Introduction: Heavy menstrual bleeding (HMB) affects over 1 million women in the UK. At menses, progesterone (P4) withdrawal drives inflammation, tissue break-down and repair of the endometrium. Glucocorticoids are mediators of inflammation and angiogenesis. Our previous studies have demonstrated that differential endometrial expression of the glucocorticoid-metabolising enzymes, 11β-HSD-1 and -2, may play a role in HMB. We hypothesise that aberrant local endometrial glucocorticoid production perturbs vascular and inflammatory mediators necessary to resolve menstruation. Our aim here was to elucidate these mechanisms using an established mouse model of menstruation in mice genetically deficient in 11β-HSD-1 or -2.
Methods and results: Mice lacking either 11β-HSD-1 (Hsd11b1−/−) or 11β-HSD-2 (Hsd11b2−/−) and C57Bl/6 WT controls (n≤4/group) underwent induced menstruation. Uteri were collected 8 and 24 h following P4 withdrawal. Tissue sections were histologically examined and graded for endometrial repair stage. Endometrial repair was significantly increased in Hsd11b1−/− mice 24 h following P4 withdrawal (P<0.05). Immunohistochemistry for CD31, an endothelial marker, revealed no difference between genotypes. RT-qPCR showed levels of Tsp1 mRNA, an angiostatic mediator, were significantly decreased in Hsd11b1−/− mice 24 h after P4 withdrawal (P<0.05), while Cox2 mRNA levels were decreased at both 8 and 24 h (P<0.05). Stereological analysis of tissues immunostained for the neutrophil marker Ly6G revealed a significant increase in neutrophil abundance in the basal endometrium of Hsd11b2−/− mice.
Conclusions: These findings suggest that local glucocorticoid tone contributes to rapidity of endometrial repair following menstruation. Alterations in glucocorticoid tone leads to vascular and inflammatory changes. Studies using a mouse model have the potential to contribute to our understanding of how aberrant local tissue glucocorticoid signalling may play a role in HMB. Further studies are now warranted.