D R AW O F I S O Y E O . IR E G I S T R A R , E N D O C R I N E U N I T

D E PA RT M E N T O F I N T E R N A L M E D I C I N EU C H

GROWTH HORMONE DEFICIENCY STATES & GROWTH HORMONE

REPLACEMENT THERAPY

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

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)

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

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.

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

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.

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.

PHYSIOLOGY OF GH ACTION

• Control of GH action• Stimulants: GHRH, Ghrelin, Oestrogen.• Inhibitors: Somatostatin (SRIF), Insulin, Glucose

load, glucocorticoid excess, IGF-1

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.

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

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

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

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.

Growth monitoring

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

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.

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.

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

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.

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.

CLINICAL PRESENTATION: ADULT TYPE

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

AETIOLOGY

• As in Childhood onset GHD• Others• Aneurysmal subarachnoid haemorrhage

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

GROWTH HORMONE STIMULATION TESTS.

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

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.

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

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).

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

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

GH REPLACEMENT THERAPY

• Contraindications• Active neoplasm• Retinopathy• Uncontrolled DM• Intracranial hypertension• Prader-Willi syn + closed epiphyses• CRF + closed epiphysis• Pregnancy

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)

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.

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.

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.

GH REPLACEMENT THERAPY: SECommon: 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.

InitiationOf GHRT

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.

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.

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

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.

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

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