In the days after Quinton "Rampage" Jackson became the latest fighter to acknowledge using testosterone replacement therapy (TRT), Nevada state athletic commission executive director Keith Kizer's phone began to light up. On the other end were fighters and managers interested in finding out how to obtain a TRT exemption.



Kizer, who had heard about Jackson's interview with Fighters Only acknowledging his usage, was not surprised. In his comments, Jackson claimed that "a lot of fighters are probably doing it but not telling anyone." That quote has since been removed from the interview, but its echo has created a stir in the mixed martial arts world, suggesting that legitimizing TRT treatment was easy.



Jackson is not only the latest of the divulged names using TRT, but also its loudest proponent. But contrary to popular belief, the number of fighters legally using TRT with the permission of state athletic commissions is quite low.



How low?

In its entire history, the Nevada state athletic commission has granted only three therapeutic use exemptions (TUE's) for TRT, Kizer told MMA Fighting. The only individuals to receive exemptions have been Dan Henderson, Todd Duffee, and most recently, Shane Roller in 2011. New Jersey Athletic Control board legal counsel Nick Lembo could not offer a specific number but said that state had given "less than five" TUE's for TRT in its history. In Ohio, only Henderson and Strikeforce fighter Bristol Marunde have ever been approved for TRT use, its state athletic commission executive director Bernie Profato told MMA Fighting.



Contrast that with the reaction of say, Dr. Don Catlin, who sits on the International Olympic Committee's medical commission responsible for reviewing TUE applications for Olympic athletes. In a recent interview with MMA Fighting regarding the possibility of active fighters needing TUE’s for TRT in MMA, Catlin remarked that the whole thing was "a joke."



Those types of broad criticisms are troubling to some combat sports regulators who feel that their goals of toeing the line between sport safety and being responsive to individual health situations are being undermined.



"I hear things like, 'Oh everyone can do it,'" Kizer said. "Well, how many exemptions have [the IOC] given out? Two. Well, we've given out three in 12 years."



According to Catlin along with many other critics, the possibility of professional athletes in their 30s needing TRT is so low, it's almost completely zero.



But new research might show those long-held beliefs to be incorrect.



The science of brain injury is still relatively new, and developing rapidly. In 2007, a paper published in the Journal of Athletic Training reported the first known connection between mild concussions and hypopituitarism, a deficiency that can lead to low testosterone.



That research, along with how traumatic brain injuries impact the pituitary gland, is being continued by Dr. Daniel F. Kelly, the director of the Brain Center and Pituitary Disorders Program at the John Wayne Cancer Institute at Saint John's Health Center in Santa Monica, California.



Kelly is currently in the midst of a study of 75 former NFL players that is expected to be published around the end of 2012. In an interview with MMA Fighting, Kelly said that preliminary data from the study suggests that pituitary damage is occurring in a subset of the retirees.



That study seems to corroborate a 2006 finding in Turkey that found that head injuries incurred by pro kickboxers have resulted in damage to the pituitary gland.



Extrapolated to MMA, it's not much of a leap to suggest that similar injuries can be occurring to this sport's fighters, for whom getting hit in the head is a daily occurrence. In fact, Dr. Fahrettin Kelestimur, a professor of endocrinology at Erciyes University in Turkey who authored the 2006 study, told MMA Fighting that the most common damage has caused growth hormone deficiency and hypogonadism, respectively. The latter problem was the one cited by Chael Sonnen as the necessity of his TRT treatments during his appeal of a California state athletic commission suspension.



"These fighters are getting repeated insults to the head, sometimes more than concussive events," Kelly said. "And if you did a careful analysis of those people, I'm sure you'd see a significant rate of pituitary gland dysfunction. That's my prediction."



The issue is complicated by the fact that it is not always possible to determine the cause of pituitary damage, according to Kelly. It's well known that steroid abuse can also damage the pituitary gland, but head trauma can cause the same affect.



That makes things cloudier for regulators like Kizer and Lembo, who work for two of the sport's leading commissions.



At the same time, they along with other regulators believe it’s important not to punish the athletes that come forward with a legitimate need by banning TRT outright. While the long-held belief that steroid use as the main cause of low testosterone among athletes might be true, it’s by no means a catch-all.



That knowledge simply just isn’t widespread. Most of the people interviewed for this story were unaware that pituitary damage could be caused by repeated blows to the head, as Kelly, the brain and pituitary expert agreed.



"Is that incrementally damaging the connection between the brain and pituitary? I think it probably is," he said. "But can we prove that there’s an exposure component that’s incrementally adding up even if it’s not even considered a concussion. I think that’s probably the case."



While MMA often points to its safety record, there are variables to the sport that cannot be controlled. Chief among them is what goes on in the gyms during training camp. While fighters who suffer knockout losses in competition are medically suspended in order to give them time to recover, those periods are rarely enforced. Some of them can’t be due to simple logistics.



If a fighter competes in Texas, for example, but calls Brazil home, there is no real way to check up on him and ensure he’s letting his brain recover from the trauma it received. Most good coaches will try to keep their athletes on the sidelines and away from head strikes in this critical recovery phase, but it’s not like that everywhere.



Take, for instance, Pat Barry’s recent explanation of why he hoped to visit Croatia soon to get in some training.



"Out there, you can punch and kick guys completely unconscious and they show up the next day," he said. " Whereas here, you can punch and kick some guys, and sometimes they don’t come back for the rest of the week."



"Which is probably a good idea," UFC president Dana White interjected.

Barry's seeming insensitivity to head injuries might be ingrained in his mentality as a fighter who is trained to be fearless even in the heat of battle, but it also might be from an attitude that is generationally rooted, though changing. A recent Centers for Disease Control and Prevention report noted that emergency room visits for children and adolescents due to sports and recreation-related traumatic brain injuries were up 60 percent in the last decade. The organization’s director of the National Center for Injury Prevention and Control attributed to the rise not to increased incidences, but to growing awareness of the dangers caused by brain injuries.



Attention to the problem of brain injury has also been slow to come to pro sports. In 2008, the collaborative Center for the Study of Traumatic Encephalopathy was founded to study brain injury, and their work has changed the NFL’s outlook on concussions and head trauma, causing rule changes in 2009 that focused on player safety. This even though as a league, the NFL has had a multi-decade head start on MMA when it comes to head injuries. MMA commissions in some instances have only been sanctioning the sport for a year or two and are still drafting regulations.

As it stands now, most commissions have no tests in place that would determine this type of problem.



Only a handful of state commissions require an MRI in order to grant a fighter’s license, but MRI’s don’t always show the problem, anyway. A blood draw is more likely to determine if an issue exists, according to Kelly. Tests for luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, growth hormone (GH) and IGF-1 (insulin-like growth factor 1) could serve as an effective screening tool to determine any pituitary damage.



Most of the blood work done through commissions prior to licensing though, is solely to test for contagious diseases.



A big problem when it comes to changing medical technology is cost. Ohio Athletic Commission executive director Bernie Profato likened it to medical issues in the world at large, recounting the story of how the son of a close friend died from a rare blood disease that doctors didn’t have the means to handle because of a lack of money to fund research.



"The more this stuff comes up, the more time medical people put into it, it extends our knowledge of it," he said. "We’re regulators, not medical people. We do what we can to put these athletes in the safest environment."



Only a handful of the regulators MMA Fighting spoke with had heard of the studies linking brain trauma with pituitary damage, but most acknowledged that such conditions are exactly why TRT TUE’s shouldn’t always be passed off as an attempt to fleece the system.



"It’s very rare, but there are some legitimate needs," Lembo said. "My biggest concern is that most commissions don’t even test for these things in the first place so we’re over-penalizing the people that are coming forward and saying, ‘Hey, do whatever you want to me. Test me before and after the fight. Test me randomly. I need this, I’m on it and I’m going to be within normal limits.’ There are a lot of commissions who don’t believe in TUE’s for any reason, but why be hard on the ones coming forward?"



Dr. Kelly, who has been working on issues pertaining to the pituitary gland for nearly 20 years, in 2008 co-authored a study that concluded chronic hypopituitarism occurred in approximately 20 percent of patients who had suffered mild, moderate or traumatic brain injury.



With the repetitive head impacts from training and competing from month to month and year to year, it’s no wonder then that professional fighters could be subject to these same types of injuries. While finishing up his NFL research, Kelly is also interested in studying boxers and, possibly, mixed martial artists to gain a more definitive understanding of a problem that still remains mostly hidden away.



"I’m sure there’s a certain level of it going on," he said. "I guess what’s really amazing, if you look at it another way, is how infrequently it occurs, and how sturdy the system is, how much damage it can take. The pituitary gland is this tiny little thing that’s less than a centimeter cubed. It’s sitting in a little, bony depression in the skull base and it’s getting banged around, and the connection is getting banged around repeatedly, yet it keeps it on ticking in most people. It’s a pretty resilient system, but only up to a point."

[Editor's Note: PEDs in MMA is a two-part series. Next week, an installment on the drug-testing landscape in MMA, and how regulators, athletes and promoters are adapting.]