Skip to main content

Advertisement

Log in

Growth hormone therapy in adults with growth hormone deficiency: a critical assessment of the literature

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

Purpose

Growth hormone (GH) therapy has been studied as treatment for clinical manifestations of adult-onset growth hormone deficiency (AO-GHD), including cardiovascular risk, bone health, and quality of life. Patients with AO-GHD typically also have significant history of pituitary pathology and hypopituitarism, which raises the question of what proportion of their clinical presentation can be attributed to GHD alone. Currently, much of the existing data for GH therapy in AO-GHD come from uncontrolled retrospective studies and observational protocols. These considerations require careful reassessment of the role of GH as a therapeutic agent in adult patients with hypopituitarism.

Methods

We contrast results from placebo-controlled trials with those from uncontrolled and retrospective studies for GH replacement in patients with hypopituitarism. We also examine the evidence for the manifestations of AO-GHD being attributed to GHD alone, as well as the data on adults with congenital, life-long untreated isolated GHD.

Results

The evidence for increased morbidity and mortality in hypopituitary patients with GHD, and for the benefits of GH therapy, are conflicting. There remains the possibility that the described clinical manifestations of AO-GHD may not be due to GHD alone, but may also be related to underlying pituitary pathology, treatment history and suboptimal hormone replacement.

Conclusions

In the setting of inconsistent data on the benefits of GH therapy, treatment of AO-GHD remains an individualized decision. There is a need for more randomized, placebo-controlled studies to evaluate the long-term outcomes of GH therapy in adults with hypopituitarism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Rosén T, Bengtsson BA (1990) Premature mortality due to cardiovascular disease in hypopituitarism. Lancet Lond Engl 336:285–288

    Article  Google Scholar 

  2. Bülow B, Hagmar L, Mikoczy Z et al (1997) Increased cerebrovascular mortality in patients with hypopituitarism. Clin Endocrinol (Oxf) 46:75–81

    Article  Google Scholar 

  3. Shalet SM, Toogood A, Rahim A, Brennan BM (1998) The diagnosis of growth hormone deficiency in children and adults. Endocr Rev 19:203–223. https://doi.org/10.1210/edrv.19.2.0329

    Article  CAS  PubMed  Google Scholar 

  4. Svensson J, Bengtsson B-A, Rosén T et al (2004) Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy. J Clin Endocrinol Metab 89:3306–3312. https://doi.org/10.1210/jc.2003-031601

    Article  CAS  PubMed  Google Scholar 

  5. Tomlinson JW, Holden N, Hills RK et al (2001) Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet Lond Engl 357:425–431

    Article  CAS  Google Scholar 

  6. Bartke A (2005) Minireview: role of the growth hormone/insulin-like growth factor system in mammalian aging. Endocrinology 146:3718–3723. https://doi.org/10.1210/en.2005-0411

    Article  CAS  PubMed  Google Scholar 

  7. Menezes Oliveira JL, Marques-Santos C, Barreto-Filho JA et al (2006) Lack of evidence of premature atherosclerosis in untreated severe isolated growth hormone (GH) deficiency due to a GH-releasing hormone receptor mutation. J Clin Endocrinol Metab 91:2093–2099. https://doi.org/10.1210/jc.2005-2571

    Article  CAS  PubMed  Google Scholar 

  8. Krzisnik C, Grgurić S, Cvijović K, Laron Z (2010) Longevity of the hypopituitary patients from the island Krk: a follow-up study. Pediatr Endocrinol Rev 7:357–362

    PubMed  Google Scholar 

  9. Aguiar-Oliveira MH, Oliveira FT, Pereira RMC et al (2010) Longevity in untreated congenital growth hormone deficiency due to a homozygous mutation in the GHRH receptor gene. J Clin Endocrinol Metab 95:714–721. https://doi.org/10.1210/jc.2009-1879

    Article  CAS  PubMed  Google Scholar 

  10. Kaji H, Chihara K (2004) Direct causes of death in Japanese patients with hypopituitarism as analyzed from a nation-wide autopsy database. Eur J Endocrinol 150:149–152

    Article  CAS  Google Scholar 

  11. Brada M, Ashley S, Ford D et al (2002) Cerebrovascular mortality in patients with pituitary adenoma. Clin Endocrinol (Oxf) 57:713–717

    Article  CAS  Google Scholar 

  12. O’Connor MM, Mayberg MR (2000) Effects of radiation on cerebral vasculature: a review. Neurosurgery 46:138–149. https://doi.org/10.1093/neurosurgery/46.1.138 (discussion 150–151)

    Article  PubMed  Google Scholar 

  13. Rim CH, Yang DS, Park YJ et al (2011) Radiotherapy for pituitary adenomas: long-term outcome and complications. Radiat Oncol J 29:156–163. https://doi.org/10.3857/roj.2011.29.3.156

    Article  PubMed  PubMed Central  Google Scholar 

  14. van Varsseveld NC, van Bunderen CC, Ubachs DHH et al (2015) Cerebrovascular events, secondary intracranial tumors, and mortality after radiotherapy for nonfunctioning pituitary adenomas: a subanalysis from the Dutch National Registry of Growth Hormone Treatment in Adults. J Clin Endocrinol Metab 100:1104–1112. https://doi.org/10.1210/jc.2014-3697

    Article  CAS  PubMed  Google Scholar 

  15. Bates AS, Bullivant B, Sheppard MC, Stewart PM (1999) Life expectancy following surgery for pituitary tumours. Clin Endocrinol (Oxf) 50:315–319

    Article  CAS  Google Scholar 

  16. Stochholm K, Gravholt CH, Laursen T et al (2006) Incidence of GH deficiency: a nationwide study. Eur J Endocrinol 155:61–71. https://doi.org/10.1530/eje.1.02191

    Article  CAS  PubMed  Google Scholar 

  17. Erfurth EM, Bulow B, Mikoczy Z, Hagmar L (2000) Low cancer incidence in patients with hypopituitarism and unsubstituted GH deficiency. Toronto, p Abst. #2037

  18. Shevah O, Laron Z (2007) Patients with congenital deficiency of IGF-I seem protected from the development of malignancies: a preliminary report. Growth Horm IGF Res 17:54–57. https://doi.org/10.1016/j.ghir.2006.10.007

    Article  CAS  PubMed  Google Scholar 

  19. Pappachan JM, Raskauskiene D, Kutty VR, Clayton RN (2015) Excess mortality associated with hypopituitarism in adults: a meta-analysis of observational studies. J Clin Endocrinol Metab 100:1405–1411. https://doi.org/10.1210/jc.2014-3787

    Article  CAS  PubMed  Google Scholar 

  20. Jasim S, Alahdab F, Ahmed AT et al (2017) Mortality in adults with hypopituitarism: a systematic review and meta-analysis. Endocrine 56:33–42. https://doi.org/10.1007/s12020-016-1159-3

    Article  CAS  PubMed  Google Scholar 

  21. Gaillard RC, Mattsson AF, Akerblad A-C et al (2012) Overall and cause-specific mortality in GH-deficient adults on GH replacement. Eur J Endocrinol 166:1069–1077. https://doi.org/10.1530/EJE-11-1028

    Article  CAS  PubMed  Google Scholar 

  22. Ehrnborg C, Ellegård L, Bosaeus I et al (2005) Supraphysiological growth hormone: less fat, more extracellular fluid but uncertain effects on muscles in healthy, active young adults. Clin Endocrinol (Oxf) 62:449–457. https://doi.org/10.1111/j.1365-2265.2005.02240.x

    Article  CAS  Google Scholar 

  23. Götherström G, Elbornsson M, Stibrant-Sunnerhagen K et al (2009) Ten years of growth hormone (GH) replacement normalizes muscle strength in GH-deficient adults. J Clin Endocrinol Metab 94:809–816. https://doi.org/10.1210/jc.2008-1538

    Article  CAS  PubMed  Google Scholar 

  24. Woodhouse LJ, Mukherjee A, Shalet SM, Ezzat S (2006) The influence of growth hormone status on physical impairments, functional limitations, and health-related quality of life in adults. Endocr Rev 27:287–317. https://doi.org/10.1210/er.2004-0022

    Article  CAS  PubMed  Google Scholar 

  25. Filipsson Nyström H, Barbosa EJL, Nilsson AG et al (2012) Discontinuing long-term GH replacement therapy: a randomized, placebo-controlled crossover trial in adult GH deficiency. J Clin Endocrinol Metab 97:3185–3195. https://doi.org/10.1210/jc.2012-2006

    Article  CAS  PubMed  Google Scholar 

  26. Hoffman AR, Kuntze JE, Baptista J et al (2004) 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. J Clin Endocrinol Metab 89:2048–2056. https://doi.org/10.1210/jc.2003-030346

    Article  CAS  PubMed  Google Scholar 

  27. Newman CB, Frisch KA, Rosenzweig B et al (2011) Moderate doses of hGH (0.64 mg/d) improve lipids but not cardiovascular function in GH-deficient adults with normal baseline cardiac function. J Clin Endocrinol Metab 96:122–132. https://doi.org/10.1210/jc.2010-1204

    Article  CAS  PubMed  Google Scholar 

  28. Chikani V, Cuneo RC, Hickman I, Ho KKY (2015) Impairment of anaerobic capacity in adults with growth hormone deficiency. J Clin Endocrinol Metab 100:1811–1818. https://doi.org/10.1210/jc.2015-1006

    Article  CAS  PubMed  Google Scholar 

  29. Chikani V, Cuneo RC, Hickman I, Ho KKY (2016) Growth hormone (GH) enhances anaerobic capacity: impact on physical function and quality of life in adults with GH deficiency. Clin Endocrinol (Oxf) 85:660–668. https://doi.org/10.1111/cen.13147

    Article  CAS  Google Scholar 

  30. Mauras N, Pescovitz OH, Allada V et al (2005) 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. J Clin Endocrinol Metab 90:3946–3955. https://doi.org/10.1210/jc.2005-0208

    Article  CAS  PubMed  Google Scholar 

  31. Christ ER, Cummings MH, Westwood NB et al (1997) The importance of growth hormone in the regulation of erythropoiesis, red cell mass, and plasma volume in adults with growth hormone deficiency. J Clin Endocrinol Metab 82:2985–2990. https://doi.org/10.1210/jcem.82.9.4199

    Article  CAS  PubMed  Google Scholar 

  32. Caidahl K, Edén S, Bengtsson BA (1994) Cardiovascular and renal effects of growth hormone. Clin Endocrinol (Oxf) 40:393–400. https://doi.org/10.1111/j.1365-2265.1994.tb03937.x

    Article  CAS  Google Scholar 

  33. Valcavi R, Gaddi O, Zini M et al (1995) Cardiac performance and mass in adults with hypopituitarism: effects of one year of growth hormone treatment. J Clin Endocrinol Metab 80:659–666. https://doi.org/10.1210/jcem.80.2.7852533

    Article  CAS  PubMed  Google Scholar 

  34. Böger RH, Skamira C, Bode-Böger SM et al (1996) Nitric oxide may mediate the hemodynamic effects of recombinant growth hormone in patients with acquired growth hormone deficiency. A double-blind, placebo-controlled study. J Clin Investig 98:2706–2713. https://doi.org/10.1172/JCI119095

    Article  PubMed  Google Scholar 

  35. Elbornsson M, Götherström G, Bosæus I et al (2013) Fifteen years of GH replacement improves body composition and cardiovascular risk factors. Eur J Endocrinol 168:745–753. https://doi.org/10.1530/EJE-12-1083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Appelman-Dijkstra NM, Claessen KMJA, Roelfsema F et al (2013) Long-term effects of recombinant human GH replacement in adults with GH deficiency: a systematic review. Eur J Endocrinol 169:R1–R14. https://doi.org/10.1530/EJE-12-1088

    Article  CAS  PubMed  Google Scholar 

  37. Maison P, Griffin S, Nicoue-Beglah M et al (2004) Impact of growth hormone (GH) treatment on cardiovascular risk factors in GH-deficient adults: a metaanalysis of blinded, randomized, placebo-controlled trials. J Clin Endocrinol Metab 89:2192–2199. https://doi.org/10.1210/jc.2003-030840

    Article  CAS  PubMed  Google Scholar 

  38. Gazzaruso C, Gola M, Karamouzis I et al (2014) Cardiovascular risk in adult patients with growth hormone (GH) deficiency and following substitution with GH: an update. J Clin Endocrinol Metab 99:18–29. https://doi.org/10.1210/jc.2013-2394

    Article  CAS  PubMed  Google Scholar 

  39. Sesmilo G, Biller BM, Llevadot J et al (2000) Effects of growth hormone administration on inflammatory and other cardiovascular risk markers in men with growth hormone deficiency. A randomized, controlled clinical trial. Ann Intern Med 133:111–122

    Article  CAS  Google Scholar 

  40. Gruson D, Alexopoulou O, Pasquet A et al (2012) Impact of growth hormone (GH) treatment on circulating Nt-proBNP concentrations and on cardiac function in adult GH-deficient patients. Scand J Clin Lab Investig 72:387–394. https://doi.org/10.3109/00365513.2012.685887

    Article  CAS  Google Scholar 

  41. Castillo AR, Zantut-Wittmann DE, Neto AM et al (2018) Panhypopituitarism without GH replacement: about insulin sensitivity, CRP levels, and metabolic syndrome. Horm Metab Res Horm Stoffwechselforschung Horm Metab 50:690–695. https://doi.org/10.1055/a-0649-8010

    Article  CAS  Google Scholar 

  42. Monson JP, Jönsson P, Koltowska-Häggström M, Kourides I (2007) Growth hormone (GH) replacement decreases serum total and LDL-cholesterol in hypopituitary patients on maintenance HMG CoA reductase inhibitor (statin) therapy. Clin Endocrinol (Oxf) 67:623–628. https://doi.org/10.1111/j.1365-2265.2007.02935.x

    Article  CAS  Google Scholar 

  43. Rosenfalck AM, Maghsoudi S, Fisker S et al (2000) The effect of 30 months of low-dose replacement therapy with recombinant human growth hormone (rhGH) on insulin and C-peptide kinetics, insulin secretion, insulin sensitivity, glucose effectiveness, and body composition in GH-deficient adults. J Clin Endocrinol Metab 85:4173–4181. https://doi.org/10.1210/jcem.85.11.6930

    Article  CAS  PubMed  Google Scholar 

  44. Svensson J, Fowelin J, Landin K et al (2002) Effects of seven years of GH-replacement therapy on insulin sensitivity in GH-deficient adults. J Clin Endocrinol Metab 87:2121–2127. https://doi.org/10.1210/jcem.87.5.8482

    Article  CAS  PubMed  Google Scholar 

  45. Attanasio AF, Jung H, Mo D et al (2011) Prevalence and incidence of diabetes mellitus in adult patients on growth hormone replacement for growth hormone deficiency: a surveillance database analysis. J Clin Endocrinol Metab 96:2255–2261. https://doi.org/10.1210/jc.2011-0448

    Article  CAS  PubMed  Google Scholar 

  46. Luger A, Mattsson AF, Koltowska-Häggström M et al (2012) Incidence of diabetes mellitus and evolution of glucose parameters in growth hormone-deficient subjects during growth hormone replacement therapy: a long-term observational study. Diabetes Care 35:57–62. https://doi.org/10.2337/dc11-0449

    Article  CAS  PubMed  Google Scholar 

  47. Woodmansee WW, Hartman ML, Lamberts SWJ et al (2010) Occurrence of impaired fasting glucose in GH-deficient adults receiving GH replacement compared with untreated subjects. Clin Endocrinol (Oxf) 72:59–69. https://doi.org/10.1111/j.1365-2265.2009.03612.x

    Article  CAS  Google Scholar 

  48. Attanasio AF, Mo D, Erfurth EM et al (2010) Prevalence of metabolic syndrome in adult hypopituitary growth hormone (GH)-deficient patients before and after GH replacement. J Clin Endocrinol Metab 95:74–81. https://doi.org/10.1210/jc.2009-1326

    Article  CAS  PubMed  Google Scholar 

  49. van der Klaauw AA, Biermasz NR, Feskens EJM et al (2007) The prevalence of the metabolic syndrome is increased in patients with GH deficiency, irrespective of long-term substitution with recombinant human GH. Eur J Endocrinol 156:455–462. https://doi.org/10.1530/EJE-06-0699

    Article  CAS  PubMed  Google Scholar 

  50. Stewart PM, Toogood AA, Tomlinson JW (2001) Growth hormone, insulin-like growth factor-I and the cortisol-cortisone shuttle. Horm Res 56(Suppl 1):1–6. https://doi.org/10.1159/000048126

    Article  CAS  PubMed  Google Scholar 

  51. Filipsson H, Monson JP, Koltowska-Häggström M et al (2006) The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients. J Clin Endocrinol Metab 91:3954–3961. https://doi.org/10.1210/jc.2006-0524

    Article  CAS  PubMed  Google Scholar 

  52. Swords FM, Carroll PV, Kisalu J et al (2003) The effects of growth hormone deficiency and replacement on glucocorticoid exposure in hypopituitary patients on cortisone acetate and hydrocortisone replacement. Clin Endocrinol (Oxf) 59:613–620

    Article  CAS  Google Scholar 

  53. Danilowicz K, Bruno OD, Manavela M et al (2008) Correction of cortisol overreplacement ameliorates morbidities in patients with hypopituitarism: a pilot study. Pituitary 11:279–285. https://doi.org/10.1007/s11102-008-0126-2

    Article  CAS  PubMed  Google Scholar 

  54. Egger A, Buehler T, Boesch C et al (2011) The effect of GH replacement therapy on different fat compartments: a whole-body magnetic resonance imaging study. Eur J Endocrinol 164:23–29. https://doi.org/10.1530/EJE-10-0702

    Article  CAS  PubMed  Google Scholar 

  55. Ohlsson C, Bengtsson BA, Isaksson OG et al (1998) Growth hormone and bone. Endocr Rev 19:55–79. https://doi.org/10.1210/edrv.19.1.0324

    Article  CAS  PubMed  Google Scholar 

  56. Biller BM, Sesmilo G, Baum HB et al (2000) Withdrawal of long-term physiological growth hormone (GH) administration: differential effects on bone density and body composition in men with adult-onset GH deficiency. J Clin Endocrinol Metab 85:970–976. https://doi.org/10.1210/jcem.85.3.6474

    Article  CAS  PubMed  Google Scholar 

  57. Barake M, Klibanski A, Tritos NA (2014) Effects of recombinant human growth hormone therapy on bone mineral density in adults with growth hormone deficiency: a meta-analysis. J Clin Endocrinol Metab 99:852–860. https://doi.org/10.1210/jc.2013-3921

    Article  CAS  PubMed  Google Scholar 

  58. Elbornsson M, Götherström G, Bosæus I et al (2012) Fifteen years of GH replacement increases bone mineral density in hypopituitary patients with adult-onset GH deficiency. Eur J Endocrinol 166:787–795. https://doi.org/10.1530/EJE-11-1072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mo D, Fleseriu M, Qi R et al (2015) Fracture risk in adult patients treated with growth hormone replacement therapy for growth hormone deficiency: a prospective observational cohort study. Lancet Diabetes Endocrinol 3:331–338. https://doi.org/10.1016/S2213-8587(15)00098-4

    Article  CAS  PubMed  Google Scholar 

  60. Biermasz NR, Hamdy NAT, Pereira AM et al (2004) Long-term skeletal effects of recombinant human growth hormone (rhGH) alone and rhGH combined with alendronate in GH-deficient adults: a seven-year follow-up study. Clin Endocrinol (Oxf) 60:568–575. https://doi.org/10.1111/j.1365-2265.2004.02021.x

    Article  CAS  Google Scholar 

  61. Biermasz NR, Hamdy NA, Janssen YJ, Roelfsema F (2001) Additional beneficial effects of alendronate in growth hormone (GH)-deficient adults with osteoporosis receiving long-term recombinant human GH replacement therapy: a randomized controlled trial. J Clin Endocrinol Metab 86:3079–3085. https://doi.org/10.1210/jcem.86.7.7669

    Article  CAS  PubMed  Google Scholar 

  62. Tritos NA, Greenspan SL, King D et al (2011) Unreplaced sex steroid deficiency, corticotropin deficiency, and lower IGF-I are associated with lower bone mineral density in adults with growth hormone deficiency: a KIMS database analysis. J Clin Endocrinol Metab 96:1516–1523. https://doi.org/10.1210/jc.2010-2662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wüster C, Abs R, Bengtsson BA et al (2001) The influence of growth hormone deficiency, growth hormone replacement therapy, and other aspects of hypopituitarism on fracture rate and bone mineral density. J Bone Miner Res 16:398–405. https://doi.org/10.1359/jbmr.2001.16.2.398

    Article  PubMed  Google Scholar 

  64. Murray RD, Columb B, Adams JE, Shalet SM (2004) Low bone mass is an infrequent feature of the adult growth hormone deficiency syndrome in middle-age adults and the elderly. J Clin Endocrinol Metab 89:1124–1130. https://doi.org/10.1210/jc.2003-030685

    Article  CAS  PubMed  Google Scholar 

  65. Toogood AA, Adams JE, O’Neill PA, Shalet SM (1997) Elderly patients with adult-onset growth hormone deficiency are not osteopenic. J Clin Endocrinol Metab 82:1462–1466. https://doi.org/10.1210/jcem.82.5.3932

    Article  CAS  PubMed  Google Scholar 

  66. Murray RD, Adams JE, Shalet SM (2006) A densitometric and morphometric analysis of the skeleton in adults with varying degrees of growth hormone deficiency. J Clin Endocrinol Metab 91:432–438. https://doi.org/10.1210/jc.2005-0897

    Article  CAS  PubMed  Google Scholar 

  67. Högler W, Shaw N (2010) Childhood growth hormone deficiency, bone density, structures and fractures: scrutinizing the evidence. Clin Endocrinol (Oxf) 72:281–289. https://doi.org/10.1111/j.1365-2265.2009.03686.x

    Article  CAS  Google Scholar 

  68. Bouillon R, Koledova E, Bezlepkina O et al (2004) Bone status and fracture prevalence in Russian adults with childhood-onset growth hormone deficiency. J Clin Endocrinol Metab 89:4993–4998. https://doi.org/10.1210/jc.2004-0054

    Article  CAS  PubMed  Google Scholar 

  69. Mazziotti G, Mormando M, Cristiano A et al (2014) Association between l-thyroxine treatment, GH deficiency, and radiological vertebral fractures in patients with adult-onset hypopituitarism. Eur J Endocrinol 170:893–899. https://doi.org/10.1530/EJE-14-0097

    Article  CAS  PubMed  Google Scholar 

  70. Mazziotti G, Porcelli T, Bianchi A et al (2010) Glucocorticoid replacement therapy and vertebral fractures in hypopituitary adult males with GH deficiency. Eur J Endocrinol 163:15–20. https://doi.org/10.1530/EJE-10-0125

    Article  CAS  PubMed  Google Scholar 

  71. Mo D, Blum WF, Rosilio M et al (2014) Ten-year change in quality of life in adults on growth hormone replacement for growth hormone deficiency: an analysis of the hypopituitary control and complications study. J Clin Endocrinol Metab 99:4581–4588. https://doi.org/10.1210/jc.2014-2892

    Article  CAS  PubMed  Google Scholar 

  72. Elbornsson M, Horvath A, Götherström G et al (2017) Seven years of growth hormone (GH) replacement improves quality of life in hypopituitary patients with adult-onset GH deficiency. Eur J Endocrinol 176:99–109. https://doi.org/10.1530/EJE-16-0875

    Article  CAS  PubMed  Google Scholar 

  73. Holdaway IM, Hunt P, Manning P et al (2015) Three-year experience with access to nationally funded growth hormone (GH) replacement for GH-deficient adults. Clin Endocrinol (Oxf) 83:85–90. https://doi.org/10.1111/cen.12691

    Article  CAS  Google Scholar 

  74. Barkan AL (2001) The “quality of life-assessment of growth hormone deficiency in adults” questionnaire: can it be used to assess quality of life in hypopituitarism? J Clin Endocrinol Metab 86:1905–1907. https://doi.org/10.1210/jcem.86.5.7443

    Article  CAS  PubMed  Google Scholar 

  75. Barbosa JAR, Salvatori R, Oliveira CRP et al (2009) Quality of life in congenital, untreated, lifetime isolated growth hormone deficiency. Psychoneuroendocrinology 34:894–900. https://doi.org/10.1016/j.psyneuen.2009.01.001

    Article  CAS  PubMed  Google Scholar 

  76. Sandberg DE, MacGillivray MH, Clopper RR et al (1998) Quality of life among formerly treated childhood-onset growth hormone-deficient adults: a comparison with unaffected siblings. J Clin Endocrinol Metab 83:1134–1142. https://doi.org/10.1210/jcem.83.4.4712

    Article  CAS  PubMed  Google Scholar 

  77. Sommer G, Gianinazzi ME, Kuonen R et al (2015) Health-Related Quality of Life of Young Adults Treated with Recombinant Human Growth Hormone during Childhood. PLoS ONE 10:e0140944. https://doi.org/10.1371/journal.pone.0140944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lynch S, Merson S, Beshyah SA et al (1994) Psychiatric morbidity in adults with hypopituitarism. J R Soc Med 87:445–447

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Li Voon Chong JSW, Groves T, Foy P et al (2002) Elderly people with hypothalamic-pituitary disease and untreated GH deficiency: clinical outcome, body composition, lipid profiles and quality of life after 2 years compared to controls. Clin Endocrinol (Oxf) 56:175–181

    Article  CAS  Google Scholar 

  80. Arwert LI, Deijen JB, Witlox J, Drent ML (2005) The influence of growth hormone (GH) substitution on patient-reported outcomes and cognitive functions in GH-deficient patients: a meta-analysis. Growth Horm IGF Res 15:47–54. https://doi.org/10.1016/j.ghir.2004.11.004

    Article  CAS  PubMed  Google Scholar 

  81. Saller B, Mattsson AF, Kann PH et al (2006) Healthcare utilization, quality of life and patient-reported outcomes during two years of GH replacement therapy in GH-deficient adults: comparison between Sweden, The Netherlands and Germany. Eur J Endocrinol 154:843–850. https://doi.org/10.1530/eje.1.02149

    Article  CAS  PubMed  Google Scholar 

  82. Underwood LE, Attie KM, Baptista J, Genentech Collaborative Study Group (2003) Growth hormone (GH) dose-response in young adults with childhood-onset GH deficiency: a two-year, multicenter, multiple-dose, placebo-controlled study. J Clin Endocrinol Metab 88:5273–5280. https://doi.org/10.1210/jc.2003-030204

    Article  CAS  PubMed  Google Scholar 

  83. Burman P, Broman JE, Hetta J et al (1995) Quality of life in adults with growth hormone (GH) deficiency: response to treatment with recombinant human GH in a placebo-controlled 21-month trial. J Clin Endocrinol Metab 80:3585–3590. https://doi.org/10.1210/jcem.80.12.8530603

    Article  CAS  PubMed  Google Scholar 

  84. Beshyah SA, Freemantle C, Shahi M et al (1995) Replacement treatment with biosynthetic human growth hormone in growth hormone-deficient hypopituitary adults. Clin Endocrinol (Oxf) 42:73–84

    Article  CAS  Google Scholar 

  85. Wallymahmed ME, Foy P, Shaw D et al (1997) Quality of life, body composition and muscle strength in adult growth hormone deficiency: the influence of growth hormone replacement therapy for up to 3 years. Clin Endocrinol (Oxf) 47:439–446

    Article  CAS  Google Scholar 

  86. Cuneo RC, Judd S, Wallace JD et al (1998) The Australian multicenter trial of growth hormone (GH) treatment in GH-deficient adults. J Clin Endocrinol Metab 83:107–116. https://doi.org/10.1210/jcem.83.1.4482

    Article  CAS  PubMed  Google Scholar 

  87. Miller KK, Wexler T, Fazeli P et al (2010) Growth hormone deficiency after treatment of acromegaly: a randomized, placebo-controlled study of growth hormone replacement. J Clin Endocrinol Metab 95:567–577. https://doi.org/10.1210/jc.2009-1611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. van der Klaauw AA, Bax JJ, Roelfsema F et al (2009) Limited effects of growth hormone replacement in patients with GH deficiency during long-term cure of acromegaly. Pituitary 12:339–346. https://doi.org/10.1007/s11102-009-0186-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Feldt-Rasmussen U, Abs R, Bengtsson B-A et al (2002) Growth hormone deficiency and replacement in hypopituitary patients previously treated for acromegaly or Cushing’s disease. Eur J Endocrinol 146:67–74. https://doi.org/10.1530/eje.0.1460067

    Article  CAS  PubMed  Google Scholar 

  90. Webb SM, Mo D, Lamberts SWJ et al (2010) Metabolic, cardiovascular, and cerebrovascular outcomes in growth hormone-deficient subjects with previous cushing’s disease or non-functioning pituitary adenoma. J Clin Endocrinol Metab 95:630–638. https://doi.org/10.1210/jc.2009-0806

    Article  CAS  PubMed  Google Scholar 

  91. Bleicken B, Hahner S, Loeffler M et al (2010) Influence of hydrocortisone dosage scheme on health-related quality of life in patients with adrenal insufficiency. Clin Endocrinol (Oxf) 72:297–304. https://doi.org/10.1111/j.1365-2265.2009.03596.x

    Article  CAS  Google Scholar 

  92. Ajmal A, McKean E, Sullivan S, Barkan A (2018) Decreased quality of life (QoL) in hypopituitary patients: involvement of glucocorticoid replacement and radiation therapy. Pituitary 21:624–630. https://doi.org/10.1007/s11102-018-0918-y

    Article  CAS  PubMed  Google Scholar 

  93. Aguiar-Oliveira MH, Souza AHO, Oliveira CRP et al (2017) Mechanisms in endocrinology: the multiple facets of GHRH/GH/IGF-I axis: lessons from lifetime, untreated, isolated GH deficiency due to a GHRH receptor gene mutation. Eur J Endocrinol 177:R85–R97. https://doi.org/10.1530/EJE-16-1047

    Article  CAS  PubMed  Google Scholar 

  94. Andrade-Guimarães AL, Aguiar-Oliveira MH, Salvatori R et al (2019) Adult individuals with congenital, untreated, severe isolated growth hormone deficiency have satisfactory muscular function. Endocrine 63:112–119. https://doi.org/10.1007/s12020-018-1763-5

    Article  CAS  PubMed  Google Scholar 

  95. Epitácio-Pereira CC, Silva GMF, Salvatori R et al (2013) Isolated GH deficiency due to a GHRH receptor mutation causes hip joint problems and genu valgum, and reduces size but not density of trabecular and mixed bone. J Clin Endocrinol Metab 98:E1710–E1715. https://doi.org/10.1210/jc.2013-2349

    Article  CAS  PubMed  Google Scholar 

  96. Barreto-Filho JAS, Alcântara MRS, Salvatori R et al (2002) Familial isolated growth hormone deficiency is associated with increased systolic blood pressure, central obesity, and dyslipidemia. J Clin Endocrinol Metab 87:2018–2023. https://doi.org/10.1210/jcem.87.5.8474

    Article  CAS  PubMed  Google Scholar 

  97. Gleeson HK, Souza AHO, Gill MS et al (2002) Lipid profiles in untreated severe congenital isolated growth hormone deficiency through the lifespan. Clin Endocrinol (Oxf) 57:89–95

    Article  CAS  Google Scholar 

  98. Oliveira JLM, Aguiar-Oliveira MH, D’Oliveira A et al (2007) Congenital growth hormone (GH) deficiency and atherosclerosis: effects of GH replacement in GH-naive adults. J Clin Endocrinol Metab 92:4664–4670. https://doi.org/10.1210/jc.2007-1636

    Article  CAS  PubMed  Google Scholar 

  99. Araujo VP, Aguiar-Oliveira MH, Oliveira JLM et al (2012) Arrest of atherosclerosis progression after interruption of GH replacement in adults with congenital isolated GH deficiency. Eur J Endocrinol 166:977–982. https://doi.org/10.1530/EJE-12-0062

    Article  CAS  PubMed  Google Scholar 

  100. Pfeifer M, Verhovec R, Zizek B et al (1999) Growth hormone (GH) treatment reverses early atherosclerotic changes in GH-deficient adults. J Clin Endocrinol Metab 84:453–457. https://doi.org/10.1210/jcem.84.2.5456

    Article  CAS  PubMed  Google Scholar 

  101. Jørgensen JOL, Juul A (2018) THERAPY OF ENDOCRINE DISEASE: growth hormone replacement therapy in adults: 30 years of personal clinical experience. Eur J Endocrinol 179(1):R47–R56. https://doi.org/10.1530/EJE-18-0306

    Article  PubMed  Google Scholar 

  102. Fleseriu M, Hashim IA, Karavitaki N et al (2016) Hormonal Replacement in hypopituitarism in adults: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 101:3888–3921. https://doi.org/10.1210/jc.2016-2118

    Article  CAS  PubMed  Google Scholar 

  103. Evidence and interpretation | Human growth hormone (somatropin) in adults with growth hormone deficiency | Guidance | NICE. In: NICE Guid. https://www.nice.org.uk/guidance/ta64/chapter/4-Evidence-and-interpretation

  104. Snyder PJ (2019) Growth hormone deficiency in adults: UpToDate. In: Date. https://www.uptodate.com/contents/growth-hormone-deficiency-in-adults?search=growth%20hormone%20deficiency%20in%20adults&source=search_result&selectedTitle=1~111&usage_type=default&display_rank=1

  105. Melmed S (2019) Pathogenesis and diagnosis of growth hormone deficiency in adults. N Engl J Med 380:2551–2562. https://doi.org/10.1056/NEJMra1817346

    Article  PubMed  Google Scholar 

  106. Whitehead HM, Boreham C, McIlrath EM et al (1992) Growth hormone treatment of adults with growth hormone deficiency: results of a 13-month placebo controlled cross-over study. Clin Endocrinol (Oxf) 36:45–52

    Article  CAS  Google Scholar 

  107. Bengtsson BA, Edén S, Lönn L et al (1993) Treatment of adults with growth hormone (GH) deficiency with recombinant human GH. J Clin Endocrinol Metab 76:309–317. https://doi.org/10.1210/jcem.76.2.8432773

    Article  CAS  PubMed  Google Scholar 

  108. Verhelst J, Abs R, Vandeweghe M et al (1997) Two years of replacement therapy in adults with growth hormone deficiency. Clin Endocrinol (Oxf) 47:485–494

    Article  CAS  Google Scholar 

  109. Baum HB, Katznelson L, Sherman JC et al (1998) Effects of physiological growth hormone (GH) therapy on cognition and quality of life in patients with adult-onset GH deficiency. J Clin Endocrinol Metab 83:3184–3189. https://doi.org/10.1210/jcem.83.9.5112

    Article  CAS  PubMed  Google Scholar 

  110. Bollerslev J, Hallén J, Fougner KJ et al (2005) Low-dose GH improves exercise capacity in adults with GH deficiency: effects of a 22-month placebo-controlled, crossover trial. Eur J Endocrinol 153:379–387. https://doi.org/10.1530/eje.1.01971

    Article  CAS  PubMed  Google Scholar 

  111. Chihara K, Kato Y, Kohno H et al (2006) Efficacy and safety of growth hormone (GH) in the treatment of adult Japanese patients with GH deficiency: a randomised, placebo-controlled study. Growth Horm IGF Res 16:132–142. https://doi.org/10.1016/j.ghir.2006.03.012

    Article  CAS  PubMed  Google Scholar 

  112. Urushihara H, Fukuhara S, Tai S et al (2007) Heterogeneity in responsiveness of perceived quality of life to body composition changes between adult- and childhood-onset Japanese hypopituitary adults with GH deficiency during GH replacement. Eur J Endocrinol 156:637–645. https://doi.org/10.1530/EJE-07-0016

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Richard J. Auchus for his critical review of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ariel L. Barkan.

Ethics declarations

Conflicts of interest

Both authors report no conflict of interest. This study was not supported by any external sources.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

He, X., Barkan, A.L. Growth hormone therapy in adults with growth hormone deficiency: a critical assessment of the literature. Pituitary 23, 294–306 (2020). https://doi.org/10.1007/s11102-020-01031-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-020-01031-5

Keywords:

Navigation