The impact of biological sex on diseases of the urinary tract

Abstract

Biological sex, being female or male, broadly influences diverse immune phenotypes, including immune responses to diseases at mucosal surfaces. Sex hormones, sex chromosomes, sexual dimorphism, and gender differences all contribute to how an organism will respond to diseases of the urinary tract, such as bladder infection or cancer. Although the incidence of urinary tract infection is strongly sex biased, rates of infection change over a lifetime in women and men, suggesting that accompanying changes in the levels of sex hormones may play a role in the response to infection. Bladder cancer is also sex biased in that 75% of newly diagnosed patients are men. Bladder cancer development is shaped by contributions from both sex hormones and sex chromosomes, demonstrating that the influence of sex on disease can be complex. With a better understanding of how sex influences disease and immunity, we can envision sex-specific therapies to better treat diseases of the urinary tract and potentially diseases of other mucosal tissues.

Fig. 1. Prevalence of bacteriuria across ages and biological sex.

The prevalence of bacteriuria, indicated by the percentages shown, is highly variable between the sexes and during life. Infancy is the only period of life during which human males have a higher risk for bacteriuria and UTI than females. During adulthood, the prevalence of bacteriuria is lower in men than women and increases with age in men or during pregnancy for women. Differences in incidence between men and women decrease in the elderly, and both sexes face high rates of recurrent infection after 85 years of age. yo years old, *UTI prevalence is shown instead of bacteriuria. This figure was drawn summarizing data from refs. ^,–,,,,,. Figures were generated with images from Servier Medical Art (www.servier.com), licensed under the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/license/by/3.0/).

Fig. 2. Changes in sex hormones in plasma and bacteriuria in women and men over time.

The global percentage of sex hormone levels, as the maximum mean testosterone and the maximum mean estradiol level, in men (blue squares) and women (red circles) and bacteriuria prevalence in men (green triangles) and women (purple diamonds) is shown over time. In infancy, UTI prevalence is represented instead of bacteriuria. In the first 6 months of life, male infants have a higher prevalence of UTI than female infants, but this sex difference is reversed during childhood and remains over the lifetime of men and women. Figure adapted from ref. with bacteriuria data from refs. ^,–,,,,,.

Fig. 3. Female and male mice have different immune responses to UTI.

The innate immune response to female mice (top) is characterized by robust cytokine expression and immune cell infiltration, which is notably absent in male mice (bottom, transparent immune cells and missing cytokines). The events depicted inside the dotted box have been observed in the context of UTI in female mice, however, it is unknown whether these events unfold in male mice with UTI. For example, both sexes have two subtypes of resident macrophages, however, whether they behave similarly in defense against infection is unknown. Notably, both sexes mount a non-sterilizing adaptive immune response to infection, although whether this response is mediated by similar mechanisms in female and male mice is unclear. Figure drawn in BioRender with data from ref. and Rousseau et al., BioRxiv, https://www.biorxiv.org/content/10.1101/2021.10.28.466224v1.