{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T20:12:11Z","timestamp":1792699931842,"version":"4.5.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,10,17]],"date-time":"2020-10-17T00:00:00Z","timestamp":1602892800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,10,17]],"date-time":"2020-10-17T00:00:00Z","timestamp":1602892800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100005760","name":"University of Gothenburg","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005760","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Rev Endocr Metab Disord"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In a seminal paper from 1990, Rosen and Bengtsson suggested that hypopituitary patients with a presumed growth hormone (GH) deficiency (GHD) have an excess mortality. Later studies have confirmed this finding but have also shown that the cause of the increased risk of death in these patients is multifactorial, including unreplaced GHD as well as non-physiological replacement therapy of other deficiencies, the etiology of hypopituitarism, and the side effects of tumor treatment. Only a few studies have investigated mortality in hypopituitary patients with GHD receiving GH replacement therapy (GHRT): these studies are retrospective observational studies with a wide range of underlying diseases but most of them show a mortality that is not different from the general population. Even though the research field of survival in GHD patients with and without GHRT is lacking prospective randomized trials, the evidence suggests that GHD in hypopituitary patients contributes to an excess mortality and modern replacement therapy including GHRT will result in a mortality that is approaching normal. Herein, we review the literature in the field of survival in GHD patients with and without GHRT. In addition, we outline the most important issues when evaluating studies in this area.<\/jats:p>","DOI":"10.1007\/s11154-020-09599-w","type":"journal-article","created":{"date-parts":[[2020,10,17]],"date-time":"2020-10-17T06:02:39Z","timestamp":1602914559000},"page":"125-133","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Growth hormone deficiency and replacement therapy in adults: Impact on survival"],"prefix":"10.1007","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0006-7726","authenticated-orcid":false,"given":"Christa C.","family":"van Bunderen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9734-0786","authenticated-orcid":false,"given":"Daniel S.","family":"Olsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,10,17]]},"reference":[{"key":"9599_CR1","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1056\/NEJM196201112660207","volume":"266","author":"MS Raben","year":"1962","unstructured":"Raben MS. Growth hormone. 2. Clinical use of human growth hormone. N Engl J Med. 1962;266:82\u20136.","journal-title":"N Engl J Med"},{"key":"9599_CR2","doi-asserted-by":"crossref","unstructured":"Falkheden T. Pathophysiological studies following hypophysectomy in man [doctoral thesis]: University of Gothenburg; 1963.","DOI":"10.1530\/acta.0.0420571"},{"issue":"26","key":"9599_CR3","doi-asserted-by":"publisher","first-page":"2551","DOI":"10.1056\/NEJMra1817346","volume":"380","author":"S Melmed","year":"2019","unstructured":"Melmed S. Pathogenesis and diagnosis of growth hormone deficiency in adults. N Engl J Med. 2019;380(26):2551\u201362.","journal-title":"N Engl J Med"},{"issue":"6","key":"9599_CR4","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1038\/nrendo.2013.77","volume":"9","author":"AY Kargi","year":"2013","unstructured":"Kargi AY, Merriam GR. Diagnosis and treatment of growth hormone deficiency in adults. Nat Rev Endocrinol. 2013;9(6):335\u201345.","journal-title":"Nat Rev Endocrinol"},{"issue":"8710","key":"9599_CR5","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/0140-6736(90)91812-O","volume":"336","author":"T Rosen","year":"1990","unstructured":"Rosen T, Bengtsson BA. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet. 1990;336(8710):285\u20138.","journal-title":"Lancet"},{"issue":"1","key":"9599_CR6","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1046\/j.1365-2265.1997.d01-1749.x","volume":"46","author":"B Bulow","year":"1997","unstructured":"Bulow B, Hagmar L, Mikoczy Z, Nordstrom CH, Erfurth EM. Increased cerebrovascular mortality in patients with hypopituitarism. Clin Endocrinol (Oxf). 1997;46(1):75\u201381.","journal-title":"Clin Endocrinol (Oxf)"},{"issue":"3","key":"9599_CR7","first-page":"1169","volume":"81","author":"AS Bates","year":"1996","unstructured":"Bates AS, Van\u2019t Hoff W, Jones PJ, Clayton RN. The effect of hypopituitarism on life expectancy. J Clin Endocrinol Metab. 1996;81(3):1169\u201372.","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"9599_CR8","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1530\/EJE-17-0340","volume":"177","author":"C Hammarstrand","year":"2017","unstructured":"Hammarstrand C, Ragnarsson O, Hallen T, Andersson E, Skoglund T, Nilsson AG, et al. Higher glucocorticoid replacement doses are associated with increased mortality in patients with pituitary adenoma. Eur J Endocrinol. 2017;177(3):251\u20136.","journal-title":"Eur J Endocrinol"},{"issue":"2","key":"9599_CR9","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1210\/jc.2014-3525","volume":"100","author":"DS Olsson","year":"2015","unstructured":"Olsson DS, Andersson E, Bryngelsson IL, Nilsson AG, Johannsson G. Excess mortality and morbidity in patients with craniopharyngioma, especially in patients with childhood onset: a population-based study in Sweden. J Clin Endocrinol Metab. 2015;100(2):467\u201374.","journal-title":"J Clin Endocrinol Metab"},{"issue":"9254","key":"9599_CR10","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1016\/S0140-6736(00)04006-X","volume":"357","author":"JW Tomlinson","year":"2001","unstructured":"Tomlinson JW, Holden N, Hills RK, Wheatley K, Clayton RN, Bates AS, et al. Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet. 2001;357(9254):425\u201331.","journal-title":"Lancet"},{"issue":"26","key":"9599_CR11","doi-asserted-by":"publisher","first-page":"1797","DOI":"10.1056\/NEJM198912283212605","volume":"321","author":"F Salomon","year":"1989","unstructured":"Salomon F, Cuneo RC, Hesp R, Sonksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med. 1989;321(26):1797\u2013803.","journal-title":"N Engl J Med"},{"issue":"8649","key":"9599_CR12","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1016\/S0140-6736(89)92328-3","volume":"1","author":"JO Jorgensen","year":"1989","unstructured":"Jorgensen JO, Pedersen SA, Thuesen L, Jorgensen J, Ingemann-Hansen T, Skakkebaek NE, et al. Beneficial effects of growth hormone treatment in GH-deficient adults. Lancet. 1989;1(8649):1221\u20135.","journal-title":"Lancet"},{"issue":"5","key":"9599_CR13","doi-asserted-by":"publisher","first-page":"2192","DOI":"10.1210\/jc.2003-030840","volume":"89","author":"P Maison","year":"2004","unstructured":"Maison P, Griffin S, Nicoue-Beglah M, Haddad N, Balkau B, Chanson P, et al. 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. 2004;89(5):2192\u20139.","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"9599_CR14","doi-asserted-by":"publisher","first-page":"R1","DOI":"10.1530\/EJE-12-1088","volume":"169","author":"NM Appelman-Dijkstra","year":"2013","unstructured":"Appelman-Dijkstra NM, Claessen KM, Roelfsema F, Pereira AM, Biermasz NR. Long-term effects of recombinant human GH replacement in adults with GH deficiency: a systematic review. Eur J Endocrinol. 2013;169(1):R1\u201314.","journal-title":"Eur J Endocrinol"},{"issue":"5","key":"9599_CR15","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1530\/EJE-11-1072","volume":"166","author":"M Elbornsson","year":"2012","unstructured":"Elbornsson M, Gotherstrom G, Bosaeus I, Bengtsson BA, Johannsson G, Svensson J. Fifteen years of GH replacement increases bone mineral density in hypopituitary patients with adult-onset GH deficiency. Eur J Endocrinol. 2012;166(5):787\u201395.","journal-title":"Eur J Endocrinol"},{"issue":"4","key":"9599_CR16","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1530\/EJE-18-0370","volume":"179","author":"C Hammarstrand","year":"2018","unstructured":"Hammarstrand C, Ragnarsson O, Bengtsson O, Bryngelsson IL, Johannsson G, Olsson DS. Comorbidities in patients with non-functioning pituitary adenoma: influence of long-term growth hormone replacement. Eur J Endocrinol. 2018;179(4):229\u201337.","journal-title":"Eur J Endocrinol"},{"issue":"1","key":"9599_CR17","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1530\/EJE-16-0450","volume":"176","author":"DS Olsson","year":"2017","unstructured":"Olsson DS, Trimpou P, Hallen T, Bryngelsson IL, Andersson E, Skoglund T, et al. Life expectancy in patients with pituitary adenoma receiving growth hormone replacement. Eur J Endocrinol. 2017;176(1):67\u201375.","journal-title":"Eur J Endocrinol"},{"issue":"10","key":"9599_CR18","doi-asserted-by":"publisher","first-page":"3151","DOI":"10.1210\/jc.2011-1215","volume":"96","author":"CC van Bunderen","year":"2011","unstructured":"van Bunderen CC, van Nieuwpoort IC, Arwert LI, Heymans MW, Franken AA, Koppeschaar HP, 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. J Clin Endocrinol Metab. 2011;96(10):3151\u20139.","journal-title":"J Clin Endocrinol Metab"},{"issue":"11","key":"9599_CR19","doi-asserted-by":"publisher","first-page":"4141","DOI":"10.1210\/jc.2014-1814","volume":"99","author":"K Stochholm","year":"2014","unstructured":"Stochholm K, Berglund A, Juul S, Gravholt CH, Christiansen JS. Socioeconomic factors do not but GH treatment does affect mortality in adult-onset growth hormone deficiency. J Clin Endocrinol Metab. 2014;99(11):4141\u20138.","journal-title":"J Clin Endocrinol Metab"},{"issue":"7","key":"9599_CR20","doi-asserted-by":"publisher","first-page":"3306","DOI":"10.1210\/jc.2003-031601","volume":"89","author":"J Svensson","year":"2004","unstructured":"Svensson J, Bengtsson BA, Rosen T, Oden A, Johannsson G. Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy. J Clin Endocrinol Metab. 2004;89(7):3306\u201312.","journal-title":"J Clin Endocrinol Metab"},{"issue":"262","key":"9599_CR21","first-page":"145","volume":"70","author":"MD Littley","year":"1989","unstructured":"Littley MD, Shalet SM, Beardwell CG, Ahmed SR, Applegate G, Sutton ML. Hypopituitarism following external radiotherapy for pituitary tumours in adults. Q J Med. 1989;70(262):145\u201360.","journal-title":"Q J Med"},{"issue":"3","key":"9599_CR22","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1210\/jc.2012-2684","volume":"98","author":"ML Hartman","year":"2013","unstructured":"Hartman ML, Xu R, Crowe BJ, Robison LL, Erfurth EM, Kleinberg DL, et al. Prospective safety surveillance of GH-deficient adults: comparison of GH-treated vs untreated patients. J Clin Endocrinol Metab. 2013;98(3):980\u20138.","journal-title":"J Clin Endocrinol Metab"},{"issue":"2","key":"9599_CR23","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1007\/s11102-016-0764-8","volume":"20","author":"DS Olsson","year":"2017","unstructured":"Olsson DS, Bryngelsson IL, Ragnarsson O. Time trends of mortality in patients with non-functioning pituitary adenoma: a Swedish nationwide study. Pituitary. 2017;20(2):218\u201324.","journal-title":"Pituitary"},{"issue":"6","key":"9599_CR24","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1530\/EJE-11-1028","volume":"166","author":"RC Gaillard","year":"2012","unstructured":"Gaillard RC, Mattsson AF, Akerblad AC, Bengtsson BA, Cara J, Feldt-Rasmussen U, et al. Overall and cause-specific mortality in GH-deficient adults on GH replacement. Eur J Endocrinol. 2012;166(6):1069\u201377.","journal-title":"Eur J Endocrinol"},{"issue":"4","key":"9599_CR25","doi-asserted-by":"publisher","first-page":"1466","DOI":"10.1210\/jc.2012-4059","volume":"98","author":"P Burman","year":"2013","unstructured":"Burman P, Mattsson AF, Johannsson G, Hoybye C, Holmer H, Dahlqvist P, et al. Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality. J Clin Endocrinol Metab. 2013;98(4):1466\u201375.","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"9599_CR26","doi-asserted-by":"publisher","first-page":"2018","DOI":"10.1210\/jc.2014-1013","volume":"99","author":"NA Tritos","year":"2014","unstructured":"Tritos NA, Johannsson G, Korbonits M, Miller KK, Feldt-Rasmussen U, Yuen KC, et al. Effects of long-term growth hormone replacement in adults with growth hormone deficiency following cure of acromegaly: a KIMS analysis. J Clin Endocrinol Metab. 2014;99(6):2018\u201329.","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"9599_CR27","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1530\/EJE-11-0558","volume":"166","author":"A Hazem","year":"2012","unstructured":"Hazem A, Elamin MB, Bancos I, Malaga G, Prutsky G, Domecq JP, et al. Body composition and quality of life in adults treated with GH therapy: a systematic review and meta-analysis. Eur J Endocrinol. 2012;166(1):13\u201320.","journal-title":"Eur J Endocrinol"},{"issue":"7","key":"9599_CR28","doi-asserted-by":"publisher","first-page":"2651","DOI":"10.1210\/jc.2015-1475","volume":"100","author":"DS Olsson","year":"2015","unstructured":"Olsson DS, Nilsson AG, Bryngelsson IL, Trimpou P, Johannsson G, Andersson E. Excess mortality in women and young adults with nonfunctioning pituitary adenoma: a Swedish nationwide study. J Clin Endocrinol Metab. 2015;100(7):2651\u20138.","journal-title":"J Clin Endocrinol Metab"},{"issue":"2","key":"9599_CR29","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1210\/jc.2004-1152","volume":"90","author":"G Minniti","year":"2005","unstructured":"Minniti G, Traish D, Ashley S, Gonsalves A, Brada M. Risk of second brain tumor after conservative surgery and radiotherapy for pituitary adenoma: update after an additional 10 years. J Clin Endocrinol Metab. 2005;90(2):800\u20134.","journal-title":"J Clin Endocrinol Metab"},{"issue":"5","key":"9599_CR30","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1530\/EJE-10-1170","volume":"164","author":"NE Kokshoorn","year":"2011","unstructured":"Kokshoorn NE, Biermasz NR, Roelfsema F, Smit JW, Pereira AM, Romijn JA. GH replacement therapy in elderly GH-deficient patients: a systematic review. Eur J Endocrinol. 2011;164(5):657\u201365.","journal-title":"Eur J Endocrinol"}],"container-title":["Reviews in Endocrine and Metabolic Disorders"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11154-020-09599-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11154-020-09599-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11154-020-09599-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,17]],"date-time":"2021-10-17T02:10:35Z","timestamp":1634436635000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11154-020-09599-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,17]]},"references-count":30,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,3]]}},"alternative-id":["9599"],"URL":"https:\/\/doi.org\/10.1007\/s11154-020-09599-w","relation":{},"ISSN":["1389-9155","1573-2606"],"issn-type":[{"value":"1389-9155","type":"print"},{"value":"1573-2606","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,17]]},"assertion":[{"value":"1 October 2020","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 October 2020","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"D S O has received consultancy fees from Pfizer, Ipsen, Novo Nordisk and Sandoz, and unrestricted research grants from Sandoz. C C v B has nothing to declare.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}