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A study might change the way sports thinks about human growth hormone

Mark Cuban, billionaire multi-tasker, grinds out the last few minutes of an hour-long workout on a stair-climber. Sweat gleams on his arms and drips steadily from his forehead onto the front of the machine, which faces an exposed brick wall in the Dallas Mavericks' capacious fitness center.

A half-dozen reporters, invited in for a pregame chat, raise microphones and tape recorders in a ragged semi-circle around the team owner. Between labored breaths, he expounds on a just-announced contract extension for coach Rick Carlisle -- an extension that is a departure from Cuban's usual negotiating practice of waiting until a deal expires. "The worst policy in the world is to be dogmatic about your policies," he says.

I wait for the beat guys to finish before I approach Cuban. He knows I want to talk about his decision to fund a first-of-its-kind clinical trial that is examining whether human growth hormone can aid recovery from anterior cruciate ligament surgery. The two-year, $800,000 exploratory study at the University of Michigan is backed by a single grant from Cuban's eponymous foundation and was approved by the U.S. Food and Drug Administration under a special exemption.

Most sports fans know HGH as a drug banned for its performance-enhancing effects and at least temporarily toxic to the reputations of athletes who have confessed to using it, like Bill Romanowski and Jason Giambi. Former New York Yankees pitcher Andy Pettitte said he used it solely to recover from an elbow injury -- a commonly held but scientifically unproven rationale.

The Michigan study could begin to pull HGH from the shadows if, as the researchers hope, it helps prevent the muscles around the knee joint from weakening to a point of no return. Recombinant (synthetic) HGH is a pharmaceutical hot button, controversially championed by the anti-aging industry and still poorly understood in many ways. Its legal uses are restricted in the United States and many other countries, limiting the drug's commercial potential and discouraging research into possible new therapeutic applications.

That strikes Cuban as dogma without proper grounding.

"I love to test and challenge any schools of thought that have not been thought out," he wrote in an August email to ESPN's Outside the Lines. "This partnership was a great first step toward finding the facts about HGH."

Unlike the investments Cuban makes on the reality-TV marketplace of "Shark Tank," there's no business plan to peruse here. This is a stake in an idea -- rethinking HGH -- that won't generate practical applications or profit for at least a decade, if ever, and is certain to hit turbulence along the way.

Cuban finishes toweling off his face and shakes my hand. I keep the pitch straightforward. His role in this story will bring more eyes to what I think is an intriguing issue. I want to make the science accessible. The issue is too nuanced for an email exchange and is best discussed in person, which is why I'm in Dallas.

He parries my every attempt. Until there are research results to discuss, he sees no upside in a more in-depth interview. He's perfectly courteous, but his mind is made up. His money line is punctuated with his familiar gotcha grin.

"I don't want this to be about me," Cuban says. "Shockingly."

Muscle atrophy is the real problem

Some of the athletes who have thrilled us the most -- soccer's Cristiano Ronaldo, basketball's Steph Curry, alpine skiing's Mikaela Shiffrin and Lindsey Vonn, or any of the great waterbug running backs who followed in Barry Sanders' intricate footsteps -- have been able to do so because of their ability to plant and pivot, cut and accelerate, twist and elude. And they have all depended on the marvelous anatomical fulcrum of their lower quadriceps muscles.

Athletes who spend years painstakingly building that foundational strength, so crucial for power and agility, can see 20 percent or more of it melt away in the days just before ACL surgery. The injury triggers swelling and the release of what lead Michigan researcher Christopher Mendias calls "angry synovial fluid."

"It seems to carry a bunch of chemical signals that shrink the muscle and cause some inflammation in the tissue right around the knee joint," Mendias says. "So if you look at the entire quadriceps muscle group, the atrophy is much more pronounced toward the knee joint."

Which is why multiple researchers are examining the same question using different approaches: Once an ACL is put back together, can the knee ever truly be as sound again? Stem cell therapy and platelet-rich plasma treatment are options getting increasing attention, and testosterone's potential is being studied. The Michigan researchers think human growth hormone has significant promise.

ACL reconstructions, using a graft from a patellar tendon or hamstring that is screwed or stapled into place, have become mechanically sound procedures that help many athletes return to action. Rehab protocol has been refined as well.

But no matter how diligently patients tackle the arduous post-op regimen -- and few could be more motivated than athletes with millions of dollars at stake -- they often wind up losing some degree of quickness or range of motion. Various studies show they can be more prone to rip up the other knee or at risk for early osteoarthritis. Some data shows younger athletes have a higher incidence of repeat tears in the same joint.

"I tell people the rehab is really two years -- you're rehabbing through the season and the offseason," says retired NFL cornerback Terrell Thomas, who had three surgeries on his right ACL, the first one in college. "It's not one of those injuries where you do your six months and move on with life."

Mendias, a Ph.D. in molecular and integrative physiology, devotes himself to the mysteries of why muscles and tendons grow and shrink and how they recover after injury. In late 2013, he read a story in which Cuban called for more research on HGH as a healing agent, then emailed the Mavs' owner. This clinical trial is the result.

In the eyes of Mendias and his partner on the project, Dr. Asheesh Bedi, it's time for HGH to be carefully and seriously explored as a possible solution to the most frustrating aspect of the roughly 250,000 ACL reconstructions performed annually in the United States.

"It's a largely successful clinical operation, but what goes unnoticed is that even though the athlete feels strong, and may exceed their baseline [strength] pre-injury, they often have persistent objective weakness nine months or a year out," says Bedi, an orthopedic surgeon who is a University of Michigan team physician and an associate team physician for the Detroit Lions. "It's easy to rest on our laurels as surgeons when potentially we should be asking for more."

Bedi and Mendias are doing their field work in a vast, low-slung building in the Domino's Farms complex on the outskirts of Ann Arbor that houses the university-owned MedSport clinic and a lab that bears Mendias' name. Their hypothesis, greatly simplified, is that HGH will help preserve the muscle around the joint by activating a protein called IGF-1 (insulin-like growth factor) that stimulates muscular growth while blocking another protein, myostatin, which is triggered by injury and curbs that growth.

The clinical trial is accepting men 18 to 35 years old, by invitation only, who are MedSport patients about to undergo ACL reconstruction for the first time. They cannot be athletes subject to NCAA, World Anti-Doping Agency or professional sports drug protocols. The first patients were enrolled in the spring of 2015, and the study is slated to end in mid-2017. Citing privacy concerns, the University of Michigan will not disclose the identity of patients involved in any ongoing clinical trial.

The study is double-blind, meaning neither the researchers nor the patients know which group is being treated with HGH and which is receiving a placebo. Both groups will be injected in the abdomen twice daily for one week pre-surgery and five weeks after. Patients will be monitored through at least six months of physical therapy, with strength in both the injured and uninjured legs tracked and overall health closely watched to ensure there are no worrisome consequences.

The short, six-week course of injections was designed to keep the study firmly in the realm of medical treatment as opposed to performance enhancement, Mendias says.

"No one's going back to the court or the field that quickly, so the effects of growth hormone are largely transient," Mendias says. "We don't think there's going to be any sort of long-term benefits, that they're gonna go back stronger than they were before they had their injury. We're hoping to get them back as close as we can to their normal strength before they had the tear."

Sounds straightforward enough -- though the researchers are probing a drug that has been the subject of more rumor and regulatory barbed wire than factual analysis for most of the past 30 years.

HGH's troubled history in America

In the United States, growth hormone can be legally prescribed for only a few strictly defined conditions such as growth deficit in children, short bowel syndrome, pituitary gland issues in adults and wasting diseases such as HIV/AIDS. But off-label prescription and black-market traffic continues to flourish everywhere from Hollywood to high school gyms. Products purporting to be HGH -- mostly fakes -- are readily available by mail order.

Originally harvested from cadavers and used to treat children with overly short stature in the 1960s and '70s, naturally produced HGH was pulled from use in the mid-1980s when it was discovered that part of the supply was contaminated with Creutzfeldt-Jakob disease, an incurable degenerative condition affecting the brain.

Recombinant growth hormone appeared on the market at roughly that time, and was included in the 1990 federal Anabolic Steroids Control Act. Athletes used it because they thought it could give them an edge, and sporting entities banned it. But that prohibition -- which is on the books of WADA and nearly all high-level professional sports -- has been largely toothless.

Distinguishing between HGH produced naturally by the body and growth hormone delivered via needle has proved to be involved and vexing. Despite two detection methods introduced in blood testing since 2004, only a dozen athletes worldwide have tested positive for synthetic HGH. Some have been ensnared in legal investigations, such as the BALCO or Biogenesis scandals. A few have been tripped up by their own recklessness, like tennis player Wayne Odesnik, who tried to bring it into Australia in his luggage in 2010 and later pleaded guilty to violating that country's drug laws.

From athletes and coaches who have been caught using growth hormone as a performance-enhancer, we know it is usually used in conjunction with testosterone or other anabolic steroids. In isolation, HGH has been found to carve away fat and build lean muscle mass but not necessarily improve strength. Other research on long-term use has revealed serious side effects including diabetes, carpal tunnel syndrome, arterial disease and joint swelling or pain, but there's little scientific consensus on how prevalent they are and at what dosage.

If informed guesstimates are to be believed, HGH use is commonplace in professional sports. Thomas says he never resorted to it but thinks many NFL players view it as an occupational necessity "to sustain strength. ... They can get big all they want, but it's maintaining that throughout the season, throughout the wear and tear, throughout the pounding of your body.

"Why not take the risk of using it if it's going to make you that much better?'' he says. "If you get that $50 million contract or whatever it may be and you do get suspended for it, you're losing four games or a couple mil. It's worth it."

A few athletes have publicly stated that the barricades should be moved. Kansas City Royals reliever Ryan Madson first spoke out on the subject in 2013 when he was trying, without success, to return to form with the Los Angeles Angels after elbow surgery. He reiterated his views during the recent World Series, telling the Los Angeles Times he had not used HGH himself but thinks it should be an option for athletes under medical supervision "in a controlled manner, so they know exactly what is going in their body and how much is being used, for rehabilitation purposes only."

Dr. Keith Baumgarten, a Sioux Falls, South Dakota, orthopedic surgeon who has worked with professional sports teams at several levels, says science is being hampered by stigma, even in animal research. He approached a pharmaceutical company a few years ago when he was putting together a study using growth hormone to accelerate injury recovery in rats.

"I wanted to use their sutures, and their response was, 'We're not gonna support a study with illicit drugs,'" Baumgarten says. Those studies didn't yield encouraging results, but he has received approval for another growth hormone study at the cellular level on human bone, tendon and ligament.

Baumgarten's interest has been deepened by his patients who are farmers and have the same urgent need to return to their fields as athletes do. "We should be trying to get ahead of the game, and if there's a potential for accelerating injury recovery, we should look at it scientifically and safely and responsibly," he says.

HGH faces a long way out of the shadows

The Michigan researchers plan to be "extremely transparent" about their findings, Mendias wrote in an email. They will publish results whether they show promise or not, he added, and will share raw data with others in the field on request. If follow-up studies are merited, they would be widened to include diverse locations and age groups, and both genders.

With many uncertainties and hurdles along the way, Mendias estimates it would take 10 to 15 years to reach the point where the FDA might consider reclassifying growth hormone.

If that were to happen, it would create an interesting challenge for elite sports.

Defining the terms for a therapeutic-use exemption for HGH -- such as dosage, length of treatment, and the interval before an athlete could return to competition -- could be daunting. Anti-doping authorities would have to craft a sophisticated solution, says Thomas H. Murray, former president of the Hastings Institute, a bioethics think tank in New York State.

"Would I deny [an] athlete the possibility of a more rapid healing and a prospect of a better life long-term with less disability from that injury just because we know some people misuse this drug for sports performance?" Murray says. "I would find that an impossible position to sustain."

Murray, a scholar with extensive experience in advising sporting entities on anti-doping policy and ethics, said caution and skepticism are warranted, even though "I don't think people are going to rip ACLs in order to take human growth hormone," he says.

"If it's approved for ACL injuries, will people then want to use it for other, less severe injuries, and push to have it administered closer to the time of performance? Yes," Murray says. "We know all that will happen. So policies like this come down to very practical things. Can you create a reasonable set of rules that would shut the door to the most obvious abuses but would leave it open for genuine therapeutic uses?"

Murray has no objection to sports owners such as Cuban funding this kind of research, as long as the leagues are giving equal attention to injury prevention. But Murray doesn't want his own open-mindedness construed as advocacy.

"It's important to have an appreciation for the irony in all of this," Murray says -- in other words, a scenario in which athletes take growth hormone so they can train harder, incur more serious injuries because of their greater size and speed, then seek relief from a drug that may have helped enhance them in the first place.

Dr. James Andrews, the orthopedic surgeon to the stars who has performed thousands of ACL reconstructions, says any potential policy change on growth hormone will be "a hard row to hoe."

But, Andrews says, a carefully controlled environment like Michigan's clinical trial is the setting to do that spadework, rather than the barely concealed, ad hoc experimentation going on in sports. "[HGH] should be studied, it should be researched, and we may find out that the benefits are worth the risk factors," Andrews says. "My hat's off to them, because that's where it needs to be evaluated."

The first NBA players who might directly benefit from Cuban's largesse are probably young teenagers now. But the Mavs owner isn't fazed by the timeline or the potential political hurdles.

Later, I email him with follow-up questions, including this: "Given your public profile, people may speculate that you have a commercial/profit-making interest in the study results if they are successful down the road. Please comment."

His response: "Of course I do. If this works, I will figure out an angle to make money from having sponsored a study that changed the game. And if it does turn out that it helps athletes recover faster, I of course benefit from my interests in the Mavs and the NBA.

"Feel free to make that the headline. It doesn't change anything at all.

"The results are the results. Either it works or it doesn't."

Investigative reporter T.J. Quinn and producer Andy Lockett of ESPN's Enterprise/Investigations Unit contributed to this report.

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