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[Michael Scally MD]

Liu X, Herbison AE. Dopamine Regulation of Gonadotropin-Releasing Hormone Neuron Excitability in Male and Female Mice. Endocrinology. Dopamine Regulation of Gonadotropin-Releasing Hormone Neuron Excitability in Male and Female Mice

Numerous in vivo studies have shown that dopamine is involved in the regulation of LH secretion in mammals. However, the mechanisms through which this occurs are not known. In this study, we used green fluorescent protein-tagged GnRH neurons to examine whether and how dopamine may modulate the activity of adult GnRH neurons in the mouse. Bath-applied dopamine (10-80 ? m) potently inhibited the firing of approximately 50% of GnRH neurons. This resulted from direct postsynaptic inhibitory actions through D1-like, D2-like, or both receptors. Further, one third of GnRH neurons exhibited an increase in their basal firing rate after administration of SCH23390 (D1-like antagonist) and/or raclopride (D2-like antagonist) indicating tonic inhibition by endogenous dopamine in the brain slice. The role of dopamine in presynaptic modulation of the anteroventral periventricular nucleus (AVPV) ?-aminobutyric acid/glutamate input to GnRH neurons was examined. Exogenous dopamine was found to presynaptically inhibit AVPV-evoked ?-aminobutyric acid /glutamate postsynaptic currents in about 50% of GnRH neurons. These effects were, again, mediated by both D1- and D2-like receptors. Neither postsynaptic nor presynaptic actions of dopamine were found to be different between diestrous, proestrous, and estrous females, or males. Approximately 20% of GnRH neurons were shown to receive a dopaminergic input from AVPV neurons in male and female mice. Together, these observations show that dopamine is one of the most potent inhibitors of GnRH neuron excitability and that this is achieved through complex pre- and postsynaptic actions that each involve D1- and D2-like receptor activation.

 

[Michael Scally MD]

Valenti D, Vignera SL, Condorelli RA, et al. Follicle-stimulating hormone treatment in normogonadotropic infertile men. Nat Rev Urol;advance online publication. http://www.nature.com/nrurol/journal/vaop/ncurrent/full/nrurol.2012.234.html

Several empirical treatments have been proposed to treat idiopathic infertility in men, including follicle-stimulating hormone (FSH). FSH administration is effective in patients with hypogonadotropic hypogonadism, which suggests it might be useful in patients with oligozoospermia who have normal FSH levels. Indeed, many studies have evaluated the efficacy of FSH administration in these patients, several of which have shown improvements in sperm parameters. By contrast, other studies have not reported any significant effect of FSH administration on conventional sperm parameters, although some of have reported the normalization of spermatozoon ultrastructural morphology, as well as reductions in DNA fragmentation, production of reactive oxygen species and aneuploidy. Contemporary studies suggest that the response to FSH treatment in oligozoospermic patients might, at least partially, reflect polymorphisms of the FSH receptor gene. Thus, FSH administration in oligozoospermic men with normal serum FSH levels might be efficacious only in selected patients. For this reason, additional studies are needed to determine the predictive factors and clinical conditions that can be used to identify patients who could benefit from FSH treatment.

 

[Michael Scally MD]

Guo W, Wong S, Li M, et al. Testosterone plus low-intensity physical training in late life improves functional performance, skeletal muscle mitochondrial biogenesis, and mitochondrial quality control in male mice. PLoS One 2012;7(12):e51180. PLOS ONE: Testosterone Plus Low-Intensity Physical Training in Late Life Improves Functional Performance, Skeletal Muscle Mitochondrial Biogenesis, and Mitochondrial Quality Control in Male Mice

Testosterone supplementation increases muscle mass in older men but has not been shown to consistently improve physical function and activity. It has been hypothesized that physical exercise is required to induce the adaptations necessary for translation of testosterone-induced muscle mass gain into functional improvements. However, the effects of testosterone plus low intensity physical exercise training (T/PT) on functional performance and bioenergetics are unknown.

In this pilot study, we tested the hypothesis that combined administration of T/PT would improve functional performance and bioenergetics in male mice late in life more than low-intensity physical training alone. 28-month old male mice were randomized to receive T/PT or vehicle plus physical training (V/PT) for 2 months.

Compare to V/PT control, administration of T/PT was associated with improvements in muscle mass, grip strength, spontaneous physical movements, and respiratory activity. These changes were correlated with increased mitochondrial DNA copy number and expression of markers for mitochondrial biogenesis. Mice receiving T/PT also displayed increased expression of key elements for mitochondrial quality control, including markers for mitochondrial fission-and-fusion and mitophagy. Concurrently, mice receiving T/PT also displayed increased expression of markers for reduced tissue oxidative damage and improved muscle quality.

CONCLUSION: Testosterone administered with low-intensity physical training improves grip strength, spontaneous movements, and respiratory activity. These functional improvements were associated with increased muscle mitochondrial biogenesis and improved mitochondrial quality control.

 

[Michael Scally MD]

A pretty naive and poor understanding of the HPTA. Unlike DM, one is unable to titrate doses of agents for BG control.

Carruthers M. Testosterone Deficiency Syndrome: Cellular and molecular mechanism of action. Curr Aging Sci. Testosterone Deficiency Syndrome: Cellular an... [Curr Aging Sci. 2012] - PubMed - NCBI

There is virtually no correlation between what are generally accepted to be the symptoms of androgen deficiency in the adult male and levels of androgens as measured by the laboratory. Now that androgen deficiency is being shown to play a part in conditions as diverse as coronary heart disease, diabetes, and metabolic syndrome, a hypothesis is needed to resolve this confusing clinical paradox. A review of the possible mechanisms in testosterone deficiency syndrome suggests that, as with insulin in adult-onset diabetes mellitus, there can be variable degrees of resistance to the action of androgens operating at several levels in the body. Therefore, the symptoms can result from impaired androgen synthesis or regulation, increased androgen binding, reduced tissue responsiveness, decreased androgen receptor activity mainly due to polymorphism and aging, and factors affecting transcription and translation at the genomic level. As with diabetes, with androgen deficiency in the adult male it is suggested that androgen deficiency should be defined as an absolute or relative deficiency of androgens or their metabolites according to the needs of that individual at that time in his life. The ways in which these considerations affect the terminology, etiology, diagnosis, and treatment of androgen-deficient states are discussed.

 

[BBC3]

Hmm, While the premise of this primer appears to be leading to a partial admission of guilt for fear induced IGNORANCE by the most profound community in the world, It appears they are going to skip the underlying cause BOAT and acknowledge SYMPTOMS incorrectly as DISEASE:drooling: - as a scapegoat method.. Whatever boat is floating I guess.

A pretty naive and poor understanding of the HPTA. Unlike DM, one is unable to titrate doses of agents for BG control.

Carruthers M. Testosterone Deficiency Syndrome: Cellular and molecular mechanism of action. Curr Aging Sci. Testosterone Deficiency Syndrome: Cellular an... [Curr Aging Sci. 2012] - PubMed - NCBI

There is virtually no correlation between what are generally accepted to be the symptoms of androgen deficiency in the adult male and levels of androgens as measured by the laboratory. Now that androgen deficiency is being shown to play a part in conditions as diverse as coronary heart disease, diabetes, and metabolic syndrome, a hypothesis is needed to resolve this confusing clinical paradox. A review of the possible mechanisms in testosterone deficiency syndrome suggests that, as with insulin in adult-onset diabetes mellitus, there can be variable degrees of resistance to the action of androgens operating at several levels in the body. Therefore, the symptoms can result from impaired androgen synthesis or regulation, increased androgen binding, reduced tissue responsiveness, decreased androgen receptor activity mainly due to polymorphism and aging, and factors affecting transcription and translation at the genomic level. As with diabetes, with androgen deficiency in the adult male it is suggested that androgen deficiency should be defined as an absolute or relative deficiency of androgens or their metabolites according to the needs of that individual at that time in his life. The ways in which these considerations affect the terminology, etiology, diagnosis, and treatment of androgen-deficient states are discussed.

 

[Michael Scally MD]

de Jong AME, Menkveld R, Lens JW, Nienhuis SE, Rhemrev JPT. Effect of alcohol intake and cigarette smoking on sperm parameters and pregnancy. Andrologia. Effect of alcohol intake and cigarette smoking on sperm parameters and pregnancy - Jong - 2012 - Andrologia - Wiley Online Library

Much has been published about smoking and alcohol intake influencing male fertility, sperm parameters and reproductive outcome. However, there is no conclusive agreement about the effects of cigarette smoking and alcohol use on these outcomes and thus no generally accepted guidelines. The combined effect of cigarette smoking and alcohol intake, though, has not been rigorously investigated. Because alcohol consumption and smoking are often seen together, this study focuses on the effect of smoking and drinking habits separately and combined on semen parameters, such as volume, sperm count, motility and morphology, and on pregnancy outcome. These suggested toxic effects are studied in a group of subfertile, asthenozoospermic men (<10% motile spermatozoa), compared with a group of ‘proven fertile’, healthy men. The extreme asthenozoospermic group has especially been chosen because of the suspected effect, that is, oxidative stress, on sperm motility. In our study, we found that cigarette smoking and alcohol intake did not differ between the subfertile and fertile group. In conclusion, cigarette smoking and alcohol consumption do not appear to significantly affect sperm parameters, such as volume, sperm count, motility and morphology or pregnancy outcome in our study population.

 

[Michael Scally MD]

Torremade-Barreda J, Rodriguez-Tolra J, Roman-Romera I, Padro-Miquel A, Rius-Moreno J, Franco-Miranda E. Testosterone-Deficiency as a Risk Factor for Hip Fracture in Eldery Men. Actas Urol Esp. Testosterone-Deficiency as a Risk Factor for ... [Actas Urol Esp. 2012] - PubMed - NCBI

OBJETIVES: Progressive loss of bone mineral density weakens the bones and increases the probability of osteoporotic fractures. It is well known that sex steroids play a role in the maintenance of bone density. This fact makes us think there might be a correlation between sex steroid levels and osteoporotic hip fractures.

MATERIAL AND METHODS: A case-control study was performed. The cases were 54 men who suffered from hip fracture. They were compared with 54 age-matched male control subjects. Levels of total testosterone, sex hormone binding globuline, albumin and oestradiol were measured in all subjects in order to calculate free testosterone and bio-testosterone levels.

RESULTS: Men who suffered from hip fracture had lower serum total testosterone (8.74 nmol/L versus 11.16 nmol/L; p=0.116) and lower free testostenone (155.1pmol/L versus 204.4pmol/L; p=0.02) than control subjects. Bio-testosterone levels were lower in patients with hip fracture (2.69 nmol/L versus 3.89 nmol/L; p=0.002), being the latter the best fracture predictor (OR: 1.58).

CONCLUSIONS: In our study population, men with hip fractures had significantly lower levels of calculated free testosterone and bio-testosterone. These findings suggest that free testosterone and bio-testosterone levels are independent predictors for osteoporotic hip fracture in eldery men.

 

[Michael Scally MD]

Rey RA, Grinspon RP, Gottlieb S, et al. Male hypogonadism: an extended classification based on a developmental, endocrine physiology-based approach. Andrology 2013;1(1):3-16. Male hypogonadism: an extended classification based on a developmental, endocrine physiology-based approach - Rey - 2012 - Andrology - Wiley Online Library

Normal testicular physiology results from the integrated function of the tubular and interstitial compartments. Serum markers of interstitial tissue function are testosterone and insulin-like factor 3 (INSL3), whereas tubular function can be assessed by sperm count, morphology and motility, and serum anti-Mullerian hormone (AMH) and inhibin B.

The classical definition of male hypogonadism refers to testicular failure associated with androgen deficiency, without considering potential deficiencies in germ and Sertoli cells. Furthermore, the classical definition does not consider the fact that low basal serum testosterone cannot be equated to hypogonadism in childhood, because Leydig cells are normally quiescent. A broader clinical definition of hypogonadism that could be applied to male patients in different periods of life requires a comprehensive consideration of the physiology of the hypothalamic-pituitary-testicular axis and its disturbances along development.

Here we propose an extended classification of male hypogonadism based on the pathophysiology of the hypothalamic-pituitary-testicular axis in different periods of life. The clinical and biochemical features of male hypogonadism vary according to the following: (i) the level of the hypothalamic-pituitary-testicular axis primarily affected: central, primary or combined; (ii) the testicular cell population initially impaired: whole testis dysfunction or dissociated testicular dysfunction, and: (iii) the period of life when the gonadal function begins to fail: foetal-onset or postnatal-onset.

The evaluation of basal testicular function in infancy and childhood relies mainly on the assessment of Sertoli cell markers (AMH and inhibin B). Hypergonadotropism should not be considered a sine qua non condition for the diagnosis of primary hypogonadism in childhood. Finally, the lack of elevation of gonadotropins in adolescents or adults with primary gonadal failure is indicative of a combined hypogonadism involving the gonads and the hypothalamic-pituitary axis.

 

[Michael Scally MD]

Haring R, Teumer A, Völker U, et al. Mendelian randomization suggests non-causal associations of testosterone with cardiometabolic risk factors and mortality. Andrology 2013;1(1):17-23. Mendelian randomization suggests non-causal associations of testosterone with cardiometabolic risk factors and mortality - Haring - 2012 - Andrology - Wiley Online Library

Prospective studies showed that low serum testosterone concentrations are associated with various cardiometabolic risk factors and mortality. However, the causal nature of these associations is controversial.

We studied 1 882 men aged 20–79 years with serum testosterone concentrations and genotyping data from the longitudinal population-based Study of Health in Pomerania. Testosterone concentrations were cross-sectionally associated with cardiometabolic risk factors, including anthropometric, lipid, blood pressure and glycaemic parameters; and prospectively with all-cause mortality (277 deaths, 14.7%) during the 10-year follow-up.

To overcome problems of residual confounding, reverse causation, or regression dilution bias in the investigated testosterone-outcome associations, we used two-stage least square regression models with previously identified polymorphisms at the SHBG gene (rs12150660) and X chromosome (rs5934505) as multiple genetic instruments in an instrumental variable (IV) approach, also known as Mendelian randomization.

In standard regression analyses, testosterone was robustly associated with a wide range of cardiometabolic risk factors. In subsequent IV analyses, no such significant associations were observed. Similarly, prospective analyses showed a consistent association of low testosterone concentrations with increased all-cause mortality risk, which was not apparent in subsequent IV analyses.

The present Mendelian randomization analyses did not detect any evidence for causal associations of testosterone concentrations with cardiometabolic risk factors and mortality, suggesting that previously reported associations might largely result from residual confounding or reverse causation.

Although testosterone assessment might improve risk prediction, implementation of testosterone replacement therapy requires further evidence of a direct effect on cardiometabolic outcomes from double-blinded randomized controlled trials and large-scale Mendelian randomization meta-analyses.

 

[Michael Scally MD]

Yen K, Lee C, Mehta HH, Cohen P. The Emerging Role of the Mitochondria-Derived Peptide Humanin in Stress Resistance. Journal of Molecular Endocrinology. http://jme.endocrinology-journals.org/content/early/2012/12/10/JME-12-0203.full.pdf

The discovery of humanin, a novel, mitochondria-derived peptide, has created a potentially new category of biologically active peptide. As more research unravels the endogenous role of humanin as well as its potential pharmacological use, its role in stress resistance has become clearer. Humanin protects cells from oxidative stress, serum starvation, hypoxia, and other insults in vitro and also improves cardiovascular disease as well as Alzheimer's disease in vivo. In this review we discuss the emerging role of humanin in stress resistance and its proposed mechanism of action.

 

[Michael Scally MD]

Paul JF, Virag R. Does Anatomy of the Pubic Arch Interfere with the Maintaining of Erection? The Journal of Sexual Medicine. Does Anatomy of the Pubic Arch Interfere with the Maintaining of Erection? - Paul - 2012 - The Journal of Sexual Medicine - Wiley Online Library

Aim.? There are men who suffer from unsustainable erections without any identified cause of erectile dysfunction, raising the question if anatomical alterations could be involved. Since early anatomical studies, it has been proposed that to achieve full penile rigidity, the blood must be blocked inside the penis by compression of the deep dorsal vein (DDV), the main venous collector under pubic symphysis. Using a recently developed caverno computed tomography (CT) scan technique, allowing the evaluation of the venous drainage of the corpora cavernosa (CC) during erection, we have studied some anatomical conditions of this important part of the erectile phenomenon.

Methods.? Puboischial rami angles were measured in axial CT images and calculated strictly on the upper insertion point of the CC, using axial submillimeter slices in 37 patients divided into 3 groups depending on the results of the caverno CT scan: (i) no leak; (ii) superficial veins leaking; and (iii) drainage through the DDV and/or preprostatic plexus. In addition same angles were measured in two randomly unselected populations of men (N = 30), and women (N = 23) who underwent pelvic CT scan for various reasons, unrelated to their sexual or genital condition.

Main Outcome Measures. The angles made by both puboischial rami were measured in patients with and without veno-occlusive dysfunction and in unselected samples of men and women.

Results. There is a significantly wider angle made by both puboischial rami in men without complete erection and without evidence of anomalous venous drainage (group 3) (72.2° ± 4.7° standard deviation [SD]), compared with both men with normal erection (group 1) (57.5 ± 5°SD) P < 0.00001, and men with incomplete erection and evidence of anomalous drainage (group 2) (57.7 ± 6°SD) P < 0.00001.

Conclusions. If confirmed in larger samples, these results raise new questions on the mechanism and the role of these significant anatomical variations, yet unknown, in maintaining or not full rigid erections.

 

[youngBuilder]

In this study, researchers determined the PK profiles of oral T alone and combined with the 5alpha-reductase inhibitor D in hypogonadal men during 28 days of dosing to assess the feasibility of this approach for treating male hypogonadism.


Amory JK, Bush MA, Zhi H, et al. Oral testosterone with and without concomitant inhibition of 5alpha-reductase by dutasteride in hypogonadal men for 28 days. J Urol 2011;185(2):626-32. Oral testosterone with and without concomitant inh... [J Urol. 2011] - PubMed result

PURPOSE: Co-administration of the 5alpha-reductase inhibitor dutasteride increases the oral testosterone bioavailability in men with experimentally induced hypogonadism. We examined oral testosterone with and without dutasteride administration in hypogonadal men for 28 days.

MATERIALS AND METHODS: We randomly assigned 43 hypogonadal men to twice daily oral doses of 150, 250 or 400 mg testosterone with 0.25 mg dutasteride, 400 mg testosterone alone or 0.25 mg dutasteride alone for 28 days in a multicenter study. Subjects underwent pharmacokinetic profiling of serum hormones on days 1 and 28. A total of 32 men completed all study procedures.

RESULTS: Serum testosterone increased in all groups on testosterone compared with that in the dutasteride only group. At the 400 mg dose the combination of testosterone and dutasteride resulted in average testosterone concentrations that were 2.7 and 4.6 times higher than in the testosterone only group on days 1 and 28, respectively (p <0.01). On day 28 average testosterone was 20% to 30% lower in all groups on testosterone and dutasteride, and 50% lower in the testosterone only group compared with day 1. Serum dihydrotestosterone was suppressed in all groups on dutasteride and increased in the testosterone only group.

CONCLUSIONS: Oral testosterone administration resulted in a therapeutic serum testosterone concentration in hypogonadal men. Dutasteride improved the oral bioavailability of testosterone while suppressing dihydrotestosterone. Compared with day 1, testosterone was decreased after 28 days of administration. Additional study is warranted of oral testosterone with dutasteride for testosterone deficiency.

What kind of oral Testosterone was this? I thought there was no type of oral Testosterone that had any bioavailability after ingestion? Was this Methyl-Test?

 

[Michael Scally MD]

Neuzillet Y, Hupertan V, Cour F, Botto H, Lebret T. A randomized, double-blind, crossover, placebo-controlled comparative clinical trial of arginine aspartate plus adenosine monophosphate for the intermittent treatment of male erectile dysfunction. Andrology. A randomized, double-blind, crossover, placebo-controlled comparative clinical trial of arginine aspartate plus adenosine monophosphate for the intermittent treatment of male erectile dysfunction - Neuzillet - 2012 - Andrology - Wiley Online Library

Efficacy and safety of l-arginine aspartate 8 g combined with 200 mg of adenosine monophosphate (AA) with placebo (PL) alone for intermittent treatment of mild-to-moderate erectile dysfunction (ED) were compared. The study design was a double-blind, PL-controlled, two-way crossover randomized clinical trial with 26 patients. Efficacy was assessed by International Index of Erectile Function (IIEF) and two additional validated questionnaires [the Erection Hardness Score (EHS) and the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS). During each crossover period, separated by a 2-week wash-out period, drugs were administered orally, 1–2 h before sexual intercourse. Primary endpoint was a change in the IIEF. Secondary endpoints were patient and investigator assessments of treatment success.

Investigators’ and patients’ assessment of efficacy was significantly improved by the combination vs. PL (p = 0.01 and p = 0.04 respectively]. EHS and EDITS questionnaires were both improved by the combination (p = 0.015 and p = 0.017 respectively). There was no significant difference in terms of tolerance between AA and PL or severe adverse events. ED patients demonstrated significant improvements in all IIEF domains with the exception of the Sexual Desire and Orgasmic Domains when treated with AA compared with PL.

This pilot phase II study showed that the on-demand oral administration at a high dosage of l-arginine aspartate–adenosine monophosphate combination may be effective in patients with mild-to-moderate ED, is very well tolerated and could be tested as a safe first-line therapy in a larger size phase III study.

 

[Michael Scally MD]

What kind of oral Testosterone was this? I thought there was no type of oral Testosterone that had any bioavailability after ingestion? Was this Methyl-Test?

Oral administration of unmodified T was previously thought to be ineffective due to hepatic metabolism. Nevertheless, we recently reported that when unmodified T is administered at a sufficient dose, serum T within the normal range was achieved in single dose PK studies without adverse effects on liver function.
….
Crystalline T as a hard gelatin capsule and D were provided by GlaxoSmithKline Research and Development.

http://download.journals.elsevierhealth.com/pdfs/journals/0022-5347/PIIS0022534710047221.pdf