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Normalization of testosterone level is associated with reduced risk of heart attack, stroke and mortality in men

Normalization of testosterone level is associated with reduced risk of heart attack, stroke and mortality in men

The effects of testosterone replacement therapy on cardiovascular outcomes such as heart attack and stroke are controversial and have been generating heated discussions among clinicians as well as researchers. This, coupled with biased media sensationalism blowing up the supposed “dangers” of testosterone therapy has created great confusion among suffering men, who could gain tremendous health benefits from testosterone therapy.1

In this editorial we report the results of a new study that examined the relationship between normalization of total testosterone levels with testosterone therapy and cardiovascular events as well as all-cause mortality, in patients without a previous history of heart attack and stroke.2 This notable study was published in the European Heart Journal on August 6th, 2015.

KEY POINTS

  • In men who have low total testosterone levels but no previous heart attack or stroke, testosterone therapy is associated with decreased risks of heart attack, stroke, and all-cause mortality during a long-term follow-up of up to 14 years.
  • Compared to non-treated men, testosterone treated men who achieved normalization of their testosterone levels had a reduction in heart attack, stroke and all-cause mortality by 24%, 36% and 56%, respectively.
  • Compared to non-treated men, testosterone treated men who failed to achieve normalization of their testosterone levels did not have a reduction in heart attack or stroke, and had significantly less benefit on mortality risk.
  • Testosterone therapy should aim for doses resulting in normalization of total testosterone level, as this is a prerequisite to achieve a reduction in heart attack and stroke.

What is known

Previously, four retrospective studies have investigated the effect of testosterone therapy on various cardiovascular disease outcomes and mortality; two reported negative effects 3,4 while the other two reported beneficial effects.5,6 Two separate retrospective studies of men in the Veterans Affairs Health System using two different databases reported opposite effects of testosterone therapy on all-cause mortality.4,6

Multiple observational studies show that low testosterone levels are associated with an increased number of cardiovascular events.1 Clinical trials examining testosterone therapy have been relatively small and of short duration, and these trials were underpowered to provide conclusive evidence related to cardiovascular events.7 Thus, more studies are needed on the effects of testosterone treatment on cardiovascular disease outcomes.

About this study

The European Heart Journal study retrospectively examined 83 010 male veterans without prior heart attack or stroke, but with documented low total testosterone levels. The subjects were categorized into 3 groups:

  • Group 1: Testosterone therapy achieving normalization of total testosterone levels.
  • Group 2: Testosterone therapy not achieving normalization of total testosterone levels.
  • Group3: Did not receive testosterone therapy.

All of the study patients had their total testosterone levels checked at least on two separate occasions. Use of testosterone therapy (injection, gel or patch) was ascertained from the medication prescription of patient medical records.

Definition of low and normal testosterone levels

Testosterone levels can vary significantly between different laboratories, even when they use the same commercial kits.8-10 Therefore, low total testosterone was considered to be present when the total testosterone level was less than the lower limit of the normal laboratory reference range reported for that particular test result. This method of classifying each test result as low or normal based on its respective laboratory reference range permitted inclusion of results from a large number of laboratories in the entire Veterans Affairs Health System during a period of over 14 years, with different test assays and different reference ranges. As there are no universal testosterone thresholds, this also eliminated any bias that may have been introduced by the use of an arbitrary cut-off value.

Testosterone replacement therapy achieved normalization of total testosterone levels in 63% patients while the rest of this group continued to have low testosterone (indicating a sub-optimal testosterone treatment). Mean duration of treatment was 3 years, with a total follow-up of up to 14 years.

What this study adds

The association of testosterone therapy with all-cause mortality, heart attack and stroke was compared between the three groups.

When compared to men not treated with testosterone (group 3), men on testosterone therapy who achieved normalization of total testosterone levels (group 1) had a significant reduction in all-cause mortality (hazard ratio (HR): 0.44), risk of heart attack (HR: 0.76), and risk of stroke (HR: 0.64).

When compared to men not treated with testosterone (group 3), men on testosterone therapy who failed to achieve normalization of total testosterone levels (group 2) did not get any protection against heart attack or stroke, and only had a modest reduction in all-cause mortality.

It was concluded that normalization of total testosterone levels with testosterone therapy is associated with a significant reduction in all-cause mortality, heart attack, and stroke during an extended follow-up period.

Commentary

This study fills an important knowledge gap in the current medical literature on testosterone treatment and cardiovascular disease / mortality outcomes. Notably, this is the first study to demonstrate that significant benefit is observed only if the testosterone treatment dose is adequate to normalize total testosterone levels. Patients who failed to achieve an adequate elevation in total testosterone levels did not experience a reduction in heart attack or stroke, and had significantly less benefit on mortality. It is also the first study in which all included subjects had at least two testosterone measurements to document normalization of testosterone levels after testosterone therapy and adherence to testosterone treatment.

A significant limitation of all retrospective studies on testosterone therapy has been the inability to fully ascertain whether patients in the treatment group actually took the testosterone medications in an adequate dose and adhered to testosterone treatment. One previous retrospective study – which associated testosterone prescriptions with an increased heart attack risk - did not even report testosterone levels at all!3 The current study overcomes these limitations by assessing follow-up testosterone levels - which is a reliable indicator for adequacy of dosing and treatment compliance – in all included study groups.

This study also differs from previous retrospective studies on testosterone therapy by having a large subject population with extensive follow-up. It clearly shows that effective testosterone therapy is associated with lower rates of heart attack and stroke in men without pre-existing heart disease, in whom low testosterone levels are documented and effective testosterone therapy (defined as normalization of testosterone levels) is provided. This study also highlights that testosterone therapy should aim for testosterone treatment doses that result in normalization of total testosterone level, as this is a prerequisite to achieve a reduction in heart attack and stroke.

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References

1. Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM. Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin. Proc. 2015;90(2):224-251.
2. Sharma R, Oni OA, Gupta K, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur. Heart J. 2015:Aug 6 [Epub ahead of print].
3. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PloS one. 2014;9(1):e85805.
4. Vigen R, O'Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829-1836.
5. Baillargeon J, Urban RJ, Kuo YF, et al. Risk of Myocardial Infarction in Older Men Receiving Testosterone Therapy. Ann. Pharmacother. 2014;48(9):1138-1144.
6. Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J. Clin. Endocrinol. Metab. 2012;97(6):2050-2058.
7. Fernandez-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 2010;95(6):2560-2575.
8. Carruthers M, Trinick TR, Wheeler MJ. The validity of androgen assays. The aging male : the official journal of the International Society for the Study of the Aging Male. 2007;10(3):165-172.
9. Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H. Position statement: Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J. Clin. Endocrinol. Metab. 2007;92(2):405-413.
10. Wheeler MJ, Barnes SC. Measurement of testosterone in the diagnosis of hypogonadism in the ageing male. Clin. Endocrinol. (Oxf). 2008;69(4):515-525.
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Last updated: 2017
G.GM.MH.04.2015.0334