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Published by American Association of Clinical Endocrinologists and American College of Endocrinology · 2017 AACE Protocol for Standardized Production of Clinical Practice Guidelines
Adult growth hormone deficiency is associated with multiple adverse metabolic abnormalities and increased cardiovascular morbidity. This guideline update summarizes current knowledge regarding the accuracy of available GH-stimulation tests, rhGH dosing regimens targeting IGF-1 normalization, and the long-term safety profile of rhGH replacement.
Key Takeaways
This 2019 update expands on the 2009 guidelines by summarizing current knowledge on the accuracy of diagnostic tests (like macimorelin and BMI-adjusted GST), addressing the heterogeneity of GH/IGF-1 assays, refining individualized rhGH dose-titration strategies targeting IGF-1 normalization, emphasizing long-term safety, addressing sports/anti-aging misuse, and discussing new long-acting GH preparations.
Consider the possibility of adult GHD in each individual patient with a history of hypothalamic-pituitary disease.
Be aware that adults can be diagnosed with GHD in childhood (CO-GHD) and adulthood (AO-GHD).
Consider the possibility of GHD in patients with isolated idiopathic GHD and hypothalamic-pituitary tumors and/or their treatment regimens.
Screening may be considered in patients with nontumoral causes of adult GHD (e.g., TBI, subarachnoid hemorrhage, ischemic stroke, CNS infections).
Recognize the differences in the etiology of CO-GHD versus AO-GHD as there are phenotypic differences.
Pediatricians should start counseling patients and caregivers early about the potential of future transition and collaborate closely with adult endocrinologists.
Follow up adults with CO-GHD caused by structural pituitary or brain tumors closely during transition due to risks of low bone mineral density and adverse cardiovascular markers.
Resuming rhGH replacement therapy in patients with confirmed persistent GHD during the transition period is recommended.
Perform GH-stimulation test(s) based on the appropriate clinical context of each patient with a reasonable clinical suspicion of GHD, with intent to initiate rhGH.
Diagnose adult GHD without stimulation testing in patients with organic hypothalamic-pituitary disease, ≥3 pituitary hormone deficiencies, and low IGF-1 (<-2.0 SDS), genetic defects, or structural brain defects.
In patients with ≤2 PHD, perform 1 GH-stimulation test to confirm diagnosis, as low IGF-1 alone is insufficient.
Retest transition patients with idiopathic isolated GHD and low/low-normal IGF-1 after at least 1 month following rhGH discontinuation.
Perform 1 or 2 GH-stimulation tests in transition patients with organic hypothalamic-pituitary disease based on the degree of clinical suspicion.
Retest most transition patients with GH-stimulation test(s) when longitudinal growth is complete and at least 1 month after pediatric rhGH therapy ends.
Retesting and rhGH therapy are not required in transition patients with idiopathic IGHD and IGF-1 ≥0 SDS.
Retesting is not required in transition patients with MPHD (≥3 PHD) and low IGF-1, genetic defects, or structural brain defects.
Consider retesting patients who initially test as GH-sufficient after radiation therapy later in transition or adulthood.
Perform GH-stimulation testing only after at least 12 months following TBI or subarachnoid hemorrhage.
Random GH and IGF-1 levels cannot be used alone for diagnosis; use GH-stimulation test(s) except in defined populations with clear organic disease.
Perform GH-stimulation tests only after all other pituitary hormone deficiencies have been optimally replaced.
Use the insulin tolerance test (ITT) as the gold-standard test; use glucagon-stimulation test (GST) and macimorelin test as alternatives if ITT is contraindicated.
Utilize BMI-appropriate GH cut-points for the GST (3 mg/L for normal/overweight with high probability; 1 mg/L for obese/overweight with low probability).
Use a peak GH cut-point of 2.8 µg/L for the macimorelin test.
In transition patients, use ITT as test of choice; consider GST and macimorelin test as alternatives.
Do not use Arginine (ARG) and levodopa (L-DOPA) testing due to low sensitivity and specificity.
Laboratories should adopt NIBSC standards and state assay methodology.
Assay manufacturers should indicate the validation of their assays.
Use the same IGF-1 assay for a given patient throughout evaluation and follow-up.
Quality-control materials should be used and widely verified.
Employ reliable sera from healthy subjects and patients with interfering conditions for assay validation.
Provide normative IGF-1 assay data from a sufficient random sample.
Laboratories should report IGF-1 SDS values alongside serum levels.
No single commercial rhGH product is suggested over another.
Use serum IGF-1 as the biomarker for guiding rhGH dose adjustments.
Individualize rhGH dosing independent of body weight, starting low and up-titrating gradually.
Target serum IGF-1 levels within the age-adjusted reference range (IGF-1 SDS between –2 and +2).
Initiate therapy at 0.1-0.2 mg/day in patients with DM, obesity, older age; use 0.3-0.4 mg/day in nondiabetic young adults <30 years and women on oral estrogen.
Follow up at 1- to 2-month intervals initially, adjusting doses by 0.1-0.2 mg/day; monitor at 6- to 12-month intervals once maintenance is achieved.
Assess serum IGF-1, fasting glucose, HbA1c, fasting lipids, BMI, waist circumference, free T4, and HPA axis at 6- to 12-month intervals.
When restarting rhGH therapy in transition patients, resuming at 50% of the childhood dose may be considered.
Monitor transition patients annually for height, weight, BMI; measure DXA and lipids periodically.
Monitor cardiovascular parameters (fasting lipids, blood pressure, heart rate) at 6- to 12-month intervals.
Measure bone mineral density at baseline; repeat at 2- to 3-year intervals if abnormal.
Perform baseline MRI in patients with post-surgical tumor remnant, and periodic MRIs during therapy.
Assess baseline and annual QoL using specific QoL-AGHDA questionnaires.
Monitor glucocorticoid and thyroid hormones closely upon rhGH initiation, as adjustments may be required.
Continue rhGH replacement indefinitely if beneficial effects are experienced.
Routine use of rhGH for conception or continued use during pregnancy is not recommended at this present time.
Use lower doses of rhGH in obese and older patients to avoid fluid retention-related side effects.
Avoid high rhGH doses to minimize side effects and aim to maintain target serum IGF-1 levels between -2 and +2 SDS.
Adjust antidiabetic medications and/or lower rhGH dose if DM develops or worsens; consider pausing rhGH to optimize DM treatment first.
Treatment with rhGH is contraindicated in patients with active malignancy (except certain skin cancers) and active proliferative or severe nonproliferative diabetic retinopathy.
Conduct rhGH treatment with caution in patients with a strong family history of cancer.
Initiate low-dose rhGH therapy at least 5 years after cancer remission is achieved, following discussion with the patient’s oncologist.
Perform continued long-term monitoring and standard cancer screening, although there is no clear evidence that rhGH increases cancer risk or tumor recurrences.
Drug testing involving urine sampling is not recommended for detecting rhGH abuse in sports.
Under no circumstances should rhGH be prescribed for sports enhancement or 'anti-aging' purposes.
Clinicians may follow the developments of long-acting GH preparations, which are currently investigational and not commercially available yet in the U.S.
Clinical Topic
Growth Hormone Deficiency
Objectives
To provide guidelines on assessment, screening, diagnostic testing, and treatment recommendations for a range of individuals with various causes of adult GHD and patients transitioning from pediatric to adult care.
Target Patient Population
Adults and patients transitioning from pediatric to adult-care services with growth hormone deficiency (GHD).
Diagnostic Criteria
Reasonable clinical suspicion combined with a failed GH-stimulation test (ITT, GST, or macimorelin). Patients with >=3 pituitary hormone deficiencies and a low IGF-1 (<-2.0 SDS), genetic defects, or hypothalamic-pituitary structural brain defects do not require stimulation testing.
Target Providers
Therapeutic Area
EndocrinologyGuideline Scope
Special Populations
System: 2017 AACE Protocol for Standardized Production of Clinical Practice Guidelines
Evidence Distribution
Evidence Levels
Recommendation Strength
Contraindications
Monitoring Guidance
Assess at 6- to 12-month intervals: serum IGF-1, fasting glucose, HbA1c, fasting lipids, BMI, waist circumference, free T4, and the hypothalamic-pituitary-adrenal axis. Conduct baseline and periodic MRIs and DXA scans if clinically indicated.
Difficulty
advanced
Learning Paths