Growth Hormone: The Goldilocks Principle
An overview of GH, and the impact of GH replacement
April 2015
Volume 6, Issue 2

Lower Peak Growth Hormone Cutoff Needed to Diagnose Growth Hormone Deficiency in Overweight and Obese Adults with Pituitary Disorders

J Clin Endocrinol Metab. 2014;99(12):4712-4719

Introduction: Obesity is associated with decreased growth hormone (GH) levels, complicating the diagnosis of growth hormone deficiency (GHD) in obese patients with pituitary disorders. This study was designed to investigate the optimal peak GH cutoff level on the glucagon simulation test (GST) for diagnosis of GHD in men who are overweight or obese.

Methods: The retrospective, cross-sectional study involved 108 men (age 18 to 45 years) with a body mass index (BMI) ≥25 kg/m2: 47 were healthy controls, 20 had total pituitary deficiency (ie, ≥3 non-GH pituitary hormone deficiencies), and 41 had partial pituitary deficiency (1–2 non-GH pituitary hormone deficiencies). All the participants underwent a standard 4-hour GST.

A receiver-operator characteristic (ROC) curve analysis was performed to calculate a diagnostic peak GH cutoff level on the GST. Healthy controls provided the negative condition (ie, not having GHD) and patients with total pituitary deficiency provided the positive condition (ie, having GHD).

Results: Using the standard peak, GH cutoff value of 3 ng/mL on the GST, 45% of healthy controls (21 of 47), 95% of total pituitary deficiency cases (19 of 20), and 80% of partial pituitary deficiency cases (33 of 41) would be classified as having GHD.

On the ROC curve analysis, the cutoff value of 3 ng/mL had a sensitivity of 95% and a specificity of 53% in diagnosing GHD. Further analysis showed that a cutoff value of 0.94 ng/mL had the greatest sensitivity (90%) and specificity (94%) in diagnosing GHD in this population of overweight/obese men (area under the curve, 0.94; P<0.0001). Using a proposed cutoff value of 1 ng/mL in this population would lead to GHD diagnosis in 6% of healthy controls (3 of 47), 90% of total pituitary deficiency cases (18 of 20), and 59% of partial pituitary deficiency cases (24 of 41).

The following factors were negatively correlated with peak GH levels in healthy controls: BMI (R=–0.35, P=0.02), visceral adipose tissue (R=–0.32, P=0.03), iliac waist circumference (R=–0.31; P=0.03), hip circumference (R=–0.30; P=0.04), and oral glucose tolerance test area under the curve (OGTT AUC; R=–0.41; P=0.004). After controlling for BMI, only OGTT AUC remained significantly associated with peak GH levels. Visceral adipose tissue was associated with a trend toward significance (P=0.06).

One of the study limitations is that only men were included in the study. However, the authors noted that prior studies using GH stimulation tests suggest that gender does not significantly alter peak stimulated GH cutoffs, and gender-specific cutoff values are not currently used in clinical practice for the diagnosis of GHD.1,2

Conclusion: Using the standard peak, GH cutoff value of 3 ng/mL on the GST may lead to significant overdiagnosis of GHD in adults who are overweight or obese and have pituitary disorders. The authors propose using a cutoff value of 1 ng/mL to preserve the sensitivity and improve the specificity of the GST in diagnosing GHD in this population.

Commentary

Tamara L. Wexler, MD, PhD, is an endocrinologist specializing in neuroendocrinology and reproductive endocrinology. She is the Director of the NYU Langone Medical Center Pituitary Center in New York, NY, as well as an Attending in Medicine at Massachusetts General Hospital, Boston, MA.

GH levels are affected by BMI, gender, estradiol (ie, oral contraceptives), and age. In overweight/obesity, GH levels are lower, perhaps due to GH hyposecretion. (IGF-1 levels, however, may be elevated; thus, low IGF-1 levels have been suggested as an indicator to help differentiate true GHD in adults with blunted GH level due to overweight/obesity.) The use of set BMI-independent cutoffs in dynamic GH testing to determine GH deficiency may thus lead to overdiagnosis.

Of the available dynamic tests for GH deficiency, only the GHRH-arginine stimulation test—not commercially available in the United States since 2008—currently has threshold levels based on BMI. Suggested BMI-based thresholds for peak GH on GHRH-arginine stimulation testing are: ≤11.0 µg/L with BMI < 25; ≤8.0 µg/L with BMI ≥ 25 but < 30; <4.0 µg with BMI ≥ 30.1,2,a BMI-dependent thresholds are still pending for insulin tolerance testing. (Diagnostic tests and criteria are further discussed in the Introduction to this issue of EndoScan.

With the unavailability of commercial recombinant GHRH in the United States, and the perceived safety concerns of the ITT insulin tolerance test, glucagon stimulation testing is a favored diagnostic test. However, the concern for overdiagnosis of GHD in patients with other reasons for low serum levels remains—namely, in this case, obesity, in which GH secretion is reduced. Dichtel and colleagues set out to determine BMI-specific cutoffs for the glucagon stimulation test, using a population of overweight and obese men.

The included cohort of interest had undergone GST between September 2009 and August 2013 at 2 sites, and consisted of male subjects with pituitary problems and proven pituitary pathology, 1-4 non-GHD pituitary deficiencies (1–2 = partial pituitary deficiency [PPD], 3–4 = total pituitary deficiency [TPD]), BMI ≥ 25 kg/m2, and no history of traumatic brain injury. Control subjects had no pituitary disorders (nor diabetes mellitus, chronic illness, or smoking), and had BMI ≥25 kg/m2 with 3 months stable weight, and waist circumference >102 cm. There was no difference in mean BMI between control, PPD, and TPD groups. By design, control subjects were not age-matched, given the decline in GH seen with age; an age-matched subanalysis was conducted.

Using retrospective cross-sectional analysis, the investigators found that current cutoff levels would lead to misclassification of 45% of 47 healthy (non-GHD) overweight/obese individuals (BMI ≥ 25 kg/m2). By ROC analysis, a 0.94 ng/mL cutoff had maximum sensitivity and specificity in this cohort; this also held true in an age-matched subanalysis.

The authors also investigated other characteristics that might predict reduced peak GH on GST. After controlling for BMI, neither waist nor hip circumference nor visceral adipose tissue were statistically significantly (P<0.05) correlated with peak GH in control subjects (though there was a trend towards association with visceral adipose tissue), but there was a statistically significant negative association with OGTT AUC.

This research demonstrates the importance of using BMI-specific thresholds in diagnostic GHD testing to avoid overdiagnosis. The authors propose a 1 ng/mL threshold for overweight/obese individuals, in place of the standard 3 ng/mL cutoff. In addition, they suggest ensuring that testing is done for the full 4 hours given their observation that 14% of all subjects had GH peaks in hour 4. Further evaluation in larger cohorts would not only confirm these observations, but add useful information by allowing investigation of appropriate GST cutoffs in women as well as men, and in separate overweight, obese, and morbidly obese populations.

Footnote
aThere is a range of similar cutoffs suggested by different research groups. Those provided here are from Cook et al and Ho et al among others.1,2

References Cited
1. Cook DM, Yuen KC, Biller BM, Kemp SF, Vance ML; American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in growth hormone-deficient adults and transition patients - 2009 update. Endocr Pract. 2009;15 Suppl 2:1-29.
2. Ho KK. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia. Eur J Endocrinol. 2007;157:695-700.

Additional References
Aimaretti G, Corneli G, Razzore P, et al. Comparison between insulin-induced hypoglycemia and growth hormone (GH)-releasing hormone + arginine as provocative tests for the diagnosis of GH deficiency in adults. J Clin Endocrinol Metab. 1998;83(5):1615-1618.

Aimaretti G, Corneli G, Razzore P, et al. Usefulness of IGF-I assay for the diagnosis of GH deficiency in adults. J Endocrinol Invest. 1998;21(8):506-511.

Qu XD, Gaw Gonzalo IT, Al Sayed MY, et al. Influence of body mass index and gender on growth hormone (GH) responses to GH-releasing hormone plus arginine and insulin tolerance tests. J Clin Endocrinol Metab. 2005;90(3):1563-1569.

Yuen KC, Biller BM, Molitch ME, Cook DM. Clinical review: Is lack of recombinant growth hormone (GH)-releasing hormone in the United States a setback or time to consider glucagon testing for adult GH deficiency? J Clin Endocrinol Metab. 2009;94(8):2702-2707.

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