Higher estrogen levels linked to more severe disease in scleroderma

June 05, 2019

Estrogen is the quintessentially female hormone.

It is surprising, then, that a Medical University of South Carolina (MUSC) study found that a type of estrogen, estradiol, was more abundant in older men with scleroderma than in postmenopausal women with the disease. The MUSC team reports the findings of their National Institutes of Health (NIH)-funded study in Arthritis Research & Therapy.

The team also found that men with scleroderma and higher levels of estradiol had more severe disease and heart involvement. Those with the Scl-70 autoantibody and higher levels of estradiol had a greater risk of death.

In scleroderma, the body makes too much connective tissue. This causes thickening of the skin and internal organs and, ultimately, organ damage. Women are three times more likely, and women in their child-bearing years nine times more likely, to have the disease than men. Men, however, have more severe disease.

Scleroderma develops in women during their child-bearing years, when estrogen levels are at their highest. This has led researchers to speculate that estrogen may play a role in the disease, as well as other autoimmune diseases.

Further fueling that speculation were findings from hormone replacement therapy trials that women's skin thickened during therapy and then returned to normal after completion of treatment.

Carol Feghali-Bostwick, Ph.D., the SmartState and Kitty Trask Holt Endowed Chair for Scleroderma Research at MUSC and senior author of the article, has previously reported that similar thickening occurred in skin cultures exposed to estradiol.

The MUSC team's recent findings provide some of the first evidence to confirm a link between high estrogen levels and the development of scleroderma. They also begin to explain why men, in whom the disease is less frequent, often have more severe symptoms.

"It seems reasonable to say that estradiol is probably one of the reasons why men have more severe disease," said Feghali-Bostwick.

"We always understood that women were more predisposed to getting autoimmune diseases," said DeAnna Baker Frost, M.D., Ph.D., an MUSC Health rheumatologist, a KL2 scholar, and first author of the article.

"We always thought that estrogen played a role, but we needed additional research to identify associations between elevated estrogen levels and clinical aspects of scleroderma. And so it was exciting to see that estrogen likely is playing a role in disease outcomes or maybe the development of autoimmune diseases."

Feghali-Bostwick, Baker Frost's mentor, is also associate director of the TL1/KL2 program and leads workforce development at the South Carolina Clinical & Translational Research (SCTR) Institute, housed at MUSC.

Feghali-Bostwick had previously shown that postmenopausal women with scleroderma have elevated estradiol levels. To see if these levels were also high in men of the same age, she and Baker Frost turned to serum samples banked at the University of Pittsburgh Scleroderma Center. Feghali-Bostwick co-directed that center before joining MUSC.

The team tested estradiol and scleroderma autoantibody levels in banked samples from 83 men aged 50 years and older with diffuse cutaneous systemic sclerosis, a type of scleroderma. They also tested samples from 37 healthy men of a similar age. They then used a variety of statistical approaches and the careful clinical annotations accompanying each sample to determine whether estradiol levels were linked to any of the clinical traits of scleroderma.

Male patients with diffuse cutaneous scleroderma had significantly higher levels of estradiol (average, 30.6 pg/mL) than both healthy men (average, 12.9 pg/mL) and postmenopausal women with the disease (24.2 pg/mL). Those with higher estradiol levels (average, 43.7 pg/mL) had significantly more heart involvement than those with lower levels (29.4 pg/mL). Finally, for patients with the Scl-70 autoantibody, increasing levels of estradiol in the serum was associated with a significantly greater risk of death.

But how is it possible for men to have such high levels of a hormone associated with the female reproductive system?

"Men can convert their testosterone to estrogen via an enzyme called aromatase," explained Feghali-Bostwick.

"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 in women as well. Preventing that conversion could be a novel therapeutic approach to scleroderma.

Aromatase inhibitors are already being used to treat women, particularly postmenopausal women, with hormone-receptor positive breast cancer. The MUSC team would like to conduct a small trial to assess the efficacy of aromatase inhibitors in patients with scleroderma.

Even if the costs of a trial in patients with scleroderma prove to be too high, Feghali-Bostwick believes there is much to learn from existing data from large breast cancer trials of aromatase inhibitors. For example, she would be very curious how the aromatase inhibitors affected patients who had both breast cancer and scleroderma.

"What happened to their scleroderma when they were treated with aromatase inhibitors?" asked Feghali-Bostwick.

"Knowing that would help inform us about the utility of aromatase inhibitors. It's hard to access the large breast cancer study data. However, doing so would provide us key information in assessing whether aromatase inhibitors have a role in scleroderma."

Meanwhile, Baker Frost is conducting experiments to establish a causal link between higher estradiol levels and scleroderma.

"I think we also have to show concretely that having high estrogen levels is the causative factor for the clinical characteristics of scleroderma," said Baker Frost.

"So 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."

The MUSC's team findings also point to estrogen as a potential environmental trigger for scleroderma. Most people who develop the disease are likely genetically susceptible. However, research suggests that the environment also plays a role. "Estrogen is around us. It's not just what your body produces," explained Feghali-Bostwick.

"There are a lot of things you get exposed to that affect estrogen levels - things like endocrine disrupters 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."
The content of the article summarized in this release is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

About MUSC

Founded in 1824 in Charleston, the Medical University of South Carolina (MUSC) is the oldest medical school in the South, as well as the state's only integrated, academic health sciences center with a unique charge to serve the state through education, research and patient care. Each year, MUSC educates and trains more than 3,000 students and 700 residents in six colleges: Dental Medicine, Graduate Studies, Health Professions, Medicine, Nursing and Pharmacy. The state's leader in obtaining biomedical research funds, in fiscal year 2018, MUSC set a new high, bringing in more than $276.5 million. For information on academic programs, visit http://musc.edu.

As the clinical health system of the Medical University of South Carolina, MUSC Health is dedicated to delivering the highest quality patient care available, while training generations of competent, compassionate health care providers to serve the people of South Carolina and beyond. Comprising some 1,600 beds, more than 100 outreach sites, the MUSC College of Medicine, the physicians' practice plan, and nearly 275 telehealth locations, MUSC Health owns and operates eight hospitals situated in Charleston, Chester, Florence, Lancaster and Marion counties. In 2018, for the fourth consecutive year, U.S. News & World Report named MUSC Health the number one hospital in South Carolina. To learn more about clinical patient services, visit http://muschealth.org.

MUSC and its affiliates have collective annual budgets of $3 billion. The more than 17,000 MUSC team members include world-class faculty, physicians, specialty providers and scientists who deliver groundbreaking education, research, technology and patient care.

About SCTR

The South Carolina Clinical and Translational Research (SCTR) Institute, a National Institutes of Health Clinical and Translational Science Awards hub, is the catalyst for changing the culture of biomedical research, facilitating sharing of resources and expertise, and streamlining research -related processes to bring about large-scale, change in the clinical and translational research efforts in South Carolina. Our vision is to improve health outcomes and quality of life for the population through discoveries translated into evidence-based practice. For more information, visit https://research.musc.edu/resources/sctr .

Medical University of South Carolina

Related Breast Cancer Articles from Brightsurf:

Oncotarget: IGF2 expression in breast cancer tumors and in breast cancer cells
The Oncotarget authors propose that methylation of DVDMR represents a novel epigenetic biomarker that determines the levels of IGF2 protein expression in breast cancer.

Breast cancer: AI predicts which pre-malignant breast lesions will progress to advanced cancer
New research at Case Western Reserve University in Cleveland, Ohio, could help better determine which patients diagnosed with the pre-malignant breast cancer commonly as stage 0 are likely to progress to invasive breast cancer and therefore might benefit from additional therapy over and above surgery alone.

Partial breast irradiation effective treatment option for low-risk breast cancer
Partial breast irradiation produces similar long-term survival rates and risk for recurrence compared with whole breast irradiation for many women with low-risk, early stage breast cancer, according to new clinical data from a national clinical trial involving researchers from The Ohio State University Comprehensive Cancer Center - Arthur G.

Breast screening linked to 60 per cent lower risk of breast cancer death in first 10 years
Women who take part in breast screening have a significantly greater benefit from treatments than those who are not screened, according to a study of more than 50,000 women.

More clues revealed in link between normal breast changes and invasive breast cancer
A research team, led by investigators from Georgetown Lombardi Comprehensive Cancer Center, details how a natural and dramatic process -- changes in mammary glands to accommodate breastfeeding -- uses a molecular process believed to contribute to survival of pre-malignant breast cells.

Breast tissue tumor suppressor PTEN: A potential Achilles heel for breast cancer cells
A highly collaborative team of researchers at the Medical University of South Carolina and Ohio State University report in Nature Communications that they have identified a novel pathway for connective tissue PTEN in breast cancer cell response to radiotherapy.

Computers equal radiologists in assessing breast density and associated breast cancer risk
Automated breast-density evaluation was just as accurate in predicting women's risk of breast cancer, found and not found by mammography, as subjective evaluation done by radiologists, in a study led by researchers at UC San Francisco and Mayo Clinic.

Blood test can effectively rule out breast cancer, regardless of breast density
A new study published in PLOS ONE demonstrates that Videssa® Breast, a multi-protein biomarker blood test for breast cancer, is unaffected by breast density and can reliably rule out breast cancer in women with both dense and non-dense breast tissue.

Study shows influence of surgeons on likelihood of removal of healthy breast after breast cancer dia
Attending surgeons can have a strong influence on whether a patient undergoes contralateral prophylactic mastectomy after a diagnosis of breast cancer, according to a study published by JAMA Surgery.

Young breast cancer patients undergoing breast conserving surgery see improved prognosis
A new analysis indicates that breast cancer prognoses have improved over time in young women treated with breast conserving surgery.

Read More: Breast Cancer News and Breast Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.