HARS may be considered a state of functional GH deficiency. Normally, GH is released in pulsatile fashion by the somatotrophic cells of the anterior pituitary in response to growth hormone-releasing hormone (GHRH), somatostatin, insulin-like growth factor (IGF-I), thyroid hormone, and glucocorticoids. Although GHRH is released primarily by the hypothalamus, it is also synthesized in the placenta, ovary, testis, lymphocyte, pancreas, and gastrointestinal tract. The complexity of GH regulation suggests the corresponding complexity of its function in the body. GH concentrations vary inversely with excess weight (obesity). Both reduced GH secretion[49
] and increased clearance have been associated with visceral adiposity in non-HIV patients[51
Rietschel and colleagues have found normal concentrations of IGF-I but reduced GH concentrations in patients with HARS, suggesting greater receptor sensitivity to GH so that a smaller amount of GH stimulates a normal amount of IGF-I release[52
]. Patients in this study were HIV-infected men in whom weight and total body fat were normal but visceral fat depots were enlarged while peripheral fat depots were reduced. The study found 33%-38% prevalence of deficient GH response in lipodystrophic subjects (peak GH stimulatory cut-off values 3.0 μg/mL to 5.0 μg/mL with arginine testing). Reduced mean overnight GH concentration (i.e., reduced basal GH concentration and reduced GH pulse amplitude associated with normal IGF-I) was observed in HAART-treated adults with excess VAT. VAT was the most significant predictor of GH secretion in these subjects.
The actions of the hypothalamic hormone, somatostatin, play a role in GH regulation as well as adipose metabolism. Release of somatostatin is counter regulatory in that it inhibits GH secretion. Koutkia and colleagues compared the difference in GH release by GHRH+arginine stimulation with GHRH alone in 13 HIV-infected men with lipodystrophy and 10 HIV-infected men without lipodystrophy after an overnight fast[27
]. VAT in the lipodystrophy group was 197 ± 19 cm2
vs 66 ± 10 cm2
for the non-lipodystrophy men, and 94 ± 13 cm2
for the comparison group. The data demonstrated GH deficiency in 18% of the lipodystrophy group vs 5.9% of the non-lipodystrophy group and 0% of the comparison group, using the stringent criterion of 3.3 ng/ml for peak GH response to GHRH-arginine. Among the lipodystrophy patients, the peak GH response to GHRH-arginine was significantly predicted by VAT (P = 0.008), FFA (P = 0.04) and insulin level (P = 0.007) in regression modeling. These data demonstrate increased frequency of GH deficiency in HIV lipodystrophy patients in conjunction with increased VAT[53
]. The addition of arginine to GHRH in the lipodystrophy patients led to a 247% greater increase in GH secretion compared to the lipodystrophy patients who received only GHRH. Since arginine blocks somatostatin's inhibition of GH release, this suggests that patients with HIV lipodystrophy and increased visceral fat have elevated somatostatin tone.
Circulating FFAs may impair GH secretion; conversely, GH replacement demonstrates marked reductions in total and net lipolysis and the availability of FFAs for hepatic reesterification[39
]. These results highlight the complex relationship between FFA and GH.
GH Secretion: Effects of Gender, Race and Fat Distribution
Koutkia et al. demonstrated that HIV-infected men with fat redistribution have significantly lower GH peak responses and higher failure rates to standardized GH stimulation testing in comparison to healthy male control subjects and to HIV-infected women of similar age and body mass[27
]. Furthermore, their data suggest that relative GH deficiency is very common among HIV-infected men, especially in those with elevated WHR, even if it was increased due to primary fat loss from the hip region. There was a gender effect – fewer HIV-infected women failed GHRH + arginine stimulation. Among men, a cutoff of 7.5 ng/ml for peak GH was used to show a failure rate of 37% vs 8% for control groups (P = 0.004). Thus, one-third of the men with fat redistribution in this study can be considered at least relatively GH deficient. In contrast to patients with true GH deficiency, e.g. due to a pituitary tumor or radiation, patients in this study were presumed to have otherwise normal pituitary function. Among women, no specific cutoff could be determined to separate HIV-infected and control subjects. This may be due to the effects of estrogen on the GH/IGF-1 axis in this relatively young population and might be different for an older or postmenopausal population.
In the same study, there were differences by race in these patients with HIV and fat redistribution. Non-Caucasian HIV-infected men had higher GH responses to stimulation than Caucasian male HIV-infected subjects. In contrast, non-Caucasian HIV-infected women, compared to Caucasian HIV-infected women, had lower GH responses.