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American Association of Clinical EndocrinologistsEndocrinology2019advanced

Management of Growth Hormone Deficiency in Adults and Patients Transitioning from Pediatric to Adult Care

Published by American Association of Clinical Endocrinologists and American College of Endocrinology · 2017 AACE Protocol for Standardized Production of Clinical Practice Guidelines

58Recommendations
357References
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Summary

AI-generated

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.

growth hormone deficiencyGHrhGHAACEendocrinologyguidelinesdiagnostic testingIGF-1

Key Takeaways

  • 1
    GH-stimulation tests should be selected based on clinical context and utilize BMI-appropriate cut-points.
  • 2
    The insulin tolerance test (ITT) remains the gold standard, but the glucagon-stimulation and macimorelin tests are valid alternatives.
  • 3
    rhGH dose titration should be highly individualized rather than weight-based, targeting an age-adjusted IGF-1 SDS between -2 and +2.
  • 4
    rhGH replacement is strictly contraindicated for active malignancy and severe diabetic retinopathy.
  • 5
    Prescribing rhGH for sports enhancement or anti-aging is illegal and unapproved.

What's New in This Version

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.

Key Recommendations

WHAT IS ADULT GHD?

  • R1

    Consider the possibility of adult GHD in each individual patient with a history of hypothalamic-pituitary disease.

    Grade BEvidence: BEL 2Screening
  • R2

    Be aware that adults can be diagnosed with GHD in childhood (CO-GHD) and adulthood (AO-GHD).

    Grade BEvidence: BEL 2Diagnosis
  • R3

    Consider the possibility of GHD in patients with isolated idiopathic GHD and hypothalamic-pituitary tumors and/or their treatment regimens.

    Grade BEvidence: Expert OpinionScreening
  • R4

    Screening may be considered in patients with nontumoral causes of adult GHD (e.g., TBI, subarachnoid hemorrhage, ischemic stroke, CNS infections).

    Grade CEvidence: BEL 2Screening

ARE THERE ANY DIFFERENCES BETWEEN CO-GHD VERSUS AO-GHD?

  • R5

    Recognize the differences in the etiology of CO-GHD versus AO-GHD as there are phenotypic differences.

    Grade AEvidence: BEL 1Diagnosis

HOW SHOULD PEDIATRIC PATIENTS WITH CO-GHD BE TRANSITIONED TO ADULT-CARE SERVICES?

  • R6

    Pediatricians should start counseling patients and caregivers early about the potential of future transition and collaborate closely with adult endocrinologists.

    Grade CEvidence: BEL 2Management

WHAT ARE THE BENEFITS OF CONTINUING rhGH REPLACEMENT IN TRANSITION PATIENTS WITH CO-GHD?

  • R7

    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.

    Grade AEvidence: BEL 1Monitoring
  • R8

    Resuming rhGH replacement therapy in patients with confirmed persistent GHD during the transition period is recommended.

    Grade AEvidence: BEL 1Treatment

WHO SHOULD BE TESTED FOR ADULT GHD?

  • R9

    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.

    Grade DEvidence: Expert OpinionDiagnosis
  • R10

    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.

    Grade CEvidence: BEL 3Diagnosis
  • R11

    In patients with ≤2 PHD, perform 1 GH-stimulation test to confirm diagnosis, as low IGF-1 alone is insufficient.

    Grade BEvidence: BEL 4Diagnosis
  • R12

    Retest transition patients with idiopathic isolated GHD and low/low-normal IGF-1 after at least 1 month following rhGH discontinuation.

    Grade BEvidence: BEL 4Diagnosis
  • R13

    Perform 1 or 2 GH-stimulation tests in transition patients with organic hypothalamic-pituitary disease based on the degree of clinical suspicion.

    Grade BEvidence: BEL 4Diagnosis
  • R14

    Retest most transition patients with GH-stimulation test(s) when longitudinal growth is complete and at least 1 month after pediatric rhGH therapy ends.

    Grade AEvidence: BEL 1Diagnosis
  • R15

    Retesting and rhGH therapy are not required in transition patients with idiopathic IGHD and IGF-1 ≥0 SDS.

    Grade CEvidence: BEL 2Diagnosis
  • R16

    Retesting is not required in transition patients with MPHD (≥3 PHD) and low IGF-1, genetic defects, or structural brain defects.

    Grade CEvidence: BEL 2Diagnosis
  • R17

    Consider retesting patients who initially test as GH-sufficient after radiation therapy later in transition or adulthood.

    Grade BEvidence: BEL 2Diagnosis
  • R18

    Perform GH-stimulation testing only after at least 12 months following TBI or subarachnoid hemorrhage.

    Grade BEvidence: BEL 2Diagnosis

HOW SHOULD ONE TEST FOR ADULT GHD?

  • R19

    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.

    Grade BEvidence: BEL 4Diagnosis
  • R20

    Perform GH-stimulation tests only after all other pituitary hormone deficiencies have been optimally replaced.

    Grade CEvidence: BEL 4Diagnosis
  • R21

    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.

    Grade BEvidence: BEL 1Diagnosis
  • R22

    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).

    Grade BEvidence: BEL 2Diagnosis
  • R23

    Use a peak GH cut-point of 2.8 µg/L for the macimorelin test.

    Grade BEvidence: BEL 2Diagnosis
  • R24

    In transition patients, use ITT as test of choice; consider GST and macimorelin test as alternatives.

    Grade CEvidence: BEL 2Diagnosis
  • R25

    Do not use Arginine (ARG) and levodopa (L-DOPA) testing due to low sensitivity and specificity.

    Grade BEvidence: BEL 2Diagnosis

WHY ARE STANDARDIZED GH AND IGF-1 ASSAYS IMPORTANT IN THE MANAGEMENT OF ADULT GHD?

  • R26

    Laboratories should adopt NIBSC standards and state assay methodology.

    Grade CEvidence: BEL 4Management
  • R27

    Assay manufacturers should indicate the validation of their assays.

    Grade CEvidence: BEL 4Management
  • R28

    Use the same IGF-1 assay for a given patient throughout evaluation and follow-up.

    Grade CEvidence: BEL 4Monitoring
  • R29

    Quality-control materials should be used and widely verified.

    Grade CEvidence: BEL 4Management
  • R30

    Employ reliable sera from healthy subjects and patients with interfering conditions for assay validation.

    Grade CEvidence: BEL 4Management
  • R31

    Provide normative IGF-1 assay data from a sufficient random sample.

    Grade CEvidence: BEL 4Management
  • R32

    Laboratories should report IGF-1 SDS values alongside serum levels.

    Grade CEvidence: BEL 4Management

HOW SHOULD INITIATION AND MONITORING OF rhGH REPLACEMENT BE UNDERTAKEN?

  • R33

    No single commercial rhGH product is suggested over another.

    Grade DEvidence: Expert OpinionTreatment
  • R34

    Use serum IGF-1 as the biomarker for guiding rhGH dose adjustments.

    Grade AEvidence: BEL 1Monitoring
  • R35

    Individualize rhGH dosing independent of body weight, starting low and up-titrating gradually.

    Grade AEvidence: BEL 1Treatment
  • R36

    Target serum IGF-1 levels within the age-adjusted reference range (IGF-1 SDS between –2 and +2).

    Grade DEvidence: Expert OpinionTreatment
  • R37

    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.

    Grade AEvidence: BEL 1Treatment
  • R38

    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.

    Grade AEvidence: BEL 1Monitoring
  • R39

    Assess serum IGF-1, fasting glucose, HbA1c, fasting lipids, BMI, waist circumference, free T4, and HPA axis at 6- to 12-month intervals.

    Grade CEvidence: BEL 2Monitoring
  • R40

    When restarting rhGH therapy in transition patients, resuming at 50% of the childhood dose may be considered.

    Grade DEvidence: Expert OpinionTreatment
  • R41

    Monitor transition patients annually for height, weight, BMI; measure DXA and lipids periodically.

    Grade DEvidence: Expert OpinionMonitoring
  • R42

    Monitor cardiovascular parameters (fasting lipids, blood pressure, heart rate) at 6- to 12-month intervals.

    Grade CEvidence: BEL 2Monitoring
  • R43

    Measure bone mineral density at baseline; repeat at 2- to 3-year intervals if abnormal.

    Grade CEvidence: BEL 4Monitoring
  • R44

    Perform baseline MRI in patients with post-surgical tumor remnant, and periodic MRIs during therapy.

    Grade CEvidence: BEL 4Monitoring
  • R45

    Assess baseline and annual QoL using specific QoL-AGHDA questionnaires.

    Grade CEvidence: BEL 4Monitoring
  • R46

    Monitor glucocorticoid and thyroid hormones closely upon rhGH initiation, as adjustments may be required.

    Grade BEvidence: BEL 1Monitoring
  • R47

    Continue rhGH replacement indefinitely if beneficial effects are experienced.

    Grade BEvidence: BEL 2Treatment

CAN rhGH BE USED DURING CONCEPTION AND PREGNANCY?

  • R48

    Routine use of rhGH for conception or continued use during pregnancy is not recommended at this present time.

    Grade CEvidence: BEL 3Treatment

WHAT ARE THE SIDE EFFECTS OF rhGH REPLACEMENT?

  • R49

    Use lower doses of rhGH in obese and older patients to avoid fluid retention-related side effects.

    Grade AEvidence: BEL 1Treatment
  • R50

    Avoid high rhGH doses to minimize side effects and aim to maintain target serum IGF-1 levels between -2 and +2 SDS.

    Grade AEvidence: BEL 1Treatment

HOW SAFE IS LONG-TERM rhGH REPLACEMENT THERAPY?

  • R51

    Adjust antidiabetic medications and/or lower rhGH dose if DM develops or worsens; consider pausing rhGH to optimize DM treatment first.

    Grade BEvidence: BEL 1Management
  • R52

    Treatment with rhGH is contraindicated in patients with active malignancy (except certain skin cancers) and active proliferative or severe nonproliferative diabetic retinopathy.

    Grade BEvidence: BEL 2Treatment
  • R53

    Conduct rhGH treatment with caution in patients with a strong family history of cancer.

    Grade BEvidence: BEL 2Treatment
  • R54

    Initiate low-dose rhGH therapy at least 5 years after cancer remission is achieved, following discussion with the patient’s oncologist.

    Grade DEvidence: Expert OpinionTreatment
  • R55

    Perform continued long-term monitoring and standard cancer screening, although there is no clear evidence that rhGH increases cancer risk or tumor recurrences.

    Grade BEvidence: BEL 2Monitoring

IS rhGH RECOMMENDED FOR SPORTS AND ANTI-AGING?

  • R56

    Drug testing involving urine sampling is not recommended for detecting rhGH abuse in sports.

    Grade AEvidence: BEL 1Screening
  • R57

    Under no circumstances should rhGH be prescribed for sports enhancement or 'anti-aging' purposes.

    Grade AEvidence: BEL 1Treatment

WHAT ARE NEW DEVELOPMENTS IN THIS FIELD?

  • R58

    Clinicians may follow the developments of long-acting GH preparations, which are currently investigational and not commercially available yet in the U.S.

    Grade CManagement

Scope & Objectives

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

Clinical EndocrinologistsPediatricians

Patient Criteria & Setting

Therapeutic Area

Endocrinology

Guideline Scope

ScreeningDiagnosisTreatmentManagement

Special Populations

Transition patientsElderly patientsCancer survivorsObese patientsPatients with diabetes mellitusPatients with traumatic brain injuryPregnant women

Evidence Grading

System: 2017 AACE Protocol for Standardized Production of Clinical Practice Guidelines

Evidence Distribution

61EL_3_weak
51EL_1_strong
357total_citations
168EL_2_intermediate
12Grade_A_recommendations
19Grade_B_recommendations
21Grade_C_recommendations
6Grade_D_recommendations
77EL_4_no_clinical_evidence

Evidence Levels

1Strong evidence (e.g., Meta-analysis of RCTs, RCTs)
2Intermediate evidence (e.g., Meta-analysis of nonrandomized trials, prospective cohorts, epidemiological studies)
3Weak evidence (e.g., Case series, single case reports, preclinical studies)
4No clinical evidence (e.g., theory, opinion, consensus, review, position, policy, guideline)

Recommendation Strength

DescriptionGrades map to the best evidence level (BEL) ratings based on highest quality supporting evidence level (EL), modified by subjective factors and recommendation qualifiers. Direct mapping: EL 1 to Grade A, EL 2 to Grade B, EL 3 to Grade C, EL 4 to Grade D. Consensus dictates upgrades or downgrades.

Safety & Contraindications

Contraindications

  • Active malignancy (other than basal-cell or squamous-cell skin cancers)
  • Active proliferative or severe nonproliferative diabetic retinopathy

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.

Authors & Contributors

Kevin C. J. YuenBeverly M. K. BillerSally RadovickJohn D. CarmichaelSina JasimKevin M. PantaloneAndrew R. Hoffman

Guideline Features

Dosing informationFlowcharts includedDrug interactions discussed

Learning Context

Difficulty

advanced

Learning Paths

Growth Hormone DeficiencyEndocrinologyDiagnostic TestingRecombinant Human Growth HormonePediatric to Adult TransitionClinical Guidelines