ICON Designated as an NIH Specialized Center of Research Excellence for Sex Differences in Medicine

"When it comes to health, sex matters," says Jill Goldstein, PhD, MPH, founder and executive director of the Innovation Center on Sex Differences in Medicine (ICON) at Massachusetts General Hospital.

Goldstein explains that males and females have different developmental pathways that start before birth and continue through puberty and into adulthood. These differences may play a greater role in understanding sex differences in the risk of developing depression, cardiovascular disease and Alzheimer's disease than you might think.

But until now, there has been relatively little research into the interplay between sex differences and health over the entire lifespan.

"Women and men are at different risks, presentations and even treatment responses for almost all chronic diseases, but medicine has been built on studies of male mice and men's health," Goldstein says. "This doesn't serve anyone, because women are not little men."

Goldstein, the Helen T. Moerschner Endowed MGH Research Institute Chair in Women's Health, and the ICON team are working to develop a better understanding of sex-specific and sex-dependent disease risk and reduce the devastating impact of these diseases.

The Center's efforts recently received a boost when the National Institutes of Health designed ICON as an official Specialized Center of Research Excellence (SCORE) for sex differences in medicine along with an $8.13 million grant to support their research efforts.

A Pressing Public Health Crisis

This year, the co-occurrence of cardiovascular disease (CVD) and major depressive disorder (MDD) will be the number one cause of disability worldwide, and women are at twice the risk of developing both.

What's more, CVD and MDD are both independent risk factors for Alzheimer's disease (AD), which could, in part, explain why women are at a higher risk for developing the disease after the age of 65 (it's not just differences in lifespan).

Goldstein and her team believe that using a three-pronged approach that identifies: a.) shared causes of MDD, CVD and AD; b) how these causes differ in men and women; and c.) how the risk develops over the course of a lifetime;, they can identify new strategies to treat and eventually prevent these disorders.

"Our brains and our physiology affect each other and this differs by one's sex, which is highly related to why there are sex differences in the co-occurrence of disorders of the brain and heart," she says.

"So it is important to understand what are the shared causes, how they differ in men and women, and what goes awry at different stages of development affecting the brain and heart in order to understand these comorbidities."

A Unique Approach

In fact, Goldstein and her team have discovered that shared causes of disorders of MDD and CVD impact men and women differently and their origins begin in fetal development.

Driven by gonadal hormones and genes, male and female brains develop at different times in utero. These hormones play a key role in organizing the nervous system. Disrupting healthy brain development in utero can impact how the individual interacts with the world after birth and this may differ for males and females.

With this as their starting point, the ICON team is reconceptualizing MDD, cardiovascular disease and Alzheimer's diseases as originating from the same roots in early development, modified by one's sex, whose causes then emerge across the lifespan as MDD, CVD and ultimately AD.

The team is investigating these questions using a multi-pronged approach that considers genetics, steroid hormones, and immune, vascular and metabolic functions.

"ICON's primary mission is to enhance and leverage these fundamental discoveries about sex differences in the brain and heart into strategies to develop sex-dependent or sex-specific therapeutics targeted to multiple organ systems," Goldstein says.

"We have an amazing opportunity to discover the shared early causes of these disorders, because targeting causes early will enhance resilience and ultimately can prevent chronic disease later in life. Using a sex differences lens provides a unique window into developing novel strategies to accomplish this."

Goals and Vision

Over the next decade, Goldstein and her team hope to reduce the co-occurrence of brain and heart disease in men and women across the globe by:

• Developing sex-dependent or sex-specific treatments and clinical care at the national and global levels
• Identifying unique approaches to maintain healthy aging across the life span using sex and gender differences
• Devising global strategies to lower morbidity and morbidity from depression and CVD among women, particularly in low resource countries

The team will also work to educate the next generation of clinicians and scientists on the role of sex and gender differences in medicine through seminars and advocacy work at the local, national and international levels.

The NIH SCORE, awarded by the NIH Office of Research on Women's Health (ORWH) and National Institute of Mental Health (NIMH), will focus on enhancing our understanding of the impact of the immune system on sex differences in the co-occurrence of depression and CVD and the development of a potential novel therapeutic device targeting the brain and heart.

"We are thrilled and honored to receive the blessing of NIH ORWH and NIMH as a designated center of research excellence on sex differences in medicine," Goldstein says.

"It not only provides a substantial foundation of funding for research and innovative translation, but it demonstrates NIH's confidence in the ICON mission and team to contribute uniquely and importantly to this critical field of sex differences in medicine in the service of precision medicine."