Measured GFR clears testosterone of driving age-related kidney function decline

Design

population-based prospective cohort with iohexol-measured GFR at three time points, linear mixed models

Population

800 men aged 50-62 without self-reported cardiovascular disease, diabetes or kidney disease; 578 at the final measurement; median follow-up 10.9 years

Primary outcome

rate of measured GFR decline by total testosterone, free testosterone and sex hormone-binding globulin

Effect

-0.02 ml/min/1.73 m2 per year (95% CI -0.04 to 0.01) per nmol/L total testosterone; -0.03 (-0.15 to 0.08) for free testosterone; -0.04 (-0.12 to 0.05) per 10 nmol/L sex hormone-binding globulin

The hypothesis that testosterone accelerates glomerular filtration rate decline in men has plausible mechanistic support and a body of observational evidence behind it. That evidence rests almost entirely on creatinine-based estimated GFR, and creatinine is produced by muscle — so a man with more testosterone has more muscle, a higher creatinine, and a lower estimated GFR without any difference in true filtration.

The Renal Iohexol Clearance Survey tested the hypothesis without that circularity. Eight hundred men aged 50 to 62 from the general population, without cardiovascular disease, diabetes or kidney disease, had plasma iohexol clearance measured directly at baseline and twice more over a median of 10.9 years.

Neither total testosterone, free testosterone nor sex hormone-binding globulin was associated with the rate of measured GFR decline. All three point estimates sat close to zero with intervals spanning it.

The positive baseline finding runs in the opposite direction to the hypothesis and is worth noting: higher total testosterone and higher sex hormone-binding globulin were associated with a higher measured GFR at baseline, not a lower one.

This is a methodological result as much as a clinical one. It is a clean demonstration that a plausible association built on estimated GFR can disappear entirely when the measurement bias is removed.

• Do not attribute declining kidney function in a man to testosterone, prescribed or endogenous, on this evidence
• Be cautious interpreting eGFR changes in anyone whose muscle mass is changing — bodybuilders, patients losing weight, those starting or stopping androgens
• Use cystatin C or a measured clearance where the creatinine-based estimate and the clinical picture disagree
• Note the population: men aged 50-62 without diabetes, cardiovascular or kidney disease, so this does not speak to testosterone in established CKD

Don't overread it

This is an observational cohort in healthy middle-aged men; it says nothing about prescribed testosterone therapy or about men with established kidney disease.

The statistics, in plain English

The estimates for decline are -0.02 ml/min/1.73 m2 per year per nmol/L of total testosterone, with a confidence interval of -0.04 to 0.01, and similarly tight nulls for free testosterone and sex hormone-binding globulin. Intervals this narrow around zero, over a median of 10.9 years with repeated direct measurement, constitute reasonable evidence of no meaningful effect rather than a failure to find one. The baseline association — higher testosterone with higher measured GFR — remains cross-sectional and observational, so it should not be read as testosterone protecting kidney function either.

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