Five-Day Pulsatile Gonadotropin-Releasing Hormone Administration Unveils Combined Hypothalamic-Pituitary-Gonadal Defects Underlying Profound Hypoandrogenism in Men with Prolonged Critical Illness1

• Published in: The journal of clinical endocrinology and metabolism 2001-07, Vol.86 (7), p.3217-3226
• Main Authors: Van den Berghe, Greet, Weekers, Frank, Baxter, Robert C., Wouters, Pieter, Iranmanesh, Ali, Bouillon, Roger, Veldhuis, Johannes D.
• Format: Article
• Language: English
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jcem.86.7.7680

Central hyposomatotropism and hypothyroidism have been inferred in long-stay intensive care patients. Pronounced hypoandrogenism presumably also contributes to the catabolic state of critical illness. Accordingly, the present study appraises the mechanism(s) of failure of the gonadotropic axis in prolonged critically ill men by assessing the effects of pulsatile GnRH treatment in this unique clinical context. To this end, 15 critically ill men (mean ± sd age, 67 ± 12 yr; intensive care unit stay, 25 ± 9 days) participated, with baseline values compared 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 μg/kg every 90 min). LH, GH, and TSH secretion was quantified by deconvolution 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 treatment. Serum concentrations of gonadal and adrenal steroids, T4, T3, insulin-like growth factor I (IGF), and IGF-binding proteins as well as circulating levels of cytokines and selected metabolic markers were measured. During prolonged critical illness, pulsatile LH secretion and mean LH concentrations (1.8 ± 2.2 vs. 6.0 ± 2.2 IU/L) were low in the face of extremely low circulating total testosterone (0.27 ± 0.18 vs. 12.7 ± 4.07 nmol/L; P < 0.0001) and relatively low estradiol (E2; 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 E2/T was elevated 37-fold in ill men (P < 0.0001) and correlated negatively with the mean serum LH concentrations (r =− 0.82; P = 0.0002). Pulsatile GH and TSH secretion were suppressed (P ≤ 0.0004), as were mean serum IGF-I, IGF-binding protein-3, and acid-labile subunit concentrations; thyroid hormone levels; and dehydroepiandrosterone sulfate. Morning cortisol was within the normal range. Serum interleukin-1β concentrations were normal, whereas interleukin-6 and tumor necrosis factor-α were elevated. Serum tumor necrosis factor-α was positively correlated with the molar E2/testosterone ratio and with type 1 procollagen; the latter was elevated, whereas osteocalcin was decreased. Ureagenesis and breakdown of bone were increased. C-Reactive protein and white blood cell counts were elevated; serum lactate levels were normal. Intermittent iv GnRH administration increased pulsatile LH secretion compared with placebo by an incr