Pituitary image: pituicytoma.

INTRODUCTION: Pituicytoma is a rare tumor arising from the neurohypophysis or pars intermedia of the adenohypophysis. CASE REPORT: A 36 year old male came to our observation presenting polydipsia, polyuria, polyphagia, decreased libido and altered sleep-wake rhythm. The biochemical tests showed hypotonic urine, mild hyperprolactinemia, hypogonadotropic hypogonadism, central hypothyroidism. Magnetic resonance revealed an expansive lesion of the suprasellar region (slightly isointense on T1, hyperintense on T2, impregnating contrast medium), that was partially removed by trans-cranial neurosurgical approach. The histopathological diagnosis was pituicytoma. After surgery, in addition to endocrine disorders, the patient presented severe neurological sequelae and hyperthermia, likely due to damage of the hypothalamus, followed by a progressive metabolic syndrome. The residual tumor was monitored by MRI, and, due to the early gradual increase in volume, was treated by stereotactic radiosurgery. DISCUSSION/CONCLUSIONS: Pituicytomas are often difficult to distinguish from other hypothalamic or pituitary lesions. However, their identification would be preferable in a pre-operative setting in order to optimize the work-up and to initiate a proactive management of the expected complications.

Interactions between vitamin D and IGF-I: from physiology to clinical practice.

The interplay between vitamin D and IGF-I is complex and occurs at both endocrine and paracrine/autocrine levels. Vitamin D has been shown to increase circulating IGF-I and IGFBP-3, with the consistent finding of a positive correlation between vitamin D and IGF-I serum values in population-based cohorts of healthy subjects. The modulation of IGF-I and IGFBP-3 concentrations by vitamin D may impact recombinant human (rh) GH dosing for the treatment of GHD. It might also underlie some of the extra-skeletal beneficial effects ascribed to vitamin D. On the other hand, IGF-I stimulates renal production of 1,25-dihydroxyvitamin D, which increases calcium and phosphate availability in the body and suppresses PTH secretion. This effect is responsible for an altered calcium-phosphate balance in uncontrolled acromegaly and might also account for the improvement in bone metabolism associated with rhGH treatment in patients with GHD. Data on the paracrine/autocrine vitamin D-IGF-I interactions are abundant, but mostly not linked to one another. As a result, it is not possible to draw a comprehensive picture of the physiological and/or pathological interrelations between vitamin D, IGF-I and IGF-binding proteins (IGFBP) in different tissues. A potential role of vitamin D action is related to its association with carcinogenesis, a paradigm being breast cancer. Current evidence indicates that, in breast tumours, vitamin D modulates the IGF-I/IGFBP ratio to decrease proliferation and increase apoptosis.

Increasing hirsutism due to a granulosa-cell tumor in a woman with polycystic ovary syndrome: case report and review of the literature.

BACKGROUND: Granulosa-cell tumors (GCT), rare malignancies that arise from sex-cord stromal cells, account for less than 5% of ovarian tumors. These tumors present with an endocrine syndrome and mass signs. Surgery is the primary treatment approach. The risk of recurrence is more frequent in the juvenile-onset form. CASE REPORT: We report the case of an obese 18-year-old Caucasian women with hirsutism and oligomenorrhea. Abdominal palpation revealed a voluminous firm mass. Hormonal evaluation documented severe hyperandrogenism. The ovary-specific tumor marker CA125 was elevated, whereas human-chorionic-gonadotropin was in the normal range. Abdominal imaging examination revealed a 19 cm mass in the left ovary. Twenty-four hours after removal of the mass, menstrual flow reappeared and androgens progressively normalized. Microscopically, the predominant pattern was one of uniform, bland, epithelioid to spindle-shaped cells. After three months, a significant weight loss was recorded, hirsutism had decreased slightly and oligomenorrhea reappeared. Δ4-Androstenedione levels remained elevated (4200 ng/L), whereas CA125 had normalized. In light of the pre-existing polycystic-ovary-syndrome (PCOS), the patient started estrogen-progestin treatment. CONCLUSION: We report an interesting case of a woman with severe hirsutism due to GCT, and a history of oligomenorrhea caused by PCOS. After surgery, a dramatic clinical improvement was observed, whereas PCOS signs persisted.

Balance between somatostatin and D2 receptor expression drives TSH-secreting adenoma response to somatostatin analogues and dopastatins.

CONTEXT: First-line therapy for thyrotropin-secreting pituitary adenomas (TSHomas) is neurosurgery, while medical treatment rests mainly on somatostatin analogues. Clinically available sst(2) -preferring analogues, octreotide and lanreotide, induce normalization of hormone levels in approximately 90% of patients and tumour shrinkage in 45%. OBJECTIVE: We evaluated somatostatin 1, 2, 3 and 5 and dopamine D2 receptor expression in tumour samples from three TSHomas, and the relationships between receptor expression, in vitro antiproliferative response and clinical data, including octreotide test and three months of therapy with octreotide long-acting repeatable (LAR). TSHoma cell proliferation was tested in vitro using octreotide, cabergoline and two chimeric compounds, BIM-23A760 and BIM-23A387. RESULTS: All patients showed significant TSH lowering to acute octreotide test, but a hormonal response to long-term treatment was observed in only two patients, showing a high sst(5) /sst(2) ratio. Patient 2, characterized by high expression of sst(2) and sst(1) and a relative lower expression of sst(5) , experienced tachyphylaxis after prolonged octreotide treatment. In vitro, the somatostatin/dopamine receptor agonist BIM-23A760 caused the highest antiproliferative effect among those tested. Combined treatment with octreotide and cabergoline displayed an additive effect of magnitude comparable to that of the other chimeric compound (BIM-23A387). Octreotide resistance was confirmed in cells isolated from the nonresponder patient, although it could be overcome by treatment with the chimeric compounds. CONCLUSIONS: A high sst(5) /sst(2) ratio might be predictive of a positive outcome to long-term treatment with somatostatin analogues in TSHomas. Moreover, combined somatostatin and D(2) receptor targeting might be considered as a potential tool to improve the response rate in octreotide-resistant tumours.

Biochemical diagnosis and assessment of disease activity in acromegaly: a two-decade experience.

The objective of this study is to assess the secretory pattern of GH after Oral Glucose Tolerance Test (OGTT) or day-curve (DC), in relation with IGF-I and to evaluate the influence of therapy on OGTT. A retrospective analysis in 279 OGTTs performed in 93 acromegalic patients in our unit from January 1988 to December 2005, in 77 patients also DC data were retrived. GH concentration was evaluated by 3 different systems (RIA, IRMA and chemiluminescence assays), and IGF-I by two RIAs. About 12% of OGTT samples were discordant with the baseline, while discordance between nadir and 120th minute was much lower (5%), with all discordant values, except one, near the cut-off lines. Correlation between DC and OGTT data was around 0.99 among all values, discordance rate between nadir and minimum DC was much lower than that with mean DC. In almost 80% of cases there was a complete concordance between OGTT and DC results, and in about 30% IGF-I was discordant with GH. Correlation analysis between IGF-I and GH was highest with DC data and lowest with OGTT baseline (T0). Considering different treatments discrepancy rates between GH and IGF-I were comparable. The best GH parameter is the minimum GH DC, although in the clinical practice the evaluation of OGTT GH in association with IGF-I is the most practical approach. In this case, the basal and T120 GH values can replace multiple sampling. Different treatment modalities do not influence the discordance rate between GH and IGF-I.

Polycythemia as rare secondary direct manifestation of acromegaly: management and single-centre epidemiological data.

Polycythemia associated with acromegaly is usually caused by the systemic manifestations of the disease, such as sleep-apnea or concomitant erythropoietin-secreting kidney tumors. The recognition of underlying pathologies requires a thorough diagnostic process. We report a unique case of acromegaly with polycythemia, not caused by commonly described manifestations of the disease, and receding with octreotide therapy. The medical history of 141 acromegalic patients followed by the Endocrinology Unit of the San Martino University Hospital in Genoa has been also reviewed, together with the literature evidence for similar cases. The diagnostic workflow and 2-years follow-up of a 43-years old acromegalic, polycythemic man with a history of past smoking, moderate hypertension, and mental retardation are described. The hematological parameters of our cohort was retrospectively compared with those of a healthy, age/gender-related control group as well. Therapy with octreotide LAR, 20 mg i.m. q28d was begun soon after diagnosis of acromegaly in the polycythemic patient. Haematocrit level, hormonal setting, as well as pituitary tumor size and visual perimetry during treatment were recorded. Octreotide LAR treatment normalized hormonal alterations, as well as hematological parameters. Polycythemia has not recurred after 2 years of therapy. The median hemoglobin and hematocrit levels of the retrospectively analyzed cohort of acromegalic were significantly lower than normal ranges of a healthy, age/sex- related control population. In conclusions, polycythemia can be a direct, albeit rare, secondary manifestation of acromegaly, that must be considered during the diagnostic work-up of acromegalic patients presenting with such disorder.

In vivo and in vitro response to octreotide LAR in a TSH-secreting adenoma: characterization of somatostatin receptor expression and role of subtype 5.

Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism and account for less than 2% of pituitary adenomas. Medical therapy with somatostatin analogues (SSAs) effectively reduces TSH secretion in approximately 80% of patients and induces shrinkage in about 45% of tumors. According with previous data, resistance to SSA treatment might be due to heterogeneity in somatostatin receptors (SSTRs) expression. We report the case of TSHoma in a 41-year-old man treated with octreotide LAR that caused a dramatic decrease of TSH and thyroid hormones and tumor shrinkage already after 3 months of pre-surgical therapy. In search of potential molecular determinants of octreotide effectiveness, we measured, in primary cultures from this tumor, SSTR and dopamine D2 receptor (D2R) expression, and octreotide and/or cabergoline effects on TSH secretion and cell proliferation. SSTR5 and D2R expression was higher than SSTR2. Octreotide significantly inhibited TSH secretion more effectively than cabergoline (P<0.001), whereas the combined treatment was comparable with cabergoline alone. Similarly, octreotide resulted more effective than cabergoline on cell proliferation, while the combination did not show any additive or synergistic effects. In conclusion, the significant antisecretive and antiproliferative effect of octreotide in this patient might be related to the high expression of SSTR5, in the presence of SSTR2. After reviewing the literature, indeed, in line with previous observations, we hypothesize that SSTR5/SSTR2 ratio in TSHomas may represent a useful marker in predicting the outcome of therapy with SSAs. The role of D2R should be further explored considering that the presence of D2R can influence SSTRs functionality.

Reduced coronary flow reserve in patients with primary hyperparathyroidism: a study by G-SPECT myocardial perfusion imaging.

PURPOSE: The mechanisms underlying increased cardiovascular risk in primary hyperparathyroidism (pHPT) have not been fully defined. Recently, this issue has become the subject of renewed interest due to the increasing evidence that the endothelium and vascular wall are targets for parathyroid hormone (PTH). The aim of this study was to measure regional coronary flow reserve (CFR) to determine whether the vascular damage induced by pHPT extends to affect the coronary microvascular function. METHODS: A total of 22 pHPT patients without a history of coronary artery disease and 7 age-matched control subjects were recruited. Dipyridamole myocardial blood flow (MBF) was assessed using 99mTc-sestamibi by measuring first-transit counts in the pulmonary artery and myocardial count rate from G-SPECT images. Baseline MBF was estimated 2 h later according to the same procedure. Regional CFR was defined as the ratio between dipyridamole and baseline MBF using a 17-segment left ventricular model. RESULTS: Three pHPT patients showed reversible perfusion defects and were excluded from the analysis. In the remaining 19, CFR was significantly lower with respect to the control subjects (1.88±0.64 vs. 3.36±0.66, respectively; p<0.01). Moreover, patients studied for more than 28 months from pHPT diagnosis showed lower CFR values than the others (1.42±0.18 vs. 2.25±0.64, respectively; p<0.01). Consequently, the time from diagnosis to the nuclear study showed a reasonable correlation with the degree of CFR impairment (Spearman's rho -0.667, p<0.02). CONCLUSION: pHPT is associated with a significant dysfunction of the coronary microcirculation. This disorder might contribute to the high cardiovascular risk of conditions characterized by chronic elevations in serum PTH levels.

Role of dopamine receptors in normal and tumoral pituitary corticotropic cells and adrenal cells.

The recent depiction of dopamine receptors (DRs) in tumors that cause Cushing's syndrome (CS) has renewed the debate about the dopamine control on pituitary-adrenal axis, and opened interesting new perspectives for medical treatment of CS. The new insights arise from the recent accurate characterization of DR subtypes expression within tumors causing CS, the discovery of new mechanisms, such as the dimerization between DRs and other G-protein coupled receptors (CPCRs), including somatostatin receptors (SSTRs), and the recent availability of new agents targeting these receptor subtypes. Corticotropic adenomas express DR subtype 2 (D(2)R), together with different SSTR subtypes (ssts), in particular sst(5). In vitro, activation of D(2)R inhibits ACTH release in the majority of cultures of corticotropic cells, whereas, in vivo, dopaminergic agents display an inhibitory effect on cortisol levels in a subset of patients with CS. In animal models the receptor profile can be deeply modulated in specific environmental conditions, that may resemble the different clinical phases of CS. The new insights about DRs and receptor-targeting drugs may offer different approaches for medical treatment of CS: combination therapies with different types of compounds, treatment with novel molecules (hybrid compounds) with a wider spectrum of activity, or even pretreatment manipulation of receptor profile. Finally, recent studies showed that D(2)R is also significantly expressed in ectopic ACTH-secreting tumors and in both normal and tumoral adrenal tissues. Dopamine-agonists may decrease cortisol levels in a number of these patients, strengthening the current (re)emerging interest in DRs as possible targets for medical treatment of CS.

Computed tomography colonography in acromegaly.

INTRODUCTION AND AIM: Acromegalic patients have an increased risk for the development of colorectal cancer. For this reason, since 1996, screening colonoscopy has been recommended in all patients with acromegaly. The aim of our study was to assess the feasibility and to evaluate the results of computed tomography (CT)-colonography in acromegaly. PATIENTS AND METHODS: We examined 23 acromegalic patients with no history of colorectal cancer (11 females and 12 males; age range 18-79 yr; disease duration range 1-15 yr) with CT-colonography. Twenty of them underwent traditional colonoscopy after the CT-colonography. RESULTS: CT-colonography examination results were adequate in 17 of 23 cases (73%). CT-colonography found 12 polyps in eight patients, 95% confirmed by traditional colonoscopy. One polyp was a sigmoid cancer, and the diagnosis was confirmed at surgery. There were no polyps found by traditional colonoscopy that CT-colonography was not able to identify. The lesions were located in right colon (two), transversum (three), left colon (five), and sigmoid colon (two). Patient acceptance of the technique was good in 65%, medium in 20%, and poor in 15%. CONCLUSION: For the first time we have demonstrated that CT-colonography has the potential ability to replace traditional colonoscopy in acromegalic patients. CT-colonography could be used as a screening modality for colon cancer in acromegaly.

Significant tumour shrinkage after 12 months of lanreotide Autogel-120 mg treatment given first-line in acromegaly.

OBJECTIVE: To evaluate GH and IGF-I control and tumour shrinkage in newly diagnosed patients with acromegaly treated first-line with lanreotide-Autogel (ATG) 120 mg. Design Open, prospective. PATIENTS: Twenty-six patients (17 women, aged 31-70 years): eight enclosed and 12 extrasellar (eight invasive) macroadenomas and six microadenomas (one invasive). ATG 120 mg initially given every 4 weeks for 12 weeks; then intervals between injections increased to every 6 or 8 weeks if GH levels were 25% tumour shrinkage: 12 of 14 with controlled disease (85.7%) and 8 of 12 with noncontrolled disease (66.7%; P = 0.49). Hyperhydrosis, paresthesiae and arthralgias significantly reduced after treatment. No patient withdrew from the study because of adverse events. CONCLUSION: ATG 120 mg in newly diagnosed patients with acromegaly controls GH and IGF-I secretion in 53.8% and induces >or= 25% tumour shrinkage in 76.9% during a 12-month period. The treatment was associated with improvement of clinical symptoms and with a good safety profile.

Ultrasound of peripheral nerves in acromegaly: changes at 1-year follow-up.

CONTEXT: We have previously demonstrated peripheral nerve enlargement in acromegaly. OBJECTIVE: The aim of this study was to use ultrasound (US) to assess any changes in the peripheral nerves of patients with acromegaly 1 year after the first evaluation. PATIENTS: We prospectively examined the median and ulnar nerve cross-sectional area (CSA) in 34 non-diabetic, patients with acromegaly (18 females and 16 males; 18-79 years) and 34 age-, sex-, BMI-matched controls, using a 17-5 MHz US probe. INTERVENTION: The median nerve was examined at the mid-forearm (MN-f) and at the carpal tunnel (MN-Ct) levels; the ulnar nerve at mid-forearm (UN-f) and at distal arm (UN-a). Patients were grouped according to the clinical control of the disease: 'improved'; 'always controlled'; 'always uncontrolled'; and 'worsened'. RESULTS: The median nerve at mid-forearm (MN-f), the ulnar nerve at mid-forearm (UN-f) and at distal arm (UN-a) were significantly reduced after 1-year follow-up in all patients (P < 0.001, P < 0.008, P < 0.012, respectively). In the 'improved' group, there was a significant reduction of median nerve CSA examined at mid-forearm (MN-f) (P = 0.02), and distal arm ulnar nerve CSA (UN-a) (P = 0.002). In the other groups no statistically significant differences in ultrasound parameters were recorded. However, UN-a, UN-f, MN-f, MN-ct were still significantly higher in all groups compared with controls (P < 0.001). CONCLUSION: These data demonstrate that median and ulnar nerves CSA are reduced after 1 year follow-up, in line with the reduction of GH/IGF-I levels. However, as the control of the disease incompletely reverts nerve enlargement, this phenomenon could be only partially reversible.

Overexpression of stromal cell-derived factor 1 and its receptor CXCR4 induces autocrine/paracrine cell proliferation in human pituitary adenomas.

PURPOSE: Hypothalamic or locally produced growth factors and cytokines control pituitary development, functioning, and cell division. We evaluated the expression of the chemokine stromal cell-derived factor 1 (SDF1) and its receptor CXCR4 in human pituitary adenomas and normal pituitary tissues and their role in cell proliferation. EXPERIMENTAL DESIGN: The expression of SDF1 and CXCR4 in 65 human pituitary adenomas and 4 human normal pituitaries was determined by reverse transcription-PCR, immunohistochemistry, and confocal immunofluorescence. The proliferative effect of SDF1 was evaluated in eight fibroblast-free human pituitary adenoma cell cultures. RESULTS: CXCR4 mRNA was expressed in 92% of growth hormone (GH)-secreting pituitary adenomas (GHoma) and 81% of nonfunctioning pituitary adenomas (NFPA), whereas SDF1 was identified in 63% and 78% of GHomas and NFPAs, respectively. Immunostaining for CXCR4 and SDF1 showed a strong homogenous labeling in all tumoral cells in both GHomas and NFPAs. In normal tissues, CXCR4 and SDF1 were expressed only in a subset of anterior pituitary cells, with a lower expression of SDF1 compared with its cognate receptor. CXCR4 and SDF1 were not confined to a specific cell population in the anterior pituitary but colocalized with discrete subpopulations of GH-, prolactin-, and adrenocorticorticotropic hormone-secreting cells. Conversely, most of the SDF1-containing cells expressed CXCR4. In six of eight pituitary adenoma primary cultures, SDF1 induced a statistically significant increase in DNA synthesis that was prevented by the treatment with the CXCR4 antagonist AMD3100 or somatostatin. CONCLUSIONS: CXCR4 and SDF1 are overexpressed in human pituitary adenomas and CXCR4 activation may contribute to pituitary cell proliferation and, possibly, to adenoma development in humans.

Efficacy and safety of high-dose long-acting repeatable octreotide as monotherapy or in combination with pegvisomant or cabergoline in patients with acromegaly not adequately controlled by conventional regimens: results of an open-label, multicentre study.

INTRODUCTION: Long-acting repeatable (LAR) octreotide i.m. is a potent, synthetic somatostatin analogue (SSA) that requires less frequent dosing and offers quality of life (QoL) benefits in acromegaly patients compared to its shorter-acting predecessor. This study investigated the efficacy and safety of high-dose Sandostatin® LAR® as monotherapy or in combination with pegvisomant or cabergoline in acromegalic patients with pituitary adenomas following previous failure of conventional SSA treatment. MATERIAL AND METHODS: After three months of high-dose Sandostatin® LAR® monotherapy (40 mg), patients who achieved biochemical control (n = 7) continued to receive the same treatment for an additional four months, whereas uncontrolled patients were randomised to receive high-dose Sandostatin® LAR® in combination with pegvisomant (n = 31) or cabergoline (n = 32). Outcomes included biochemical response at eight months, QoL, and safety. RESULTS: After three months, 3 of 68 (4.4%) evaluable patients achieved a biochemical control (BC) as assessed by levels of growth hormone and insulin-like growth factor-1. At eight months, 4 of 67 (6.0%) patients achieved BC, including one receiving monotherapy and three receiving Sandostatin® LAR® plus cabergoline. Partial response rate, improvements in acromegaly signs and symptoms, and changes in QoL were similar for all three groups. All treatments were well tolerated with a slight excess of adverse events in the combination arms. There were no deaths or serious adverse events leading to treatment discontinuation. CONCLUSION: These data demonstrate that high-dose Sandostatin® LAR® as monotherapy or in combination with pegvisomant or cabergoline is a feasible salvage option in patients with pituitary adenomas not adequately controlled on conventional SSA regimens.

Ultrasound measurement of median and ulnar nerve cross-sectional area in acromegaly.

CONTEXT: Acromegalic patients may complain of sensory disturbances in their hands. OBJECTIVE: Our objective was to examine median (MN) and ulnar nerves (UN) of acromegalic patients with ultrasound (US) and to determine whether nerve abnormalities correlate with clinical parameters and nerve conduction studies (NCS). PATIENTS: We prospectively examined the MN and UN in 34 nondiabetic, acromegalic patients (18 females and 16 males; age range 18-79 yr) and 34 sex-, age-, and body mass index-matched controls with 17-5 MHz US. INTERVENTION: The MN was examined at the carpal tunnel (MN-Ct) and at mid-forearm (MN-f) levels; the UN at the mid-forearm (UN-f) and distal arm (UN-a). A total of 272 nerve cross-sectional areas (CSA) were recorded from both patients and controls. In addition, 22 patients underwent NCS. RESULTS: Nerves of acromegalic patients (MN-Ct=16.5+/-4.4 mm2; MN-f=10.5+/-2.4 mm2; UN-f=9.5+/-3.0 mm2; UN-a=13.1+/-3.7 mm2) had significantly (P<0.0001) greater CSA compared with controls (MN-Ct=7.4+/-1.7 mm2; MN-f=5.5+/-1.4 mm2; UN-f=5.3+/-1.4 mm2; UN-a=6.6+/-1.7 mm2). NCS displayed at least one abnormality in 59% of patients. Acromegalic patients, grouped according to disease activity (14 controlled, 8 partially controlled, 12 uncontrolled), had significantly (P<0.0001) greater CSA compared with controls. Nerve CSA were significantly greater in uncontrolled patients compared to controlled, both at MN-Ct and at UN-f levels (P<0.01). Abnormal NCS were observed in five of seven uncontrolled patients and four of nine controlled patients. IGF-I levels, but not GH levels, were correlated with CSA (r=0.34), whereas disease duration correlated with both nerve CSA and NCS (r=0.33 and r=0.31). CONCLUSION: US identified a significantly increased volume of MN and UN in acromegalic patients. Peripheral nerve enlargement in acromegaly seems to be an intrinsic feature of the disease related to clinical control, disease duration, and IGF-I levels.

No greater incidence or worsening of cardiac valve regurgitation with somatostatin analog treatment of acromegaly.

CONTEXT: Excess GH and IGF-I in acromegaly are associated with reduced life expectancy due to cardiovascular complications. OBJECTIVE: The objective of the study was to investigate the prevalence, incidence, and severity of cardiac valve regurgitation before and after somatostatin-analog treatment in acromegaly. DESIGN: This was a prospective, observer-blinded, multicenter, 12-month study. SETTING: The study was conducted at 33 specialist centers. PATIENTS: The study population consisted of 225 adult patients with acromegaly without significant cardiac valve abnormalities or prior valve-replacement surgery, matched for age, sex, and center/country/study. INTERVENTIONS: Interventions included initiation/continuation of lanreotide (n = 107) or octreotide treatment (n = 118), tailored for optimal disease control. MAIN OUTCOME MEASURES: Relative risk of new/worsening regurgitation in any valve at 12 months compared with baseline, was measured. RESULTS: At baseline, almost 80% of patients had some degree of cardiac valve regurgitation, although none was severe. The risk of developing new/worsening regurgitation in any valve at 12 months was nonsignificant and similar for the cohorts [adjusted odds ratio 0.86; 95% confidence interval (CI) 0.41-1.82; P = 0.694; relative risk 1.04; 95% CI 0.67-1.60; risk difference 0.01; 95% CI -0.13 to 0.16]. For 54% of patients, the severity of regurgitation stayed the same during the study. At baseline, significant valve regurgitation occurred in 18% of patients (lanreotide cohort) and 13% (octreotide cohort) and at 12 months in 18% of each cohort. CONCLUSIONS: The incidence of valve regurgitation did not change over 12 months of treatment with somatostatin analogs, and most cases were physiologic or mild in severity. There was no significant difference between somatostatin analogs in the risk of developing new/worsening valve regurgitation or significant regurgitation after 1 yr.

Correlation of in vitro and in vivo somatotropic adenoma responsiveness to somatostatin analogs and dopamine agonists with immunohistochemical evaluation of somatostatin and dopamine receptors and electron microscopy.

OBJECTIVE AND PATIENTS: Twenty-four pituitary adenomas from acromegalic patients (13 females, 11 males; age range 19-65 yr) were characterized for somatostatin receptor subtype 2A (sst(2A)), dopamine D(2) receptor (D(2)R), GH, and prolactin (PRL) expression by immunohistochemistry, and results correlated with the in vitro and in vivo hormone responses to octreotide and quinagolide. In nine cases, GH and PRL content was further studied by immunoelectron microscopy. RESULTS: Immunoreactivity was semiquantitatively scored as 2 (>50% stained cells), 1 (10-50% stained cells), and 0 (<10% stained cells). Sst(2A) was scored as 2 in 13 cases, 1 in 10, and 0 in one; D(2)R was scored as 2 in 13 cases, 1 in nine, and 0 in 2; GH was 2 in 15 cases and 1 in nine; PRL was 2 in six cases, 1 in 13, and 0 in 5. Sst(2A) was positively correlated with in vitro (P = 0.003) and in vivo (P = 0.006) percent GH suppression by octreotide and with the chronic suppression of IGF-I by somatostatin analogs (P =0.008). D(2)R was positively correlated with in vitro percent GH (P =0.000) and PRL (P =0.005) suppression by quinagolide. Electron microscopy revealed two pure somatotroph adenomas, five somatomammotrophs with a variable coexpression of GH and PRL in the same cells, and two tumors consisting of mixed cell types, which were less sensitive to quinagolide and octreotide. CONCLUSION: Sst(2A) and D(2)R are frequently coexpressed in adenomas from acromegalic patients, and immunohistochemistry may be helpful in characterizing receptor expression in pituitary adenomas to select patients responsive to different treatments.

Effects of uremia and inflammation on growth hormone resistance in patients with chronic kidney diseases.

Resistance to the anabolic action of growth hormone may contribute to the loss of strength and muscle mass in adult patients with chronic kidney disease. We tested this hypothesis by infusing growth hormone in patients to levels necessary to saturate hormone receptors. This led to a significant decrease of plasma potassium and amino acid levels in control and hyperkalemic patients with chronic kidney disease. These effects were completely or partially blunted in patients with elevated C-reactive protein levels. In forearm perfusion studies, growth hormone caused a further decrease in the negative potassium and protein balance of hemodialysis patients without inflammation but no effect was seen in patients with inflammation. Only IL-6 levels and age were found to be independent correlates in these growth hormone-induced variations in plasma potassium and blood amino acids. This shows that although a resistance to pharmacologic doses of growth hormone is not a general feature of patients with chronic kidney disease, there is a subgroup characterized by blunted growth hormone action. Our results support the hypothesis that uremia with inflammation, but not uremia per se, inhibits downstream growth hormone signaling contributing to muscle atrophy.

Treatment of a pituitary metastasis from a neuroendocrine tumour: case report and literature review.

Herein we report a rare case of a pituitary metastasis from a neuroendocrine tumour mimicking an adenoma. Moreover, starting from this unusual case, the relevant literature concerning the diagnosis and management of patients with metastasis at pituitary level is reviewed. A 69-year-old woman was admitted to our Unit for severe headache, diplopia, and critical visual field impairment. MRI showed a large pituitary mass compressing the optic chiasm and infiltrating the cavernous sinus. Trans-sphenoidal biopsy revealed a pituitary metastasis from a neuroendocrine tumour, in line with the multiple liver lesions that were already considered metastases from an ileal primary neuroendocrine tumour. In vitro receptor characterisation of both pituitary and liver tissues by immunohistochemistry showed a heterogeneous somatostatin receptor subtype pattern, with a predominant expression of sst(2) within the pituitary lesion. However, the liver metastasis receptor profile was completely different from the pituitary. Octreotide LAR was administered first, followed by receptor radiometabolic therapy with radiolabelled somatostatin analogues ((90)Y-DOTATOC and (177)Lu-DOTATATE). After 16 months, MRI showed a significant shrinkage of the sellar mass. Moreover, disappearance of diplopia and visual defects, together with a considerable improvement in quality of life were gradually recorded. To our knowledge, this is the first case of combined treatment using "cold" and radiolabelled octreotide in a pituitary metastasis from a neuroendocrine tumour.

The association of fasting insulin concentrations and colonic neoplasms in acromegaly: a colonoscopy-based study in 210 patients.

CONTEXT: Hyperinsulinemia is associated with colon carcinoma in the general population. PATIENTS with acromegaly are considered to be at risk for developing colonic lesions and typically have hyperinsulinemia. OBJECTIVE: Our objective was to evaluate the role of fasting insulin levels on the prevalence of colonic adenomatous polyps or adenocarcinoma in acromegaly. DESIGN: This is an analytical, observational, prospective study. PATIENTS: A total of 210 patients (111 women, 99 men, age 20-82 yr) undergoing complete colonoscopy at diagnosis of acromegaly were included in this study. RESULTS: Colonic lesions were found in 81 patients (38.6%), and consisted of hyperplastic polyps in 33 (15.7%), adenomatous polyps in 42 (20.0%), and adenocarcinoma in six patients (2.8%). Polyps were single in 22 cases (27.1%). Fasting insulin levels were significantly lower in patients without lesions (16.0 +/- 7.5 mU/liter) than in patients with hyperplastic polyps (22.4 +/- 8.8 mU/liter; P < 0.01), adenomatous polyps (38.0 +/- 15.9 mU/liter; P < 0.0001), and adenocarcinoma (59.0 +/- 30.6 mU/liter; P < 0.0001). Fasting insulin levels were also lower in patients with hyperplastic polyps than in those with adenomatous polyps (P < 0.01). The odds ratio for harboring colonic adenomas was 14.8 (95% confidence interval 4.4-51.2; P < 0.0001) and 8.6 times higher (95% confidence interval 2.8-29.0; P < 0.0001) in patients with fasting insulin levels in the upper tertile [>/=27.1 mIU/liter (n = 28)] compared with the lower [12.1 to <27.1 mIU/liter (n = 74)], respectively. CONCLUSION: An increase in fasting insulin levels is associated with an 8.6- to 14.8-fold increased risk of presenting with colonic adenomas in acromegaly.