OnLine First 2013

[Michael Scally MD]

Fabregat A, Pozo OJ, Marcos J, Segura J, Ventura R. The use of LC-MS/MS for the open detection of steroid metabolites conjugated with glucuronic acid. Anal Chem. The use of LC-MS/MS for the open detection of steroid metabolites conjugated with glucuronic acid - Analytical Chemistry (ACS Publications)

In humans, conjugation with glucuronic acid is the most important phase II metabolic reaction of steroidal compounds. Glucuronoconjugated metabolites have been conventionally studied by using beta-glucuronidase enzymes to release the phase I metabolites. It is well known that hydrolysis with beta-glucuronidase presents some limitations that may result on the underestimation of some conjugates. The aim of the present work was to develop and to evaluate liquid chromatography-tandem mass spectrometry (LC-MS/MS) scan methods for the open detection of steroid glucuronides in urine samples. The mass spectrometric behavior of thirteen representative steroid glucuronides, used as a model compounds, was studied. Characteristic ionization and collision induced dissociation behaviors were observed depending of the steroid glucuronide structure. Neutral loss (NL of 176, 194, 211 and 229 Da) and precursor ion (PI of m/z 141, 159 and 177, in positive mode; and m/z 75, 78 and 113, in negative mode) scan methods were evaluated. The NL scan method was chosen for the open detection of glucuronoconjugated steroids due to its sensitivity and the structural information provided by this method. The application of the NL scan method to urine samples collected after testosterone (T) undecanoate administration revealed the presence of two testosterone T metabolites which remain conjugated as glucuronides after an enzymatic hydrolysis of the urine. 3alpha,6beta-dihydroxy-5alpha-androstan-17-one (6beta-hydroxyandrosterone) glucuronide and 3alpha,6beta-dihydroxy-5beta-androstan-17-one (6beta-hydroxyetiocholanolone) glucuronide were established as the structures for these metabolites, by comparing the structure of the steroids released after chemical hydrolysis with reference materials. An increase of 50-300 folds of these metabolites after an oral administration of T undecanoate was observed, proving that their determination can be useful in the doping control field. Moreover, these results exemplify that significant information might be missed, unless direct methods for the direct determination of steroid glucuronides are employed.

 

[Michael Scally MD]

Simo R, Barbosa-Desongles A, Hernandez C, Selva DM. IL1beta down-regulation of sex hormone-binding globulin production by decreasing HNF-4alpha via MEK-1/2 and JNK MAPK pathways. Mol Endocrinol 2013;26(11):1917-27. IL1? Down-regulation of Sex Hormone-Binding Globulin Production by Decreasing HNF-4? Via MEK-1/2 and JNK MAPK Pathways

Patients suffering from low-grade chronic inflammatory diseases, such as rheumatoid arthritis, osteoarthritis, diabetes, and obesity, have low plasma sex hormone-binding globulin (SHBG) levels. These diseases are characterized among other features by high plasma IL1beta levels.

The aim of the present study is to explore whether IL1beta could regulate hepatic SHBG production to account for low SHBG levels in these diseases. We provide evidence that daily IL1beta treatment reduces SHBG production in HepG2 cells by the down-regulation of HNF-4A via the MAPK kinase (MEK)-1/2 and c-Jun N-terminal kinase (JNK) MAPK signaling pathways through the activation c-Jun transcription factors.

The human SHBG promoter sequence contains two putative activator protein 1 (AP1) binding sites recognized by c-Jun transcription factors, but they are not necessary for the IL1beta-induced down-regulation of SHBG promoter activity in luciferase reporter gene assays. Daily treatment with IL1beta reduces hepatic nuclear factor (HNF)-4alpha mRNA and protein levels via the MEK-1/2 and JNK MAPK signaling pathways. Moreover, IL1beta rapidly decreased HNF-4alpha mRNA and protein levels while increased phospho-c-Jun protein levels after the treatment. Finally, daily IL1beta treatment of human SHBG transgenic mice reduced plasma SHBG and SHBG mRNA levels. Moreover, IL1beta treatment also reduced HNF-4alpha mRNA and protein levels while increased hepatic phospho-c-Jun protein levels.

Our results show that IL1beta reduces hepatic SHBG production by decreasing HNF-4alpha via MEK-1/2 and JNK MAPK pathways. In addition, our findings suggest that IL1beta could be involved the low plasma SHBG levels reported in chronic low-grade inflammatory diseases.

 

[Michael Scally MD]

Glesby MJ, Albu J, Chiu YL, et al. Recombinant Human Growth Hormone and Rosiglitazone for Abdominal Fat Accumulation in HIV-Infected Patients with Insulin Resistance: A Randomized, Double-Blind, Placebo-Controlled, Factorial Trial. PLoS One 2013;8(4):e61160. PLOS ONE: Recombinant Human Growth Hormone and Rosiglitazone for Abdominal Fat Accumulation in HIV-Infected Patients with Insulin Resistance: A Randomized, Double-Blind, Placebo-Controlled, Factorial Trial

Background - Recombinant human growth hormone (rhGH) reduces visceral adipose tissue (VAT) volume in HIV-infected patients but can worsen glucose homeostasis and lipoatrophy. We aimed to determine if adding rosiglitazone to rhGH would abrogate the adverse effects of rhGH on insulin sensitivity (SI) and subcutaneous adipose tissue (SAT) volume.

Methodology/Principal Findings - Randomized, double-blind, placebo-controlled, multicenter trial using a 2×2 factorial design in which HIV-infected subjects with abdominal obesity and insulin resistance were randomized to rhGH 3 mg daily, rosiglitazone 4 mg twice daily, combination rhGH + rosiglitazone, or double placebo (control) for 12 weeks. The primary endpoint was change in SI by frequently sampled intravenous glucose tolerance test from entry to week 12. Body composition was assessed by whole body magnetic resonance imaging (MRI) and dual Xray absorptiometry (DEXA).

Seventy-seven subjects were randomized of whom 72 initiated study drugs. Change in SI from entry to week 12 differed across the 4 arms by 1-way ANCOVA (P = 0.02); by pair-wise comparisons, only rhGH (decreasing SI; P = 0.03) differed significantly from control. Changes from entry to week 12 in fasting glucose and glucose area under the curve on 2-hour oral glucose tolerance test differed across arms (1-way ANCOVA P = 0.004), increasing in the rhGH arm relative to control. VAT decreased significantly in the rhGH arms (?17.5% in rhGH/rosiglitazone and ?22.7% in rhGH) but not in the rosiglitazone alone (?2.5%) or control arms (?1.9%). SAT did not change significantly in any arm. DEXA results were consistent with the MRI data. There was no significant rhGH x rosiglitazone interaction for any body composition parameter.

Conclusions/Significance - The addition of rosiglitazone abrogated the adverse effects of rhGH on insulin sensitivity and glucose tolerance while not significantly modifying the lowering effect of rhGH on VAT.

 

[Michael Scally MD]

Shah K, Majeed Z, Jonason J, O'Keefe RJ. The Role of Muscle in Bone Repair: The Cells, Signals, and Tissue Responses to Injury. Curr Osteoporos Rep. The Role of Muscle in Bone Repair: The Cells, Signals, and Tissue Responses to Injury - Online First - Springer

Bone repair is a complicated process that includes many types of cells, signaling molecules, and growth factors. Fracture healing involves a temporally and spatially regulated biologic process that involves recruitment of stem cells to the injury site, tissue specific differentiation, angiogenesis, and remodeling. In light of its proximity to bone and abundant vascularity, muscle is an important potential source of cells and signals for bone healing. More complete understanding of the role of muscle in bone formation and repair will provide new therapeutic approaches to enhance fracture healing. Recent studies establish that muscle-derived stem cells are able to differentiate into cartilage and bone and can directly participate in fracture healing. The role of muscle-derived stem cells is particularly important in fractures associated with more severe injury to the periosteum. Sarcopenia is a serious consequence of aging, and studies show a strong association between bone mass and lean muscle mass. Muscle anabolic agents may improve function and reduce the incidence of fracture with aging.

 

[Michael Scally MD]

Beattie MC, Chen H, Fan J, Papadopoulos V, Miller P, Zirkin BR. Aging and Luteinizing Hormone Effects on Reactive Oxygen Species Production and DNA Damage in Rat Leydig Cells. Biology of Reproduction 2013;88(4):100, 1-7. http://www.biolreprod.org/content/88/4/100.abstract

We observed previously that after long-term suppression of luteinizing hormone (LH) and thus of Leydig cell steroidogenesis, restimulation of the Leydig cells by LH resulted in significantly higher testosterone production than by age-matched cells from control rats. These studies suggest that stimulation over time may elicit harmful effects on the steroidogenic machinery, perhaps through alteration of the intracellular oxidant-to-antioxidant balance. Herein we compared the effects of LH stimulation on stress response genes, formation of intracellular reactive oxygen species (ROS), and ROS-induced damage to ROS-susceptible macromolecules (DNA) in young and in aged cells. Microarray analysis indicated that LH stimulation resulted in significant increases in expression of genes associated with stress response and antiapoptotic pathways. Short-term LH treatment of primary Leydig cells isolated from young rats resulted in transiently increased ROS levels compared to controls. Aged Leydig cells also showed increased ROS soon after LH stimulation. However, in contrast to the young cells, ROS production peaked later and the time to recovery was increased. In both young and aged cells, treatment with LH resulted in increased levels of DNA damage but significantly more so in the aged cells. DNA damage levels in response to LH and the levels of intracellular ROS were highly correlated. Taken together, these results indicate that LH stimulation causes increased ROS production by young and aged Leydig cells and that while DNA damage occurs in cells of both ages, there is greater damage in the aged cells.

 

[Michael Scally MD]

Seftel AD, de la Rosette J, Birt J, Porter V, Zarotsky V, Viktrup L. Coexisting lower urinary tract symptoms and erectile dysfunction: a systematic review of epidemiological data. International Journal of Clinical Practice 2013;67(1):32-45. Coexisting lower urinary tract symptoms and erectile dysfunction: a systematic review of epidemiological data - Seftel - 2012 - International Journal of Clinical Practice - Wiley Online Library

Objective: Assess and categorise the available prevalence data on coexistent LUTS and ED in the general population and among individuals consulting a healthcare provider for any reason or when seeking treatment for LUTS and/or ED.

Methods: Literature search of English-language articles published during the last 15 years.

Results: Of 23 relevant studies identified, 12 used both the International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF) as assessment tools and 11 used alternative approaches. In studies using both IPSS and IIEF, overall prevalence of coexistent LUTS/ED of any severity was not assessable for men in the general population, but rates ranged from 14–37% based on alternative assessments. In the general male population, 13–29% had moderate to severe LUTS and 8–35% had moderate to severe ED. In studies using both IPSS and IIEF, overall prevalence of coexistent LUTS and ED of any severity was 71–80% among men seeking treatment for LUTS, and 74% based on alternative assessments. Among men who sought treatment for either condition, 67–100% had moderate to severe LUTS and 43–59% had moderate to severe ED. Coexistence of LUTS and ED increased with age, ranging from 59–86% among men aged 40s to 60s in primary care to 79–100% in treatment-seeking men with LUTS aged 50s to 70s. Impact on QoL varied, but health-related QoL was generally worse in treatment-seeking men compared with men in the general population.

Conclusions: Although less than one-third of middle-aged and older men in the general population have coexisting LUTS and ED, most men seeking treatment for either LUTS or ED have both conditions. Symptom severity and impact on QoL in each condition increase when LUTS and ED coexist.

 

[Michael Scally MD]

Ryu J-K, Suh J-K. Therapeutic Angiogenesis as a Potential Future Treatment Strategy for Erectile Dysfunction. World J Mens Health 2013;30(2):93-8. :: WJMH :: The World Journal of Men's Health

The cavernous endothelium plays a crucial role in regulating the tone of the underlying smooth muscle and physiologic penile erection. Recently, the link between erectile dysfunction (ED) and cardiovascular disease was unveiled, and the main etiology of ED was found to be vasculogenic. Although oral phosphodiesterase-5 inhibitors are generally effective for men with ED, such therapies do not cure underlying vasculopathy in the corpus cavernosum tissue. This review addresses current preclinical protein, gene, and cell or stem cell therapies for enhancing cavernous endothelial regeneration and restoring erectile function.

 

[Michael Scally MD]

Ivell R, Wade JD, Anand-Ivell R. INSL3 as a Biomarker of Leydig Cell Functionality. Biol Reprod. http://www.biolreprod.org/content/early/2013/04/12/biolreprod.113.108969.abstract

Insulin-like factor 3 (INSL3) is a small peptide hormone made and secreted uniquely by mature Leydig cells in the testes of all mammals. Importantly this expression and secretion appears to be constitutive and therefore reflects the differentiation status and number of the Leydig cells present, differing thereby from testosterone which is acutely and homeostatically regulated by the hormones of the HPG axis. As a consequence, the measurement of INSL3 either as mRNA in the testis, or as secreted peptide circulating in the blood, provides an excellent assessment of Leydig cell differentiation, for example, during fetal development, puberty or in aging, or following exposure to endocrine disrupting agents. Whereas INSL3 is proving increasingly useful as a biomarker for testis status, less is known about its functions, particularly in the adult male. Current evidence points to autocrine, paracrine and endocrine roles, acting through the G-protein coupled receptor called RXFP2, although more research is required to characterize these functions in detail.

 

[Michael Scally MD]

Daka B, Rosen T, Jansson PA, Larsson CA, Rastam L, Lindblad U. Low sex hormone-binding globulin is associated with hypertension: a cross-sectional study in a Swedish population. BMC Cardiovasc Disord 2013;13(1):30. BMC Cardiovascular Disorders | Abstract | Low sex hormone-binding globulin is associated with hypertension: a cross-sectional study in a Swedish population

BACKGROUND: The aim of this study was to investigate the association of sex hormone-binding globulin (SHBG) and hypertension in a Swedish population.

METHODS: The study is based on a random sample of a Swedish population of men and women aged 30--74 years (n=2,816). Total testosterone, oestradiol and SHBG were measured in 2,782 participants. Free androgen index was then calculated according to the formula FAI=100 x (Total testosterone)/SHBG. Hypertension was diagnosed according to JNC7.

RESULTS: In men, but not in women, significant association between SHBG and both diastolic (diastolic blood pressure: beta=-0.143 p<0.001) and systolic blood pressure (systolic blood pressure beta=-0.114 p<0.001) was found. The association was still significant after adjusting for age, body mass index (BMI), homeostatic model assessment insulin resistance (HOMA-IR), triglycerides, high density lipoproteins (HDL) and C-reactive protein (CRP) (diastolic blood pressure: beta=-0.113 p<0.001; systolic blood pressure beta=-0.093 p=0.001). An inverse association was observed between SHBG and hypertension in both men (B=-0.024 p<0.001) and women (B=-0.022 p<0.001). The association was still significant in women older than 50 years after adjustments for age, BMI, physical activity, CRP and alcohol consumption (B=-0.014, p=0.008).

CONCLUSION: In conclusion, these results show a strong association between SHBG and blood pressure independent of major determinants of high blood pressure. This association might be addressed to direct effects of SHBG in endothelial cells through the receptor for SHBG. If this is confirmed by other observational and experimental studies, it might become a new field for the development of therapies for lowering blood pressure.

 

[Michael Scally MD]

Are there estrogen-responsive kisspeptin neurons in males?

Dror T, Franks J, Kauffman AS. Analysis of Multiple Positive Feedback Paradigms Demonstrates a Complete Absence of LH Surges and GnRH Activation in Mice Lacking Kisspeptin Signaling. Biol Reprod. http://www.biolreprod.org/content/early/2013/04/12/biolreprod.113.108555.abstract

Kisspeptin stimulates GnRH neurons via the kisspeptin receptor, Kiss1r. In rodents, estrogen-responsive kisspeptin neurons in the rostral hypothalamus have been postulated to mediate estrogen-induced positive feedback induction of the preovulatory LH surge. However, conflicting evidence exists regarding the ability of mice lacking Kiss1r to display LH surges in response to exogenous hormones. Whether the discrepancy reflects different mouse strains used and/or utilization of different surge-induction paradigms is unknown. Here, we tested multiple hormonal paradigms in one Kiss1r KO model to see which paradigms, if any, could generate circadian-timed LH surges. Kiss1r KO and WT females were ovariectomized, given sex steroids in various modes, and assessed several days later for LH levels in the morning or evening (when surges occur). Serum LH levels were very low in all morning animals, regardless of genotype or hormonal paradigm. In each paradigm, virtually all WT females displayed clear LH surges in the evening, whereas none of the KO females demonstrated LH surges. The lack of LH surges in KO mice reflects a lack of GnRH secretion, rather than diminished pituitary responsiveness from a lifetime lack of GnRH exposure, because KO mice responded to GnRH priming with robust LH secretion. Moreover, high cfos-GnRH coexpression was detected in WT females in the evening, whereas low cfos-GnRH coexpression was present in KO females at all time-points. Our findings conclusively demonstrate that WT females consistently display LH surges under multiple hormonal paradigms, whereas Kiss1r KO mice do not, indicating that kisspeptin-Kiss1r signaling is mandatory for GnRH/LH surge induction.

 

[Michael Scally MD]

Roberts CK, Croymans DM, Aziz N, Butch AW, Lee CC. Resistance training increases SHBG in overweight/obese, young men. Metabolism: clinical and experimental. Elsevier

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. 36 participants (BMI 31.4kg/m2, age 22years) were randomized into an RT (12weeks of training, 3/week) or control group (C, 12weeks 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. 12weeks 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. In overweight/obese young men, RT increases SHBG and lowers FAI in obese young adult men.

 

[Michael Scally MD]

Bolland MJ, Grey A, Horne AM, Reid IR. Testosterone Levels Following Decreases in Serum Osteocalcin. Calcif Tissue Int. Testosterone Levels Following Decreases in Serum Osteocalcin - Online First - Springer

Recent preclinical studies suggest that osteoblasts are able to induce testosterone production by the testis, a process mediated by osteocalcin. Bisphosphonates substantially reduce osteocalcin levels. If osteocalcin is an important regulator of testosterone levels in adult men, it would be expected that the substantial reductions in osteocalcin induced by zoledronate would impact negatively on testosterone levels. Previously, we carried out a 2-year randomized, controlled trial of annual 4 mg zoledronate in 43 HIV-infected men. To explore the relationship between osteocalcin and testosterone further, we measured serum testosterone at baseline, 3 months, and 2 years; luteinizing hormone at 3 months and 2 years; and total osteocalcin at 2 years in 28 trial participants with available blood samples. At 2 years, total osteocalcin was 39 % lower in the zoledronate group than the placebo group (zoledronate mean 10.1 [SD 3.0] mug/L, placebo 16.5 [SD 4.9] mug/L, P = 0.003). Despite these substantial differences in osteocalcin levels, testosterone levels did not change over time in either group and there were no between-group differences over time, P = 0.4 (mean change at 2 years [adjusted for baseline levels] in zoledronate group -0.4 nmol/L, 95 % CI -2.5 to 1.6; placebo group 0.4 nmol/L, 95 % CI -1.6 to 2.5). Luteinizing hormone was within the normal range and did not differ between the groups at either 3 months or 2 years. Thus, the absence of a change in testosterone despite a substantial reduction in osteocalcin following zoledronate treatment argues against a biologically significant role for osteocalcin in the regulation of testosterone in adult men. This provides reassurance that men receiving potent antiresorptive drugs are not at risk of iatrogenic hypogonadism.

 

[Michael Scally MD]

Pang XN, Hu Y, Yuan Y, Shen JP, Zha XY, Sun X. Lower levels sex hormone-binding globulin independently associated with metabolic syndrome in pre-elderly and elderly men in China. J Geriatr Cardiol 2013;10(1):28-33. Lower levels sex hormone-binding globulin independently associated with metabolic syndrome in pre-elderly and elderly men in China

OBJECTIVE: To examine the relationship between sex hormone-binding globulin (SHBG) and the metabolic syndrome (MetS) in pre-elderly and elderly men in China.

METHODS: A cross-sectional study was done among 437 men, aged 45 to 94 years old. Early morning fasting sera were assayed for total testosterone (TT), SHBG and other biochemical markers. Free testosterone (FT) was calculated.

RESULTS: The SHBG level of the MetS group was significantly lower than those without MetS 35.70 (25.18, 47.10) nmol/L vs. 41.90 (31.80, 55.20) nmol/L; P < 0.001). As the number of MetS components increases, SHBG and TT levels became lower. SHBG correlated with age, as did TT and most of metabolic components. Body mass index (BMI), high density lipoprotein-cholesterol (HDL-C), triglyceride (TG), and TT remained independently associated with SHBG by multivariate regression analysis. In a logistic regression taking MetS as the dependent variable, SHBG (95% confidence interval (95% CI): 0.975-0.994, P = 0.018) and homeostasis model assessment for insulin resistance (HOMA-IR) (95%CI: 1.535-2.647, P < 0.001) were included in the final model.

CONCLUSIONS: Lower SHBG is independently associated with MetS among pre-elderly and elderly men. SHBG may be an independent predictor of MetS, but the mechanism of how SHBG is involved in MetS requires further studied.

 

[Michael Scally MD]

Lindqvist AS, Moberg T, Eriksson BO, Ehrnborg C, Rosen T, Fahlke C. A retrospective 30-year follow-up study of former Swedish-elite male athletes in power sports with a past anabolic androgenic steroids use: a focus on mental health. Br J Sports Med. A retrospective 30-year follow-up study of former Swedish-elite male athletes in power sports with a past anabolic androgenic steroids use: a focus on mental health -- Lindqvist et al. -- British Journal of Sports Medicine

BACKGROUND: The knowledge concerning the long-term effect of former anabolic androgenic steroids (AAS)-use on mental health is sparse.

AIM: This study aims to investigate whether previous AAS-use affects mental health, present sociodemographic data, sport activity and substance abuse in a retrospective 30-year follow-up study of former elite athletes.

METHODS: Swedish male-elite power sport athletes (n=683) on the top 10 national ranking lists during any of the years 1960-1979 in wrestling, Olympic lifting, powerlifting and the throwing events in track and field answered a questionnaire.

RESULTS: At least 20% of the former athletes admitted previous AAS-use. They had more often sought professional expertise for mental problems and had used illicit drugs compared to those not having used AAS. The AAS-users also differed in former sport activity pattern compared to non AAS-users.

CONCLUSIONS: It is clear that a relationship exists between use of AAS and mental-health problems. Further studies need to be done in order to clarify this relationship.

 

[Michael Scally MD]

[NO] Effect of Androgen-replacement Therapy on Prostate Growth

Cui Y, Zhang Y. The Effect of Androgen-replacement Therapy on Prostate Growth: A Systematic Review and Meta-analysis. European Urology. ScienceDirect.com - European Urology - The Effect of Androgen-replacement Therapy on Prostate Growth: A Systematic Review and Meta-analysis

Context - Androgen-replacement therapy (ART) is a widely accepted form of treatment worldwide for aging men with late-onset hypogonadism syndrome. Urologists have been concerned about the possibility of ART causing prostate growth.

Objective - To assess the relationship between ART and prostate growth.

Evidence acquisition - A literature review was performed to identify all published randomized controlled trials (RCTs) of androgen treatment for hypogonadism. The search included the Medline, Embase, and Cochrane Controlled Trials Register databases. The reference lists of the retrieved studies were also investigated. A systematic review and meta-analysis were conducted.

Evidence synthesis - Results of 16 RCTs involving a total of 1030 patients were analyzed. Seven RCTs were short-term (<12 mo) and nine were long-term (12–36 mo) comparisons of ART with a placebo; ART was administered transdermally, orally, or by injection. Respective p values for injection, transdermal administration, and oral administration of short-term ART were as follows: PSA level: 0.07, 0.01, and 0.95; prostate volume: 0.70, 0.79, and 0.32; IPSS: 0.78, 0.98, and no oral; Qmax: 0.92, no transdermal, and 0.10. Respective p values for injection, transdermal administration, and oral administration of long-term ART were as follows: PSA level: 0.42, 0.51, and 0.57; prostate volume: 0.35, 0.59, and 0.47; IPSS: 0.34, 0.32, and 0.97; Qmax: 0.11, 0.63, and no oral. Neither short-term nor long-term ART showed significant changes in the four determinants of prostate growth investigated compared with placebo.

Conclusions - This meta-analysis shows that regardless of the administration method, neither short-term nor long-term ART increases the risk of prostate growth. Further high-quality, prospective studies are required to confirm this observation.

 

[Michael Scally MD]

Jensen TK, Andersson A-M, Skakkebaek NE, et al. Association of Sleep Disturbances With Reduced Semen Quality: A Cross-sectional Study Among 953 Healthy Young Danish Men. American Journal of Epidemiology. Association of Sleep Disturbances With Reduced Semen Quality: A Cross-sectional Study Among 953 Healthy Young Danish Men

Several studies have found an association between sleep duration and morbidity and mortality, but no previous studies have examined the association between sleep disturbances and semen quality. We conducted a cross-sectional study among 953 young Danish men from the general population who were recruited in Copenhagen at the time of determination of fitness for military service between January 2008 and June 2011. All of the men delivered a semen sample, had a blood sample drawn, underwent a physical examination, and answered a questionnaire including information about sleep disturbances. Sleep disturbances were assessed on the basis of a modified 4-item version of the Karolinska Sleep Questionnaire, which includes questions on sleep patterns during the past 4 weeks. Sleep disturbances showed an inverse U-shaped association with sperm concentration, total sperm count, percent motile and percent morphologically normal spermatozoa, and testis size. Men with a high level of sleep disturbance (score >50) had a 29% (95% confidence interval: 2, 48) lower adjusted sperm concentration and 1.6 (95% confidence interval: 0.3, 3.0) percentage points’ fewer morphologically normal spermatozoa than men with a sleep score of 11–20. This appears to be the first study to find associations between sleep disturbances and semen quality. In future studies, investigators should attempt to elucidate mechanistic explanations and prospectively assess whether semen quality improves after interventions restoring a normal sleeping pattern.

 

[Michael Scally MD]

Betatrophin: A Hormone that Controls Pancreatic ? Cell Proliferation

Highlights
• Betatrophin causes a specific increase in pancreatic ? cell replication
• Betatrophin is a secreted protein expressed in liver and fat
• The increase in ? cell replication and mass improves glycemic control


Yi P, Park J-S, Melton Douglas A. Betatrophin: A Hormone that Controls Pancreatic ? Cell Proliferation. Cell. Cell - Betatrophin: A Hormone that Controls Pancreatic ? Cell Proliferation

Replenishing insulin-producing pancreatic ? cell mass will benefit both type I and type II diabetics. In adults, pancreatic ? cells are generated primarily by self-duplication. We report on a mouse model of insulin resistance that induces dramatic pancreatic ? cell proliferation and ? cell mass expansion. Using this model, we identify a hormone, betatrophin, that is primarily expressed in liver and fat. Expression of betatrophin correlates with ? cell proliferation in other mouse models of insulin resistance and during gestation. Transient expression of betatrophin in mouse liver significantly and specifically promotes pancreatic ? cell proliferation, expands ? cell mass, and improves glucose tolerance. Thus, betatrophin treatment could augment or replace insulin injections by increasing the number of endogenous insulin-producing cells in diabetics.

 

[Michael Scally MD]

Gates MA, Mekary RA, Chiu GR, Ding EL, Wittert GA, Araujo AB. Sex Steroid Hormone Levels and Body Composition in Men. Journal of Clinical Endocrinology & Metabolism. Sex Steroid Hormone Levels and Body Composition in Men

Background: Previous studies indicate that testosterone (T) is positively correlated with lean mass and inversely correlated with fat mass in men; however, the directionality of these associations, as well as the association with other hormones including estradiol (E2) and SHBG, is unclear.

Methods: We examined cross-sectional and longitudinal associations of E2, T, SHBG, and E2/T ratio with body composition among men ages 30 to 79 in the Boston Area Community Health/Bone Survey. Total, trunk, and appendicular lean and fat mass were measured by dual-energy x-ray absorptiometry at baseline, and weight and waist/hip circumference were measured at baseline and follow-up. Partial Pearson correlation coefficients were used to estimate the linear relationship between each body composition measure and log-transformed hormone variable.

Results: In cross-sectional analyses of 821 men, T, calculated free T, and SHBG were inversely correlated with fat mass, weight, body mass index, waist/hip circumference, and waist-to-hip ratio, with multivariable-adjusted correlations ranging from ?0.13 to ?0.37. Calculated free E2 was positively correlated with percentage total (r = .13) and trunk (r = .15) fat mass, and E2/T was positively correlated with all measures examined (r = .13–.40). There were no significant multivariable-adjusted longitudinal associations between baseline hormone levels and change in weight, body mass index, waist/hip circumference, or waist-to-hip ratio after an average follow-up of 4.8 years.

Conclusions: We observed significant cross-sectional associations between hormone levels, including E2, T, and E2/T, and body composition measures in men. Longitudinal analyses showing no influence of baseline hormone levels on change in anthropometric measures imply that body composition affects hormone levels and not the reverse.

 

[Michael Scally MD]

Maggio M, Cattabiani C, Lauretani F, et al. SHBG and endothelial function in older subjects. Int J Cardiol. ScienceDirect.com - International Journal of Cardiology - SHBG and endothelial function in older subjects

BACKGROUND: Endothelial dysfunction is predictor of cardiovascular diseases that have different prevalence in men and women before menopause. Sex hormones and sex hormone binding globulin (SHBG), novel risk factors for diabetes and cardiovascular diseases even in older individuals, might explain this difference. However, the relationship between these hormones and endothelial function has never been addressed in the elderly.

METHODS AND RESULTS: 430 men and,424 women 70years older of Prospective Study of the Vasculature in Uppsala Seniors study, with complete data on SHBG, testosterone(T), estradiol(E2), endothelium-independent vasodilation (EIDV), endothelium-dependent vasodilation(EDV), flow-mediated vasodilation (FMD) and the pulse wave analysis (reflection index, RI) were evaluated. Multivariate regression analysis adjusted for confounders was used to assess the relationship between T, E2, SHBG and endothelial function. In men we found a positive relationship between SHBG and EDV (beta+/-SE 3.60+/-0.83, p<0.0001), EIDV (2.42+/-0.58, p<0.0001) but not with FMD. The relationship between SHBG and EDV and EIDV was maintained after adjustment for sex (1.64+/-0.47, p<0.001 and 1.79+/-0.35, p<0.0006, respectively). After adjustment for confounders, the relationship between SHBG and EDV and EIDV was still statistically significant (2.63+/-0.90 and 1.86+/-0.63, p=0.004 for both). In women SHBG and EIDV were positively associated (1.58+/-0.46; p=0.0007), and this relationship was independent of sex (1.79+/-0.35; p<0.001). No significant interaction SHBG *SEX was found for EIDV (p=0.72). In a combined analysis in two sexes, SHBG and EIDV were positively associated (1.13+/-0.45; p=0.01). SHBG was not associated with EDV, FMD and RI. No significant relationship was found between T or E2 and EDV, EIDV, FMD or RI in both sexes.

CONCLUSIONS: In older men SHBG, but not T and E2, is positively and independently associated with EDV in resistance arteries. In both sexes, SHBG was positively and independently associated with EIDV.

 

[Michael Scally MD]

Ohlsson C, Nilsson ME, Tivesten Ã, et al. Comparisons of Immunoassay and Mass Spectrometry Measurements of Serum Estradiol Levels and Their Influence on Clinical Association Studies in Men. Journal of Clinical Endocrinology & Metabolism. Comparisons of Immunoassay and Mass Spectrometry Measurements of Serum Estradiol Levels and Their Influence on Clinical Association Studies in Men

Context: Immunoassay-based techniques, routinely used to measure serum estradiol (E2), are known to have reduced specificity, especially at lower concentrations, when compared with the gold standard technique of mass spectrometry (MS). Different measurement techniques may be responsible for the conflicting results of associations between serum E2 and clinical phenotypes in men.

Objective: Our objective was to compare immunoassay and MS measurements of E2 levels in men and evaluate associations with clinical phenotypes.

Design and Setting: Middle-aged and older male subjects participating in the population-based Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2599), MrOS US (n = 688), and the European Male Aging Study (n = 2908) were included.

Main Outcome Measures: Immunoassay and MS measurements of serum E2 were compared and related to bone mineral density (BMD; measured by dual energy x-ray absorptiometry) and ankle-brachial index.

Results: Within each cohort, serum E2 levels obtained by immunoassay and MS correlated moderately (Spearman rank correlation coefficient rS 0.53–0.76). Serum C-reactive protein (CRP) levels associated significantly (albeit to a low extent, rS = 0.29) with immunoassay E2 but not with MS E2 levels. Similar associations of immunoassay E2 and MS E2 were seen with lumbar spine and total hip BMD, independent of serum CRP. However, immunoassay E2, but not MS E2, associated inversely with ankle-brachial index, and this correlation was lost after adjustment for CRP.

Conclusions: Our findings suggest interference in the immunoassay E2 analyses, possibly by CRP or a CRP-associated factor. Although associations with BMD remain unaffected, this might imply for a reevaluation of previous association studies between immunoassay E2 levels and inflammation-related outcomes.