The Ki-67 labeling index may predict clinical outcome in postsurgical management of acromegalic patients. We suggest routine Ki-67 evaluation in GH-secreting pituitary adenomas.
Obesity is characterized by increased leptin levels and insulin resistance, whereas blunted GH secretion is paired with normal, low, or high plasma IGF-I levels. To investigate body composition in human obesity and the interactions among the GH-IGF-I axis, leptin, and insulin resistance [measured with the homeostasis model assessment (HOMA) score], we studied 15 obese females, aged 23-54 yr (mean age, 42.7 +/- 2.6), with a body mass index (BMI) of 44.02 +/- 1.45 kg/m(2), who underwent treatment by biliopancreatic diversion (BPD), before and after surgery (16-24 months; BMI, 28.29 +/- 0.89 kg/m(2)). Our controls were 15 normal females, aged 28-54 yr (mean age, 40.8 +/- 2.3 yr), with a BMI of 27.52 +/- 0.53 kg/m(2). Insulin and leptin levels and HOMA scores were higher pre-BPD than in the controls. The GH response to GHRH was blunted, with a GH peak and GH area under the curve (AUC) significantly lower than those in controls. IGF-I and IGF-binding protein-3 (IGFBP-3) were also lower than control values. After surgery, BMI, fat mass, lean body mass, HOMA, insulin, and leptin significantly decreased. Furthermore, the GH response to GHRH severely increased; IGF-I and IGFBP-3 levels did not significantly vary. Considering all subjects, correlation analysis showed a strong positive correlation between insulin and leptin, and a negative correlation between insulin and GH peak and between insulin and GH AUC. Regression analysis performed grouping pre- and post-BPD indicated that leptin and GH peak or AUC could best be predicted from insulin levels. The surgical treatment of severe obesity after stabilization of body weight decreases BMI and fat mass while preserving normal lean body mass as well as positively influencing insulin sensitivity and thus aiding the normalization of leptin levels. The insulin reduction may be mainly involved in the increase in the GH response to GHRH through various possible central and peripheral mechanisms while decreasing the peripheral sensitivity to GH itself, as shown by the stable nature of the IGF-I and IGFBP-3 values. Our findings suggest that the changes in insulin levels are the starting point for changes in both leptin levels and the somatotrope axis after BPD.
The GHR genotype could be useful in predicting dose and individual response to pegvisomant in acromegaly.
Several recent studies have reported beneficial effects of pegvisomant monotherapy on glucose homeostasis for acromegalic patients resistant to somatostatin analogs (SSA). The aim of our longitudinal study was to test whether these beneficial effects on glucose homeostasis would also occur during combined pegvisomant + SSA treatment amongst partially SSA-resistant acromegalic patients. Ten non-diabetic, partially SSA-resistant acromegalic patients underwent a 12-month SSA+pegvisomant treatment after SSA-only therapy. Glucose homeostasis was evaluated at disease diagnosis, at the end of the SSA treatment and after 6 and 12 months of combined SSA+pegvisomant treatment. The addition of pegvisomant treatment was accompanied by a significant improvement in insulin and glycemic responses to the oral glucose tolerance test, without any significant changes in fasting plasma glucose, glycosylated haemoglobin, homeostatic model assessment-derived insulin resistance index and homeostatic model assessment-derived beta-cell function. Moreover, the number of patients with glucose intolerance did not significantly change during the 12-month combined treatment, notwithstanding the significant decrease in serum IGF-1 values. Therefore, our findings suggest that the combined pegvisomant and SSA treatment may not be able to restore normal clinical and biochemical glycometabolic features occurring in acromegalic patients resistant to SSA, while a slight but significant improvement in some biochemical features may be expected.
Prolactinomas in males can be voluminous macroadenomas invading the surrounding structures. Medical therapy with dopamine agonists (the treatment of choice for these tumours) may be ineffective in the case of pharmacological resistance. In such cases, even surgical and/or radiation therapy cannot be curative due to the invasive potential of the adenoma. Hence, the appropriate therapeutic approach for these tumours is still a relevant clinical problem for endocrinologists. We report the history of an adolescent male who was diagnosed with a large invasive macroprolactinoma in 2002. He had severe bitemporal hemianopsia and hypopituitarism; prolactin levels at diagnosis were higher than 8,000 ng/ml. Medical therapy with cabergoline was initiated and resulted in decreased prolactin levels but not complete normalisation (maximal tolerated dose 3 mg/day). However, due to the worsening of the visual defect, the patient was operated in July 2004 through the trans-nasal approach and 2 years later through both the transcranial and the transphenoidal approaches. After the second surgery, a significant reduction of tumour mass was obtained. Immunohistochemistry for somatostatin receptors (sstr) subtypes showed a positive staining with the anti-sstr5 antibody. A scintigraphy with 111In-pentetreotide (Octreoscan) revealed a very intense tracer uptake in the sellar region. The administration of long-acting octreotide was initiated. After 12 months of therapy, prolactin levels normalised for the first time. Pituitary MRI did not reveal any tumor progression during a 2-year follow-up. This is a case of an invasive dopamine-resistant macroprolactinoma that was successfully controlled by extensive surgery and combined treatment with cabergoline and octreotide. The expression and functionality of sstr should be investigated in these tumours since a combined therapy with cabergoline and octreotide may be a good therapeutic course of action for select cases.
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