American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Growth Hormone Deficiency in Adults and Patients Transitioning from Pediatric to Adult Care

      ABSTRACT

      Objective: The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPG).
      Methods: Recommendations are based on diligent reviews of clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols.
      Results: The Executive Summary of this 2019 updated guideline contains 58 numbered recommendations: 12 are Grade A (21%), 19 are Grade B (33%), 21 are Grade C (36%), and 6 are Grade D (10%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 357 citations of which 51 (14%) are evidence level (EL) 1 (strong), 168 (47%) are EL 2 (intermediate), 61 (17%) are EL 3 (weak), and 77 (22%) are EL 4 (no clinical evidence).
      Conclusion: This CPG is a practical tool that practicing endocrinologists and regulatory bodies can refer to regarding the identification, diagnosis, and treatment of adults and patients transitioning from pediatric to adult-care services with growth hormone deficiency (GHD). It provides guidelines on assessment, screening, diagnostic testing, and treatment recommendations for a range of individuals with various causes of adult GHD. The recommendations emphasize the importance of considering testing patients with a reasonable level of clinical suspicion of GHD using appropriate growth hormone (GH) cut-points for various GH–stimulation tests to accurately diagnose adult GHD, and to exercise caution interpreting serum GH and insulin-like growth factor-1 (IGF-1) levels, as various GH and IGF-1 assays are used to support treatment decisions. The intention to treat often requires sound clinical judgment and careful assessment of the benefits and risks specific to each individual patient. Unapproved uses of GH, long-term safety, and the current status of long-acting GH preparations are also discussed in this document.
      LAY ABSTRACT
      This updated guideline provides evidence-based recommendations regarding the identification, screening, assessment, diagnosis, and treatment for a range of individuals with various causes of adult growth-hormone deficiency (GHD) and patients with childhood-onset GHD transitioning to adult care. The update summarizes the most current knowledge about the accuracy of available GH–stimulation tests, safety of recombinant human GH (rhGH) replacement, unapproved uses of rhGH related to sports and aging, and new developments such as long-acting GH preparations that use a variety of technologies to prolong GH action. Recommendations offer a framework for physicians to manage patients with GHD effectively during transition to adult care and adulthood. Establishing a correct diagnosis is essential before consideration of replacement therapy with rhGH. Since the diagnosis of GHD in adults can be challenging, GH–stimulation tests are recommended based on individual patient circumstances and use of appropriate GH cut-points. Available GH–stimulation tests are discussed regarding variability, accuracy, reproducibility, safety, and contraindications, among other factors. The regimen for starting and maintaining rhGH treatment now uses individualized dose adjustments, which has improved effectiveness and reduced reported side effects, dependent on age, gender, body mass index, and various other individual characteristics. With careful dosing of rhGH replacement, many features of adult GHD are reversible and side effects of therapy can be minimized. Scientific studies have consistently shown rhGH therapy to be beneficial for adults with GHD, including improvements in body composition and quality of life, and have demonstrated the safety of short- and long-term rhGH replacement.
      Abbreviations: AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; AHSG = alpha-2-HS-glycoprotein; AO-GHD = adult-onset growth hormone deficiency; ARG = arginine; BEL = best evidence level; BMD = bone mineral density; BMI = body mass index; CI = confidence interval; CO-GHD = childhood-onset growth hormone deficiency; CPG = clinical practice guideline; CRP = C-reactive protein; DM = diabetes mellitus; DXA = dual-energy X-ray absorptiometry; EL = evidence level; FDA = Food and Drug Administration; FD-GST = fixed-dose glucagon stimulation test; GeNeSIS = Genetics and Neuroendocrinology of Short Stature International Study; GH = growth hormone; GHD = growth hormone deficiency; GHRH = growth hormone–releasing hormone; GST = glucagon stimulation test; HDL = high-density lipoprotein; HypoCCS = Hypopituitary Control and Complications Study; IGF-1 = insulin-like growth factor-1; IGFBP = insulin-like growth factor–binding protein; IGHD = isolated growth hormone deficiency; ITT = insulin tolerance test; KIMS = Kabi International Metabolic Surveillance; LAGH = long-acting growth hormone; LDL = low-density lipoprotein; LIF = leukemia inhibitory factor; MPHD = multiple pituitary hormone deficiencies; MRI = magnetic resonance imaging; P-III-NP = procollagen type-III amino-terminal pro-peptide; PHD = pituitary hormone deficiencies; QoL = quality of life; rhGH = recombinant human growth hormone; ROC = receiver operating characteristic; RR = relative risk; SAH = subarachnoid hemorrhage; SDS = standard deviation score; SIR = standardized incidence ratio; SN = secondary neoplasms; T3 = triiodothyronine; TBI = traumatic brain injury; VDBP = vitamin D-binding protein; WADA = World Anti-Doping Agency; WB-GST = weight-based glucagon stimulation test

      INTRODUCTION

      Adult growth hormone deficiency (GHD) results from decreased growth hormone (GH) secretion from the anterior pituitary gland that is more pronounced than the physiologic decline of the growth hormone–releasing hormone (GHRH)-GH-insulin-like growth factor-1 (IGF-1) axis associated with aging. This clinical entity is associated with numerous adverse metabolic abnormalities (
      • Di Somma C.
      • Pivonello R.
      • Pizza G.
      • et al.
      Prevalence of the metabolic syndrome in moderately-severly obese subjects with and without growth hormone deficiency.
      ). Furthermore, it is likely, although not definitively proven, that adult GHD per se contributes to increased cardiovascular morbidity and mortality that has been observed in patients with a variety of pituitary disorders compared to the general population (
      • Stochholm K.
      • Laursen T.
      • Green A.
      • et al.
      Morbidity and GH deficiency: a nationwide study.
      ).
      In a patient where the clinician is suspicious of adult GHD, establishing the diagnosis is essential before replacement therapy with recombinant human GH (rhGH) can be considered. In 1985, rhGH first became commercially available in the United States (U.S.), and since then, there is now accumulating evidence of its beneficial effects in reversing many (
      • Allo Miguel G.
      • Serraclara Pla A.
      • Partida Munoz M.L.
      • Martinez Diaz-Guerra G.
      • Hawkins F.
      Seven years of follow up of trabecular bone score, bone mineral density, body composition and quality of life in adults with growth hormone deficiency treated with rhGH replacement in a single center.
      ), but not all (
      • Weber M.M.
      • Biller B.M.
      • Pedersen B.T.
      • Pournara E.
      • Christiansen J.S.
      • Hoybye C.
      The effect of growth hormone (GH) replacement on blood glucose homeostasis in adult nondiabetic patients with GH deficiency: real-life data from the NordiNet((R)) International Outcome Study.
      ), of the metabolic abnormalities associated with this condition. Nonetheless, there is still some controversy in the U.S. regarding the appropriate use of rhGH therapy in adults with GHD, largely stemming from a combination of factors that include the high cost of therapy (rhGH costs approximately $18,000 to $30,000 per year depending on the dose and brand used) (
      • Cook D.
      • Owens G.
      • Jacobs M.
      Human growth hormone treatment in adults: balancing economics and ethics.
      ), need to administer daily injections which can be burdensome for some patients and caregivers, lack of awareness among some clinicians regarding the indications and benefits of rhGH in adults, difficulty to safely conduct GH–stimulation tests in physician offices, and concerns about whether there are adverse effects after long-term therapy. In addition, there is still a misconception by some regarding the difference between true adult GHD (i.e., lower GH secretion than normal for the appropriate age and sex due to acquired and genetic causes) versus the physiologic decline in endogenous GH secretion due to aging, and the continued inappropriate and unapproved use of rhGH in nonmedical conditions (i.e., sports and aging).
      The benefits and utilization of rhGH replacement therapy in adults and young patients transitioning from pediatric to adult-care services (herein referred to as “transition” patients) with GHD have previously been detailed by the American Association of Clinical Endocrinologists (AACE), with its clinical practice guideline (CPG) first published in 2009 (
      • Cook D.M.
      • Yuen K.C.
      • Biller B.M.
      • Kemp S.F.
      • Vance M.L.
      American Association of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in growth hormone-deficient adults and transition patients - 2009 update: executive summary of recommendations.
      ). Since then, several recent studies have further demonstrated the safety of long-term rhGH replacement in adults with GHD (
      • van Bunderen C.C.
      • van Nieuwpoort I.C.
      • Arwert L.I.
      • et al.
      Does growth hormone replacement therapy reduce mortality in adults with growth hormone deficiency? Data from the Dutch National Registry of Growth Hormone Treatment in adults.
      ,
      • Berglund A.
      • Gravholt C.H.
      • Olsen M.S.
      • Christiansen J.S.
      • Stochholm K.
      Growth hormone replacement does not increase mortality in patients with childhood-onset growth hormone deficiency.
      ), but whether long-term rhGH treatment improves outcomes such as cardiovascular mortality and fracture rates remains to be fully established. On the other hand, the incidence of diabetes mellitus (DM) in adults on long-term rhGH therapy has been shown to be increased in some studies (
      • Attanasio A.F.
      • Jung H.
      • Mo D.
      • et al.
      Prevalence and incidence of diabetes mellitus in adult patients on growth hormone replacement for growth hormone deficiency: a surveillance database analysis.
      ,
      • Luger A.
      • Mattsson A.F.
      • Koltowska-Haggstrom M.
      • et al.
      Incidence of diabetes mellitus and evolution of glucose parameters in growth hormone-deficient subjects during growth hormone replacement therapy: a long-term observational study.
      ), while others have not observed any change after long-term treatment (
      • Weber M.M.
      • Biller B.M.
      • Pedersen B.T.
      • Pournara E.
      • Christiansen J.S.
      • Hoybye C.
      The effect of growth hormone (GH) replacement on blood glucose homeostasis in adult nondiabetic patients with GH deficiency: real-life data from the NordiNet((R)) International Outcome Study.
      ,
      • Stochholm K.
      • Johannsson G.
      Reviewing the safety of GH replacement therapy in adults.
      ). Furthermore, even after over 20 years of rhGH replacement aimed at normalizing serum IGF-1 levels in adults with GHD, there are no robust data to suggest that the risk of cancer, secondary neoplasms (SN) and hypothalamic-pituitary tumor recurrence is increased, although it remains possible that a longer period of follow-up may still be needed to discern any small increases in these risks.
      Early studies utilized rhGH doses in replacement regimens that took into consideration of body weight or body surface area, and dose adjustments were based on body composition outcomes, analogous to pediatric practice (
      • Bengtsson B.A.
      • Eden S.
      • Lonn L.
      • et al.
      Treatment of adults with growth hormone (GH) deficiency with recombinant human GH.
      ), but side effects were frequently observed that were mainly due to the fluid-retaining effects of rhGH. In light of these observations, rhGH treatment regimens now use dose-titration strategies targeting serum IGF-1 normalization to account for interindividual differences in GH sensitivity that takes into consideration age, gender, body mass index (BMI), and various other baseline characteristics (
      • Yuen K.C.
      • Cook D.M.
      • Rumbaugh E.E.
      • Cook M.B.
      • Dunger D.B.
      Individual IGF-I responsiveness to a fixed regimen of low-dose growth hormone replacement is increased with less variability in obese compared to non-obese adults with severe growth hormone deficiency.
      ). The utilization of individualized, stepwise dose adjustments based on serum IGF-1 levels has resulted in improved treatment efficacy, provided the patient is treatment-adherent, and reductions in reported side effects (
      • Hoffman A.R.
      • Kuntze J.E.
      • Baptista J.
      • et al.
      Growth hormone (GH) replacement therapy in adult-onset gh deficiency: effects on body composition in men and women in a double-blind, randomized, placebo-controlled trial.
      ,
      • Hoffman A.R.
      • Strasburger C.J.
      • Zagar A.
      • et al.
      Efficacy and tolerability of an individualized dosing regimen for adult growth hormone replacement therapy in comparison with fixed body weight-based dosing.
      ).
      Adult GHD is most often associated with damage to the hypothalamic-pituitary region as a result of tumors, and/or treatment with surgery and radiation (
      • Brabant G.
      • PE M.
      • Jonsson P.
      • Polydorou D.
      • Kreitschmann-Andermahr I.
      Etiology, baseline characteristics, and biochemical diagnosis of GH deficiency in the adult: are there regional variations?.
      ). Nonetheless, in the past decade, several other subpopulations of patients, such as those with traumatic brain injury (TBI), subarachnoid hemorrhage, ischemic stroke, and infections in the central nervous system, have been described to be at risk for developing adult GHD. For these patients, clinicians may be required to consider undertaking further biochemical testing to assess for adult GHD (
      • Pekic S.
      • Popovic V.
      Diagnosis of endocrine disease: Expanding the cause of hypopituitarism.
      ,
      • Tanriverdi F.
      • Kelestimur F.
      Classical and non-classical causes of GH deficiency in adults.
      ). However, the diagnostic accuracy and reliability of currently available GH–stimulation tests in these groups of patients have not been adequately studied. Clinicians are therefore now faced with the possibility of assessing these patient populations, where neither testing nor long-term treatment efficacy has been evaluated extensively in large sample sizes.
      The purpose of this update to the 2009 AACE adult GHD CPG (
      • Cook D.M.
      • Yuen K.C.
      • Biller B.M.
      • Kemp S.F.
      • Vance M.L.
      American Association of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in growth hormone-deficient adults and transition patients - 2009 update: executive summary of recommendations.
      ) is to summarize current knowledge about the accuracy of available GH–stimulation tests, heterogeneity of commercially available GH and IGF-1 assays, safety of rhGH replacement, misuse of rhGH in sports and aging, and new developments in this field. In this CPG, evidence-based practical recommendations are offered as a framework to clinicians for better and effective management of patients with GHD transitioning from pediatric to adult-care services and into adulthood.

      METHODS

      This CPG was developed in accordance with the 2017 AACE Protocol for Standardized Production of Clinical Practice Guidelines (
      • Mechanick J.I.
      • Pessah-Pollack R.
      • Camacho P.
      • et al.
      American Association of Clinical Endocrinologists and American College of Endocrinology Protocol for Standardized Prodcution of Clinical Practice Guidelines, Algorithms, and Checklists -- 2017 Update.
      ), whereby AACE and the American College of Endocrinology (ACE) have updated the work-flow for clinical practice tools to prioritize clinical problem-solving and management (Fig. 1). The 2017 AACE/ACE CPG production strategy began with an environmental scan of the disease “space” to identify the most relevant clinical problems and needs facing the clinical endocrinologist (e.g., diagnosis of adult GHD or treatment of adult GHD in elderly patients and those with a distant history of cancer). This updated CPG methodology provides a framework for patient-first language, greater detail for evidence ratings, and structure for the involvement of the American College of Endocrinology Scientific Referencing Subcommittee, a dedicated resource for the rating of evidence, mapping of grades, and general oversight of the entire CPG production process. A critical improvement in the 2017 AACE/ACE CPG production strategy is to create documents that are easier to use and less cumbersome. Nevertheless, as with all white papers and increasing diligence on the part of the writing team, it is inevitable that an element of subjectivity will be encountered in certain areas and clinical discretion must be recognized by the reader when interpreting the information.
      Fig. 1
      Fig. 12017 AACE/ACE CPG Production Strategy. Current AACE CPG prioritizes real-world clinical problem solving by first determining key issues to be examined, then creating a pragmatic CPA approach, and then providing the problem-oriented scientific substantiation in the form of focused CPA-driven CPG and patient safety CC. This is followed by implementation and validation strategies and after a CPG is validated, there will be an evaluation step. AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; ASeRT = ACE Scientific Referencing Team; CC = clinical checklist; CPA = clinical practice algorithm; CPG = clinical practice guidelines.
      Reference citations in the text of this document include the reference number, and numerical (evidence level [EL] 1 to 4), semantic, and methodology descriptors (Table 1) (
      • Mechanick J.I.
      • Pessah-Pollack R.
      • Camacho P.
      • et al.
      American Association of Clinical Endocrinologists and American College of Endocrinology Protocol for Standardized Prodcution of Clinical Practice Guidelines, Algorithms, and Checklists -- 2017 Update.
      ). All primary writers have made disclosures regarding multiplicities of interests and have attested that they are not employed by industry. In addition, all primary writers are current good-standing AACE members and credentialed experts in this field. Primary writers submitted contributions to specific clinical questions, which were subsequently reviewed, discussed, and integrated into the final document. This input provides the basis for the recommendations herein. The format of this CPG is based upon specific and relevant clinical questions.
      Table 12017 American Association of Clinical Endocrinologists Protocol of Clinical Practice Guidelines - Step I Evidence Ratinga
      Recommendations (labeled “R”) are assigned grades that map to the best evidence level (BEL) ratings based on the highest quality supporting EL (Table 1), evidence analysis, and subjective factors (Table 2) (
      • Mechanick J.I.
      • Pessah-Pollack R.
      • Camacho P.
      • et al.
      American Association of Clinical Endocrinologists and American College of Endocrinology Protocol for Standardized Prodcution of Clinical Practice Guidelines, Algorithms, and Checklists -- 2017 Update.
      ), all of which have been rated based on recommendation qualifiers (Table 3) (
      • Mechanick J.I.
      • Pessah-Pollack R.
      • Camacho P.
      • et al.
      American Association of Clinical Endocrinologists and American College of Endocrinology Protocol for Standardized Prodcution of Clinical Practice Guidelines, Algorithms, and Checklists -- 2017 Update.
      ). The EL of scientific substantiation, specific EL subjective factors (for individual citations), recommendation qualifiers (for aggregate evidence base for an individual recommendation), and EL to recommendation grade mapping have been more clearly delineated for transparency, allowing for more interpretative flexibility (Table 1, Table 2, Table 3, Table 4) (
      • Mechanick J.I.
      • Pessah-Pollack R.
      • Camacho P.
      • et al.
      American Association of Clinical Endocrinologists and American College of Endocrinology Protocol for Standardized Prodcution of Clinical Practice Guidelines, Algorithms, and Checklists -- 2017 Update.
      ). Details regarding each recommendation may be found in the upcoming corresponding section of the CPG Evidence Base Appendix that includes a complete list of supporting references. Thus, the process leading to a final recommendation and grade is not rigid, but rather incorporates complex expert integration of objective and subjective factors meant to reflect optimal real-life clinical decision-making, options, and individualization of care. This document is a guideline; since individual circumstances and clinical presentations differ from patient to patient, ultimate clinical management is based on what is in the best interest of the patient that would also involve the patient's input (“patient-centered care”) and reasonable clinical judgment by the treating clinician.
      Table 22017 American Association of Clinical Endocrinologists Protocol for Production of Clinical Practice Guidelines - Step II: Evidence Analysis and Subjective Factorsa
      Table 32017 American Association of Clinical Endocrinologists Protocol for Production of Clinical Practice Guidelines - Step III: Recommendation Qualifiersa
      Table 42017 American Association of Clinical Endocrinologists Protocol for Production of Clinical Practice Guidelines: Step IV - Grading of Recommendations; How Different Evidence Levels Can Be Mapped to the Same Recommendation Gradea
      This CPG was extensively reviewed and approved by all of the primary writers, other invited experts, the AACE Publications Committee, the AACE Board of Directors, and the ACE Board of Trustees before submission for peer review by Endocrine Practice.
      EXECUTIVE SUMMARY

      Q1. WHAT IS ADULT GHD?

      • R1. The clinician should consider the possibility of adult GHD in each individual patient with a history of hypothalamic-pituitary disease, as this condition is a well-defined clinical entity that is associated with excess morbidity and mortality (Grade B; BEL 2).
      • R2. The clinician should be aware that adults can be diagnosed with GHD in childhood (childhood-onset GHD [CO-GHD]) and adulthood (adult-onset GHD [AO-GHD]) (Grade B; BEL 2).
      • R3. The most common causes of CO-GHD and AO-GHD are isolated idiopathic GHD and hypothalamic-pituitary tumors and/or their treatment regimens, respectively; hence, the possibility of GHD should be considered in these patients (Grade B; based primarily on expert opinion of the committee).
      • R4. Several nontumoral causes of adult GHD (e.g., TBI, subarachnoid hemorrhage, ischemic stroke, and infections in the central nervous system) have been increasingly described in the past decade, and screening may be considered although the accuracy and reliability of GH–stimulation tests for the diagnosis of adult GHD have not been studied extensively in these populations (Grade C; BEL 2).

      Q2. ARE THERE ANY DIFFERENCES BETWEEN CO-GHD VERSUS AO-GHD?

      • R5. It is recommended that clinicians recognize the differences in the etiology of CO-GHD versus AO-GHD as there are differences in the phenotypic features which are due to the fact that CO-GHD occurs during the developmental years and that adults with CO-GHD may have had a longer duration of being GH-deficient than their AO-GHD counterparts (Grade A; BEL 1).

      Q3. HOW SHOULD PEDIATRIC PATIENTS WITH CO-GHD BE TRANSITIONED TO ADULT-CARE SERVICES?

      • R6. Transition is a vulnerable period when adolescents may drop out of follow-up medical care. Pediatricians should start counseling patients and caregivers early about the potential of future transition and collaborate closely with adult endocrinologists closer to the time to facilitate a seamless transition to adult endocrine-care services (Grade C; BEL 2).

      Q4. WHAT ARE THE BENEFITS OF CONTINUING rhGH REPLACEMENT IN TRANSITION PATIENTS WITH CO-GHD?

      • R7. It is recommended that adults with CO-GHD caused by structural pituitary or brain tumors be followed up closely during transition as these patients tend to have lower bone mineral density, impaired bone microarchitecture, and more adverse body composition abnormalities and cardiovascular risk markers than those with AO-GHD (Grade A; BEL 1).
      • R8. Resuming rhGH replacement therapy in patients with confirmed persistent GHD during the transition period after achievement of final height is recommended, as most studies have reported long-term improvement in body composition, bone health, quality of life, and lipid metabolism in adulthood (Grade A; BEL 1).

      Q5. WHO SHOULD BE TESTED FOR ADULT GHD?

      • R9. GH–stimulation test/s should only be performed based on the appropriate clinical context of each individual patient with a history suggestive of a reasonable clinical suspicion of GHD, and with the intent to initiate rhGH replacement if the diagnosis is confirmed (Grade D; based on expert opinion).
      • R10. The diagnosis of adult GHD can be made without the need for performing GH–stimulation testing in certain patient subtypes, such as patients with organic hypothalamic-pituitary disease (e.g., suprasellar mass with previous surgery and cranial irradiation) and biochemical evidence of multiple pituitary hormone deficiencies (MPHD) (≥3 pituitary hormone deficiencies &lsqb;PHD]) together with low-serum IGF-1 levels (< -2.0 standard deviation score &lsqb;SDS]), genetic defects affecting the hypothalamic-pituitary axes, and hypothalamic-pituitary structural brain defects (Grade C; BEL 3).
      • R11. In patients with ≤2 PHD, low-serum IGF-1 levels (<-2.0 SDS) alone are not sufficient to make a diagnosis of adult GHD; clinicians should perform 1 GH-stimulation test to confirm the diagnosis (Grade B; BEL 4; upgraded by consensus based on expert opinion).
      • R12. After longitudinal growth is completed in transition patients with idiopathic isolated GHD, those with low-normal (between 0 to -2 SDS) or low (< -2 SDS) serum IGF-1 levels should be retested for GHD with GH–stimulation tests after at least 1 month following discontinuation of rhGH therapy (Grade B; BEL 4; upgraded by consensus based on expert opinion).
      • R13. After longitudinal growth is completed in transition patients with isolated GHD (IGHD) and the presence of organic hypothalamic-pituitary disease (e.g., craniopharyngioma, pituitary hypoplasia, ectopic posterior pituitary, or previous cranial irradiation), the number of GH–stimulation tests to be undertaken should be guided by the degree of clinical suspicion for GHD. If clinical suspicion is high, 1 GH–stimulation test is sufficient, but if clinical suspicion is low, then a second GH–stimulation test should be performed (Grade B; BEL 4; upgraded by consensus based on expert opinion).
      • R14. To continue rhGH replacement in adulthood, retesting for GHD with GH–stimulation test/s is recommended in most transition patients, especially patients with idiopathic isolated GHD and serum IGF-1 SDS <0, when longitudinal growth is complete, and at least 1 month after discontinuation of pediatric rhGH therapy (Grade A; BEL 1).
      • R15. Patients with idiopathic IGHD and serum IGF-1 ≥0 SDS are likely to have a normal GH–stimulation test; hence, retesting and rhGH therapy in these patients after completion of longitudinal growth are not required (Grade C; BEL 2; downgraded due to inconsistent results).
      • R16. Retesting is not required in transition patients with MPHD (≥3 PHD) and low-serum IGF-1 levels (<-2.0 SDS), patients with genetic defects affecting the hypothalamic-pituitary axes, and patients with hypothalamic-pituitary structural brain defects, and rhGH therapy may be continued in these patients without interruption (Grade C; BEL 2; downgraded due to inconsistent results).
      • R17. The risk for development of persistent GHD after radiation therapy is increased with higher radiation doses and longer duration of time since the therapy. Retesting those patients who initially test as GH–sufficient may be performed later in the transition period or in adulthood to rule out delayed GHD (Grade B; BEL 2).
      • R18. TBI and subarachnoid hemorrhage are now recognized clinical conditions that may cause GHD, but because GHD may be transient in these patients, GH–stimulation testing should be performed only after at least 12 months following the event (Grade B; BEL 2).

      Q6. HOW SHOULD ONE TEST FOR ADULT GHD?

      • R19. Random serum GH and IGF-1 levels cannot be used alone to make the diagnosis of adult GHD, and GH–stimulation test/s should be performed to confirm the diagnosis with the exception of certain subpopulations, such as patients with organic hypothalamic-pituitary disease (e.g., suprasellar mass with previous surgery and cranial irradiation) who have MPHD (≥3 PHD) and low serum IGF-1 levels (<-2.0 SDS), patients with genetic defects affecting the hypothalamic-pituitary axes, and patients with hypothalamic-pituitary structural brain defects (Grade B; BEL 4; upgraded by consensus based on expert opinion).
      • R20. GH–stimulation tests should only be performed after all other PHD have been optimally replaced with stable hormone replacement doses (Grade C; BEL 4; upgraded by consensus based on expert opinion).
      • R21. The insulin tolerance test (ITT) remains the gold-standard test to establish the diagnosis of adult GHD using a peak GH cut-point of 5 μg/L. However, this test is increasingly used less frequently in the U.S. because of safety concerns, laboriousness, potential to cause severe hypoglycemia, and contraindicated in certain patients, such as elderly patients and those with seizure disorders and cardio/cerebrovascular disease. For adults suspected to have GHD and if the ITT is contraindicated or is not feasible to be performed in these patients, the glucagon-stimulation test (GST) and the macimorelin test could be considered as alternative tests (Grade B; BEL 1).
      • R22. For the GST, we recommend utilizing BMI-appropriate GH cut-points to diagnose adult GHD to reduce the possibility of misclassifying GH-sufficient patients because increased BMI is associated with decreased glucagon-induced GH stimulatory effect. We recommend using the GH cut-point of 3 μg/L for normal-weight (BMI <25 kg/m2) and overweight (BMI 25 to 30 kg/m2) patients with a high pretest probability, and a lower GH cut-point of 1 μg/L for obese (BMI >30 kg/m2) and overweight (BMI 25 to 30 kg/m2) patients with a low pretest probability. In patients with glucose intolerance, the diagnostic accuracy of the GST remains unclear (Grade B; BEL 2).
      • R23. For the macimorelin-stimulation test, the U.S. Food and Drug Administration (FDA) approved this test for use as a diagnostic test for adult GHD in December, 2017, and selected the GH cut-point of 2.8 μg/L to differentiate patients with normal GH secretion from those with GHD. However, it is not yet known whether BMI-adjusted peak GH cut-points for this test are needed for over-weight and obese patients (Grade B; BEL 2).
      • R24. For transition patients, a feasible and validated GH–stimulation test has been less well studied. In this patient population, the ITT (using a GH cut-point ≤5.0 μg/L) may be utilized, but if the test is contraindicated or not feasible to be performed, the GST (using a GH cut-point of 3 μg/L for normal-weight &lsqb;BMI <25 kg/m2] patients and overweight &lsqb;BMI 25 to 30 kg/m2] patients with a high pretest probability, and a lower GH cut-point of 1 μg/L for overweight &lsqb;BMI 25 to 30 kg/m2] patients with a low pretest probability and obese &lsqb;BMI >30 kg/m2] patients) and the macimorelin test (using a GH cut-point ≤2.8 mg/L) can be considered as alternative tests (Grade C; BEL 2).
      • R25. Arginine (ARG) and levodopa (L-DOPA) testing have not been systematically evaluated and validated, and because these tests have low sensitivity and specificity in adults and transition patients with suspected GHD, we do not recommend utilizing these tests (Grade B; BEL 2).

      Q7. WHY ARE STANDARDIZED GH AND IGF-1 ASSAYS IMPORTANT IN THE MANAGEMENT OF ADULT GHD?

      • R26. Substantial heterogeneity exists among currently utilized assays due to different standard preparations for calibration of GH immunoassays and lack of harmonization between various GH assays. It is recommended that laboratories adopt the standards set by the National Institute for Biological Standards and Control and state their methodology of analyses, including reporting serum GH levels in mass units without reliance of conversion factors (Grade C; BEL 4; upgraded by consensus based on expert opinion).
      • R27. It is suggested that all assay manufacturers indicate the validation of their assay, including specification of the GH isoforms detected, analyte being measured, specificities of the antibodies used, and presence or absence of GH–binding protein interference (Grade C; BEL 4; upgraded by consensus based on expert opinion).
      • R28. Differences in serum IGF-1 assay performance should be considered when evaluating and monitoring rhGH therapy in adults with GHD, and, if possible, the same IGF-1 assay should be used for a given patient throughout evaluation for diagnosis and follow-up (Grade C; BEL 4; upgraded by consensus based on expert opinion).
      • R29. Quality-control materials should be used, widely verified, and disseminated among laboratories for uniformity (Grade C; BEL 4; upgraded by consensus based on expert opinion).
      • R30. Because certain conditions such as DM, malnutrition, chronic liver disease, and renal diseases may lower serum IGF-1 levels that may not be due to GHD, reliable sera from healthy subjects and from such patients should be employed for validation of the assays (Grade C; BEL 4).
      • R31. Normative IGF-1 assay data should be provided by each laboratory and should include a sufficient random sample of individuals from a wide range of ages to achieve clinical efficacy and minimize the induction of side effects (Grade C; BEL 4; upgraded by consensus based on expert opinion).
      • R32. Laboratories, in addition to reporting serum IGF-1 levels, should report IGF-1 SDS values (Z-scores) (Grade C; BEL 4; upgraded by consensus based on expert opinion).

      Q8. HOW SHOULD INITIATION AND MONITORING OF rhGH REPLACEMENT BE UNDERTAKEN?

      • R33. The use of one commercial rhGH product is not suggested over another, as there is no evidence that one rhGH product is more advantageous than another (Grade D).
      • R34. It is recommended to use serum IGF-1 as the biomarker for guiding rhGH dose adjustments (Grade A; BEL 1).
      • R35. It is recommended to individualize rhGH dosing independent of body weight, starting with a low dose, and gradually up-titrating the dose to normalize serum IGF-1 levels with the primary aim of minimizing the induction of side effects (Grade A; BEL 1).
      • R36. Serum IGF-1 levels should be targeted within the age-adjusted reference range (IGF-1 SDS between -2 and +2) provided by the laboratory utilized. This decision should consider the pretreatment IGF-1 SDS and the circumstances and tolerability of each individual patient. Because some patients may only tolerate lower rhGH doses frequently limited by side effects, whereas others may require higher rhGH doses to achieve desired clinical effects, the goals of treatment should be the clinical response, avoidance of side effects, and targeting serum IGF-1 levels to fall within the age-adjusted reference range (IGF-1 SDS between -2 and + 2) (Grade D; based on expert opinion of the committee).
      • R37. It is recommended to initiate rhGH therapy using low GH dosages (0.1 to 0.2 mg/day) in GH-deficient patients with concurrent DM, obesity, older age, and previous gestational DM to avoid impairment of glucose metabolism. Higher rhGH starting doses (0.3 to 0.4 mg/day) are advised in nondiabetic young adults <30 years of age and women on oral estrogen therapy (Grade A; BEL 1).
      • R38. After starting on rhGH therapy, it is recommended to follow patients at 1- to 2-month intervals initially, increasing the rhGH dose in increments of 0.1 to 0.2 mg/day based on the clinical response, serum IGF-1 levels, side effects, and individual considerations. Once maintenance doses are achieved, follow-up can be implemented at approximately 6- to 12-month intervals. Shorter follow-up time intervals and smaller dose increments can be implemented especially for the elderly, and those with other comorbidities, such as DM (Grade A; BEL 1).
      • R39. When maintenance rhGH doses are achieved, the following parameters may be assessed at approximately 6- to 12-month intervals: serum IGF-1, fasting glucose, hemoglobin A1c, fasting lipids, BMI, waist circumference, waist-to-hip ratio, serum-free T4, and the hypothalamic-pituitary-adrenal axis via early morning cortisol or cosyntropin stimulation test, if clinically indicated (Grade C; BEL 2; primarily based on expert opinion of the committee).
      • R40. When restarting rhGH therapy in transition patients, resuming rhGH at 50% of the dose used in childhood may be considered. Serum IGF-1 levels should be monitored to avoid exceeding the upper limit of the normal range (IGF-1 >2 SDS). The dose should be modified based on the clinical response, serum IGF-1 levels, side effects, and individual patient considerations (Grade D; based on expert opinion of the committee).
      • R41. In transition patients, annual measurements of height, weight, BMI, and waist and hip circumference are recommended, measuring bone mineral density and fasting lipids after discontinuing rhGH therapy as a baseline assessment, and subsequently every 2 to 3 years and every year, respectively (Grade D; based on expert opinion of the committee).
      • R42. Adults with GHD have an increased risk of cardiovascular morbidity and mortality, and currently, there are no definitive outcome data that confirm that treating this condition would mitigate this risk as long-term prospective, controlled clinical trials are still lacking. Therefore, clinicians should monitor cardiovascular parameters at 6- to 12-month intervals and include fasting lipids, systolic and diastolic blood pressure, and heart rate, while more detailed examinations such as electrocardiogram, echocardiogram, and carotid echo-Doppler examinations may be performed if clinically indicated according to local best clinical practice (Grade C; BEL 2; based on expert opinion of the committee).
      • R43. Adults with GHD have an increased risk of developing osteopenia and osteoporosis. Measurement of bone mineral content and bone mineral density is suggested in GH-deficient patients before starting rhGH therapy. If the initial bone dual-energy X-ray absorptiometry (DXA) scan is abnormal, clinicians should repeat bone DXA scans at 2- to 3-year intervals to assess the need for additional bone-treatment modalities (Grade C; BEL 4; upgraded by consensus based on expert opinion).
      • R44. Clinicians should perform baseline magnetic resonance imaging (MRI) in patients with any post-surgical tumor remnant in the hypothalamic-pituitary region before initiating rhGH, and periodic MRIs during rhGH therapy (Grade C; BEL 4; upgraded by consensus based on expert opinion).
      • R45. Because untreated adults with GHD frequently report impaired quality of life (QoL), clinicians should consider assessing baseline QoL using specific Quality of Life in Adult Growth Hormone Deficiency Assessment (QoL-AGHDA) questionnaires before rhGH treatment is commenced, and at 12-month intervals to determine whether there is a change or sustained impact of rhGH therapy on QoL (Grade C; BEL 4).
      • R46. Interactions of GH with other pituitary hormone axes may affect glucocorticoid and thyroid hormone requirements; hence, these hormones should be monitored closely, especially before initiation of rhGH therapy, as introduction of these hormones or dose increments may be required while on rhGH therapy. When stable new glucocorticoid and thyroid hormone doses are established, less frequent monitoring may be undertaken, unless symptoms develop or radiotherapy is administered (Grade B; BEL 1).
      • R47. The optimal duration of rhGH replacement therapy remains unclear. If patients on rhGH replacement experience beneficial effects on QoL and objective improvements in biochemistry, body composition, and bone mineral density, rhGH treatment can be continued indefinitely (Grade B; BEL 2).

      Q9. CAN rhGH BE USED DURING CONCEPTION AND PREGNANCY?

      • R48. Previous studies support the use of rhGH while seeking fertility, and continuing rhGH during pregnancy does not appear to impact the outcomes of either mother or fetus. However, more data are still needed regarding the safety of rhGH. Routine use of rhGH for conception or continued use during pregnancy in women with GHD cannot be recommended at this present time (Grade C; BEL 3).

      Q10. WHAT ARE THE SIDE EFFECTS OF rhGH REPLACEMENT?

      • R49. Side effects are related mainly to fluid retention effects and are typically seen during initiation and dose escalation of rhGH, and generally respond to dose reductions or cessation of therapy. Lower doses of rhGH are recommended in obese and older patients who are generally more susceptible to the side effects of rhGH replacement (Grade A; BEL 1).
      • R50. It is recommended to avoid the use of high rhGH doses to minimize the risk of side effects and aim to maintain target serum IGF-1 levels within the age-adjusted laboratory reference range (IGF-1 SDS between -2 and + 2) (Grade A; BEL 1).

      Q11. HOW SAFE IS LONG-TERM rhGH REPLACEMENT THERAPY?

      • R51. If DM develops during rhGH therapy, or if rhGH therapy is considered in patients with concurrent DM, use of low-dose rhGH therapy, and addition and/or adjustments in antidiabetic medications are suggested. If pre-existing DM worsens while on rhGH therapy, it is reasonable to initiate or increase the doses of antidiabetic therapy or discontinue rhGH therapy and optimize treatment of DM first before considering resuming rhGH therapy in these patients (Grade B; BEL 1).
      • R52. Treatment with rhGH in patients with a history of active malignancy (other than basal-cell or squamous-cell skin cancers) and active proliferative or severe nonproliferative diabetic retinopathy is contra-indicated (Grade B; BEL 2).
      • R53. Treatment with rhGH should be conducted with caution in patients with a strong family history of cancer (Grade B; BEL 2).
      • R54. For adults with GHD and a history of cancer who have expressed a desire to start rhGH replacement therapy, such therapy may be considered based on each individual circumstance, and low-dose rhGH therapy should only be initiated at least 5 years after cancer remission is achieved and after discussion with the patient's oncologist (Grade D; based on expert opinion of the committee).
      • R55. After over 20 years of adult rhGH replacement, there are no data to suggest that rhGH replacement in adults increases the risk of cancer or accelerates recurrences of tumors in the hypothalamic-pituitary region; however, for the purposes of safety surveillance, continued long-term monitoring and standard cancer screening should still be performed (Grade B; BEL 2).

      Q12. IS rhGH RECOMMENDED FOR SPORTS AND ANTI-AGING?

      • R56. Detection of rhGH abuse poses many challenges because GH is a naturally occurring substance which has a short half-life after subcutaneous and intravenous injection, is released in a pulsatile fashion, and the levels increase after exercise. Drug testing involving urine sampling is not recommended as this method of testing has not been shown to be accurate and reliable, whereas repeated blood sampling over 24-hours is neither practical nor feasible in the sports setting (Grade A; BEL 1).
      • R57. In the U.S., off-label distribution or marketing of GH for the enhancement of athletic performance or to treat aging or aging-related conditions is illegal and punishable by imprisonment. Under no circumstances should rhGH be prescribed for sports or for “anti-aging” purposes (Grade A; BEL 1).

      Q13. WHAT ARE NEW DEVELOPMENTS IN THIS FIELD?

      • R58. The frequency of daily injections is thought to be one of the major factors contributing to nonadherence with rhGH therapy, and weekly long-acting GH (LAGH) preparations are currently under development, which may facilitate improvement in adherence. Clinicians may follow the developments of LAGH preparations, which are currently investigational and not commercially available yet in the U.S. (Grade C).

      UPDATED EVIDENCE BASE FOR 2019

      In this update, there are 357 citations of which 51 (14%) are EL 1 (strong), 168 (47%) are EL 2 (intermediate), 61 (17%) are EL 3 (weak), and 77 (22%) are EL 4 (no clinical evidence). The evidence base presented here provides relevant information for the recommendations in the Executive Summary.

      Q1. WHAT IS ADULT GHD?

      Adult GHD is a well-defined clinical entity characterized by decreased lean body mass and increased fat mass, dyslipidemia, cardiac dysfunction, decreased fibrinolysis and premature atherosclerosis, decreased muscle strength and exercise capacity, decreased bone mineral density (BMD), increased insulin resistance, and impaired QoL (
      • de Boer H.
      • Blok G.J.
      • Van der Veen E.A.
      Clinical aspects of growth hormone deficiency in adults.
      ). Recent studies have demonstrated increased mortality in patients with hypopituitarism (
      • Olsson D.S.
      • Trimpou P.
      • Hallen T.
      • et al.
      Life expectancy in patients with pituitary adenoma receiving growth hormone replacement.
      ,
      • Burman P.
      • Mattsson A.F.
      • Johannsson G.
      • et al.
      Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality.
      ), particularly in women and in patients diagnosed at a younger age (
      • Jasim S.
      • Alahdab F.
      • Ahmed A.T.
      • et al.
      Mortality in adults with hypopituitarism: a systematic review and meta-analysis.
      ,
      • Olsson D.S.
      • Nilsson A.G.
      • Bryngelsson I.L.
      • Trimpou P.
      • Johannsson G.
      • Andersson E.
      Excess mortality in women and young adults with nonfunctioning pituitary adenoma: a Swedish nationwide study.
      ). It is possible that GHD per se may play a role in contributing to the excess morbidity and mortality rates among patients with hypopituitarism (
      • Stochholm K.
      • Laursen T.
      • Green A.
      • et al.
      Morbidity and GH deficiency: a nationwide study.
      ,
      • Stochholm K.
      • Gravholt C.H.
      • Laursen T.
      • et al.
      Mortality and GH deficiency: a nationwide study.
      ,
      • Pappachan J.M.
      • Raskauskiene D.
      • Kutty V.R.
      • Clayton R.N.
      Excess mortality associated with hypopituitarism in adults: a meta-analysis of observational studies.
      ), although other factors such as under- (
      • Burman P.
      • Mattsson A.F.
      • Johannsson G.
      • et al.
      Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality.
      ) or overtreatment (
      • Hammarstrand C.
      • Ragnarsson O.
      • Hallen T.
      • et al.
      Higher glucocorticoid replacement doses are associated with increased mortality in patients with pituitary adenoma.
      ,
      • Zueger T.
      • Kirchner P.
      • Herren C.
      • et al.
      Glucocorticoid replacement and mortality in patients with nonfunctioning pituitary adenoma.
      ) of glucocorticoid replacement therapy for secondary adrenal insufficiency and the underlying etiology of the hypothalamic-pituitary disease are also important contributing factors (
      • Stochholm K.
      • Laursen T.
      • Green A.
      • et al.
      Morbidity and GH deficiency: a nationwide study.
      ,
      • Stochholm K.
      • Gravholt C.H.
      • Laursen T.
      • et al.
      Mortality and GH deficiency: a nationwide study.
      ,
      • Regal M.
      • Paramo C.
      • Sierra S.M.
      • Garcia-Mayor R.V.
      Prevalence and incidence of hypopituitarism in an adult Caucasian population in northwestern Spain.
      ,
      • Tomlinson J.W.
      • Holden N.
      • Hills R.W.
      • et al.
      Association between premature mortality and hypopituitarism. West Midlands Prospectivve Hypopituitary Study Group.
      ).
      GHD may present as CO-GHD or AO-GHD and may occur either as IGHD or associated with MPHD. The true prevalence and incidence rate of adult GHD is difficult to estimate. A reasonable estimate may be obtained from the prevalence data for pituitary macroadenomas (
      • Joustra S.D.
      • Claessen K.M.
      • Dekkers O.M.
      • et al.
      High prevalence of metabolic syndrome features in patients previously treated for nonfunctioning pituitary macroadenoma.
      ), which is approximately 1:10,000 population. Adult-onset GHD has been estimated to affect 1 per 100,000 people annually, while its incidence rate is approximately 2 per 100,000 when CO-GHD patients are included (
      • Stochholm K.
      • Gravholt C.H.
      • Laursen T.
      • et al.
      Incidence of GH deficiency - a nationwide study.
      ), with approximately 15 to 20% of the cases being transition of CO-GHD into adulthood (
      • Allen D.B.
      • Backeljauw P.
      • Bidlingmaier M.
      • et al.
      GH safety workshop position paper: a critical appraisal of recombinant human GH therapy in children and adults.
      ). Combining both AO-GHD and CO-GHD yields an overall prevalence of 2 to 3 per 10,000 population (
      • Nicolson A.
      • Toogood A.A.
      • Rahim A.
      • Shalet S.M.
      The prevalence of severe growth hormone deficiency in adults who received growth hormone replacement in childhood &lsqb;see comment].
      ). The incidence rate appears to be higher in males in the CO-GHD group and in the AO-GHD group >45 years of age (
      • Stochholm K.
      • Gravholt C.H.
      • Laursen T.
      • et al.
      Incidence of GH deficiency - a nationwide study.
      ).
      The most frequent cause of CO-GHD is idiopathic and may not be associated with other PHD. Other causes of CO-GHD include congenital causes (e.g., genetic abnormalities), brain structural defects (e.g., agenesis of corpus callosum, optic nerve hypoplasia, empty sella syndrome, encephalocele, hydrocephalus, arachnoid cyst, midline facial defects such as single central incisor, cleft lip, and cleft palate), and acquired causes (e.g., perinatal insults, brain tumors such as craniopharyngioma and germinomas, and pituitary adenomas) (Table 5) (
      • Molitch M.E.
      • Clemmons D.R.
      • Malozowski S.
      • Merriam G.R.
      • Vance M.L.
      • Endocrine S.
      Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline.
      ). By contrast, AO-GHD is most commonly acquired from hypothalamic-pituitary tumors and/or their treatment (Table 5) (
      • Molitch M.E.
      • Clemmons D.R.
      • Malozowski S.
      • Merriam G.R.
      • Vance M.L.
      • Endocrine S.
      Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline.
      ). Additionally, especially in the last decade, there has been an increasing number of studies reporting nontumoral causes of hypopituitarism associated with GHD that were previously unrecognized, such as TBI (including blast-induced TBI), subarachnoid hemorrhage (SAH), ischemic stroke, and central nervous system infections (
      • Booij H.A.
      • Gaykema W.D.C.
      • Kuijpers K.A.J.
      • Pouwels M.J.M.
      • den Hertog H.M.
      Pituitary dysfunction and association with fatigue in stroke and other acute brain injury.
      ).
      Table 5Conditions and Treatment That Can Cause Adult Growth Hormone Deficiency (GHD), and Requirements for GH-Stimulation Testing
      The primary goal of rhGH therapy in children is growth promotion to normalize final adult height (
      • Sävendahl L.
      • Polak M.
      • Backeljauw P.
      • et al.
      Treatment of children with growth hormone in the US and Europe: Long-term follow-up from NordiNet IOS and ANSWER program.
      ), whereas for adult patients, the main goal of treatment is to reverse the adverse metabolic consequences of hormone deficiency and improve QoL (
      • Allo Miguel G.
      • Serraclara Pla A.
      • Partida Munoz M.L.
      • Martinez Diaz-Guerra G.
      • Hawkins F.
      Seven years of follow up of trabecular bone score, bone mineral density, body composition and quality of life in adults with growth hormone deficiency treated with rhGH replacement in a single center.
      ). Because the primary treatment goals differ for pediatric and adult patients, the transition to final adult height represents an important juncture for re-assessment of GHD, continuation of rhGH replacement in adulthood for those patients who remain GH-deficient and planning for implementation of long-term surveillance for those patients who are GH-sufficient.

      Q2. ARE THERE ANY DIFFERENCES BETWEEN CO-GHD VERSUS AO-GHD?

      In CO-GHD, the cause is commonly hypothalamic in origin because of impaired endogenous GHRH secretion (
      • Gelato M.C.
      • Malozowski S.
      • Caruso-Nicoletti M.
      • et al.
      Growth hormone (GH) responses to GH-releasing hormone during pubertal development in normal boys and girls: comparison to idiopathic short stature and GH deficiency.
      ), with the most frequently reported diagnosis being IGHD (
      • Maghnie M.
      • Triulzi F.
      • Larizza D.
      • et al.
      Hypothalamic-pituitary dysfunction in growth hormone-deficient patients with pituitary abnormalities.
      ). By contrast, the majority of AO-GHD is acquired from damage to the hypothalamic-pituitary region, most often caused by tumors, or by treatment with surgery and/or radiotherapy. Due to differences in the etiology (
      • Attanasio A.F.
      • Lamberts S.W.
      • Matranga A.M.
      • et al.
      Adult growth hormone (GH)-deficient patients demonstrate heterogeneity between childhood onset and adult onset before and during human GH treatment. Adult Growth Hormone Deficiency Study Group.
      ), phenotypic differences between adults with CO-GHD and those with AO-GHD have been described, as these differences may be related to the fact that CO-GHD occurs during development and that adults with CO-GHD may have had longer duration of being GH-deficient than AO-GHD patients.
      Endogenous GH secretion declines with age (
      • Iranmanesh A.
      • Lizarralde G.
      • Veldhuis J.D.
      Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men.
      ,
      • Zadik Z.
      • Chalew S.A.
      • McCarter Jr., R.J.
      • Meistas M.
      • Kowarski A.A.
      The influence of age on the 24-hour integrated concentration of growth hormone in normal individuals.
      ), thus making it difficult to reliably differentiate between older patients with GHD and the physiologic decline of serum GH levels due to aging in normal subjects, hence the need to use GH–stimulation test/s in most patients and adopting appropriate GH cut-points. When compared with patients with AO-GHD, adults with CO-GHD tend to have lower BMI, waist-to-hip ratio, serum IGF-1 levels (
      • Attanasio A.F.
      • Lamberts S.W.
      • Matranga A.M.
      • et al.
      Adult growth hormone (GH)-deficient patients demonstrate heterogeneity between childhood onset and adult onset before and during human GH treatment. Adult Growth Hormone Deficiency Study Group.
      ), and poorer social outcomes (
      • Mitra M.T.
      • Jonsson P.
      • Akerblad A.C.
      • et al.
      Social, educational and vocational outcomes in patients with childhood-onset and young-adult-onset growth hormone deficiency.
      ). Additionally, adults with CO-GHD due to organic hypothalamic-pituitary disease (e.g., craniopharyngioma, pituitary hypoplasia, ectopic posterior pituitary, or previous cranial irradiation) tend to have more severe long-term health consequences than those with AO-GHD, particularly with decreased muscle mass (
      • Ogle G.D.
      • Moore B.
      • Lu P.W.
      • Craighead A.
      • Briody J.N.
      • Cowell C.T.
      Changes in body composition and bone density after discontinuation of growth hormone therapy in adolescence: an interim report.
      ), BMD (
      • Johannsson G.
      • Albertsson-Wikland K.
      • Bengtsson B.A.
      Discontinuation of growth hormone (GH) treatment: metabolic effects in GH-deficient and GH-sufficient adolescent patients compared with control subjects. Swedish Study Group for Growth Hormone Treatment in Children.
      ), and cardiac function (
      • Longobardi S.
      • Cuocolo A.
      • Merola B.
      • et al.
      Left ventricular function in young adults with childhood and adulthood onset growth hormone deficiency.
      ).

      Q3. HOW SHOULD PEDIATRIC PATIENTS WITH CO-GHD BE TRANSITIONED TO ADULT-CARE SERVICES?

      Human development significantly changes during the transition age, arbitrarily defined as starting in late puberty and ending with full adult maturation when peak bone mass is achieved (
      • Rosenfeld R.G.
      • Nicodemus B.C.
      The transition from adolescence to adult life: physiology of the ‘transition’ phase and its evolutionary basis.
      ). Teenagers undergo a period of physical growth, sexual maturation, and cognitive development, and form their own identities to achieve independence from their parents. Navigating the health care of young adults with CO-GHD becomes particularly challenging during this time, making it a high-risk period for these patients to inconsistently utilize specialized endocrine care (
      • Hokken-Koelega A.
      • van der Lely A.J.
      • Hauffa B.
      • et al.
      Bridging the gap: metabolic and endocrine care of patients during transition.
      ). Transition patients are defined herein as adolescents (usually 15 to 18 years of age) with CO-GHD who have been treated with rhGH in childhood and have attained final adult height. In patients with persistent GHD after retesting, continuation of rhGH treatment is needed in order for these patients to obtain full somatic maturation, normalization of body composition and BMD, QoL, and lipid metabolism in adulthood (
      • Aimaretti G.
      • Attanasio R.
      • Cannavo S.
      • et al.
      Growth hormone treatment of adolescents with growth hormone deficiency (GHD) during the transition period: results of a survey among adult and paediatric endocrinologists from Italy. Endorsed by SIEDP/ISPED, AME, SIE, SIMA.
      ).
      Because the transition of medical care from childhood to adulthood is generally considered a vulnerable period in the life of a young person, it is very important that the transition of these patients to adult endocrine services be as seamless as possible. In fact, there is evidence that morbidity and mortality increase for young individuals following the transition from pediatric to adult services (
      • Kipps S.
      • Bahu T.
      • Ong K.
      • et al.
      Current methods of transfer of young people with Type 1 diabetes to adult services.
      ). Effective transition has been shown to improve long-term outcomes (
      • Harden P.N.
      • Walsh G.
      • Bandler N.
      • et al.
      Bridging the gap: an integrated paediatric to adult clinical service for young adults with kidney failure.
      ,
      • Prestidge C.
      • Romann A.
      • Djurdjev O.
      • Matsuda-Abedini M.
      Utility and cost of a renal transplant transition clinic.
      ) and patient experience (
      • Shaw K.L.
      • Watanabe A.
      • Rankin E.
      • McDonagh J.E.
      Walking the talk. Implementation of transitional care guidance in a UK paediatric and a neighbouring adult facility.
      ). However, despite the evidence of the risks associated with a poorly managed move to adult services and availability of potential solutions, studies continue to show that the move remains ad hoc and an unsatisfactory experience for transition patients (
      • Nagra A.
      • McGinnity P.M.
      • Davis N.
      • Salmon A.P.
      Implementing transition: Ready Steady Go.
      ).
      It is a common belief by some pediatricians that transition should only begin shortly prior to transfer to adult services. Conversely, studies have shown that starting transition early at around 11 to 12 years of age leads to better knowledge and skills (
      • Shaw K.L.
      • Southwood T.R.
      • McDonagh J.E.
      Young people's satisfaction of transitional care in adolescent rheumatology in the UK.
      ), offers the patient and caregiver more time to prepare for adult services, and allows patients to move through the process at their own individual pace. Additionally, having close collaboration, frequent communication, and common transition clinics staffed by pediatric and adult endocrinologists may be beneficial, and can take place around the time of final height and completion of puberty. The pediatrician should effectively set expectations to prepare the child and parents for the possibility that rhGH treatment might need to be resumed in adulthood. The adult endocrinologist taking over future follow-up should be aware that obtaining adult height and completing puberty does not mean that the adolescent is fully matured in a physiologic and psychologic sense.

      Q4. WHAT ARE THE BENEFITS OF CONTINUING rhGH REPLACEMENT IN TRANSITION PATIENTS WITH CO-GHD?

      Low BMD, impaired bone microarchitecture and abnormal body composition tend to be more frequently observed in young adults with CO-GHD and underlying structural pituitary or brain tumors than those with idiopathic GHD (
      • Yuen K.C.
      • Koltowska-Häggström M.
      • Cook D.M.
      • et al.
      Clinical characteristics and effects of GH replacement therapy in adults with childhood-onset craniopharyngioma compared with those in adults with other causes of childhood-onset hypothalamic-pituitary dysfunction.
      ). In these patients, the abnormal body composition may manifest as increased fat mass, decreased lean body mass, and adverse cardiovascular risk markers, with lower high-density lipoprotein (HDL)-cholesterol and higher low-density lipoprotein (LDL)-cholesterol that is more pronounced than patients with AO-GHD (
      • Carroll P.V.
      • Drake W.M.
      • Maher K.T.
      • et al.
      Comparison of continuation or cessation of growth hormone (GH) therapy on body composition and metabolic status in adolescents with severe GH deficiency at completion of linear growth.
      ). Beyond transition, a longitudinal study reported delayed timing of peak bone mass at the lumbar spine and a rapid decline in BMD over the following 2 years in adolescents with CO-GHD who discontinued rhGH treatment after final height was achieved (
      • Baroncelli G.I.
      • Bertelloni S.
      • Sodini F.
      • Saggese G.
      Longitudinal changes of lumbar bone mineral density (BMD) in patients with GH deficiency after discontinuation of treatment at final height; timing and peak values for lumbar BMD.
      ), whereas in another study, a longer interval without rhGH replacement was associated with lower BMD in the femoral neck (
      • Tritos N.A.
      • Hamrahian A.H.
      • King D.
      • et al.
      A longer interval without GH replacement and female gender are associated with lower bone mineral density in adults with childhood-onset GH deficiency: a KIMS database analysis.
      ). Therefore, these patients are at risk of not achieving peak bone mass as a consequence of discontinuing rhGH treatment at final height.
      However, studies documenting results of rhGH treatment of patients with CO-GHD have been somewhat inconsistent. Some studies have demonstrated increased BMD and improved lipid profiles after 2 years of rhGH therapy compared with untreated patients (
      • Attanasio A.F.
      • Shavrikova E.
      • Blum W.F.
      • et al.
      Continued growth hormone (GH) treatment after final height is necessary to complete somatic development in childhood-onset GH-deficient patients.
      ), while others have failed to show any benefit from continuation of rhGH therapy 2 years after final height is achieved (
      • Boot A.M.
      • van der Sluis I.M.
      • Krenning E.P.
      • de Muinck Keizer-Schrama S.M.
      Bone mineral density and body composition in adolescents with childhood-onset growth hormone deficiency.
      ,
      • Mauras N.
      • Pescovitz O.H.
      • Allada V.
      • et al.
      Limited efficacy of growth hormone (GH) during transition of GH-deficient patients from adolescence to adulthood: a phase III multicenter, double-blind, randomized two-year trial.
      ). These discordant results may be explained by the fact that in the studies reporting improvement (
      • Attanasio A.F.
      • Shavrikova E.
      • Blum W.F.
      • et al.
      Continued growth hormone (GH) treatment after final height is necessary to complete somatic development in childhood-onset GH-deficient patients.
      ), the majority of patients had MPHD (defined as ≥3 PHD other than GHD), had stopped taking rhGH therapy for 1 to 6 years, and had an average age of re-initiation of rhGH therapy of 18 to 23 years. In the 2 studies (
      • Boot A.M.
      • van der Sluis I.M.
      • Krenning E.P.
      • de Muinck Keizer-Schrama S.M.
      Bone mineral density and body composition in adolescents with childhood-onset growth hormone deficiency.
      ,
      • Mauras N.
      • Pescovitz O.H.
      • Allada V.
      • et al.
      Limited efficacy of growth hormone (GH) during transition of GH-deficient patients from adolescence to adulthood: a phase III multicenter, double-blind, randomized two-year trial.
      ) that did not show efficacy of rhGH therapy, the majority of patients had idiopathic IGHD, an average age of 16 years, and time without rhGH therapy of only about 1 month. Furthermore, BMD may not be a reliable method of assessment of skeletal integrity in young adults with CO-GHD because continued bone maturation in some of these patients is still ongoing in an enlarging skeleton. The positive effects of GH on cortical and trabecular microarchitecture has been demonstrated in some studies (
      • Yang H.
      • Yan K.
      • Yuping X.
      • et al.
      Bone microarchitecture and volumetric bone density impairment in young male adults with childhood-onset growth hormone deficiency.
      ,
      • Silva P.P.B.
      • Amlashi F.G.
      • Yu E.W.
      • et al.
      Bone microarchitecture and estimated bone strength in men with active acromegaly.
      ,
      • Kužma M.
      • Kužmová Z.
      • Zelinková Z.
      • et al.
      Impact of the growth hormone replacement on bone status in growth hormone deficient adults.
      ), and this may be more relevant in predicting future risk of fractures and prevention than actual BMD in these patients.
      It is important to evaluate patients for persistence of GHD at the time of completion of longitudinal growth, as those patients who remain GH-deficient can be at risk of developing adverse metabolic outcomes upon cessation (
      • Attanasio A.F.
      • Shavrikova E.
      • Blum W.F.
      • et al.
      Continued growth hormone (GH) treatment after final height is necessary to complete somatic development in childhood-onset GH-deficient patients.
      ,
      • di Iorgi N.
      • Secco A.
      • Napoli F.
      • et al.
      Deterioration of growth hormone (GH) response and anterior pituitary function in young adults with childhood-onset GH deficiency and ectopic posterior pituitary: a two-year prospective follow-up study.
      ,
      • Yang H.
      • Wang L.
      • Qiu X.
      • et al.
      Body composition and metabolic health of young male adults with childhood-onset multiple pituitary hormone deficiency after cessation of growth hormone treatment.
      ) that may be mitigated by resuming rhGH therapy (
      • Carroll P.V.
      • Drake W.M.
      • Maher K.T.
      • et al.
      Comparison of continuation or cessation of growth hormone (GH) therapy on body composition and metabolic status in adolescents with severe GH deficiency at completion of linear growth.
      ,
      • Drake W.M.
      • Carroll P.V.
      • Maher K.T.
      • et al.
      The effect of cessation of growth hormone (GH) therapy on bone mineral accretion in GH-deficient adolescents at the completion of linear growth.
      ,
      • Conway G.S.
      • Szarras-Czapnik M.
      • Racz K.
      • et al.
      Treatment for 24 months with recombinant human GH has a beneficial effect on bone mineral density in young adults with childhood-onset GH deficiency.
      ,
      • Clayton P.
      • Gleeson H.
      • Monson J.
      • Popovic V.
      • Shalet S.M.
      • Christiansen J.S.
      Growth hormone replacement throughout life: insights into age-related responses to treatment.
      ). While the majority of patients with IGHD are not GH-deficient in adulthood (
      • Bonfig W.
      • Bechtold S.
      • Bachmann S.
      • et al.
      Reassessment of the optimal growth hormone cut-off level in insulin tolerance testing for growth hormone secretion in patients with childhood-onset growth hormone deficiency during transition to adulthood.
      ,
      • Longobardi S.
      • Merola B.
      • Pivonello R.
      • et al.
      Reevaluation of growth hormone (GH) secretion in 69 adults diagnosed as GH-deficient patients during childhood.
      ), children with MPHD and structural pituitary or brain tumors and/or genetic mutations are likely to remain persistently GH-deficient (
      • Molitch M.E.
      • Clemmons D.R.
      • Malozowski S.
      • Merriam G.R.
      • Vance M.L.
      • Endocrine S.
      Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline.
      ). In these patients, retesting for GHD is not required and rhGH replacement can be continued without interruption.
      Current published data suggest that rhGH therapy has the greatest impact on body composition (
      • Attanasio A.F.
      • Shavrikova E.
      • Blum W.F.
      • et al.
      Continued growth hormone (GH) treatment after final height is necessary to complete somatic development in childhood-onset GH-deficient patients.
      ,
      • Underwood L.E.
      • Attie K.M.
      • Baptista J.
      Growth hormone (GH) dose-response in young adults with childhood-onset GH deficiency: a two-year, multicenter, multiple-dose, placebo-controlled study.
      ), muscle strength (
      • Hulthén L.
      • Bengtsson B.A.
      • Sunnerhagen K.S.
      • Hallberg L.
      • Grimby G.
      • Johannsson G.
      GH is needed for the maturation of muscle mass and strength in adolescents.
      ), and cardiovascular risk markers (
      • Capalbo D.
      • Lo Vecchio A.
      • Farina V.
      • et al.
      Subtle alterations of cardiac performance in children with growth hormone deficiency: results of a two-year prospective, case-control study.
      ,
      • Colao A.
      • Di Somma C.
      • Salerno M.
      • Spinelli L.
      • Orio F.
      • Lombardi G.
      The cardiovascular risk of GH-deficient adolescents.
      ), including improvements in dyslipidemia (
      • Elbornsson M.
      • Gotherstrom G.
      • Bosaeus I.
      • Bengtsson B.A.
      • Johannsson G.
      • Svensson J.
      Fifteen years of GH replacement improves body composition and cardiovascular risk factors.
      ), with a lesser impact on BMD (
      • Attanasio A.F.
      • Shavrikova E.
      • Blum W.F.
      • et al.
      Continued growth hormone (GH) treatment after final height is necessary to complete somatic development in childhood-onset GH-deficient patients.
      ), insulin sensitivity (
      • Norrelund H.
      • Vahl N.
      • Juul A.
      • et al.
      Continuation of growth hormone (GH) therapy in GH-deficient patients during transition from childhood to adulthood: impact on insulin sensitivity and substrate metabolism.
      ), and QoL (
      • Hazem A.
      • Elamin M.B.
      • Bancos I.
      • et al.
      Body composition and quality of life in adults treated with GH therapy: a systematic review and meta-analysis.
      ). Despite the lack of compelling data (
      • Ahmid M.
      • Perry C.G.
      • Ahmed S.F.
      • Shaikh M.G.
      Growth hormone deficiency during young adulthood and the benefits of growth hormone replacement.
      ), several studies have reported that untreated GHD during the transition period can adversely impact somatic and metabolic development (
      • Tritos N.A.
      • Hamrahian A.H.
      • King D.
      • et al.
      A longer interval without GH replacement and female gender are associated with lower bone mineral density in adults with childhood-onset GH deficiency: a KIMS database analysis.
      ,
      • Yang H.
      • Wang L.
      • Qiu X.
      • et al.
      Body composition and metabolic health of young male adults with childhood-onset multiple pituitary hormone deficiency after cessation of growth hormone treatment.
      ,
      • Courtillot C.
      • Baudoin R.
      • Du Souich T.
      • et al.
      Monocentric study of 112 consecutive patients with childhood onset GH deficiency around and after transition.
      ), although it remains challenging to establish whether these alterations may affect future morbidity and mortality. Larger and longer-term studies are needed to determine whether the metabolic alterations in transition GH-deficient patients persist in later adulthood, and whether continuation of rhGH replacement improves long-term overall health.

      Q5. WHO SHOULD BE TESTED FOR ADULT GHD?

      Because the presenting symptoms and signs of adults with GHD are typically nonspecific and resemble those of the metabolic syndrome, clinicians should perform a comprehensive evaluation, including performing GH–stimulation testing in the appropriate clinical context of patients with a reasonable probability of GHD (Table 5), and with the intent to initiate rhGH replacement should the diagnosis be confirmed. The exception is that GH–stimulation testing is not required in certain patients who meet the criteria that predicts adult GHD with high specificity (
      • Hartman M.L.
      • Crowe B.J.
      • Biller B.M.
      • Ho K.K.
      • Clemmons D.R.
      • Chipman J.J.
      Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency?.
      ). These patients include those with organic hypothalamic-pituitary disease (e.g., suprasellar mass with previous surgery and cranial irradiation) who have MPHD (defined as ≥3 pituitary hormone deficits) and low serum IGF-1 levels (<-2.0 SDS) (as the probability of GHD being documented on stimulation testing is >95%) (
      • Hartman M.L.
      • Crowe B.J.
      • Biller B.M.
      • Ho K.K.
      • Clemmons D.R.
      • Chipman J.J.
      Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency?.
      ), patients with genetic defects affecting the hypothalamic-pituitary axes, and those with hypothalamic-pituitary structural brain defects (
      • Molitch M.E.
      • Clemmons D.R.
      • Malozowski S.
      • Merriam G.R.
      • Vance M.L.
      • Endocrine S.
      Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline.
      ). In patients with ≤2 PHD, low serum IGF-1 levels (<-2.0 SDS) alone cannot be used to make the diagnosis of adult GHD and clinicians should perform a GH–stimulation test to confirm the diagnosis in these patients. In contrast, after longitudinal growth is completed in transition patients with idiopathic IGHD and low-normal (between 0 to -2 SDS) or low (<-2 SDS) serum IGF-1 levels, GHD and deficiency of 1 or 2 additional pituitary hormones, IGHD with pituitary hypoplasia or ectopic posterior pituitary, and previous history of cranial irradiation, retesting for GHD should be performed after at least 1 month following discontinuation of rhGH therapy.
      The number of GH–stimulation tests needed in transition patients with childhood IGHD or suspected hypothalamic GHD is dependent on the level of the clinician's suspicion. If the suspicion is high, such as IGHD with pituitary hypoplasia or ectopic posterior pituitary and previous cranial irradiation and a low-normal (<0 SDS) serum IGF-1 level is detected, clinicians should perform one GH–stimulation test. If the suspicion is low (e.g., in patients with no visible sellar abnormality on MRI and no other PHD) and the serum IGF-1 level is low-normal (<0 SDS), then clinicians should perform 2 different GH–stimulation tests using appropriate peak GH cut-points. Conversely, a large number of patients with IGHD and serum IGF-1 ≥0 SDS show normalization of endogenous GH secretion when retested at the time or after adult height is achieved (
      • Meazza C.
      • Gertosio C.
      • Pagani S.
      • et al.
      Is retesting in growth hormone deficient children really useful?.
      ,
      • Secco A.
      • di Iorgi N.
      • Napoli F.
      • et al.
      Reassessment of the growth hormone status in young adults with childhood-onset growth hormone deficiency: reappraisal of insulin tolerance testing.
      ); therefore, retesting and rhGH therapy in these patients are not required. For other transition patients with CO-GHD, it is recommended that these patients be retested to confirm the diagnosis when longitudinal growth is completed. The exception are patients with MPHD and low serum IGF-1 levels (<-2 SDS) or a known hypothalamic-pituitary congenital/genetic defect, where the likelihood of GHD is high, and retesting is not required (
      • Aimaretti G.
      • Attanasio R.
      • Cannavo S.
      • et al.
      Growth hormone treatment of adolescents with growth hormone deficiency (GHD) during the transition period: results of a survey among adult and paediatric endocrinologists from Italy. Endorsed by SIEDP/ISPED, AME, SIE, SIMA.
      ). Additionally, the risk for development of persistent GHD after previous childhood radiation treatment is increased with higher radiation doses and longer duration of time post-therapy (
      • Sklar C.A.
      • Antal Z.
      • Chemaitilly W.
      • et al.
      Hypothalamic-pituitary and growth disorders in survivors of childhood cancer: an Endocrine Society Clinical Practice Guideline.
      ,
      • Gleeson H.K.
      • Gattamaneni H.R.
      • Smethurst L.
      • Brennan B.M.
      • Shalet S.M.
      Reassessment of growth hormone status is required at final height in children treated with growth hormone replacement after radiation therapy.
      ). In these patients, retesting those who initially tested as GH-sufficient may be performed later in the transition period or later in adulthood. It is important to note that GHD may be associated with normal serum IGF-1 levels appropriate for age and sex in AO-GHD patients, although in these patients, serum IGF-1 levels are generally <0 SDS (
      • Baum H.B.
      • Biller B.M.
      • Katznelson L.
      • et al.
      Assessment of growth hormone (GH) secretion in men with adult-onset GH deficiency compared with that in normal men--a clinical research center study.
      ). Thus, in an appropriate clinical context with reasonable clinical suspicion, a serum IGF-1 in the bottom half of the reference range (i.e., between 0 to -2 SDS) should not dissuade the clinician from considering the possibility of GHD and performing further GH–stimulation testing.
      Adults with CO-GHD due to structural hypothalamic-pituitary lesions, and those with a previous history of TBI or radiation require retesting for GHD. Patients with CO-GHD who underwent GH–replacement therapy should also be retested for GHD as adults, unless the patient is known to have genetic mutations (especially in early-appearing transcription factors), or irreversible structural hypothalamic-pituitary damage. Congenital GHD is often associated with a variety of hypothalamic-stalk-pituitary anatomic abnormalities, ranging from pituitary hypoplasia to stalk agenesis and ectopically located posterior pituitary adjacent to the hypothalamus (
      • Maghnie M.
      • Salati B.
      • Bianchi S.
      • et al.
      Relationship between the morphological evaluation of the pituitary and the growth hormone (GH) response to GH-releasing hormone plus arginine in children and adults with congenital hypopituitarism.
      ). For these patients, further testing for GHD after adult height is achieved may be considered if the clinical suspicion is high in these patients to assess for persistent GHD in adulthood (
      • Leger J.
      • Danner S.
      • Simon D.
      • Garel C.
      • Czernichow P.
      Do all patients with childhood-onset growth hormone deficiency (GHD) and ectopic neurohypophysis have persistent GHD in adulthood?.
      ,
      • Penta L.
      • Cofini M.
      • Lucchetti L.
      • et al.
      Growth hormone (GH) therapy during the transition period: should we think about early retesting in patients with idiopathic and isolated GH deficiency?.
      ).
      Tumors in the pituitary and hypothalamic region are the most common causes of adult GHD (
      • Brabant G.
      • PE M.
      • Jonsson P.
      • Polydorou D.
      • Kreitschmann-Andermahr I.
      Etiology, baseline characteristics, and biochemical diagnosis of GH deficiency in the adult: are there regional variations?.
      ) and may result in partial or complete hypopituitarism from tumor compression or following treatment with surgery and/or irradiation. The most common lesions are pituitary adenomas, craniopharyngiomas, and Rathke's cleft cysts. Other less common conditions that require testing for adult GHD include tumors in the hypothalamus (e.g., hypothalamic hamartoma) (
      • Feuillan P.
      • Peters K.F.
      • Cutler Jr., G.B.
      • Biesecker L.G.
      Evidence for decreased growth hormone in patients iwth hypothalamic hamartoma due to Palliseter-Hall syndrome.
      ), infiltrative diseases of the hypothalamus and stalk (e.g., Langerhans cell histiocytosis, sarcoidosis and tuberculosis), and autoimmune hypophysitis. More recently, central nervous system infections (
      • Schaefer S.
      • Boegershausen N.
      • Meyer S.
      • Ivan D.
      • Schepelmann K.
      • Kann P.H.
      Hypothalamic-pituitary insufficiency following infectious diseases of the central nervous system.
      ,
      • Tsiakalos A.
      • Xynos I.D.
      • Sipsas N.V.
      • Kaltsas G.
      Pituitary insufficiency after infectious meningitis: a prospective study.
      ), ischemic stroke (
      • Booij H.A.
      • Gaykema W.D.C.
      • Kuijpers K.A.J.
      • Pouwels M.J.M.
      • den Hertog H.M.
      Pituitary dysfunction and association with fatigue in stroke and other acute brain injury.
      ,
      • Karamouzis I.
      • Pagano L.
      • Prodam F.
      • et al.
      Clinical and diagnostic approach to patients with hypopituitarism due to traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), and ischemic stroke (IS).
      ,
      • Lillicrap T.
      • Garcia-Esperon C.
      • Walker F.R.
      • et al.
      Growth hormone deficiency is frequent after recent stroke.
      ), SAH (
      • Booij H.A.
      • Gaykema W.D.C.
      • Kuijpers K.A.J.
      • Pouwels M.J.M.
      • den Hertog H.M.
      Pituitary dysfunction and association with fatigue in stroke and other acute brain injury.
      ,
      • Giritharan S.
      • Cox J.
      • Heal C.J.
      • Hughes D.
      • Gnanalingham K.
      • Kearney T.
      The prevalence of growth hormone deficiency in survivors of subarachnoid haemorrhage: results from a large single centre study.
      ,
      • Karamouzis I.
      • Pagano L.
      • Prodam F.
      • et al.
      Clinical and diagnostic approach to patients with hypopituitarism due to traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), and ischemic stroke (IS).
      ), meningoencephalitis (
      • Pekic S.
      • Popovic V.
      Diagnosis of endocrine disease: Expanding the cause of hypopituitarism.
      ), and hemorrhagic fever due to hantaviruses (
      • Pekic S.
      • Popovic V.
      Diagnosis of endocrine disease: Expanding the cause of hypopituitarism.
      ) are also reported as potential causes of GHD. However, as these are uncommon causes of adult GHD, confirmation of the diagnosis with GH–stimulation testing is required. Specifically, in TBI and SAH patients, GHD may be transient especially within the first year after the event (
      • Tolli A.
      • Borg J.
      • Bellander B.M.
      • Johansson F.
      • Hoybye C.
      Pituitary function within the first year after traumatic brain injury or subarachnoid haemorrhage.
      ). In these patients where there is a reasonable level of clinical suspicion, GH–stimulation testing should only be performed at least 12 months after the event (
      • Tolli A.
      • Borg J.
      • Bellander B.M.
      • Johansson F.
      • Hoybye C.
      Pituitary function within the first year after traumatic brain injury or subarachnoid haemorrhage.
      ).
      In patients with IGHD and serum IGF-I ≥0 SDS, which accounts for the majority of individuals with childhood GHD (
      • Bonfig W.
      • Bechtold S.
      • Bachmann S.
      • et al.
      Reassessment of the optimal growth hormone cut-off level in insulin tolerance testing for growth hormone secretion in patients with childhood-onset growth hormone deficiency during transition to adulthood.
      ,
      • Longobardi S.
      • Merola B.
      • Pivonello R.
      • et al.
      Reevaluation of growth hormone (GH) secretion in 69 adults diagnosed as GH-deficient patients during childhood.
      ), many will demonstrate normal GH responses when retested after final height is achieved. In these patients, retesting and rhGH therapy are not required; however, it is reasonable to continue long-term follow-up in case they develop delayed GHD. Conversely, young adults with organic GHD in childhood as a consequence of a sellar lesion, pituitary surgery, high-dose irradiation to the hypothalamic-pituitary axis, or a combination of these resulting in MPHD (
      • Berberoglu M.
      • Siklar Z.
      • Darendeliler F.
      • et al.
      Evaluation of permanent growth hormone deficiency (GHD) in young adults with childhood onset GHD: a multicenter study.
      ) and those with structural pituitary abnormalities (e.g., pituitary hypoplasia, pituitary stalk agenesis, and posterior pituitary ectopia) (
      • Maghnie M.
      • Strigazzi C.
      • Tinelli C.
      • et al.
      Growth hormone (GH) deficiency (GHD) of childhood onset: reassessment of GH status and evaluation of the predictive criteria for permanent GHD in young adults.
      ) often remain GH-deficient. Re-assessment for GHD is recommended to confirm the diagnosis, followed by rhGH replacement at adult doses for those patients with persistent GHD. Factors that can increase the likelihood of developing adult GHD after cranial irradiation include higher radiation doses, younger age, and a longer interval after completion of radiotherapy (
      • Mulder R.L.
      • Kremer L.C.
      • van Santen H.M.
      • et al.
      Prevalence and risk factors of radiation-induced growth hormone deficiency in childhood cancer survivors: a systematic review.
      ). In cases where there is no suggestive clinical history (Table 5), evaluation for adult GHD should not be performed. Recommended treatment algorithms for the transition and adult patients are shown in Figures 2 and 3, respectively.
      Fig. 2
      Fig. 2Algorithm for testing transition patients with clinical suspicion of GHD.
      Fig. 3
      Fig. 3Algorithm for testing adult patients with clinical suspicion of GHD.

      Q6. HOW SHOULD ONE TEST FOR ADULT GHD?

      The diagnosis of adult GHD is often challenging due to lack of a single biologic endpoint, such as growth failure seen in children with the disorder. As GH levels decline with aging, it is important to differentiate between age-related physiologic decline in GH levels and pathologic GHD that usually has an identifiable cause. Additionally, GH is secreted by the pituitary gland episodically in a pulsatile pattern, and modified by age, gender, and BMI, whereas serum IGF-1 levels can be lowered by factors such as protein or calorie malnutrition, poorly controlled DM, chronic illness, renal failure, and chronic liver disease (
      • Puche J.E.
      • Castilla-Cortazar I.
      Human conditions of insulin-like growth factor-I (IGF-I) deficiency.
      ). Hence, random serum GH and IGF-1 levels cannot be used alone and GH–stimulation test/s may be performed to establish the diagnosis in most patients, with the exception of certain subpopulations such as those with organic hypothalamic-pituitary disease (e.g., suprasellar mass with previous surgery and cranial irradiation) who have MPHD and low serum IGF-1 levels (<-2.0 SDS) (
      • Hartman M.L.
      • Crowe B.J.
      • Biller B.M.
      • Ho K.K.
      • Clemmons D.R.
      • Chipman J.J.
      Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency?.
      ), patients with genetic defects affecting the hypothalamic-pituitary axes, and those with hypothalamic-pituitary structural brain defects (
      • Molitch M.E.
      • Clemmons D.R.
      • Malozowski S.
      • Merriam G.R.
      • Vance M.L.
      • Endocrine S.
      Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline.
      ).
      The diagnosis of adult GHD is dependent upon the accuracy and reliability of the GH–stimulation test utilized. All GH–stimulation tests are based on the concept that a pharmacologic agent can be administered to provoke pituitary GH secretion, with serum GH levels measured at timed serum-sampling intervals, and the peak serum GH level compared against a validated GH cut-point to interpret the test. Historically, the ITT has been widely accepted as the gold-standard GH–stimulation test, but this test is labor-intensive, contraindicated in the elderly and in adults with seizure disorders and cardio/cerebrovascular disease, can be unpleasant for the patient, and is potentially hazardous. Because of these limitations associated with the ITT, this test has in recent years been used less frequently in the U.S. (
      • Gordon M.B.
      • Levy R.A.
      • Gut R.
      • Germak J.
      Trends in growth hormone stimulation testing and growth hormone dosing in adult growth hormone deficiency patients: results from the ANSWER Program.
      ).
      Finding a reliable alternative to the ITT for the diagnosis of adult GHD has been a challenge. After the removal of recombinant GHRH (injectable sermorelin) from the market in the U.S. in July, 2008, the GHRH plus ARG test could no longer be performed (
      • Yuen K.C.
      • Biller B.M.
      • Molitch M.E.
      • Cook D.M.
      Clinical review: Is lack of recombinant growth hormone (GH)-releasing hormone in the United States a setback or time to consider glucagon testing for adult GH deficiency?.
      ). Furthermore, ARG used alone has poor diagnostic accuracy unless a very low peak GH cut-point of 0.4 μg/L is used (
      • Biller B.M.
      • Samuels M.H.
      • Zagar A.
      • et al.
      Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency.
      ). Therefore, based on available data (
      • Conceicao F.L.
      • da Costa e Silva A.
      • Leal Costa A.J.
      • Vaisman M.
      Glucagon stimulation test for the diagnosis of GH deficiency in adults.
      ,
      • Gomez J.M.
      • Espadero R.M.
      • Escobar-Jimenez F.
      • et al.
      Growth hormone release after glucagon as a reliable test of growth hormone assessment in adults.
      ), the GST was suggested as the alternative test to the ITT, replacing the GHRH plus ARG test (
      • Yuen K.C.
      • Biller B.M.
      • Molitch M.E.
      • Cook D.M.
      Clinical review: Is lack of recombinant growth hormone (GH)-releasing hormone in the United States a setback or time to consider glucagon testing for adult GH deficiency?.
      ). The GST has become the most commonly used diagnostic agent because of its availability, reproducibility, safety, lack of influence by gender and hypothalamic cause of GHD, and relatively few contraindications (
      • Gordon M.B.
      • Levy R.A.
      • Gut R.
      • Germak J.
      Trends in growth hormone stimulation testing and growth hormone dosing in adult growth hormone deficiency patients: results from the ANSWER Program.
      ). The accuracy of GST is acceptable in normal-weight individuals, but because peak GH secretion decreases with increasing BMI (
      • Pijl H.
      • Langendonk J.G.
      • Burggraaf J.
      • et al.
      Altered neuroregulation of GH secretion in viscerally obese premenopausal women.
      ,
      • Utz A.L.
      • Yamamoto A.
      • Bluss P.
      • Breu J.
      • Miller K.K.
      Androgens may mediate a relative preservation of IGF-I levels in overweight and obese women despite reduced growth hormone secretion.
      ), a lower peak GH cut-point of 1 μg/L has been proposed for overweight/obese patients (
      • Yuen K.C.
      • Tritos N.A.
      • Samson S.L.
      • Hoffman A.R.
      • Katznelson L.
      American Association of Clinical Endocrinologists and American College of Endocrinology Disease State Clinical Review: Update on growth hormone stimulation testing and proposed revised cut-point for the glucagon stimulation test in the diagnosis of adult growth hormone deficiency.
      ). The main disadvantages of the GST are its long duration (3 to 4 hours) with multiple blood draws, the need for intramuscular administration, and not infrequent gastrointestinal side effects (
      • Yuen K.C.
      • Biller B.M.
      • Katznelson L.
      • et al.
      Clinical characteristics, timing of peak responses and safety aspects of two dosing regimens of the glucagon stimulation test in evaluating growth hormone and cortisol secretion in adults.
      ). In December, 2017, the U.S. FDA approved oral macimorelin for use as a diagnostic test for adult GHD in the U.S. (

      US Food and Drug AdministrationDrug trials snapshot: Macrilen. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-marcrilen. Accessed July, 2018. (EL 4; NE)

      ). The macimorelin test has been demonstrated to be safe, effective, highly reproducible, and has excellent tolerability, with sensitivity and specificity comparable to the ITT (
      • Garcia J.M.
      • Biller B.M.K.
      • Korbonits M.
      • et al.
      Macimorelin as a diagnostic test for adult growth hormone deficiency.
      ) and the GHRH plus ARG test (
      • Garcia J.M.
      • Swerdloff R.
      • Wang C.
      • et al.
      Macimorelin (AEZS-130)-stimulated growth hormone (GH) test: validation of a novel oral stimulation test for the diagnosis of adult GH deficiency.
      ). Because the macimorelin test is simple, well tolerated with minimal side effects, and of shorter duration with only 3 to 4 blood draws compared to other GH–stimulation tests, it is anticipated that its use will increase over time.
      In transition patients, a feasible and validated GH–stimulation test with optimal peak GH cut-points has been less well-studied. In a systematic review by Sfeir et al (
      • Sfeir J.G.
      • Kittah N.E.N.
      • Tamhane S.U.
      • et al.
      Diagnosis of growth hormone deficiency as a late effect of radiotherapy in survivors of childhood cancers.
      ) comparing transition patients with childhood cancer to non-childhood cancer survivors, the authors propose the use of ITT as the test of choice but not the GHRH plus ARG test given the primarily hypothalamic dysfunction of childhood cancer survivors (
      • Darzy K.H.
      • Thorner M.O.
      • Shalet S.M.
      Cranially irradiated adult cancer survivors may have normal spontaneous GH secretion in the presence of discordant peak GH responses to stimulation tests (compensated GH deficiency).
      ). In this regard, the ITT is recommended as the test of choice even though its performance is largely based on the general population and historic experience. If the ITT is contraindicated or not feasible to perform, the GST and the macimorelin test may be considered as alternative tests, but data remain scarce regarding the peak GH cut-points for these tests in this group of patients. By contrast, ARG and L-DOPA testing have not been systematically evaluated, but because these tests have a low specificity for confirming GHD in adults (
      • Biller B.M.
      • Samuels M.H.
      • Zagar A.
      • et al.
      Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency.
      ), neither test should be used.
      It is important to note that GH–stimulation test/s should only be conducted after all the other PHD have been optimally replaced with stable hormone-replacement doses because over- or under-replacement of the other endocrine axes can potentially affect the results of GH testing. Caution should also be exercised when interpreting the results of GH–stimulation tests in overweight/obese adults, especially as obesity is common in patients with tumors in the hypothalamic-pituitary region (
      • Yuen K.C.
      • Biller B.M.
      • Katznelson L.
      • et al.
      Clinical characteristics, timing of peak responses and safety aspects of two dosing regimens of the glucagon stimulation test in evaluating growth hormone and cortisol secretion in adults.
      ,
      • Bredella M.A.
      • Torriani M.
      • Thomas B.J.
      • et al.
      Peak growth hormone-releasing hormon-arginine-stimulated growth hormone is unversely associated with intramyocellular and intrahepatic lipid content in premenopausal women with obesity.
      ). Obesity is a state of functional, relative GHD, associated with decreased spontaneous secretion, pulses, and half-life of GH (
      • Iranmanesh A.
      • Lizarralde G.
      • Veldhuis J.D.
      Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men.
      ,
      • Van Dam E.W.
      • Roelfsema F.
      • Helmerhorst F.H.
      • et al.
      Low amplitude and disorderly spontaneous growth hormone release in obese women with or without polycystic ovary syndrome.
      ,
      • Veldhuis J.D.
      • Iranmanesh A.
      • Ho K.K.
      • Waters M.J.
      • Johnson M.L.
      • Lizarralde G.
      Dual defects in pulsatile growth hormone secretion and clearance subserve the hyposomatotropism of obesity in man.
      ). Furthermore, nonalcoholic fatty liver disease also is increasingly observed now in overweight and obese adults with GHD (
      • Nishizawa H.
      • Iguchi G.
      • Murawaki A.
      • et al.
      Nonalcoholic fatty liver disease in adult hypopituitary patients with GH deficiency and the impact of GH replacement therapy.
      ), with diminished hepatic GH signaling (
      • Rufinatscha K.
      • Ress C.
      • Folie S.
      • et al.
      Metabolic effects of reduced growth hormone action in fatty liver disease.
      ) and lower serum IGF-1 levels (
      • Sumida Y.
      • Yonei Y.
      • Tanaka S.
      • et al.
      Lower levels of insulin-like growth factor-1 standard deviation score are associated with histo-logical severity of non-alcoholic fatty liver disease.
      ) being associated with increasing severity of the disease. By contrast, serum IGF-1 levels are less affected by obesity per se, presumably due to increased hepatic GH sensitivity, resulting in discordance between GH and IGF-1 levels in these patients. This notion has been substantiated by a greater IGF-1 response to a single bolus of GH administration (
      • Gleeson H.K.
      • Lissett C.A.
      • Shalet S.M.
      Insulin-like growth factor-I response to a single bolus of growth hormone is increased in obesity.
      ) and larger increments and decreased individual variability of serum IGF-1 levels to low rhGH replacement doses in obese adults with GHD (
      • Yuen K.C.
      • Cook D.M.
      • Rumbaugh E.E.
      • Cook M.B.
      • Dunger D.B.
      Individual IGF-I responsiveness to a fixed regimen of low-dose growth hormone replacement is increased with less variability in obese compared to non-obese adults with severe growth hormone deficiency.
      ).
      Common limitations associated with currently available GH–stimulation tests include GH responses to the ITT and GST that show intra-individual variability, and a lack of normative data based on age, gender, and BMI with the ITT, GST, and macimorelin test with variable peak GH cut-points, depending on which test is used. For the ITT and GST, the peak GH cut-points have been previously accepted as 3 to 5 μg/L and 2.5 to 3 μg/L, respectively (
      • Cook D.M.
      • Yuen K.C.
      • Biller B.M.
      • Kemp S.F.
      • Vance M.L.
      American Association of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in growth hormone-deficient adults and transition patients - 2009 update: executive summary of recommendations.
      ,
      • Molitch M.E.
      • Clemmons D.R.
      • Malozowski S.
      • Merriam G.R.
      • Vance M.L.
      • Endocrine S.
      Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline.
      ,
      • Ho K.K.
      Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia.
      ). For the macimorelin test, a peak GH cut-point of 2.8 μg/L was suggested in 2017 by the FDA in its approval, although data from a pivotal Phase-3 trial indicated that higher sensitivity can be achieved while maintaining high specificity using a higher GH cut-point of 5.1 μg/L (
      • Garcia J.M.
      • Biller B.M.K.
      • Korbonits M.
      • et al.
      Macimorelin as a diagnostic test for adult growth hormone deficiency.
      ), suggesting that this higher GH cut-point could accurately capture all the GH-deficient patients and did not misclassify those who were GH-sufficient. Another limitation associated with currently available GH–stimulation tests include the paucity of data for specific populations of adult GHD, such as patients with TBI, uncontrolled DM, SAH, and transition patients. An ideal GH–stimulation test should possess several desired characteristics that include the ability to reliably distinguish patients with GHD patients from GH–sufficient individuals, safe and easy accessibility of the test agent, high test reproducibility, and little to minimal side effects. From a practical standpoint, it would be advantageous if the test is inexpensive, simple and quick to perform. The different test characteristics of currently available GH–stimulation tests in the U.S. are summarized in Table 6.
      Table 6Different Characteristics of Available GH-Stimulation Tests

       Q6.1. GH–stimulation tests currently available in the U.S.

       Insulin Tolerance Test

      The ITT has historically been accepted as the “gold standard” test for the assessment of adult GHD, with a GH cut-point of 3 to 5 μg/L when adequate hypoglycemia (blood glucose <40 mg/dL) is achieved. This GH cut-point was initially proposed by Hoffman et al (
      • Hoffman D.M.
      • O'Sullivan A.J.
      • Baxter R.C.
      • Ho K.K.
      Diagnosis of growth-hormone deficiency in adults.
      ) in 1994 based on GH responses to insulin-induced hypoglycemia, mean 24-hour serum GH levels derived from 20-minute sampling, and serum IGF-1 and insulin-like growth factor–binding protein (IGFBP)-3 levels in 23 patients considered GH-deficient due to organic pituitary disease, and in 35 sex-matched normal subjects of similar age and BMI. The ranges of stimulated peak GH responses separated GH-deficient (0.2 to 3.1 μg/L) from GH-sufficient (5.3 to 42.5 ng/mL) patients. However, there was overlap in mean serum 24-hour GH, IGF-1, and IGFBP-3 levels demonstrating the challenge in utilizing these biochemical tests alone to reliably determine GH reserve.
      Disadvantages of the ITT are that it requires close medical supervision by a physician, is unpleasant for patients as it can cause severe hypoglycemia, and has important potential adverse effects (e.g., seizures and altered consciousness resulting from neuroglycopenia). This test is contra-indicated in the elderly and in patients with a history of cardiovascular and cerebrovascular disease and seizures. Furthermore, inducing adequate hypoglycemia in normoglycemic and/or hyperglycemic obese patients with insulin resistance (
      • Lee P.
      • Greenfield J.R.
      • Ho K.K.
      Factors determining inadequate hypoglycaemia during insulin tolerance testing (ITT) after pituitary surgery.
      ) may be challenging, necessitating the use of higher insulin doses (0.15 to 0.2 IU/kg), thus increasing the risk of delayed hypoglycemia after test completion. Although the ITT demonstrates good sensitivity, its lack of reproducibility on repeat testing is another limitation. Differences in peak GH responses have been demonstrated in healthy subjects undergoing ITT at varying times (
      • Pfeifer M.
      • Kanc K.
      • Verhovec R.
      • Kocijancic A.
      Reproducibility of the insulin tolerance test (ITT) for assessment of growth hormone and cortisol secretion in normal and hypopituitary adult men.
      ) and in women at different times of their menstrual cycle (
      • Hoeck H.C.
      • Vestergaard P.
      • Jakobsen P.E.
      • Laurberg P.
      Test of growth hormone secretion in adults: poor reproducibility of the insulin tolerance test.
      ).

       Glucagon-Stimulation Test

      Glucagon is relatively more potent than ARG or clonidine in stimulating GH secretion (
      • Aimaretti G.
      • Baffoni C.
      • DiVito L.
      • et al.
      Comparisons among old and new provocative tests of GH secretion in 178 normal adults.
      ,
      • Rahim A.
      • Toogood A.A.
      • Shalet S.M.
      The assessment of growth hormone status in normal young adult males using a variety of provocative agents.
      ) and has been assessed in elderly subjects (
      • Tavares A.B.W.
      • Seixas-da-Silva I.A.
      • Silvestre D.H.S.
      • Pinheiro M.F.C.
      • Vaisman M.
      • Conceicao F.L.
      Growth hormone and cortisol secretion in the elderly evaluated using the glucagon stimulation test.
      ) and against the ITT in evaluating GH reserve in patients following pituitary surgery (
      • Berg C.
      • Meinel T.
      • Lahner H.
      • Yuece A.
      • Mann K.
      • Petersenn S.
      Diagnostic utility of the glucagon stimulation test in comparison to the insulin tolerance test in patients following pituitary surgery.
      ). However, the mechanisms of the GH–stimulatory effect of glucagon remain unclear.
      Gomez et al (
      • Gomez J.M.
      • Espadero R.M.
      • Escobar-Jimenez F.
      • et al.
      Growth hormone release after glucagon as a reliable test of growth hormone assessment in adults.
      ) and Conceicao et al (
      • Conceicao F.L.
      • da Costa e Silva A.
      • Leal Costa A.J.
      • Vaisman M.
      Glucagon stimulation test for the diagnosis of GH deficiency in adults.
      ) compared the diagnostic characteristics of GST to ITT and included a control group matched for age and sex in both studies, and for BMI in one study (
      • Gomez J.M.
      • Espadero R.M.
      • Escobar-Jimenez F.
      • et al.
      Growth hormone release after glucagon as a reliable test of growth hormone assessment in adults.
      ). Both studies demonstrated that a GH cut-point of 3 μg/L provided optimal sensitivity and specificity (
      • Conceicao F.L.
      • da Costa e Silva A.
      • Leal Costa A.J.
      • Vaisman M.
      Glucagon stimulation test for the diagnosis of GH deficiency in adults.
      ,
      • Gomez J.M.
      • Espadero R.M.
      • Escobar-Jimenez F.
      • et al.
      Growth hormone release after glucagon as a reliable test of growth hormone assessment in adults.
      ). Gomez et al (
      • Gomez J.M.
      • Espadero R.M.
      • Escobar-Jimenez F.
      • et al.
      Growth hormone release after glucagon as a reliable test of growth hormone assessment in adults.
      ) also found an inverse correlation between age (R = -0.389, P<.01) and BMI (R = -0.329, P<.05) with peak GH levels in healthy controls. However, it is important to note that this study was conducted in a European cohort, where obesity is less prevalent than the U.S. population (
      • Mathus-Vliegen E.M.
      Prevalence, pathophysiology, health consequences and treatment options of obesity in the elderly: a guideline.
      ). By contrast, Conceicao et al (
      • Conceicao F.L.
      • da Costa e Silva A.
      • Leal Costa A.J.
      • Vaisman M.
      Glucagon stimulation test for the diagnosis of GH deficiency in adults.
      ) demonstrated that peak GH levels were not affected by age in either the control or patient group, and there were no sex differences. In another study, Berg et al (
      • Berg C.
      • Meinel T.
      • Lahner H.
      • Yuece A.
      • Mann K.
      • Petersenn S.
      Diagnostic utility of the glucagon stimulation test in comparison to the insulin tolerance test in patients following pituitary surgery.
      ) demonstrated a lower peak GH cut-point of 2.5 μg/L with 95% sensitivity and 79% specificity. This study reported lower peak GH levels with GST compared to ITT (5.1 versus 6.7 μg/L, P<.01) and a positive correlation between peak GH levels during ITT and GST (R = 0.88, P<.0001), but no correlation between BMI or age to peak GH responses (
      • Leong K.S.
      • Walker A.B.
      • Martin I.
      • Wile D.
      • Wilding J.
      • MacFarlane I.A.
      An audit of 500 subcutaneous glucagon stimulation tests to assess growth hormone and ACTH secretion in patients with hypothalamic-pituitary disease.
      ,
      • Littley M.D.
      • Gibson S.
      • White A.
      • Shalet S.M.
      Comparison of the ACTH and cortisol responses to provocative testing with glucagon and insulin hypoglycaemia in normal subjects.
      ). However, these (
      • Conceicao F.L.
      • da Costa e Silva A.
      • Leal Costa A.J.
      • Vaisman M.
      Glucagon stimulation test for the diagnosis of GH deficiency in adults.
      ,
      • Gomez J.M.
      • Espadero R.M.
      • Escobar-Jimenez F.
      • et al.
      Growth hormone release after glucagon as a reliable test of growth hormone assessment in adults.
      ,
      • Berg C.
      • Meinel T.
      • Lahner H.
      • Yuece A.
      • Mann K.
      • Petersenn S.
      Diagnostic utility of the glucagon stimulation test in comparison to the insulin tolerance test in patients following pituitary surgery.
      ) and other studies (
      • Aimaretti G.
      • Baffoni C.
      • DiVito L.
      • et al.
      Comparisons among old and new provocative tests of GH secretion in 178 normal adults.
      ,
      • Rahim A.
      • Toogood A.A.
      • Shalet S.M.
      The assessment of growth hormone status in normal young adult males using a variety of provocative agents.
      ,
      • Ghigo E.
      • Bartolotta E.
      • Imperiale E.
      • et al.
      Glucagon stimulates GH secretion after intramuscular but not intravenous administration. Evidence against the assumption that glucagon per se has a GH-releasing activity.
      ,
      • Orme S.M.
      • Price A.
      • Weetman A.P.
      • Ross R.J.
      Comparison of the diagnostic utility of the simplified and standard i.m. glucagon stimulation test (IMGST).
      ) did not specifically evaluate patients with hyperglycemia and glucose intolerance. Hence, the diagnostic accuracy of the GST in testing for GHD in patients with glucose intolerance remains unclear.
      Advantages of the GST are its reproducibility, safety, and lack of influence by sex and hypothalamic origin of the GHD (
      • Yuen K.C.
      • Biller B.M.
      • Molitch M.E.
      • Cook D.M.
      Clinical review: Is lack of recombinant growth hormone (GH)-releasing hormone in the United States a setback or time to consider glucagon testing for adult GH deficiency?.
      ), whereas disadvantages include the long test duration (3 to 4 hours) with multiple blood draws, and the fact that an intramuscular injection is required. Commonly reported side effects include nausea, vomiting, and headaches ranging from <10% (
      • Berg C.
      • Meinel T.
      • Lahner H.
      • Yuece A.
      • Mann K.
      • Petersenn S.
      Diagnostic utility of the glucagon stimulation test in comparison to the insulin tolerance test in patients following pituitary surgery.
      ) to 34% (
      • Leong K.S.
      • Walker A.B.
      • Martin I.
      • Wile D.
      • Wilding J.
      • MacFarlane I.A.
      An audit of 500 subcutaneous glucagon stimulation tests to assess growth hormone and ACTH secretion in patients with hypothalamic-pituitary disease.
      ), and mainly occur between 60 to 210 minutes; side effects tend to resolve by 240 minutes into the test (
      • Yuen K.C.
      • Biller B.M.
      • Katznelson L.
      • et al.
      Clinical characteristics, timing of peak responses and safety aspects of two dosing regimens of the glucagon stimulation test in evaluating growth hormone and cortisol secretion in adults.
      ). The side effects of the GST have been reported to be more pronounced in elderly subjects with underlying cardiovascular and neurologic comorbidities, where symptomatic hypotension, hypoglycemia, and seizures may be potentiated (
      • Tavares A.B.
      • Seixas-da-Silva I.A.
      • Silvestre D.H.
      • Paixao Jr., C.M.
      • Vaisman M.
      • Conceicao F.L.
      Potential risks of glucagon stimulation test in elderly people.
      ).
      Previous studies have examined the diagnostic utility of the GST for adult GHD, but BMI was not taken into consideration (
      • Conceicao F.L.
      • da Costa e Silva A.
      • Leal Costa A.J.
      • Vaisman M.
      Glucagon stimulation test for the diagnosis of GH deficiency in adults.
      ,
      • Berg C.
      • Meinel T.
      • Lahner H.
      • Yuece A.
      • Mann K.
      • Petersenn S.
      Diagnostic utility of the glucagon stimulation test in comparison to the insulin tolerance test in patients following pituitary surgery.
      ) or included only controls with normal BMIs (
      • Aimaretti G.
      • Baffoni C.
      • DiVito L.
      • et al.
      Comparisons among old and new provocative tests of GH secretion in 178 normal adults.
      ,
      • Rahim A.
      • Toogood A.A.
      • Shalet S.M.
      The assessment of growth hormone status in normal young adult males using a variety of provocative agents.
      ). Several retrospective studies have questioned the diagnostic accuracy of the GST when the GH cut-point of 3 μg/L is used in obese/overweight adults (
      • Yuen K.C.
      • Biller B.M.
      • Katznelson L.
      • et al.
      Clinical characteristics, timing of peak responses and safety aspects of two dosing regimens of the glucagon stimulation test in evaluating growth hormone and cortisol secretion in adults.
      ,
      • Dichtel L.E.
      • Yuen K.C.
      • Bredella M.A.
      • et al.
      Overweight/Obese adults with pituitary disorders require lower peak growth hormone cutoff values on glucagon stimulation testing to avoid overdiagnosis of growth hormone deficiency.
      ,
      • Wilson J.R.
      • Utz A.L.
      • Devin J.K.
      Effects of gender, body weight, and blood glucose dynamics on the growth hormone response to the glucagon stimulation test in patients with pituitary disease.
      ) and in those with glucose intolerance (
      • Yuen K.C.
      • Biller B.M.
      • Katznelson L.
      • et al.
      Clinical characteristics, timing of peak responses and safety aspects of two dosing regimens of the glucagon stimulation test in evaluating growth hormone and cortisol secretion in adults.
      ,
      • Wilson J.R.
      • Utz A.L.
      • Devin J.K.
      Effects of gender, body weight, and blood glucose dynamics on the growth hormone response to the glucagon stimulation test in patients with pituitary disease.
      ). In a prospective study performed by Hamrahian et al (
      • Hamrahian A.H.
      • Yuen K.C.
      • Gordon M.B.
      • Pulaski-Liebert K.J.
      • Bena J.
      • Biller B.M.
      Revised GH and cortisol cut-points for the glucagon stimulation test in the evaluation of GH and hypothalamic-pituitary-adrenal axes in adults: results from a prospective randomized multicenter study.
      ), improved diagnostic accuracy was demonstrated when a lower GH cut-point was utilized. Yuen et al (
      • Yuen K.C.
      • Biller B.M.
      • Katznelson L.
      • et al.
      Clinical characteristics, timing of peak responses and safety aspects of two dosing regimens of the glucagon stimulation test in evaluating growth hormone and cortisol secretion in adults.
      ) evaluated GSTs performed in 515 patients, and found that BMI, and fasting, peak, and nadir glucose levels inversely correlated with peak GH levels. Dichtel et al (
      • Dichtel L.E.
      • Yuen K.C.
      • Bredella M.A.
      • et al.
      Overweight/Obese adults with pituitary disorders require lower peak growth hormone cutoff values on glucagon stimulation testing to avoid overdiagnosis of growth hormone deficiency.
      ) evaluated 3 groups of overweight/obese men: controls who were younger than the patients, patients with 3 to 4 pituitary hormone deficits, and patients with 1 to 2 pituitary hormone deficits. Using receiver operating characteristic (ROC) analysis, a GH cut-point of 0.94 μg/L provided optimal sensitivity (90%) and specificity (94%), whereas BMI and the amount of visceral adipose tissue inversely correlated with peak GH levels in controls. Almost half of the healthy overweight/obese individuals (45%) failed the GST using the 3 μg/L GH cut-point. Diri et al (
      • Diri H.
      • Karaca Z.
      • Simsek Y.
      • et al.
      Can a glucagon stimulation test characterized by lower GH cut-off value be used for the diagnosis of growth hormone deficiency in adults?.
      ) evaluated 216 patients with pituitary disease and 26 healthy controls and compared the GST to the ITT. These investigators used a GH cut-point of 3.0 μg/L for the ITT and 2 GH cut-points of 3.0 μg/L and 1.07 μg/L for the GST, yielding the diagnosis of adult GHD in 86.1%, 74.5%, and 54.2% of patients, respectively. In addition, patient age, BMI, and number of pituitary hormone deficits correlated with IGF-1 and peak GH levels. Twelve out of 26 (46.2%) healthy subjects failed the GST using a GH cut-point of 3.0 mg/L, but none were misclassified when the cut-point was lowered to 1.07 μg/L. Wilson et al (
      • Wilson J.R.
      • Utz A.L.
      • Devin J.K.
      Effects of gender, body weight, and blood glucose dynamics on the growth hormone response to the glucagon stimulation test in patients with pituitary disease.
      ) studied 42 patients with a high pretest probability of adult GHD. After excluding 10 patients with severe GHD based on peak GH levels ≤0.1 mg/L, these investigators found that body weight negatively correlated with GH area under the curve (R = -0.45; P = .01) and peak GH response (R = -0.42; P = .02) and positively correlated with nadir blood-glucose levels (R = 0.48; P<.01). By contrast, nadir blood-glucose levels during GSTs inversely correlated with GH area under the curve (r = -0.38; P = .03) and peak GH (r = -0.37; P = .04), implying that patients with higher nadir blood-glucose levels tended to have a lesser GH response to glucagon stimulation. Finally, Hamrahian et al (
      • Hamrahian A.H.
      • Yuen K.C.
      • Gordon M.B.
      • Pulaski-Liebert K.J.
      • Bena J.
      • Biller B.M.
      Revised GH and cortisol cut-points for the glucagon stimulation test in the evaluation of GH and hypothalamic-pituitary-adrenal axes in adults: results from a prospective randomized multicenter study.
      ) compared the fixed-dose GST (FD-GST: 1 mg or 1.5 mg in patients >90 kg body weight) and weight-based GST (WB-GST: 0.03 mg/kg) with the ITT using a GH cut-point of 3.0 μg/L. Patients with hypothalamic-pituitary disease and 1 to 2 (n = 14) or ≥3 (n = 14) PHD, and 14 control subjects matched for age, sex, estrogen status, and BMI underwent the ITT, FD-GST, and WB-GST in random order. Using ROC analysis, the optimal GH cut-point was 1.0 (92% sensitivity, 100% specificity) for FD-GST and 2.0 μg/L (96% sensitivity and 100% specificity) for WB-GST.
      It remains unclear whether hyperglycemia influences peak GH responses to glucagon stimulation independent of central adiposity, and whether different GH cut-points should be used for patients with underlying impaired glucose tolerance or DM when being tested by the GST. Furthermore, no peak GH responses have been studied using the GST in normal controls >70 years of age, and none of the previous studies included patients with uncontrolled DM. Studies by Yuen et al (
      • Yuen K.C.
      • Biller B.M.
      • Katznelson L.
      • et al.
      Clinical characteristics, timing of peak responses and safety aspects of two dosing regimens of the glucagon stimulation test in evaluating growth hormone and cortisol secretion in adults.
      ) and Wilson et al (
      • Wilson J.R.
      • Utz A.L.
      • Devin J.K.
      Effects of gender, body weight, and blood glucose dynamics on the growth hormone response to the glucagon stimulation test in patients with pituitary disease.
      ) have shown that higher blood-glucose levels during the GST were associated with lower peak GH responses; hence, caution is recommended when interpreting abnormal GST results in patients with glucose intolerance. In light of these findings (
      • Yuen K.C.
      • Biller B.M.
      • Katznelson L.
      • et al.
      Clinical characteristics, timing of peak responses and safety aspects of two dosing regimens of the glucagon stimulation test in evaluating growth hormone and cortisol secretion in adults.
      ,
      • Dichtel L.E.
      • Yuen K.C.
      • Bredella M.A.
      • et al.
      Overweight/Obese adults with pituitary disorders require lower peak growth hormone cutoff values on glucagon stimulation testing to avoid overdiagnosis of growth hormone deficiency.
      ,
      • Wilson J.R.
      • Utz A.L.
      • Devin J.K.
      Effects of gender, body weight, and blood glucose dynamics on the growth hormone response to the glucagon stimulation test in patients with pituitary disease.
      ), we recommend utilizing BMI-appropriate peak GH cut-points for the GST to diagnose adult GHD to reduce the possibility of misclassifying patients with adequate endogenous GH secretion as GH-deficient. For normal-weight (BMI <25 kg/m2) and overweight (BMI 25 to 30 kg/m2) patients with a high pretest probability, we recommend using the GH cut-point of 3 μg/L, whereas for obese (BMI >30 kg/m2) and over-weight (BMI 25 to 30 kg/m2) patients with a low pretest probability, we recommend using the lower GH cut-point of 1 μg/L.

       Macimorelin Test

      Macimorelin (formerly known as AEZS-130, ARD-07, and EP-01572) is an orally active ghrelin-mimetic that binds to the ghrelin GHS-R1a receptor with similar affinity to ghrelin. It is a pseudotripeptide with increased stability and oral bioavailability compared with other GH secretagogues, such as GHRP-6. It is readily absorbed in the gastrointestinal tract and effectively stimulates endogenous GH secretion in healthy volunteers with good tolerability (
      • Piccoli F.
      • Degen L.
      • MacLean C.
      • et al.
      Pharmacokinetics and pharmacodynamic effects of an oral ghrelin agonist in healthy subjects.
      ).
      An open-label, crossover, multicenter trial tested the diagnostic accuracy of a single oral dose of macimorelin (0.5 mg/kg) compared to GHRH plus ARG in adults with GHD and healthy matched controls (
      • Garcia J.M.
      • Swerdloff R.
      • Wang C.
      • et al.
      Macimorelin (AEZS-130)-stimulated growth hormone (GH) test: validation of a novel oral stimulation test for the diagnosis of adult GH deficiency.
      ). Peak GH levels were 2.36 ± 5.69 and 17.71 ± 19.11 μg/L in adults with GHD and healthy controls, respectively, with an optimal GH cut-point ranging between 2.7 and 5.2 μg/L (
      • Garcia J.M.
      • Swerdloff R.
      • Wang C.
      • et al.
      Macimorelin (AEZS-130)-stimulated growth hormone (GH) test: validation of a novel oral stimulation test for the diagnosis of adult GH deficiency.
      ). Macimorelin showed good discrimination comparable to GHRH plus ARG, with peak GH levels that were inversely associated with BMI in controls. In another open-label, randomized, 2-way crossover study, oral macimorelin was compared to the ITT (
      • Garcia J.M.
      • Biller B.M.K.
      • Korbonits M.
      • et al.
      Macimorelin as a diagnostic test for adult growth hormone deficiency.
      ). Using GH cut-point levels of 2.8 μg/L for macimorelin and 5.1 μg/L for ITT, negative agreement was 95.4% (95% confidence interval &lsqb;CI], 87 to 99%), positive agreement was 74.3% (95% CI, 63 to 84%), sensitivity was 87%, and specificity was 96%. Macimorelin was found to be well-tolerated, reproducible, and safe. Based on these data (
      • Garcia J.M.
      • Biller B.M.K.
      • Korbonits M.
      • et al.
      Macimorelin as a diagnostic test for adult growth hormone deficiency.
      ,
      • Garcia J.M.
      • Swerdloff R.
      • Wang C.
      • et al.
      Macimorelin (AEZS-130)-stimulated growth hormone (GH) test: validation of a novel oral stimulation test for the diagnosis of adult GH deficiency.
      ), the U.S. FDA approved macimorelin for use as a diagnostic test for adult GHD in December, 2017, and selected the GH cut-point of 2.8 μg/L to differentiate patients with normal GH secretion from those with GHD. However, when the GH cut-point was increased to 5.1 μg/L and used for both tests, negative agreement remained unchanged at 94% (95% CI, 85 to 98%), positive agreement was higher at 82% (95% CI, 72 to 90%), and sensitivity was increased to 92% while specificity remained unchanged at 96% (
      • Garcia J.M.
      • Biller B.M.K.
      • Korbonits M.
      • et al.
      Macimorelin as a diagnostic test for adult growth hormone deficiency.
      ). Because measured serum GH levels are dependent on the GH assays used, it is important to note that the 5.1 μg/L is identical to the cut-point accepted for the ITT (
      • Biller B.M.
      • Samuels M.H.
      • Zagar A.
      • et al.
      Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency.
      ) and may be considered in patients with a high pre-test probability to allow clinicians using a different GH assay to apply a cut-point related to the assay used to evaluate ITT results in their local laboratory.
      Advantages of the macimorelin test is that there is no need for parenteral administration compared to the ITT, GHRH plus ARG, or GST, and no concern for hypoglycemia. In addition, the duration of the test is only 90 minutes, with only 4 sample collections required, in contrast with more sample collections over 2 hours for the ITT and 3 to 4 hours for the GST. One of the limiting factors of this test is the cost of the drug (one 60 mg macimorelin packet costs approximately $4,500) (

      Monthly Prescribing Reference. Macrilen Rx. Available at: https://www.empr.com/drug/macrilen/. Accessed August 28, 2019. (EL 4; NE)

      ), which is relatively more expensive than insulin and glucagon. Mild dysgeusia was the most commonly reported side effect, which did not require any intervention and resolved spontaneously (
      • Garcia J.M.
      • Biller B.M.K.
      • Korbonits M.
      • et al.
      Macimorelin as a diagnostic test for adult growth hormone deficiency.
      ). Importantly, there are potential drugs that may interact with macimorelin and cause prolongation of the QT interval or reduce plasma macimorelin concentrations leading to false-positive test results (
      • Garcia J.M.
      • Biller B.M.K.
      • Korbonits M.
      • et al.
      Macimorelin as a diagnostic test for adult growth hormone deficiency.
      ). Hence, careful assessment of the patient's concurrent medications is recommended as well as discontinuation of strong CYP3A4 inducers, provided this is considered safe by the prescribing physician and with sufficient washout time prior to testing.
      Following its approval by the FDA in December, 2017, and because macimorelin is a shorter and simpler alternative to other agents, this test is expected to be utilized more frequently over time, particularly if the cost of macimorelin becomes more affordable. However, further studies with larger number of patients including children, adolescents, elderly, and those with obesity, DM, TBI, SAH, and renal or hepatic dysfunction will be needed to determine the sensitivity and specificity of macimorelin in these subpopulations. Furthermore, in patients with hypothalamic defects, it is not clear whether the macimorelin test may yield false-positive results. Future studies are needed to improve the palatability of this drug and to help outline any potential safety issues associated with this test (i.e., concomitant use with drugs that induces QT prolongation). Hence, with this notion, the GST and the macimorelin test could be considered as alternative tests if the ITT is contra-indicated or not feasible to be conducted in some patients.

      Q7. WHY ARE STANDARDIZED GH AND IGF-1 ASSAYS IMPORTANT IN THE MANAGEMENT OF ADULT GHD?

      Accurate measurement of serum GH and IGF-1 levels is critical for making the diagnosis of adult GHD. Specific GH cut-point levels on GH–stimulation tests must be interpreted in the context of the analytical method used. Circulating GH is present in several different isoforms and isomers, including the most common variant of 22 kd, and other smaller molecules, such as the 20 kd GH variant (
      • Ribeiro de Oliveira Longo Schweizer J.
      • Ribeiro-Oliveira Jr., A.
      • Bidlingmaier M.
      Growth hormone: isoforms, clinical aspects and assays interference.
      ). Monoclonal antibodies that bind to a specific molecular form of GH are used to limit detection to the 22 kd GH, without detecting other GH isoforms. Other molecules that are similar to GH (e.g., placental GH) could potentially cross-react and affect the measurement of GH levels. GH–binding protein, to which ~50% of circulating GH is bound, can also cause interference in GH assays.
      Substantial heterogeneity exists among currently utilized assays due to different standard preparations for calibration of GH immunoassays and lack of harmonization between various GH assays. This makes it difficult to directly compare diagnostic cut-points across different published studies. Another source of confusion when interpreting data from GH–stimulation tests has been that some laboratories report GH levels in mU/L, whereas others have used μg/L (
      • Junnila R.K.
      • Strasburger C.J.
      • Bidlingmaier M.
      Pitfalls of insulin-like growth factor-I and growth hormone assays.
      ). Differences in IGF-1 assay performance should also be considered when evaluating for GHD and while monitoring GH replacement. A robust reference population is necessary, with details provided by the laboratory. This is especially true for IGF-1, since there are physiologic changes based on gender, age, and probably several other factors that have not been well established. Thus, it is recommended that all assay manufacturers adopt the standards provided by the National Institute for Biological Standards and Control and report their methodology to clinicians by indicating the validation of their assay, which should include specification of the GH isoforms detected (20 kd GH, 22 kd GH, and other isoforms), the analyte being measured, the specificities of the antibodies used, and the presence or absence of GH–binding protein interference. The adoption of this recommendation might lead to improvement in the accuracy of diagnosis and follow-up of pathologic conditions, and facilitate the comparison of results from different assays.
      To demonstrate the potential discrepancies among GH and IGF-1 assays, samples of identical concentrations were sent to laboratories in the United Kingdom as part of the United Kingdom National External Quality Assessment Service (
      • Pokrajac A.
      • Wark G.
      • Ellis A.R.
      • Wear J.
      • Wieringa G.E.
      • Trainer P.J.
      Variation in GH and IGF-I assays limits the applicability of international consensus criteria to local practice.
      ). These identical samples were analyzed by 104 centers for the GH sample and 23 centers for the IGF-1 sample, utilizing 14 distinct GH assay techniques and 6 IGF-1 assay techniques. Serum GH and IGF-1 levels demonstrated a 2.5-fold difference between the lowest and highest results from the various assays, with differences that classified the same patient as having the disease in one laboratory and normal in another laboratory. These data emphasize the importance of using the same GH and IGF-1 assay from the same laboratory for a given patient during evaluation, and if possible, using the same IGF-1 assay from the same laboratory throughout follow-up.

       Q7.1. What are some aspects of hormone measurements that help standardize laboratory results?

      Over the past decade, there have been consensus statements addressing the measurement of serum GH and IGF-1 levels, and there have been calls for harmonization and standardization of techniques (
      • Clemmons D.R.
      Consensus statement on the standardization and evaluation of growth hormone and insulin-like growth factor assays.
      ). Laboratory results can be improved with the use of a single universally accepted standard preparation for GH and for IGF-1. International standards for GH and IGF-1 are both available. The second international standard for somatropin, which is a recombinant DNA-derived human GH standard 98/574 has been assigned units of 1.95 mg per ampule and has a conversion of 1 mg to 3 IU, with recommended reporting in mass units (
      • Clemmons D.R.
      Consensus statement on the standardization and evaluation of growth hormone and insulin-like growth factor assays.
      ). IGF-1 international standard 02/254 is the most current World Health Organization–approved reference standard for IGF-1 and has been analyzed in several laboratories for purity, activity, and stability (
      • Clemmons D.R.
      Consensus statement on the standardization and evaluation of growth hormone and insulin-like growth factor assays.
      ).

       Q7.2. Are there other ways to improve GH and IGF-1 assay reliability?

      Implementing certain measures may improve the reliability of serum GH and IGF-1 measurements. In addition to using the World Health Organization reference standard 02/254 for IGF-1, standard reference samples should be available for quality control. Methods that either eliminate or minimize binding-protein interference should be implemented, validated, and communicated as part of the results for each assay. Methods employed to reduce or eliminate GH–binding protein and IGFBP interference should demonstrate efficacy. Conditions such as DM, malnutrition, chronic liver disease, and renal diseases that can interfere with serum IGF-1 measurement (
      • Puche J.E.
      • Castilla-Cortazar I.
      Human conditions of insulin-like growth factor-I (IGF-I) deficiency.
      ) should be studied further, and reliable sera from healthy subjects and from such patients should be employed for validation of assays. Normative IGF-1 assay data should include a sufficient random sample of individuals from a wide range of ages, with those individuals taking medication and with conditions known to affect the GH-IGF-1 axis excluded. Results should be reported in both mass units and as an SDS score (also known as a Z-score) to allow for inter-assay comparison. The same GH assay should be used when comparing the results of different GH–stimulation tests in the same patient.

      Q8. HOW SHOULD INITIATION AND MONITORING OF rhGH REPLACEMENT BE UNDERTAKEN?

      In the U.S., rhGH (somatropin marketed under various trade names) is approved by the FDA for adult GHD. As somatropin is synthetic human GH, there is no evidence that one commercial product is different or more advantageous than another, apart from differences in pen devices, electronic auto-injector devices that are user-friendly, dose per mg adjustments, and whether the product requires refrigeration. Therefore, one rhGH commercial product is not recommended over another because there are no prospective head-to-head trials comparing the clinical efficacy of one commercial product with another.
      Serum IGF-1 levels remain the most widely used biomarker for rhGH dose adjustments even though these levels correlate weakly with clinical endpoints in rhGH treatment (
      • Johannsson G.
      • Bidlingmaier M.
      • Biller B.M.K.
      • et al.
      Growth Hormone Research Society perspective on biomarkers of GH action in children and adults.
      ). In a randomized open-label, clinical study, van Bunderen et al (
      • van Bunderen C.C.
      • Lips P.
      • Kramer M.H.
      • Drent M.L.
      Comparison of low-normal and high-normal IGF-1 target levels during growth hormone replacement therapy: A randomized clinical trial in adult growth hormone deficiency.
      ) demonstrated that in adults treated with rhGH replacement to reach a high-normal IGF-1 target level, waist circumference decreased, and QoL improved compared to those with a low-normal IGF-1 target level, but higher serum IGF-1 levels were associated with more myalgia, and lower serum IGF-1 levels with more general fatigue. More recent data by the same group of investigators (
      • van Bunderen C.C.
      • Deijen J.B.
      • Drent M.L.
      Effect of low-normal and high-normal IGF-1 levels on memory and wellbeing during growth hormone replacement therapy: a randomized clinical trial in adult growth hormone deficiency.
      ) showed that female patients may have a narrower therapeutic dose window; a high-normal IGF-1 target level was associated with impaired prefrontal cognitive functioning, whereas a low-normal target IGF-1 level was observed in patients with decreased vigor.
      It is recommended that patients be started on a low initial rhGH dose, independent of body weight but guided by age, gender, and concomitant medications. The exceptions are young women, especially those on oral estrogen replacement or oral contraceptives, and transition patients, who may require higher initial and final doses (
      • Cook D.M.
      • Ludlam W.H.
      • Cook M.B.
      Route of estrogen administration helps to determine growth hormone (GH) replacement dose in GH-deficient adults.
      ). On balance, it is reasonable to start with rhGH doses of 0.3 to 0.4 mg/day in patients <30 years old, 0.2 to 0.3 mg/day in patients between 30 to 60 years old and lower doses of 0.1 to 0.2 mg/day in older (>60 years old) patients, obese patients, patients with DM, and patients susceptible to glucose intolerance with gradual dose up-titration to minimize the risk of rhGH-induced glucose tolerance (Table 7). After starting rhGH therapy, it is recommended to follow up patients at 1- to 2-month intervals initially and to consider increasing rhGH doses in increments of 0.1 to 0.2 mg/day. Data are scarce regarding the ideal target serum IGF-1 level.
      Table 7American Association of Clinical Endocrinologists Recommendations for Recombinant Human Growth Hormone (rhGH) Replacement Therapy in Adults With Growth Hormone Deficiency (GHD)
      As a general rule, it is recommended to titrate the rhGH dose to reach serum IGF-1 levels within the age-adjusted reference range provided by the laboratory utilized (IGF-1 SDS between -2 and +2). However, this decision should take into consideration the patient's pretreatment IGF-1 SDS and the circumstances and tolerability of each individual patient. Because some patients may only tolerate lower rhGH doses frequently limited by side effects, whereas others may tolerate and require higher rhGH doses to achieve the desired clinical effects, the goals of treatment for each individual patient should be the clinical response, avoidance of side effects, and targeting serum IGF-1 levels to fall within the age-adjusted reference range (IGF-1 SDS between -2 and +2). Once maintenance doses are achieved, follow-up can be implemented at 6- to 12-month intervals. Shorter follow-up time intervals and smaller dose increments may be needed for elderly patients and those with other comorbidities such as DM to assess tolerability and side effects of therapy. Table 8 summarizes the various factors to consider in rhGH dose selection in adults with GHD.
      Table 8Factors That May Affect Changes in rhGH Dosing
      In transition patients, resuming rhGH doses at 50% of the dose last used in childhood is suggested, as these patients tend to be more tolerant of higher doses. The dose of rhGH should be gradually adjusted; it is suggested to titrate the dose to achieve the normal range of age-adjusted IGF-1 SDS and to avoid exceeding the upper limit of the normal range (IGF-1 >2 SDS), with dose adjustments based on clinical response and avoidance of any adverse effects (Table 8). Height, weight, BMI, and waist and hip circumference can be measured annually, whereas BMD and fasting lipids can be measured after discontinuing rhGH therapy as a baseline assessment, and subsequently every 2 to 3 years and every year, respectively.
      Subcutaneous injections are administered in the evening to mimic physiologic endogenous GH secretion (
      • Ho K.Y.
      • Evans W.S.
      • Blizzard R.M.
      • et al.
      Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations.
      ). The high degree of interindividual variability in both subcutaneous rhGH absorption and GH sensitivity (
      • Hoybye C.
      • Weber M.M.
      • Pournara E.
      • Tonnes Pedersen B.
      • Biller BMK.
      Is GH dosing optimal in female patients with adult-onset GH deficiency? An analysis from the NordiNet® International Outcome Study.
      ) makes an individualized, stepwise upward titration method preferable to standard weight-based dosing strategies. Women using oral estrogen as replacement therapy or for contraceptive purposes are more GH-resistant than men (
      • Kelly J.J.
      • Rajkovic I.A.
      • O'Sullivan A.J.
      • Sernia C.
      • Ho K.K.
      Effects of different oral oestrogen formulations on insulin-like growth factor-I, growth hormone and growth hormone binding protein in post-menopausal women.
      ,
      • O'Sullivan A.J.
      • Ho K.K.
      Route-dependent endocrine and metabolic effects of estrogen replacement therapy.
      ) because estrogen attenuates GH action on the liver, the principal site of IGF-1 synthesis, resulting in lower IGF-1 generation (
      • Ho K.K.
      • Gibney J.
      • Johannsson G.
      • Wolthers T.
      Regulating of growth hormone sensitivity by sex steroids: implications for therapy.
      ,
      • Leung K.C.
      • Johannsson G.
      • Leong G.M.
      • Ho KKY.
      Estrogen regulation of growth hormone action.
      ). Women require more exogenous GH than men to achieve comparable IGF-1 SDS, and even with higher doses, the effects of rhGH on body composition in women may be blunted (
      • Burman P.
      • Johansson A.G.
      • Siegbahn A.
      • Vessby B.
      • Karlsson F.A.
      Growth hormone (GH)-deficient men are more responsive to GH replacement therapy than women.
      ). Switching women to transdermal estrogen patches may allow lower rhGH doses to be used for equivalent IGF-1 responses (
      • Cook D.M.
      • Ludlam W.H.
      • Cook M.B.
      Route of estrogen administration helps to determine growth hormone (GH) replacement dose in GH-deficient adults.
      ), presumably by lowering the estrogen exposure to the liver. Given the expense of rhGH therapy, using estrogen patches instead of tablets to facilitate the use of lower GH doses may be a cost-effective measure.
      Monitoring other pituitary hormone axes also should be undertaken closely after commencement of rhGH replacement therapy, as there may be interactions with other concurrent hormone replacements (
      • Hubina E.
      • Mersebach H.
      • Rasmussen A.K.
      • et al.
      Effect of growth hormone replacement therapy on pituitary hormone secretion and hormone replacement therapies in GHD adults.
      ). Replacement of rhGH has been reported to decrease serum-free thyroxine (T4) and increase thyronine (T3) levels by increasing the extrathyroidal conversion of T4 to T3 without altering thyroid-stimulating hormone levels in some studies (
      • Behan L.A.
      • Monson J.P.
      • Agha A.
      The interaction between growth hormone and the thyroid axis in hypopituitary patients.
      ). In addition, serum cortisol levels may decline because rhGH therapy can inhibit the enzyme 11 β-hydroxysteroid dehydrogenase type 1, resulting in a shift in cortisol metabolism favoring cortisone production (
      • Toogood A.A.
      • Taylor N.F.
      • Shalet S.M.
      • Monson J.P.
      Modulation of cortisol metabolism by low-dose growth hormone replacement in elderly hypopituitary patients.
      ). Although the changes are generally relatively small and do not produce significant clinical effects in most patients, occasionally these effects of rhGH on free T4 and cortisol may unmask clinical central hypothyroidism (
      • Agha A.
      • Walker D.
      • Perry L.
      • et al.
      Unmasking of central hypothyroidism following growth hormone replacement in adult hypopituitary patients.
      ) and hypoadrenalism (
      • Toogood A.A.
      • Taylor N.F.
      • Shalet S.M.
      • Monson J.P.
      Modulation of cortisol metabolism by low-dose growth hormone replacement in elderly hypopituitary patients.
      ). Hence, regular monitoring of serum-free T4 levels during rhGH treatment is recommended in patients with central hypothyroidism, and in patients already on levothyroxine replacement, these doses should be increased as necessary. By contrast, in GH-deficient patients with low-normal serum-free T4 levels, levothyroxine replacement may be considered before starting rhGH therapy. Similarly, the hypothalamic-pituitary-adrenal axis should be assessed before and during rhGH therapy (
      • Giavoli C.
      • Libe R.
      • Corbetta S.
      • et al.
      Effect of recombinant human growth hormone (GH) replacement on the hypothalamic-pituitary-adrenal axis in adult GH-deficient patients.
      ). Any clinical deterioration after starting rhGH may be related to unmasking of central hypoadrenalism, either newly developed in those without a prior diagnosis of central hypoadrenalism or insufficient dosing of glucocorticoids in patients already taking replacement. Hence, testing for central hypoadrenalism is recommended in patients not already on glucocorticoid replacement who develop symptoms of adrenal insufficiency on initiation of rhGH or after a dose increase. In patients already on glucocorticoid replacement, small increases of the glucocorticoid dose may be helpful in determining whether insufficient replacement was the underlying cause of the symptoms. When stable new glucocorticoid and thyroid hormone doses are established, less frequent monitoring may be undertaken, unless symptoms develop or radiotherapy is administered.
      Once stable rhGH doses are maintained, clinicians should monitor the following parameters at approximately 6- to 12-month intervals: serum IGF-1, fasting glucose, hemoglobin A1c, fasting lipids, BMI, waist circumference, waist-to-hip ratio, serum-free T4, and the hypothalamic-pituitary-adrenal axis via early morning cortisol or cosyntropin-stimulation test (in patients not on glucocorticoid replacement), if clinically indicated. Additionally, evaluation of overall clinical status including assessment of QoL using the specific QoL-AGHDA questionnaire (
      • Koltowska-Haggstrom M.
      • Hennessy S.
      • Mattsson A.F.
      • Monson J.P.
      • Kind P.
      Quality of life assessment of growth hormone deficiency in adults (QoL-AGHDA): comparison of normative reference data for the general population of England and Wales with results for adult hypopituitary patients with growth hormone deficiency.
      ,
      • McKenna S.P.
      • Doward L.C.
      • Alonso J.
      • et al.
      The QoL-AGHDA: an instrument for the assessment of quality of life in adults with growth hormone deficiency.
      ) at 12-month intervals is suggested. Because adults with GHD have an increased risk of cardiovascular morbidity and mortality, based on expert opinion of the committee, cardiovascular parameters to consider monitoring during follow-up include systolic and diastolic blood pressure, and heart rate, while more detailed examinations such as electrocardiogram, echocardiogram, and carotid echo-Doppler examinations may be performed if clinically indicated according to local best clinical practice. As noted above, a low threshold for assessing the hypothalamic-pituitary-adrenal axis via early morning cortisol or cosyntropin-stimulation test (in patients not already taking glucocorticoid replacement) is suggested whenever patients experience symptoms suggestive of adrenal insufficiency, particularly after a dose increase of rhGH is made. Measurements of bone mineral content and BMD at baseline before starting rhGH therapy should be undertaken, and if the initial bone DXA scan is abnormal, bone DXA scans should be repeated at 2- to 3-year intervals to assess the need for additional bone-treatment modalities. In cases where the etiology of GHD was a tumor in the hypothalamic-pituitary region, baseline and periodic MRI scans should be undertaken before and during rhGH therapy to monitor the size of the pituitary lesion or any changes in post-surgical residual tumor. The parameters to monitor in adults with GHD while on GH replacement are summarized in Table 9.
      Table 9Parameters to be Monitored in Adults With GHD on rhGH Replacement
      An important question that is frequently debated is whether rhGH administration should be continued throughout life. Other pituitary replacement hormones are continued indefinitely, with the exception of estrogen. If patients taking rhGH replacement report significant QoL benefits and/or there are objective improvements, such as in cardiovascular risk markers, BMD, body composition, or physical activity tolerance, then rhGH treatment can be continued indefinitely (
      • Appelman-Dijkstra N.M.
      • Claessen K.M.
      • Hamdy N.A.
      • Pereira A.M.
      • Biermasz N.R.
      Effects of up to 15 years of recombinant human GH (rhGH) replacement on bone metabolism in adults with growth hormone deficiency (GHD): the Leiden Cohort Study.
      ,
      • Gibney J.
      • Wallace J.D.
      • Spinks T.
      • et al.
      The effects of 10 years of recombinant human growth hormone (GH) in adult GH-deficient patients.
      ). If there are neither subjective nor objective benefits of treatment after at least 12 to 18 months of treatment, the option of discontinuing rhGH treatment can be discussed with the patient. If treatment is discontinued, a 6-month follow-up appointment with the patient is recommended because some patients may reconsider resuming rhGH replacement therapy, noting in retrospect that their QoL was better while on treatment.

      Q9. CAN rhGH BE USED DURING CONCEPTION AND PREGNANCY?

      Growth hormone and the gonadotropic axis are inter-related throughout life, starting with the regulation of onset of puberty (
      • Franks S.
      Growth hormone and ovarian function.
      ). Mechanistic studies have shown that GH and IGF-1 can stimulate the hypothalamic-pituitary-gonadal axis at all levels (
      • Chandrashekar V.
      • Zaczek D.
      • Bartke A.
      The consequences of altered somatotropic system on reproduction.
      ) by influencing gonadotropin release, estradiol production by granulosa cells, oocyte maturation, fertility and lactation, and enhanced ovarian response to gonadotropins (
      • Chandrashekar V.
      • Zaczek D.
      • Bartke A.
      The consequences of altered somatotropic system on reproduction.
      ). Furthermore, dynamic changes of other hormones occur during pregnancy, paralleled by the development of the placenta, which secretes placental GH. During pregnancy, circulating placental GH levels rise, peaking at 36 weeks to levels comparable to those seen in acromegaly. This is accompanied by a sharp decline in pituitary GH levels that become undetectable by the 24th week of gestation (
      • Freemark M.
      Placental hormones and the control of fetal growth.
      ). Therefore, the true benefit of rhGH replacement in women with GHD at the time of pregnancy remains unclear.
      Because GH stimulates the hypothalamic-pituitary-gonadal axis at all levels, there is evidence that GHD may negatively affect the maturation of reproductive organs, delay the onset of puberty, and decrease ovarian function and fertility. Female patients with childhood-onset hypopituitarism have lower fertility rates (
      • Vila G.
      • Luger A.
      Growth hormone deficiency and pregnancy: any role for substitution?.
      ) and poorer pregnancy outcomes (
      • Hall R.
      • Manski-Nankervis J.
      • Goni N.
      • Davies M.C.
      • Conway G.S.
      Fertility outcomes in women with hypopituitarism.
      ). Although rhGH use during conception and pregnancy is not approved by the FDA, there have been questions about rhGH use for achieving fertility and whether patients taking rhGH replacement have satisfactory pregnancy outcomes. When rhGH was administered as an adjuvant treatment in in vitro fertilization/intracytoplasmic sperm injection cycles for poor responders, Bassiouny et al (
      • Bassiouny Y.A.
      • Dakhly D.M.R.
      • Bayoumi Y.A.
      • Hashish N.M.
      Does the addition of growth hormone to the in vitro fertilization/intracytoplasmic sperm injection antagonist protocol improve outcomes in poor responders? A randomized, controlled trial.
      ) reported no identifiable impact on pregnancy outcomes. However, its place in routine in vitro fertilization and ovulation induction treatment cycles is still debatable. Part of the difficulty in clarifying the place (or lack of) for rhGH in the treatment of female infertility is that the drug is expensive, it is unclear what the appropriate dose to study is, when in (or before) a cycle it should be employed, or even in which subgroup of patients it should be used, as studies have been underpowered.
      In terms of using rhGH replacement in relation to improving conception and pregnancy outcomes, several studies have been conducted, albeit with small sample sizes. Giampietro et al (
      • Giampietro A.
      • Milardi D.
      • Bianchi A.
      • et al.
      The effect of treatment with growth hormone on fertility outcome in eugonadal women with growth hormone deficiency: report of four cases and review of the literature.
      ) reported 4 cases of infertility in women with isolated GHD and normal pituitary-gonadal axis function in which rhGH replacement therapy improved dysmenorrhea and led to successful conception and pregnancies. A retrospective study of 25 women with GHD who underwent pregnancy without rhGH replacement therapy found that untreated GHD during pregnancy was not detrimental to the fetus (
      • Curran A.J.
      • Peacey S.R.
      • Shalet S.M.
      Is maternal growth hormone essential for a normal pregnancy?.
      ), while another study of 4 women with GHD found that after discontinuing rhGH when pregnancy was confirmed, there were no pregnancy complications and healthy babies were delivered (
      • Giampietro A.
      • Milardi D.
      • Bianchi A.
      • et al.
      The effect of treatment with growth hormone on fertility outcome in eugonadal women with growth hormone deficiency: report of four cases and review of the literature.
      ). In one case report of a normal pregnancy and a healthy fetus, rhGH replacement was continued until there was sufficient placental GH production (
      • Muller J.
      • Starup J.
      • Christiansen J.S.
      • Jorgensen J.O.
      • Juul A.
      • Skakkebaek N.E.
      Growth hormone treatment during pregnancy in a growth hormone-deficient woman.
      ). Others have proposed maintaining rhGH replacement during the first trimester, decreasing the dose during the second trimester, and discontinuing it during the third trimester; this has also been associated with successful pregnancy outcomes (
      • Wiren L.
      • Boguszewski C.L.
      • Johannsson G.
      Growth hormone (GH) replacement therapy in GH-deficient women during pregnancy.
      ). In the largest series published using data derived from the Pfizer Kabi International Metabolic Surveillance (KIMS) database of 201 pregnancies from 14 European countries and the U.S., Vila et al (
      • Vila G.
      • Akerblad A.C.
      • Mattsson A.F.
      • et al.
      Pregnancy outcomes in women with growth hormone deficiency.
      ) reported that nearly all women with GHD taking rhGH replacement continued treatment during the time they sought fertility. Nearly one third of patients continued treatment throughout the pregnancy, and rhGH therapy did not appear to affect pregnancy outcomes. Recently, Correa et al (
      • Correa F.A.
      • Bianchi P.H.M.
      • Franca M.M.
      • et al.
      Successful pregnancies after adequate hormonal replacement in patients with combined pituitary hormone deficiencies.
      ) prospectively evaluated the outcomes of fertility treatment in 5 women with CO-GHD, confirming that adequate hormone replacement, including for GHD, led to good pregnancy outcomes. However, because the data remain inconsistent in terms of the role of rhGH replacement during conception and continuation during pregnancy, until further safety data involving larger patient numbers become available, continuation of rhGH use for conception and pregnancy cannot be routinely recommended.

      Q10. WHAT ARE THE SIDE EFFECTS OF rhGH REPLACEMENT?

      The majority of side effects of short-term GH replacement therapy are related to sodium and water-retaining properties and reduction in insulin sensitivity, whereas long-term concerns are mainly related to the potential induction of cell growth and proliferation in response to GH and IGF-1, raising the theoretical possibility of increased risk of tumor recurrence and de novo neoplasia.
      Early studies used weight-based GH–dosing regimens, resulting in high daily doses of GH in patients with high body weight and more frequent side effects that included peripheral edema, arthralgia, myalgia, muscle stiffness, carpal tunnel syndrome, paresthesia, and worsening glucose tolerance (
      • Bengtsson B.A.
      • Eden S.
      • Lonn L.
      • et al.
      Treatment of adults with growth hormone (GH) deficiency with recombinant human GH.
      ). These effects are usually seen in obese and older patients, and generally respond to dose reduction or cessation of therapy altogether. The most serious side effect is benign intracranial hypertension presenting with symptoms of papilledema and headaches, which has been reported in children (
      • Loukianou E.
      • Tasiopoulou A.
      • Demosthenous C.
      • Brouzas D.
      Pseudotumor cerebri in a child with idiopathic growth hormone insufficiency two months after initiation of recombinant human growth hormone treatment.
      ), but rarely in adults (
      • Vischi A.
      • Guerriero S.
      • Giancipoli G.
      • Lorusso V.
      • Sborgia G.
      Delayed onset of pseudotumor cerebri syndrome 7 years after starting human recombinant growth hormone treatment.
      ). In summary, minimizing the risk of side effects is recommended by avoiding high rhGH doses and maintaining target serum IGF-1 levels within the age-adjusted laboratory reference range (IGF-1 SDS between -2 and + 2).

      Q11. HOW SAFE IS LONG-TERM rhGH REPLACEMENT THERAPY?

      The safety of rhGH replacement therapy can be improved by selecting an appropriate dose to minimize the risk of inducing side effects. Symptoms of over-replacement are less common with the use of low, fixed, nonweight-based dosing, followed by gradual upward dose titrations based on maintaining serum IGF-1 levels in the normal range. Long-term safety concerns have included risks for development or worsening of glucose intolerance or DM, theoretical concerns about neoplasia, tumor recurrence, or residual tumor growth, and effects of rhGH replacement on cardiovascular morbidity and mortality. A literature review by Stochholm et al (
      • Stochholm K.
      • Kiess W.
      Long-term safety of growth hormone-A combined registry analysis.
      ) using PubMed, EMBASE, and Google Scholar to identify all relevant safety data from manufacturers' GH registries published between 1988 and 2016 provided reassuring mortality data in children and adults treated with long-term rhGH replacement therapy. Additionally, the risk of stroke, new malignancy, leukemia, extracranial tumors, or recurrence of intracranial malignancy was not increased in patients without risk factors (
      • Stochholm K.
      • Kiess W.
      Long-term safety of growth hormone-A combined registry analysis.
      ). Conversely, the risk of SN, particularly in those who had received cranial irradiation was increased (
      • Stochholm K.
      • Kiess W.
      Long-term safety of growth hormone-A combined registry analysis.
      ). In these patients, treatment with rhGH should be conducted with caution and monitored closely during follow-up. In a systematic review by Kokshoorn et al (
      • Kokshoorn N.E.
      • Biermasz N.R.
      • Roelfsema F.
      • Smit J.W.
      • Pereira A.M.
      • Romijn J.A.
      GH replacement therapy in elderly GH-deficient patients: a systematic review.
      ) of 534 GH-deficient patients aged 60 to 80 years, treatment with rhGH decreased LDL-cholesterol levels and improved QoL, but other parameters were unchanged. Because data about the effects of rhGH replacement in patients >80 years of age are scarce, the efficacy and safety of long-term rhGH replacement in octogenarians with GHD remain unclear. In these patients, it is recommended that treatment with rhGH be based on each individual circumstance, such as pre-existing risk factors and underlying comorbidities as well as efficacy.

       Q11.1. Is there a risk of worsening glycemic control with rhGH replacement?

      Untreated adults with GHD are predisposed to increased insulin resistance (
      • Johansson J.O.
      • Fowelin J.
      • Landin K.
      • Lager I.
      • Bengtsson B.A.
      Growth hormone-deficient adults are insulin-resistant.
      ) and multiple features that resemble metabolic syndrome, which carries an increased risk of development of DM (
      • Johannsson G.
      • Bengtsson B.A.
      Growth hormone and the metabolic syndrome.
      ). Recombinant human GH replacement induces beneficial effects on body composition, forming a rationale for improvement in insulin resistance with treatment, and dyslipidemia. Concerns for the development of DM in GHD patients treated with rhGH replacement therapy stem from early studies demonstrating a 6-fold relative risk of developing DM in treated pediatric GHD compared with untreated patients (
      • Cutfield W.S.
      • Wilton P.
      • Bennmarker H.
      • et al.
      Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment.
      ), increased prevalence of DM among participants in the KIMS database studies compared with reference populations (
      • Verhelst J.
      • Mattsson A.F.
      • Camacho-Hubner C.
      • Luger A.
      • Abs R.
      The prevalence of the metabolic syndrome and associated cardiovascular complications in adult-onset GHD during GH replacement: a KIMS analysis.
      ,
      • Luger A.
      • Mattsson A.F.
      • Koltowska-Haggstrom M.
      • et al.
      Incidence of diabetes mellitus and evolution of glucose parameters in growth hormone-deficient subjects during growth hormone replacement therapy: a long-term observational study.
      ), as well as reports of DM developing during long-term surveillance of rhGH therapy (
      • Gotherstrom G.
      • Bengtsson B.A.
      • Bosaeus I.
      • Johannsson G.
      • Svensson J.
      A 10-year, prospective study of the metabolic effects of growth hormone replacement in adults.
      ). Notably, no increase in prevalence or incidence was observed in treated patients in the Hypopituitary Control and Complications Study (HypoCCS) when accounting for BMI, age, and gender (
      • Attanasio A.F.
      • Jung H.
      • Mo D.
      • et al.
      Prevalence and incidence of diabetes mellitus in adult patients on growth hormone replacement for growth hormone deficiency: a surveillance database analysis.
      ). With conflicting results in the literature, the overall effect of rhGH replacement on the development of DM is unclear. Evaluation of prospective studies indicates that shorter-term GH replacement can adversely affect glucose metabolism; conversely, low-dose rhGH replacement improves (
      • Yuen K.C.
      • Roberts Jr., C.T.
      • Frystyk J.
      • et al.
      Short-term, low-dose GH therapy improves insulin sensitivity without modifying cortisol metabolism and ectopic fat accumulation in adults with GH deficiency.
      ,
      • Arafat A.M.
      • Mohlig M.
      • Weickert M.O.
      • Schofl C.
      • Spranger J.
      • Pfeiffer A.F.
      Improved insulin sensitivity, preserved beta cell function and improved whole-body glucose metabolism after low-dose growth hormone replacement therapy in adults with severe growth hormone deficiency: a pilot study.
      ,
      • Yuen K.C.
      • Frystyk J.
      • White D.K.
      • et al.
      Improvement in insulin sensitivity without concomitant changes in body composition and cardiovascular risk markers following fixed administration of a very low growth hormone (GH) dose in adults with severe GH deficiency.
      ) or normalizes insulin sensitivity that may be related to the reduction in total body fat mass (
      • Hwu C.M.
      • Kwok C.F.
      • Lai T.Y.
      • et al.
      Growth hormone (GH) replacement reduces total body fat and normalizes insulin sensitivity in GH-deficient adults: a report of one-year clinical experience.
      ).
      Recent systematic reviews and meta-analyses have evaluated the safety of rhGH treatment in relation to glucose metabolism. A review of 27 studies with a mean of 166 patient years demonstrated a range of DM prevalence of 0 to 16.9%, with the highest among patients with treated Cushing disease (
      • Stochholm K.
      • Johannsson G.
      Reviewing the safety of GH replacement therapy in adults.
      ,
      • Webb S.M.
      • Mo D.
      • Lamberts S.W.
      • et al.
      Metabolic, cardiovascular, and cerebrovascular outcomes in growth hormone-deficient subjects with previous cushing's disease or non-functioning pituitary adenoma.
      ). Six studies selected in the systematic review were randomized placebo-controlled studies, 2 studies analyzing the same cohort compared treated and untreated patients, and 4 studies compared treated patients with reference populations. A trend toward an increase in incidence of DM during the first year of treatment was found. Traditional risk factors such as age and BMI were noted to be associated with an increased risk of DM, but there was no association of risk of DM with the dose of rhGH (