Testosterone Replacement Therapy and Cardiovascular Risk: Is There A Link?

The history of testosterone therapy and its association to cardiovascular events

Hypogonadism is defined as “biochemically low testosterone levels in the setting of a cluster of clinical symptoms, which may include reduced sexual desire (libido) and activity, decreased spontaneous erections, decreased energy and depressed mood” (1). 

Men may also present with reductions in muscle mass and strength, increased fat mass, decreased bone mineral density, and anemia (2). Due to these conditions, many men have resorted to using testosterone therapy as a means to correct the imbalance of this important hormone.

Testosterone therapy has been in the market for more than 70 years for the treatment of testosterone deficiency.

Early studies in the 1940s documented little risk and even reported benefits for peripheral vascular disease and angina pectoris (3). In fact, an improvement of angina pectoris in 91% of patients was shown in those who received testosterone (4).

An abundance of studies in the last 20 years have published data that testosterone deficiency is associated with an increased risk of developing atherosclerosis, cardiovascular disease, worsening osteoporosis and increased mortality. What's more, testosterone therapy has been found to have a beneficial effect on multiple risk factors and biomarkers related to these conditions. 

An attempt was made in order to quantify the cost burden imposed by testosterone deficiencies’ cardiometabolic conditions.

It was projected that low serum testosterone levels are involved in the development of approximately 1.3 million new cases of cardiovascular disease, 1.1 million new cases of diabetes, and over 600,000 of osteoporosis-related fractures. It was also established that, over a 20-year period, testosterone deficiency may be directly responsible for approximately $190 to $525 billion in inflation-adjusted United States health care expenditures (5).  

When you take into consideration that diabetes, dyslipidemia, hypertension, and obesity are risk factors for cardiovascular disease, and that testosterone deficiency contributes to increased fat mass and insulin resistance, it is practical to believe that testosterone deficiency increases cardiovascular disease by increasing these risk factors.

Additionally, any therapeutic modality that alleviates these risk factors is expected to reduce the risk of developing cardiovascular disease. Numerous intervention studies with the use of testosterone therapy demonstrate improvements in lipid profile, inflammation, obesity, waist circumference, glycemic control and blood pressure (3).

These important results have found a genuine biological mechanism to explain the increased mortality among men with testosterone deficiency (3,6).

There is extensive debate surrounding some high impact publications with questionable methodologies and controversial conclusions that suggested significant cardiovascular risk for men on testosterone therapy while other research suggests benefits (7-11).

In light of this controversy the American Urological Association issued a policy statement stating that, based upon current evidence, definitive answers on the cardiovascular risks of testosterone therapy are not currently available (1).

Much of the concern is due to the increases in blood viscosity resulting from increased red blood cell mass centers on the potential increased risk for venous thromboembolism, myocardial infarction, and cerebrovascular accidents (12).

However, there is very little evidence supporting an increased risk of these negative conditions in men on testosterone therapy (13).

Due to an increase awareness of men’s health issues, including androgen deficiency, the use of testosterone therapy is growing.

Testosterone prescription sales tripled in men over 40 years old and quadrupled in men 18-45 years old over the last decade (14). Given the large increase in testosterone prescriptions, as well as partly defined indications for therapy, it is paramount that we thoroughly understand the risks and benefits of testosterone therapy.

Testosterone-Induced Erythrocytosis Risk

Polycythemia and erythrocytosis are used interchangeably to refer to an abnormal elevation of hemoglobin or hematocrit. Whereas stimulation of erythropoiesis is therapeutic in the treatment of anemias, an unclear understanding of the thromboembolic potential of testosterone-induced elevations in hemoglobin and hematocrit requires attentive screening.

In the clinical setting, erythrocytosis generally translates to hemoglobin > 18.5g/dl or hematocrit > 52% in males, though this definition varies (15). The Endocrine Society uses a hematocrit > 50% as a relative contraindication to initiation of testosterone therapy, and hematocrit > 54% as a reason to stop therapy (2).

Other professional societies utilize hematocrit ranging from 52–55% as thresholds to modify or discontinue testosterone therapy.

An increase in hematocrit is related with increased blood viscosity, reduced venous return and increased platelet adhesiveness (16,17).

Clinical and academic interest currently resides with persistently elevated hemoglobin and hematocrit and the possible increased risk for thromboembolic events and ischemic conditions due to blood hyperviscosity, particularly in the setting of testosterone-induced erythrocytosis (18).

The figure below (adapted from Ohlander 2018 (15) illustrates the proposed direct and indirect effects of testosterone on erythropoiesis.

To date, no randomized or prospective studies have observed a direct relationship between testosterone therapy-induced erythrocytosis and thromboembolic events. 

There are a few studies that observed a correlation of testosterone therapy, elevated hematocrit and cardiovascular risk but these studies have serious methodological flaws and are not randomized controlled trials (7,8,10,19).  

The following two studies published in 2013-14 brought considerable media attention after they reported patients receiving testosterone therapy were at an increased risk of developing cardiovascular disease. 

Let’s take a look at each one so we can get a clear understand of the methodological flaws: 

• The first one was a retrospective national cohort study of 8,709 men with a total testosterone level lower than 300 ng/dL who had undergone coronary angiography within the Veterans Administration health care system. They aimed to evaluate the association between the use of testosterone therapy and all-cause mortality, myocardial infarction, and stroke (10).
• Although there were no statistically significant differences in overall rate of events at 180, 365, and 540 days, the authors reported that the overall rate of myocardial infarction, stroke and death was higher in men receiving testosterone therapy when compared to untreated men. However, the actual rate of adverse events was half (10.1%) in the testosterone treatment group vs. 21.2% in the control group. The authors failed to acknowledge these numbers and came to a paradoxical interpretation based on complex statistics that included adjustment for more than 50 variables (3).
• In addition, after multiple criticisms, the article underwent 2 official corrections. One was for misreporting primary results as “absolute risk” and the second was in response to a letter that challenged the exclusion of men who had suffered adverse events in the non-testosterone group. All these errors prompted many medical societies and physicians from multiple countries to request a retraction of this article.
• The second article that gained media attention was a retrospective cohort study from a health insurance database that reported a comparison of rates of nonfatal myocardial infarction in the period up to 90 days after testosterone prescription vs. myocardial infarction rates 12 months prior to testosterone prescription (8). 
• The database included a total of 55,593 subjects with a post-prescription period defined as time to first prescription refill, which ranged from 30 to 90 days. Patients who did not refill their initial prescription were analyzed an additional 90 days (total of 180 days). These patients were compared to a control group which consisted of 167,279 men who received a prescription for a phosphodiesterase type 5 inhibitor (medication used to treat erectile dysfunction).  Authors found an increased relative risk of myocardial infarction post-testosterone prescription to pre-prescription. This was even higher in a subgroup analysis of men older than 65 years old. They reported no increase in myocardial infarction rate in the phosphodiesterase type 5 inhibitor group.
• However, the study had several flaws. First of all, the termination in the study, nonfatal myocardial infarction, was determined by use of an insurance diagnosis code without medical record verification that a myocardial infarction actually occurred. An error rate as high as 12% has previously been reported when such measures are not clarified (3). Additionally, cardiovascular risk factors such as diabetes, hypertension, smoking history, and elevated cholesterol were not accounted for.
• Furthermore, they compared the treatment group with men who received a medication that is used for a different indication, making the comparison dissimilar and unparalleled. It is unknown whether the testosterone prescriptions were ever filled and even if they were, a short and limited exposure to testosterone therapy of 30 to 90 days allows for the possibility that any detected increased risk of myocardial infarction was secondary to an underlying condition rather than from testosterone therapy.
• The FDA concluded in July 2014 that “it is difficult to attribute the increased risk for non-fatal myocardial infarction seen in this study to testosterone alone and not consider that the study participants might have remained hypogonadic and thus at higher risk for non-fatal myocardial infarction” (20).

It’s clear after breaking down what was actually looked at in the two examples above how inappropriately portrayed findings can propagate misconstrued information for years to come.  

During the same time of these two studies above, a meta-analysis published of all randomized controlled trials related to testosterone therapy and cardiovascular risk concluded that the available evidence “does not support a causal role between testosterone supplementation and adverse CV events when hypogonadism is properly diagnosed and replacement therapy correctly performed”(21).  

An updated meta-analysis in 2018 by the same authors examined all available data from pharmaco-epidemiological studies as well as randomized placebo-controlled trials in order to verify whether testosterone therapy represents a possible risk factor for cardiovascular morbidity and mortality (22).

The clinical implications of this analysis are that pharmaco-epidemiological studies showed that testosterone therapy might reduce cardiovascular risk, but this effect was not confirmed when randomized placebo-controlled trials were considered.

The authors acknowledged a few limitations of this analysis which are 1) properly powered randomized placebo-controlled trials with a primary cardiovascular end point, in men with late-onset hypogonadism, are not yet available and 2) the duration of all studies evaluated in their meta-analysis were relatively short, reaching a maximum of 3 years.  

They concluded that data from randomized placebo-controlled trials recommend that treatment with testosterone is not effective in reducing cardiovascular risk, however, when testosterone therapy is correctly applied, it is not linked with an increase in cardiovascular risk and it may have a beneficial effect in some sub-populations (22).

With regard to the risk of cardiovascular events, despite the lack of evidence, the FDA has mandated that testosterone manufacturers add a warning to testosterone labels indicating “a possible increased risk of heart attacks and strokes in patients taking testosterone” (23).

Effects of Testosterone Formulation

Of the available testosterone formulations, short acting IM injections (T cypionate and enanthate) have the highest incidence of erythrocytosis, approaching 40% (24).

Recent studies support a unified hypothesis in which testosterone formulation, dose, and pharmacokinetics collectively determine the risk of erythrocytosis by establishing the duration of supraphysiological testosterone levels (25).

Testosterone formulations that result in stable serum concentrations (pellets, transdermal gels and patches, and extended-release intramuscular testosterone) result in a low incidence of erythrocytosis that is dependent on dose and serum level, and independent of duration of therapy (26).

Recommendations

Testosterone dosing should generally follow manufacturer and physician-prescribed recommendations. For at risk populations (type 2 diabetics, smokers, obese men), injectable testosterone formulations should be considered only after potential adverse hematological responses are discussed with the physician and patient.

Additional factors for selecting testosterone formulations in consideration of hematologic effects include age, which is an independent risk factor for erythrocytosis in the setting of testosterone therapy (26). 

For patients who meet criteria for and desire testosterone therapy, a baseline hemoglobin and hematocrit should be assessed. After initiation of therapy, the Sexual Medicine Society of North America advises that men should be “monitored regularly” for erythrocytosis (27). 

Based on Endocrine Society Clinical Practice Guidelines, once a hematocrit > 54% is reached, testosterone therapy should either be discontinued, or therapeutic phlebotomy offered to reduce the risk of potential future thromboembolic events (2).

Excessive Blood Clotting (Hypercoagulation) in people not on testosterone therapy

We all clot and it is a very ordinary part of healing. When you get a scrape, cut or wound, your body forms blood clots (thickened masses of blood tissue) to help stop the bleeding. Proteins in your blood called fibrins work with small blood cell fragments called platelets, to form the clot. This is called coagulation, a process that helps the body when an injury occurs because it slows blood loss.

After bleeding has stopped and healing has occurred, the body normally breaks down and removes the clots. But there are times when blood clots form too easily or don't dissolve properly and travel through the body limiting or blocking blood flow.

This is called excessive blood clotting or hypercoagulation, and can be very dangerous. In a case of excessive blood clotting, these clots can form in, or travel to, the arteries or veins in the brain, heart, kidneys, lungs and limbs, which in turn can cause heart attack, stroke, damage to the body’s organs or even death.

Contributing factors

Many factors can cause excessive blood clotting including certain diseases and conditions, genetic mutations and medicines. These causes fall into two categories: acquired and genetic.

• Acquired means that excessive blood clotting was triggered by another disease or condition. Smoking, overweight and obesity, pregnancy, use of birth control pills, cancer, prolonged bed rest, or car or plane trips where someone is sitting for longer periods of times, are a few examples.

• The genetic, or inherited, source of excessive blood clotting is less common and is usually due to genetic defects. These defects usually occur in the proteins needed for blood clotting and can also occur with the substances that delay or dissolve blood clots.

Acquired and genetic sources of excessive blood clotting are not related but a person can have both.

Below is a more extensive list of acquired and inherited conditions that can cause troublesome blood clots, as well as serious conditions that are associated with blood clots:

• Antiphospholipid syndrome
• Arteriosclerosis / atherosclerosis
• Certain medications, such as oral contraceptives and hormone therapy drugs
• Coronavirus disease 2019 (COVID-19)
• Deep vein thrombosis (DVT) 
• Factor V Leiden
• Family history of blood clots
• Heart arrhythmia (heart rhythm problems)
• Heart attack
• Heart failure
• Obesity
• Peripheral artery disease (PAD)
• Polycythemia vera
• Pregnancy
• Prolonged sitting or bed rest
• Pulmonary embolism (blood clot in an artery in the lung)
• Smoking
• Stroke
• Surgery

Self-care measures

To reduce your risk of developing blood clots, try these tips:

• Avoid sitting for long periods. If you travel by airplane, walk the aisle periodically. For long car trips, stop and walk around frequently.
• Move. After you've had surgery or been on bed rest, the sooner you get up and move around, the better.
• Drink plenty of fluids when traveling. Dehydration can contribute to the development of blood clots.
• Change your lifestyle. Lose weight, lower high blood pressure, stop smoking and exercise regularly.  In obese men, regular aerobic exercise helped reverse blood clot formation by increasing amounts of a critical blood clot dissolver called tissue-type plasminogen activator (t-PA) (28).

In Summary

Erythrocytosis is often a limiting variable in patients on testosterone therapy. Direct and indirect effects related to supraphysiologic testosterone levels are thought to mediate the effects on erythrocytosis.

The true mechanism of erythrocytosis and its role on thromboembolic events remains unclear, though few data support an increased risk of cardiovascular events resulting from testosterone-induced erythrocytosis.

There is a huge need for large multicenter randomized controlled trials in order to properly study testosterone therapy, its effects on hemoglobin and hematocrit, and the clinical significance of treatment induced elevations in red blood cell mass.

References:

1. AUA. (2015) AUA Position Statement on Testosterone Therapy 2014. http://www.auanet.org/education/testosterone-therapy.cfm.

2. Bhasin, S., Cunningham, G. R., Hayes, F. J., Matsumoto, A. M., Snyder, P. J., Swerdloff, R. S., Montori, V. M., and Task Force, E. S. (2010) Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 95, 2536-2559

3. Morgentaler, A., Miner, M. M., Caliber, M., Guay, A. T., Khera, M., and Traish, A. M. (2015) Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc 90, 224-251

4. Lesser, M. A. (1946) Testosterone propionate therapy in one hundred cases of angina pectoris. J Clin Endocrinol Metab 6, 549-557

5. Moskovic, D. J., Araujo, A. B., Lipshultz, L. I., and Khera, M. (2013) The 20-year public health impact and direct cost of testosterone deficiency in U.S. men. J Sex Med 10, 562-569

6. Haring, R., Volzke, H., Steveling, A., Krebs, A., Felix, S. B., Schofl, C., Dorr, M., Nauck, M., and Wallaschofski, H. (2010) Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79. Eur Heart J 31, 1494-1501

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8. Finkle, W. D., Greenland, S., Ridgeway, G. K., Adams, J. L., Frasco, M. A., Cook, M. B., Fraumeni, J. F., Jr., and Hoover, R. N. (2014) Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 9, e85805

9. Muraleedharan, V., Marsh, H., Kapoor, D., Channer, K. S., and Jones, T. H. (2013) Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol 169, 725-733

10. Vigen, R., O'Donnell, C. I., Baron, A. E., Grunwald, G. K., Maddox, T. M., Bradley, S. M., Barqawi, A., Woning, G., Wierman, M. E., Plomondon, M. E., Rumsfeld, J. S., and Ho, P. M. (2013) Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 310, 1829-1836

11. Zhao, C., Moon du, G., and Park, J. K. (2013) Effect of testosterone undecanoate on hematological profiles, blood lipid and viscosity and plasma testosterone level in castrated rabbits. Can Urol Assoc J 7, E221-225

12. Braekkan, S. K., Mathiesen, E. B., Njolstad, I., Wilsgaard, T., and Hansen, J. B. (2010) Hematocrit and risk of venous thromboembolism in a general population. The Tromso study. Haematologica 95, 270-275

13. Schreijer, A. J., Reitsma, P. H., and Cannegieter, S. C. (2010) High hematocrit as a risk factor for venous thrombosis. Cause or innocent bystander? Haematologica 95, 182-184

14. Rao, P. K., Boulet, S. L., Mehta, A., Hotaling, J., Eisenberg, M. L., Honig, S. C., Warner, L., Kissin, D. M., Nangia, A. K., and Ross, L. S. (2017) Trends in Testosterone Replacement Therapy Use from 2003 to 2013 among Reproductive-Age Men in the United States. J Urol 197, 1121-1126

15. Ohlander, S. J., Varghese, B., and Pastuszak, A. W. (2018) Erythrocytosis Following Testosterone Therapy. Sex Med Rev 6, 77-85

16. Guyton, A. C., and Richardson, T. Q. (1961) Effect of hematocrit on venous return. Circ Res 9, 157-164

17. Wells, R. E., Jr., and Merrill, E. W. (1962) Influence of flow properties of blood upon viscosity-hematocrit relationships. J Clin Invest 41, 1591-1598

18. Jin, Y. Z., Zheng, D. H., Duan, Z. Y., Lin, Y. Z., Zhang, X. Y., Wang, J. R., Han, S., Wang, G. F., and Zhang, Y. J. (2015) Relationship Between Hematocrit Level and Cardiovascular Risk Factors in a Community-Based Population. J Clin Lab Anal 29, 289-293

19. Krauss, D. J., Taub, H. A., Lantinga, L. J., Dunsky, M. H., and Kelly, C. M. (1991) Risks of blood volume changes in hypogonadal men treated with testosterone enanthate for erectile impotence. J Urol 146, 1566-1570

20. Administration, U. F. a. D. (2014) Citizen petition denial response from FDA CDER to Public Citizen., FDA  http://www.regulations.gov/#!documentDetail;D=FDA-2014-P-0258-0003., Washington, D.C.

21. Corona, G., Maseroli, E., Rastrelli, G., Isidori, A. M., Sforza, A., Mannucci, E., and Maggi, M. (2014) Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert Opin Drug Saf 13, 1327-1351

22. Corona, G., Rastrelli, G., Di Pasquale, G., Sforza, A., Mannucci, E., and Maggi, M. (2018) Testosterone and Cardiovascular Risk: Meta-Analysis of Interventional Studies. J Sex Med 15, 820-838

23. Seftel, A. D. (2015) Re: Testosterone Products: Drug Safety Communication - FDA Cautions about Using Testosterone Products for Low Testosterone due to Aging; Requires Labeling Change to Inform of Possible Increased Risk of Heart Attack and Stroke. J Urol 194, 759-760

24. Rhoden, E. L., and Morgentaler, A. (2004) Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 350, 482-492

25. Ip, F. F., di Pierro, I., Brown, R., Cunningham, I., Handelsman, D. J., and Liu, P. Y. (2010) Trough serum testosterone predicts the development of polycythemia in hypogonadal men treated for up to 21 years with subcutaneous testosterone pellets. Eur J Endocrinol 162, 385-390

26. Coviello, A. D., Kaplan, B., Lakshman, K. M., Chen, T., Singh, A. B., and Bhasin, S. (2008) Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. J Clin Endocrinol Metab 93, 914-919

27. SMSNA. (2016) Consensus Statement and White Paper1 Executive Summary: Adult Onset Hypogonadism (AOH) 2015. http://www.smsna.org/V1/about/position-statements. 

28. Van Guilder, G. P., Hoetzer, G. L., Smith, D. T., Irmiger, H. M., Greiner, J. J., Stauffer, B. L., and DeSouza, C. A. (2005) Endothelial t-PA release is impaired in overweight and obese adults but can be improved with regular aerobic exercise. Am J Physiol Endocrinol Metab 289, E807-813