AAS and Cardiovascular/Pulmonary Function

[Michael Scally MD]

[OA] Lipid Management in Patients with Endocrine Disorders

This guideline will provide the practicing endocrinologist with an approach to the assessment and treatment of dyslipidemia in patients with endocrine diseases, with the objective of preventing cardiovascular (CV) events and triglyceride-induced pancreatitis.

The guideline reviews data on dyslipidemia and atherosclerotic cardiovascular disease (ASCVD) risk in patients with endocrine disorders and discusses the evidence for the correction of dyslipidemia by treatment of the endocrine disease. The guideline also addresses whether treatment of the endocrine disease reduces ASCVD risk.

This guideline focuses on lipid and lipoprotein abnormalities associated with endocrine diseases, including diabetes mellitus, and whether treatment of the endocrine disorder improves not only the lipid abnormalities, but also CV outcomes. Based on the available evidence, recommendations are made for the assessment and management of dyslipidemia in patients with endocrine diseases.

Newman CB, Blaha MJ, Boord JB, et al. Lipid Management in Patients with Endocrine Disorders: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism 2020;105. https://doi.org/10.1210/clinem/dgaa674

 

[Michael Scally MD]

[OA] Sudden Cardiac Death in Anabolic-Androgenic Steroid Users

Background and objectives: Anabolic-androgenic steroids (AASs) are a group of synthetic molecules derived from testosterone and its related precursors. AASs are widely used illicitly by adolescents and athletes, especially by bodybuilders, both for aesthetic uses and as performance enhancers to increase muscle growth and lean body mass. When used illicitly they can damage health and cause disorders affecting several functions.

Sudden cardiac death (SCD) is the most common medical cause of death in athletes. SCD in athletes has also been associated with the use of performance-enhancing drugs. This review aimed to focus on deaths related to AAS abuse to investigate the cardiac pathophysiological mechanism that underlies this type of death, which still needs to be fully investigated.

Materials and Methods: This review was conducted using PubMed Central and Google Scholar databases, until 21 July 2020, using the following key terms: "((Sudden cardiac death) OR (Sudden death)) AND ((androgenic anabolic steroid) OR (androgenic anabolic steroids) OR (anabolic-androgenic steroids) OR (anabolic-androgenic steroid))". Thirteen articles met the inclusion and exclusion criteria, for a total of 33 reported cases.

Results: Of the 33 cases, 31 (93.9%) were males while only 2 (61%) were females. Mean age was 29.79 and, among sportsmen, the most represented sports activity was bodybuilding. In all cases there was a history of AAS abuse or a physical phenotype suggesting AAS use; the total usage period was unspecified in most cases.

In 24 cases the results of the toxicological analysis were reported. The most detected AASs were nandrolone, testosterone, and stanozolol. The most frequently reported macroscopic alterations were cardiomegaly and left ventricular hypertrophy, while the histological alterations were foci of fibrosis and necrosis of the myocardial tissue.

Conclusions: Four principal mechanisms responsible for SCD have been proposed in AAS abusers: the atherogenic model, the thrombosis model, the model of vasospasm induced by the release of nitric oxide, and the direct myocardial injury model. Hypertrophy, fibrosis, and necrosis represent a substrate for arrhythmias, especially when combined with exercise. Indeed, AAS use has been shown to change physiological cardiac remodeling of athletes to pathophysiological cardiac hypertrophy with an increased risk of life-threatening arrhythmias.

Torrisi M, Pennisi G, Russo I, et al. Sudden Cardiac Death in Anabolic-Androgenic Steroid Users: A Literature Review. Medicina (Kaunas). 2020 Nov 4;56(11):E587. doi: 10.3390/medicina56110587. PMID: 33158202. https://www.mdpi.com/1010-660X/56/11/587/htm

 

[Michael Scally MD]

Another paper showing higher #LDL #cholesterol and #apoB causes shorter life.

 

[malfeasance]

is apoB something that is normally tested when running standard blood tests?

 

[Michael Scally MD]

Polypill with or without Aspirin in Persons without Cardiovascular Disease

BACKGROUND - A polypill comprising statins, multiple blood-pressure–lowering drugs, and aspirin has been proposed to reduce the risk of cardiovascular disease.

METHODS - Using a 2-by-2-by-2 factorial design, we randomly assigned participants without cardiovascular disease who had an elevated INTERHEART Risk Score to receive a polypill (containing 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril) or placebo daily, aspirin (75 mg) or placebo daily, and vitamin D or placebo monthly.

We report here the outcomes for the polypill alone as compared with matching placebo, for aspirin alone as compared with matching placebo, and for the polypill plus aspirin as compared with double placebo.

For the polypill-alone and polypill-plus-aspirin comparisons, the primary outcome was death from cardiovascular causes, myocardial infarction, stroke, resuscitated cardiac arrest, heart failure, or revascularization. For the aspirin comparison, the primary outcome was death from cardiovascular causes, myocardial infarction, or stroke. Safety was also assessed.

RESULTS - A total of 5713 participants underwent randomization, and the mean follow-up was 4.6 years. The low-density lipoprotein cholesterol level was lower by approximately 19 mg per deciliter and systolic blood pressure was lower by approximately 5.8 mm Hg with the polypill and with combination therapy than with placebo.

The primary outcome for the polypill comparison occurred in 126 participants (4.4%) in the polypill group and in 157 (5.5%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.63 to 1.00).

The primary outcome for the aspirin comparison occurred in 116 participants (4.1%) in the aspirin group and in 134 (4.7%) in the placebo group (hazard ratio, 0.86; 95% CI, 0.67 to 1.10).

The primary outcome for the polypill-plus-aspirin comparison occurred in 59 participants (4.1%) in the combined-treatment group and in 83 (5.8%) in the double-placebo group (hazard ratio, 0.69; CI, 0.50 to 0.97).

The incidence of hypotension or dizziness was higher in groups that received the polypill than in their respective placebo groups.

CONCLUSIONS - Combined treatment with a polypill plus aspirin led to a lower incidence of cardiovascular events than did placebo among participants without cardiovascular disease who were at intermediate cardiovascular risk.

Yusuf S, Joseph P, Dans A, et al. Polypill with or without Aspirin in Persons without Cardiovascular Disease. New England Journal of Medicine 2020. https://www.nejm.org/doi/abs/10.1056/NEJMoa2028220

 

[Michael Scally MD]

Polypill with or without Aspirin in Persons without Cardiovascular Disease

BACKGROUND - A polypill comprising statins, multiple blood-pressure–lowering drugs, and aspirin has been proposed to reduce the risk of cardiovascular disease.

METHODS - Using a 2-by-2-by-2 factorial design, we randomly assigned participants without cardiovascular disease who had an elevated INTERHEART Risk Score to receive a polypill (containing 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril) or placebo daily, aspirin (75 mg) or placebo daily, and vitamin D or placebo monthly.

We report here the outcomes for the polypill alone as compared with matching placebo, for aspirin alone as compared with matching placebo, and for the polypill plus aspirin as compared with double placebo.

For the polypill-alone and polypill-plus-aspirin comparisons, the primary outcome was death from cardiovascular causes, myocardial infarction, stroke, resuscitated cardiac arrest, heart failure, or revascularization. For the aspirin comparison, the primary outcome was death from cardiovascular causes, myocardial infarction, or stroke. Safety was also assessed.

RESULTS - A total of 5713 participants underwent randomization, and the mean follow-up was 4.6 years. The low-density lipoprotein cholesterol level was lower by approximately 19 mg per deciliter and systolic blood pressure was lower by approximately 5.8 mm Hg with the polypill and with combination therapy than with placebo.

The primary outcome for the polypill comparison occurred in 126 participants (4.4%) in the polypill group and in 157 (5.5%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.63 to 1.00).

The primary outcome for the aspirin comparison occurred in 116 participants (4.1%) in the aspirin group and in 134 (4.7%) in the placebo group (hazard ratio, 0.86; 95% CI, 0.67 to 1.10).

The primary outcome for the polypill-plus-aspirin comparison occurred in 59 participants (4.1%) in the combined-treatment group and in 83 (5.8%) in the double-placebo group (hazard ratio, 0.69; CI, 0.50 to 0.97).

The incidence of hypotension or dizziness was higher in groups that received the polypill than in their respective placebo groups.

CONCLUSIONS - Combined treatment with a polypill plus aspirin led to a lower incidence of cardiovascular events than did placebo among participants without cardiovascular disease who were at intermediate cardiovascular risk.

Yusuf S, Joseph P, Dans A, et al. Polypill with or without Aspirin in Persons without Cardiovascular Disease. New England Journal of Medicine 2020. https://www.nejm.org/doi/abs/10.1056/NEJMoa2028220

Just take the 5 pills separately.
But probably don't need 5 pills (3 of the 5 pills were BP meds).
Just take an aspirin, one blood pressure med, and a statin. This is what I do!

 

[Michael Scally MD]

 

[Michael Scally MD]

Sharma G, Martin SS, Blumenthal RS. Effects of Omega-3 Fatty Acids on Major Adverse Cardiovascular Events: What Matters Most: the Drug, the Dose, or the Placebo? JAMA. Published online November 15, 2020. Effects of Omega-3 Fatty Acids on Major Adverse Cardiovascular Events

Hypertriglyceridemia is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD), independent of low-density lipoprotein cholesterol (LDL-C) control.1 Standard treatment strategies have included lifestyle modification, weight and diabetes management, and statin therapy. Previous triglyceride-lowering trials with niacin, fibrates, and mixed omega-3 fatty acids have not demonstrated consistent risk reduction of ASCVD.1,2 However, strong evidence has recently emerged for the role of eicosapentaenoic acid (EPA), an omega-3 fatty acid, in its highly purified ethyl ester derivative, icosapent ethyl (IPE), in addition to statin treatment, for ASCVD risk reduction.1,2

Omega-3 fatty acids can have a broad range of effects on inflammation, oxidation, stability of phospholipid membranes, and the composition and volume of atherosclerotic plaque.3 These effects may differ between EPA and docosahexaenoic acid (DHA), another omega-3 fatty acid. EPA has stable extended conformation in cell membranes while DHA integrates in a disordered manner in vitro.2,4


Curfman G. Do Omega-3 Fatty Acids Benefit Health? JAMA. Published online November 15, 2020. Do Omega-3 Fatty Acids Benefit Health?

An important clinical trial of omega-3 fatty acids in patients at high risk of cardiovascular disease is published in JAMA.1 In the STRENGTH trial (the Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia), 13 078 patients were randomized to receive 4 g/d of a carboxylic acid formulation of omega-3 fatty acids (a combination of eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) or corn oil as a comparator.

After a median follow-up of 42 months, there was no significant difference between the omega-3 fatty acid group (6539 patients) and the corn oil group (6539 patients) in the primary end point, a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and hospitalization for unstable angina. This end point was observed in 12% of the omega-3 patients vs 12.2% of the corn oil patients (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84).

The null result is similar to another recent, large (25 871 participants) omega-3 clinical trial, VITAL (Vitamin D and Omega-3 Trial), that also reported no significant benefit of an omega-3 preparation, compared with placebo, on cardiovascular events in a primary prevention population (hazard ratio, 0.97 [95% CI, 0.85-1.12]; P = .69).2 However, in this trial, the daily dose of the omega-3 preparation (1 g/d of a combination of EPA and DHA) was much lower than in the STRENGTH trial.

By contrast, the results of STRENGTH directly contradict the results of the REDUCE-IT trial (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial).3 …


Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial. JAMA. Published online November 15, 2020. Omega-3 Fatty Acids vs Corn Oil and Major Adverse Cardiovascular Events in Patients at High Risk

Key Points

Question In statin-treated patients with high cardiovascular risk, high triglycerides, and low HDL cholesterol levels, does adding a carboxylic acid formulation of omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) to background therapy improve cardiovascular outcomes?

Findings In this randomized clinical trial of 13 078 patients that was stopped early, daily supplementation with omega-3 fatty acids, compared with corn oil, resulted in no significant difference in a composite outcome of major adverse cardiovascular events (hazard ratio, 0.99)

Meaning These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in patients with high cardiovascular risk.


Importance It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk.

Objective To determine the effects on cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk.

Design, Setting, and Participants A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13 078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa.

Interventions Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or corn oil, which was intended to serve as an inert comparator (n = 6539), in addition to usual background therapies, including statins.

Main Outcomes and Measures The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization.

Results When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84). A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil–treated patients (14.7%).

Conclusions and Relevance Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients.

 

[Michael Scally MD]

 

[Michael Scally MD]

The Fraud of Fish Oil Is Exposed. Will Kale Be Next?
https://www.wsj.com/articles/the-fraud-of-fish-oil-is-exposed-will-kale-be-next-11605810445

For more years than I care to remember, I have taken a daily capsule of fish oil because it’s supposed to be good for your heart. Fish oil capsules are disgusting, and just thinking about ingesting them every morning has ruined my breakfasts for years. But for decades I have taken one for the team. Sometimes two.

Now a pair of rigorously scientific studies presented at the American Heart Association’s Scientific Sessions, an event I never miss, provide seemingly indisputable evidence that fish oil has no effect whatsoever on cardiovascular health. The studies, which tested thousands of subjects, do not come right out and say it, but the underlying message is clear: Taking fish oil supplements is just another weird thing people in northern California dreamed up in the 1980s.


Sharma G, Martin SS, Blumenthal RS. Effects of Omega-3 Fatty Acids on Major Adverse Cardiovascular Events: What Matters Most: the Drug, the Dose, or the Placebo? JAMA. Published online November 15, 2020. https://jamanetwork.com/journals/jama/fullarticle/2773118

Hypertriglyceridemia is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD), independent of low-density lipoprotein cholesterol (LDL-C) control.1 Standard treatment strategies have included lifestyle modification, weight and diabetes management, and statin therapy. Previous triglyceride-lowering trials with niacin, fibrates, and mixed omega-3 fatty acids have not demonstrated consistent risk reduction of ASCVD.1,2 However, strong evidence has recently emerged for the role of eicosapentaenoic acid (EPA), an omega-3 fatty acid, in its highly purified ethyl ester derivative, icosapent ethyl (IPE), in addition to statin treatment, for ASCVD risk reduction.1,2

Omega-3 fatty acids can have a broad range of effects on inflammation, oxidation, stability of phospholipid membranes, and the composition and volume of atherosclerotic plaque.3 These effects may differ between EPA and docosahexaenoic acid (DHA), another omega-3 fatty acid. EPA has stable extended conformation in cell membranes while DHA integrates in a disordered manner in vitro.2,4


Curfman G. Do Omega-3 Fatty Acids Benefit Health? JAMA. Published online November 15, 2020. https://jamanetwork.com/journals/jama/fullarticle/2773119

An important clinical trial of omega-3 fatty acids in patients at high risk of cardiovascular disease is published in JAMA.1 In the STRENGTH trial (the Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia), 13 078 patients were randomized to receive 4 g/d of a carboxylic acid formulation of omega-3 fatty acids (a combination of eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) or corn oil as a comparator.

After a median follow-up of 42 months, there was no significant difference between the omega-3 fatty acid group (6539 patients) and the corn oil group (6539 patients) in the primary end point, a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and hospitalization for unstable angina. This end point was observed in 12% of the omega-3 patients vs 12.2% of the corn oil patients (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84).

The null result is similar to another recent, large (25 871 participants) omega-3 clinical trial, VITAL (Vitamin D and Omega-3 Trial), that also reported no significant benefit of an omega-3 preparation, compared with placebo, on cardiovascular events in a primary prevention population (hazard ratio, 0.97 [95% CI, 0.85-1.12]; P = .69).2 However, in this trial, the daily dose of the omega-3 preparation (1 g/d of a combination of EPA and DHA) was much lower than in the STRENGTH trial.

By contrast, the results of STRENGTH directly contradict the results of the REDUCE-IT trial (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial).3 …


Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial. JAMA. Published online November 15, 2020. https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2020.22258

Key Points

Question In statin-treated patients with high cardiovascular risk, high triglycerides, and low HDL cholesterol levels, does adding a carboxylic acid formulation of omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) to background therapy improve cardiovascular outcomes?

Findings In this randomized clinical trial of 13 078 patients that was stopped early, daily supplementation with omega-3 fatty acids, compared with corn oil, resulted in no significant difference in a composite outcome of major adverse cardiovascular events (hazard ratio, 0.99)

Meaning These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in patients with high cardiovascular risk.

 

[Michael Scally MD]

SAMSON Trial Makes Its Case to Cut Statin Side Effects
https://www.medscape.com/viewarticle/940801

Howard: The take-home message from SAMSON is that patients really do suffer from statin side effects. But the thing is, they are not caused by the statin molecules; they are caused by the act of taking the pill. And the symptoms are almost as bad if they take a placebo.

Mandrola: That is remarkable. How did you design this and how did you work through this trial?

…


Wood FA, Howard JP, Finegold JA, et al. N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side Effects. New England Journal of Medicine 2020. https://doi.org/10.1056/NEJMc2031173

Statins are often discontinued because of side effects,1,2 even though some blinded trials have not shown an excess of symptoms with statins as compared with placebo.3,4 Patients who had previously discontinued statins because of side effects that occurred within 2 weeks after the initiation of treatment were enrolled in a double-blind, three-group, n-of-1 trial to test whether symptoms would be induced by a statin or placebo. …

 

[Michael Scally MD]

[OA] How the love of muscle can break a heart: Impact of anabolic androgenic steroids on skeletal muscle hypertrophy, metabolic and cardiovascular health.

It is estimated 6.4% of males and 1.6% of females globally use anabolic-androgenic steroids (AAS), mostly for appearance and performance enhancing reasons. In combination with resistance exercise, AAS use increases muscle protein synthesis resulting in skeletal muscle hypertrophy and increased performance.

Primarily through binding to the androgen receptor, AAS exert their hypertrophic effects via genomic, non-genomic and anti-catabolic mechanisms. However, chronic AAS use also has a detrimental effect on metabolism ultimately increasing the risk of cardiovascular disease (CVD).

Much research has focused on AAS effects on blood lipids and lipoproteins, with abnormal concentrations of these associated with insulin resistance, hypertension and increased visceral adipose tissue (VAT). This clustering of interconnected abnormalities is often referred as metabolic syndrome (MetS).

Therefore, the aim of this review is to explore the impact of AAS use on mechanisms of muscle hypertrophy and markers of MetS. AAS use markedly decreases high-density lipoprotein cholesterol (HDL-C) and increases low-density lipoprotein cholesterol (LDL-C). Chronic AAS use also appears to cause higher fasting insulin levels and impaired glucose tolerance and possibly higher levels of VAT; however, research is currently lacking on the effects of AAS use on glucose metabolism.

While cessation of AAS use can restore normal lipid levels, it may lead to withdrawal symptoms such as depression and hypogonadism that can increase CVD risk. Research is currently lacking on effective treatments for withdrawal symptoms and further long-term research is warranted on the effects of AAS use on metabolic health in males and females.

[OA] McCullough, D., Webb, R., Enright, K.J. et al. How the love of muscle can break a heart: Impact of anabolic androgenic steroids on skeletal muscle hypertrophy, metabolic and cardiovascular health. Rev Endocr Metab Disord (2020). https://doi.org/10.1007/s11154-020-09616-y

 

[Michael Scally MD]

 

[Michael Scally MD]

Testosterone Therapy and Cardiovascular Risk: A Critical Analysis of Studies Reporting Increased Risk

Background - Treatment of “adult-onset hypogonadism” (AOH) with exogenous testosterone therapy (TTh) to raise serum testosterone (T) levels may influence cardiovascular (CV) risk factors in patients with AOH, whereas low endogenous T levels are associated with an increased CV risk and mortality.

Aim - To critically evaluate studies reporting increased CV risk associated with TTh and to provide an overview of the risks and benefits of restoring T levels through exogenous TTh.

Methods - A review of publications focusing on the association between TTh and increased CV risk was conducted, and the study methodologies and conclusions of each were critically evaluated. Further, recent clinical and epidemiological studies associating AOH or TTh with a change in CV risk, and pertinent hematologic and vascular effects noted in animal studies and in vitro, as well as in clinical practice were also reviewed.

Outcomes - A review of the literature shows that untreated testosterone deficiency and/or low T is associated with an increase in CV risk and adverse outcomes, with numerous studies and meta-analyses to support a positive association between exogenous TTh and an improvement in CV risk factors in men with AOH.

Results - Numerous studies in the literature demonstrate the positive benefits of using TTh; however, since 2013, some publications have suggested a link to increased CV risk associated with TTh. A number of these studies retrospectively analyzed insurance claims databases using diagnosis codes, procedures codes, and prescription information. Many reviews published since have pointed out the methodological flaws and debatable conclusions of these studies.

Clinical Implications - A careful assessment of the patient's current health status and CV risk factors should be weighed against the benefits and possible risks resulting from TTh, and consideration should be given to deferring treatment pending resolution or stabilization of CV disease or risk factors.

Strengths & Limitations - In this review, we provide an in-depth analysis of studies reporting increased CV risk with TTh. Many of the studies were not well-designed, randomized, double-blind, prospective clinical trials but rather post hoc analyses of cohort data. These studies may reflect bias in how treatment and nontreatment decisions are made or reflect conclusions based on widely cited methodological flaws.

Conclusion - Appropriate patient selection supported by low pre-treatment T levels and monitoring T levels during treatment with the goal of achieving and maintaining physiologic levels all contribute to the safe and effective use of TTh in men with AOH.

Khera M, Miner M, Jaffe J, et al. Testosterone Therapy and Cardiovascular Risk: A Critical Analysis of Studies Reporting Increased Risk. J Sex med 2020;XX:XXX–XXX. https://www.jsm.jsexmed.org/article/S1743-6095(20)30994-2/fulltext

 

[Michael Scally MD]

[OA] Decompensated Non-Ischemic Cardiomyopathy Induced by Anabolic-Androgenic Steroid Abuse

A 30-year-old male presented to the emergency department with dyspnea, fatigue, orthopnea, and paroxysmal nocturnal dyspnea for the past three months. The patient admitted to anabolic steroid use for the past 11 years.

Transthoracic echocardiography was significant for severely dilated left ventricle, diffuse hypokinesis, ejection fraction < 15%, and grade II diastolic dysfunction. The patient was diagnosed with decompensated, non-ischemic cardiomyopathy stage C, and New York Heart Classification (NYHA) class III > IV, likely from use of anabolic steroids, after a negative workup for other etiologies.

On follow-up after continuation of guideline-directed medical therapy, the patient demonstrated improved heart failure status (NYHA class I > II). Cardiomyopathy is a rare but important adverse effect of anabolic steroids to consider.

Sodhi P, Patel MR, Solsi A, Bellamkonda P. Decompensated Non-Ischemic Cardiomyopathy Induced by Anabolic-Androgenic Steroid Abuse. Cureus. 2020 Nov 13;12(11):e11476. doi: 10.7759/cureus.11476. PMID: 33329972; PMCID: PMC7734701. Decompensated Non-Ischemic Cardiomyopathy Induced by Anabolic-Androgenic Steroid Abuse

 

[Michael Scally MD]

Acute Myocardial Infarction and Anabolic-androgenic Steroids

Introduction: Coronary artery disease (CAD) represents approximately 390 thousand deaths per year in Brazil and is associated, among other predictors, with the use of anabolic and androgenic steroids (AAS).

Objective: To analyze a clinical case of a patient who suffered AMI after abuse of AAS. A systematic literature review has been carried out to physiologically analyze the main factors that can lead to AMI with the use of these hormones.

Methods: Case Report: The EVR patient, 41 years old, denies any comorbidities or use of medications. He has been admitted to the emergency room due to typical angina-precordial pain in tightness associated with eventual back pain and paresthesia of both upper limbs, after intense physical effort at the gym, without improvement at rest, and with partial improvement after first care at the health unit.

The patient was hypertensive in an emergency bed after the occurrence of ST elevation. The patient alleges the use of anabolic steroids for one month. The patient presented with obstructive atherosclerotic coronary artery disease with total occlusion of the anterior descending artery. Systematic review: A total of 89 clinical studies have been compared and submitted to eligibility analysis, with 50 studies selected, according to the PRISMA rules.

Results and conclusion: AAS can increase protein synthesis, muscle growth, and erythropoiesis. However, abuse of AAS has a toxic cardiovascular effect, which significantly increases the incidence of cardiovascular diseases.

Mustafa EM, Filho IJZ, Ferreira VRR, et al. AMI and Anabolic-androgenic Steroids: Case Report with Systematic Review. Curr Cardiol Rev. 2020 Dec 31. doi: 10.2174/1573403X16999201231203405. Epub ahead of print. PMID: 33390145. Ami and Anabolic-androgenic Steroids: Case Report with Systematic Review

 

[Michael Scally MD]

[OA] Testosterone, Cardiomyopathies, and Heart Failure

Testosterone exerts an important regulation of cardiovascular function through genomic and nongenomic pathways. It produces several changes in cardiomyocytes, the main actor of cardiomyopathies, which are characterized by pathological remodeling, eventually leading to heart failure.

Testosterone is involved in contractility, in the energy metabolism of myocardial cells, apoptosis, and the remodeling process. In myocarditis, testosterone directly promotes the type of inflammation that leads to fibrosis, and influences viremia with virus localization. At the same time, testosterone exerts cardioprotective effects that have been observed in different studies.

There is increasing evidence that low endogenous levels of testosterone have a negative impact in some cardiomyopathies and a protective impact in others. This review focuses on the interrelationships between testosterone and cardiomyopathies and heart failure.

Diaconu R, Donoiu I, Mirea O, Bălşeanu TA. Testosterone, cardiomyopathies, and heart failure: a narrative review. Asian J Androl. 2021 Jan 12. doi: 10.4103/aja.aja_80_20. Epub ahead of print. PMID: 33433530. Testosterone, cardiomyopathies, and heart failure: a narrative review Diaconu R, Donoiu I, Mirea O, Bălşeanu TA, - Asian J Androl

 

[Michael Scally MD]

[OA] Effect of Atorvastatin on Testosterone Levels

Background - Statins are one of the most prescribed classes of drugs worldwide. Atorvastatin, the most prescribed statin, is currently used to treat conditions such as hypercholesterolaemia and dyslipidaemia. By reducing the level of cholesterol, which is the precursor of the steroidogenesis pathway, atorvastatin may cause a reduction in levels of testosterone and other androgens.

Testosterone and other androgens play important roles in biological functions. A potential reduction in androgen levels, caused by atorvastatin might cause negative effects in most settings. In contrast, in the setting of polycystic ovary syndrome (PCOS), reducing excessive levels of androgens with atorvastatin could be beneficial.

Objectives

Primary objective - To quantify the magnitude of the effect of atorvastatin on total testosterone in both males and females, compared to placebo or no treatment.

Secondary objectives - To quantify the magnitude of the effects of atorvastatin on free testosterone, sex hormone binding globin (SHBG), androstenedione, dehydroepiandrosterone sulphate (DHEAS) concentrations, free androgen index (FAI), and withdrawal due to adverse effects (WDAEs) in both males and females, compared to placebo or no treatment.

Search methods - The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to 9 November 2020: the Cochrane Hypertension Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; ;two international trials registries, and the websites of the US Food and Drug Administration, the European Patent Office and the Pfizer pharmaceutical corporation. These searches had no language restrictions. We also contacted authors of relevant articles regarding further published and unpublished work.

Selection criteria - RCTs of daily atorvastatin for at least three weeks, compared with placebo or no treatment, and assessing change in testosterone levels in males or females.

Data collection and analysis - Two review authors independently screened the citations, extracted the data and assessed the risk of bias of the included studies. We used the mean difference (MD) with associated 95% confidence intervals (CI) to report the effect size of continuous outcomes,and the risk ratio (RR) to report effect sizes of the sole dichotomous outcome (WDAEs).

We used a fixed‐effect meta‐analytic model to combine effect estimates across studies, and risk ratio to report effect size of the dichotomous outcomes. We used GRADE to assess the certainty of the evidence.

Main results - We included six RCTs involving 265 participants who completed the study and their data was reported. Participants in two of the studies were male with normal lipid profile or mild dyslipidaemia (N = 140); the mean age of participants was 68 years. Participants in four of the studies were female with PCOS (N = 125); the mean age of participants was 32 years.

We found no significant difference in testosterone levels in males between atorvastatin and placebo, MD ‐0.20 nmol/L (95% CI ‐0.77 to 0.37). In females, atorvastatin may reduce total testosterone by ‐0.27 nmol/L (95% CI ‐0.50 to ‐0.04), FAI by ‐2.59 nmol/L (95% CI ‐3.62 to ‐1.57), androstenedione by ‐1.37 nmol/L (95% CI ‐2.26 to ‐0.49), and DHEAS by ‐0.63 μmol/l (95% CI ‐1.12 to ‐0.15).

Furthermore, compared to placebo, atorvastatin increased SHBG concentrations in females by 3.11 nmol/L (95% CI 0.23 to 5.99). We identified no studies in healthy females (i.e. females with normal testosterone levels) or children (under age 18). Importantly, no study reported on free testosterone levels.

Authors' conclusions - We found no significant difference between atorvastatin and placebo on the levels of total testosterone in males. In females with PCOS, atorvastatin lowered the total testosterone, FAI, androstenedione, and DHEAS. The certainty of evidence ranged from low to very low for both comparisons. More RCTs studying the effect of atorvastatin on testosterone are needed.

Shawish MI, Bagheri B, Musini VM, Adams SP, Wright JM. Effect of atorvastatin on testosterone levels. Cochrane Database of Systematic Reviews 2021. https://doi.org//10.1002/14651858.CD013211.pub2

 

[Michael Scally MD]

[OA] Testosterone Activates Glucose Metabolism Through AMPK And Androgen Signaling In Cardiomyocyte Hypertrophy

Background - Testosterone regulates nutrient and energy balance to maintain protein synthesis and metabolism in cardiomyocytes, but supraphysiological concentrations induce cardiac hypertrophy. Previously, we determined that testosterone increased glucose uptake—via AMP-activated protein kinase (AMPK)—after acute treatment in cardiomyocytes.

However, whether elevated glucose uptake is involved in long-term changes of glucose metabolism or is required during cardiomyocyte growth remained unknown. In this study, we hypothesized that glucose uptake and glycolysis increase in testosterone-treated cardiomyocytes through AMPK and androgen receptor (AR).

Methods - Cultured cardiomyocytes were stimulated with 100 nM testosterone for 24 h, and hypertrophy was verified by increased cell size and mRNA levels of β-myosin heavy chain (β-mhc). Glucose uptake was assessed by 2-NBDG. Glycolysis and glycolytic capacity were determined by measuring extracellular acidification rate (ECAR).

Results - Testosterone induced cardiomyocyte hypertrophy that was accompanied by increased glucose uptake, glycolysis enhancement and upregulated mRNA expression of hexokinase 2. In addition, testosterone increased AMPK phosphorylation (Thr172), while inhibition of both AMPK and AR blocked glycolysis and cardiomyocyte hypertrophy induced by testosterone. Moreover, testosterone supplementation in adult male rats by 5 weeks induced cardiac hypertrophy and upregulated β-mhc, Hk2 and Pfk2 mRNA levels.

Conclusion - These results indicate that testosterone stimulates glucose metabolism by activation of AMPK and AR signaling which are critical to induce cardiomyocyte hypertrophy.

Troncoso, M.F., Pavez, M., Wilson, C. et al. Testosterone activates glucose metabolism through AMPK and androgen signaling in cardiomyocyte hypertrophy. Biol Res 54, 3 (2021). Testosterone activates glucose metabolism through AMPK and androgen signaling in cardiomyocyte hypertrophy

 

[Michael Scally MD]

[OA] Anabolic-Androgenic Steroids and Cardiometabolic Derangements

Anabolic-androgenic steroids (AAS) are commonly used among both competitive athletes and recreational athletes in order to gain a performance edge.

Unfortunately, AAS generally carries a broad range of short term and long term adverse effects. These include endocrinological abnormalities, cardiovascular risks, psychological issues, and largely adverse effects on every organ system in the human body.

While testosterone, and at times oxandrolone, are used for clinical purposes, AAS generally encompasses a very broad range of synthetic compounds that are used at high doses.

In this case report, we look at a patient who has used the vast majority of common anabolic steroids over the past three decades and how these compounds may affect long-term metabolic and cardiovascular health. The purpose is to provide a primary care approach to this patient population.

Farzam K. Anabolic-Androgenic Steroids and Cardiometabolic Derangements. Cureus. 2021 Jan 5;13(1):e12492. doi: 10.7759/cureus.12492. PMID: 33564503; PMCID: PMC7861066. Anabolic-Androgenic Steroids and Cardiometabolic Derangements