In this study, the largest analysis undertaken to define the prevalence of subnormal free testosterone concentrations in obese men, the data show clearly that 40% of all obese nondiabetic men and 49% of morbidly obese nondiabetic men had subnormal free testosterone concentrations. Furthermore, there was an inverse relationship between free testosterone concentrations and BMI. According to the National Health and Nutrition Examination Survey (NHANES) 2003–2004 data, 31% of all adult men in U.S. are obese and 2.8% are morbidly obese (14
). Thus, in view of the fact that almost one-third of the U.S. population is obese, these observations have profound pathophysiological, clinical, epidemiological, and public health implications. This study is also the first to comprehensively assess the comparative prevalence of subnormal free testosterone concentrations with obesity and diabetes separately and together when they coexist.
Our study shows that diabetic men with and without obesity have lower free testosterone concentrations than nondiabetic men after adjustment for age or BMI. The effect of having diabetes on the free testosterone concentration in a 60-year-old man was similar to that of an increase in BMI of 6 kg/m2
(equal to weight gain of 25 kg in a 180-cm [6-feet] tall man) in a man without diabetes. The elevated insulin resistance of type 2 diabetic men compared with that of obese men may explain these findings. Cross-sectional analysis of the NHANES III data (101 diabetic and 1,312 nondiabetic men) has shown that low androgens are associated with the presence of diabetes in men (15
). The prevalence of low free testosterone concentrations was not mentioned in that analysis. The mean calculated free testosterone concentrations were similar in diabetic and nondiabetic men. We found a small (6%) but statistically significant difference in the age- and BMI-adjusted free testosterone concentrations of diabetic and nondiabetic men. The larger number of diabetic subjects in our study might explain the difference in our data and that from NHANES III. The mean age and BMI of NHANES III subjects (57 years and 29.5 kg/m2
) were lower than those of our diabetic study subjects. Consistent with the NHANES III study, we did not find a difference in SHBG concentrations of diabetic and nondiabetic men.
The prevalence of low free testosterone in diabetic men was higher in all BMI categories compared with that in nondiabetic men. Whereas nondiabetic men showed an increase in prevalence of subnormal free testosterone across BMI categories, there was no significant change in the prevalence of low free testosterone with increasing BMI in the diabetic men. This is attributable to the high prevalence of low free testosterone in lean diabetic men (45% after adjustment for age). Nevertheless, we found that free testosterone concentrations decreased significantly with increasing BMI in both diabetic and nondiabetic men. In the morbidly obese subjects, we found that there was a nonsignificant trend toward lower free testosterone concentrations and higher prevalence of subnormal free testosterone in diabetic men compared with that in nondiabetic men. This could be due to smaller numbers of morbidly obese men in the study (51 diabetic and 57 nondiabetic).
Free testosterone concentrations were negatively related to age in our study. We found that obese men had a smaller age-related decline of free testosterone concentrations compared with that in nonobese men. This result suggests an independent effect of BMI-related factors on free testosterone concentrations. Although our study cannot answer questions about the causes of low free testosterone in the obese and type 2 diabetic men, several prior studies have addressed this question (10
It has been suggested that the increase in adipose tissue mass in obesity may result in increased aromatase activity and thus lead to a greater conversion of testosterone into estradiol (12
). An increase in estradiol concentrations would lead to the suppression of hypothalamic gonadotropin-releasing hormone and pituitary gonadotropin secretion. This would result in the reduction of both testosterone secretion by Leydig cells and spermatogenesis in the seminiferous tubules. Young overweight and obese men are indeed known to have a decrease in sperm count (17
). However, there hitherto has been no study demonstrating that estradiol concentrations are actually elevated in obese or diabetic patients with subnormal testosterone concentrations. If indeed, this result is confirmed, aromatase inhibition could be a therapeutic strategy in future. Unfortunately, estradiol concentrations are not available in our study.
The other possible mechanism involved in the pathogenesis of obesity-related low free testosterone is insulin resistance. The selective deletion of the insulin receptor gene from neurons results in a syndrome of hypogonadotrophic hypogonadism in mice in addition to a state of systemic insulin resistance (16
). It is therefore possible that insulin resistance at the hypothalamic level contributes to the pathogenesis of this syndrome. The concurrent presence of marked inflammation may contribute to insulin resistance because inflammatory mediators such as tumor necrosis factor-α and interleukin-6 may interfere with insulin signal transduction (18
). Clearly, further investigation is necessary to define the etiology of this syndrome.
In view of the increasing prevalence of obesity even in younger populations, it would be important to conduct a similar study in young individuals at the prime of their reproductive years. It is relevant that the prevalence of hypogonadotropic hypogonadism is greater than 50% in patients with type 2 diabetes aged between 18 and 35 years (19
We also found that SHBG concentrations are negatively related to BMI and positively to age. SHBG concentrations decrease with insulin resistance, and low SHBG concentrations are predictive of future development of type 2 diabetes (20
). Although this finding has been well established in previous studies, the pathophysiological mechanisms behind these associations are not known and need to be explored in future studies.
One of the limitations of our study is that we could not differentiate between type 1 and type 2 diabetes in our study subjects. The presence of diabetes was recorded by a physician. However, because >90% of diabetic individuals have type 2 diabetes and this number is even higher in those aged >45 years, this issue is not likely to affect the overall conclusions of this study. We have previously shown that the prevalence of hypogonadism in type 1 diabetes is markedly lower than that in type 2 diabetes (5
). Only 17 patients were receiving insulin monotherapy, and thus they may have type 1 diabetes. Excluding these men did not change the results of the study.
It is well known that there is a significant day-to-day variability in hormone concentrations, especially testosterone. As for most epidemiological or cross-sectional studies, the testosterone concentrations in the HIM study were measured only once. In view of the variability in testosterone concentrations, this is a limitation. However, it is not likely that the prevalence of low testosterone concentrations would have been altered after repeated measurements because the probability of testosterone concentrations rising or falling with repeated measurements is statistically equal. The issue of repeated measurements is important in the context of diagnosing hypogonadism clinically in the context of a single patient. The fact that our study included a moderately large number of participants also helps to diminish the effect of hormonal variability on study effects and the relationship with BMI.
We did not have a validated questionnaire for erectile dysfunction and symptoms of hypogonadism. Therefore, we cannot comment on the frequency of symptomatic hypogonadism in our study. It has been shown in the past that a high percentage of diabetic men with low testosterone concentrations have symptomatic hypogonadism (3
). Lower testosterone concentrations are inversely related to visceral adiposity (3
). However, waist circumference or body composition imaging was not available in our study. Another limitation of our study is that the subjects were not required to be fasting when providing blood samples. It has recently been shown that an oral glucose load of 75 g can acutely lower total testosterone concentrations by 25% (23
). However, in a prior analysis of these data, no difference was found in total testosterone concentrations from blood samples drawn between 8 a.m.
and 10 a.m.
vs. 10 a.m.
and 12:00 p.m.
In conclusion, 40% of obese nondiabetic men, aged ≥45 years have subnormal free testosterone concentrations; 26% of normal-weight nondiabetic men and 44% of normal-weight diabetic men had subnormal free testosterone concentrations. The combination of obesity and diabetes increases the prevalence of subnormal free testosterone concentrations to 50%. Thus, both obesity and diabetes appear to exert independent effects on the prevalence of low free testosterone concentrations in addition to age. In view of the high rates of prevalence of subnormal free testosterone in patients with obesity or diabetes, concentrations of free testosterone should be measured in these populations especially when these conditions occur concomitantly.