Evidence linking hypogonadism and diabetes cannot be ignored

Diabetes (either type 1 or type 2)2 and male hypogonadism are commonly comorbid.1 Male hypogonadism is associated with insulin resistance and is a risk factor for the development of type 2 diabetes mellitus.1 There is also an association between type 1 diabetes, insulin resistance and testosterone deficiency (TD).2 However, testosterone deficiency remains undiagnosed and untreated in many diabetic men.1

To improve diabetes control and general health, diabetic men should be screened for testosterone deficiency to enable testosterone replacement therapy (TRT) if required.¹ TRT not only restores testosterone levels in deficient men; in doing so, it also optimises diabetes treatment.³

Testosterone and type 2 diabetes

Men with diabetes have considerably lower testosterone levels compared to men in the general population.¹ Low testosterone levels are an indicator of insulin resistance and are associated with a high risk of developing type 2 diabetes in the future. There are also data showing that hypogonadism is more prevalent in men with diabetes than in non-diabetic men.

A study in the United Kingdom found that 42% of men with type 2 diabetes also had low or borderline levels of free testosterone.⁴ Furthermore, in a population of type 2 diabetic men, it was found that 33% had testosterone levels that were sufficiently low to be classified as hypogonadal.³ The association between type 2 diabetes and hypogonadism also appears to be age-related. In a group of type 2 diabetic men, approximately 30% of those aged 40–49 had hypogonadism, while about 64% of men aged greater than 69 had the condition.⁴

Low testosterone is associated with obesity and abdominal obesity, which is an important risk factor for insulin resistance and, in turn, the development of type 2 diabetes. Increasing deposition of abdominal fat is also associated with hypogonadism and results in altered hormonal interactions, in particular increased conversion of testosterone to oestradiol by aromatase. This exacerbates central obesity and hypogonadism.³

Testosterone, sex hormone binding globulin and insulin resistance

In men undergoing testosterone withdrawal, there is evidence of increasing insulin and glucose levels, further supporting a link between hypogonadism, insulin sensitivity and type 2 diabetes mellitus. The exact mechanisms by which testosterone exerts these effects have not yet been elucidated, though a likely hypothesis is through reducing the amount of free fatty acids that the liver is exposed to.³ There is also evidence that low levels of sex hormone binding globulin, the main carrier protein for testosterone, may independently increase insulin resistance and confound the effects of testosterone deficiency.² 

Testosterone and type 1 diabetes mellitus

Prevalence of low testosterone in type 1 diabetic men is also greater than in the general population of men. For example, in one study 20% of type 1 diabetic men had low levels of free testosterone (FT) and low FT was associated with increasing insulin resistance. Prevalence of low FT also increased with age and was statistically similar to prevalence in type 2 diabetics after data were controlled for confounding factors such as age and body mass index (BMI).²

Low testosterone is also associated with insulin resistance in type 1 diabetics. Insulin resistance is common in men with type 1 diabetes and increases the risk of adverse health outcomes for these patients.²

A proactive approach to screening needed

A proactive approach to screening diabetic men for testosterone deficiency is needed to ensure hypogonadism is diagnosed and treated. However, there are numerous barriers to effective screening, which relate to both patients and practitioners.¹

Currently there is no recommendation for routine assessment of testosterone as there is for the assessment of other common diabetic comorbidities such as ocular disease. As such, practitioners may be under-educated about the importance of assessing testosterone.

According to Dr Neale Cohen, General Manager of Diabetes Services at Baker IDI, the low level of general awareness is compounded by diagnostic difficulties.

“Testosterone deficiency is not a condition that is screened for routinely unless there is symptomatic evidence of erectile or sexual dysfunction and there is considerable controversy regarding the cut-offs used to identify cases of TD. However, often the symptoms are non-specific, such as tiredness and mood changes, and without the appropriate blood tests, mild forms of TD will go undiagnosed,” Dr Cohen said.

Time constraints may lead practitioners to focus on acute complications of diabetes in a consultation. Practitioners may also lack confidence to proactively discuss sexual matters with their patients and they may focus on the diagnosis of erectile dysfunction and its treatment with phosphodiesterase-5 (PDE-5) inhibitors.¹

Patients may similarly be embarrassed to discuss sexual matters with their doctor. In addition, because testosterone levels generally decline gradually over many years, men may not notice their changing sexuality, or may think it is just a normal part of ageing rather than a treatable condition.¹

Overcoming barriers to screening

There are, however, several strategies that can be employed to increase patient and practitioner awareness of low testosterone in diabetes and improve diagnosis of hypogonadism. There are a range of screening tools available to practitioners which are designed to assess symptoms of testosterone deficiency (including sexual and non-sexual symptoms such as depression and changing body composition). Practitioners also need to be alert to patient cues that may indicate sexual problems (for example, a patient asking if diabetes “affects a man’s nature”).¹

Increasing patient awareness of the associations between diabetes, low testosterone and sexual symptoms (including low libido and erectile dysfunction) is also important.

“The key to increasing diagnosis of hypogonadism is to promote awareness of the condition in patients.  In particular, physicians should stress the association of TD with diabetes, obesity and metabolic syndrome,” said Dr Cohen.

Where time constraints may prevent practitioners from providing education during consultations, displaying posters and educational material in the waiting room is an important strategy.¹

Testosterone replacement improves markers of diabetes

Overcoming barriers to screening is important to ensure that testosterone-deficient men are diagnosed and their condition treated. However, there is some debate about what level of TD should be eligible for TRT.

“TRT is approved for treatment of testosterone deficiency in Australia and available on the PBS, but only in quite significant cases where the testosterone levels of the patient are below 8.0 nmol/L.  There is ongoing debate regarding how to set this cut-off,” said Dr Cohen.

Despite reluctance amongst some practitioners to use TRT in diabetic men for fear of adverse cardiovascular events, available data do not associate increased cardiovascular risk with TRT.¹ On the contrary, there is considerable evidence that TRT for diabetic men has numerous health benefits, including improved low density lipoprotein (LDL) cholesterol and lipoprotein(a), as well as measures of body composition.⁵

There is evidence that treatment of newly diagnosed type 2 diabetic men can improve markers of diabetic disease.  One study demonstrated that significant improvements in glycaemic control, waist circumference and C-reactive protein were achieved by modifying diet, and that the administration of TRT in addition to a modified diet was significantly more effective again.⁹ This position is supported by Dr Cohen, although he suggests more research is needed in some areas.

“There is considerable evidence showing that TRT can have benefits for lean body mass, fat mass, bone density, insulin resistance and general wellbeing/psychosocial effects.  However, there is still quite a bit of controversy regarding the benefits for cardiovascular health and blood glucose control. Further studies are needed in these areas,” Dr Cohen said.

Treating hypogonadism is important in its own right and has been associated with improved sexual function, body composition and quality of life. In diabetic men, it also optimises the effect of diabetes treatment.³ For example, in one trial, hypogonadal type 2 diabetic men treated with TRT showed significant reductions in fasting blood glucose, glycated haemoglobin and fasting insulin sensitivity. These men also experienced reductions in waist circumference and waist–hip ratio and improvements in cholesterol levels.³ Other studies conducted amongst men with type 2 diabetes or metabolic syndrome have returned similarly positive results, including reduced body mass and body fat mass;^6,7 reduced BMI, weight and waist circumference;^8,9 reduced insulin sensitivity and/or improved glucose control;^5,7,9 and reductions in inflammatory markers such as C-reactive protein.^7,8

Evidence that cannot be ignored

Evidence supporting the use of TRT in testosterone-deficient men is compelling. With the increasing prevalence of type 2 diabetes mellitus, optimising treatment and improving outcomes for diabetics is of increasing public health importance.¹ TRT restores testosterone levels in diabetic men without increasing the risk of cardiovascular events.⁵ Furthermore, treating testosterone deficiency is important in its own right and can improve quality of life through correcting low libido and erectile dysfunction,³ improving body composition,⁸ and alleviating androgen deficiency related mood disorders.¹⁰

The benefits of early diagnosis and treatment of testosterone deficiency are significant and include improved diabetes control and general health. Thus practitioners should take a proactive approach to educating their diabetic patients about these associations and make screening them for testosterone deficiency a routine practice.¹

References

1. Rice D, Branningham R, Campbell K, et al. Men’s health, low testosterone and diabetes: Individualised treatment and an interdisciplinary approach [online]. Chicago, IL: American Association of Diabetes Education; 2008 [cited 20 March 2010]. Available from: URL link
2. Grossman M, Thomas MC, Panagiotopoulos S, et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab. 2008;93(5):1834-40. [Abstract | Full text]
3. Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type two diabetes. Eur J Clin Endocrinol. 2006;154(6): 899-906. [Abstract | Full text]
4. Kapoor D, Aldred H, Clark S, et al. Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes: Correlations with bioavailable testosterone and visceral adiposity. Diabetes Care. 2007;30(4):911-7. [Abstract | Full text]
5. Jones TH, Arver S, Behre HM, et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care. 2011;34(4):828-37. [Abstract]
6. Svatberg J, Agledahl I, Figenschau Y, et al. Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip. Int J Impot Res. 2008;20(4): 378-87. [Abstract]
7. Aversa A, Bruzziches R, Francomano D, et al. Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: Results from a 24-month, randomized, double-blind, placebo-controlled study. J Sex Med. 2010;7(10):3495-503. [Abstract]
8. Kalinchenko SY, Tishova YQ, Mskhalaya GJ, et al. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: The double-blinded placebo-controlled Moscow study. Clin Endocrinol. 2010;73(5):602-12. [Abstract]
9. Heufelder A, Saad F, Bunck G and Gooren L. Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl. 2009;30(6):726-33. [Abstract | Full text]
10. Nieschlag E, Swerdloff R, Behre HM, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAU recommendations. J Androl. 2006;27(2):135-7. [Full text]

More information

For more information on testosterone deficiency in men, including testosterone tests and testosterone replacement therapy, see Testosterone Deficiency.