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Open access

Xinlei Chen, Liru Hu, Caojie Liu, Guangcheng Ni and Yuwei Zhang

Objective: The proportion of incidentally discovered pheochromocytomas and paragangliomas(PPGL) has increased over time. However, our knowledge of them is quite limited. The purpose of this retrospective study is to generalize the commonalities in incidentally discovered PPGL, offer evidences for clinical diagnosis and management.

Methods: 526 patients were included in our study after filtration from the database of West China Hospital of Sichuan University between May, 2007 and December, 2016.Among the patients, 148 of them were incidental findings and 378 of them were suspected findings. All patients’ demography and tumor characteristics were recorded in detail, especially hemodynamic records and hormonal assays. The reasons for taking radiography were also collected. Most patients received preoperative medical preparation . Intraoperative and postoperative courses as well as surgical outcomes were also analyzed to identify differences between incidental findings and suspected findings.

Results: Incidentally discovered PPGL took up 28.1% of the study population. Suspected PPGLs had a higher prevalence of hypertension, lower proportion of non-functioning PPGL, higher prevalence of MEN2 and better post-surgical blood pressure recovery than incidental finding group. However, patients in the incidental finding group showed no significant difference in preoperative blood pressure and hormonal assays with suspected findings in metaphrine and normetaphrine in plasma and urine (P>0.05).

Conclusions: Due to the development of technology, more PPGLs are discovered incidentally. Considering the tumor characteristics and surgical outcome, surgical decisions should be made more cautiously.

Open access

Dirk-Jan van Beek, Rachel S van Leeuwaarde, Carolina Rc Pieterman, Menno R. Vriens and Gerlof D. Valk

Rare diseases pose specific challenges in the field of medical research to provide physicians with evidence based guidelines derived from studies with sufficient quality. An example of these rare diseases is multiple endocrine neoplasia type 1 (MEN1), which is an autosomal dominant endocrine tumor syndrome with an estimated occurrence rate of 2-3 per 100.000. For this complex disease, characterized by multiple endocrine tumors, it proves difficult to perform both adequate and feasible studies. The opinion of patients themselves is of utmost importance to identify the gaps in the evidence based medicine regarding clinical care. In the search for scientific answers to clinical research questions, the aim for best available evidence is obvious. Observational studies within patient cohorts, although prone to bias, seem the most feasible study design regarding the disease prevalence. Knowledge and adaptation to all types of bias is demanded in the strive for answers. Guided by our research on MEN1 patients, we elaborate on strategies to identify sufficient patients, to maximize and maintain patient enrollment and to standardize the data collection process. Preferably, data collection is performed prospectively, however, under certain conditions data storage in a longitudinal retrospective database with a disease-specific framework is suitable. Considering the global challenges on observational research on rare diseases, we propose a stepwise approach from clinical research questions to scientific answers.

Open access

Natalie Rogowski-Lehmann, Aikaterini Geroula, Aleksander Prejbisz, Henri J. L. M. Timmers, Felix Megerle, Mercedes Robledo, Martin Fassnacht, Stephanie Fliedner, Martin Reincke, Anthony Stell, Andrzej Januszewicz, Jacques Lenders, Graeme Eisenhofer and Felix Beuschlein

Context. Pheochromocytomas and paragangliomas (PPGLs) are rare but potentially harmful tumors that can vary in their clinical presentation. Tumors may be found due to signs and symptoms, as part of a hereditary syndrome or following an imaging procedure.

Objective. To investigate potential differences in clinical presentation between PPGLs discovered by imaging (iPPGLs), symptomatic cases (sPPGLs) and those diagnosed during follow-up because of earlier disease/known hereditary mutations (fPPGL).

Design. Prospective study protocol, which has enrolled patients from 6 European centers with confirmed PPGLs.

Setting and Patients. Data were analyzed from 235 patients (37% iPPGLs, 36% sPPGLs, 27% fPPGLs) and compared for tumor volume, biochemical profile, mutation status, presence of metastases and self-reported symptoms.

Results. iPPGL patients were diagnosed at a significantly higher age than fPPGLs (p<0.001), found to have larger tumors (p=0.003) and higher metanephrine and normetanephrine levels at diagnosis (p=0.021). Significantly lower than in sPPGL, there was a relevant number of self-reported symptoms in iPPGL (2.9 vs. 4.3 symptoms, p<0.001). In 16.2% of iPPGL, mutations in susceptibility genes were detected, although this proportion was lower than in fPPGL (60.9%) and sPPGL (21.5%).

Conclusions. Patients with PPGLs detected by imaging were older, have higher tumor volume and more excessive hormonal secretion in comparison to those found as part of a surveillance program. Presence of typical symptoms indicates that in a relevant proportion of those patients the PPGL diagnosis had been delayed.

Précis: Pheochromocytoma/paraganglioma discovered by imaging are often symptomatic and carry a significant proportion of germline mutations in susceptibility genes.

Open access

Qiuli Liu, Lin-ang Wang, Jian Su, Dali Tong, Weihua Lan, Luofu Wang, Gaolei Liu, Jun Zhang, Victor Wei Zhang, Dianzheng Zhang, Rongrong Chen, Qingyi Zhu and Jun Jiang

Context and objectives: Congenital adrenal hyperplasia (CAH) is one of the most prevalent, and potentially severe, genetic inborn errors of steroid synthesis directly affecting metabolism. Most patients are diagnosed and treated at an early age. There have been very limited reports of adults with CAH-associated adrenal myelolipomas. We aimed to analyze two families with CAH-associated giant adrenal myelolipomas caused by defects in CYP21A2 and CYP17A1 genes.

Participants and Methods: A total of 14 individuals from two unrelated families were identified with either CYP21A2 or CYP17A1 mutations. Of note, 5 patients were found with adrenal myelolipomas. Total DNA isolated from the peripheral blood of the two probands was screened for potential mutations in the following susceptibility genes of CAH: CYP21A2, CYP11B1, CYP17A1, HSD17B3, HSD3B2, ARMC5, and STAR using Target Capture-Based Deep Sequencing; and Sanger sequencing was conducted for the family members to detect the potential mutations.

Results: In family 1, molecular genetics sequencing revealed a compound heterozygous mutation (c.293-13C>G / c.518T>A, p.I173N) in CYP12A2 in the patient and his brother. In family 2, all three female patients with adrenal myelolipomas were found to have a compound heterozygous mutation (c.1118A>T, p.H373L / c.1459_1467del9, p.D487_F489del) in CYP17A1.

Conclusion: To avoid giant CAH-associated adrenal myelolipomas in adults, it is important to identify CAH early so appropriate treatment can be initiated to interrupt the chronic adrenal hyperstimulation resulting from increased ACTH. Genetic testing and counseling could be useful in CAH.

Open access

Jin Kyu Oh, Young Jae Im, Kwanjin Park and Jae-Seung Paick

Although it is well known that penile growth is dependent on androgens, few clinical studies have reported successful treatment of micropenis with testosterone, likely due to concerns regarding the efficacy and safety of prolonged testosterone use. Thus, we assessed the synergenic effects of growth hormone (GH) treatments with and without testosterone on phallic growth in a rat model of micropenis. Fifty Sprague–Dawley rats were assigned to control (C), microphallus (MP), testosterone (T), GH (G) and GH plus testosterone (GT) treatment groups, and microphallus was induced by secondary hypogonadism. Pre-pubertal treatments with testosterone, GH or the combination were initiated from 7 days after birth and were maintained until 12 weeks of age. To assess the efficacy of treatments, phallic dimensions were determined and histological markers of cavernosal integrity were evaluated. Skeletal and gonadal safety profiles of the treatments were then assessed according to right tibial lengths and testicular weights, respectively. No monotreatments normalised penile dimensions, whereas combination treatments led to complete restoration. The combination treatment also prevented decreases in histological indicators of cavernosal integrity, including smooth muscle actin and collagen III expression levels and fat globule accumulation and sinusoidal density. These synergenic effects of GH treatments on penile growth may follow changes in androgen receptor expression levels and were accompanied by decreased testicular volume losses. Although the physiological conditions of phallic growth differ between humans and rats, this proof-of-concept study provides a strategy for circumventing the problems of testosterone monotherapy for human micropenis.

Open access

Ali Abbara, Sophie Clarke, Pei Chia Eng, James Milburn, Devavrata Joshi, Alexander N Comninos, Rozana Ramli, Amrish Mehta, Brynmor Jones, Florian Wernig, Ramesh Nair, Nigel Mendoza, Amir H Sam, Emma Hatfield, Karim Meeran, Waljit Singh Dhillo and Niamh M Martin

Purpose: To review the clinical and biochemical characteristics and clinical outcome of patients presenting with pituitary apoplexy to a tertiary centre.

Methods: We retrospectively reviewed the clinical features, predisposing factors, biochemistry and clinical outcome of patients presenting with pituitary apoplexy to Imperial College Healthcare NHS Trust between 1991 to 2015.

Results: We identified 64 patients with pituitary apoplexy (more complete clinical records were available in 52 patients). The median age at presentation was 46.7 years (IQR 31.5-57.0 years). Pituitary apoplexy was the first presentation of pituitary disease in 38/52 of patients and predisposing factors were identified in 28/52. Pituitary apoplexy predominantly occurred in patients with non-functioning pituitary adenomas (47/52). Headache was most commonly described as sudden-onset, severe, lateralising to the frontal or temporal regions. Symptoms of meningeal irritation were reported in 7/18 and visual abnormalities in 22/35. A pre-treatment serum cortisol <100nmol/l was recorded in 12/31 of patients. All patients with visual disturbance had some resolution of their visual symptoms whether managed surgically (14/14) or conservatively (5/5), although pituitary endocrine function did not fully recover in any patient.

Conclusions: In conclusion, these data describe the clinical features of pituitary apoplexy to aid the clinician in diagnosing this rare emergency presentation of pituitary disease. Prospective multicentre studies of the presentation of pituitary apoplexy are required to further characterise presentation and outcomes.

Open access

Mirian Romitti, Vitor C Fabris, Patricia K Ziegelmann, Ana Luiza Maia and Poli Mara Spritzer

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder affecting women of reproductive age. PCOS has been associated with distinct metabolic and cardiovascular diseases and with autoimmune conditions, predominantly autoimmune thyroid disease (AITD). AITD has been reported in 18-40% of PCOS women, depending on PCOS diagnostic criteria and ethnicity. The aim of this systematic review and meta-analysis was to summarize the available evidence regarding the likelihood of women with PCOS also having AITD in comparison to a reference group of non-PCOS women. We systematically searched EMBASE and MEDLINE for non-interventional case control, cross-sectional, or cohort studies published until August 2017. The Ottawa–Newcastle Scale was used to assess the methodological quality of studies. Statistical meta-analysis was performed with R. Thirteen studies were selected for the present analysis, including 1,210 women diagnosed with PCOS and 987 healthy controls. AITD was observed in 26.03% and 9.72% of PCOS and control groups respectively. A significant association was detected between PCOS and chance of AITD (OR= 3.27, 95%CI 2.32-4.63). Notably, after geographical stratification, the higher risk of AITD in PCOS women persisted for Asians (OR= 4.56, 95%CI 2.47–8.43), Europeans (OR= 3.27, 95%CI 2.07–5.15), and South Americans (OR= 1.86, 95 %CI 1.05–3.29). AIDT is a frequent condition in PCOS patients, and might affect thyroid function. Thus, screening for thyroid function and thyroid-specific autoantibodies should be considered in patients with PCOS even in the absence of overt symptoms. This systematic review and meta-analysis is registered in PROSPERO under number CRD42017079676.

Open access

Federica Saponaro, Alessandro Saba, Sabina Frascarelli, Concetta Prontera, Aldo Clerico, Marco Scalese, Maria Rita Sessa, Filomena Cetani, Simona Borsari, Elena Pardi, Antonella Marvelli, Claudio Marcocci, Claudio Passino and Riccardo Zucchi

Objectives: The aims of this paper were to evaluate the levels of Vitamin D (VitD) in patients with Heart Failure (HF), compared to a control group, to assess the effects of VitD on HF outcome and to compare VitD measurement between LIAISON immunoassay and HPLC-MS-MS methods in this population.

Design and Methods: We collected clinical, biochemical and outcome data from 247 patients with HF and in a subgroup of 151 patients, we measured VitD both with LIAISON and HPLC-MS-MS.

Results: HF patients had statistically lower 25OHD levels (45.2±23.7 nmol/l vs 58.2±24.0 nmol/l, p<0.001) and a statistically higher prevalence of VitD insufficiency (61.1% vs 39.5%, p<0.001) and deficiency (24.7% vs 6.6%, p<0.001), compared to healthy controls. There was a significant inverse relationship between baseline 25OHD and risk of HF related death, with a HR of 0.59 (95% CI 0.37-0.92, p=0.02), confirmed in a multivariate adjusted analysis. Kaplan-Meier survival analyses showed that VitD insufficiency was associated with reduced survival in HF patients (log rank p=0.017).

There was a good agreement between LIAISON and HPLC-MS-MS (Cohen's kappa coefficient 0.70), but the prevalence of vitamin D insufficiency was significantly higher with the former compared to the latter method (58.3%, n=88 vs 55.6%, n=84, p<0.001). LIAISON underestimated the 25OHD levels and showed a mean relative bias of -0.739% with 95% of limits of agreement (-9.00 to +7.52%), when compared to HPLC-MS-MS.

Conclusions: 25OHD levels adequately measured by HPLC-MS-MS, showed to be low in HF population and to be correlated with HF-related risk of death.

Open access

Anastasia P Athanasoulia-Kaspar, Matthias K. Auer, Gunter K. Stalla and Mira Jakovcevski

Objective: Patients with non-functioning pituitary adenomas exhibit high morbidity and mortality rates. Growth hormone deficiency and high doses of glucocorticoid substitution therapy have been identified as corresponding risk factors. Interestingly, high levels of endogenous cortisol in, e.g., patients with post-traumatic stress disorder or patients with Cushing's disease have been linked to shorter telomere length. Telomeres are noncoding DNA regions located at the end of chromosomes consisting of repetitive DNA sequences which shorten with ageing and hereby determine cell survival. Therefore, telomere length can serve as a predictor for the onset of disease and mortality in some endocrine disorders (e.g., Cushing's disease).

Design/Methods: We examine telomere length from blood in patients (n = 115) with non-functioning pituitary adenomas (NFPA) in a cross-sectional case control (n = 106, age-, gender- matched) study using qPCR. Linear regression models were used to identify independent predictors of telomere length.

Results: We show that patients with NFPA exhibited shorter telomeres than controls. No significant association of indices of growth hormone deficiency (IGF-1-level-SDS, years of unsubstituted growth hormone deficiency etc.) with telomere length was detected. Interestingly, linear regression analysis showed that hydrocortisone replacement dosage in patients with adrenal insufficiency (n = 52) was a significant predictor for shorter telomere length (β = 0.377; p = 0.018) independent of potential confounders. Median split analysis revealed that higher hydrocortisone intake (> 20 mg) was associated with significantly shorter telomeres.

Conclusion: These observations strengthen the importance of adjusted glucocorticoid treatment in NFPA patients with respect to morbidity and mortality rates.

Open access

María J Gomora, Flavia Morales-Vasquez, Enrique Pedernera, Delia Perez-Montiel, Horacio López-Basave, Antonio R Villa, Azucena Hernandez-Martinez, Esteban Mena and Carmen Mendez

The significance of the presence of androgen receptor (AR), estrogen receptor alpha (ER), and progesterone receptor (PR) in ovarian cancer patient survival has been a matter of numerous studies. This study was aimed to describe the expression profile of the three sexual steroid receptors in high grade serous, endometrioid, mucinous and low grade serous ovarian carcinoma and its association to the proliferation index in patients with primary ovarian carcinoma diagnosis, before any treatment. Eighty-one samples were obtained from the National Institute of Cancerology in Mexico City and were evaluated for the presence of AR, ER, PR and Ki67 by immunohistochemistry. The four subtypes of ovarian carcinoma displays a specific profile of the eight possible combinations of the steroid receptors with significant differences within the profile and the histological subtypes. High-grade serous carcinoma was characterized by a high frequency of both, triple negative and AR+ ER- PR+ profiles. Endometrioid carcinoma presented a higher frequency of triple positive profile. The presence of only AR+ profile was not observed in the endometrioid tumors. The relationship of the receptor profile with the proliferation index in the tumor epithelium shows that the expression of only ER is associated to a reduced proliferation index in endometrioid carcinoma. Steroid hormone receptor expression and co-expression could help characterize ovarian carcinoma.