Sexual dimorphism in atrophic effects of topical glucocorticoids is driven by differential regulation of atrophogene REDD1 in male and female skin

Abstract

Topical glucocorticoids, well-known anti-inflammatory drugs, induce multiple adverse effects, including skin atrophy. The sex-specific effects of systemic glucocorticoids are known, but sexual dimorphism of therapeutic and side effects of topical steroids has not been studied. We report here that female and male mice were equally sensitive to the anti-inflammatory effect of glucocorticoid fluocinolone acetonide (FA) in ear edema test. At the same time, females were more sensitive to FA-induced skin atrophy. We recently reported that REDD1 (regulated in development and DNA damage 1) plays central role in steroid atrophy. We found that REDD1 was more efficiently activated by FA in females, and that REDD1 knockout significantly protected female but not male mice from skin atrophy. Studies using human keratinocytes revealed that both estradiol and FA induced REDD1 mRNA/protein expression, and cooperated when they were combined at low doses. Chromatin immunoprecipitation analysis confirmed that REDD1 is an estrogen receptor (ER) target gene with multiple estrogen response elements in its promoter. Moreover, experiments with GR and ER inhibitors suggested that REDD1 induction by these hormones was interdependent on functional activity of both receptors. Overall, our results are important for the development of safer GR-targeted therapies suited for female and male dermatological patients.

Glucocorticoid-Induced Skin Atrophy: The Old and the New

“…The subject of topical GC sexual dimorphism remains an open one, more research being needed in this direction. 45 , 46 …”

“…The subject of topical GC sexual dimorphism remains an open one, more research being needed in this direction. 45,46 Another issue of growing concern is the topical GC withdrawal, as "steroid addiction" can lead to problems such as patient adherence to treatment and failure of prescribed treatment. There are 2 types of steroid withdrawal, morphologically distinct: the papulopustular one and the erythemato-edematous one, with overlapping signs and symptoms.…”

Effects of Delgocitinib Ointment 0.5% on the Normal Mouse Skin and Epidermal Tight Junction Proteins in Comparison With Topical Corticosteroids

“…Although female mice are reportedly more sensitive to skin atrophy induced by topical glucocorticoids, 10 TCSs induce skin atrophy regardless of gender. 11,12 Although TCSs have been the mainstay of pharmacotherapy in AD over the past decades, long-term use of TCSs can cause specific adverse reactions such as steroid flushes and skin atrophy.…”

“…Only female mice were used in the present study since they are easier to be handled compared to male mice and are commonly selected for this type of studies. Although female mice are reportedly more sensitive to skin atrophy induced by topical glucocorticoids, 10 TCSs induce skin atrophy regardless of gender. 11,12…”

Intermittent glucocorticoid treatment enhances skeletal muscle performance through sexually dimorphic mechanisms

“…Studies investigating the molecular effects of glucocorticoids on skeletal muscle have often been evaluated in a single sex (2,17,46) or with results from both sexes analyzed in aggregate, missing the biological effects of sex-specific responses (3,19,20). Studies in liver (21) and more recently in skin (47) suggest males and females can have distinct responses to synthetic glucocorticoid treatment. Male muscle was characterized by increased IGF1/PI3K signaling activation, a pathway strongly implicated in muscle growth (25).…”