Corticotropin-releasing hormone deficiency results in impaired analgesic response during CFA-induced inflammation.

PURPOSE: Corticotropin-releasing hormone (CRH) plays an important role in relief of pain by releasing analgesia-associated molecules in several inflammatory states. During inflammation, peripheral CRH acts on cells of the immune system to stimulate the local expression of proopiomelanocortin (POMC) and the production of ß-endorphin, which in turn binds to opioid receptors on sensory neurons to produce antinociception. In the present study, we further investigated the role of endogenous CRH in inflammatory pain by determining the effects of Crh-deficiency on this process. METHODS: For this purpose, we used Crh-deficient (Crh-/-) mice and their wildtype (Crh + / +) littermates in the CFA (Complete Freund's Adjuvant)-induced inflammatory pain model. Pain thresholds were evaluated with the Hargreaves apparatus. RESULTS: Our experiments showed that Crh deficiency led to increased pain response, which was associated with decreased POMC mRNA levels in locally inflamed paws of these mice. Furthermore, Crh-/- mice had higher paw edema than Crh + / + mice. Histological evaluation of inflamed paw tissues revealed increased inflammatory response in Crh-/- mice. Protein levels of proinflammatory cytokines, such as IL-6, TNF-α, and IL-1ß, were higher in inflamed tissue of Crh-/- mice compared to wildtype mice. Corticosterone replacement increased the pain threshold of Crh-/- mice, restored their paw volume to the levels of wildtype mice, and significantly reduced their proinflammatory cytokine levels. Furthermore, glucocorticoid administration significantly increased POMC mRNA expression in the inflamed paw. CONCLUSION: Our data suggest that genetic deficiency of CRH is associated with increased pain. This effect is likely attributable to the accompanying glucocorticoid insufficiency and is in part mediated by opioids expressed locally.

Immunosuppressed non-responders to two doses of mRNA SARS-CoV-2 vaccines achieve an immune response comparable to those of immunocompetent individuals after a third dose.

The SARS-CoV-2 vaccines trigger the production of neutralizing antibodies to the SARS-CoV-2 spike (S) protein and induce a T cell-mediated immune response. However, the antibody titers that confer protection against the SARS-CoV-2 virus are currently not well-established. While immunocompetent individuals achieve a high level of immune response after SARS-CoV-2 vaccination, it now appears that a high proportion of immunosuppressed or immunocompromised, patients exhibit low or no response to two doses of the vaccines. Most non-responders are on treatment with either glucocorticoids, mycophenolate-mofetil (MMF), the anti-CD20 monoclonal antibody rituximab, calcineurin inhibitors like cyclosporine and tacrolimus, rapamycin (mTOR) signaling cascade inhibitors (i.e., sirolimus and everolimus), azathioprine, or methotrexate given for a variety of diseases including autoimmune disorders, hematological malignancies, and solid cancers, while recipients of solid organ transplants also fall within this category. Recently, several published reports have suggested that a third dose of these vaccines induces an elevated antibody response against the SARS-CoV-2 S protein.

Discovery of a stable tripeptide targeting the N-domain of CRF1 receptor.

The corticotropin-releasing factor (CRF) and its CRF1 receptor (CRF1R) play a central role in the maintenance of homeostasis. Malfunctioning of the CRF/CRF1R unit is associated with several disorders, such as anxiety and depression. Non-peptide CRF1R-selective antagonists have been shown to exert anxiolytic and antidepressant effects on experimental animals. However, none of them is in clinical use today because of several side effects, thus demonstrating the need for the development of other more suitable CRF1R antagonists. In an effort to develop novel CRF1R antagonists we designed, synthesized and chemically characterized two tripeptide analogues of CRF, namely (R)-LMI and (S)-LMI, having their Leu either in R (or D) or in S (or L) configuration, respectively. Their design was based on the crystal structure of the N-extracellular domain (N-domain) of CRF1R/CRF complex, using a relevant array of computational methods. Experimental evaluation of the stability of synthetic peptides in human plasma has revealed that (R)-LMI is proteolytically more stable than (S)-LMI. Based on this finding, (R)-LMI was selected for pharmacological characterization. We have found that (R)-LMI is a CRF antagonist, inhibiting (1) the CRF-stimulated accumulation of cAMP in HEK 293 cells expressing the CRF1R, (2) the production of interleukins by adipocytes and (3) the proliferation rate of RAW 264.7 cells. (R)-LMI likely blocked agonist actions by interacting with the N-domain of CRF1R as suggested by data using a constitutively active chimera of CRF1R. We propose that (R)-LMI can be used as an optimal lead compound in the rational design of novel CRF antagonists.

The complex and bidirectional interaction between sex hormones and exercise performance in team sports with emphasis on soccer.

A constant topic reported in the lay press is the effect of sex hormones on athletic performance and their abuse by athletes in their effort to enhance their performance or to either boost or sidestep their hard, protracted, and demanding training regimens. However, an issue that it is almost never mentioned is that the athletic training itself affects the endogenous production of androgens and estrogens, while also being affected by them. Among sports, soccer is a particularly demanding activity, soccer players needing to possess high levels of endurance, strength, and both aerobic and anaerobic capacity, with the very great physiological, metabolic, physical, and psychological exertion required of the players being both influenced by sex steroids and, reciprocally, affecting sex steroid levels. This review focuses on the currently available knowledge regarding the complex relationship between athletic training and competition and sex steroid hormone adaptation to the demands of the exercise effort. In the first part of the review, we will examine the effects of endogenous testosterone, estrogen, and adrenal androgens on athletic performance both during training and in competition. In the second part, we will explore the reciprocal effects of exercise on the endogenous sex hormones while briefly discussing the recent data on anabolic androgenic steroid abuse.

Novel stable analogues of the neurotensin C-terminal hexapeptide containing unnatural amino acids.

Neurotensin (NT) (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) exerts a dual function as a neurotransmitter/neuromodulator in the central nervous system and as a hormone/cellular mediator in periphery. This dual function of NT establishes a connection between brain and peripheral tissues that renders this peptide a central player in energy homeostasis. Many biological actions of NT are mediated through its interaction with three types of NT receptors (NTS receptors). Despite its role in energy homeostasis, NT has a short half-life that hampers further determination of the biological actions of this peptide and its receptors in brain and periphery. The short half-life of NT is due to the proteolytic degradation of its C-terminal side by several endopeptidases. Therefore, it is important to synthesize NT analogues with resistant bonds against metabolic deactivation. Based on these findings, we herein report the synthesis of ten linear, two cyclic and two dimeric analogues of NT with modifications in its structure that improve their metabolic stability, while retaining the ability to bind to NTS receptors. Modifications at position 11 (introduction of D-Tyrosine (OEthyl) [D-Tyr(Et)] or D-1-naphtylalanine [D-1-Nal] were combined with introduction of a L-Lysine or a D-Arginine at positions 8 or 9, and 1-[2-(aminophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid (AOPC) at positions 7 or 8, resulting in compounds NT4-NT21. AOPC is an unnatural amino acid with promise in applications as a building block for the synthesis of peptidomimetic compounds. To biologically evaluate these analogues, we determined their plasma stability and their binding affinities to type 1 NT receptor (NTS1), endogenously expressed in HT-29 cells, Among the fourteen NT analogues, compounds, NT5, NT6, and NT8, which have D-Tyr(Et) at position 11, bound to NTS1 in a dose-response manner and with relatively high affinity but still lower than that of the natural peptide. Despite their lower binding affinities compared to NT, the NT5, NT6, and NT8 exhibited a remarkably higher stability, as a result of their chemistry, which provides protection from enzymatic activity. These results will set the basis for the rational design of novel NT molecules with improved pharmacological properties and enhanced enzymatic stability.

Selective antagonism of CRF1 receptor by a substituted pyrimidine.

The corticotrophin-releasing factor (CRF) and its type 1 receptor (CRF1R) regulate the hypothalamic-pituitary-adrenal axis, as well as other systems, thus playing a crucial role in the maintenance of homeostasis. Non-peptide CRF1R-selective antagonists exert therapeutic effects on experimental animals with abnormal regulation of their homeostatic mechanisms. However, none of them is as yet in clinical use. In an effort to develop novel small non-peptide CRF1R-selective antagonists, we have synthesized a series of substituted pyrimidines described in a previous study. These small molecules bind to CRF1R, with analog 3 having the highest affinity. Characteristic structural features of analog 3 are a N,N-bis(methoxyethyl)amino group at position 6 and a methyl in the alkythiol group at position 5. Based on the binding profile of analog 3, we selected it in the present study for further pharmacological characterization. The results of this study suggest that analog 3 is a potent CRF1R-selective antagonist, blocking the ability of sauvagine, a CRF-related peptide, to stimulate cAMP accumulation in HEK 293 cells via activation of CRF1R, but not via CRF2R. Moreover, analog 3 blocked sauvagine to stimulate the proliferation of macrophages, further supporting its antagonistic properties. We have also constructed molecular models of CRF1R to examine the interactions of this receptor with analog 3 and antalarmin, a prototype CRF1R-selective non-peptide antagonist, which lacks the characteristic structural features of analog 3. Our data facilitate the design of novel non-peptide CRF1R antagonists for clinical use.

Effect of a 6-week supervised detraining period on bone metabolism markers and their association with ergometrics and components of the hypothalamic-pituitary-gonadal (HPG) axis in professional male soccer players.

The aim of this study was to examine the effect of a supervised 6-week detraining period on bone metabolism markers, and their association with ergometrics, and components of the hypothalamic-pituitary-gonadal (HPG) axis in elite male professional soccer players. Sixty-seven soccer players (mean age ± SD 23.4 ± 5.2 years) that were following a supervised training program participated in this study. Players were tested twice: immediately after the conclusion of the competition period, and following the detraining period, for the determination of bone-turnover rates, ergometrics, and components of the HPG-axis. The detraining period resulted in significant reduction in osteocalcin [OC] (p < 0.001), C-terminal propeptide of collagen type-I [CICP] (p = 0.002), and bone-alkaline-phosphatase [b-ALP] (p < 0.001) values, while C-terminal telopeptide [CTX] was increased (p < 0.001). No significant relationships were apparent between bone biomarkers and body weight, body-fat %, total testosterone, free testosterone, estradiol, follicle-stimulating hormone, and luteinizing hormone in both experimental sessions (p > 0.05). Similarly, despite the deterioration in ergometrics after detraining (all p < 0.001), no significant correlations were evident (p > 0.05) between bone biomarkers and maximal oxygen consumption, squat jump, countermovement jump, and 20 m sprint performance, and also between % change of bone biomarkers and ergometrics, apart from a weak relationship (p = 0.041) between OC and VO2max of questionable value. Our results suggest that the 6-week soccer off-season detraining period in our study negatively affected bone physiology as reflected by the suppression of bone-formation rate and a parallel induction of bone resorption. The cause of this acute alteration of bone-turnover rates is not related to the examined components of the HPG-axis, although parallels is not associated with the changes in ergometrics.

Serum chemerin levels are negatively associated with male fertility and reproductive hormones.

STUDY QUESTION: Are chemerin levels different in subfertile men compared to men from the general population, and how does chemerin relate to reproductive hormonal status? SUMMARY ANSWER: Chemerin is negatively associated to LH, SHBG and estradiol and lower levels of chemerin are detected among subfertile men compared to controls. WHAT IS KNOWN ALREADY: Adipokines have pleiotropic effects on tissue homeostasis and have been shown to affect both sex steroid production and action. Among adipokines the newly characterized chemokine chemerin is suggested to influence testosterone production in males, but whether serum levels associate with testosterone or male subfertility has not yet been reported. STUDY DESIGN, SIZE, DURATION: Case control study comprising a consecutive group of men from infertile couples referred to Reproductive Medicine Centre at Skane University Hospital from 2006 through 2012, and age-matched controls. Participants were enrolled in years 2011-2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: Males from infertile couples (n = 180) aged 18-50 years with sperm concentration <20 × 106/ml and age-matched controls (n = 139) from the general population were enrolled. Serum concentrations of total testosterone (TT), calculated free testosterone (cFT), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2) and sex-hormone binding globuline (SHBG) as well as the adipokines chemerin, adiponectin and leptin were measured. Anthropometrics and biochemical parameters of glucose and lipid metabolism were assessed. MAIN RESULTS AND THE ROLE OF CHANCE: Chemerin levels were lower in subfertile men compared to controls (mean diff. 7.1 ng/ml; 95% CI, 3.7; 11 ng/ml; P < 0.001) even after adjustment for BMI. After adjustment for age, BMI, smoking, leptin and adiponectin, chemerin associated negatively with LH (ß = -4.2; P = 0.02), E2 (ß = -10; P = 0.004) and SHBG (ß = -7.4, P = 0.003). Men with elevated LH levels had lower chemerin levels compared to those with LH levels within the normal range (mean diff. 4.8 ng/ml; 95% CI, 0.16; 9.4 ng/ml; P = 0.04). LIMITATIONS, REASONS FOR CAUTION: Single sample blood test with immunoassays for determination of hormone levels. Heterogeneous group of subfertile subjects. WIDER IMPLICATIONS OF THE FINDINGS: Even though chemerin has been positively associated with BMI, inverse association with subfertility suggests that it is independently linked to reproductive function, a hypothesis that warrants further assessment. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from EU Interreg V (ReproUnion) program as well as Swedish Governmental Fund for Clinical Research. The authors have no conflicts of interest.

Review of mobile applications for optimizing the follow-up care of patients with diabetes.

BACKGROUND: Several smartphone applications aim at facilitating communication between patients and healthcare providers. In this review, we evaluate and compare the most promising applications in the field of diabetes mellitus (DM) and obesity. Most applications monitor body weight, fasting or postprandial blood glucose, glycosylated hemoglobin (Hgb) A1c (HgbA1c), and units and types of insulin used. METHODS: Nine clinically tested applications and two Web platforms were grouped into three categories that were evaluated and compared. Group 1 included seven applications focusing mainly on monitoring DM, fitness and weight, blood glucose levels, and HbA1c. Group 2 included two applications that focus on insulin dosage calculators and glucose self-monitoring tests. Group 3 included two web-platforms that interact with patients via SMS (short message service) messaging. RESULTS: A common feature of the applications examined was the limited number of clinical parameters tested, the small number of subjects taking part in the evaluation, and the fact that the controls were not randomized. Furthermore, the interfaces of the applications varied and were not standardized. Finally, another common characteristic across applications was the lack of standardization of the interface and the overall structure due to language barriers, the devices usually having been designed around a specific language. Lastly, most applications lacked a critical mass of evaluators and were thus not worthy of being considered of serious clinical relevance. CONCLUSIONS: The current smartphone applications for DM are characterized by a limited number of participants, a small number of parameters, and a lack of standardization.

Sarcopenic obesity.

Sarcopenic obesity, a chronic condition, is today a major public health problem with increasing prevalence worldwide, which is due to progressively aging populations, the increasing prevalence of obesity, and the changes in lifestyle during the last several decades. Patients usually present to healthcare facilities for obesity and related comorbidities (type 2 diabetes mellitus, non-alcoholic fatty liver disease, dyslipidemia, hypertension, and cardiovascular disease) or for non-specific symptoms related to sarcopenia per se (e.g., fatigue, weakness, and frailty). Because of the non-specificity of the symptoms, sarcopenic obesity remains largely unsuspected and undiagnosed. The pathogenesis of sarcopenic obesity is multifactorial. There is interplay between aging, sedentary lifestyle, and unhealthy dietary habits, and insulin resistance, inflammation, and oxidative stress, resulting in a quantitative and qualitative decline in muscle mass and an increase in fat mass. Myokines, including myostatin and irisin, and adipokines play a prominent role in the pathogenesis of sarcopenic obesity. It has been suggested that a number of disorders affecting metabolism, physical capacity, and quality of life may be attributed to sarcopenic obesity, although it is not as yet established whether sarcopenia and obesity act synergistically. There is to date no approved pharmacological treatment for sarcopenic obesity. The cornerstones of its management are weight loss and adequate protein intake combined with exercise, the latter in order to reduce the loss of muscle mass observed during weight loss following diet unpaired with exercise. A consensus on the definition of sarcopenic obesity is considered essential to facilitate the performance of mechanistic studies and clinical trials aimed at deepening our knowledge, thus enabling improved management of affected individuals in the near future.

The Multi-faceted Profile of Corticotropin-releasing Factor (CRF) Family of Neuropeptides and of their Receptors on the Paracrine/Local Regulation of the Inflammatory Response.

BACKGROUND: The corticotropin releasing factor (CRF) family of neuropeptides, CRF and the Urocortins, and their receptors are present not only within the central nervous system but also in the periphery at various locations and at the sites of inflammation where they influence its progress in a complex local / paracrine manner. OBJECTIVE AND METHODS: This review summarizes current knowledge regarding the regulation of inflammatory process by CRF family of neuropeptides and receptors with a special sight into their role in inflammatory pain and in chronic low grade inflammation that occurs in obesity. For this purpose, we searched for relevant peer-reviewed research articles using bibliographic databases. RESULTS: The CRF neuropeptides are either produced locally, by components of the inflammatory response or they may reach the inflammation sites via postganglionic sympathetic and sensory afferent nerve transport. It now appears that most immune cells taking part in the inflammatory process express CRF receptor type 1 (CRF1R) and type 2 (CRF2R) and thus represent targets of CRF neuropeptides. Indeed, mast cells, monocytes / macrophages, neutrophils and other types of immune cells express both types of the CRF receptors. In addition to their role in the pathophysiology of inflammation, CRF and its receptors also exert modulatory effects on inflammatory pain. Finally, it now appears that the CRF system is also present in adipose tissue and may play a crucial role in the development of the chronic low grade inflammation, which is characteristic of obesity. CONCLUSION: The local effects of the CRF family of neuropeptides can be either pro- or antiinflammatory depending on concentration of each type of neuropeptide present and the ratio of the local expression of their receptors CRF1R and CRF2R.

Adiponectin levels may help assess the clinical repercussions of obesity irrespective of body mass index.

OBJECTIVE: Adiponectin is the major product of adipose tissue. The aim of this study was to associate adiponectin levels with adipose tissue and metabolic indices. DESIGN: Plasma samples of 274 non-diabetic volunteers were collected to evaluate for adiponectin, inflammatory markers, insulin and lipid parameters. Body fat composition was measured by DEXA. RESULTS: As expected, adiponectin levels correlated with body mass index (BMI) and gender but a wide scattering was evident. When the population was divided into two groups per median levels of adiponectin (11.94 µg/mL), adiponectin was correlated with various metabolic indices. Persons displaying relatively high adiponectin levels [17.7(CI:14.8-21.0]µg/mL; MEDIAN (25%-75%)] exhibited lower levels of inflammatory markers (hs-CRP, plasminogen, erythrocyte sedimentation rate), circulating lipids and markers of insulin sensitivity (fasting blood glucose, insulin, HbA1c and HOMA-IR) compared to those individuals displaying low-adiponectin levels [8.9(CI:6.9-10.6)µg/mL]. The percentage of high-adiponectin individuals decreased from 69.6% in the normal-BMI group to 36.5% in the obese-BMI group. Average adiponectin levels in the high-adiponectin normal-BMI group were significantly higher compared to the high-adiponectin obese-BMI group (p=0.014). Regarding body fat, only the individuals with high adiponectin levels in either the combined population or within the obese-BMI group displayed low levels of waist-to-hip ratio. Interestingly, high-adiponectin levels within the obese-BMI group were associated with higher legs fat than trunk fat as compared to the low-adiponectin obese-BMI group. CONCLUSIONS: Our data suggest that the distribution of adiponectin above or below a cutoff level may offer additional clinical information over and above that of BMI grouping regarding inflammatory profile, insulin-sensitivity and adiposity.

Selective and differential interactions of BNN27, a novel C17-spiroepoxy steroid derivative, with TrkA receptors, regulating neuronal survival and differentiation.

Nerve growth factor (NGF) holds a pivotal role in brain development and maintenance, been also involved in the pathophysiology of neurodegenerative diseases. Here, we provide evidence that a novel C17-spiroepoxy steroid derivative, BNN27, specifically interacts with and activates the TrkA receptor of NGF, inducing phosphorylation of TrkA tyrosine residues and down-stream neuronal survival-related kinase signaling. Additionally, BNN27 potentiates the efficacy of low levels of NGF, by facilitating its binding to the TrkA receptors and differentially inducing fast return of internalized TrkA receptors into neuronal cell membranes. Furthermore, BNN27 synergizes with NGF in promoting axonal outgrowth, effectively rescues from apoptosis NGF-dependent and TrkA positive sympathetic and sensory neurons, in vitro, ex vivo and in vivo in NGF null mice. Interestingly, BNN27 does not possess the hyperalgesic properties of NGF. BNN27 represents a lead molecule for the development of neuroprotective TrkA receptor agonists, with potential therapeutic applications in neurodegenerative diseases and in brain trauma.

Vitamin D levels in a large Mediterranean cohort: reconsidering normal cut-off values.

OBJECTIVE: The determination of the normal range of 25-hydroxyvitamin D [25-(OH)D], though currently based on suppression of PTH levels, still remains a controversial issue. The 25-(OH)D levels exhibit gender and seasonal variability, the latter attributed in part to changes of insolation. DESIGN: The aim of this cross-sectional study was to estimate the levels of 25-(OH)D on the island of Crete and their correlation with metabolic, hormonal and bone turnover parameters. The study was performed over a period of five years and involved 8,183 male and female individuals (8,042 analyzed). RESULTS: Our results are as follows: (1) 25-(OH)D was significantly lower than expected (19.48±9.51 and 18.01±9.01 (ng/mL+SD) in males and females, respectively); (2) seasonal variation of 25-(OH)D was observed in both sexes (females < males), with values peaking in August; (3) a decline of 25-(OH)D was evident with advancing age, with lower levels in females compared to males up to menopause and no apparent difference between the genders thereafter; (4) levels of 25-(OH)D were lower in renal function impairment, diabetes/insulin resistance and inflammation, while no correlation was detectable in thyroid dysfunction; (5) normalization of PTH levels was observed at ~20 ng/mL 25-(OH)D. At the same cut-off level, a significant decrease of all measured bone turnover indices (b-ALP, osteocalcin and CTX) was evident. CONCLUSION: Based on the above data, it appears that a cut-off level of 25-(OH)D close to 20 ng/mL better reflects the physiology of our population.

Muscular effects of vitamin D in young athletes and non-athletes and in the elderly.

Muscles are major targets of vitamin D. Exposure of skeletal muscles to vitamin D induces the expression of multiple myogenic transcription factors enhancing muscle cell proliferation and differentiation. At the same time vitamin D suppresses the expression of myostatin, a negative regulator of muscle mass. Moreover, vitamin D increases the number of type II or fast twitch muscle cells and in particular that of type IIA cells, while its deficiency causes type IIA cell atrophy. Furthermore, vitamin D supplementation in young males with low vitamin D levels increases the percentage of type IIA fibers in muscles, causing an increase in muscular high power output. Vitamin D levels are strongly associated with exercise performance in athletes and physically active individuals. In the elderly and in adults below the age of 65, several studies have established a close association between vitamin D levels and neuromuscular coordination. The aim of this review is to appraise our current understanding of the significance of vitamin D on muscular performance in both older and frail individuals as well as in younger adults, athletes or non-athletes with regard to both ordinary everyday musculoskeletal tasks and peak athletic performance.

In prostate cancer, low adiponectin levels are not associated with insulin resistance.

PURPOSE: Adiponectin, an adipose tissue-derived hormone with insulin-sensitizing effect, has been inversely associated with several hormonally dependent malignancies. Prostate cancer is associated with low levels of adiponectin, which have been proposed as an independent risk factor for this malignancy. Aim of this study was to examine whether hypoadiponectinaemia in prostate is associated with insulin resistance. EXPERIMENTAL DESIGN: Plasma samples and covariate data in the context of a case-control study of 300 Greek men were evaluated including 75 patients with prostate cancer, 75 patients with benign prostatic hyperplasia (BPH) and 150 age-matched healthy controls. RESULTS: Patients with prostate cancer had significantly lower plasma adiponectin levels compared with the other two groups, that is BPH patients and healthy controls (7.4 ± 5 ng/mL vs. 11.5 ± 6.4 ng/mL and 12.8 ± 8 ng/mL, respectively). On the other hand, no statistically significant differences were found between patients with prostate cancer and the other two groups for both HOMA-IR and QUICKI (P-value = 0.551). As expected, in all three groups, the levels of adiponectin correlated negatively with HOMA-IR (rho = -0.214, P-value = 0.006), QUICKI (rho = 0.214, P-value = 0.006) and insulin levels (rho = 0.942, P-value < 0.001). CONCLUSION: In spite of what would have been expected from the relevant literature, our data suggest that the hypoadiponectinaemia in prostatic cancer does not appear to be associated with insulin resistance.

Serum miR-155 as a potential biomarker of male fertility.

STUDY QUESTION: Are serum levels of micro-RNAs miR-155 and miR-146a associated with male fertility, low-grade systemic inflammation (LGSI) and androgens? SUMMARY ANSWER: miR-155 was associated with male subfertility independent of LGSI or androgens while miR-146a was only weakly associated with subfertility and LGSI. WHAT IS KNOWN ALREADY: Male subfertility has been associated with LGSI as well as with androgen deficiency. miR-155 and miR-146a are central regulators of inflammation and their level in cells and in the serum has been associated with several inflammatory conditions. STUDY DESIGN, SIZE, DURATION: In this case-control study, two independent groups of 60 subjects each (exploratory and confirmatory cohort) were randomly selected from an ongoing study on subfertile men (in total: hypogonadal; n = 40, eugonadal; n = 40 and control group n = 39) at a University Hospital Reproductive Medicine Centre. Individuals were matched for age. PARTICIPANTS/MATERIALS, SETTING, METHODS: Total RNA was isolated from cell-free serum. As internal control a synthetic miRNA, UniSp6, was added to each sample prior to extraction. miRNA expression levels were measured by real-time RT-PCR and presented as fold difference (arbitrary units, U) from control. Sera from these individuals had been previously analyzed for hormone and cytokine levels. MAIN RESULTS AND THE ROLE OF CHANCE: Serum levels of miR-155 were associated with levels of miR-146a (P < 0.0001), but only miR-146a was associated with inflammatory markers. miR-155 was strongly associated with subfertility (for subfertile group 1.88 U, 95% confidence interval (CI) 1.6-2.1 U versus 1.15, 95% CI 1.0-1.2 U in controls; P = 0.001). Receiver operating characteristic curve analysis indicated that miR-155 but not miR-146a can be used as a marker of subfertility. MiR-155 with a cutoff value of 1.77 had 47% sensitivity and 95% specificity for identifying subfertility and a positive predictive value (PPV) and negative predictive value (NPV) of 95 and 47%, respectively. When used in combination with FSH, sensitivity and specificity were 80 and 100%, respectively, while PPV and NPV were 100 and 71%, respectively, those values being higher than for the FSH alone. Repeating the results obtained in the exploratory cohort in an independent confirmatory cohort reduced the risk of a chance finding. LIMITATIONS, REASONS FOR CAUTION: Although the results from the exploratory cohort were confirmed in the confirmatory cohort, studies from other centers are needed to establish the role of miR-155 as a new biomarker of male fertility. Furthermore, the role of this marker in distinguishing between different groups of male subfertility is to be elucidated. WIDER IMPLICATIONS OF THE FINDINGS: Association of the inflammatory miRNA miR-155 with male fertility contributes to our understanding of the pathophysiology of subfertility and suggests a novel biomarker. Serum miR-155 in combination with FSH has higher diagnostic specificity and sensitivity compared with FSH alone. STUDY FUNDING/COMPETING INTERESTS: This work was supported by grants from Swedish Governmental Grant (ALF), Skane county council research and development foundation, Skane University Hospital Fonds and by the EU and Greek funds under the action 'Education and lifelong learning' program THALIS-FAT-VESSEL (No 379527). The authors have no competing interests to disclose.

The impact of adipose tissue-derived factors on the hypothalamic-pituitary-gonadal (HPG) axis.

Adipose tissue produces factors, including adipokines, cytokines and chemokines which, when released, systemically exert endocrine effects on multiple tissues thereby affecting their physiology. Adipokines also affect the hypothalamic-pituitary-gonadal (HPG) axis both centrally, at the hypothalamic-pituitary level, and peripherally acting on the gonads themselves. Among the adipokines, leptin, adiponectin, resistin, chemerin and the peptide kisspeptin have pleiotropic actions on the HPG axis affecting male and female fertility. Furthermore, adipokines and adipose tissue-produced factors readily affect the immune system resulting in inflammation, which in turn impact the HPG axis, thus evidencing a link between metabolic inflammation and fertility. In this review we provide an overview of the existing extensive bibliography on the crosstalk between adipose tissue-derived factors and the HPG axis, with particular focus on the impact of obesity and the metabolic syndrome on gonadal function and fertility.

Dehydroepiandrosterone: an ancestral ligand of neurotrophin receptors.

Dehydroepiandosterone (DHEA), the most abundant steroid in humans, affects multiple cellular functions of the endocrine, immune, and nervous systems. However, up to quite recently, no receptor has been described specifically for it, whereas most of its physiological actions have been attributed to its conversion to either androgens or estrogens. DHEA interacts and modulate a variety of membrane and intracellular neurotransmitter and steroid receptors. We have recently reported that DHEA protects neuronal cells against apoptosis, interacting with TrkA, the high-affinity prosurvival receptor of the neurotrophin, nerve growth factor. Intrigued by its pleiotropic effects in the nervous system of a variety of species, we have investigated the ability of DHEA to interact with the other two mammalian neurotrophin receptors, ie, the TrkB and TrkC, as well as their invertebrate counterparts (orthologs) in mollusks Lymnaea and Aplysia and in cephalochordate fish Amphioxus. Amazingly, DHEA binds to all Trk receptors, although with lower affinity by 2 orders of magnitude compared with that of the polypeptidic neurotrophins. DHEA effectively induced the first step of the TrkA and TrkC receptors activation (phosphorylation at tyrosine residues), including the vertebrate neurotrophin nonresponding invertebrate Lymnaea and Aplysia receptors. Based on our data, we hypothesize that early in evolution, DHEA may have acted as a nonspecific neurotrophic factor promoting neuronal survival. The interaction of DHEA with all types of neurotrophin receptors offers new insights into the largely unidentified mechanisms of its actions on multiple tissues and organs known to express neurotrophin receptors.