2. Recommendations for GH Treatment in Children and Adolescents
M.Hashemipour ,MD,
Professor of pediatric endocrinology
Isfahan university of medical science
April

3. Outline Normal growth Growth monitoring & short stature
Evaluation of short stature
Indications for Growth Hormone therapy in children
Is GH mitogenic ??
GH Replacement and Risk of Cancer
What is the good response to GH?
How long can we continue GH therapy?

4. Outline Persistent GHD GH therapy in adults
Contraindications to GH therapy

5. The height of an individual
Depends on
Ggenetics
Nnutritional status
Hormonal milieu
various environmental factors

6. Normal Growth 

7. Normal range for height
3rd -97th
–2 SD +2 SD
Growth chart2
1. Hermanussen. Horm Res Pediatr 2010:74:153–64; 2.

8. Phases of Growth The infantile phase The childhood phase
The infantile phase
The childhood phase
The pubertal phase

9. Growth velocity 1st yr 25 cm / yr 2nd yr 12 – 14 cm / yr
3rd yr – 8 cm / yr
4th yr to puberty – 6 cm / yr 9

10. Increase height Girls grow an average of 23 to 28 cm during puberty
Boys grow an average of 26 to 28 cm during puberty
Post menarche cm
In the beginning of menses
Girls have achieved to %95 of their height

11. Growth monitoring & short stature

12. Importance of growth monitoring
indicator of general health and well-being
identification of disorders in the apparently normal child
Growth retardation is recognised as a relatively early sign of poor health .

13. Growth velocity A minimum interval of 6 months.
9 – 12 months are preferable
Velocity growth is important than HTth 13

14. Accurate determination of growth rate is important
Seasonal variation
Fall-Winter: slow
Spring-Summer: Faster

15. Subnormal growth rate 2 yr < 7 cm 3 yr < 6.5 cm
4 yr - Puberty < 4 cm
Growth rate <25th 2 times

16. Subnormal growth Height Dropping Across 2 Major Percentile Lines
on the Growth Chart

17. Evaluation

18. Which children should be evaluate?
Ht. Between Mean SD
No Lab Tests, Observe Growth rate
Ht. Between 2SD SD
Screening Tests if Normal, Observe Growth rate
Ht.> 3SD< Mean
Screening Tests follow Full Pituitary Assessment

19. Which children should not to be evaluated?
Short children
Normal height velocity
Gonadal dygenesis

20. investigations FBS CBC ESR, CRP Electrolytes liver enzymes
Celiac panel
Ca, p , AlkP
BUN,Cr

21. investigations Urinalysis and pH Karyotype Bone age IGF 1, IGF BP3 TFT
Prolactin
Cranial imaging- MRI

22. Bone Age Normal bone age within ±2 years of CA Estimation of height
To guess underline disease
Not to increase height when
BA=14-15Y Girls
BA=16-17Y Boys

23. Who needs to do GH provocative test s?
Severe short stature (height <−3SD)
Height <−2SD with height velocity <−1SD over 1 year
Height velocity <−2SD over 1 year
Child with sellar–suprasellar mass
Child with signs and symptoms of an intracranial lesion

24. How to define GH deficiency after GH dynamic tests ?
GH level <10 ng/ml : subnormal
Cutoff <7 ng/ml : severe GHD
GHRH–arginine ≤19 ng/ml is suggested because of its high potency.

25. Should we treat based on GH provocative test results?
We recommend against reliance on GH provocative test results as the sole diagnostic criterion of GHD.

26. Indications for Growth Hormone therapy in children

27. History of growth hormone therapy27 27 27

28. GH Therapy FDA Approval
Growth hormone deficiency
Chronic renal failure
Turner Syndrome
SHOX gene abnormality
Prader-Willi Syndrome
SGA
Idiopathic short stature
Noonan Syndrome

29. indications of GH treatment
Crohn's disease
Cystic fibrosis
Chondrodysplasia
Height Deficit at Puberty
X-linked hypophosphatemic rickets.
AIDS wasting or cachexia
Short-bowel syndrome
JRA

30. GH Treatment of GHD First indication for rhGH approved by FDA.
Use of GH to normalize AH and avoid extreme shortness.

31. Indications for GH therapy in SGA
In Europe
Height is less than 2.5 SDS below the mean for age and sex at 4 years of age.
In United States
Height remains less than 2.5 standard deviation scores (SDS) below the mean for age and sex at 2 years of age
All possible causes of SS should be ruled out

32. Pathophysiology of short stature in SGA
Increase GH and IGFBP1
Decrease IGF-1, IGF-2 and insulin in cord
GH deficiency

33. Body composition after GH therapy in SGA
increase growth velocity
Changes in body composition
increasing the muscle and lean body mass
Decreasing adipose tissue content

34. Idiopathic short stature
Stature <2.25 SD mean for age
No endocrine, metabolic disease
Often normal growth velocity
No biochemical condition
Often normal IGF-I & IGFBP-3
Normal GH responses stimulate test

35. ISS& GH Therapy FDA in 2003 Height <-2.25 SD mean
Epiphyses are not closed
Expected adult height is less than
160 cm for boys
150 cm for girls

36. First percentile to perhaps the 10th Controversy about GH therapy
ISS& GH Therapy
Optimal age for initiating treatment
3 yr to early puberty
It is estimated that it would cost US$100,000 or more to treat someone, but might only move them from the
First percentile to perhaps the 10th
Controversy about GH therapy

37. ISS& GH Therapy
Approximately 5-cm (2-inch) increase in AH with approximately 5 years of GH treatment
Patients and their parents/guardians should be counseled that not starting GH therapy at all is an option

38. ISS& Height improvement
Ht SDS improvement after 12 months of therapy should be assessed
Discontinuation of GH therapy should be considered if adequate height gain has not been achieved

39. Prader-Willi Syndrome
Genetic
Microdeletion of a part of the paternal chromosome 15q11-13
uniparental maternal disomy of the same region

40. Prader-Willi Syndrome
Neonatal hypotonia
Cryptorchidism
Hypothalamic dysfunction
lack of satiety and obesity
some with adrenal insufficiency
Cognitive and behavioral differences
scoliosis

41. Prader-Willi Syndrome
Developmental delay
Hypogonadism
Increased risk of cardiovascular diseases
Diabetes mellitus
Osteoporosis

42. GH therapy & Prader-Willi Syndrome
The inspiratory and expiratory muscle strength improved
Decrease in the apnea-hypopnea index (AHI)
improvements in motor development, muscle tone
improvements in cognition and behavior
Decrease adiposity

43. GH therapy & Prader-Willi Syndrome
improvement in growth velocity
improvements final height
improvements in head circumference
increase adiponectin is deemed highly Beneficial due to its protective effect on the cardiovascular system and insulin resistance

44. Factors contributing to GH Resistance in chronic kidney disease
Resistance to GH and IGF-I
Serum concentration of GH increased, metabolic clearance decreased
GH receptor expression decreased
Signal transduction of GHR impaired
IGF-I production decreased
IGF activity decreased by inhibitory IGF binding proteins

45. Height velocity < 25th centile over a one year period
indications of growth hormone therapy in CKD : .
Height velocity < 25th centile over a one year period
Height < 3 th or drifting across the centiles
One year post trasplantation
CRF/Dialysis/Nephrotics

46. Turner syndrome

47. Symptoms Swollen hands and feet Wide and webbed neck
Absent or incomplete development at puberty, including sparse pubic hair and small breasts
Broad, flat chest shaped like a shield
Drooping eyelids
Short height
Vaginal dryness
Low-set ears.
Low hairline at back of neck

48. Turner syndrome SHOX gene haploinsufficiency
Bone tissue resistance to IGF

49. Growth From Birth Day Recent studies have demonstrated
Growth velocity is indeed subnormal
in the first 18 months
One to three year
A loss of about 8 to 9 cm by age 3 years

50. Growth From Birth Day Height SDS At birth –0.5 -– -1.24
At ag 1 yr –1.5
At age –1.8
At age

51. GH Treatment Should be initiated the height falls
Below the fifth percentile for age
which occurs between two and five years of age
Thus early initiation and duration of therapy are important
As soon as growth failure is evident

52. TS& GH response Factors predictive of taller adult stature
Tall parental heights
young age at initiation of therapy, as early as 9 months,
A long duration of therapy
A high GH dose.

53. Discontinue Therapy in TS
Therapy may be continued until
satisfactory height
girls Bone age >14years
yearly growth velocity falls to less than cm/year

54. Noonan Syndrome Pulmonary valvular stenosis facial dysmorphy
Hypertelorism
paddle neck
Thoracic cage excavation
Deafness
Hypogonadism
Cryptorchidism
intellectual disability
Bleeding diathesis
Lymphedem

55. Skeletal Dysplasia & GH
Reports of response to GH are variable
Some data indicate little change in growth rate, even when higher than conventional dosages are used
More recent studies suggest that GH therapy can increase growth rate and height z-score in a dose-dependent manner without significant side effects
Effects on ultimate height remain unknown

56. Treatment of short stature

57. GH as an Anabolic hormone
Improved lean tissue mass, height and weight gain, and decreased protein catabolism
AIDS, Crohn’s disease and chronic ulcerative colitis ,cystic fibrosis

58. may slightly hasten the appearance of a second neoplasm
GH Replacement and Risk of recurrent Cancer in Patients with previous malignancies
There is many controversial in Patients with previous malignancies or history of radiation therapy about recurrence and second malignancy
may slightly hasten the appearance of a second neoplasm
Not increase risk of second neoplasm

59. Is GH mitogenic ??
Most recurrences occur within the first 2 years of treatment
A standard waiting period of 12 months to establish “successful therapy”of the primary tumor

60. GH Replacement and Cancer Risk
IGF-I and GH are mitogenic, anti-apoptotic, and their receptors are found in tumors
Colon, breast, thyroid, and prostate cancer
Hodgkin’s disease?
Data suggest permissive/facilitative rather than causative role for GH in oncogenesis

61. GH Replacement and Cancer Risk
incidence of new-onset leukemia or malignancies is not increased
High-normal levels of free IGF-I may increase rates of breast and prostate cancers

62. Safety of GH Therapy in Children with Malignancy Risk
Certain patient groups who receive GH treatment carry an intrinsic risk of developing malignancies, including those with Neurofibromatosis type 1, Fanconi anemia, Downs and Bloom syndromes.
we recommend providing counseling regarding the lack of evidence concerning GH effect on malignancy risk in these groups

63. Decision-making For children with acquired GHD due to effects of a primary malignancy
We recommend shared decision-making that involves the patient, family, oncologist, and treating endocrinologist.
Before of treatment, we recommend sharing with families the most recent data about risks, including the potential effect of GH treatment on the timing of second neoplasm occurrence.

64. Safety of GH Therapy in Diabets type 1
GH Therapy in Diabetes mellitus is not contraindication
Needs close observation

65. Growth-Promoting Treatment: Expansion of Use
GH treatment poses some possible serious long term adverse events that are not acceptable risks in a healthy child with normal AH potential
Regardless of parents’ ability to pay, GH treatment for height augmentation in children who do not fit the criteria of ISS should be discouraged

66. Before Treatment
The degree of physical and/or psychosocial disability that an individual child suffers due to short stature could be used to determine which children should receive GH therapy

67. Before Treatment For children considered not to be at risk
we recommend that counseling includes information about the unknown long-term (i.e., post treatment) risks of neoplasia and other side effects
Be informed about the uncertainty regarding long-term safety

68. Before Treatment
30% increase in all-cause mortality compared to the general population
Bone tumor-related (5.00; CI 1.01–14)
Circulatory system (3.07; CI 1.4–5.8)
Cerebral hemorrhage (6.66; CI 1.8–17) events

69. What is the good response to GH?
After one year of therapy
An increase in HV of 50% or at least 2.5 cm/year above the baseline HV
Height SDS should increase at least
0.25 SDS (1-2SDS)in the first year

70. How long we can continue GH therapy?
Continue treatment until linear growth decreases to less than 2.0 to 2.5 cm/year
BA 13 to 13.5 years in girls
BA 15.5 to 16 years in boys.16 – 17
Patient has reached satisfactory adult height
Epiphyses have fused

71. How to monitor a child on rhGH therapy ?
Height, Weight, Body proportions, Waist
3 monthly
Height velocity
6 monthly
Bone age,IGF1
Annually

72. 96 % of children with MPHD have persistent GHD.
Do all children with GHD require reassessment during transition to adulthood ?
50 % of children with isolated idiopathic GHD do not have persistent disease .
96 % of children with MPHD have persistent GHD.

73. Transitional phase
We recommend GH provocative testing to evaluate the function of the somatotropic axis in the transition period if indicated by a low IGF-I level.
Many young adults who had GHD in childhood have normal GH

74. Persistent GHD Multiple ( ≥ 3) pituitary hormone deficiencies
GHD with a documented causal genetic mutation
GHD with a specific pituitary/hypothalamic structural defect except ectopic posterior pituitary

75. GH therapy in adults pituitary adenomas Craniopharyngioma
Empty sella syndrome
Sheehan’s syndrome.

76. Signs and symptoms of adult GHD
impaired contractility of the heart
Reduced lean body mass and strength of muscles
Increased body fat
Reduced BMD
Reduced exercise performance
increased plasma cholesterol ,fibrinogen and homocysteine
Adults with GHD have a significantly increased risk of death from cardiovascular causes
Decreased quality of life

77. Provocative testing is advised
Testing can be performed after a trial of at least 1 month off GH treatment
Needs in all of condition except persistent GHD

78. GH Treatment: Balance of Benefit, Risk, and Cost
For children with ISS who do not have GHD, the benefits of achieving taller stature via GH treatment are uncertain and of a lesser magnitude than the treatment benefits experienced by children with GHD.

79. Adverse effects of GH treatment
In first 8 weeks – Benign Intracranial Hypertension
Peripheral edema
Carpal tunnel syndrome
Arthralgia & Myalgia
Slipped capital femoral epiphysis (SCFE 0.4 to 2.5 years
Scoliosis
Central adrenal and thyroid axes deficiency

80. Adverse effects of GH treatment
SAGhE showed an increase in overall mortality in the French subgroup of GH-treated patients with ISS, GHD and SGA

81. Contraindications for GH therapy
Acute critical illnesses caused by open heart,abdominal surgery, multiple accidental trauma
Acute respiratory failure
Closed epiphysis
Active infection or sepsis
Active neoplasm
History of cancer shorter than 1-2 years

82. Contraindications for GH therapy
End-stage diabetic microangiopathy including proliferative retinopathy, nephropathy
Benign cranial hypertension
pregnant women should be discontinued in the second trimester ,resumed after delivery
Application of GH during lactation requires further examination.

83. Contraindications for GH therapy
The GH administration in nursing mothers is another questionable issue, because safety of the infant
Has not been determined yet and, therefore, the
application of GH during lactation requires further examination

84. Conclusion
Short stature per se is not a disease, and the relationship between AH and adult quality of life is weak and poorly understood
Not recommended GH to any child with short stature
Psychological counseling should always be offered for patients suffering due to their stature

85. Referrences Clinical Rounds in Endocrinology 2016
Horm Res Paediatr 2016
UP TO DATE 2016
Uptodate 2013
WILLIAMS 2011
SPERLING 2014
Pharmacol Rep. 2007 Sep-Oct;59(5):500-1