What is growth hormone deficiency?

Growth Hormone Deficiency: Overview

Definition and Pathophysiology

Growth hormone deficiency (GHD) is a clinical syndrome characterized by impaired production of GH by the pituitary gland, resulting in growth failure, short stature, and metabolic abnormalities that significantly impact quality of life. 1, 2

GHD represents a state of GH insensitivity characterized by deficiency of functional insulin-like growth factor 1 (IGF-1), which mediates the growth-promoting effects of GH. 3 The condition can manifest as:

• Isolated GHD: Affecting only GH secretion, with an estimated prevalence of 1 per 4,000-10,000 live births 2
• Multiple pituitary hormone deficiency: GHD occurring alongside deficiencies of other pituitary hormones, which is the most frequent pituitary deficit following pituitary surgery or radiotherapy 3

The Ras/MAPK signaling pathway plays a major role in mediating intracellular signaling of IGF-1, and dysregulation of this pathway contributes to growth failure. 3 In chronic kidney disease specifically, GHD results from reduced GH receptor expression in target organs like the liver, disturbed GH receptor signaling via the JAK2-STAT5 pathway, and increased IGF binding capacity due to excess IGF binding proteins. 3

Clinical Presentation

In Children and Adolescents

Diminished height velocity is the single most important clinical indicator beyond absolute height when evaluating for GHD. 4, 1 Key clinical features include:

• Growth failure: Height below the 3rd percentile with velocity below the 25th percentile indicates pathologic short stature requiring evaluation 3
• Severe growth retardation: Particularly evident in infancy, the most sensitive phase for growth-suppressing effects of GH insensitivity 3
• Short stature: Present in approximately two-thirds of children with certain genetic conditions associated with GHD 3
• Delayed puberty: May occur alongside growth failure, with hypogonadotropic hypogonadism requiring monitoring 3

Associated Clinical Findings

Beyond growth failure, additional clinical manifestations may be present depending on etiology:

• Neonatal hypoglycemia: Can be the presenting sign in congenital GHD 2
• Micropenis in males: May indicate congenital hypopituitarism 2
• Metabolic abnormalities: Including altered body composition with increased adipose-to-lean mass ratio 3
• Reduced bone mineral density: Particularly difficult to normalize even with treatment 3
• Impaired quality of life: Affecting self-esteem and social rehabilitation 3

Diagnostic Evaluation

Initial Assessment

Bone age assessment via radiography of the left wrist is the priority diagnostic study to determine remaining growth potential and whether epiphyses remain open. 3, 4 The diagnostic workup should include:

• Growth velocity documentation: Six months of growth cessation or persistent velocity below the 25th percentile beyond 3 months in infants or 6 months in older children warrants evaluation 3, 4
• Mid-parental target height calculation: To assess genetic potential and compare against current height 4
• Longitudinal growth chart review: From infancy to identify patterns of growth deceleration 4
• Thyroid function testing: TSH and free T4 to exclude hypothyroidism, a readily treatable cause of growth failure 4, 5

Confirmatory Testing

Two GH stimulation tests showing peak GH levels <20 mIU/L are necessary to confirm the diagnosis of GHD before initiating treatment. 6 However, important caveats exist:

• Random serum GH measurements are not recommended for screening (except in neonates) due to episodic and pulsatile GH secretion throughout the lifespan 7
• Existing stimulation test methods can be inaccurate, difficult to perform, and imprecise 7
• Multiple factors affect interpretation including patient age, specific test used, timing of measurements, and heterogeneity of GH and IGF-1 assays 7

Imaging and Genetic Evaluation

• MRI of the pituitary gland: Should be performed to diagnose defects in hypophyseal and hypothalamic structures 6, 5
• Genetic testing: May identify specific etiologies, particularly in congenital cases 2

Treatment Approach

Indications for GH Therapy

Prompt initiation of GH replacement is strongly recommended for children with proven GH deficiency who have not completed linear growth, given the limited window of opportunity to normalize body composition, promote catch-up growth, and attain normal adult height. 3

Specific indications include:

• Persistent growth failure: Height below the 3rd percentile AND height velocity below the 25th percentile beyond 3 months in infants or 6 months in children, once other treatable risk factors have been addressed 3
• Documented GH deficiency: Confirmed by appropriate dynamic testing 3
• Open epiphyses: Bone age assessment must demonstrate growth potential 3, 4

Treatment Regimen

GH should be administered at dosages of 0.045-0.05 mg/kg per day (or conventional replacement doses of 0.025 mg/kg per day) by daily subcutaneous injections until the patient reaches final height. 3

Key treatment principles:

• Early initiation: Administered early in life at adequate dosage, GH replacement therapy may significantly increase ultimate adult height 6
• Assessment timing: For post-surgical or post-radiotherapy patients, routinely assess for GH deficiency within 3 months after intervention 3
• Duration: Continue until bone age exceeds 14.0 years in females, growth rate falls below 2 cm/year, or epiphyseal closure occurs 4

Adjunctive Therapies

In specific situations, additional interventions may optimize outcomes:

• GnRH analogue therapy: Can be added to delay puberty and epiphyseal closure, enabling adequate catch-up growth 3
• Aromatase inhibitors: Combined treatment with GH may reduce bone maturation induced by estradiol in pubertal patients 3
• Sex steroid replacement: Required for patients with disturbed pubertal progression to enhance growth velocity 3

Contraindications

GH therapy must not be started in cases of:

• Closed or near-closed epiphyses: No growth potential remains 3, 4
• Active tumor: Presence of malignancy is an absolute contraindication 3
• Uncontrolled diabetes mellitus: Must be stabilized first 3
• Known hypersensitivity: To GH or its constituent parts 3

Special Populations

Post-Cushing Disease Remission

Children in remission from Cushing disease with growth retardation should be evaluated for GH deficiency with appropriate dynamic testing and receive early GH replacement therapy. 3 GH deficiency is the most frequent pituitary deficit following transsphenoidal surgery and pituitary irradiation. 3

Chronic Kidney Disease

In children with CKD, GHD results from a state of GH insensitivity that can be overcome by supraphysiological doses of recombinant human GH. 3 Treatment stimulates IGF-1 synthesis, normalizes somatomedin bioactivity, and promotes longitudinal growth. 3

Post-Radiotherapy

Radiotherapy-induced GH deficiency is universal by 5 years post-treatment, with multiple hormone deficiencies developing in approximately 20% at 5 years and 80% at 10-15 years post-radiotherapy. 5 This requires ongoing surveillance and hormone replacement as deficiencies develop gradually over years. 5

Genetic Syndromes

In conditions like 22q11.2 deletion syndrome and cardio-facio-cutaneous syndrome, GH deficiency is rare but when present, responds well to GH therapy. 3 Height and weight should be measured regularly, and GH therapy considered if testing indicates deficiency. 3

Monitoring and Follow-Up

During Treatment

• Growth velocity assessment: Regular monitoring to ensure adequate response 1, 8
• Bone age progression: Periodic radiographs to track skeletal maturation 3
• Adherence support: Daily injections over many years can affect adherence, requiring ongoing support 1
• Metabolic monitoring: Assessment of glucose metabolism and lipid profiles 2

Transition to Adulthood

At the end of longitudinal growth during the transition phase, it is necessary to re-evaluate GH secretion to determine if adult GHD is present and requires continued treatment. 1, 2 The benefits of continuing GH therapy throughout the transition period include:

• Improved body composition and bone mineral density 2
• Better metabolic health and quality of life 2
• Alleviation of physical and psychological problems from adult GHD 2

Long-Term Surveillance

Lifelong annual clinical assessment is essential for all patients with hypopituitarism, including those with GHD. 5 This includes:

• Monitoring for recurrence: In cases of acquired GHD, particularly post-tumor treatment 3
• Assessment of other pituitary hormones: Additional deficiencies can develop over time, especially after radiotherapy 3, 5
• Psychiatric and neurocognitive monitoring: Long-term cognitive and memory problems may persist despite treatment 3

Treatment Efficacy and Outcomes

Treatment with recombinant human GH is effective and safe, but there remains a substantial fraction of children who do not achieve adult height within the normal range even with current treatment regimens. 8 Factors affecting outcomes include:

• Age at diagnosis and treatment initiation: Earlier treatment generally yields better results 3, 6
• Severity of deficiency: More severe deficiency may require higher doses or longer treatment 8
• Adherence to daily injections: Critical for optimal outcomes over many years of treatment 1
• Underlying etiology: Congenital versus acquired GHD may have different prognoses 1, 2

Common Pitfalls and Caveats

Diagnostic Errors

• Assuming pathology without bone age assessment: Growth cessation at age 17 most likely represents normal completion of growth rather than disease 4
• Relying on random GH measurements: These are not useful due to pulsatile secretion patterns 7
• Failing to exclude thyroid dysfunction: A readily treatable cause that must be ruled out before diagnosing idiopathic short stature 4
• Misinterpreting stimulation test results: Multiple factors including age, test type, and assay variability affect interpretation 7

Treatment Errors

• Starting GH therapy with closed epiphyses: No benefit when growth potential is exhausted 3, 4
• Inadequate dosing: Suboptimal doses may not overcome GH insensitivity, particularly in conditions like CKD 3
• Delayed initiation: Missing the critical window in infancy and early childhood limits final height potential 3, 6
• Failing to address other hormone deficiencies: In multiple pituitary hormone deficiency, adrenal insufficiency must be treated first before thyroid or GH replacement 5

Monitoring Failures

• Inadequate long-term surveillance: Particularly after radiotherapy, where deficiencies develop gradually over 10-15 years 5
• Not reassessing at transition: GH secretion should be re-evaluated at the end of linear growth to determine need for adult replacement 1, 2
• Overlooking psychiatric effects: Long-term cognitive and quality of life impacts require ongoing monitoring 3