Low Testosterone’s Lethal Impact

By Daniel A. Shoskes, MD, MSc, FRCSC

The diagnosis of low testosterone (T) and the risks and benefits of testosterone replacement therapy (TRT) remain controversial.

While established guidelines for TRT do exist, the past several years have seen an explosion in prescriptions for TRT, with the majority of men lacking the clinical and laboratory testing necessary to guide safe and effective treatment. The surge in TRT has led to a backlash from physicians and payers against TRT use, especially for the stereotypical aging male trying to regain lost youth.

By contrast, there are at-risk patient populations with low T for whom TRT has the potential to both improve and prolong life. Low T is particularly common in men with HIV/AIDS, type 2 diabetes and end-stage renal disease, and is associated with poor survival of those with these diseases.

Indeed, for men on dialysis, low T is independently associated with death within three years. In type 2 diabetes, TRT has been shown to improve glucose control and prolong life.

Querying the Chronic Kidney Disease Registry

Few studies have looked at TRT in renal failure and disease.

To explore the impact of low T in men with renal disease (but who are not yet on dialysis), we used the Cleveland Clinic Chronic Kidney Disease (CKD) Registry, focusing on men with CKD stages 3-4 (estimated glomerular filtration rate [eGFR] 15 to 59 mL/min/1.73 m2).

We identified 2,633 such men in the database who had a serum T measurement. Low T was identified in 54 percent and was more likely with lower eGFR, diabetes and a higher body mass index. In a multivariable Cox analysis, when compared with the highest quintile (T 512 to 7,469 ng/dL), the two lowest quintiles of T (100 to 225 ng/dL and 226 to 301 ng/dL) were associated with significantly higher mortality (HR 1.70, 95% confidence interval [CI] 1.21-2.39, and HR 1.56, 95% CI 1.12-2.19, respectively).

Examining Low T’s Effect on Survival

The next obvious question is whether low T is a marker of other illness or disease burden or whether it is actually a mechanistic target that can be treated with TRT to improve survival. This is still an open question.

Following successful kidney transplant, men with low T commonly have their T levels normalize. Many do not, however, especially if they are diabetic.

Given the negative impact of low T on survival in renal disease, we next wished to study the effect of low T on renal transplant patient survival and graft survival. We utilized a quick and convenient resource: All patients have serum collected and frozen on the day of their transplant for use if needed in future immunologic testing.

We identified such samples in male patients transplanted six to 10 years ago, and were able to measure T and retrospectively correlate it with the clinical outcomes during the subsequent five years.

There were 197 male renal transplant recipients with sufficient serum to run the assay. Patients ranged in age from 14 to 75 years (mean 48.9 years). There were 100 living and 97 deceased donors, and 53 (27 percent) of the recipients were diabetic. Serum T ranged from 48 to 2,013 ng/dL (mean 477 ± 251.3) and was low (< 220 ng/dL) in 24 patients.

Low T’s Disease Marker Potential

Low T transplant recipients had worse one-year patient survival (75 vs. 95 percent, p = 0.003), three-year patient survival (62.5 vs. 86.1 percent, p = 0.008), one-year graft survival (62.5 vs. 92.4 percent) and three-year graft survival (50 vs. 76.3 percent, p = 0.01) than those whose T had normalized.

Survival curves showed significantly worse patient survival (p= 0.004) and graft survival (p = 0.02) for low T (Figures 1 and 2). In multivariable analysis, low T was independently associated with patient death (HR 2.27, 95% CI 1.19-4.32) and graft loss (HR 2.05, 95% CI 1.16-3.62).

Figure 1. Renal transplant patient survival comparing low and normal T levels.

Figure 2. Renal transplant graft survival in patients with low and normal T levels.

As we have shown in these two studies, there may be a unique opportunity to study low T in men with renal dysfunction and renal transplantation, both as a marker for disease severity and as a target for TRT.

Dr. Shoskes is a staff member of Cleveland Clinic Glickman Urological & Kidney Institute’s Department of Urology and of the Transplant Center. He is a Professor of Surgery at Cleveland Clinic Lerner College of Medicine.