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Testimony

Statement by
Lawrence  A. Tabak, D.D.S., Ph.D
Principal Deputy Director
National Institutes of Health
U.S. Department of Health and Human Services (HHS)

on
GH Testing in the NFL: Is the Science Ready? 

before
Commitee on Oversight and Government Reform
United States House of Representatives


Wednesday December 12, 2012

Good morning Chairman Issa, Ranking Member Cummings, and distinguished members of the Committee.  My name is Dr. Lawrence Tabak, and I am the Principal Deputy Director of the National Institutes of Health.  We understand the public health significance of the issue you are exploring – human growth hormone (hGH) testing in the NFL – and are pleased to participate in this hearing to describe our understanding of the state of the science pertaining to the non-medical use of recombinant hGH (rhGH), including its adverse effects, and to discuss the prevailing method for detecting illicit use of rhGH in professional sports.

HGH is a natural product of the pituitary gland with essential roles in human development.  Much of our current understanding about the physiological and psychological effects of hGH on the human body comes from decades of studying and treating patients suffering from growth hormone disorders.  NIH has had a long history of supporting breakthrough research to understand and treat the often devastating effects of deficient (e.g., hypogonadism) or excessive (e.g., pituitary tumors) function in the growth hormone system.

Human growth hormone therapies have become a mainstay of modern medicine, particularly after the development, in 1985, of a safe and reliable source of rhGH, a synthetic protein produced by recombinant deoxyribonucleic acid (DNA) technology that has a sequence identical to that of the primary pituitary-derived hGH.  The hGH can stimulate tissue growth, linear growth (height), and protein, carbohydrate, lipid, and mineral metabolism.  It promotes fat loss and increases lean body mass.  The FDA has approved rhGH for a number of clinical indications associated with growth hormone deficiency in both adults and children, including the treatment of short stature, chronic renal insufficiency, and several genetic or congenital disorders, such as Turner, Noonan, and Prader-Willi syndromes.  In patients with growth hormone deficiency, rhGH administration improves aspects of exercise capacity and some studies have suggested that it improves mood, including low energy and psychiatric comorbidities like general anxiety disorder and depression (1-3). 

Given the well-documented ability of rhGH to spur tissue build up and burn fat, some athletes began abusing rhGH (non-medical use is defined as abuse) in an attempt to enhance their performance.  Further increasing the appeal of rhGH for competitive athletes is the fact that it also stimulates production of another hormone (Insulin-like growth Factor-1 (IGF-1)) that inhibits the breakdown of proteins.  There are claims that inhibiting protein breakdown can help prevent some of the muscle and tendon damage that results from chronic abuse of anabolic steroids.  This effect is unproven but it may explain why rhGH is reportedly often used in combination with anabolic steroids at high doses and for several months (4, 5), a phenomenon that is bound to complicate our understanding of any potential consequences of non-medical rhGH use.

While the evidence shows that hGH spurs tissue build up and burns fat, the studies performed to date found little or no evidence that the increased lean body mass that can result from using unnaturally high doses of rhGH has any effects on boosting strength, power, or aerobic capacity in healthy individuals (6-8).  Non-medical use of rhGH might actually decrease performance by increasing exercise-induced buildup of lactic acid in the muscles, which promotes muscular fatigue, cramps, and soreness.  Based on well-documented evidence of the side effects of rhGH administration to adults with growth hormone deficiency (9), athletes who abuse rhGH are putting themselves at risk of these same adverse consequences.  Moreover, it is estimated that athletes are taking doses that are up to 10 times higher than those used therapeutically (10). 

Although much of what is known about the adverse effects associated with high-dose rhGH abuse is derived from individual case reports, anecdotal evidence, or therapeutic records, what we know about the biology of rhGH and long clinical history of treating patients with it point to a worrisome list of possible adverse consequences.  For example, athletes who chronically use rhGH for non-medical reasons may develop some of the features of acromegaly (or adult onset gigantism) (10).  They are also at risk for developing hypoglycemia and diabetes, cardiomyopathy, drug-induced hepatitis, renal failure, soft tissue edema, joint pain, carpal tunnel syndrome, and increased fatigue.

The available information suggests that athletes who dose themselves with rhGH are taking serious risks with their health.  Moreover, they may not realize that there is no scientific evidence that the practice will improve their performance or resilience in competition.

Knowledge of a) the potentially adverse health consequences associated with rhGH abuse, b) the “asterisk” epidemic that has compromised the outcomes in sports and c) the use of rhGH and other performance-enhancing drugs among teenagers (8, 11), prompted efforts to develop and deploy a sensitive, reliable method for testing of illicit use of rhGH. 

The development of such a test presented a formidable challenge, for several reasons:

  1. the predominant naturally-occurring form of hGH and its recombinant version are virtually indistinguishable,
  2. normal concentrations of circulating hGH fluctuate widely throughout the day, and
  3. hGH concentrations in urine are low and do not necessarily correlate with blood concentrations.

These technical obstacles have been overcome with the development of several testing approaches.  The predominant method in use relies on a smart cocktail of specific antibodies that recognize and specifically bind to different versions (isoforms) of hGH and compares their abundance to that of the only isoform (the 22kD) that is identical to the recombinant version relative to all other naturally occurring isoforms.  A positive test would be one in which the ratio of the 22kD isoform relative to the other isoform falls above  a previously established threshold or reference range based on results from a demographically diverse population.

Based on most published reviews, the scientific validity and robustness of this test has been upheld by numerous studies, carried out around the world by hGH experts and with different populations.  Questions can always be raised about whether a given test, even one whose reliability has been established under most circumstances, also has universal validity.  In this case, the ability of the test to approach universal validity hinges on how the reference range has been established.  In science, universal validity is almost never achievable for reasons I will now explain. 

There is a well-known but small inter-individual variability in the hGH system within the athletic population, which could theoretically affect the universal applicability of the reference range (12, 13).  However, based on the existing literature, over 90 percent of that variability can be explained just by age and gender differences, making a positive test unlikely to be the result of chance variability (14).  And yet, the job of a scientist is to acknowledge the possibility, even if remote, of gaps in our knowledge that could change the prevailing view.  For example, greater bone mineral density in adult African American men compared with White males has been associated with greater hGH secretion (15, 16).  While this observation does not diminish the rigorously demonstrated and widely accepted validity of the test as currently deployed, it does point to the kind of complexities and confounders that scientists always try to take into account when developing a new clinical test.  

I thank you for this opportunity to provide you with testimony.

References

1. Maric NP, Doknic M, Pavlovic D, Pekic S, Stojanovic M, Jasovic-Gasic M et al. Psychiatric and neuropsychological changes in growth hormone-deficient patients after traumatic brain injury in response to growth hormone therapy. J Endocrinol Invest 2010 Dec; 33(11): 770-775.

2. Arwert LI, Deijen JB, Muller M, Drent ML. Long-term growth hormone treatment preserves GH-induced memory and mood improvements: a 10-year follow-up study in GH-deficient adult men. Horm Behav 2005 Mar; 47(3): 343-349.

3. Chaplin JE, Kristrom B, Jonsson B, Hagglof B, Tuvemo T, Aronson AS et al. Improvements in behaviour and self-esteem following growth hormone treatment in short prepubertal children. Horm Res Paediatr 2011; 75(4): 291-303.

4. Parkinson AB, Evans NA. Anabolic androgenic steroids: a survey of 500 users. Med Sci Sports Exerc 2006 Apr; 38(4): 644-651.

5. Perry PJ, Lund BC, Deninger MJ, Kutscher EC, Schneider J. Anabolic steroid use in weightlifters and bodybuilders: an internet survey of drug utilization. Clin J Sport Med 2005 Sep; 15(5): 326-330.

6. Birzniece V, Nelson AE, Ho KK. Growth hormone administration: is it safe and effective for athletic performance. Endocrinol Metab Clin North Am 2010 Mar; 39(1): 11-23, vii.

7. Liu H, Bravata DM, Olkin I, Friedlander A, Liu V, Roberts B et al. Systematic review: the effects of growth hormone on athletic performance. Ann Intern Med 2008 May 20; 148(10): 747-758.

8. Calfee R, Fadale P. Popular ergogenic drugs and supplements in young athletes. Pediatrics 2006 Mar; 117(3): e577-589.

9. Powrie J, Weissberger A, Sonksen P. Growth hormone replacement therapy for growth hormone-deficient adults. Drugs 1995 May; 49(5): 656-663.

10. Holt RI, Sonksen PH. Growth hormone, IGF-I and insulin and their abuse in sport. Br J Pharmacol 2008 Jun; 154(3): 542-556.

11. Rickert VI, Pawlak-Morello C, Sheppard V, Jay MS. Human growth hormone: a new substance of abuse among adolescents? Clin Pediatr (Phila) 1992 Dec; 31(12): 723-726.

12. Erotokritou-Mulligan I, Bassett EE, Cowan DA, Bartlett C, McHugh C, Sonksen PH et al. Influence of ethnicity on IGF-I and procollagen III peptide (P-III-P) in elite athletes and its effect on the ability to detect GH abuse. Clin Endocrinol (Oxf) 2009 Jan; 70(1): 161-168.

13. Holt RI, Bassett EE, Erotokritou-Mulligan I, McHugh C, Cowan D, Bartlett C et al. Moving one step closer to catching the GH cheats: The GH-2004 experience. Growth Horm IGF Res 2009 Aug; 19(4): 346-351.

14. Erotokritou-Mulligan I, Eryl Bassett E, Cowan DA, Bartlett C, Milward P, Sartorio Aet al. The use of growth hormone (GH)-dependent markers in the detection of GH abuse in sport: Physiological intra-individual variation of IGF-I, type 3 pro-collagen (P-III-P) and the GH-2000 detection score. Clin Endocrinol (Oxf) 2009 Apr; 72(4): 520-526.

15. Wright NM, Renault J, Willi S, Veldhuis JD, Pandey JP, Gordon L et al. Greater secretion of growth hormone in black than in white men: possible factor in greater bone mineral density--a clinical research center study. J Clin Endocrinol Metab 1995 Aug; 80(8): 2291-2297.

16.       Bell NH, Gordon L, Stevens J, Shary JR. Demonstration that bone mineral density of the lumbar spine, trochanter, and femoral neck is higher in black than in white young men. Calcif Tissue Int 1995 Jan; 56(1): 11-13.

Last revised: June 18, 2013