A talk recently about the HIM study at MGH (Hypogonadism In Men, Clin trial NCT00114114) prompted me to wonder about testosterone from the renal perspective.
Testosterone is important for several aspects of male health, including fertility, bone density, fat and muscle mass, and sexual function. Men with prostate cancer who are chemically or surgically castrated lose bone mass, lean body mass, have an increase in fat and a loss of libido and erectile function. However, the effects of testosterone at levels between what is considered normal (~500 ng/mL) and very low ( under 100 ng/mL in chemically castrated men) are still unclear and the subject of the HIM study.
Men on dialysis have a lot of the same changes reported with low testosterone levels: loss of lean muscle, loss of fertility, loss of libido and sexual function. Consistent with this, in a recent study of dialysis patients, testosterone levels in 47% of men were below 300 ng/mL (=hypogonadism); previous studies had reported that up to 2/3rds of men on dialysis have hypogonadism by this definition. Increased time on dialysis/ higher clearance apparently has no effect on testosterone levels. Part of the low testosterone comes from disruption of the normal pituitary pulsatile secretion of gonadotropin releasing hormone (GnRH) in renal failure, which is not restored with dialysis.
Hypogonadism has been associated with anemia, and one of the goals of this study was to see if daily testosterone gel application will reduce the need for rhEPO in a male dialysis cohort (it did not). Interestingly, the article discussed that prior to rhEPO, one of the available therapies for anemia in dialysis patients were IM injections of androgens.
Unfortunately, topical application of testosterone (100mg daily for 6 months) in this dialysis cohort of 66 randomized men also failed to improve lean muscle mass, bone density, sexual function or mood (as assessed by questionnaire), although the rise in serum testosterone with therapy was modest at best.
Interest in improving or affecting testosterone levels in the dialysis population was recently increased after this prospective study linked low serum testosterone (in this case defined as levels under 233 ng/mL) to increased cardiovascular mortality. Here, a cohort of 126 male HD patients was followed for an average of a little over 3 years. 52% of the men had a testosterone deficiency (here defined as less than 288 ng/mL, similar with prior studies), and only ~20% had testosterone levels in the normal range.
The authors then divided the group in those that had a testosterone level below the 33rd percentile (below 233 ng/mL) vs the rest. The group with the lowest levels seemed overall slightly sicker (lower albumin, more inflammatory markers, higher epo dose, more baseline CVD). Over the observation period, ~50% of the cohort died, with the majorty of deaths from cardiovascular causes. Low testosterone levels (below the 33rd percentile) seemed predictive of mortality, even after adjustment for a history of CVD, although the significance was lost after adjustment for serum creatinine levels, perhaps reflecting a common etiology.
While these results are interesting, and even if a direct causal link is proven between low testosterone and CV mortality in the dialysis population, the difficulties of testosterone supplementation highlighted in the prior study give me pause.
Dr. Marta Hristova
Thank you for your comment. It is a good question about what to measure: in this case, they measured both total testosterone, sex-hormone-binding-globulin (SHBG), and albumin and calculated the "free" and the "bioavailable" testosterone from those three parameters. I think bioavailable is the free+albumin bound hormone fraction, which is presumed to be easier to dissociate than the one bound to SHBG. The article reported the association with total testosterone and mortality, and in the analysis controlled for SHBG and albumin. It is not clear to me which is the best parameter to measure, though, and that will hopefully be refined as people look at this association more. Marta
Interesting, as ever – but in this case it would be simplicity itself to do an RCT of replacement versus placebo. Also, should we look at total testosterone, or free testosterone, in this population ?