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Open access

Christian Høst, Anders Bojesen, Mogens Erlandsen, Kristian A Groth, Kurt Kristensen, Anne Grethe Jurik, Niels H Birkebæk and Claus H Gravholt

Context and objective

Males with Klinefelter syndrome (KS) are typically hypogonadal with a high incidence of metabolic disease, increased body fat and mortality. Testosterone treatment of hypogonadal patients decrease fat mass, increase lean body mass and improve insulin sensitivity, but whether this extends to patients with KS is presently unknown.

Research design and methods

In a randomized, double-blind, placebo-controlled, BMI-matched cross-over study, 13 males with KS (age: 34.8 years; BMI: 26.7 kg/m2) received testosterone (Andriol®) 160 mg per day (testosterone) or placebo treatment for 6 months. Thirteen age- and BMI-matched healthy controls were recruited. DEXA scan, abdominal computed tomography (CT) scan and a hyperinsulinemic–euglycemic clamp, muscle strength and maximal oxygen uptake measurement were performed.

Results

Total lean body mass and body fat mass were comparable between testosterone-naïve KS and controls using DEXA, whereas visceral fat mass, total abdominal and intra-abdominal fat by CT was increased (P < 0.05). Testosterone decreased total body fat (P = 0.01) and abdominal fat by CT (P = 0.04). Glucose disposal was similar between testosterone-naïve KS and controls (P = 0.3) and unchanged during testosterone (P = 0.8). Free fatty acid suppression during the clamp was impaired in KS and maximal oxygen uptake was markedly lower in KS, but both were unaffected by treatment. Testosterone increased hemoglobin and IGF-I.

Conclusion

Testosterone treatment in adult males with KS for 6 months leads to favorable changes in body composition with reductions in fat mass, including abdominal fat mass, but does not change measures of glucose homeostasis.

Open access

Pablo Abellán-Galiana, Carmen Fajardo-Montañana, Pedro Riesgo-Suárez, Marcelino Pérez-Bermejo, Celia Ríos-Pérez and José Gómez-Vela

Objectives

To analyze the usefulness of plasma ACTH in predicting CD remission after surgery and to evaluate the prognostic usefulness of ACTH measurement after the cortisol and ACTH nadir (48 h prior to discharge).

Design

A prospective study was made of 65 patients with CD operated upon between 2005 and 2016.

Methods

Postsurgery plasma ACTH and cortisol were measured every 6 h, in the absence of corticosteroid coverage. Hydrocortisone was started in the presence of adrenal insufficiency or cortisol <55.2 nmol/L. Plasma ACTH was again determined before discharge.

Main outcome measure

Usefulness of plasma ACTH in predicting CD remission.

Results

Remission at 3 months of CD was achieved in 56 of 65 cases, with late recurrence in 18 of 58 cases. Following resection, the ACTH nadir was significantly lower referred to late remission (2.8 vs 6.5 pmol/L; P = 0.031) and higher for recurrence (2.1 vs 4.8 pmol/L; P < 0.001), and identical results were obtained for the ACTH values before discharge. In the analysis of the ROC curves, nadir and before discharge ACTH values <1.9 pmol/L and <2.6 pmol/L were respectively indicative of early remission (AUC 0.827; P < 0.001); <6.2 pmol/L of remission at 3 months (AUC 0.847; P = 0.001) and >3.2 pmol/L of recurrence (AUC 0.810; P < 0.001) in both ACTH values. A time to ACTH nadir <46 h was indicative of early remission (AUC 0.751; P = 0.001), while a time >39 h was indicative of recurrence (AUC 0.773; P = 0.001).

Conclusions

We propose an ACTH value <3.3 pmol/L as a good long-term prognostic marker in the postoperative period of CD. Reaching the ACTH nadir in less time is associated to a lesser recurrence rate.

Open access

Maria Cristina De Martino, Richard A Feelders, Claudia Pivonello, Chiara Simeoli, Fortuna Papa, Annamaria Colao, Rosario Pivonello and Leo J Hofland

Adrenocortical carcinomas (ACCs) are rare tumors with scant treatment options for which new treatments are required. The mTOR pathway mediates the intracellular signals of several growth factors, including the insulin-like growth factors (IGFs), and therefore represents a potential attractive pathway for the treatment of several malignancies including ACCs. Several mTOR inhibitors, including sirolimus, temsirolimus and everolimus, have been clinically developed. This review summarizes the results of the studies evaluating the expression of the mTOR pathway components in ACCs, the effects of the mTOR inhibitors alone or in combination with other drugs in preclinical models of ACCs and the early experience with the use of these compounds in the clinical setting. The mTOR pathway seems a potential target for treatment of patients with ACC, but further investigation is still required to define the potential role of mTOR inhibitors alone or in combination with other drugs in the treatment of ACC patients.

Open access

B Shahida, P Sahlstrand Johnson, R Jain, H Brorson, P Åsman, M Lantz and T Planck

Background

Smoking is a strong risk factor for the development of Graves’ ophthalmopathy (GO). Immediate early genes (IEGs) are overexpressed in patients with active GO compared to healthy controls. The aim of this study was to study the effects of tobacco smoking and simvastatin on preadipocytes and orbital fibroblasts (OFs) in the adipogenic process.

Methods

Cigarette smoke extract (CSE) was generated by a validated pump system. Mouse 3T3-L1 preadipocytes or OFs were exposed to 10% CSE with or without simvastatin. Gene expression was studied in preadipocytes and OFs exposed to CSE with or without simvastatin and compared to unexposed cells or cells treated with a differentiation cocktail.

Results

In 3T3-L1 preadipocytes, Cyr61, Ptgs2, Egr1 and Zfp36 expression levels were two-fold higher in cells exposed to CSE than in unexposed cells. Simvastatin downregulated the expression of these genes (1.6-fold, 5.5-fold, 3.3-fold, 1.4-fold, respectively). CSE alone could not stimulate preadipocytes to differentiate. Scd1, Ppar-γ and adipogenesis were downregulated in simvastatin-treated preadipocytes compared to nontreated preadipocytes 18-, 35- and 1.7-fold, respectively. In OFs, similar effects of CSE were seen on the expression of CYR61 (1.4-fold) and PTGS2 (3-fold). Simvastatin downregulated adipogenesis, PPAR-γ (2-fold) and SCD (27-fold) expression in OFs.

Conclusion

CSE upregulated early adipogenic genes in both mouse 3T3-L1 preadipocytes and human OFs but did not by itself induce adipogenesis. Simvastatin inhibited the expression of both early and late adipogenic genes and adipogenesis in preadipocytes and human OFs. The effect of simvastatin should be investigated in a clinical trial of patients with GO.

Open access

Roberto Cosimo Melcangi, Livio Casarini, Marco Marino, Daniele Santi, Samantha Sperduti, Silvia Giatti, Silvia Diviccaro, Maria Grimoldi, Donatella Caruso, Guido Cavaletti and Manuela Simoni

Context

Post-finasteride syndrome (PFS) occurs in patients with androgenic alopecia after suspension of the finasteride treatment, leading to a large variety of persistent side effects. Despite the severity of the clinical picture, the mechanism underlying the PFS symptoms onset and persistence is still unclear.

Objective

To study whether epigenetic modifications occur in PFS patients.

Methods

Retrospective analysis of a multicentric, prospective, longitudinal, case–control clinical trial, enrolling 16 PFS patients, compared to 20 age-matched healthy men. Main outcomes were methylation pattern of SRD5A1 and SRD5A2 promoters and concentration of 11 neuroactive steroids, measured by liquid chromatography-tandem mass spectrometry, in blood and cerebrospinal fluid (CSF) samples.

Results

SRD5A1 and SRD5A2 methylation analysis was performed in all blood samples (n = 16 PFS patients and n = 20 controls), in 16 CSF samples from PFS patients and in 13 CSF samples from controls. The SRD5A2 promoter was more frequently methylated in CSF of PFS patients compared to controls (56.3 vs 7.7%). No promoter methylation was detected in blood samples in both groups. No methylation occurred in the SRD5A1 promoter of both groups. Unmethylated controls compared to unmethylated SRD5A2 patients showed higher pregnenolone, dihydrotestosterone and dihydroprogesterone, together with lower testosterone CSF levels. Andrological and neurological assessments did not differ between methylated and unmethylated subjects.

Conclusions

For the first time, we demonstrate a tissue-specific methylation pattern of SRD5A2 promoter in PFS patients. Although we cannot conclude whether this pattern is prenatally established or induced by finasteride treatment, it could represent an important mechanism of neuroactive steroid levels and behavioural disturbances previously described in PFS.

Open access

Arno Téblick, Lies Langouche and Greet Van den Berghe

Critical illness is hallmarked by major changes in all hypothalamic–pituitary–peripheral hormonal axes. Extensive animal and human studies have identified a biphasic pattern in circulating pituitary and peripheral hormone levels throughout critical illness by analogy with the fasting state. In the acute phase of critical illness, following a deleterious event, rapid neuroendocrine changes try to direct the human body toward a catabolic state to ensure provision of elementary energy sources, whereas costly anabolic processes are postponed. Thanks to new technologies and improvements in critical care, the majority of patients survive the acute insult and recover within a week. However, an important part of patients admitted to the ICU fail to recover sufficiently, and a prolonged phase of critical illness sets in. This prolonged phase of critical illness is characterized by a uniform suppression of the hypothalamic–pituitary–peripheral hormonal axes. Whereas the alterations in hormonal levels during the first hours and days after the onset of critical illness are evolutionary selected and are likely beneficial for survival, endocrine changes in prolonged critically ill patients could be harmful and may hamper recovery. Most studies investigating the substitution of peripheral hormones or strategies to overcome resistance to anabolic stimuli failed to show benefit for morbidity and mortality. Research on treatment with selected and combined hypothalamic hormones has shown promising results. Well-controlled RCTs to corroborate these findings are needed.

Open access

Lena-Maria Levin, Henry Völzke, Markus M Lerch, Jens-Peter Kühn, Matthias Nauck, Nele Friedrich and Stephanie Zylla

Objective

Chemerin and adiponectin are adipokines assumed to be involved in the development of metabolic syndrome-related phenotypes like hepatic steatosis. We aimed to evaluate the associations of circulating chemerin and adiponectin concentrations with liver enzymes, liver fat content, and hepatic steatosis in the general population.

Methods

Data of 3951 subjects from the population-based Study of Health in Pomerania (SHIP-TREND) were used. Hepatic steatosis was assumed when either a hyperechogenic liver (assessed via ultrasound) or a magnetic resonance imaging (MRI)-quantified liver fat content >5% was present. Adjusted sex-specific quantile and logistic regression models were applied to analyze the associations of chemerin and adiponectin with liver enzymes, liver fat content and hepatic steatosis.

Results

The observed associations of chemerin and adiponectin with liver enzymes were very divergent depending on sex, fasting status and the specific enzyme. More consistent results were seen in the analyses of these adipokines in relation to MRI-quantified liver fat content. Here, we observed inverse associations to adiponectin in both sexes as well as a positive (men) or U-shaped (women) association to chemerin. Similarly, the MRI-based definition of hepatic steatosis revealed strongly consistent results: in both sexes, high chemerin concentrations were associated with higher odds of hepatic steatosis, whereas high adiponectin concentrations were associated with lower odds.

Conclusion

Our results suggest a role of these adipokines in the pathogenesis of hepatic steatosis independent of metabolic or inflammatory disorders. However, experimental studies are needed to further clarify the underlying mechanisms and the inter-play between adipokine concentrations and hepatic steatosis.

Open access

Piera Rizzolo, Valentina Silvestri, Virginia Valentini, Veronica Zelli, Agostino Bucalo, Ines Zanna, Simonetta Bianchi, Maria Grazia Tibiletti, Antonio Russo, Liliana Varesco, Gianluca Tedaldi, Bernardo Bonanni, Jacopo Azzollini, Siranoush Manoukian, Anna Coppa, Giuseppe Giannini, Laura Cortesi, Alessandra Viel, Marco Montagna, Paolo Peterlongo, Paolo Radice, Domenico Palli and Laura Ottini

Breast cancer in men is a rare and still poorly characterized disease. Inherited mutations in BRCA1, BRCA2 and PALB2 genes, as well as common polymorphisms, play a role in male breast cancer genetic predisposition. Male breast cancer is considered a hormone-dependent tumor specifically related to hyperestrogenism. Polymorphisms in genes involved in estrogen biosynthesis and metabolism pathways, such as CYP17A1 and CYP1B1, have been associated with breast cancer risk. Here, we aimed to investigate the role of CYP17A1 and CYP1B1 polymorphisms in male breast cancer risk. A series of 597 male breast cancer cases and 1022 male controls, recruited within the Italian Multicenter Study on male breast cancer, was genotyped for CYP17A1 rs743572, CYP1B1 rs1056836 and rs1800440 polymorphisms by allelic discrimination real-time PCR with TaqMan probes. Associations with male breast cancer risk were estimated using logistic regression. No statistically significant associations between male breast cancer risk and the three analyzed polymorphisms emerged. Similar results were obtained also when BRCA1 /2 mutational status was considered. No significant differences in the distribution of the genotypes according to estrogen receptor status emerged. In conclusion, our study, based on a large series of male breast cancer cases, is likely to exclude a relevant role of CYP17A1 and CYP1B1 polymorphisms in male breast cancer predisposition. Overall, these results add new data to the increasing evidence that polymorphisms in these genes may not be associated with breast cancer risk.

Open access

Simonetta Piana, Eleonora Zanetti, Alessandra Bisagni, Alessia Ciarrocchi, Davide Giordano, Federica Torricelli, Teresa Rossi and Moira Ragazzi

The NOTCH signaling is an evolutionarily conserved signaling pathway that regulates cell–cell interactions. NOTCH family members play a fundamental role in a variety of processes during development in particular in cell fate decisions. As other crucial factors during embryogenesis, NOTCH signaling is aberrantly reactivated in cancer where it has been linked to context-dependent effects. In thyroid cancer, NOTCH1 expression has been associated to aggressive features even if its in vivo expression within the entire spectrum of thyroid tumors has not definitively established. A series of 106 thyroid specimens including non-neoplastic lesions, benign and malignant tumors of common and rare histotypes, were investigated by immunohistochemistry to assess NOTCH1 expression. Extent of positivity and protein localization were investigated and correlated with clinical and morphological parameters. NOTCH1 positivity was predominantly associated with papillary carcinomas and only occasionally found in follicular carcinomas. Poorly differentiated and undifferentiated thyroid carcinomas showed only a partial positivity. NOTCH1 expression pattern also seemed differently distributed according to histotype. Our data confirm a role of NOTCH1 in thyroid cancer and highlight for the first time the specific involvement of this pathway in papillary carcinomas. Our data also indicate that other thyroid malignancies do not rely on NOTCH1 signaling for development and progression.

Open access

María L Bacigalupo, Verónica G Piazza, Nadia S Cicconi, Pablo Carabias, Andrzej Bartke, Yimin Fang, Ana I Sotelo, Gabriel A Rabinovich, María F Troncoso and Johanna G Miquet

Transgenic mice overexpressing growth hormone (GH) spontaneously develop liver tumors, including hepatocellular carcinoma (HCC), within a year. The preneoplastic liver pathology in these mice recapitulates that observed in humans at high risk of developing hepatic cancer. Although increased expression of galectin 1 (GAL1) in liver tissue is associated with HCC aggressiveness, a link between this glycan-binding protein and hormone-related tumor development has not yet been explored. In this study, we investigated GAL1 expression during liver tumor progression in mice continuously exposed to high levels of GH. GAL1 expression was determined by Western blotting, RT-qPCR and immunohistochemistry in the liver of transgenic mice overexpressing GH. Animals of representative ages at different stages of liver pathology were studied. GAL1 expression was upregulated in the liver of GH-transgenic mice. This effect was observed at early ages, when animals displayed no signs of liver disease or minimal histopathological alterations and was also detected in young adults with preneoplastic liver pathology. Remarkably, GAL1 upregulation was sustained during aging and its expression was particularly enhanced in liver tumors. GH also induced hepatic GAL1 expression in mice that were treated with this hormone for a short period. Moreover, GH triggered a rapid increment in GAL1 protein expression in human HCC cells, denoting a direct effect of the hormone on hepatocytes. Therefore, our results indicate that GH upregulates GAL1 expression in mouse liver, which may have critical implications in tumorigenesis. These findings suggest that this lectin could be implicated in hormone-driven liver carcinogenesis.