Everything about Growth hormone for a short seminar

1. GROWTH HORMONE THERAPY
Presented by: Surg Lt Cdr Manas R Mishra
Guide: Lt Col Deepak Joshi

2. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
HISTORY
 First use : Evans & Long 1921 (Gigantism in rats from beef
pituitary)
 Species Specificity
 pit hGH : 1945
 Therapeutic use: 1958

3. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
 By April 1985: 900 patients
 Very limited supply of pit hGH :1985
 Stopped in most countries that year
 CJD: UK &USA, i.p: 40 yrs
 Synthetic GH

4. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
BASIC PHYSIOLOGY
 191 AA single chain PP
 Pituitary: Somatotropes: Synthesis, storage, secretion
 Gene: 17q22-24
 Pulsatile secretion
 Regulation
 (by Hypothalamic Hormones): GHRH, Somatostatin,
Grehlin
 Physiologic factors: Sleep, exercise, physical stress,
trauma, acute illness, puberty, fasting, and hypoglycemia
stimulate the release of GH
 Hyperglycemia, hypothyroidism, glucocorticoids inhibit
GH release.

5. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
MOA
 GH binds to receptor molecules on the surface of target
cells.
 The GH receptor is a 620-amino-acid, single-chain
molecule with an extracellular domain
 JAK STAT mechanism
 GH binding induces receptor dimerization and activation
of Jak2 kinase and other protein substrates initiates a
series of events that leads to alterations in nuclear gene
transcription.
 The signal transducer and activator of transcription 5b
(STAT5b) plays a critical role in linking receptor
activation to changes in gene transcription.

6. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
BIOLOGICAL EFFECTS
 Linear growth,
 Bone thickness,
 Soft tissue growth,
 Protein synthesis,
 Fatty acid release from adipose tissue,
 Insulin resistance, and blood glucose.
 The mitogenic actions of GH are mediated through
increases in the synthesis of insulin-like growth factor 1
(IGF-1), somatomedin C

7. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
FDA APPROVED GH USES IN CHILDREN
 Growth hormone deficiency/ insufficiency
 Chronic renal insufficiency pretransplantation
 Turner syndrome
 Small for gestational age or IUGR babies, who have not
reached a normal height range by age 2 years
 Prader-Willi syndrome
 Children with idiopathic short stature who are >2.25 SD
below the mean in height and unlikely to catch up in height.

8. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
OFF LABEL USES
 Noonan Syndrome
 SHOX gene deficiency
 Chondrodysplasia (Japan)

9. DIAGNOSIS OF
GROWTH HORMONE DEFICIENCY

10. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
HISTORY & PHYSICAL EXAMINATION
 Neonatal:
 Hypoglycemia,
 Prolonged jaundice,
 Microphallus,
 Traumatic delivery
 Cranial irradiation
 Craniofacial midline abnormalities
 Consanguinity &/or affected family member
 Head trauma or CNS infection/infiltration

11. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
FOR IMMEDIATE INVESTIGATION :
 Height > 3 SD below the mean
 Height > 1.5 SD below mid-parental height
 In absence of short stature,
 Ht Velocity > 2 SD below the mean over 1 year or
 > 1.5 SD over 2 years
 Signs of an intracranial lesion
 Signs of MPHD

12. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
RADIOLOGICAL EVALUATION
 Bone age on wrist Xray
 CNS imaging by MRI/CT
 Suspected intracranial lesion
 Optic nerve hypoplasia/ SOD
 Other structural/developmental anomaly
 Confirmed IGHD/ MPHD
 Record
 Pituitary height &/or volume, stalk anatomy
 Position of posterior pituitary bright signal

13. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
BIOCHEMICAL ASSESSMENT OF GHD
 GH provocation tests
 Provocative agents (Arginine, Clonidine, Glucagon, Insulin
& l-Dopa), but limited reference data are presently available
for each test
 At our setup: Clonidine 2mcg/kg
 Traditionally diagnosis of GHD made with peak GH
< 10µg/L

14. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
OTHERS: EXPENSIVE
 IGF-I & IGFBP-3 values
 Use reference ranges standardized for age & sex
 Values > 2SD below the mean strongly suggest an
abnormality in GH axis

15. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
CONFOUNDING FACTORS
 Nutritional status
 Concomitant medication
 Psychosocial conditions
 Rule out other causes of GH deficiency
 Hypothyroidism
 Chronic systemic illness
 Turners Syndrome
 Skeletal disorders

16. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
INDICATIONS AND GOALS OF GHD RX
 Patients with proven GHD should be treated with rhGH
as soon as possible after the diagnosis is made
 Primary objectives of the therapy of GHD are:
Normalization of height during childhood
 Attainment of normal adult height
 Normally growing patients with craniopharyngioma
& GHD should be considered for therapy with GH for
 Metabolic and body composition benefits
 Enhancement of pubertal growth

17. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
MODE OF ADMINISTRATION OF GH
 Intramuscular : initially fearing immunogenic Rxn
 At present: subcutaneous
 Intranasal: Underway
 Time: Evening
 higher GH levels, greater IGF response and better
metabolic profile compared to
 morning or afternoon administration.
 GH is routinely used in the range of 25-50 µg/kg/day
 A dose-response relationship exists in terms of height
velocity in the first two years of therapy

18. SPECIFIC DOSING
Diagnosis Doses
Mcg/kg/day Mg/m2/day
GH Deficiency 23-39 0.7-1.0
Turner Syndrome 45-50 1.4
CRF 45-50 1.4
PWS 35 1.0
SGA 35 1.0
SHOX def 45-50 1.4

19. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
EVALUATION OF RESPONSE TO GH
 The determination of the growth response to GH treatment
is the single most important parameter in the monitoring of
the child with GHD
 Increase in height and change in height velocity are useful
in clinical practice to assess the response to GH
 For comparative purposes, data should be expressed as:
the increase in height /year
 IGF levels and IGFBP-3

20. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
 Other optional ( for specific circumstances)
 Serum leptin,
 Bone markers
 GH antibodies
 Lipid profiles
 Fasting insulin
 Bone age

21. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
FACTORS AFFECTING THE RESPONSE TO GH
 Every effort should be made to diagnose and treat children
at the youngest possible age
 It is very important to maximize height with GH therapy
before the onset of puberty
 If this is achieved, then modulation of the GH dose during
puberty may not be necessary

22. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
MONITORING OF GH THERAPY
 Baseline clinical evaluation
 Measurement of insulin-like growth factor 1 (IGF1)
 bone age assessment,
 thyroid function testing (in GH-deficient patients),
 adrenal function testing
 clinical assessment for scoliosis
 monitoring of HbA1c levels

23. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
RECOGNIZED SIDE-EFFECTS
 Intracranial hypertension
 Musculoskeletal symptoms:edema, carpal tunnel syndrome,
and musculoskeletal aches and pains related to fluid retention
 Scoliosis: more prevalent in patients with TS or PW
syndrome. may be exacerbated when growth is accelerated
 Slipped capital femoral epiphysis
 Obstructive sleep apnea: GH stimulates adenotonsillar growth
 Pancreatitis

24. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
SAFETY ISSUES
 GH increases the peripheral conversion of thyroxine (T4) to
tri-iodothyronine
 GH Therapy unmask pre-existing central
hypothyroidism
 GH increases the tissue conversion of active cortisol to
inactive cortisone.
 Others:
 Prepubertal gynecomastia,
 Arthralgia,
 Edema

25. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
Certain patient groups who receive GH treatment carry an
intrinsic risk of developing malignancies, including those with
Neurofibromatosis type 1, Fanconi anemia, Downs and Bloom
syndromes.
• such children be carefully monitored with regard to tumor
formation
SAFETY - GH THERAPY IN CHILDREN
MALIGNANCY RISK

26. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
 Has been reported in 1/1000 children receiving GH
treatment; may be underestimate
 Headache in children on GH treatment should be carefully
evaluated
 Fundoscopic examination should be performed before
initiation of GH treatment and repeated when clinically
indicated
SAFETY - GH THERAPY IN CHILDREN
BENIGN INTRACRANIAL HYPERTENSION

27. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
 Reduction of insulin sensitivity is physiologic effect of GH,
however, glucose homeostasis is maintained.
 No increase in incidence of diabetes, either type 1 or type
2, associated with GH treatment
 These patients inherently at risk of developing diabetes -
these should be carefully monitored
 Diabetes mellitus is not contraindication to GH treatment in
children
SAFETY - GH THERAPY IN CHILDREN
GLUCOSE METABOLISM

28. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
 No data to support discontinuation of GH replacement
treatment during illness
 Risk of hypoglycemia should be considered in children with
GH deficiency who discontinue GH treatment
GH THERAPY IN CHILDREN
GH TREATMENT AND INTERCURRENT ILLNESS

29. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
Issues related to GH treatment in patients with non-GH
deficient disorders
• Monitoring glucose homeostasis in Turner syndrome
• Glucose homeostasis and lipid profiles in chronic renal
failure
• In patients with chronic renal failure treated with GH who
receive renal transplant
• Assessment of graft function and surveillance for
development of malignancy
SAFETY - GH THERAPY IN CHILDREN

30. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
LONG TERM CARE
 GH replacement is most likely a lifelong treatment
 Dose requirements are likely to change
 Dosage needs careful monitoring in relation to increasing
age & perceived benefits
 If benefits are no longer tangible, a trial of withdrawal of GH
may be indicated

31. Dr Manas Ranjan Mishra, Dept Of Pediatrics AFMC
Thank
You