What are the typical presentation and treatment of adult growth hormone (GH) deficiency in adults with a history of pituitary disease, pituitary surgery, or radiation therapy?

Presentation of Adult Growth Hormone Deficiency

Adults with growth hormone deficiency (GHD) following pituitary disease, surgery, or radiation present with a constellation of metabolic, cardiovascular, musculoskeletal, and psychological abnormalities that collectively constitute the "adult GHD syndrome," requiring systematic evaluation and consideration for GH replacement therapy to reduce morbidity and improve quality of life. 1, 2

Clinical Presentation

Metabolic and Body Composition Abnormalities

• Increased visceral adiposity and total body fat mass, particularly central/abdominal obesity, with reduced lean body mass and muscle mass 1, 2, 3
• Dyslipidemia with elevated LDL cholesterol and unfavorable lipid profiles 1, 4
• Insulin resistance and impaired glucose metabolism, increasing risk for type 2 diabetes 1, 4
• Reduced extracellular fluid volume 4

Musculoskeletal Manifestations

• Decreased bone mineral density (BMD) with increased fracture risk, particularly vertebral fractures 5, 1, 4
• Proximal myopathy with reduced muscle strength, impaired stair climbing ability, and difficulty straightening up 5
• Reduced exercise capacity and physical performance 1, 2, 4
• Muscle atrophy that persists even after remission of underlying pituitary disease 5

Cardiovascular Risk Profile

• Impaired cardiac function and reduced myocardial performance 2, 6
• Increased cardiovascular and cerebrovascular disease risk, contributing to elevated mortality 5, 1
• Abnormal lipid profiles that worsen cardiovascular risk 1, 2

Psychological and Quality of Life Impact

• Decreased energy levels and reduced vitality 1, 4, 3
• Impaired quality of life with social isolation and reduced positive well-being 1, 2, 4
• Depressed mood and increased anxiety 4, 3
• Cognitive dysfunction and memory deficits that may persist long-term 5
• Reduced sleep quality and objective reductions in marital and socioeconomic performance 3

Other Clinical Features

• Reduced sweating ability and impaired thermoregulation 6
• Subnormal kidney function 6
• Abnormal thyroid hormone metabolism 6
• Reduced energy expenditure 6

Epidemiology and Risk Factors

Prevalence After Pituitary Disease/Treatment

• GHD prevalence varies significantly with timing of assessment after pituitary surgery: 50-60% when tested within 2 years post-surgery, declining to 8-13% when tested more than 2 years post-surgery 5
• Post-radiotherapy GHD is extremely common: 36% at 99 months after remission, with GH deficiency becoming universal by 5 years post-radiotherapy 5
• Multiple hormone deficiencies develop progressively: approximately 20% at 5 years and 80% at 10-15 years post-radiotherapy 7

High-Risk Populations Requiring Evaluation

Only evaluate patients with clear risk factors for pituitary dysfunction to avoid overdiagnosis 1:

• Sellar masses or pituitary tumors 1
• History of pituitary surgery 1
• Cranial or craniospinal radiation therapy 7, 1
• Traumatic brain injury 1
• Subarachnoid hemorrhage 1
• Childhood-onset GHD with closed epiphyses 8
• Hypothalamic disease 8

Special Populations

• GHD in Cushing's disease patients is more common in women and younger patients, with higher rates of diabetes, hypertension, bone loss, fractures, and worse quality of life compared to other GHD etiologies 5
• Patients with macroadenomas and aggressive surgical resection are at highest risk for hypopituitarism 5

Diagnostic Approach

Critical Timing Considerations

• Wait at least 6-12 months after pituitary surgery before assessing for GHD, as postoperative HPA axis recovery is often delayed 5
• Evaluate and replace other pituitary hormone deficiencies first, particularly adrenal insufficiency, before testing for GHD 7, 1
• Never initiate thyroid hormone before glucocorticoid replacement, as this can precipitate life-threatening adrenal crisis 7

Screening Tests

• IGF-I levels alone are insensitive for diagnosing adult GHD and should not be used as the sole diagnostic criterion 5
• IGF-I levels can be in the lower half of normal range even with confirmed GHD on dynamic testing 5
• Morning laboratory assessment should include thyroid function, cortisol/ACTH, gonadal hormones, and prolactin 7

Dynamic Stimulation Testing

Dynamic testing is required in most cases to confirm GHD diagnosis 1:

• Insulin tolerance test remains the gold standard stimulation test 5, 1
• Glucagon stimulation test is an alternative option 5, 1
• GHRH-arginine test can be used (showed 65% GHD rate at median 3 years post-surgery) 5
• Macimorelin stimulation test is newly approved, though prevalence data in this population are not yet available 5

Exceptions to Dynamic Testing Requirement

Patients with ≥3 additional pituitary hormone deficiencies are very likely to have GHD and do not require dynamic testing 5, 1:

• Multiple pituitary hormone deficiencies due to organic disease 8
• Congenital/genetic GHD 8

Imaging

• MRI of the sella with dedicated pituitary cuts is required for comprehensive evaluation 7

Treatment Considerations

Indications for GH Replacement

GH replacement should be considered routine management for adults with confirmed hypopituitarism and GHD 2:

• Adults with childhood-onset GHD whose epiphyses are closed should be reevaluated before continuation at reduced adult doses 8
• Adults with adult-onset GHD due to pituitary disease, hypothalamic disease, surgery, radiation, or trauma 8

Dosing for Adults

• Start with no more than 0.04 mg/kg/week given as daily subcutaneous injection 8
• Dose may be increased at 4- to 8-week intervals according to individual requirements 8
• Weight-based dosing should be adjusted regularly 8

Benefits of GH Replacement

GH replacement improves or normalizes many features of adult GHD 2, 6:

• Decreased body weight, waist circumference, and visceral adiposity 5
• Improved total and LDL cholesterol profiles 5
• Improved bone mineral density 5, 6
• Enhanced quality of life and psychological well-being 5, 2
• Increased lean body mass and muscle strength 2, 6
• Improved exercise capacity 2, 6
• Normalized energy expenditure and thermoregulation 6
• Improved myocardial and kidney function 6

Important Caveats About GH Treatment

• In patients with pre-existing glucose intolerance, GH may worsen glucose metabolism 5
• GH treatment has not yet been shown in randomized prospective trials to reverse metabolic syndrome or cardiovascular/cerebrovascular complications 5
• If GH replacement is implemented earlier than 2 years after pituitary surgery, retest periodically to determine whether GH secretion has normalized upon HPA axis recovery 5

Adjunctive Management

• Physical rehabilitation is recommended for all patients with CS-associated myopathy, as it does not spontaneously resolve during remission 5
• Consider bisphosphonates and vitamin D/calcium supplementation for bone protection 5

Long-Term Monitoring

Surveillance Requirements

• Lifelong annual clinical and biochemical monitoring is essential for all patients with hypopituitarism 7, 9
• Monitor for both under-replacement and over-replacement 7
• Ongoing surveillance is mandatory as radiation-induced deficiencies develop gradually over years 7
• Monitor for psychiatric and neurocognitive effects long-term 5, 7
• In young adults, monitor pubertal progression and bone mineral density prior to adult transition 9

Monitoring During Treatment

• Do not use TSH to monitor central hypothyroidism; use free T4 levels instead 7
• Regular assessment of IGF-I levels, body composition, lipid profiles, and glucose metabolism 8
• Periodic evaluation for side effects and treatment efficacy 8

Critical Pitfalls to Avoid

• Never diagnose GHD based on random GH levels, as GH secretion is pulsatile 1
• Do not rely solely on IGF-I levels for diagnosis in adults 5, 1
• Do not overlook the need to test and replace other pituitary hormones first, especially adrenal insufficiency 7, 1
• Do not assume GHD is permanent in the early post-surgical period; many patients recover GH secretion over time 5
• Be aware that radiation-induced deficiencies develop gradually and require long-term surveillance 7
• Do not initiate GH in patients with pre-existing severe glucose intolerance without careful monitoring 5