After Hours: The Progesterone Story

Don Stein always believed there was a reason why some brain-injured rats suffered fewer deficits than others with similar injuries. Finding that reason – and getting other scientists to believe it – took some persistence.

Two important changes of direction

Don Stein’s artistic parents, already surprised by his scientific bent, were stunned when he applied to Michigan State University. Living in the Bronx, recalls Stein, anything beyond the Hudson River seemed a foreign country. But MSU had a great veterinary school, and Stein had spent his high school summers working on chicken and dairy farms to prepare himself for a career as a vet.

Once there, however, he ran up against a quota system, still in place in the 1950s, that limited the number of Jewish students admitted to many professional schools.

MSU’s biology and psychology departments were more welcoming, and he began studying to become a clinical psychologist. But an internship after graduation changed his course again. If he were really going to help the men he saw at the Battle Creek Veterans Hospital, many with serious brain injuries unresponsive to treatment, he would need to know a lot more about the brain.

A brain injury mystery

At the University of Oregon, James McGaugh and Dan Kimble set their young Ph.D. student to studying how learning and memory change after damage to the hippocampus.

In a moment that launched decades of fascination, Stein noticed that almost a third of his injured rats survived without measurable cognitive deficits. In what would become a familiar refrain over those decades, he was warned against becoming distracted by biological variation.

As a post-doctoral fellow at the Massachusetts Institute of Technology, working on motor recovery after injury to the caudate nucleus, Stein again noted some rats were virtually unscathed despite injuries that produced devastating impairments in others. Again he was urged to stay on task. They told him that once he was on his own, he could investigate whatever unlikely theories he wanted.

Keeping his day job

Orthodox science in the 1960s held that once the brain was damaged, there was no possibility of repair or functional recovery, beyond a small amount of compensation. One of the things Stein loved about his first academic job, at Clark University, in Worcester, Massachusetts, was Clark’s tolerance of the unorthodox. Exploring plasticity and brain repair, the young professor authored some of the first books on recovery after brain injury.

Brain injury research, however, was neither Stein’s day job (teaching psychobiology was) nor his only interest. An avid biker and tennis player, he learned French during a Fulbright postdoc in Paris, started painting and photography, and followed politics closely. In 1980, after a sabbatical as an AAAS science and engineering congressional fellow, he helped found the first non-partisan organization to lobby for more funding for science and science education. That experience took him to Rutgers University to serve as dean of the graduate school and vice provost for research.

In 1995, Stein became dean of the graduate school and vice provost at Emory University, where he continued his public life as an administrator and his after-hours life in the lab, at first in a second-hand doublewide trailer he cheerfully landscaped with pink flamingos.

Four scientific turning points

Identifying the protective hormone.

Early on, Stein had realized that the rats that recovered better after serious traumatic brain injury were female, an observation that fit anecdotal reports about brain injury in women. Estrogen seemed the obvious candidate, but he could find no correlation between estrogen levels and recovery. Stein then turned to another hormone that, in hindsight, had all the characteristics needed.

Progesterone was best known as a pregnancy hormone, even though it occurs naturally in both male and female brains. Progesterone levels fluctuate sharply during estrus in rats and menstruation in women, and the levels shoot up dramatically during pregnancy. Since many processes involved in fetal development are similar to those in tissue repair, Stein asked himself whether higher levels of progesterone at the time of injury could explain why some females had better outcomes.

While Stein was at Clark, colleagues in the field of reproductive physiology at the Worcester Foundation for Experimental Biology (where the Pill was discovered) taught him how to manipulate naturally occurring progesterone levels in female rats. Sure enough, rats brain-injured when progesterone was high did much better than those injured when it was low.

Changing outcomes.

Stein then injected the hormone in male and female rats within 24 hours after severe injury to the frontal cortex. In the quarter century since he had begun his research, much had been discovered about the cascade of cellular events following traumatic brain injury (TBI). Stein’s progesterone-treated rats – males as well as females – showed signs of protection on every measure. They had virtually no brain swelling, a major cause of cell death after TBI. Progesterone diminished the release of free radicals, toxic by-products of injured cells that damage still-functioning cells. Progesterone also calmed the inflammation-causing response of immune cells to the toxins produced by dying cells and blood cells escaping from tiny hemorrhages. Most importantly, it dramatically reduced the loss of behavioral functions caused by the severe damage to the brain.

Moving into humans.

Up until now, the progesterone research had been a fairly lonely business, except for Stein’s dedicated graduate and post-doc students. Publication of these findings first caught the attention of the CDC, then the NIH. Researchers elsewhere began validating his results. But the real turning point was when Emory emergency medicine physicians Art Kellermann and David Wright decided Stein’s rat studies might hold the key to helping the TBI patients they saw with heart-breaking regularity. Wright repeated some of Stein’s rat research with the same promising results. Then, in collaboration with colleagues in biostatistics, emergency medicine, trauma, neurology and other Emory departments, Wright, Kellermann and Stein planned a three-year clinical trial, funded by NIH. Eighty of 100 patients who had suffered TBI shortly before arriving at Grady Memorial Hospital’s trauma center were given high levels of progesterone in addition to standard care. Patients with severe brain damage given progesterone showed more than a 50 percent reduction in mortality. Furthermore, progesterone patients with moderate brain injury had significantly improved functional outcomes. There were no serious side effects of the treatment. A new four-year, $27 million, NIH phase 3 clinical trial is now underway, headed by Wright, involving 1,140 TBI patients across 31 level-1trauma centers throughout the United States. A second, independent industry-sponsored national and international trial is also enrolling over 1,200 patients with severe TBI.

The NIH trial will end in 2014, the industry trial thereafter. If progesterone works as well as it did in the smaller trials, clinicians will have the first new treatment for TBI in 30 years and the first-ever safe and effective treatment.

TBI and beyond.

It may have been lonely at first, but today, the Asa G. Candler professor of emergency medicine and neurology collaborates with numerous colleagues across Emory and around the world. More than 200 publications now support the benefits of progesterone in brain injury -- and in soft tissue injuries, cardiovascular disease, multiple sclerosis, and other areas. Clinical trials are in planning for stroke and pediatric TBI. A growing number of clinicians believe progesterone should be given routinely in all cases of trauma, given the lack of serious side effects. Stein and his team are working with Emory chemists to create a stable, highly soluble progesterone product that could become part of emergency response med-pacs at home and in the military, where TBI is the signature injury. New, very early stage collaborative research with colleagues in the Winship Cancer Institute suggests that high doses of progesterone may also reduce the size of certain deadly tumors such as neuroblastoma.