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Expert snapshot Comorbidities common with hypogonadism Metabolic syndrome Type 2 diabetes Obesity Sleep apnea Chronic obstructive pulmonary disease Anemia

The objectives of the HIM study were to identify men with hypogonadism and comorbidities in patients presenting to primary care physicians’ offices. Results revealed that several common medical conditions are significantly associated with low levels of testosterone: hypertension, hyperlipidemia, diabetes, and obesity (P<.001 for all). Asthma/chronic obstructive pulmonary disease was also correlated with hypogonadism (P=.013).6

A cross-sectional study by Rhoden and colleagues (N=746) in a urology center evaluated the relationship between type 2 diabetes and serum free and total testosterone levels.12 Subnormal total testosterone levels were more strongly associated with elevated body mass index (BMI) and waist:hip ratio than with diabetes, indicating that total testosterone levels are more influenced by obesity and central adiposity.12 Although the physiologic reason has not been established, it has been shown that as BMI increases, there is a parallel decrease in SHBG and total and free testosterone levels.13

A study of more than 350 men by Kapoor and colleagues took this association a step further, evaluating both biochemical measures of testosterone and symptoms of hypogonadism as they relate to the presence of type 2 diabetes.14 Results showed that symptomatic hypogonadism is highly prevalent in men with type 2 diabetes, with ED being the most common symptom of hypogonadism in men with diabetes (>70%). This highlights the importance of measuring testosterone in men presenting with ED and type 2 diabetes, a condition frequently seen by primary care clinicians.

It has been established that metabolic syndrome is associated with subsequent development of type 2 diabetes and cardiovascular disease. Similar to the association between low testosterone levels and the prevalence of type 2 diabetes, low testosterone levels are also associated with higher prevalence of metabolic syndrome.15,16 Muller and colleagues showed that lower levels of testosterone and SHBG in aging men are independently associated with lower insulin sensitivity and an increased risk of metabolic syndrome.15

Makhsida and colleagues conducted a review from 1988 to 2004 of the associations between hypogonadism, testosterone, and metabolic syndrome and concluded that not only is hypogonadism a component of metabolic syndrome, but testosterone therapy may “have the tremendous potential to slow

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Cardiovascular disease Sarcopenia Depression Rheumatoid arthritis Osteoporosis, frailty Memory loss

or halt the progression from metabolic syndrome to overt diabetes or cardiovascular disease via beneficial effects on insulin regulation, lipid profile, and blood pressure.”17

Another condition seen often in primary care is depression. The Rancho Bernardo Study (N=856; men aged 50-89 y) showed an association between bioavailable testosterone and mild depression as measured by Beck Depression Index scores.18 The authors concluded that testosterone therapy may improve depressed mood in older men with low levels of bioavailable testosterone, although the overall data on the effect of testosterone on mood are mixed.

Studies report that low levels of testosterone are associated with increased mortality. In a retrospective study (N=858),19 male veterans aged 40 years and older who had testosterone levels measured were followed for 8 years. After adjusting for age, morbidity, and other clinical covariates, low testosterone levels (<250 ng/dL) were associated with increased mortality (P<.001).

Similarly, The Rancho Bernardo Study (N=794), a prospective study that followed men with low testosterone (<241 ng/dL) for up to 20 years, demonstrated that low testosterone in older men was associated with increased mortality, particularly from cardiovascular disease and respiratory diseases, independent of multiple risk factors and preexisting comorbid conditions.20

The associations between testosterone and coronary artery disease, diabetes, metabolic syndrome, obesity, and BMI are clearly significant. Because primary care physicians are on the frontline to recognize, diagnose, and then treat hypogonadism, it is important for them to be aware of the nuances and challenges associated with this condition. A variety of effective treatment options are available, and a multidisciplinary approach may be warranted for the complicated patient.

Key messages Hypogonadism:

  • Is associated with aging

  • Is common, underdiagnosed, and undertreated, despite observable symptoms

  • Is associated with chronic medical conditions that may negatively affect overall health

  • May impact mortality

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