A4M Response Blackman Article -JAMA 2002

I. Precedent for Safety and Efficacy: Dr. Daniel Rudman's 1990 Landmark Study

On July 5, 1990, an article by Dr. Daniel Rudman and colleagues at the Medical College of Wisconsin appearing in the New England Journal of Medicine established one of the most important milestones in the history of clinical anti-aging medicine. Rudman's article documented the world's first clinical trial of human growth hormone (HGH) replacement in elderly men. Comparing the effects of six months’ of HGH injections on twelve men, ages 61 to 81, with an age-matched control group, the researchers showed clear benefits to the therapy. Men administered HGH gained an average of 8.8% in lean body mass and lost 14% in fat (without diet or exercise), improved their skin texture and tone, and increased their bone density. In language rarely used in conservative medical journals, the researchers wrote: "The effects of six months of human growth hormone on lean body mass and adipose-tissue mass were equivalent in magnitude to the changes incurred during 10 to 20 years of aging."

[Rudman D, Feller AG, Nagraj HS, Lalitha PY, Goldberg AF, Schlenker RA, Cohn L, Rudman IW, Mattson DE. "Effects of human growth hormone in men over 60 years old," N Engl J Med, 1990 Jul 5:323(1):1-6.]

The 2002 Blackman study is a repeat of the Rudman work of twelve years ago. Both administered GH to adults at low dosages. Both observed that adult GH replacement therapy is of value for increasing lean muscle mass and decreasing fat mass.

II. Side Effect Profile

Adult GH replacement therapy may cause transient blood sugar elevation during the course of treatment. Short-term blood sugar elevation is not equivalent to diabetic disease. The Blackman study does a disservice to the public by suggesting that adult GH replacement therapy leads to the diabetic state and pancreatic damage. Diabetes is a permanent physiological condition, and a symptomatic rise in blood sugar as may result from adult GH replacement therapy has not been clinically shown to cause diabetes. The A4M is unaware of any peer-reviewed published scientific paper implicating adult GH replacement therapy with the onset of a permanent diabetic state.

In the anti-aging clinical setting, adult GH replacement therapy employs doses of GH that are 1/3 of that used in the 2002 Blackman study or the 1990 Rudman study, and both studies utilized doses at 1/3 to 1/2 that used in the pediatric setting for the treatment of dwarfism. The attenuated low-dose therapies have been proven effective in ten years of application by physician members of the A4M. The short-lived alteration of blood sugar level, as well as other side effects, that may result from GH therapy cease when a proper titration of therapy is achieved or when the treatment is discontinued. The A4M is unaware of any reported cases of clinical diabetes in this specific application. When the proper dosing customized to the anti-aging patient is reached, and coupled with regular laboratory testing and clinical examination, our member physicians are able to limit adverse effects of GH replacement therapy in adult patients.

It is the position of the A4M that the side effect profile of GH therapy is nominal when the dosage is properly determined and monitored by a qualified endocrinologist or anti-aging physician.

III. A4M Literature Review

In a literature review conducted by the A4M, we find an overwhelming number of peer-reviewed scientific studies published in the past 24 months that clearly support the benefits of adult GH replacement therapy, associated with negligible side effects, when administered judiciously by a qualified physician. These studies include:

Body Composition/Cardiac Function/Bone Density &endash; ie Aging Intervention

JUNE 2002 (University of Toronto, Toronto, Ontario, Canada): Dr. Ezzat and colleagues administered GH to 67 men and 48 women found to be growth hormone deficient. After a six-month treatment period, lean body mass increased by an average of 2.1 kg, decrease in fat mass of 2.8 kg, and of 2.1 kg, greatly improved left ventricular systolic function, and significantly restored ejection fraction ("approaching normalcy"). GH treatment was well tolerated, with adverse events primarily related to effects on fluid balance. In both men and women, the researchers found "No apparent relationship between IGF-I levels and the occurrence or severity of adverse events. GH replacement therapy in adults demonstrated beneficial effects on lean body mass composition … [and] … cardiac function improvement."

[Ezzat S, Fear S, Gaillard RC, Gayle C, Landy H, Marcovitz S, Mattioni T, Nussey S, Rees A, Svanberg E. Gender-specific responses of lean body composition and non-gender-specific cardiac function improvement after GH replacement in GH-deficient adults. J Clin Endocrinol Metab. 2002 Jun;87(6):2725-33.]

APRIL 2002 (Hypoptiuitary Control and Complications Study International Advisory Board [an organization studying the efficacy and safety of GH therapy of adult GH-deficient patients in clinical practice]): Dr. Attanasio and colleagues reported on a three-year course of GH therapy administered to adult onset GH-deficient patients. Lean body mass increase was found to be greatest in the those younger than 40 years old, less but still significant in the middle group (40-60 years), and unchanged in older (>60 years). Conversely, decreases in the low-density lipoprotein/HDL ratio were insignificant in the younger patients, but proved to be significant in the middle and older age groups. The researchers submit that "these observational data showed significant long-term efficacy of adult GH replacement therapy on body composition and lipid profiles and indicate that age is an important predictor of response."

[Attanasio AF, Bates PC, Ho KK, Webb SM, Ross RJ, Strasburger CJ, Bouillon R, Crowe B, Selander K, Valle D, Lamberts SW; The Hypoptiuitary Control and Complications Study International Advisory Board Human growth hormone replacement in adult hypopituitary patients: long-term effects on body composition and lipid status--3-year results from the HypoCCS Database. J Clin Endocrinol Metab. 2002 Apr;87(4):1600-6.]

OCTOBER 2001 (University Hospital, Goteborg, Sweden): Dr. Gotherstrom and colleagues at the Research Centre for Endocrinology and Metabolism studied a five-year course of GH replacement in 70 men and 48 women (mean age 49.3 years), with adult-onset GH deficiency. , They found a sustained increase in lean body mass and a decrease in body fat. The GH treatment increased total body bone mineral content as well as lumbar and femur neck bone mineral content. Total cholesterol and low density lipoprotein cholesterol decreased, and high density lipoprotein cholesterol increased. Serum concentrations of triglycerides and hemoglobin A(1c) were reduced. In conclusion, the researchers state: "Five years of GH substitution in GH-deficient adults is safe and well tolerated. The effects on body composition, bone mass, and metabolic indices were sustained. The effects on body composition and low density lipoprotein cholesterol were seen after 1 yr, whereas the effects on bone mass, triglycerides, and hemoglobin A(1c) were first observed after years of treatment."

[Gotherstrom G, vensson J, Koranyi J, Alpsten M, Bosaeus I, Bengtsson B, Johannsson G, "A prospective study of 5 years of GH replacement therapy in GH-deficient adults: sustained effects on body composition, bone mass, and metabolic indices," J Clin Endocrinol Metab. 2001 Oct;86(10):4657-65]

OCTOBER 2001 (University Hospital, Uppsala, Sweden): Dr. Gillberg and team found that three months of low-dose GH on 64 GH-deficient adults increased serum levels of insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3 and lipoprotein (a), reduced total and low density lipoprotein cholesterol levels, and resulted with greater lean body mass and decreased fat mass. The researchers suggest, "This fixed low-dose regime resulted in improvements in body composition and lipid profile, without causing serious side effects. This is therefore a valid method to institute GH replacement in adults."

[Gillberg P, Bramnert M, Thoren M, Werner S, Johannsson G, "Commencing growth hormone replacement in adults with a fixed low dose. Effects on serum lipoproteins, glucose metabolism, body composition, and cardiovascular function," Growth Horm IGF Res. 2001 Oct;11(5):273-81]

Quality of Life &endash; ie Self-Perceived Wellness in Aging:

NOVEMBER 2001 (KIGS/KIMS Outcomes Research, Pharmacia AB, Stockholm, Sweden): Data concerning visits to the doctor, number of days in hospital, and amount of sick leave were obtained from patients included in KIMS (Pharmacia International Metabolic Database), a large pharmacoepidemiological survey of hypopituitary adults with GH deficiency. Of the 304 patients surveyed, visits to the doctor, number of days in hospital, and amount of sick leave decreased significantly after 12 months of GH therapy. Patients also needed less assistance with daily activities, although this was significant only for the men. After 12 months of GH treatment, Quality of Life (assessed by the QoL-Assessment of GHD in Adults questionnaire) improved, as did both the amount of physical activity and the patients' satisfaction with their level of physical activity. Dr. Hernberg and colleagues thus conclude that "GH replacement therapy, in previously untreated adults with growth hormone deficiency, produces significant decreases in the use of healthcare resources, which are correlated with improvements in quality of life."

[Hernberg-Stahl E, Luger A, Abs R, Bengtsson BA, Feldt-Rasmussen U, Wilton P, Westberg B, Monson JP; KIMS International Board., KIMS Study Group. Pharmacia International Metabolic Database, "Healthcare consumption decreases in parallel with improvements in quality of life during GH replacement in hypopituitary adults with GH deficiency," J Clin Endocrinol Metab. 2001 Nov;86(11):5277-81]

SEPTEMBER 2001 (Universität München, Munich, Germany): Dr. Herschbach and colleagues from the Institut und Poliklinik für Psychosomatische Medizin found scores across numerous psychometric markers improved progressively in adults administered GH replacement therapy.

[Herschbach P, Henrich G, Strasburger CJ, Feldmeier H, Marin F, Attanasio AM, Blum WF. Development and psychometric properties of a disease-specific quality of life questionnaire for adult patients with growth hormone deficiency. Eur J Endocrinol. 2001 Sep;145(3):255-65.]

JUNE 2001 (Royal Liverpool University Hospital, United Kingdom): Dr. Ahmad and team found that weight-based GH replacement resulted in significant improvements in both body composition and quality of life as early as one month after the initiation of treatment, and persisted at three months. Noting that "most importantly, these changes occur in the absence of side-effects," the researchers "therefore suggest the use of low-dose GH therapy, maintaining IGF-I between the median and upper end of the age-related reference range, for the treatment of adult growth hormone deficiency."

[Ahmad AM, Hopkins MT, Thomas J, Ibrahim H, Fraser WD, Vora JP. Body composition and quality of life in adults with growth hormone deficiency; effects of low-dose growth hormone replacement. Clin Endocrinol (Oxf). 2001 Jun;54(6):709-17.]

In conclusion, it is the position of the A4M that adult GH replacement therapy is safe and efficacious when administered judiciously by a qualified endocrinologist or anti-aging physician. Of all of the hormones in-use for adult replacement, GH has the most extensive history of rigorous scientific trials and practical clinical application. We ask that you be mindful that the Blackman et al study advocates for the continuance of controlled studies; the A4M concurs that thorough and objective scientific data on adult GH replacement therapy should continue to be collected through both research studies and applied clinical utilization.

• LA Times, November 13, 2002