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 Researchers at the University of Alabama, Birmingham (UAB) have made a breakthrough discovery that the female sex hormone, estrogen, may be able to save the lives of wounded soldiers and trauma patients who have suffered up to 60 percent blood loss. Irshan Chaudry, director of the Center for Surgical Research at UAB, has spent 19 years on this sensitive research and recently received a $10 million U.S. Department of Defense contract to begin human safety testing trials of the synthetic estrogen, known as E2. 
 
 Untreated blood loss is the primary cause of death for soldiers in battle, and is preventable in many circumstances. Indeed, between 2001 and 2011, more than 80 percent of U.S. soldiers’ deaths during combat resulted from preventable blood loss and septicemia. Often, soldiers are wounded in locations where they can’t be quickly transported to a field hospital, which leaves medics very little time to treat them. 
 
 “The golden period after injury, when one needs transport to an ER to have a good benefit of surviving trauma, is one hour,” Chaudry tells mental_floss. “The longer you wait, the more deleterious the effects.” The goal of the treatment is to buy the soldiers enough time to make it alive to a field hospital. “Six hours should be more than adequate to get them to treatment,” he says. 
 
 When a person or animal loses blood, minute blood vessels collapse, which results in decreased oxygenation to the tissues. If that is not corrected, the cells gradually die, the organs shut down, and then eventually, so does the entire organism. “Anything we can do to prevent that decrease of microcirculation is good,” Chaudry says. He paraphrases British trauma researcher Harry Berrington Stoner: “The body is like a swamp after blood loss, and anything that can turn it into a running brook is the answer.” 
 
 What makes estrogen such a life-saving hormone? Surprisingly, estrogen receptors are found in every cell of the body, and in the mitochondria, in both males and females. “When estrogen receptors are active, they produce more ATP [the “energy currency” of cells], which we need for literally everything we do,” says Chaudry. “When we lose blood through trauma, the production of ATP decreases.” 
 
 In 1997, Chaudry and his co-researcher Rene Zellweger discovered the immune-boosting and cardiovascular bolstering effects of estrogen by accident. They were using mice to study infections in trauma-hemorrhaged patients. Instead of male mice, the vendor accidentally sent female mice, which Zellweger did not want to use due to their fluctuating hormones. Yet Chaudry pushed ahead with the study and they found the females were more infection-tolerant—resisting septicemia—than Chaudry had predicted. 
 
 Excited, Chaudry ordered more female mice and repeated the experiment. The second time around, the experiment failed. He wondered what was different. "We realized it may have been that we got the females at different points in their cycles,” he says. Sure enough, the first batch of infection-tolerant female mice had been at the proestrus phase of their menstrual cycles, just prior to ovulation, when estrogen levels are highest. 
 
 Next, they tested the E2 on blood loss, a common trauma issue, and found that E2 significantly improved cardiovascular and liver function in patients who had lost up to as much as 60 percent of total blood volume; it worked by dilating blood vessels and moving fluid from tissues to blood more efficiently. It also reduced inflammatory cytokines and staved off death or organ failure by three hours. 
 
 In 2005, the U.S. Defense Advanced Research Projects Agency (DARPA), held a competition seeking a treatment that would keep a soldier alive for at least three hours after significant, almost universally fatal blood loss [PDF]. Chaudry and his researchers stepped up. They used a version of E2 that was microencapsulated with cyclodextrin—a sugar-like compound—to make it water-soluble. 
 
 Since then, Chaudry’s synthetic estrogen has been engineered, with the help of DARPA, to a variant called ethinyl estradiol-3-sulfate, or EE-3-SO4. A syringe of this version can buy mice and horses up to six hours before they show signs of organ failure or death. “There is a lot of edema after trauma, so if we can pull that fluid back from the tissue into blood circulation, it maintains a state of permissive hypotension, enough to sustain life and protect the animals,” he says. 
 
 Meanwhile, EE-3-SO4 may have benefits for victims of brain trauma as well. In research, the estrogen also reduced cerebral edema, increased blood flow to the brain, and reduced brain cell death. 
 
 Both estrogen variants have the potential for applications in civilian trauma in conditions where they can’t immediately get to a hospital. 
 
 Currently waiting to begin the filing process for FDA approval, Chaudry is confident that within a year they will be approved to begin human safety trials. His hope is that eventually all emergency vehicles will carry pre-loaded estrogen syringes, ready at a moment’s notice to literally make the difference between life and death. 

 Irshad Chaudry, Ph.D. 
 
 ‘Wasting our time’ 
 
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 Mechanistic studies 
 
 Human trials 
 
 Breakthrough research suggests a female sex hormone may be the key to saving lives on the battlefield, where between 2001 and 2011 more than 80 percent of potentially preventable U.S. war injury deaths resulted from blood loss.The hormone shows the promise of prolonged survival despite massive loss of blood and could be carried in a small autoinjector for use.In a landmark step – after 19 years of research by Irshad Chaudry, Ph.D. – the University of Alabama at Birmingham has received a $10 million U.S. Department of Defense contract funded by the Combat Casualty Care Research Program, US Army Medical Research and Materiel Command, Fort Detrick MD, to begin testing its potentially life-saving synthetic estrogen for safety in humans. The long path to this breakthrough for Chaudry, who is director of the Center for Surgical Research in the UAB School of Medicine , was prompted by a mistake; in 1997 he and postdoctoral fellow Rene Zellweger, M.D., received the wrong shipment of mice.Chances like that are a beguiling part of science. Alexander Fleming discovered the penicillin mold through fluke contamination in a Petri dish. Charles Goodyear created vulcanized rubber after accidental stove contact. The hint leading to the first microwave oven began when radar researcher Percy Spencer reached in his pocket and found his chocolate bar had melted.Chaudry and Zellweger’s spark of serendipity came during study of a serious complication seen in trauma-hemorrhaged patients – the bacterial blood infections that are called sepsis. These infections can strike days, weeks or months after severe trauma and blood loss, causing single or multiple organ failure, long hospital stays and death of patients. “The cost to society is substantial, and the onset of sepsis after trauma is a major, worldwide problem,” Chaudry said.Chaudry and Zellweger were examining the mechanism by which sepsis produces multiple organ failure and death in a murine model. But when Zellweger received a group of female, not male, mice, he told Chaudry they were unsuitable because female hormone levels vary too much.Chaudry told Zellweger to use the female mice, and the result was astonishing. All of the female mice resisted sepsis without any treatment.“I was excited,” Chaudry said, “and he was puzzled.” So they repeated the work with another group of female mice, but this time the untreated septic mice all succumbed to the infection — a seeming paradox.“See, we’re wasting our time,” said Zellweger. But the researchers solved the puzzle when they realized that the two groups may have been at different stages of their estrous cycles. By pure chance, the females of the first group had been at the proestrous phase, that moment when estrogen hormones levels are at their peak. In animal models, Chaudry and colleagues soon learned that a dose of the estrogen 17β-estradiol (E2) could protect males and females against septicemia, regardless of the female estrous phase. The estrogen affects the immune system and cardiovascular responses, which typically are profoundly depressed after trauma.Chaudry and his colleagues next tested E2 for another trauma problem — blood loss. They found that after massive blood loss, and an additional prolonged hypotensive period, followed by intravenous fluid resuscitation, E2 significantly improved heart performance, heart output and liver function. E2 also attenuated an increase in interleukin-6, a pro-inflammatory cytokine.About this time, in 2005, the U.S. Defense Advanced Research Projects Agency, DARPA, announced a vital goal: finding a way to stretch the time that a severely wounded soldier with blood loss could stay alive. This would give the warfighter a better chance of reaching a field hospital for definitive surgical and medical care.The agency held a competition with a simple and unequivocal criterion – produce a treatment that enables survival at least three hours after significant, almost universally fatal blood loss. Any research programs that passed this first trial then would face a Phase II challenge of six-hour survival. Furthermore, the therapeutic material had to be deliverable in a small volume, for easy future inclusion in a battlefield pack.Chaudry and his colleagues discovered that E2 could allow survival for three hours without any fluid resuscitation, and long-term survival if fluid resuscitation was provided after 3 hours. The prolonged period of low blood pressure after blood loss significantly affects mitochondrial function, endoplasmic reticulum stress markers and inflammatory cytokine production, but E2 was able to diminish those changes. Low blood pressure reduces the delivery of oxygen to tissues and to the mitochondria, which voraciously consume oxygen to produce energy in the form of ATP. Thus, oxygen deprivation is a burden for tissues and mitochondria under low blood flow conditions.In the three-hour challenge, Chaudry and his colleagues used E2 that was microencapsulated within cyclodextrin to make it water soluble. For the six-hour challenge, with the help of DARPA, UAB had a synthetic estrogen variant called ethinyl estradiol-3-sulfate, or EE-3-SO4 synthetized by a pharmaceutical company. Six-hour survival rates of 50 and 80 percent were seen with EE-3- SO4 in porcine and murine models respectively, even in the absence of fluid resuscitation. These results from a multi-site study led by Chaudry, which were reported in 2014 and 2015, provided the needed proof of principle for initial clinical studies.Out of 10 initial Surviving Blood Loss programs funded by DARPA, UAB was the only one that met the challenge of 6 hour survival after 60 percent blood loss in the absence of fluid resuscitation.DARPA’s six-hour aim was solely survival, but Chaudry has continued mechanistic studies of how EE-3- SO4 produces beneficial effects. The estrogen appears to interact with the different types of estrogen receptors in all types of tissues in both men and women. Using selective estrogen-receptor antagonists or agonists for the different types of estrogen receptors, Chaudry’s research team continues to look at which type of receptor is important for EE-3- SO4 action in different tissues.Besides improved heart function, EE-3- SO4 appears to dilate blood vessels and speed the movement of fluid from the tissue compartment into the blood compartment (the interstitial fluid of the tissue compartment has about twice the volume compared to the average volume of blood in adult humans). Lowering this resistance to improve blood flow to vital organs hails back to the great challenge to trauma recovery seen by the noted English trauma researcher Harry Berrington “Berry” Stoner, M.D. He wrote that the body’s blood system is like a swamp after trauma, and anything that turns the swamp into a running brook is the answer for treating shock.DARPA was key to finding a company to manufacture pharmaceutical grade EE-3-SO4 under U.S. Food and Drug Administration Good Manufacturing Practice. Also, in preparation for an investigational new drug application to the FDA, some of the pre-clinical animal experiments have had to be done in institutions under FDA Good Laboratory Practice.UAB has applied for patent protection for EE-3-SO4. Beyond its battlefield potential, one important application could be domestic trauma patients, given that earlier E2 results that have shown reduced mortality and septicemia. Also, EE-3- SO4 may have a third beneficial effect – treatment after traumatic brain injury. In experiments, the estrogen is able to reduce cerebral edema, increase brain blood flow, increase cognitive function and memory, and lessen brain cell death. Thus, EE-3- SO4 may prove to be a triple boon for trauma victims.Trauma is the leading cause of U.S. deaths for people under 47 years of age, according to the federal Centers for Disease Control and Prevention. Because trauma hits all ages of people, it represents 30 percent of all U.S. life-years-lost each year, a far larger loss than cancer, 16 percent of all lost life-years, or heart disease, 12 percent.“If we can prevent sepsis and multiple organ failure after trauma,” Chaudry said, “insurance companies will gladly reimburse drug costs because there will be great cost benefits and the quality of life will be better.”“If these study findings translate to the battlefield,” Chaudry wrote in his recent paper last June, “additional time will be available for transport of the wounded to safer locations where standard resuscitation measures can be accomplished.”Likewise, the so-called “golden-hour” after injury for needed fluid resuscitation may be prolonged to 6 hours if small volume of E2 is administered shortly after injury in patients at the scene of an accident in rural areas where transportation to a Level 1 Trauma Center takes more than an hour.Chaudry’s 19-year study of the effect of estrogen began at the Shock and Trauma laboratories, Michigan State University, and at the Center for Surgical Research at Brown University School of Medicine. Chaudry moved to UAB in 2000. He has had many collaborators since his initial 1997 paper with Zellweger and other colleagues in the journal Critical Care Medicine.UAB’s B.L. Harbert Institute of Innovation and Entrepreneurship is managing two pending U.S. patent applications of EE-3-SO4, with Irshad H. Chaudry, William J. Hubbard and Zheng F. Ba listed as the inventors.The recent Chaudry papers on six-hour survival, published in the Journal of Trauma and Acute Care Surgery and Journal of Surgical Research, include co-authors from UAB, the Keith Pharmacology Research Group, Andover, Massachusetts; Fast-Track Drugs and Biologics, North Potomac, Maryland; Texas A&M Institute for Preclinical Studies, Texas A&M University; and NDA Partners, Falls Church, Virginia.Funding for this recent research came through DARPA grant #W911NF-07-1-0917.
– More than 80% of US soldiers' deaths between 2001 and 2011 were the result of blood loss and septicemia. There's limited time to save trauma victims experiencing significant blood loss—the so-called "golden hour"—and researchers at the University of Alabama have been working for 19 years on a way to extend that time so that wounded soldiers and remote trauma victims are more likely to survive the long trip to a hospital. They think they've hit upon the secret ingredient—a synthetic version of the female sex hormone estrogen, and they've received a $10 million Defense Department grant to test it on humans. The breakthrough dates back to 1997 and is actually the result of a mistake. Researchers got an order of female mice instead of males; they almost didn't use the mice because of how much female hormone levels fluctuate, but they went ahead and were astonished to find that all of them resisted sepsis without any other treatment. When they tried it again with another batch of females it failed—because the mice were in a different part of their estrous cycles with lowered estrogen. After further testing, they found that synthetic estrogen also improves heart and liver function, even after 60% blood loss, because it dilates blood vessels, moving fluid more efficiently, reports Mental Floss. The latest estrogen variant, EE-3-SO4, helps prolong life for up to six hours post-trauma and could help not just trauma victims in general, but especially those with traumatic brain injuries. (This form of estrogen fuels lust and racy behavior.)