Transcript Growth hormone deficiency

INDICATIONS OF GH TREATMENT
Dr : Reem Murad
FDA-APPROVED INDICATIONS
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1985 -- Growth hormone deficiency
1993 -- Chronic renal insufficiency
1996 - adults GH deficiency
1997 -- Turner syndrome
2000 -- Prader-Willi syndrome
2001 -- Small for gestational age
2003 -- Idiopathic short stature (ISS)
2006- SHOX haploinsufficiency,
2007- Noonan syndrome
GROWTH HORMONE DEFICIENCY (GHD)
GH is absolutely indicated
 Efficacy demonstrated in large international
databases with growth velocity in first year of
therapy of 8-10 cm
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TURNER’S SYNDROME
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Phenotypic female
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Early ovarian failure
Short stature
Congenital heart defects
Hypothyroidism
Hearing loss
Osteoporosis
SGA
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a birth weight or length, more than 2 SD below
the mean for the gestational age and sex, for a
reference population.
SGA
guidelines are for FDA for the US. You can start
growth hormone treatment from the age of 2,
dosage is 70 mcg/kg,
 The European Agency Evaluation of Medicinal
Products says to start at the age of 4, the
height should be below -2.5, no catch-up
growth, less than -- or more than 1 SD below
the mean parental height, and the dosage is 35
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CRF
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Poor nutrition, 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
Dose in CRI > dose in GHD…( partial GH resistance).
50 µg/kg/d = 0.35 mg/kg/wk
Growth failure due to CRF is an approved indication for
GH therapy before transplantation
PRADER-WILLI SYNDROME
1/15,000 births
 Neonatal hypotonia and
cryptorchidism
 Hypothalamic dysfunction:
lack of satiety and
subsequent obesity; low sex
hormones and growth
hormone; some with adrenal
insufficiency
 Cognitive and behavioral
differences
 Cause is lack of expression of
paternal genes at 15q11-13
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NOONAN SYNDROME
an autosomal dominant disorder
 shares clinical features with TS,
 growth retardation usually in the absence
of GH deficiency
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IDIOPATHIC SHORT STATURE (ISS)
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Children who are 2.25 standard deviations below the mean
for height, with slow growth velocity and no other
diagnosable cause for short stature
IDIOPATHIC SHORT STATURE
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diopathic short stature (ISS) is a clinical description
rather than a disease.
A practical definition of ISS is a height below 2 standard
deviations (SD) of the mean for age, in the absence of
any endocrine, metabolic, or other disease that explains
the short stature .
In defining ISS for the indication of growth hormone
treatment, the US Food and Drug Administration (FDA)
uses the more stringent criterion of 2.25 SD below the
mean and a predicted adult height that is below the
normal range; this corresponds to an adult height <63
inches for males and <59 inches for females.
ISS
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ISS is a normal variant of growth.
Other normal variants are familial short stature (FSS) and
constitutional delay of growth and puberty (CDGP),
sometimes called constitutional short stature for prepubertal
children.
there is overlap between these variants, and many healthy
children with short stature have growth characteristics
consistent with more than one of these categories.
Children with ISS often have normal growth velocity,
no biochemical or other evidence for a specific growthrestricting condition, and have normal results of growth
hormone stimulation tests.
do not have growth hormone deficiency
ISS
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Treatment with (GH) for idiopathic short stature (ISS) is
controversial for two reasons.
First, the response to growth hormone is highly variable,
probably because of the heterogeneous endocrinologic
profile in children with ISS, and those children who respond
to growth hormone treatment may have only modest
increases in linear growth.
Second, there is little evidence that short stature represents
a substantial psychosocial burden to most short children.
The possible psychosocial benefit must be weighed against
the substantial cost and possible adverse effects of
treatment.
SHOX HAPLOINSUFFICIENCY
It is a gene The short stature homeobox (SHOX) located on
both the X and Y chromosom,
Located : pseudoautosomal regions at distal end of the X & Y
chromosomes at Xp22.3 & Yp11.3.
 associated with short stature in humans if mutated or
present in only one copy haploinsufficiency
 Discovered in 1997
 SHOX has an important role as mediator linear growth
 the SHOX gene has been found to play a role in idiopathic
short stature, Leri –weill dyschondrsteosis and Langer
mesomelic dysplasia.
 The SHOX gene is composed of 6 different exons and is
located in the pseudoautosomal region (PAR1) of the X
chromosome and Y chromosome.
 50 different mutations of SHOX gene.
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GROWTH HORMONE THERAPY
IN ADULTS
Growth hormone therapy may be approved for
the treatment of a dult with any of the
following conditions:
 A. Documented GHD in childhood
OR
 B. Documented hypopituitarism as a result of
pituitary disease, hypothalamic disease,
surgery, radiation therapy, Traum a or
aneurismal subarachnoid hemorrhage.
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THE DIAGNOSIS OF GHD
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1 A subnormal response to Two standard growth hormone
stimulation tests (possible stimulation tests include, but are not
limited to: insulin - induced hypoglycemia and combined arginine
growth hormone releasing hormone); defined as
Serum GH concentration of ≤5 ng/ml when using insulin induced
hypoglycemia testing;
b. Serum GH concentration of ≤4.1 ng/ml when using arginine;
OR
2. Subnormal response to 1 stimulation test for adults with
documented hypothalamic or pituitary disease An one or more
additional pituitary hormone deficits;
OR
3. Documented presence of at least three other pituitary hormone
deficiencies (growth hormone stimulation tests are not required in
this subgroup of individuals
IN ADULTS
approved uses of GH include:
 Short bowel syndrome
 HGH deficiency due to pituitary tumors or their
treatment.
 Muscle-wasting disease associated with
HIV/AIDS.
TREATMENT OF
AIDS WASTING SYNDROME
AIDS wasting syndrome defined as : a greater
than 10% of baseline weight loss that cannot
be explained by a Concurrent illness other than
HIV infection.
 Treatment is continued until this definition is
no longer met .
 Individuals treated with GH for A IDS wasting
must simultaneously be treated with antiviral
therapy
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SHORT BOWEL SYNDROME
the treatment of short bowel syndrome in
Individuals specialized nutritional support in
conjunction with optimal management of short
bowel syndrome.
 Specialized nutrition support may consist of a
high - carbohydrate, low - fat diet adjusted for
individual requirements
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NOT LICENSED INDICATIONS
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Short stature conditions where there have been
trials of treatment with GH but outcome is not
clear (not licensed indications):
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• Skeletal dysplasia
• Rheumatoid arthritis
• Down syndrome
• Short stature with prolonged steroid use
ACHONDROPLASIA
ACHONDROPLASIA
Autosomal Dominant Disorder.
 Affects about 1 in 25,000 people.
 About 98% of those with achondroplasia have a
point mutation in the FGFR3 gene at 4p16.3
that encodes fibroblast growth factor receptor 3.
 Growth response to GH is generally less than
that observed in children treated for classic GH
deficiency and declines after initial acceleration
 Effects on ultimate height remain unknown
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GLUCOCORTICOID-TREATED CHILDREN
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daily GH therapy for children with stable GC-treated
illness or who had undergone renal transplantation show
more consistent resumption of normal growth velocity
during 1–3 years of treatment
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Responsiveness to GH appears greatest in those on
moderate-dosage GC regimens with stable, nonarthritic
underlying disease.
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Persistence of disease activity and higher GC dosage
(e.g., prednisone dosage >0.35 mg/kg/day) interfere with
GH responsiveness
GROWTH HORMONE IS INVESTIGATIONAL?
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A.After renal transplant
B. Anabolic therapy, except for AIDS, provided to
counteract acute or chronic catabolic illness (e.g.
surgery, trauma, cancer, chronic hemodialysis)
producing catabolic (protein Wasti ng) changes in both
adult S and children
C. Anabolic therapy to enhance body mass or strength
for professional, recreational or social reasons
D. Constitutional delay of growth and development
E. Cystic Fibrosis
F Growth hormone treatment in combination with GnRH
agonist (Lupron) as a treatment of precocious puberty
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G. Hypophosphatemic rickets
H. Osteogenesis imperfecta
I. Osteoporosis
J. Short stature associated with growth hormone insensitivity (Laron Syndrome)
K. Therapy in older adults with normally occurring decrease in GH, who are not congenitally GH
deficient and who have no evidence of organic pituitary disease (this is referred to as Age - related
GH deficiency)
L. Treatment of congestive heart failure (CHF)
M. Treatment of individuals with burns
N. Treatment of fibromyalgia
O. Treatme nt of glucocorticoid - induced growth failure
P. Treatment of HIV lipodystrophy (fat redistribution syndrome), also referred to as altered body
habitus (e.g. buffalo hump), associated with antiviral therapy in individuals with HIV - infection
Q. Treatment of intrau terine growth restriction (IUGR) or Russell - Silver Syndrome that does not
result in SGA
R. Treatment of obesity
GH AS AN ANABOLIC HORMONE
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Anabolic effects of GH therapy have also created interest
in its use as ancillary therapy for several chronic
illnesses
GH has been shown to improve the body composition of
patients with acquired immunodeficiency syndrome’s
(AIDS) wasting syndrome (another FDA-approved use of
GH)
Improved lean tissue mass, height and weight gain, and
decreased protein catabolism have been reported in
children with Crohn’s disease and chronic ulcerative
colitis
In children with cystic fibrosis, a randomized controlled
trial showed significant improvements in height and
weight gain, lean tissue mass, and pulmonary function,
accompanied by decreased hospitalization time
HYPOPHOSPHATE RICKETS & GH
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In normal kidneys, GH increases renal phosphate
retention
Consequently, GH has been administered to poorly
growing children with X-linked hypophosphatemic rickets
Phosphate retention, bone markers, and radial bone
mineral density increased only in the GH-treated group
Additional long-term studies are needed to verify the value
of long-term GH therapy for patients with this disorder
Thank you