Sonja Siegel

Diagnostic delay is associated with psychosocial impairment in acromegaly

The aim of this study was to systematically assess health care utilisation, diagnostic delay and psychosocial impairment in patients with acromegaly in rural versus urban health care environments. 41 patients with acromegaly were questioned to time lapse of symptom onset, first seeking medical advice and time of acromegaly diagnosis. Quality of life (QoL), and psychosocial impairment (depression, daytime sleepiness, sleep disturbances, disturbances of body image) were measured by self-assessment questionnaires. Patients were grouped into living in rural health care environments (RHCE, nxa0=xa022 patients) or urban health care environments (UHCE, nxa0=xa019 patients) using data on population density from the German Federal Statistical Office. RHCE patients waited significantly longer (2.5 vs. 0.89xa0years; pxa0=xa0.025) after symptom onset before seeking medical advice, but diagnosis of acromegaly was established at least as quickly as in UHCE (1.45 vs. 2.74xa0years; n.s.). There was a consistent trend toward more psychosocial impairment in UHCE which reached significance for sleep disturbances (pxa0=xa0.004). For all patients significant correlations between time delay of diagnostic process (defined as first visit to the doctor because of acromegaly-related symptoms and establishment of acromegaly diagnosis) and psychological QoL, depression, daytime sleepiness, sleep disorders and body image emerged. Patients with acromegaly in UHCE experienced more psychosocial impairment than patients in RHCE. The correlation of significantly increased psychosocial impairment and delay of diagnosis by the physician may reflect long-lasting embitterment in patients with acromegaly and should be considered during psychosocial counselling.

From first symptoms to final diagnosis of Cushing's disease: experiences of 176 patients

OBJECTIVEnTo obtain structured information on the diagnostic delay in patients with Cushings disease (CD) from the patients perspective to provide leverage points for earlier diagnosis.nnnDESIGNnThe study includes 176 patients with ACTH-dependent CD who had received pituitary surgery completed a self-developed questionnaire on their symptomatology before the illness was diagnosed, the course and length of the diagnostic process, and the role of the involved health care professionals.nnnMETHODSnData were analyzed statistically. Answers in free text options were categorized and counted.nnnRESULTSnThe overall diagnostic process took 3.8±4.8 years (median 2 years), during which 4.6±3.8 (1-30) physicians were consulted, most frequently the family physician (FP; 83.0%). The presented symptoms were various and often vague, e.g. poor general condition (at FPs), or very common in the field of the visited specialist (i.e. skin changes at dermatologists). Women recognized the first CD symptoms themselves significantly more frequently than men, whereas physicians recognized CD symptoms significantly more frequently in males.nnnCONCLUSIONnA clear difficulty of diagnosing CD seems that patients describe isolated symptoms to the FP or the respective specialists according to their fields of specialization. As FPs are contacted most frequently, they should be trained to recognize the broad spectrum of CD symptoms, especially in female patients with weight gain, and initiate endocrinological referral.

Validation of the Tuebingen CD-25 Inventory as a Measure of Postoperative Health-Related Quality of Life in Patients Treated for Cushing's Disease

Background: To evaluate the construct and criterion validity of the Tuebingen Cushings disease quality of life inventory (Tuebingen CD-25) for application in patients treated for Cushings disease (CD). Methods: A total of 176 patients with adrenocorticotropin hormone-dependent CD (144 of them female, overall mean age 46.1 ± 13.7 years) treated at 3 large tertiary referral centers in Germany were studied. Construct validity was assessed by hypothesis testing (self-perceived symptom reduction assessment) and contrasted groups (patients with vs. without hypercorticolism). For this purpose, already existing data from 55 CD patients was used, representing the hypercortisolemic group. Criterion validity (concurrent validity) was assessed in relation to the Cushings quality of life questionnaire (CushingQoL), the Short Form 36 health survey (SF-36), and the body mass index (BMI). Results: Patients with self-perceived remarkable symptom reduction had significant lower Tuebingen CD-25 scores (i.e. better health-related quality of life) than patients with self-perceived insufficient symptom reduction (p < 0.05). Similarly, the mean scores of the Tuebingen CD-25 scales were lower in patients without hypercortisolism (total score 27.0 ± 17.2) compared to those with hypercortisolism (total score 45.3 ± 22.1; each p < 0.05), providing evidence for construct validity. Criterion validity was confirmed by the correlations between the Tuebingen CD-25 total score and the CushingQoL (Spearmans coefficient -0.733), as well as all scales of the SF-36 (Spearmans coefficient between -0.447 and -0.700). Conclusion: The analyses presented in this large-sample study provide robust evidence for the construct and criterion validity of the Tuebingen CD-25.

Variation of the baseline characteristics and treatment parameters over time: an analysis of 15 years of growth hormone replacement in adults in the German KIMS database

The purpose of this study is to examine potential implications of changes in the approach to adult growth hormone (GH) replacement (GHR) over the last 15 years. Therefore, we analysed the German KIMS database as one of the largest single country pharmacoepidemiological databases on adult GH deficiency (GHD). Based on the date of their first GH application patients were assigned to three intervals (1995–1999, 2000–2004, 2005–2009). A multivariate analysis of variance with interval and sex as independent variables was conducted. Differences were analysed with respect to IGF-I standard deviation score (SDS), quality of life, latency between GHD diagnosis and first GH dose, body mass index, waist–hip ratio, lipid profile, and GH dose. All analyses were conducted at baseline, 1xa0year, and 3xa0years of GHR. We detected significant associations between time interval and patient characteristics at baseline and with treatment effects. Recently, patients with less severe GHD (mean IGF-I SDS: −2.1, −1.6, −1.0 in the 1st, 2nd and 3rd interval; pxa0=xa00.000) are treated with lower GH starting doses (mean 0.30, 0.19, 0.21xa0mg/day in the 1st, 2nd and 3rd interval; pxa0=xa00.000). In the first time interval, IGF-I SDS was not normalized in females after 3xa0years of GHR. The results of our analysis demonstrate prominent changes in patient characteristics and handling of GHR. They highlight that approach to therapy and patient inclusion criteria change over time and may represent an important confounder for any analysis in epidemiological surveillance surveys.

PREDICTORS OF QUALITY OF LIFE IN 165 PATIENTS WITH ACROMEGALY: RESULTS FROM A SINGLE-CENTER STUDY

OBJECTIVEnEven if treated, acromegaly has a considerable impact on patient quality of life (QoL); despite this, the exact clinical determinants of QoL in acromegaly are unknown. This study retrospectively examines a cohort of treated patients with acromegaly, with the aim of identifying these determinants.nnnMETHODSnRetrospective survey analysis, with 165 patients included in the study. All patients completed a survey, which included demographic data and the clinical details of their disease, the Short Form-36 Health Survey (SF-36), the revised Beck Depression Inventory (BDI-II), and the Bern Embitterment Inventory (BEI). Stepwise regression was used to identify predictors of QoL.nnnRESULTSnThe strongest predictors of the physical component score of the SF-36 were (in order of declining strength of association): Delay between first presentation of the disease and diagnosis, body mass index (BMI), number of doctors visited before the diagnosis of acromegaly, and age at diagnosis. For the mental component score, the strongest predictors were: number of doctors visited, previous radiotherapy, and age at study entry; and, for the BDI-II score: number of doctors visited, previous radiotherapy, age at study entry, and employment status at the time of diagnosis. The following were predictors of the BEI score: number of doctors visited, and age at study entry.nnnCONCLUSIONnDiagnostic delay and lack of diagnostic acumen in medical care provision are strong predictors of poor QoL in patients with acromegaly. Other identified parameters are radiotherapy, age, BMI, and employment status. An efficient acromegaly service should address these aspects when devising disease management plans.nnnABBREVIATIONSnBDI-II = Beck Depression Inventory II BEI = Bern Embitterment Inventory BMI = body mass index IGF-1 = insulin-like growth factor 1 MCS = mental component summary (score) PCS = physical component summary (score) QoL = quality of life SDS = standard deviation score SF-36 = Short Form-36 Health Survey.

Coping strategies have a strong impact on quality of life, depression, and embitterment in patients with Cushing’s disease

PurposeQuality of life (QoL) and psychosocial well-being are substantially impaired in patients with Cushing’s disease (CD), not only at the acute illness stage but also after therapy; however, the reason for these impairments remains unclear.MethodsIn this cross-sectional, patient-reported outcome study, we conducted a postal survey on psychosocial impairment and coping strategies in patients after surgical treatment of CD in three large tertiary referral centers. In total, 176 patients with CD completed a compilation of self-assessment inventories pertaining to depression (Hospital Anxiety and Depression Scale, HADS), QoL (Short Form SF-36, Tuebingen CD; Tuebingen CD-25), coping style (Freiburg questionnaire on coping with illness, FKV-LIS), and embitterment (Bern Embitterment Inventory), on average 6.8xa0±xa06.66xa0years after surgery. Regression analyses were performed to identify predictors of psychosocial impairment.ResultsAt the time of the study, 21.8xa0% of patients suffered from anxiety, 18.7xa0% experienced an above-average feeling of embitterment, and 13.1xa0% suffered from depression. Maladaptive coping styles (FKV-LIS subscales depressive coping and minimizing importance) emerged as robust and strong predictors of psychosocial impairment in all inventories; while age, sex, and hydrocortisone intake failed to explain the variance in these measures.ConclusionSimilar to several studies in non-pituitary patient cohorts (e.g., patients with multiple sclerosis or lower back pain), our results indicate that psychosocial impairment in CD is significantly influenced by how the patient deals with the illness. Therefore, psychological training of positive coping styles could be a helpful complementary therapy in the overall treatment strategy of CD.

EZH2 is highly expressed in pituitary adenomas and associated with proliferation

Enhancer of zeste homolog 2 (EZH2) is a core epigenetic regulator, playing a crucial role in cell cycle regulation. The protein is known to be associated with proliferation and worse outcome in several tumor entities. In this study, we immunohistochemically investigated the expression pattern of EZH2 in a large cohort of pituitary tumors. These results were correlated with clinical features and double immunofluorescence stainings (DIS) were conducted to evaluate co-expression of EZH2 and proliferation marker Ki-67. Furthermore, we analyzed the effect of EZH2 inhibition on cell proliferation in vitro using the pituitary cell line AtT-20. While in the normal anterior pituitary EZH2 was almost absent, the cohort of tumors showed enhanced expression levels (pu2009≤u20090.0005). This was positively associated with Ki-67 indices (ru2009=u20090.834, pu2009≤u20090.0005) and DIF confirmed a predominant co-expression of both markers. In vitro experiments revealed a significant (pu2009≤u20090.05) decrease of tumor cell proliferation using the EZH2 inhibitor GSK126. Our results further support that epigenetic events are involved in the pathogenesis and biology of pituitary adenomas (PA). Therefore, EZH2 may function as a new potential target for therapeutic interventions in PA.

Expression pattern of neuronal intermediate filament α-internexin in anterior pituitary gland and related tumors

Purposeα-Internexin (INA) is a class IV neuronal intermediate filament protein that maintains the morphogenesis of neurons. It is expressed in developing neuroblasts and represents the major component of the cytoskeleton in cerebellar granule cells of adult central nervous system tissue. Data concerning INA expression in the human frontal pituitary lobe and related adenomas (PA) is missing.MethodsUsing immunohistochemistry we examined the distribution pattern of INA in a large cohort of 152 PA, 11 atypical PA, 4 pituitary carcinomas and 20 normal pituitaries (overall nxa0=xa0187). Quantity of INA protein expression was semi-quantitatively evaluated and grouped into five categories (0xa0=xa00xa0%; 1xa0=xa0>0–5xa0%; 2xa0=xa0>5–35xa0%; 3xa0=xa0>35–80xa0%; 4xa0=xa0>80xa0% of cells).ResultsCellular staining intensity of INA appeared significantly higher in gonadotropinomas (Go, nxa0=xa062), null cell adenomas (NC, nxa0=xa07) and thyrotropinomas (TSHomas, nxa0=xa07) compared to the other tumor subtypes (pxa0≤xa00.001). Furthermore, Go and NC showed a peculiar pseudorosette-like staining pattern surrounding blood vessels in 85.5xa0% (59/69) of cases. Interestingly, areas exhibiting homogenous INA staining were often associated with oncocytic cell changes and decreased immunohistochemically detectable hormone expression. Only 8.5xa0% (8/94) of other PA showed a comparable INA distribution (pxa0≤xa00.001).ConclusionGo, NC as well as TSHomas exhibit high levels of intracellular INA protein indicating neuronal transdifferentiation. A possible impact on pathogenesis and endocrine activity needs further investigation.

Oro-dental pathologies in acromegaly

PurposeOro-dental pathologies (ODP) such as enlargement of the tongue, mandibular prognathism, and spaced teeth are characteristic features of acromegaly. Their frequency of occurrence during the course of the disease is largely unresolved. Purpose of this study was to assess ODP and oro-dental treatments in patients with acromegaly with regard to the length of the diagnostic process, tumor histology, and quality of life (QoL).MethodsSingle-center retrospective survey study using questionnaires on dental symptoms, diagnostic process, and treatment in patients with acromegaly operated on a growth hormone-secreting pituitary adenoma. The association between ODP and QoL was assessed using the Short-Form 36 (SF-36) Health Survey.Results145/314 patients completed the questionnaires. 80.7% were affected by any ODP, most frequently enlargement of the tongue (57.9%), spaced teeth (42.8%), mandibular growth (24.1%), and mandibular prognathism (22.1%). ODP were significantly more frequent in patients with sparsely vs. densely granulated adenomas (pu2009=u20090.045). Early diagnosis within 2 years was associated with significantly fewer ODP than later diagnosis (68.5 vs. 87.2%, pu2009=u20090.009). Treatments included dental crowns (16.6%), dental bridges (12.4%), dental implants (9.7%), dental prostheses (3.4%), orthodontal (i.e., braces, 6.9%), and surgical correction of the teeth (2.1%). Physical QoL was significantly lower in patients with ODP than in those without (pu2009=u20090.014).ConclusionIn our large series of patients, four of five patients were affected by ODP at any time during the course of the disease. The results highlight the importance of early identification and treatment of oro-dental problems in patients with acromegaly as hallmarks of the disease.