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

Deanna Baker Frost,Carol Feghali-Bostwick,Bethany Wolf,Christine Peoples,Maureen Laffoon,Jessica Fike,Thomas A Medsger,Katherine Silver

doi:10.1186/s13075-019-1870-6

Deanna Baker Frost, Carol Feghali-Bostwick + Show 6 more

Open Access

https://doi.org/10.1186/s13075-019-1870-6

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Abstract

BackgroundSystemic 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.MethodsWe 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.ResultsMale 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.ConclusionsdcSSc 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.

Highlights

Systemic sclerosis (SSc) is a female-predominant disease, characterized by excessive extracellular matrix deposition (ECM) with dermal and internal organ fibrosis
Systemic sclerosis (SSc) is an autoimmune, connective tissue disease of unknown etiology characterized by immune system dysregulation and excessive extracellular matrix (ECM) synthesis [1, 2]
We reported that post-menopausal female dcSSc patients have significantly higher levels of serum estrogens compared to age-matched healthy volunteers [11]

Summary

Introduction

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 postmenopausal women with diffuse cutaneous (dc)SSc have higher serum E2 levels compared to similar aged, healthy controls. As in most autoimmune diseases, there is a female predominance in SSc with a female to male ratio of 3:1, which increases to 9:1 during childbearing years [1]. E2, one of the forms of estrogen, is found in the serum of non-pregnant females, with higher levels during the childbearing years and reduced levels after menopause [9]. Older males have higher levels of circulating E2 than post-menopausal females, predominantly due to the conversion of E2 from testosterone. Older males have increased fat mass, and since aromatase is expressed in fat, there is greater E2 conversion [10]

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