Our data show clearly that the mean total and free testosterone concentrations in young patients with type 2 diabetes are significantly lower than those in patients with type 1 diabetes. Eight of 24 type 2 diabetic patients had low free testosterone concentrations. According to previously published data, normal free testosterone concentrations in young men (age 21–29 years) are 0.278–0.777 nmol/l (11
). The mean free testosterone concentration of type 2 diabetic patients in our study was 0.296 nmol/l. This is clearly low for a group in its peak reproductive years. Fourteen of 24 patients had free testosterone concentrations <0.278nmol/l. Thus, this small sample of younger patients with type 2 diabetes had a prevalence of hypogonadism of 33% on the basis of the standard normal ranges. However, if the normal range from a study on younger male subjects aged 20–29 years is used, 14 of 24 (58%) type 2 diabetic subjects were subnormal. Consistent with our previous data, hypogonadal patients had inappropriately low LH and FSH concentrations and thus had hypogonadotrophic hypogonadism (1
). It is also noteworthy that all the eugonadal type 2 diabetic patients were not obese, and, therefore, the prevalence of hypogonadotrophic hypogonadism in obese type 2 diabetic patients was even higher.
Patients with type 1 diabetes, on the other hand, had much higher total and free testosterone concentrations that were comparable with those observed in younger normal subjects. Three of 38 patients had subnormal free testosterone concentrations and therefore were hypogonadal. Two of them were morbidly obese (BMI 57 and 41.4 kg/m2, respectively). These patients’ hypogonadal state could, in part, be attributed to gross obesity. One other patient who was markedly underweight (BMI 15.8 kg/m2) had subnormal total and free testosterone concentrations. He was being investigated for malabsorption and anorexia nervosa. The rest had middle- to high-normal total and free testosterone concentrations similar to those observed in normal subjects, consistent with their age. The group with normal total and free testosterone included five other patients with nonmorbid obesity and type 1 diabetes.
Since the association of obesity with type 2 diabetes led to a greater chance of developing hypogonadotrophic hypogonadism, and its existence in type 1 diabetes occurred only in association with morbid obesity, BMI is a major determinant of hypogonadotrophic hypogonadism. It is well known that obesity is inversely associated with free and total testosterone concentrations in middle-aged and elderly men. A recent report from the Netherlands found a 35.6% prevalence of hypogonadotrophic hypogonadism in obese men (mean age 58 years). The study population included type 2 diabetic men. Comparison of prevalence of hypogonadotrophic hypogonadism in type 2 diabetic and nondiabetic obese men was not available in this publication. We (1
) and others (2
) have described that the negative association of BMI with free testosterone is also present in middle-aged (mean age 53–58 years) type 2 diabetic men. These men have a high prevalence (33–50%) of hypogonadotrophic hypogonadism.
Nielsen et al. (11
) examined testosterone concentrations of 615 nonobese and 70 obese young Danish men (aged 20–29 years) in association with subcutaneous and visceral fat mass, measured by dual-energy X-ray absorptiometry and magnetic resonance imaging. The purpose of this study was to investigate the impact of obesity on reference intervals for testosterone in young men. The reference interval of plasma free testosterone in nonobese men was 0.29–0.78 nmol/l and in obese men 0.23–0.67 nmol/l. Total and bioavailable testosterone concentrations were negatively related to all measures of fat mass. A total of 23% of obese young men had subnormal total testosterone concentrations, while 10% had subnormal total and bioavailable testosterone concentrations. Thus, obesity without diabetes may be related to hypogonadotrophic hypogonadism.
The strength of our current report is that it describes the prevalence of hypogonadotrophic hypogonadism in young type 2 diabetic men (aged 18–35 years; mean age 28 years). In addition, BMI was inversely related to free testosterone. Since testosterone falls with age, it is important to highlight that BMI is negatively associated with hypogonadotrophic hypogonadism, even at an early age in men, and that there is a very high prevalence of hypogonadotrophic hypogonadism (58% on the basis of age-matched control subjects) in young type 2 diabetic men. Using the reference range for obese young men (11
), the prevalence of hypogonadotrophic hypogonadism in young type 2 diabetic men is 33%. This prevalence is higher than the rate of 10% found in young obese men (11
). More focused investigations on the relationship of obesity, especially visceral adiposity, in type 2 diabetic men (using imaging techniques or surrogate clinical measures such as waist circumference) to total and free testosterone concentrations are required.
While obesity contributes to the association of type 2 diabetes with hypogonadotrophic hypogonadism, the association is not entirely dependent on obesity. In our first study on type 2 diabetic men, we found that 31% of lean type 2 diabetic men also had hypogonadotrophic hypogonadism (1
). It is likely that factors other than obesity also contribute to hypogonadotrophic hypogonadism (13
). It is possible that the association is mediated via insulin resistance. Type 2 diabetic patients generally have higher insulin resistance, while all obese men are not insulin resistant. A recent analysis (14
) from the Third National Health and Nutrition Examination Survey showed that low androgens were a risk factor for type 2 diabetes in men. In multivariable models adjusted for age, race/ethnicity, and adiposity, men in the lowest tertile of free testosterone concentrations were four times more likely to have type 2 diabetes compared with men in the third tertile (odds ratio 4.12 [95% CI 1.25–13.55]). Whether obesity or insulin resistance is the major determinant of hypogonadotrophic hypogonadism has to be addressed in future studies, and the pathogenesis of hypogonadotrophic hypogonadism needs to be defined. It has been suggested that increased aromatase activity in the adipose tissue may lead to a greater degree of conversion from testosterone to estradiol and that the excess of estradiol suppresses the hypothalamus hypophyseal axis. On the other hand, it has also been shown that the deletion of the insulin receptor gene in neurons of mice leads to hypogonadotrophic hypogonadism. Thus, the insulin-resistant state in the hypothalamus may lead to hypogonadotrophic hypogonadism.
As previously reported, the concentrations of SHBG tended to be low in type 2 diabetic subjects and to be middle to high normal in type 1 diabetic subjects (4
). Despite corrections made to total testosterone concentrations on the basis of SHBG, the concentrations of calculated free testosterone remained markedly lower in type 2 diabetes and relatively high in type 1 diabetes.
These observations have several clinical implications, since low testosterone concentrations may contribute to the impairment of sexual function, diminished libido, and erectile dysfunction. Furthermore, the lack of testosterone during these crucial years may lead to diminished peak bone mass and the lack of development or loss of skeletal muscle (7
). In addition, these patients may develop increased adiposity and, therefore, may become more insulin resistant (2
). Clearly, patients with type 2 diabetes, especially if they are obese, need further focused attention and systematic investigation. This is even more relevant to younger type 2 diabetic patients. Furthermore, patients with hypogonadotrophic hypogonadism and type 2 diabetes have been shown to have very high C-reactive protein concentrations (16
). Thus, they may be at a heightened risk of atherosclerosis and cardiovascular disease. Indeed, low testosterone concentrations in male subjects are known to be associated with enhanced cardiovascular risk in observational studies (17
). A Japanese study (19
) has shown that free testosterone (but not total testosterone) concentrations are inversely related to carotid intimal medial thickness in type 2 diabetic patients. Since free testosterone was measure by radioimmunoassay in that study, these findings need to be confirmed by using a more reliable assay.
In addition, these patients are also candidates for infertility, since subnormal FSH concentrations are likely to adversely affect the development of seminiferous tubules and spermatogenesis. Indeed, in two patients with hypogonadotrophic hypogonadism and type 1 diabetes, we have found marked oligospermia following semen analysis (A. Chandel, S.D., S.T., and P.D., unpublished observations). The treatment plans for such patients should include not only testosterone therapy but also the consideration of gonadotropin therapy in order to restore fertility.
In conclusion, young patients with type 2 diabetes have significantly lower plasma concentrations of total and free testosterone, with inappropriately low LH and FSH concentrations, when compared with type 1 diabetic patients of a comparable age. The prevalence of absolute or relative hypogonadism is also markedly higher in this group. There is an inverse relationship between BMI and total and free testosterone concentrations. Type 2 diabetic patients with obesity appear to be at a greater risk of hypogonadotrophic hypogonadism than those without. The implications for their sexual and reproductive function, as well as the underlying defect of insulin resistance, are profound. This area requires careful further assessment and investigation.