Human growth hormone helps small kids grow, but some call its wider use shortsighted.
BY CECILIA CAPUZZI SIMON, The Washington Post, September 30, 2003 >>
In the mid-1950s, scientists figured out how to extract human growth hormone from the dead, taking it from the pituitary glands of cadavers and injecting it into small children to make them grow. It was a rare and precious substance, doled out only to the neediest children, those whose bodies were deficient in the hormone.
Then, 18 years ago, bioengineered growth hormone became available in abundance. Pharmaceutical companies began to produce it, creating a billion-dollar market serving hormone-deficient children and adults and children with four other conditions that stunt growth -- about 200,000 patients worldwide. But use of the hormone was still limited to those with diagnosable medical conditions.
That changed in July, when the Food and Drug Administration (FDA) gave approval to Eli Lilly and Co. to market Humatrope, its brand of human growth hormone (HGH), to unusually short but apparently healthy children.
From supporters' point of view, this will help streamline access to the drug for up to 400,000 U.S. children with idiopathic -- meaning, of unknown cause -- short stature (ISS), who were routinely denied treatment or insurance coverage for HGH because doctors could not diagnose an underlying medical cause of their growth problems.
But Eli Lilly's findings show that ISS kids on an HGH regimen similar to that used in growth hormone deficiency can add an average three inches to their final adult height. (Hormone-deficient kids typically show more growth.)
This should help children like Spencer Davies of Mauston, Wis. At 6 years old, he was as small as his 2-year-old sister. Doctors didn't know what caused his abnormal growth, though clearly something was wrong. After 18 months of HGH therapy, he has grown four inches.
It may also help kids like 14-year-old Annie Harms of International Falls, Minn. In second grade, she was smaller than most kindergartners. Her severe short stature also baffled doctors. She had no obvious underlying medical condition, but her lack of growth caused urinary tract problems that resulted in years of constant infection. Her projected adult height had been 4 feet 9 inches. Now on HGH, she is expected to grow to 5 feet 2 inches.
Davies and Harms received HGH after the dogged efforts of their parents and doctors, who diligently charted the children's growth and medical conditions and petitioned pharmaceutical companies and insurers for coverage.
Treating ISS kids is nothing new -- some 10,000 in the United States had received HGH before the July ruling. Any doctor can prescribe it, but drug companies have set tight restrictions on its distribution for children, generally making it available only through pediatric endocrinologists and only to patients with severe short stature whose doctors have made a strong medical case for treatment, according to David Allen, director of endocrinology at the University of Wisconsin Children's Hospital in Madison.
Athletes who use HGH to build muscles and strength, and baby boomers who believe it has anti-aging benefits have an easier time getting the hormone. Doctors at anti-aging clinics, for example, prescribe it to patients able and willing to pay for it. HGH can also be purchased over the Web. As Allen explains, "Adults are a lot more resourceful than kids in getting what they want."
While there is evidence that HGH builds muscle mass and reduces fat in non-deficient adults, it can have side effects including edema, insulin resistance and joint pain. "People who take it do so at their own risk and peril," says Pinchas Cohen, chief of pediatric endocrinology at the University of California, Los Angeles (UCLA).
The HGH protocol for children is not undertaken casually. It usually consists of six-per-week injections at a cost of $20,000 to $40,000 annually; for ISS kids, insurance coverage for HGH treatment is unpredictable. Side effects are rare, but they include an increased risk of diabetes, abnormal bone growth in the hip, breast budding in boys and intracranial pressure. Less is known about longer-term risks of HGH, especially in ISS kids.
Not everyone is pleased by the FDA's decision. Some pediatric endocrinologists, whose professional society had recently taken a position against HGH therapy for ISS kids, expressed shock after the decision. Even some on the FDA advisory panel who voted in favor of the new policy were discomfited.
In the weeks that followed, sociologists, journalists and other health care professionals chimed in: Does shortness need a cure? Have we opened the floodgates to HGH abuse? Do we know enough about the long-term effects of treating kids with a powerful hormone? Will parents of average-height -- or even tall -- kids pressure doctors to add a few inches to their children? Doesn't somebody have to be at the bottom of the childhood growth chart?
"We don't like to treat otherwise normal kids as though they have a disease," says Glenn Braunstein, head of the advisory panel and chairman of medicine at Cedars-Sinai Medical Center in Los Angeles. "But let's call this the way it is: We're not treating a disease state. This is a cosmetic issue."
Growth hormone does many things besides promote growth, and many endocrinologists think it has been misnamed. HGH regulates metabolism, converts fat into muscle and affects lipid levels. It is being studied as a treatment for AIDS patients and others with wasting diseases as well as in burn patients and people who have received transplanted organs.
Though levels of the hormone drop after growth is done and as one ages, it is necessary to good health. Adults with growth hormone deficiency are likely to have an abnormal fat/muscle ratio and reduced strength, exercise capacity, cold tolerance, bone mineral content and cardiac output. They are at greater risk for cardiac death and psychosocial problems including depression, irritability and low libido.
Before the FDA's decision, HGH was approved for treatment of deficiency and any of four growth-stunting conditions: Turner's syndrome and Prader-Willi syndrome; chronic renal insufficiency; and children born small for their gestational age.
Ironically, under this system some patients treated with HGH for the approved conditions are taller than kids with idiopathic short stature. Eli Lilly used this fact in its arguments before the FDA advisory panel to support the new indication for Humatrope.
"Growth hormone treatment in other conditions treats the short stature or growth failure, and not the disease," said Raymond Hintz, professor of pediatrics at Stanford University Medical Center, at the hearing conducted by the FDA panel. "It is, in fact, unfair not to offer such treatment to [other] children that have just as much of a problem."
"What would have been the reason to turn them down?" asks Paul Woolf, chairman of medicine at Crozer-Chester Medical Center in Upland, Pa., who served on the FDA advisory panel, which voted 8-2 to support the new use. "That it costs too much? That's a public policy issue, not the mission of the FDA."
Lilly's research included two randomized, double-blind, placebo- controlled studies involving 300 kids. They determined that, on average, an HGH regimen could safely add 1.5 inches (with three injections per week) to three inches (with six weekly shots) to an ISS child's final adult height.
Lilly promised to do no direct-to-consumer advertising, instead marketing only to pediatric endocrinologists, and it promised to follow its ISS patients and collect long-term safety data. It set parameters to qualify for treatment: 2.25 standard deviations below the norm for a child's age and sex.
This will make treatment available to about one in 100 children. For a 10-year-old boy or girl, that's a height below 4 feet 1 inch, or a corresponding adult height below 4 feet 11 inches for women and 5 feet 3 inches for men.
Lilly expects that 10 percent of eligible U.S. children -- about 40,000 -- will receive treatment. With the $20,000 to $40,000 per year price tag for the drug, and about four to six years of treatment, the business potential of expanded use of HGH, even by the company's estimates, is clear.
Woolf says he was convinced the ISS kids in Lilly's studies experienced growth. "But I was not convinced that that growth could make a difference" to them, he said.
The panel went back and forth with the question. Lilly's position was that the possibility of 1.5 to three more inches of final height, weighed against the risk of side effects, was a risk- benefit assessment that the child and the family should be free to make. The FDA had not made quality-of-life markers a requirement for approval of HGH in other conditions, the company argued.
The committee ultimately agreed with Lilly that the decision should be made by the family.
"Is it clinically relevant?" asks Braunstein of the inches that might be gained. "That's in the eye of the beholder. If the family is fully informed, and the parent and child think it is, then it is. Personally, to me, it doesn't seem worth it. If you're going from 5- 1 to 5-4, you're still short."
Many studies show no correlation between size and quality of life, though the taller a person is, the happier he is with his height, says David Sandberg, associate professor of psychiatry and pediatrics at the State University of New York at Buffalo. Sandberg's summary of the psychosocial literature on short stature, published in the Western Journal of Medicine in 2000, found that the psychosocial adaptation of short children -- even those referred for medical evaluation -- fell within the normal range.
But those findings contradict the results of other studies. In those, short people are often seen as less competent than taller persons, and are less likely to advance in their professions, as Lewis Underwood reported in a 1991 article in the journal Acta Paediatrica Scandinavica. Henry Biller, co-author of "Stature and Stigma: The Biopsychosocial Development of Short Males," (Lexington Books, 1987), says there is evidence that short males, who make up two-thirds to three-quarters of the children being treated with HGH, are less likely when compared with average or tall men to marry or father children and are more likely to suffer self-image problems.
Chris Hamre, 34, who was growth-hormone-deficient and measured 4 feet 1 inch at 12 years old, remembers taunts of "midget" (even as an adult), sitting out youth baseball games on the bench and even being mocked because of his size by his high school principal at a crowded pep rally.
"Society doesn't expect much of shorter males," says Hamre, who was treated with natural growth hormone and now measures 5 feet 4 inches. Perhaps, he says, he uses his height too much as a crutch, but he feels underemployed in his job as a file clerk and was uncomfortable enough living in his native California to move to New York, where he feels there is more diversity in size.
Laurie Davies, mother of Spencer, recalls that her son was "stressed" by his size. "He hated being him," she says. Now 71/2, Spencer was put on HGH a year and a half ago.
The boy says the four inches he has gained make him feel better. "I felt like I was small," he says. "And I wished I could get bigger. Now I can reach taller places, like the top of the TV set or light switches."
Annie Harms's parents gave her the choice to pursue HGH therapy when she was 12. She travels 41/2 hours to Minneapolis for appointments with her endocrinologist every three months so he can monitor her therapy. "My family would like me however I was," she says. "But I was sick of being small. It was time for me to grow. I wanted to be like my friends." She grew an inch after her first three months on HGH. The average growth for a child before puberty is two inches per year.
Members of the advisory panel heard emotional appeals from parents of short kids being treated with HGH and from normal-size adults who were exceptionally short children until they took HGH.
One advocate who received natural HGH therapy as a child literally dropped to his knees before the committee: "On my knees today, I stand two inches taller than the first endocrinologist told my mother I would ever reach as an adult," said Deno Andrews, now 32 years old and 5 feet 7 inches when standing up.
Sandberg counsels children with growth disorders at Women and Children's Hospital of Buffalo. He cautions that while there are many compelling anecdotal accounts of children who have suffered because of their size, there are many short children who are untroubled.
This new indication for using HGH, say Sandberg and others, could further stigmatize people with short stature and cause parents of short children who are doing well to seek unnecessary therapy. It's even possible that the HGH regimen itself can make a child with otherwise healthy self-esteem feel that something is wrong.
Tallness, says Sandberg and others, is a relative concept: It can only be sustained if you are taller than someone else. "If everyone gets the treatment, nobody gets the benefit," Sandberg says.
In other words, somebody has to hold the short end of the stick. But who? Members of small-stature ethnic groups? Girls, who are less frequently referred for treatment? The uneducated or the poor, who lack resources to pay for the treatment?
Many insurance companies balk at paying for HGH treatment, even for patients with a medical diagnosis. Susan Pisano, of the American Association of Health Plans, says the organization's members are reviewing whether to cover Humatrope for ISS kids, but at least one company, Cigna, made clear through a spokeswoman that the new indication for HGH does not treat "illness or injury" and therefore the drug will not be covered.
It may be better, say Sandberg and others, to teach short children coping skills than to subject them to years of injections with a drug that has a track record only two decades long. "If you have a psychosocial stressor," says Sandberg, "my knee-jerk response is to develop a psychosocial intervention."
That line of reasoning makes some formerly short kids outraged. Why, they ask, should the individual be made to bear the burdens of societal stereotypes that they are powerless to change? If a child is born with a cleft palate, they reason, there's no debate about whether it should be fixed -- even though it is a primarily cosmetic, non-life-threatening condition.
"In a perfect world, no one cares about your height," says Deno Andrews. "But I live in the world of reality. It's not up to people with no vested interest in this sector to make across-the-board claims. They're not the ones who had a miserable childhood because they were short. People against the use of growth hormone in ISS kids would whistle another tune if it was their child with the problem. I knew what I hated about being short. And I knew that those needles every day got me away from it."
The pediatric endocrinologists who have made it their professional mission to help short kids move into the normal range for height are treading cautiously with this new use of HGH.
They are -- or are supposed to be -- the primary dispensers of the drug. And they take their stewardship of it gravely.
"Is this a Pandora's box?" asks David R. Brown, pediatric endocrinologist at Children's Hospitals and Clinics in Minneapolis. "I think there is a real danger of that."
Brown and others worry that HGH could become a widely used therapy in general pediatric practice and eventually elsewhere -- say, with the baby boomers and athletes who like HGH's metabolic properties. They are concerned that if public demand for HGH grows, the calculated steps they have been trained to take to weed out medical problems in short-stature kids could eventually be bypassed.
Sidney Wolfe, an internist and the director of Public Citizen's Health Research Group, who testified at the hearing against the new indication, says: "If ever there was a setup for off-label use of a drug, we have it now. There is nothing to stop anyone from prescribing growth hormone. We will be subjecting a huge number of people to burdensome treatments for a tiny advantage with significant risks."
Not every ISS child will grow with HGH therapy. Even in the Lilly study, some children did not respond to treatment. "We don't really understand the physiology [of ISS]," says Allen, of the University of Wisconsin Children's Hospital. "The umbrella is being cast over a number of children with ill-defined growth problems. That raises the question, how do you draw the line to avoid overuse?"
Cohen, of UCLA, has studied the long-term effects of HGH. He is "comfortable" with the new indication, he says, but he, too, urges caution. "If we are not careful to treat only those who we think will benefit, and instead blindly prescribe growth hormone, this will come back to bite us."
Pediatric endocrinologists already know what that feels like. When they first treated HGH-deficient children 40 years ago, they used natural growth hormone from the cadavers. Almost 8,000 American children were treated with it until 1984.
That year, treatment was abruptly stopped when a 20-year-old man who had taken natural HGH as a child died from Creutzfeldt-Jakob disease (CJD). The human version of mad cow disease, Creutzfeldt- Jakob ravages the neurological system and is always fatal. Unknowingly, doctors had injected contaminated growth hormone into some patients.
To date, 26 Americans and 136 others around the world treated with natural HGH before 1977 have contracted Creutzfeldt-Jakob disease. The disease can take decades to incubate and manifest. The two latest cases were reported in April.
David Davis, who received natural HGH from 1974 to 1977, says he lives with the "specter of CJD" every day, and he is angry. "HGH is one of the defining factors of my life," says the 5-4 Davis, who is 40. "Would I rather be 5-4 than 4-6? Of course I'll take 5-4. But that was bad medicine. A lot of us who didn't gain much [in height] are now living with it."
There's no fear of CJD with synthesized growth hormone. But remembering the dangers of past use of hormones, Davis says, "puts this new indication in context."