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

 Short stature  Small for age.  Reduce bone age.  Pituitary & Hypothalamic disease

 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

 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 100% if 3-4 pituitary hormone deficits exist  Childhood-onset growth hormone deficiency ◦ all patients should be re-tested as adults before continuing treatment with GH

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

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

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

 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

Diagnosis of GH related Growth Failure  For establishing GH deficiency ◦ Two provocative tests (GH levels < 10 mIU/L)  Partial GH deficiency ◦ Borderline response between mIU/L in one or two provocative tests  Rule Out other Causes of Dwarfism ◦ Chromosomal analysis ◦ X-Ray skull ◦ Thyroid function tests.

 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

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 > 20mIU/L means adequate stimulation

 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 minutes  Pulse is monitored during the test  Blood specimen taken 10 minutes after the cessation of exercise

 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 Kg: 250 mg  Patient < 15 Kg: 125 mg

 Sampling  5 ml venous blood is collected at 0 (basal)  60 minutes after L- Dopa administration  Interpretation  GH level > 20 mIU/L Normal response  GH level between mIU/L -suggestive of partial GH deficiency  GH levels < 10 mIU/L - GH deficiency

 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

 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.

 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 1meg/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 mU/L

 Sleep Test  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 ≥ 15 mU/L ---- normal 

 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 

 B.Biochemical Markers of GH Action  Serum IGF-I ◦ 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

 Patients who should be treated: ◦ all patients with documented severe growth hormone deficiency  Goal of therapy: ◦ to correct abnormalities associated with severe growth hormone deficiency

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

 Start with a low dose ◦ mg / day ( U / day) ◦ subcutaneously at bedtime  Monitor response carefully ◦ clinically and biochemically  Increase dose slowly ◦ no more frequently than at monthly intervals

 Women aged 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

 Good clinical practice requires regular imaging of any residual pituitary disease ◦ GH replacement does not impose any need to intensify this  A baseline MRI or CT scan is to be recommended before GH replacement is started

 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