Low back pain (LBP) is the world’s leading cause of disability and is increasing in prevalence more rapidly than any other pain condition. Intervertebral disc (IVD) degeneration and facet joint osteoarthritis (FJOA) are two common causes of LBP, and both occur more frequently in elderly women than in other populations. Moreover, osteoarthritis (OA) and OA pain, regardless of the joint, are experienced by up to twice as many women as men, and this difference is amplified during menopause. Changes in estrogen may be an important contributor to these pain states. Receptors for estrogen have been found within IVD tissue and nearby joints, highlighting the potential roles of estrogen within and surrounding the IVDs and joints. In addition, estrogen supplementation has been shown to be effective at ameliorating IVD degeneration and OA progression, indicating its potential use as a therapeutic agent for people with LBP and OA pain. This review comprehensively examines the relationship between estrogen and these pain conditions by summarizing recent preclinical and clinical findings. The potential molecular mechanisms by which estrogen may relieve LBP associated with IVD degeneration and FJOA and OA pain are discussed.

Musculoskeletal conditions are known to involve biological, psychological, social and, often, lifestyle elements. However, these domains are generally considered in isolation from each other. This siloed approach is unlikely to be adequate to understand the complexity of these conditions and likely explains a major component of the disappointing effects of treatment. This paper presents a hypothesis that aims to provide a foundation to understand the interaction and integration between these domains. We propose a hypothesis that provides a plausible link between psychology and lifestyle factors with tissue level effects (such as connective tissue dysregulation/accumulation) in musculoskeletal conditions that is founded on understanding the molecular basis for interaction between systemic and local inflammation. The hypothesis provides plausible and testable links between mind and body, for which empirical evidence can be found for many aspects. We present this hypothesis from the perspective of connective tissue biology and pathology (fibrosis), the role of inflammation locally (tissue level), and how this inflammation is shaped by systemic inflammation through bidirectional pathways, and various psychological and lifestyle factors via their influence on systemic inflammation. This hypothesis provides a foundation for new consideration of the development and refinement of personalized multidimensional treatments for individuals with musculoskeletal conditions.