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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 5 1705-1709
Copyright © 2007 by The Endocrine Society

The Diagnosis of Partial Growth Hormone Deficiency in Adults with a Putative Insult to the Hypothalamo-Pituitary Axis

Robert D. Murray, Martin Bidlingmaier, Christian J. Strasburger and Stephen M. Shalet

Department of Endocrinology (R.D.M., S.M.S.), Christie Hospital, Manchester M20 4BX, United Kingdom; St. James’s University Hospital (R.D.M.), Leeds LS9 7TF, United Kingdom; Medizinische Klinik-Innenstadt (M.B.), Ludwig-Maximilians Universitat, D-80336 Munich, Germany; and Charite Universitatsmedizin (C.J.S.), D-10117 Berlin, Germany

Address all correspondence and requests for reprints to: Professor S. M. Shalet, Department of Endocrinology, Christie Hospital National Health Service Trust, Wilmslow Road, Manchester M20 4BX, United Kingdom. E-mail: stephen.m.shalet{at}man.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Similar to patients with severe GH deficiency (GHD), those with a more moderate impairment of GH secretion [GH insufficiency (GHI)] have abnormal body composition, dyslipidemia, and insulin resistance. Given the inherent problems in the diagnosis of severe GHD, the situation is likely to be even more difficult in individuals with GHI.

Objective: The objective of the study was to examine the utility of GH stimulation tests and GH-dependent proteins in the diagnosis of GHI.

Design: The study was a cross-sectional, case-controlled study.

Patients: The study included 31 patients with GHD, 23 with GHI [peak GH 3–7 µg/liter (9–21 mU/liter)], and 30 age- and sex-matched controls.

Main Outcome Measures: Demographic and biochemical markers of GH status were measured.

Results: Nineteen of the patients with GHI (83%) had no additional anterior pituitary hormone deficits. Ten GHI patients showed discordant GH status based on the two GH stimulation tests performed. GH status was defined by the highest peak GH value achieved; in four this was to the insulin tolerance test (ITT), four the arginine test, and two the GHRH-arginine test. In five of the six patients in whom GH status was not defined by the ITT, peak GH levels to the ITT were in the range 2.4–2.9 µg/liter. IGF-I values for the GHI adults were significantly lower than the control subjects (121 ± 48 vs. 162 ± 75 µg/liter; P < 0.05); however, only six (26%) had values below the 10th percentile of levels seen in the control group. IGF binding protein-3 and acid labile subunit levels of the GHI adults were not significantly different from the controls.

Conclusion: The diagnosis of GHI in an individual is extremely difficult because the patients rarely exhibit additional pituitary hormone deficits, and levels of GH-dependent proteins are normal in the majority. Diagnosis relies heavily on GH stimulation tests and requires two tests in all patients to define GHI; obesity when present is potentially a major confounder.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE DIAGNOSIS OF GH deficiency (GHD) relies on GH stimulation tests and the measurement of GH-dependent proteins, namely IGF-I and IGF binding protein (IGFBP)-3. Each GH stimulation test has a differing capacity to release GH and to reliably separate GHD individuals from normal subjects (1, 2). The most robustly validated test is the insulin tolerance test (ITT). In children the peak GH response to the ITT correlates with height velocity of GHD children and correlates inversely with the growth response to GH replacement therapy (3). In adults the peak response to the ITT separates severely GHD individuals from normal subjects (1). In contrast to the ITT many of the widely used GH stimulation tests have poorly validated cutoff values for the diagnosis of GHD, and few data exist to indicate whether they can reliably separate GHD individuals from normal subjects. GH stimulation tests are plagued by poor reproducibility and false-fail results (2, 4, 5), in addition to being labor intensive.

As a consequence of the problems associated with GH stimulation tests and to improve convenience for the patient, the use of GH-dependent proteins as a surrogate measure of GH status has been explored. IGF-I, IGFBP-3, and acid labile subunit (ALS) have been the primary candidates. Of these IGF-I has proven to have the greatest sensitivity (6, 7). In patients with an insult to their hypothalamo-pituitary axis an IGF-I value below the normal age-related reference range is highly suggestive of GHD. A normal IGF-I value, however, does not exclude GHD, and with increasing age a greater proportion of severely GHD adults have a normal IGF-I value (8, 9).

The ITT remains the GH stimulation test of choice for establishing GH status in the adult, and an arbitrary peak GH response of less than 3 µg/liter (9 mU/liter) has been accepted for the diagnosis of severe GHD (10). A study from our unit examining the response to a variety of GH stimulation tests in 24 normal individuals showed a mean peak GH response to the ITT of 36 µg/liter (108 mU/liter), with all subjects achieving a peak GH response greater than 7 µg/liter (21 mU/liter) (2). Therefore, it is inevitable that there is a cohort of adults who have received an insult to their hypothalamo-pituitary axis, in whom the degree of GHD is less than severe. Furthermore, it is now clear that like patients with severe GHD, those with a more moderate impairment of GH status have abnormal body composition, dyslipidemia, and insulin resistance (11, 12, 13, 14). Given the inherent problems with GH stimulation tests and GH-dependent proteins in the diagnosis of severe GHD, the diagnosis of partial GHD [GH insufficiency (GHI)] in an individual patient is likely to be even more difficult. In the current study, we examined the utility of GH stimulation tests and estimation of GH-dependent proteins in adult patients with varying degrees of impaired GH status.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

The study cohort comprised three age- and gender-matched groups. Two groups comprised hypopituitary patients, and the third healthy individuals. Patients attending the Endocrine Investigation Unit at the Christie Hospital for assessment of anterior pituitary function were recruited to the study. Exclusion criteria included renal disease, hepatic disease, diabetes mellitus, ischemic heart disease, epilepsy, and age greater than 60 yr. No patient had received GH replacement therapy in the preceding 12 months and all were receiving stable anterior pituitary hormone replacement, if indicated, for at least 6 months before entering the study. The patient groups were defined according to the result of provocative tests of GH secretion. GH status was ascertained in 54 patients at risk of hypopituitarism from a primary hypothalamo-pituitary pathology or cranial irradiation (Table 1Go) (10). All patients were required to undergo two tests of GH reserve to confirm their GH secretory status, except in the setting of panhypopituitarism and a peak GH response to the ITT of less than 0.33 µg/liter (15), or conversely a normal GH response to the first provocative test (peak GH > 7 µg/liter). The GH stimulation test of choice was the ITT (n = 49 of 54). In addition, patients underwent the following GH provocative tests: arginine (n = 27), glucagon (n = 7), or GHRH plus arginine (n = 16). GHD was defined as a peak GH response of less than 3 µg/liter to all stimulation tests undertaken (n = 31) (10). GHI was defined by a peak GH response of less than 7 µg/liter to both provocative tests but greater than 3 µg/liter to at least one of the two tests (n = 23). The only exception to the above criteria for definition of GH status was for the GHRH plus arginine test. Respective values, when using the GHRH plus arginine test for the diagnosis of GHD and GHI, as defined by previous studies in our unit, were less than 9 and 9–21 µg/liter (12), consistent with the 3-fold greater GH response to the GHRH plus arginine test, compared with the ITT (13, 16, 17). Thirty age- and sex-matched normal subjects were recruited to provide control data for GH-dependent proteins.


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  		TABLE 1. Primary diagnosis in patients with a putative insult to the hypothalamo-pituitary axis subgrouped according to GH status

 
Study protocol

The patients presented fasting, and blood was drawn, centrifuged, and the sera stored at –80 C for analysis later. Sera was used to measure IGF-I, IGFBP-3, and ALS, and measurements were performed in a single batch. The study was approved by South Manchester Area Health Authority ethics committee. All subjects were provided with written and verbal information concerning the study, and all subjects gave written informed consent.

Assays

GH estimations were performed by a two-site immunoradiometric assay measured against the reference standard NIBSC 88/624 (1 µg/liter = 3 mU/liter). IGF-I levels were measured by the automated Advantage chemiluminescent IGF-I assay system (Nichols Diagnostics Institute, Bad Nauheim, Germany). In our hands, intraassay coefficient of variation (CV) was 11.5, 5.1, and 3.5% at concentrations of 42, 262, and 522 ng/ml, respectively. At the same concentrations, between-assay CV was 10.6, 10.6, and 10.2%. The lower limit of quantification was 17 ng/ml, the linear range was 17–1000 ng/ml. Age- and sex-adjusted reference ranges for this method have been published (18). IGFBP-3 was determined by ELISA using a commercially available kit (Diagnostic Systems Laboratories, Inc., Webster, TX). Samples were analyzed in duplicate. Sensitivity was 0.04 ng/ml, with intraassay CVs at 4.6, 27.4, and 74.4 ng/ml of 9.6, 9.5, and 7.3%, respectively. Interassay CVs at 5.6, 25.1, and 65.6 ng/ml were 11.4, 10.4, and 8.2%, respectively. Serum ALS (units per liter) were measured in duplicate by sandwich immunometric assay using monoclonal antibodies directed against specific N- and C-terminal oligopeptides (19). To optimize immunorecognition, samples were pretreated with 3 M urea and 0.05% sodium dodecyl sulfate. A serum pool of healthy male volunteers was used for calibration and assigned 1000 U/liter. The assay range is 500-5000 u/liter, and the intra- and interassay CVs were less than 9%.

Statistics

Data are presented as mean ± SD. Differences between data from the three groups were examined using ANOVA. Nonpaired data were compared using the t test. Correlations were examined using Pearson’s test. P < 0.05 was deemed significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Demographics

The patient cohort comprised 31 GHD adults (15 females) of mean age 35.4 ± 11.2 yr with a body mass index (BMI) of 26.5 ± 6.5 kg/m2 and 23 GHI adults (12 females) of mean age 30.3 ± 12.1 yr and BMI 25.2 ± 5.0 kg/m2. The control group comprised 30 healthy adults (15 females) aged 30.9 ± 11.5 yr and BMI 23.8 ± 3.9 kg/m2. There were no significant differences in age, gender distribution, or BMI among the three groups.

GH stimulation tests

By definition, all patients with severe GHD showed peak GH responses to all stimulation tests undertaken, consistent with their GH status. All 23 patients with GHI underwent two GH stimulation tests. Ten of the 23 patients had discordant results between their two tests of GH reserve. All 10 patients underwent the ITT, seven of the 10 the AST, and the remaining three the GHRH plus arginine test. In terms of GHI classification in four patients the ITT was the more potent of the two tests performed; additional tests were the AST (n = 3) and the GHRH plus arginine test (n = 1). In these cases the GH status was defined by the ITT. In the remaining six patients, the GH status was defined by the second test of GH reserve, the AST in four patients and the GHRH plus arginine test in the remaining two. In these latter six patients, the median peak GH level to the ITT was 2.6 µg/liter (range 1.6–2.9), with only one patient having a peak GH level less than 2.4 µg/liter (Fig. 1AGo).


Figure 1
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  		FIG. 1. A, Peak GH responses to the ITT in patients in whom GH status was characterized on the basis of two GH stimulation tests. #, Six patients with discordant peak GH levels to the two tests performed, in whom the peak GH response to the ITT was the lesser of the two values. B, IGF-I values for hypopituitary adults subgrouped according to GH status into those with severe GHD (n = 31) and GHI (n = 23) and compared with age- and sex-matched healthy controls. The dashed line represents the 10th centile for the control subjects. The dotted lines are the median values for each subgroup. *, P < 0.05, compared with controls subjects.

 
Anterior pituitary hormone deficits

Within the cohort of GHD adults, 14 (45%) had no additional anterior pituitary hormone deficits, eight had one additional hormone deficit, three two additional deficits, and six were panhypopituitary. Nineteen (83%) of the patients with GHI had no additional hormone deficiencies, three of the remaining four patients had only one additional hormone deficit, and the remaining patient was panhypopituitary. Of the six patients defined as GHI but with a peak GH response to the ITT of less than 3 µg/liter (Fig. 1AGo), five showed no additional anterior pituitary hormone deficits and the sixth was on stable replacement with thyroxine, hydrocortisone, and sex steroids.

GH-dependent proteins (Table 2Go)

IGF-I levels were lower in both the GHD (85 ± 43 vs. 162 ± 75 µg/liter; P < 0.001) and GHI (121 ± 48 vs. 162 ± 75 µg/liter; P < 0.05) adults, compared with the age-matched control group. IGF-I SD score (SDS) reflected absolute IGF-I levels, being significantly lower in the GHD adults (–1.81 ± 0.69 vs. –0.95 ± 0.85; P < 0.001) and GHI adults (–1.67 ± 0.55 vs. –0.95 ± 0.85; P < 0.01), compared with the control group. There was no difference in IGF-I or IGF-I SDS between the two patient groups. Compared with the control subjects, IGF-I values were below the 10th percentile in 16 of 31 (52%) and six of 23 patients (26%) with GHD and GHI respectively (Fig. 1BGo). There was no difference in age of GHI patients with IGF-I values above and below the 10th percentile. IGF-I values of the patient cohort correlated positively with the peak response to the ITT (r = 0.41, P < 0.003).


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  		TABLE 2. Mean levels of the GH-dependent proteins IGF-I, IGFBP-3, and ALS in hypopituitary patients, according to GH status, and control subjects

 
IGFBP-3 levels did not differ significantly between the controls (4859 ± 905 µg/liter) and either patient group. GHD adults had a significantly lower IGFBP-3 level, compared with GHI adults (4060 ± 1600 vs. 5047 ± 1486 µg/liter; P < 0.05). Ten (32%) and four (17%) of the GHD and GHI patients, respectively, had IGFBP-3 values below the 10th percentile of the control subjects.

ALS levels were significantly lower in the GHD adults, compared with the controls (1223 ± 559 vs. 1790 ± 486 U/liter; P < 0.001) and GHI adults (1223 ± 559 vs. 1628 ± 588 U/liter; P < 0.05). ALS values were below the 10th percentile in 15 GHD adults (48%) and two GHI adults (9%).

Correlations

Within the patient cohort, the peak GH level to the ITT correlated with lean body mass (r = 0.31, P = 0.03) and percentage body fat mass (r = –0.36, P = 0.01). No correlation was observed between the peak GH level to the ITT and BMI (r = 0.01, P = 0.93).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Our data highlight the difficulties in diagnosing GHI in adults in whom an insult to the hypothalamo-pituitary axis may have occurred; such an insult may be caused by a mass lesion, surgery or irradiation. Unlike patients with severe GHD, most of whom have multiple pituitary hormone deficiencies, the vast majority of patients with GHI defined by GH stimulation tests have no additional hormone deficits, and GH-dependent protein levels are normal in around 75% of patients. Thus, the diagnosis of GHI will inevitably rely almost exclusively on GH stimulation tests.

There have been a number of studies that have documented the impact of GHI on biological end points known to be affected by GH status. GHI individuals have a similar phenotype to adults with severe GHD but the abnormalities are of a lesser magnitude, and correlate with the peak GH response to provocative tests (20). GHI adults have reduced muscle mass and increased fat mass (12, 13), with the majority of the excess fat mass confined to the trunk (12). Despite abnormalities of body composition bone mineralization is reportedly normal (21, 22), suggesting that there is a variable threshold effect of GH on different GH-dependent biological end points. GHI adults are insulin resistant (11, 14) and have an adverse lipid profile (13, 14), which in part relates to their adverse body composition. Evidence for systolic and diastolic cardiac dysfunction in GHI adults has also been documented (23). The impact of GH replacement in these individuals is not yet known; however, it is the stipulated therapeutic policy of certain countries to offer GH replacement to all adult GHD patients on the basis that impaired GH status is known to have a number of adverse health sequelae, and replacement therapy is available. In such an environment it naturally follows that adults with lesser degrees of GHD will be considered for GH replacement, providing they can be identified biochemically and the financial resources are available to do so.

Toogood et al. (15) showed the prevalence of severe GHD, defined by a peak GH response of less than 2 µg/liter (5 mU/liter), in patients with two or three additional anterior hormone deficits was approximately 91%. The proportion of patients with severe GHD declined with increasing preservation of the remainder of anterior pituitary function. In patients with GHI, we report 83% of patients to have no additional anterior pituitary hormone deficits. Evidence of other anterior pituitary dysfunction, therefore, will aid diagnosis of GHI in few individuals.

Of the GH-dependent serum proteins, IGF-I has shown the greatest utility as a diagnostic tool in severe GHD. Measurement of IGFBP-3 and ALS, although also GH-dependent, add little further information to the diagnosis of GHD in adult hypopituitary patients (6), and the current data confirm this also to be true for GHI adults. Although the most useful of the GH-dependent proteins, there are a number of caveats to the use of IGF-I in the diagnosis of GHD in the adult. IGF-I status is not exclusively dependent on GH status, serum IGF-I levels being influenced by insulin, thyroid hormones, nutritional status, and renal and hepatic disease. There is significant inter- and intraassay variability, with little standardization between manufacturers. Additionally, IGF-I values are age dependent with highest values during puberty after which levels decline with increasing age, necessitating construction of a robust age-related range for normative values. Ghigo et al. (8) determined the prevalence of IGF-I values below the normative range in a cohort of GHD adults aged 20–80 yr. Values were below the third percentile for normal subjects in 91.4, 50, and 7.7% of patients aged 20–40, 41–60, and 61–80 yr, respectively. These and other data (9) confirm that the use of IGF-I as a diagnostic tool for severe GHD declines with increasing age. Within our cohort of GHD adults, 52% had an IGF-I value less than the 10th percentile of the control subjects, in keeping with previous studies. The prevalence of IGF-I values below the 10th percentile in the GHI adults in our cohort, of average age 30 yr, was 26%. With increasing age it is likely that the prevalence of GHI adults with IGF-I values below the 10th percentile will be even less, resulting in few GHI patients with subnormal values.

The current definition of a peak GH level of less than 3 µg/liter for the diagnosis of severe GHD in the adult is not without some substance (1), but it is arbitrarily used across all age groups (10). This value provides separation of GHD adults from healthy normal subjects. Data from GH stimulation tests in normal individuals, however, show the vast majority of individuals to have a peak GH response greater than 7 µg/liter (2). We therefore defined GHI as a peak GH response of greater than 3 µg/liter but less than 7 µg/liter. As a result of the poor reproducibility of GH stimulation tests (4, 5), all patients were required to undergo two tests to define GH status. Of the 23 patients defined as GHI, the results of the two stimulation tests were discordant in 10. In six of these 10 patients, the GH status was defined by the second test of GH secretion, having been defined as GHD when using the ITT alone. Notably, the peak GH response to the ITT in these six patients was only marginally below the cutoff of 3.0 µg/liter. It is foreseeable, therefore, that a number of patients defined as isolated GHD using a single GH stimulation test will, if subjected to a second test, be redefined as GHI. This dilemma is highlighted by recent data from Colao et al. (14), who reassessed the GH status of 27 hypopituitary adults who were defined as GHI using a single stimulation test (GHRH plus arginine) at baseline. They demonstrated 41% of the cohort to be GHD and 26% to have normal GH status after a mean follow-up of 60 months. The patients in whom GH status changed at reassessment were more likely to have baseline peak GH values at the extremities of the range defining GHI. The discordance between GH stimulation tests observed in GHI adults accompanied by poor reproducibility may, at least in part, explain the large percentage of patients requiring reclassification of their GH status in the absence of evidence for progression of the underlying disease. The evolution to GHD from GHI was, however, supported by deterioration in biochemical parameters adding weight to a true decline in GH status in a minority of these individuals (14). The presented data therefore provide support for the use of two GH stimulation tests to reliably diagnose GHI and isolated GHD.

Although GH stimulation tests have the greatest utility in the diagnosis of GHI, significant problems remain when diagnosing individuals rather than analyzing group data. In an obese individual with a peak GH response to a stimulation test of between 3 and 7 µg/liter, it may be difficult, in the absence of additional pituitary hormone deficits or a low serum IGF-I, to determine whether the impaired GH response truly reflects impaired GH status or is the consequence of the increased fat mass (24, 25). With almost total reliance on GH stimulation tests, abnormal body composition is likely to be a greater confounder in the diagnosis of GHI rather than GHD. In the current study, fat mass was significantly increased within the GHI cohort despite a similar BMI to the control group (12); the lower IGF-I levels of the group, however, provided support for the overall group diagnosis of GHI. Despite the reduced IGF-I levels, however, it is impossible to exclude completely the possibility that the peak GH response in some individuals included within this cohort is the consequence of their increased fat mass rather than the putative insult to the hypothalamo-pituitary axis.

There has recently been concern over the increasing diagnosis of isolated idiopathic GH deficiency of adult onset (26). There is no convincing evidence in the medical literature for the large-scale existence of this diagnosis, and it is extremely probable that such a diagnosis therefore reflects the fallibility of GH stimulation testing if used in an inappropriate clinical setting; predictably overweight individuals, with no history of any possible insult to the hypothalamo-pituitary axis, who complain of lethargy. The recognition of the existence of GHI in adults has the potential to benefit a significant subset of patients, but it could also lead to increasing use of GH therapy in adults who have no pituitary disease whatsoever. The diagnosis of GHI using GH stimulation tests in an individual therefore remains difficult and formal biochemical assessment of GH status should not be undertaken in a patient unless there is a clinical history or examination findings suggestive of damage to the hypothalamo-pituitary axis.

In conclusion, like abnormalities of all other endocrine systems, GHD in the adult exists in a continuum from severe through moderate to mild merging seamlessly into normality. Whereas the distinction between groups of patients with these varying degrees of impaired GH status is possible biochemically, the diagnosis of GHI in an individual adult may be extremely difficult; adults with GHI rarely exhibit additional anterior pituitary hormone deficits, and levels of the GHdependent proteins IGF-I, IGFBP-3, and ALS are normal in the vast majority of patients. Diagnosis therefore relies heavily on GH stimulation tests and requires two tests in all such patients to confirm GH status; obesity, if present, is potentially a major confounder.


   Acknowledgments
 
The authors thank Pfizer Corp. for financial support.


   Footnotes
 
This work was supported by Pfizer Corp.

R.D.M. has nothing to declare. M.B. received research support and lecture fees from Pfizer and Biopartners. C.J.S. received consulting fees from Pfizer, Eli Lilly, and Ipsen and lecture fees from Pfizer, Eli Lilly, and Ipsen. S.M.S. received consulting fees from NovoNordisk and Pfizer and lecture fees from NovoNordisk, Pfizer, Eli Lilly, and Ipsen.

First Published Online February 27, 2007

Abbreviations: ALS, Acid labile subunit; BMI, body mass index; CV, coefficient of variation; GHD, GH deficiency; GHI, GH insufficiency; IGFBP, IGF binding protein; ITT, insulin tolerance test; SDS, SD score.

Received September 19, 2006.

Accepted February 13, 2007.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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