B99

Growth Hormone Defi ciency (1 of 8)

YesGHD in adult

No

YesGHD in child

Not all products are available or approved for above use in all countries.Specifi c prescribing information may be found in the latest MIMS.

1Patient presents w/ signs &

symptoms suggestive of growth hormone deficiency (GHD)

2DIAGNOSIS

Is GHD confi rmed?

ALTERNATIVE DIAGNOSIS

A Growth hormone replacement therapy

A Growth hormone replacement therapy• Surgical care may

also be required

B FOLLOWUP & MONITORING OF ADULT PATIENT

B FOLLOWUP & MONITORING OF PEDIATRIC PATIENT

1 CLINICAL PRESENTATION

• Growth hormone defi ciency (GHD) is a congenital or an acquired growth hormone (GH) axis disruption in the higher brain, hypothalamus or pituitary which results in short stature

• May occur at any ageChildren• Short stature• Severely decreased height velocity• Hypoglycemia or prolonged jaundice in the neonateAdults• GHD syndrome

- Decreased lean body mass & increased fat mass- Dyslipidemia, insulin resistance, vascular endothelial dysfunction- Reduced left ventricular mass, impaired systolic function- Reduced sweating- Impaired quality of life

• Other clinical manifestations:- Lack of vigor- Emotional lability (eg depressed mood/aff ect) - Feeling of social isolation- Decreased exercise capacity- Reduced bone density & increased risk of fracture, osteopenia

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GHD

B100

Growth Hormone Defi ciency (2 of 8)

Not all products are available or approved for above use in all countries.Specifi c prescribing information may be found in the latest MIMS.

2 DIAGNOSIS

Adults• GHD in adults refl ects an absence of 2 hormones, GH & insulin-like growth factor-1 (IGF-1), aff ecting the

process of glucose-insulin metabolism, lipolysis & bone remodelling• Either adult-onset GHD (AOGHD) or childhood-onset GHD (COGHD) & may occur as either isolated GHD

or as multiple pituitary hormone defi cienciesHistory• Pituitary adenoma• Surgery &/or radiation treatment of pituitary adenomas or cranial radiation for other disorders• Defi ciency of other pituitary hormones may occur concurrently w/ GH defi ciency• Previous childhood GHDPhysical Exam• Reduced lean body mass w/ increased weight, body fat predominantly in the abdominal region• � in & dry skin• Cool peripheries• Poor venous access• Blunt aff ectLab Tests• Diagnosis of GHD is based on subnormal GH secretion in response to a stimuli

- � ere are various stimulation tests available for the diagnosis of GHD• Insulin tolerance test (ITT)

- Gold standard test for diagnosing adult GHD- Insulin-induced hypoglycemia provides strong stimulus for GH secretion- Contraindicated in seizures, cardio/cerebrovascular disease, elderly >60 years- Should only be performed in specialized endocrine units

• Serum IGF-1 concentration is also used to confi rm GHD: Decreased levels than the gender- & age-specifi c lower limit of normal is confi rmatory of GHD

• Acceptable alternative stimulation tests include:- Growth hormone-releasing hormone (GHRH) + Arginine (ARG) test

- Traditionally, the alternative test of choice- In cases of hypothalamic GHD (where GHRH + ARG test may produce false-negative result), a normal

test result warrants further testing (test of choice would be ITT, followed by glucagon or possibly, ARG alone)

- ARG + Levodopa (L-Dopa) - Alternative test used in the absence of GHRH- Highly sensitive (95%) but w/ low sensitivity (75%)

- Glucagon test- Recommended alternative test when ITT is undesirable or when GHRH + ARG test is unavailable- In recent years, has been increasingly used in US & Europe as alternative test of choice due to unavailability

of GHRH + Arg test in these regions- Other advantages include safety, reproducibility, lack of infl uence by gender & hypothalamic cause of GHD

& relatively few contraindications- BMI-appropriate GH cut-off points are recommended to diagnose adult GHD

- ARG test alone- Alternative when ITT & glucagon tests are unavailable- Use w/ caution since fewer data are available about its accuracy in GHD diagnosis- It should be limited to non-obese adolescents as it is very dependent on body mass index

- Macimorelin test- Recommended alternative test when ITT is contraindicated or not possible- GH cut-off point: 2.8 mcg/L- Advantages include safety, high reproducibility, eff ectivity, excellent tolerability w/ minimal side eff ects,

shorter duration of testing, no need for parenteral administration, & w/ sensitivity & specifi city comparable to ITT

- Further studies are needed to determine the safety profi le & diagnostic value in children, adolescents, elderly, in patients w/ obesity, diabetes mellitus (DM), traumatic brain injury, subarachnoid hemorrhage, & renal or hepatic dysfunction

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GHD

B101

Growth Hormone Defi ciency (3 of 8)

2 DIAGNOSIS

AdultsLab Tests (Cont'd)• � e following conditions are considered GH defi cient & do not require further GH stimulation tests: Serum

IGF-1 levels below the age- & sex-appropriate reference range when off GH therapy, irreversible hypothalam-ic-pituitary structural lesions & those w/ evidence of panhypopituitarism (at least 3 pituitary hormone defi ciencies) - It is important to note that severe GHD may also be associated w/ normal serum IGF-1 levels (nearly always

<50th percentile)- Clinicians should therefore consider GHD in a patient w/ an IGF-1 <50th percentile & perform further testing

• Body mass index (BMI) should be used w/ GHRH + ARG test since BMI has a well-validated eff ect on GH responses to GHRH & ARG stimulation

• Aneurysmal subarachnoid hemorrhage & traumatic brain injury may cause transient GHD; GH stimulation testing is therefore recommended to be done at least 12 months after the event

Children• GHD in children refl ects a congenital or an acquired GH axis disruption in the higher brain, hypothalamus or

pituitary which results in short stature• Mainly idiopathic & usually identifi ed because of growth failure• Exclude other causes of growth failure using appropriate tests

- Eg hypothyroidism, chronic systemic diseases, skeletal diseases & Turner syndrome• Diagnose GHD based on an integration of all results obtained from physical exam, imaging & lab tests• In idiopathic isolated GHD of childhood (hypothalamic GHD), ITT or glucagon stimulation tests are

recommendedHistory• Any of the following may indicate GHD:

- In the neonate: Hypoglycemia, prolonged jaundice- History of microphallus or traumatic delivery- Head trauma, central nervous system (CNS) infection or cranial radiation- Consanguinity &/or aff ected family member- Craniofacial midline abnormalities

Physical Examination• Height & weight evaluation

- Plot weight & height measurements on growth charts which will graphically depict changes in growth & growth velocity

• Short stature may suggest GH defi ciency & immediate investigation should be conducted if any of the following criteria are present: - Severe short stature [defi ned as height >3 standard deviation (SD) below population mean] - Height >2 SD below population mean w/ 1-year height velocity >1 SD below mean for chronological age or

(in child age >2 years), a 1-year decrease of >0.5 SD in height- In the absence of short stature, a 1-year height velocity >2 SD below the mean or a 2-year height velocity

>1.5 SD below the mean (especially GH manifesting during infancy or in organic acquired GHD) - Height >1.5 SD below midparental height: Male [(paternal height in cm) + (maternal height in cm + 13)]

divided by 2; female [(paternal height in cm - 13) + (maternal height in cm)] divided by 2- Signs indicative of an intracranial lesion- Signs of multiple pituitary hormone defi ciencies (MPHD) - Neonatal signs & symptoms of GHD

• Other clinical features/fi ndings of GHD in children- Increased subcutaneous fat, especially around the trunk- Lower BMI & waist-to-hip ratio compared w/ AOGHD- Immature facies, w/ a prominent forehead & depressed midfacial development- Delayed dentition- Delayed average age of pubertal onset- In males, the phallus may be small- Lower serum IGF-1 & IGF binding protein-3 (IGFBP-3) levels compared w/ AOGHD- More reduced muscle & bone mass, & reduced cardiac function as compared w/ AOGHD

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GHD

B102

Growth Hormone Defi ciency (4 of 8)

Not all products are available or approved for above use in all countries.Specifi c prescribing information may be found in the latest MIMS.

2 DIAGNOSIS (CONT’D)

Children (Cont'd)Radiological Procedures• Magnetic resonance imaging (MRI) or computed tomography (CT) of brain

- Performed to defi ne the anatomy of the hypothalamic-pituitary region & to identify intracranial tumors, optic nerve hypoplasia, septo-optic dysplasia or other structural or developmental anomalies

• Radiograph studies to estimate bone age- Left wrist & hand for children 1 year of age or older- Knee & ankle for infants <1 year old

Lab Tests• Serum GH Level

- In newborns, serum GH level <20 mcg/L is highly suggestive of GHD- GH level measured in neonates w/ hypoglycemia but no metabolic disorder

- After the newborn period, random serum GH levels are not reliable indicators of GHD due to the pulsatile nature of GH secretion

• GH Stimulation (Provocative) Tests- At least 2 provocative tests are ideal to ascertain the diagnosis due to high frequency of false-negative results

- Minimum of 2 provocative tests w/ low peak levels of GH, poor linear growth, & delayed skeletal age is highly indicative of chronic GHD

- Only 1 GH stimulation test is required in children w/ CNS pathology, cranial irradiation or genetic defects- Provocative tests in children w/ peak GH concentration <10 mcg/L supports GHD diagnosis:

- Insulin tolerance test (ITT): GH level ≤5.0 mcg/L indicative of GHD; contraindicated in patients w/ cardiovascular disease, cerebrovascular disease & seizure disorders

- GHRH w/ or without arginine: GH level <4.1 mcg/L indicates GHD in a GHRH-arginine test- Clonidine, Levodopa, Propranolol- Glucagon w/ or without beta-blockers: Peak GH of ≤3.0 mcg/L indicative of GHD & possible initiation of

treatment- May consider sex steroid priming prior to conducting GH provocative test in prepubertal children (boys

>11 years old & girls >10 years old) to improve diagnostic specifi city- May choose not to proceed w/ this test if patients have other fi ndings that clearly indicates GHD [pituitary

abnormality, newborns w/ congenital pituitary abnormality, extreme short stature (height <-3 SD), signifi -cantly reduced IGF-1 & IGFBP-3 levels, & delayed bone age manifested by an infant or young child w/ no known nutritional defi ciency]

• Insulin-like Growth Factor-1 (IGF-1) or Somatomedin Test & Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Test- Produced when the liver & other tissues are stimulated by GH- IGF-1 is a direct refl ection of the concentrated level of functional GH secretion

- More stable measurable concentrations compared to the pulsatile secretion of GH- IGFBP-3 is a major serum carrier protein for IGF-1 & is GH-dependent

- Better diff erentiates low versus low-normal IGFBP-3 levels in young children compared to somatomedin test

- Values ≥2 SD below the mean for IGF-1 or IGFBP-3 strongly suggest an abnormality in the GH axis, if other causes of low IGF have been excluded

- However, normal values for IGF-1 & IGFBP-3 can be found in children w/ GHD- Low levels may be seen in patients w/ GH insensitivity, hypothyroidism, DM, renal failure, &

malignancy• Other Tests

- Acid-labile subunit test- Used to rule out postreceptor defects, specifi cally a dysfunction in the acid-labile subunit as a cause of

IGF-1 defi ciency- Postreceptor defects are more common in patients w/ GH resistance/insensitivity syndrome & not GHD - More studies are needed to establish the use of this test for IGF-1/IGFBP-3 level determination in GHD

- Patients w/ GHD may have increased total cholesterol, low-density lipoprotein-cholesterol (LDL-C), apoli-poprotein B & triglyceride (TG) levels & decreased high-density lipoprotein-cholesterol (HDL-C)

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GHD

B103

Growth Hormone Defi ciency (5 of 8)

ALTERNATIVE DIAGNOSISEndocrine Causes• Growth hormone resistance• Hypothyroidism• Cushing’s syndrome

• Parathyroid or vitamin D disorders• Delayed puberty (GnRH defi ciency)

Non-endocrine Causes• Syndromes (Turner, Noonan, Russell-Silver, etc)• Skeletal dysplasia• Chronic disease, infl ammation• Psychosocial short stature• Constitutional delay of growth & puberty• Malnutrition• Intrauterine growth retardation (IUGR), small for gestational age (SGA)IGF Defi ciency• May be caused by GH insensitivity, IGF resistance, GH defi ciency secondary to hypothalamic dysfunction or

pituitary GH defi ciencyIdiopathic Short Stature (ISS) • Genetic & non-genetic short stature manifested as height of >2.25 SD below the corresponding mean height

for age, sex & population group, w/ constitutional delayed growth & maturation• Systemic, endocrine, nutritional & chromosomal abnormalities, especially GHD should have been ruled out

A GROWTH HORMONE REPLACEMENT THERAPYSomatropin• A synthetic polypeptide human growth hormone of recombinant DNA originFactors Aff ecting Dosing• Physiologic factors

- Pubertal girls & premenopausal women secrete more GH than their male counterpart mainly due to the underlying estrogen-antagonistic eff ects on GH action in women- Higher GH doses are therefore required among female patients

• Concomitant medications- Use of oral estrogen as replacement therapy or for contraception purposes in women renders them more

GH-resistant than men, thus, requiring a higher dose to achieve equivalent IGF-1 responses- Use of transdermal estrogen patches may help lower the GH dose needed to achieve equivalent IGF-1 response

• Obesity- Characterized by marked decrease in both spontaneous & stimulated GH secretion but w/ normal or

low-normal serum IGF-1 levels which is probably secondary to enhanced hepatic responsiveness to exogenous GH- Obese GH-defi cient patients may be started on low doses (0.1-0.2 mg/day) to reduce risk of worsening

glucose tolerance• Compliance

- Patients may at times fi nd it diffi cult to comply w/ daily injections- Using the same total weekly dose, patients may administer his/her injections on an alternate day or thrice-

weekly basis• Other factors that may increase GH dose: Low serum IGF-1 levels, young patients regardless of type• Others factors that may decrease GH dose: High serum IGF-1 levels, elderly patients, worsening glucose

tolerance, side eff ectsGH Replacement � erapy in Adult • Indicated for GHD due to pituitary diseases from known causes (eg pituitary tumor, irradiation, trauma,

reconfi rmed childhood GHD, etc)• Treatment must be individualized independent of body weight, starting w/ a low dose & gradually titrating up

until serum IGF-1 levels are normal w/ minimal side eff ects• Serum IGF-1 is the recommended biomarker for GH dose adjustments• Aim for serum IGF-1 levels in the middle of the normal range appropriate for age & sex, except when side

eff ects are signifi cant- Consider a trial of higher GH doses as long as serum IGF-1 levels remain within the normal range

Not all products are available or approved for above use in all countries.Specifi c prescribing information may be found in the latest MIMS.

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GHD

B104

Growth Hormone Defi ciency (6 of 8)

A GROWTH HORMONE REPLACEMENT THERAPYGH Replacement � erapy in Adult (Cont'd)• Eff ects:

- Increase in bone density- Increase in lean tissue- Decrease in adipose tissue- Modulate lipoprotein metabolism (eg decreased serum LDL) - Improved mood & motivation- Improved exercise capacity- Increase in cardiac contractility

• Use lower GH doses (0.1-0.2 mg/day) in all patients w/ diabetes or who are susceptible to glucose intolerance, & elderly >60 years old

• It is recommended to retest patients transitioning from pediatric to adult care (especially those w/ isolated GHD)

GH Replacement � erapy in Children• Indicated for GHD in children, Turner syndrome, Prader-Willi syndrome, Noonan syndrome, short children

small for gestational age, children w/ short stature homeobox-containing gene (SHOX) defi ciency, & children w/ impaired growth due to chronic kidney disease

• May also be used for children w/ ISS shorter than -2.25 SD score whose epiphyses are not closed, & w/ expected adult height below the normal range [160 cm (<63 inches) for males, 150 cm (<59 inches) for females]

• Eff ects:- Induce normal statural growth- Correction of hypoglycemia

• Target for treatment:- Satisfactory response is defi ned as an increase in height velocity of at least 2-2.5 cm/year above pretreatment

velocity- Achieve acceptable adult height

• Replacement is continued until attainment of bone age of 14 years (girls) & 16 years (boys) or if the child has achieved at least 10th percentile of adult height

• In certain patients, surgical therapy may also be needed for congenital anomalies & pituitary tumorsGonadotropin-Releasing Hormone (GnRH) Agonist• Studies found GnRH agonists to be eff ective when given concurrently w/ recombinant GH• May delay epiphyseal fusion & prolong growth during puberty• Increases height & velocity in some growth hormone-defi cient pediatric patientsRecombinant IGF-1/Mecasermin• Alternative treatment for patients w/ GH receptor abnormalities, STAT5b gene defects, & those w/ severe GH

defi ciency unresponsive to therapy due to development of antibodies against GH• Further studies are needed to prove its effi cacy in GHD

Not all products are available or approved for above use in all countries.Specifi c prescribing information may be found in the latest MIMS.

B FOLLOW-UP & MONITORING OF ADULT PATIENT• Monitor monthly initially for response to treatment & adjust dose accordingly• Plasma glucose should be checked initially & every 3 months• Once maintenance doses are achieved, measurement of serum FBS, IGF-1, hemoglobin A1c, waist circumference,

waist-to-hip ratio, BMI, serum free T4, & clinical assessment of hypothalamic-pituitary-adrenal axis or by early morning cortisol or cosyntropin stimulation test (in patients not on glucocorticoid replacement), testosterone, & fasting lipid panel should be done every 6-12 months

• DEXA (Dual Energy X-ray Absorptiometry) scan is recommended prior to & during GH therapy- 1st DEXA scan after initiation of GH replacement should be done at approximately 2 years later & repeated

at 2-3 year intervals • MRI is recommended at baseline in patients w/ any postsurgical tumor remnant in the hypothalamic-pituitary

region before starting GH therapy- Periodic MRI is recommended while on GH therapy

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GHD

B105

Growth Hormone Defi ciency (7 of 8)

Not all products are available or approved for above use in all countries.Specifi c prescribing information may be found in the latest MIMS.

C FOLLOW-UP & MONITORING OF PEDIATRIC PATIENT• Close follow-up care w/ an endocrinologist is recommended to monitor the child’s growth, assessment of

potential adverse eff ects, & to adjust the dose of GH therapy• Initial follow-up should be every month; thereafter, visits may be less frequent but should be at least 2x/year• Monitor every 3-6 months for response to treatment & adjust dose accordingly

- Serum IGF-1 & IGFBP-3 levels should be obtained annually to eff ectively monitor treatment adherence & response

- Dose should be reduced if serum IGF-1 levels increases above the normal range- Monitor thyroid function every 6 months- Bone age, HbA1c levels, & adrenal function should also be assessed regularly- Monitor patients for hyperglycemia because GH may reduce insulin sensitivity; patients w/ DM may need

to adjust their insulin during treatment• Continue GH therapy if there is persistent GHD even after adult height is achieved to obtain full skeletal/

muscle maturation during the transition period• GHD may persist to adult life

- Retesting may be required especially in idiopathic GHD patients (retest using adult criteria after 1-3 months without GH therapy)

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GHD

B106

Growth Hormone Defi ciency (8 of 8)

1Prescribed end points: IGF-I in normal range for age & sex (increase dose if IGF-1 is low & decrease dose if IGF-1 is above normal range), improvement in blood lipid profi le, body composition (change in lipolysis & increase in bone density) & waist-hip ratio, in-creased muscle strength & exercise performance, better quality of life & reduction in CV risk factors.

All dosage recommendations are for non-pregnant & non-breastfeeding women, & non-elderly adults w/ normal renal & hepatic function unless otherwise stated.

Not all products are available or approved for above use in all countries.Products listed above may not be mentioned in the disease management chart but have been

placed here based on indications listed in regional manufacturers’ product information.Specifi c prescribing information may be found in the latest MIMS.

Please see the end of this section for the reference list.

Dosage Guidelines

TROPHIC HORMONES & RELATED SYNTHETIC DRUGS

Drug Dosage Remarks

Somatropin (rDNA origin)

Adults:Individualize dosageInitial dose0.15-0.3 mg/day SCMay increase dose based on patient’s response & side eff ectsMax dose1 mg/day (3 IU/day)Children:Individualize dosage0.07-0.1 IU/kg/day SC or0.025-0.035 mg/kg/day SC/IM or2.1-3 IU/m2 BSA/day SC or0.7-1 mg/m2 BSA/day SC/IM

Adverse Reactions• Adults: Paresthesia, arthralgia, myalgia,

stiff ness in the extremities, peripheral edema

• Children: Transient local skin reactionsSpecial Instructions• Somatropin should not be given when

there is evidence of tumour activity; anti-tumour therapy must be completed prior to initiating therapy

• Should not be used for growth promotion in children w/ closed epiphyses

• Somatropin may induce a state of insulin resistance & in some patients, hyperglycemia; patients should therefore be observed for evidence of glucose intolerance

• Test thyroid function after initiation of Somatropin treatment & after dose adjustments

• Doses should be individualized for each patient; adjust dose based on patient’s clinical response (prescribed endpoints1, tolerance to side eff ects)

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