Acromegaly is a rare disorder caused by chronic growth hormone (GH) hypersecretion. While diagnostic and therapeutic methods have advanced, little information exists on trends in acromegaly ...characteristics over time. The
, a relational database, is designed to assess the profile of acromegaly patients at diagnosis and during long-term follow-up at multiple treatment centers. The following results were obtained at diagnosis. The study population consisted of 3173 acromegaly patients from ten countries; 54.5% were female. Males were significantly younger at diagnosis than females (43.5 vs 46.4 years;
< 0.001). The median delay from first symptoms to diagnosis was 2 years longer in females (
= 0.015). Ages at diagnosis and first symptoms increased significantly over time (
< 0.001). Tumors were larger in males than females (
< 0.001); tumor size and invasion were inversely related to patient age (
< 0.001). Random GH at diagnosis correlated with nadir GH levels during OGTT (
< 0.001). GH was inversely related to age in both sexes (
< 0.001). Diabetes mellitus was present in 27.5%, hypertension in 28.8%, sleep apnea syndrome in 25.5% and cardiac hypertrophy in 15.5%. Serious cardiovascular outcomes like stroke, heart failure and myocardial infarction were present in <5% at diagnosis. Erythrocyte levels were increased and correlated with IGF-1 values. Thyroid nodules were frequent (34.0%); 820 patients had colonoscopy at diagnosis and 13% had polyps. Osteoporosis was present at diagnosis in 12.3% and 0.6-4.4% had experienced a fracture. In conclusion, this study of >3100 patients is the largest international acromegaly database and shows clinically relevant trends in the characteristics of acromegaly at diagnosis.
Summary
Objective The estimated prevalence of acromegaly is 40–125 per million. The diagnosis of acromegaly is often delayed due to deficits in recognizing the signs of the disease. It is not known ...how many subjects with increased IGF‐1 levels have acromegaly. We aimed to assess the prevalence of acromegaly in primary care by screening for elevated IGF‐1 levels.
Design A cross‐sectional, epidemiological study (the DETECT study).
Patients A total of 6773 unselected adult primary care patients were included.
Measurements We measured IGF‐1 in all patients and recommended further endocrine evaluation in all patients with elevated IGF‐1 levels (> 2 age‐dependent SDS).
Results Of 125 patients with elevated IGF‐1 levels, 76 patients had indeterminate results and acromegaly could be excluded in 42 patients. One patient had known florid acromegaly. Two patients had newly diagnosed acromegaly and pituitary adenomas. Four patients had biochemical acromegaly but refused further diagnostics. This corresponds to a prevalence of 1034 per million patients.
Conclusions Our study shows a high prevalence of undiagnosed acromegaly in primary care. These results imply that acromegaly is underdiagnosed and stress the importance of detecting acromegaly.
Male hypogonadism is characterized by abnormally low serum testosterone levels associated with typical symptoms, including mood disturbance, sexual dysfunction, decreased muscle mass and strength, ...and decreased bone mineral density. By restoring serum testosterone levels to the normal range using testosterone replacement therapy, many of these symptoms can be relieved. For many years, injectable testosterone esters or surgically implanted testosterone pellets have been the preferred treatment for male hypogonadism. Recently, newer treatment modalities have been introduced, including transdermal patches and gels. The development of a mucoadhesive sustained-release buccal tablet is the latest innovation, which will provide patients with an additional option. The availability of new treatment modalities has helped to renew interest in the management of male hypogonadism, highlighting the need to address a number of important but previously neglected questions in testosterone replacement therapy. These include the risks and benefits of treatment in different patient populations (e.g. the elderly) and the need for evidence-based diagnosis and treatment monitoring guidelines. While some recommendations have been developed in individual countries, up-to-date, internationally accepted evidence-based guidelines that take into account national differences in clinical practice and healthcare delivery would optimize patient care universally.
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.
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).
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).
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.
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.
Cushing syndrome is caused by an excess of adrenocorticotropic hormone (ACTH) production by neuroendocrine tumors, which subsequently results in chronic glucocorticoid excess. We found that retinoic ...acid inhibits the transcriptional activity of AP-1 and the orphan receptors Nur77 and Nurr1 in ACTH-secreting tumor cells. Retinoic acid treatment resulted in reduced pro-opiomelanocortin transcription and ACTH production. ACTH inhibition was also observed in human pituitary ACTH-secreting tumor cells and a small-cell lung cancer cell line, but not in normal cells. This correlated with the expression of the orphan receptor COUP-TFI, which was found in normal corticotrophs but not in pituitary Cushing tumors. COUP-TFI expression in ACTH-secreting tumor cells blocked retinoic acid action. Retinoic acid also inhibited cell proliferation and, after prolonged treatment, increased caspase-3 activity and induced cell death in ACTH-secreting cells. In adrenal cortex cells, retinoic acid inhibited corticosterone production and cell proliferation. The antiproliferative action and the inhibition of ACTH and corticosterone produced by retinoic acid were confirmed in vivo in experimental ACTH-secreting tumors in nude mice. Thus, we conclude that the effects of retinoic acid combine in vivo to reverse the endocrine alterations and symptoms observed in experimental Cushing syndrome.
Summary
Background Several studies have reported a high prevalence of hypopituitarism after traumatic brain injury (TBI). Risk stratification is a prerequisite for cost‐effective hormonal screening ...of these patients. However, it is still unclear which risk factors predispose patients to develop anterior hypopituitarism after TBI.
Objective To assess clinical and radiological risk factors for post‐traumatic hypopituitarism.
Patients and methods Seventy‐eight consecutive patients (52 men, 26 women; mean age 36·0 years, range 18–65 years) with mild, moderate or severe TBI were studied. Endocrine and clinical parameters were assessed 3 and 12 months after TBI.
Results We found diffuse axonal injury, basal skull fracture and older age to be major risk factors of post‐traumatic hypopituitarism.
Conclusions We have defined specific risk factors for the development of post‐traumatic hypopituitarism that are consistent with pathophysiological considerations. These findings might help to identify at‐risk patients.
Somatic mutations or loss of von Hippel-Lindau (pVHL) happen in the majority of VHL disease tumors, which present a constitutively active Hypoxia Inducible Factor (HIF), essential for tumor growth. ...Recently described mechanisms for pVHL modulation shed light on the open question of the HIF/pVHL pathway regulation. The aim of the present study was to determine the molecular mechanism by which RSUME stabilizes HIFs, by studying RSUME effect on pVHL function and to determine the role of RSUME on pVHL-related tumor progression. We determined that RSUME sumoylates and physically interacts with pVHL and negatively regulates the assembly of the complex between pVHL, Elongins and Cullins (ECV), inhibiting HIF-1 and 2α ubiquitination and degradation. We found that RSUME is expressed in human VHL tumors (renal clear-cell carcinoma (RCC), pheochromocytoma and hemangioblastoma) and by overexpressing or silencing RSUME in a pVHL-HIF-oxygen-dependent degradation stability reporter assay, we determined that RSUME is necessary for the loss of function of type 2 pVHL mutants. The functional RSUME/pVHL interaction in VHL-related tumor progression was further confirmed using a xenograft assay in nude mice. RCC clones, in which RSUME was knocked down and express either pVHL wt or type 2 mutation, have an impaired tumor growth, as well as HIF-2α, vascular endothelial growth factor A and tumor vascularization diminution. This work shows a novel mechanism for VHL tumor progression and presents a new mechanism and factor for targeting tumor-related pathologies with pVHL/HIF altered function.
Abstract
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.
The German ACROSTUDY: past and present Buchfelder, M; Schlaffer, S; Droste, M ...
European Journal of Endocrinology,
11/2009, Letnik:
161 Suppl 1
Journal Article
Recenzirano
Odprti dostop
Pivotal studies have demonstrated that pharmacotherapy with pegvisomant (Somavert) is a highly effective treatment for acromegaly. Since clinical experience with the drug was very limited, the ...Pegvisomant Observational Study was launched in Germany immediately with the drug becoming commercially available to patients early in 2004. Its purpose was to record safety and efficacy data on as many patients as possible. As of 12th August 2008 a total of 371 patients (185 males, 186 females) had been included in the study. They were on pegvisomant therapy for an average of 118 weeks. Median and mean doses of pegvisomant were 15 and 16.4 mg/day respectively. Treatment efficacy was monitored by IGF1 levels and the patients symptoms were evaluated by completion of a questionnaire (patient-assessed acromegaly symptom questionnaire). Safety data included liver function tests, fasting glucose, HbA1c measurements, and tumor size monitoring by repeated magnetic resonance imaging. Normalization of IGF1 ranged from 55.7% of the 273 patients assessed after 6 months to 71.3% of 202 patients assessed after 24 months of treatment. It was 70.7% after 36 months (133 patients), 64.8% at 48 months (71 patients), and 58.4% after 60 months (24 patients). In 39 patients (10.9%) treatment was discontinued due to serious adverse events or adverse events with 25 (6.7%) of these patients having a potential causal relationship with the pegvisomant treatment. Liver function tests became abnormal in 20 patients and another three patients were recorded to have hepatobiliary disorders. Tumor size increase was reported in 20 patients, but only confirmed in nine patients by careful revision of all available images. Local injection site reactions were observed in 12 patients. In conclusion, in this large group of pegvisomant-treated patients, long-term data for up to 5 years of treatment are now available. In 71.3% of patients with previously not sufficiently treatable acromegaly, IGF1 levels were normalized by pegvisomant therapy. Elevated transaminases usually normalized after discontinuation but in half of the affected patients also despite continuation of treatment without dose alteration. Tumor progression was a rare event. It did not exceed the expected rate in patients with acromegaly not treated with pegvisomant. As from this presently largest database of acromegalic patients treated with pegvisomant, long-term results are encouraging. The German data are now merged into the global ACROSTUDY and will constitute a major portion of the international ACROSTUDY project as a continuing global web-based observational study.
Abstract 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.
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