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Is Testosterone replacement therapy (TRT) necessary or symptom chasing?

In a world where it is increasingly normal to be convinced that we fall into a risk classification, need a treatment and can convince our doctor accordingly, negating any experience that he or she might have. The marketeers and economists that run pharmaceutical companies are doing a great job of increasing profits. Before we keep looking for the next wonder treatment we should take stock of what food and exercise can do.

Testosterone can be increased by some very simple strategies such as:

  1. Having adequate liver and vitamin A in the diet to assist in the conversion of cholesterol to pregnenolone – the base hormone responsible for production of testosterone and other androgens.
  2. Ensuring that adequate energy and thyroid hormone are available to maintain communication of the hypothalamic- pituitary- (signalling centres for hormone production-brain to testicles) gonadal axis.
  3. Understanding stress, sleep and interactions between excesses of estrogen and their impact on testosterone production.
  4. Less understood but increasingly keeping mobile communication devices out of pockets and bags that are close to reproductive tissue, including females (ovaries, endometrium etc), appears to be a pragmatic approach in the future. Steroid producing tissues have increased production of problematic compounds that may be prone to damage.

Here’s some of the technical aspects to the situation that are taken from a recent assignment as part of my masters degree..

Introduction

Testosterone is a hormone found in both males and females but is the major reproductive hormone in men that also has a variety of other beneficial functions for maintaining physical and psychological aspects to health. Testosterone levels may decrease with disease and/or be part of an age related decline of output. The use of testosterone supplementation has increased substantially in recent years counter these states, primarily due to increased marketing as an agent of change for energy, strength, fat loss and sexual function. Whilst its use appears beneficial in some areas, caution has been recommended on the effects of T supplementation use and it’s effects on the cardiovascular system.

 Diagnosis

Testosterone (T) is the most important androgen found in males and produced primarily within the testes, when low it is defined as hypogonadism. Hypogonadism is classified as either primary, derived from the testes or secondary, which involves the hypothalamus, pituitary or derived from illness or disease. A low serum testosterone (<300ng/dL) is suggestive, but not definitive of hypogonadism and measurements of luteinising (LH) and follicle stimulating hormone (FSH) is used to establish a primary or secondary diagnosis (Crawford & Kennedy, 2016). A worry trend is that despite striking increases of testosterone prescription a substantial amount (approximately 29% in this review) of patients often fail to have their levels checked prior to undertaking testosterone replacement therapy (TRT). (Corona G, Rastrelli, Maseroli, Sforza, & Maggi, 2015). Additionally only 45 % had their testosterone levels checked during or post TRT intervention.

Low testosterone and cardiovascular risk

Previous studies have highlighted an increase in all cause mortality associated with low testosterone levels in men (Araujo et al., 2011). Conditions that increase risk of mortality related to low testosterone are increased abdominal obesity, inflammatory biomarkers, dyslipidaemia, diabetes mellitus and metabolic syndrome. However the diagnosis of an isolated low testosterone level should be qualified by ruling out other potential diagnosis such as long-term illness, nutritional deficiencies and other endocrine issues such as subclinical or overt hypothyroidism.

Testosterone supplementation and risks

A number of studies and meta analysis have demonstrated a number of beneficial effects of TRT which extend to increased sexual satisfaction, muscle mass, strength mood and metabolic function (Corona G et al., 2015) (Gagliano-Jucá & Basaria, 2017). However the suggested risk to increased CV adverse events have appeared vague in many studies and previous extrapolations/anecdotes between men having increased levels of testosterone (and therefore increased cardiac risk) and females having less testosterone and more oestrogen were not just problematic but incorrect. Many studies have correlated low testosterone to low biomarkers of health and increased cardiovascular disease (Pastuszak, Kohn, Estis, & Lipshultz, 2017) (Kloner, Carson, Dobs, Kopecky, & Mohler, 2016).

TRT reductionism and treating symptoms

A comprehensive review of the data compiled by Oskui et al (Mesbah Oskui, P., French, W.J., Herring, 2013) described the major CV implications of TRT which can be observed below. The authors draw attention to previously conducted studies, that did not show any relationships between low levels of testosterone and CV risk and suggest that both the subfraction of testosterone (Total T compared to Free T) and method of analysis for CVD were inappropriate and therefore unreliable for inclusion. 

Cardiovascular analysis Studies Major findings
Association between T and mortality 8 8/8 studies found relationship between low T and increased all cause and CV mortality.
Type 2 DM 6 6/6 studies showed improved insulin sensitivity through HOMA-IR/HgA!c and improved blood glucose
Cholesterol 3 2/3 studies found no change to LDL/HDL from TRT
Markers of inflammation (primarily C reactive protein CRP) 8 4/8 studies found reduced CRP
Intima media thickness 8 8/8 found an inverse relationship between low T and IMT

The above studies reviewed by the authors, established a link between low levels of testosterone and increases in mortality (all cause and CV), insulin sensitivity and increases in intima media thickness that are resolved by TRT. Yet markers for lipids and inflammation markers such as CRP are less convincing. Hypothyroidism is related to low testosterone and hypogonadic states mainly through hypothalamic-pituitary dysfunction. Treatment of hypothyroid and subclinical hypothyroid states also resolves low testosterone and hypogonadic states, decreases intima media thickness, improves insulin sensitivity and decreases lipid levels (Crawford & Kennedy, 2016), (Krassas, Poppe, & Glinoer, 2010),(Donnelly & White, 2000) (Gao, Zhang, Zhang, Yang, & Chen, 2013). Is TRT the correct therapy for many males, given a) the rapid increases in often undiagnosed and prescription and b) when hypogonadic states, that have similar (cardiac) manifestations and are improved beyond the effects of TRT, are resolved with thyroid hormone?

Another factor concerning reliability of the studies used in previous meta analysis is the size to determine true risk between CV adverse events and TRT (Onasanya et al., 2016). The authors suggesting that to achieve a two-sided p value of 0.05 and power of 80% some 17664 participants would need to study to clarify any relationship. Observational data conducted over 5 years suggested that control groups treated with testosterone in short term had a lower mortality (HR 0.88 95 % CI 0:84 – 0.93) than controls (Wallis et al., 2016). From the meta analysis and other studies discussed above both age (>65) and predisposition to existing disease states may indicate the likelihood of adverse CV events when treated with TRT.

Another draw back of meta-analysis is the inclusion of data and bias produced by pharmaceutical companies that may not be adequately reflected or assessed. Much like cardiovascular end point studies being scarce. Testosterone studies that are funded by financial interests are usually in place to validate the benefits of TRT and fail to evaluate CV adverse events as end points. The increased adequate sample size needed to validate the safety and efficacy of this treatment often increase cost and decrease profit margin over time. The many studies that have been conducted so far, show much smaller sample sizes and a wide range of TRT delivery and dosing.

In a recent case crossover analysis that is not included in any current meta analysis, Layton et al (Layton et al., 2018) found a unique association between testosterone injections and short term cardio (and cerebrovascular) events in older men. Increased associations with myocardial infarction and stroke, post testosterone injection showed odds ratio (OR) were increased for all outcomes, OR =1.45 (95%: CI 1.07, 1.98).

Summary

Testosterone replacement does appear to have many positive effects on a number of markers related to cardiovascular health which include sexual performance, increased muscle mass, metabolic health, physical performance and decreasing mortality in a younger population. However, despite the many benefits of TRT the use of this therapy may have significant risk in late onset hypogonadal states, in ages >65 years of age, those susceptible to conditions associated with erythrocytosis and an association with acute cardiac events exists. It remains essential to ensure that not only adequate analysis of hypogonadal states are present but to ascertain if low testosterone levels are merely a symptom of other endocrine disturbances, such as hypothyroidism which has striking similarities to low levels of testosterone.

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References:

1.Araujo, A. B., Dixon, J. M., Suarez, E. a, Murad, M. H., Guey, L. T., & Wittert, G. a. (2011). Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis. The Journal of Clinical Endocrinology and Metabolism, 96(10), 3007–19. http://doi.org/10.1210/jc.2011-1137

2.Basaria, S., Davda, M. N., Travison, T. G., Ulloor, J., Singh, R., & Bhasin, S. (2013). Risk Factors Associated with Cardiovascular Events During Testosterone Administration in Older Men with Mobility Limitation. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 68(2), 153–60. http://doi.org/10.1093/gerona/gls138

  1. Corona G, G., Rastrelli, G., Maseroli, E., Sforza, A., & Maggi, M. (2015). Testosterone Replacement Therapy and Cardiovascular Risk: A Review. The World Journal of Men’s Health, 33(3), 130–42. http://doi.org/10.5534/wjmh.2015.33.3.130
  2. Crawford, M., & Kennedy, L. (2016). Testosterone replacement therapy: role of pituitary and thyroid in diagnosis and treatment. Translational Andrology and Urology, 5(6), 850–858. http://doi.org/10.21037/tau.2016.09.01
  3. Donnelly, P., & White, C. (2000). Testicular dysfunction in men with primary hypothyroidism; Reversal of hypogonadotrophic hypogonadism with replacement thyroxine. Clinical Endocrinology, 52(2), 197–201. http://doi.org/10.1046/j.1365-2265.2000.00918.x
  4. Gagliano-Jucá, T., & Basaria, S. (2017). Trials of testosterone replacement reporting cardiovascular adverse events. Asian Journal of Andrology, 19(May), 1–7. http://doi.org/10.4103/aja.aja
  5. Gao, N., Zhang, W., Zhang, Y., Yang, Q., & Chen, S. (2013). Carotid intima-media thickness in patients with subclinical hypothyroidism: A meta-analysis. Atherosclerosis, 227(1), 18–25. http://doi.org/10.1016/j.atherosclerosis.2012.10.070
  6. Kloner, R. A., Carson, C., Dobs, A., Kopecky, S., & Mohler, E. R. (2016). Testosterone and Cardiovascular Disease. Journal of the American College of Cardiology. http://doi.org/10.1016/j.jacc.2015.12.005
  7. Krassas, G. E., Poppe, K., & Glinoer, D. (2010). Thyroid Function and Human Reproductive Health. Endocrine Reviews, 31(5), 702–755. http://doi.org/10.1210/er.2009-0041
  8. Layton, J. B., Li, D., Meier, C. R., Sharpless, J. L., Stürmer, T., & Brookhart, M. A. (2018). Injection testosterone and adverse cardiovascular events: A case-crossover analysis. Clinical Endocrinology. http://doi.org/10.1111/cen.13574
  9. Mesbah Oskui, P., French, W.J., Herring, M. J. et al. (2013). Testosterone and the Cardiovascular System: A comprehensive Review of the Clinical Literature. Journal of the American Heart Association. http://doi.org/10.1161/JAHA.113.000272
  10. Onasanya, O., Iyer, G., Lucas, E., Lin, D., Singh, S., & Alexander, G. C. (2016). Association between exogenous testosterone and cardiovascular events: an overview of systematic reviews. The Lancet Diabetes and Endocrinology. http://doi.org/10.1016/S2213-8587(16)30215-7
  11. Pastuszak, A. W., Kohn, T. P., Estis, J., & Lipshultz, L. I. (2017). Low Plasma Testosterone Is Associated With Elevated Cardiovascular Disease Biomarkers. The Journal of Sexual Medicine, 14(9), 1095–1103. http://doi.org/10.1016/j.jsxm.2017.06.015
  12. Roos, A., Bakker, S. J. L., Links, T. P., Gans, R. O. B., & Wolffenbuttel, B. H. R. (2007). Thyroid function is associated with components of the metabolic syndrome in euthyroid subjects. The Journal of Clinical Endocrinology and Metabolism, 92(2), 491–6. http://doi.org/10.1210/jc.2006-1718
  13. Udovcic, M., Pena, R. H., Patham, B., Tabatabai, L., & Kansara, A. (2017). Hypothyroidism and the Heart. Methodist DeBakey Cardiovascular Journal, 13(2), 55–59. http://doi.org/10.14797/mdcj-13-2-55
  14. Wallis, C. J. D., Lo, K., Lee, Y., Krakowsky, Y., Garbens, A., Satkunasivam, R., … Nam, R. K. (2016). Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study. The Lancet. Diabetes & Endocrinology, 4(6), 498–506. http://doi.org/10.1016/S2213-8587(16)00112-1
  15. Xu, L., Freeman, G., Cowling, B. J., & Schooling, C. M. (2013). Testosterone therapy and cardiovascular events among men: A systematic review and meta-analysis of placebo-controlled randomized trials. BMC Medicine, 11(1). http://doi.org/10.1186/1741-7015-11-108