Endocrine Lecture

The Mitchell Report

• Named 86 professional baseball players suspected of using performance enhancing drugs

• Implicated drugs include anabolic steroids and recombinant human growth hormone (rHGH)

Players Response

• Andy Pettitte– “In 2002 I was injured. I had heard that human growth

hormone could promote faster healing for my elbow. For this reason, and only this reason, for two days I tried human growth hormone.”

• Fernando Vina– Tried rHGH after injuring his knee and hamstring in

2003. – "For me, it was to try to get back on the field, that was

the bottom line."

www.espn.com

What’s The Deal?

• My ankle hurts.

• I feel old.

• Where can I get some rHGH?

Growth Hormone

• Released from anterior pituitary

• Stimulated by GHRH• Inhibited by

somatostatin

Melmed, S. “Acromegaly” NEJM 2006:355;2558-73

Growth Hormone

• Acts on growth hormone receptor in cell membrane – mostly located in liver– Activate JAK2/STAT kinase leading to

transcription of target proteins– Induce synthesis of Insulin-like growth factor I

(IGF-I)

Melmed, S. “Acromegaly” NEJM 2006:355;2558-73

Growth Hormone

• Overall affect (mediated through IGF-I)– Maintain lean mass– Increase salt and water retention– Antagonize insulin action– Lipolysis– Anabolic affect on bone – Reported increase energy level and libido

Causes: Growth Hormone Deficiency

Causes: Growth Hormone “Deficiency”

• Age???– IGF-I levels decrease with age– Lean body mass decreases with age

• Are the two related?

Growth Hormone Deficiency

• Diagnosis1) Clinical evidence of deficiency with a cause

2) Low IGF-I (Age related comparison)

3) Positive provocative test• Hypoglycemia-induce• L-dopa or arginine

• Note: Dropping batting average or fastball speed not adequate “clinical evidence”

rHGH in Sports

• Initial use in early 1990s• Studied initially due to high GH spikes

during sustained anaerobic exercise• High abuse potential:

– Difficult to detect in drug screen– Improved VO2 max (slight) and muscle

strength (anecdotal only)– Anecdotal improved wound healing (no

supporting data)

Saugy, M. “Human growth hormone doping in sport.” Br J Sports Med 2006;40(Suppl I):i35–i39

rHGH in Adults

rHGH in Adults

• Study involved 12 men in treatment arm and 9 in no treatment arm (NOT PLACEBO)

• Treatment arm: rHGH 0.03 mg/kg – increased every month until IGF-I >500

• No significant difference in:– Impaired fasting glucose incidence, edema,

cholesterol panel

• In treatment arm:– Significant increase in lean body mass and lumbar

bone density– Significantly higher blood pressure and blood glucose

Rudman, D. “Effects of HGH on Men Greater than 60 Years Old.” NEJM 1990:323;1-6

rHGH in Adults

Rudman, D. “Effects of HGH on Men Greater than 60 Years Old.” NEJM 1990:323;1-6

rHGH in Adults

Blackman, M. “Growth Hormone and Sex Steroid Administration in Healthy Aged Men and Women.” JAMA 2002:288;2282-92

rHGH in Adults

• Evaluated 131 men and women with rHGH versus placebo with sex hormone or placebo– 26 week study– “Normalized” GH and

sex hormone levels

Blackman, M. “Growth Hormone and Sex Steroid Administration in Healthy Aged Men and Women.” JAMA 2002:288;2282-92

rHGH in Adults

• Significant outcomes:– Lean body mass

increased in rHGH group regardless of sex steroids

– Increased VO2 max in rHGH + testosterone group

• Not significant:– Muscle strength

(measured as grip strength)

Blackman, M. “Growth Hormone and Sex Steroid Administration in Healthy Aged Men and Women.” JAMA 2002:288;2282-92

rHGH in Adults

• Significant adverse events:– Carpal tunnel syndrome– Arthralgias (up to 46% of rHGH group)– Edema– Impaired Fasting Glucose

• DMII occurred in 6 treatment versus 1 placebo (p – 0.06)

• No significant change:– PSA– Blood pressure– Hematocrit

Blackman, M. “Growth Hormone and Sex Steroid Administration in Healthy Aged Men and Women.” JAMA 2002:288;2282-92

rHGH in Adults

• Conclusion:– rHGH and sex steroids have beneficial effects

in an elderly population– Adverse effects of this therapy may limit use– Use of rHGH in the elderly should be confined

to clinical trials.

Blackman, M. “Growth Hormone and Sex Steroid Administration in Healthy Aged Men and Women.” JAMA 2002:288;2282-92

rHGH in Adults

Lau, H. Ann Intern Med. 2002;137:190-196.

rHGH in Adults

• Meta analysis:– Total articles included - 31– Total study populations - 18– Total patients treated - 220– Mean treatment duration - 27 weeks

Lau, H. Ann Intern Med. 2002;137:190-196.

Lau, H. Ann Intern Med. 2002;137:190-196.

Results

• No significant change in weight– Improvement only in lean body mass

• No significant change in cholesterol profile• To few studies to interpret glucose affect

Lau, H. Ann Intern Med. 2002;137:190-196.

Lau, H. Ann Intern Med. 2002;137:190-196.

Conclusions

• rHGH is likely beneficial in patients with clearly demonstrated GH deficiency

• There is no convincing data to suggest benefit in normal aging or injury recovery

• The adverse effects of rHGH, while unlikely to increase short-term mortality, will limit widespread use

My Conclusions

• There is no evidence for improved muscle strength, injury recovery, or overall well-being in healthy adults treated with rHGH

• Improvements seen in professional athletes are likely related to combination therapy including sex steroids and epogen

• rHGH is not a safe medication to commonly use without proven deficiency

Sources• Blackman, M. “Growth Hormone and Sex Steroid Administration in Healthy Aged Men

and Women.” JAMA 2002:288;2282-92• Cook, D. “Shouldn’t Adults with Growth Hormone Deficiency Be Offered Growth

Hormone Replacement Therapy?” Ann Intern Med. 2002;137:197-201.• Gola, M. “Clinical Review: Growth Hormone and Cardiovascular Risk Factors.” J

Endo Metabol 2005:90(3):1864–1870• Isley, W. “Growth Hormone Therapy for Adults: Not Ready for Prime Time?” Ann

Intern Med. 2002;137:190-196.• Lau, H. “Systematic Review: The Safety and Efficacy of Growth Hormone in the

Healthy Elderly.” Ann Intern Med. 2002;137:190-196.• Melmed, S. “Acromegaly” NEJM 2006:355;2558-73• Noakes, T. “Tainted Glory — Doping and Athletic Performance.” NEJM

2004:351;847-9• Rudman, D. “Effects of HGH on Men Greater than 60 Years Old.” NEJM 1990:323;1-

6• Saugy, M. “Human growth hormone doping in sport.” Br J Sports Med 2006;40(Suppl

I):i35–i39• Vance, M. “Growth Hormone for the Elderly?” NEJM 1990:323;52-3