Table 2:
• Primary drivers of biological differences |
○ Sex-specific gene expression: X and Y chromosomes and genetic imprinting of autosomes |
○ Sex hormone-dependent changes |
▪ Androgen surge during development |
• Permanent differences in organ and tissue structure |
• Epigenetic regulation of gene expression |
▪ Persistent sex hormone differences from puberty and throughout life, female menopause |
• Biological differences secondary to primary drivers |
○ Impact of menses: iron deficiency |
○ Impact of pregnancy: large, reversible changes in kidney function, potential sensitization to foreign antigens |
○ Impact of gender differences in behaviour and lifestyles on biological variables |
○ Different energy metabolism |
○ Different disease susceptibility, e.g. in women |
▪ Increased susceptibility to autoimmunity (e.g. lupus nephritis) and urinary tract infection |
▪ Increased susceptibility to heart failure with preserved ejection fraction |
○ Different response to therapeutic interventions |
○ Different resilience to specific forms of cell death (e.g. ferroptosis) |
○ Different interaction with the gut microbiota |
Both primary drivers of biological differences and some examples of biological consequence of these primary drivers are shown. Molecular mechanisms have been well characterized in mice, but the clinical relevance of many of the findings remains unclear. Conversely, the molecular basis of some epidemiological differences observed in humans remain poorly characterized.