Estradiol levels are elevated in older men with diffuse cutaneous SSc and are associated with decreased survival

Abstract

Background Systemic sclerosis (SSc) is a female-predominant disease, characterized by excessive extracellular matrix deposition (ECM) with dermal and internal organ fibrosis. Considering the sex-based disparity in disease incidence, estradiol (E2), an estrogen form with pro-fibrotic effects, may play a role in SSc. We reported that post-menopausal women with diffuse cutaneous (dc)SSc have higher serum E2 levels compared to similar aged, healthy controls. Since males with SSc tend to have more severe disease, we examined serum E2 in dcSSc males in relation to disease characteristics and survival. Methods We measured serum E2 in 83 dcSSc men > 50 years old from the University of Pittsburgh Scleroderma Center and similar aged healthy controls. Using statistical modeling, we examined the associations between serum E2, internal organ involvement, autoantibody profiles, and survival. Results Male dcSSc patients had significantly higher serum E2 levels compared to healthy males and similar aged dcSSc post-menopausal women. Male dcSSc patients with high serum E2 had significantly more heart involvement, a trend for higher skin thickness progression rate, and worse survival. Using Cox regression modeling, increased serum E2 levels in anti-Scl-70 antibody-positive dcSSc males were associated with an increased risk of death. Conclusions dcSSc males > 50 years old have higher levels of serum E2 compared to healthy controls and dcSSc post-menopausal women. Elevated serum E2 levels in dcSSc males are associated with heart involvement, trend to progression of dermal fibrosis, and, if anti-Scl-70 antibody positive, worse survival. Our study expands on previous work implicating E2 in dermal fibrosis in SSc and associates E2 levels with internal organ involvement and survival. These data suggest a role for estrogen imbalance in dcSSc.

Elucidating the cellular mechanism for E2-induced dermal fibrosis

“…We extend those findings in this report to suggest that ERα signaling blockade can also prevent E2-induced Col22A1 transcription ex vivo . These results, in conjunction with our previous findings showing that circulating E2 levels are elevated in patients with SSc [ 20 ] suggest that fulvestrant is a promising therapeutic option in patients with SSc.…”

“…Our group has shown that E2 levels are increased in post-menopausal women with SSc, and E2 induced dermal thickening and increased fibronectin (FN) in an ex vivo human skin organ culture model and in primary human dermal fibroblasts [ 19 ]. Elevated E2 levels in patients with SSc are associated with reduced survival [ 20 ], suggesting a role for E2 in SSc-fibrosis.…”

Sexual Dimorphism in Innate Immunity: The Role of Sex Hormones and Epigenetics

“…Nevertheless, a large-scale longitudinal study demonstrated that untreated hypogonadism in men increases the risk of both lupus and rheumatoid arthritis (104). Moreover, men with autoimmune thyroid disease and diffuse cutaneous systemic sclerosis have been shown to have higher levels of circulating estradiol compared to unaffected males (105)(106)(107). Together, these studies indicate a protective role of testosterone in autoimmunity.…”

Morphological and Functional Changes in Skin of Adult Male Rats Chronically Treated with Letrozole, a Nonsteroidal Inhibitor of Cytochrome P450 Aromatase

“…However, conversion of testosterone to E2 by aromatase results in healthy older males having higher levels of circulating E2 than postmenopausal women. This is also associated with older males having increased adipose tissue, in which aromatase is expressed [ 3 ]. We have previously shown a significant reduction (43%) in serum 17β-estradiol (E2) [ 25 ] with no significant difference in the level of circulating testosterone after treatment of adult male rats with letrozole.…”