogrel, statin, and heparin for acute coronary syndrome (ACS). The transthoracic echocardiogram showed reduced left ventricular systolic function (ejection fraction 40%) with apical hypokinesia. The cardiac troponins increased serially from 3 to 8 (units).

Coronary angiography was performed which showed proximal to middle spiral dissection of the left anterior descending artery with severe distal stenosis. The left main right coronary and left circumflex arteries were normal [Figure 1]. The case was referred for surgery by interventional cardiologist as percutaneous coronary intervention was not preferred because of a long segment of dissection in artery, ongoing ischemia, and the presence of significant lesion distal to dissection.

Individuals with a history of ACS but without evidence of ongoing ischemia and no significant stenosis on cardiac angiography may be managed with medical treatment. Medical treatment was not a choice in our patient due to ongoing ischemia.

 

[Michael Scally MD]

[OA] Five-Year Prospective Study on Cardiovascular Events, In Patients with Erectile Dysfunction and Hypotestosterone

Objective: Testosterone levels play a role in cardiac and vascular pathology. In the present study we investigated the prognostic significance of this hormone for cardiovascular outcome, in a 5-year follow-up.

Materials and methods: Our cohort included 802 adult subjects, from 40 to 80 years. Patients were excluded if they had a past history of peripheral or coronary artery disease, and revascularization. A blood sample was drawn to valuate testosterone level, and we considered normal testosterone levels 300 ng/dl.

FMD (flow mediated dilatation) of the brachial artery was assessed by measuring the increase of the brachial artery diameter during reactive hyperemia after transient forearm ischemia. B-mode longitudinal images of the brachial artery were obtained at the level of the antecubital fossa. The FMD was defined as the percentage change in the brachial artery diameter 60 s after releasing the ischemic cuff.

Erectile dysfunction (ERD) was assessed by the International Index of Erectile Function-5 (IIEF-5) score questionnaire. We considered composite end points including the following major adverse cardiovascular events (MACEs)

Results: Subjects with lower serum testosterone levels (n = 332) had higher prevalence of traditional cardiovascular risk factors, such as hypertension (p = 0.009), diabetes (p = 0.03), dyslipidemia (p < 0.0001), obesity (p = 0.002), and endothelial function score (p < 0.0001).

AMI, death after AMI, major stroke and all clinical events were more frequent (p < 0.001) in patients with testosterone levels < 300 ng/dl. Further, by multiple logistic regression analysis we found that only dyslipidemia (p = 0,001), obesity (p = 0,007), testosterone < 300 ng/dl (p < 0,0001) and ED (p < 0,0001) were independent predictors of future events.

Conclusions: A therapeutic intervention on testosterone may not only have a positive effect on the cardiovascular system but also an important role in preventing new cardiovascular events.

Iacona R, Bonomo V, Di Piazza M, et al. Five-year prospective study on cardiovascular events, in patients with erectile dysfunction and hypotestosterone. Arch Ital Urol Androl. 2017;89(4). Five-year prospective study on cardiovascular events, in patients with erectile dysfunction and hypotestosterone | Iacona | Archivio Italiano di Urologia e Andrologia

 

[Michael Scally MD]

Hypertension Limbo: Balancing Benefits, Harms, and Patient Preferences Before We Lower the Bar on Blood Pressure

The recent hypertension guideline from the American College of Cardiology (ACC), the American Heart Association (AHA), and partner organizations raises important questions about hypertension diagnosis and treatment. The guideline differs substantially from those of other organizations, including the American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP).

Here, we examine these differences, focusing on pharmacologic treatment of adults older than 60 years. Strengths of the ACC/AHA guideline include its emphasis on the importance of blood pressure (BP) measurement technique and lifestyle changes. However, the guideline falls short in weighing the potential benefits against potential harms, costs, and anticipated variation in individual patient preferences.

…

The expanded definition of hypertension would label millions of persons as unwell and lowers the BP threshold for diagnosis and treatment, with no supporting evidence that it optimally balances benefits, harms, and patient preferences. Lower SBP targets (<130 mm Hg), as suggested by the ACC/AHA guideline, may be reasonable for some older adults, but what may be good for some is not necessarily good for most.

Performance measures should encourage treatment to a target less than 150 mm Hg in most patients aged 60 years or older with accurately measured SBP that is persistently at or above 150 mm Hg because evidence suggests that this will provide substantial benefit with acceptable harms and costs for most patients.

Clinical policy focused on lower SBP targets should permit a choice based on a patient's risk profile, susceptibility to harms, and treatment preferences.

Wilt TJ, Kansagara D, Qaseem A. Hypertension Limbo: Balancing Benefits, Harms, and Patient Preferences Before We Lower the Bar on Blood Pressure. Ann Intern Med. [Epub ahead of print 23 January 2018]. Balancing Benefits, Harms, and Patient Preferences for Hypertension | Annals of Internal Medicine | American College of Physicians

 

[Michael Scally MD]

Jury declares Abbvie's Androgel didn't cause man's lung clots, Abbvie didn't falsely market medication
https://cookcountyrecord.com/stories/511322575-jury-declares-abbvie-s-androgel-didn-t-cause-man-s-lung-clots-abbvie-didn-t-falsely-market-medication

After split verdicts in two prior trials over alleged harmful side effects and alleged misleading marketing of its testosterone replacement drug led to questionable verdicts worth more than $140 million each, drugmaker Abbvie has scored a clean win in the latest jury review of a plaintiff’s claims over the promotion and health impacts of Androgel.

On Jan. 26, a federal jury in Chicago sided with North Chicago-based Abbvie in the third of a series of so-called bellwether trials in a massive class action involving thousands of claims against Abbvie and other drugmakers who distribute so-called testosterone replacement therapy medications.

 

[Michael Scally MD]

Streja D. The final word about LDL-cholesterol lowering. Current Opinion in Endocrinology, Diabetes and Obesity. The final word about LDL-cholesterol lowering : Current Opinion in Endocrinology, Diabetes and Obesity

 

[Michael Scally MD]

 

[Michael Scally MD]

A personal viewpoint by Dr Børge G. Nordestgaard with review of results from a huge survey in Denmark of more than 500 000 people on statins from the Danish population.

Nordestgaard BG. Why do the Media report negative news about statins? European heart journal 2018;39:337-8. Why do the Media report negative news about statins? | European Heart Journal | Oxford Academic

Are you a physician working according to evidence-based medicine?

I am sure you are. So, you tell yourself and your patients that taking a statin daily to reduce cholesterol levels substantially reduces the risk of heart attack, stroke, and early death.

In fact, for prevention of common multifactorial disease in adults nothing in the history of medicine has ever been shown more convincingly. You know that, and you also know that most likely none of your patients will ever experience any side effects from statins, i.e. according to the evidence from double-blind randomised trials where neither patients nor physicians are aware of who gets active statin and who gets placebo. Double-blind evidence shows that roughly only one in a thousand experience statin-related muscle symptoms.

 

[Michael Scally MD]

Jones T H, Kelly DM. Randomized controlled trials – mechanistic studies of testosterone and the cardiovascular system. Asian J Androl [Epub ahead of print] [cited 2018 Feb 10]. Available from: Randomized controlled trials – mechanistic studies of testosterone and the cardiovascular system Jones T H, Kelly DM, - Asian J Androl

Testosterone deficiency is common in men with cardiovascular disease (CVD), and randomized placebo-controlled trials (RCTs) have reported beneficial effects of testosterone therapy on exercise-induced cardiac ischemia in chronic stable angina, functional exercise capacity, maximum oxygen consumption during exercise (VO2max) and muscle strength in chronic heart failure (CHF), shortening of the Q-T interval, and improvement of some cardiovascular risk factors. Testosterone deficiency is associated with an adverse CV risk profile and mortality.

Clinical and scientific studies have provided mechanistic evidence to support and explain the findings of the RCTs. Testosterone is a rapid-onset arterial vasodilator within the coronary circulation and other vascular beds including the pulmonary vasculature and can reduce the overall peripheral systemic vascular resistance.

Evidence has demonstrated that testosterone mediates this effect on vascular reactivity through calcium channel blockade (L-calcium channel) and stimulates potassium channel opening by direct nongenomic mechanisms. Testosterone also stimulates repolarization of cardiac myocytes by stimulating the ultra-rapid potassium channel-operated current. Testosterone improves cardiac output, functional exercise capacity, VO2maxand vagally mediated arterial baroreceptor cardiac reflex sensitivity in CHF, and other mechanisms.

Independent of the benefit of testosterone on cardiac function, testosterone substitution may also increase skeletal muscle glucose metabolism and enhance muscular strength, both factors that could contribute to the improvement in functional exercise capacity may include improved glucose metabolism and muscle strength.

Testosterone improves metabolic CV risk factors including body composition, insulin resistance, and hypercholesterolemia by improving both glucose utilization and lipid metabolism by a combination of genomic and nongenomic actions of glucose uptake and utilization expression of the insulin receptor, glucose transporters, and expression on regulatory enzymes of key metabolic pathways. The effect on high-density lipoprotein-cholesterol (HDL-C) differs between studies in that it has been found to fall, rise, or have no change in levels.

Testosterone replacement can suppress the levels of circulating pro-inflammatory cytokines and stimulate the production of interleukin-10 (IL-10) which has anti-inflammatory and anti-atherogenic actions in men with CVD. No effect on C-reactive protein has been detected. No adverse effects on clotting factors have been detected. RCTs have not clearly demonstrated any significant evidence that testosterone improves or adversely affects the surrogate markers of atherosclerosis such as reduction in carotid intima thickness or coronary calcium deposition.

Any effect of testosterone on prevention or amelioration of atherosclerosis is likely to occur over years as shown in statin therapy trials and not months as used in testosterone RCTs. The weight of evidence from long-term epidemiological studies supports a protective effect as evidenced by a reduction in major adverse CV events (MACEs) and mortality in studies which have treated men with testosterone deficiency. No RCT where testosterone has been replaced to the normal healthy range has reported a significant benefit or adverse effect on MACE nor has any recent meta-analysis.

 

[Michael Scally MD]

Jones T H, Kelly DM. Randomized controlled trials – mechanistic studies of testosterone and the cardiovascular system. Asian J Androl [Epub ahead of print] [cited 2018 Feb 10]. Available from: Randomized controlled trials – mechanistic studies of testosterone and the cardiovascular system Jones T H, Kelly DM, - Asian J Androl

Testosterone deficiency is common in men with cardiovascular disease (CVD), and randomized placebo-controlled trials (RCTs) have reported beneficial effects of testosterone therapy on exercise-induced cardiac ischemia in chronic stable angina, functional exercise capacity, maximum oxygen consumption during exercise (VO2max) and muscle strength in chronic heart failure (CHF), shortening of the Q-T interval, and improvement of some cardiovascular risk factors. Testosterone deficiency is associated with an adverse CV risk profile and mortality.

Clinical and scientific studies have provided mechanistic evidence to support and explain the findings of the RCTs. Testosterone is a rapid-onset arterial vasodilator within the coronary circulation and other vascular beds including the pulmonary vasculature and can reduce the overall peripheral systemic vascular resistance.

Evidence has demonstrated that testosterone mediates this effect on vascular reactivity through calcium channel blockade (L-calcium channel) and stimulates potassium channel opening by direct nongenomic mechanisms. Testosterone also stimulates repolarization of cardiac myocytes by stimulating the ultra-rapid potassium channel-operated current. Testosterone improves cardiac output, functional exercise capacity, VO2maxand vagally mediated arterial baroreceptor cardiac reflex sensitivity in CHF, and other mechanisms.

Independent of the benefit of testosterone on cardiac function, testosterone substitution may also increase skeletal muscle glucose metabolism and enhance muscular strength, both factors that could contribute to the improvement in functional exercise capacity may include improved glucose metabolism and muscle strength.

Testosterone improves metabolic CV risk factors including body composition, insulin resistance, and hypercholesterolemia by improving both glucose utilization and lipid metabolism by a combination of genomic and nongenomic actions of glucose uptake and utilization expression of the insulin receptor, glucose transporters, and expression on regulatory enzymes of key metabolic pathways. The effect on high-density lipoprotein-cholesterol (HDL-C) differs between studies in that it has been found to fall, rise, or have no change in levels.

Testosterone replacement can suppress the levels of circulating pro-inflammatory cytokines and stimulate the production of interleukin-10 (IL-10) which has anti-inflammatory and anti-atherogenic actions in men with CVD. No effect on C-reactive protein has been detected. No adverse effects on clotting factors have been detected. RCTs have not clearly demonstrated any significant evidence that testosterone improves or adversely affects the surrogate markers of atherosclerosis such as reduction in carotid intima thickness or coronary calcium deposition.

Any effect of testosterone on prevention or amelioration of atherosclerosis is likely to occur over years as shown in statin therapy trials and not months as used in testosterone RCTs. The weight of evidence from long-term epidemiological studies supports a protective effect as evidenced by a reduction in major adverse CV events (MACEs) and mortality in studies which have treated men with testosterone deficiency. No RCT where testosterone has been replaced to the normal healthy range has reported a significant benefit or adverse effect on MACE nor has any recent meta-analysis.

Potential detrimental metabolic actions of testosterone deficiency. In testosterone deficiency, excess deposition of fat resulting from poor lipid and glucose control and inadequate storage capacity in subcutaneous adipose depots may lead to “overspill” into visceral fat.

Concurrently, testosterone deficiency and elevated circulating glucose and lipid cause further metabolic dysregulation in visceral adipose tissue, with ensuing metabolic consequences in liver and muscle, resulting in lipid accumulation.

This ectopic lipid accumulation has pathological consequences when it is ultimately deposited in tissues such as the liver (hepatic steatosis) and the arterial wall (atherosclerosis).

 

[Michael Scally MD]

Jones T H, Kelly DM. Randomized controlled trials – mechanistic studies of testosterone and the cardiovascular system. Asian J Androl [Epub ahead of print] [cited 2018 Feb 10]. Available from: Randomized controlled trials – mechanistic studies of testosterone and the cardiovascular system Jones T H, Kelly DM, - Asian J Androl

Testosterone deficiency is common in men with cardiovascular disease (CVD), and randomized placebo-controlled trials (RCTs) have reported beneficial effects of testosterone therapy on exercise-induced cardiac ischemia in chronic stable angina, functional exercise capacity, maximum oxygen consumption during exercise (VO2max) and muscle strength in chronic heart failure (CHF), shortening of the Q-T interval, and improvement of some cardiovascular risk factors. Testosterone deficiency is associated with an adverse CV risk profile and mortality.

Clinical and scientific studies have provided mechanistic evidence to support and explain the findings of the RCTs. Testosterone is a rapid-onset arterial vasodilator within the coronary circulation and other vascular beds including the pulmonary vasculature and can reduce the overall peripheral systemic vascular resistance.

Evidence has demonstrated that testosterone mediates this effect on vascular reactivity through calcium channel blockade (L-calcium channel) and stimulates potassium channel opening by direct nongenomic mechanisms. Testosterone also stimulates repolarization of cardiac myocytes by stimulating the ultra-rapid potassium channel-operated current. Testosterone improves cardiac output, functional exercise capacity, VO2maxand vagally mediated arterial baroreceptor cardiac reflex sensitivity in CHF, and other mechanisms.

Independent of the benefit of testosterone on cardiac function, testosterone substitution may also increase skeletal muscle glucose metabolism and enhance muscular strength, both factors that could contribute to the improvement in functional exercise capacity may include improved glucose metabolism and muscle strength.

Testosterone improves metabolic CV risk factors including body composition, insulin resistance, and hypercholesterolemia by improving both glucose utilization and lipid metabolism by a combination of genomic and nongenomic actions of glucose uptake and utilization expression of the insulin receptor, glucose transporters, and expression on regulatory enzymes of key metabolic pathways. The effect on high-density lipoprotein-cholesterol (HDL-C) differs between studies in that it has been found to fall, rise, or have no change in levels.

Testosterone replacement can suppress the levels of circulating pro-inflammatory cytokines and stimulate the production of interleukin-10 (IL-10) which has anti-inflammatory and anti-atherogenic actions in men with CVD. No effect on C-reactive protein has been detected. No adverse effects on clotting factors have been detected. RCTs have not clearly demonstrated any significant evidence that testosterone improves or adversely affects the surrogate markers of atherosclerosis such as reduction in carotid intima thickness or coronary calcium deposition.

Any effect of testosterone on prevention or amelioration of atherosclerosis is likely to occur over years as shown in statin therapy trials and not months as used in testosterone RCTs. The weight of evidence from long-term epidemiological studies supports a protective effect as evidenced by a reduction in major adverse CV events (MACEs) and mortality in studies which have treated men with testosterone deficiency. No RCT where testosterone has been replaced to the normal healthy range has reported a significant benefit or adverse effect on MACE nor has any recent meta-analysis.

Putative beneficial effects of testosterone on heart failure. Evidence from multiple clinical, experimental, and mechanistic studies suggests potential beneficial testosterone actions on heart failure.

 

[Michael Scally MD]

Taler SJ. Initial Treatment of Hypertension. New England Journal of Medicine 2018;378:636-44. NEJM - Error

 

[Michael Scally MD]

Layton JB, Li D, Meier CR, Sharpless JL, Stürmer T, Brookhart MA. Injection Testosterone and Adverse Cardiovascular Events: A Case-crossover Analysis. Clinical Endocrinology. Injection Testosterone and Adverse Cardiovascular Events: A Case‐crossover Analysis

Context Exogenous testosterone administration may affect blood clotting, polycythemia, and may increase atherosclerosis, though any association with cardiovascular events is unclear. While the literature is inconclusive, some studies have suggested testosterone use may increase short-term risk of cardiovascular events and stroke, and injection testosterone may convey higher risks than other dosage forms.

Objective We sought to evaluate the short-term cardiovascular risk of receiving injection testosterone.

Design We conducted a case-crossover analysis comparing injection testosterone exposure in the seven days prior to an outcome event to referent windows in the past to estimate the acute association of cardiovascular outcomes with the receipt of testosterone injections.

Patients We identified adult male testosterone users hospitalized with myocardial infarction (MI), stroke, or a composite of MI, stroke, or unstable angina in US commercial claims (2000-2013) or Medicare (2007-2010) databases.

Measurements We identified testosterone use for the patients from pharmacy dispensing claims or in-office procedure codes in the insurance billing data.

Results We identified 2,898 commercially-insured men with events and recent testosterone use, and 339 from Medicare. Injected testosterone was associated with an increased risk of adverse events (composite outcome of myocardial infarction, stroke, or unstable angina) in the immediate post-injection period for the older, Medicare population only: commercial insurance, OR=0.98 (95% CI: 0.86-1.12); Medicare, OR=1.45 (1.07, 1.98). This association was either greatly attenuated or not present when evaluating receipt of any testosterone dosage forms (injection, gel, patch, implant): commercial insurance, OR=1.01 (0.92, 1.11); Medicare, OR=1.26 (95% CI: 0.98-1.63).

Conclusions Testosterone injections were uniquely associated with short-term risk of acute cardio- and cerebrovascular events in older adult men following injection receipt.

 

[Old]

Layton JB, Li D, Meier CR, Sharpless JL, Stürmer T, Brookhart MA. Injection Testosterone and Adverse Cardiovascular Events: A Case-crossover Analysis. Clinical Endocrinology. Injection Testosterone and Adverse Cardiovascular Events: A Case‐crossover Analysis

Context Exogenous testosterone administration may affect blood clotting, polycythemia, and may increase atherosclerosis, though any association with cardiovascular events is unclear. While the literature is inconclusive, some studies have suggested testosterone use may increase short-term risk of cardiovascular events and stroke, and injection testosterone may convey higher risks than other dosage forms.

Objective We sought to evaluate the short-term cardiovascular risk of receiving injection testosterone.

Design We conducted a case-crossover analysis comparing injection testosterone exposure in the seven days prior to an outcome event to referent windows in the past to estimate the acute association of cardiovascular outcomes with the receipt of testosterone injections.

Patients We identified adult male testosterone users hospitalized with myocardial infarction (MI), stroke, or a composite of MI, stroke, or unstable angina in US commercial claims (2000-2013) or Medicare (2007-2010) databases.

Measurements We identified testosterone use for the patients from pharmacy dispensing claims or in-office procedure codes in the insurance billing data.

Results We identified 2,898 commercially-insured men with events and recent testosterone use, and 339 from Medicare. Injected testosterone was associated with an increased risk of adverse events (composite outcome of myocardial infarction, stroke, or unstable angina) in the immediate post-injection period for the older, Medicare population only: commercial insurance, OR=0.98 (95% CI: 0.86-1.12); Medicare, OR=1.45 (1.07, 1.98). This association was either greatly attenuated or not present when evaluating receipt of any testosterone dosage forms (injection, gel, patch, implant): commercial insurance, OR=1.01 (0.92, 1.11); Medicare, OR=1.26 (95% CI: 0.98-1.63).

Conclusions Testosterone injections were uniquely associated with short-term risk of acute cardio- and cerebrovascular events in older adult men following injection receipt.

Can't help wonder if this is largely due to the practice of infrequent injections. The common practice to inject 200mg every 2 weeks creates a few days of supraphysiological levels followed by a long decline to near hypogonadal levels ... only to be 'hit' again with supraphysiological levels.

TE has a terminal half-life of 4.5 days*. So 2 weeks is roughly 1/10th dose (over 3 half-lives) before next injection. This hardly mimics natural production. And for those more prone to thrombosis (such as high Lp(a)), it could be just enough to spell disaster.

To imply gel is inherently safer may just obscure the bad practice of infrequent injections. Certainly gels have no risk of abscess and better match a daily cycle, but they produce more DHT which may be good or bad (and not what the article is about anyway).

* Behre HM, Nieschlag E. 2004 Comparative pharmacokinetics of testosterone esters. In: Nieschlag E, Behre HM, eds. Testosterone: Action, Deficiency, Substitution, ed 3. p417

 

[Michael Scally MD]

Anawalt BD, Yeap BB. Conclusions about testosterone therapy and cardiovascular risk. Asian journal of andrology 2018. Conclusions about testosterone therapy and cardiovascular risk Anawalt BD, Yeap BB, - Asian J Androl

In this issue of Asian Journal of Andrology (AJA), several experts have reviewed the latest data on the potential and known effects of endogenous and exogenous testosterone (T) on cardiovascular risk. In the review by Meyer and Wittert, low endogenous serum T appears to be associated with higher risk of cardiovascular disease and overall mortality in certain populations such as Klinefelter syndrome and older men, but not in men with congenital hypogonadotropic hypogonadism.[1] Whether this association is causal or whether low serum testosterone is a marker of other risk factors for cardiovascular disease such as obesity, diabetes mellitus, or other systemic disease is unknown.

In Yeap's review of the relationship between circulating endogenous testosterone and its major metabolites, dihydrotestosterone, and estradiol, he raises the provocative hypotheses that there might be differential effects on cardiovascular and cerebrovascular risk related to endogenous testosterone and dihydrotestosterone concentrations.[2]

Based on the same epidemiological studies, Yeap postulates that there might be a U-shaped curve for circulating endogenous androgen concentrations such that lower and higher concentrations might confer greater risk of cardiovascular events and all-cause mortality than midrange concentrations.

Shores demonstrates in a carefully done review of studies of large prescription databases (including >200 000 men) that testosterone therapy is not associated with overall mortality, myocardial infarction, stroke, or deep venous thrombosis events.[3]

These reviews of epidemiological data on the relationship between cardiovascular risk and endogenous or exogenous testosterone do not provide definitive answers to the controversy surrounding the risks and benefits of testosterone therapy with respect to myocardial infarction, stroke, venothrombotic disease, or mortality. Jones and Kelly review the data from randomized controlled studies of the effects of testosterone therapy on the underlying mechanisms of ischemic heart disease and heart failure.[4]

They conclude that testosterone has favorable direct vasodilatory effects on coronary vasculature and peripheral system vascular resistance and positive effects on cardiac and skeletal muscle function that might also be favorable. Jones and Kelly also provide some data that testosterone might provide metabolic benefits including improved insulin sensitivity and favorable changes in body composition.

However, Gagliano-Juca and Basaria present a more cautionary note in their review of randomized trials of testosterone therapy that reported cardiovascular adverse events.[4] As they note, some randomized controlled trials have reported increased cardiovascular events in older men with prevalent cardiovascular disease.[5]

Although the United States Testosterone Trial, the largest placebo-controlled trial of testosterone therapy in older men to date, did not demonstrate increased cardiovascular events after one year of testosterone replacement therapy compared to placebo, there was an increased risk of progression of non-calcified coronary plaque.[6],[7]

Because testosterone replacement therapy is commonly prescribed to men around the world, it is essential to continue to study the potential cardiovascular risks and benefits of testosterone administration. In addition, testosterone and other androgens are being developed as potential novel therapies.

For example, Zitzmann reviews some of the data on the potential cardiovascular effects of male hormonal contraceptive regimens that are under development.[8] Finally, An and Gu remind us in their commentary that more studies on the safety of testosterone therapy must be done in Asia, the site of the largest population of men in the world.[9]

It is common to conclude reviews with a clarion call for more research, but it is particularly important to have carefully designed research on the effects of androgen therapy on men's health. Low serum testosterone concentrations are common in middle-aged and older men, and testosterone therapy is commonly prescribed to men with low serum testosterone concentrations and no defined pathology of the hypothalamic-pituitary-testicular axis.

Yet, the evidence of safety and benefit for such practice is minimal. There are no large, long term (>1 year) randomized controlled studies of testosterone therapy that include cardiovascular outcomes, and there is no requirement for systematic post-marketing data collection of safety outcomes in men treated with testosterone.

However, data from such studies will not be available for many years, and clinicians must practice based on current scientific knowledge. Based on the reviews in this issue of AJA, it appears likely that testosterone replacement therapy does not cause marked increases in risk of cardiovascular events. On the other hand, clinicians must exercise prudence in the use of testosterone in men with prevalent atherosclerotic coronary and cerebrovascular disease.

At a minimum, we clinicians should inform middle aged and older men and men with ischemic heart disease or a history of cerebrovascular events that there is a controversy about the cardiovascular risk of testosterone therapy, and we should discuss and weigh the potential benefits against the potential risks before initiating testosterone therapy in any man.

 

[Michael Scally MD]

Miner M, Morgentaler A, Khera M, Traish AM. The state of testosterone therapy since the fda's 2015 labeling changes: indications and cardiovascular risk. Clin Endocrinol (Oxf) 2018. http://onlinelibrary.wiley.com/doi/10.1111/cen.13589/abstract

OBJECTIVE: A label change for testosterone (T) products in March 2015 followed a highly-publicized FDA advisory committee meeting in September 2014. Changes included a warning of possible increased cardiovascular (CV) risks and restriction of indicated populations to younger men with a limited set of known etiologies of testosterone deficiency (TD). These changes greatly impacted clinical practice and public perception of T therapy (TTh). Our aim was to review these changes in light of subsequently published studies.

DESIGN: We identified 23 studies through June 2017, including 12 clinical trials and 11 observational studies. The Testosterone Trials included 790 men 65y and older with TD without known etiology, assigned to 1y T gel or placebo.

RESULTS: Demonstrated benefits of T included sexual activity and desire, physical activity, and mood. There were 9 major adverse CV events (MACE) in the T arm and 16 in the placebo arm. No study reported increased MACE with TTh. A 3y RCT showed no difference in carotid atherosclerosis. Several large observational studies reported reduced CV events with TTh, including one showing progressively reduced CV and mortality risk with greater duration of TTh. Men whose serum T normalized with TTh had reduced risk of MI and death compared with men whose T levels failed to normalize.

CONCLUSION: We conclude that existing evidence fails to support increased CV risk with TTh; on the contrary, there is evidence suggestive of real-world CV benefits. Finally, existing evidence provides benefits of TTh in older men without known etiology for T deficiency.

 

[Old]

Miner M, Morgentaler A, Khera M, Traish AM. The state of testosterone therapy since the fda's 2015 labeling changes: indications and cardiovascular risk. Clin Endocrinol (Oxf) 2018. The state of testosterone therapy since the fda's 2015 labeling changes: indications and cardiovascular risk

OBJECTIVE: A label change for testosterone (T) products in March 2015 followed a highly-publicized FDA advisory committee meeting in September 2014. Changes included a warning of possible increased cardiovascular (CV) risks and restriction of indicated populations to younger men with a limited set of known etiologies of testosterone deficiency (TD). These changes greatly impacted clinical practice and public perception of T therapy (TTh). Our aim was to review these changes in light of subsequently published studies.

DESIGN: We identified 23 studies through June 2017, including 12 clinical trials and 11 observational studies. The Testosterone Trials included 790 men 65y and older with TD without known etiology, assigned to 1y T gel or placebo.

RESULTS: Demonstrated benefits of T included sexual activity and desire, physical activity, and mood. There were 9 major adverse CV events (MACE) in the T arm and 16 in the placebo arm. No study reported increased MACE with TTh. A 3y RCT showed no difference in carotid atherosclerosis. Several large observational studies reported reduced CV events with TTh, including one showing progressively reduced CV and mortality risk with greater duration of TTh. Men whose serum T normalized with TTh had reduced risk of MI and death compared with men whose T levels failed to normalize.

CONCLUSION: We conclude that existing evidence fails to support increased CV risk with TTh; on the contrary, there is evidence suggestive of real-world CV benefits. Finally, existing evidence provides benefits of TTh in older men without known etiology for T deficiency.

Thank you. Do you have a PDF copy of the whole study available?

 

[Michael Scally MD]

Thank you. Do you have a PDF copy of the whole study available?

Enjoy ...

 

[Michael Scally MD]

[OA] Yoshihisa A, Suzuki S, Sato Y, et al. Relation of Testosterone Levels to Mortality in Men with Heart Failure. American Journal of Cardiology. http://dx.doi.org/10.1016/j.amjcard.2018.01.052

We aimed to investigate the impact of testosterone on prognosis of heart failure (HF), as well as underlying cardiac function, cardiac damage and exercise capacity.

We analyzed consecutive 618 men with HF (age 65.9 years). These patients were divided into quartiles based on their serum levels of total testosterone (TT):

1st (TT>631 ng/dl, n=154),
2nd (462<TT≤631 ng/dl, n=155),
3rd (300<TT≤462 ng/dl, n=156) and
4th (TT≤300 ng/dl, n=153) quartiles.

In the Kaplan-Meier analysis (mean 1281 days), all-cause mortality progressively increased throughout from the 1st to the 4th groups. In the multivariable Cox proportional hazard analysis, TT was found to be an independent predictor of all-cause mortality (hazard ratio 0.929, P=0.042).

In addition, we compared the parameters of echocardiography and cardiopulmonary exercise testing, as well as levels of B-type natriuretic peptide and cardiac troponin I among the four groups. Left ventricular ejection fraction and B-type natriuretic peptide did not differ among the groups. In contrast, the 4th quartile, compared to 1st, 2nd and 3rd groups, had higher levels of troponin I and lower peak VO2 (P<0.05, respectively).

Decreased serum testosterone is associated with myocardial damage, lower exercise capacity, and higher mortality in men with HF.

 

[Michael Scally MD]

Doleeb S, Thohan V. TESTOSTERONE-INDUCED CARDIOMYOPATHY: STRONG MUSCLES, WEAK HEART. Journal of the American College of Cardiology 2018;71:A2370. TESTOSTERONE-INDUCED CARDIOMYOPATHY: STRONG MUSCLES, WEAK HEART

Background - The gender differences in cardiovascular disease prevalence and severity may, in part, be related to differences in endogenous sex hormones. Exogenous anabolic steroid use is increasing among athletes in the United States and may lead to adverse cardiovascular outcomes.

Case - A 53-year-old, otherwise healthy bodybuilder was seen in the emergency room for exertional dyspnea and presyncope with a duration of 3 months. Physical examination showed a muscular male, tachycardia and tachypnea, and a pansystolic murmur prominent in the apex; chest X-ray showed cardiomegaly.

The echocardiogram showed severe mitral regurgitation, a left ventricular (LV) ejection fraction (EF) of 15% (vs. 57% three years prior), severe global LV hypokinesis, grade III/IV diastolic dysfunction, and severe pulmonary hypertension.

He was admitted for heart failure management and evaluation, which included normal coronary catheterization, iron panel and thyroid studies, as well as a negative blood viral panel (human immunodeficiency virus, Lyme disease and hepatitis).

During outpatient clinical care, he admitted intramuscular testosterone use for bodybuilding; his testosterone level was 30160.0 ng/dL (normal 280-1100 ng/dL).

Decision-making - The patient was counseled about the risk of anabolic steroid use and was optimized on standard heart failure medical therapy with a focus on maximal tolerated doses of carvedilol. Repeat echocardiograms at 3 months and 6 months showed improvement of EF to 39% and 54%, respectively.

Conclusion - Anabolic steroids are a synthetic derivative of testosterone and may be a rare but reversible cause of cardiomyopathy in young, otherwise healthy athletes. Physicians need to have a high index of suspicion when evaluating patients, and discuss this rare and potentially fatal side effect.