The levels of evidence (1 to 4) and the recommendation grades (A to D) are defined at the end of the "Major Recommendations" field.
Executive Summary of Recommendations
The following recommendations (labeled "R") are evidence based (Grades A, B, and C) or are based on expert opinion because of a lack of conclusive clinical evidence (Grade D). The BEL, which corresponds to the best conclusive evidence found, accompanies the recommendation grade in this Executive Summary.
R1. Growth hormone deficiency (GHD) is a well-recognized clinical syndrome in adults that is associated with significant comorbidities if untreated (Grade A; BEL 1).
R2. Growth hormone (GH) should only be prescribed to patients with clinical features suggestive of adult GHD and biochemically proven evidence of adult GHD (Grade A; BEL 1).
R3. No data are available to suggest that GH has beneficial effects in treating aging and age-related conditions and the enhancement of sporting performance; therefore, the guideline developers do not recommend the prescription of GH to patients for any reason other than the well-defined approved uses of the drug (Grade A; BEL 1).
Recommendations and Evidence Base for the Care of Transition Patients with GHD
R4. Patients with childhood-onset GHD (COGHD) previously treated with GH replacement in childhood should be retested after final height is achieved and GH therapy discontinued for at least 1 month to ascertain their GH status before considering restarting GH therapy. Exceptions include those with known mutations, those with embryopathic/congenital defects, those with irreversible hypothalamic-pituitary structural lesions, and those with evidence of panhypopituitarism (at least 3 pituitary hormone deficiencies) and serum insulin-like growth factor-I (IGF-I) levels below the age- and sex-appropriate reference range off GH therapy (Grade A; BEL 1).
R5. For childhood GH treatment of conditions other than GHD, such as Turner's syndrome and idiopathic short stature, there is no proven benefit to continuing GH treatment in adulthood; hence, there is no indication to retest these patients when final height is achieved (Grade B; BEL 2).
R6. The preferred GH stimulation test to establish the diagnosis of adult GHD in patients with childhood-onset GHD is the insulin tolerance test (ITT). Acceptable alternative stimulation tests include the growth hormone releasing hormone (GHRH)+arginine (ARG) test, the glucagon test, and, rarely, the ARG test alone (Grade A; BEL 1).
R7. In patients with hypothalamic GHD, e.g., idiopathic isolated GHD of childhood, the GHRH+ARG test may be misleading; hence, an ITT or glucagon stimulation test should be used (Grade A; BEL 1).
R8. Similar cut points for GH stimulation testing in the transition patients coming off GH therapy are applicable as for adults (Grade B; BEL 2).
R9. On restarting GH therapy, the starting dose of GH in transition patients should be approximately 50% of the dose between the pediatric doses required for growth and the adult dose (Grade C; BEL 3).
Recommendations and Evidence Base for the Diagnosis of Adult GHD
R10. Patients with irreversible hypothalamic-pituitary structural lesions and those with evidence of panhypopituitarism (at least 3 pituitary hormone deficiencies) and serum IGF-I levels below the age- and sex-appropriate reference range when off GH therapy are deemed to be GH deficient and do not require further GH stimulation testing (Grade A; BEL 1).
R11. The ITT remains the gold-standard test for diagnosing adult GHD. Acceptable alternative stimulation tests to diagnose adult GHD include the GHRH+ARG test, the glucagon test, and, rarely, the ARG test alone (Grade A; BEL 1).
R12. Appropriate GH cut points based on body mass index (BMI) should be used with the GHRH+ARG test, because body mass index has a well-validated effect on GH responses to GHRH and ARG stimulation (Grade A; BEL 1).
R13. In patients where the ITT is not desirable and when recombinant GHRH is not available, the glucagon test is a reliable alternative, but not the levodopa and clonidine tests (Grade C; BEL 3).
R14. Patients with hypothalamic GHD may demonstrate false-negative responses to the GHRH+ARG test. If the peak GH level is above the cut point in such patients, then these patients should be retested, if possible, with the ITT, glucagon test, or, rarely, the ARG test alone (using appropriate cut points) (Grade A; BEL 1).
R15. Traumatic brain injury and aneurysmal subarachnoid hemorrhage are now recognized conditions causing GHD. However, in patients with these conditions, GHD may be transient; therefore, the task force recommends GH stimulation testing to be performed at least 12 months after the event (Grade B; BEL 2).
Recommendations and Evidence Base for GH-dosing Regimens in Adults with GHD
R16. Dosing of GH replacement therapy in all patients should be individualized (Grade A; BEL 1).
R17. As GH-deficient women with an intact hypothalamic-pituitary-gonadal axis and women on oral estrogens are generally more GH resistant than men, these patients will require higher initiation and maintenance doses of GH than their male counterparts to achieve an equivalent clinical and biochemical response (Grade B; BEL 2).
R18. There are insufficient data regarding its safety to make recommendations about the use of GH during pregnancy (Grade D).
R19. The sensitivity to side effects of exogenous GH is greater in elderly GH-deficient patients; therefore, the starting dose, size of dose adjustments, and target serum IGF-I levels should be reduced when GH replacement is considered (Grade B; BEL 2).
R20. For patients with compliance issues, clinicians may consider administering GH injections on alternate days or three times per week using the same total weekly dosage (Grade C; BEL 3).
R21. There is no evidence that one GH product is more advantageous over the other, apart from differences in pen devices, dose increments and decrements, and whether or not the product requires refrigeration; therefore, the task force does not recommend the use of one commercial GH preparation over another (Grade D; BEL 4).
R22. GH dosing regimens should be individualized independent of body weight, starting with a low dose, and then gradually increasing this to the minimal dose that normalizes serum IGF-I levels without causing unacceptable side effects (Grade A; BEL 1).
R23. Initiating and maintaining GH therapy using low GH dosages (0.1–0.2 mg/day) may be more appropriate in GH-deficient patients with concurrent diabetes, obesity, and in those with previous gestational and family history of diabetes so as not to aggravate blood glucose levels (Grade A; BEL 1).
R24. After initiating GH therapy, physicians should follow up on patients at 1- to 2-month intervals, and the GH dosage should be increased in steps of 0.1 to 0.2 mg/day based on clinical response, serum IGF-I levels, side effects, and individual considerations. Longer time intervals and smaller dose increments may be needed for older patients (Grade A; BEL 1).
Recommendations and Evidence Base for Monitoring the Efficacy of GH Replacement in Adults with GHD
R25. When maintenance doses are achieved, serum IGF-I, fasting glucose levels, hemoglobin A1c, body mass index, waist circumference, waist-to-hip ratio, serum-free thyroxine (T4), and assessment of the hypothalamic-pituitary-adrenal axis clinically or via early morning cortisol or cosyntropin stimulation test (in patients not on glucocorticoid replacement), testosterone and fasting lipid panel, and overall clinical status should be performed at 6- to 12-month intervals (Grade B; BEL 2).
R26. Adults with GHD have an increased risk of cardiovascular morbidity and mortality; therefore, cardiovascular parameters to consider monitoring during follow-up include fasting lipid profile, systolic and diastolic blood pressure, heart rate, and electrocardiogram results, while more expensive and complex examinations such as echocardiogram and carotid echo-Doppler examinations should be performed only if clinically indicated (Grade C; BEL 3).
R27. Adults with GHD have an increased risk of developing osteopenia and osteoporosis; therefore, the task force recommends measurement of bone mineral content and bone mineral density (BMD) in GH-deficient patients before starting GH therapy. If the initial bone dual-energy X-ray absorptiometry (DEXA) scan is abnormal, repeat bone DEXA scans are recommended at 2- to 3-year intervals to assess the need for additional bone-treatment modalities (Grade B; BEL 2).
R28. In GH-deficient adults on GH replacement therapy with pituitary microadenomas or postsurgery residual pituitary tumor, periodic magnetic resonance imaging should be undertaken to assess the size of the tumor (Grade C; BEL 3).
R29. Adults with GHD have diminished quality of life (QOL); therefore, the task force recommends a specific questionnaire be administered to adults with GHD before they begin GH treatment; subsequently, these adults should be evaluated annually to determine whether there is a change or sustained impact of GH therapy on quality of life (Grade C; BEL 3).
R30. No data are available regarding titrating the GH dose to the ideal target serum IGF-I level; therefore, the task force recommends targeting the serum IGF-I level to the middle of the age- and sex-appropriate reference range quoted by the laboratory utilized (50th percentile or 0 standard deviation score [SDS]). This decision should be based on the circumstances of each individual patient (Grade D; BEL 4).
R31. Interaction of GH with other pituitary hormone axes may influence thyroid, glucocorticoid, and testosterone requirements that may necessitate dose adjustments of these hormones (Grade C; BEL 3).
R32. No data are available regarding the optimal length of GH replacement; therefore, the task force recommends that if patients on GH replacement report significant quality of life benefits and objective improvements in biochemistry and body composition, then GH treatment should be continued indefinitely. However, if the patient reports neither subjective nor objective benefits, then it is reasonable to consider discontinuing GH treatment altogether (Grade D; BEL 4).
Recommendations and Evidence Base for Safety of GH Replacement in Adults with GHD
R33. If diabetes mellitus is diagnosed during GH therapy, or if GH therapy is considered for patients with concurrent diabetes mellitus, adjustments in anti-diabetic medications and treatment with low-dose GH therapy may be necessary. Alternatively, it is reasonable to withhold or discontinue GH therapy and to optimize the treatment of the diabetes before reconsidering later resumption of low-dose GH replacement in these patients (Grade D; BEL 4).
R34. Growth hormone treatment is contraindicated in patients with a previous history of malignancy or in the presence of active malignancy (Grade D; BEL 4).
R35. No data are available to suggest that GH therapy is associated with causing or accelerating recurrences of pituitary-region tumors; therefore, the task force recommends continued long-term surveillance of patients with pituitary-region tumors regardless of whether or not these patients are treated with GH therapy (Grade D; BEL 4).
Level of Scientific Substantiation in Evidence-Based Medicine*
||Prospective, randomized, controlled trials—large
||Data are derived from a substantial number of trials, with adequate statistical power involving a substantial number of outcome data subjects
Large meta-analyses using raw or pooled data or incorporating quality ratings
Well-controlled trial at one or more centers
Consistent pattern of findings in the population for which the recommendation is made (generalizable data)
Compelling nonexperimental, clinically obvious evidence (for example, use of insulin in diabetic ketoacidosis); "all-or-none" indication
||Prospective controlled trials with or without randomization—limited body of outcome data
||Limited number of trials, small population sites in trials
Well-conducted single-arm prospective cohort study
Limited but well-conducted meta-analyses
Inconsistent findings or results not representative for the target population
Well-conducted case-controlled study
||Other experimental outcome data and nonexperimental data
||Nonrandomized, controlled trials
Uncontrolled or poorly controlled trials
Any randomized clinical trial with 1 or more major or 3 or more minor methodologic flaws
Retrospective or observational data
Case reports or case series
Conflicting data with weight of evidence unable to support a final recommendation
||Inadequate data for inclusion in level 1, 2, or 3; necessitates an expert panel's synthesis of the literature and a consensus
*Levels 1, 2, and 3 represent a given level of scientific substantiation or proof. Level 4 represents unproven claims. It is the "best evidence" based on the individual ratings of clinical reports that contributes to a final grade recommendation (see the "Grades of Recommendations" below).
Grade-Recommendation Protocol Adopted by the American Association of Clinical Endocrinologists*
||≥1 conclusive level 1 publications demonstrating benefit >> risk
||Action recommended for indications reflected by the published reports
Action based on strong evidence
Action can be used with other conventional therapy or as first-line therapy
||No conclusive level 1 publication
≥1 conclusive level 2 publications demonstrating benefit >> risk
|Action recommended for indications reflected by the published reports
If the patient refuses or fails to respond to conventional therapy; must monitor for adverse effects, if any
Action based on intermediate evidence
Can be recommended as second-line therapy
||No conclusive level 1 or 2 publication
≥1 conclusive level 3 publications demonstrating benefit >> risk
No risk at all and no benefit at all
|Action recommended for indications reflected by the published reports
If the patient refuses or fails to respond to conventional therapy, provided there are no significant adverse effects; "No objection" to recommending their use
"No objection" to continuing their use
Action based on weak evidence
||No conclusive level 1, 2, or 3 publication demonstrating benefit >> risk
Conclusive level 1, 2, or 3 publications demonstrating risk >> benefit
Patient is advised to discontinue use
Action not based on any evidence
*The final recommendation grades were determined by the primary writers by consensus on the basis of (1) "best evidence" ratings (see "Levels of Scientific Substantiation" table above) and (2) subjective factors.