• Pituitary-independent effect of octreotide on IGF-I generation.

      Pokrajac, Ana; Frystyk, Jan; Flyvbjerg, Allan; Trainer, Peter J; Department of Endocrinology, Christie NHS Foundation Trust, Manchester, M20 4BX, United Kingdom. (2009)
      Background: Somatostatin analogues (SSTAs) are frequently used for medical treatment of acromegaly. The rationale for their use is based on inhibition of pituitary GH secretion; however, there is in vitro evidence that octreotide also acts to inhibit hepatic IGF-I generation. Aim&Design: We studied the pituitary-independent effects of octreotide on IGF-I generation in 11 severely GH deficient humans (age 38, range 23-52; 7 male; BMI 24.7+/-3 kg/m2; peak stimulated GH <3mug/L; 3+/-1 pituitary hormone deficiencies) on a stable dose of GH replacement (0.4+/-0.1 mg) for at least 6 months. Patients were studied before and after 50 mug of subcutaneous octreotide three times a day for 7 days. Results: At study entry, all patients had total IGF-I within age- and gender-related reference range (SDS 0.4+/-1.0). Octreotide treatment resulted in a significant fall in total IGF-I (by 18%, 208+/-89 vs. 173+/-62 mug/L, P=0.04), free IGF-I (by 13%, 0.83+/-0.36 vs. 0.70+/-0.33 mug/L, P=0.01) and IGFBP-3 (6%, 4475+/-745 vs. 4209+/-912 mug/L, P=0.02). Octreotide suppressed fasting insulin from 8.1+/-3.4 to 6.3+/-4.1 mU/L (P=0.01) and was associated with a rise in fasting glucose from 5.2+/-0.9 to 5.8+/-0.9 mmol/L (P<0.01). IGFBP-1 increased by 84% from 42+/-26 to 95+/-52 mug/L (P=0.04). Conclusion: Our study demonstrates that octreotide induces a significant fall in IGF-I in severely GH deficient adults on fixed-dose of GH replacement. This is the evidence for a non-pituitary action of octreotide on the GH/IGF-I axis, most likely by antagonizing the action of GH on hepatic IGF-I generation and indirectly, by suppressing insulin secretion.
    • Use of a GH receptor antagonist (GHRA) to explore the relationship between GH and IGF-I in adults with severe GH deficiency (GHD).

      Berg, C A; Pokrajac, Ana; Bidlingmaier, M; Strasburger, Christian J; Shalet, Stephen M; Trainer, Peter J; Department of Endocrinology, Christie Hospital, Manchester, UK. (2009-03)
      OBJECTIVE: At diagnosis, approximately 50% of adults with severe GH deficiency (GHD) have an IGF-I within the reference range. It is unclear whether in such patients serum IGF-I levels are regulated by factors other than GH. DESIGN AND PATIENTS: We performed a double-blind, randomized, placebo-controlled, cross-over study to investigate the effect of the GH receptor antagonist - pegvisomant (20 mg daily for 14 days) on GH and IGF-I levels in three cohorts: patients with GHD and a normal IGF-I (NORMS); patients with GHD and a low IGF-I (LOWS) and healthy volunteers (CONS). RESULTS: Pegvisomant decreased IGF-I in CONS and NORMS [158.5 (101-206) vs. 103 (77-125) microg/l, P < 0.01; 124 (81-136) vs. 95 (51-113) microg/l, P < 0.01 respectively], but not in LOWS [31 (< 31-32) vs. 34.5 (< 31-38) microg/l], and this was associated with an increase in mean 24 h GH in CONS [0.49 (0.12-0.89) to 1.38 (0.22-2.45) microg/l (P = 0.03)] and in NORMS [69 (0-320)% from 0.1 (< 0.1-0.13) to 0.17 (0.11-0.42) microg/l (P = 0.03)], but not in the LOWS. The peak GH response to arginine was increased by pegvisomant in CONS and NORMS [6.1 (0.8-9) vs. 20.4 (13.1-28.8) microg/l, P = 0.03; 0.4 (0.1-0.5) vs. 0.5 (0.3-0.6) microg/l, respectively], but not in LOWS. CONCLUSIONS: These data indicate that patients with severe GHD with a normal IGF-I are able to increase GH secretion in response to a pegvisomant-induced fall in IGF-I, whereas those with low IGF-I levels are unable to increase GH secretion. Therefore circulating IGF-I appears to be GH-independent in GHD patients with a low IGF-I, but remains partially GH-dependent in GHD patients with a normal IGF-I.