Luteal phase oral dexamethasone administration alters the endometrial steroid milieu

We previously published the DexFEM trial, which showed that in women with heavy menstrual bleeding (HMB), oral dexamethasone reduces menstrual blood loss. Here, we report a pharmacodynamic analysis exploring the likely mechanism for this effect. We studied oral dosing with dexamethasone during the mid-luteal phase of two menstrual cycles (1.5 mg daily, 5 days) in five women with HMB (six recruited aged 41–50 years, one withdrew before treatment). Steroid hormones were profiled in serum and endometrium by liquid chromatography-tandem mass spectrometry (LC-MS/MS). We found that following oral dosing, dexamethasone reached the endometrium and that, compared to the preceding control cycle, cortisol (active), cortisone (inactive) and intermediate 11-deoxycortisol were reduced in all samples assessed, both endometrial (n = 4) and serum (n = 5). Concentrations of androgens, androstenedione and testosterone were reduced in serum but not in all tissue samples. This proof-of-concept pharmacodynamic study supports the inference that dexamethasone is effective in HMB by altering endometrial glucocorticoid concentrations. Significance statement New treatments are needed for HMB, a debilitating symptom experienced by many women. The association previously found between local endometrial glucocorticoid deficiency and HMB stimulated research into the role for glucocorticoids in the physiological process of menstruation. We report a proof-of-concept experimental medicine study profiling steroids in endometrial biopsies, demonstrating that dexamethasone administered orally penetrates the endometrium and is associated with changes in circulating endogenous steroid profiles (glucocorticoids and androgens) and in glucocorticoids in the endometrium. Dexamethasone thus has potential utility to modify glucocorticoid profiles and endometrial steroids in those with HMB. These findings augment the results of the recently reported adaptive clinical trial we conducted, also in women with HMB, showing that oral dexamethasone reduces menstrual blood loss.