There are some unique aspects of the present study’s design that are worth mentioning. First, this is the only sizeable study investigating the effects of GH on glucose homeostasis and body composition in TS with a contemporaneous untreated control group and the only study specifically examining abdominal fat accumulation. Second, the girls in this study were receiving community-based care, in contrast to previous studies all based on highly structured and closely supervised clinical trials. We found that GH-treated girls were leaner, with less abdominal fat and normal glucose tolerance compared to never-treated girls in the current study, and compared to TS girls in studies prior to the era of GH treatment (3
). The untreated group demonstrated a striking accumulation of intra-abdominal, or visceral adipose tissue (VAT) that was not seen in the GH-treated group. Visceral fat does not normally increase to this extent in pubertal girls, although it may in boys (25
). The excessive abdominal adiposity in untreated girls was associated with reduced insulin sensitivity and impaired glucose tolerance. Thus girls treated with GH during childhood seemed avoid the development of central, abdominal adiposity and the adverse metabolic phenotype typical of girls with TS. The present findings are novel and remarkable because it was predicted by some that GH treatment would increase insulin resistance and risk for diabetes in girls with TS. To the contrary, this study suggests that untreated girls may be at greater risk for insulin resistance and diabetes due to their excessive adiposity.
These findings suggest that GH’s salutary effects on body composition outweigh acute effects of insulin antagonism in girls with TS. GH’s anti-insulin effects stem from its role as a counter-regulatory hormone, mobilizing lipids from adipose tissue to provide muscle-sparing energy substrate. The GH-induced acute elevation of free fatty acids impairs insulin-stimulated glucose uptake by muscle. These GH effects may be beneficial evolutionarily as they promote extraction of fat for energy utilization and sparing of muscle during fasting or famine. GH administered at bedtime stimulates intense lipolysis with liberation of free fatty acids that are elevated though the morning hours (26
). Previous diagnoses of insulin resistance associated with GH treatment were based on metabolic studies carried out the morning after a bedtime GH dose (14
). In the present study and in an earlier study by Wilson et al.(18
), GH was not administered the night before testing, and neither study found insulin resistance in GH-treated girls compared with contemporaneous TS controls. In fact, both studies found fewer IGT cases in GH-treated groups. These observations suggest that insulin resistance noted in proximity to GH dosing is without lasting adverse effects.
The metabolic phenotype of post-pubertal TS girls is very similar to that of GH-deficient patients, i.e., excessive abdominal adiposity associated with insulin resistance that is reversed with GH treatment (28
). Girls with TS are treated with pharmacologic GH to increase final height, but are not usually thought to be GH deficient as part of the syndrome. Evaluation of the GH-IGF system is complicated, however, by differences in body composition and estrogen status of girls and women with TS compared to conventional controls (29
). GH treatment may be helpful in non-GHD individuals with visceral obesity by reducing abdominal fat and improving insulin sensitivity (28
). As noted above, the accumulation of visceral fat around the time of puberty in girls with TS is more typical of males than females (25
). This trait may be related to the fact that the majority of girls with TS– similar to males - carry a single normal maternal X-chromosome, which is associated with excessive visceral adiposity, independent of sex steroid effects (30
The persistence of the beneficial effects on body composition among girls with TS in the years after cessation of GH therapy was unexpected. In older adults GH’s anabolic effects are generally transient and recede within months after discontinuation of GH. It is possible, as a matter of speculation, that GH may have more persistent effects on body composition in children than in older adults. For instance, GH may reduce adipocyte cell number or volume, and/or increase myocyte mass. Alternatively, or in addition, it is likely that improved physical fitness and self esteem associated with GH treatment may lead to adoption of healthy active lifestyle with ongoing salutary effects. In addition, GH treated girls were probably under closer medical surveillance than untreated girls, and may have benefited from medical advice on nutrition and weight control. Clearly further study with long-term follow-up of treated vs. untreated girls is essential to clarify our observations.
Potential selection bias is an important concern in any non-randomized study. In this case, one might consider that obese girls are less likely to be diagnosed early or less likely to be offered GH treatment. However, no study subject reported not being offered or advised against the use of GH because of obesity or any other medical concern. Moreover, obesity should attract more rather than less medical attention. However, overweight is associated with taller height is many children, so they might have been less likely to be identified because of short stature. The fact that a high prevalence of obesity(22
) and impaired glucose tolerance (3
) was found among (non GH-treated) girls with TS years ago suggests that our observations in untreated girls reflect the typical metabolic phenotype in TS, and that the healthy body composition and glucose tolerance in the GH treated groups is due to GH treatment rather than selection bias. Since GH treatment is known to reduce adiposity and improve body composition in other disorders - the improved body composition in our GH-Rx groups is biologically plausible.
Clearly these interesting and novel findings need further investigation, with ongoing longitudinal study to determine the longevity of the relative protection from abdominal adiposity in GH-treated girls.