Five-day pulsatile gonadotropin-releasing hormone administration unveils combined hypothalamic-pituitary-gonadal defects underlying profound hypoandrogenism in men with prolonged critical illness

Central hyposomatotropism and hypothyroidism have been inferred in long-sta y intensive care patients. Pronounced hypoandrogenism presumably also contr ibutes to the catabolic state of critical illness. Accordingly, the present study appraises the mechanism(s) of failure of the gonadotropic axis in pr olonged critically ill men by assessing the effects of pulsatile GnRH treat ment in this unique clinical context. To this end, 15 critically ill men (mean +/- so age, 67 +/- 12 yr; intensiv e care unit stay, 25 +/- 9 days) participated, with baseline values compare d with those of 50 age- and BMI-matched healthy men. Subjects were randomly allocated to 5 days of placebo or pulsatile iv GnRH administration (0.1 mu g/kg every 90 min). LH, GH, and TSH secretion was quantified by deconvoluti on analysis of serum hormone concentration-time series obtained by sampling every 20 min from 2100-0600 h at baseline and on nights 1 and 5 of treatme nt. Serum concentrations of gonadal and adrenal steroids, T-4, T-3, insulin -like growth factor I (IGF), and IGF-binding proteins as well as circulatin g levels of cytokines and selected metabolic markers were measured. During prolonged critical illness, pulsatile LH secretion and mean LH conce ntrations (1.8 +/- 2.2 vs. 6.0 +/- 2.2 IU/L) were low in the face of extrem ely low circulating total testosterone (0.27 +/- 0.18 vs. 12.7 +/- 4.07 nmo l/L; P < 0.0001) and relatively low estradiol (E-2; 58.3 +/- 51.9 vs. 85.7 +/- 18.6 pmol/L; P = 0.009) and sex hormone-binding globulin (39.1 +/- 11.7 vs. 48.6 +/- 27.8 nmol/L; P = 0.01). The molar ratio of E-2/T was elevated 37-fold in ill men (P < 0.0001) and correlated negatively with the mean se rum LH concentrations (r = -0.82; P = 0.0002). Pulsatile GH and TSH secreti on were suppressed (P less than or equal to 0.0004), as were mean serum IGF -I, IGF-binding protein-3, and acid-labile sub unit concentrations; thyroid hormone levels; and dehydroepiandrosterone sulfate. Morning cortisol was w ithin the normal range. Serum interleukin-1 beta concentrations were normal , whereas interleukin-6 and tumor necrosis factor-alpha were elevated. Seru m tumor necrosis factor-alpha was positively correlated with the molar E-2/ testosterone ratio and with type 1 procollagen; the latter was elevated, wh ereas osteocalcin was decreased. Ureagenesis and breakdown of bone were inc reased. C-Reactive protein and white blood cell counts were elevated; serum lactate levels were normal. Intermittent iv GnRH administration increased pulsatile LH secretion compar ed with placebo by an increment of +8.1 +/- 8.1 IU/L at 24 h (P = 0.001). T his increase was only partially maintained after 5 days of treatment. GnRH pulses transiently increased serum testosterone by +174% on day 2 (P = 0.05 ), whereas all other endocrine parameters remained unaltered. GnRH tended t o increase type 1 procollagen (P = 0.06), but did not change serum osteocal cin levels or bone breakdown. Ureagenesis was suppressed (P < 0.0001), and white blood cell count (P = 0.0001), C-reactive protein (P = 0.03), and lac tate level (P = 0.01) were increased by GnRH compared with placebo infusion s. In conclusion, hypogonadotropic hypogonadism in prolonged critically ill me n is only partially overcome with exogenous iv GnRH pulses, pointing to com bined hypothalamic-pituitary-gonadal origins of the profound hypoandrogenis m evident in this context. In view of concomitant central hyposomatotropism and hypothyroidism, evaluating the effectiveness of pulsatile GnRH interve ntion together with GH and TSH secretagogues will be important.