Effect of the Seasons

A number of environmental and biological factors may have an influence over an individual’s risk of developing fibrosis, and the chances of recovering from it. The body is a highly complex system of processes, with a large number of interactions and feedback effects between hormones and cells, and scientific advances in understanding are made regularly. Small alterations in one hormone can have powerful effects on many functions including stress, digestion, fertility and immune system function.

While the science behind the existence of these environmental and biological factors is sound, it’s not yet clear to what extent they impact on fibrotic processes.

The processes and functions of the body are governed by signalling factors the body makes called hormones. Hormones include growth factors and cytokines that signal cells in different parts of the body to start, stop, increase or decrease specific activities.

Recent research indicates that one of the main stress hormones, called cortisol, is significantly increased in winter in both men and women [1], with the effect greater at higher latitudes.

This may have implications for those at risk of arthrofibrosis if they are planning surgery, since increased cortisol increases levels of proteins that make resistant scar tissue and adhesions. Cortisol also increases the risk of infection. This suggests that the seasonal timing of surgery may impact on recovery, with winter being the least-best season and autumn the best season.

Seasonal timing of surgery may impact on recovery, with winter being the least-best season and autumn the best season.

Seasonal changes in hormones have been well studied in animals, and recent research indicates that humans also have significant seasonal alterations in their levels of a range of hormones. For example, the winter increase in the levels of cortisol increases the expression of lysyl oxidase (LOX), an enzyme (protein) that upregulates the production of scar tissue [2] and cross-links collagen in scar tissue. Highly cross-linked collagen is a hallmark of fibrotic tissue [3] and LOX is strongly implicated in fibrosis [2].

LOX increases cell to collagen adhesion via focal adhesion kinase (FAK), thus increasing both scar tissue production, stiffness and adhesions. In addition, LOX upregulates IL-6, a pro-fibrotic and pro- inflammatory cytokine [2].

References

1. Tendler, A. et al. Hormone seasonality in medical records suggests circannual endocrine circuits. Proc Natl Acad Sci U S A 118, doi:10.1073/pnas.2003926118 (2021).

2. Nguyen, X.-X. M. et al. Lysyl Oxidase Directly Contributes to Extracellular Matrix Production and Fibrosis in Systemic Sclerosis. Am J Physiol Lung Cell Mol Physiol, doi:10.1152/ajplung.00173.2020 (2020).

3. Kalamajski, S., Bihan, D., Bonna, A., Rubin, K. & Farndale, R. W. Fibromodulin interacts with collagen cross-linking sites and activates lysyl oxidase. Journal of Biological Chemistry, doi:10.1074/jbc.M115.693408 (2016).