Low Testosterone Syndrome Rx: Still Waiting for Godot

A little bit of knowledge can be a dangerous thing, and I am proof. At one stage in my career, I collaborated with a basic scientist who studied gender-mediated differences in vascular endothelium. In an animal model, estrogen was good for nitric oxide production, testosterone was not. Nitric oxide is a vasodilator, and presumably, its generation is why women experience relative estrogen-mediated protection from cardiovascular disease, that is, at least until menopause. So, when a 2010 article in the New England Journal of Medicine¹ suggested that supplementing testosterone in older men with hypogonadotropic hypogonadism (primary testosterone deficiency, or HH) could lead to myriad cardiovascular (CV) risks, it made sense to me. That is where my “little bit of knowledge” comes in. There is a lot more to the saga and much of the information is essential to decision making in primary care practice on whether or not testosterone replacement is indicated.

The primary care office is where a man who has symptoms of HH, or suspects he might, based on the warnings-and promises-put forth in ubiquitous network television advertising, is likely to present first. Should we be wary of the potential CV risks associated with testosterone replacement? We know more today, but we have a long way to go.

The study just cited¹ was roundly criticized. To start, it was small (N=209). While it found that 23 men in the testosterone replacement cohort experienced CV events compared with only 5 in the non-replacement group, there was a serious confounding issue. Men in the testosterone limb had increased activity levels after receiving testosterone replacement when compared with men in the control group. The heightened level of physical activity-and not receiving testosterone per se-may have been the CV culprit. Thank goodness that study did not end the debate.

Let’s look at other data and then raise questions that should be answered in the next few years.

First, there is some evidence that my initial presumption-testosterone is bad for the CV system-may be off base. In a 2008 study² of 794 older men (median age, approximately 74 years), participants with testosterone levels in the lowest quartile experienced a 40% greater relative risk of death than those with higher levels. If testosterone is bad for CV health, this does not make sense. It appears that testosterone may have vascular benefits that would have been missed in the one-dimensional animal model that shaped my original thinking. Data presented at the 2013 annual meeting of the Endocrine Society³ revealed that testosterone replacement in men with type 2 diabetes changed 2 kg of fat into 2 kg of lean body mass.³ These results suggest that testosterone might also confer potential CV benefits. It did. On follow-up, testosterone supplementation increased insulin sensitivity by 25%. 

So, I began my journey incorrectly. Testosterone is not a malicious vascular toxin. And, it may have benefits. But at this stage of research, a low level of testosterone alone cannot be the sole indicator for replacement. In some clinical situations, low testosterone levels may be a marker for general health. Low testosterone levels in persons with AIDS offers an example. Further clarification of the benefits, downsides, and optimum replacement targets is awaited. While we wait, however, how should primary care practitioners respond to a deluge of requests for testosterone treatments? Here are some good rules to practice by:

1. Every man who requests a testosterone replacement prescription should undergo a complete evaluation. The testosterone blood draw should be done in early morning and 3 values should be obtained. Afternoon levels can be falsely low. If FSH and LH levels suggest a pituitary etiology, testosterone replacement is not the answer. You may be missing a prolactinoma.

2. Obesity can lower testosterone. As a result, a low screening testosterone level in an obese man should prompt a search for other CV risk factors consequent to insulin resistance. Exercise and weight loss may be a reasonable place to start.
 

3. Long-term oxycodone ingestion can lower testosterone levels. Is the patient depressed or under significant stress?

4. Certain disease states, such as CKD, HIV, and cirrhosis, may be responsible for decreased testosterone levels. Primary issues such as these need to be identified and addressed before replacement is prescribed as the answer. 

All the indications for and the benefits and downsides of testosterone replacement therapy are not known, at least as of yet. Until Godot arrives with some answers (and I suspect he will), complete primary care evaluation before prescribing replacement testosterone is the only safe way to proceed.

References
1. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363:109-122.
2. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008;93:68-75.
3. Dhindsa SS, Batra M, Kuhadiya ND, et al. Testosterone replacement decreases insulin resistance in hypogonadal men with type 2 diabetes. ENDO 2013; Abstract OR22-1.Endocr Rev, Vol. 34 (03_MeetingAbstracts): OR22-1