Update on Growth Hormone Testing and Management

Transcription

1 American Association of Clinical Endocrinologists 27 th Annual Scientific and Clinical Congress Boston, MA Friday, May 18, 2018 Update on Growth Hormone Testing and Management Kevin C.J. Yuen, MD, FRCP(UK), FACE Professor of Medicine and Medical Director Barrow Neurological Institute Pituitary Center University of Arizona College of Medicine Phoenix, AZ 85013

2 Disclosures Received research grants from Pfizer, Novo Nordisk, Versartis, OPKO Biologics, and Aerterna Zentaris Served on the advisory boards for Pfizer, Novo Nordisk, Sandoz, Versartis and Aerterna Zentaris

3 Outline Clinical features of adult GHD Diagnosis and testing for adult GHD Current approaches of managing adult GHD New developments

4 WHAT IS ADULT GH DEFICIENCY AND WHY TREAT?

5 Features of adult GHD Decreased lean body mass Bone mineral density Physical performance Central fat deposition Glucose intolerance Dyslipidemia Psychosocial issues Low self-esteem Depression Mental fatigue Poor memory Impaired cognition Social isolation Dissatisfaction with body image Cardiac capacity Intima-media thickness Cummings DE, et al. Ann Rev Med. 2003;54:

6 Effects of GH replacement in adults with GHD: body composition, lipids, BP and glucose A meta-analysis of blinded, randomized, placebo-controlled trials Maison P, et al. J Clin Endocrinol Metab May;89(5):

7 Effects of GH replacement in adults with GHD: bone mineral density Johannsson G, et al. J Clin Endocrinol Metab Aug;81(8):

8 Effects of GH replacement in adults with GHD: exercise capacity Chikani V, et al. Clin Endocrinol 2016 Oct;85(4):660-8

9 Effects of GH replacement in adults with GHD: QoL and sick day leave Time (months) Sick leave (days/6 months) Baseline 12.2 ± ± ± ± ± 2.5 Elbornsson M, et al. Eur J Endocrinol 2017;176: Verhelst J, et al. Clin Endocrinol (Oxf) 1997 Oct;47:

10 Effects of GH replacement in adults with GHD: partner s response to health questionnaire Burman et al. J Clin Endocrinol Metab.80: ,1995.

11 Life expectancy in adults with NFPA receiving GH replacement therapy Olsson DS, et al. Eur J Endocrinol Jan;176(1):67-75

12 WHO SHOULD WE TEST FOR ADULT GHD? Patients with signs and symptoms of hypothalamic-pituitary disease plus confirmation of endocrine, structural and/or genetic cause

13 Causes of adult GHD Congenital Genetic Transcription factor defects: POU1F1, PROP-1, LHX3/4, HESX-1, PITX-2 GHRH receptor gene defects GH gene defects GH receptor/post receptor defects Associated with structural brain defects Septo-optic dysplasia Empty sella syndrome Encephalocele Hydrocephalus Arachnoid cyst Associated with midline facial defects Single central incisor Cleft lip/palate Acquired Traumatic brain injury Hypothalamic/pituitary tumors Pituitary adenoma (micro- and macro-) Craniopharyngioma Rathke s cleft cyst Glioma/astrocytoma Germinoma Metastatic tumor Infiltrative/granulomatous diseases Sarcoidosis/tuberculosis Langerhans cell histiocytosis Lymphocytic hypophysitis Miscellanoeus Post-surgery CNS infections Severe blood loss/stroke/sah Irradiation (cranial or whole body) Idiopathic Adapted from Molitch M, et al. J Clin Endocrinol Metab 2011;96(6):

14 HOW DO WE TEST FOR ADULT GHD? Serum IGF-I level/s One or two GH stimulation tests

15 Pulsatile pattern of 24-hr GH secretion in a 30 y/o vs 60 y/o adult 25 Sleep 20 GH (µg/l) Clock time

16 Serum IGF-I levels throughout life Men (n = 81) Women (n = 71) IGF-I ( g/l) Age (years) Hilding A, et al. J Clin Endocrinol Metab. 1999; 84(6):

17 Examples of low IGF-I that may not be caused by GHD Malnutrition Poorly controlled diabetes Untreated hypothyroidism Kidney failure Liver disease Fibromyalgia Assay variability

18 Review of current consensus guidelines on diagnosis and treatment of adult GHD Pts to be re-tested Pts not requiring testing GRS 2007 AACE 2009 Endo Society Idiopathic GHD - TBI/SAH - Congenital anomalies - Previous surgery/dxt - Proven genetic disease - 3 or more pituitary hormone deficits & low IGF-I Hypothalamic GHD - Pts with irreversible hypothalamic-pituitary structural lesion - 3 or more pituitary hormone deficits & low IGF-I Idiopathic GHD - Pts with structural hypothalamic-pituitary lesions and multiple pituitary hormone deficits - Proven genetic disease Time interval for pts to be retested GH stimulation test 1 st choice Alternatives > 1 mth for transition pts > 1 mth for transition pts > 12 mths in TBI/SAH pts -ITT - GHRH + ARG - Glucagon - GHRH + GHRP -ITT - GHRH + ARG - Glucagon - Arginine > 1 mth for transition pts -ITT - GHRH + ARG - Glucagon GH dosing Titrate to IGF-I Titrate to IGF-I Titrate to IGF-I

19 GH DOSING STRATEGIES

20 Recommendations for starting GH doses in adults with GHD Age < 30 years: mg/day Age years: mg/day Age >60 years: mg/day * Use lower GH doses ( mg/day) in patients with diabetes or who are susceptible to glucose intolerance Cook DM, Yuen KC, et al. on behalf of AACE CPG Endocr Pract 2009; 15(suppl 2):1-29

21 Case 1: 26-year old woman with GHD due to NFA Status GH dose/day IGF-I (RR: ) On OCP 2.0 mg 210 ng/ml Stop OCP 2.0 mg 610 ng/ml 6 mths after stopping 1.0 mg 328 ng/ml 12 mths after stopping 0.8 mg 294 ng/ml

22 Women on oral estrogen require higher doses of GH to normalize their IGF-I levels * P < 0.05 by ANOVA 100% 70% Cook DM, et al. J Clin Endocrinol Metab 1999; 84(11):

23 How do we adjust the GH dose when patient is on oral estrogen and when oral estrogen is stopped? General rule: Start or reduce the GH dose by ~ 50% for oral estrogen users Start or reduce the GH dose by ~ 30% in transdermal estrogen users Cook DM, Yuen KC, et al. on behalf of AACE CPG Endocr Pract 2009; 15(suppl 2):1-29

24 Case 2: 36-year old woman with Sheehan syndrome (1) Gestational diabetes 5 yrs ago Gradual weight gain Increasing fatigue and scanty menses Peak GH after ITT 1.8 ng/ml IGF-I 103 ng/ml (RR: ng/ml)

25 Case 2: 36-year old woman with Sheehan syndrome (2) Date Weight (lbs) Fasting glucose (mg/dl) HbA1c (%) IGF-I (ng/ml) GH dose (mg/day) 3/5/ /2/ /5/

26 High GH dose (mean dose 6.7 µg/kg/day) impairs insulin sensitivity and postload glucose tolerance OGTT (mean + SEM) Top: Glucose v time Middle: Insulin v time Bottom: C-peptide v time Before GH After GH Rosenfalck, et al. J Clin Endocrinol Metab 2000; 85:

27 Effects of low dose GH therapy in GHD adults: Insulin sensitivity (clamp studies) 8 P < 0.02 Baseline Month 12 M-value (mg/kg/min) Low dose (0.1 mg/day) Std dose (0.5 mg/day) Untreated controls Yuen KCJ, et al. Clin Endocrinol (Oxf) 2005; 63(4):

28 Effects of low dose GH therapy in GHD adults: Bioactive IGF-I 1.2 p < 0.01 Baseline Month 12 Bioactive IGF-I (ng/ml) p < Low dose (0.1 mg/day) Std dose (0.5 mg/day) Untreated controls Yuen KCJ, et al. Clin Endocrinol (Oxf) 2005; 63(4):

29 Recommendations for glucose control during GH therapy Encourage weight reduction Start with low GH doses initially GH dose reduction Anticipate glucose problems if patient is: - overweight/obese - previous Hx of gestational diabetes Adjust or add anti-diabetic medications Cook DM, Yuen KC, et al. on behalf of AACE CPG Endocr Pract 2009; 15(suppl 2):1-29

30 Case 3: 62-year old woman with hypopituitarism (1) Non-functioning macroadenoma, TSS in 2016 On Levothyroxine 75 mcg/day and Hydrocortisone 10 mg/day Started on low dose GH therapy (0.2 mg/day) as fasting glucose levels were 115 mg/dl Since starting GH therapy, feeling more tired especially in the evenings

31 Case 3: 62-year old woman with hypopituitarism (2) Admitted to the ER with nausea, and lightheadedness AM cortisol 5.8 µg/dl (RR: 8-23 µg/dl) and free T4 1.1 ng/dl (RR ng/dl) Treated with IV fluids and IV Hydrocortisone Dose of PO Hydrocortisone increased to 20 mg daily (15/5) and Levothyroxine to 100 mcg/day, while GH dose kept at 0.3 mg/day Symptomatically much better

32 Cortisol metabolism regulated by 11βHSD 1 and 2 Seckle et al. Endocrinology.142: ,2002.

33 GH inhibits 11βHSD1 activity at low doses in hypopituitary patients Ratio of urine cortisol to cortisone metabolites (Fm/Em) * * * P < 0.05 vs. baseline * 0 Baseline GH dose 0.17 mg/d GH dose 0.33 mg/d GH dose 0.50 mg/d Toogood et al. J Clin Endocrinol Metab 2000;85(4):

34 Alteration in circulating thyroid hormones during GH replacement Glynn et al. Clin Endocrinol (Oxf) 2017 May;86(5): Behan et al. Clin Endocrinol (Oxf) 2011 Mar;74(3):

35 Use of IGF-I as a biomarker for GH dosing Aim for IGF-I within the mid- to upper half of normal range for age and gender, unless side-effects prohibit Do not use IGF-I as the only determinant; also consider body composition, glucose, lipids and QoL changes Be aware of differences and changes in IGF-I assays

36 Factors that can affect GH dosing dose dose Suboptimal IGF-I levels Addition of estrogen Change from TD to PO estrogen To increase lipolysis Ongoing impaired QoL Elevated IGF-I levels Discontinuation of estrogen Change from PO to TD estrogen Pregnancy and elderly Side-effects (e.g., muscle and joint pains) Consider increasing glucocorticoid (especially when doses are small) and thyroid hormone doses

37 NEW DEVELOPMENTS

38 A) Lower GH cut-point for the GST ROC curve analysis to determine the cut-off peak GH response during the GST Gomez, et al. Clin Endocrinol (Oxf) 2002;56:

39 Recent GST studies suggesting the effects of central adiposity and glucose intolerance in decreasing peak GH levels (1) Yuen et al. Pituitary 2013 Jun;16: Retrospective, 5 center experience of 515 GSTs - BMI, and glucose tolerance inversely correlated with peak GH Dichtel et al. J Clin Endocrinol Metab 2014 Dec;19: Retrospective, 2-center, cross-sectional study - ~50% healthy overweight/obese individuals failed the GST using the GH cutpoint of 3 g/l - GH cut-point of 0.94 g/l provided 90% sensitivity and 94% specificity

40 Recent GST studies suggesting the effects of central adiposity and glucose intolerance in decreasing peak GH levels (2) Diri et al. Pituitary 2015 Dec;18: Retrospective, single-center study - Using a cut-point of 3.0 g/l, 46.2 % failed the GST, but using the GH cut-point of 1.07 g/l, none of the healthy controls failed the GST Wilson et al. Growth Horm IGF Res 2016 Feb;26: Retrospective, single-center study - Obese patients, particularly females, had lower GH AUCs and higher nadir BGs during GST compared with non-obese patients Hamrahian et al. Pituitary 2016 Jun;19: Prospective, multi-center study - GH cut-point of 1.0 g/l provided 92% sensitivity and 100% specificity

41 ENDOCRINE PRACTICE Vol 22 No. 10 October 2016 To reduce the possibility of over-diagnosing adult GHD in overweight/obese patients with the GST, a lower GH cut-point of 1 g/l should be considered

42 B) Oral Macimorelin GH test Diagnostic accuracy comparable to the GHRH-arginine test for the diagnosis of adult GHD Garcia JR, et al J Clin Endocrinol Metab 2013, 98,

43 Oral Macimorelin GH test Validation Phase 3 study comparing with the ITT for the diagnosis of adult GHD Obtained FDA approval on December 20, 2017 Greater pituitary GH secretion than the ITT Sensitivity (87%) and specificity (96%) with cut-point of 2.8 g/l vs ITT cutpoint of 5.1 g/l Highly reproducible and safe Garcia JR, et al. Late breaking abstract 99 th Endocrine Society Annual Meeting Endo 2017, Orlando, FL, April 2017

44 C) Long-acting GH preparations Problems with daily GH injections Inconvenient, painful and distressing Variability in clinical outcomes may reflect differences in adherence to daily GH injections Published data and clinical experience indicate that nonadherence to daily injections increases over time Life circumstances can interfere with adherence By decreasing injection frequency, long-acting GH preparations may improve adherence and thereby potentially maximize clinical efficacy

45 C) Long-acting GH preparations

46 Eur J Endocrinol Jun;174(6):C1-8.

47 Conclusions (1) Adult GHD is associated with a cluster of detrimental factors that affect body composition, CV system, QoL, and mortality Sustained benefits of GH replacement have been demonstrated Diagnosis of adult GHD requires clinical judgment, measurement of IGF-I levels, and use of appropriate GH stimulation test/s GH replacement therapy should be individualized based on symptoms, biomarkers, and avoidance of AEs

48 Conclusions (2) Glucose tolerance may worsen when GH is used in patients with high pre-treatment risk To improve the GST diagnostic accuracy in overweight/obese patients, a lower GH cut-point of 1 g/l should be utilized The oral macimorelin test is recently FDA-approved, and likely will be the preferred alternative test to the ITT Daily GH injections can be burdensome, leading to nonadherence, and long-acting GH preparations currently being developed might address these issues

49 9th International Congress of the Growth Hormone Research & IGF Societies September 14 17, 2018 SAVE THE DATE The Westin Seattle th Ave. Seattle, Washington grs igf2018.com

50 THANK YOU FOR YOUR ATTENTION!