Testosterone Concentrations In Young Patients With Diabetes Mellitus

Main Category: Diabetes
Also Included In: Urology / Nephrology;  Endocrinology
Article Date: 19 Sep 2008 - 9:00 PST

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UroToday.com - Although it has been known for two decades that males with type 2 diabetes have low testosterone concentrations and that subjects with low testosterone concentrations are likely to develop type 2 diabetes, the issue of low testosterone concentrations has been treated as a marker associated with type 2 diabetes and features of the metabolic syndrome(1-3). These studies were based on total testosterone concentrations. The first study to attract attention towards the low testosterone concentrations as a feature of clinically relevant hypogonadism in type 2 diabetic males (age range: 28 to 80 years) was based on free testosterone concentrations(4).

Dhindsa and colleagues demonstrated that one third of males with type 2 diabetes had subnormal free testosterone concentrations and that most of these patients had TT and FT concentrations in the low normal or subnormal range. This was associated with SHBG concentrations in the low normal range. This study also demonstrated that these patients had inappropriately low LH and FSH concentrations. Thus, these patients had hypogonadotrophic hypogonadism (HH).

Total and free testosterone concentrations were also inversely related to age as expected and to BMI. However, hypogonadism was not entirely dependent upon obesity since 25% of non-obese patients(31% of lean and 21% of overweight) also had HH(4). This observation has now been confirmed by studies from the UK, Brazil, Italy and Australia(5-8). Clearly, therefore, HH occurs frequently in males with type 2 diabetes. Type 2 diabetic men with low testosterone have also been found to have a high prevalence of symptoms suggestive of hypogonadism(5). All of the above studies were based on middle aged patients.

The first study to investigate the occurrence of HH in younger patients with type 2 diabetes has recently been published(9). In this study, patients between the ages of 18 and 35 years were shown to have HH at a rate of 58%. However, in this study all hypogonadal patients were obese since type 2 diabetes in the young is largely dependent on the presence of obesity. Nevertheless, the presence of HH at such a high rate is alarming because such patients with HH are in their prime reproductive years and are likely not only to suffer from features of low testosterone concentrations but also potentially from impaired spermatogenesis. The issue of spermatogenesis and fertility needs to be investigated further. Obesity itself has also been associated with decreased spermatogenesis(10). It is not yet known whether the decreased sperm count in obesity is due to low FSH, low testosterone or to some other factor associated with obesity.

In contrast to the frequent occurrence of HH in type 2 diabetes, this syndrome does not occur in type 1 diabetes. This has been confirmed in studies of both middle aged and young type 1 diabetes(9; 11). Indeed, these patients have high normal total testosterone concentrations partly because they have high normal SHBG concentrations. Therefore, their FT concentrations tend to be in the mid normal range.

The pathophysiological mechanisms underlying HH in type 2 diabetes are not clear. It has been suggested that the increase in adipose tissue mass in obesity associated with type 2 diabetes may result in an increase in aromatase activity and thus to a greater conversion of testosterone into estradiol(12; 13). An increase in estradiol concentrations would lead to the suppression of hypothalamic GnRH and pituitary gonadotrophin secretion(14; 15). This would result in the reduction of both testosterone secretion by Leydig cells and spermatogenesis in the seminiferous tubules. This would be consistent with the inverse relationship between testosterone concentrations and BMI. However, as mentioned above, type 2 diabetics with a normal weight may also suffer from HH and thus the state of HH is not entirely dependent upon obesity. The other possible mechanism involved in the pathogenesis of HH is insulin resistance. The selective deletion of the insulin receptor gene from neurons results in a syndrome of HH in addition to a state of systemic insulin resistance(16). Thus, insulin action and insulin responsiveness in the brain are necessary for the adequate function of hypothalamo-hypophyseal axis. In addition, it is known that the incubation of hypothalamic neurons with insulin results in the facilitation of secretion of GnRH(17; 18). 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 since inflammatory mediators like TNF-α and IL-6 may interfere with insulin signal transduction(19). Clearly, further investigation is necessary to define the etiology of this syndrome.

The problem of HH is not confined to just sexual and reproductive function but also possibly to cardiovascular disease and atherosclerosis since these patients also have markedly elevated CRP concentrations. Indeed, there is an inverse relationship between CRP and T and calculated FT concentrations(20). CRP concentrations in these patients are amongst the highest described. The mean CRP in HH patients from two studies is 6.5 and 7.5 mg/L respectively while the mean CRP from patients with type 2 diabetes and normal testosterone concentrations is around 3 mg/l(8; 20). Furthermore, these patients also tend to have mild normocytic normochromic anemia. They also have an increase in total and subcutaneous adiposity and a diminution in skeletal muscle mass(21).

As a consequence of increased adiposity, diminished skeletal muscle mass and possibly due to a potential insulin sensitizing effect of testosterone (still under investigation), HH is probably associated with insulin resistance. One recent study has shown that testosterone replacement therapy in type 2 diabetic males with HH reduces insulin resistance significantly(22). Another recent study has demonstrated that the withdrawal of testosterone from patients on long term treatment with testosterone for hypogonadism not related to diabetes even for a short period of two weeks leads to a significant increase in insulin resistance(23). Further studies are necessary to confirm these and to define other beneficial effects of testosterone replacement therapy.

The presence of type 2 diabetes in over 20 million in the US leads us to estimate that approximately 3.5 million patients may have HH. Among them, a sizable number are likely to be in their prime reproductive years. This is going to pose a substantial load at the public health level in terms of inadequate sexual function and potential infertility. These issues need to be addressed appropriately in terms of the understanding of the pathogenic mechanisms and the correct strategies for treatment. Last but not the least we have think about the prevention of the massive and progressive epidemic of type 2 diabetes which in its wake now brings hypogonadism and the associated morbidity.

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Written by Paresh Dandona, MD, Sandeep Dhindsa, MD and Ajay Chaudhuri, MD, as part of Beyond the Abstract on UroToday.com.

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