What estrogen really does and what happens without it

To better understand human biology, scientists often turn to mice, with whom we share about 90 percent of disease-related genes. But for decades, that research has been conducted primarily on male mice.

That imbalance has influenced everything from our understanding of basic physiology to drug development.

After decades of research, Holly Ingraham, a world-renowned molecular biologist and elected member of the National Academy of Sciences, has a different perspective. She has spent her career reshaping how scientists think about sex differences in health and disease.

She will discuss that work at the next Maury Strauss Distinguished Public Lecture at 5:30 p.m. Thursday, Jan. 22, at the Fralin Biomedical Research Institute at VTC in Roanoke.

“Dr. Ingraham’s work reflects exactly what this lecture series is meant to showcase: how advances in biomedical science can inform real-world health for all people,” said Michael Friedlander, executive director of the Fralin Biomedical Research Institute at VTC and vice president for Health Sciences and Technology at Virginia Tech. “Her talk will help audiences understand how hormones and neural circuits shape female physiology across the lifespan, with implications for conditions ranging from bone loss during lactation to gut sensitivity in irritable bowel syndrome.”

Her hormone-focused research has led to findings related to sex-dependent neurocircuits, estrogen and hormone signaling in metabolism, gut-brain signaling in irritable bowel syndrome, and age-related hormone depletion that could lead to new treatments for osteoporosis and bone fractures.

“Most of what we think about in terms of female physiology is all centered around just reproductive issues,” Ingraham said in an interview with The Physiologist Magazine. “But we are missing many more dimensions in women's health, resulting from the dynamic and adaptive responses in female physiology across the lifespan.”

Ingraham leads a research lab at the University of California, San Francisco, where she studies how hormones affect female physiology at a mechanistic level. 

“We know generally what hormones do, but we don’t really know how,” she said in an interview with Jan Witkowski of the Cold Spring Harbor Laboratory.

After Ingraham decided to use her mechanistic biology background to study female physiology, her team began investigating what estrogen does in the brain. They found that “when you get rid of estrogen in one set of neurons in the hypothalamus, you get this incredibly strong bone phenotype, only in females,” Ingraham said.

It was a brain-body connection she hadn’t anticipated.

The results seemed to contradict estrogen’s established role in protecting bone tissue. Declining estrogen levels during and after menopause put perimenopausal women at increased risk for osteoporosis, an illness that reduces bone density and makes bones more susceptible to fracture.

Ingraham's team placed the estrogen knockout mice on a high-fat diet, expecting that the nutritional challenge would have downstream neuronal effects leading to a loss in the strong bone phenotype. From there, her lab used genomic tools to find what was causing the bone-mass increases.

“We found this hormone that we didn't expect to be a hormone, because scientists get ruts in their brain and they think something has to look, quack like a duck," Ingraham said. Further investigation revealed that not only was the implicated hormone — brain-derived cellular communication network factor 3, or CCN3 — responsible for the increase in bone mass, it was also produced in females exclusively during lactation.

The discovery answered a longstanding question about how skeletal tissue recovers bone mass and density after breastfeeding, which occurs during a period of low estrogen production; during lactation, estrogen levels plummet to concentrations similar to those in postmenopausal women. As breastfeeding strips calcium directly from maternal bones, mothers can lose 4 to 7 percent of their bone density.

Yet despite losing significant bone mass while nursing, women's skeletons recover. Thanks to the Ingraham lab’s findings, scientists had a clearer picture of the molecular mechanisms that explain why.

Ingraham said the discovery was probably the best piece of data she had seen in her career, calling it a once-in-a-decade “wow moment.”

Ingraham was elected to the American Association for the Advancement of Science (AAAS) in 2012, the American Academy of Arts and Sciences (AAAS) in 2019, and the National Academy of Sciences (NAS) in 2021. She was awarded the 2024 Federation of American Societies for Experimental Biology Excellence in Science Lifetime Achievement Award in recognition of her work in hormone signaling and sex-dependent physiological regulation.

Through the support of late Roanoke business leader and philanthropist Maury Strauss, the lecture is free and open to the public.

The program begins with a reception at 5 p.m. followed by the lecture at 5:30 p.m. at the Fralin Biomedical Research Institute at 2 Riverside Circle in Roanoke. The lecture will also be livestreamed.