GROWTH HORMONE DEFICIENCY Brig Waqar Azim MBBS MCPS

GROWTH HORMONE DEFICIENCY Brig Waqar Azim MBBS, MCPS, Dip Family Medicine, FCPS, OJT Endocrinology Prof & HOD Pathology CMH Lahore

Childhood Growth Hormone Deficiency � Short stature � Small for age. � Reduce bone age. � Pituitary & Hypothalamic disease

Adult Growth Hormone Deficiency � Clinical ◦ features include alterations in body composition � reduced lean body mass & bone mineral density � increase in fat mass, particularly abdominal ◦ ◦ ◦ dry skin with reduced sweating reduced muscle strength & exercise performance impaired sense of well-being and other psychological complaints

Indication for Growth Hormone Assesment � Stunted growth in children � Those with evidence of hypothalamic or pituitary disease or cranial irradiation ◦ likelihood of deficiency increases with number of pituitary hormone deficits � approaches exist 100% if 3 -4 pituitary hormone deficits � Childhood-onset ◦ growth hormone deficiency all patients should be re-tested as adults before continuing treatment with GH

GROWTH HORMONE ASSESSMENT Assessment suspected GH deficiency after clinical and radiological assessment ◦ Detailed history and thorough physical examination ◦ Exact chronological age of the child ◦ Determination of percentile of height and weight according to the standard height and weight chart ◦ Parental height and weight ◦ bone age of the patient - x- ray of the non dominant wrist

GROWTH HORMONE ASSESSMENT Assessment suspected GH deficiency after clinical and radiological assessment ◦ Detailed history and thorough physical examination ◦ Exact chronological age of the child ◦ Determination of percentile of height and weight according to the standard height and weight chart ◦ Parental height and weight ◦ bone age of the patient - x- ray of the non dominant wrist

GROWTH HORMONE STIMULATION TEST Stimulation test: GH stimulation includes ◦ Exercise stimulation test ◦ L-Dopa stimulation test ◦ Clonidine stimulation test ◦Insulin stress test ◦ Arginine stimulation test ◦ Sleep Test

Biochemical Diagnosis of Adult GH Deficiency (GHD) � Dynamic ◦ ◦ ◦ tests of GH secretion patients should be on stable & adequate replacement of other hormonal deficits before testing the insulin tolerance test is the diagnostic test of choice providing adequate hypoglycaemia is achieved, this test distinguishes GH deficiency from the reduced GH secretion with ageing & obesity

GROWTH HORMONE STIMULATION TEST(CONTD) Diagnosis of GH related Growth Failure � � � For establishing GH deficiency ◦ Two provocative tests (GH levels < 10 m. IU/L) Partial GH deficiency ◦ Borderline response between 10 - 20 m. IU/L in one or two provocative tests Rule Out other Causes of Dwarfism ◦ Chromosomal analysis ◦ X-Ray skull ◦ Thyroid function tests.

The Insulin Tolerance Test in GHD � Should be performed in experienced endocrine units where the test is performed frequently � Contraindicated in those with ECG evidence of ischaemic heart disease and in those with seizure disorders ◦ in these people, alternative tests should be used

Insulin Tolerance Test Principle Hypoglycaemia induced by IV insulin is a potent stimules for GH secretion. Procedure Basal Growth hormone levels IV insulin (0. 15 U/kg) is given Hypoglycaemia 2. 2 mmol/L should ge obtained. GH levels are measured at 30, 60, 90 &180 min Interpertation > 20 m. IU/L means adequate stimulation

GROWTH HORMONE STIMULATION TEST(CONTD) � � � � � � � EXERCISE STIMULATION TEST Principle: Strenuous physical exercise causes GH secretion in normal subjects Preparation: ◦ Fasting over night ◦ Early in the morning (0800 hours) Procedure: Basal blood specimen for GH Rigorous exercise on a tread mill for 15 -20 minutes Pulse is monitored during the test Blood specimen taken 10 minutes after the cessation of exercise

GROWTH HORMONE STIMULATION TEST(CONTD) � � � L- DOPA STIMULATION TEST Principle L- Dopa stimulates growth hormone (GH) secretion from the anterior pituitary gland measurements of which (GH) serve as a test of anterior pituitary function Preparation Overnight fast At 0800 hrs Procedure Basal sample for GH L- Dopa is administered orally preferably with food and milk Patient > 30 Kg: 500 mg Patient between 15 - 30 Kg: 250 mg Patient < 15 Kg: 125 mg

GROWTH HORMONE STIMULATION TEST(CONTD) � Sampling � 5 ml venous blood is collected at 0 (basal) � 60 minutes after L- Dopa administration � Interpretation � GH level > 20 m. IU/L Normal response � GH level between 10 - 20 m. IU/L -suggestive of partial GH deficiency � GH levels < 10 m. IU/L - GH deficiency

GROWTH HORMONE STIMULATION TEST(CONTD) � Arginine Test � Prepration NPO atleast 8 hrs prior to the test � Procedure 1. Base line serum GH and somatomedin-C levels 2. Inject 0. 5 g/kg (maximum 30 g) arginine over 30 min IV 3. Serum GH levels at 30, 60, 90, 120 mins

GROWTH HORMONE STIMULATION TEST(CONTD) � Glucagon stimulation test Indications Particularly useful when insulin induced hypoglycaemia is contraindicated. � Contraindication Hypothyroidism Marked adrenal failure Diabetes millitus � Principle Glucagon stimulates release of GH and ACTH by Hypothalamic stimulation and therefore indirectly stimulates cortisol. �

GROWTH HORMONE STIMULATION TEST(CONTD) GHRH -ARGININE STIMULATION TEST � Indication � To confirm persistence of childhood GH deficiency in early adulthood if ITT is contraindicated, pt is over weight or has DM. � Procedure Baseline GH and IGF-1 level Inject GHRH 1 meg/kg (maximum dose 100 meg) as bolus. Infuse 0. 5 g/kg arginine as a 10% solution in normal saline over 30 min. � Take sample for GH (but not for IGF-1) at 30, 60, 90, 120 & 150 min after start of arginine infusion. Monitor pule and blood pressure every 15 min Interpertaion GH level > 20 m. U/L

GROWTH HORMONE STIMULATION TEST(CONTD) � Sleep � � Take advantage of known rise in GH conc. occuring with deep sleep. Sample is obtained 60 – 90 mins after on set of sleep. Patient must be in the hospital or a clinical research centre for testing. Interpertation: � GH � Test ≥ 15 m. U/L ---- normal

Number of Provocative Tests Needed to Establish Diagnosis of GHD � One test in reconfirmation of childhood-onset GHD � One test only in adults with hypothalamic or pituitary disease and one or more pituitary hormonal deficits � Two test in adults with isolated GHD �

Biochemical Diagnosis of Adult GH Deficiency (GHD) � B. Biochemical � Serum ◦ ◦ � IGF-I Markers of GH Action only of value with age-adjusted normal ranges a normal serum IGF-I does not exclude GHD a serum IGF-I below the normal range is suggestive of GHD (in absence of confounding conditions e. g. malnutrition, liver disease, hypothyroidism) of greater value in presence of 2 or more hormonal deficiencies

B. TREATMENT of GROWTH HORMONE DEFICIENCY in ADULTS

Treatment of Growth Hormone Deficiency � Patients ◦ all patients with documented severe growth hormone deficiency � Goal ◦ who should be treated: of therapy: to correct abnormalities associated with severe growth hormone deficiency

Dose Selection � Objective: ◦ To maximise benefit and minimise side effects In practice, optimum dose varies greatly ◦ ◦ sensitivity increase with age men more sensitive than women

Starting GH Replacement � Start ◦ ◦ with a low dose 0. 15 - 0. 30 mg / day (0. 45 - 0. 90 U / day) subcutaneously at bedtime � Monitor ◦ clinically and biochemically � Increase ◦ response carefully dose slowly no more frequently than at monthly intervals

Target Dose of GH � Women aged 30 - 50 secrete on average 0. 2 mg / day and men 0. 1 mg / day � Sensitivity varies considerably between patients and probably between the sexes � The daily dose rarely exceeds 1 mg (3 U) � Doses used now are lower than previously and are no longer based on body weight or surface area

Monitoring Treatment Efficacy Clinical & Safety Issues � Good clinical practice requires regular imaging of any residual pituitary disease ◦ �A GH replacement does not impose any need to intensify this baseline MRI or CT scan is to be recommended before GH replacement is started

Conclusions � Growth hormone stimulation tests should confirm GH deficiency � Those receiving GH replacement should remain under supervision of an endocrinologist specialising in pituitary disorders � Monthly GH monitoring initially but once stabilised can usually be reduced to one or two times a year