Growth Hormone

Therapy

Guided By : Dr. Arif Vohra

Presented by : Dr. Mitul Kasundra

 Growth Hormone
 Growth hormone, also called somatotropic
hormone or somatotropin, is a small protein
molecule that contains 191 amino acids in a single
chain and has a molecular weight of 22,000.
released by Anterior Pituitary by somatotroph cells

 It causes growth of almost all tissues of the

body that are capable of growing.

 It promotes increased sizes of the cells and

increased mitosis, with development of greater
numbers of cells and specific differentiation of cells
such as bone growth cells and early muscle cells
Regulation of GH Secretion
 Production of growth hormone is modulated by
many factors, including stress, exercise, nutrition,
sleep and growth hormone itself. However, its
primary controllers are two hypothalamic hormones
and one hormone from the stomach.
 Growth hormone-releasing hormone (GHRH) is a
hypothalamic peptide that stimulates both the
synthesis and secretion of growth hormone.
 Somatostatin (SS) produced by several tissues in
the body, including the hypothalamus, inhibits GH
release.
 Ghrelin secreted from the stomach binds to
receptors on somatotrophs and potently stimulates
secretion of growth hormone.
DIURNAL VARIATION OF GROWTH HORMONE
PHYSIOLOGICAL FUNCTION OF GROWTH
HORMONE
 Reduces liver uptake of glucose.
 Promotes gluconeogenesis in the liver.
 Increases protein synthesis.
 Increases muscle mass through sarcomere
hyperplasia.
 Promotes lipolysis.
 Stimulates division and multiplication of
chondrocytes of cartilage.
 Increasing height in children and adolescents.
 Increases calcium retention, and strengthens
and increases the mineralization of bone
 Stimulates the growth of all internal organs
excluding brain.
 Contributes to the maintenance and
function of pancreatic islets.
 Stimulates the immune system
Causes of GH Deficiency
 CONGENITAL :
 Idiopathic
 Birth trauma/ perinatal insult: breech,
forceps , perinatal insult
 Structural brain defects:

a. anencephaly
holoprosencephaly
pituitary aplasia-hypoplasia
midfacial anomalies-cleft lip &palate
septo-optic dysplasia
solitary maxxilary central incisor
 Identified genetic mutations
 Familial isolated GH deficiency

a.autosomal recessive and dominant,x-

linked
b.bioinactive growth hormone
 Familial multiple pituitary deficiencies

a.autosomal recessive mutations-HESXI

(SOD),LHX3,LHX4,SOX3,PROP-1,PIT-1
b. autosomal dominant type 2- PIT-1.
c.sex linked type-3- GH,TSH,ACTH ,LH &FSH
deficiency
d. pallister hall syndrome
 GH receptor defect(GH insensitivity)
 IGF-1 synthetic defect
 ACQUIRED:
 trauma :birth trauma/ perinatal insult
 Infection:meningitis,encephalitis
 CNS tumours.
 Hypothyrodism
 Psychological deprivation
Clinical Features of GHD
 Neonatal period: hypoglycemic convulsion,
prolong jaundice,micropenis, cryptorchidism,
history of breech delivery but height is not
affected till infancy.
 Children:
 Reduced growth velocity much below 10th
percentile for age with normal body
proportions
 Weight is equal to or more than expected for
his height.
 Skeletal maturation delayed.
 In males,genitalia
underdeveloped,microgenitalia
 Examination
• Skin- thin, prematurely aged
 elbow-limited extensibility
• Sparse hair growth before 7 yrs
• Prominent forehead, frontal bossing
• Skull-normal head circumference, craniofacial
disproportion due to small facies,delayed
frontanelle closure
• Small facies
• Hypo plastic nasal bridge
• Shallow orbit
• Delayed eruption of teeth
• High pitched voice
When to suspect GHD
 Severe short stature(height<-3SD)
 Severe growth retardation ( height velocity
standard deviation <-2 SD over 12 months)
 Bone age and height age are assessed in
relation to chronological age.
 Physiological & systemic causes of short
stature to be ruled out.
Diagnosis
Midparental height
bone age
Growth velocity over 12 months
Chart 1
 Initial clinical and bone age assessment
Severe short stature(height<-3SD)
Low growth velocity <10th percentile(often<3 cm/year)
Target height below -2SD mid-parent height

IGF-1 AND IGF binding protein level

if significantly low (-2SD for age) indicates

abnormal hypothalamic pituitary or IGF axis

GH stimulation test
If all GH levels are below 5ng/ml-growth hormone deficiency,
5-10 ng/ml-partial growth hormone deficiency
 Chart 2
GH stimulation test
poor response to test. GH deficiency present.
exclude other pituitary hormone deficiency.
neuroimaging for pituitary size,morphology and
to exclude neoplasm
high basal and peak GH- GH insensitivity. Check
level of GH binding protein.

normal response. Follow up and check for

sustained
deceleration of growth.
Stimulation test
 Prior to stimulation test euthyroid state eessential
before testing.
 Propranolo 0.75 microgram/kg oral maximum up to
40 mg 2 hours before glucagon or l-dopa test
enhances GH secretion.
 Priming with sx steroids in short children with
delayed puberty and a bone age of 10 tears or more.
 Two standard provocative tests are usually
recommended unless ther is overwhelming clinical
evidences.
 All tests are done after overnight fast.
 Specificity with a normal GH response is nearly 98
percent.
MRI & Genetic other hormone
testing
 Imaging studies is useful in evaluation of GH
deficiency to rule out organic causes and in
studying pituitary morphology , size. E.g.
ectopic posterior pituitary with anterior
pituitary hypoplasia and an interruption of or
absence of pituitary stalk.
 In a newborn with suspected GH deficiency
USG may help detect midline defects and
associated cerebral anomalies.
 Molecular genetic testing used in inherited
forms of GH deficiency.
History of growth hormone therapy
 extracted growth hormone was used since
the late 1950s until the late 1980s when its
use was replaced by recombinant GH.
 1981, the new American corporation
Genentech, after collaboration with Kabi,
developed and started trials of recombinant
human growth hormone (rHGH) made by a
new technology (recombinant DNA) in which
human genes were inserted into bacteria so
that they could produce unlimited amounts
of the protein.
 Initially,growth hormone was injected
intramuscularly
 In mid 1980s, it was shown as effective when
administered as a subcutaneous injection
 Early in its use, growth hormone was
administered twice weekly; this was increased
to 3 times weekly when the higher frequency
was shown to result in an increased growth
response
 6-7 injections per week were shown to yield
an even better growth response than
administering injections 3 times per week
 Daily administration is now commonly used
 USE of Growth hormone in 6 conditions
approved by FDA
 growth hormone deficiency
 turner syndrome
 Noonan syndrome
 Chronic renal failure
 Idiopathic short stature
 Prader willi syndrome
 Small for gestational age
 SHOX gene mutations and leri weill dychondrosteosis
 Short bowel syndrome
 AIDS (catabolic states)

 Otheruses xlinked hypophosphatemic rickets(study

going on)
Administration of growth hormone
 GH is administered daily by subcutaneous
injection in the evening 6-7 times a week,
varying the site of injection.
 Increased frequency of GH administration
improves growth rate, suggesting the so-
called pulsing message of GH to its target
cells
 administration of GH is recommended in
evening as GH half life is more prolonged.
And forms higher peaks than with morning
injections.
 First year of treatment usually produces the
greatest growth increment
 Seasonal variation in growth rate during GH
therapy, with peaks in the summer and
nadirs in the winter has also been described
DOSE:
 GH dose used to be measured in
international units but now milligrams are
used universally(1 mg=3 IU).
 IN children, body size dosing is used based
on body weight (mg/kg) or body surface area
(mg/m2).
 Body weight method has advantage of
increase GH dose during puberty there by
mimicking the physiological increase. While
per body surface area prevents excessive
dosing in obese patients.
INITIATION:
 Before initiation of GH of therapy, other
treatable causes of short stature should be
either be excluded or adequately treated.
 Initial assessment should include a bone age
and an estimation of predicted adult height.
 Adequate growth data must be gathered over
12 months.
 The data will provide a comparison for the
growth response on GH therapy.
 In children with severe GH deficiency and
chronic renal failure it has been to commence
GH therapy at 50 percent of the normal
replacement dose and increase the dose
during first month to avoid adverse effect of
GH doses in various conditions

Indication Mg/m2/week Mg/kg/week

Growth hormone 4.5-9.5 0.16-0.30
deficiency
Chronic renal failure 9.5 0.35
Turner syndrome 9.5 0.35
Idiopathic short 7.5-9.5 0.23-0.35
stature
Small for 7.5-9.5 0.23-0.35
gestational age
Prader willi 4.5-7.5 0.16-0.23
syndrome
DOSE TITRATION:
1. Aim of GH therapy is to induce catch
up growth (growth velocity >50th
percentile for a child’s bone age) and
to achieve height standard deviation
score within the target range for the
family background.
2. Once the target range is attained, aim
of therapy is to maintain an
individual’s height standard deviation
score to achieve final height equal to
their midparental height.
3. IGF 1 Level
Monitoring
Height,weight, GV (3-6 monthly)
Pubertal staging (peripubertal age)
Bone age
Psychological Evaluation
Laboratory
◦ IGF 1
◦ RBS
◦ HB1AC
◦ Thyroid Function
Cessation of GH therapy

 Reaching an acceptable height close to

target height.
 Growth velocity decreasing to less than
2cm/year.
 Bone age reaching 16years in boys or 14
years in girls.
Adverse effects
Incidence 0.023-0.05 adverse
events/patient/year
 In first 8 weeks – Benign Intracranial Hypertension
◦ Has been reported in 1 in 1000 children receiving
GH treatment
◦ due to the increase in salt and water retention
 complain of headache, loss of vision, nausea or
vomiting.
 resolves rapidly when growth hormone treatment
is stopped
 GH can usually then be restarted at a lower dose,
and the dose slowly increased without further
problems
 Slipped capital femoral epiphysis (SCFE)
◦ Children with GHD require close monitoring
for the symptoms of SCFE, most commonly
pain in the hip or knee, or a limp
 In children with scoliosis, the degree of the
scoliosis may get worse when growth is
accelerated with growth hormone treatment
 GH excess reduces insulin sensitivity, and
given the trend toward higher dosages, it is
important to assess a GH dosage’s effect on
carbohydrate metabolism
 IGF-1 has mitogenic and anti-apoptic actions.
Certain patient groups who receive GH
treatment carry an intrinsic risk of developing
malignancies, including those with, growth
hormone deficiency due to cranial
irradiation,Fanconi anemia, Downs and Bloom
syndromes, , such children be carefully
monitored with regard to tumor formation. So
monitoring of IGF-1 is essential during high
dose GH therapy.
 Increase malanin production lead to skin
pigmentation
 Pancreatitis.
 Acromegaly
 Gynecomastia
 Indications of growth hormone therapy:

growth hormone deficiency:

 GH therapy in children with growth hormone
deficiency induces initial rapid catch –up growth
during the first 2-3 years of treatment , increasing
growth velocity 2-4 fold above the pretreatment
growth rate during the 1 year of therapy. Over all aim
for this period of catch-up growth is for the individual
to attain a height standard deviation score within the
target range for family as calculated from midparental
height.
 Younger age at commencement of GH therapy
positively influences final height outcome.
 If GH deficiency diagnosed ,screen for other pituitary
hormones deficits and perform neuroimaging
 Consider gonadotropin releasing hormone analouge
at the onset of puberty if standard deviation of height
is poor at onset of puberty, height ,135 cm in males
and ,130 cm in females.
 Puberty is early or rapidly progressive.
 If growth hormone is diagnosed, screen for other
pituitary hormone deficits and perform neuroimaging.
 In hypogondal patient,sex steroid replacement should
be started at 12-13 years of age in girls and 12.5-13.5
year of age in boys.
 At final height
 Reassess GH status,the underlying condition and
adequacy of other pituitary hormones replacement
therapies.
 Considerongoing therapy in adolescent /adults with
severe growth hormone deficiency(growth
hormone<3microgram/l).

 Reassessment of GH status at final height: when

response to GH therapy declines below 2 cm per year,
it is presumed that final height is reached. After final
height has been achieved, GH therapy should be
discontinued and GH status reassessed to identify
those with persistent severe GROWTH HORMONE
DEFICIENCY(peak GH <5 ng/ml). Discontinuation of
GH therapy is recommended for a period of 1-3
months before retesting. Patient undergoing
reassessment of GH status should have their serum
IGF-1 level measured and one or two provocative tests
of GH secretion performed.
 Efficacy
demonstrated in large international
databases with growth velocity in first year of
therapy of 8-10 cm.

 Daily subcutaneous injection 6-7 times a week.

 Consider ongoing therapy in adolescent /adults
with severe growth hormone deficiency(growth
hormone<3microgram/l)
TURNER SYNDROME:

 Growth hormone testing is not necessary.

 Gh therapy should be started either
 When height falls below -2standard
deviation on standard growth chart or short
stature becomes a problem for child or by
the age of 8 years.
 In general female pubertal induction with
estrogen should be started at a bone age of
11 years or chronological age of 12-13
years.
Noonan syndrome

 Consider GH therapy for those children

shorter than -2.25 standard deviation with a
predicted height below 160 cm(males) or
150cm(females).
 DOSE: between 0.23 mg/kg/week and
0.46mg/kg/week have been used.
Idiopathic Short Stature
 Consider GH therapy <2.25 SD (-1.2%)
below the mean in height and predicted
height below 160 cm(males) or
150(females).
 the most effective GH therapy will require
substantial growth acceleration prior to
puberty.
 Gh therapy to start when height falls below
-2 SD on standard growth chart.
Small for gestational age
 GH therapy is approved in child with small
for gestational age who have following
criteria:
 <-2 SD birth weight or length
 <-2.5SD for age and gender at 4 yrs of age
or older
 > 1 SD below mid parent height.
 Start GH therapy early at 4-6 years
Chronic renal failure

 Poornutrition, anemia, and chronic metabolic

acidosis contribute to the growth failure

 Elevated GH level, exaggerated responses to

provocative stimuli, depressed serum IGF-1
levels, and increased levels of IGF-1 binding
protein (in particular IGFBP-1) suggest
resistance to the action of GH .

 In
general, responsiveness to GH appears to
be inversely related to the degree of renal
function impairment and metabolic
compromise.
Prader willi syndrome
Etiology of the growth hormone deficiency
 Primary hypothalamic dysfunction
 Secondary to obesity

GH treatment of these pts increases height

velocity and lean body mass and decreases
adiposity

Examination of upper airway and sleep is

mandatory.
Advantages of Growth Hormone
Replacement
 Improves linear growth
 Body composition changes producing a
reduction in total and visceral fat and
increase in lean body mass
 Appropriate onset of puberty and adequate
development of primary and secondary
sexual organs.
 Improved psychological development of the
child because of adequate physical and
sexual development of child.
 Increases bone mineral density.
 Prevention of hypoglycemic convulsion.
IGF-1 THERAPY
 IGF-1 therapy is the only treatment in states of
growth failure in children with primary IGF deficiency.
E.g. GH resistance such as laron syndrome or with
growth hormone gene deletion who have developed
neutralizing antibodies to GH.
 IGF-1 is administered by onceor twice daily injection
as the half life is shorter than for GH.
 adverse effects are mostly caused by over-dosage
but acute insulin like side effects are also observed.
 usual daily dose in children ranges 100-200
microgram/kg.
 It is less effective and the response is not
comparable to GH response in children with growth
hormone deficiency.