Sex Differences

MIR Research Provides Powerful Insights

By Kristi Luther

Robert J. Gropler, MD, senior vice chair and division director of radiological sciences, recalls a time in 2007 when he and collaborators were wondering whether biological sex differences in myocardial metabolism were worth exploring in their research. “Pilar Herrero came into our office and kept saying, ‘There’s something here,’” Gropler says. Herrero, who since passed away, specialized in quantitative imaging analytics and modeling of cardiac PET images. “She felt strongly there was something to learn from studying males and females. It took a lot of work to find an answer, but it turns but the answer is yes, there is.”

Sex differences are illuminating a potentially powerful strategy in the advancement of personalized medicine and the fight against disease. While developing new therapies and drugs remains a key aspect of advancing personalized medicine, those paths also require years and countless dollars. Instead, understanding sex differences could help MIR researchers make a more immediate impact by allowing existing therapies to be optimized more precisely and trials to be structured more effectively. 

“I think MIR is leading the way on this in many areas,” says Gropler, a professor of radiology. Broadly speaking, research has shown that healthy males are more dependent on sugars and amino acids for cellular metabolism in various organs, while females are more dependent on fatty acids. MIR researchers are working to better understand these sex differences in normal cellular metabolism, which could provide powerful insights into how various diseases — such as different types of cancers and cardiovascular disease — can be treated. 

An Invariably Lethal Disease   

In 2022, a team of researchers investigated glioblastoma (GBM) — an aggressive, fast-growing cancer and the most common malignant brain tumor in adults. Recognizing GBM as “an invariably lethal disease,” Joseph E. Ippolito, MD, PhD, associate professor of radiology, and collaborators set out to explore whether biological sex may underlie differences in brain tumor glutamine metabolism, a hallmark of cancer development. 

Rivaling GBM’s lethality is its elusiveness. Jasmin Sponagel, PhD, a postdoctoral research associate and lead author of the research team’s paper, felt compelled to study glioblastoma considering the last major advancement was when Temozolomide was added as a chemotherapeutic — over 20 years ago. 

“We’re all seeing the same thing with sex differences —all in different areas, in different organs,” says Robert J. Gropler, MD, senior vice chair and division director of radiological sciences.

The collaboration between the Ippolito Lab; the Rubin Lab, led by Joshua B. Rubin, MD, PhD, professor of pediatrics; the Patti Lab, led by Gary J. Patti, PhD, the Michael and Tana Powell Professor of Chemistry; as well as counterparts at Memorial Sloan Kettering Cancer Center consisted of a metabolite abundance assessment in a previously published dataset of 757 metabolites in 44 male and 32 female, newly diagnosed GBM surgical specimens. 

The findings were published in a paper titled “Sex differences in brain tumor glutamine metabolism reveal sex-specific vulnerabilities to treatment” in Med by Cell Press. Ultimately, the team found there were clinically important sex differences in targetable elements of metabolism, indicating that more research recognizing sex-based metabolism could illuminate ways to improve current treatments for this notoriously aggressive cancer. Previous GBM research highlighted the significance of sex-based differences: males are 60% more likely to develop GBM than females; and females respond better to therapy, resulting in a notably longer survival rate. 

In diabetic patients, females have a higher instance of cardiovascular complications and incidence of heart failure. 

Further accentuating the impact of sex differences across pathologies, Ippolito and Sponagel also recently studied glucose metabolism in lung cancer, the leading cause of cancer-related death. In a similar fashion to brain tumors, males have a higher lung cancer mortality rate than females, and the researchers disovered that male lung cancers utilize glucose to supply tumorigenesis to a greater extent than female tumors. 

Ippolito emphasizes that considering how the trio of chromosomes, epigenetics and sex hormones play into cancer biology may be a catalyst for precision medicine. “I think what we’re getting at here is advancing personalized medicine,” he says. “We’re starting with looking at sex.” 

Seeing the Same Thing  

The GBM study builds on an expansive history of research on sex differences at MIR. Gropler’s team — in collaboration with Linda R. Peterson, MD, professor of medicine and radiology — found that healthy normal females are more dependent on fatty acids for their cardiac metabolism, while males are more dependent on glucose. Females also had higher blood flow and oxygen consumption and were slightly less efficient in their heart work than the males. 

“And that’s just among normal volunteers,” Gropler says. “We then took those findings and showed that pattern persisted through multiple diseases, including heart failure, dilated cardiomyopathy, obesity and diabetes, and was a key determinant of how these diseases impacted the heart.” 

In diabetic patients, females have higher incidences of cardiovascular complications and heart failure. “It turns out, with diabetes mellitus, it forces the heart to use more fats as opposed to glucose,” Gropler says. This becomes magnified in females due to their underlying increased reliance on fatty acid metabolism.

“I think the most immediate dream for future clinical approaches would be to actually consider sex in a clinical setting.” 

Similar findings regarding sex differences extend across MIR’s research enterprise, including research on brain metabolism that determined “brain age.” In 2019, Manu S. Goyal, MD, associate professor of radiology, alongside MIR collaborators Marcus E. Raichle, MD, and Andrei G. Vlassenko, MD, PhD, found that from a metabolic perspective, female brains appear to be about three years younger than male brains of the same chronological age. The relative youthfulness of female brains was found even in the youngest participants in their 20s. And Ippolito previously showed that abdominal visceral fat affects the odds of women surviving kidney cancer as well as lymphoma, but not for men. 

“We’re all seeing the same thing with sex differences,” says Gropler. “Manu saw the same thing, Joe saw the same thing — all in different areas, in different organs.”

Without Looking at Sex, You Might Miss Something

Clinical studies have historically centered on males and do not consistently or adequately capture data on biological sex differences. “I think the most immediate dream for future clinical approaches would be to actually consider sex in a clinical setting,” Sponagel says. “If you merge everyone together, you’re going to lose valuable results.” 

In 2019, Manu S. Goyal, MD found that female brains appear to be about three years younger than male brains of the same age.

Gropler learned this firsthand when he and colleagues were studying diabetic medications and how they impacted metabolism in Type 2 diabetes mellitus. With male and female data pooled, the research team didn’t see any differences. Once they included sex differences, however, it became clear that therapeutic regimens impact myocardial metabolism and diastolic function differently in males than in females. 

Two things can happen when you leave out sex differences as a factor in preclinical and clinical studies, Gropler says. “One, you may underestimate the disease in one of the two sexes. Or worse yet, you may come to the conclusion that there is no effect. Without looking at sex, you might miss something really important.” 

Published in Focal Spot Fall/Winter 2022 Issue