Hirsutism induced by hyperandrogenism can be associated with polycystic ovary syndrome, 21-hydroxylase (OH) deficiency or androgen-secreting tumors, including ovarian and adrenal tumors. Adrenal androgen-secreting tumors are frequently malignant. Adrenal oncocytomas represent rare causes of hyperandrogenism. The aim of the study was to investigate steroidogenic enzyme expression and steroid secretion in an androgen-secreting adrenal oncocytoma in a young woman presenting with hirsutism. Hyperandrogenism was diagnosed on the basis of elevated plasma Δ4-androstenedione and testosterone levels. Pelvic ultrasound was normal, CT scanning revealed a right adrenal mass. Androgens were assessed in adrenal and ovarian vein samples and proved a right adrenal origin. Adrenalectomy normalized androgen levels and the adrenal tumor was diagnosed as an oncocytoma. Real time-PCR, immunohistochemistry and cell culture studies were performed on tumor explants to investigate the steroid secretion profile. Among enzymes required for cortisol synthesis, 17α-OH and 3β-hydroxysteroid dehydrogenase 2 (3β-HSD2) were highly expressed whereas 21-OH and 11β-OH were weakly produced at the mRNA and/or protein levels. Enzymes involved in testosterone production, 17β-HSD5 and 17β-HSD3, were also detected. ACTH receptor was present in the tissue. Cortisol, Δ4-androstenedione and testosterone secretions by cultured cells were increased by ACTH. These results provide the first demonstration, to our knowledge, of abnormal expression profile of steroidogenic enzymes in an adrenocortical oncocytoma. Our results also indicate that Δ4-androstenedione hypersecretion resulted from high 17α-OH and 3β-HSD2 expression in combination with low expression of 21-OH and 11β-OH. Testosterone production was ascribed to occurrence of 17β-HSD5 and 17β-HSD3. Finally, our results indicate that androgen secretion was stimulated by ACTH.
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Milène Tetsi Nomigni, Sophie Ouzounian, Alice Benoit, Jacqueline Vadrot, Frédérique Tissier, Sylvie Renouf, Hervé Lefebvre, Sophie Christin-Maitre, and Estelle Louiset
Jung Soo Lim, Seung-Eun Lee, Jung Hee Kim, Jae Hyeon Kim, and The Korean Adrenal Gland and Endocrine Hypertension Study Group, Korean Endocrine Society
To evaluate the clinical characteristics and prognostic factors in patients with adrenocortical carcinoma (ACC) in South Korea.
A nationwide, registry-based survey was conducted to identify pathologically proven ACC at 25 tertiary care centers in South Korea between 2000 and 2014. Cox proportional hazard model and log-rank test were adopted for survival analysis.
Two hundred four patients with ACC were identified, with a median follow-up duration of 20 months (IQR 5–52 months). The median age at diagnosis was 51.5 years (IQR 40–65.8 years), and ACC was prevalent in women (n = 110, 53.9%). Abdominal pain was the most common clinical symptom (n = 70, 40.2%), and ENSAT stage 2 was most common (n = 62, 30.4%) at the time of diagnosis. One hundred sixty-nine patients underwent operation, while 17 were treated with other modalities. The remission rate was 48%, and median recurrence-free survival time was 46 months. Estimated 5-year recurrence-free rate was 44.7%. There were more women, large tumor, atypical mitosis, venous invasion, and higher mitotic count in cancer recurrence group. Estimated 5-year overall survival and disease-specific survival rates were 64.5 and 70.6%, respectively. Higher ENSAT stage and advanced pathologic characteristics were risk factors for all-cause mortality of ACC. Large tumor size and cortisol-secreting tumor were additional risk factors for ACC-specific death.
We report the first epidemiologic study regarding ACC in an Asian population. ENSAT stage 4; lymph node involvement; non-operative group; and invasion of vein, sinusoid, or capsule were associated with an increased risk for all-cause mortality.
Yang Lv, Xu Han, Chunyan Zhang, Yuan Fang, Ning Pu, Yuan Ji, Dansong Wang, Xu Xuefeng, and Wenhui Lou
Chromogranin A (CgA) and neuron-specific enolase (NSE) are important markers for neuroendocrine tumors; however, the clinical value of combining these markers has not been well studied. In this study, we investigated the utility of each marker individually and in combination for patients with nonfunctional pancreatic neuroendocrine tumors (NF-pNETs).
Patients and Methods
In this study, NF-pNET patients and controls were recruited from December 2011 to March 2016; 784 serum samples from peripheral vein were collected. The clinical characteristics and biomarker values of all the individuals were recorded and analyzed. Tumor burdens were calculated by CT/MRI scan. Receiver-operating characteristic curves were constructed to assess the diagnostic predictive values; sensitivity and specificity were calculated to determine the cut-off value. Therapeutic responses reflected on the changes of the biomarkers’ concentration were assessed by the RECIST criterion. Clinical relations between the prognosis and the biomarker values were also analyzed. Statistical significance was defined as P value less than 0.05.
Among the 167 NF-pNETs patients, 82 were males (49.1%) and the mean age was 50.0 (17.4). The mean CgA values of G1, G2 and G3 NF-pNENs were 75, 121 and 134 μg/L (P < 0.05), respectively. In NF-pNETs, CgA correlated with the WHO tumor grade (WHO G1 vs G2, P < 0.05); the linear regression relationships were found between the tumor burdens (both in pancreas and liver) and CgA concentration (P < 0.001); changes in CgA and NSE concentrations also reflect treatment response (P < 0.001).
CgA and NSE are important diagnostic and follow-up markers in patients with NF-pNETs. The combined monitoring of CgA and NSE possesses more accuracy than individual values of CgA and NSE at predicting prognosis and disease progression.
P R van Dijk, S J J Logtenberg, K H Groenier, N Kleefstra, H J G Bilo, and H J Arnqvist
In type 1 diabetes mellitus (T1DM), low concentrations of IGF1 and high concentrations of IGF-binding protein 1 (IGFBP1) have been reported. It has been suggested that these abnormalities in the GH–IGF1 axis are due to low insulin concentrations in the portal vein. We hypothesized that the i.p. route of insulin administration increases IGF1 concentrations when compared with the s.c. route of insulin administration. IGF1 and IGFBP1 concentrations in samples derived from an open-label, randomized cross-over trial comparing the effects of s.c. and i.p. insulin delivery on glycaemia were determined. T1DM patients were randomized to receive either 6 months of continuous i.p. insulin infusion (CIPII) through an implantable pump (MIP 2007C, Medtronic) followed by 6 months of s.c. insulin infusion or vice versa with a washout phase in between. Data from 16 patients who had complete measurements during both treatment phases were analysed. The change in IGF1 concentrations during CIPII treatment was 10.4 μg/l (95% CI −0.94, 21.7 μg/l; P=0.06) and during s.c. insulin treatment was −2.2 μg/l (95% CI −13.5, 9.2 μg/l; P=0.69). When taking the effect of treatment order into account, the estimated change in IGF1 concentrations was found to be 12.6 μg/l (95% CI −3.1, 28.5 μg/l; P=0.11) with CIPII treatment compared with that with s.c. insulin treatment. IGFBP1 concentrations decreased to −100.7 μg/l (95% CI −143.0, −58.3 μg/l; P<0.01) with CIPII treatment. During CIPII treatment, parts of the GH–IGF1 axis changed compared with that observed during s.c. insulin treatment. This supports the hypothesis that the i.p. route of insulin administration is of importance in the IGF1 system.
Jiaxi Li, Pu Huang, Jing Xiong, Xinyue Liang, Mei Li, Hao Ke, Chunli Chen, Yang Han, Yanhong Huang, Yan Zhou, Ziqiang Luo, Dandan Feng, and Chen Chen
Ghrelin regulates body weight, food intake, and blood glucose. It also regulates insulin secretion from pancreatic islet cells. LEAP2 is a newly discovered endogenous ligand of the growth hormone secretagogue’s receptor (GHSR). It not only antagonizes the stimulation of GHSR by ghrelin but also inhibits the constitutive activation of GHSR as an inverse agonist. Type 2 diabetes (T2D) patients have endocrine disorders with metabolic imbalance. Plasma levels of ghrelin and LEAP2 may be changed in obese and T2D patients. However, there is no report yet on circulating LEAP2 levels or ghrelin/LEAP2 ratio in T2D patients. In this study, fasting serum ghrelin and LEAP2 levels in healthy adults and T2D patients were assessed to clarify the association of two hormones with different clinical anthropometric and metabolic parameters.
A total of 16 females and 40 males, ages 23–68 years old normal (n = 27), and T2D patients (n = 29) were enrolled as a cross-sectional cohort.
Serum levels of ghrelin were lower but serum levels of LEAP2 were higher in T2D patients. Ghrelin levels were positively correlated with fasting serum insulin levels and HOMA-IR in healthy adults. LEAP2 levels were positively correlated with age and hemoglobin A1c (HbA1c) in all tested samples. Ghrelin/LEAP2 ratio was negatively correlated with age, fasting blood glucose, and HbA1c.
This study demonstrated a decrease in serum ghrelin levels and an increase in serum LEAP2 levels in T2D patients. LEAP2 levels were positively correlated with HbA1c, suggesting that LEAP2 was associated with T2D development. The ghrelin/LEAP2 ratio was closely associated with glycemic control in T2D patients showing a negative correlation with glucose and HbA1c.
Ann-Cathrin Koschker, Bodo Warrings, Caroline Morbach, Florian Seyfried, Nicole Rickert, Pius Jung, Andreas Geier, Ulrich Dischinger, Maike Krauthausen, Martin J Herrmann, Christine Stier, Stefan Frantz, Uwe Malzahn, Stefan Störk, Martin Fassnacht, and the WAS Study Group
Obesity is a rapidly emerging health problem and an established risk factor for cardiovascular diseases. Bariatric surgery profoundly reduces body weight and mitigates sequelae of obesity. The open, randomized controlled Würzburg Adipositas Studie (WAS) trial compares the effects of Roux-en-Y gastric bypass (RYGB) vs psychotherapy-supported lifestyle modification in morbidly obese patients. The co-primary endpoint addresses 1-year changes in cardiovascular function (peak VO2 during cardiopulmonary exercise testing) and the quality of life (QoL) (Short-Form-36 physical functioning scale). Prior to randomization, all included patients underwent a multimodal anti-obesity treatment for 6–12 months. Thereafter, the patients were randomized and followed through month 12 to collect the primary endpoints. Afterwards, patients in the lifestyle group could opt for surgery, and final visit was scheduled for all patients 24 months after randomization. Sample size calculation suggested to enroll 90 patients in order to arrive at minimally 22 patients per group evaluable for the primary endpoint. Secondary objectives were to quantify changes in body weight, left ventricular hypertrophy, systolic and diastolic function (by echocardiography and cardiac MRI), functional brain MRI, psychometric scales, and endothelial and metabolic function. WAS enrolled 93 patients (72 women, median age 38 years, BMI 47.5 kg/m2) exhibiting a relevantly compromised exercise capacity (median peakVO2 18.3 mL/min/kg) and the QoL (median physical functioning scale 50). WAS is the first randomized controlled trial focusing on the effects of RYGB on cardiovascular function beyond hypertension. In addition, it will provide a wealth of high-quality data on the cerebral, psychiatric, hepatic, and metabolic function in obese patients after RYGB.
Wang-shu Liu, Ling-yan Hua, Su-xiang Zhu, Feng Xu, Xue-qin Wang, Chun-feng Lu, Jian-bin Su, and Feng Qi
The aim of the study was to explore whether plasma stromal cell-derived factor 1 (SDF-1) levels are associated with the EZSCAN score and its derived indicators in patients with type 2 diabetes (T2D).
From July 2020 to December 2020, a total of 253 patients with T2D were consecutively recruited. Serum SDF-1 levels were measured by sandwich ELISA. EZSCAN test was applied to evaluate the sudomotor function of each patient, and based on the results, EZSCAN score, cardiac autonomic neuropathy risk score (CANRS) and cardiovascular risk score (CVDRS) were calculated by particular algorithms. In addition, other relevant clinical data were also collected.
With increasing tertiles of serum SDF-1 levels, the CANRS and CVDRS significantly increased (both Pfor trend <0.001), while the EZSCAN score significantly decreased (Pfor trend <0.001). Moreover, serum SDF-1 levels were significantly and positively correlated with the CANRS and CVDRS (r = 0.496 and 0.510, respectively, both P < 0.001), and negatively correlated with the EZSCAN score (r = −0.391, P < 0.001). Furthermore, multivariate linear regression analyses were constructed, and after adjusting for other clinical covariates, serum SDF-1 levels were independently responsible for EZSCAN score (β = −0.273, t = −3.679, P < 0.001), CANRS (β = 0.334, t = 5.110, P < 0.001) and CVDRS (β = 0.191, t = 4.983, P = 0.003).
SDF-1 levels in serum were independently associated with the EZSCAN score and its derived indicators, such as CANRS and CVDRS in patients with T2D.
Gabriella Oliveira Lima, Alex Luiz Menezes da Silva, Julianne Elba Cunha Azevedo, Chirlene Pinheiro Nascimento, Luana Rodrigues Vieira, Akira Otake Hamoy, Luan Oliveira Ferreira, Verônica Regina Lobato Oliveira Bahia, Nilton Akio Muto, Dielly Catrina Favacho Lopes, and Moisés Hamoy
Low plasma levels of vitamin D causes bone mineral change that can precipitate osteopenia and osteoporosis and could aggravate autoimmune diseases, hypertension and diabetes. The demand for vitamin D supplementation becomes necessary; however, the consumption of vitamin D is not without risks, which its toxicity could have potentially serious consequences related to hypervitaminosis D, such as hypercalcemia and cerebral alterations. Thus, the present study describes the electroencephalographic changes caused by supraphysiological doses of vitamin D in the brain electrical dynamics and the electrocardiographic changes. After 4 days of treatment with vitamin D at a dose of 25,000 IU/kg, the serum calcium levels found were increased in comparison with the control group. The electrocorticogram analysis found a reduction in wave activity in the delta, theta, alpha and beta frequency bands. For ECG was observed changes with shortened QT follow-up, which could be related to serum calcium concentration. This study presented important evidence about the cerebral and cardiac alterations caused by high doses of vitamin D, indicating valuable parameters in the screening and decision-making process for diagnosing patients with symptoms suggestive of intoxication.
M Ahmid, C G Perry, S F Ahmed, and M G Shaikh
Until quite recently, the management of children with growth hormone deficiency (GHD) had focussed on the use of recombinant human GH (rhGH) therapy to normalise final adult height. However, research over the past two decades that has demonstrated deficits in bone health and cardiac function, as well as impaired quality of life in adults with childhood-onset GHD (CO-GHD), has questioned this practice. Some of these studies suggested that there may be short-term benefits of rhGH in certain group of adolescents with GHD during transition, although the impact of GHD and replacement during the transition period has not been adequately investigated and its long-term benefits remain unclear. GH therapy remains expensive and well-designed long-term studies are needed to determine the cost effectiveness and clinical benefit of ongoing rhGH during transition and further into adulthood. In the absence of compelling data to justify widespread continuation of rhGH into adult life, there are several questions related to its use that remain unanswered. This paper reviews the effects of growth hormone deficiency on bone health, cardiovascular function, metabolic profile and quality of life during transition and young adulthood.
Rossella Cannarella, Teresa Mattina, Rosita A Condorelli, Laura M Mongioì, Giuseppe Pandini, Sandro La Vignera, and Aldo E Calogero
Insulin-like growth factor 1 receptor (IGF1R), mapping on the 15q26.3 chromosome, is required for normal embryonic and postnatal growth. The aim of the present study was to evaluate the IGF1R gene expression and function in three unrelated patients with chromosome 15 structural abnormalities. We report two male patients with the smallest 15q26.3 chromosome duplication described so far, and a female patient with ring chromosome 15 syndrome. Patient one, with a 568 kb pure duplication, had overgrowth, developmental delay, mental and psychomotor retardation, obesity, cryptorchidism, borderline low testis volume, severe oligoasthenoteratozoospermia and gynecomastia. We found a 1.8-fold increase in the IGF1R mRNA and a 1.3-fold increase in the IGF1R protein expression (P < 0.05). Patient two, with a 650 kb impure duplication, showed overgrowth, developmental delay, mild mental retardation, precocious puberty, low testicular volume and severe oligoasthenoteratozoospermia. The IGF1R mRNA and protein expression was similar to that of the control. Patient three, with a 46,XX r(15) (p10q26.2) karyotype, displayed intrauterine growth retardation, developmental delay, mental and psychomotor retardation. We found a <0.5-fold decrease in the IGF1R mRNA expression and an undetectable IGF1R activity. After reviewing the previously 96 published cases of chromosome 15q duplication, we found that neurological disorders, congenital cardiac defects, typical facial traits and gonadal abnormalities are the prominent features in patients with chromosome 15q duplication. Interestingly, patients with 15q deletion syndrome display similar features. We speculate that both the increased and decreased IGF1R gene expression may play a role in the etiology of neurological and gonadal disorders.