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 TD 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 potentiating 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.
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:
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).
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).
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.
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 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:
To reduce your risk of developing blood clots, try these tips:
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.
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4.Lesser, M. A. (1946) Testosterone propionate therapy in one hundred cases of angina pectoris. J Clin Endocrinol Metab 6, 549-557
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15.Ohlander, S. J., Varghese, B., and Pastuszak, A. W. (2018) Erythrocytosis Following Testosterone Therapy. Sex Med Rev 6, 77-85
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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
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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
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27.SMSNA. (2016) Consensus Statement and White Paper1 Executive Summary: Adult Onset Hypogonadism (AOH) 2015. http://www.smsna.org/V1/about/position-statements.
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