One function of the glucocorticoid receptor (GR) in corticotroph cells is to suppress the transcription of the gene encoding proopiomelanocortin (POMC), the precursor of the stress hormone ...adrenocorticotropin (ACTH). Cushing disease is a neuroendocrine condition caused by partially glucocorticoid-resistant corticotroph adenomas that excessively secrete ACTH, which leads to hypercortisolism. Mutations that impair GR function explain glucocorticoid resistance only in sporadic cases. However, the proper folding of GR depends on direct interactions with the chaperone heat shock protein 90 (HSP90, refs. 7,8). We show here that corticotroph adenomas overexpress HSP90 compared to the normal pituitary. N- and C-terminal HSP90 inhibitors act at different steps of the HSP90 catalytic cycle to regulate corticotroph cell proliferation and GR transcriptional activity. C-terminal inhibitors cause the release of mature GR from HSP90, which promotes its exit from the chaperone cycle and potentiates its transcriptional activity in a corticotroph cell line and in primary cultures of human corticotroph adenomas. In an allograft mouse model, the C-terminal HSP90 inhibitor silibinin showed anti-tumorigenic effects, partially reverted hormonal alterations, and alleviated symptoms of Cushing disease. These results suggest that the pathogenesis of Cushing disease caused by overexpression of heat shock proteins and consequently misregulated GR sensitivity may be overcome pharmacologically with an appropriate HSP90 inhibitor.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Sexual orientation is usually considered to be determined in early life and stable in the course of adulthood. In contrast, some transgender individuals report a change in sexual orientation. A ...common reason for this phenomenon is not known.
We included 115 transsexual persons (70 male-to-female "MtF" and 45 female-to-male "FtM") patients from our endocrine outpatient clinic, who completed a questionnaire, retrospectively evaluating the history of their gender transition phase. The questionnaire focused on sexual orientation and recalled time points of changes in sexual orientation in the context of transition. Participants were further asked to provide a personal concept for a potential change in sexual orientation.
In total, 32.9% (n = 23) MtF reported a change in sexual orientation in contrast to 22.2% (n = 10) FtM transsexual persons (p = 0.132). Out of these patients, 39.1% (MtF) and 60% (FtM) reported a change in sexual orientation before having undergone any sex reassignment surgery. FtM that had initially been sexually oriented towards males ( = androphilic), were significantly more likely to report on a change in sexual orientation than gynephilic, analloerotic or bisexual FtM (p = 0.012). Similarly, gynephilic MtF reported a change in sexual orientation more frequently than androphilic, analloerotic or bisexual MtF transsexual persons (p =0.05).
In line with earlier reports, we reveal that a change in self-reported sexual orientation is frequent and does not solely occur in the context of particular transition events. Transsexual persons that are attracted by individuals of the opposite biological sex are more likely to change sexual orientation. Qualitative reports suggest that the individual's biography, autogynephilic and autoandrophilic sexual arousal, confusion before and after transitioning, social and self-acceptance, as well as concept of sexual orientation itself may explain this phenomenon.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights • Somatostatin is a wide-range antisecretory peptide that binds to five receptors (SSTR1–5). • SSTR1, 2, 3 and 5 exert their antiproliferative actions and SSTR4 its pro-proliferative ...action through unique pathways. • SSTR2 targeting sensitizes tumor cells to antitumor activity of mammalian target of rapamycin (mTOR) inhibitors. • Co-targeting of SSTR1, 2, 3 and 5 and dopamine receptor type 2 (D2DR) yields potent therapeutic outcomes. • SSTR signaling factors are putative biomarkers of somatostatin analog response.
Abstract
Context
First-generation somatostatin receptor ligands (fg-SRLs) represent the mainstay of medical therapy for acromegaly, but they provide biochemical control of disease in only a subset of ...patients. Various pretreatment biomarkers might affect biochemical response to fg-SRLs.
Objective
To identify clinical predictors of the biochemical response to fg-SRLs monotherapy defined as biochemical response (insulin-like growth factor (IGF)-1 ≤ 1.3 × ULN (upper limit of normal)), partial response (>20% relative IGF-1 reduction without normalization), and nonresponse (≤20% relative IGF-1 reduction), and IGF-1 reduction.
Design
Retrospective multicenter study.
Setting
Eight participating European centers.
Methods
We performed a meta-analysis of participant data from 2 cohorts (Rotterdam and Liège acromegaly survey, 622 out of 3520 patients). Multivariable regression models were used to identify predictors of biochemical response to fg-SRL monotherapy.
Results
Lower IGF-1 concentration at baseline (odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.72–0.95 IGF-1 ULN, P = .0073) and lower bodyweight (OR = 0.99, 95% CI 0.98–0.99 kg, P = .038) were associated with biochemical response. Higher IGF-1 concentration at baseline (OR = 1.40, (1.19–1.65) IGF-1 ULN, P ≤ .0001), the presence of type 2 diabetes (oral medication OR = 2.48, (1.43–4.29), P = .0013; insulin therapy OR = 2.65, (1.02–6.70), P = .045), and higher bodyweight (OR = 1.02, (1.01–1.04) kg, P = .0023) were associated with achieving partial response. Younger patients at diagnosis are more likely to achieve nonresponse (OR = 0.96, (0.94–0.99) year, P = .0070). Baseline IGF-1 and growth hormone concentration at diagnosis were associated with absolute IGF-1 reduction (β = 0.90, standard error (SE) = 0.02, P ≤ .0001 and β = 0.002, SE = 0.001, P = .014, respectively).
Conclusion
Baseline IGF-1 concentration was the best predictor of biochemical response to fg-SRL, followed by bodyweight, while younger patients were more likely to achieve nonresponse.
Summary
Objective
There is a paucity of studies on adherence to growth hormone treatment in growth hormone deficient (GHD) adults. Therefore, this study reports on adherence to GH‐replacement therapy ...in adults with GHD, with a special focus on the course and potential predictors of nonadherence.
Design
Retrospective single‐centre cohort study.
Patients
From the local patient database, 179 suitable patients with GHD were identified.
Measurements
The primary outcome was adherence assessed by calculating the percentage of available prescription data in comparison with recommended GH dosages over a mean follow‐up period of 92·4 months. Patients were categorized into five adherence categories ranging from <20% to >80%.
Results
Mean overall adherence was 74·0%, with 52·9% of patients falling into the adherence group of >80% and 8·8% of <20%. There was a significant drop in adherence (9·8%) between the first and second years of treatment (P < 0·001). Patients with childhood‐onset GHD were significantly less adherent to GH treatment than patients with adult‐onset GHD (62·0% vs 77·0%, P = 0·012); however, this finding was no longer significant after including age as a covariate. Frequency of IGF‐1 levels lying outside the age‐ and sex‐specific reference range was not a good indicator for adherence.
Conclusion
Although overall adherence was relatively high in our study sample, there is a significant amount of patients who should be regarded as nonadherent. This applies in particular to younger patients. Treating physicians should be aware of the fact that IGF‐1 levels do not seem to be a good indicator for adherence.
Somatostatin limits cell growth by inhibiting the proliferative activity of growth factor receptors. In this study, it is shown that in pituitary tumor cells, the somatostatin analogue octreotide ...produces its antiproliferative action by inducing the expression the tumor suppressor gene Zac1. ZAC/Zac1 induces cell cycle arrest and apoptosis and is highly expressed in normal pituitary, mammary, and ovarian glands but is down-regulated in pituitary, breast, and ovarian tumors. Knocking down Zac1 by RNA interference abolished the antiproliferative effect of octreotide in pituitary tumor cells, indicating that Zac1 is necessary for the action of octreotide. The effect of octreotide on Zac1 expression was pertussis toxin sensitive and was abolished after transfection with a dominant negative vector for SHP-1. Zac1 is a target of the phosphatidylinositol 3-kinase (PI3K) survival pathway. Octreotide treatment decreased the tyrosine phosphorylation levels of the PI3K regulatory subunit p85, induced dephosphorylation of phosphoinositide-dependent kinase 1 (PDK1) and Akt, and activated glycogen synthase kinase 3beta (GSKbeta). Therefore, in pituitary tumor cells, somatostatin analogues produce their antiproliferative action by acting on the PI3K/Akt signaling pathway and increasing Zac1 gene expression.
The anterior pituitary gland has the ability to respond to complex signals derived from central and peripheral systems. Perception of these signals and their integration are mediated by cell ...interactions and cross-talk of multiple signaling transduction pathways and transcriptional regulatory networks that cooperate for hormone secretion, cell plasticity, and ultimately specific pituitary responses that are essential for an appropriate physiological response. We discuss the physiopathological and molecular mechanisms related to this integrative regulatory system of the anterior pituitary gland and how it contributes to modulate the gland functions and impacts on body homeostasis.
Context:
The delay between onset of first symptoms and diagnosis of the acromegaly is 6–10 yr. Acromegaly causes typical changes of the face that might be recognized by face classification software.
...Objective:
The objective of the study was to assess classification accuracy of acromegaly by face-classification software.
Design:
This was a diagnostic study.
Setting:
The study was conducted in specialized care.
Participants:
Participants in the study included 57 patients with acromegaly (29 women, 28 men) and 60 sex- and age-matched controls.
Interventions:
We took frontal and side photographs of the faces and grouped patients into subjects with mild, moderate, and severe facial features of acromegaly by overall impression. We then analyzed all pictures using computerized similarity analysis based on Gabor jets and geometry functions. We used the leave-one-out cross-validation method to classify subjects by the software. Additionally, all subjects were classified by visual impression by three acromegaly experts and three general internists.
Main Outcome Measure:
Classification accuracy by software, experts, and internists was measured.
Findings:
The software correctly classified 71.9% of patients and 91.5% of controls. Classification accuracy for patients by visual analysis was 63.2 and 42.1% by experts and general internists, respectively. Classification accuracy for controls was 80.8 and 87.0% by experts and internists, respectively. The highest differences in accuracy between software and experts and internists were present for patients with mild acromegaly.
Conclusions:
Acromegaly can be detected by computer software using photographs of the face. Classification accuracy by software is higher than by medical experts or general internists, particularly in patients with mild features of acromegaly. This is a promising tool to help detecting acromegaly.
Context: To date, it is unclear which measure of obesity is the most appropriate for risk stratification.
Objective: The aim of the study was to compare the associations of various measures of ...obesity with incident cardiovascular events and mortality.
Design and Setting: We analyzed two German cohort studies, the DETECT study and SHIP, including primary care and general population.
Participants: A total of 6355 (mean follow-up, 3.3 yr) and 4297 (mean follow-up, 8.5 yr) individuals participated in DETECT and SHIP, respectively.
Interventions: We measured body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), and waist-to-hip ratio (WHR) and assessed cardiovascular and all-cause mortality and the composite endpoint of incident stroke, myocardial infarction, or cardiovascular death.
Results: In both studies, we found a positive association of the composite endpoint with WHtR but not with BMI. There was no heterogeneity among studies. The relative risks in the highest versus the lowest sex- and age-specific quartile of WHtR, WC, WHR, and BMI after adjustment for multiple confounders were as follows in the pooled data: cardiovascular mortality, 2.75 (95% confidence interval, 1.31–5.77), 1.74 (0.84–3.6), 1.71 (0.91–3.22), and 0.74 (0.35–1.57), respectively; all-cause mortality, 1.86 (1.25–2.76), 1.62 (1.22–2.38), 1.36 (0.93–1.69), and 0.77 (0.53–1.13), respectively; and composite endpoint, 2.16 (1.39–3.35), 1.59 (1.04–2.44), 1.49 (1.07–2.07), and 0.57 (0.37–0.89), respectively. Separate analyses of sex and age groups yielded comparable results. Receiver operating characteristics analysis yielded the highest areas under the curve for WHtR for predicting these endpoints.
Conclusions: WHtR represents the best predictor of cardiovascular risk and mortality, followed by WC and WHR. Our results discourage the use of the BMI.
Measures of abdominal obesity but not body mass index predict cardiovascular risk and mortality.
Previous experimental research on testosterone (T) and psychological traits is inconclusive. Thus, we performed the first large-scale observational study of the association between T and ...dispositional optimism / pessimism. We used prospective data from 6,493 primary-care patients (3,840 women) of the DETECT study (Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment), including repeated immunoassay-based measurement of serum T and optimism / pessimism assessed by the revised Life-Orientation Test (LOT-R). Cross-sectional and longitudinal associations of baseline T and one-year change in T with optimism and pessimism were investigated using age- and multivariable-adjusted regression models. Cross-sectional analyses showed no association of T with optimism or pessimism in both sexes. Longitudinal analyses also showed no association of baseline T with optimism or pessimism at four-year follow-up. Multivariable analyses of total LOT-R score yielded similarly non-significant results (beta-coefficient per unit change in T for men: -0.01 (95% CI: -0.24-0.22), women: 0.08 (-0.03-0.20)). Furthermore, change in T was not related to optimism or pessimism at four-year follow-up. The present observational study of a large-scale prospective sample showed no association of T with optimism or pessimism. Integrating further experimental and interventional evidence from alternative methodological approaches would strengthen this conclusion and establish stronger evidence about the potential hormonal basis of psychological traits.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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