What should future research include to examine the link between testosterone and diabetes?

A large, long-term randomized controlled trial is needed.

The mechanisms underlying testosterone deficiency in type 2 diabetes are multifactorial. Increased levels of insulin and adipose tissue likely contribute as both lower sex hormone-binding globulin and total circulating testosterone, which is often the criteria for defining testosterone deficiency in men.

In addition, adipose tissue expresses the enzyme aromatase, which converts testosterone to estradiol, the latter being a potent inhibitor of gonadotropin production by the pituitary, lowering androgen production. Additional factors such as cytokines are likely involved as well, but these remain to be determined.

In addition, chronic illness in general tends to lower testosterone levels by an unknown mechanism. Biologically, this makes some sense, since why waste energy on reproduction if an organism is significantly stressed.

Stephanie Page

Testosterone replacement therapy is a controversial issue, mostly because large, long-term, randomized controlled trials with hard endpoints such as cardiovascular events, prostate cancer and mortality have not been done.

That being said, there may be benefits of androgen replacement in hypogonadal men. Positive changes in body composition and some metabolic endpoints suggest that testosterone replacement to normal levels might be beneficial to a man’s metabolic health. But we have been fooled before!

We need a large, long-term randomized controlled trial of testosterone treatment in men. Millions of men are using testosterone, and we don’t know the true risks and benefits. Yet prescriptions continue to rise.

Funding agencies need to look seriously at tackling these long-term trials with hard endpoints. In the meantime, studies targeting the molecular mechanisms which link sex steroids and insulin resistance in men will be very important in terms of understanding the pathophysiology and developing targeted therapies.

Stephanie Page, MD, PhD, is an Assistant Professor in the Division of Metabolism and Endocrinology at the University of Washington in Seattle.

It is critical to look at cardiovascular risk.

Hypogonadal men are noted to have a decrease in energy, mood and libido. They may also manifest a decrease in sexual hair, blood count, muscle mass, strength and bone mineral density.

Although patients with hypogonadism have an increase in fat mass to lean body mass ratio, treatment with testosterone replacement will usually not resolve obesity if present in these individuals.

Jerald Marifke

This is not to say that treatment for documented hypogonadism is not beneficial or indicated. Patients with diabetes often have low bone mineral density studies, but I am not aware of evidence that this is more prevalent in the third that are affected by hypogonadism, so I think it is important to realize that many disorders can be multifactorial.

I definitely believe more research is needed from larger randomized controlled trials about the effects of treatment of hypogonadal men with testosterone on other factors such as diabetes or the metabolic syndrome. Data from these trials could support some of the initial positive effects we have seen from smaller trials.

It is also extremely important to document testosterone deficiency correctly. Testosterone is produced in a diurnal pattern, and the samples have to be collected appropriately to avoid falsely low measurements.

Elderly patients, the obese and other specific individuals need an evaluation with an estimate of free testosterone, not just total, because the total measurement is affected inappropriately from changes in sex hormone-binding globulin.

It will also be critical to look at cardiovascular risk with testosterone therapy in these particular populations. We know from past experience that therapies that address part of the syndrome (ie, glucose control) may not always have a significant impact on lowering cardiovascular morbidity and mortality.

That is clearly one of the ultimate goals in patients with diabetes and the metabolic syndrome.

Jerald Marifke, MD, FACE, is an Endocrinologist practicing at Froedtert, Hospital and an Assistant Professor at the Medical College of Wisconsin, both in Milwaukee.