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EDITORIAL |
Department of Endocrinology, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden
Address all correspondence and requests for reprints to: Gudmundur Johannsson, M.D., Ph.D., Department of Endocrinology, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. E-mail: gudmundur.johannsson{at}gu.se.
The data presented by Makimura et al. (1) in this issue of the Journal raise the question of whether we have overlooked an important confounder in the stimulation tests used to diagnose severe GH deficiency (GHD) in adults.
Makimura et al. (1) studied the influence of weight, body mass index (BMI), and other specific measures of central and peripheral adiposity on the peak GH response to arginine (Arg)-GHRH stimulation. In lean, overweight, and obese otherwise healthy men, the peak serum GH response was inversely correlated to all measures of weight, BMI, fat mass, and fat mass distribution (r = –0.44 to –0.56). These data suggest a tight correlation between all measures of adiposity and the stimulated peak GH response. More importantly, the study demonstrated that measures of abdominal obesity were strongly and independently associated with the peak GH level. The effect size was a 1-µg/liter decrease in peak-stimulated GH for each 1 cm increase in waist circumference independent of age and BMI. If visceral adipose tissue (measured using computed tomography) was included in a multiple regression model, BMI, total abdominal fat mass, and sc abdominal fat mass no longer showed a statistically significant correlation to peak GH response.
When analyzed separately, subjects with a waist circumference less than 102 cm had a mean peak GH response of 26.9 µg/liter, and those with a waist circumference 102 cm or higher had a more than 3-fold lower mean response, 7.9 µg/liter. This difference was much greater than the differences observed among the lean, overweight, and obese groups. Using well-defined BMI-adjusted criteria (2), a number of healthy men in the group with abdominal obesity would have been classified as having severe GHD.
It is well known that spontaneous and stimulated GH secretion is attenuated by obesity (3, 4). More recently, abdominal fat mass and, in particular, visceral fat mass have had an independent inverse association with the GH secretion that is stronger than that of age, gender, or BMI (5, 6). This means that age and gender differences in spontaneous GH secretion in adults may be, in part, explained by differences in the degree of abdominal obesity. The mechanism for this relationship is not established, but increased levels of free fatty acids (7) or increased free levels of IGF-I (8) in adiposity can act by negative feedback on the hypothalamic-pituitary axis to reduce GH secretion. A reverse mechanism has also been proposed, that subjects prone to have low GH secretion will increase their visceral adipose tissue more than others and become abdominally obese (9).
The most widely used tests and those recommended by recent clinical guidelines have considered obesity and age as important confounders in the evaluation of GHD (10). The insulin tolerance test (ITT) and the Arg-GHRH test both demonstrate a peak that is independent of age (11, 12). Severe GHD is defined by a peak GH response to hypoglycemia of less than 3–5.1 µg/liter, depending on the population studied and the composition of the control group (11, 13, 14). The peak may be reduced by obesity but has not explicitly been studied, and BMI adjusted diagnostic criteria have not been established for the ITT. Moreover, there are no available data on the impact of abdominal obesity on the peak GH response to the ITT.
BMI adjusted cutoff levels for the GH peak are only available for the Arg-GHRH stimulation test, in which severe GHD is defined differently for lean, overweight, and obese patients. The study by Makimura et al. (1) highlights again that central adiposity is a stronger predictor of the GH response to a stimulation test than general measures of adiposity such as BMI. By using the Arg-GHRH test in their study, which is being increasingly used for the diagnosis of GHD in adults, it becomes even clearer that the most important confounder is not BMI, but central adiposity. As of today no stimulation test uses central adiposity as a confounder in the interpretation of test results. Makimura et al. (1) have elegantly shown the value of waist circumference, a simple measurement of central adiposity in the evaluation of the Arg-GHRH stimulation test. By including waist circumference, this stimulation test could become even more specific in the evaluation of severe GHD in adults.
Abdominal obesity and increased weight are common clinical features in adults with severe GHD (15). In patients with multiple pituitary hormone deficiencies, the tests used to diagnose GHD have high specificity (13). However, the need to diagnose severe GHD in patients with traumatic brain injury and subarachnoid hemorrhage, and the attempt to define partial GHD in adults emphasize the need for the increased accuracy of the diagnostic tests. Therefore, confounders such as abdominal obesity may become increasingly important because an overweight subject with less marked abdominal obesity may be cleared by a test, whereas a patient with the same BMI and more marked abdominal obesity will be defined as having severe GHD.
The problem is even larger when trying to distinguish patients with no, partial, or severe GHD, and the term partial GHD in adults is not generally accepted in the scientific community (10). An example of the aforementioned situation can be seen in studies that have made an attempt to define partial GHD and that have included measures of central adiposity in their protocol. Tauber et al. (16) followed adolescents 1 yr after completion of growth and after stopping GH treatment. At retesting, partial GHD was defined as a peak GH response between 3 and 11.8 µg/liter. Boys who were considered to have partial GHD had a larger intra-abdominal fat mass and waist circumference than patients with normal GH levels. This was not apparent in the girls. In another study including only adults, partial GHD was defined as the highest GH peak of between 3 and 7 µg/liter during two independent stimulation tests (17). Waist circumference demonstrated a continuous increase from controls, GH sufficiency, partial GHD, and severe GHD. Only patients with severe GHD had a statistically significant difference in waist circumference from healthy controls. Based on the findings of Makimura et al. (1), these data could mean that central adiposity determined whether some patients were diagnosed with severe GHD, partial GHD, or GH sufficiency rather than their severity of the underlying hypothalamic-pituitary disorder.
Finally, another aspect of the study by Makimura et al. (1) should be considered. It has been shown that subjects with low GH secretion have more abdominal obesity and increased numbers of metabolic risk factors for cardiovascular disease (18), and administration of GH to subjects with abdominal obesity will reduce abdominal fat mass and improve their metabolic status (9, 19). Although GH secretion will increase with massive weight loss (20), it does not preclude the possibility that the low GH secretion in abdominal obesity contributes to a more adverse metabolic profile in obese subjects.
The data produced by Makimura et al. (1) highlight some major issues related to the association between the somatotropic axis and adiposity. Most importantly for the clinical practice is their finding that abdominal obesity is a stronger confounder than BMI in interpreting the results of the Arg-GHRH stimulation test. This finding has an impact on how to evaluate the GH response during the diagnosis of severe GHD in adults, in particular in patients with less severe hypothalamic-pituitary disease. The next task in clinical neuroendocrinology is to produce diagnostic criteria for GHD that include an adjustment for abdominal obesity.
It is clear from this study that some healthy subjects who were overweight, obese, or who have abdominal obesity will have a test result indicating severe GHD. Whether this is a manifestation of the reduced specificity of this test in (abdominal) obesity or an indicator of overall impaired GH secretion with metabolic consequences remains to be demonstrated. Therefore, the guidelines from the Growth Hormone Research Society have stated that testing for GHD should only be performed in subjects in which there is an intention to treat with GH and there is a well-defined underlying hypothalamic-pituitary disorder (10, 21).
Footnotes
Disclosure Statement: The author has nothing to disclose.
Abbreviations: Arg, Arginine; BMI, body mass index; GHD, GH deficiency; ITT, insulin tolerance test.
Received September 12, 2008.
Accepted September 19, 2008.
References
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