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In the vast majority of cases, basal serum GH and IGF-1 levels are markedly increased in patients with obvious clinical signs and symptoms of acromegaly. The oral glucose tolerance test (OGTT) is useful for diagnosis in the minority of patients who have weak GH hypersecretion. The cutoff for a "normal" GH nadir in the OGTT remains to be agreed. The type of GH assay, its sensitivity, the type of standard used by the manufacturer, the patient's age and especially gender, must all be taken into account. Recent studies using new highly sensitive assays suggest an upper normal GH nadir of 0.71 microg/l for female healthy patients, but no "universal" cut-off has yet been defined for healthy males (from 0.057 to 0.25 microg/l). The 1 microg/l cutoff proposed for the diagnosis of acromegaly in a 2000 consensus should be abandoned in favor of a 0.30 microg/l cutoff. Clinicians should know which assay is used, together with its sensitivity and the standard, before making therapeutic decisions. A more pragmatic view should probably be adopted when assessing the treatment response. Indeed, if "cure" is defined not with the <1 microg/l GH nadir but on the basis of healthy control values, many patients will not be considered controlled. However, the clinical relevance of such goal (e.g. achieving GH nadir <0.4 microg/l rather than <1 microg/l) in terms of prognosis and prediction of outcome on long term is not firmly established. Thus, from a pragmatic point of view, achieving a normal age-adjusted IGF-1 level and a GH nadir below 1 microg/l during OGTT will probably remain relevant for defining remission and good disease control in terms of morbidity and mortality in acromegaly.

The development of highly sensitive and specific GH assays has necessitated a critical re-evaluation of the biochemical criteria needed for the diagnosis of acromegaly. Use of these assays has revealed that GH levels after oral glucose in healthy subjects and postoperative patients with active acromegaly can be significantly less than previously recognized with older GH assays. In order to assess GH criteria for newly diagnosed acromegaly with a modern assay we have evaluated GH levels in 25 patients referred to our Neuroendocrine Unit for evaluation of untreated acromegaly. All patients underwent measurement of basal GH and IGF-I levels and 15 of these patients also underwent oral glucose tolerance testing for GH suppression (OGTT). Basal GH levels were < 1.0 microg/L at diagnosis in 5 of these 25 patients. Nadir GH levels were less than 1 microg/L also in 5 of 15 patients, and as low as 0.42 microg/L. All patients had elevated IGF-I levels preoperatively and pathological confirmation of a GH secreting pituitary tumor at the time of transsphenoidal surgery. The clinical presentations of these patients was variable. Most patients presented with classical manifestations of acromegaly, but 3 of the 5 patients with low nadir GH values had only very subtle signs of acromegaly. Although most newly diagnosed patients have classically elevated GH levels and obvious clinical features of acromegaly, early recognition of disease may uncover patients with milder biochemical and clinical abnormalities. The diagnosis should not be discounted in patients who have elevated IGF-I levels, but have basal or nadir GH levels less than 1 microg/L. Conventional GH criteria for the diagnosis of acromegaly cannot be applied to the use of modern sensitive and specific GH assays.

Pituitary tumors cause considerable morbidity due to local invasion, hypopituitarism, or hormone hypersecretion. In many cases, no suitable drug therapies are available, and surgical excision is currently the only effective treatment. We have recently demonstrated abundant expression of nuclear hormone receptor PPAR-gamma in human pituitary tumors of different subtypes. PPAR-gamma activators (thiazolidinediones) induced G0-G1 cell-cycle arrest and apoptosis in human, and murine corticotroph, somatolactotroph, and gonadotroph pituitary tumor cells, and suppressed in vitro hormone secretion. In vivo development and growth of murine corticotroph, somatolactotroph and gonadotroph tumors, generated by subcutaneous injection of ACTH-secreting AtT20, PRL- and GH-secreting GH3, and LH-secreting LbetaT2, and alpha-T3 cells, was markedly suppressed in rosiglitazone treated mice, and plasma ACTH, and serum corticosterone, GH, PRL and LH levels were attenuated in all treated animals. PPAR-gamma is an important novel molecular target in pituitary adenoma cells and as PPAR-gamma ligands inhibit tumor cell growth and ACTH, GH, PRL and LH secretion in vitro and in vivo, thiazolidinediones are proposed as a novel oral medical management for pituitary tumors.

Aim: Several studies have demonstrated the efficacy of octreotide LAR administered intramuscularly at 4-week intervals in the treatment of acromegaly. In contrast, few data are available on the time course of GH and IGF-1 plasma levels following octreotide LAR withdrawal. This prompted us to study these parameters for up to 20 weeks following drug withdrawal in a group of 18 acromegalic patients treated for one year., Design and Patients: We studied 18 patients treated with octreotide LAR 10 mg (n = 2), 20 mg (n = 15) and 30 mg (n = 1) every 4 weeks for one year. GH (mean level during a 4-hour daily profile) and IGF-1 concentrations were measured at the end of treatment, just before the last injection (baseline) and then 15 +/- 2 weeks (first control) after the last injection. In patients with GH levels below 2.5 micrograms/L and/or normal IGF-1 at the first control, a second control was performed four to eight weeks later., Results: After one year of treatment with octreotide LAR, the mean plasma GH concentration was 1.91 +/- 1.25 micrograms/L (mean +/- SE) and the mean IGF-1 concentration was 440 +/- 251 micrograms/L. Among the 18 patients, 13 had mean plasma GH concentrations below 2.5 micrograms/L and seven could be considered as well-controlled (normal IGF1 and mean GH levels below 2.5 micrograms/L). After treatment withdrawal, the plasma GH concentration remained below 2.5 micrograms/L at the first and the second controls in 2 of the 13 (15%) patients with suppressed GH levels on baseline. Among the seven well-controlled patients on baseline (GH levels below 2.5 micrograms/L and normal IGF-1), one (15%) remained well-controlled, one (15%) kept GH levels below 2.5 micrograms/L but increased IGF-1 levels, and one (15%) kept normal IGF-1 levels but increased mean GH levels at the first control. This hormonal status remained unchanged at the second control in these 3 patients., Conclusions: These results show long-lasting suppression of GH secretion after treatment withdrawal in some acromegalic patients treated for 12 months with octreotide LAR. The duration of GH suppression after treatment withdrawal is variable. Mean GH levels remained below 2.5 micrograms/L in 15% of our patients for up to 21 weeks following withdrawal of octreotide LAR. In practice, it may be preferable to wait several months after long-acting somatostatin analog withdrawal before reassessing hormone status. Owing this long-lasting effect, a dose reduction to 10 mg and/or a longer interval between injections could be considered for very good responders, as this would lead to considerable cost savings without affecting GH or IGF-1 control.