OnLine First 2013

[Michael Scally MD]

Narayanan RP, Gittins M, Siddals KW, et al. Atorvastatin administration is associated with dose-related changes in IGF bioavailability. European Journal of Endocrinology. http://www.eje-online.org/content/early/2013/01/18/EJE-12-0844.abstract

Objective: Insulin-like growth factor (IGF) levels, their binding proteins (IGFBPs), and high-dose statin therapy, have all been linked to the development of diabetes. We aimed to identify whether atorvastatin caused dose-related changes in IGF proteins.

Design and methods: We measured IGF1, IGF2, IGFBP1 and IGFBP3 concentrations at baseline, 6 months and 12 months in PANDA trial participants with type 2 diabetes randomised to 10mg (n=59) vs 80mg (n=60) of atorvastatin (N=119; mean (SD): age 64(10) years; 83% male; HbA1c 61(10) mmol/mol; blood pressure 131/73 mmHg.

Results: Atorvastatin was associated with overall reductions in circulating IGF1, IGF2 and IGFBP3 concentrations. The adjusted mean (95% CI) between-group differences that indicate dose-related changes in IGF proteins were not significant for: IGF1: -3 (-21 to 14) ng/ml; IGF2: -23 (-65 to 18) ng/ml; and IGFBP3: -0.34 (-0.71 to 0.03) µg/ml; negative values indicating numerically greater lowering with high-dose). The IGFBP1 concentration did not change overall with atorvastatin therapy overall but the adjusted mean (95% CI) between-group difference indicating a dose-related change in log IGFBP1 was highly significant -0.41 (-0.69 to 0-0.13, p=0.004).

Conclusion: IGF1, IGF2 and IGFBP3 concentrations all decreased following atorvastatin therapy. A differential effect of low vs high dose atorvastatin on IGFBP1 concentrations was observed with likely implications for IGF bioavailability. The dose-related differential impact of atorvastatin treatment on concentration of IGF proteins merits investigation as a mechanism to explain the worsening of glucose tolerance with statin therapy.

 

[Michael Scally MD]

Markle JG, Frank DN, Mortin-Toth S, et al. Sex Differences in the Gut Microbiome Drive Hormone-Dependent Regulation of Autoimmunity. Science. Sex Differences in the Gut Microbiome Drive Hormone-Dependent Regulation of Autoimmunity

Microbial exposures and sex hormones exert potent effects on autoimmune diseases, many of which are more prevalent in women. Here, we demonstrate a direct interaction between sex hormones and early life microbial exposures on the control of autoimmunity in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). Colonization by commensal microbes elevated serum testosterone and protected NOD males from T1D. Transfer of gut microbiota from adult males to immature females altered the recipient's microbiota, resulting in elevated testosterone and metabolomic changes, reduced islet inflammation and autoantibody production, and robust T1D protection. These effects were dependent on androgen receptor activity. Thus, the commensal microbial community alters sex hormone levels and regulates autoimmune disease fate in individuals with high genetic risk.

 

[Michael Scally MD]

Djulbegovic B, Kumar A, Glasziou PP, et al. New treatments compared to established treatments in randomized trials. Cochrane Database Syst Rev 2012;10:MR000024. New treatments compared to established treatments in randomized trials - The Cochrane Library - Djulbegovic - Wiley Online Library

BACKGROUND: The proportion of proposed new treatments that are 'successful' is of ethical, scientific, and public importance. We investigated how often new, experimental treatments evaluated in randomized controlled trials (RCTs) are superior to established treatments.

OBJECTIVES: Our main question was: "On average how often are new treatments more effective, equally effective or less effective than established treatments?" Additionally, we wanted to explain the observed results, i.e. whether the observed distribution of outcomes is consistent with the 'uncertainty requirement' for enrollment in RCTs. We also investigated the effect of choice of comparator (active versus no treatment/placebo) on the observed results.

SEARCH METHODS: We searched the Cochrane Methodology Register (CMR) 2010, Issue 1 in The Cochrane Library (searched 31 March 2010); MEDLINE Ovid 1950 to March Week 2 2010 (searched 24 March 2010); and EMBASE Ovid 1980 to 2010 Week 11 (searched 24 March 2010).

SELECTION CRITERIA: Cohorts of studies were eligible for the analysis if they met all of the following criteria: (i) consecutive series of RCTs, (ii) registered at or before study onset, and (iii) compared new against established treatments in humans.

DATA COLLECTION AND ANALYSIS: RCTs from four cohorts of RCTs met all inclusion criteria and provided data from 743 RCTs involving 297,744 patients. All four cohorts consisted of publicly funded trials. Two cohorts involved evaluations of new treatments in cancer, one in neurological disorders, and one for mixed types of diseases. We employed kernel density estimation, meta-analysis and meta-regression to assess the probability of new treatments being superior to established treatments in their effect on primary outcomes and overall survival.

MAIN RESULTS: The distribution of effects seen was generally symmetrical in the size of difference between new versus established treatments. Meta-analytic pooling indicated that, on average, new treatments were slightly more favorable both in terms of their effect on reducing the primary outcomes (hazard ratio (HR)/odds ratio (OR) 0.91, 99% confidence interval (CI) 0.88 to 0.95) and improving overall survival (HR 0.95, 99% CI 0.92 to 0.98). No heterogeneity was observed in the analysis based on primary outcomes or overall survival (I(2) = 0%). Kernel density analysis was consistent with the meta-analysis, but showed a fairly symmetrical distribution of new versus established treatments indicating unpredictability in the results. This was consistent with the interpretation that new treatments are only slightly superior to established treatments when tested in RCTs. Additionally, meta-regression demonstrated that results have remained stable over time and that the success rate of new treatments has not changed over the last half century of clinical trials. The results were not significantly affected by the choice of comparator (active versus placebo/no therapy).

AUTHORS' CONCLUSIONS: Society can expect that slightly more than half of new experimental treatments will prove to be better than established treatments when tested in RCTs, but few will be substantially better. This is an important finding for patients (as they contemplate participation in RCTs), researchers (as they plan design of the new trials), and funders (as they assess the 'return on investment'). Although we provide the current best evidence on the question of expected 'success rate' of new versus established treatments consistent with a priori theoretical predictions reflective of 'uncertainty or equipoise hypothesis', it should be noted that our sample represents less than 1% of all available randomized trials; therefore, one should exercise the appropriate caution in interpretation of our findings. In addition, our conclusion applies to publicly funded trials only, as we did not include studies funded by commercial sponsors in our analysis.

 

[Michael Scally MD]

Dihydrotestosterone Synthesis Bypasses Testosterone

Pathways Of DHT Synthesis From Adrenal DHEA

DHEA is converted by 3?-hydroxysteroid dehydrogenase/isomerase (3?HSD) to AD. In the conventional pathway, AD is first transformed to T (red arrow), which is then converted by SRD5A to DHT. In the alternative pathway, AD is the principal substrate for SRD5A and is converted to 5?-dione (blue arrow), a necessary precursor to DHT. Both 5?-dione and DHT are reversibly interconvertible by 3?-hydroxysteroid dehydrogenases (3?HSD) to the other 5?-reduced steroids, androsterone (AST) and 5?-androstane-3?,17?-diol (Adiol), respectively.

Chang K-H, Li R, Papari-Zareei M, et al. Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. Proceedings of the National Academy of Sciences 2012;108(33):13728-33. Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer

In the majority of cases, advanced prostate cancer responds initially to androgen deprivation therapy by depletion of gonadal testosterone. The response is usually transient, and metastatic tumors almost invariably eventually progress as castration-resistant prostate cancer (CRPC). The development of CRPC is dependent upon the intratumoral generation of the potent androgen, dihydrotestosterone (DHT), from adrenal precursor steroids. Progression to CRPC is accompanied by increased expression of steroid-5?-reductase isoenzyme-1 (SRD5A1) over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. DHT synthesis in CRPC is widely assumed to require 5?-reduction of testosterone as the obligate precursor, and the increased expression of SRD5A1 is thought to reflect its role in converting testosterone to DHT. Here, we show that the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5?-reduction of androstenedione by SRD5A1 to 5?-androstanedione, which is then converted to DHT. This alternative pathway is operational and dominant in both human CRPC cell lines and fresh tissue obtained from human tumor metastases. Moreover, CRPC growth in mouse xenograft models is dependent upon this pathway, as well as expression of SRD5A1. These findings reframe the fundamental metabolic pathway that drives CRPC progression, and shed light on the development of new therapeutic strategies.


Campbell TJ, Tindall DJ, Figg WD. Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer. Cancer Biol Ther 2012;13(5):237-8. Landes Bioscience Journals: Cancer Biology & Therapy

Androgen deprivation therapy is the frontline treatment for metastatic prostate cancer; however, because the majority of cases of advanced prostate cancer progress to castration-resistant prostate cancer (CRPC), there is a considerable need to better understand the synthesis of intratumoral concentrations of the androgen receptor (AR) agonist, 5alpha-dihydrotestosterone (DHT) in CRPC. In a recent article in the Proceedings of the National Academy of Sciences, Chang et al. show that, contrary to widely held assumptions, the dominant pathway to DHT synthesis does not involve testosterone as a precursor to DHT, but instead involves the conversion of Delta ( 4) -androstenedione (AD) to 5alpha-dione (AD-->5alpha-dione-->DHT) by the steroid-5alpha-reductase isoenzyme 1 (SRD5A1). The authors show that it is this alternative pathway that drives the progression of CRPC, and they confirm these findings in six established human prostate cancer cell lines as well as in the metastatic tumors from two patients with CRPC. Such findings open the door to new areas of research and to the development of new therapeutic targets in CRPC.

 

[Michael Scally MD]

Mosekilde L, Vestergaard P, Rejnmark L. The Pathogenesis, Treatment and Prevention of Osteoporosis in Men. Drugs. The Pathogenesis, Treatment and Prevention of Osteoporosis in Men - Online First - Springer

Testosterone stimulates longitudinal and appositional growth during childhood, whereas estrogen induces epiphysial closure. During adulthood, testosterone continues to stimulate periosteal growth, whereas estrogen is important for the maintenance of trabecular bone mass and structure. In males, testosterone is aromatized to estradiol. Both free and bioavailable plasma levels of testosterone and estradiol decrease with age in males, and fracture risk is associated with low estradiol levels. Testosterone may increase muscle mass and prevent fractures related to falls. Younger hypogonadal males should be treated with testosterone to attain peak bone mass and increase bone mineral density (BMD). Older hypogonadal males should be treated in cases of osteoporosis, reduced muscle strength and increased risk of falling. Secondary hyperparathyroidism caused by calcium and vitamin D insufficiency may reduce bone mass and strength and increase fracture risk and should be avoided. Since calcium supplementation has been associated with an increased risk of cardiovascular complications and renal stones, the dose should be tailored to the habitual daily calcium intake. Lifestyle-related risk factors (smoking, alcohol consumption, lack of physical activity and low body weight) should be addressed. The antifracture efficacy of antiresorptive and anabolic treatment for osteoporosis has not been documented in larger randomized controlled studies. However, changes in BMD and bone markers suggest similar effects in males and females of bisphosphonates (alendronate, risedronate, ibandronate, zoledronic acid), nasal calcitonin, denosumab and teriparatide (parathyroid hormone [1-34]). The antiresorptive drugs should be used in males with BMD T-score less than -2.5 and one or more risk factors, or with hip and vertebral fractures. It seems appropriate to recommend a higher cut-off T-score (e.g. less than -1.0 standard deviation [SD]) in glucocorticoid-induced osteoporosis and in patients receiving androgen deprivation therapy because of the fast initial bone loss. Anabolic treatment should be used in more severe spinal fracture cases, including glucocorticoid-induced osteoporosis.

 

[Michael Scally MD]

Brioude Fdr, Bouligand Jrm, Francou B, et al. Two Families with Normosmic Congenital Hypogonadotropic Hypogonadism and Biallelic Mutations in KISS1R (KISS1 Receptor): Clinical Evaluation and Molecular Characterization of a Novel Mutation. PLoS ONE 2013;8(1):e53896. PLOS ONE: Two Families with Normosmic Congenital Hypogonadotropic Hypogonadism and Biallelic Mutations in KISS1R (KISS1 Receptor): Clinical Evaluation and Molecular Characterization of a Novel Mutation

Context - KISS1R mutations have been reported in few patients with normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110).

Objective - To describe in detail nCHH patients with biallelic KISS1R mutations belonging to 2 unrelated families, and to functionally characterize a novel KISS1R mutation.

Results - An original mutant, p.Tyr313His, was found in the homozygous state in 3 affected kindred (2 females and 1 male) from a consanguineous Portuguese family. This mutation, located in the seventh transmembrane domain, affects a highly conserved amino acid, perturbs the conformation of the transmembrane segment, and impairs MAP kinase signaling and intracellular calcium release. In the second family, a French Caucasian male patient with nCHH was found to carry two recurrent mutations in the compound heterozygous state (p.Leu102Pro/Stop399Arg). In this man, pulsatile GnRH (Gonadotropin Releasing Hormone) administration restored pulsatile LH (Luteinizing Hormone) secretion and testicular hormone secretion. Later, long-term combined gonadotropin therapy induced spermatogenesis, enabling 3 successive pregnancies that resulted in 2 miscarriages and the birth of a healthy boy.

Conclusion - We show that a novel loss-of-function mutation (p.Tyr313His) in the KISS1R gene can cause familial nCHH, revealing the crucial role of this amino acid in KISS1R function. The observed restoration of gonadotropin secretion by exogenous GnRH administration further supports, in humans, the hypothalamic origin of the gonadotropin deficiency in this genetic form of nCHH.

 

[Michael Scally MD]

Leung GNW, Kwok WH, Wan TSM, Lam KKH, Schiff PJ. Metabolic studies of formestane in horses. Drug Testing and Analysis. Metabolic studies of formestane in horses - Leung - 2013 - Drug Testing and Analysis - Wiley Online Library

Formestane (4-hydroxyandrost-4-ene-3,17-dione) is an irreversible steroidal aromatase inhibitor with reported abuse in human sports. In 2011, our laboratory identified the presence of formestane in a horse urine sample from an overseas jurisdiction. This was the first reported case of formestane in a racehorse. The metabolism of formestane in humans has been reported previously; however, little is known about its metabolic fate in horses. This paper describes the in vitro and in vivo metabolic studies of formestane in horses, with the objective of identifying the target metabolite with the longest detection time for controlling formestane abuse. In vitro metabolic studies of formestane were performed using homogenized horse liver. Seven in vitro metabolites, namely 4-hydroxytestosterone (M1), 3?,4?-dihydroxy-5?-androstan-17-one (M2a), 3?,4?-dihydroxy-5?-androstan-17-one (M2b), 3?,4?-dihydroxy-5?-androstan-17-one (M2c), androst-4-ene-3?,4,17?-triol (M3a), androst-4-ene-3?,4,17?-triol (M3b), and 5?-androstane-3?,4?,17?-triol (M4) were identified. For the in vivo studies, two thoroughbred geldings were each administered with 800 mg of formestane (32 capsules of Formadex) by stomach tubing. The results revealed that the parent drug and seven metabolites were detected in post-administration urine. The six in vitro metabolites (M1, M2a, M2b, M2c, M3a, and M3b) identified earlier were all detected in post-administration urine samples. In addition, 3?,4?-dihydroxy-5?-androstan-17-one (M2d), a stereoisomer of M2a/M2b/M2c, was also identified. This study has shown that the detection of formestane administration would be best achieved by monitoring 4-hydroxytestosterone (M1) in the glucuronide-conjugated fraction. M1 could be detected for up to 34 h post-administration. In blood samples, the parent drug could be detected for up to 34 h post administration.

 

[Michael Scally MD]

Associations Between Brominated Flame Retardants In House Dust And Hormone Levels

Highlights
? Brominated flame retardants (BFRs) including PBDEs and alternates were measured.
? Exposure to BFRs is characterized from concentrations in participant vacuum bag dust.
? Exposure to PBDEs and alternate FRs was associated with alterations in hormone levels.


Johnson PI, Stapleton HM, Mukherjee B, Hauser R, Meeker JD. Associations between brominated flame retardants in house dust and hormone levels in men. Science of The Total Environment 2013;445-446(0):177-84. ScienceDirect.com - Science of The Total Environment - Associations between brominated flame retardants in house dust and hormone levels in men

Brominated flame retardants (BFRs) are used in the manufacture of a variety of materials and consumer products in order to meet fire safety standards. BFRs may persist in the environment and have been detected in wildlife, humans and indoor dust and air. Some BFRs have demonstrated endocrine and reproductive effects in animals, but human studies are limited.

In this exploratory study, we measured serum hormone levels and flame retardant concentrations [31 polybrominated diphenyl ether (PBDE) congeners and 6 alternate flame retardants] in house dust from men recruited through a US infertility clinic. PBDE congeners in dust were grouped by commercial mixtures (i.e. penta-, octa- and deca-BDE).

In multivariable linear regression models adjusted by age and body mass index (BMI), significant positive associations were found between house dust concentrations of pentaBDEs and serum levels of free T4, total T3, estradiol, and sex hormone binding globulin (SHBG), along with an inverse association with follicle stimulating hormone (FSH). There were also positive associations of octaBDE concentrations with serum free T4, thyroid stimulating hormone (TSH), luteinizing hormone (LH) and testosterone and an inverse association of decaBDE concentrations with testosterone. Hexabromocyclododecane (HBCD) was associated with decreased SHBG and increased free androgen index. Dust concentrations of bis-tribromophenoxyethane (BTBPE) and tetrabromo-diethylhexylphthalate (TBPH) were positively associated with total T3.

These findings are consistent with our previous report of associations between PBDEs (BDE 47, 99 and 100) in house dust and hormone levels in men, and further suggest that exposure to contaminants in indoor dust may be leading to endocrine disruption in men.

 

[Michael Scally MD]

Killick R, Wang D, Hoyos CM, Yee BJ, Grunstein RR, Liu PY. The effects of testosterone on ventilatory responses in men with obstructive sleep apnoea: a randomised, placebo-controlled trial. J Sleep Res. The effects of testosterone on ventilatory responses in men with obstructive sleep apnoea: a randomised, placebo-controlled trial - Killick - 2013 - Journal of Sleep Research - Wiley Online Library

We recently showed that testosterone therapy worsens sleep-disordered breathing at 6-7 weeks, but not after 18 weeks, in men with obstructive sleep apnea. Changes in ventilatory chemoreflexes may be responsible. The effect of testosterone on ventilatory chemoreflexes in men with obstructive sleep apnea has not been systematically studied before. Twenty-one obese men with obstructive sleep apnea, a subgroup of our recent report, were randomised in an 18-week, randomised, double-blind, placebo-controlled, parallel group trial to three intramuscular injections (0, 6, 12 weeks) of either 1000 mg testosterone undecanoate (n = 10) or placebo (n = 11). Awake ventilatory chemoreflex testing was performed before (week 0), during (week 6) and at the end of treatment (week 18) to determine the ventilatory carbon dioxide recruitment threshold and chemosensitivity. Sleep and breathing was assessed by overnight polysomnography at 0, 7 and 18 weeks. Serum hormones levels were measured at every visit. A significant increase in blood testosterone levels (5.65 nmol L(-1) , 0.51-10.8 nmol L(-1) , P = 0.03) and lean muscle mass (2.36 kg, 0.8-3.9 kg, P = 0.007) between the two groups was observed as expected. No significant differences were seen in ventilatory chemoreflexes between the two groups at 6 weeks or at 18 weeks. However, positive correlations were observed between changes in serum testosterone and hyperoxic ventilatory recruitment threshold (r = 0.55, P = 0.03), and between changes in hyperoxic ventilatory recruitment threshold and time spent with oxygen saturations during sleep <90% (r = 0.57, P = 0.03) at 6-7 weeks, but not at 18 weeks. Time-dependent alterations in ventilatory recruitment threshold may therefore mediate the time-dependent changes in sleep breathing observed with testosterone.

 

[Michael Scally MD]

Testosterone Modulation Of Anxiety

Highlights
? Suppression of testosterone (T) by a GnRH agonist lowers anxiety in male rhesus monkeys tested in a 2-min stare condition of the Human Intruder Paradigm; exogenous T restores baseline anxiety levels.
? Reduced LH may underlie the beneficial effects of the GnRH on anxiety.
? T promotes an adaptive arousal response in face of an immediate social threat.


Suarez-Jimenez B, Gore HE, Hachey J, King HM, Lacreuse A. Testosterone modulation of anxiety in gonadally-suppressed male rhesus monkeys: A role for gonadotropins? Pharmacol Biochem Behav. ScienceDirect.com - Pharmacology Biochemistry and Behavior - Testosterone modulation of anxiety in gonadally-suppressed male rhesus monkeys: A role for gonadotropins?

Testosterone (T) has repeatedly been shown to have anxiolytic properties in rodents, but findings in primates are more mixed. To examine the effects of exogenous T on anxiety, we tested pharmacologically-castrated adult male rhesus monkeys in a modified version of the Human Intruder Paradigm, which measured defensive responses to an unfamiliar human staring directly at them for 2 minutes.

Monkeys were tested at 2weeks intervals during 4 experimental conditions lasting 4weeks each: at baseline, during treatment with the gonadotropin releasing hormone (GnRH) agonist Leuprolide acetate (200mug/kg; Lupron phase), during treatment with Lupron+T enanthate (TE, 5mg/kg; TE phase) and during treatment with Lupron+oil vehicle (oil phase).

We found that the number of anxious behaviors was lower during periods of low T (Lupron only and Lupron+oil phases) than during the Lupron+TE phase. No change in pacing or watching behavior was observed. Thus, in contrast to rodent data, we found no evidence for anxiolytic properties of T in male rhesus monkeys. Rather, T supplementation restored baseline levels of anxiety in Lupron-treated monkeys. These discrepant findings may be best explained by the low levels of gonadotropins achieved by the GnRH agonist.

We suggest that Lupron-induced luteinizing hormone (LH) suppression reduced anxiety and that this effect was abolished by T administration. This interpretation is consistent with the view that T increases emotional reactivity to a potential threat and facilitates adaptive arousal response in face of immediate social challenge.

 

[Michael Scally MD]

Eisenberg ML, Hsieh TC, Pastuszak AW, et al. The relationship between anogenital distance and the androgen receptor CAG repeat length. Asian J Androl. http://www.nature.com/aja/journal/vaop/ncurrent/full/aja2012126a.html

Anogenital distance (AGD) is used to define degree of virilization of genital development, with shorter length being associated with feminization and male infertility. The first exon of the androgen receptor (AR) consists of a polymorphic sequence of cytosine-adenine-guanine (CAG) repeats, with longer CAG repeat lengths being associated with decreased receptor function. We sought to determine if there is an association between AGD and AR CAG repeat length. A cross-sectional, prospective cohort of men evaluated at a urology clinic at a single institution was recruited. AGD (the distance from the posterior scrotum to the anal verge) and penile length (PL) were measured. Sanger DNA sequence analysis was used to define CAG repeat length. AGD and CAG repeat lengths in 195 men were determined. On unadjusted analysis, there was no linear relationship between CAG repeat length and PL (P=0.17) or AGD (P=0.31). However, on sub-population analyses, those men with longer CAG repeat lengths (>26) had significantly shorter AGDs compared to men with shorter CAG repeat lengths. For example, the mean AGD was 41.9 vs. 32.4 mm with a CAG repeat length </=26 vs. >26 (P=0.01). In addition, when stratifying the cohort based on AGD, those with AGD less than the median (i.e. 40 mm) had a longer CAG repeat length compared to men with an AGD >40 mm (P=0.02). In summary, no linear relationship was found between AGD and AR CAG repeat length overall.

 

[Cag]

Smith RP, Coward RM, Kovac JR, Lipshultz LI. The evidence for seasonal variations of testosterone in men. Maturitas. Elsevier

Ample evidence exists to support the concept of diurnal variations in testosterone levels; however, substantiation for seasonal fluctuations is sparse and inconsistent. Since circadian disparities exist, laboratory screening for hypogonadism has traditionally been conducted using serum testosterone levels obtained in the early morning. Should circannual variability of testosterone be confirmed, it would make the monitoring of testosterone levels more difficult while forcing the development of seasonal reference standards to allow for comparison. Moreover, decisions to begin treatment and adjustment of practice patterns would likely follow. This review thoroughly explores all of the available evidence concerning seasonal variations in testosterone levels. The impacts of melatonin, vitamin D, sleep-wake cycles, light exposure, physical activity, BMI, and waist circumference are also discussed. Current research suggests that while some evidence exists to support the notion of seasonal testosterone variations, the discussed inconsistencies preclude the incorporation of this concept into current clinical standards.

With a CAG repeat > 40, and exhibiting signs of muscle wasting and sporadic fatigue and mood issues, a discussion on how to track and regulate daily (hourly) testosterone fluctuations would be appreciated.

 

[Michael Scally MD]

Small G et al. PET scanning of brain tau in retired National Football League players: Preliminary findings. Am J Geriatr Psychiatry 2013;21:138-44. http://www.espn.go.com/pdf/2013/0122/espn_otl_CTELiving.pdf

Objective: Mild traumatic brain injury due to contact sports may cause chronic behavioral, mood, and cognitive disturbances associated with pathological deposition of tau protein found at brain autopsy. To explore whether brain tau deposits can be detected in living retired players, we used positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]- 2-naphthyl}ethylidene)malononitrile (FDDNP).

Methods: Five retired National Football League players (age range: 45 to 73 years) with histories of mood and cognitive symptoms received neuropsychiatric evaluations and FDDNP-PET. PET signals in subcortical (caudate, putamen, thalamus, subthalamus, midbrain, cerebellar white matter) and cortical (amygdala, frontal, parietal, posterior cingulate, medial and lateral temporal) regions were compared with those of five male controls of comparable age, education, and body mass index.

Results: FDDNP signals were higher in players compared with controls in all subcortical regions and the amygdala, areas that produce tau deposits following trauma.

Conclusions: The small sample size and lack of autopsy confirmation warrant larger, more definitive studies, but if future research confirms these initial findings, FDDNP-PET may offer a means for premorbid identification of neurodegeneration in contact-sports athletes.

 

[Michael Scally MD]

Sun M, Shen W, Zhong M, Wu P, Chen H, Lu A. Nandrolone attenuates aortic adaptation to exercise in rats. Cardiovasc Res. Nandrolone attenuates aortic adaptation to exercise in rats

AIMS: In this study, we investigated the interaction between exercise-induced mitochondrial adaptation of large vessels and the effects of chronic anabolic androgenic steroids (AASs).

METHODS AND RESULTS: Four groups of Sprague-Dawley rats were studied: (i) sedentary, (ii) sedentary + nandrolone-treated, (iii) aerobic exercise trained, and (iv) trained + nandrolone-treated. Aerobic training increased the levels of aortic endothelial nitric oxide synthase (eNOS) and heme oxygenase-1 (HO-1) in accordance with improved acetylcholine-induced vascular relaxation. These beneficial effects were associated with induction of mitochondrial complexes I and V, increased mitochondrial DNA copy number, and greater expression of transcription factors involved in mitochondrial biogenesis/fusion. We also observed enhanced mitochondrial autophagy pathway activity, including increased conversion of LC3-I to LC3-II and greater expression of beclin1 and autophagy-related protein-7 (ATG7). The levels of thiobarbituric acid-reactive substances and protein carbonyls remained unchanged, whereas significant increases in catalase and mitochondrial manganese superoxide dismutase (MnSOD) levels were observed in the aortas of trained animals, when compared with sedentary controls. Nandrolone increased oxidative stress biomarkers and inhibited exercise-induced increases of eNOS, HO-1, catalase, and MnSOD expression. In addition, it also attenuated elevated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) and mitofusin-2 expression, and further up-regulated LC3II conversion, beclin1, ATG7, and dynamin-related protein-1 expression.

CONCLUSION: These results demonstrate that nandrolone attenuates aortic adaptations to exercise by regulating mitochondrial dynamic remodelling, including down-regulation of mitochondrial biogenesis and intensive autophagy.

 

[Michael Scally MD]

Kaufman JM, Audran M, Bianchi G, et al. Efficacy and Safety of Strontium Ranelate in the Treatment of Osteoporosis in Men. Journal of Clinical Endocrinology & Metabolism. Efficacy and Safety of Strontium Ranelate in the Treatment of Osteoporosis in Men

Context: Strontium ranelate reduces vertebral and nonvertebral fracture risk in postmenopausal osteoporosis.

Objective: The objective of this study was to determine the efficacy and safety of strontium ranelate in osteoporosis in men over 2 years (main analysis after 1 year).

Design: This was an international, unbalanced (2:1), double-blind, randomized placebo-controlled trial (MALEO [MALE Osteoporosis]).

Setting: This international study included 54 centers in 14 countries.

Participants: Participants were 261 white men with primary osteoporosis.

Intervention: Strontium ranelate at 2 g/d (n = 174) or placebo (n = 87) was administered.

Main Outcome Measures: Lumbar spine (L2–L4), femoral neck, and total hip bone mineral density (BMD), biochemical bone markers, and safety were measured.

Results: Baseline characteristics were similar in both groups in the whole population (age, 72.9 ± 6.0 years; lumbar spine BMD T-score, ?2.7 ± 1.0; femoral neck BMD T-score, ?2.3 ± 0.7). Men who received strontium ranelate over 2 years had greater increases in lumbar spine BMD than those who received placebo (relative change from baseline to end, 9.7% ± 7.5% vs 2.0% ± 5.5%; between-group difference estimate (SE), 7.7% (0.9%); 95% confidence interval, 5.9%–9.5%; P < .001). There were also significant between-group differences in relative changes in femoral neck BMD (P < .001) and total hip BMD (P < .001). At the end of treatment, mean levels of serum cross-linked telopeptides of type I collagen, a marker of bone resorption, were increased in both the strontium ranelate group (10.7% ± 58.0%; P = .022) and the placebo group (34.9% ± 65.8%; P < .001). The corresponding mean changes of bone alkaline phosphatase, a marker of bone formation, were 6.4% ± 28.5% (P = .005) and 1.9% ± 25.4% (P = .505), respectively. After 2 years, the blood strontium level (129 ± 66 ?mol/L) was similar to that in trials of postmenopausal osteoporosis. Strontium ranelate was generally well tolerated.

Conclusions: The effects of strontium ranelate on BMD in osteoporotic men were similar to those in postmenopausal osteoporotic women, supporting its use in the treatment of osteoporosis in men.

 

[Michael Scally MD]

Michihara S, Shin N, Watanabe S, Morimoto Y, Okubo T, Norimoto H. A Kampo formula, saikokaryukotsuboreito, improves serum testosterone levels of castrated mice and its possible mechanism. Aging Male. An Error Occurred Setting Your User Cookie

The term "late-onset hypogonadism (LOH)" is recommended to express the symptoms in middle-aged males with decreased testosterone. Although androgen replacement therapy (ART) might be an effective way to manage LOH, the risk of testosterone supplementation in elderly men is still concerned. On the other hand, to avoid adverse effects of ART, Kampo medicine (traditional Chinese-Japanese medicine) is often a first choice to treat LOH in Japan. However, their pharmacological studies are few. In this study, castrated mice was used as an LOH animal model for examining the pharmacological effects of a Kampo formula, saikokaryukotsuboreito (shortly SKRBT) on serum testosterone levels and seminal vesicles weights. Furthermore, an attempt to elucidate its pharmacological mechanism, inhibition of SKRBT and its components against aromatase were also examined with the enzyme-based assay. As a result, SKRBT improved significantly both the decline of serum testosterone levels and decrease of seminal vesicles weight of castrated mice at a dose of 125 mg/kg with a non dose-dependent manner. SKRBT and two components Scutellariae radix and Rhei rhizoma exhibited inhibitory activities with the IC(50) values of 145, 29.2 and 29.7 microg/ml, respectively. These results suggested that the aromatase inhibitory activity of SKRBT may contribute, to a different extent, to the improvement of serum testosterone levels.

 

[Michael Scally MD]

Porst H, Burnett A, Brock G, et al. SOP Conservative (Medical and Mechanical) Treatment of Erectile Dysfunction. J Sex Med 2013;10(1):130-71. SOP Conservative (Medical and Mechanical) Treatment of Erectile Dysfunction - Porst - 2013 - The Journal of Sexual Medicine - Wiley Online Library

Introduction. Erectile dysfunction (ED) is the most frequently treated male sexual dysfunction worldwide. ED is a chronic condition that exerts a negative impact on male self-esteem and nearly all life domains including interpersonal, family, and business relationships.

Aim. The aim of this study is to provide an updated overview on currently used and available conservative treatment options for ED with a special focus on their efficacy, tolerability, safety, merits, and limitations including the role of combination therapies for monotherapy failures.

Methods. The methods used were PubMed and MEDLINE searches using the following keywords: ED, phosphodiesterase type 5 (PDE5) inhibitors, oral drug therapy, intracavernosal injection therapy, transurethral therapy, topical therapy, and vacuum-erection therapy/constriction devices. Additionally, expert opinions by the authors of this article are included.

Results.
• Level 1 evidence exists that changes in sedentary lifestyle with weight loss and optimal treatment of concomitant diseases/risk factors (e.g., diabetes, hypertension, and dyslipidemia) can either improve ED or add to the efficacy of ED-specific therapies, e.g., PDE5 inhibitors.
• Level 1 evidence also exists that treatment of hypogonadism with total testosterone < 300 ng/dL (10.4 nmol/L) can either improve ED or add to the efficacy of PDE5 inhibitors.
• There is level 1 evidence regarding the efficacy and safety of the following monotherapies in a spectrum-wide range of ED populations: PDE5 inhibitors, intracavernosal injection therapy with prostaglandin E1 (PGE1, synonymous alprostadil) or vasoactive intestinal peptide (VIP)/phentolamine, and transurethral PGE1 therapy.
• There is level 2 evidence regarding the efficacy and safety of the following ED treatments: vacuum-erection therapy in a wide range of ED populations, oral L-arginine (3-5 g), topical PGE1 in special ED populations, intracavernosal injection therapy with papaverine/phentolamine (bimix), or papaverine/phentolamine/PGE1 (trimix) combination mixtures.
• There is level 3 evidence regarding the efficacy and safety of oral yohimbine in nonorganic ED. There is level 3 evidence that combination therapies of PDE5 inhibitors + either transurethral or intracavernosal injection therapy generate better efficacy rates than either monotherapy alone.
• There is level 4 evidence showing enhanced efficacy with the combination of vacuum-erection therapy + either PDE5 inhibitor or transurethral PGE1 or intracavernosal injection therapy.
• There is level 5 evidence (expert opinion) that combination therapy of PDE5 inhibitors + L-arginine or daily dosing of tadalafil + short-acting PDE5 inhibitors pro re nata may rescue PDE5 inhibitor monotherapy failures.
• There is level 5 evidence (expert opinion) that adding either PDE5 inhibitors or transurethral PGE1 may improve outcome of penile prosthetic surgery regarding soft (cold) glans syndrome.
• There is level 5 evidence (expert opinion) that the combination of PDE5 inhibitors and dapoxetine is effective and safe in patients suffering from both ED and premature ejaculation.

 

[Michael Scally MD]

Gautier A, Bonnet F, Dubois S, et al. Associations between visceral adipose tissue, inflammation and sex steroid concentrations in men. Clinical Endocrinology 2013;78(3):373-8. Associations between visceral adipose tissue, inflammation and sex steroid concentrations in men - Gautier - 2013 - Clinical Endocrinology - Wiley Online Library

Context In men, obesity and the metabolic syndrome are accompanied by decreased testosterone levels, but little is known about the associations between visceral adipose tissue (VAT), VAT-related inflammation and sex steroids.

Objective To examine the relative impact of VAT, abdominal subcutaneous adipose tissue (SAT) and interleukin 6 (IL-6), a marker of VAT-induced inflammation, on testosterone (T) and 17?-oestradiol (E2) levels in dysmetabolic men. Methods We study the NUMEVOX cohort of 229 men, aged 27–77 years, who all had at least one metabolic syndrome criterion (on average three). IL-6, C-reactive protein, Homeostasis Model Assessment of (HOMA) insulin resistance index (HOMA-IR), liver enzymes, E2, LH, sex hormone-binding globulin (SHBG), T, waist circumference and body mass index (BMI) were measured; bioavailable testosterone (BT) was calculated from T and SHBG; MRI-assessed VAT and SAT were analysed in 109 of these men.

Results Visceral adipose tissue was strongly correlated with E2 (Spearman r = 0•38, P < 0•001) and with BT/E2 ratio (r = ?0•42, P < 0•001), while SAT was not correlated with either. IL-6 was correlated with E2 (r = 0•19, P = 0•007), BT (r = ?0•19, P = 0•006) and BT/E2 ratio (r = ?0•30 P < 0•001). In multivariate linear analysis, the relation between VAT and E2 was independent of age, BMI (P = 0•008), leptin (P < 0•001), T and SHBG. Log(IL-6) was significantly inversely related with log(BT) (P = 0•032) independently of age, VAT, leptin and HOMA-IR.

Conclusions 17?-oestradiol levels were positively associated with VAT, but not with SAT, while T and BT were negatively and independently associated with IL-6. The significant inverse association between IL-6 and T suggests an important role of low-grade visceral fat inflammation in the central hypogonadism associated with the metabolic syndrome.

 

[Michael Scally MD]

Wimpissinger F, Springer C, Stackl W. International online survey: female ejaculation has a positive impact on women's and their partners' sexual lives. BJU Int. International online survey: female ejaculation has a positive impact on women's and their partners' sexual lives - Wimpissinger - 2013 - BJU International - Wiley Online Library

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?:
• Genital secretions during female orgasm (female ejaculation) have been a matter of controversy for centuries. Scientific work on this essential part of female sexual function has been able to differentiate between female ejaculation, urinary incontinence and vaginal transudate. According to earlier studies, less than 50% of women actually do ejaculate during sexual stimulation. Few affected women discuss female ejaculation with their physician - partly because of its physiological nature, partly through embarrassment.
• To gain knowledge on the characteristics of female ejaculation and its impact on women's sexual lives, an online questionnaire has been designed and published internationally. In this way, data from 320 women who perceive ejaculation could be acquired. Most women and their partners perceive female ejaculation as an enrichment of their sexual lives.

OBJECTIVE:
• To study characteristics of female ejaculation as perceived by healthy women.
• To evaluate whether fluid emission during sexual activity has an impact on women's or their partners' sexual lives.

MATERIALS AND METHODS:
• An online questionnaire consisting of 23 questions addressing the participants' characteristics, aspects of perceived female ejaculation, and its impact on women's and their partners' lives was published internationally on various online platforms.

RESULTS:
• Over a period of 18 months, 320 women from all over the world were included in the study (excluding women below the age of 18 years and double entries).
• The women's mean age was 34.1 years (+/-11.1) and their mean age at first ejaculation was 25.4 years. Most women ejaculate a few times a week.
• The volume of ejaculation is approximately 2 oz (29.1%), and the fluid is usually clear as water (83.1%).
• For most women (78.8%) and their partners (90.0%), female ejaculation is an enrichment of their sexual lives, whereas 14 women (4.4%) stated that their partners were unaware of their potential ejaculation.

CONCLUSIONS:
• Perceived female ejaculation - and its onset - occurs in women of all ages.
• Most women who ejaculate do so on a regular basis.
• Female ejaculation is an enrichment of the sexual lives of women as well as their partners.

 

[Michael Scally MD]

Nematollahi-Mahani SN, Azizollahi GH, Baneshi MR, Safari Z, Azizollahi S. Effect of folic acid and zinc sulphate on endocrine parameters and seminal antioxidant level after varicocelectomy. Andrologia. Effect of folic acid and zinc sulphate on endocrine parameters and seminal antioxidant level after varicocelectomy - Nematollahi-Mahani - 2013 - Andrologia - Wiley Online Library

Varicocele is among the most common problems which may lead to male infertility. Spermatogenesis is impaired as a consequence of this vascular defect, through mechanisms that are not well described. This study aimed to evaluate serum hormonal level (inhibin B, FSH and testosterone) and seminal plasma antioxidant defence levels after folic acid and zinc sulphate administration in varicocelectomised patients. Participants were randomly allocated to four experimental groups. Our randomisation schedule was as follows: zinc sulphate/folic acid, folic acid, zinc sulphate and placebo. The patients underwent varicocelectomy, before which a blood and semen sample were obtained and also three and six months after varicocelectomy for evaluation of blood hormonal level (FSH, testosterone, inhibin B) and seminal oxidative stress status (nitric oxide, superoxide dismutase, total antioxidant capacity). Patients in different groups took orally one capsule per day after dinner following varicocelectomy for 6 months. A significant rise in peripheral blood inhibin B and seminal plasma activity was detected in the zinc sulphate/folic acid group after 6 months. The present clinical trial indicates a change in the hormonal status of varicocelectomised patients following long-term administration of zinc sulphate and folic acid.