Standards of care for medical management of acromegaly in pituitary tumor centers of excellence (PTCOE).

PURPOSE: A series of consensus guidelines on medical treatment of acromegaly have been produced in the last two decades. However, little information is available on their application in clinical practice. Furthermore, international standards of acromegaly care have not been published. The aim of our study was to report current standards of care for medical therapy of acromegaly, using results collected through an audit performed to validate criteria for definition of Pituitary Tumor Centers of Excellence (PTCOE). METHODS: Details of medical treatment approaches to acromegaly were voluntarily provided by nine renowned international centers that participated in this audit. For the period 2018-2020, we assessed overall number of acromegaly patients under medical treatment, distribution of patients on different treatment modalities, overall biochemical control rate with medical therapy, and specific control rates for different medical treatment options. RESULTS: Median number of total patients and median number of new patients with acromegaly managed annually in the endocrinology units of the centers were 206 and 16.3, respectively. Median percentage of acromegaly patients on medical treatment was 48.9%. Among the patients on medical treatment, first-generation somatostatin receptor ligand (SRL) monotherapy was used with a median rate of 48.7%, followed by combination therapies with a median rate of 29.3%. Cabergoline monotherapy was used in 6.9% of patients. Pegvisomant monotherapy was used in 7 centers and pasireotide monotherapy in 5 centers, with median rates of 7.9% and 6.3%, respectively. CONCLUSIONS: Current standards of care in PTCOEs include use of first-generation SRLs as the first medical option in about 50% of patients, as recommended by consensus guidelines. However, some patients are kept on this treatment despite inadequate control suggesting that cost-effectiveness, availability, patient preference, side effects, and therapeutic inertia may play a possible role also in PTCOE. Moreover, at odds with consensus guidelines, other monotherapies for acromegaly appear to have a marginal role as compared to combination therapies as extrapolated from PTCOE practice data. Presence of uncontrolled patients in each treatment category suggest that further optimization of medical therapy, as well as use of other therapeutic tools such as radiosurgery may be needed.

Pilot study to define criteria for Pituitary Tumors Centers of Excellence (PTCOE): results of an audit of leading international centers.

PURPOSE: The Pituitary Society established the concept and mostly qualitative parameters for defining uniform criteria for Pituitary Tumor Centers of Excellence (PTCOEs) based on expert consensus. Aim of the study was to validate those previously proposed criteria through collection and evaluation of self-reported activity of several internationally-recognized tertiary pituitary centers, thereby transforming the qualitative 2017 definition into a validated quantitative one, which could serve as the basis for future objective PTCOE accreditation. METHODS: An ad hoc prepared database was distributed to nine Pituitary Centers chosen by the Project Scientific Committee and comprising Centers of worldwide repute, which agreed to provide activity information derived from registries related to the years 2018-2020 and completing the database within 60 days. The database, provided by each center and composed of Excel® spreadsheets with requested specific information on leading and supporting teams, was reviewed by two blinded referees and all 9 candidate centers satisfied the overall PTCOE definition, according to referees' evaluations. To obtain objective numerical criteria, median values for each activity/parameter were considered as the preferred PTCOE definition target, whereas the low limit of the range was selected as the acceptable target for each respective parameter. RESULTS: Three dedicated pituitary neurosurgeons are preferred, whereas one dedicated surgeon is acceptable. Moreover, 100 surgical procedures per center per year are preferred, while the results indicated that 50 surgeries per year are acceptable. Acute post-surgery complications, including mortality and readmission rates, should preferably be negligible or nonexistent, but acceptable criterion is a rate lower than 10% of patients with complications requiring readmission within 30 days after surgery. Four endocrinologists devoted to pituitary diseases are requested in a PTCOE and the total population of patients followed in a PTCOE should not be less than 850. It appears acceptable that at least one dedicated/expert in pituitary diseases is present in neuroradiology, pathology, and ophthalmology groups, whereas at least two expert radiation oncologists are needed. CONCLUSION: This is, to our knowledge, the first study to survey and evaluate the activity of a relevant number of high-volume centers in the pituitary field. This effort, internally validated by ad hoc reviewers, allowed for transformation of previously formulated theoretical criteria for the definition of a PTCOE to precise numerical definitions based on real-life evidence. The application of a derived synopsis of criteria could be used by independent bodies for accreditation of pituitary centers as PTCOEs.

Polymorphisms in the glucocorticoid receptor gene and in the glucocorticoid-induced transcript 1 gene are associated with disease activity and response to glucocorticoid bridging therapy in rheumatoid arthritis.

Glucocorticoids (GC) are widely used in rheumatoid arthritis (RA). Ongoing active disease due to GC resistance may unfavorably influence long-term disease outcome in RA. We studied the association between the presence of glucocorticoid receptor (GR) and glucocorticoid-induced transcript 1 (GLCCI1) gene polymorphisms, which modulate GC sensitivity, and baseline disease activity score (DAS) and efficacy of GC bridging therapy in RA. We prospectively studied in vivo GC sensitivity in 138 patients with recent-onset or longstanding RA. In vivo GC sensitivity was expressed as the relative decrease in DAS following 2 weeks of standardized GC therapy. All patients were genotyped for the GR polymorphisms BclI (rs41423247), N363S (rs6195), 9ß (rs6198), ER22/23EK (rs6189 + rs6190), and the GLCCI1 variant rs37972 and subsequently divided in groups carrying a polymorphism associated with increased GC sensitivity (BclI-G allele, N363S-G allele, GLCCI1-C allele) or decreased GC sensitivity (9ß-G allele, ER22/23EK-A/A allele, GLCCI1-T allele). Differences in baseline DAS and relative decrease in DAS in the different genotype groups were analyzed using analysis of covariance and linear regression. Baseline DAS was higher in patients who carried polymorphisms of the GR and GLCCI1 genes associated with decreased GC sensitivity. GLCCI1 genotype, but not GR genotypes, was associated with improvement in DAS in male patients with RA. The GLCCI1 gene minor allele (rs37972) may be associated with less efficient GC bridging therapy in male RA patients. Carriers of the BclI-G, N363S-G, or GLCCI1-C alleles had lower levels of baseline disease activity, suggesting a role for the GLCCI1 and GR gene in regulation of GC sensitivity to endogenously produced cortisol.

A consensus on the diagnosis and treatment of acromegaly complications.

In March 2011, the Acromegaly Consensus Group met to revise and update the guidelines on the diagnosis and treatment of acromegaly complications. The meeting was sponsored by the Pituitary Society and the European Neuroendocrinology Association and included experts skilled in the management of acromegaly. Complications considered included cardiovascular, endocrine and metabolic, sleep apnea, bone diseases, and mortality. Outcomes in selected, related clinical conditions were also considered, and included pregnancy, familial acromegaly and invasive macroadenomas. The need for a new disease staging model was considered, and design of such a tool was proposed.

Cortisol diurnal rhythm and quality of life after successful medical treatment of Cushing's disease.

Cushing's disease (CD) is associated with severely impaired quality of life (QoL). Moreover, the physiological cortisol diurnal rhythm (CDR) is disturbed in CD. QoL can improve after successful surgery, the primary treatment for CD. We evaluated the effects of medical treatment on QoL and CDR. In 17 patients, stepwise medical treatment was applied with the somatostatin analog pasireotide, the dopamine agonist cabergoline and the adrenal-blocking agent ketoconazole. After 80 days, 15/17 (88%) patients had reached normal urinary free cortisol excretion (UFC). Subsequently, patients continued medical therapy or underwent surgery. UFC, plasma and salivary CDR and QoL-related parameters (assessed using 5 questionnaires: Nottingham Health Profile, Hospital Anxiety and Depression Scale, Multidimensional Fatigue Index-20, RAND-36, CushingQoL) were measured. At baseline, 5/17 patients had preserved CDR. In 6/12 patients with disturbed baseline CDR, recovery was observed, but without any correlation with QoL. QoL was significantly impaired according to 18/20 subscales in CD patients compared to literature-derived controls. According to the RAND-36 questionnaire, patients reported more pain at day 80 (p < 0.05), which might reflect steroid-withdrawal. Generally, QoL did not improve or deteriorate after 80 days. CushingQoL scores seemed to improve after 1 year of remission in three patients that continued medical therapy (p = 0.11). CDR can recover during successful pituitary- and adrenal-targeted medical therapy. Patients with CD have impaired QoL compared to controls. Despite the occurrence of side-effects, QoL does not deteriorate after short-term biochemical remission induced by medical therapy, but might improve after sustained control of hypercortisolism.

Addition of insulin glargine or NPH insulin to metformin monotherapy in poorly controlled type 2 diabetic patients decreases IGF-I bioactivity similarly.

AIMS/HYPOTHESIS: The aim of this study was to compare IGF-I bioactivity 36 weeks after the addition of insulin glargine (A21Gly,B31Arg,B32Arg human insulin) or NPH insulin to metformin therapy in type 2 diabetic patients who had poor glucose control under metformin monotherapy. METHODS: In the Lantus plus Metformin (LANMET) study, 110 poorly controlled insulin-naive type 2 diabetic patients were randomised to receive metformin with either insulin glargine (G+MET) or NPH insulin (NPH+MET). In the present study, IGF-I bioactivity was measured, retrospectively, in 104 out of the 110 initially included LANMET participants before and after 36 weeks of insulin therapy. IGF-I bioactivity was measured using an IGF-I kinase receptor activation assay. RESULTS: After 36 weeks of insulin therapy, insulin doses were comparable between the G+MET (68 ± 5.7 U/day) and NPH+MET (71 ± 6.2 U/day) groups (p = 0.68). Before insulin therapy, circulating IGF-I bioactivity was similar between the G+MET (134 ± 9 pmol/l) and NPH+MET (135 ± 10 pmol/l) groups (p = 0.83). After 36 weeks, IGF-I bioactivity had decreased significantly (p = 0.001) and did not differ between the G+MET (116 ± 9 pmol/l) and NPH+MET (117 ± 10 pmol/l) groups (p = 0.91). At baseline and after insulin therapy, total IGF-I concentrations were comparable in both groups (baseline: G+MET 13.3 ± 1.0 vs NPH+MET 13.3 ± 1.0 nmol/l, p = 0.97; and 36 weeks: 13.4 ± 1.0 vs 13.1 ± 0.9 nmol/l, p = 0.71). Total IGF-I concentration did not change during insulin therapy (13.3 ± 0.7 vs 13.3 ± 0.7 nmol/l, baseline vs 36 weeks, p = 0.86). CONCLUSIONS/INTERPRETATION: Addition of insulin glargine or NPH insulin to metformin monotherapy in poorly controlled type 2 diabetic patients decreases serum IGF-I bioactivity in a similar manner.

Immunohistochemical localization and quantitative expression of somatostatin receptors in normal human spleen and thymus: Implications for the in vivo visualization during somatostatin receptor scintigraphy.

BACKGROUND: [111In-DTPA-D-Phe1]-octreotide scintigraphy allows the visualization of SRIF receptor (SSR)-expressing tumors, including thymic tumors, and normal tissues. While the spleen is clearly visualized, the thymus is not depicted, although both contain SSR. AIM: We evaluated whether the heterogeneity, the type, and the amount of SSR might explain this contrasting finding. MATERIALS, METHODS, AND RESULTS: By ligand-binding the number of [125I-Tyr11]-SRIF- 14 binding sites resulted comparable between the two tissues, whereas the number of [125I-Tyr3]-octreotide sites was significantly higher in the spleen (p<0.001). Quantitative RTPCR showed a significantly higher expression of sst2A mRNA in the spleen, whereas a significantly higher expression of SRIF and sst3 in the thymus. The highest density of sst2A in the spleen is in line with the in vivo uptake of [111In-DTPA-D-Phe1]- octreotide, which is considered a sst2-preferring ligand. The specificity is confirmed by the evidence that in vivo [111In-DTPA- D-Phe1]-octreotide uptake can be abolished during chronic administration of "cold" octreotide. Immunohistochemistry confirmed a preferential expression of sst2A on microenvironmental cells and of sst3 on lymphoid cells. CONCLUSIONS: The heterogeneity of SSR expression and the higher SRIF content explain the lack of thymus visualization during scintigraphy, whereas thymic tumors, which do not express SRIF, are visualized. Apart from the affinity of the radioligand, also the efficacy of the internalization is crucial for the in vivo uptake, and both heterogeneity and SRIF content affect this process. These observations might have an important impact when interpretating in vivo visualization of SSR-positive lesions, and when treatment with novel SRIF analogs is considered.

Rapid decrease in adrenal responsiveness to ACTH stimulation after successful pituitary surgery in patients with Cushing's disease.

OBJECTIVE: The aim of this study was to investigate the effects of transsphenoidal surgery (TS) on the adrenal sensitivity to ACTH (adrenocorticotropin) stimulation in patients with Cushing's disease (CD). METHODS: We measured the cortisol response to 1 µg synthetic ACTH (1-24) 6 days after pituitary surgery in 45 patients with CD. Mean follow-up period was 56·5 months (SE 4·7). RESULTS: In 24 of 28 patients in sustained remission after pituitary surgery, peak cortisol concentrations below 774 nm (28·0 µg/dl) were recorded after stimulation with 1 µg synthetic ACTH (86%). Two patients with recurrent disease after initial remission (late relapse) also showed ACTH-stimulated peak cortisol levels below 774 nM. Fourteen of 15 patients with persistent CD after surgery (early failure) showed absolute peak cortisol levels >774 nm in response to ACTH stimulation. CONCLUSION: Patients in remission after pituitary surgery for CD showed a rapid decrease of adrenal responsiveness to exogenous ACTH stimulation. This phenomenon may be explained by ACTH-receptor down-regulation in the adrenal cortex after complete removal of the pituitary corticotroph adenoma. In our study, the postoperative low-dose ACTH stimulation test had a sensitivity of 93% and a specificity of 87% in predicting immediate remission of CD after pituitary surgery.

Current management practices for acromegaly: an international survey.

To determine whether peer-reviewed consensus statements have changed clinical practice, we surveyed acromegaly care in specialist centers across the globe, and determined the degree of adherence to published consensus guidelines on acromegaly management. Sixty-five acromegaly experts who participated in the 7th Acromegaly Consensus Workshop in March 2009 responded. Results indicated that the most common referring sources for acromegaly patients were other endocrinologists (in 26% of centers), neurosurgeons (25%) and primary care physicians (21%). In sixty-nine percent of patients, biochemical diagnoses were made by evaluating results of a combination of growth hormone (GH) nadir/basal GH and elevated insulin like growth factor-I (IGF-I) levels. In both Europe and the USA, neurosurgery was the treatment of choice for GH-secreting microadenomas and for macroadenomas with compromised visual function. The most widely used criteria for neurosurgical outcome assessment were combined measurements of IGF-I and GH levels after oral glucose tolerance test (OGTT) 3 months after surgery. Ninety-eight percent of respondents stated that primary treatment with somatostatin receptor ligands (SRLs) was indicated at least sometime during the management of acromegaly patients. In nearly all centers (96%), the use of pegvisomant monotherapy was restricted to patients who had failed to achieve biochemical control with SRL therapy. The observation that most centers followed consensus statement recommendations encourages the future utility of these workshops aimed to create uniform management standards for acromegaly.

Biochemical predictors of outcome of pituitary surgery for Cushing's disease.

OBJECTIVE: Transsphenoidal surgery (TS) is the primary therapy for Cushing's disease (CD). The aims of this retrospective study were twofold: (i) investigate early and late results of TS for CD, and (ii) evaluate various postoperative tests in order to predict the outcome of TS. METHODS: We reviewed the long-term outcome in 79 patients with CD who underwent TS (median follow-up 84 months, range 6-197). Within 2 weeks after surgery, morning serum cortisol concentrations were obtained (n = 78) and corticotropin-releasing hormone (CRH) (n = 53) and metyrapone tests (n = 72) were performed. Three groups of outcome were identified: sustained remission, early failure (persistent CD), and late relapse. RESULTS: Immediate postoperative remission was achieved in 51 patients (65%), whereas 28 patients (35%) had persistent CD after TS. Ten patients developed recurrent CD after initial remission (20%). Morning cortisol: all relapses but one recorded serum cortisol >50 nmol/l. A cortisol threshold value of 200 nmol/l has a positive predictive value of 79% for immediate surgical failure (negative predictive failure [NPV] 97%). CRH test: CRH-stimulated peak cortisol > or =600 nmol/l predicted early failure in 78% (NPV 100%). All relapses recorded CRH-stimulated peak cortisol >or =485 nmol/l. Metyrapone test: 11-deoxycortisol >or =345 nmol/l predicted an early failure in 86% of cases (NPV 94%). CONCLUSION: Predictive factors of surgical failure are morning cortisol >or =200 nmol/l, 11-deoxycortisol >or =345 nmol/l after metyrapone and CRH-stimulated cortisol >or =600 nmol/l. CRH and/or metyrapone testing are not superior to morning cortisol concentration in the prediction of outcome of TS. Careful long-term follow-up remains necessary independent of the outcome of biochemical testing.

Effects of somatostatin analogs on a growth hormone-releasing hormone secreting bronchial carcinoid, in vivo and in vitro studies.

CONTEXT: A 56-yr-old woman presented with acromegaly, a pulmonary mass, and elevated levels of GHRH, GH, and IGF-I. Histological examination revealed a bronchial carcinoid with positive staining for GHRH. Somatostatin analogs (SAs) can play an important role in the treatment of neuroendocrine tumors, dependent on the somatostatin receptor subtype (sst) expression pattern. The sst pattern in bronchial carcinoids and effects of SAs have not been extensively investigated, particularly not for the recently developed universal SA SOM230 (Pasireotide) that has high affinity for sst1, 2, 3, and 5. OBJECTIVE: Our objective was to investigate the in vivo response of a GHRH-producing bronchial carcinoid to octreotide (OCT), its sst-expression profile, and in vitro responses to different SAs, including SOM230. METHODS: In vivo, 50 microg OCT was administered, and plasma GH and GHRH responses were determined. In vitro, the expression of ssts was analyzed by quantitative PCR. Furthermore, the effects of SOM230 and OCT on GHRH secretion were evaluated in primary cell cultures of the carcinoid tissue. RESULTS: In vivo, OCT administration fully suppressed GH and GHRH levels. In vitro, sst1 mRNA was most abundant, followed by sst2 and sst5. Both SOM230 and OCT inhibited GHRH production dose dependently (SOM230 100 nm vs. control, P = 0.01; OCT 110 nm vs. control, P = 0.05). CONCLUSIONS: In this case of a GHRH-producing bronchial carcinoid, we demonstrated that SOM230 was a potent inhibitor of GHRH production in vitro and was at least equally potent compared with OCT. Therefore, SOM230 may be a potential therapeutic agent to control GHRH secretion in ectopic acromegaly.

Tissue mRNA expression of the glucocorticoid receptor and its splice variants in fatal critical illness.

BACKGROUND: Critical illness results in activation of the hypothalamic-pituitary-adrenal (HPA) axis, which might be accompanied by a peripheral adaptation in glucocorticoid sensitivity. Tissue sensitivity is determined by the active glucocorticoid receptor GRalpha, of which two splice variants involving the hormone-binding domain exist, GRbeta and GR-P. OBJECTIVE: To study tissue mRNA expression of the GR and its splice variants in fatal critical illness. DESIGN AND METHODS: We assessed mRNA expression of the GRalpha, GRbeta and GR-P variants in liver (n = 58) and muscle (n = 65) of patients who had died after intensive care, and had been randomized for insulin treatment. We analysed whether GR mRNA expression was associated with insulin treatment, cortisol levels and glucocorticoid treatment. RESULTS: GRalpha and GR-P mRNA constituted 87 +/- 8% and 13 +/- 2%, respectively, of total GR mRNA in liver. GRbeta mRNA could only be amplified in five liver samples. All variants were present in most muscle samples (alpha = 96 +/- 11%, P = 3.9 +/- 0.4%, beta = 0.010 +/- 0.002%). GR expression was not associated with insulin therapy. A strong positive relationship was observed between the different GR variants in both liver and muscle (P < 0.001 for all). Serum cortisol levels were negatively associated with liver GRalpha and muscle GR-P expression (P < 0.05). mRNA expression of both liver GRalpha and GR-P, but not muscle GR, was substantially lower in patients who had received exogenous glucocorticoids (P < 0.01). CONCLUSION: We demonstrate the presence of GRalpha and GR-P mRNA in liver and of GRalpha, GRbeta and GR-P mRNA in muscle, with no evidence for altered splicing in critical illness. In contrast to muscle GR, liver GR expression was substantially lower in patients receiving exogenous glucocorticoids.

Somatostatin and dopamine receptors as targets for medical treatment of Cushing's Syndrome.

Somatostatin (SS) and dopamine (DA) receptors are widely expressed in neuroendocrine tumours that cause Cushing's Syndrome (CS). Increasing knowledge of specific subtype expression within these tumours and the ability to target these receptor subtypes with high-affinity compounds, has driven the search for new SS- or DA-based medical therapies for the various forms of CS. In Cushing's disease, corticotroph adenomas mainly express dopamine receptor subtype 2 (D(2)) and somatostatin receptor subtype 5 (sst(5)), whereas sst(2) is expressed at lower levels. Activation of these receptors can inhibit ACTH-release in primary cultured corticotroph adenomas and compounds that target either sst(5) (pasireotide, or SOM230) or D(2) (cabergoline) have shown significant efficacy in subsets of patients in recent clinical studies. Combination therapy, either by administration of both types of compounds separately or by treatment with novel somatostatin-dopamine chimeric molecules (e.g. BIM-23A760), appears to be a promising approach in this respect. In selected cases of Ectopic ACTH-producing Syndrome (EAS), the sst(2)-preferring compound octreotide is able to reduce cortisol levels effectively. A recent study showed that D(2) receptors are also significantly expressed in the majority of EAS and that cabergoline may decrease cortisol levels in subsets of these patients. In both normal adrenal tissue as well as in adrenal adenomas and carcinomas that cause CS, sst and DA receptor expression has been demonstrated. Although selected cases of adrenal CS may benefit from sst or DA-targeted treatment, its total contribution to the treatment of these patients is likely to be low as surgery is effective in most cases.

The endocrinology of aging.

Most aging individuals die from atherosclerosis, cancer, or dementia; but in the oldest old, loss of muscle strength resulting in frailty is the limiting factor for an individual's chances of living an independent life until death. Three hormonal systems show decreasing circulating hormone concentrations during normal aging: (i) estrogen (in menopause) and testosterone (in andropause), (ii) dehydroepiandrosterone and its sulphate (in adrenopause), and (iii) the growth hormone/insulin-like growth factor I axis (in somatopause). Physical changes during aging have been considered physiologic, but there is evidence that some of these changes are related to this decline in hormonal activity. Hormone replacement strategies have been developed, but many of their aspects remain controversial, and increasing blood hormone levels in aging individuals to those found during mid-adult life has not been uniformly proven to be safe and of benefit.

Cushing's disease in dogs and humans.

BACKGROUND: Cushing's disease (CD) is a common endocrinological disorder in dogs with an estimated incidence of 1 to 2 cases/1,000 dogs/year. This is in contrast to humans in whom CD is rare. The clinical presentation of CD, however, is highly similar between dogs and humans, with characteristic signs, such as abdominal obesity, weight gain, fatigue, muscle atrophy and skin changes. Canine CD may therefore serve as an animal model for human CD, especially since therapeutic canine hypophysectomy can generate substantial amounts of primary corticotroph adenoma tissue for in vitro research purposes. In a recent study, we found that dopamine (DA) D(2) and somatostatin (SS) receptor subtypes are well expressed in canine corticotroph adenomas, but there are some distinct differences compared with the expression profile observed in human CD. These differences need to be considered when using canine CD as a model to evaluate the efficacy of novel DA/SS compounds for potential use in human CD. CASE REPORT: This case involves an 8-year-old female dog that developed signs of exercise intolerance, muscle weakness and polyuria/polydipsia due to an adrenocorticotropic hormone-secreting pituitary adenoma. The dog underwent curative transsphenoidal hypophysectomy and has remained in complete remission in the 3.5 years since surgery.

Expression and functional analysis of dopamine receptor subtype 2 and somatostatin receptor subtypes in canine cushing's disease.

Cushing's disease (CD) is a severe disorder characterized by chronic hypercortisolism due to an ACTH-secreting pituitary adenoma. Transsphenoidal adenomectomy is the treatment of choice in humans with CD, but recurrences occur frequently. Finding an effective and safe medical treatment for CD may improve long-term clinical outcome. The recent demonstration of expression of somatostatin receptor subtypes (mainly sst5) and dopamine receptor subtype 2 (D2) in human corticotroph adenomas offers the possibility for medical treatment of CD with novel somatostatin analogs and dopamine agonists. Investigation of the effects of these drugs is hampered by the low incidence of CD in humans. Interestingly, CD is a frequent disorder in dogs with striking clinical similarities with CD in humans. Therefore, we investigated the expression and functional role of D2 and somatostatin receptors in corticotroph adenoma cells from 13 dogs with active CD that underwent therapeutic hypophysectomy and normal anterior pituitary cells from five dogs. Quantitative RT-PCR and immunohistochemistry revealed that both in CD and normal anterior pituitary, sst2 was the predominant receptor subtype expressed, whereas D2 was modestly expressed and sst5 was expressed only at very low levels. In primary cultures of canine adenomas (n = 7), the sst2-preferring agonist octreotide also showed the strongest ACTH-suppressive effects. In conclusion, canine corticotroph adenomas provide an interesting model to study CD, but differences in somatostatin and dopamine receptor expression between humans and dogs should be taken into account when using dogs with CD as a model to evaluate efficacy of novel somatostatin analogs and dopamine agonists for human CD.

Low circulating insulin-like growth factor I bioactivity in elderly men is associated with increased mortality.

CONTEXT: Low IGF-I signaling activity prolongs lifespan in certain animal models, but the precise role of IGF-I in human survival remains controversial. The IGF-I kinase receptor activation assay is a novel method for measuring IGF-I bioactivity in human serum. We speculated that determination of circulating IGF-I bioactivity is more informative than levels of immunoreactive IGF-I. OBJECTIVE: Our objective was to study IGF-I bioactivity in relation to human survival. DESIGN, SETTING, AND STUDY PARTICIPANTS: We conducted a prospective observational study at a clinical research center at a university hospital of 376 healthy elderly men (aged 73-94 yr). MAIN OUTCOME MEASURES: IGF-I bioactivity was determined by the IGF-I kinase receptor activation assay. Total and free IGF-I were determined by IGF-I immunoassays. Mortality was registered during follow-up (mean 82 months). RESULTS: During the follow-up period of 8.6 yr, 170 men (45%) died. Survival of subjects in the highest quartile of IGF-I bioactivity was significantly better than in the lowest quartile, both in the total study group [hazard ratio (HR) = 1.8; 95% confidence interval (95% CI) = 1.2-2.8; P = 0.01] as well as in subgroups having a medical history of cardiovascular disease (HR = 2.4; 95% CI = 1.3-4.3; P = 0.003) or a high inflammatory risk profile (HR = 2.3; 95% CI = 1.2-4.5; P = 0.01). Significant relationships were not observed for total or free IGF-I. CONCLUSION: Our study suggests that a relatively high circulating IGF-I bioactivity in elderly men is associated with extended survival and with reduced cardiovascular risk.

Salivary cortisol is related to atherosclerosis of carotid arteries.

BACKGROUND: Dysregulation of the hypothalamic-pituitary-adrenal axis has been suggested as an independent risk factor for ischemic heart disease. The aim of our study was to evaluate whether two markers of the hypothalamic-pituitary-adrenal axis activity, the level of salivary cortisol and the diurnal salivary cortisol pattern, are associated with atherosclerosis of the carotid arteries in an elderly population. METHODS AND RESULTS: A total of 1866 participants of the Rotterdam Study, a population-based cohort study in the elderly, provided four salivary cortisol samples throughout 1 d, and underwent ultrasonography to examine the presence of plaques in the common, internal, and bifurcation sites of both carotid arteries. Two summary measures of the separate cortisol values were computed: area under the curve (AUC), which is a measure of total cortisol exposure while awake; and the slope, which is a measure of diurnal cortisol decline. RESULTS: Total cortisol exposure while awake (AUC) was associated with higher plaque scores (beta = 0.08 per sd of AUC, 95% confidence interval 0.00-0.16; P = 0.04) in a fully adjusted linear regression model. Persons with an AUC in the highest tertile had a higher number of plaques of carotid arteries compared with those in the lowest tertile (3.08 vs. 2.80, 95% confidence interval of difference 0.09-0.48; P = 0.005). There was no relation between diurnal cortisol decline and plaque score. CONCLUSION: Our results support the hypothesis that increased total cortisol exposure is independently associated with atherosclerosis of the carotid arteries.

Guidelines for the treatment of growth hormone excess and growth hormone deficiency in adults.

The V Consensus Group Meeting on 'Guidelines for Treatment of GH Excess and GH Deficiency in the Adult' was an international workshop held on February 20-22, 2006 in Santa Monica, California, USA. The principal aim of this meeting was to provide guidelines for the evaluation and treatment of adults with either form of abnormal GH secretion: GH excess or GH deficiency. The workshop included debates as to the choice of primary treatment, discussions of the targets for adequate treatment, and concluded with presentations on open issues germane to adult GH treatment including the role of GH in malignancies, the impact of longterm treatment on bone, and a cost-benefit analysis. The meeting was comprised of 66 delegates representing 13 different countries.

Ethnic differences in outcomes of diabetes care and the role of self-management behavior.

OBJECTIVE: Ethnic differences in outcomes of outpatient diabetic care and the role of self-management behavior and its determinants in explaining observed differences. METHODS: Face-to-face interviews were held with 102 Turkish or Moroccan, and 102 native Dutch diabetic patients to measure self-management behavior and determinants of self-management (as derived from the Attitudes-Social support self-Efficacy model, and Personal Models and Barriers). A medical record review was conducted to measure ethnic differences in outcomes of diabetes care. Data were analyzed using multiple linear regression. RESULTS: Outcomes differed significantly with ethnic minorities having higher levels of lipids (risk difference=RD=0.7%; CI: 0.3-1.2) and HbA1c (RD=0.9%; CI: 0.4-1.4) than native Dutch patients. Differences in self-management could not explain the ethnic differences in outcomes. Self-efficacy explained 18% of the ethnic differences in HbA1c. Beliefs about seriousness of diabetes and social support regarding diabetes management together explained 47% of the ethnic differences in lipids. CONCLUSION: This study provides evidence for ethnic differences in outcomes of diabetes care. Self-efficacy is the most important determinant in explaining the differences in HbA1c. PRACTICE IMPLICATIONS: For diabetes practice this suggests that strengthening patients' self-efficacy may improve the control of HbA1c and may result in a decrease of ethnic differences. The relationship between behavioral determinants like seriousness and social support and outcomes of diabetes care was differential by ethnic group, implying that caution is required when applying behavioral models to different ethnic groups.