Sex difference in human diseases: mechanistic insights and clinical implications

Abstract

Sex characteristics exhibit significant disparities in various human diseases, including prevalent cardiovascular diseases, cancers, metabolic disorders, autoimmune diseases, and neurodegenerative diseases. Risk profiles and pathological manifestations of these diseases exhibit notable variations between sexes. The underlying reasons for these sex disparities encompass multifactorial elements, such as physiology, genetics, and environment. Recent studies have shown that human body systems demonstrate sex-specific gene expression during critical developmental stages and gene editing processes. These genes, differentially expressed based on different sex, may be regulated by androgen or estrogen-responsive elements, thereby influencing the incidence and presentation of cardiovascular, oncological, metabolic, immune, and neurological diseases across sexes. However, despite the existence of sex differences in patients with human diseases, treatment guidelines predominantly rely on male data due to the underrepresentation of women in clinical trials. At present, there exists a substantial knowledge gap concerning sex-specific mechanisms and clinical treatments for diverse diseases. Therefore, this review aims to elucidate the advances of sex differences on human diseases by examining epidemiological factors, pathogenesis, and innovative progress of clinical treatments in accordance with the distinctive risk characteristics of each disease and provide a new theoretical and practical basis for further optimizing individualized treatment and improving patient prognosis.

Fig. 1

Sex-related mechanisms of cardiovascular dysfunction mainly include hormone and epigenetics regulation. Thyroid hormone can lead to cardiovascular dysfunction by up-regulating the expression of genes encoding sodium/potassium transporter ATPase. Prolactin blocked the mitogen-activated protein kinase activation, accelerating impaired cardiovascular function. E2 down-regulated the type I and III collagen gene expression, promoting myocardial stiffness. DNA methylation, histone modification, and non-coding RNA regulation lead to sex differences in cardiovascular pathophysiology and cardiac functional performance in individuals and offspring. This figure was created with the aid of BioRender (https://biorender.com/). AHR aromatic hydrocarbon receptor, Akt protein kinase B, ECM extracellular matrix, ERα estrogen receptor α, HDAC histone deacetylase, HIF-1a hypoxia-inducible factor-1α, PI3K phosphoinositide 3-kinase, OGG1 oxoguanine-DNA glycosylase-1, PPAR-γ peroxisome proliferator-activated receptor-γ, ROS reactive oxygen species, SIRT Sirtuin, SMAD3 Smad family member 3, TGFβ transforming growth factor β, VEGF vascular endothelial growth factor

Fig. 2

The regulation of sex hormones and gene affects insulin sensitivity, lipid metabolism, glucose homeostasis, and oxidative stress responses. Hormone regulation mainly includes estrogen receptor α, estrogen receptor β, sex hormone binding globulin, androgen receptor and testosterone. In the metabolic diseases regulated by gene signaling, the genes with higher expression in males than in females mainly include Angiotensinogen gene M235T polymorphism, AGTR1rs5186 polymorphism AA genotype, Kiss 1, Igf2 and H19. However, the genes that women expressed more than men mainly included ACE D allele carriers, Kiss1r mRNA, ACE2, Hsa-miR-660 and Hsa-miR-532. Hormonal and gene signaling regulate insulin sensitivity, lipid metabolism, glucose homeostasis, and oxidative stress responses, thereby influencing the occurrence of metabolic diseases. This figure was created with the aid of BioRender (https://biorender.com/). ACE angiotensin-converting enzyme, AGTR1 angiotensin II type 1 receptor gene

Fig. 3

This figure shows the mechanisms of sex differences that regulate cancer, including estrogen, androgen signaling pathways and gene expression. Estrogen receptors affect the occurrence of various tumors such as hepatocellular carcinoma by regulating PTPRO, miR-23a and IL1a. Androgen receptors promote the proliferation of tumor cells by regulating SVIP and miR-125b. KDM6A, KDM5D and SIK2 regulate the expression of many genes and thus affect the progression of many cancers. This figure was created with the aid of BioRender (https://biorender.com/). Akt protein kinase B, Cdkn1a cyclin-dependent kinase inhibitor 1 A, CUL4A cullin 4A, FASN fatty acid synthase, HMGCR hydroxy-3-methylglutaryl-CoA reductase, IL Interleukin, KDM6A X-linked lysine demethylase 6A, KDM5D histone lysine specific demethylase 5D, PERP p53 apoptosis effector related to PMP22, PI3K Phosphoinositide 3-kinase, PTPRO: Protein tyrosine phosphatase receptor type O, SIK2 Salt inducible kinase 2, SREBP1c sterol regulatory element binding protein 1c, SREBP2 sterol regulatory element binding protein 2, STAT3 Signal transduction and activator of transcription 3, SVIP small VCP/p97 interacting protein, XIAP X-linked inhibitor of apoptosis protein, ZEB1 Zinc Finger E-Box Binding Homeobox 1

Fig. 4

The pathogenesis of sex-based autoimmune diseases. Estrogen, sex chromosomes and epigenetic regulation are the main causes of sex-related autoimmune disease. These factors can play a role by affecting B cells, T cells, dendritic cells, Toll-like receptors, related immune genes on X chromosome, DNA methylation and miRNA. Affecting B cells can make B cells mature and increase the secretion of plasma cells and antibodies. Estrogen also affects the activation of DC through TLR signal pathway. These factors can lead to the increase of inflammatory factors IL-6, IL-8 and type I interferon resulting in autoimmune activation. Related immune genes encoded by X chromosome, such as CXCR3, CD40LG, CXorf21, CD183, also play an important role in immune activation. In addition, due to the increase of X chromosome inactivation escape genes, the number of X chromosome may be an important reason for sex bias immune function. In epigenetic regulation, estrogen can lead to global DNA hypomethylation by down-regulating the expression of mRNA and protein in DNMT1. Therefore, the decrease of DNA methylation at X promoter site will lead to abnormal expression of X-linked genes. In addition, miRNA can play a role in autoimmune diseases in a sex-specific manner. Let-7e-5p, miR-98-5p, miR-145a-5p, has-miR-10b-5p can exert immune response by regulating the expression of inflammation-related genes such as IL-1 and IFNα. This figure was created with the aid of BioRender (https://biorender.com/). CD40LG Chemokine receptor 40 Ligand, CD183 Chemokine receptor 183, CXCR3 C-X-C motif chemokine receptor 3, CXorf21 Chromosome X open reading frame 21, DC Dendritic cells, DNMT DNA methyltransferase, IFN interferon, IL interleukin, TLR Toll-like receptor

Fig. 5

Mechanisms related to sex differences in neurodegenerative diseases: including estrogen, sex chromosomes and microglia. Compared with men, women have higher levels of estrogen. Estrogen can not only reduce the depletion of binding and expression of dopamine and dopamine transporter in the striatum, but also reduce the loss of tyrosine hydroxylase immunoreactive neurons and weaken glial activation. This effect makes estrogen play a protective role in Parkinson’s syndrome. In addition, estrogen also plays a protective role in Alzheimer’s disease. This is not only shown in that estrogen can not only induce dephosphorylation of tau protein and prevent hyperphosphorylation in its neurons, but also protect neurons from β-amyloid toxicity, oxidative stress and excitotoxicity. In addition, activation of gray matter microglia plays a key role in neurodegenerative diseases, which can not only lead to synaptic phagocytosis and synaptic loss, but also lead to oxidative stress and mitochondrial damage. The accumulation of brain-specific genes on the X chromosome in the sex chromosome puts them in a unique position that affects the response of the central nervous system to injury. X chromosome can cause the loss of axon and myelin sheath of spinal cord, Purkinje cell and myelin sheath of cerebellum and synapse loss of cerebral cortex. This figure was created with the aid of BioRender (https://biorender.com/)