Postnatal testosterone may be an important mediator of the association between prematurity and male neurodevelopmental disorders: a hypothesis

Abstract

Children born premature are at risk for neurodevelopmental disorders, including autism and schizophrenia. This piece advances the hypothesis that altered androgen exposure observed in premature infants is an important mediator of the neurodevelopmental risk in males associated with prematurity. Specifically, the alterations of normative physiologic postnatal activations of the hypothalamic-pituitary-gonadal axis that occur in preterm males are hypothesized to contribute to the risk of neuropsychiatric pathology of prematurity through altered androgen-mediated organizational effects on the developing brain. The physiology of testosterone and male central nervous system development in full-term births is reviewed and compared to the developmental processes of prematurity. The effects of the altered testosterone physiology observed within prematurity outside of the central nervous system are reviewed as a segue into a discussion of the effects within the nervous system, with a special focus on autism spectrum disorders and attention deficit hyperactivity disorder. The explanatory power of this model is reviewed as a supplement to the preexisting models of prematurity and neurodevelopmental risk, including infection and other perinatal central nervous system insults. The emphasis is placed on altered androgen exposure as serving as just one among many mediators of neurodevelopmental risk that may be of interest for further research and evidence-based investigation. Implications for diagnosis, management and preventative treatments conclude the piece.

Potential role of pre- and postnatal testosterone levels in attention-deficit/hyperactivity disorder: is there a sex difference?

“…The possible explanation is that T has been implicated in dominant behavior and muscular physiology change but does not necessarily cause aggression or externalized problem behaviors. 23 , 24 The findings in this study do not support the assumption that current T levels influence ADHD behavior.…”

“…Postnatal T activation from childhood to puberty potentially influences behavioral and physiological change, as well as neurodevelopment. 23 , 24 Postnatal T levels are usually determined by analyzing the current (activational) T concentration in saliva or peripheral blood. 25 Several studies have investigated the relationship between current T level and ADHD.…”

Does Methylphenidate Reduce Testosterone Levels in Humans? A Prospective Study in Children with Attention-Deficit/Hyperactivity Disorder

“…In all patients, changes in salivary testosterone levels were not significantly correlated with changes in any behavioral symptom or index of the CPT. Some studies have suggested that testosterone causes physiological alteration but does not necessarily cause ADHD-like manifestations ( Dorn et al, 2009 ; Rice, 2015 ; van der Meij et al, 2016 ). The finding of our study supports this point of view.…”

The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

“…Preterm children with very low birth weight (VLBW; 1000-1500 g) or extremely low birth weight (ELBW; under 1000 g) are at increased risk for ASD [374][375][376]. A number of hypotheses have been put forward to explain these high rates of ASD: prenatal and neonatal complications like sensory impairment associated with prematurity, white matter abnormalities, and cerebellar impairment which occurred more commonly among preterm infants [372,377,378]; as well as altered androgen exposure observed in premature infants [379]. Also, gene-environment interactions and prematurity may combine to increase the risk for poor neurodevelopmental outcomes [380].…”