GH Replacement therapy for Adult GH Deficiency Current Literature and Clinical Practice Ron Rothenberg MD

Transcription

1 GH Replacement therapy for Adult GH Deficiency Current Literature and Clinical Practice Ron Rothenberg MD The following potential conflict of interest relationships are germane to my presentation. Equipment: N/A Speakers Bureau: N/A Stock Shareholder: N/A Grant/Research Support: N/A Consultant: N/A Status of FDA devices used for the material being presented Enter Device Name or state N/A Status of off-label use of devices, drugs or other materials that constitute the subject of this presentation N/A

2 GH Replacement therapy for Adult GH Deficiency Current Literature and Clinical Practice Ron Rothenberg MD

3 GH Physiology What data on GH Replacement Therapy (GHRT) is in the medical literature in the past few years? Does GHRT increase the risk of cancer? Are there significant side effects to GHRT? What are the practical aspects of GHRT based on medical literature and clinical experience? GH and inflammation?

4 + STOMACH GHRH GHRP Hypothalamus GHRELIN + Anterior Pituitary - - Somatostatin + IGF-1 LIVER + + GH + + THYMUS BRAIN GONAD - Muscle, Bone, Cartilage FAT

5 Type Growth Hormone into Pubmed February 11, 2008: 56,192 citations January 29, , 413 citations November 11, ,360 citations

6 Exponential decline in GH release after % decline per decade after puberty Negative correlation of GH release and BMI GH has half life of 14 minutes IGF-1 has half life of < 10 minutes

7 IGFBP s 6 IGF Binding Proteins Inhibit and Enhance IGF Actions IGF-1 + IGFBP-3 + Acid Labile Subunit = Ternary Complex Half-Life of Ternary Complex = 15 hours IGFBP-3 has independent actions and inhibits cancer through p53

8

9

10 Low IGF-1 poor muscle strength and mobility in women Low IGF-1: poor knee extensor muscle strength slow walking speed difficulty with mobility tasks Cappola AR et al. Association of IGF-I levels with muscle strength and mobility in older women. J Clin Endocrinol Metab 2001 Sep;86 (9):

11 GH deficiency = decreased longevity in humans Patients with absent GH-1 gene compared to siblings Males, 56 vs. 75 yr (P < ) Females, 46 vs. 80 yr (P < ) Besson A et al. Reduced longevity in untreated patients with isolated growth hormone deficiency. J Clin Endocrinol Metab Aug;88 (8):

12 Ageing and Longevity are related to GH/IGF-1 Old males with higher IGF-1do not show age related decrease in Testosterone, LBM and increase in fat mass GH determines life potential Ruiz-Torres A et al. Ageing and longevity are related to growth hormone/insulin-like growth factor-1 secretion. Gerontology Nov-Dec;48(6):401-7.

13 Adult GHD and Mortality Mortality increased childhood onset/adult onset GHD Hazard Ratio Males 1.9 Females 3.4 Stochholm, K et al. Mortality and GH Deficiency a Nationwide Study. European Journal of Endocrinology. (2007)

14

15 Is GH RT a Fountain of Youth? No If we were to stay perfect why alter a perfect system Since we are on a programmed course of destruction, GHRT is a way to help to maintain Quality of Life Treat if patient has AGHD Risk/Benefit analysis Work in Progress Rothenberg, R. Quality of Life Improves with GH Therapy. Anti-Aging Medical News, Summer-fall p 34.

16 AGHD GH Replacement Neurocognitive decline Improved memory, alertness and concentration

17 GH and the brain GH exerts profound effects on CNS Improves Cognitive capabilities Memory Alertness Motivation, Work Capacity GH receptors present in the brain Hypothalamus, choroid plexus, hippocampus GH crosses BBB Nyberg F. Growth Hormone in the Brain: Characteristics of Specific Brain Targets for the Hormone and Their Functional Significance. Front Neuroendocrinol 2000 Oct;21(4):

18 GH and the Brain IGF-1 correlated with cognitive function in men average age 69 GH deficiency correlated with poor emotional and psychosocial functioning Aleman A et al. Insulin-Like Growth Factor-I and Cognitive Function in Healthy Older Men J Clin Endocrinol Metab 84: , 1999

19 GH and Alzheimer s IGF-I exerts cytoprotection against A beta amyloid induced neuronal cell death Takako Niikura et al. Insulin-Like Growth Factor I (IGF-I) Protects Cells from Apoptosis by Alzheimer's V642I Mutant Amyloid Precursor Protein through IGF-I Receptor in an IGF-Binding Protein-Sensitive Manner The Journal of Neuroscience, March 15, 2001, 21(6):

20 GH Cognitive Review GH and IGF-1 cross BBB and have brain receptors especially in hippocampus and amygdala, frontoparietal cortex Effects are mediated by an interaction with the NMDA receptor, and may lead to neuronal regeneration and increased neurotransmitter activity. GH and IGF-1 correlated with cognitive function in multiple studies In GHD GHRT improves processing speed and attention van Dam PS. Somatropin therapy and cognitive function in adults with growth hormone deficiency : a critical review. Treat Endocrinol. 2006;5(3):

21 AGHD GH Replacement Reduced bone density Reversal of osteoporosis Logobardi, J Endocinol Invest, May 1999 Bone density significantly improved with GH therapy

22 GH and Bone Increases formation and strength of cortical bone. Synergistic effect with exercise Lower IGF in Hip Fx patients H. Oxlund, et al Growth Hormone and Mild Exercise in Combination Markedly Enhance Cortical Bone Formation and Strength in Old Rats Endocrinology, April 1998, p Vol. 139, No 4 Colao A. Bone loss is correlated to the severity of growth hormone deficiency in adult patients with hypopituitarism. J Clin Endocrinol Metab 1999 Jun;84(6): Hedstrom M. Hip fracture patients, a group of frail elderly people with low bone mineral density, muscle mass and IGF-I levels. Acta Physiol Scand 1999 Dec;167(4):347-50

23 GH Rx Hip Fx Double blind, controlled, 6 weeks Rx 20 micro grams/kg/day > 75 years old, IGF returned to 50 year old level Return to pre-fracture living: 94 vs. 75% Statistically Significant, well tolerated Van Der Lely et al. Use of human GH in elderly patients with accidental hip fracture. Eur J Endocrinol 2000 Nov;143(5):

24 GH and bone density 18 month study - men Increase bone density, bone turnover, lean body mass Body fat decreased Low incidence of side effects Baum HB et al. Effects of physiologic growth hormone therapy on bone density and body composition in patients with adult-onset growth hormone deficiency. A randomized, placebocontrolled trial. Ann Intern Med 1996 Dec 1;125(11):883-90

25 AGHD Increased CV deaths GH Replacement Increased CV function Improves lipid profile? Reverses atherosclerosis Reduced carotid intima thickness Improves dilated cardiomyopathy Gibney et al. The effects of 10 years of GH in adult GH deficient patients J Endocrin Metab 1999 August

26 GHD - increased cardiovascular risk Abnormal body composition, Unfavorable lipid profile, Increased fibrinogen Increased C-reactive protein levels, Insulin resistance, Early atherosclerosis Endothelial dysfunction Impaired left ventricular (LV) performance Colao A et al. Beginning to end: Cardiovascular implications of growth hormone (GH) deficiency and GH therapy. Growth Horm IGF Res May 9

27 GHRT reverses risks Reduces body fat and visceral adipose tissue Reduces low-density lipoprotein cholesterol and triglyceride levels Improves endothelial function Reduces intima media thickness Improves LV performance

28 Growth Hormone Treatment in Dilated Cardiomyopathy Double blind, placebo controlled 2 IU/day x 12 weeks GH induced increase in IGF-1 predicted change in ejection fraction IGF-1 increase > 80 pg/ml caused notable improvement in ejection fraction 5% Perrot, A. et al. Growth Hormone Treatment in Dilated Cardiomyopathy J Card. Surg 2001;16:

29 IGF-1 increase <80 IGF-1 increase >80

30 GH, CHF, Exercise Capacity GH treatment 4 IU = 1.33 mg every other day Improved all parameters of Exercise Capacity Fazio, S et al. Effects of Growth Hormone on Exercise Capacity and Cardiopulmonary Performance in Patients with Chronic Heart Failure. J Clin Endocrinol Metab Aug 14

31 GH and Atherosclerosis GH normalized Intima Media thickness of carotid artery (IMT) by 3 months improvement continued 18 months IMT negatively correlated with IGF-1 No significant change in lipids Direct effect on arterial wall via NO? Pfeifer M et al. Growth Hormone (GH) Treatment Reverses Early atherosclerotic Changes in GH-Deficient Adults J Clin Endocrinol Metab 84: , 1999 Borson-Chazot F. et al. Decrease in Carotid Intima- Media Thickness after One Year Growth Hormone (GH) Treatment in Adults with GH Deficiency J Clin Endocrinol Metab 84: , 1999

32 GH and Refractory Heart Failure GH Rx increased GH level IGF-1 Ejection fraction 13% to 28% Dobutamine discontinued Bocchi EA et al. Growth hormone for optimization of refractory heart failure treatment. Arq Bras Cardiol 1999 Oct;73(4):391-8

33 IGF-1 inverse with BP Inverse with BP and 2 hour glucose and triglyceride levels Vasodilator, NO actions Hunt KJ et al A potential inverse association between insulin-like growth factor I and hypertension in a cross-sectional study. Ann Epidemiol Jul;16(7):563-71

34 GH and Homocysteine HC Decreased in GH treated (average 1.2 µmol/l, p =.047) Changes in HC were negatively correlated with changes in IGF-I. Not with folate, vitamin B12, total T 3, C-reactive protein, interleukin-6, or insulin levels. Sesmilo G. et al. Effects of GH Administration on Homocysteine Levels in Men with GH Deficiency: A Randomized Controlled Trial. The Journal of Clinical Endocrinology & Metabolism Vol. 86, No , 2001

35 GH and coronary inflammation GH deficient adults have increased CV mortality Inflammatory markers are predictive of CV events C-Reactive Protein increased in GH deficiency With GH Replacement therapy C Reactive protein decreased Visceral and Subcutaneous fat decreased No change in cholesterol, HDL Sesmilo G et al. Effects of growth hormone administration on inflammatory and other cardiovascular risk markers in men with growth hormone deficiency. A randomized, controlled clinical trial. Ann Intern Med 2000 Jul 18;133(2):111-22

36 GH and CRP GH deficiency = Increased CRP GH treatment = Decreased CRP Andreassen et al. Concentrations of the acute phase reactants highsensitive C-reactive protein and YKL- 40 and of interleukin-6 before and after treatment in patients with acromegaly and growth hormone deficiency. Clin Endocrinol (Oxf) Aug 28

37 Inflammatory Cytokines decreased IGF-1 Growth hormone (GH) and insulinlike growth factor (IGF)-I are potent regulators of muscle mass in health and disease Inflammation, TNF alpha produce catabolism thru inhibition of IGF-1 Lang CH et al. Cytokine inhibition of JAK-STAT signaling: a new mechanism of growth hormone resistance. Pediatr Nephrol Nov 10

38 GH, Heart Failure, Inflammation Proinflammatory cytokines contribute to chronic heart failure. 4 IU GH every other day Significant Decrease in TNF alpha and IL-6 Significant clinical improvement and exercise capacity improvement Adamopoulos S et al. Growth hormone administration reduces circulating proinflammatory cytokines and soluble Fas/soluble Fas ligand system in patients with chronic heart failure secondary to idiopathic dilated cardiomyopathy. Am Heart J 2002 Aug;144(2):359-64

39 Lower IGF-1 = More CV disease Risk of IHD increased 38% for every 40 ng/dl decrease of IGF-1 3 x higher with lowest IGFBP-1 IGF-1 stimulates NO production and increases blood flow Patients with GH deficiency have premature atherosclerosis Laughlin GA et al. The prospective association of serum insulin-like growth factor I (IGF-I) and IGFbinding protein-1 levels with all cause and cardiovascular disease mortality in older adults: the Rancho Bernardo Study. J Clin Endocrinol Metab Jan;89(1):

40 GH/IGF-1 and Immune System Connection between neuroendocrine and immune systems Aging, stress and nutrition effect GH/IGF-1 IGF-1 needed for lymphocyte maturation and function IGF-1 restores age-related thymic involution in rodents IGF-1 restores damaged immune system Decline in T and B cells are restored by GH Clark R. The somatogenic hormones and insulin-like growth factor-1: stimulators of lymphopoiesis and immune function. Endocr Rev Apr;18(2):157-7 Burgess W et al. The immune-endocrine loop during aging: role of growth hormone and insulin-like growth factor-i. Neuroimmunomodulation 1999 Jan-Apr;6(1-2):56-68

41

42 Thymic Involution Control IGF-1 GH IGF-1 + GH

43 AGHD Abnormal Body fat and distribution GH Replacement Increased Lean body mass and Decreased abdominal fat Decreases abdominal fat by up to 50%

44 GH and Body Composition GH deficiency abnormal body composition increase adipose mass and decrease in muscle mass insulin resistance and decreased muscle strength Long term GH replacement normalizes these abnormalities Christiansen, J. Effects of GH upon body composition.. Growth Hormone in Adults, 1996, Cambridge University Press

45

46 GH and obesity GH secretion impaired in obesity IGF-1 and BP s may be normal due to secretion by adiopocytes GH decreases adiposity inhibits lipoprotein lipase enhances lipolysis improves dyslipidemia Nam SY et al. Growth Hormone and Adipocyte Function in Obesity. Horm Res 2000 Jul;53 Suppl S1:87-97

47 Middle age men with low GH and abdominal obesity 9 months of GH treatment 9.5 micrograms/kg/day Decreased fat, abdominal visceral 18% and subcutaneous 6% Improved insulin sensitivity Total Cholesterol, LDL, Triglycerides decreased Diastolic BP decreased Johannsson G et al. GH treatment of abdominally obese men reduces abdominal fat mass, improves glusoce and lipoprotein metabolism and reduces diastolic BP. J Clin Endocinol Metab 1997;82:

48 GH +/- Sex Steroids and Subcutaneous and Visceral Fat HRT = Estraderm + Provera T = Testosterone Enanthate 100 mg q 2 weeks ( Testosterone Lite ) GH = 20 micrograms/kg 3 x a week For 70 kg 20 x 70 = 1400 micrograms =1.4 mg = 4.2 mg = 12.6 IU/week Munzer T et al. Effects of GH and/or sex steroid administration on abdominal subcutaneous and visceral fat in healthy aged women and men. J Clin Endocrinol Metab 2001 Aug;86(8):

49 Percent change in Visceral Fat 14% 16%

50 GH Rx = fat loss and increased HDL Obese men and women, Double blind, placebo controlled Diet and Exercise GH 0.2 to 0.4 in men or 0.6 mg /day in women x 6 months Body weight (from body fat) decreased months and persisted P=.04 No adverse effects on glucose and insulin One drop out due to edema HDL increased 19% in GH group Albert SG et al. Low-dose recombinant human growth hormone as adjuvant therapy to lifestyle modifications in the management of obesity.clin Endocrinol Metab Feb;89(2):

51 GH and Obese postmenopausal women 40 postmenopausal women with abdominal obesity Randomized, double-blind, placebo-controlled, 12-month trial with GH (0.67 mg/d). Improved insulin sensitivity and reduced abdominal visceral fat and total and low-density lipoprotein cholesterol concentrations Franco C et al. Growth hormone treatment reduces abdominal visceral fat in postmenopausal women with abdominal obesity: a 12-month placebo-controlled trial. J Clin Endocrinol Metab Mar;90(3):

52 Complimentary effects of T and GH Sattler F et al. Testosterone Threshold Levels and Lean Tissue Mass Targets Needed to Enhance Skeletal Muscle Strength and Function: The HORMA Trial. J Gerontol A Biol Sci Med Sci Nov 8. Sattler F et al. Testosterone and Growth Hormone Improve Body Composition and Muscle Performance in Older Men. JCEM : March 17

53 AGHD Impaired physical performance GH Replacement Increased exercise capacity Johansson, J. Psychosocial and CNS effects.. Growth Hormone in Adults 1996, Cambridge University Press

54 AGHD Chronic fatigue, depression GH Replacement Sense of well being Improved Quality of Life Gibney et al. The effects of 10 years of GH in adult GH deficient patients J Endocrin Metab 1999 August

55 GH and Quality of Life GH deficient adults GH RT improved Quality of Life Improved (all significant p values) Energy Vitality Anxiety Depression Well-being Self-control Gilchrist FJ et al. The effect of long-term untreated growth hormone deficiency (GHD) and 9 years of GH replacement on the quality of life (QoL) of GHdeficient adults. Clin Endocrinol (Oxf) 2002 Sep;57(3):363-70

56 Does GH cause cancer? Extensive studies of the outcome of GH replacement in childhood cancer survivors show no evidence of an excess of de novo cancers, and more recent surveillance of children and adults treated with GH has revealed no increase in observed cancer risk. Jenkins PJ et al. Does growth hormone cause cancer? Clin Endocrinol (Oxf) Feb;64(2):

57 IGF, BPs and Breast CA IGF-I, IGFBP-1, IGFBP-3, and GH levels were not associated with breast cancer risk Schernhammer ES et al. Insulin-like growth factor-i, its binding proteins (IGFBP-1 and IGFBP-3), and growth hormone and breast cancer risk in The Nurses Health Study II. Endocr Relat Cancer Jun;13(2):

58 Safety of GH and cancer GH treatment of adults with GHD is safe Although there has been some concern about an increased risk of cancer, reviews of existing, wellmaintained databases of treated patients have shown this theoretical risk to be nonexistent Molitch ME. Diagnosis of GH deficiency in adults-- how good do the criteria need to be? J Clin Endocrinol Metab 2002 Feb;87(2):473-6

59 GH Replacement and cancer Tumor recurrence not greater than in patients not on GH No increase in cancer in children on GH replacement No evidence of an increased risk of malignancy, recurrent or de novo. Shalet SM, Brennan BM, Reddingius RE. Growth hormone therapy and malignancy. Horm Res 1997;48 Suppl 4:29-32

60 GH Replacement and cancer risk There is no data to suggest that IGF-1 and IGF BP 3 modulate cancer risk in GH treated patients. Current labeling for GH states that active malignancy is a contraindication There are no data to support this labeling. Current knowledge does not warrant additional warning about cancer risk No evidence that GH increases cancer recurrence or de novo cancer or leukemia Increased risk of cancer in hypopituitary adults Growth Hormone Research Society. J Clin Endo Metab, May 2001

61 GH RT and Brain Tumor Recurrence Children with brain tumors, S/P Cranial Radiotherapy 180 treated with GH 891 not treated with GH In treated patients Decreased risk of recurrence RR Decreased risk of mortality RR Swerdlow A. et al. Growth Hormone Treatment of Children with Brain Tumors and Risk of Tumor Recurrence. The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 12, December 2000

62 GH RT and Brain Tumor Recurrence Brain tumors most common solid neoplasm in children Life expectancy increasing morbidity increasing GH deficiency GH use increased exponentially No increased risk of tumor progression, recurrence or new CNS or non CNS tumor or leukemia Bogarin R et al. Growth hormone treatment and risk of recurrence or progression of brain tumors in children: a review. Childs Nerv Syst Jan 14

63 Irradiation of hypothalamic pituitary axis for a tumor remote from the hypothalamic pituitary axis most common cause of GH deficiency in these patients Recurrence rate was less in all studies RR 0.6 to 0.8 Bogarin R et al. Growth hormone treatment and risk of recurrence or progression of brain tumors in children: a review. Childs Nerv Syst Jan 14

64 Low IGF-1 associated with Prostate Cancer IGF1 lower in Prostate Ca patients than controls: 125 vs. 158 IGF1 higher 6 months after radical prostatectomy: 125 vs. 148 No association of IGF1 and PSA IGF1 decreased with age Baffa R et al. Low serum insulin-like growth factor 1 (IGF-1): a significant association with prostate cancer. Tech Urol 2000 Sep;6(3):

65 IGF and cancer mortality Positive association in men > 50 y/o No association in women No association with all cause mortality No IGF BP3 measurements p =.039 Jacqueline M. Major, Gail A. Laughlin, Donna Kritz-Silverstein, Deborah L. Wingard and Elizabeth Barrett-Connor. Insulin-Like Growth Factor-I and Cancer Mortality in Older Men The Journal of Clinical Endocrinology & Metabolism Vol. 95, No March 2010

66 Anti-cancer effect of GH? GH stimulates glutathione production which decreases NFKB resulting in apoptosis of cancer cells Cherbonnier C et al. Potentiation of tumour apoptosis by human growth hormone via glutathione production and decreased NF-kappaB activity. Br J Cancer Sep 15;89(6):

67 Dx of GH Deficiency Phenotype Clinical Provocation tests L-arginine, GHRH, Insulin Inconsistent, Impractical, Potentially dangerous IGF-1 Optimal range Do not need to chase IGF-1 24 hour urine Ref range (Meridian) pg/24 hrs Optimal range 5000 pg/24 hours

68 Dx AGHD Suspect in Brain Injuries (TBI, SAH, Tumors) Suspect in Cranial Irradiation Suspect in hypopituitarism Normal IGF-I levels do not rule out severe GHD Very low IGF-I levels in patients highly suspected for GHD skip provocative tests Ghigo E et al. Diagnosis of adult GH deficiency. Growth Horm IGF Res Feb;18(1):1-16.

69 Stimulation tests Insulin hypoglycemia dangerous GHRH + L-Arginine GHRH no longer available Mentioned in package insert Explain why you considered stim tests and ruled out use

70 Dx of Adult GHD ITT (Insulin Tolerance Test) is the standard GH < 5 micrograms/l Hypoglycemia from ITT potentially dangerous IGF-1 < 84 96% predictive 1/3 of patients with GHD by ITT have normal IGF-1 Molitch ME. Diagnosis of GH deficiency in adults--how good do the criteria need to be? J Clin Endocrinol Metab 2002 Feb;87(2):473-6 Abs R. Update on the diagnosis of GH deficiency in adults. Eur J Endocrinol Apr;148 Suppl 2:S3-8.

71 Molitch, JCEM 2002 IGF-1 < 84 microgram/l has 96% predictive value of DX of AGHD per stimulation test 3 or 4 other pituitary deficiencies and IGF-1 < 94 sensitivity 100% but specificity of only 30% 1/3 of patients with AGHD by stimulation test have IGF-1 in normal range The stimulated GH levels currently used are somewhat arbitrary I am dubious about using only GH response to a provocative test as the criterion for labeling patients as having GHD

72 IGF-1 for Endocrine dx AGHD Years >60 GHD <74 <85 <74 No GHD Normal IGF-1 does not R/O AGHD Aimaretti G. Usefulness of IGF-1 assay for the diagnosis of GH deficiency in adults. J Endocrinol Invest Sep;21(8):506-11

73 GH testing Variability in GH and IGF-1 testing Biochemical testing should always be interpreted in a clinical context and never serve as stand alone criteria for establishing a diagnosis. Strassberger C et al. How robust are laboratory measures of growth hormone status? Hormone Research 2005; 64:1-5

74 GHD Phenotype Increased truncal and visceral fat Decreased lean mass Osteopenia, glucose intolerance associated with insulin resistance Lipid profile consistent with increased atherogenic risk Decreased exercise capacity Altered cardiac structure and function Diminished quality of life. Frohman LA. Controversy about treatment of growth hormone-deficient adults: a commentary. Ann Intern Med 2002 Aug 6;137(3):202-4

75 Isolated GH deficiency Hypertension Fractures Dyslipidemia Obesity Type 2 Diabetes Poor Quality of Life GH Treatment improved above Abs, R et al. Isolated growth hormone (GH) deficiency in adult patients: baseline clinical characteristics and responses to GH replacement in comparison with hypopituitary patients. A sub-analysis of the KIMS database. Growth Horm IGF Res Oct;15(5):

76 GH Replacement - Side Effects Edema and Arthralgia Related to low frequency high dose schedule Related to giving mg/kg dose instead of gradual increase from low dose Reversible with decrease of dose Vance M. et al. GH Therapy in Adults and Children. NEJM October 14, 1999

77 GH Estrogen, Testosterone Estrogens should be administered by the parenteral route in women and testosterone be replaced in men to optimize the benefits of GH replacement. Ho KK et al. Regulating of growth hormone sensitivity by sex steroids: implications for therapy. Front Horm Res. 2006;35:115-28

78 Female taking oral Estrogen HRT or BCP s No significant IGF-1 increase No significant clinical improvement Changing to transdermal estrogens: improved IGF-1 and clinical effects Less than effects in men

79 T Augments Overnight GH Secretion 100 mg T IM q 2 weeks x 26 weeks Total T increased 33% E2 increased 31% SHBG decreased 17% GH secretion increased 1.9 x IGF-1 increased 22% IGFBP-3 no change Muniyappa R et al. Long-Term Testosterone Supplementation Augments Overnight Growth Hormone Secretion in Healthy Older Men. Am J Physiol Endocrinol Metab. 2007

80 GH RT and Insulin GH RT can increase insulin resistance Patients are not lifestyle compliant with zone diet and resistance and aerobic diet are most susceptible Testosterone RT attenuates this increased insulin resistance in men Insulin resistance can improve as well, especially after 1st month Caution diabetics on Insulin or oral hypoglycemics that that requirements might increase or decrease

81 GH decreases Insulin Resistance (Nam) Obese type II diabetics - 25 kcal/kg IBW diet GH 0.15mg/kg/week For 100 kg pt = 15mg/week = 45 IU/week GH group vs Placebo Group Greater fat loss Greater Visceral fat decrease Increased Lean Body Mass Increased Glucose disposal rate Decreased Insulin in FFA

82 Conclusion Low-dose GH treatment combined with dietary restriction resulted not only in a decrease of visceral fat but also in an increase of muscle mass with a consequent improvement of the insulin resistance observed in obese type 2 diabetic patients. Nam SY et al. Low-dose growth hormone treatment combined with diet restriction decreases insulin resistance by reducing visceral fat and increasing muscle mass in obese type 2 diabetic patients. Int J Obes Relat Metab Disord 2001 Aug;25(8):1101-7

83 GH - Fibromyalgia IGF-1 < 250 Functional GH deficiency mg/day Standard therapy with or without GH Significant improvement of Fibromyalgia parameters Cuatrecasas G et al. Growth hormone as concomitant treatment in severe fibromyalgia associated with low IGF-1 serum levels. BMC Musculoskelet Disord Nov 30

84 Perioperative GH Improved muscle mass, muscle strength, fatigue Accelerated healing Kissrneyer-Nielsen P et al. Perioperative Growth Hormone Treatment and Functional Outcome After Major Abdominal Surgery: A Randomized, Double-blind, Controlled Study. Annals of Surgery, Vol. 229(2) February 1999

85 GH and Burns Randomized prospective study GH (.1-.2 mg/kg/d) in massive burns Improved growth, lean body mass, less scarring and improved resting energy use CONCLUSION: long-term treatment GH enhanced recovery Branski LK et al. Randomized Controlled Trial to Determine the Efficacy of Long- Term Growth Hormone Treatment in Severely Burned Children., Ann Surg Sep 2

86 GH and Brain Injury GH deficiency, is common among survivors of traumatic brain injury (TBI) tested several months or years following head trauma. Moderate-to severe head trauma or mild trauma Onset can evolve over years following injury. Assessment of the GH-IGF axis IGF-I, plus dynamic GH testing is indicated. Popovic V et al. Hypopituitarism following traumatic brain injury. Growth Horm IGF Res Jun;15(3):

87 Some degree of hypopituitarism is found in 35-40% of TBI patients Untreated TBI induced hypopituitarism contributes to the chronic neurobehavioral problems seen in many head-injured patients Subjects treated with GH experience significant improvements in concentration, memory, depression, anxiety and fatigue. Pituitary failure can occur even in minor head injuries and is poorly recognized.

88 TBI and SAH high risk for hypo-pit 1/3 to ½ have anterior pit. abnormalities GH/IGF in 15-20% Sx may mimic brain trauma May be psych sx Increase morbidity and mortality Urban RJ et al. Anterior hypopituitarism following traumatic brain injury. Brain Inj May;19(5):

89 Appropriate hormone replacement therapy for those patients with both TBI and TBI-induced pituitary function impairment could, for the first time, allow treatment and correction of underlying causes of TBI sequelae rather than merely symptomatic treatment.

90 Current GH Controversy Can Dx of AGHD be made without a stimulation test on the basis of clinical picture and IGF-1? Endocrine literature supports this idea Molitch ME. Diagnosis of GH deficiency in adults-- how good do the criteria need to be? J Clin Endocrinol Metab 2002 Feb;87(2):473-6 Savine R. Growth hormone replacement for the somatopause. Horm Res 2000;53 Suppl 3:37-41Savine R. et al.

91 GH OTC Secretagogues OTC Products Some may work to a limited extent No published evidence in peer reviewed medical literature Proprietary unpublished studies can claim increase in IGF-1 Do not contain significant amounts of GH GH is Prescription Drug and cannot be sold OTC Large molecule (191 AA) not bioavailable orally

92 Secretagogue True GH Secretagogues exist. (but we can t get them yet) Growth Hormone Releasing Peptides Hexarelin Ipamorelin Hypothalamic and Pituitary action Johansen et al. Ipamorelin a new ghrp induces longitudinal bone growth in rats. GH and IGF Research 1999, Ghrelin secreted by the stomach Endogenous ligand for GHRP receptor Powerful orexigenic agent Wren AM et al. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion, Endocrinology 2000 Nov;141(11):4325-8

93 Oral L-Arginine 5 g No Increase in GH Young or old Resting or exercise Marcell TJ et al. Oral arginine does not stimulate basal or augment exercise-induced GH secretion in either young or old adults. Gerontol A Biol Sci Med Sci 1999 Aug; 54(8) :M395-9

94 GH and oral Arginine 5, 9, or 13 grams PO At 60 min up to 100% increase in GH Limited by GI side effects Collier SR et al. Growth hormone responses to varying doses of oral arginine. Growth Horm IGF Res Apr;15(2):136-9.

95 GH and stem cells Improves quality and quantity of adult stem cells and endothelial progenitor cells

96 GH, NO, EPC CV disease = low NO bioavailablity and Decreased EPC s Healthy middle aged adults Rxed with GH Diastolic BP Decreased NO increased Increased circulating EPC s Thum T et al. Growth hormone treatment improves markers of systemic nitric oxide bioavailability via insulin-like growth factor-1. J Clin Endocrinol Metab Aug 28

97 IGF-1 and cardiac stem cells IGF-1 prevents cardiac stem cell senescense and prevents aging cardiomyopathy Torella D et al. Cardiac stem cell and myocyte aging, heart failure, and insulinlike growth factor-1 overexpression. Circ Res Mar 5;94(4):514-24

98 GH RT Algorithm Possible plan Everything in this field is controversial Many different approaches Work in Progress Changes are continuously necessary Women need higher doses than men for same IGF-1 and clinical results Average male dose 0.4 mg/day Average female dose 0.6 mg/day

99 Time: First thing in the morning or before bed. Avoid using when Insulin high after meals Frequency: single dose daily, no big deal if occasional doses are missed, BID might be slightly better Ramp up doses mg x 3 = IU Take it easy with insulin resistance, maybe start Testosterone first in men How long to continue: forever until something better comes along

100 Arguments against GH RT Cost Increased Insulin Resistance Side effects Not long enough studies Other ways to achieve same benefits Isley WL. Growth hormone therapy for adults: not ready for prime time? Ann Intern Med 2002 Aug 6;137(3):190-6

101 Arguments for GH RT Safe Less Morbidity and Mortality - CV Disease Body Composition: Bone, Muscle, Fat, Visceral Fat Less Inflammation Better QoL Less Sick Days Improved Exercise Capacity Cook DM. Shouldn't adults with growth hormone deficiency be offered growth hormone replacement therapy? Ann Intern Med 2002 Aug 6;137(3):

102 Peter H Sonksen 1998, 8, Growth hormone is essential for normal adult life, and without it life expectancy is shortened, energy and vitality reduced and the quality of this life is impaired. The medical case for GH replacement is now proven beyond any reasonable medical and scientific doubt.

103 Adult Growth Hormone Deficiency Is pt > 40 y/o? YES Suspect AGHD NO YES Get Baseline IGF check yearly NO Get baseline IGF, consider stim test YES Is IGF in youthful range? ng/ml? Stim test positive? NO YES No GHRT YES YES NO Consider other rx testosterone,diet exercise, Consider AGHD with nl IGF- ie obesity GHRT Evaluate other hormones?ghrt

104

105 Adult Growth Hormone Deficiency -3- IGF in youthful range YES 0.4 mg tolerated in 12 weeks? NO Decrease dose to 0.2 mg YES NO Keep dose at 0.4 mg Too high >500 Too Low <250 Decrease dose to 0.2 mg Increase dose to 0.6 mg In 3 months Titrate dose Range mg Average 0.4 male Average 0.6 female Side effects Glucose Insulin q 3months 1st year q 6 months 2nd year

106 Adult Growth Hormone Deficiency -4- Side Effects? Edema Arthralgia Decrease dose Low dose diuretics Decrease dose Anti-inflammatory Resolved? Resolved? YES NO YES NO Continue lower dose D/C diuretics Consider inc dose after 1 month Continue low dose D/C anti-inflammatories D/C GH Consider lower dose after 1 month D/C GH Consider lower dose after 1 month

107 Adult Growth Hormone Deficiency -5- Paresthesias Side effects? Glucose Intolerance Hyperglycemia? Increased serum Insulin? mild? severe? Strict diet limiting high glycemic index carbs Exercise:Resistance and Aerobic Cont GH Decrease dose if patient distressed Hold GH 1 week Decrease dose Treat men with testosterone for free T in young range if no contraindication Resolved? Decrease dose YES NO Cont low dose Consider increase in 1 month D/C GH Consider lower dose after 1 month YES Resolved? NO Cont lower dose Consider increase after 1-2 months D/C GH Consider restart Lifestyle change Testosterone RX