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Low Testosterone Concentrations in Men With Type 2 Diabetes
Testosterone replacement therapy may ameliorate features of hypogonadism such as upper abdominal obesity, the loss of skeletal muscle, and other aspects of the metabolic syndrome like insulin resistance, inflammation, and increased cardiovascular risk.
By Paresh Dandona, BSc, MB BS, DPhil, FRCP; Sandeep Dhindsa, MD; Anil Chandel, MD; AND Shehzad Topiwala, MD
Although it has been known for two decades that males with type 2 diabetes have low testosterone concentrations and that individuals with low testosterone are likely to develop type 2 diabetes, the issue of low testosterone 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 toward low testosterone as a feature of clinically relevant hypogonadism in type 2 diabetic males (age range, 28–80 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 total testosterone and free testosterone levels in the low-normal or subnormal range. These patients had sex hormone-binding globulin (SHBG) concentrations in the low-normal range. This study also demonstrated that these patients had inappropriately low luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels and responded to gonadotrophin-releasing hormone (GnRH) challenge with an appropriate increase in LH and FSH values. Thus, these patients had hypogonadotrophic hypogonadism (HH) probably due to inadequate GnRH secretion from the hypothalamus.
In these patients, total and free testosterone concentrations were also inversely related to age as expected and to body mass index (BMI). Hypogonadism, however, was not entirely dependent on obesity, as 25% of nonobese patients (31% lean and 21% overweight) also had HH.4 This observation has now been confirmed by studies from the United Kingdom, Brazil, Italy, and Australia.5-8 Clearly, therefore, HH occurs frequently in males with type 2 diabetes. Men with type 2 diabetes and low testosterone have also been found to have a high prevalence of symptoms suggestive of hypogonadism.5 The duration of diabetes and A1C levels do not affect testosterone levels in type 2 diabetes.4 All of the previously mentioned studies were based on middle-aged patients.
HH IN YOUNGER MEN WITH DIABETES
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%. In this study, however, all hypogonadal patients were obese, as type 2 diabetes in the young largely depends 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 low testosterone 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.
HIGH CRP AND ANEMIA
The problem of HH is not confined to just sexual and reproductive function but also possibly to cardiovascular disease and atherosclerosis, as these patients also have markedly elevated C-reactive protein (CRP) concentrations. We found an inverse relationship between CRP and testosterone and calculated free testosterone amounts.11 This observation has been confirmed in other larger studies.8 CRP levels in these patients are among the highest described. The mean CRP in HH patients from two studies is 6.5 mg/L and 7.5 mg/L respectively, and the mean CRP from patients with type 2 diabetes and normal testosterone is 3.2 mg/L.8,11
Furthermore, these patients also tend to have mild normocytic normochromic anemia. The patients with mild anemia were noted to have elevated or high normal erythropoietin concentrations. Thus, the lower hematocrit is due to the suppression of erythropoiesis rather than mediated by the kidney through a reduction in erythropoietin secretion. Interestingly, there is an inverse relationship between CRP and the hematocrit in type 2 diabetic patients.
DIMINSHED BMD, LOWER PSA
Patients with HH have also been shown to have a diminished bone mineral density (BMD) in their appendicular skeleton and the ribs, whereas the BMD in their vertebrae and the femoral neck is normal.12 It is of interest that individuals with diabetes have an increased risk of fracture.13 HH may contribute to the increased risk of fracture in type 2 diabetic men. Plasma prostate specific antigen (PSA) concentrations are significantly lower in type 2 diabetics compared with healthy individuals.14
Because they are significantly related to plasma testosterone amounts, the lower concentrations of PSA in type 2 diabetics may be due to the frequently low testosterone levels in this population.15 It is relevant that the incidence of prostatic cancer in patients with type 2 diabetes is known to be lower than that in a healthy population, whereas several other cancers are known to be more common in this condition.16,17
Men with type 2 diabetes and HH also have an increase in total and subcutaneous adiposity and a diminution in skeletal muscle mass.12 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.18 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 2 weeks leads to a significant increase in insulin resistance.19 Further studies are necessary to confirm these and to define other beneficial effects of testosterone replacement therapy.
HH DOES NOT OCCUR IN TYPE 1 DIABETES
In contrast to the frequent occurrence of HH in patients with type 2 diabetes, this syndrome does not occur in those with type 1 diabetes. This has been confirmed in studies of both middle-aged and young individuals with type 1 diabetes.9,20 Indeed, these patients have high-normal total testosterone partly because they have high-normal SHBG concentrations. Therefore, their free testosterone levels tend to be in the mid-normal range. It is of interest, however, that testosterone values are inversely related to BMI even in patients with type 1 diabetes.9,20
The pathophysiological mechanisms underlying HH in individuals with 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.21,22 An increase in estradiol concentrations would lead to the suppression of hypothalamic GnRH and pituitary gonadotrophin secretion.23,24 This would result in the reduction of both testosterone secretion by Leydig cells and spermatogenesis in the seminiferous tubules. This finding would be consistent with the inverse relationship between testosterone levels and BMI. As mentioned previously, however, normal-weight patients with type 2 diabetes may also suffer from HH, and thus the state of HH does not entirely depend on obesity.
HH AND INSULIN RESISTANCE
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.25 Thus, insulin action and insulin responsiveness in the brain are necessary for the adequate function of the hypothalamo-hypophyseal axis. In addition, it is known that the incubation of hypothalamic neurons with insulin results in the facilitation of GnRH secretion.26,27 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, as inflammatory mediators such as tumor necrosis factor-alpha and interleukin-6 may interfere with insulin signal transduction.28 Clearly, further investigation is necessary to define the etiology of this syndrome.
The presence of type 2 diabetes in more than 20 million individuals in the United States 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 least, we have to think about preventing the massive and progressive epidemic of type 2 diabetes that in its wake now brings hypogonadism and associated morbidity.
Paresh Dandona, BSc, MB BS, DPhil, FRCP; Sandeep Dhindsa, MD; Anil Chandel, MD; and Shehzad Topiwala, MD, are in the Division of Endocrinology, Diabetes and Metabolism at the State University of New York at Buffalo (SUNY Buffalo) and Kaleida Health. Dr. Dandona is also Director, Diabetes-Endocrinology Center of Western NY, Chief of Endocrinology, and a Distinguished Professor at SUNY Buffalo. He may be reached at pdandona@KaleidaHealth.org; phone: 716-887-4523; or fax: 716-887-4773.
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