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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 12 5784-5789
Copyright © 2003 by The Endocrine Society

High Risk of Adrenal Insufficiency in Adults Previously Treated for Idiopathic Childhood Onset Growth Hormone Deficiency

Martin Lange, Ulla Feldt-Rasmussen, Ole Lander Svendsen, Knud William Kastrup, Anders Juul and Jørn Müller

Department of Endocrinology (M.L., U.F.-R., O.L.S.), Rigshospitalet, DK-2100 Copenhagen, Denmark; Department of Paediatrics (K.W.K.), Glostrup County Hospital, DK-2600 Glostrup, Denmark; and Department of Growth and Reproduction (A.J., J.M.), Rigshospitalet, DK-2100 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Martin Lange, Department of Endocrinology, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: mlange{at}rh.dk.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The aim was to reevaluate a group of adults treated for idiopathic childhood onset GH deficiency (GHD) after 18 yr without GH treatment.

Twenty-six (11 females) patients participated. All but two had isolated GHD. Childhood diagnosis was established by insulin tolerance test (ITT). The patients were retested with an ITT to evaluate adult GH status. In five patients, an arginine and a synacthen test were performed instead of an ITT.

Eleven of 25 patients had a subnormal cortisol response to ITT or synacthen. Ten patients had a GH peak less than 3.0 µg/liter (0.5. ± 0.5 µg/liter), whereas 16 patients displayed a normal GH response (12.3 ± 10.6 µg/liter) after ITT. IGF-I values were decreased in the patients with a pathological retest as well as in patients with a normal GH response compared with controls (P < 0.005).

In 26 idiopathic childhood onset GHD patients, 44% of the patients had developed adrenal insufficiency; 38.5% had persistent GHD in adulthood, using the same test in both childhood and adulthood. Patients having a normal GH test had decreased IGF-I levels, compared with controls, indicating impaired function of a seemingly normal GH axis. It is imperative that pituitary axes other than the GH axis are tested at regular intervals, even in the absence of GHD in adulthood.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
GROWTH RETARDATION IN childhood caused by GH deficiency (GHD) has been successfully treated with GH substitution therapy for decades. A somewhat unnoticed aspect of childhood onset (CO) GHD, apart from impaired final height, is the risk of developing poor bone mineralization, abnormal body composition, and impaired quality of life (1, 2). Similarly, adult patients suffering from GHD also have abnormal bone mineralization, abnormal cardiovascular status, decreased quality of life, abnormal lipid metabolism, and abnormal body composition. GH treatment has been demonstrated to improve these conditions (3). Patients treated for CO GHD who still have GHD in adulthood should therefore receive continued, probably life-long, GH treatment once final height has been reached, to prevent the morbidity and possible mortality associated with severe GHD (4).

Based on the observation that a proportion of CO GHD patients do not have severe GHD in adulthood (5, 6, 7, 8, 9, 10, 11, 12, 13), it is currently recommended that all CO GHD patients should be retested once final height is reached (4). A number of centers are not routinely evaluating patients treated for isolated CO GHD for other hormone deficiencies once the diagnosis of isolated GHD has been made, because it is considered unlikely that these should develop in otherwise-stable patients. One exception to this is patients treated with radiation, because it is well documented that endocrinopathies may develop decades after the radiotherapy. However, these patients rarely have isolated GHD (14, 15).

The reason for the discrepancy of GH response to dynamic testing in childhood and adulthood is often explained by differences in the choice of test and the cut-off level defining GHD. In childhood, the tests of choice are clonidine, arginine, glucagon, or the L-DOPA tests (16), whereas some of these tests in adult endocrinology are considered to be associated with a high risk of false-positive results. In adults, the insulin tolerance test (ITT) is the gold standard (4). This test has not been performed in children for the past decade in a number of countries because of concerns of side effects, or even deaths, when performed by inexperienced personnel (17, 18).

The aim of the present study was to reevaluate a group of adults treated for idiopathic CO GHD after 18 yr without GH treatment and whose original diagnosis was made by ITT in childhood and a clonidine test in adolescence/early adulthood (5).


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
In the period 1987–89, most patients having received GH treatment because of GHD in Denmark were included in a cross-sectional trial, evaluating current GH status and status in general. One-hundred seventy-three patients participated. Results of a clonidine retest of the patients and relationship to IGF-I and IGF-binding protein-3 have previously been published (5).

Patients

Twenty-six (11 females) of the patients, all treated for idiopathic CO GHD, who had been lost to follow-up after final height were contacted again and included in the present study. None of them had received GH treatment since cessation of linear growth (i.e. had been off GH treatment for a mean period of 17.8 ± 5 yr).

Twenty-four patients were considered to have isolated GHD in childhood. Of these, five patients received T4 treatment because it was believed that the GH-induced conversion of T4 to T3 might lead to hypothyroidism. They were, however, never demonstrated to suffer from either primary or secondary hypothyroidism, and the treatment was terminated, together with their GH treatment, at final height in all but one patient, who was considered to have true hypothyroidism because of symptoms and continued on T4 treatment.

One patient considered to have GHD and gonadal insufficiency in childhood was treated with T4 because of fear of GH-treatment-induced hypothyroidism. The patient had spontaneous puberty and was, after final height and cessation of GH treatment, considered to have isolated GHD.

The final patient was, in childhood, considered to suffer from GHD, true hypothyroidism, and adrenal insufficiency. The patient did not develop spontaneous puberty and was consequently considered also to have gonadal insufficiency.

After final height was reached, only two patients continued on hormonal replacement treatment. Twenty-four patients had therefore not received hormonal substitution therapy for a mean of 12 yr.

A flowchart of the patients’ endocrinopathies is depicted in Fig. 1Go.



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  		FIG. 1. Flowchart of patient endocrinopathies from childhood to adulthood. Five patients, considered to have isolated GHD in childhood, were treated with T4 because of fear of GH-treatment-induced hypothyroidism. After cessation of GH treatment at final height, one of these patients was considered to have true hypothyroidism and continued on T4 treatment. One patient, considered to have GHD and gonadal insufficiency in childhood, was treated with T4 because of fear of GH-treatment-induced hypothyroidism. The patient had spontaneous puberty and was, after final height and cessation of GH treatment, considered to have isolated GHD.

 
Original diagnosis of GHD

The original diagnosis of GHD in childhood was made by ITT (n = 24) or arginine test (n = 2). Furthermore, in a follow-up study, all patients were retested with a clonidine test in 1987–89, together with measurements of IGF-I and IGF-binding protein-3. Patients were not receiving GH treatment during the study period (5). A synacthen (short-acting ACTH test) test was performed in all patients in 1987–89.

Retesting of GHD

In the present study, the diagnosis was reevaluated by ITT (n = 21), performed as previously described (19), or by an arginine test (n = 5) in case of contraindications. Furthermore, a synacthen test was performed in connection with the arginine test.

One patient was on hydrocortisone substitution; accordingly, cortisol was not measured during ITT in this patient. Twenty-six healthy subjects acted as IGF-I controls, individually matched to the patients according to age, gender, height, weight, and body mass index (BMI). A maximum difference in height of 10 cm was defined as a requirement. Patient and control demographics at diagnosis, at retest in 1987–89, and in the present study are given in Tables 1Go and 2Go.


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  		TABLE 1. Patient demographics at baseline, at retest in 1987–89, and in the present study

 

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  		TABLE 2. Patient and control demographics in present study according to presence or absence of GHD in adulthood

 
Test procedures

When an ITT was performed, GH and cortisol were measured at -15, 0, 15, 30, 45, 60, and 90 min. The procedures of the ITT performed in childhood (unpublished) were comparable with the present procedures. However, insulin dose was 0.05 IU/kg in childhood, compared with 0.1 IU/kg in adulthood. Both in childhood and adulthood, nadir blood glucose was required to be less than 2.2 M in order for the test to be successful.

The arginine test was performed in case of contraindications to ITT (abnormal ECG, history of atrial fibrillation, and concerns of poor patient cooperation during the test). In brief, arginine (0.5 g/kg; maximum, 30 g) was infused iv over 30 min. The arginine test was supplemented with a synacthen test. In brief, 250 µg synacthen was administered iv as a bolus. Cortisol was measured at 0 and 30 min.

Assays

GH was analyzed, using a previously published method (20), in childhood and by a double-antibody RIA (AutoDELFIA, Wallac Oy, Turku, Finland) at retesting. By this assay, the minimal detectable concentration was 0.03 mIU/liter. The intraassay coefficient of variation (CV) was 2% at levels less than 1 mIU/liter, 5% at 18 mIU/liter, and 2% at 44 mIU/liter. The interassay CV was 5% at 6 mIU/liter, 4% at 33 mIU/liter, and 4% at 48 mIU/liter. For comparative reasons, the adult unit of mIU/liter was converted to µg/liter by dividing the values by 2.6 (according to WHO standard 80/505).

Cortisol was analyzed by a RIA assay in childhood, and by a time-resolved fluoroimmunoassay (AutoDelfia, Wallac Oy) in adulthood. Intraassay CV was 3.6% at 212 nM, 2.9% at 520 nM, and 3.2% at 781 nM. Interassay CV was 1.9% at 212 nM, 0.8% at 520 nM, and 1.4% at 781 nM. A cortisol response, to either ITT or synacthen, less than 500 nM was considered abnormal in both the 1987–89 trial and the present trial.

IGF-I was measured by a RIA using previously published methods (21). IGF-I SD score (SDS) was calculated using previously published reference material (21).

TSH was measured by a time-resolved fluoroimmunoassay (AutoDelfia, Wallac Oy). Intraassay CV was 1.3–4.7%. Interassay CV was 1.7–4.8%.

Total T4 was measured by fluorescence polarization immunoassay technology (IMx, Abbott Laboratories, Diagnostics Division, Abbott Park, Chicago, IL). Intraassay CV was 1.8–5.0%, and interassay CV was less than 4.5%.

Total T3 was measured by a microparticle enzyme immunoassay (IMx, Abbott Laboratories, Diagnostics Division). The intra- and interassay CVs were 3.6–8.0% and 5.1–7.9%, respectively.

FSH and LH were measured by time-resolved immunofluorimetric assay (AutoDelfia, Wallac Oy) with detection limits of 0.06 and 0.05 IU/liter, respectively. Intraassay and interassay CV’s were less than 8% in both assays.

This study was performed in accordance with the Declaration of Helsinki and approved by the local ethics committee.

Statistics. All variables entering an analysis followed a normal distribution as determined by the Kolmogorov-Smirnovs test for normality. When comparing groups, a t test for independent samples was used. Pearson’s correlation analysis was used for correlation analyses. P- values < 0.05 were considered statistically significant. Results are given as mean ± SD.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The cortisol response to insulin-induced hypoglycemia in the present study was subnormal (<500 nM) in 11 of the 25 patients. None of these patients were known to suffer from adrenal insufficiency. One of the patients was on thyroid substitution therapy. Leaving out this patient, the cortisol response in 11 of 24 patients perceived in adolescence as having isolated idiopathic GHD (by Clonidine testing) showed a subnormal cortisol response to ITT. Six of these had concomitant GHD in adulthood. Seventeen of 25 patients displayed a lower cortisol response to the current ITT, compared with the synacthen response in 1987–89. Stimulated cortisol levels were lower in adulthood, compared with results obtained in adolescence by a synacthen test; however, this did not reach statistical significance (534 ± 147 nM vs. 613 ± 178 nM, respectively, P = 0.09) (Fig. 2Go). Because of an overall lack of overt daily addisonian symptoms and because of the absence of clinical addisonian stigmata of primary adrenal insufficiency, the patients were considered to suffer from secondary adrenal insufficiency.



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  		FIG. 2. Cortisol response to synacthen test in adolescence (n = 25) and ITT (n = 21) or synacthen test in adulthood (n = 4). Eleven patients showed suboptimal response in adulthood. Seventeen patients showed decreased response, compared with their response in adolescence. A peak cortisol level of 500 nM is marked by a dotted line. Values below this line were considered abnormal.

 
Only 10 patients of 26 CO GHD patients suffered from GHD when retested in adulthood using the currently recommended criteria of GH peak less than 3.0 µg/liter for GHD in adulthood (4). Using the childhood cut-off level (7.5 µg/liter) used in Denmark at that time for GHD, 18 patients suffered from GHD. All patients but seven displayed an increased GH reserve/GH secretion ability in adulthood, compared with childhood. Mean GH peak tended to be higher in adulthood (7.7 ± 10.1 µg/liter vs. 4.6 ± 2.8 µg/liter, respectively); however, this did not reach statistical significance (Fig. 3Go).



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  		FIG. 3. GH response to dynamic stimulation in childhood (24 ITTs and two arginine tests) and adulthood (21 ITTs and five arginine tests). Only 10 patients had GH response less than 3 µg/liter in adulthood.

 
A positive correlation was found between current GH peak and childhood GH peak (r = 0.42, P = 0.04) (Fig. 4Go). No correlation was found between current GH peak and serum IGF-I or IGF-I SDS. Both IGF-I and IGF-I SDS, however, correlated significantly with the childhood GH peak (r = 0.55, P = 0.006; and r = 0.60, P = 0,002, respectively).



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  		FIG. 4. The correlation between GH peak in childhood and GH peak in adulthood to ITT (n = 24 in childhood and 21 in adulthood, respectively) or arginine (n = 2 in childhood and 5 in adulthood, respectively).

 
IGF-I SDS was -1.5 ± 1.4 (range, -4.8 to 1.2) in the whole patient population. Statistically, this was not significantly different from the adolescence IGF-I SDS [-1.25 ± 1.8 (range, -4.65 to 2.8)]. A significant correlation existed between the adolescence and adult IGF-I SDS levels (r = 0.7, P = 0.0001). In the 16 patients not having adult GHD, IGF-I SDS was -1.0 ± 0.8 (range, -2 to 1.2), whereas it was -2.5 ± 1.7 (range, -4.8 to 0.2) in the 10 patients having persistent GHD (P = 0.006) upon retesting. When comparing IGF-I to the matched controls, both groups had decreased IGF-I levels (156 ± 39 ng/ml vs. 199 ± 41 ng/ml (P = 0.005) and 105 ± 63 ng/ml vs. 215 ± 49 ng/ml (P = 0.0004), respectively) (Fig. 5Go).



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  		FIG. 5. IGF-I levels in CO GHD patients, with and without persistent adult GHD, and their respective controls. *, P < 0.04, compared with controls.

 
No difference existed between groups on the thyroid axis or in basal LH levels. FSH levels were significantly lower in the whole patient group, compared with controls. This difference was caused by decreased FSH levels in the patients not having GHD at retesting (Table 3Go).


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  		TABLE 3. Patient and control status on the thyroid and gonadal axes

 
One patient had developed additional thyroid and gonadal deficiency since 1989.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The demonstration of development of adrenal deficiency in 44% of the patients, using the cut-off line of our laboratory during a 12-yr period, is striking and clinically very important. Most patients with multiple hormone deficiency or with etiology other than idiopathic GHD are frequently subject to thorough endocrine evaluation, whereas this is often not the case for patients with idiopathic, isolated GHD. Thus, there is a potentially increased risk of undiagnosed adrenal insufficiency in patients with isolated CO GHD. In particular, CO GHD patients who do not have GHD in adulthood are at risk of being lost to follow-up. In the present study, 11 of 25 (44%) had developed insufficient cortisol response to adequate stimulus; and, importantly, 5 of these patients had impaired adrenal function without having GHD by the adult criteria.

The clinical relevance of the findings is illustrated by the fact that, based on the results obtained in adulthood, four patients were started on regular cortisol substitution treatment, and the remainder of the patients with suboptimal cortisol response were equipped with an emergency card to carry at all times, stating their potential adrenal insufficiency.

Adult GHD is associated with a number of severe conditions (3). Continuous treatment of CO GHD patients into adulthood is therefore considered mandatory in most countries if the diagnosis can be confirmed. Several authors have, however, demonstrated that a smaller or larger proportion (10–87.5%) of CO GHD patients do not have severe adult GHD according to consensus guidelines (4), when retested in adulthood (5, 6, 7, 8, 9, 10, 11, 12, 13).

The patient groups studied and reported in the literature are different with respect to age, gender, and body composition, which are known to influence results of most GH stimulation tests. Patients with idiopathic GHD have a relatively low prevalence of adult GHD (12); while, for example, patients with a structural disease (mass lesion, pituitary surgery, or cranial irradiation) (7, 22, 23) and multiple pituitary hormone deficiencies (19, 24, 25) in childhood have a high risk of adult GHD. CO disease attributable to genetic defects in GH synthesis is never reversible (26).

Explanations have been proposed as to why a larger or smaller proportion of the CO GHD populations do not have GHD, according to current adult consensus guidelines: 1) In the definition of CO GHD, the present standard cut-off level for GH peak in response to stimulation is 10 µg/liter (16). In adults, the cut-off level is 3 µg/liter when using insulin-induced hypoglycemia as stimulus (4). Both levels are arbitrarily chosen. The adult level is deliberately low to render only severely GH-deficient patients eligible, subject to adult GH-replacement therapy. These differences may provide part of the explanation why some patients will have GHD by childhood definitions but not by adult definitions (19). 2) A variety of possible stimulation tests exist in the diagnosis of both CO and AO GHD. The stimulatory potency varies between tests (27); and if different tests are used in childhood and adulthood, the result may vary in the same patient. 3) A number of the tests used in childhood are associated with poor reproducibility and a relatively high risk of false- positive results (28).

Some patients with idiopathic CO GHD may actually normalize their GH secretory capacity (12). These findings are supported by the present study, evaluating a larger patient group of idiopathic CO GHD patients again, using the same test in both childhood and adulthood.

A positive correlation was found between current GH peak and childhood GH peak. The significance may, however, be dependent on a single outlier. This rather poor correlation is in support of a development in secretory capacity from childhood to adulthood. Difference in GH response to ITT may be caused by differences in insulin doses used. However, all patients reached a nadir blood glucose less than 2.2 mM in both childhood and adulthood; and differences in insulin doses are probably, to a large extent, a reflection of differences in insulin sensitivity.

The interpretation of both GH and cortisol results are, in part, limited by the fact that different assays were used in childhood/adolescence and adulthood. However, all assays were calibrated at regular intervals using WHO standards, and the cut-off limit for cortisol levels was unchanged. It therefore seems reasonable to compare the results over time.

These methodological issues aside, the finding of adrenal insufficiency in 44% of a group of former patients not considered to have endocrinopathies other than possible GHD is both striking and worrying.

IGF-I levels did not correlate with the hypoglycemia- induced GH secretion in adulthood, which has previously been described by others (29, 30, 31) and ourselves (19). Interestingly, IGF-I and IGF-I SDS correlated significantly with the childhood hypoglycemia-induced GH peak, suggesting a closer relationship between adult IGF-I levels and childhood GH reserve and clinical features (impaired height) than between adult IGF-I levels and adult GH reserve. Furthermore, the demonstration of below-normal IGF-I levels in CO GHD adults with an apparently normal GH secretion indicates that a subgroup of these patients may still be regarded as IGF-I deficient. IGF-I SDS seemed to be stable over time, and adolescence and adult IGF-I SDS correlated significantly, which was not the case for hypoglycemia-induced GH response.

In conclusion, we found that: 1) Forty-four percent of the patients had developed adrenal insufficiency since adolescence, stressing the need for continuous, regular endocrine evaluation, even in this population and even in the absence of adult GHD, in order not to miss a silently evolving, potentially lethal, adrenal insufficiency. 2) Ten out of 26 patients with idiopathic CO GHD (38.5%) had GHD when retested in adulthood, using the same test and procedure in both childhood and adulthood. 3) Patients treated for CO GHD, but not having adult GHD, by present standards, seem to have decreased IGF-I levels (compared with healthy controls).


   Acknowledgments
 
The invaluable technical assistance of technician Lisbeth Kirkegaard and Kirsten Jørgensen is highly appreciated.


   Footnotes
 
This study was supported by Grant no. 22-00-0349 from the Danish Medical Research Council.

Abbreviations: BMI, Body mass index; CO, childhood onset; CV, coefficient of variation; GHD, GH deficiency; ITT, insulin tolerance test; SDS, SD score.

Received March 26, 2003.

Accepted August 30, 2003.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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