Somatostatin receptors, adenylate cyclase activity, and growth hormone (GH) response to octreotide in GH-secreting adenomas

Abstract

To determine the cellular mechanism(s) of the variability in GH responsiveness to octreotide in acromegaly, somatostatin (SRIH) receptor status was studied in 37 GH-secreting adenomas. SRIH receptor binding was always present in all GH-secreting adenomas either in membrane preparations (Exp A; n = 17) or by quantitative autoradiography (Exp B; n = 20). In membranes, maximal binding capacities ranged from 83-2331 fmol/mg protein; affinity was in the nanomolar range (Kd, 1.3 +/- 0.2 nmol/L). By quantitative autoradiography, SRIH-14 and octreotide were equally active in displacing [125I]SRIH binding in tumors (Spearman correlation rho = 0.92). IC50 values ranged from 3-22 nmol/L (mean +/- SE, 8.0 +/- 1.3 nmol/L). In Exp A, basal adenylate cyclase (AC) activity was high in 7 tumors (841 +/- 306 pmol/L cAMP x 30 min/mg protein) compared to that in the other 10 (252 +/- 92 pmol/L cAMP x 30 min/mg protein). In these 7 tumors, GH-releasing hormone (0.1 mumol/L) stimulation of AC was lower (53 +/- 11% vs. 297 +/- 48%), whereas SRIH (1 mumol/L) inhibition was higher (52 +/- 5% vs. 34 +/- 5%). Similar results were obtained with Exp B tumors. In both experiments, no correlation was apparent between SRIH-binding capacity and inhibition of AC. In Exp B, a variable decrease in mean plasma GH levels was observed (> or = 80% in 5 patients, between 50-80% in 8 patients, and < or = 50% in 5 patients) after a single sc injection of octreotide (100 micrograms). A modest correlation was found between the GH response to octreotide and SRIH-binding capacity (rho = 0.48) or SRIH inhibition of AC (rho = 0.61). The IC50 values to displace SRIH binding were lower in poorly responsive patients than in highly responsive ones (IC50, 4.6 +/- 1.9 and 13.9 +/- 2.7 nmol/L, respectively). These data indicate that an absence of SRIH receptors cannot account for the weak response to SRIH therapy in 20-30% of acromegalic patients. Alternatively, the weak correlation between either SRIH binding or SRIH inhibition of AC with octreotide inhibition of plasma GH levels might reflect the heterogeneity of SRIH receptor subtypes in GH-secreting adenomas.