Testosterone differentially regulates targets of lipid and glucose metabolism in liver, muscle and adipose tissues of the testicular feminized mouse: Beyond the Abstract


Testosterone is no longer a hormone limited to reproductive/sexual medicine but is rather a multi-system hormone with much wider range of actions. Research is uncovering these actions and suggests that testosterone may have the potential to protect against heart and diabetes deaths.



Worldwide the prevalence of cardiovascular disease is much greater in men than women. Even after correcting for differences in risk factors between the two sexes, men are still twice as likely to develop heart disease as women. This evidence taken together with numerous case reports of sudden heart attacks amongst male athletes abusing anabolic steroids, led to the belief that testosterone exerts a detrimental influence upon the cardiovascular system.

However, evidence has emerged over recent years to suggest that a number of the cellular mechanisms intimate to the development of cardiovascular disease and risk factors for it are beneficially modulated by testosterone. Several studies indicate that it is low levels of testosterone, rather than testosterone, that is associated with disease. As men age their circulating levels of testosterone decline and incidence of disease increases.

The potentially protective actions of testosterone are now being recognised through the study of men whose circulating testosterone concentrations are reduced. Many of these studies draw clear associations between low testosterone and metabolic disorders, type 2 diabetes and cardiovascular risk; to the extent that low testosterone is now considered an independent risk factor for heart disease and related comorbidities as recognised by the by a science advisory from the American Heart Association1.

The detailed mechanisms of how testosterone may offer this protection is not fully known and research continues to investigate its specific actions to try and harness the therapeutic potential of this hormone.

In data recently published in Endocrine2 and also presented at the Endocrine Society annual meeting in San Diego 2015 which won the Presidential prize and was featured on the BBC (http://www.bbc.co.uk/news/health-31869054), we investigated the underlying mechanisms by which testosterone might have these beneficial effects in a mouse model of testosterone deficiency. 

Male mice with severely reduced testosterone displayed a negative expression profile of key enzymes and molecules involved in lipid and glucose metabolism. These effects were noted to be different in different tissues with the greatest changes seen in the liver and fat tissue located under the skin, also known as subcutaneous fat. 

The way we process energy in the form of lipid and glucose, particularly in times of excess, and where it is stored can greatly influence the development of metabolic diseases such as type 2 diabetes, fatty liver disease and other risk factors for heart disease. If low testosterone is preventing certain aspects of correct metabolic function in specific tissues of the body, disease may be more likely. This is exactly what we saw in these mice.

We believe that subcutaneous fat acts as an energy ‘sink’ or a ‘buffer’ whereby excess lipid can be stored relatively safely compared to when it is stored elsewhere in the body. When this buffering no longer takes place excess fat is pushed into other tissues where pathological consequences are more apparent. In our mice with low testosterone we saw greatly increased lipid accumulation in the liver and arteries indicative of non-alcoholic fatty liver disease and atherosclerosis (the pre-cursor to heart disease). This may explain why men with low testosterone are at increased risk of type 2 diabetes, often have a negative body composition with more fat and are at a greater risk of dying from heart disease.

Testosterone replacement therapy (TRT)

Evidence from epidemiological studies of patients with androgen deficiency and experimental findings from exploratory mechanistic investigations such as this, therefore lead to the question of whether testosterone can be used as an important therapy in the fight against type 2 diabetes and cardiovascular disease in men with existing low levels. 

This issue is often met with controversy. With TV adverts in the US heralding testosterone as the ‘elixir of life’ proclaiming to treat everything from lack of energy to weight gain, the commercial push for older men to have replacement therapy generates some scepticism among clinicians that the reported benefits are more financially rather than clinically driven.

The majority of TRT trials do indeed demonstrate beneficial effects on men’s health, however, a few recent high-profile publications fly in the face of this research and suggest testosterone has negative cardiovascular actions with one clinical trial stopped early due to higher rate of cardiovascular-related events in the treatment group. These studies have been criticised since there is no indication that the men had been monitored to check their testosterone levels weren't overshooting the physiological range, or even that they had been diagnosed with testosterone deficiency properly in the first place.

Before being prescribed testosterone, patients should have reliable morning baseline measurements taken. But research published in 2013 found that a quarter of men prescribed testosterone in a very large US sample hadn't been tested at all3. This poor diagnosis and over-treatment may be the cause of potentially detrimental cardiovascular effects of testosterone.

It is important, however, that the therapeutic potential of testosterone is not overlooked due to these current controversies and “hormonophobia”. If studies do show that replacing testosterone to normal is safe, and that is key, then it could increase the lifespan of many men. In fact many studies including our own are already demonstrating that careful testosterone replacement, where levels are titrated to within the mid- to upper-normal range, results in a positive effect in men with type 2 diabetes and at least a neutral effect or possibly a cardio-protective action4. However, large long-term safety outcome studies are required to further provide the necessary evidence.

Taking both sides of the argument into consideration, evidence may therefore suggest that low testosterone levels and testosterone levels above the normal range have an adverse effect on heart disease, but replacing to within the physiological window may be beneficial. The potential therapeutic value of testosterone replacement therapy, therefore, comes down to three important factors; accurate diagnosis and identification of men who will benefit from treatment, titration of the dosage to ensure physiological levels are achieved, and careful monitoring of patients throughout treatment.

Furthermore, filling the gap in the knowledge of how testosterone takes its effects at the tissue, cell and molecular level would allow mechanistic insight to support or oppose the use of testosterone as a therapy. In our androgen deficient mouse model, replacing testosterone back to wild-type levels reduced some of the negative impact on the way metabolism was controlled in the liver, muscle and fat tissue by reverting the expression of key targets involved in lipid and glucose control back to those seen in wild-type mice. Testosterone replacement also reduced lipid accumulation in the liver and arteries in these mice, protecting against disease progression.

Whether or not testosterone replacement should be considered as a component in obesity, type 2 diabetes and cardiovascular therapy in men requires evidence from large and appropriately controlled clinical trials along with further detailed mechanistic studies. However, there is now enough supportive evidence to consider such investigations as imperative to endocrine research.

Written by: Daniel Kelly, MD, Sheffield Hallam University

Read the Abstract

References

[1] Levine, G.N., D'Amico, A.V., Berger, P., Clark, P.E., Eckel, R.H., Keating, N.L., Milani, R.V., Sagalowsky, A.I., Smith, M.R., Zakai, N., American Heart Association Council on Clinical Cardiology and Council on Epidemiology and Prevention, the American Cancer Society, and the American Urological Association: Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology 2010; 121, 833-840.

[2] Kelly DM, Akhtar S, Sellers DJ, Muraleedharan V, Channer KS, Jones TH. Testosterone differentially regulates targets of lipid and glucose metabolism in liver, muscle and adipose tissues of the testicular feminised mouse. Endocrine. 2016 Aug 4. [Epub ahead of print].

[3] Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in Androgen Prescribing in the United States, 2001 to 2011. JAMA Intern Med. 2013;173(15):1465-1466.

[4] Jones, T.H., Arver, S., Behre, H.M., Buvat, J., Meuleman, E., Moncada, I., Morales, A.M., Volterrani, M., Yellowlees, A., Howell, J.D., Channer, K.S., Investigators, T.: Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 2010; 34, 828-837.





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