Recommendations for GH Treatment in Children and Adolescents M.Hashemipour ,MD, Professor of pediatric endocrinology Isfahan university of medical science April 19-21 2017

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?

Outline Persistent GHD GH therapy in adults Contraindications to GH therapy

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

Normal Growth 

Normal range for height 3rd -97th –2 SD +2 SD Growth chart2 1. Hermanussen. Horm Res Pediatr 2010:74:153–64; 2. http://www.who.int/childgrowth/en/

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

Growth velocity 1st yr 25 cm / yr 2nd yr 12 – 14 cm / yr 3rd yr 7 – 8 cm / yr 4th yr to puberty 4 – 6 cm / yr 9

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 1-7cm In the beginning of menses Girls have achieved to %95 of their height

Growth monitoring & short stature

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 .

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

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

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

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

Evaluation

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

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

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

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

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

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

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.

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.

Indications for Growth Hormone therapy in children

History of growth hormone therapy 27 27 27

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Turner syndrome

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

Turner syndrome SHOX gene haploinsufficiency Bone tissue resistance to IGF

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

Growth From Birth Day Height SDS At birth –0.5 -– -1.24 At ag 1 yr –1.5 At age 1.5 –1.8 At age 3 -3.0

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

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.

Discontinue Therapy in TS Therapy may be continued until satisfactory height girls Bone age >14years yearly growth velocity falls to less than 2-2.5 cm/year

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

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

Treatment of short stature

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

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

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

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

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

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

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.

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

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

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

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

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

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

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 14 - 15 BA 15.5 to 16 years in boys.16 – 17 Patient has reached satisfactory adult height Epiphyses have fused

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

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.

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

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

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

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

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

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.

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

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

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

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.

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

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

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