Objectives: A birthweight centile (BWC) less than the 25th increases the risk of adverse perinatal outcomes, with a greater incident for males than females. This male disadvantage may be due to changes to placental-specific androgen signalling: a signalling axis that is regulated by the differential expression and localisation of androgen receptor (AR) protein variants.

Methods: We characterised global and AR-mediated transcriptomic signatures in term placentae (≥37 weeks gestation) across BWC subcategories (<10th, 10-30th, >30th) using RNA-seq and gene set enrichment analysis. Relationships between AR-mediated transcripts and AR protein variants in female and male <10th BWC placentae were analysed.

Results: There were minimal changes to transcriptomic signatures in female placentae between BWC subcategories. In males, AR-mediated transcripts were upregulated in <10th BWC placentae when compared with both 10-30th and >30th BWC placentae; this coincided with an upregulation of gene sets involved in hypoxia and a downregulation of gene sets involved in mitochondrial function. In the absence of AR-mediated transcripts, gene sets involved in vasculature development, immune function, and cell adhesion were upregulated in <10th and 10th-30th when compared with >30th BWC placentae. Distinct clusters were observed between cytoplasmic and nuclear AR protein variants and AR-mediated transcripts in males but not females.

Conclusion: Together, our findings indicate activation of AR signalling in male placentae may contribute to reduced growth outcomes, the mechanisms for which may be due to distinct AR protein variant expression profiles.