(Stroke. 2005;36:931.)
© 2005 American Heart Association, Inc.
Letters to the Editor |
Diagnosing Growth Hormone Deficiency After Aneurysmal Subarachnoid Hemorrhage
Department of Neurosurgery, University Hospital Aachen, Aachen, Germany
To the Editor:
We read with interest the article by Dimopoulou1 on hypopituitarism after aneurysmal subarachnoid hemorrhage (SAH). Although this topic deserves the attention of the neurological community treating these patients, especially those readers who, from the scope of the journal cannot be expected to be familiar with diagnostic criteria for endocrine disorders, deserve to be assured about the soundness of the proposed definitions of neuroendocrine dysfunction and the conclusions derived thereof. In the case of the authors’ definition of growth hormone deficiency (GHD) in SAH patients, this should be questioned for several reasons.
The authors assume inadequate growth hormone secretion indicative of GHD in their patients if IGF-I levels are <2 standard deviations for the appropriate age range, quoting an article by Aimaretti et al.2 However, insulin-like growth factor (IGF)-I levels do not only reflect growth hormone (GH) secretory status but also are influenced by several other factors. Therefore, low IGF-I levels can only be considered a parameter of impaired GH secretion if malnutrition, liver failure, poorly controlled diabetes mellitus, and uremia are ruled out.3
It is well-known that the IGF-I levels observed in hypopituitary patients and the normal range of IGF-I levels progressively overlap with advancing age of the patients. Along these lines, the authors fail to acknowledge that the article by Aimaretti et al demonstrates that the diagnostic value of a single IGF-I measurement in predicting GHD is only given in individuals before the age of 40 and is compromised in patients beyond that age. Taking into account the mean age of 50 years in the patients of Dimopoulou, the low IGF-I level criterion for diagnosing GHD cannot be valid for this patient group.
Furthermore, the authors do not specify which assay was used for measuring IGF-I and their given local reference values are different from the age-related normal values provided by Aimaretti et al, determined with the Pantec assay. Therefore, it can be assumed that a different assay was used for measuring IGF-I by Dimopoulou et al. In fact, the IGF-I ranges given by Dimopoulou et al coincide with the normal ranges published on the Nichols Web site for the Nichols Advantage assay. Should the authors have used this assay, they should also have used the age-specific reference values by Brabant et al,4 because every assay requires a sufficiently large normative database to allow interpretation of results and these normative data cannot be extrapolated between assay methods.
In consideration of the age peak of aneurysmal SAH between 40 and 60 years, the criterion of IGF-I 2 standard deviations less than normal is not sufficient for predicting GHD in these patients, and a number of SAH patients with IGF-I levels normal for this age group might be erroneously not diagnosed as GH-deficient and vice versa.
In fact, in our patient group of 40 patients tested with the insulin tolerance test at least 1 year after aneurysmal SAH, only 1 patient with severe GHD (defined as peak GH value <3 µg/L in the insulin tolerance test) had an IGF-I level <2 SD below normal and in 3 of these GH-deficient patients IGF-I was well within the normal range.5 In summary, we feel diagnosis of GHD in SAH patients should be established by means of GH provocative testing because for the reasons stated. IGF-I measurement lacks sufficient specificity and sensitivity to establish or rule out GHD in these patients.
References
- Dimopoulou I, Kouyialis AT, Tzanella M, Armaganidis A, Thalassinos N, Sakas DE, Tsagarakis S. High incidence of neuroendocrine dysfunction in long-term survivors of aneurysmal subarachnoid hemorrhage. Stroke. 2004; 35: 2884–2889.
[Abstract/Free Full Text] - Aimaretti G, Corneli G, Baldelli R, Di SC, Gasco V, Durante C, Ausiello L, Rovere S, Grottoli S, Tamburrano G, Ghigo E. Diagnostic reliability of a single IGF-I measurement in 237 adults with total anterior hypopituitarism and severe GH deficiency. Clin Endocrinol (Oxf). 2003; 59: 56–61.[CrossRef][Medline] [Order article via Infotrieve]
- LeRoith D, Clemmons D, Nissley P, Rechler MM. NIH conference. Insulin-like growth factors in health and disease. Ann Intern Med. 1992; 116: 854–862.
- Brabant G, zur Muhlen A, Wuster C, Ranke MB, Kratzsch J, Kiess W, Ketelslegers JM, Wilhelmsen L, Hulthen L, Saller B, Mattsson A, Wilde J, Schemer R, Kann P. Serum insulin-like growth factor I reference values for an automated chemiluminescence immunoassay system: results from a multicenter study. Hormone Res. 2003; 60: 53–60.[CrossRef][Medline] [Order article via Infotrieve]
- Kreitschmann-Andermahr I, Hoff C, Saller B, Niggemeier S, Pruemper S, Hutter BO, Rohde V, Gressner A, Matern S, Gilsbach JM. Prevalence of pituitary deficiency in patients after aneurysmal subarachnoid hemorrhage. J Clin Endocrinol Metab. 2004; 89: 4986–4992.
[Abstract/Free Full Text]
Response:
Department of Critical Care Medicine, Evangelismos Hospital, National & Kapodistrian University of Athens, Athens, Greece
Department of Endocrinology and Metabolism, Athens’ Polyclinic, Athens, Greece
We thank Drs Kreitschmann-Andermahr and Gilsbach for their comments about our article.1 They raised the question of whether low insulin-like growth factor (IGF)-I concentrations are a reliable indicator of growth hormone deficiency (GHD). We agree that the best way to diagnose GHD is by provocative stimulation, with insulin tolerance test (ITT) representing the gold standard.2 However, ITT has potential risks and there is some concern about its safety in patients with a previous cerebrovascular insult. Therefore, we used IGF-I levels to screen for changes of the GH axis. Low IGF-I levels can be considered indicative of GHD if malnutrition, liver failure, poorly controlled diabetes mellitus, and uremia are ruled out, and this was the case in our study population.1
Drs Kreitschmann-Andermahr and Gilsbach state that we failed to acknowledge from the quoted article by Aimaretti et al3 that IGF-I measurements are of diagnostic value only for patients younger than age 40 years because older patients with GHD may have IGF-I levels within the age-related normal range.3 However, in our study, only low IGF-I levels were considered as indicating GHD.
Drs Kreitschmann-Andermahr and Gilsbach correctly identified the use of the Nichols Advantage assay in our study, and we agree that the reference range reported by the manufacturers may have some impact on the interpretation of our data. A reanalysis on the basis of the age-related normative data given by Brabant et al4 demonstrated that all 11 patients, considered to have GHD, had IGF-I <–1 standard deviation, and 7 of these patients had IGF-I concentrations well below –2 standard deviations for their age. This is consistent with our previous finding of IGF-I levels compatible with GHD in a substantial (albeit lower than previously reported) proportion of our patients.
The issue of what is the best way to diagnose adult GHD is controversial. Currently, provocative stimulation is the best way. However, when treating patients with GHD, GH doses are titrated so that IGF-I is kept in the age-related normal range.2 This is an inconsistent conundrum because IGF-I can be normal to begin with, and yet that is the goal of therapy.5 Thus, although a low IGF-I has a lower diagnostic yield, it may be of more clinical relevance when considering treatment of GHD. This seems to be also appreciated by Drs Kreitschmann-Andermahr and Gilsbach; in their extensive study,6 they considered low GH responses to ITT as indicating true GHD when IGF-I levels were below –1 SD. To summarize, in the future, IGF-I levels will be increasingly considered as a criterion for decision-making in GHD patients. At present, Drs Kreitschmann-Andermahr’s and Gilsbach’s6 study and our study1 have contributed to bring into light the fact that neuroendocrine dysfunction is a neglected adverse outcome of subarachnoid hemorrhage that may possibly have a negative impact on patients’ lives.
References
- Dimopoulou I, Kouyialis AT, Tzanella M, Armaganidis A, Thalassinos N, Sakas DE, Tsagarakis S. High incidence of neuroendocrine dysfunction in long-term survivors of aneurysmal subarachnoid hemorrhage. Stroke. 2004; 35: 2884–2889.
- Anonymous. Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society Workshop on Adult Growth Hormone Deficiency. J Clin Endocrinol Metab. 1998; 83: 379–381.
[Abstract/Free Full Text] - Aimaretti G, Corneli G, Baldelli R, Di SC, Gasco V, Durante C, Ausiello L, Rovere S, Grottoli S, Tamburrano G, Ghigo E. Diagnostic reliability of a single IGF-I measurement in 237 adults with total anterior hypopituitarism and severe GH deficiency. Clin Endocrinol (Oxf). 2003; 59: 56–61.
- Brabant G, zur Muhlen A, Wuster C, Ranke MB, Kratzsch J, Kiess W, Ketelslegers JM, Wilhelmsen L, Hulthen L, Saller B, Mattsson A, Wilde J, Schemer R, Kann P. Serum insulin-like growth factor I reference values for an automated chemiluminescence immunoassay system: Results from a multicenter study. Hormone Research. 2003; 60: 53–60.
- Molitch ME. Editorial: Diagnosis of GH deficiency in adults—How good do the criteria need to be? J Clin Endocrinol Metab. 2002; 87): 473–476.
[Free Full Text] - Kreitschmann-Andermahr I, Hoff C, Saller B, Niggemeier S, Pruemper S, Hutter BO, Rohde V, Gressner A, Matern S, Gilsbach JM. Prevalence of pituitary deficiency in patients after aneurysmal subarachnoid hemorrhage. J Clin Endocrinol Metab. 2004; 89: 4986–4992.
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