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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 10 5030-5034
Copyright © 2004 by The Endocrine Society

Prevalence of Adrenocorticotropin Deficiency in Children with Idiopathic Growth Hormone Deficiency

Emily C. Walvoord, Marc B. Rosenman and Erica A. Eugster

Department of Pediatrics, Section of Endocrinology and Diabetology (E.C.W., E.A.E.) and Children’s Health Services Research (M.B.R.), Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, Indiana 46202; and Regenstrief Institute (M.B.R.), Indianapolis, Indiana 46202

Address all correspondence and requests for reprints to: Emily C. Walvoord, Department of Pediatrics, Section of Endocrinology and Diabetology, Indiana University School of Medicine, 702 Barnhill Drive, Room 5960, Indianapolis, Indiana 46202. E-mail: ewalvoor{at}iupui.edu.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
We sought to determine the prevalence of ACTH deficiency in children with GH deficiency (GHD) of unknown etiology with and without TSH deficiency and to correlate the structural characteristics of the hypothalamic-pituitary region on magnetic resonance imaging (MRI) with TSH and ACTH status. The electronic medical records system of a children’s hospital was used to identify all patients less than 18 yr of age with GHD. TSH and ACTH deficiency were defined as being present if the patient was prescribed replacement hormone therapy. The medical records of 236 GHD subjects were reviewed, and the results of their MRI scans were recorded. Ninety had hypothalamic-pituitary-adrenal axis testing, and nine were ACTH deficient (10% of those tested; 4% of all subjects). Twenty-one (9%) of 236 were TSH deficient. All of the ACTH-deficient subjects were also TSH deficient: eight of nine had a gross abnormality on MRI, and one did not have an MRI report in the medical record. We conclude that patients with GHD, normal thyroid function, and no gross abnormalities on MRI do not need hypothalamic-pituitary-adrenal testing because no ACTH-deficient subjects would have been missed using this strategy (95% confidence interval, 0–5%).


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
GROWTH HORMONE DEFICIENCY (GHD) occurs in approximately one in 3500 children in the United States (1) and is caused by a heterogeneous group of abnormalities. Most cases are classified as idiopathic GHD (IGHD), which is presumed to result from abnormal hypothalamic production of GHRH or from disturbed pituitary secretion of GH. Other etiologies of GHD include central nervous system (CNS) tumors, brain malformations, hydrocephalus, or the effects of CNS surgery or radiation therapy. Approximately one third of children with IGHD also suffer from other anterior pituitary hormone deficiencies. Of children with IGHD, 11–29% have insufficient pituitary TSH production and 6–11% are unable to generate appropriate ACTH levels in response to stress (2, 3). The degree of overlap of these hormone deficiencies is unclear and has not been reported in a large cohort of patients. The literature suggests that it is extremely rare for children with GHD to have ACTH deficiency without concomitant TSH deficiency or an organic brain lesion.

Recommendations are not well established regarding the necessity for complete evaluation of the hypothalamic-pituitary axis in children diagnosed with GHD of unknown etiology. Some clinicians do not evaluate for ACTH deficiency if the hypothalamic-pituitary-thyroid (H-P-T) axis is intact, as deduced from normal thyroid function tests, and the pituitary appears structurally normal on magnetic resonance imaging (MRI). Others assess the hypothalamic-pituitary-adrenal (H-P-A) axis, even if H-P-T axis abnormalities are not found. Adequate evaluation of the H-P-A axis involves provocative testing, which is costly and sometimes difficult in children. Conversely, failure to identify secondary adrenal insufficiency has life-threatening consequences. Therefore, it is important to establish whether H-P-A testing should be routine in all children with GHD.

We report a retrospective, cross-sectional study of the prevalence of ACTH deficiency in a large group of patients with GHD of unknown etiology with and without TSH deficiency. We also describe the results of the MRI scans of these patients to determine whether there is a correlation between structural characteristics of the hypothalamic-pituitary region and ACTH status.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Electronic and written medical records were used to assemble a cohort of patients with GHD. The Regenstrief Medical Record System is a computerized database that includes laboratory results, diagnoses, and radiographic reports for Riley Hospital for Children (Indianapolis, IN) (4). This system was searched for all patients less than 18 yr of age between 1990 and 2000 with peak stimulated GH levels less than 10 µg/liter (10 ng/ml). Between 1995 and 2000, GH levels were measured by a chemiluminescent assay (Nichols Institute Diagnostics, San Clemente, CA) with an interassay coefficient of variation between 5 and 8% and an intraassay coefficient of variation of less than 5%. Assay information for before 1995 was not available. Over the 10-yr time period, arginine and L-dopa were used for the majority of the GH stimulation tests, with clonidine being used infrequently.

Patients with any diagnoses that could possibly explain their GHD, such as brain tumor, cranial irradiation, hydrocephalus, Prader-Willi syndrome, chromosomal abnormality, periventricular leukomalacia, etc., were excluded: first, by review of electronically stored International Classification of Diagnoses (9th revision) codes; and second, by review of each written medical record. Patients with previously unknown CNS structural abnormalities found on MRI after the diagnosis of GHD was made, such as an ectopic posterior pituitary, were included. For each patient with GHD, additional data were abstracted from the written medical record.

Subjects were considered TSH and/or ACTH deficient if their treating physician had prescribed replacement therapy after testing. The criteria generally followed by the attending physicians to define ACTH deficiency during this time period included either a cortisol of less than 18 µg/dl (4 pmol/liter) in response to ACTH stimulation or a 11-desoxycortisol (compound S) level of less than 7 µg/dl (0.2 pmol/liter) after metyrapone suppression to a cortisol of less than 5 µg/dl (138 nmol/liter). First morning cortisol levels were rarely used and the cortisol level deemed sufficient to rule out ACTH deficiency varied between clinicians, with subjects considered ACTH sufficient if they had a first morning cortisol between 10 and 20 µg/dl (276–552 nmol/liter).

When available, the results of MRI scans of the pituitary region were recorded. MRI scans were divided into three categories: normal, hypoplastic anterior pituitary, or midline abnormality such as ectopic posterior pituitary, abnormal infundibular stalk, or empty sella.

The data were analyzed using SPSS version 10.0 (SPSS, Chicago, IL). Data for GH level and age are presented as mean ± SD. Confidence intervals for proportions were constructed using binomial estimates. The study protocol was reviewed and approved by the Institutional Review Board of Indiana University-Purdue University Indianapolis (Indianapolis, IN).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Between 1990 and 2000, there were 860 patients with maximum GH levels less than 10 µg/liter. Of these, 236 subjects had IGHD and were eligible for the final analysis. The reasons for excluding the others are shown in Fig. 1Go. The mean peak stimulated GH level for the 236 subjects was 5.8 ± 2.7 µg/liter, and the mean age at diagnosis of GHD was 9.0 ± 4.5 yr. There were 177 males and 59 females. Two hundred nineteen subjects were white, 11 were nonwhite, and the races of six were unknown.



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  		FIG. 1. Identification of study cohort.

 
Of the 236 GHD subjects studied, 21 (9%) had TSH deficiency. Ninety subjects had undergone H-P-A testing. The methodology was an overnight metyrapone test for the majority of subjects, with an ACTH stimulation test being the next most common, followed by a single morning cortisol measurement. Insulin tolerance tests were infrequently used. Nine subjects were judged to be ACTH deficient (10% of those tested; 4% of all subjects) by their treating physician and had been prescribed glucocorticoid replacement. Of these, two had a history of neonatal hypoglycemia. One of the nine subjects on glucocorticoid replacement had no documentation of H-P-A axis evaluation. All of the ACTH-deficient subjects were also TSH deficient (Fig. 2Go). Three of the 21 patients with TSH deficiency did not have H-P-A axis testing. In the subset of 90 patients that had H-P-A axis testing, the predictive value of normal H-P-T function for normal H-P-A function was 100% (95% confidence interval, 95–100%).



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  		FIG. 2. TSH and ACTH status of subjects.

 
Subjects with GHD alone had a mean peak GH of 6.1 ± 2.6 µg/liter and a mean age at diagnosis of 9.1 ± 4.4 yr. Subjects with GHD and TSH deficiency but no evidence of ACTH deficiency had a mean peak GH of 3.9 ± 2.9 µg/liter and a mean age at diagnosis of 9.2 ± 5.8 yr. Subjects with GH, TSH, and ACTH deficiency had a mean peak GH of 2.3 ± 2.9 µg/liter and a mean age at diagnosis of 5.3 ± 2.5 yr (Table 1Go).


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  		TABLE 1. Peak stimulated GH levels (micrograms per liter)

 
Eight of the nine ACTH-deficient subjects had a midline abnormality on MRI, either an ectopic posterior pituitary or an interrupted stalk (Table 2Go). One subject with ACTH deficiency did not have a documented MRI.


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  		TABLE 2. Pituitary function

 
Twenty-six subjects without ACTH deficiency had a structural midline abnormality. Three of these subjects also had TSH deficiency. Of these three, two had ectopic posterior pituitaries and hypoplastic anterior pituitaries on MRI and one had a computed tomography scan that revealed a hypoplastic anterior pituitary without a visible pituitary stalk. The other 23 subjects had isolated GHD, and their MRI findings included ectopic posterior pituitary (n = 7), hypoplastic corpus callosum (n = 2), empty sella (n = 4), and no visible posterior pituitary bright spot (n = 4). One patient each had the following as a principal finding: thin-appearing stalk, pituitary cyst, pituitary microadenoma, Dandy Walker cyst, asymmetric pituitary, and a Chiari malformation. Of these 26 subjects, 16 underwent H-P-A testing.

Of the three subjects with TSH deficiency who were not tested for H-P-A deficiency, two had a normal MRI, and one did not have an MRI result in the written record.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Currently, no specific recommendations exist regarding additional evaluation of anterior pituitary function in children diagnosed with IGHD. Most pediatric endocrinologists routinely obtain thyroid function tests on all poorly growing children regardless of their GH status. However, the decision whether to evaluate the H-P-A axis in all children with GHD varies between centers and clinicians.

A number of studies have documented that a significant percentage of children with GHD of unknown etiology also have other anterior pituitary hormone deficiencies. TSH deficiency is the most common. Among adults with GHD, gonadotropin deficiency is the second most common hormonal deficiency (5). ACTH deficiency is uncommon in children with GHD and has rarely been reported in the absence of an organic brain lesion. The coexistence of ACTH deficiency in the setting of TSH sufficiency in children with GHD has been addressed only in passing.

The largest such study reviewed 1366 children with IGHD (2). Twenty-nine percent were found to have TSH deficiency, whereas 11% had ACTH deficiency, and 4% had gonadotropin deficiency. Overall, 33% of the children were deficient in one or more hormones other than GH, but it was not noted whether any of the children with ACTH deficiency had normal thyroid function. Smaller studies of children with IGHD have reported TSH deficiency rates of 11–50% and ACTH deficiency rates of 6–26% (3, 6, 7, 8). These studies also did not report a cross-tabulation of the coincidence of ACTH and TSH deficiency.

There are sporadic cases of patients with IGHD who, during adult life, developed ACTH deficiency. However, all of these patients also had either TSH deficiency or a gross anatomical abnormality of the hypothalamic-pituitary region (8, 9). A recent publication that examined a small number of adults with a history of childhood-onset GHD found that 11 (44%) of the 25 patients retested had a subnormal cortisol response (<18 µg/dl) to either insulin-induced hypoglycemia or a 250-µg synachten test (10). No MRI data were published. This is the only report of the biochemical development of ACTH deficiency in adults who had been diagnosed with isolated GHD during childhood. Why this phenomenon has not been clinically recognized before is unclear, particularly if the incidence of cortisol deficiency is truly 44% in adults with a history of childhood GHD. Larger studies are needed to evaluate this initial report. To our knowledge, the only account of children with GHD and ACTH deficiency without TSH deficiency was published in 1968 (11). Three children with this unique combination were reported.

Adequate evaluation the H-P-A axis requires provocative testing. The arguable gold standard is the measurement of cortisol during hypoglycemia, typically during an insulin tolerance test. These tests can be risky in young children and require intensive monitoring. Thus, they are no longer performed in children at many centers. High- or low-dose ACTH stimulation testing can accurately diagnose secondary cortisol deficiency (12), as can metyrapone testing. However, an ACTH stimulation test requires a visit to a testing center and insertion of an IV. Overnight metyrapone testing, which was the method most frequently employed during the study period, involves an early morning trip to a laboratory for a venipuncture and a theoretical risk of hypocortisolism during the test period. Both ACTH stimulation and metyrapone suppression tests cost between $250 and $350 at our center.

Ideally, one could identify the children at risk for ACTH deficiency based on hormonal and structural findings, thus decreasing the total number of children who require H-P-A axis testing. Multiple pituitary hormone deficiency (MPHD) is rarely found in the setting of a normal MRI and is frequently associated with an ectopic posterior pituitary and an absent stalk (13, 14, 15). A number of groups have studied the correlation between abnormal MRI findings and anterior pituitary hormone deficiencies. One of the largest studies compared 39 patients with MPHD with 46 patients with isolated GHD. On gadolinium-diethylenetriamine pentaacetic acid-enhanced MRI, no patient with isolated GHD had an absent pituitary infundibulum, although four of 46 had a thin infundibulum. Conversely, only 23% of MPHD patients had a normal infundibulum, and all nine patients with ACTH deficiency had an ectopic posterior pituitary, a hypoplastic anterior pituitary, and absence of the infundibulum (16).

Although most cases of IGHD and hypopituitarism are still considered sporadic, genetic causes are being identified with increasing frequency. Multiple transcription factors that regulate embryogenesis of the pituitary gland have been extensively studied and have contributed greatly to our understanding of the developmental cascade that leads to normal pituitary development and function. Because of a unique set of regulatory genes, differentiation of the corticotroph cell line occurs fairly early during development, whereas somatotrophs and thyrotrophs differentiate near the end of pituitary development (17, 18). Therefore, based on our current understanding, which includes multiple human and animal models, developmental defects that result in hypopituitarism with disruption of both somatotroph and corticotroph function would always also involve disruption of thyrotroph function (19, 20, 21, 22).

Our finding of a 9% incidence of TSH deficiency and 4% incidence of ACTH deficiency in children with IGHD is slightly lower than what others have reported. The criterion used by pediatric endocrinologists currently as well as during this study period to define GHD, a peak level less than 10 µg/liter, may be more inclusive than that used in earlier studies. This less stringent peak GH level might explain the lower prevalence of MPHD in our study population.

The results of our study suggest that ACTH deficiency is exceedingly unlikely in the setting of normal pituitary anatomy and TSH sufficiency. Although a variety of methods were used to determine ACTH sufficiency in our patients, the lack of uniformity reflects the cross-section of clinical practice, and all are acceptable methods of diagnosing ACTH deficiency. Not all subjects underwent H-P-A axis testing, and it is possible that some ACTH-deficient patients may have been missed or that some patients may go on to develop ACTH deficiency later. However, based on our review of written medical records, no patients were started on cortisol replacement after an adrenal crisis. That is, there appear to have been no missed cases of ACTH deficiency.

In conclusion, we suggest that children with IGHD, normal thyroid function, and no gross abnormalities on MRI do not need H-P-A testing. None of our IGHD subjects with normal thyroid function tests had ACTH deficiency, and all IGHD subjects with ACTH deficiency had an MRI with a gross abnormality of the hypothalamic pituitary region. This revised testing strategy could help to lessen the inconvenience and discomforts involved in H-P-A axis testing as well as help to contain medical costs by reducing unnecessary procedures.


   Acknowledgments
 
We thank Jane Wang, Ph.D., for extracting the data from the Regenstrief Medical Record System, Ms. Paulette Thornton for her tireless effort in finding charts, and Dr. Simon Rhodes for his thoughtful suggestions in the preparation of this manuscript.


   Footnotes
 
This work was supported by National Institutes of Health Grant F32-DK10028-01, by Eli Lilly & Co. (Indianapolis, IN), and by Amersham Biosciences Inc. (Piscataway, NJ; to E.C.W.).

Abbreviations: CNS, Central nervous system; GHD, GH deficiency; H-P-A, hypothalamic-pituitary-adrenal; H-P-T, hypothalamic-pituitary-thyroid; IGHD, idiopathic GHD; MPHD, multiple pituitary hormone deficiency; MRI, magnetic resonance imaging.

Received February 25, 2004.

Accepted July 9, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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