Hypogonadism, Muscle Weakness, and Multimorbidity in Men

Hypogonadism, Muscle Weakness, and Multimorbidity in Men

STUDY: Peterson MD, Belakovskiy A, McGrath R, Yarrow JF. Testosterone Deficiency, Weakness, and Multimorbidity in Men. Scientific reports. 2018;8(1):5897.

Low testosterone is associated with deterioration of the musculoskeletal system, commonly manifesting as osteopenia and sarcopenia, and ultimately frailty.1,2 Furthermore, low testosterone is independently associated with various obesity-related chronic diseases in men, including type 2 diabetes and cardiovascular disease3-5, as well as with higher rates of all-cause mortality.6-10

However, it is unknown what constitutes optimal physiological levels of testosterone in men, and what effects different testosterone levels have on disease risk. Here we present the results of a study that evaluated the association between hypogonadism, also known as testosterone deficiency, muscle weakness and multimorbidity in men.11 The prevalence of multimorbidity was examined among young, middle-aged, and older men, with and without testosterone deficiency.

Key Points

  • Men with hypogonadism - including younger men - have a significantly higher prevalence of multimorbidity compared to age-matched men with normal testosterone levels.
  • Compared to high testosterone levels, low and moderate testosterone levels are associated with a 2.9-fold and 1.7-fold increased risk of multimorbidity.
  • Low and moderate testosterone levels are associated with increased risk of multimorbidity even after adjusting for obesity and grip strength.
  • Low testosterone and weakness in men are independently associated with multimorbidity at all ages; however, multimorbidity is most prevalent among young and older men with testosterone deficiency.

What is known about testosterone, muscle strength / weakness and health

Low testosterone is strongly associated with worse health outcomes in men, including reduced sexual activity, obesity, insulin resistance, inflammation, dyslipidemia, metabolic syndrome, atherosclerosis, cardiovascular events and mortality, as well as depressed mood, reduced motivation, fatigue, frailty, anemia, bone loss and decreased quality of life.12-22

Testosterone also has multiple effects on skeletal muscle23, and low testosterone levels are associated with reduced muscle mass, strength and physical performance.24-26 Not surprisingly, testosterone therapy that normalizes testosterone levels (i.e. increases testosterone levels by a magnitude that is large enough within the physiological range to achieve health benefits) increases muscle mass and strength.27-30

However, there are scant data on the association between testosterone, muscle strength/weakness and risk of chronic disease across the adult life span among men in the general population.

What this study adds

The primary purpose of this study was to evaluate the association between hypogonadism and muscle weakness with chronic multimorbidity in a large, population-representative sample of U.S. men. Data were collected from 2011-2012 The National Health and Nutrition Examination Survey (NHANES) which provides relevant information about prevalence of chronic diseases and total testosterone, as well as direct measures of muscle strength. The study also analysed the effect of different testosterone levels among young, middle-aged, and older men on prevalence of multimorbidity.

Multimorbidity was defined as the presence of at least two chronic conditions among a list of risk factors and chronic diseases; obesity BMI ≥30 kg/m2, elevated waist circumference >102 cm, hypertriglyceridemia, low HDL cholesterol, hypertension, diabetes, arthritis, cardiovascular disease, stroke, emphysema, depression. Muscle strength was assessed using a handgrip dynamometer. Grip strength was normalized as strength per kg bodyweight.

Hypogonadism was defined as <300 ng/dL (10.4 nmol/L). Testosterone levels were defined as low, medium and high for each age group, as follows:

Testosterone status 20 - 39.9 years 40 - 59.9 years ≥60 years
High testosterone >16.9 nmol/L >15.3 nmol/L >15 nmol/L
  >488 ng/dL >440 ng/dL >433 ng/dL
Medium testosterone 12 - 16.9 nmol/L 10.1 - 15.3 nmol/L 10.1 - 15 nmol/L
  347-488 ng/dL 291-440 ng/dL 290-433 ng/dL
Low testosterone <12 nmol/L 10.1 nmol/L 10.1 nmol/L
  <347 ng/dL <291 ng/dL <290 ng/dL

Prevalence of hypogonadism (<300 ng/dL [10.4 nmol/L]) was 31% for the entire NHANES population, and 23%, 36%, and 35% for young, middle-aged, and older men, respectively. As illustrated in figures 1-3, the prevalence of individual risk factors and chronic diseases was significantly higher in men with hypogonadism as compared to men with normal testosterone levels. In younger and older men, the prevalence of multimorbidity was also significantly higher in men with hypogonadism compared to men with normal testosterone levels.

Figure 1: Differences in prevalence of risk factors and chronic diseases in young men age 20-39.9 years with hypogonadism (<10.4nmol/L or <300 ng/dL)
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Figure 1: Differences in prevalence of risk factors and chronic diseases in young men age 20-39.9 years with hypogonadism (<10.4nmol/L or <300 ng/dL) versus normal testosterone (>10.4 nmol/L or >300 ng/dL).

Figure 2: Differences in prevalence of risk factors and chronic diseases in middle-aged men age 40-59.9 years with hypogonadism
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Figure 2: Differences in prevalence of risk factors and chronic diseases in middle-aged men age 40-59.9 years with hypogonadism (<10.4nmol/L or <300 ng/dL) versus normal testosterone (>10.4 nmol/L or >300 ng/dL).

Figure 3: Differences in prevalence of risk factors and chronic diseases in older men age ≥60 years with hypogonadism (<10.4nmol/L or <300 ng/dL)
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Figure 3: Differences in prevalence of risk factors and chronic diseases in older men age ≥60 years with hypogonadism (<10.4nmol/L or <300 ng/dL) versus normal testosterone (>10.4 nmol/L or >300 ng/dL).

Data from Peterson MD, Belakovskiy A, McGrath R, Yarrow JF. Testosterone Deficiency, Weakness, and Multimorbidity in Men. Scientific reports. 2018;8(1):5897.

Both testosterone and muscle strength were robustly associated with multimorbidity. Testosterone levels were significantly correlated with grip strength, even after adjusting for age, race/ethnicity, income and education.

Compared to the high testosterone group, the low and moderate testosterone groups had a 2.9-fold and 1.6-fold increased risk of multimorbidity. This increased risk remained even after adjusting for muscle strength.

It was concluded that low testosterone and weakness in men are independently associated with multimorbidity at all ages; however, multimorbidity is more prevalent among young and older men with testosterone deficiency.

Commentary

The present study shows a higher prevalence of hypogonadism, 31%, in a large population-representative sample of U.S. men across the adult age-span than what has been previously reported. It is especially notable that among young men, nearly one out of four (22.6%) had hypogonadism and one out of five (17.4%) had multimorbidity. The finding that young men with low and moderate testosterone have a significantly higher risk of multimorbidity than young men with high testosterone levels provides a rationale for checking testosterone levels even among young men, particularly those with existing obesity, diabetes, cardiovascular disease, hypertension, depression, low HDL cholesterol, or hypertriglyceridemia, as each of these conditions are significantly more common in those with testosterone deficiency. This is in accordance with the 2016 American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Comprehensive Clinical Practice Guidelines for Medical Care of Patients with Obesity.31 The AACE/ACE guidelines recommend that all men, regardless of age, who have an increased waist circumference (≥102 cm) or who are obese (BMI ≥30) or have type 2 diabetes should have their testosterone levels checked.31 The American Diabetes Association recommends in their 2018 Standards of Medical Care in Diabetes that testosterone should be measured in men with type 2 diabetes who have symptoms or signs of hypogonadism, such as decreased sexual desire (libido) or activity, or erectile dysfunction.32

Considering the strong association between low testosterone and multimorbidity even in young men, it is possible that low testosterone may play a causal role in chronic disease development. Early detection and treatment of low testosterone in young men could possibly slow progression, or potentially stop disease development entirely. This warrants further research. If confirmed in prospective studies, this could change screening guidelines for hypogonadism, as well as have a significant impact on the development of risk factors and/or chronic diseases, such as obesity, metabolic syndrome, cardiovascular disease and type 2 diabetes, the prevalence of which has reached epidemic proportions over the last decade.

In the present study, different thresholds were used to define low, medium and high testosterone levels for each age group. However, definitive age-specific reference ranges do not exist and there are insufficient data to define optimal target testosterone levels during treatment.33 The aim of therapy is therefore to restore testosterone levels to the mid-normal range for healthy young men34, and then adjust the dose on an individual basis based on patient response.33

It is notable that the reduced risk of multimorbidity in the group with the highest testosterone level remained significant even after adjusting for grip strength, which is a strong predictor of physical function and risk of diabetes, cardiovascular disease, and mortality, particularly cardiovascular mortality, in men.35-42 This suggests that testosterone confers protection above and beyond its well-established beneficial effects on muscle and strength.

The results from the present study confirm findings from previous studies, which showed that higher testosterone levels are associated with better health outcomes. The MrOS (Osteoporotic Fractures in Men) Study showed that men in the group with the highest testosterone levels (≥19.1 nmol/L or ≥550 ng/dL) had a 30% lower risk of cardiovascular events compared with men in groups with lower testosterone levels (hazard ratio: 0.70). This association remained after adjustment for traditional cardiovascular risk factors.15 A large meta-analysis of observational studies including over 16 000 men reported a 55% higher all-cause mortality (relative risk: 1.55) in men with baseline testosterone levels below 16.9 nmol/L (487 ng/dL).6 Interestingly, this threshold is about the same as that used in the present study to define high testosterone levels. Other studies have reported that each 1 nmol/L (29 ng/dL) incremental increase in testosterone levels, even for men in the eugonadal range, was associated with a reduced all-cause and cardiovascular mortality.5,8,43 Several large population-based prospective studies show increased prevalence of cardiovascular risk factors and increased all-cause mortality in both young and older men with low testosterone, compared to men with high testosterone levels.6-10

Low testosterone has traditionally been considered "old men's problem". However, as the present study shows11, as well as other studies44, low testosterone can also affect younger men. This suggests that the underlying changes in hormonal and metabolic dysregulation that lead to multimorbidity are gradual and develop throughout the adult lifespan. Hence, a young age does not make men immune to low testosterone and its health consequences.

Another notable finding is the high prevalence of obesity and abdominal obesity among young men, especially young men with hypogonadism. In all age groups, men with hypogonadism had a significantly higher prevalence of abdominal obesity and obesity.

The present study provides a rationale for men who are obese or have elevated waist circumference, hypertension, low HDL, hypertriglyceridemia, cardiovascular disease, diabetes or depression to have their testosterone levels checked regularly. Considering the significantly increased risk for multimorbidity with low testosterone in young and older men, treatment with testosterone therapy in hypogonadal men is warranted regardless of age.

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Last updated: 2018
G.MKT.GM.MH.01.2018.0500