Hypogonadism and neurocognitive outcomes among childhood cancer survivors

Abstract

Objective: Childhood cancer survivors are at risk for hypogonadism. The impact of hypogonadism on neurocognitive impairment and emotional distress in the non-cancer population has been shown; however, the relationship among the childhood cancer survivor population is unknown. We aimed to evaluate the contribution of hypogonadism to neurocognitive impairment and emotional distress among survivors.

Design: Cross-sectional study using retrospective cohort.

Methods: In total, 3628 survivors who completed standard neurocognitive tests (six domains: processing speed, memory, executive function, attention, academics, and global cognition) and self-reported emotional distress were included in our study. Participants were stratified by sex and gonadal status. Outcomes were compared between hypogonadal and eugonadal groups by multivariable analysis, adjusting for established predictors, and mediation analyses to determine the direct/indirect effects of hypogonadism on outcomes.

Results: The hypogonadal group exhibited a higher prevalence of neurocognitive impairment across domains, but no difference in emotional distress. Hypogonadal females exhibited higher relative risk (1.7, 95% CI, 1.2-2.5) for impaired visual processing speed, compared to eugonadal females after adjusting for cancer-related variables. In mediation models, hypogonadism had a significant direct (P < .01) and indirect (from P < .01) impact on impairment in visual processing speed among females. Males demonstrated direct (P = .03) and indirect (P = .04) impact of hypogonadism on motor processing speed.

Conclusion: Processing speed may be the most vulnerable neurocognitive domain associated with hypogonadism in survivors, while other domains were mainly impacted by cancer-related variables. Our findings support the need for further evaluation of the impact of sex hormone replacement therapy on neurocognitive function.

Keywords: childhood cancer survivors; hormone replacement therapy; hypogonadism; neurocognitive dysfunction; sex hormone.

Figure 1.

Study participants. SJLIFE, St. Jude Lifetime Cohort study.

Figure 2.

Paths for the mediation of hypogonadal effects on neurocognitive function. Final path models are presented for each neurocognitive outcome in which any direct effects of hypogonadism on neurocognitive outcome were noted (P < 0.05): (A) visual processing speed in females, (B) visual-motor processing speed in females, (C) motor processing speed in males. Each model includes only significant paths and is labeled with standardized coefficients. CFI, comparative fit index; RMSEA, Root Mean Square Error of Approximation.