HDL cholesterol subfractions and the effect of testosterone replacement in hypogonadism

Written by Ben Bunting: BA, PGCert. (Sport & Exercise Nutrition) // British Army Physical Training Instructor // S&C Coach.

Compared to baseline, men treated with testosterone replacement had significantly lower levels of total cholesterol, HDL cholesterol subfractions, and HDL2 cholesterol subfractions than men who were not treated. The differences were statistically significant. 


Hypogonadism is an important problem that affects the male population. It is particularly common among older men, obese men, and men with type 2 diabetes.

It affects the levels of two vital hormones in the body, testosterone and luteinizing hormone. Both of these hormones are important for a man's sexual response and are produced by the testes.

The production of testosterone in the testes is controlled by the pituitary gland in the brain. Low levels of testosterone in the body result in decreased libido, reduced erections, and impaired sperm production.

While the prevalence of hypogonadism in men has increased considerably over the last few decades, there is still a lot of uncertainty surrounding the diagnosis and treatment of this disease.

Although significant advances have been made, questions remain about the risks and benefits of testosterone therapy for aging men.

The purpose of this article is to address these questions and provide a comprehensive review of studies on hypogonadism in older men.

Several studies have shown that hypogonadism can increase the risk of cardiovascular disease.

However, these studies haven't been large enough to determine a causal relationship between low testosterone and increased cardiovascular risks.

Nevertheless, concerns over the link between TRT and increased risk of CVD have led to changes in labeling for testosterone products.

A morning serum total testosterone level test is a reliable and inexpensive screening test for hypogonadism.

The test measures the total amount of free testosterone plus protein-bound testosterone. The value above 300 ng/dL is an indication of hypogonadism.

For a more definitive diagnosis, the patient should undergo a second assay.

Taking testosterone replacement therapy may increase the patient's energy level and improve physical appearance.

However, it has been associated with an increased risk of heart attack, stroke, and prostate cancer. Despite these risks, testosterone replacement therapy is not recommended for aging men. Additionally, it can result in dependence on the hormone.

If you suspect that you may have hypogonadism, it's important to see a doctor before starting testosterone replacement therapy.

The effects of testosterone replacement therapy can include improved sexual function, improved energy levels, and better muscle and bone health. However, the benefits of testosterone replacement therapy may be limited in older men.

For this reason, the Endocrine Society recommends that you monitor your testosterone replacement therapy for possible side effects.

Hormonal regulation of lipids

Testosterone is a male hormone that can improve cardiovascular health. It is known to lower total cholesterol and affect the composition of HDL cholesterol subfractions.

Testosterone also affects lipids and insulin levels. These changes in cholesterol are important because they affect the risk of cardiovascular events.

Several authors have conducted studies to determine the effect of testosterone replacement therapy on HDL cholesterol subfractions.

They have shown that testosterone reduces high-density lipoprotein (HDL) cholesterol by inhibiting 7a-hydroxylase, an enzyme that contributes to bile formation.

In addition, testosterone raises hepatic lipase activity, which is responsible for hydrolyzing the triacylglycerol component of circulating chylomicrons.

Another study reported that progesterone does not interfere with the beneficial effects of estrogen on lipid metabolism.

In a multicenter, randomized trial, it did not alter the cholesterol-inducing effects of oral estrogen.

However, the authors note that progesterone has strong progestogenic and antiestrogenic properties.

Although progesterone is supposed to neutralize the protective effects of estrogens on blood lipids, their findings are not yet conclusive.

This study also noted that transdermal testosterone treatment reduces HDL2 cholesterol in men.

However, testosterone replacement did not increase cardiovascular risk in men and did not affect the vascular reactivity.

However, it did lower total cholesterol. The study did not report any cardiovascular events.

Moreover, it also demonstrated that testosterone inhibits platelet aggregation. This effect was also confirmed in a study involving people with Klinefelter syndrome.

It induced irreversible aggregation in 70% of patients. Moreover, it also increased concentrations of 8-iso-PGF2a and 11-dehydro-thromboxane B2.

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Effect of testosterone on cholesterol

Studies on the effect of testosterone replacement on HDL cholesterol subfraction levels have produced mixed results.

While overall cholesterol levels did not change, there was an increase in HDL subfractions. In addition, patients receiving testosterone replacement therapy showed improvements in their BMI and waist circumference.

Although long-term data are not available, clinical studies show that low testosterone levels are associated with increased risk of CVD.

As more is known about HDL biology, the relationship between HDL-C and CVD risk is likely to be elucidated. Moreover, research efforts are expanding to include alternative HDL composition and function metrics.

Researchers have found that testosterone treatment reduces LDL-cholesterol levels and reduces the atherogenic fraction.

In addition, it decreased the HDL2-C cholesterol subfraction. However, there are still some questions about the effect of testosterone on CVD risk. There are a number of possible mechanisms behind this association.

Studies have also shown that transdermal testosterone decreases HDL cholesterol and does not affect the endothelium-dependent vascular reactivity in men.

However, there are no studies to determine a direct relationship between testosterone replacement and cardiovascular events. Therefore, further studies will be necessary before a conclusion can be drawn.

One objective of the Testosterone Trials' cardiovascular sub-trial was to evaluate plaque volume in the coronary arteries.

This study involved men aged 65 years or older who had self-reported symptoms of male hypogonadism.

The authors measured plaque volume in two different types of plaque - low-attenuation plaque and fibrous-fatty plaque. Then they calculated the total plaque volume, including the noncalcified and dense calcium plaque.

While the effects of testosterone replacement on HDL cholesterol subfraction levels are not clear, a high dose of the hormone has positive metabolic and behavioral effects in healthy men.

Furthermore, high-dose testosterone can improve glucose utilisation and reduce cardiovascular risk factors. The use of a permeation-enhanced testosterone transdermal system can also improve the safety of the treatment in hypogonadal men.

A cross-sectional study involving more than 5,000 men found that testosterone supplementation increased erythropoiesis and physical activity. However, short-term physical activity may precipitate a heart attack, stroke, or acute left ventricular dysfunction.

Effect of testosterone on vascular tone

Testosterone is a key male hormone that decreases as we age and has important implications for cardiovascular risk.

Low levels of testosterone have been linked with increased arterial stiffness and impairment of endothelial function in men.

While the role of androgens in vascular aging remains largely unclear, it is known that testosterone may regulate inflammation and oxidative stress.

In addition, testosterone levels may also influence vascular adaptation to exercise.

Testosterone treatment has a significant impact on vascular tone and blood flow. While testosterone does not directly affect the heart, it has a significant impact on artery walls and the development of atheromas.

While testosterone replacement therapy may not be a cure for heart failure, it can reduce the risk of heart attack and stroke.

The mechanism by which testosterone affects cardiovascular health is still not fully understood, but previous research has shown that low levels of testosterone are a risk factor for cardiovascular disease.

Furthermore, hypogonadism is linked to endothelial dysfunction, and it has been associated with cardiovascular risk in men with renal disease.

EndoPAT machines are used to measure changes in peripheral arterial tone and nitric oxide-mediated endothelial relaxation.

The effects of testosterone on cholesterol are unknown but there is evidence that testosterone replacement therapy reduces LDL2 cholesterol and increases HDL2 cholesterol.

In addition, testosterone has a prothrombotic effect and has been shown to increase thromboxane A2 receptor density in platelets. There are, however, no known effects on coagulation.

It has been shown that testosterone levels are lower in diabetics than in non-diabetics. This relationship becomes less pronounced after controlling for age and obesity.

In a study of male rats with right-heart failure, testosterone treatment improved cardiac function.

This is a promising sign that testosterone replacement can improve cardiac function and cardiac healing. However, there are potential side effects of testosterone treatment, including water retention.

Although this is common and can occur at physiological levels, it should not be mistaken for the presence of HF.

In males, decreased testosterone levels have been linked to a higher incidence of atrial fibrillation. Although the mechanisms involved are still unknown, the decline in testosterone is thought to play a role.


The effect of testosterone replacement therapy on HDL cholesterol levels has been studied by several researchers.

Testosterone is thought to increase the efflux capacity of HDL and decrease the level of low-density lipoprotein (LDL) cholesterol.

Additionally, it increases the activity of hepatic lipase, which hydrolyzes the triacylglycerol component of circulating chylomicrons.

Three meta-analyses comparing testosterone replacement therapy with cholesterol levels have been published.

These studies show that testosterone replacement therapy can reduce total cholesterol levels and HDL cholesterol subfractions. The effect was greater in patients who had low levels of testosterone.

However, there were no differences between testosterone levels and HDL cholesterol levels in patients with baseline testosterone levels of more than 10 nmol/L.

A sub-trial examining the cardiovascular effects of testosterone replacement was conducted with elderly men.

These men were tested for testosterone levels on two occasions and self-reported symptoms of male hypogonadism.

Testosterone was administered to men with a baseline testosterone level of 250-275 ng/dL, who had self-described symptoms of male hypogonadism, and two follow-up visits.

These men were also evaluated for plaque volume in coronary arteries. Fibrous-fatty and low-attenuation plaques were assessed, as were dense calcium plaques.

The effect of testosterone replacement therapy on HDL cholesterol is not uniform and appears to depend on patient age, dosage, and route of androgen administration.

However, this finding does not mean that men taking testosterone replacement therapy will not experience cardiovascular benefits.

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