Growth hormone deficiency can occur in children or adults. In children, it presents as short stature and delayed growth. In adults, non-specific symptoms include reduced energy, quality of life, and increased cardiovascular risk. Growth hormone deficiency is investigated through stimulation tests and IGF-1 levels and treated with recombinant human growth hormone via daily injections, with doses titrated based on response. Treatment aims to normalize growth in children and improve symptoms and quality of life in adults.

1. D R A W O F I S O Y E O . I
R E G I S T R A R , E N D O C R I N E U N I T
D E PA R T M E N T O F I N T E R N A L M E D I C I N E
U C H
GROWTH HORMONE
DEFICIENCY STATES & GROWTH
HORMONE REPLACEMENT
THERAPY

2. OUTLINE
• Introduction
• Physiology of GH action
• Aetiology of GH deficiency
• GH deficiency in children
• GH deficiency in adults
• Investigations of GH deficiency
• GH replacement therapy
• Conclusion

3. INTRODUCTION
• Growth hormone action, deficiency states and its
treatment has been an area of great interest in the last
few decades.
• GHD is one of the causes of short stature, which a
obvious clinical condition with social implications.
• Cadaver-derived pituitary GH (1958 to 1985)
• Human recombinant GH (since 1985)

4. PHYSIOLOGY OF GH ACTION
• GH is a 191 Amino acid polypeptide hormone
synthesized, stored and secreted by the somatotroph
cells of the anterior pituitary gland.
• GH synthesis and release is controlled by many
hormonal agents including GHRH, Somatostatin,
Ghrelin, IGF-1, Thyroid hormones and glucocorticoids.
• Growth hormone is secreted in pulses (after infancy).
• Secretion is increased in puberty and decreases
subsequently

5. PHYSIOLOGY OF GH ACTION
• GHBP: high & low affinity binding proteins.
• Growth Hormone Binding Proteins binds GH and
dampen the fluctuation of GH level associated with its
pulsatile secretion.
• Growth promoting activities mediated through IGF-
1(somatomedins)
• While GH activity begins in-utero, it continues to be
secreted into adulthood after cessation of growth,
suggesting a metabolic role in adult life.

6. GROWTH HORMONE ACTION
• Direct Effect: mediated directly via GH binding on its
receptor on target cells. E.g lipolysis in adipocytes.
• Indirect effect: mediated via IGF-1, includes most of its
growth promoting action

7. GH: EFFECTS ON GROWTH
• Via IGF-1, stimulates proliferation of chondrocytes
resulting in bone growth, it ↑ bone length before
epyphyseal closure, and its width after.
• It also stimulates the differentiation and proliferation of
myoblasts.
• It also stimulates amino acid uptake and protein
synthesis in other tissues.

8. METABOLIC EFFECTS OF GH
• GH : Anabolic, Anti-insulin effects at hepatic and
peripheral sites = ↓glucose utilization. ↑Lipolysis, ↓effect
of insulin on the tissues (IGT).
• ↑Lipolysis – fat mobilization (activates hormone sensitive
lipase/ ↓FFA re-esterification), ↓ Fat deposition.
• Protein anabolism: ↑A.acid uptake, ↑ protein synthesis.
• GH is degraded by kidneys and is ↑ in CRF.

9. PHYSIOLOGY OF GH ACTION
• Control of GH action
• Stimulants: GHRH, Ghrelin, Oestrogen.
• Inhibitors: Somatostatin (SRIF), Insulin, Glucose load,
glucocorticoid excess, IGF-1

10. CHILDHOOD GH DEFICIENCY
• Onset in childhood. Congenital or acquired
• Incidence is 1 in every 3800 live birth. M:F =1.3:1
• Presents more often than the adult onset type.
• Patients typically present with impaired growth rate.
• Typical presentation before age 3. others present at
puberty due to absence of growth spurt.
• Many patients presents present with multiple hormone
deficiencies.

11. CHILDHOOD GH DEFICIENCY
• Patients typically present with impaired growth rate.
• Typical presentation before age 3. others present at
puberty due to absence of growth spurt.
• Many patients presents present with multiple hormone
deficiencies

12. AETIOLOGY
• Genetic defects
• GHRH receptor
• Pituitary transcription factors
• PROP-1, PIT-1, Rpx/Hexx-1, PTX-2/Rieg, Lhx-3
• GH-1 gene
• Type Ia, Ib, II & III, Multiple GH family gene
deletions, bioinactive GH, GH- receptor defects
(Laron syndrome), IGF-1 & IGF-receptor defects

13. AETIOLOGY
• Congenital Cranial and CNS abnormalities.
• SOD (septo-optic dysplasia)
• Cleft lip & Palate
• Empty sella syndrome
• Horencephaly and anencephaly
• Pituitary hypoplasia & aplasia
• Thin or absent pituitary stalk
• Hydrocephalus

14. AETIOLOGY : ACQUIRED CAUSES
• Neoplasms: Craniopharyngiomas
• CNS infections : meningitis, granulomatous dx
• Trauma: perinatal events, head injury
• Metabolic: hemochromatosis
• Infiltrative conditions: langerhans histocytosis,
sarcoidosis, lymphocytic hypophysis
• Radiation tx of head and neck.
• Brain surgery.

15. Growth monitoring

16. CHILDHOOD GH DEF:
CLINICAL PRESENTATION
• Delayed growth
• Micropenis, undescended testis.
• Increased fat
• Short stature
• High pitched voice
• Perinatal hx: pregnancy, perinatal events, prolonged jaundice
• Micropenis, undescended testis.
• Increased fat
• High pitched voice
• Low threshold for hypoglycemia

17. OTHER HISTORY
• Growth hx : Birth wt & length, parental height, parental
pubertal age, previous growth pattern, nutritional hx & hx
of chronic dx.
• Headaches
• Visual disturbances
• Symptoms of chronic illness
• Family history of delayed growth
• Symptoms of other associated hormonal deficiencies.

18. CHILDHOOD GH DEF:
CLINICAL PRESENTATION
• Growth chart.
• Growth rate < 4-5cm/year
• Proportions:
• Arm span
• Upper segment : lower segment
• Pubertal status (Tanner stage)
• Dysmorphic features of specific syndromic causes e.g
Turner’s, Noonans, Russell silver syndromes.

19. CHILDHOOD GH DEF:
CLINICAL PRESENTATION
• Parental height centiles
• CNS, examine fundi, visual fields
• Obesity
• Goitre
• Stigmata of chronic disease: cardiac, GI, liver, renal
• Blood pressure

20. ADULT GH DEF
• Childhood onset AGHD or Adult onset GHD.
• Adult onset incidence is 10 per million
• Some Childhood GH deficiency patients grow into
adulthood with persisting hormonal deficits
• Because of the associated alteration in body
composition, there is ↑ CV risk factors and ↓ life
expectancy.
• Usually associated with other ant. Pit hormonal def.
• Usually seen in patients with known pituitary dx.

21. CLINICAL PRESENTATION: ADULT TYPE
• Known Head/Pituitary disease/intervention
• Symptoms are non-specific
• Reduced quality of life : ↓energy & drive, poor
concentration, low self esteem/depression, social
isolation.
• Altered body composition : ↑fat mass with truncal
distribution, ↓lean body mass, ↑W/H ratio.
• ↓Exercise capacity, ↓max O2 intake
• ↓ bone mass (osteopenia/osteoporosis), ↓body hair.

22. CLINICAL PRESENTATION: ADULT TYPE
• Cardiovascular risk factors:
• Dyslipidaemia (esp ↑LDL)
• Insulin resistance
• Atherosclerosis
• Impaired LV function
• ↑fibrinogen, ↓ fibrinolytic activity.

23. AETIOLOGY
• As in Childhood onset GHD
• Others
• Aneurysmal subarachnoid haemorrhage

24. INVESTIGATION
• In children:
• Growth charts
• Exclude non-hormonal causes of growth delay
• Growth hormone stimulation tests.
• Serum IGF-1 levels, IGFBP3
• Karyotyping
• Brain imaging: MRI, CT,
• Assess other hypothalamic pituitary axis.
• Others tailored to specific situations

25. GROWTH HORMONE STIMULATION
TESTS.
• ITT (preferred)
• GHRH+arginine test
• Glucagon test
• Arginine test
• Maximal GH provocation < 7 ng/ml.

26. OTHER INVESTIGATIONS
• Anthropometry : BMI, WC, W/H
• FPG + 2HPP, HbA1C
• Fasting serum lipids
• Bone density (DEXA scans)
• Urinalysis, U & E
• LFTs, ECG
• Haemoglobin analysis, FBC.
• QoL assessment : AGHDA, Nothingham Health Profile,
General Well Being-Schedule.

27. DIAGNOSIS: CHILDHOOD TYPE
• Short stature that is inappropriate for the parental heights
• Subnormal growth rate: ie a height velocity of < 25th centile
OR <4cm/yr over two successive years or <3rd centile over
one year in a pre-pubertal children, <8cm/yr in puberty.
• As part of multiple pituitary hormone deficiencies.
• Growth delay confirmed by delayed skeletal maturation.
• Clinical and/or imaging evidence of a structural disorder of
the hypothalamo-pituitary axis; this includes previous cranial
irradiation.
• Exclusion of other genetic, psychosocial and systemic causes
of growth failure.
• Biochemical evidence of GH deficiency

28. DIAGNOSIS: ADULT TYPE
• Severe GH deficiency (peak response of < 3ng/ml
during ITT or equivalent test) AND
• Perceived impairment of quality of life (QoL) as
demonstrated by a score of a least 11 in the disease-
specific QoL-AGHDA questionnaire. AND
• Already receiving full replacement with other deficient
pituitary hormones as required.
• Known hypothalamic pituitary dx with other hormonal
deficiencies(3+) + low IGF-1(unexplained).

29. CONSEQUENCES IN ADULT
• ↑Cardiovascular M & M : ↑atheromatous plaques,
↓ejection fraction, and abnormal left ventricular diastolic
filling.
• Metabolic complications: dyslipideamia, insulin
resistance and their consequences.
• Osteopenia/Osteoporosis/Fractures
• ↓Quality of life

30. GH REPLACEMENT THERAPY
• Indications for Childhood GHRT:
• 1. Short stature due to growth hormone deficiency
• Idiopathic isolated GH deficiency
• Congenital hypopituitarism e.g. anomalies of the pituitary gland such as septo-
optic dysplasia
• Acquire hypopituitarism e.g. craniopharyngioma & post cranial irradiation & neuro-
surgery
• 2. Severe constitutional short stature amenable to GH therapy.
• Turner Syndrome (Confirmed by chromosome analysis)
• 3. The treatment of growth failure associated with chronic renal failure –
before epiphyseal closure (on dialysis or post renal transplant).
• 4. Prader-Willi syndrome
• 5. Small for gestational age.
• ± Skeletal dysplasia
• ± Nonnan syndrome

31. GH REPLACEMENT THERAPY
• Contraindications
• Active neoplasm
• Retinopathy
• Uncontrolled DM
• Intracranial hypertension
• Prader-Willi syn + closed epiphyses
• CRF + closed epiphysis
• Pregnancy

32. GH REPLACEMENT THERAPY
• Parenteral Human recombinant GH
• Given subcutaneously in daily doses (usually nightly)
• Initiate at low doses
• Usual doses:
• Children: Somatotropin [0.02–0.05 (mg/kg per day)] OR 0.7 –
1.0 mg/m2/day
• Adults: Somatotropin (0.1–1.25 mg daily)

33. GH REPLACEMENT THERAPY
• Adult females require slightly higher doses than matched
males.
• Women on oestrogen replacement tx usually require
higher doses as well
• Titrate dose upwards till IGF-1 normalises or side effects
develop.
• Avoid IGF-1 range in the upper quarter percentile for age
and sex.

34. GH REPLACEMENT THERAPY
• Expect clinical improvement in 2 – 4 monthsif no clinical
response in 6 months, discontinue treatment.
• Continue monitoring laboratory parameters during tx to
assess response : IGF-I, FPG, HbA1c, BMI, waist
circumference, waist-to-hip ratio, serum-free T4, and
assessment of the hypothalamic-pituitary-adrenal axis.

35. GHRT: TRANSITION PATIENTS:
• Retest after final height is achieved (D/C GH therapy for
1month) to ascertain their GH status before considering
restarting GH therapy.
• Exceptions include those with known mutations,
congenital defects, irreversible hypothalamic-pituitary
structural lesions, OR those with evidence of
panhypopituitarism (at least 3 pituitary hormone
deficiencies) and low serum IGF-I levels off GH therapy
• For short stature not due to GHD, discontinue Rx.

36. GH REPLACEMENT THERAPY: SE
Common:
Edema, arthralgias, and myalgias
Others:
Atrial fibrillation Iatrogenic acromegaly
Benign intracranial hypertension Increase in melanocytic nevi
Carpal tunnel syndrome Muscle stiffness
Headache Paresthesias
Hyperglycemia/IGT Tinnitus
lipodystrophy Skin reaction(inflammatory)
? Neoplasia: new, recurrence.

37. Initiation
Of GHRT

38. GH REPLACEMENT THERAPY
• When to stop GHRT
• Poor response,<50% ↑in growth velocity after 1yr
• Temporarily after renal transplant x 1yr
• No significant ↑ in QoL at 9months
• After achieving final height in non-GH deficient Growth
• Otherwise, continue indefinitely.

39. GH THERAPY
• Other use of GH theraphy: (controversial)
• Catabolic states: burns, trauma, surgery, prolonged TPN, organ
failure.
• Osteoporosis
• HIV cachexia
• Aging
• In multiple pit hormone deficiency, Treat other hormonal
deficiency first, especially thyroid axis before GHRT.

40. OTHER RX
• Mecasermin, a human insulin-like growth factor-I (rhIGF-
I), is licensed to treat growth failure in children and
adolescents with severe primary IGF -1 deficiency

41. CONCLUSION
• GHD is a disorder which is increasingly being more
recognised.
• In children, one must rule out other more likely
differential diagnosis before GH evaluation and adults
require a high index of suspicion.
• GHRT is expensive, but the potential benefits far
outweighs the cost in true GHD.

42. REFERENCES
• Harrison's Principle of Internal Medicine 17ed
• Kronenberg: Williams Textbook of Endocrinology, 11th
ed.
• Pediatric endocrinology: a practical clinical guide, Sally
Radovick
• Medscape emedicine
• NICE Guidelines
• AACE Guidelines 2009