Predictors and outcomes in primary depression care (POKAL) - a research training group develops an innovative approach to collaborative care.

BACKGROUND: The interdisciplinary research training group (POKAL) aims to improve care for patients with depression and multimorbidity in primary care. POKAL includes nine projects within the framework of the Chronic Care Model (CCM). In addition, POKAL will train young (mental) health professionals in research competences within primary care settings. POKAL will address specific challenges in diagnosis (reliability of diagnosis, ignoring suicidal risks), in treatment (insufficient patient involvement, highly fragmented care and inappropriate long-time anti-depressive medication) and in implementation of innovations (insufficient guideline adherence, use of irrelevant patient outcomes, ignoring relevant context factors) in primary depression care. METHODS: In 2021 POKAL started with a first group of 16 trainees in general practice (GPs), pharmacy, psychology, public health, informatics, etc. The program is scheduled for at least 6 years, so a second group of trainees starting in 2024 will also have three years of research-time. Experienced principal investigators (PIs) supervise all trainees in their specific projects. All projects refer to the CCM and focus on the diagnostic, therapeutic, and implementation challenges. RESULTS: The first cohort of the POKAL research training group will develop and test new depression-specific diagnostics (hermeneutical strategies, predicting models, screening for suicidal ideation), treatment (primary-care based psycho-education, modulating factors in depression monitoring, strategies of de-prescribing) and implementation in primary care (guideline implementation, use of patient-assessed data, identification of relevant context factors). Based on those results the second cohort of trainees and their PIs will run two major trials to proof innovations in primary care-based a) diagnostics and b) treatment for depression. CONCLUSION: The research and training programme POKAL aims to provide appropriate approaches for depression diagnosis and treatment in primary care.

Neuropsychiatric and cardiometabolic comorbidities in patients with previously diagnosed Cushing's disease: a longitudinal observational study.

INTRODUCTION: Only few studies have systematically investigated neuropsychiatric aspects in patients with Cushing's disease (CD). Pain syndromes have been described in patients with pituitary adenomas, but so far no systematical investigation has been conducted in patients with CD. Additionally, CD has an association with cardiometabolic comorbidities which ultimately leads to increased morbidity and mortality. Long-term treatment of the hypercortisolic state cannot prevent the persistence of an unfavourable cardiometabolic risk profile. Finally, chronic hypercortisolism is known to impact the health-related quality of life (HRQoL). We aim to systematically investigate the neuropsychiatric and cardiometabolic comorbidities, as well as assess the HRQoL, in patients with previously diagnosed CD in a longitudinal fashion. METHODS AND ANALYSIS: In this longitudinal study, we will assess 20 patients with CD displaying biochemical control 24 months after recruitment in the initial cross-sectional study (n=80). This will be a mixed cohort including patients after surgical, after radiation therapy and/or under current medical treatment for CD. Primary outcomes include changes in mean urinary free cortisol and changes in specific pain patterns. Secondary/exploratory neuropsychiatric domains include depression, anxiety, personality, sleep, body image and quality of life. Secondary/exploratory cardiometabolic domains include anthropometric parameters, cardiometabolic risk biomarkers and insulin resistance. Additional domains will be investigated if warranted by clinical indication. Safety assessment under medical therapy will include liver enzymes, ECG abnormalities and hyperglycaemia. ETHICS AND DISSEMINATION: Risk of damage from study-conditioned measures is very small and considered ethically justified. Dual-energy X-ray absorptiometry may call for detailed fracture risk assessment. However, the radiation dose is very small and only administered on clinical indication; therefore, it is considered ethically justified. This protocol has been approved by the local medical ethics committee.

Specific behaviour, mood and personality traits may contribute to obesity in patients with craniopharyngioma.

INTRODUCTION: Patients with craniopharyngioma (CP) often suffer from obesity, but the underlying causes are still not fully understood. We compared CP to patients with nonfunctioning pituitary adenoma (NFPA) and to a control group (CG) using standardized questionnaires to investigate whether behavioural, mood or personality traits contribute to obesity. METHODS: We compared 31 patients with CP (42% male, 53 ± 15·1 years) to 26 patients with NFPA (71% male, 63·2 ± 10·3 years) and to age- and gender-matched local CG (ratio 2:1). Normative data from the literature are included for reference. Patients were asked to complete eleven standardized questionnaires. Two questionnaires were used to evaluate eating disorders (FEV, EDE-Q), one depression (BDI), one anxiety (STAI), three health-related quality of life (SF-36, EuroQoL, QoL-AGHDA), one sleepiness (Epworth Sleepiness Scale), two personality (EPQ-RK, TPQ) and one body image (FKB-20). RESULTS: Patients with CP scored significantly higher in conscious hunger perception (FEV, CP 5·8 ± 3·2 scores, NFPA 3·6 ± 3·3 scores, CG 3·0 ± 2·5, P < 0·001). They had similar scores for BDI compared with NFPA, but higher scores to CG (P < 0·001, CP 10·6 ± 8·3, NFPA 7·5 ± 5·7, CG 4·96 ± 4·2). CP and NFPA scored higher than CG for anxiety and personality traits such as harm avoidance, fatigability and asthenia and slightly higher for neuroticism. No differences were seen for EDE-Q, quality of life, daytime sleepiness and body image between CP and NFPA. However, differences could be observed to normative data from the literature. CONCLUSION: Obesity in patients with CP might be influenced by eating disorders, negative mood alterations and increased anxiety-related personality traits.

Clinical characteristics of pain in patients with pituitary adenomas.

OBJECTIVE: Clinical presentation of pituitary adenomas frequently involves pain, particularly headache, due to structural and functional properties of the tumour. Our aim was to investigate the clinical characteristics of pain in a large cohort of patients with pituitary disease. DESIGN: In a cross-sectional study, we assessed 278 patients with pituitary disease (n=81 acromegaly; n=45 Cushing's disease; n=92 prolactinoma; n=60 non-functioning pituitary adenoma). METHODS: Pain was studied using validated questionnaires to screen for nociceptive vs neuropathic pain components (painDETECT), determine pain severity, quality, duration and location (German pain questionnaire) and to assess the impact of pain on disability (migraine disability assessment, MIDAS) and quality of life (QoL). RESULTS: We recorded a high prevalence of bodily pain (n=180, 65%) and headache (n=178, 64%); adrenocorticotropic adenomas were most frequently associated with pain (n=34, 76%). Headache was equally frequent in patients with macro- and microadenomas (68 vs 60%; P=0.266). According to painDETECT, the majority of the patients had a nociceptive pain component (n=193, 80%). Despite high prevalence of headache, 72% reported little or no headache-related disability (MIDAS). Modifiable factors including tumour size, genetic predisposition, previous surgery, irradiation or medical therapy did not have significant impact neither on neuropathic pain components (painDETECT) nor on headache-related disability (MIDAS). Neuropathic pain and pain-related disability correlated significantly with depression and impaired QoL. CONCLUSIONS: Pain appears to be a frequent problem in pituitary disease. The data suggest that pain should be integrated in the diagnostic and therapeutic work-up of patients with pituitary disease in order to treat them appropriately and improve their QoL.

IGF-I levels and depressive disorders: results from the Study of Health in Pomerania (SHIP).

In vitro and in vivo models revealed that the somatotropic system exerts central effects on the central nervous system. Disturbances to this system such as in the case of growth hormone deficiency or growth hormone excess, are associated with a wide range of psychiatric disorders. Nonetheless, there is no epidemiological data available regarding the influence of growth hormone and its mediator, insulin-like growth factor I (IGF-I), on depressive disorders. The objective of this study was to investigate whether endogenous IGF-I levels may predict depression in humans. We included 4079 adult subjects from the Study of Health in Pomerania (SHIP), a population-based study with a 5-year follow-up period. The main predictor was the baseline IGF-I value categorized in three levels as <10th percentile, between the 10th and the 90th percentile (the reference group) and >90th percentile. The outcome measure was the incidence of depressive disorders according to the Composite International Diagnostic-Screener (CID-S). After adjustment for potential confounding variables, females with IGF-I levels below the 10th percentile had a higher incidence of depressive disorders during follow-up (OR 2.70 95% CI 1.38-5.28, p=0.004) compared to females within the reference group (10th-90th percentile). Among males, those with IGF-I levels above the 90th percentile had a higher risk of depressive disorder (OR 3.26 95% CI 1.52-6.98, p=0.002) than those within the 10th-90th percentile. In conclusion we can demonstrate that low IGF-I levels in females and high IGF-I levels in males predict the development of depressive disorders in this general adult population sample.

PIK3CA and APC mutations are synergistic in the development of intestinal cancers.

Human colorectal cancers are known to possess multiple mutations, though how these mutations interact in tumor development and progression has not been fully investigated. We have previously described the FCPIK3ca* murine colon cancer model, which expresses a constitutively activated phosphoinositide-3 kinase (PI3K) in the intestinal epithelium. The expression of this dominantly active form of PI3K results in hyperplasia and invasive mucinous adenocarcinomas. These cancers form via a non-canonical mechanism of tumor initiation that is mediated through activation of PI3K and not through aberrations in WNT signaling. Since the Adenomatous Polyposis Coli (APC) gene is mutated in the majority of human colon cancers and often occurs simultaneously with PIK3CA mutations, we sought to better understand the interaction between APC and PIK3CA mutations in the mammalian intestine. In this study, we have generated mice in which the expression of a constitutively active PI3K and the loss of APC occur simultaneously in the distal small intestine and colon. Here, we demonstrate that expression of a dominant active PI3K synergizes with loss of APC activity resulting in a dramatic change in tumor multiplicity, size, morphology and invasiveness. Activation of the PI3K pathway is not able to directly activate WNT signaling through the nuclear localization of CTNNB1 (ß-catenin) in the absence of aberrant WNT signaling. Alterations at the transcriptional level, including increased CCND1, may be the etiology of synergy between these activated pathways.

The effect of the ANKK1/DRD2 Taq1A polymorphism on weight changes of dopaminergic treatment in prolactinomas.

Treatment with dopamine agonists in patients with prolactinomas has been associated with weight loss in short term studies. However, long-term studies on weight changes are lacking. Taq1A is a restriction fragment length polymorphism considered as a gene marker for the DRD2 gene. The presence of at least one A1 allele is linked to reduced brain dopaminergic activity due to reduced receptor binding and lower density of the dopamine 2 receptor. We aimed at testing the hypothesis that the dopaminergic treatment in prolactinoma patients leads to sustained weight loss and that the presence of diminished weight loss response under dopamine agonists is associated with the minor A1 allele of Taq1A.We included n = 44 patients (17 male and 27 female, 26 macroadenomas and 18 microadenomas) with prolactinomas treated with dopamine agonists. Outcome measures were weight and body mass index (BMI) change under dopaminergic treatment after 2 years with regard to Taq1A status and sex. We observed that the dopaminergic treatment leads to a significant mean weight loss of 3.1 ± 6.25 kg after 2 years. Regarding Taq1A polymorphisms, 21 patients were carriers of at least one A1 allele and 23 patients had a genotype of A2/A2. However, the presence of the A1 allele was neither associated with the mean BMI at baseline nor with an altered weight loss response under dopamine agonist therapy. Our results implicate that the dopaminergic treatment leads to a sustained weight loss in patients with prolactinomas after 2 years. However, there was no association to the A1 allele of Taq1A, observation that needs to be analysed in larger cohorts.

Factores de riesgo para el desarrollo de delirium postoperatorio en pacientes adultos mayores: estudio clínico prospectivo analítico / Risk factors for the development of postoperative delirium in elderly patients: prospective analytical trial

Determinar si existe asociación entre algunos factores de riesgo en el desarrollo de delirium en la población adulta mayor de dos servicios quirúrgicos del Hospital Regional de Talca. Material y Método: Se realizó un estudio clínico prospectivo, que incluyó todos los pacientes mayores de 65 años que se sometieron a cirugía traumatológica o urológica electiva en un período de 3 meses. Para evaluar cuantitativamente el delirium se utilizaron el Test Mental Abreviado (TMA) y el test “Confussion Assessment Method” (CAM). Se midió la incidencia de delirio y se analizó su relación con deterioro cognitivo previo, edad, analfabetismo, enfermedades crónicas, fractura de cadera, uso de benzodiazepinas y tiempo quirúrgico. Resultados: De un total de 81 pacientes (55 por ciento hombres; rango de edad 74,9 +/- 7,9), el 39,5 por ciento presentó delirium. De los factores de riesgo incluidos en el estudio sólo tienen asociación estadísticamente significativa, la edad (p = 0,033) y el analfabetismo (p = 0,000). Conclusión: El delirium postoperatorio es una complicación frecuente del paciente adulto mayor que se somete a cirugía, donde la edad y el analfabetismo son factores predisponentes, los que deben ser considerados en la evaluación preanestésica con el objetivo de disminuir la incidencia de este cuadro...

Objective: Evaluate the association of some possible risk factors in the development of post surgery delirium in the elderly population at two surgical services at the Regional Hospital of Talca. Materials and Methods: We performed a prospective clinical study, which included all patients older than 65 years who underwent elective orthopedic surgery or urological surgery in a period of 3 months. Two tests were administered to quantitatively evaluate the delirium: Abbreviated Mental Test (AMT) and Confusion Assessment Method (CAM). We analyzed the association between delirium and possible risk factors such as prior cognitive impairment, age, illiteracy, chronic disease, hip fracture, use of benzodiazepines and surgical time. Results: Of a total of 81 patients (55 per cent male, age range 74.9 +/- 7.9), 39.5 per cent had delirium. Of the risk factors included in the study only statistically significant association with age (p = 0.033) and illiteracy (p = 0.000). Conclusions: Postoperative delirium is a common complication of elderly patient who undergoes surgery, where age and illiteracy are predisposing factor, should be considered in the preanesthetic assessment in order to reduce the incidence of this condition...

Increased prevalence of anxiety-associated personality traits in patients with Cushing's disease: a cross-sectional study.

BACKGROUND/AIMS: Chronic hypercortisolism in Cushing's disease (CD) has been suggested to contribute to an altered personality profile in these patients. We aimed to test this hypothesis and attempted to determine the effects of disease- and treatment-related factors that might moderate an altered personality in CD. METHODS: We assessed 50 patients with CD (74% biochemically controlled) and compared them to 60 patients with non-functioning pituitary adenomas (NFPA) and 100 age- and gender-matched mentally healthy controls. Personality was measured by two standardized personality questionnaires, TPQ (Cloninger personality questionnaire) and EPQ-RK (Eysenck personality questionnaire-RK). RESULTS: Compared to mentally healthy controls, CD patients reported significantly less novelty-seeking behaviour, including less exploratory excitability and less extravagance. On harm avoidant subscales, they presented with more anticipatory worries and pessimism, higher fear of uncertainty, shyness with strangers, fatigability and asthenia. Moreover, CD patients appeared to be less extraverted, more neurotic and socially desirable. CD patients differed from NFPA patients in terms of higher neuroticism scores, and NFPA patients did not show altered novelty-seeking behaviour or extraversion. In the subgroup analysis, CD patients with persistent hypercortisolism displayed significantly higher fear of uncertainty, fatigability and asthenia, indicating high harm avoidance in total, than those in biochemical remission. CONCLUSION: Patients with CD showed a distinct pattern of personality traits associated with high anxiety in combination with traits of low externalizing behaviour. Such personality changes should be taken into account in the diagnosis and treatment of CD patients, as they might interfere with the patient-physician communication and/or challenge the patients' social and psychological functioning.

Changes in BMI and management of patients with childhood onset growth hormone deficiency in the transition phase.

OBJECTIVE: We aimed at evaluating BMI changes during GH therapy pause, to assess the transfer pattern between children and adult medical services in our clinic and to confirm the previous growth hormone deficiency (GHD) diagnosis. DESIGN: Retrospective cohort study. METHODS: We identified 75 transition patients (age at first visit <25 years) with pituitary deficiency (ICD-10:E.23) and GHD referred to our clinic between 2000-2009. RESULTS: Out of 75 patients with GHD (45 males, 30 females), 20 subjects suffered from an idiopathic GHD (iGHD) and 55 from an organic GHD (oGHD). During the GH therapy pause (26.4±34.8 months), we observed a significant BMI increase (23.6±4.4 to 27.1±7.2, p=0.02). Most males with iGHD discontinued endocrinologic control and GH substitution completely (5 patients out of 20) or after the first contact (3 patients out of 20). Most females with GHD continued medical control after transferral (22 patients). We retested 34/75 patients with GHD (45.3%). The preferred test was the growth hormone-releasing hormone-arginine (GHRH-arginine) (20/34 patients, 58.9%), followed by the insulin hypoglycemia test (IHT) alone (9 patients). 4 patients received both, the GHRH-arginine and the IHT. Seven retested patients with iGHD (63.6%) and all oGHD retested patients were still deficient. CONCLUSIONS: Our results provide information on negative effects of the discontinuation of GH treatment during the transition phase and should help to improve the compliance with treatment in this group of patients. Paediatric and adult endocrinologists participating together in a transition programme should emphasize on the positive effect of GH substitution in adulthood. Efforts should be made to particularly improve the transferral of male adolescents with iGHD, since they seem to escape medical care.

Efecto de la sedación en el desarrollo de delirium en pacientes adultos mayores sometidos a cirugía con anestesia espinal: estudio clínico prospectivo / Effect of sedation in the development of delirium in elderly patients undergoing surgery with spinal anesthesia: a prospective clinical study

Determinar la ocurrencia de delirium postoperatorio en pacientes adultos mayores sometidos a cirugía con anestesia espinal con y sin sedación. Material y Método: Se realizó un estudio clínico prospectivo descriptivo, que incluyó todos los pacientes mayores de 65 años que se sometieron a cirugía traumatológica o urológica electiva con anestesia espinal en un período de 3 meses. Para evaluar cuantitativamenteel delirium se utilizaron 2 herramientas: Test Mental Abreviado (AMT, por sus siglas en inglés) y Confussion Assessment Method (CAM) durante el postoperatorio inmediato, a las 24, 48 y 72 h; y se comparó la ocurrencia de delirium en los grupos con y sin sedación. Resultados: La incidencia de delirium postoperatorio fue del 50 por ciento en pacientes con sedación versus un 36,8 por ciento en quienes no la recibieron, lo que no demostró ser significativamente mayor (p = 0,268). Sin embargo, se encontró en ambos grupos un patrón de presentación temporal del delirium diferente, que si bien no fue significativo (p = 0,136), muestra una clara tendencia. Conclusiones: El delirium postoperatorio en el paciente anciano es una complicación frecuente, en el cual el uso de benzodiazepinas podría jugar un rol, tanto en su incidencia como en sus características temporales...

Determining the occurrence of postoperative delirium in elderly patients undergoing surgery with spinal anesthesia with or without sedation. Materials and Methods: We performed a prospective clinical study, which included all patients older than 65 years who underwent elective urological surgery or trauma with spinal anesthesia in a period of three months. To quantitatively evaluate delirium using 2 tools: Abbreviated Mental Test (AMT) and Confusion Assessment Method (CAM) during the immediate postoperative period, at 24, 48 and 72 hours, and compared the occurrence of delirium in the groups with and without sedation. Results: The incidence of postoperative delirium was 50 percent in patients with sedation versus 36.8 percent in those who did not, which is not shown to be significantly higher (p = 0.268). However, both groups found a pattern of temporal presentation of delirium different, but was not significant (p = 0.136), showing a clear trend. Conclusions: Postoperative delirium in the elderly is a common complication in which the use of benzodiazepines may play a role in both its incidence and temporal characteristics...

Polymorphisms of the drug transporter gene ABCB1 predict side effects of treatment with cabergoline in patients with PRL adenomas.

INTRODUCTION: Treatment with dopamine agonists in patients with prolactin (PRL) adenomas and Parkinson's disease is associated with central side effects. Central side effects may depend on a substance's ability to pass the blood-brain barrier, which can be actively controlled by transporter molecules such as the P-glycoprotein (P-gp) encoded by the ABCB1 gene. MATERIALS AND METHODS: We aimed to determine whether cabergoline is transported by the P-gp and whether polymorphisms of its encoding ABCB1 gene predict central side effects of cabergoline therapy in patients with PRL adenomas. i) In an experimental mouse model lacking the homologues of the human ABCB1 gene (Abcb1ab double knockout mouse model), we examined whether cabergoline is a substrate of the P-gp using eight mutant and eight wild-type mice. ii) In a human case-control study including 79 patients with PRL adenomas treated with cabergoline at the Max Planck Institute of Psychiatry in Munich, we investigated the association of four selected ABCB1 gene single nucleotide polymorphisms (SNPs) (rs1045642, rs2032582, rs2032583 and rs2235015), with the occurrence of central side effects under cabergoline therapy. RESULTS: i) In the experimental mouse model, we observed that brain concentrations of cabergoline were tenfold higher in the mutant mice compared with their wild-type littermates, implying that cabergoline is indeed a substrate of the transporter P-gp at the blood-brain barrier level. ii) In the human study, we observed significant negative associations under cabergoline for the C-carriers and heterozygous CT individuals of SNP rs1045642 with two central side effects (frequency of fatigue and sleep disorders) and for the G-carriers of SNP rs2032582 with the enhancement of dizziness. For the SNPs rs2235015 and rs2032583, no associations with central side effects under cabergoline were found. DISCUSSION: This is the first study demonstrating that individual ABCB1 gene polymorphisms, reflecting a different expression and function of the P-gp, could predict the occurrence of central side effects under cabergoline. Our findings can be viewed as a step into personalised therapy in PRL adenoma patients.

Distinct dopaminergic personality patterns in patients with prolactinomas: a comparison with nonfunctioning pituitary adenoma patients and age- and gender-matched controls.

INTRODUCTION: Personality patterns such as extraversion and novelty seeking have been associated with an altered dopaminergic activity in healthy subjects. Patients with prolactinomas have been described as exhibiting an altered dopaminergic tone and are often treated with dopamine agonists. Little is known about the personality traits of this patient group. Hence, we aimed at examining whether patients with prolactinomas exhibit modified personality patterns compared to patients with nonfunctioning pituitary adenomas and healthy controls. SUBJECTS/METHODS: In this cross-sectional study, 86 patients with prolactinomas and 58 patients with nonfunctioning pituitary adenomas (NFPA) were compared with 172 mentally healthy age- and gender-matched controls. To assess personality traits, standardized personality questionnaires (Eysenck personality questionnaire-EPQ-RK and Tridimensional Personality Questionnaire devised by Cloninger-TPQ) were administered. RESULTS: Patients with either prolactinomas or NFPA showed a distinct personality profile compared to the normal population, characterized by increased neuroticism and they also answered in a socially desirable mode. On harm-avoidant total and subscales, they presented with a higher fear of uncertainty and also increased fatigability and asthenia. The prolactinoma patients, when contrasted with the 'clinical' control group of patients with NFPA and after post hoc tests for multiple comparisons following the Bonferroni-Holm procedure showed significantly reduced extraversion (p = 0.044) and increased shyness with strangers (p = 0.044), tending to be more neurotic and present lower scores in the novelty seeking subscale impulsiveness. CONCLUSION: This is, to our knowledge, the first study providing new evidence of an altered personality profile of prolactinoma patients which might affect the patient-doctor relationship, treatment and patient's quality of life.

Risk factors associated with the metabolic syndrome in abdominal obesity.

Obesity is associated with the metabolic syndrome. However, not all obese individuals have cardiovascular risk factors (CVRF). It is not clear how many abdominally obese individuals are free of CVRF and what distinguishes them from the group of obese individuals with CVRF. In this study, we aimed to assess the associated factors and prevalence of abdominal obesity without CVRF. In our cross-sectional analysis, we included n = 4244 subjects from the Study of Health in Pomerania (SHIP), a population-based study and n = 6671 subjects from the Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment (DETECT) study, a representative primary care study in Germany. We defined abdominal obesity by waist-to-height ratio (WHtR) of 0.5 or greater. We assessed how many subjects with abdominal obesity had CVRF based on the definition of the metabolic syndrome. We analysed which conditions were associated with the absence of CVRF in abdominal obesity. In SHIP and DETECT, 2652 (62.5%) and 5126 (76.8%) subjects had a WHtR ≥ 0.5. Among those with a WHtR ≥ 0.5, 9.0% and 13.8% were free of CVRF and 49.9% and 52.7% had at least two CVRF in SHIP and DETECT, respectively. In both studies, after backward elimination, age, male sex, body mass index and high liver enzymes and unemployment were consistently inversely associated with the absence of CVRF. Among abdominally obese subjects, the prevalence of metabolically healthy subjects is low. Conditions consistently associated with the absence of CVRF in abdominal obesity are younger age, female sex, low BMI, and normal liver enzymes, the latter likely reflecting the absence of steatohepatitis.

A case of an acromegalic patient resistant to the recommended maximum GH receptor antagonist dosage.

BACKGROUND: The competitive GH receptor antagonist pegvisomant is reported to normalise IGF-1 levels in up to 97 % of acromegalic patients at a maximum dosage of 40 mg/d. Description of Case: We present an acromegalic patient resistant to the recommended maximum GH receptor antagonist dosage. The 60-year-old male patient presenting with typical clinical signs of acromegaly has underwent multiple transsphenoidal surgeries and pituitary irradiation, while currently available pharmacological therapies for acromegaly have been exhausted. RESULTS: Biochemical control of the disease could only be achieved until uptitration of pegvisomant to 60 mg/d which was tolerated well. CONCLUSIONS: The current treatment algorithm for acromegaly should be modified to treat cases of persistent and uncontrolled disease.

All-cause mortality and serum insulin-like growth factor I in primary care patients.

OBJECTIVE: Previous population-based studies provided conflicting results regarding the association of total serum insulin-like growth factor I (IGF-I) and mortality. The aim of the present study was to assess the relation of IGF-I levels with all-cause mortality in a prospective study. DESIGN: DETECT (Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment) is a large, multistage, and nationally representative study of primary care patients in Germany. The study population included 2463 men and 3603 women. Death rates were recorded by the respective primary care physician. Serum total IGF-I levels were determined by chemiluminescence immunoassays and categorized into three groups (low, moderate, and high) according to the sex- and age-specific 10th and 90th percentiles. RESULTS: Adjusted analyses revealed that men with low [hazard ratio (HR) 1.70 (95% confidence interval [CI] 1.05-2.73), p=0.03] and high [HR 1.76 (95% CI 1.09-2.85), p=0.02] IGF-I levels had higher risk of all-cause mortality compared to men with moderate IGF-I levels. The specificity of low IGF-I and high IGF-I levels increased with lower and higher cut-offs, respectively. No such association became apparent in women. CONCLUSIONS: The present study revealed a U-shaped relation between IGF-I and all-cause mortality in male primary care patients.

The acute effect of a single application of cabergoline on endogenous GH levels in patients with acromegaly on pegvisomant treatment.

OBJECTIVE: Treatment with pegvisomant, an antagonist of growth hormone (GH) receptors, increases GH levels in a dose dependent manner. Cabergoline can suppress GH secretion in approximately 40% of acromegalic patients. However, the acute effects of cabergoline have not been studied in patients treated with pegvisomant. We performed this cross-sectional study to evaluate endogenous GH after an additional single cabergoline administration. DESIGN: 9 acromegalic patients on pegvisomant therapy were included. A 6h GH profile after pegvisomant alone (P) and a 9h profile in combination with oral cabergoline 0.5mg (PC) were performed. After 3 or 6h, all patients received a standardized light mixed meal. Endogenous serum GH and pegvisomant levels were measured by special in-house assays. The GH assay showed no interference with pegvisomant. RESULTS: Endogenous GH levels at baseline did not differ significantly between the profiles (P: 16.5 µg/l (range 3.2-36.6 µg/l), PC: 8.0 µg/l (1.6-48 µg/l), p>0.05). In both profiles, GH fluctuated before meal. GH decreased more pronounced in PC but this decrease was not statistically significant. After meal, a significant decline in endogenous GH levels from 16.4 µg/l (0.4-27.1 µg/l, 100%) to 8.1 µg/l (0.2-24.7 µg/l, 66%) appeared in P at 300 min (p<0.01). Also in PC a decline from 7.8 µg/l (1.1-29.6 µg/l, 100%) to 5.2 µg/l (0.4-23.9 µg/l, 75%) at 300 min was observed but it was not significant. CONCLUSION: Endogenous GH is not significantly decreased after a single oral cabergoline application during pegvisomant treatment in acromegaly.

Adverse anthropometric risk profile in biochemically controlled acromegalic patients: comparison with an age- and gender-matched primary care population.

GH and IGF-1 play an important role in the regulation of metabolism and body composition. In patients with uncontrolled acromegaly, cardiovascular morbidity and mortality are increased but are supposed to be normalised after biochemical control is achieved. We aimed at comparing body composition and the cardiovascular risk profile in patients with controlled acromegaly and controls. A cross-sectional study. We evaluated anthropometric parameters (height, weight, body mass index (BMI), waist and hip circumference, waist to height ratio) and, additionally, cardiovascular risk biomarkers (fasting plasma glucose, HbA1c, triglycerides, total cholesterol, HDL, LDL, and lipoprotein (a), in 81 acromegalic patients (58% cured) compared to 320 age- and gender-matched controls (ratio 1:4), sampled from the primary care patient cohort DETECT. The whole group of 81 acromegalic patients presented with significantly higher anthropometric parameters, such as weight, BMI, waist and hip circumference, but with more favourable cardiovascular risk biomarkers, such as fasting plasma glucose, total cholesterol, triglycerides and HDL levels, in comparison to their respective controls. Biochemically controlled acromegalic patients again showed significantly higher measurements of obesity, mainly visceral adiposity, than age- and gender-matched control patients (BMI 29.5 +/- 5.9 vs. 27.3 +/- 5.8 kg/m(2); P = 0.020; waist circumference 100.9 +/- 16.8 vs. 94.8 +/- 15.5 cm; P = 0.031; hip circumference 110.7 +/- 9.9 vs. 105.0 +/- 11.7 cm; P = 0.001). No differences in the classical cardiovascular biomarkers were detected except for fasting plasma glucose and triglycerides. This effect could not be attributed to a higher prevalence of type 2 diabetes mellitus in the acromegalic patient group, since stratified analyses between the subgroup of patients with acromegaly and controls, both with type 2 diabetes mellitus, revealed that there were no significant differences in the anthropometric measurements. Biochemically cured acromegalic patients pertain an adverse anthropometric risk profile, mainly because of elevated adiposity measurements, such as BMI, waist and hip circumference, compared to an age- and gender-matched primary care population.

Macroscopic brain architecture changes and white matter pathology in acromegaly: a clinicoradiological study.

Although long-term exposure of the brain to increased GH/IGF-1 likely influences cerebral functions, no in vivo studies have been directed towards changes of the brain structure in acromegaly. Here, we used high resolution magnetic resonance images to compare volumes of gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) of forty-four patients with acromegaly to an age and gender matched, healthy control group (n = 44). In addition, white matter lesions (WMLs) were quantified and graded. Patients exhibited larger GM (+3.7% compared with controls, P = 0.018) and WM volumes (+5.1%, P = 0.035) at the expense of CSF. Differences of WML counts between patients and controls were subtle, however, showing more patients in the 21-40 lesions category (P = 0.044). In conclusion, this MRI study provides first evidence that acromegalic patients exhibit disturbances of the macroscopic brain tissue architecture. Furthermore, acromegalic patients may have an increased risk of neurovascular pathology, likely due to secondary metabolic and vascular comorbidities.

Is there a neuroendocrinological rationale for testosterone as a therapeutic option in depression?

Depression is a disease of growing incidence and economic burden worldwide. In view of increasing treatment resistance, new therapeutic approaches are urgently needed. In addition to its gonadal functions, testosterone has many effects on the central nervous system. An association between testosterone levels and depressive symptoms has been proposed. Many hormones and neurotransmitters are involved in the aetiology and the course of depression including serotonin, dopamine, noradrenaline, vasopressin and cortisol. Testosterone is known to interact with them. Preclinical data suggest that testosterone has antidepressant potential. However, the data from clinical studies have been inconsistent. This review provides a critical overview on the currently available preclinical and clinical literature and concludes with clinical recommendations.