Despite laudable progress towards social gender equality, there are undeniable biological differences between males and females that extend beyond typical sexual characteristics. Sex differences in fetal growth have long been recognised, with males growing faster and being larger than females at birth. Numerous studies have demonstrated a fetal sex bias in the incidence of pregnancy complications such as preeclampsia, suggesting these growth differences are not inconsequential. This sexual inequality is almost certainly orchestrated by the placenta, however the precise molecular mechanisms underpinning these phenomena remain elusive.

Advances in high-throughput gene expression profiling are profoundly influencing the way we approach such complex biological questions. To investigate sex differences in the human placenta, we employed novel bioinformatics and meta-analysis methods to create a fully re-annotated transcriptome dataset from 302 publicly available gene expression microarrays. By using inverse-variance linear modelling, we show 142 genes (FDR P-values <0.05) are differentially expressed between male and female placentas. A majority of these genes are autosomal (62%) and show distinct patterns of chromosomal clustering. Twenty X-chromosome genes show higher expression in female placentas revealing patterns indicating region-wide loss of X chromosome inactivation.

Using gene ontology enrichment analyses, we show these differences extend beyond the expected hormone regulatory functions to processes such as RNA binding, histone methylation and the regulation of chemotaxis. Additionally, we detected higher female expression from all genes in the CGB cluster (19q13.32), which encode the beta subunit of human chorionic gonadotropin (hCG), a hormone involved in maintenance of pregnancy, maternal immune tolerance and trophoblast invasion.

This genome-wide expression profiling of the human placenta demonstrates the existence of previously unappreciated sex differences in placental gene expression. Our findings highlight the importance of considering fetal sex in both research and clinical settings, as the presentation, symptoms and response to treatment may differ significantly between sexes.