Testosterone levels and anemia in older men
July 2017
Anemia is a common concern among the elderly; after the age of 50 years, anemia prevalence increases rapidly, especially in men.1-4 In community studies, the prevalence of anemia in older men has been reported to range from 11%1 to 28%.3,5 The decline of hemoglobin and development of anemia with age is not part of "normal aging"; it is a sign of health deterioration and disease.3,6
Several studies have suggested that anemia is an independent risk factor for mortality.3,5,7,8 Men with anemia may be at higher mortality risk than women; in a large-scale investigation of 6880 elderly patients seen in the primary care clinics, even mild anemia without severe comorbidities was associated with nearly double the risk for all-cause mortality in men, but not in women.4 Anemia also has been shown to pose a greater risk in men with myocardial infarction than in women.9 Therefore, laboratory investigation of anemia in men older than 50 years is warranted. It is alarming that anemia is rarely acknowledged and investigated among patients.10
Here we summarize the results of The Anemia Trial of the Testosterone Trials.11
KEY POINTS
- Testosterone treatment of older men with low testosterone levels and unexplained anemia corrected the anemia more than placebo. This treatment also corrected anemia more than placebo in men who had anemia of known causes, such as iron deficiency.
- Testosterone deficiency in older men results in decreased hemoglobin levels, which can cause mild anemia.
- Correcting testosterone deficiency increases hemoglobin levels and tends to correct the anemia, even in the presence of a coexisting cause of anemia (such as iron and/or vitamin B12 deficiencies, chronic inflammation).
What is known
The WHO (World Health Organization) defines anemia as hemoglobin levels less than 13 g/dL in men and less than 12 g/dL in women.12 The reference range for hemoglobin levels in men is 14-17.5 g/dL (reference ranges may vary depending on laboratory, instruments, and methods).13
Anemia has numerous health consequences – summarized in table 1 - which historically have not been acknowledged among health care professionals. In the ARIC (Atherosclerosis Risk in Communities) study, which included 14,410 subjects (6,267 men and 8,143 women), nearly 10% were found to have low hemoglobin.14 During a follow-up of 6.1 years, 3.8% of the subjects had cardiovascular disease events and it was concluded that anemia is an independent risk factor for cardiovascular disease outcomes.14
In the CADILLAC study (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications), 12.8% of 2082 patients of any age with acute myocardial infarction had anemia, which was strongly associated with adverse outcomes and increased mortality.15
In a study of 1410 consecutive patients with acute coronary syndromes (ACS), anemia was detected in 27% of the CAS patients.16 Anemia was found to be an independent predictive factor of mortality and had incremental predictive value to the GRACE risk score for early clinical outcomes (the GRACE score stratifies risk in patients with diagnosed ACS to estimate their in-hospital and 6-month to 3-year mortality17).16
An analysis of 422,855 patients with ACS showed that 28% of patients presenting with ACS are anemic and that these patients are older, have a greater prevalence of renal disease, peripheral vascular disease, diabetes mellitus, and previous acute myocardial infarction, and are less likely to receive evidence-based therapies shown to improve clinical outcomes.18 It was also found that anemia is independently associated with 30-day and 1-year mortality.18 It was concluded that the prevalence of anemia in a national UK ACS cohort is clinically significant. Patients with anemia are older and multi-morbid and less likely to receive evidence-based therapies shown to improve clinical outcomes, with the presence of anemia independently associated with mortality outcomes.18
Worse quality of life
- Fatigue, weakness, and dyspnea
- Increased frailty
- Higher rates of disabilities
- Lower muscular strength and physical performance
- Lower cognitive function, dementia, and depression
Increased healthcare utilization
- Higher hospitalization rates
- Longer lengths of stay
- Higher readmission rates.
Increased fracture risk independent of bone mineral density19
Increased morbidity
- Increased odds of developing cardiovascular disease
- Worse outcomes in cardiovascular conditions such as myocardial infarction and heart failure
- Worse outcomes in other diseases such as cancer and renal failure
Increased morbidity
- Double the mortality risk even with mild anemia (hemoglobin >10 g/dL)
- High mortality rates in nursing home residents
Table 1. Summary of adverse outcomes observed in elderly with anemia.6
Table adapted from Halawi R, Moukhadder H, Taher A. Anemia in the elderly: a consequence of aging? Expert review of hematology. 2017;10(4):327−335
Often, there is an underlying etiology for the anemia.6 Several causes of anemia in the elderly are recognized, including iron and vitamin B12 deficiencies, chronic inflammation and disease, chronic renal insufficiency, and the myelodysplastic syndromes.6 However, in approximately one-third of older adults with anemia no recognized cause can be found.1,20-22 No treatment has been shown to ameliorate this unexplained anemia.
One possible cause of unexplained anemia in older men is testosterone deficiency, because testosterone levels decline as men age23,24, in parallel with declining hemoglobin levels1-4, and testosterone treatment of men with low testosterone increases hemoglobin levels.25,26 Further support for this comes from population studies showing that low testosterone levels are significantly associated with unexplained anemia.2728
Although testosterone treatment of older men with low testosterone levels has been shown to increase their hemoglobin concentrations29-31, few studies have specifically addressed the effect of testosterone in anemic men, and none has examined the effect of testosterone on men with unexplained anemia.
What this study adds
The main goal of The Anemia Trial of the Testosterone Trials was to test the hypothesis that testosterone treatment of men aged 65 years or older with low testosterone levels and unexplained anemia would increase hemoglobin levels.11
The Anemia Trial enrolled 788 men 65 years or older who had average testosterone levels of less than 9.5 nmol/L (275 ng/dL). Of 788 participants, 126 were anemic (hemoglobin below 12.7 g/dL), 62 of whom had no known cause. Mean age was 75 years and body mass index (BMI) 31 kg/m2.
They were randomized to receive testosterone gel or a placebo gel, applied to the skin daily. The goal of testosterone treatment was to increase testosterone levels to within the normal range for young men and maintain it during the one year treatment period. The initial dose was 5 g of 1% gel. Blood testosterone levels were measured at months 1, 2, 3, 6, and 9, and the dose was adjusted after each measurement, if necessary, to achieve the target range of 17.3-27.7 nmol/L (500–800 ng/dL).
Compared with placebo, testosterone treatment for 12 months significantly increased hemoglobin levels and reduced the prevalence of both unexplained anemia and anemia of known cause.11 These increases may be of clinical value, as suggested by the magnitude of the changes and the correction of anemia in most men. Measurement of testosterone levels might be considered in men 65 years or older who have unexplained anemia and symptoms of low testosterone levels.11
Commentary
An important finding in The Anemia Trial of the Testosterone Trials is that testosterone treatment reduces prevalence of anemia in hypogonadal men, regardless of underlying cause of anemia, known or unexplained.11 This is notable considering that there is no established treatment of unexplained anemia.
The improvement in hemoglobin levels by testosterone treatment in men who have unexplained anemia supports the suggestion that testosterone deficiency may contribute to the development of anemia, even in the absence of other causes.25-28 The improvement in hemoglobin levels by testosterone treatment in men who have anemia of known cause suggests that this anemia is due to both the known cause (such as iron and/or vitamin B12 deficiencies, chronic inflammation) as well as to low testosterone levels.11 Therefore, evaluation of unexplained anemia in older men with symptoms consistent with hypogonadism should include measurement of testosterone levels.
In line with the adverse outcomes observed in elderly with anemia (table 1)6, increases in hemoglobin levels with testosterone treatment were associated with improvement in walking and vitality, as well as with men’s impression of change in overall health and energy.11 This suggests that the increase in hemoglobin levels and amelioration of anemia with testosterone treatment is clinically meaningful.
References
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- Salive ME, Cornoni-Huntley J, Guralnik JM, et al. Anemia and hemoglobin levels in older persons: relationship with age, gender, and health status. J Am Geriatr Soc. 1992;40(5):489-496. Return to content
- Izaks GJ, Westendorp RG, Knook DL. The definition of anemia in older persons. JAMA. 1999;281(18):1714-1717. Return to content
- Endres HG, Wedding U, Pittrow D, Thiem U, Trampisch HJ, Diehm C. Prevalence of anemia in elderly patients in primary care: impact on 5-year mortality risk and differences between men and women. Curr Med Res Opin. 2009;25(5):1143-1158. Return to content
- Dong X, Mendes de Leon C, Artz A, Tang Y, Shah R, Evans D. A population-based study of hemoglobin, race, and mortality in elderly persons. J Gerontol A Biol Sci Med Sci. 2008;63(8):873-878. Return to content
- Halawi R, Moukhadder H, Taher A. Anemia in the elderly: a consequence of aging? Expert review of hematology. 2017;10(4):327-335. Return to content
- Denny SD, Kuchibhatla MN, Cohen HJ. Impact of anemia on mortality, cognition, and function in community-dwelling elderly. Am J Med. 2006;119(4):327-334. Return to content
- Zakai NA, French B, Arnold AM, et al. Hemoglobin decline, function, and mortality in the elderly: the cardiovascular health study. Am J Hematol. 2013;88(1):5-9. Return to content
- Tsujita K, Nikolsky E, Lansky AJ, et al. Impact of anemia on clinical outcomes of patients with ST-segment elevation myocardial infarction in relation to gender and adjunctive antithrombotic therapy (from the HORIZONS-AMI trial). Am J Cardiol. 2010;105(10):1385-1394. Return to content
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- Roy CN, Snyder PJ, Stephens-Shields AJ, et al. Association of Testosterone Levels With Anemia in Older Men: A Controlled Clinical Trial. JAMA internal medicine. 2017;177(4):480-490. Return to content
- WHO. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System. Geneva, World Health Organization, 2011 (WHO/NMH/NHD/MNM/11.1) http://www.who.int/vmnis/indicators/haemoglobin.pdf, accessed July 9th, 2017 Return to content
- Hemoglobin Concentration (Hb). Available at http://emedicine.medscape.com/article/2085614-overview (accessed July 9thm 2017). 2014. Return to content
- Sarnak MJ, Tighiouart H, Manjunath G, et al. Anemia as a risk factor for cardiovascular disease in The Atherosclerosis Risk in Communities (ARIC) study. J Am Coll Cardiol. 2002;40(1):27-33. Return to content
- Nikolsky E, Aymong ED, Halkin A, et al. Impact of anemia in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention: analysis from the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial. J Am Coll Cardiol. 2004;44(3):547-553. Return to content
- Meneveau N, Schiele F, Seronde MF, et al. Anemia for risk assessment of patients with acute coronary syndromes. Am J Cardiol. 2009;103(4):442-447. Return to content
- Littnerova S, Kala P, Jarkovsky J, et al. GRACE Score among Six Risk Scoring Systems (CADILLAC, PAMI, TIMI, Dynamic TIMI, Zwolle) Demonstrated the Best Predictive Value for Prediction of Long-Term Mortality in Patients with ST-Elevation Myocardial Infarction. PloS one. 2015;10(4):e0123215. Return to content
- Mamas MA, Kwok CS, Kontopantelis E, et al. Relationship Between Anemia and Mortality Outcomes in a National Acute Coronary Syndrome Cohort: Insights From the UK Myocardial Ischemia National Audit Project Registry. Journal of the American Heart Association. 2016;5(11). Return to content
- Valderrabano RJ, Lee J, Lui LY, et al. Older Men with Anemia Have Increased Fracture Risk Independent of Bone Mineral Density. J Clin Endocrinol Metab. 2017. Return to content
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- Snyder PJ, Peachey H, Berlin JA, et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab. 2000;85(8):2670-2677. Return to content
- Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374(7):611-624. Return to content
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- Wang C, Cunningham G, Dobs A, et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 2004;89(5):2085-2098. Return to content
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