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.
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.