Disclosures Adult Growth Hormone Deficiency (GHD) PI of research grants to Massachusetts General Hospital from: Novo Nordisk Opko Versartis Beverly MK Biller MD, FACP Occasional consultant to: Novo Nordisk Professor of Medicine Pfizer Harvard Medical School Versartis Neuroendocrine Clinical Center Massachusetts General Hospital Boston, MA Case Newspaper: USA TODAY • 43 year old man - surgery, radiation for benign pituitary tumor • Panhypopituitary on triple hormone replacement (thyroid, cortisol, testosterone); otherwise healthy • Read about GHD in a well-known publication: “ sounds just like me, especially the excess abdominal fat ” • Worried about his risk of cardiovascular disease and osteoporosis with a strong family history of both • Asked endocrinologist for treatment with GH What journal had he read?
GH studied in adults with: • Aging (“somatopause”) • Cardiomyopathy • Catabolic states – Respiratory failure – Burns – AIDS wasting * • Short bowel syndrome * Illicit use by athletes • GH deficiency * – Childhood onset (CO) Bodybuilding – Adult onset (AO) Baseball Olympics * FDA approved uses Hypopituitarism in patients with traumatic Causes of Adult GHD brain injury and subarachnoid hemorrhage • Tumors • Infiltrative/infectious/inflammatory – Pituitary tumors – Hypophysitis Patients evaluated 3m after the event – Craniopharyngioma – Sarcoidosis – Meningioma – Histiocytosis X – Rathke’s cleft cyst – Tb and fungal diseases – Germinoma – Others – Others • Trauma/vascular injury • Surgery – Head trauma – Transsphenoidal – Apoplexy – Craniotomy – Sheehan syndrome • Cranial radiation RT • Other – Brain, head/neck tumors – Childhood onset n=100 n=40 • Idiopathic – Pituitary or whole-brain RT • Organic Adapted from Cook DM Growth Horm IGF Res 1999 Aimaretti Clin Endo 2004 61: 320
Percentage of specific pituitary deficits Adult GHD - Clinical Features following TBI and SAH • Body composition altered – Fat mass increased – Lean body mass decreased – Skeletal muscle strength decreased • Cardiovascular (CV) issues – Increased risk of CV death – Lipids abnormal – Other CV markers abnormal • Bone mineral density decreased • Quality of life diminished Chronic trauma a risk as well Retired boxers He was most worried about fat, cardiovascular risk & bone; let’s discuss those 1 st Ask about CNS events Aimaretti Clin Endo 2004 61: 320 Cardiovascular Deaths in Hypopituitarism Increased cardiovascular (CV) mortality in adult GHD 60 observed Possible Mechanisms 50 • Abnl body composition (high waist/fat, visceral fat) Number 40 • Lipid abnormalities of expected 30 • Decreased QOL: low motivation, less exercise Deaths • Decreased fibrinolytic activity 20 • Increased number of arterial plaques 10 • Increased intima-media thickness 0 • Endothelial cell dysfunction 0 10 20 30 40 • Altered inflammatory process Years After Diagnosis Rosen Lancet
BODY Severity of GHD: Before GH COMPOSITION Clinical implications: Body composition by CT Subcutaneous fat Visceral fat Lean mass Very severe: GH peak lowest in severe GHD < 3 on Arg-GHRH test * Fat mass highest in severe GHD Normals * 6 months on GH Decreased fat: - subcutaneous * p<0.05 vs. all - visceral other groups Bengtson JCEM Colao JCEM Regional decreases in adipose tissue Studies all show decreased body fat on GH replacement with 6m of GH replacement Head/ Trunk 1 Legs (SC) Viscera Arms neck 0 0 -1 Percent Change -10 -2 Fat -3 (% ) -4 -20 -5 -6 -30 -7 Salomon Bengtsson Weaver Johannsson n= 24 N= 10 N= 22 N= 68 -40 Whitehead Hansen Baum Attanasio N= 14 N= 29 N= 32 N= 173 Newman Endocrinologist Bengtsson JCEM
With GH replacement Increased cardiovascular (CV) mortality in adult GHD fat mass decreases , lean mass increases Body composition benefit requires continued GH replacement Possible Mechanisms Body fat Lean mass • Abnl body composition (high waist/fat, visceral fat) 1 4 GH • Lipid abnormalities Placebo 0 period period • Decreased QOL: low motivation, less exercise 3 -1 Percent • Decreased fibrinolytic activity Kg -2 2 • Increased number of arterial plaques GH -3 Placebo • Increased intima-media thickness period 1 period -4 • Endothelial cell dysfunction -5 0 • Altered inflammatory process 0 6 12 18 24 30 36 0 6 12 18 24 30 36 Months Months Biller JCEM Carotid artery intima media thickness: Increased cardiovascular (CV) mortality in adult GHD Decreased during GH replacement Controls Possible Mechanisms Intima media thickness (mm) Pre-GH Tx 0.70 • Abnl body composition (high waist/fat, visceral fat) GH replacement • Lipid abnormalities 0.65 * N = 11 • Decreased QOL: low motivation, less exercise * * 0.60 * p < 0.001 vs. controls • Decreased fibrinolytic activity * * p < 0.01 vs. controls • Increased number of arterial plaques 0.55 • Increased intima-media thickness 0.50 • Endothelial cell dysfunction • Altered inflammatory process 0.45 Controls Pretreatment 3 mo 6 mo 12 mo 18 mo GHD Pfeifer JCEM
Increased cardiovascular (CV) mortality in adult GHD • Atherosclerosis: chronic inflammatory condition 4 th Quartile: • Markers of inflammation predict CV risk 3 fold C-Reactive Protein (CRP) increased risk - acute phase reactant of MI, 2 fold - highest quartile predictive of vascular events increased risk (Ridker NEJM, Circulation) of CVA - Physicians health study: 3 fold MI, 2 fold CVA - Women’s health study: 5.5 fold MI Mean CRP in GHD patients pre-tx at 4 th quartile in nls � increased risk of CV events GHD mean shifted down one quartile on replacement Sesmilo Ann Int Med 2000 Sesmilo Ann Int Med 2000
Adult GH replacement Adult GHD - Clinical Features Summary of cardiovascular (CV) risk markers • GH replacement in GHD reduces markers of CV risk • Body composition altered – Fat mass increased - Visceral fat – Lean body mass decreased - Carotid intima-media thickness – Skeletal muscle strength decreased - Serum Markers of CV risk • Cardiovascular (CV) issues - CRP – Increased risk of CV death - Interleukin-6 – Lipids abnormal - Serum Amyloid A (borderline) – Other CV markers abnormal - Homocysteine - Tissue plasminogen activator - Lipids (not all studies) • Bone mineral density decreased • Long term prospective studies of CV mortality are needed Severity of GHD: GH effects on bone in adults Clinical implications: Bone Density IGF-1 2.5 2.5 GH Femoral Neck Lumbar Spine IGF-1 1.5 1.5 Lowest t-scores in very severe GHD t score GH IGF-1 0.5 0.5 -0.5 -0.5 • Bone cells have receptors for GH and IGF-1 -1.5 -1.5 * * * * • GH and IGF-1 stimulate cell division in bone growth plates in vitro * -2.5 * -2.5 Very Severe Partial Non Controls Very Severe Partial Non Controls • In vivo data show that GH stimulates bone growth severe GHD GHD GHD severe GHD GHD GHD GHD GHD • GHD is associated with low bone density (< 3mcg/ L ARG-GHRH) *p<0.001 very severe vs. partial, non-GHD, and controls **p<0.05 severe vs. very severe and controls Colao JCEM
Lumbar spine BMD Fracture Frequency in GHD Multicenter study in 67 patients with GHD Double-blind, placebo-controlled vs daily GH for 2 years Odds ratio for a fracture = 3.49 30 (1.85-6.56, 95% confidence interval; 5 * ‡ * Fracture Frequency (%) U Penn, MGH, Brown, *P <0.001) ‡ * Case Western, Mayo, 25 % change from baseline Men 4 Oregon, St. Louis U GH 20 3 ‡ 2 15 1 10 PL ‡ p < 0.05, within group 0 change from baseline 5 -1 * p<0.05 for comparison of change from baseline, 0 GH vs PL -2 GH Deficiency Normals 0 6 12 18 24 Duration of treatment (months) Rosen Eur J Endocrinol Snyder JBMR Adult GH replacement Adult GHD - Clinical Features Summary of bone and bone marker results • Body composition altered • Increased bone turnover (formation and resorption) – Fat mass increased – Lean body mass decreased – Skeletal muscle strength decreased • BMD very consistently increased in longer studies – ~5% in lumbar spine at 2 years, 10% at 5 years • Cardiovascular (CV) issues – ~2.5% in femoral neck – Increased risk of CV death – No change in proximal radius – Lipids abnormal – Other CV markers abnormal • Remaining questions – Gender difference, women show less response • Bone mineral density decreased – Combination with other drug, further ↑ with bisphosphonates – Fracture rates • Quality of life diminished
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