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Link between testosterone and diabetes: Many questions remain
Prospective studies should define potential benefit, harm of testosterone therapy in men with diabetes, metabolic syndrome.
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According to recent research, about 50% of men with type 2 diabetes are testosterone deficient, and some researchers have suggested that these low testosterone levels may increase the risk of heart disease. Because no clear link between testosterone and diabetes has been established, the efficacy of treating a low testosterone level is not clear.
“One of the problems with these studies is that, in many circumstances, these are ‘association’ studies,” Yasser Ousman, MD, CDE, associate director of the diabetes team at Washington Hospital Center, in Washington D.C., told Endocrine Today. “They do not confirm a cause and effect relationship."
“Because serum testosterone concentration is influenced by a number of medical states, in particular obesity, it is not surprising that some studies find an association between low testosterone and a less favorable outcome,” he said.
“Patients with the lowest serum testosterone concentration tend to be more obese, less fit and less healthy overall. The association between low serum testosterone and a poorer outcome may simply be reflective of the poorer overall medical condition or health of the patient in question, and the low testosterone may simply be a ‘marker’ of that poorer health state,” Ousman said.
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Photo by: So Young Pak |
These points are important to remember when evaluating a person with low testosterone, he said. Otherwise there may be a tendency to overprescribe testosterone to patients only on the basis of low testosterone concentration, patients who otherwise are not hypogonadal.
Finding the link
T. Hugh Jones, MD, BSc (Hons), FRCP, consultant physician and endocrinologist at Barnsley Hospital NHS Foundation Trust and professor of andrology at the University of Sheffield, United Kingdom, said the correlation between testosterone and diabetes is currently difficult to pinpoint but it is known that hypogonadism is associated with reduced insulin sensitivity.
“There is no definitive answer to this question as it is likely to be a combination of cause and consequence,” he said.
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“There is evidence from aging studies including the Massachusetts male aging study, that low testosterone is a risk factor for future development of diabetes. Men with a genetic cause of hypogonadism are more likely to develop diabetes, and androgen suppression treatment for prostate carcinoma leads to increased risk of developing diabetes.”
Because low T is known to be associated with a reduction in insulin sensitivity, the one possible consequence is linked with adipose tissue, Jones said.
Amanda Denney, MD, medical director of the Diabetes and Endocrine Center at The Christ Hospital, Cincinnati, agreed. Although Denney said that obesity plays a role, she noted that it does not fully account for the increased risk of hypogonadism. About one-third of lean men with type 2 diabetes have hypogonadotropic hypogonadism as well.
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Increased aromatase activity in adipose tissue may increase the conversion of testosterone to estradiol, she said. “This increased estradiol may in turn cause hypothalamic-pituitary suppression.”
“Adipose tissue, especially visceral adipose tissue, has an enzyme aromatase which breaks down testosterone into estradiol,” Jones said. “Therefore the greater the abdominal fat content, the more testosterone breakdown. Low testosterone stimulates pluripotent stem cells to develop into fat cells and not muscle cells. It is well known that hypogonadism is associated with increased body fat content.”
The body’s response should be to produce more testosterone to compensate; however, it is unable to do this because substances produced by fat cells estradiol and adipocytokines inhibit this action, according to Jones.
Statin therapy
Jones’ team recently analyzed the effect of statins on testosterone levels in a cross-sectional epidemiological study of men with type 2 diabetes. According to the researchers, this is the first study to fully analyze testosterone levels and hypogonadal symptoms and to compare that to the efficacy of statin use in a population receiving routine medical management.
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The results of the data analysis were published on the Diabetes Care website and included data on about half the population. The study was carried out in 2000 to 2002 where 169 men had routine treatment with statins, 81 were assigned atorvastatin, 66 simvastatin, 15 pravastatin and another statin in seven patients. Patients treated with statins did not differ significantly from untreated individuals in age, waist circumference, body mass index, HbA1c level or blood pressure.
“Our study showed that statins have no effect on the biologically active components of testosterone (bioavailable or free testosterone), ie, statins do not cause testosterone deficiency or cause any change in an individual’s biologically active circulating level of testosterone,” Jones said.
“Total testosterone is the commonly used test for hypogonadism,” Jones said. “Atorvastatin but not simvastatin in this study lowered the total testosterone significantly (P=0.017). In borderline cases of testosterone deficiency in diabetic men, this could lead to a misdiagnosis of hypogonadism in borderline cases which may lead to inappropriate treatment of men with testosterone replacement therapy.”
Defining hypogonadism
Ousman noted that because the study is an observational study, the relevance of the data is limited. “The main message we get from such studies is that defining hypogonadism in males can be sometimes difficult for a number of reasons,” he said.
“One of the reasons is the difficulty in interpreting total testosterone concentrations that are borderline low. In this particular study, statins were found to be associated with lower total testosterone but other studies have not confirmed that. There may be other reasons why patients on atorvastatin in this study had lower total testosterone than those who were not on the drug,” he said.
“In any case, this study highlights some of the issues we deal with when evaluating patients with suspected hypogonadism,” Ousman said.
So should the study change practice?
“There is a high prevalence of hypogonadism in men with type 2 diabetes; however, there are confounding factors such as statin use which may lead to misdiagnosis of hypogonadism,” Jones said. “In borderline cases, a measure of free or bioavailable testosterone should be considered.”
Testosterone in young patients
Paresh Dandona, MD, chief of endocrinology at the State University of New York at Buffalo, recently reported that young patients with type 2 diabetes have significantly lower concentrations of testosterone than patients at a comparable age with type 1 diabetes, thus placing them at greater risk for atherosclerosis and infertility.
Dandona and colleagues had previously found that patients with type 2 diabetes have a frequent occurrence of hypogonadotropic hypogonadism. This was not true for those with type 1 diabetes, according to the 2004 study. These studies, in patients with a mean age of 55 years, showed low plasma concentrations of testosterone and low levels of luteinizing hormone and follicle-stimulating hormone.
The researchers then turned their focus on the total and free testosterone concentrations in young men aged 18 to 35. The study, published in Diabetes Care, showed the results of measured serum testosterone levels in 38 men with type 1 diabetes (mean age 25.45) and 24 with type 2 diabetes (mean age 27.87).
The total testosterone concentrations were significantly lower in those with type 2 diabetes than in those with type 1 (11.14 vs. 22.89 nmol/L, P<0.001) as were the free testosterone concentrations (0.296 vs. 0.489 nmol/L, P<0.001). A third of the patients with type 2 diabetes were hypogonadal compared with 8% of the patients with type 1 diabetes.
Obese patients with type 2 diabetes appear to be at a greater risk of hypogonadotropic hypogonadism than those without.
“The implications for their sexual and reproductive function, as well as the underlying defect of insulin resistance, are profound,” the researchers concluded, calling for careful assessment and investigation. Men with type 2 diabetes with low free testosterone also have anemia, low bone density and lower concentrations of PSA, which may influence prostate cancer risk and detection, according to Dandona.
Testosterone in elderly men
“These [young] patients have a defect in their hypothalamus which leads to diminished release of GnRH which in turn results in low LH and FSH release from the pituitary gland and consequently low testosterone release from the testicles,” Dandona told Endocrine Today.
Dandona said he does not believe that testosterone therapy is the exact answer. “Testosterone therapy has definite benefits, but it does not restore fertility. In these young patients we shall have to use gonadotrophin injections.”
“Again, the mechanism of hypogonadotropic hypogonadism in men with diabetes has not been fully elucidated. Likely it is the same mechanism in men with type 2 diabetes across all ages.”
According to Denney, the more interesting question in young men is how this will affect their future reproductive and sexual health. “Also, men with secondary hypogonadism and type 2 diabetes have been shown to have higher CRP levels, so does this affect their future cardiovascular risk?”
“The answers are not known, and need further investigation,” she said.
Ousman said that there has been a lot of interest in testosterone therapy for elderly men. We know that aging is associated with a slow but progressive decline in testosterone levels, muscular mass and muscular strength.
“To my knowledge the benefits of such an intervention have been far from impressive,” Ousman said. “This is one example that illustrates the fact that we cannot simply prescribe testosterone to treat a number or a blood level. We need more prospective studies to better define the benefits and potential harm of testosterone use in men with chronic conditions such as diabetes and metabolic syndrome. In addition to evaluating the potential benefits of androgen therapy in terms of libido, sense of well being, erectile function, we should also look at hard end points, such as cardiovascular morbidity and mortality, and bone fracture risk.”
Testosterone therapy
It has been routine practice that if biochemical testosterone deficiency is associated with symptoms of hypogonadism, then testosterone substitution should be considered.
Jones and colleagues reported in the European Journal of Endocrinology that testosterone replacement therapy in men with type 2 diabetes in a placebo controlled crossover study improved insulin resistance and glycemic control and reduced waist circumference. Preliminary data from the TIMES2 study, a multi-center European study that was presented at the Endocrine Society’s 90th Annual Meeting, held last year in San Francisco, confirmed that testosterone replacement significantly reduced insulin resistance in hypogonadal men with metabolic syndrome and type 2 diabetes, according to Jones. Further results from this trial are slated to be presented soon he said.
“I am very cautious in using testosterone, especially in younger men,” said Stanley Korenman, MD, associate dean for ethics, David Geffen School of Medicine at UCLA.
“They are rendered infertile, and sometimes restoring fertility when they want it is difficult. The decreased testosterone may be temporary, and they are put in the position of rather long-term therapy,” Korenman said.
“Testosterone medication is progressively increasing in the population as the fear of prostate cancer stimulation recedes and the readily available transdermal preparations are paid by the insurers,” Korenman said.
Serge Jabbour, MD, FACP, FACE, associate professor of clinical medicine at Jefferson Medical College of Thomas Jefferson University, Philadelphia, agreed. “Testosterone therapy has great effects not only on sexual function and libido but also on overall well-being, metabolic syndrome and bone density. It also helps build up lean body mass and helps decrease fat mass, both leading to improvement in metabolic syndrome.”
“Of course, we have to make patients aware that regular monitoring of PSA for prostate cancer is required on testosterone therapy because any underlying prostate cancer can flare up,” Jabbour said.
Future studies should better define normal testosterone levels (per decade of life) and make the gold standard assay more widely available, he said.
Future studies
Denney said that further research is needed “to elucidate the pathogenesis of hypogonadotropic hypogonadism. We need dedicated studies regarding the relationship between obesity, specifically visceral adiposity, in men with type 2 diabetes and hypogonadism.”
“Is it obesity or insulin resistance that plays the larger role in this problem?” Denney said.
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“We are very used to looking at surrogate markers as endocrinologists,” said Glenn D. Braunstein, MD, chair of the department of medicine at Cedars-Sinai Medical Center, Los Angeles.
“If A equals B and B equals C, then A equals C. But that’s not always true. I think we have a lot of associations that we can see, and they may not be cause and effect associations. If we find low testosterone, that doesn’t mean giving testosterone will make type 2 diabetes go away,” Braunstein said.
It is now established that one-third to a half of middle-aged and young men with type 2 diabetes have low free testosterone concentrations. The mechanistic reason behind this association is not clear and needs further research. Dandona and colleagues are researching atherosclerosis, cardiovascular risks and inflammation to assess the effect of testosterone and other agents on sexual function and cardiovascular events. It is likely that testosterone replacement therapy in the long term may decrease adiposity and insulin resistance, according to Dandona. “It is interesting that discontinuation of testosterone for two weeks in men on long-term testosterone replacement leads to an increase in insulin resistance,” he said. – by Angelo Milone
What should future
research include to examine the link between testosterone and diabetes?
For more information:
- Diabetes Care. 2006;29:2289-2294.
- Diabetes Care. 2007;30:911-917.
- Diabetes Care. 2008;31:2013-2017.
- Diabetes Care. DOI:10.2337/dc08-1183.
- Endocr Pract. 2008;14:1000-1005.
- Eur J Endocrinol. 2006;154:899-906.
- J Clin Endocrinol Metab. 2004;89:5462-5468.
- J Clin Endocrinol Metab. 2007;92:4254-4259
- Jones TH, et al. Abstract P3-422. A placebo-controlled study on the effects of transdermal testosterone gel in hypogonadal men with type 2 diabetes or metabolic syndrome in diabetic control and insulin sensitivity: The TIMES2 study. Presented at: The Endocrine Society’s 90th Annual Meeting; June 15-18, 2008; San Francisco.