Limited Utility of Biochemical Screening for Pituitary Deficiencies and Adverse Effects in Idiopathic GH Deficiency

Stephen Zborovski; Mark R. Palmert; Jennifer Harrington

Disclosures

J Endo Soc. 2019;3(5):1022-1030. 

In This Article

Abstract and Introduction

Abstract

Context: In children with isolated growth hormone (GH) deficiency (GHD), routine biochemical screening for multiple pituitary hormone deficiencies (MPHD) and adverse effects related to growth hormone (GH) treatment are frequently performed. More evidence is needed to support this practice.

Objectives: To evaluate the rate of development of MPHD among children initially diagnosed with isolated GHD and to assess the utility of screening tests to identify complications of GH therapy.

Design: Retrospective analysis of subjects treated with GH since 2005. For the first objective, only subjects diagnosed with GHD were included. Subjects were excluded if GHD was associated with an acquired disorder or condition known to be associated with pituitary abnormalities. For the second objective, other GH-treated diagnoses were included.

Patients: A total of 328 subjects (171 with GHD, 154 with idiopathic short stature, and three with SHOX deficiency).

Results: In subjects with isolated GHD, MPHD was diagnosed in seven (4.2%) after a mean of 35.4 months (range, 9.4 to 68.0). Sex, age at diagnosis, duration of GH, and peak stimulated GH levels were not associated with developing MPHD. Among subjects with an MRI abnormality, 13.9% developed MPHD (OR, 6.3; 95% CI, 1.2 to 33.7). In the entire cohort, three subjects (0.9%) developed dysglycemia, and no subject had persistently abnormal liver or renal function tests.

Conclusions: There is a limited role for routine biochemical screening for MPHD in children with idiopathic isolated GHD or for adverse effects in otherwise healthy children. Routine biochemical screening for MPHD should be limited to those with an abnormal MRI.

Introduction

Growth hormone (GH) deficiency (GHD) in children results from the inability of the pituitary gland to produce sufficient GH to maintain glucose homeostasis and/or to achieve normal growth velocity. GHD has traditionally been diagnosed by the presence of a suboptimal GH response during stimulation testing, prompted by an evaluation for short stature or decreased growth velocity. GHD can be isolated or can occur in the context of multiple pituitary hormone deficiencies (MPHD). There are many organic causes of GHD, including brain tumors, trauma, surgery, radiation, and genetic abnormalities. However, GHD is often not associated with such conditions and is instead termed "idiopathic."

As part of the clinical management of children with GHD, routine screening laboratory tests are often requested. These tests are done in children with isolated GHD to monitor for the development of additional pituitary hormone deficiencies and in these and other children on GH to screen for possible adverse effects associated with GH treatment. Children with GHD due to an organic cause are at high risk of developing additional pituitary hormone deficiencies and should be routinely tested for the development of other abnormalities.[1] Children with idiopathic GHD are also often routinely screened for the development of MPHD; however, the available evidence indicates that the rationale for screening in this population is less clear. Likewise, what "safety" laboratories should be done to screen for adverse effects of treatment has not been clearly established. For this, the rationale is probably strongest for dysglycemia screening as outlined in the Pediatric Endocrine Society GH guidelines,[2] but other tests are sometimes done as well, including assessments for renal and hepatic injury. Even for dysglycemia, although it is apparent that children on GH with underlying risk factors for the development of insulin resistance should be monitored,[2–5] it is less clear whether screening is warranted in all children on GH. Given the common use of GH to treat patients in pediatric endocrinology practices, it is conceivable that a large amount of unnecessary laboratory testing may be done.

The reported rate of the development of MPHD in children with idiopathic isolated GHD ranges from 2% to 44%. An observational trial using data from the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) found that only 2.0% of children with isolated idiopathic GHD developed MPHD.[6] This study relied on data reported at the discretion of local investigators and included subjects with a normal MRI as well as subjects in whom MRI results were not available. Tsai et al.[7] examined the records of 52 subjects with isolated idiopathic GHD and found an overall rate of the subsequent development of MPHD to be 28.8%, but the rate was only 3.8% in children with a normal MRI. However, in this report there was no description of how hormone deficiencies were defined, what deficiencies developed, or the timeframe in which they appeared. The longest follow-up study of children with isolated idiopathic GHD demonstrated a much higher rate of eventual MPHD of 44.6% (37/83 subjects).[8]

Large observational cohort studies have suggested that children treated with GH have an increased risk for impaired glucose tolerance and type 2 diabetes mellitus compared with the general population.[3–5] In each study, dysglycemia was most frequently found in subjects with underlying risk factors (e.g., obesity, malignancy, or Turner syndrome) and less frequently in otherwise healthy children with isolated idiopathic GHD. Therefore, it is not clear if nonobese and otherwise healthy children on GH treatment warrant regular routine screening.

More research is required to determine the need for routine laboratory screening in children treated with GH. In this study, we assessed the utility of commonly performed tests among children with isolated idiopathic GHD by evaluating data from 328 subjects in our clinic.

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