Testosterone Treatment and Mortality

[Michael Scally MD]

Testosterone Treatment and Mortality in Men with Low Testosterone Levels

Low testosterone levels are common in older men and are associated with adverse outcomes such as diabetes, obesity, cardiovascular events, sarcopenia, osteoporosis, and decreased libido. Researchers previously reported that men with low testosterone levels had increased mortality with an approximate doubling in mortality risk compared with men with normal testosterone levels. These results were confirmed in several other studies, whereas some studies did not find this association. The negative studies generally differed from the other studies in that they examined younger men with higher testosterone levels.

Over the past decade, testosterone prescriptions have increased markedly in the United States from 700,000/yr in 2000 to 2,700,00 in 2008. Given the dramatic increase in the use of testosterone, a major public health issue is to clarify the risks and benefits of testosterone treatment in the health of older men with low testosterone levels. Some testosterone treatment trials in older men with low testosterone levels have shown beneficial effects, such as increased strength, muscle mass, bone mineral density, insulin sensitivity, and libido.

Although these testosterone treatment trials reported positive results, there is ongoing concern about the risk of incident prostate cancer or prostate cancer mortality because studies have not been large enough or long enough to address this. In addition, a recent testosterone treatment trial in frail, elderly men was stopped early due to a greater occurrence of cardiovascular-related events in testosterone treated men. This was an unexpected finding because a testosterone treatment trial in a similar population of frail elderly men found no increased cardiovascular risk, and a meta-analysis of testosterone treatment trials reported no increased cardiovascular risks with testosterone treatment. The report of adverse cardiovascular events associated with testosterone treatment highlights the need for further data on the risks and benefits of testosterone treatment in older men, particularly given the large numbers of older men who are prescribed testosterone.

This is the first study to examine specifically the association between testosterone treatment and mortality in men with low testosterone levels. Testosterone treatment was associated with decreased mortality in an observational cohort of middle-aged male veterans with low total testosterone levels and high chronic medical morbidity. Due to the limitations of the observational study design, these results should be viewed cautiously and cannot be interpreted as showing beneficial effects of testosterone treatment or as establishing a causal relationship between testosterone treatment and reduced mortality. However, these results do provide impetus for conducting a large scale, double-blind, placebo-controlled clinical trial to better understand the effect of testosterone treatment on the health of older men.


Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone Treatment and Mortality in Men with Low Testosterone Levels. Journal of Clinical Endocrinology & Metabolism. http://jcem.endojournals.org/content/early/2012/04/11/jc.2011-2591.abstract (Testosterone Treatment and Mortality in Men with Low Testosterone Levels)

Context: Low testosterone levels in men have been associated with increased mortality. However, the influence of testosterone treatment on mortality in men with low testosterone levels is not known.

Objective: The objective of the study was to examine the association between testosterone treatment and mortality in men with low testosterone levels.

Design: This was an observational study of mortality in testosterone-treated compared with untreated men, assessed with time-varying, adjusted Cox proportional hazards regression models. Effect modification by age, diabetes, and coronary heart disease was tested a priori.

Setting: The study was conducted with a clinical database that included seven Northwest Veterans Affairs medical centers.

Patients: Patients included a cohort of 1031 male veterans, aged older than 40 yr, with low total testosterone [?250 ng/dl (8.7 nmol/liter)] and no history of prostate cancer, assessed between January 2001 and December 2002 and followed up through the end of 2005.

Main Outcome Measure: Total mortality in testosterone-treated compared with untreated men was measured.

Results: Testosterone treatment was initiated in 398 men (39%) during routine clinical care. The mortality in testosterone-treated men was 10.3% compared with 20.7% in untreated men (P<0.0001) with a mortality rate of 3.4 deaths per 100 person-years for testosterone-treated men and 5.7 deaths per 100 person-years in men not treated with testosterone. After multivariable adjustment including age, body mass index, testosterone level, medical morbidity, diabetes, and coronary heart disease, testosterone treatment was associated with decreased risk of death (hazard ratio 0.61; 95% confidence interval 0.42–0.88; P = 0.008). No significant effect modification was found by age, diabetes, or coronary heart disease.

Conclusions: In an observational cohort of men with low testosterone levels, testosterone treatment was associated with decreased mortality compared with no testosterone treatment. These results should be interpreted cautiously because residual confounding may still be a source of bias. Large, randomized clinical trials are needed to better characterize the health effects of testosterone treatment in older men with low testosterone levels.

 

[Nemesis RR]

The way I see it even if it does not increase lifespan an individuals quality of life is greatly improved.

 

[Michael Scally MD]

The way I see it even if it does not increase lifespan an individuals quality of life is greatly improved.

What if they found it had shortened!

 

[pinkman]

I had levels of 250ng/dl already at age 21 and this fucking endocrinologist sent me home telling me it's all good. This damn asshole.

 

[Nemesis RR]

What if they found it had shortened!

As long as it isnt to long. Living with no energy, brain fog that started affecting a great carreer, slowly losing muscle, and being cranky because of being tired is no fun. All of this is GONE.

 

[lineguy]

It's great that you post the information here Dr., but since this is not a forum composed primarily of scientists or researchers, someone should point out the classic "correlation vs. causation" issue.

People who leave their low testosterone untreated are obviously less likely to have their health monitored and maintained. So, naturally their rate of disease and mortality would be higher.

What is more interesting and relevant is what kind of diseases and problems testosterone actually causes. I know virtually nothing about that.

 

[hypohypophysis]

I for one would rather die younger with a higher quality of life than live forever with no quality of life. More importantly, the decision should be mine to decide, not a doctor's, not the government's, and not my insurance company's. It's my life, I'll live according to the decisions and values I hold, and as long as I'm not affecting anyone else in doing so, I should be allowed to. Smoking tobacco is completely legal, and much worse for your health than testosterone, undeniably, yet testosterone is a schedule III controlled substance and tobacco is over-the-counter to anyone over 18. How does that make sense?

 

[pinkman]

Smoking tobacco is completely legal, and much worse for your health than testosterone, undeniably, yet testosterone is a schedule III controlled substance and tobacco is over-the-counter to anyone over 18. How does that make sense?

[ame=http://www.youtube.com/watch?v=QpLWHrIuJaI]The Dillinger Escape Plan - Fight The Power(Public Enemy Cover) - YouTube[/ame]

 

[Demondosage]

the problem with alot of these studies are all of the variables. You could have a normal man receiving TRT who is in fairly good health but doesnt exercise, an elderly man in excellent health who exercises and eats right but still has low T levels, an elderly man with extrmely high cholesterol who eats garbage and grease, an elderly man with excellent health but a genetic predisposition to heart problems due to family history-I could go on and on, I take studies like these with a grain of salt. One of my good friends has been using boatloads of steroids and GH for several years (30 yrs of steroids, occasionally taking his total mg's to 5 grams when getting ready for a contest) he has been using GH for the past 10 yrs solid. He is 56 yrs old, he had some problems with his bloodwork, took almost a year off everything and started back on very low dosages and 2 iu's/day of GH. His bloodwork is back to almost everything in normal ranges now, he is 265 lbs fairly lean @ 6' tall. At 56 yrs old, despite all of those years of cycling steroids and GH, I'm sure his bloodwork would beat most other men his age.

 

[Michael Scally MD]

Caveat Emptor - Does Testosterone Treatment Reduce Mortality in Men

Wu FCW. Caveat Emptor: Does Testosterone Treatment Reduce Mortality in Men? Journal of Clinical Endocrinology & Metabolism 2012;97(6):1884-6. http://jcem.endojournals.org/content/97/6/1884.extract (Caveat Emptor: Does Testosterone Treatment Reduce Mortality in Men?)

Much interest and controversy surround the clinical implications of the age-related decline in circulating testosterone (T) in aging men (1) and the decision to treat symptomatic men with androgen replacement (2, 3). There is a seductive simplicity to the conceptualization of low T in the elderly man as a straightforward problem of an age-related deficiency state—boosting the hormone level with treatment will remedy multiple problems of senescence whether they are sexual dysfunction, mobility limitation, diabetes, or cardiovascular disease. But the apparent relationships between T and various physiological deficits and adverse clinical outcomes are likely to be the result of complex interactions (bidirectional, nonlinear, and multilevel) between many coexisting factors, some of which are known but others not. Low T may also be considered as a normal (adaptive) response to an abnormal environment (e.g.starvation, obesity) or pathological conditions (e.g. diabetes, cardiovascular diseases, organ failure, or cancer) common in the elderly (4, 5). If this is the case, T treatment is not only unphysiological and inappropriate but may also potentially cause adverse effects (6).

Further debate has been fueled by several epidemiological studies, some but not others reporting an inconsistent association between low endogenous T and increased all-cause and cardiovascular mortality (7–10). This raises the stakes regarding the importance of T beyond symptomatic and quality of life improvements to broader issues of general health and longevity, positing important questions such as: is T a risk marker for poor health and mortality; does T treatment reduce mortality in men; and what might be the mechanisms that link variations in T with risks/causes of death? Invoking the cardiometabolic risks that commonly coexist with low T does not provide definitive answers (11, 12), especially to all-cause mortality. Randomized controlled trials of T treatment to prolong life or reduce cardiovascular events are highly challenging and costly and thus unlikely to be supported. Against this background, the question addressed in the study by Shores et al. (13) in this issue of the JCEM, the first to specifically investigate the relationships between T treatment and mortality in middle-aged and elderly men with low T, is therefore highly topical and timely, given that the long-term risk-benefit ratio of T treatment in older men is presently unknown. But the publication of this work should come with a prominent “health warning.”

Using the database from seven U.S. Veterans Administration (VA) medical centers, the authors performed a retrospective observational study comparing all-cause mortality in T-treated (n = 398) vs. untreated (n = 633) hypogonadal men [mean age, 62.1 yr; with an average 6.7 comorbid conditions and T < 250 ng/dl (8.7 nmol/liter)] followed for 40.5 months. Shores et al. (13) report a significantly lower mortality rate of 10.3% in the treated men compared with 20.7% in the untreated men, with a hazard ratio of 0.61 (95% confidence interval, 0.42–0.88; P = 0.008). It is important to highlight the limitations of this study to amplify the concerns expressed in the paper. (The discussion on the study limitations is more than twice as long as the discussion on the actual results of the study.)

Study Limitations

Study design

The retrospective observational design carries a substantial risk of primary selection bias due to the nonrandom assignment of exposure (in this case, T treatment). The authors attempted to adjust out a priori confounding effects, estimate effects modified by coexisting conditions (diabetes and cardiovascular disease) by subanalyses, and account for selection bias through propensity analysis (accuracy score of only 0.66). Unfortunately, notwithstanding these efforts, the real possibility of residual confounding and inevitable selection bias in this study could not be completely dismissed or erroneous conclusions discounted. This major drawback is further compounded by a series of further study limitations discussed below.

Lack of basic clinical description and diagnosis of study subjects

Due to the retrospective database retrieval, much of the essential information that normally forms the basic clinical description of a study cohort was not available, seriously opening the study to errors of misclassification. Reasons for measuring T were unknown. Although sexual dysfunction is likely to be a major trigger in the primary care setting, this may have introduced significant bias for including men with vascular pathologies. Symptoms were not described, and the diagnosis of hypogonadism could not be established, thereby creating uncertainties as to the exact conditions being treated. The decision to treat was based on only a single T value, which did not subscribe to current recommended clinical practice (14) and could have led to men who were not hypogonadal receiving treatment. Importantly, the indications for treatment or no treatment were unknown, and as the authors conceded, physicians may have selected healthier men for T treatment or not considered treatment in men who were less well. This could have a major impact on the conclusions of the study. No free T or SHBG data were included in two comparator populations with different age and body mass index, and both of these parameters may have influenced the clinical decision to treat based on T levels below threshold. Time of blood sampling was not standardized—a significant heterogeneity factor that may have weakened the association between T and all-cause mortality (10).

Short duration of T treatment

The short duration of T treatment of 13.1 months in relation to the relatively short follow-up period of 40.5 months throws doubt on whether the intervention was the cause of the lower mortality in the treated group and also raises questions regarding the specificity of possible mechanisms that could have influenced all-cause mortality.

No information on cause of death

Unfortunately, there was no information available on causes of death in this study. Recent interventional trials on the effects of cardiovascular disease risk factors showed only minimal improvements in insulin sensitivity and cholesterol levels in 6 months (15), casting further doubts on the plausibility and relevance of cardiometabolic pathways. The sensitivity analysis in the study also appears to exclude preexisting cardiovascular disease and diabetes as possible effect modifiers.

No information on treatment discontinuation, compliance, and therapeutic range of T achieved

Without documented information on treatment compliance and the levels of T achieved during treatment, it is difficult to conclude that raising T in the treated men was directly responsible for the observed lower mortality. The treatment discontinuation rate was not reported. This is particularly important because the secondary analysis, censoring men who stopped T treatment, showed an insignificant reduction in mortality risk (hazard ratio, 0.65; P = 0.098). This implies not only a substantive loss of power, but also the small number of events and probably a fair percentage of dropouts or discontinuations. Again, reasons for discontinuation were not available.

High morbidity/mortality sample

The cohort studied had an average of 6.7 comorbid conditions and a higher average mortality rate of 16.7% in 4 yr, which is said to be typical of VA men but higher than that of the general population of a similar age. As noted by the authors, the present results therefore are not generalizable to populations of healthier men.

Clinical Implications

Due to the multiple drawbacks listed above as well as the intrinsic limitations of an observational study, a causal relationship between T treatment and lower all-cause mortality has not been established by this work. The results reported here must therefore not be interpreted as indicating that T treatment can lower mortality risks in men. The cautions appropriately highlighted by the authors in their conclusion and echoed in this editorial must be heeded to avoid misinterpretation or misquotation of these findings to be a clarion call for the use of T for life span extension.

An ever-increasing number of middle-aged and elderly men are presenting to endocrinologists and primary care physicians with mostly nonspecific symptoms and borderline or low normal levels of T. Clinicians should be aware that their current practice in dealing with these patients is burdened by uncertainties and at times equivocal or weakly-supported guidelines. Perhaps the most compelling lesson of this publication is not that T treatment can lower mortality, but rather to highlight our overly simplistic and rudimentary understanding of how changes in T may or may not contribute to the health of aging men. To address this challenge demands a much broader systems understanding of the biological (including genetic), socioeconomic, and environmental mechanisms underpinning the complex relationships between T and the health of aging men. This should then provide an informed basis for the design of pivotal randomized placebo-controlled prospective studies.

A broader perspective is the historic underappreciation of, and consequently the underfunding of research into, men's health as a public health target, despite the higher mortality rates compared with that of women. In contrast to the substantial research efforts into hormone replacement therapy for the menopause and improvement of women's health, the continuing paucity of evidence-based information on male sex hormone and health status of men is remarkable and regrettable.


References

1. Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, O'Neill TW, Bartfai G, Casanueva FF, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Boonen S, Vanderschueren D, Labrie F, Huhtaniemi IT 2010 Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 363:123–135.

2. Swerdloff R, Wang C 2011 Testosterone treatment of older men—why are controversies created? J Clin Endocrinol Metab 96:62–65.

3. Cunningham GR, Toma SM 2011 Why is androgen replacement in males controversial? J Clin Endocrinol Metab 96:38–52.

4. Karagiannis A, Harsoulis F 2005 Gonadal dysfunction in systemic diseases. Eur J Endocrinol 152:501–513.

5. Kaufman JM, Vermeulen A 2005 The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 26:833–876.

6. Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, Eder R, Tennstedt S, Ulloor J, Zhang A, Choong K, Lakshman KM, Mazer NA, Miciek R, Krasnoff J, Elmi A, Knapp PE, Brooks B, Appleman E, Aggarwal S, Bhasin G, Hede-Brierley L, Bhatia A, Collins L, LeBrasseur N, Fiore LD, Bhasin S 2010 Adverse events associated with testosterone administration. N Engl J Med 363:109–122.

7. Ruige JB, Mahmoud AM, De Bacquer D, Kaufman JM 2011 Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis. Heart 97:870–875.

8. Hyde Z, Norman PE, Flicker L, Hankey GJ, Almeida OP, McCaul KA, Chubb SA, Yeap BB 2012 Low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in Men Study. J Clin Endocrinol Metab 97:179–189.

9. Corona G, Rastrelli G, Monami M, Guay A, Buvat J, Sforza A, Forti G, Mannucci E, Maggi M 2011Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. Eur J Endocrinol 165:687–701.

10. Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA 2011 Endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab 96:3007–3019.

11. Wu FC, von Eckardstein A 2003 Androgens and coronary artery disease. Endocr Rev 24:183–217.

12. Yeap BB 2010 Androgens and cardiovascular disease. Curr Opin Endocrinol Diabetes Obes 17:269–276.

13. Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM 2012 Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 97:2050–2058.

14. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM 2010 Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 95:2536–2559.

15. Jones TH, Arver S, Behre HM, Buvat J, Meuleman E, Moncada I, Morales AM, Volterrani M, Yellowlees A, Howell JD, Channer KS 2011 Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 34:828–837.

 

[BBC3]

The interesting differentiation will be when they start discerning/documenting at what age the subjects began the therapy. For example, will supplementing testosterone prevent hormone driven cancers(if given early enought) that it would otherwise fuel if the cancer is already set up? And what will the outcome be for individuals metabolizing testosterone to high esterogens, or androgens? Right now these studies are just SHIT TALKIN....

Even more importantly, would estrogen mitigators be essential in preventing illness. In obese men? In women in general? It does seem like breast cancer is on the rise and at younger ages.. They have never really checked men for TT levels historically, so you still have to wonder has it always been the case? Are Xenoestrogens really an issue?

 

[Michael Scally MD]

Yeap BB. Testosterone therapy and mortality in US veterans. Asian J Androl. http://www.nature.com/aja/journal/vaop/ncurrent/full/aja201274a.html

Whether lower testosterone levels are a causal factor or biomarker for disease in older men remains fiercely debated, as randomized controlled trials with endpoints of cardiovascular events or mortality are lacking. Here, a recent retrospective study in US veterans is discussed, which compares mortality rates in men who were and were not prescribed testosterone.