OnLine First 2013

[Michael Scally MD]

Montoya ER, Terburg D, Bos PA, et al. Testosterone administration modulates moral judgments depending on second-to-fourth digit ratio. Psychoneuroendocrinology. ScienceDirect.com - Psychoneuroendocrinology - Testosterone administration modulates moral judgments depending on second-to-fourth digit ratio

Moral judgment involves the interplay of emotions and social cognitions. The male sex-hormone testosterone might play a role in moral reasoning as males are more utilitarian than females in their moral decisions, and high salivary testosterone levels also are associated with utilitarian moral decisions. However, there is no direct evidence for a role of testosterone in moral reasoning. Recent testosterone administration studies show effects on cognitive empathy and social cooperation, which depend on right-hand's second-to-fourth (2D:4D) digit ratio, a proxy for prenatal sex-hormone (testosterone-versus-estradiol) priming. Here, in a placebo-controlled within-subjects design using 20 young females we show that 2D:4D predicts 44% of the variance in the effects of testosterone administration on moral judgment. Subjects who show an increase in utilitarian judgments following testosterone administration have significantly higher than average 2D:4D (relatively high prenatal estradiol priming), while subjects showing more deontological judgments following testosterone administration have near-significantly lower 2D:4D (relatively high prenatal testosterone priming). We argue that prenatally-organized differences in aromatase, i.e. conversion from testosterone to estradiol in the brain, might underlie these effects. Our findings suggest that early neurodevelopmental effects of sex steroids play a crucial role in the activational effects of hormones on moral reasoning later in life.

 

[Michael Scally MD]

Chan A-W, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 Statement: Defining Standard Protocol Items for Clinical Trials. Annals of Internal Medicine. 2013 Jan. Annals of Internal Medicine | SPIRIT 2013 Statement: Defining Standard Protocol Items for Clinical Trials

The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol guidelines vary greatly in content and quality. This article describes the systematic development and scope of SPIRIT (Standard Protocol Items:Recommendations for Interventional Trials) 2013, a guideline for the minimum content of a clinical trial protocol.The 33-item SPIRIT checklist applies to protocols for all clinical trials and focuses on content rather than format. The checklist recommends a full description of what is planned; it does not prescribe how to design or conduct a trial. By providing guidance for key content, the SPIRIT recommendations aim to facilitate the drafting of high-quality protocols. Adherence to SPIRIT would also enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, sponsors, funders, research ethics committees or institutional review boards, peer reviewers, journals, trial registries, policymakers, regulators, and other key stakeholders.

 

[Michael Scally MD]

You T, Disanzo BL, Arsenis NC. Aerobic Exercise Training Attenuates Obesity-Related Hypogonadism in Male Rats. Med Sci Sports Exerc. Aerobic Exercise Training Attenuates Obesity-Related Hypogon... : Medicine & Science in Sports & Exercise

Hypogonadism is associated with obesity and other features of metabolic syndrome in males.

PURPOSE: The purpose of this study was to compare lean and obese male Zucker rats on their reproductive endocrine function in response to aerobic exercise training.

METHODS: Lean (Fa/Fa) and obese (fa/fa) male Zucker rats at 2 months of age were randomly assigned to a sedentary and an aerobic exercise training group (lean sedentary: n = 7, lean exercise: n = 8, obese sedentary, n = 7, obese exercise: n = 7). The exercise group walked on a rat treadmill, starting at 10 m/min for 20 min and building up to 20 m/min for 60 min, 5 times per week for 8 weeks. Serum levels of total and free testosterone, and testicular levels of testosterone, as well as epididymal and inguinal adipose tissue monocyte chemotactic protein 1 (MCP-1) release levels were measured.

RESULTS: There were significant obesity and exercise interactions on serum levels of total and free testosterone, and testicular levels of testosterone (all P < 0.05). Compared to lean sedentary rats, obese sedentary rats had lower serum and testicular testosterone levels (0.72- to 0.74-fold, all P < 0.001). There were no group differences between lean sedentary and lean exercise rats on serum and testicular testosterone levels. However, compared to the obese sedentary group, the obese exercise group had higher serum and testicular testosterone levels (1.37- to 1.47-fold, all P < 0.05). In the whole cohort, serum and testicular testosterone levels were inversely related to epididymal adipose tissue MCP-1 secretion (r = -0.40 to r = -0.45, all P < 0.05).

CONCLUSIONS: Our results support that aerobic exercise training could improve severe obesity related hypogonadism in male Zucker rats. The underlying mechanism needs to be further clarified.

 

[Michael Scally MD]

Delhanty PJ, Huisman M, Baldeon-Rojas LY, et al. Des-acyl ghrelin analogs prevent high-fat-diet-induced dysregulation of glucose homeostasis. Faseb J. Des-acyl ghrelin analogs prevent high-fat-diet-induced dysregulation of glucose homeostasis

There is clinical evidence that des-acyl ghrelin (DAG) favorably modulates glucose and lipid metabolism, although its mode of action is unknown. A murine model of prediabetes was used to assess possible mechanisms of action for DAG and a newly developed bioactive analog, AZP531. C57BL/6J mice were infused with saline, DAG, or AZP531 continuously for 4 wk, and fed either normal diet (ND) or normal diet for 2 wk followed by a high-fat diet (HFD) for 2 wk. Compared with mice in the ND group, HFD increased body and fat mass, caused glucose intolerance and insulin resistance, had proinflammatory effects in white adipose tissue, and caused lipid accumulation in brown adipose tissue. DAG and AZP531 treatment prevented HFD-induced proinflammatory effects, stimulated expression of mitochondrial function markers in brown adipose tissue, and prevented development of a prediabetic metabolic state. AZP531 also prevented a HFD-induced increase in acyl ghrelin levels. Our data indicate DAG analogs as potential treatment for the prevention of metabolic syndrome.

 

[Michael Scally MD]

Oguz F, Eltas A, Beytur A, Akdemir E, Uslu MO, Gunes A. Is There a Relationship Between Chronic Periodontitis and Erectile Dysfunction? J Sex Med. Is There a Relationship Between Chronic Periodontitis and Erectile Dysfunction? - O?uz - 2012 - The Journal of Sexual Medicine - Wiley Online Library

Introduction. Chronic periodontitis (CP) is characterized with inflammation of the gingival tissues, which causes endothelial dysfunction in different organs.

Aim. In this study, we investigated the association of CP with the erectile dysfunction (ED).

Methods. The study group included 80 male patients with ED and 82 male patients without ED (control), aged between 30 and 40 years. The International Index of Erectile Function (IIEF) questionnaire was used to assess male sexual function, particularly the presence or absence of ED.

Main Outcome Measures. The patients in the study and control groups were statistically compared according to their plaque index (PI), bleeding on probing (BoP), probing depth (PD), and clinical attachment level (CAL).

Results. In the non-ED and the ED groups, the mean age was 35.7 +/- 4.8 and 34.9 +/- 4.9 years, respectively. Patients' characteristics including body mass index, household income, and education status were similar in both groups (P > 0.05). Nineteen patients (23%) had severe CP in the non-ED group; 42 patients (53%) had severe CP in the ED group. Logistic regression analysis showed a significantly high association between ED and the severity of CP (odds ratio: 3.29, 95% confidence interval: 1.36-9.55, P < 0.01). The mean values of PI, BoP, and the percentages of sites with PD >4 mm and sites with CAL >4 mm were significantly higher in the ED group than in the control group (P < 0.05). The mean values of PD and CAL were not significantly different in the two groups (P > 0.05). The decayed, missing, filled teeth scores were also significantly higher in the ED group than in the non-ED group (P < 0.05).

Conclusion. Our results have suggested that CP had a high association with ED in young adults at 30-40 years. We think that it will be of benefit to consider periodontal disease as a causative clinical condition of ED in such patients.

 

[Michael Scally MD]

Towards A Decade Of Detecting New Analogues Of Sildenafil, Tadalafil And Vardenafil In Food Supplements

Highlights

? Analogues of sildenafil, tadalafil, and vardenafil are predominantly found as adulterants in food supplements.
? Analogues are essentially experimental drugs which were discarded from the drug discovery process for having deficiencies.
? The number of analogues of ED drugs identified increased from 1 in 2003 to at least 46 in 2011.
? Most analogues were described in patent literature or were derived from the disclosed information.
? Food supplements adulterated with analogues pose a high health risk but little is known about the actual harm caused.


Venhuis BJ, de Kaste D. Towards a decade of detecting new analogues of sildenafil, tadalafil and vardenafil in food supplements: a history, analytical aspects and health risks. J Pharm Biomed Anal 2012;69:196-208. ScienceDirect.com - Journal of Pharmaceutical and Biomedical Analysis - Towards a decade of detecting new analogues of sildenafil, tadalafil and vardenafil in food supplements: A history, analytical aspects and health risks

The scale at which erectile dysfunction (ED) medicines are obtained outside of the official health system rivals and possibly exceeds legitimate sales. According to literature a high-risk segment of this market is occupied by adulterated food supplements. The principle adulterants identified were structural analogues of the registered ED drugs sildenafil, tadalafil, and vardenafil. Currently, at least 46 different analogues have been reported and still more are expected. The intellectual origin of analogues was found in patent literature which described the drug discovery process. Patent literature offers a flexible approach to synthesize hundreds of analogues. Most of the analogues currently known had long been disclosed in patent literature. Screening for (new) analogues is best carried out by using advanced LC-MS/MS techniques that focus on marker fragment ions. Analogues are experimental drugs in essence because most have no known efficacy or safety profile. Their use in seemingly harmless food supplements is expected to cause serious adverse effects. However, few reports have emerged in literature on actual harm. Considering the exposure to analogues and their adverse effects being unknown a gross underreporting of complaints is expected.

 

[Michael Scally MD]

Genetic Control of Obesity and Gut Microbiota Composition

Highlights

º Detailed analysis of diet-induced obesity in more than 100 inbred mouse strains
º Identification of 11 genetic loci associated with obesity and dietary responsiveness
º Significant overlap between mouse loci with human GWAS loci for obesity
º Strain-specific shifts in gut microbiota composition in response to dietary intervention


Parks Brian W, Nam E, Org E, et al. Genetic Control of Obesity and Gut Microbiota Composition in Response to High-Fat, High-Sucrose Diet in Mice. Cell metabolism 2013;17(1):141-52. Cell Metabolism - Genetic Control of Obesity and Gut Microbiota Composition in Response to High-Fat, High-Sucrose Diet in Mice

Obesity is a highly heritable disease driven by complex interactions between genetic and environmental factors. Human genome-wide association studies (GWAS) have identified a number of loci contributing to obesity; however, a major limitation of these studies is the inability to assess environmental interactions common to obesity. Using a systems genetics approach, we measured obesity traits, global gene expression, and gut microbiota composition in response to a high-fat/high-sucrose (HF/HS) diet of more than 100 inbred strains of mice. Here we show that HF/HS feeding promotes robust, strain-specific changes in obesity that are not accounted for by food intake and provide evidence for a genetically determined set point for obesity. GWAS analysis identified 11 genome-wide significant loci associated with obesity traits, several of which overlap with loci identified in human studies. We also show strong relationships between genotype and gut microbiota plasticity during HF/HS feeding and identify gut microbial phylotypes associated with obesity.

 

[Michael Scally MD]

Miyake R, Uchimura T, Li X, Imasaka T. Fluorescence lifetime imaging microscopy for the monitoring of green fluorescent protein-tagged androgen receptors in living cells. Chem Pharm Bull (Tokyo) 2013;61(1):82-4. https://www.jstage.jst.go.jp/article/cpb/61/1/61_c12-00428/_article

Fluorescence lifetime imaging microscopy (FLIM) was used to monitor the interaction between androgen receptor (AR) tagging of a green fluorescent protein (GFP) and the ligands in living cells. The fluorescence lifetime of the AR-GFP without ligands was ca. 3.1 ns, which was reduced to ca. 2.5 ns after treatment with agonist 5alpha-dihydrotestosterone. On the other hand, the fluorescence lifetime of AR-GFP was not changed after treatment with antagonist hydroxyflutamide. The reaction kinetics was simulated in the present study, and the obtained results indicated the possibility of the presence of an intermediate complex during the reaction. FLIM can be used to record the ratio of the AR as it reacts with an agonist, and, therefore, it is useful for acquiring information concerning the interaction between AR and ligands in living cells.

 

[Michael Scally MD]

Lowe NM, Medina MW, Stammers AL, et al. The relationship between zinc intake and serum/plasma zinc concentration in adults: a systematic review and dose-response meta-analysis by the EURRECA Network. Br J Nutr 2012;108(11):1962-71. Cambridge Journals Online - Abstract

Dietary Zn recommendations vary widely across Europe due to the heterogeneity of approaches used by expert panels. Under the EURopean micronutrient RECommendations Aligned (EURRECA) consortium a protocol was designed to systematically review and undertake meta-analyses of research data to create a database that includes ‘best practice’ guidelines which can be used as a resource by future panels when setting micronutrient recommendations. As part of this process, the objective of the present study was to undertake a systematic review and meta-analysis of previously published data describing the relationship between Zn intake and status in adults. Searches were performed of literature published up to February 2010 using MEDLINE, Embase and the Cochrane Library. Data extracted included population characteristics, dose of Zn, duration of study, dietary intake of Zn, and mean concentration of Zn in plasma or serum at the end of the intervention period. An intake–status regression coefficient () was estimated for each individual study, and pooled meta-analysis undertaken. The overall pooled for Zn supplementation on serum/plasma Zn concentrations from randomised controlled trials and observational studies was 0•08 (95 % CI 0•05, 0•11; P < 0•0001; I 2 84•5 %). An overall of 0•08 means that for every doubling in Zn intake, the difference in Zn serum or plasma concentration is (20•08 = 1•06), which is 6 %. Whether the dose–response relationship, as provided in the present paper, could be used as either qualitative or quantitative evidence to substantiate the daily Zn intake dose necessary to achieve normal or optimal levels of biomarkers for Zn status remains a matter of discussion.

 

[Michael Scally MD]

Roberts CK, Croymans DM, Aziz N, Butch AW, Lee CC. Resistance training increases SHBG in overweight/obese, young men. Metabolism. ScienceDirect.com - Metabolism - Resistance training increases SHBG in overweight/obese, young men

Objective - Evidence suggests that SHBG affects glycemic control, predicts both T2D and metabolic syndrome, and is low in obese subjects. We sought to determine if resistance exercise training (RT) can increase sex hormone-binding globulin (SHBG) and ameliorate levels of related steroid hormones in overweight/obese, sedentary young men.

Materials/Methods - 36 participants (BMI 31.4 kg/m2, age 22 years) were randomized into an RT (12 weeks of training, 3/week) or control group (C, 12 weeks no training), and assessed for changes in SHBG, cortisol, testosterone, free testosterone (FT) and free androgen index (FAI). In addition, body composition and oral glucose tolerance testing was performed.

Results - 12 weeks of RT increased SHBG (P = 0.01) and decreased FAI (P < 0.05) and cortisol (P < 0.05) compared to C. FT decreased in RT (P = 0.01). Total testosterone did not change in either group. These changes were noted without weight loss, and in concert with increases in lean body mass (P = 0.0002 vs C) and decreases in glucose area under the curve (AUC) (P = 0.004), insulin AUC (P = 0.03), and total (P = 0.002) and trunk (P = 0.003) fat mass in RT.

Conclusion - In overweight/obese young men, RT increases SHBG and lowers FAI in obese young adult men.

Abbreviations - T2D, Type 2 diabetes; RT, Resistance training; C, Control; SHBG, Sex hormone-binding globulin; FT,Free testosterone; FAI, Free androgen index; AUC, Area under the curve; CVD, Cardiovascular disease; ECG, Electrocardiogram; RM, Repetition maximum; DB, Dumbbell; BB, Barbell; CTRC, Clinical and Translational Research Center; OGTT, Oral glucose tolerance test; DXA, Dual energy x-ray absorptiometry; CTRL, Clinical and Translational Research Laboratory; LBM, Lean body mass; BMI, Body mass index; WC, Waist circumference; MAD, Median absolute deviation

 

[Michael Scally MD]

Depot Differences In Gene Expression Specific In Males Or In Females Or Common In Both Sexes

Venn diagram depicts number of genes that were differentially expressed between gluteal and abdominal sc adipose tissue, either in a sex-specific way (only in males or only in females) or in both sexes.

Karastergiou K, Fried SK, Xie H, et al. Distinct Developmental Signatures of Human Abdominal and Gluteal Subcutaneous Adipose Tissue Depots. Journal of Clinical Endocrinology & Metabolism 2012;98(1):362-71. Distinct Developmental Signatures of Human Abdominal and Gluteal Subcutaneous Adipose Tissue Depots

Context: Fat distribution differs in men and women, but in both sexes, a predominantly gluteal-femoral compared with abdominal (central) fat distribution is associated with lower metabolic risk. Differences in cellular characteristics and metabolic functions of these depots have been described, but the molecular mechanisms involved are not understood.

Objective: Our objective was to identify depot- and sex-dependent differences in gene expression in human abdominal and gluteal sc adipose tissues.

Design and Methods: Abdominal and gluteal adipose tissue aspirates were obtained from 14 premenopausal women [age 27.5 ± 7.0 yr, body mass index (BMI) 27.3 ± 6.2 kg/m2, and waist-to-hip ratio 0.82 ± 0.04] and 21 men (age 29.7±7.4 yr, BMI 27.2 ± 4.5 kg/m2, and waist-to-hip ratio 0.91 ± 0.07) and transcriptomes were analyzed using Illumina microarrays. Expression of selected genes was determined in isolated adipocytes and stromal vascular fractions from each depot, and in in vitrocultures before and after adipogenic differentiation.

Results: A total of 284 genes were differentially expressed between the abdominal and gluteal depot, either specifically in males (n = 66) or females (n = 159) or in both sexes (n = 59). Most notably, gene ontology and pathway analysis identified homeobox genes (HOXA2, HOXA3, HOXA4, HOXA5,HOXA9, HOXB7, HOXB8, HOXC8, and IRX2) that were down-regulated in the gluteal depot in both sexes (P = 2 × 10?10). Conversely, HOXA10 was up-regulated in gluteal tissue and HOXC13 was detected exclusively in this depot. These differences were independent of BMI, were present in both adipocytes and stromal vascular fractions of adipose tissue, and were retained throughout in vitro differentiation.

Conclusions: We conclude that developmentally programmed differences may contribute to the distinct phenotypic characteristics of peripheral fat.

 

[Michael Scally MD]

van der Klaauw AA, Keogh JM, Henning E, et al. Postprandial Total Ghrelin Suppression Is Modulated by Melanocortin Signaling in Humans. Journal of Clinical Endocrinology & Metabolism. Postprandial Total Ghrelin Suppression Is Modulated by Melanocortin Signaling in Humans

Contents: Ghrelin is implicated in meal initiation because circulating levels increase before and fall after meal consumption. In rodents, ghrelin stimulates food intake via hypothalamic circuits expressing the melanocortin 4 receptor (MC4R).

Objective: The aim of the study was to investigate the impact of central melanocortinergic tone on ghrelin secretion in humans.

Design/Setting/Patients/Main Outcome Measure: We measured plasma total ghrelin before and after 3 standardized meals in patients with MC4R mutations and obese and lean controls. Fasting total ghrelin, area under the curve, and early (30-min) and intermeal postprandial total ghrelin suppression (the percentage difference between the premeal and the 30-min postprandial or intermeal nadir total ghrelin concentration) were calculated.

Results: Fasting total ghrelin concentrations and area under the curve for total ghrelin concentrations were significantly decreased in both obese groups compared to lean controls (fasting total ghrelin: lean controls, 1083 ± 203 pg/ml; and obese controls, 696 ± 81 pg/ml; MC4R: 609 ± 99 pg/ml, P < .05). Early and intermeal postprandial total ghrelin suppression was attenuated in MC4R-deficient patients compared to lean controls (P < .05); a similar pattern was observed for early postprandial suppression in comparison with obese controls, but this difference did not reach statistical significance (P = .09).

Conclusions: These findings are consistent with a role for central melanocortinergic signaling in modulating meal-related total ghrelin suppression.

 

[Michael Scally MD]

Murdter TE, Schroth W, Bacchus-Gerybadze L, et al. Activity Levels of Tamoxifen Metabolites at the Estrogen Receptor and the Impact of Genetic Polymorphisms of Phase I and II Enzymes on Their Concentration Levels in Plasma. Clin Pharmacol Ther 2012;89(5):708-17. Clinical Pharmacology & Therapeutics - Abstract of article: Activity Levels of Tamoxifen Metabolites at the Estrogen Receptor and the Impact of Genetic Polymorphisms of Phase I and II Enzymes on Their Concentration Levels in Plasma

The therapeutic effect of tamoxifen depends on active metabolites, e.g., cytochrome P450 2D6 (CYP2D6) mediated formation of endoxifen. To test for additional relationships, 236 breast cancer patients were genotyped forCYP2D6, CYP2C9, CYP2B6, CYP2C19, CYP3A5, UGT1A4, UGT2B7, andUGT2B15; also, plasma concentrations of tamoxifen and 22 of its metabolites, including the (E)-, (Z)-, 3-, and 4?-hydroxymetabolites as well as their glucuronides, were quantified using liquid chromatography–tandem mass spectrometry (MS). The activity levels of the metabolites were measured using an estrogen response element reporter assay; the strongest estrogen receptor inhibition was found for (Z)-endoxifen and (Z)-4-hydroxytamoxifen (inhibitory concentration 50 (IC50) 3 and 7 nmol/l, respectively). CYP2D6 genotypes explained 39 and 9% of the variability of steady-state concentrations of (Z)-endoxifen and (Z)-4-hydroxytamoxifen, respectively. Among the poor metabolizers, 93% had (Z)-endoxifen levels below IC90 values, underscoring the role of CYP2D6 deficiency in compromised tamoxifen bioactivation. For other enzymes tested, carriers of reduced-function CYP2C9(*2, *3) alleles had lower plasma concentrations of active metabolites (P < 0.004), pointing to the role of additional pathways.

 

[Michael Scally MD]

Highlights
? Estradiol, estrone and estriol are the main physiological estrogens.
? A structural marker for these estrogens is a phenolic A ring.
? ?5-androstenediol, 5?-androstanediol and 27-hydroxycholesterol also are estrogens.
? These estrogens have a saturated A ring with a 3?-hydroxyl and a C19 methyl group.
? Further studies of these “alternative” estrogens are warranted.


Baker ME. What are the Physiological Estrogens? Steroids. ScienceDirect.com - Steroids - What are the Physiological Estrogens?

Estradiol [E2] is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Delta(4) bond and a C19 methyl group. Crystal structures of E2 in the estrogen receptor [ER] confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including Delta5-androstenediol, 5alpha-androstanediol and 27-hydroxycholesterol, which have a saturated A ring containing a 3beta-hydroxyl and a C19 methyl group, also mediate physiological responses through binding to estrogen receptor-alpha [ERalpha] and ERbeta. Moreover, selective estrogen response modulators [SERMs] with diverse structures also regulate transcription of ERalpha and ERbeta. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by ERalpha and ERbeta a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities.

 

[Michael Scally MD]

Jauch-Chara K, Schmid SM, Hallschmid M, Oltmanns KM, Schultes B. Pituitary-Gonadal and Pituitary-Thyroid Axis Hormone Concentrations before and during a Hypoglycemic Clamp after Sleep Deprivation in Healthy Men. PLoS ONE 2013;8(1):e54209. PLOS ONE: Pituitary-Gonadal and Pituitary–Thyroid Axis Hormone Concentrations before and during a Hypoglycemic Clamp after Sleep Deprivation in Healthy Men

Total sleep deprivation (TSD) exerts strong modulatory effects on the secretory activity of endocrine systems that might be related to TSD-induced challenges of cerebral glucose metabolism. Here, we investigate whether TSD affects the course of male pituitary-gonadal and pituitary-thyroid axis related hormones during a subsequent 240-min hypoglycemic clamp.

Ten healthy men were tested on 2 different conditions, TSD and 7-hour regular sleep. Circulating concentrations of total testosterone, prolactin (PRL), thyroid stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxin (fT4) were measured during baseline and a subsequent hypoglycemic clamp taking place in the morning.

Basal, i.e. at 07:00 am measured, concentrations of total testosterone (P = 0.05) and PRL (P<0.01) were lower while the values of TSH (P = 0.02), fT3 (P = 0.08), and fT4 (P = 0.04) were higher after TSD as compared to regular sleep. During the subsequent hypoglycemic clamp (all measurements from baseline to the end of the clamp analyzed) total testosterone concentrations in the regular sleep (P<0.01) but not in the TSD condition (P = 0.61) decreased, while PRL levels increased (P = 0.05) irrespectively of the experimental condition (P = 0.31). TSH concentrations decreased during hypoglycemia (P<0.01), with this decrease being more pronounced after TSD (P = 0.04). However, at the end of the hypoglycemic clamp concentrations all of the above mentioned hormones did not differ between the two sleep conditions.

Our data indicate a profound influence of TSD on male pituitary-gonadal and pituitary-thyroid axis hormones characterized by reduced basal testosterone and PRL levels and increased TSH levels. However, since concentrations of these hormones measured at the end of the 240-min hypoglycemic clamp were not affected by TSD it can be speculated that the influence of TSD on the two endocrine axes is rather short lived or does not interact in an additive manner with their responses to hypoglycemia.

 

[Michael Scally MD]

Zhong L, Sun J, Liu GH, Zhu YJ, Zhu J. Research on the steroidogenesis of proliferated Leydig cells in vitro. J Artif Organs. Research on the steroidogenesis of proliferated Leydig cells in vitro - Online First - Springer

Several treatments for patients with primary hypogonadism are available, but these are associated with major complications. In this study, we explored the possibility of testosterone secretion by proliferated Leydig cells embedded in Matrigel with the aim of developing a source of endogenous testosterone supplement for recipients while reducing the need for donor material. Leydig cells were isolated and proliferated in vitro. The expression of 3beta-hydroxysteroid dehydrogenase, cholesterol side-chain cleaving enzyme (CYP11A1), and 17alpha-hydroxylase/17,20-lyase (CYP17A1) was analyzed to confirm the purity and steroidogenesis capability of Leydig cells. The proliferated cells were then embedded in three-dimensional Matrigel, and following culture the supernatant medium was collected for measurement of testosterone concentration by radioimmunoassay.

The biological behavior of the Leydig cells in the Matrigel was carefully observed under the microscope. Approximately 6.0 x 10(5) Leydig cells were obtained from one testis after primary culture in vitro. Aliquots of 1.0 x 10(5) Leydig cells were mixed with Matrigel, with the amount of cells in one pellet being equal to that in an adult testis. Leydig cells gradually formed aggregates when maintained in Matrigel. A rapid and constant linear increase in testosterone levels was detected in the supernatant medium.

Our results demonstrate that Matrigel is a perfect support matrix for Leydig cells. Proliferated Leydig cells embedded in Matrigel have a great steroidogenesis reserve. In our study, they contributed to continuous steroidogenesis, which implies that the pellet may provide the physiological demand for endogenous androgen once engrafted in vivo. This system may ultimately provide a novel alternative treatment for people who are in need of androgen replacement.

 

[Michael Scally MD]

Dong Y, Du RC, Jiang YT, Wu J, Li LL, Liu RZ. Impact of chromosomal translocations on male infertility, semen quality, testicular volume and reproductive hormone levels. J Int Med Res 2012;40(6):2274-83. http://www.jimronline.net/content/full/2012/40/6/2088.pdf

OBJECTIVE: To analyse the relationship between male infertility and chromosomal translocations, and the influence of different types of chromosomal translocations on semen quality, testicular volume and hormone levels.

METHODS: A retrospective cohort of infertile men was recruited for chromosomal analysis using standard Giemsa stain banding. Physical examinations, semen analysis, hormonal analysis and the detection of azoospermia factor (AZF) microdeletions were carried out. Men with normal fertility were used as controls.

RESULTS: Among the 1056 infertile men, 22 had chromosomal translocations (2.1%), including seven with Robertsonian translocations (0.7%), 11 with autosome-autosome reciprocal translocations (1.0%) and four with gonosome-autosome reciprocal translocations (0.4%). Left and right testicular volumes of patients with chromosomal translocations were significantly smaller than those in the fertile control group. There were no significant differences in hormone levels between patients with chromosomal translocations and fertile controls, except for significantly lower testosterone levels in patients with Robertsonian and gonosome-autosome reciprocal translocations compared with the controls. All AZF microdeletion analyses showed normal results.

CONCLUSIONS: Chromosomal translocations may cause reductions in testicular volume and testosterone level, which may impact spermatogenesis, resulting in azoospermia or oligozoospermia and male infertility.

 

[Michael Scally MD]

Upadhyaya SK, Sharma A, Rai DK, Thawani V. Anabolic androgenic steroids in delayed diagnosis of tuberculosis. J Pharmacol Pharmacother 2012;3(4):345-7. http://www.jpharmacol.com/article.asp?issn=0976-500X;year=2012;volume=3;issue=4;spage=345;epage=347;aulast=Upadhyaya

This is the first case report depicting masking of symptoms of intestinal tuberculosis by anabolic androgenic steroids (AAS) causing delay in diagnosis which lead to a major surgery. Negative tuberculosis skin test (TST) probably due to immunomodulating effects of AAS also contributed to the delay. Patient also had early dependence on AAS and rapid growth of scrotal sebaceous cysts, findings of which have not yet been reported.

 

[Michael Scally MD]

Kirk D, Misita C. Spuriously Elevated Testosterone Measurements Caused by Application of Testosterone Gel at or Near the Phlebotomy Site (January). Ann Pharmacother. http://www.theannals.com/content/early/2013/01/16/aph.1R543.full.pdf

OBJECTIVE: To report 2 cases of spuriously elevated testosterone measurements caused by contamination of blood samples by testosterone gel applied near the phlebotomy site.

CASE SUMMARIES: A 21-year-old male with primary hypogonadism and a 67-year-old male with secondary hypogonadism were prescribed standard replacement doses of testosterone gel. The patients' symptoms improved without adverse effects. However, their measured testosterone levels rose above the target range and paradoxically increased further despite decreasing the testosterone dose. In both cases, the gel had been applied near the site of venipuncture on the day of blood sampling. Subsequent testosterone measurements from blood obtained after the gel was applied away from the upper/mid arms were in therapeutic range.

DISCUSSION: To our knowledge, falsely elevated testosterone concentrations due to contamination of blood samples by testosterone gel have been reported only once (PubMed search, 1966-September 2012). In the cases we describe, application of the Naranjo probability scale suggests a probable likelihood that sample contamination caused the falsely elevated testosterone measurements. Health care professionals should recognize and take measures to prevent this problem, which could lead to inappropriate dose changes in hypogonadal patients.

CONCLUSIONS: The application of testosterone gel at or near the site of venipuncture can markedly increase the measured serum testosterone concentration.

 

[Michael Scally MD]

Wegner CJ, Kim B, Lee J. Trust your gut: galvanizing nutritional interest in intestinal cholesterol metabolism for protection against cardiovascular diseases. Nutrients 2013;5(1):208-22. Nutrients | Free Full-Text | Trust Your Gut: Galvanizing Nutritional Interest in Intestinal Cholesterol Metabolism for Protection Against Cardiovascular Diseases

Recent studies have demonstrated that the intestine is a key target organ for overall health and longevity. Complementing these studies is the discovery of the trans-intestinal cholesterol efflux pathway and the emerging role of the intestine in reverse cholesterol transport. The surfacing dynamics of the regulation of cholesterol metabolism in the intestine provides an attractive platform for intestine-specific nutritional intervention strategies to lower blood cholesterol levels for protection against cardiovascular diseases. Notably, there is mounting evidence that stimulation of pathways associated with calorie restriction may have a large effect on the regulation of cholesterol removal by the intestine. However, intestinal energy metabolism, specifically the idiosyncrasies surrounding intestinal responses to energy deprivation, is poorly understood. The goal of this paper is to review recent insights into cholesterol regulation by the intestine and to discuss the potential for positive regulation of intestine-driven cholesterol removal through the nutritional induction of pathways associated with calorie restriction.