Persistent Hypogonadotropic Hypogonadism in Men After Severe Traumatic Brain Injury: Temporal Hormone Profiles and Outcome Prediction

Abstract

Objective: To (1) examine relationships between persistent hypogonadotropic hypogonadism (PHH) and long-term outcomes after severe traumatic brain injury (TBI); and (2) determine whether subacute testosterone levels can predict PHH.

Setting: Level 1 trauma center at a university hospital.

Participants: Consecutive sample of men with severe TBI between 2004 and 2009.

Design: Prospective cohort study.

Main measures: Post-TBI blood samples were collected during week 1, every 2 weeks until 26 weeks, and at 52 weeks. Serum hormone levels were measured, and individuals were designated as having PHH if 50% or more of samples met criteria for hypogonadotropic hypogonadism. At 6 and 12 months postinjury, we assessed global outcome, disability, functional cognition, depression, and quality of life.

Results: We recruited 78 men; median (interquartile range) age was 28.5 (22-42) years. Thirty-four patients (44%) had PHH during the first year postinjury. Multivariable regression, controlling for age, demonstrated PHH status predicted worse global outcome scores, more disability, and reduced functional cognition at 6 and 12 months post-TBI. Two-step testosterone screening for PHH at 12 to 16 weeks postinjury yielded a sensitivity of 79% and specificity of 100%.

Conclusion: PHH status in men predicts poor outcome after severe TBI, and PHH can accurately be predicted at 12 to 16 weeks.

Figure 1

Serum levels of testosterone (upper) and LH (lower) by persistent hypogonadotropic hypogonadism (PHH) status after severe TBI in men. Data represent mean ± SEM. Testosterone levels were significantly lower in the PHH group at week 1 (p<0.05) and weeks 6–52 (p<0.001). LH levels were significantly lower in the PHH group at weeks 10, 12 (p<0.05), 14 (p<0.01), 16, and 24 (p<0.05).

Figure 2

A: Receiver operating characteristic (ROC) curve analysis for initial screening test of testosterone serum values to predict PHH status. The 100% sensitivity cutoff point was selected (13.47 nmol/L). Subjects testing positive (below the cutoff) in the screening test were analyzed in a confirmatory test. B: ROC curve analysis for confirmatory test of testosterone serum values to predict PHH status. The 100% specificity cutoff point was selected (9.05 nmol/L). Two-step testing of serum testosterone yielded an overall sensitivity of 78.6% and specificity of 100% for prediction of PHH.

Figure 3

Diagnosis of post-traumatic hypogonadotropic hypogonadism should be incorporated into a full endocrinological workup for hypopituitarism in order to determine an appropriate course of therapy. Adrenal insufficiency, hypothyroidism, and hyperprolactinemia should all be treated prior to hypogonadism since these hormones may affect testosterone levels. In the absence of these endocrinopathies, two-step testosterone testing is recommended to detect persistent hypogonadotropic hypogonadism (PHH). This should be conducted between 12–16 weeks after TBI. If a testosterone screening test level is below 13.5 nmol/L, then a second confirmatory test should be conducted. If the confirmatory test level is below 9.05 nmol/L, then this individual is at risk for poor outcome, and treatment for PHH may be beneficial.