Maternal, childhood and adolescent influences on Leydig cell functional capacity and circulating INSL3 concentration in young adults: Importance of childhood infections and body mass index.

Abstract

Background: The constitutive Leydig cell hormone insulin-like peptide 3 (INSL3) is considered a good estimate of the adult Leydig cell functional capacity and appears to remain relatively consistent throughout adult male life, only gradually declining into old age. Importantly, in younger men it appears to predict hypogonadism and hence later health and morbidity.

Objectives: Here, we have used the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort of boys and young men to assess those factors during pregnancy, infancy, childhood, and adolescence, when the adult-type Leydig cell population is being established, which by association might influence the final circulating INSL3 concentration in young adulthood.

Methods: A wide range of clinical, anthropometric and lifestyle parameters were assessed from up to 2000 boys and young men based on direct medical measurement and/or by targeted questionnaires. Scalar variables used bivariate correlation analysis, whereas comparative statistics, such as t-tests, were applied to categorical variables.

Results: Maternal parameters, such as maternal smoking, gestational age, or being small for gestational age (SGA) appeared to have no association with adult INSL3 levels. Of all the parameters assessed, those with greatest impact on young adult Leydig cell status appeared to be childhood and adolescent body mass index (BMI) and early childhood infectious disease. Particularly, chickenpox in infancy had a marked and significant negative association with INSL3 (reduced by 10%-14%) at both 17 and 24 years. Being overweight (> 85th percentile) at 13 years was associated with a 20% reduction in young adult INSL3. In contrast, childhood and adolescent inflammatory factors and cigarette exposure appeared to have no long-lasting impact on adult Leydig cell status.

Limitations: This retrospective cohort study is limited by relatively small numbers and by its correlative analysis. The hypotheses generated will need to be validated in more extensive, in-depth studies.

Lay summary: The testis hormone INSL3 is considered a good estimate of the gonadal capacity to make testosterone. It is relatively constant throughout adult male life, only gradually declining into old age. Importantly, in younger men reduced INSL3 appears to predict hypogonadism and hence later health and morbidity. Whilst showing low within-individual variation, between individuals INSL3 can vary more than 10- up to 100-fold. The source of this variance is unknown but is believed to have its origin during childhood and adolescence. Analysis of data from the ALSPAC cohort implies that of various parameters assessed, only childhood and adolescent BMI as well as early infectious disease, in particular chickenpox, have any influence on young adult INSL3 concentration, respectively reducing circulating levels each by 10%-20%. More research is needed to understand the mechanisms how these factors influence testis function, what can be done as mitigation, and what other factors may be involved.