Older men with diffuse cutaneous systemic scleroderma (dcSSc) have more estradiol, a form of estrogen, compared with postmenopausal women with the disease, which may explain why scleroderma tends to be more severe in men, a study has found.
Researchers also found that male patients with higher levels of estradiol had more severe disease and heart involvement, and that those with Scl-70 autoantibodies and higher levels of estradiol had a greater risk of death.
The study, “Estradiol levels are elevated in older men with diffuse cutaneous SSc and are associated with decreased survival,” was conducted by researchers at the Medical University of South Carolina (MUSC), and published in the journal Arthritis Research & Therapy.
Compared with men, women are three times more likely to have systemic scleroderma; women in fertile years (when estrogen levels are at their highest) have nine times the chance of developing the disease. However, men often have more severe disease — including more severe interstitial lung disease (ILD), currently the leading cause of death among SSc patients.
Some findings made scientists believe there is a link between estrogen and SSc, namely that women in fertile age are more prone to the disease, and that women receiving hormone replacement therapy — typically estrogen-based — experience skin thickening. More recently, researchers at MUSC also reported a similar thickening in a human skin organ culture model exposed to estradiol.
Estradiol (E2) is a powerful reproductive hormone working both in men and women. It is one of the forms of estrogen, attaining its highest levels in women during childbearing years, and decreasing after menopause.
It is important to note, however, that circulating levels of estradiol in healthy older males normally surpass that of post-menopausal women, mostly because of the conversion of testosterone into estradiol.
Given the possible link between estrogen and SSc, researchers were interested in understanding whether greater E2 levels in older men could be associated with their tendency to have worse SSc.
Researchers therefore measured levels of estradiol and scleroderma autoantibodies (autoreactive antibodies, typically associated with autoimmune diseases) in serum samples from 83 men older than 50 with dcSSs. To obtain reference values, the team also tested samples of 37 healthy men of similar age.
Samples were banked at the University of Pittsburgh Scleroderma Center.
The team investigated whether estradiol levels were linked to any of the clinical traits of scleroderma, including internal organ involvement, autoantibody profiles, or patient survival.
Results showed that male SSc patients had significantly higher levels of estradiol (average of 30.6 pg/mL) compared to healthy males (average of 12.9 pg/mL) and post-menopausal women with the disease (24.2 pg/mL).
Also, male patients with higher serum estradiol levels had significantly more heart involvement than those with lower levels, and a trend for higher skin thickness progression rate, and a worse survival rate.
Additionally, those positive for Scl-70 autoantibodies and increased estradiol levels had a significantly increased risk of death.
“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,” the researchers stated.
“Men can convert their testosterone to estrogen via an enzyme called aromatase,” Carol Feghali-Bostwick, PhD, endowed chair for scleroderma research at MUSC, and the study’s senior author, said in a press release. “They’re converting testosterone in their tissues. You don’t to have to have ovaries to make estrogen. Other tissues can also form estrogen.”
Aromatase can convert other tissues such as fat into estrogen, also in women. Therefore, the MUSC team suggested that preventing such conversion could be a novel therapeutic approach for scleroderma.
Aromatase inhibitors are already being used to treat women, particularly postmenopausal women, with hormone-receptor positive breast cancer. Now, MUSC researchers would like to conduct a small trial to assess the efficacy of aromatase inhibitors in patients with scleroderma.
Another way of gathering key information, researchers noted, is to look at large breast cancer datasets to see what happens to women who also had scleroderma after taking aromatase inhibitors to treat their cancer.
Meanwhile, DeAnna Baker Frost, MD, PhD, a MUSC Health rheumatologist and first author of the study, is conducting further experiments to demonstrate that higher estradiol can be a cause of clinical traits of scleroderma.
“We’re doing a lot of studies with human tissues, and soon tissues from scleroderma patients, to show that if we treat these cells and tissues with estrogen, then the downstream effects will be the high levels of tissue scarring that you see with scleroderma,” Frost said.
The findings also suggested that the environment may also play a role.
“Estrogen is around us,” Feghali-Bostwick said. “There are a lot of things you get exposed to that affect estrogen levels,” namely endocrine disrupters (chemicals that interfere with hormone secretion or action) and estrogen mimics.
“So I think it’s just part of understanding what environmental factors may be involved in the development not just of scleroderma but also of related autoimmune diseases,” Feghali-Bostwick said.