A validated age-related normative model for male total testosterone shows increasing variance but no decline after age 40 years

Abstract

The diagnosis of hypogonadism in human males includes identification of low serum testosterone levels, and hence there is an underlying assumption that normal ranges of testosterone for the healthy population are known for all ages. However, to our knowledge, no such reference model exists in the literature, and hence the availability of an applicable biochemical reference range would be helpful for the clinical assessment of hypogonadal men. In this study, using model selection and validation analysis of data identified and extracted from thirteen studies, we derive and validate a normative model of total testosterone across the lifespan in healthy men. We show that total testosterone peaks [mean (2.5-97.5 percentile)] at 15.4 (7.2-31.1) nmol/L at an average age of 19 years, and falls in the average case [mean (2.5-97.5 percentile)] to 13.0 (6.6-25.3) nmol/L by age 40 years, but we find no evidence for a further fall in mean total testosterone with increasing age through to old age. However we do show that there is an increased variation in total testosterone levels with advancing age after age 40 years. This model provides the age related reference ranges needed to support research and clinical decision making in males who have symptoms that may be due to hypogonadism.

Figure 1. The validated model, log-adjusted testosterone values.

Our dataset (n = 10,098) of log-adjusted observed total testosterone for ages 3–88 years, split into normative ranges determined by mean predicted values (blue line) and one (red), two (blue), three (green), and four (purple) standard deviations higher and lower than the predicted values.

Figure 2. Residual analysis.

The residuals are the variations in log-adjusted observed values from the log-adjusted age-related mean value predicted by the model. The residuals have excellent goodness of fit to an ideal Gaussian curve (r² = 0.99). 71% of the residuals are within one standard deviations (SD) of the mean, 95% within 2 SD, and 99% within 3SD. The percentages for an ideal Gaussian distribution are 68%, 95% and 99% respectively.

Figure 3. Exemplar of model validation stage.

High test and training errors represent underfit (i.e. insufficient model parameters to accurately capture essential features of the dataset), and high test errors represent overfit (i.e. a model that will not generalise to accurately predict new data). The optimal number of model parameters is seven in this instance, and in the analysis of the four other cross validation sets.

Figure 4. The validated model.

Our dataset (n = 10,098) of observed total testosterone for ages 3–88 years, split into normative ranges determined by mean predicted values (blue line) and one (red), two (blue), three (green), and four (purple) standard deviations higher and lower than the predicted values.

Figure 5. The validated model in centiles.

Normative ranges for the model of total testosterone from ages 3–88 years. In the average case (red line) total testosterone remains constant for age >40. However, the variance in normative ranges increases for these ages, with 1^st to 99^th centile ranges of 5.6–27.6 nmol/L at age 35 years and 4.1–33.1 nmol/L at age 88 years.