High and Low GH: an update of diagnosis and management of GH disorders

Transcription

1 High and Low GH: an update of diagnosis and management of GH disorders Georgia Chapter-AACE 2017 Laurence Katznelson, MD Professor of Medicine and Neurosurgery Associate Dean of Graduate Medical Education Stanford University School of Medicine Stanford, California

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3 Acromegaly

4 J Clin Endocrinol Metab 99: , 2014

5 Case 35-yo male presents with 4 mo headaches. Has a 12 yo son. Has diffuse joint aches and fatigue. 4 months of snoring. Several years of tingling in his hands. No medications. BP 160/94. Slightly enlarged thyroid gland without nodules Broadening of nose and increased teeth spacing Positive Tinel s sign bilaterally Hands and feet were thick and multiple skin tags were noted visual fields: bilateral quadrantanopsia

6 Diagnosis We recommend measurement of IGF-1 levels in patients with typical clinical manifestations of acromegaly. We recommend against relying on the use of random GH levels to diagnose acromegaly. In patients with elevated or equivocal serum IGF-1 levels, we recommend confirmation of the diagnosis by finding lack of suppression of GH to < 1 ng/ml following documented hyperglycemia during an oral glucose load.

7 Diagnosis, contd. Following biochemical diagnosisof acromegaly, we recommend performingan imaging study (MRI preferable)to visualize tumor size and appearance, as well as parasellarextent.

8 Approach to co-morbidities We suggest screening for colon neoplasiawith colonoscopy at diagnosis. We suggest a thyroid ultrasound if there is palpable thyroid nodularity Cardiac evaluation if there are signs and symptoms Did not recommend routine ECG or ECHO

9 Acromegaly Confirmed : Serum IGF-1 = 980 ng/ml (nl< 240) Serum Prolactin = 48 ng/dl Remaining pituitary function intact What should be the initial management? 1) Dopamine agonist 2) Somatostatin analog 3) Pegvisomant 4) Transsphenoidal Surgery 5) Stereotactic radiotherapy

10 Therapy Transsphenoidal surgery recommended as the primary therapy in most patients. We suggest againstthe routine use of preoperative medical therapy to improve biochemical control after surgery. For patients with severe pharyngeal thickness and sleep apnea, or high output heart failure, we suggest medical therapy preoperatively to reduce surgical risk. In a patient with parasellardisease makingtotalsurgical resection unlikely, we suggest surgical debulkingto improve subsequent response to medical therapy.

11 Surgery: Post Operative Assessment Following surgery, Measure IGF-1 levels and a random GH 12 weeks or later. We also suggest measuring a nadir GH level after a glucose load in a patient with a GH greater than 1 mcg/l.

12 Post op 3 months Post operative serum IGF-1 = 2.5XULN Symptoms of sweating improved but still present Remaining pituitary function intact What would be your next step? A. Re-operation B. Fractionated Radiotherapy C. Stereotactic radiotherapy D. Dopamine agonist E. Somatostatin analog (SRL) F. Pegvisomant

13 Somatostatin Analogs Directly inhibit GH Medical Therapy Targets of the GH/IGF-I Pathway Octreotide, lanreotide, pasireotide Dopamine Agonists D 2 receptor Directly inhibit GH Cabergoline, bromocriptine GHR Antagonist Targets tissues Directly inhibits IGF-I secretion Pegvisomant IGF-I GH-Secreting Tumor Somatostatin SSA DA Agonist X GH X GH GHRH + Increased Somatic Growth & Metabolic Dysfunction GHR Antagonist

14 Next steps Repeat Surgery In this case, repeat surgery would not be curative Medical Therapy Radiation Therapy

15 Somatostatin Receptor Ligands (SRLs) Initial reports suggested IGF-1 normalization in 60% Preselected subjects? Patient heterogeneity Differences in protocol length IGF-1 normalization achieved by a SRL in both drug-naive and postoperative patients is approximately 17 35% Mercado et al. Clin Endo (2007);66:859 Colao et al. JCEM (2014);99:791

16 Pasireotide versus Octreotide in Acromegaly: A Headto-Head Superior Study JCEM (2014);99:791 Proportion of patients with GH <2.5 μg/l and normal IGF-1 after 12 months of treatment with pasireotide LAR or octreotide LAR Adverse Event: Hyperglycemia 57% pasireotide 22% octreotide

17 40 mg pasireotide LAR q 28 days, 60 mg pasireotide LAR q 28d, or continued treatment with octreotide or lanreotide (active control) for 24 wk. 40 mg pas (25%) 60 mg pas (26%) Control (0%)

18 Van der lelyet al. JCEM (2012);97:1589 Acrostudy n = 1288 were treated with pegvisomant for a mean of 3.7 After 5 yr, 63.2%of subjects had normal IGF-I levels at a mean dose of 18 mg/d. Pegvisomant

19 Combination Medical Therapy Given an incomplete reduction in serum IGF-1 with Octreotide LAR, it is very reasonable to combine Octreotide LAR with pegvisomantfor improved control. Can use pegvisomantin weekly or twice a week dosing Potentially result in lower dose of Octreotide LAR and possibly lower overall costs Cabergoline?

20 Growth Hormone Deficiency

21 Case 48 yo male 1 year following TSS for nonfunctioning pituitary macroadenoma Normal pituitary function Fatigued, and notes increase in abdominal girth Reduced short term memory, attention span IGF-1 82 ng/dl

22 GH/IGF-I mediated effects Brain Liver Hypothalamus GHRH SMS + _ GH Anterior pituitary IGF-1 (Insulin-like Growth Factor-1) Somatic, Metabolic Effects

23 GH Levels in Young and Elderly 10 Young women Young men GH (µg/l) Elderly women Elderly men Time (h) Russell-Aulet M, et al. J Gerontol A Biol Sci Med Sci

24 Serum IGF-I in GH-Deficient Patients Men (n = 81) Women (n = 71) IGF-I (µg/l) Age (years) Hilding A, et al. J Clin Endocrinol Metab

25 Case With low IGF-1: GH deficiency? Need further testing?

26 Adult onset Growth Hormone Deficiency Endocrine Society Guidelines JCEM, June 2011, 96(6):1587 Insulin Tolerance Test Glucagon stim test: mechanism of action unknown. Relative hypoglycemia, with initial increase then decrease? induction of norepinephrine secretion in stimulating GH and ACTH release via α-receptors

27 Comparison of peak GH levels during ITT and GST. Individual values during ITT (circles) and GST (squares) are demonstrated. Correlates well with ITT, though peak GH values lower and approximately 14% discordance with ITT Berg C et al. Eur J Endocrinol 2010;162:

28 Dichtel et al, JCEM (2014),99: pituitary disease, 47 controls: all BMI >25 GST GH cutoff 1 ng/ml GH cutoff 3 ng/ml % subjects reclassified as GH sufficient using GH 1 cutoff Need lower GH cutoff for overweight subjects

29 Glucagon stimulation testing (GST): Recent updates Until a potent, safe and reliable test becomes available, the GST should remain as the alternative to the ITT in the United States. To reduce over-diagnosing adult GHD in overweight/obese patients with the GST, propose utilizing a lower GH cut-point of 1 ng/ml. Need to incorporate BMI and degrees of glucose tolerance. Yuen et al. Endo Pract (2016)

30 Predictors of GHD Hartman et al, JCEM (2002);87:477 Presence of either: three or four axis deficiencies, or serum IGF-I less than 84 μg/liter (11 nmol/liter) yielded a positive predictive value for adult GHD of 95%.

31 Percentage of Single Pituitary Deficits in Patients With TBI (100) and SAH (40), 3 Months After the Event Percentage Secondary Hypoadrenalism Secondary Hypothyroidism Secondary Hypogonadism Severe GHD Does the hypopituitarism improve or worsen during convalescence? Impact of hypopituitarism on convalescence in patients with TBI? Is there a role for GH therapy? Aimaretti, G. et al., Clin Endocrinol 2004;61:320-6.

32 Benefits of GH Treatment Quality of Life Improvements in sense of well being + Hypothalamus Somatostatin GHRH Pituitary Bone Metabolism Attainment of peak bone mass Linear Growth Catch-up growth Normalized adult height Growth Hormone Adipose Tissue Reduction in visceral fat Muscle Increase in lean body mass Allen DB. In: Lifshitz F, ed. Pediatric Endocrinology. 4th ed

33 Case Glucagon stimulation test performed: Peak GH 0.8 ng/ml GHD

34 GH Dosing Considerations in Adults Low dose ( mg/day) to start Monthly titration based on clinical and IGF-1 response Serum glucose and HgA 1c Age-appropriate cancer screening Periodic pituitary MRI in patients with prior pituitary tumor Higher doses for premenopausal women or women taking oral estrogen Monitor thyroid and adrenal function Growth Hormone Research Society. J Clin Endocrinol Metab 1998;83: