Abstract

Somatostatin analogues (SSA) constitute the mainstay of pituitary-targeted pharmacological treatment in acromegaly, but half of the patients are resistant to their anti-secretory and tumor shrinking effects. The successful management of acromegaly in addition to targeting biochemical control involves the treatment of the metabolic comorbidities and hypopituitarism that is managed with hormone replacement. The aim of this study was to analyze the impact of the concomitant antidiabetic treatment with metformin and hormone replacement on the response to SSA. Data were collected from 49 acromegalic patients: 45 had transsphenoidal surgery (35 as primary therapy), 36 SSA (octreotide or lanreotide; 11 as primary treatment). All acromegalic patients with diabetes mellitus (25%) received metformin. Hypopituitarism affected 18 patients. Binary logistic regression analysis (SPSS software) showed no correlation between SSA (p=0.71) and transsphenoidal surgery (p=0.541) on the incidence of pituitary insufficiency. Regression analysis showed no correlation between IGF-1 lowering response to SSA and substitution treatment with hydrocorticosterone, testosterone, or L-thyroxin (variance inflation factor <3). Linear regression analysis showed no correlation between age, gender, disease duration, other treatment modalities (hydrocorticosterone, testosterone, or L-thyroxin) and change of IGF-1 levels after SSA treatment. However, the same analysis showed correlation between metformin therapy and IGF-1 levels after SSA treatment (p=0,031; R-square change: 0,135; R-square: 0,321). In a series of in vitro experiments, metformin alone significantly suppressed GH secretion at the 1mM concentration (64±13) and similar observations were obtained on the rat GH promoter activity and GH secretion from rat immortalized GH-secreting GH3 cells. In vitro investigation on 7 human acromegalic tumours showed that metformin (500nM) enhances the GH-suppressive effect of octreotide (1nM) (63±13% versus 81±12). These preliminary observations indicate that hormone replacement does not affect SSA response, but metformin treatment improves SSA response in terms of IGF-1 reduction most likely through directly suppressing GH production in somatotroph tumor cells.