Sex-differences in prostaglandin signaling: a semi-systematic review and characterization of PTGDS expression in human sensory neurons

Abstract

There is increasing evidence of sex differences in underlying mechanisms causing pain in preclinical models, and in clinical populations. There are also important disconnects between clinical pain populations and the way preclinical pain studies are conducted. For instance, osteoarthritis pain more frequently affects women, but most preclinical studies have been conducted using males in animal models. The most widely used painkillers, nonsteroidal anti-inflammatory drugs (NSAIDs), act on the prostaglandin pathway by inhibiting cyclooxygenase (COX) enzymes. The purpose of this study was to analyze the preclinical and clinical literature on the role of prostaglandins and COX in inflammation and pain. We aimed to specifically identify studies that used both sexes and investigate whether any sex-differences in the action of prostaglandins and COX inhibition had been reported, either in clinical or preclinical studies. We conducted a PubMed search and identified 369 preclinical studies and 100 clinical studies that matched our inclusion/exclusion criteria. Our analysis shows that only 17% of preclinical studies on prostaglandins used both sexes and, out of those, only 19% analyzed or reported data separated by sex. In contrast, 79% of the clinical studies analyzed used both sexes. However, only 6% of those reported data separated by sex. Interestingly, 14 out of 15 preclinical studies and 5 out of 6 clinical studies that analyzed data separated by sex have identified sex-differences. This builds on the increasing evidence of sex-differences in prostaglandin signaling and the importance of sex as a biological variable in data analysis. The preclinical literature identifies a sex difference in prostaglandin D2 synthase (PTGDS) expression where it is higher in female than in male rodents in the nervous system. We experimentally validated that PTGDS expression is higher in female human dorsal root ganglia (DRG) neurons recovered from organ donors. Our semi-systematic literature review reveals a need for continued inclusivity of both male and female animals in prostaglandins studies and data analysis separated by sex in preclinical and clinical studies. Our finding of sex-differences in neuronal PTGDS expression in humans exemplifies the need for a more comprehensive understanding of how the prostaglandin system functions in the DRG in rodents and humans.

Pathology of pain and its implications for therapeutic interventions

“…Additionally, prostaglandin and antidiuretic hormone also have close associations with pain susceptivity in females. 438 , 439 However, there is still a lack of mechanistic investigations into non-sex hormones.…”

Female-selective mechanisms promoting migraine

“…A key observation is sexual dimorphism in transcript for CGRP that is expressed at higher levels in DRG neurons recovered from human female, compared to male, donors [ 62 ]. Additionally, transcriptome analysis of non-neuronal satellite cells in post-mortem human DRG have also been found to differ between male and female tissues suggesting additional sexually dimorphic mechanisms that may promote neuronal activation and signaling [ 67 , 68 ]. Most recently, sexual dimorphism has been observed in human nociceptors at the protein and functional level [ 65 ].…”

RNA-Seq Reveals Sex Differences in Gene Expression during Peripheral Neuropathic Inflammation and in Pain Relief from a COX-2 Inhibiting Theranostic Nanoemulsion

“…With the National Institute of Health's requirement for investigators to include sex as a biological variable (NOT-OD-15-102), more sex differences have been revealed in the development of neuropathic inflammatory hypersensitivity and pain [12,13]. A few studies have evaluated the expression differences between sexes experiencing neuroinflammatory pain [14][15][16][17][18][19]. For example, during neuroinflammation, RNA expression patterns suggest an involvement of T cells, as well as activation of immune signaling pathways, changes in neuronal plasticity, and enrichment from other gene pathways involved in the neuronal immune crosstalk [15,18,20].…”