AAS and Cardiovascular/Pulmonary Function

[Michael Scally MD]

High Density Lipoprotein Function Is Reduced in Patients Affected by Genetic or Idiopathic Hypogonadism

BACKGROUND: Low testosterone levels are associated with an increased incidence of cardiovascular (CV) events, but the underlying biochemical mechanisms are not fully understood. The clinical condition of hypogonadism offers a unique model to unravel the possible role of lipoprotein-associated abnormalities in CV risk.

In particular, the assessment of the functional capacities of high-density lipoproteins (HDL) may provide novel insights besides traditional risk factors. To determine whether reduced testosterone levels correlate with lipoprotein function, HDL cholesterol efflux capacity (CEC) and serum cholesterol loading capacity (CLC) were evaluated in a series of genetic and idiopathic hypogonadal patients and control subjects.

METHODS AND RESULTS: Primary and secondary hypogonadal patients presented with lower HDL ATP-binding cassette transporter A1 (ABCA1)-, ATP binding cassette transporter G1 (ABCG1) - and aqueous diffusion-mediated CEC (-19.6%, -40.9% and -12.9%, respectively), with a 16.2% decrement of total CEC. In the whole series, positive correlations between testosterone levels and both total HDL CEC (r2= 0.359, p= 0.0001) and ABCG1 HDL CEC (r2= 0.367, p= 0.0001) were observed.

Conversely, serum CLC was markedly raised (+43%) in hypogonadals, being increased, to a higher extent, in primary vs secondary hypogonadism (18.45 +/- 2.78 vs 15.15 +/- 2.10 microg cholesterol/mg protein) and inversely correlated with testosterone levels (r2= 0.270, p= 0.001). HDL-C concentrations did not correlate with either testosterone levels, HDL CEC (total, ABCG1 and ABCA1) or serum CLC.

CONCLUSION(S): In hypogonadal patients pro-atherogenic lipoprotein-associated changes are associated with lower cholesterol efflux and increased influx, thus offering an explanation for a potentially increased CV risk.

Adorni MP, Zimetti F, Cangiano B, et al. High density lipoprotein function is reduced in patients affected by genetic or idiopathic hypogonadism. The Journal of clinical endocrinology and metabolism 2019. High density lipoprotein function is reduced in patients affected by genetic or idiopathic hypogonadism

 

[Old]

Diminished Cholesterol Efflux Mediated by HDL and Coronary Artery Disease in Anabolic Androgenic Steroid Users

Highlights
· Anabolic androgenic steroids (AAS) abuse impairs the cholesterol efflux mediated by HDL.
· AAS abuse seems to be correlated with lower cholesterol efflux and subclinical coronary artery disease (CAD).
· We found at least 2 coronary arteries with plaques in 25% of AAS users.

BACKGROUND AND AIMS: Anabolic androgenic steroids (AAS) have been associated with coronary artery disease (CAD). AAS abuse leads to a remarkable decrease in high-density lipoprotein (HDL) plasma concentration, which could be a key factor in the atherosclerotic process.

Moreover, not only the concentration of HDL, but also its functionality, plays a pivotal role in CAD. We tested the functionality of HDL by cholesterol efflux and antioxidant capacity. We also evaluated the prevalence of CAD in AAS users.

METHODS: Twenty strength-trained AAS users (AASU) age 29+/-5yr, 20 age-matched strength-trained AAS nonusers (AASNU), and 10 sedentary controls (SC) were enrolled in this cross-sectional study.

Functionality of HDL was evaluated by (14)C-cholesterol efflux and the ability of HDL in inhibiting LDL oxidation. Coronary artery was evaluated with coronary computed tomography angiography.

RESULTS: Cholesterol efflux was lower in AASU compared with AASNU and SC (20 vs. 23 vs. 24%, respectively, p<0.001). However, the lag time for LDL oxidation was higher in AASU compared with AASNU and SC (41 vs 13 vs 11min, respectively, p<0.001).

We found at least 2 coronary arteries with plaques in 25% of AASU. None of the AASNU and SC had plaques. The time of AAS use was negatively associated with cholesterol efflux.

CONCLUSIONS: This study indicates that AAS abuse impairs the cholesterol efflux mediated by HDL. Long-term AAS use seems to be correlated with lower cholesterol efflux and early subclinical CAD in this population.

Souza FR, Dos Santos MR, Porello RA, et al. Diminished cholesterol efflux mediated by HDL and coronary artery disease in young male anabolic androgenic steroid users. Atherosclerosis 2019;283:100-5. https://www.atherosclerosis-journal.com/article/S0021-9150(19)30084-X/abstract

High Density Lipoprotein Function Is Reduced in Patients Affected by Genetic or Idiopathic Hypogonadism

BACKGROUND: Low testosterone levels are associated with an increased incidence of cardiovascular (CV) events, but the underlying biochemical mechanisms are not fully understood. The clinical condition of hypogonadism offers a unique model to unravel the possible role of lipoprotein-associated abnormalities in CV risk.

In particular, the assessment of the functional capacities of high-density lipoproteins (HDL) may provide novel insights besides traditional risk factors. To determine whether reduced testosterone levels correlate with lipoprotein function, HDL cholesterol efflux capacity (CEC) and serum cholesterol loading capacity (CLC) were evaluated in a series of genetic and idiopathic hypogonadal patients and control subjects.

METHODS AND RESULTS: Primary and secondary hypogonadal patients presented with lower HDL ATP-binding cassette transporter A1 (ABCA1)-, ATP binding cassette transporter G1 (ABCG1) - and aqueous diffusion-mediated CEC (-19.6%, -40.9% and -12.9%, respectively), with a 16.2% decrement of total CEC. In the whole series, positive correlations between testosterone levels and both total HDL CEC (r2= 0.359, p= 0.0001) and ABCG1 HDL CEC (r2= 0.367, p= 0.0001) were observed.

Conversely, serum CLC was markedly raised (+43%) in hypogonadals, being increased, to a higher extent, in primary vs secondary hypogonadism (18.45 +/- 2.78 vs 15.15 +/- 2.10 microg cholesterol/mg protein) and inversely correlated with testosterone levels (r2= 0.270, p= 0.001). HDL-C concentrations did not correlate with either testosterone levels, HDL CEC (total, ABCG1 and ABCA1) or serum CLC.

CONCLUSION(S): In hypogonadal patients pro-atherogenic lipoprotein-associated changes are associated with lower cholesterol efflux and increased influx, thus offering an explanation for a potentially increased CV risk.

Adorni MP, Zimetti F, Cangiano B, et al. High density lipoprotein function is reduced in patients affected by genetic or idiopathic hypogonadism. The Journal of clinical endocrinology and metabolism 2019. High density lipoprotein function is reduced in patients affected by genetic or idiopathic hypogonadism

So here are two reports that lower HDL is "pro-atherogenic". This has been stated for many years.

So why do the new [2018] guidelines for Cholesterol Treatment completely omit consideration for HDL? These guidelines target LDL to be < 70 mg/dL. Docs are saying they are not to bother looking at HDL.


Again, this second study regarding "hypogonadals" indicate they have lower HDL. The first study indicates "hypergonadals" have the same problem, lower HDL.

So its a bell shaped curve. However, the first study was hardly robust with only 20 AAS users. Also, did they ever use orals!?! An important question since oral steroids absolutely tank HDL.

That is a consideration for readers here - just how important is it that one uses orals and not just stick with ihormones that don't tank HDL so bad.

 

[cfreetenor]

What would you want to know about AAS and heart health before your first cycle? Currently my thinking:

Be meticulous with fish oil protocol and healthy fat intake

Frequent low-moderate intensity cardio, general heart healthy lifestyle (I like hiking and fighting)

Minimal to judicious use of stimulants

Aspirin regimen of 81mg a day

My first five cycles won’t include more than

Test
EQ
Adex (Letro for emergencies)
Nolvadex
HcG (maybe)
Superdrol (I don’t drink or smoke)
Low dose Tren (all cycles would include weight/strength gain goals)

Anything else someone with heart consciousness should keep in mind?

 

[Havah]

What makes you think 81mg a day of aspirine is "good for your hearth"?

Also i d go as far as saying the only judicous dose of stimulants when on gear is Zero

 

[cfreetenor]

What makes you think 81mg a day of aspirine is "good for your hearth"?

Also i d go as far as saying the only judicous dose of stimulants when on gear is Zero

That includes caffeine, which I can’t cut out completely without side effects and constipation. But I’ve no interest in Clen or anything like that.

 

[Havah]

That includes caffeine, which I can’t cut out completely without side effects and constipation. But I’ve no interest in Clen or anything like that.

Sounds reasonnable enough
How about the aspirine tho

 

[cfreetenor]

Aspirin is bad? I’ve always heard differently

 

[gear_solid]

Baggish AL, Weiner RB, Kanayama G, et al. Long-Term Anabolic-Androgenic Steroid Use Is Associated With Left Ventricular Dysfunction. Circ Heart Fail 2010;3(4):472-6. Long-Term Anabolic-Androgenic Steroid Use Is Associated With Left Ventricular Dysfunction -- Baggish et al. 3 (4): 472 -- Circulation: Heart Failure

Background—Although illicit anabolic-androgenic steroid (AAS) use is widespread, the cardiac effects of long-term AAS use remain inadequately characterized. We compared cardiac parameters in weightlifters reporting long-term AAS use to those in otherwise similar weightlifters without prior AAS exposure.

Methods and Results—We performed 2D tissue-Doppler and speckle-tracking echocardiography to assess left ventricular (LV) ejection fraction, LV systolic strain, and conventional indices of diastolic function in long-term AAS users (n=12) and otherwise similar AAS nonusers (n=7). AAS users (median [quartile 1, quartile 3] cumulative lifetime AAS exposure, 468 [169, 520] weeks) closely resembled nonusers in age, prior duration of weightlifting, and current intensity of weight training. LV structural parameters were similar between the two groups; however, AAS users had significantly lower LV ejection fraction (50.6% [48.4, 53.6] versus 59.1% [58.0%, 61.7%]; P=0.003 by two-tailed Wilcoxon rank sum test), longitudinal strain (16.9% [14.0%, 19.0%] versus 21.0% [20.2%, 22.9%]; P=0.004), and radial strain (38.3% [28.5%, 43.7%] versus 50.1% [44.3%, 61.8%]; P=0.02). Ten of the 12 AAS users showed LV ejection fractions below the accepted limit of normal ( 55%). AAS users also demonstrated decreased diastolic function compared to nonusers as evidenced by a markedly lower early peak tissue velocity (7.4 [6.8, 7.9] cm/s versus 9.9 [8.3, 10.5] cm/s; P=0.005) and early-to-late diastolic filling ratio (0.93 [0.88, 1.39] versus 1.80 [1.48, 2.00]; P=0.003).

Conclusions—Cardiac dysfunction in long-term AAS users appears to be more severe than previously reported and may be sufficient to increase the risk of heart failure.

What is considered long term though? 5 years? 4 years?

 

[Michael Scally MD]

[OA] Piccirillo G, Moscucci F, Pofi R, et al. Changes in left ventricular repolarization after short-term testosterone replacement therapy in hypogonadal males. Journal of endocrinological investigation 2019. Changes in left ventricular repolarization after short-term testosterone replacement therapy in hypogonadal males

BACKGROUND AND AIM: Evidences suggest that androgen deficiency is associated with sudden cardiac death (SCD). Our purpose was to analyse some electrocardiographic (ECG) markers of repolarization phase in hypogonadal patients either at baseline or after testosterone replacement therapy (TRT).

PATIENTS AND METHODS: Baseline and after 6 months of testosterone replacement therapy, 14 hypogonadal patients and 10 age-matched controls underwent a short-term ECG recordings at rest and immediately after a maximal exercise test. The following ECG parameters have been collected: QTe (the interval between the q wave the end of T wave), QTp (the interval between the q wave and the peak of T wave), and Te (the interval between the peak and the end of T wave).

RESULTS: At baseline, in the hypogonadal patients, corrected QTe and QTp values were longer at rest than in the controls at rest (p < 0.05), whereas, during the recovery phase, only the QTp remained significantly longer (p < 0.05). After TRT, hypogonadal patients showed an improvement only in Te (p < 0.05). Conversely, any difference between hypogonadal patients and control subjects was found with respect to the markers of temporal dispersion of repolarization phases, except for a worse QTp --> Te coherence (p = 0.001) obtained during the recovery phase.

CONCLUSIONS: In conclusion, at rest, hypogonadal patients suffer from a stable increase in the myocardial repolarization phase without an increase in its temporal dispersion and, hence, the SCD risk seems to be low.

 

[Michael Scally MD]

[OA] Schooling CM, Ng J. Reproduction and longevity - A Mendelian randomization study of gonadotropin-releasing hormone and ischemic heart disease. bioRxiv 2018:472548. Reproduction and longevity A Mendelian randomization study of gonadotropin-releasing hormone and ischemic heart disease

Background: According to well-established evolutionary biology theory reproduction trades-off against longevity, implying that upregulating the reproductive axis might drive major diseases. We assessed whether the central driver of reproduction gonadotropin-releasing hormone 1 (GnRH1) had a causal effect on the leading cause of global morbidity and mortality, i.e. ischemic heart disease (IHD). As a contrast we similarly examined the role of GnRH2 because it is more a driver of female sexual behavior.

Methods: We applied strong (p-value <5x10-6) and independent genetic predictors of GnRH1 and GnRH2 to an extensively genotyped IHD case (n=76,014) - control (n=264,785) study using multiplicative random effects inverse variance weighted (IVW), weighted median, MR-Egger and MR-PRESSO estimates.

Results: GnRH1, predicted by 11 genetic variants, was positively associated with IHD (IVW odds ratio (OR) 1.04 per effect size, 95% confidence interval (CI) 1.01 to 1.08), but GnRH2, predicted by 15 genetic variants, was not (IVW OR 0.98, 95% CI 0.95 to 1.02).

Conclusions: GnRH1 is a potential IHD genetic target. Apart from demonstrating a central tenet of evolutionary biology in humans, our study suggests that existing treatments and environmental factors targeting GnRH1, its drivers or consequences could be re-purposed to prevent and treat IHD. Given, the importance of reproduction to the human species, many such exposures likely exist.

 

[Michael Scally MD]

Luo S, Au Yeung SL, Zhao JV, Burgess S, Schooling CM. Association of genetically predicted testosterone with thromboembolism, heart failure, and myocardial infarction: mendelian randomisation study in UK Biobank. BMJ (Clinical research ed) 2019;364:l476. Association of genetically predicted testosterone with thromboembolism, heart failure, and myocardial infarction: mendelian randomisation study in UK Biobank

Objective To determine whether endogenous testosterone has a causal role in thromboembolism, heart failure, and myocardial infarction.

Design Two sample mendelian randomisation study using genetic variants as instrumental variables, randomly allocated at conception, to infer causality as additional randomised evidence.

Setting Reduction by Dutasteride of Prostate Cancer Events (REDUCE) randomised controlled trial, UK Biobank, and CARDIoGRAMplusC4D 1000 Genomes based genome wide association study.

Participants 3225 men of European ancestry aged 50-75 in REDUCE; 392 038 white British men and women aged 40-69 from the UK Biobank; and 171 875 participants of about 77% European descent, from CARDIoGRAMplusC4D 1000 Genomes based study for validation.

Main outcome measures Thromboembolism, heart failure, and myocardial infarction based on self reports, hospital episodes, and death.

Results Of the UK Biobank participants, 13 691 had thromboembolism (6208 men, 7483 women), 1688 had heart failure (1186, 502), and 12 882 had myocardial infarction (10 136, 2746).

In men, endogenous testosterone genetically predicted by variants in the JMJD1C gene region was positively associated with thromboembolism (odds ratio per unit increase in log transformed testosterone (nmol/L) 2.09, 95% confidence interval 1.27 to 3.46) and heart failure (7.81, 2.56 to 23.8), but not myocardial infarction (1.17, 0.78 to 1.75). Associations were less obvious in women.

In the validation study, genetically predicted testosterone (based on JMJD1C gene region variants) was positively associated with myocardial infarction (1.37, 1.03 to 1.82). No excess heterogeneity was observed among genetic variants in their associations with the outcomes. However, testosterone genetically predicted by potentially pleiotropic variants in the SHBG gene region had no association with the outcomes.

Conclusions Endogenous testosterone was positively associated with thromboembolism, heart failure, and myocardial infarction in men. Rates of these conditions are higher in men than women. Endogenous testosterone can be controlled with existing treatments and could be a modifiable risk factor for thromboembolism and heart failure.

 

[Michael Scally MD]

Rubinsztajn R, Przybylowski T, Maskey-Warzechowska M, Karwat K, Chazan R. Serum testosterone depression as a factor influencing the general condition in chronic obstructive pulmonary disease patients. Advances in clinical and experimental medicine : official organ Wroclaw Medical University 2019. http://www.advances.umed.wroc.pl/ahead-of-print/94153.pdf

BACKGROUND: Testosterone has been recognized for its anabolic properties. It has been documented that in patients with chronic obstructive pulmonary disease (COPD), chronic hypoxia, disease severity, smoking, and corticosteroid treatment may contribute to low testosterone levels.

OBJECTIVES: The aim of the study was to evaluate the incidence of decreased serum testosterone concentration in male COPD patients and its influence on their condition.

MATERIAL AND METHODS: The study group consisted of 90 male patients, aged 67.2 +/-8.8 years in all stages of airflow limitation severity (mild n = 6, moderate n = 43, severe n = 28 and very severe n = 13) Serum testosterone concentration was evaluated using ELISA method (Testosterone ELISE LDN). Decreased serum testosterone level was defined as a value of less than 3 ng/mL. Testosterone levels were related clinical features of COPD.

RESULTS: Serum testosterone concentration did not differ in patients with different stages of airflow limitation severity (3.8 +/-0.7 ng/mL for mild: 3.6 +/-2.1 ng/mL for moderate; 3.4 +/-1.2 ng/mL for severe and 3.7 +/-1.7 ng/mL for very severe, respectively). Decreased serum testosterone was found in 30 patients (group A). There were no differences in age, the number of exacerbations or CRP concentration between patients with decreased and the normal serum testosterone group (group B). Group A was characterized by a lower FEV1, shorter 6-minute walking distance, longer smoking history and higher BMI, but no differences in body composition and densitometry results were found.

CONCLUSIONS: Serum testosterone depression may occur in as much as 30% of male COPD patients in all COPD stages of severity. The relationship between serum testosterone and negative COPD prognostic factors indicates its influence on the natural history of the disease.

 

[Michael Scally MD]

Determination of Boldenone in Postmortem Specimens Including Blood and Urine Samples

Highlights
· Boldenone is used by athletes, fitness trainer and bodybuilder.
· An LC–MS/MS assay to quantify boldenone in biological specimens was developed.
· This method was applied to postmortem case who injected boldenone in his shoulder.
· Endogenous levels of boldenone in blood and urine samples were determined.

Boldenone (BOLD), one of androgenic anabolic steroids (AAS), although banned in humans, is still available illegally. AAS abuse has previously been associated with various cardiovascular adverse events including acute myocardial infarction, arrhythmia, and sudden death.

In this study, the concentration of BOLD was determined in postmortem specimens from the corpse of a human male who intentionally injected BOLD undecylenate into his shoulder muscle. In addition, the endogenous levels of BOLD in the blood and urine samples of young human males have been reported.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with solid-phase extraction (SPE) was developed and validated for the analysis of BOLD in blood, muscular tissue and urine samples. The validation parameters including linearity, accuracy, precision, matrix effect, and recovery were satisfactory.

The concentrations of BOLD in the blood of 20 young human males who didn't take BOLD were under the limit of quantitation (LOQ, 0.5 ng/mL). Additionally, the mean level of BOLD in the urine samples was 3.19 +/- 1.65 ng/mL (range: 0.37 6.02 ng/mL). The concentrations of BOLD in the victim's blood from the femoral vein and heart were 140.44 and 25.74 ng/mL, respectively. On the other hand, those in the muscular tissue from the injection site and the urine sample were 142.3 ng/g and 3474 ng/mL, respectively.

Park M, Sim J, Jeon Y, Yeon S, Lee J, In S. Determination of boldenone in postmortem specimens including blood and urine samples using LC-MS/MS. Journal of pharmaceutical and biomedical analysis 2019;169:111-5. https://www.sciencedirect.com/science/article/abs/pii/S073170851831882X

 

[Michael Scally MD]

Rubinsztajn R, Przybylowski T, Maskey-Warzechowska M, Karwat K, Chazan R. Serum testosterone depression as a factor influencing the general condition in chronic obstructive pulmonary disease patients. Advances in clinical and experimental medicine : official organ Wroclaw Medical University 2019. Serum testosterone depression as a factor influencing the general condition in chronic... - Abstract - Europe PMC

BACKGROUND: Testosterone has been recognized for its anabolic properties. It has been documented that in patients with chronic obstructive pulmonary disease (COPD), chronic hypoxia, disease severity, smoking, and corticosteroid treatment may contribute to low testosterone levels.

OBJECTIVES: The aim of the study was to evaluate the incidence of decreased serum testosterone concentration in male COPD patients and its influence on their condition.

MATERIAL AND METHODS: The study group consisted of 90 male patients, aged 67.2 +/-8.8 years in all stages of airflow limitation severity (mild n = 6, moderate n = 43, severe n = 28 and very severe n = 13). Serum testosterone concentration was evaluated using ELISA method (Testosterone ELISE LDN). Decreased serum testosterone level was defined as a value of less than 3 ng/mL. Testosterone levels were related clinical features of COPD.

RESULTS: Serum testosterone concentration did not differ in patients with different stages of airflow limitation severity (3.8 +/-0.7 ng/mL for mild: 3.6 +/-2.1 ng/mL for moderate; 3.4 +/-1.2 ng/mL for severe and 3.7 +/-1.7 ng/mL for very severe, respectively).

Decreased serum testosterone was found in 30 patients (group A). There were no differences in age, the number of exacerbations or CRP concentration between patients with decreased and the normal serum testosterone group (group B).

Group A was characterized by a lower FEV1, shorter 6-minute walking distance, longer smoking history and higher BMI, but no differences in body composition and densitometry results were found.

CONCLUSIONS: Serum testosterone depression may occur in as much as 30% of male COPD patients in all COPD stages of severity. The relationship between serum testosterone and negative COPD prognostic factors indicates its influence on the natural history of the disease.

 

[Michael Scally MD]

[OA] [Mice] de Souza ÉLP, Dias RL, Rios RS, et al. Effects of Supraphysiological Doses of Steroids on the Left Ventricle of Sedentary Mice: Morphometric Analysis. J Morphol Sci. Thieme E-Journals - Journal of Morphological Sciences / Full Text

Anabolic androgenic steroids (AAS) are synthetic compounds derived from testosterone, which are widely used in supraphysiological doses by people seeking an aesthetic effect. The objective of the present experiment was to evaluate the possible morphometric changes in the cardiac left ventricle caused by the administration of supraphysiological doses of the anabolic steroids testosterone cypionate and stanozolol in the hearts of young sedentary mice, to serve as a comparative parameter with young mice that were submitted to exercise.

We have used 60 hearts of sedentary young Swiss mice, aged ∼ 90 days old (young-adult), with a body weight between 40 and 50 g. The animals were divided into three groups: the control group, the testosterone cypionate group, and the stanozolol group. For the analysis, 10 distinct sections of the apex, of the middle region, and of the base of the heart were selected, followed by an optical microscope measurement with a 2.5x magnification.

The results obtained show an increase in both myocardial thickness and left ventricular cavity diameter in the two groups of male animals in relation to the control group; however, in females, an increase in the thickness of the left ventricular myocardium was observed only for the stanozolol group.

These results suggest that the cardiac alterations observed in the present study may be directly related to some signs and symptoms already described in the literature, such as hypertension, arrhythmias, infarction, sudden death, and other cardiovascular diseases.

 

[Michael Scally MD]

Testosterone Therapy: An Assessment of the Clinical Consequences of Changes in Hematocrit and Blood Flow Characteristics

Introduction Clinical guidelines indicate that hematocrit should be monitored during testosterone replacement therapy (TTh), with action taken if a level of 0.54 is exceeded.

Aim To consider the extent of changes in hematocrit and putative effects on viscosity, blood flow, and mortality rates after TTh.

Methods We focused on literature describing benefits and possible pitfalls of TTh, including increased hematocrit. We used data from the BLAST RCT to determine change in hematocrit after 30 weeks of TTh and describe a clinical case showing the need for monitoring.

We consider the validity of the current hematocrit cutoff value at which TTh may be modified. Ways in which hematocrit alters blood flow in the micro- and macro-vasculature are also considered.

Main Outcome Measures The following measures were assessed:
(i) change in hematocrit,
(ii) corresponding actions taken in clinical practice, and
(iii) possible blood flow changes following change in hematocrit.

Results Analysis of data from the BLAST RCT showed a significant increase in mean hematocrit of 0.01, the increase greater in men with lower baseline values. Although 0 of 61 men given TTh breached the suggested cutoff of 0.54 after 30 weeks, a clinical case demonstrates the need to monitor hematocrit.

An association between hematocrit and morbidity and mortality appears likely but not proven and may be evident only in patient subgroups. The consequences of an increased hematocrit may be mediated by alterations in blood viscosity, oxygen delivery, and flow. Their relative impact may vary in different vascular beds.

Conclusions TTh can effect an increased hematocrit via poorly understood mechanisms and may have harmful effects on blood flow that differ in patient subgroups. At present, there appears no scientific basis for using a hematocrit of 0.54 to modify TTh; other values may be more appropriate in particular patient groups.

König CS, Balabani S, Hackett GI, Strange RC, Ramachandran S. Testosterone Therapy: An Assessment of the Clinical Consequences of Changes in Hematocrit and Blood Flow Characteristics. Sexual Medicine Reviews 2019. https://www.sciencedirect.com/science/article/pii/S2050052119300095

 

[Michael Scally MD]

[OA] Testosterone Replacement Therapy and The Risk of Adverse Cardiovascular Outcomes and Mortality

Background - The risk of adverse cardiovascular events and mortality associated with testosterone replacement therapy is controversial. The purpose of this report was to evaluate the effect of testosterone replacement therapy (TRT) in men with secondary hypogonadism on the risk of myocardial infarction (MI), stroke (CVA) or all-cause mortality.

Methods - A retrospective cohort study was conducted using the Cleveland Clinic’s electronic health record. Men ≥40 years of age, with at least two testosterone levels < 220 ng/dL, with one level obtained between 7 am and 10 am, were identified.

Men with primary hypogonadism, secondary hypogonadism related to overt hypothalamic pituitary pathology, human immunodeficiency virus infection, metastatic cancer, and select contraindications to TRT, were excluded.

Men exposed to TRT were matched to controls that were not exposed. A survival analysis was performed on the composite outcome of MI, CVA, or all-cause mortality.

Results - One hundred sixty-five patients exposed to TRT (treatment group) were matched with 210 not exposed to TRT (comparison group).

The prevalence of established cardiovascular disease (CVD) was 20.0% in the treatment group vs. 17.1% in the comparison group (P = 0.478).

The median [interquartile range (IQR)] age (years) and BMI (kg/m2) were 55 (49, 62) and 35.6 (32.1, 40.1) in the treatment group, and 55 (49, 61.7) and 36.3 (32.1, 40.8) in the comparison group, respectively. There were 12 (7.3%) events observed in the treatment group, and 16 (7.6%) in the comparison group.

The median time (years) to the composite event was 2.1 (IQR 0.9, 4.6) and 1.8 (IQR 0.6, 3.4) for treatment and comparison groups, respectively. No difference in the risk of the combined cardiovascular endpoint was observed between the treatment group vs the comparison group, hazard ratio (HR) 0.81 (95% Confidence Interval [CI]: 0.38–1.71; P = 0.57).

Conclusion - In hypogonadal men with a modest prevalence of established CVD, TRT was not observed to confer a protective or adverse effect on the risk of MI, CVA or all-cause mortality.

Pantalone KM, George J, Ji X, et al. Testosterone replacement therapy and the risk of adverse cardiovascular outcomes and mortality. Basic and Clinical Andrology 2019;29:5. Testosterone replacement therapy and the risk of adverse cardiovascular outcomes and mortality

 

[Michael Scally MD]

Adelborg K, Rasmussen TB, Norrelund H, Layton JB, Sorensen HT, Christiansen CF. Cardiovascular Outcomes and All-cause Mortality Following Measurement of Endogenous Testosterone Levels. The American journal of cardiology 2019. https://www.ajconline.org/article/S0002-9149(19)30287-5/abstract

Although reduced testosterone levels are common in aging populations, the clinical consequences remain to be further explored. We examined whether low total testosterone levels are associated with stroke (ischemic and hemorrhagic), myocardial infarction (MI), venous thromboembolism (VTE), and all-cause mortality in adult men.

We conducted a cohort study in the Central Denmark Region (2000 to 2015). We included all men with a first-ever laboratory testosterone result and computed the 5-year risks of cardiovascular outcomes and all-cause mortality. Propensity score-weighted hazard ratios were computed, comparing persons with normal versus low testosterone levels. Individuals were censored at testosterone treatment during follow-up (3%). We identified 4,771 men with low testosterone levels and 13,467 with normal levels.

Persons with low testosterone levels were older (median ages, 55 years vs 50 years) and had more co-morbidities than men with normal testosterone levels. Persons with low testosterone had higher 5-year risks of stroke (2.4% vs 1.5%), MI (1.5% vs 1.2%), VTE (1.4% vs 0.9%), and all-cause mortality (17.8% vs 6.8%) than persons with normal testosterone levels.

After propensity score-weighting, the associations with cardiovascular outcomes reached unity. The 5-year hazard ratios were 1.14 (95% confidence intervals [CIs] 0.87 to 1.49) for stroke, 0.95 (95% CI 0.70 to 1.30) for MI, 1.10 (95% CI 0.78 to 1.55) for VTE, whereas it was 1.48 (95% CI 1.32 to 1.64) for all-cause mortality.

In conclusion, low testosterone level was a strong predictor for cardiovascular outcomes and all-cause mortality in unadjusted models, however only the association between low testosterone and all-cause mortality persisted after adjustment for age and co-morbidity.

 

[Michael Scally MD]

[OA] Sudden Death in Athletes

Sudden death in athletes has been a tragic occurrence in the fields of sports medicine, cardiology, primary care, and pediatrics. By far the most common cause of unexpected death for a younger athlete on the competitive field is cardiac illness; usually that of congenital etiology. However, the use of ANABOLIC STEROIDS, peptide hormones, and stimulants have led to the emergence of acquired heart disease in younger and middle-aged athletes. In contrast, sudden death in an older athlete is typically due to atherosclerotic coronary artery disease.[1]

There are a variety of congenital heart illnesses that occur in the general population. Most of them categorize into structural and non-structural varieties. Congenital structural heart disease will generally affect blood flow within the heart and flow from the heart. Examples include hypertrophic obstructive cardiomyopathy (HOCM), arrhythmogenic right ventricular dysplasia (ARVD), and coronary artery anomalies.[2] Non-structural heart disease involves defects in the electrical system of the heart which may induce unstable and dangerous arrhythmias.

Examples include long QT syndrome, Brugada syndrome, Wolff-Parkinson-White (WPW) syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVD). Other congenital structural and non-structural heart diseases exist and have been described previously in the setting physical activity and athletics.[3] Also, drug-induced cardiac effects are of important notice. ANABOLIC STEROIDS and peptide hormones induce structural changes in the heart. Stimulants can cause dangerous arrhythmias.[4]

These conditions can clinically manifest as syncope/pre-syncope, and in some instances can present as sudden, unexpected death. The associated mortality underscores the importance of early screening and identification of existing heart disease in athletes. Many athletes with pre-existing heart disease are often asymptomatic with a cardiac arrest being the initial manifestation of underlying pathology.

The challenging aspect of identifying affected athletes is adequately screening the general population without excessive and unnecessary invasive testing. A thorough sports physical examination including an assessment of personal history, family history, physical exam, and an electrocardiogram can be a useful screening tool in asymptomatic and low-risk athletes. Higher risk athletes, such as those who have abnormal findings or have symptoms, may require more extensive testing.

Upon arriving at a diagnosis, an athlete will undergo risk stratification. Then, a long-term treatment regime is initiated to minimize the risk of sudden cardiac death. Medical management is a common option, while surgical intervention is reserved for specific cases. Inserting an implantable cardioverter-defibrillator (ICD) is appropriate for anyone considered to be at risk for cardiac arrest secondary to a fatal arrhythmia. The decision to continue or abandon the sport of choice results from shared decision making between the physician and patient.

The purpose of this article is to review the causes of sudden death in athletes with a significant focus on the most common etiologies in younger athletes and their presentation and evaluation.

Farzam K, Ahmad T. Sudden Death in Athletes. [Updated 2019 Apr 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: Sudden Death in Athletes - StatPearls - NCBI Bookshelf

 

[Michael Scally MD]

[OA] Testosterone Replacement Therapy and The Risk of Adverse Cardiovascular Outcomes and Mortality

Background: The risk of adverse cardiovascular events and mortality associated with testosterone replacement therapy is controversial. The purpose of this report was to evaluate the effect of testosterone replacement therapy (TRT) in men with secondary hypogonadism on the risk of myocardial infarction (MI), stroke (CVA) or all-cause mortality.

Methods: A retrospective cohort study was conducted using the Cleveland Clinic's electronic health record. Men >/=40 years of age, with at least two testosterone levels < 220 ng/dL, with one level obtained between 7 am and 10 am, were identified.

Men with primary hypogonadism, secondary hypogonadism related to overt hypothalamic pituitary pathology, human immunodeficiency virus infection, metastatic cancer, and select contraindications to TRT, were excluded.

Men exposed to TRT were matched to controls that were not exposed. A survival analysis was performed on the composite outcome of MI, CVA, or all-cause mortality.

Results: One hundred sixty-five patients exposed to TRT (treatment group) were matched with 210 not exposed to TRT (comparison group). The prevalence of established cardiovascular disease (CVD) was 20.0% in the treatment group vs. 17.1% in the comparison group (P = 0.478). The median [interquartile range (IQR)] age (years) and BMI (kg/m(2)) were 55 (49, 62) and 35.6 (32.1, 40.1) in the treatment group, and 55 (49, 61.7) and 36.3 (32.1, 40.8) in the comparison group, respectively.

There were 12 (7.3%) events observed in the treatment group, and 16 (7.6%) in the comparison group. The median time (years) to the composite event was 2.1 (IQR 0.9, 4.6) and 1.8 (IQR 0.6, 3.4) for treatment and comparison groups, respectively.

No difference in the risk of the combined cardiovascular endpoint was observed between the treatment group vs the comparison group, hazard ratio (HR) 0.81 (95% Confidence Interval [CI]: 0.38-1.71; P = 0.57).

Conclusion: In hypogonadal men with a modest prevalence of established CVD, TRT was not observed to confer a protective or adverse effect on the risk of MI, CVA or all-cause mortality.

Pantalone KM, George J, Ji X, et al. Testosterone replacement therapy and the risk of adverse cardiovascular outcomes and mortality. Basic Clin Androl 2019;29:5. Testosterone replacement therapy and the risk of adverse cardiovascular outcomes and mortality