• Credits
  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

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• Q. Summarize how testosterone is converted to different metabolities and how it acts on different tissues ?
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• Q. What is the current status of CV risk of Testosterone ?
  • It is uncertain
  • However FDA and Endocrine Society requires the labelling of Testosterone to real possiblity of increased risk of MI and Stroke with Testosterone use
• Q. Does Testosterone replacement in Elderly males increase CV risk ?
  • No
• Q. So what is the final word on T and CV risk ?
  • Endocrine society and FDA mandates label saying Testosterone is associated with increase MI and stroke
  • However, in hypogondal male with low Testosterone  use of T is NOT associated with increase CV risk
  • Injectable > gel associated with more risk
• Q. What are the gold standards for measuring testosterone ?
  • Total testosterone- LC-MS/MS
  • Free Testosterone - Equilibrium dialysis
• Q. What happens to testosterone, LH and SHBG with age ?
  • 1. Free testosterone rapidly declining with age in men
  • 2. LH increasing with age in men
  • 3. SHBG increasing with age in men
  • 4. Total testosterone slowly declining with age in men
  • 
• Q. What is leucocyte telomere length and what is it's importance ?
  • Leucocyte telomere length is a measure of biological aging.
  • It is a marker used to assess the rate of cellular aging.
  • Longer leucocyte telomere length is associated with slower biological aging.
  • Basically telomere length shortens with aging
  • If telomere is longer- this means the aging is slower
  • There is interest in studying the association between leucocyte telomere length and testosterone levels in middle-aged and older men.
  • 
• Q. What is functional hypogonadism ?
  • Functional hypogonadism refers to a condition in which there is low circulating testosterone (T) concentration in men due to reduction or suppression of the hypothalamic-pituitary-testicular (HPT) axis function, rather than a primary disorder of the HPT axis. It is commonly found in conditions such as aging, obesity, and systemic illnesses. In functional hypogonadism, the HPT axis is intact but the production of testosterone is reduced
  • Treatment of functional hypogonadism is an area of debate
• Q. What happens to SHBG levels in obesity ?
  • In obesity, there is a decrease in SHBG (Sex Hormone Binding Globulin) levels.
  • Adipose tissue, particularly visceral adipose tissue, produces various factors that can influence SHBG production.
  • In obesity, there is an increase in insulin resistance and hyperinsulinemia, which can directly suppress SHBG production in the liver.
  • Adipose tissue also produces pro-inflammatory cytokines, such as TNF-alpha and IL-6, which can further decrease SHBG levels.
  • Additionally, obesity is associated with increased levels of circulating free fatty acids, which can inhibit SHBG synthesis.
  • On the other hand estrogen increases SHBG levels - but the above factors overall reduce SHBG
  • All this leads to reduction in total testosterone levels in obese men
• Q. What is the difference between the prospective studies showing correlation between testosterone levels and Cardiovascular disease done with immunoassay vis a vis studies done using mass spectrometry ?
  • The difference between prospective studies using immunoassay and those using mass spectrometry to assess the correlation between testosterone levels and cardiovascular disease (CVD) is as follows:
  • Studies using immunoassay:
    • Immunoassays have been the standard method for measuring circulating sex hormones, including testosterone.
    • Immunoassays can exhibit non-specificity and method-dependent bias, particularly at lower hormone concentrations.
    • Immunoassays provide informative results, but they may not be as accurate as mass spectrometry.
    • Studies using immunoassays have shown mixed results regarding the association of total testosterone (T) concentrations with the incidence of CVD events.
    • Some studies have reported no association between total T concentrations and myocardial infarction (MI) or ischemic heart disease (IHD) events.
    • Other studies have shown associations between low total T concentrations and increased incidence of stroke or IHD.
    • There have been conflicting associations between total estradiol (E2) concentrations and stroke or MI.
  • Studies using mass spectrometry:
    • Mass spectrometry is regarded as the gold standard for measuring hormone concentrations.
    • Mass spectrometry provides more accurate and reliable results compared to immunoassays.
    • Studies using mass spectrometry have shown associations between higher total testosterone concentrations and lower risk of CVD events in older men.
    • There may be a predilection for lower testosterone, measured by mass spectrometry, to be associated with stroke risk.
    • Total estradiol (E2) concentrations have not been consistently associated with CVD outcomes in studies using mass spectrometry.
    • Some studies using mass spectrometry have reported a U-shaped association between dihydrotestosterone (DHT) concentrations and CVD events or stroke risk.
  • In summary, studies using mass spectrometry generally provide more accurate and reliable results compared to immunoassays. They have shown associations between higher total testosterone concentrations and lower risk of CVD events, while also highlighting the potential role of DHT and the lack of consistent associations with total estradiol concentrations.
• Q. So overall what is the conclusion- is low testosterone associated with higher risk of cardiovascular disease in older men ?
  • Yes. Epidemiological studies suggest a possible association of lower endogenous testosterone concentrations with increased risk of CVD events in middle-aged and older men.
• Q. What are the potential mechanism that explain this phenomenon ?
  • The potential mechanisms that may explain the association between androgens (including testosterone) and cardiovascular disease (CVD) in men are not fully understood. However, here are some potential mechanisms that have been proposed:
    • Cholesterol Accumulation: Androgens may exert protective effects against atherosclerosis by reducing cholesterol accumulation and the development of atheromatous plaque. Animal studies have shown that testosterone treatment can reduce cholesterol accumulation and necrotic cores within plaque.
    • Neointimal Formation and Vascular Smooth Muscle Proliferation: Androgens, including testosterone, may inhibit neointimal plaque formation and vascular smooth muscle proliferation. Studies have shown that testosterone treatment can inhibit plaque development and reduce intimal area in animal models of neointimal plaque formation.
    • Endothelial Function and Inflammation: Androgens may improve endothelial function and reduce inflammation, which are important factors in the development of CVD. Clinical studies have shown mixed results, with some suggesting that testosterone treatment can reduce markers of endothelial cell activation and inflammation.
    • Arterial Stiffness: Androgens may improve arterial stiffness, which is a risk factor for CVD. Some studies have suggested that testosterone treatment can improve arterial stiffness, but more research is needed.
    • Other Mechanisms: Androgens may also exert protective effects against CVD through other mechanisms, such as modulation of lipid metabolism, regulation of blood pressure, and effects on insulin sensitivity.
  • It is important to note that the actions of sex hormones are complex and can occur through both androgen receptor (AR)-dependent and AR-independent mechanisms. Further research is needed to fully understand the mechanisms by which androgens may influence CVD risk in men.
• Q. Is there a link between inflammation and atherosclerosis ?
  • Yes, a mechanistic link likely exists between inflammation and atherosclerosis. This is supported by several studies and reviews.
  • Statin therapy, which lowers both LDL cholesterol and C-reactive protein (CRP) concentrations, has been shown to reduce the risk of cardiovascular events in a primary prevention setting in adults with LDL <3.4 mmol/L and high-sensitivity CRP ≥2.0 mg/L.
• Q. What is canakinumab ?
  • Canakinumab is a monoclonal antibody that targets interleukin-1β.
  • It has been used as an anti-inflammatory intervention in clinical trials.
  • In a secondary prevention setting in adults with high-sensitivity CRP ≥2.0 mg/L, canakinumab demonstrated a modest reduction in major cardiovascular events
• Q. What role does testosterone play in this process ?
  • Several evidence has shown that testosterone reduced the inflammatory process
  • Several studies suggest that testosterone can reduce inflammation.
  • Testosterone has been shown to reduce the production of inflammatory cytokines from monocytes, macrophages, and endothelial cells in vitro.
• Q. Which other anti-inflammatory drug has shown to reduce atherosclerosis risk ?
  • Colchicine
• Q, What is the impact of testosterone on angina ?
  • Testosterone therapy has been reported to decrease the frequency and severity of angina attacks. This was observed in case series from the 1940s where intramuscular testosterone propionate was used as a treatment.
  • A study conducted in 2000 found that low-dose transdermal testosterone therapy improved angina threshold in men with chronic stable angina.
  • Another study in 2002 found that the effect of intravenous testosterone on myocardial ischemia in men with coronary artery disease.
  • However, these are individual studies and more comprehensive research is needed to fully understand the impact of testosterone on angina.
• Q. What is the impact of exogenous testosterone on vascular function ?
  • Testosterone supplementation has been shown to improve both endothelial function and arterial stiffness in men with low baseline testosterone concentrations, according to uncontrolled open-label studies.
• Q. What is it's impact on cholesterol levels ?
  • Testosterone's impact on cholesterol levels is complex and can depend on various factors such as the dose, route of administration, type of androgen, and the subject population.
  • Cross-sectional studies of middle-aged men have found a positive relationship between serum testosterone levels and plasma HDL-cholesterol concentrations.
  • Lower testosterone levels in men are associated with higher levels of dense LDL particles and triglycerides.
  • Supraphysiological doses of testosterone and non-aromatizable androgens frequently used by bodybuilders can decrease plasma HDL-cholesterol levels.
  • 
• Q. What is the impact of testosterone on carotid intima-media thickness ?
  • The carotid artery intimal media thickness, a marker of generalized atherosclerosis, is negatively associated with circulating testosterone levels.
  • Lower plasma testosterone levels have been linked to elevated carotid intima-media thickness, particularly in elderly men.
• Q. What about coronary atherosclerosis ?
  • Testosterone has been shown to have a beneficial effect on exercise-induced myocardial ischemia in men with coronary artery disease. This effect may be related to a direct vasodilator effect of testosterone on the coronary arteries, resulting in increased coronary blood flow.
  • Testosterone replacement has been shown to increase the time to 1-mm ST-segment depression, a measure of myocardial ischemia.
  • However, in another study, there were no differences between the placebo or testosterone groups in peak heart rate, systolic blood pressure, maximal rate pressure product, perfusion imaging scores, or the onset of ST-segment depression.
  • In the Testosterone’s Effects on Atherosclerosis Progression in Aging Men (TEAAM) Trial, neither the progression of common carotid artery intima-media thickness (CCA-IMT) nor coronary artery calcium scores differed between the men randomized to the testosterone and placebo groups.
  • Therefore, the impact of testosterone on coronary atherosclerosis appears to be complex and may depend on individual health factors and the presence of conditions such as coronary artery disease.
• Q. Are there any trials that have shown adverse CV outcome due to exogenous testosterone use ?
  • One study reported an increase in coronary atheroma assessed using coronary computed tomography angiography in older men receiving testosterone therapy over 12 months.
  • A randomized trial of testosterone therapy in older men with mobility limitations reported an excess of adverse events in the treatment arm.
  • However, larger recent trials in middle-aged to older men did not find any excess of cardiovascular adverse events with testosterone treatment.
  • Meta-analyses of testosterone trials generally have not shown an increase in cardiovascular adverse events.
  • Retrospective case-control studies of health insurance databases have produced inconsistent results, associating testosterone prescriptions with either increased or decreased risk of cardiovascular events, and with lower mortality.
  • The effects of exogenous androgens in the form of testosterone therapy seeking to maintain physiological circulating androgen concentrations on the cardiovascular system remain uncertain
• Q. What are the effects of androgen abuse on CV outcome ?
  • Androgen abuse is linked to various cardiovascular effects, including myocardial dysfunction and accelerated coronary atherosclerosis. However, the long-term consequences are likely underestimated due to underreporting and non-systematic follow-up. The effects of exogenous androgens on the cardiovascular system remain uncertain, necessitating further research.
• Q. Which CV event has the strongest link with low endogenous testosterone levels in middle and old age men ?
  • Stroke
• Q. What is the impact of testosterone on reducing risk of type 2 diabetes in men ?
  • The T4DM trial, one of the largest testosterone trials conducted to-date, evaluated the effects of 2 years of testosterone treatment in men aged 50 to 74 years with impaired glucose tolerance or newly diagnosed type 2 diabetes and a serum testosterone concentration below 404 ng/dL.
  • The trial found that testosterone treatment in conjunction with a lifestyle program was associated with a lower proportion of participants with type 2 diabetes.
  • The T4DM trial reported that testosterone treatment reduced the risk of type 2 diabetes at two years by 40% beyond the effect of the lifestyle intervention.
  • However, it is important to note that the men enrolled in the T4DM trial were not hypogonadal.
• Q. Is there a difference in cardiovascular risk in patient at risk of de-novo atherosclerosis versus those already having CV disease ?
  • Yes
  • A similar effect has also been seen with relation with HRT in post-menopausal women
  • Testosterone does reduce denovo inflammation and atherosclerosis- however the impact on someone with pre-existing atherosclerosis is uncertain
• Q. What is the TRAVERSE trial ?
  • The TRAVERSE trial is a cardiovascular safety study designed to evaluate the impact of testosterone treatment on cardiovascular health.
  • The primary endpoint of the study is myocardial infarction, stroke, or death due to cardiovascular causes.
  • The trial aims to enroll 6,000 men who will be randomized to receive either transdermal testosterone gel or a placebo.
  • The study is also set to examine outcomes related to prostate cancer, sexual function, bone fractures, depression, anemia, and diabetes.
  • The TRAVERSE trial is expected to address the issue of cardiovascular safety of testosterone treatment, primarily in a secondary prevention setting.
  • The trial commenced recruitment in 2018 of men aged 45-80 years with testosterone levels less than 10.4 nmol/L (or less than 300 ng/dl) who have evidence of cardiovascular disease or are at increased risk for cardiovascular disease.
• Q. Are the results of this trial published ?
  • Yes the results of this trial were recently published in NEJM
  • This was a non-inferiority trial
• Q. What kind of patients were included in this trial ?
  • Middle-aged and older men with hypogonadism with
    • Established cardiovascular disease
    • elevated cardiovascular risk
  • To be specific - patients included were
    • 45-80 years of age
    • Preexisting cardiovascular disease or
    • an increased cardiovascular risk
    • One symptom of hypogonadism
    • Two serum testosterone measurement <300 ng/dl
• Q. What was the medication they received
  • Daily transdermal 1.62% testosterone gel - given to maintain testosterone levels between 350-750 ng/dl versus placebo
• Q. What was the mean duration of treatment and follow-up ?
  • Mean duration of treatment was 22 months and mean duration of follow-up was about 30 months
• Q. What was the conclusion of the trial ?
  • Transdermal testosterone gel is non-inferior to placebo in terms of CV risk
    • "In men with hypogonadism and preexisting or a high risk of cardiovascular disease, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events"
• Q. Any risk of any adverse events ?
  • A higher incidence of atrial fibrillation, of acute kidney injury, and of pulmonary embolism was observed in the testosterone group. There was an increased risk of non-fatal arrythmias
  • Though there was an increase of PSA levels, no increase risk of prostate events
  • 
• Q. What about the risk of diabetes mellitus ?
  • Similar in both the groups
• Q. Based on the current evidence what are the clinical practice recommendations ?
  • 1. Based on the current TRAVERSE trial- Transdermal testosterone is CV safe in middle age men with proven hypogonadism and high risk or already having CV disease
  • 2. In patients with hypogonadism clearly the benefit outweighs the risk
  • 3. We however do not know the status in normal men - little evidence for that
  • 4. We are also not very clear whether the route of administration has an impact
  • 5. Testosterone may also prevent diabetes mellitus- even in men without obvious hypogonadism
  • 6. Testosterone reduces inflammation and has some benefit on vascular and endothelial functions

References:

1. Lincoff AM, Bhasin S, Flevaris P, Mitchell LM, Basaria S, Boden WE, Cunningham GR, Granger CB, Khera M, Thompson Jr IM, Wang Q. Cardiovascular Safety of Testosterone-Replacement Therapy. New England Journal of Medicine. 2023 Jun 16.
2. Yeap BB, Dwivedi G. Androgens and cardiovascular disease in men. Endotext [Internet]. 2022 Dec 14.