A paradoxical gender dissociation within the growth hormone/insulin-like growth factor I axis during protracted critical illness

Female gender appears to protect against adverse outcome from prolonged cri tical illness, a condition characterized by blunted and disorderly GH secre tion and impaired anabolism. As a sexual dimorphism in the GH secretory pat tern of healthy humans and rodents determines gender differences in metabol ism, we here compared GH secretion and responsiveness to GH secretagogues i n male and female protracted critically ill patients. GH secretion was quan tified by deconvolution analysis and approximate entropy estimates of 9-h n octurnal time series in 9 male and 9 female patients matched for age (mean +/- SD, 67 +/- 11 and 67 +/- 15 yr), body mass index, severity and duration of illness, feeding, and medication. Serum concentrations of PRL, TSH, cor tisol, and sex steroids were measured concomitantly. Serum levels of GH-bin ding protein, insulin-like growth factor I (IGF-I), IGF-binding proteins (I GFBPs), and PRL were compared with those of 50 male and 50 female community -living control subjects matched for age and body mass index. In a second s tudy, GH responses to GHRH (1 mu g/kg), GH-releasing peptide-2 (GHRP-8; 1 m u g/kg) and GHRH plus GHRP-2 (1 and 1 mu g/kg) were examined in comparable, carefully matched male (n = 15) and female (n = 15) patients. Despite identical mean serum GH concentrations, total GH output, GH half-li fe, and number of GH pulses, critically ill men paradoxically presented wit h less pulsatile (mean +/- so pulsatile GH fraction, 39 +/- 14% vs. 67 +/- 20%; P = 0.002) and more disorderly (approximate entropy, 0.946 +/- 0.113 v s. 0.805 +/- 0.147; P = 0.02) GH secretion than women. Serum IGF-I, IGFBP-3 , and acid-labile subunit (ALS) levels were low in patients compared with c ontrols, with male patients revealing lower IGF-I (P = 0.01) and ALS (P = 0 .005) concentrations than female patients. Correspondingly, circulating IGF -I and ALS levels correlated positively with pulsatile (but not with nonpul satile) GH secretion. Circulating levels of GH-binding protein and IGFBP-1, -2, and -6 were higher in patients than controls, without a detectable gen der difference. In female patients, PRL levels were 3-fold higher, and TSH and cortisol tended to be higher: than levels in males. In both genders, es trogen levels were more than 8-fold higher than normal, and testosterone (2 .25 +/- 1.94 vs. 0.97 +/- 0.39 nmol/L; P = 0.03) and dehydroepiandrosterone sulfate concentrations were low. In male patients, low testosterone levels were related to reduced GH pulse amplitude (r = 0.91; P = 0.0008). GI-I re sponses to GHRH were relatively low and equal in critically ill men and wom en (7.3 +/- 9.4 us. 7.8 +/- 4.1 mu g/L; P = 0.99). GH responses to GHRP-2 i n women (93 +/- 38 mu g/L) were supranormal and higher (P < 0.0001) than th ose in men (28 +/- 16 mu g/L). Combining GHRH with GHRP-8 nullified this ge nder difference (77 +/- 58 in men vs. 120 +/- 69 mu g/L in women; P = 0.4). In conclusion, a paradoxical gender dissociation within the GH/IGF-I axis i s evident in protracted critical illness, with men showing greater loss of pulsatility and regularity within the GH secretory pattern than women (desp ite indistinguishable total GH output) and concomitantly lower IGF-I and AL S levels. Less endogenous GHRH action in severely ill men compared with wom en, possibly due to profound hypoandrogenism, accompanying loss of the puta tive endogenous GHRP-like ligand action with prolonged stress in both gende rs may explain these novel findings.