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Departments of Endocrinology and Medicine, St. Vincent’s University Hospital Elm Park, and The Conway Institute of Biomolecular and Biomedical Research, University College, Dublin 24, Ireland
Address all correspondence and requests for reprints to: James Gibney, Department of Endocrinology and Diabetes, Adelaide and Meath Hospital, Tallaght, Dublin 24, Ireland. E-mail james.gibney{at}amnch.ie.
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Abstract |
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Objective: The objective of the study was to determine whether use of the overnight metyrapone test (OMT) and plasma IGF-I SD scores (SDS) could provide a cost-effective alternative to the ITT.
Design: This was a retrospective chart review.
Setting: The study was conducted at a teaching hospital.
Participants and Intervention: Charts from 100 patients with organic pituitary disorders were reviewed. All underwent the OMT unless 0900 h plasma cortisol was less than 80 or greater than 450 nmol/liter when ACTH deficiency or ACTH sufficiency, respectively, was diagnosed. Patients were considered GH deficient if the age-related IGF-I SDS was less than –3 or if they had three or more other pituitary hormone deficiencies. Patients were considered GH sufficient if age-related IGF-I SDS was greater than the 95th centile established from patients with known GH deficiency. Thirty-three underwent an ITT.
Main Outcome Measures: The proportion of patients in whom ACTH and GH reserve could be assessed using OMT/IGF-I SDS was measured. The concordance with results was obtained from ITT.
Results: Fifty-five patients were ACTH sufficient and 45 were ACTH deficient. Twenty-one were GH sufficient and 33 were GH deficient based on IGF-I SDS and other pituitary hormone deficiencies, whereas 46 could not be classified. There was near-uniform concordance between OMT/IGF-I SDS and ITT. Initial investigation using OMT/IGF-I SDS resulted in a significant cost saving.
Conclusions: ACTH and GH reserve can be accurately and cost-effectively investigated using OMT/IGF-I SDS in approximately 50% of patients with organic pituitary disorders.
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Introduction |
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Among the alternative approaches to assessing ACTH reserve, only the metyrapone test is accepted as a reliable approach to examining the entire hypothalamic-pituitary-adrenal axis (2, 3, 4). We previously demonstrated that the overnight metyrapone test (OMT), an inexpensive and convenient test without contraindications that can be carried out in the outpatient setting, is highly comparable with the ITT (5, 6). The metyrapone test is not widely used because 11-deoxycortisol assays have not been routinely available. Furthermore, because the recognition of the adult GH deficiency (GHD) syndrome, the ITT is often preferred because it allows simultaneous assessment of GH reserve.
Serum IGF-I, which reflects integrated endogenous GH secretion in normal, acromegalic and GHD subjects, is the most useful indirect biochemical marker of GH activity. Assessment of IGF-I in adult GHD, however, is complex because there is a significant overlap of IGF-I levels between normal subjects and GHD patients, with up to half of all patients with confirmed GHD having IGF-I levels in the low-normal age-dependent range (7, 8, 9, 10). For this reason, plasma levels of IGF-I have not traditionally been used in the diagnosis of GHD, which instead is based on dynamic tests of pituitary GH secretory capacity. Recently more detailed analysis using comparison with age-related normal ranges has demonstrated that many GHD patients have plasma IGF-I levels that are more than 2 or even 3 SD below age-related mean normal values, whereas very few have IGF-I levels above age-related mean normal values (8, 9, 11, 12). Analysis of more than 800 hypopituitary adults enrolled in the Hypopituitary Control and Complications Study has revealed that an IGF-I level less than a value that approximates to 3 SD below the mean adult value for normal subjects has a specificity of 94% for GHD (11), and analysis of more than 800 subjects with proven GHD enrolled in the KIMS database has enabled development of 95th percentiles for IGF-I sd scores (SDS), above which the likelihood of GHD is by definition only 5% (13).
Further useful information concerning GH status can be obtained from the patient’s clinical history. Previous reports suggested that patients with three or more pituitary hormone deficits (PHDs) other than GH have a probability between 91 and 99% of GHD (7, 10, 14), and this was confirmed by the Hypopituitary Control and Complications Study database in which it was demonstrated that the presence of three or four other PHDs is highly predictive with specificity of 96 and 99%, respectively, of GHD (11). This approach to diagnosis has recently been recognized by the Clinical Guidelines Subcommittee of The Endocrine Society (15), who have advised that in this circumstance, provocative testing is optional (15).
We hypothesized that by using the OMT and measuring plasma IGF-I in patients with organic pituitary disorders, we could determine ACTH reserve in all patients, diagnose GH sufficiency (GHS) in those patients whose plasma IGF-I were greater the 95th centile for GHD subjects, and diagnose GHD in which plasma IGF-I was more than 3 SD below the mean value for normal subjects or in those who had three or more other PHDs. The aims of the study were to: 1) determine what proportion of patients with pituitary disorders could be identified using these criteria; 2) provide preliminary validation of this approach in patients who underwent both OMT/IGF-I measurement and ITT; and 3) compare the cost-effectiveness of the two approaches. In line with recommendations for testing for GHD, the study was limited to patients with known pituitary disorders (16).
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Subjects and Methods |
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Case notes of 100 consecutive patients with organic pituitary insufficiency from a single center, in whom testing of pituitary function was carried out, were examined (Table 1
). Approval for the study was obtained from the Research Ethics Committee, St. Vincent’s University Hospital. The OMT was performed in all subjects unless 0900 h cortisol was less than 80, or greater than 450, nmol/liter when they were respectively diagnosed as ACTH deficient (ACTH-D) or sufficient (ACTH-S). Plasma levels of IGF-I were measured in all subjects. TSH, gonadotrophin, and anti-diuretic hormone deficiencies were recorded in all subjects. ITT was carried out in 33 of these subjects.
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Metyrapone (30 mg/kg body weight) was taken orally at midnight with a snack either as an outpatient or in the hospital in the case of patients admitted for other reasons. The next morning between 0800 and 0900 h, plasma samples were taken for measurement of 11-deoxycortisol and cortisol. The OMT was deemed to be normal when 11-deoxycortisol was greater than 200 nmol/liter and abnormal when both the 11-deoxycortisol and cortisol levels were less than 200 nmol/liter (5).
Where the ITT was performed, blood was drawn for measurement of glucose, cortisol, and GH before and at 30, 45, 60, 90, and 120 min after the administration of short-acting insulin 0.1–0.3 IU/kg iv, with the insulin dose adjusted to the patient’s clinical status. Satisfactory hypoglycemia was considered to have occurred when the plasma glucose fell to less than 2.2 mmol/liter. ACTH deficiency was diagnosed if the peak cortisol response was less than 500 nmol/l and GH deficiency was diagnosed if the peak GH response was less than 3 ng/ml (9).
Secondary hypothyroidism was diagnosed if free T4 levels were below the normal reference range and associated with low or normal TSH levels (17). Secondary hypogonadism was diagnosed in male subjects if testosterone levels measured in the morning were low and associated with low or normal gonadotrophin levels (18). Secondary hypogonadism was diagnosed in female subjects if they were amenorrheic with low estradiol levels and low or normal gonadotrophin levels (19). Where the diagnosis of secondary hypothyroidism or secondary hypogonadism was unclear, TRH or LHRH testing, respectively, was carried out. A normal response to the TRH test was defined as a TSH rise of more than 2 mU/liter with a peak at 20 min and a return toward baseline at 60 min, whereas a normal response to the LHRH test was defined as a 3- to 10-fold increase in LH over basal and a 1.5- to 3-fold increase in FSH over basal (20, 21).
Assay methodology
Cortisol, GH, and IGF-I levels were quantified by chemiluminescent immunoassay (Immulite 2000; Diagnostic Products Corp., Los Angles, CA). 11-Deoxycortisol was measured by an in-house competitive RIA using a 3[H]-labeled 11-deoxycortisol tracer (Amersham, Buckinghamshire, UK) and a specific antibody (ICN Pharmaceuticals Inc., Orangeburg, New York) after diethyl ether extraction as previously described (5). The 11-deoxycortisol immunoassay had interassay coefficients of variation of 12% at 22 nmol/liter, 8% at 252 nmol/liter, and 7% at 468 nmol/liter (n = 42).
Data analysis
Results are expressed as mean (SD). An age-related reference range for IGF-I was established as previously described (22) from a population of normal volunteers (n = 136, 75 males, age range 17–63 yr). Because these data were not normally distributed, they were logarithmically transformed before analysis. IGF-I SDS values were calculated as the number of SDs above (+ values) or below (– values) the age-related population mean. IGF-I SDS values were also calculated using the manufacturer’s reference range. The cost of carrying out ITT, OMT, and plasma IGF-I measurement was calculated from the cost of administered pharmaceutical compounds, cost of assay kits and disposables, and in the case of the ITT the cost of a day-case bed and medical care by one nonconsultant hospital doctor for 4 h. Other labor costs were not included.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Testing of ACTH status
Early-morning cortisol was less than 80 nmol/liter in 10 subjects who were diagnosed as ACTH-D, and greater than 450 nmol/liter in 10 subjects who were diagnosed as ACTH sufficient. All other subjects underwent OMT. 11-Deoxycortisol levels were greater than 200 nmol/liter in 45 subjects who were diagnosed as ACTH-S and 11-deoxycortisol levels were less than 200 nmol/liter in 35 subjects in whom the simultaneous cortisol concentration was also less than 200 nmol/liter who were diagnosed as being ACTH-D. Therefore, a total of 55 subjects were ACTH-S and 45 were ACTH-D.
Testing of GH status (Fig. 1)
Twenty-one subjects had IGF-I SDS of greater than the published 95% limits for GHD subjects and were diagnosed as GHS. Seven patients had four and 23 had three other PHDs. Seventeen had IGF-I SDS of less than –3 for normal subjects, 14 of whom had three or four other PHDs. In total, therefore, 33 subjects were classified as GHD. Forty-six subjects could not be classified in terms of GH status. The proportion of patients, stratified by age, in whom a diagnosis of GH status could be made is shown in Table 2. Results did not differ when IGF-I SDS was calculated from the manufacturer’s reference range.
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There was close concordance between OMT/IGF-I SDS and ITT (Table 1
). Seventeen subjects were ACTH-S by ITT. Fifteen of these subjects were ACTH-S by OMT, but 2 were ACTH-D, one of whom had three other PHDs. Sixteen subjects were ACTH-D by ITT. All of these subjects were also ACTH-D by OMT. Eleven subjects were GHS by ITT. Five of these were identified as GHS by IGF-I/PHDs, whereas five could not be classified using these criteria. One subject with known hepatic dysfunction exhibited a normal GH response to ITT but an IGF-I SDS of –3.47. Twenty-two subjects were GHD by ITT. Eleven of these were identified as GHD by IGF-I/PHDs, whereas 11 could not be classified using these criteria.
Cost-effectiveness
We compared the relative cost of evaluating pituitary function using the OMT and IGF-I for initial investigation, compared with using the ITT in all patients. If GH status was determined by the presence of extreme IGF-I levels as outlined above and by the presence of other PHDs, then the ITT could be avoided in 54% of patients and an overall cost saving of 40% made. If the IGF-I level was not considered adequate to establish GH sufficiency and if subjects are classified as GHD if they had three or four other PHDs or an IGF-I SDS less than –3, the ITT could be avoided in 51% of subjects and a 35% cost saving made. If the IGF-I level was not considered adequate to establish GH sufficiency and if subjects were classified as GHD only if they had three or four other PHDs, the ITT could still be avoided in 30% of subjects and a 14% cost saving made.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Early-morning cortisol levels were diagnostic of ACTH deficiency or sufficiency in 20% of subjects, whereas the OMT was necessary in 80%. We previously reported our experience of the OMT in a cohort of 398 patients, many of whom had pituitary disorders (5). No serious side effects of the test occurred and near-uniform concordance was demonstrated with the ITT. More than a decade after publication of that report, we are not aware of any report of clinical glucocorticoid deficiency that subsequently occurred in any patient who was considered ACTH-S based on OMT. These results stand in contrast to the short synacthen test, which is sometimes used as a surrogate test of hypothalamic-pituitary-adrenal axis activity on the basis that the adrenal gland will respond to an exogenous bolus of synthetic ACTH only when there is adequate endogenous ACTH reserve. There have been numerous reports that a normal response to the short synacthen test is sometimes observed in subjects with secondary adrenal insufficiency, making this test unsuitable in patients with pituitary disorders (6, 23, 24, 25, 26, 27, 28). In the current study, no subject deemed ACTH-S by OMT showed a subnormal response to ITT, but two subjects failed the OMT and subsequently passed the ITT. One of these patients also had three other PHDs, strongly supporting the presence of ACTH-D as indicated by the OMT. This is in keeping with previous reports that the OMT is more sensitive in diagnosis of hypothalamic-pituitary-adrenal axis deficiency than the ITT (2, 23). It is not known whether an abnormal OMT response is clinically important in subjects who have a normal response to ITT, but there have been reports of clinically evident cortisol deficiency improving with hydrocortisone replacement in subjects who had passed the ITT (29).
After the recognition of the GHD syndrome and the beneficial effects of GH replacement in adults, diagnosis of GHD has become increasingly important. Due to the pulsatile nature of GH release and its short half-life in the systemic circulation, measurement of circulating levels of GH is not useful. Hoffman et al. (9) compared the ITT with indirect markers of GH action and demonstrated that only the ITT clearly separated GHD from normal subjects. Notably, there was a large overlap in plasma IGF-I levels between GHD and normal subjects, an observation that has been confirmed in larger studies. However, another important observation from that study was that low plasma IGF-I levels were seen only in GHD subjects, and based on this the authors suggested that in the appropriate clinical setting, a plasma IGF-I level lower than that seen in normal subjects might be sufficient to diagnose GHD, whereas a level greater than that seen in GHD subjects might be sufficient to exclude GHD. Later studies also demonstrated that subjects with three or four other PHDs were very unlikely to be GHS, and this was confirmed in an analysis of more than 800 subjects with pituitary disorders in which Hartman et al. (11) demonstrated a specificity for GHD of 94–95% in subjects who had an IGF-I level less than 84 ng/ml (approximating to an SDS of –3) or who had three other PHDs. In the current study, 33% of the study population could be diagnosed as GHD based on these criteria. Comparison with ITT showed excellent concordance, with only one subject with hepatic dysfunction having a discrepant result. This is to be expected because hepatic dysfunction is known to be associated with low IGF-I and confirms that IGF-I measurement will not be useful in such patients.
Less attention has been given to an upper limit of IGF-I that occurs in GHD. Whereas some GHD patients, particularly of adult onset, have IGF-I levels that are within the lower half of the normal range, few have levels above mean values for normal subjects (8, 9). Reference data from subjects with proven GHD allowed us to construct 95% percentiles above which the likelihood of GHD is only 5%. Twenty-one percent of the patients we studied fell into this category, none of whom had three or more other PHDs or failed the ITT. Although by definition 5% of patients would be incorrectly considered GHS using this approach, it is unlikely that this misdiagnosis would affect management because IGF-I levels are already in the target range for GH replacement (30), and safety concerns exist about maintenance of IGF-I levels, even at the upper end of normal (31).
It is likely that the applicability of the approach to diagnosis of hypopituitarism outlined in this paper will vary among different patient populations. First, the OMT can be carried out only where metyrapone is routinely commercially available. This is currently not the case in all countries including the United States. Second, it may be less suitable in patient populations in which hormone deficiencies emerge over a number of years, such as patients under follow-up after radiotherapy. In such patients, it is to be expected that GHD would precede deficiency of other pituitary hormones, and therefore, awaiting the emergence of other PHDs would unnecessarily delay the diagnosis of GHD. Finally, our observation that IGF-I SDS was more likely to differentiate GHD from normal subjects among the younger age groups was unsurprising and in keeping with previously published data (8, 32). This reflects the observation that IGF-I levels decline in normal subjects but show little correlation with age in GHD subjects. However, in the population studied, a greater number of older subjects could be diagnosed as GHD based on having three or four other PHDs, and therefore, the proportion who required further testing was actually less than in younger subjects. Overall, our findings indicate that in a typical general endocrinology population with a wide age range, testing with ITT can be avoided in more than half of all patients with suspected hypopituitarism with a significant cost saving.
Whereas availability of reliable 11-deoxycortisol assays may be an issue in some centers, we anticipate that the ongoing replacement of RIAs with more specific liquid chromatographic mass spectrophotometric-based assays will make the proposed approach to testing more widely applicable. Application of our findings to clinical practice requires consideration of the balance between the practicality, cost, and safety of test procedures and the necessary precision of diagnosis. The following approach for assessment of ACTH and GH status optimizes cost-effectiveness and retains sufficient accuracy. Initial assessment includes early-morning blood sampling for cortisol and IGF-I levels. Where plasma cortisol is indicative of either ACTH deficiency or sufficiency, the OMT is not carried out. Where plasma cortisol is between 80 and 450 nmol/liter, OMT is carried out and a diagnosis made of ACTH-S or ACTH-D. Other PHDs are established and causes other than GHD of a low IGF-I such as hepatic dysfunction, hypothyroidism, and malnutrition excluded. Patients with IGF-I SDS greater than the 95th centile for GHD patients are considered GHS with 95% specificity and only in exceptional cases considered for GH replacement. Patients with three or four PHDs are considered GHD with, respectively, 95 and 99% specificity and according to the Clinical Guidelines Subcommittee of The Endocrine Society (15) are suitable for GH replacement in the appropriate clinical setting. Patients with IGF-I SDS less than –3 are considered GHD with 94% specificity, although currently are required to undergo provocative testing if GH replacement is considered because this is not yet recognized by relevant professional bodies as adequate evidence of GHD. All other subjects should undergo provocative testing if GH replacement is considered. Application of this approach would result in avoidance of provocative testing in more than half of all patients with pituitary disorders and a significant cost saving.
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Footnotes |
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First Published Online July 29, 2008
Abbreviations: ACTH-D, ACTH deficient; ACTH-S, ACTH sufficient; GHD, GH deficiency; GHS, GH sufficiency; ITT, insulin tolerance test; OMT, overnight metyrapone test; PHD, pituitary hormone deficit; SDS, SD scores.
Received January 22, 2008.
Accepted July 22, 2008.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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