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[Michael Scally MD]

Genes Affecting the Risk of Coronary Artery Disease Identified

An international consortium of scientists reports the discovery of five new genes that affect the risk of developing coronary artery disease (CAD) and heart attacks. Coronary artery disease is the most common cause of premature death and disability in the world and has a strong but incompletely characterized genetic contribution.

The consortium examined 49,094 genetic variants in ~2,100 genes of cardiovascular relevance in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent, and 4,394 cases and 4,259 controls of South Asian origin) and replicated their principal findings in an additional 17,121 CAD cases and 40,473 controls.

Researchers report the novel association of variants in or near four genes with CAD and in additional studies identifies potential mechanisms by which some of these novel variants affect CAD risk. Interestingly, they found that these variants, as well as the majority of previously reported CAD variants, have similar associations in Europeans and South Asians. Contrary to prior expectations, many previously suggested candidate genes did not show evidence of any effect on CAD risk, and neither did they identify any novel low frequency alleles with strong effects amongst the genes tested. Discovery of novel genes associated with heart disease may help to further understand the etiology of cardiovascular disease and identify new targets for therapeutic interventions.


The IBCKCADC. Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease. PLoS Genet 2011;7(9):e1002260. PLoS Genetics: Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease

Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ~2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression.

We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3<10?33;LPA<10?19; 1p13.3<10?17) as well as three recently discovered loci (COL4A1/COL4A2,ZC3HC1, CYP17A1<5×10?7). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06–1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ~4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003).

This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.

 

[Michael Scally MD]

Patterns Of Sexual Arousal In Homosexual, Bisexual, And Heterosexual Men

The purpose of the current study was to determine if self identified bisexual, heterosexual, and homosexual men show differential genital and subjective arousal patterns to video presentations of heterosexual (two women, without same-sex contact, engaging in sex with a man), homosexual (three men engaging in sex), lesbian (two women engaging in sex), and bisexual (two men engaging in sex with one another and with a woman) sexual behaviors. Researchers predicted that bisexual men would show higher levels of sexual arousal to bisexual erotic material than to other types of erotic stimuli, and that a bisexual stimulus would induce relatively low levels of response in heterosexual and homosexual men.

The results indicate that that this is indeed the case. Bisexual men did not differ in their responses to homosexual stimuli (depicting men engaging in sex) from homosexual men, and they did not differ in their responses to heterosexual (depicting two women engaged in sex with a man) and lesbian stimuli (depicting women engaging in sex) from heterosexual men. However, bisexual men displayed higher levels of both genital and subjective sexual arousal to a bisexual stimulus (depicting a man engaged in sex with both another man and a woman) than either homosexual or heterosexual men. In addition, bisexual men tended to show arousal levels to the lesbian stimulus that were midway between the levels shown by homosexual and heterosexual men.


Cerny JA, Janssen E. Patterns of sexual arousal in homosexual, bisexual, and heterosexual men. Arch Sex Behav 2011;40(4):687-97. http://www.iub.edu/~kinsey/publications/PDF/Patterns_of_Sexual_Arousal.pdf

The purpose of this study was to determine if self-identified bisexual, heterosexual, and homosexual men show differential genital and subjective arousal patterns to video presentations of bisexual, heterosexual, male homosexual, and lesbian sexual interactions. It was predicted that, relative to heterosexual and homosexual stimuli, bisexual men would show the highest levels of sexual arousal to bisexual erotic material, while this stimulus would induce relatively low levels of response in heterosexual and homosexual men. A sample of 59 men (19 homosexual, 13 bisexual, and 27 heterosexual) were presented with a series of 4-min sexual videos while their genital and subjective sexual responses were measured continuously. Bisexual men did not differ significantly in their responses to male homosexual stimuli (depicting men engaging in sex) from homosexual men, and they did not differ significantly in their responses to heterosexual (depicting two women, without same-sex contact, engaged in sex with a man) and lesbian (depicting women engaging in sex) stimuli from heterosexual men. However, bisexual men displayed significantly higher levels of both genital and subjective sexual arousal to a bisexual stimulus (depicting a man engaged in sex with both a man and a woman) than either homosexual or heterosexual men. The findings of this study indicate that bisexuality in men is associated with a unique and specific pattern of sexual arousal.

 

[Michael Scally MD]

Anterior Cingulate Cortex Gamma Aminobutyric Acid in Anhedonia

The anterior cingulate cortex (ACC) is the frontal part of the cingulate cortex, which resembles a "collar" form around the corpus callosum, the fibrous bundle that relays neural signals between the right and left cerebral hemispheres of the brain.

Adolescent major depressive disorder (MDD), a severe neuropsychiatric illness that is associated with significant morbidity and heightened suicide risk, remains poorly understood because of its inherent heterogeneity and symptomatic overlap with other psychopathologies. Therefore, investigating specific symptoms of the disorder has the potential to advance our understanding of the neurobiology of MDD.

An ideal candidate for such a focused investigation is anhedonia: the reduced capacity to experience pleasure and a core symptom of MDD that is prevalent and highly variable in adolescents with MDD. Among depressed adolescents, up to 59% are reported to present with significant anhedonia. Anhedonia has been associated with dysfunction of the dopaminergic brain system and the neural circuitry of reward. However, the direct mechanisms have not been determined.

Growing preclinical and clinical evidence has associated dysregulation of both aminobutyric acid (GABA) and glutamate, respectively the major inhibitory and excitatory amino acid neurotransmitters, with anhedonia and MDD pathophysiology. In support of this view are clinical studies that have reported decreased cerebrospinal fluid and blood GABA levels in melancholic MDD, in which the presence of anhedonia is essential for diagnosis. In addition, proton magnetic resonance spectroscopy (1H MRS) studies in adults have documented decreases of cortical GABA in melancholic MDD and decreases of glutamine (the molecular precursor of GABA and glutamate) in anhedonic depressed patients, further implicating these neurotransmitter systems in anhedonia.

In the present study, researchers aimed to extend prior work in adults to adolescents and assess GABA levels in the anterior cingulate cortex (ACC), a brain region strongly implicated in MDD. Structurally, both postmortem and magnetic resonance imaging (MRI) studies of MDD have shown a reduction in volume in the subgenual region of the ACC. - Multiple functional neuroimaging , and 1H MRS studies in adult - and pediatric - populations have supported a role for the ACC in MDD, and as a region that is part of the reward neural circuitry, - the ACC is highly relevant to anhedonia.

Based on prior 1H MRS data in adult MDD, they hypothesized that ACC GABA levels would be decreased in psychotropic medication–free adolescents with MDD compared with group-matched healthy controls (HCs). In secondary analyses and by analogy to melancholic MDD data in adults, - they also postulated that the subset of patients categorized as anhedonic would have decreased ACC GABA levels compared with both nonanhedonic patients and HCs and that ACC GABA levels would negatively correlate with severity of MDD episodes and with anhedonia scores. In light of evidence linking metabolic dysregulation of glutamate and glutamine to MDD and anhedonia, they explored potential group differences in Glx (combined resonances of glutamate and glutamine).

In this first study, to examine brain GABA/w levels in adolescents with MDD, researchers found significant decreases of this inhibitory neurotransmitter in the ACC of adolescents with MDD compared with HC subjects. In addition, they found significant differences in ACC GABA/w between adolescents with anhedonia and both nonanhedonic depressed adolescents and HCs but no differences between the latter 2 groups. There were negative associations between ACC GABA/w and severity of depressive episodes, as well as between ACC GABA/w and anhedonia scores in the full MDD group and in the combined sample of adolescents with MDD and HCs. However, they did not detect differences in Glx/w between adolescents with MDD and controls or in any of the subgroups nor did they detect an association between Glx/w and severity of MDD symptoms. An incidental finding is the significantly decreased WM fraction in the ACC voxel of adolescents with MDD compared with controls.


Gabbay V, Mao X, Klein RG, et al. Anterior Cingulate Cortex {gamma}-Aminobutyric Acid in Depressed Adolescents: Relationship to Anhedonia. Arch Gen Psychiatry:archgenpsychiatry.2011.131. Arch Gen Psychiatry -- Abstract: Anterior Cingulate Cortex {gamma}-Aminobutyric Acid in Depressed Adolescents: Relationship to Anhedonia, October 3, 2011, Gabbay et al. 0 (2011): archgenpsychiatry.2011.131v1

Context Anhedonia, a core symptom of major depressive disorder (MDD) and highly variable among adolescents with MDD, may involve alterations in the major inhibitory amino acid neurotransmitter system of {gamma}-aminobutyric acid (GABA).

Objective To test whether anterior cingulate cortex (ACC) GABA levels, measured by proton magnetic resonance spectroscopy, are decreased in adolescents with MDD. The associations of GABA alterations with the presence and severity of anhedonia were explored.

Design Case-control, cross-sectional study using single-voxel proton magnetic resonance spectroscopy at 3 T. Setting Two clinical research divisions at 2 teaching hospitals.

Participants Twenty psychotropic medication-free adolescents with MDD (10 anhedonic, 12 female, aged 12-19 years) with episode duration of 8 weeks or more and 21 control subjects group matched for sex and age.

Main Outcome Measures Anterior cingulate cortex GABA levels expressed as ratios relative to unsuppressed voxel tissue water (w) and anhedonia scores expressed as a continuous variable.

Results Compared with control subjects, adolescents with MDD had significantly decreased ACC GABA/w (t = 3.2; P < .003). When subjects with MDD were categorized based on the presence of anhedonia, only anhedonic patients had decreased GABA/w levels compared with control subjects (t = 4.08; P < .001; PTukey < .001). Anterior cingulate cortex GABA/w levels were negatively correlated with anhedonia scores for the whole MDD group (r = -0.50; P = .02), as well as for the entire participant sample including the control subjects (r = -0.54; P < .001). Anterior cingulate cortex white matter was also significantly decreased in adolescents with MDD compared with controls (P = .04).

Conclusions These findings suggest that GABA, the major inhibitory neurotransmitter in the brain, may be implicated in adolescent MDD and, more specifically, in those with anhedonia. In addition, use of a continuous rather than categorical scale of anhedonia, as in the present study, may permit greater specificity in evaluating this important clinical feature.

 

[Michael Scally MD]

The Effects of Kisspeptin-10 on Reproductive Hormone Release Show Sexual Dimorphism

[For some recent posts on Kisspeptin, see: Kisspeptin-10 Is a Potent Stimulator of LH and Increases Pulse Frequency in Men – https://thinksteroids.com/community/posts/764648 ; Kisspeptin-54 injection stimulates activity of the human GnRH pulse generator in healthy women - https://thinksteroids.com/community/posts/757300 ; Kisspeptin Resets the Hypothalamic GnRH Clock in Men https://thinksteroids.com/community/posts/755947 ]


The kisspeptins are critical regulators of mammalian reproductive physiology. In humans, inactivating mutations of the kisspeptin receptor (KISS1R) cause pubertal failure, and activating mutations can lead to precocious puberty. The human kisspeptin peptides, kisspeptin- 10, -13, -14, and -54, are named according to their number of constituent amino acids. All kisspeptin peptides share the C-terminal decapeptide sequence, kisspeptin- 10, which is required for biological activity in vitro.

Central or peripheral administration of the shorter kisspeptin peptide, kisspeptin-10, has been demonstrated to stimulate gonadotropin release in several mammalian species. This effect is abolished by preadministration of an antagonist to the hypothalamic hormone GnRH. Kisspeptin-10 is therefore thought to stimulate the release of GnRH from the hypothalamus, which then stimulates gonadotropin release from the pituitary gland. The longer kisspeptin peptide, kisspeptin-54, has also been shown to stimulate gonadotropin release in rodents. In addition, administration of kisspeptin-54 stimulates gonadotropin secretion in humans. Kisspeptin therefore has the potential to become a novel therapy for treatment of reproductive disorders in humans.

The shorter amino acid sequence of kisspeptin-10 makes it simpler and cheaper to synthesize than kisspeptin- 54. Future kisspeptin therapies may therefore be based upon kisspeptin-10 rather than kisspeptin-54. It is therefore therapeutically important to determine whether kisspeptin- 10 can stimulate reproductive hormone release in healthy men and women. Kisspeptin-10 stimulates gonadotropin release in male rhesus monkeys. Furthermore, two recent reports have suggested that kisspeptin-10 administration to healthy men stimulates gonadotropin release. Although kisspeptin-10 is known to stimulate gonadotropin release in animals, there are no published data examining the effects of administering kisspeptin-10 to female primates or humans.

In summary, this is the first clinical study to report the effects of kisspeptin-10 administration on gonadotropin release in women and to compare the effects of kisspeptin- 10 between men and women. Kisspeptin-10 robustly stimulates gonadotropin release in men but fails to stimulate gonadotropin release in healthy female volunteers in the follicular phase of the menstrual cycle when administered by iv bolus injection, sc bolus injection, or iv infusion. These experiments reveal sexual dimorphism in the responsiveness of healthy human volunteers to kisspeptin- 10 administration. These findings have important clinical implications for the potential therapeutic use of kisspeptin- 10 to treat disorders of reproduction.


Jayasena CN, Nijher GMK, Comninos AN, et al. The Effects of Kisspeptin-10 on Reproductive Hormone Release Show Sexual Dimorphism in Humans. Journal of Clinical Endocrinology & Metabolism. The Effects of Kisspeptin-10 on Reproductive Hormone Release Show Sexual Dimorphism in Humans

Background: Kisspeptin peptides are critical in human reproductive physiology and are potential therapies for infertility. Kisspeptin-10 stimulates gonadotropin release in both male and female rodents. However, few studies have investigated the effects of kisspeptin-10 on gonadotropin release in humans, and none have investigated the effect in women. If kisspeptin is to be useful for treating reproductive disease, its effects in both men and women must be established.

Aim: To compare the effects of kisspeptin-10 administration on reproductive hormone release in healthy men and women.

Methods: Intravenous bolus kisspeptin-10 was administered to men and women (n = 4–5 per group). Subcutaneous bolus and iv infusion of kisspeptin-10 was also administered to female women (n = 4–5 per group). Circulating reproductive hormones were measured.

Results: In healthy men, serum LH and FSH were elevated after iv bolus kisspeptin-10, at doses as low as 0.3 and 1.0 nmol/kg, respectively. In healthy women during the follicular phase of the menstrual cycle, no alterations in serum gonadotropins were observed after iv bolus, sc bolus, or iv infusion of kisspeptin-10 at maximal doses of 10 nmol/kg, 32 nmol/kg, and 720pmol/kg/min, respectively. In women during the preovulatory phase, serum LH and FSH were elevated after iv bolus kisspeptin-10 (10 nmol/kg).

Conclusion: Kisspeptin-10 stimulates gonadotropin release in men as well as women during the preovulatory phase of menstrual cycle but fails to stimulate gonadotropin release in women during the follicular phase. The sexual dimorphism of the responsiveness of healthy men and women to kisspeptin-10 administration has important clinical implications for the potential of kisspeptin-10 to treat disorders of reproduction.

 

[Michael Scally MD]

Higher HDL Lowers Cardiovascular Risk in Type 2 Diabetes

The study was funded by Takeda Pharmaceuticals America, which makes a diabetes medication called Actos (pioglitazone) that other studies have shown modestly raises HDL.

Increasing levels of high-density lipoproteins, better known as HDL or "good" cholesterol, reduced the risk for heart attack and stroke among patients with diabetes. The observational study, one of the largest of its kind, examined the medical records of more than 30,000 patients with diabetes and also found that patients whose HDL levels decreased had more heart attacks and strokes.

Researchers studied patients with diabetes because they are more prone to heart disease with a lifetime risk as high as 87 percent, according to a paper from the landmark Framingham heart study published 2008. While there is considerable evidence that reducing the amount of low-density lipoprotein, also known as LDL or "bad" cholesterol, can reduce the risk of heart disease, the relationship between HDL cholesterol and heart disease is less clear.

The study included 30,067 patients who entered Kaiser Permanente diabetes registries in Oregon, Washington and Georgia between 2001 and 2006. These patients had at least two HDL cholesterol measurements between 6 and 24 months apart. Most patients (61 percent) had no significant change in HDL levels; in 22 percent of patients, HDL levels increased by at least 6.5 mg/dl (milligrams per deciliter of blood); in 17 percent of patients, HDL levels decreased by at least that same amount.

After obtaining the cholesterol measurement, researchers followed the patients for up to 8 years to see if they were hospitalized for a heart attack or stroke. Patients whose HDL levels increased had 8 percent fewer heart attacks and strokes than patients whose HDL levels remained the same, while patients whose HDL levels decreased had 11 percent more heart attacks and strokes. This study was observational so there was no intervention to change HDL levels, and although many patients were on statins to reduce their "bad" cholesterol, very few were on medications to improve HDL.

Past studies on this topic have reached contradictory conclusions. A study published in 2009 in the Archives of Internal Medicine found that for every 5 mg/dl improvement in HDL cholesterol level patients saw a 21 percent decrease in heart attack risk. But a systematic review of more than 100 clinical trials published in the British Medical Journal in 2009 found that increasing HDL cholesterol did not reduce the risk of heart disease or death.

Earlier this year the National Institutes of Health stopped a clinical trial using large doses of the B Vitamin niacin to boost HDL levels because the patients, who were already taking statins to reduce their "bad" cholesterol, saw no added reduction in heart attacks when they added niacin. Niacin is one of very few medications to increase HDL, but it can also have side effects such as flushing, vomiting, dizziness and itching.

People can raise their HDL levels without medication by keeping their weight down, changing their diet, avoiding tobacco smoke, and increasing exercise. Medical experts believe that HDL or "good" cholesterol carries the "bad" cholesterol away from the arteries and back to the liver where it is processed and passed from the body. According to the American Diabetes Association, a good target for women should be at least 50 mg/dl of HDL and for men at least 40 mg/dl. Levels of 60 mg/dl or higher are thought to protect against heart disease.


Nichols GA, Vupputuri S, Rosales AG. Change in High-Density Lipoprotein Cholesterol and Risk of Subsequent Hospitalization for Coronary Artery Disease or Stroke Among Patients With Type 2 Diabetes Mellitus. The American journal of cardiology 2011;108(8):1124-8. Elsevier

The association between the changes in high-density lipoprotein (HDL) cholesterol and the risk of cardiovascular (CVD) or cerebrovascular hospitalization among patients with type 2 diabetes remains unclear. We conducted a retrospective observational cohort study of 30,067 members of the Kaiser Permanente Northwest and Georgia regions, who had type 2 diabetes and 2 HDL cholesterol measurements 6 to 24 months apart in 2001 to 2006. We followed up the cohort for ?8 years (through 2009) to determine whether the change in HDL cholesterol was associated with subsequent CVD hospitalization. We examined the HDL cholesterol change continuously and by 3 categories: HDL cholesterol increased ?6.5 mg/dl, decreased ?6.5 mg/dl, or remained within ±6.4 mg/dl. The Cox regression models were adjusted for the baseline HDL cholesterol and demographic and clinical risk factors. During a mean follow-up of 55.8 ± 23.8 months, 3,023 patients (10.1%) experienced a CVD hospitalization. After multivariate adjustment, each 5 mg/dl of baseline HDL cholesterol was significantly associated with a 6% lower CVD hospitalization risk (hazard ratio 0.94 per 5 mg/dl, 95% confidence interval 0.92 to 0.95, p <0.0001) and each 5-mg/dl increase in HDL cholesterol was associated with a 4% CVD risk reduction (hazard ratio 0.96, 95% confidence interval 0.94 to 0.99, p <0.003). In the categorical analysis, a ?6.5-mg/dl HDL cholesterol decrease was associated with an 11% increased CVD risk (hazard ratio 1.11, 95% confidence interval 1.00 to 1.24, p = 0.047) and a ?6.5-mg/dl increase was associated with an 8% CVD risk reduction (hazard ratio 0.92, 95% confidence interval 0.84 to 1.01, p = 0.077) relative to those with stable HDL cholesterol. In conclusion, our results add to the growing body of evidence that increasing the HDL cholesterol levels might be an important strategy for CVD risk reduction. The prevention of HDL cholesterol decreases could be equally important.

 

[Michael Scally MD]

Low Free Testosterone Predicts Mortality from Cardiovascular Disease But Not Other Causes

Since time immemorial, the ability to resist the effects of aging and prolong life has been a universal human desire. For millennia, alchemists sought in vain for an elixir of life, while more recently, 19th-century physicians attempted to produce a rejuvenating tonic from animal testicular extracts.

The discovery and synthesis of sex steroids in the first half of the 20th century renewed interest in this idea, and testosterone therapy was widely promoted for the male climacteric. However, this term is misleading, because there are clear sex differences in age-related hormonal decline. In women, a marked and abrupt reduction in estrogen and progesterone is observed during menopause, while in men, testosterone peaks in early adulthood, then decreases by a modest 1–2% per year for the remainder of life. Nonetheless, these changes are temporally associated with many features of aging, and debate remains as to whether decreased sex hormone output contributes to the aging process.

Hypogonadism is associated with components of the frailty syndrome, such as sarcopenia and decreased bone mineral density, but evidence is strongest for a role in the cardiovascular system. Low testosterone is associated with risk factors for cardiovascular disease (CVD), including insulin resistance, metabolic syndrome, and type 2 diabetes, and predicts the development of atherosclerosis and cardiovascular events. Conversely, testosterone replacement generally improves abdominal obesity, insulin sensitivity, and the lipid profile, although decreases in high-density lipoprotein are also reported. Testosterone therapy has also been shown to improve physical function in elderly men with features of frailty.

Nonetheless, androgenic anabolic steroid abuse is associated with cardiomyopathy and sudden death, and a recent testosterone trial was terminated after excess cardiovascular events in the treatment group. Epidemiological studies also conflict. Some report low testosterone predicts all-cause mortality, while others report no association or that higher levels are associated with increased cardiovascular but reduced respiratory mortality. The ability to draw conclusions from the data is further limited by differences in age range, definition of endpoints, and in the few studies examining cause specific mortality, failure to control for the problem of competing risks. Additionally, no previous study has examined the relationship between mortality and gonadotropins, which together with testosterone, may provide better risk stratification than testosterone levels alone.

Researchers designed the present analysis to explore associations between sex hormones and cause-specific mortality in a cohort of men aged 70–88 yr at baseline. They initially examined all-cause mortality and then performed a series of subanalyses for deaths due to CVD, respiratory diseases, cancer, and all remaining causes (as a composite). They hypothesized that men with low testosterone or elevated LH would be at higher risk of all-cause mortality and that this would be attributable to CVD, but not other causes, during a follow-up period of approximately 5 yr.

In this study of older men, low free testosterone and high LH were associated with increased CVD mortality; men with both low free testosterone and high LH were at greatest risk. Elevated SHBG was associated with non-CVD mortality, while higher testosterone was associated with lung cancer. This is the first time that LH has been associated with CVD mortality in older men and that testosterone has been associated with lung cancer mortality.


Hyde Z, Norman PE, Flicker L, et al. Low Free Testosterone Predicts Mortality from Cardiovascular Disease But Not Other Causes: The Health in Men Study. Journal of Clinical Endocrinology & Metabolism. Low Free Testosterone Predicts Mortality from Cardiovascular Disease But Not Other Causes: The Health in Men Study

Context: Low testosterone is associated with all-cause mortality, but the relationship with cause-specific mortality is uncertain.

Objective: Our objective was to explore associations between testosterone and its related hormones and cause-specific mortality.

Design: This was a population-based cohort study.

Setting and Participants: Demographic and clinical predictors of mortality, and testosterone, SHBG, and LH were measured from 2001–2004 in 3637 community-dwelling men aged 70–88 yr (mean, 77 yr).

Main Outcome Measure: Cause of death was obtained via electronic record linkage until December 31, 2008.

Results: During a mean follow-up period of 5.1 yr, there were 605 deaths. Of these, 207 [34.2%; 95% confidence interval (CI) = 30.4–38.1%] were due to cardiovascular disease (CVD), 231 to cancer (38.2%; 95% CI = 34.3–42.1%), 130 to respiratory diseases (21.5%; 95% CI = 18.2–24.8%), and 76 to other causes (12.6%; 95% CI = 9.9–15.2%). There were 39 deaths attributable to both cancer and respiratory diseases. Lower free testosterone (hazard ratio = 1.62; 95% CI = 1.20–2.19, for 100 vs. 280 pmol/liter), and higher SHBG and LH levels were associated with all-cause mortality. In cause-specific analyses, lower free testosterone (sub-hazard ratio = 1.71; 95% CI = 1.12–2.62, for 100 vs. 280 pmol/liter) and higher LH predicted CVD mortality, while higher SHBG predicted non-CVD mortality. Higher total testosterone and free testosterone levels (sub-hazard ratio = 1.96; 95% CI = 1.14–3.36, for 400 vs. 280 pmol/liter) were associated with mortality from lung cancer.

Conclusions: Low testosterone predicts mortality from CVD but is not associated with death from other causes. Prevention of androgen deficiency might improve cardiovascular outcomes but is unlikely to affect longevity otherwise.

 

[Michael Scally MD]

Low Testosterone Associated With Obesity and the Metabolic Syndrome Contributes to Sexual Dysfunction and Cardiovascular Disease Risk in Men With Type 2 Diabetes

Epidemiological studies support a bidirectional relationship between serum testosterone and obesity as well as between testosterone and the metabolic syndrome. Low serum total testosterone predicts the development of central obesity and accumulation of intra-abdominal fat. Also, low total and free testosterone and SHBG levels are associated with an increased risk of developing the metabolic syndrome, independent of age and obesity. Lowering serum T levels in older men with prostate cancer treated with androgen deprivation therapy increases body fat mass. Conversely, high BMI, central adiposity, and the metabolic syndrome are associated with and predict low serum total and to a lesser extent free testosterone and SHBG levels. Because obesity suppresses SHBG and as a result total testosterone concentrations, alterations in SHBG confound the relationship between testosterone and obesity.

Low total testosterone or SHBG levels are associated with type 2 diabetes, independent of age, race, obesity, and criteria for diagnosis of diabetes. In longitudinal studies, low serum total and free testosterone and SHBG levels were independent predictors of type 2 diabetes. In these studies, SHBG levels were stronger predictors of diabetes than total or free testosterone. Because type 2 diabetes is often associated with obesity, which suppresses SHBG and in turn total testosterone levels, both obesity and SHBG levels represent important confounding factors in the relationship between testosterone and type 2 diabetes. The prevalence of low free testosterone levels is higher in diabetic men compared with nondiabetic men. However, a recent longitudinal study found that free testosterone did not predict the development of type 2 diabetes. In this study, the association of total testosterone and of SHBG with diabetes was not significant after adjusting for waist circumference or central obesity. Also, low SHBG was found to be a strong independent predictor of type 2 diabetes. Finally, in prospective studies, androgen deprivation therapy either using bilateral orchidectomy or gonadotropin-releasing hormone agonist in older men with prostate cancer is associated with an increased risk of diabetes and CVD.

A number of epidemiological studies support associations of obesity, the metabolic syndrome, type 2 diabetes, and low serum testosterone with sexual dysfunction including erectile dysfunction (ED). These studies highlight the complex often multidirectional relationships among obesity, metabolic status, low testosterone, and ED in men.

Complex multidirectional interactions between testosterone and obesity, metabolic syndrome, and type 2 diabetes mediated by cytokines and adipokines leading to comorbidities such as ED and increased CVD risk. FFA, free fatty acids; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PAI-1, plasminogen activator inhibitor-1.


Wang C, Jackson G, Jones TH, et al. Low Testosterone Associated With Obesity and the Metabolic Syndrome Contributes to Sexual Dysfunction and Cardiovascular Disease Risk in Men With Type 2 Diabetes. Diabetes Care 2011;34(7):1669-75. Low Testosterone Associated With Obesity and the Metabolic Syndrome Contributes to Sexual Dysfunction and Cardiovascular Disease Risk in Men With Type 2 Diabetes

Men with obesity, the metabolic syndrome, and type 2 diabetes have low total and free testosterone and low sex hormone–binding globulin (SHBG). Conversely, the presence of low testosterone and/or SHBG predicts the development of metabolic syndrome and type 2 diabetes. Visceral adiposity present in men with low testosterone, the metabolic syndrome, and/or type 2 diabetes acts through proinflammatory factors. These inflammatory markers contribute to vascular endothelial dysfunction with adverse sequelae such as increased cardiovascular disease (CVD) risk and erectile dysfunction. This review focuses on the multidirectional impact of low testosterone associated with obesity and the metabolic syndrome and its effects on erectile dysfunction and CVD risk in men with type 2 diabetes. Whenever possible in this review, we will cite recent reports (after 2005) and meta-analyses.

 

[Michael Scally MD]

Continuous Glucose Monitoring
http://www.endo-society.org/guidelines/final/upload/FINAL-Standalone-Color-CGM-Guideline.pdf

 

[Michael Scally MD]

Efficacy And Safety Of Once-Daily Dosing Of Udenafil In The Treatment Of Erectile Dysfunction

Zhao C, Kim SW, Yang DY, et al. Efficacy and safety of once-daily dosing of udenafil in the treatment of erectile dysfunction: results of a multicenter, randomized, double-blind, placebo-controlled trial. Eur Urol 2011;60(2):380-7. http://www.europeanurology.com/article/S0302-2838(11)00278-8 / http://www.europeanurology.com/article/S0302-2838(11)00278-8/pdf

BACKGROUND: A once-daily dosing regimen with a phosphodiesterase type 5 inhibitor is needed for the treatment of erectile dysfunction (ED), in part because of the behavioral complexities associated with sexual intimacy. Many patients prefer spontaneous rather than scheduled sexual activities or they anticipate frequent sexual encounters. The pharmacokinetic profiles of udenafil with a time of maximal concentration of 1.0-1.5h and a terminal half-life of 11-13 h make udenafil a good candidate for once-daily dosing.

OBJECTIVE: To evaluate the efficacy and safety of once-daily dosing of udenafil in the treatment of ED.

DESIGN, SETTING, AND PARTICIPANTS: This multicenter randomized double-blind, placebo-controlled, fix-dosed clinical trial involved 237 patients with ED. The subjects, who were treated with placebo or udenafil (25mg, 50mg, or 75 mg) once daily for 12 wk, were asked to complete the International Index of Erectile Function (IIEF), the Sexual Encounter Profile (SEP) diary, and the Global Assessment Questionnaire (GAQ) during the study.

MEASUREMENTS: The primary outcome parameter was the change from baseline for the IIEF erectile function domain (EFD) score. The secondary outcome parameters were SEP questions 2 and 3, the shift to normal rate (EFD >/= 26), and the response to the GAQ.

RESULTS AND LIMITATIONS: Compared with placebo, patients who took 50mg or 75 mg of udenafil had a significantly improved IIEF-EFD score. Similar results were observed in comparing questions 2 and 3 in the SEP diary and the GAQ. Flushing was the most common treatment-related adverse event, which was transient and mild to moderate in severity.

CONCLUSIONS: Udenafil significantly improved erectile function among ED patients when administered in doses of 50mg or 75 mg once daily for 12 wk. Daily administration of udenafil (50mg) may be another treatment option for ED.

 

[Michael Scally MD]

Androgen-To-Estrogen Conversion Deficiency [Aromatase] Confers Paradoxical Postischemic Cardioprotection

Sex differences in cardiovascular disease have been attributed to the modulatory actions of gonadally derived sex hormones. The conventional view is that estrogen affords a level of cardiovascular protection in women, whereas an androgenic influence is generally considered a cardiovascular liability in men. However, there is accumulating evidence to indicate that the actions of these sex hormones on the heart may be more complex than would be suggested by this simple contrast.

Animal models of ischemia/reperfusion have shown improved myocardial viability and functional recovery in female hearts compared with males, although experimental design factors, including the length of ischemia, may be crucial in determining the occurrence of immediate postischemic protection. Systemic estrogen suppression through ovariectomy generally diminishes functional recovery and increases injury in ischemia/reperfusion. This effect may be reversed with chronic estrogen administration, but in some contexts, estrogen supplementation has been found to exacerbate injury.

Other studies provide evidence of a protective role for testosterone in ischemia/reperfusion. Chronic testosterone supplementation in male rat hearts increases postischemic function and improves survival. Furthermore, dihydrotestosterone improves functional recovery in ovariectomized female rats to levels similar to that observed in control, intact females. The role of estrogens and androgens in cardiac ischemia has yet to be clearly defined, and a more nuanced understanding is required.

Estrogen production depends on androgen availability, and the levels of these two steroids are linked through the enzymatic actions of aromatase (CYP19a1), converting testosterone to estradiol. Although ovaries are the primary source of systemic estrogen in females, numerous cell types have also been shown to express aromatase and produce estrogen (e.g. bone and adipocytes), exerting a paracrine/ autocrine action in the milieu of fluctuating circulating hormone levels. Aromatase has been shown to be expressed in immature hearts/cardiomyocytes, suggesting potential for the presence of intracardiac androgen- estrogen conversion. Aromatase expression in the adult myocardium has not been previously identified.

Previous studies assessing the effects of chronic sex hormone manipulation on the ischemic heart have focused on systemic, gonadally derived sex hormones. No studies to date have considered the possibility that suppression of androgen conversion to estrogen in nongonadal tissues, including the heart, may impact on myocardial function. Using a female genetic model of aromatase deficiency, the goal of this study was to investigate the effects of global estrogen withdrawal (in all tissues, including cardiac and gonadal) on the ex vivo heart responses to ischemia/reperfusion challenge.

Surprisingly they have found that in the estrogen-deficient/testosterone replete state, cardiac mechanical function is markedly enhanced post-ischemia/ reperfusion (although in a context of increased arrhythmogenesis). The studies indicate that androgen-to-estrogen conversion may be of pathophysiologic importance and suggest the possibility that estrogen suppression may offer inotropic benefit in the acute ischemia/reperfusion setting with appropriate arrhythmia management.


Bell JR, Mellor KM, Wollermann AC, et al. Aromatase Deficiency Confers Paradoxical Postischemic Cardioprotection. Endocrinology. Aromatase Deficiency Confers Paradoxical Postischemic Cardioprotection

The conventional view is that estrogen confers female cardioprotection. Estrogen synthesis depends on androgen availability, with aromatase regulating conversion of testosterone to estradiol. Extragonadal aromatase expression mediates estrogen production in some tissues, but a role for local steroid conversion has not yet been demonstrated in the heart.

This study's goal was to investigate how aromatase deficiency influences myocardial function and ischemic resilience. RT-PCR analysis of C57Bl/6 mouse hearts confirmed cardiac-specific aromatase expression in adult females. Functional performance of isolated hearts from female aromatase knockout (ArKO) and aromatase wild-type mice were compared. Left ventricular developed pressures were similar in aerobic perfusion, but the maximal rate of rise of ventricular pressure was modestly reduced in ArKO hearts (3725 ± 144 vs. 4272 ± 154 mm Hg/sec, P < 0.05). After 25 min of ischemia, the recovery of left ventricular developed pressure was substantially improved in ArKO (percentage of basal at 60 min of reperfusion, 62 ± 8 vs. 30 ± 6%; P < 0.05). Hypercontracture was attenuated (end diastolic pressure, 25 ± 5 vs. 51 ± 1 mm Hg; P < 0.05), and lactate dehydrogenase content of coronary effluent was reduced throughout reperfusion in ArKO hearts. This was associated with a hyperphosphorylation of phospholamban and a reduction in phosphorylated Akt. Immediately after reperfusion, ArKO hearts exhibited increased incidence of ventricular premature beats (194 ± 70 vs. 46 ± 6, P < 0.05). These observations indicate more robust functional recovery, reduced cellular injury, and modified cardiomyocyte Ca2+ handling in aromatase-deficient hearts.

Our findings indicate that androgen-to-estrogen conversion may be of pathophysiologic importance to the heart and challenge the notion that estrogen deficiency is deleterious. These studies suggest the possibility that aromatase suppression may offer inotropic benefit in the acute ischemia/reperfusion setting with appropriate arrhythmia management.

 

[Michael Scally MD]

Noninvasive Analytical Estimation of Endogenous Gonadotropin Releasing Hormone (GnRH) Drive

In humans and animals, one of the earliest markers of pathophysiology is subtle erosion of interlinked physiological processes, reflecting impairment of homeostatic control. Thus, early quantification of regulatory failure in vivo is fundamental to interventional medicine and restorative therapy. A major technical hurdle is the inability to measure all key components of the regulatory system directly except via invasive procedures, which may disrupt the interactions being studied.

In endocrine axes, one or more unobserved central nervous system signals often constitute primary regulatory components, which supervise observed (measurable) peripheral signals. The male gonadal axis represents such a system, wherein the GnRH secretory burst is a crucial but unobserved brain signal that evokes pituitary LH pulses and, thereby, secondarily testicular testosterone (T) secretion. Rising T concentrations in turn repress GnRH outflow. The present work uses the male hypothalamo-gonadotrope-Leydig cell axis as a prototype to model unobserved GnRH signals based upon observed LH and T pulses.

The methodology introduced here revises and complements an earlier GnRH-LH-T construct. Data from the rat, mouse, monkey, and in less measure human collectively motivate several pivotal innovations.

First, researchers extend the original paradigm of graded competitive GnRH-receptor antagonism to include simultaneous injection of a fixed, submaximally effective GnRH pulse as an external calibrating signal. The objective is normalized estimation of endogenous GnRH outflow and action, rather than mathematical construction of a virtual (unscaled or relative) GnRH signal.

Second, T or its metabolites, rather than exclusively inhibiting GnRH action at the pituitary level via the estrogen receptor, are here formulated as repressing pulsatile GnRH release at the hypothalamic level.

Third, instead of attempting to quantify GnRH’s drive of sample-by-sample LH secretion rates, a GnRH pulse is formulated as amplifying LH secretory- burst mass (size). Analogously, T is rendered as repressing GnRH secretory-burst mass.

And fourth, by measuring serum concentrations of graded doses of a competitive GnRH-receptor antagonist [ganirelix (GRX)] and a fixed dose of agonist (injected GnRH), they incorporate relevant right-shifts in GnRH potency across four strata of partial GnRH-receptor block in each individual.

The resultant analyses provide a possible basis for explaining previously conflicting data in the endocrine literature, which allege both attenuated and augmented T feedback in the aging male.

A previous model of gonadal-axis dynamics predicted attenuation of systemic T’s inhibitory feedback onto virtual GnRH-stimulated pituitary LH secretion in the aging male. The present revised analytical model quantifies augmentation (heightening) of T feedback onto estimated (externally calibrated) hypothalamic GnRH release in older individuals.

These two conclusions are complementary rather than contradictory. In particular, the first model evaluated a virtual (scale independent) continuous GnRH signal defined by its net drive of the LH secretion rate under negative feedback by T and/or its metabolites acting on the combined hypothalamic release and pituitary effect of endogenous GnRH. To obviate this duality of interpretation, they here introduce a complementary ensemble construct of T-related feedback onto hypothalamic GnRH release with no direct T effect on pituitary GnRH action. The new analysis of T feedback at the hypothalamic level indicates that age strongly augments T’s inhibition of brain GnRH secretion, thereby putatively reducing GnRH’s availability at the pituitary to stimulate LH pulses. In conjunction with the earlier outcome, the new findings provide a logical explanation for previously conflicting conclusions in the literature that age both reduces and accentuates suppression of LH secretion by systemic concentrations of T or its metabolites. The emergent concept would be that age attenuates T feedback at the pituitary level and augments T feedback on the hypothalamus.


Keenan DM, Clarke IJ, Veldhuis JD. Noninvasive Analytical Estimation of Endogenous GnRH Drive: Analysis Using Graded Competitive GnRH-Receptor Antagonism and a Calibrating Pulse of Exogenous GnRH. Endocrinology. Noninvasive Analytical Estimation of Endogenous GnRH Drive: Analysis Using Graded Competitive GnRH-Receptor Antagonism and a Calibrating Pulse of Exogenous GnRH

Homeostatic control of endocrine systems proceeds via feedforward (agonistic, stimulatory) and feedback (antagonistic, inhibitory) interactions mediated via implicit dose-response functions. However, neither the feedback/feedforward pathways nor the dose-response interfaces are directly observed in vivo. Thus, the goal was to formulate and estimate an ensemble construct of time-varying feedback/feedforward interactions among GnRH, LH, and testosterone (T) in the male gonadal axis. The new analytical model revises and extends an earlier construct by: 1) allowing systemic T concentrations to inhibit hypothalamic GnRH output; 2) estimating GnRH outflow after injection of a calibrating pulse of biosynthetic GnRH; 3) framing the pituitary response to GnRH as a secretory burst, rather than continuous LH release; and 4) regressing feedback and feedforward ensemble parameters on age, rather than evaluating age dichotomously. Application of this methodology in 21 men aged 23-72 yr unveiled age-related 1) diminution of GnRH efficacy normalized for the decline in free T with age (P = 0.016), 2) potentiation of maximal T feedback onto (inhibition of) GnRH secretion (P = 0.006), and 3) accentuation of hypothalamic GnRH's sensitivity to T repression (P = 0.003). Outcomes were specific, because injected GnRH agonist and antagonist concentrations were invariant of age. We conclude that combining experimental and analytical strategies may provide a noninvasive means to investigate and decipher feedback determinants of unobserved endocrine signal(s).

 

[Michael Scally MD]

Clearly an outlier, but this is enough to stir the pot!

Kocoglu H, Alan C, Soydan H, et al. Association between the androgen levels and erectile function, cognitive functions and hypogonadism symptoms in aging males. Aging Male. Association between the androgen levels and erect... [Aging Male. 2011] - PubMed - NCBI

Purpose: Aging in men is characterized by a moderate decrease in plasma testosterone (T) levels. However, the association between partial androgen deficiency of the aging male and clinical symptoms and the ideal screening test are controversial. In this study, we investigated the association between the androgen levels and erectile function, cognitive functions and hypogonadism symptoms in aging males.

Materials and methods: We investigated the association between total (TT), calculated free (FT) and bioavailable (BT) testosterone, and various clinical and laboratory parameters in 103 healthy males, 50?80 years old. Biochemical assessment was done after overnight fasting. Questionnaires were used to test for hypogonadism symptoms, erectile and cognitive functions.

Results: TT levels were not correlated with aging in this study. However, FT and BT were found to decrease with age due to rising sex hormone binding globulin. TT levels were strongly correlated with FT and BT levels (respectively p = 0.0001, p = 0.0001). TT, FT and BT were only correlated with cognitive functions (p = 0.012, p = 0.004, p = 0.02 respectively). There was no correlation between TT, FT and BT levels and erectile function and hypogonadism symptoms.

Conclusion: T values in our study sample did not correlate with clinical signs and symptoms of hypogonadism. Thus, according to our data, symptoms in the aging male should not be indiscriminately assigned to a decrease in TT, FT or BT levels.

 

[Michael Scally MD]

Arterial Calcium Adds Little to CT Angiography

Coronary artery calcification score may be a helpful prognostic tool when combined with other risk factors, but by itself it is not a reliable predictor of cardiovascular events, researchers found.


Villines TC, Hulten EA, Shaw LJ, et al. Prevalence and Severity of Coronary Artery Disease and Adverse Events Among Symptomatic Patients With Coronary Artery Calcification Scores of Zero Undergoing Coronary Computed Tomography Angiography: Results From the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) Registry. J Am Coll Cardiol:j.jacc.2011.10.851. Prevalence and Severity of Coronary Artery Disease and Adverse Events Among Symptomatic Patients With Coronary Artery Calcification Scores of Zero Undergoing Coronary Computed Tomography Angiography: Results From the CONFIRM (Coronary CT Angiography
http://content.onlinejacc.org/cgi/reprint/j.jacc.2011.10.851v1.pdf

Objectives: The purpose of this study was to describe the prevalence and severity of coronary artery disease (CAD) in relation to prognosis in symptomatic patients without coronary artery calcification (CAC) undergoing coronary computed tomography angiography (CCTA).

Background: The frequency and clinical relevance of CAD in patients without CAC are unclear.

Methods: We identified 10,037 symptomatic patients without CAD who underwent concomitant CCTA and CAC scoring. CAD was assessed as <50%, 50%, and 70% stenosis. All-cause mortality and the composite endpoint of mortality, myocardial infarction, or late coronary revascularization ( 90 days after CCTA) were assessed.

Results: Mean age was 57 years, 56% were men, and 51% had a CAC score of 0. Among patients with a CAC score of 0, 84% had no CAD, 13% had nonobstructive stenosis, and 3.5% had 50% stenosis (1.4% had 70% stenosis) on CCTA. A CAC score >0 had a sensitivity, specificity, and negative and positive predictive values for stenosis 50% of 89%, 59%, 96%, and 29%, respectively. During a median of 2.1 years, there was no difference in mortality among patients with a CAC score of 0 irrespective of obstructive CAD. Among 8,907 patients with follow-up for the composite endpoint, 3.9% with a CAC score of 0 and 50% stenosis experienced an event (hazard ratio: 5.7; 95% confidence interval: 2.5 to 13.1; p < 0.001) compared with 0.8% of patients with a CAC score of 0 and no obstructive CAD. Receiver-operator characteristic curve analysis demonstrated that the CAC score did not add incremental prognostic information compared with CAD extent on CCTA for the composite endpoint (CCTA area under the curve = 0.825; CAC + CCTA area under the curve = 0.826; p = 0.84).

Conclusions: In symptomatic patients with a CAC score of 0, obstructive CAD is possible and is associated with increased cardiovascular events. CAC scoring did not add incremental prognostic information to CCTA.

 

[Michael Scally MD]

Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy

In this trial involving patients with established, nonacute cardiovascular disease and low levels of baseline HDL cholesterol who achieved and maintained low levels of LDL cholesterol (<70 mg per deciliter) while receiving intensive statin treatment, extended-release niacin plus simvastatin as compared with simvastatin alone was associated with significant increases in HDL cholesterol levels and decreases in triglyceride levels, but there was no significant reduction in the primary composite end point of cardiovascular events over a mean follow-up period of 36 months. A very high percentage of patients (94%) were already taking a statin at trial entry, and many had taken one for long periods; 20% had taken niacin previously. At 2 years of follow-up, among patients assigned to niacin, LDL cholesterol levels had decreased by an additional 12.0% to a median of 62 mg per deciliter and HDL cholesterol levels had increased by 25.0% to 42 mg per deciliter, whereas in the placebo group, LDL cholesterol levels had decreased minimally to a median of 68 mg per deciliter and HDL cholesterol levels had increased by 9.8% to 38 mg per deciliter.


Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy. New England Journal of Medicine. MMS: Error

BACKGROUND - In patients with established cardiovascular disease, residual cardiovascular risk persists despite the achievement of target low-density lipoprotein (LDL) cholesterol levels with statin therapy. It is unclear whether extended-release niacin added to simvastatin to raise low levels of high-density lipoprotein (HDL) cholesterol is superior to simvastatin alone in reducing such residual risk.

METHODS - We randomly assigned eligible patients to receive extended-release niacin, 1500 to 2000 mg per day, or matching placebo. All patients received simvastatin, 40 to 80 mg per day, plus ezetimibe, 10 mg per day, if needed, to maintain an LDL cholesterol level of 40 to 80 mg per deciliter (1.03 to 2.07 mmol per liter). The primary end point was the first event of the composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization.

RESULTS - A total of 3414 patients were randomly assigned to receive niacin (1718) or placebo (1696). The trial was stopped after a mean follow-up period of 3 years owing to a lack of efficacy. At 2 years, niacin therapy had significantly increased the median HDL cholesterol level from 35 mg per deciliter (0.91 mmol per liter) to 42 mg per deciliter (1.08 mmol per liter), lowered the triglyceride level from 164 mg per deciliter (1.85 mmol per liter) to 122 mg per deciliter (1.38 mmol per liter), and lowered the LDL cholesterol level from 74 mg per deciliter (1.91 mmol per liter) to 62 mg per deciliter (1.60 mmol per liter). The primary end point occurred in 282 patients in the niacin group (16.4%) and in 274 patients in the placebo group (16.2%) (hazard ratio, 1.02; 95% confidence interval, 0.87 to 1.21; P=0.79 by the log-rank test).

CONCLUSIONS - Among patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of less than 70 mg per deciliter (1.81 mmol per liter), there was no incremental clinical benefit from the addition of niacin to statin therapy during a 36-month follow-up period, despite significant improvements in HDL cholesterol and triglyceride levels.

 

[Michael Scally MD]

This review focuses on mammalian muscle fiber heterogeneity, with the goal to relate the new mechanistic studies on signaling pathways to an integrative description of the function and structure of different types of skeletal muscle fibers. They first review the different aspects of muscle fiber specialization from excitability to metabolism, from contraction mechanism to calcium kinetics aiming to an integrated view. They then consider the variations in fiber type profile in relation to species, gender, and individual polymorphism; the process of fiber diversification during development; and the fiber type remodeling in adult skeletal muscle. Finally, they consider selected signaling pathways, leading to muscle fiber specialization and the underlying adaptive changes in muscle plasticity.


Schiaffino S, Reggiani C. Fiber Types in Mammalian Skeletal Muscles. Physiological Reviews 2011;91(4):1447-531. Fiber Types in Mammalian Skeletal Muscles

Mammalian skeletal muscle comprises different fiber types, whose identity is first established during embryonic development by intrinsic myogenic control mechanisms and is later modulated by neural and hormonal factors. The relative proportion of the different fiber types varies strikingly between species, and in humans shows significant variability between individuals. Myosin heavy chain isoforms, whose complete inventory and expression pattern are now available, provide a useful marker for fiber types, both for the four major forms present in trunk and limb muscles and the minor forms present in head and neck muscles. However, muscle fiber diversity involves all functional muscle cell compartments, including membrane excitation, excitation-contraction coupling, contractile machinery, cytoskeleton scaffold, and energy supply systems. Variations within each compartment are limited by the need of matching fiber type properties between different compartments. Nerve activity is a major control mechanism of the fiber type profile, and multiple signaling pathways are implicated in activity-dependent changes of muscle fibers. The characterization of these pathways is raising increasing interest in clinical medicine, given the potentially beneficial effects of muscle fiber type switching in the prevention and treatment of metabolic diseases.

 

[Michael Scally MD]

Androgen Receptor Repression of GnRH Gene Transcription

A fundamental concept in hypothalamic-pituitary gonadal (HPG) axis regulation is the steroid hormone feedback loop, whereby gonadal steroids feedback to regulate hypothalamic control of reproduction. Due to the lack of sensitivity of classical methods used to colocalize steroid receptors with GnRH-expressing neurons, it was believed that this feedback occurred indirectly through interneurons expressing the steroid hormone nuclear receptors. However, it has become clear that GnRH neurons do express steroid hormone receptors that can serve as direct targets of the feedback loop. Hypothalamic GnRH neurons have been shown to express estrogen receptor (ER)Beta in vivo, and a GnRH-expressing cell line, GT1, expresses androgen receptor (AR), ERAlpha, ERbeta, and progesterone receptor (PR)A.

The AR is a ligand-activated transcription factor, a member of the nuclear receptor superfamily, and is closely related to PR and glucocorticoid receptor (GR). AR mediates various biological effects of androgens in a wide array of reproductive processes, including sexual differentiation and maturation, spermatogenesis, and gonadotropin regulation. Proper regulation of androgen signaling in the HPG pathway is important to maintain mammalian fertility. Despite the importance of androgens in overall reproductive health, the mechanism by which they act upon the hypothalamus remains unclear.

It is difficult to colocalize GnRH neurons and nuclear receptors due to the low numbers, heterogeneity, and dispersion of GnRH neurons in vivo, as well as the low abundance of nuclear receptors. The difficulty of studying the small, dispersed population of GnRH neurons in vivo led to the creation of a GnRH-expressing neuronal cell line, GT1-7. The GT1-7 cell line was created using GnRH-simian virus 40 T-antigen transgenic mice. GT1-7 cells express GnRH mRNA and exhibit pulsatile secretion of GnRH peptide with the 30-min interpulse interval appropriate for the mouse. They also express neuronal markers, including presynaptic vesicle proteins and extend neurites ending in growth cones or contacts with other cells. Thus, the GT1-7 cell line represents an excellent model system for the GnRH neuron that allows the study of GnRH synthesis and secretion in response to steroid hormone treatments.

Androgens decrease GnRH expression and secretion from the hypothalamus in vivo. Androgens have a repressive effect on GnRH gene expression in vitro, although the mechanism of this effect has not been determined. In addition, due to the complex feedback loops of the HPG axis, the necessity for AR expression in the GnRH neuron in vivo and its effects on fertility are yet to be elucidated. Previous reports demonstrated that androgens regulate synthesis and secretion of gonadotropins at the level of both the hypothalamus and the pituitary. Androgens have been reported to decrease GnRH expression and secretion from the hypothalamus, which leads to repression of both FSH and LH secretion from the pituitary. Research showed decreased levels of GnRH mRNA in GT1-7 cells after 24 h of treatment with 5Alpha- dihydrotestosterone (DHT). Interestingly, GnRH secretion from GT1-7 cells was stimulated by DHT through a membrane-initiated event, and this was distinct from the mechanism of transcriptional repression.

Steroid hormone regulation of GnRH transcription and secretion is crucial for the proper function of the HPG axis. This report identifies a complex interaction between multiple transcription factors at GnRH-P that is involved in AR repression, with Oct-1 playing a central role. This mechanism is similar to that previously shown for GR, the only other nuclear receptor whose interaction with Oct-1 on GnRH-P has been studied. The similarity of GnRH transcriptional regulation by AR and GR suggests that direct repression of GnRH gene expression by classical nuclear receptors is an important aspect of the hormonal regulation of fertility.


Brayman MJ, Pepa PA, Berdy SE, Mellon PL. Androgen Receptor Repression of GnRH Gene Transcription. Molecular Endocrinology. Androgen Receptor Repression of GnRH Gene Transcription

Alterations in androgen levels lead to reproductive defects in both males and females, including hypogonadotropic hypogonadism, anovulation, and infertility. Androgens have been shown to down-regulate GnRH mRNA levels through an androgen receptor (AR)-dependent mechanism. Here, we investigate how androgen regulates expression from the GnRH regulatory region in the GT1-7 cell line, a model of GnRH neurons.

A synthetic androgen, R1881, repressed transcription from the GnRH promoter (GnRH-P) in an AR-dependent manner, and liganded AR associated with the chromatin at the GnRH-P in live GT1-7 cells. The three known octamer-binding transcription factor-1 (Oct-1) binding sites in GnRH-P were required for AR-mediated repression, although other sequences were also involved. Although a multimer of the consensus Oct-1 binding site was not repressed, a multimer of the cluster of Oct-1, Pre-B cell leukemia transcription factor (Pbx)/Prep, and NK2 homeobox 1 (Nkx2.1) binding sites, found at ?106/?91 in GnRH-P, was sufficient for repression. In fact, overexpression of any of these factors disrupted the androgen response, indicating that a balance of factors in this tripartite complex is required for AR repression. AR bound to this region in EMSA, indicating a direct interaction of AR with DNA or with other transcription factors bound to GnRH-P at this sequence.

Collectively, our data demonstrate that GnRH transcription is repressed by AR via multiple sequences in GnRH-P, including three Oct-1 binding sites, and that this repression requires the complex interaction of several transcription factors.

 

[Michael Scally MD]

Erectile Dysfunction Study Shows High Prevalence of Peripheral Neuropathy

Spanish researchers have uncovered clear links between erectile dysfunction (ED) and peripheral neuropathy, according to a paper in the December issue of the urology journal BJUI. The research team, which included experts on both neurophysiology and urology, studied 90 consecutive patients with sexual problems recruited from the hospital's Department of Andrology.

ED was diagnosed using the five-item version of the International Index of Erectile Dysfunction (IIEF-5) and the occurrence of peripheral neuropathy was predicted using the Neuropathy Symptom Score. A range of neurophysiology tests were carried out to assess the presence of large and small fibreperipheral neuropathy.

The researchers found that:

• The average age of the men in the study was 54 years of age. Ten per cent were under 40 and only two per cent were over 70.

• No significant correlation between IIEF-5 scores and increasing age was found. In fact, younger patients had lower (worse) IIEF-5 scores, which could be due to higher expectations or a higher number of organic risk factors.

• Just under a third of the patients (30 per cent) had cardiovascular disease, 16 per cent had neurogenic risk factors (relating to the nerves or nervous system) 16 per cent had diabetes and 11 per cent had no risk factors. Just over seven per cent had been diagnosed with mental health issues.

• Patients with more severe symptoms of peripheral neuropathy showed lower (worse) IIEF-5 scores and required more aggressive therapies.

• Neurophysiological exploration confirmed that just under 69 per cent of patients had neurological pathology. Of these, 61 per cent had some type of peripheral neuropathy and eight per cent had myelopathy -- problems with their spinal chord.

• Just under 38 per cent of the patients had polyneuropathy, which occurs when a number of the peripheral nerves throughout the body malfunction simultaneously. Of these nine per cent had small fibre neuropathy, damage to the smallunmyelinated peripheral nerve fibres, and just over 14 per cent had pudendal neuropathy, affecting the somatic nerve in the pelvic region.

• The findings of the sympathetic skin response tests underlined the importance of checking nerve problems in the pelvic area, as response alterations were much more common in the penis than hand or foot.

• No association between neurophysiological diagnosis and IIEF-5 scores was detected, but a statistical association was found between neuropathy and the Neuropathy Symptom Scores.


Valles-Antuña C, Fernandez-Gomez J, Fernandez-Gonzalez F. Peripheral neuropathy: an underdiagnosed cause of erectile dysfunction. BJU International 2011;108(11):1855-9. Peripheral neuropathy: an underdiagnosed cause of erectile dysfunction - Valles-Antu[]a - 2011 - BJU International - Wiley Online Library

OBJECTIVES To assess the prevalence of peripheral neuropathy in patients with erectile?• To evaluate the reliability of clinical tests such as the?dysfunction (ED).• five-item version of the International Index of Erectile Function (IIEF-5) and the Neuropathy Symptom Score (NSS) classification system in predicting the concurrence of peripheral neuropathy.

PATIENTS We studied 90 patients who were consecutively recruited from the?AND METHODS • Anamnesis?Department of Andrology of the Central Hospital of Asturias.• The severity of ED was?included questions about risk factors related to ED.• classified according to IIEF-5 scores and symptoms of peripheral neuropathy Neurophysiological tests included?were assessed using the NSS.• electromyography, nerve conduction studies, evoked potentials from pudendal and Small fibre function was?tibial nerves as well as bulbocavernosus reflex.• assessed using quantitative sensory tests and sympathetic skin response. Statistical analysis was performed using the SPSS-11 program.

RESULTS Patients with more severe symptoms of peripheral neuropathy showed lower?• (worse) IIEF-5 scores (P= 0.015) and required more aggressive therapies (P < Neurophysiological exploration confirmed neurological pathology in?0.001).• 68.9% of patients, of whom 7.8% had myelopathy and 61.1% peripheral Polyneuropathy was found in 37.8% of the patients, of whom 8.9% had?neuropathy.• pure small fibre polyneuropathy, and pudendal neuropathy was diagnosed in No association between neurophysiological diagnosis and IIEF-5 score?14.4%.• was detected, but a statistical association was found between neuropathy and NSS scores.

CONCLUSIONS Up to now, the impact of peripheral neuropathy in the pathogenesis of ED has?• been underestimated. The combination of anamnesis and an ad hoc neurophysiological protocol showed its high prevalence and provided a more In future, clinical practice should optimize the?accurate prognosis.• assessment of pelvic small fibre function.

 

[Michael Scally MD]

Dekker MJHJ, Tiemeier H, Luijendijk HJ, et al. The Effect of Common Genetic Variation in 11Beta-Hydroxysteroid Dehydrogenase Type 1 on Hypothalamic-Pituitary-Adrenal Axis Activity and Incident Depression. Journal of Clinical Endocrinology & Metabolism. http://jcem.endojournals.org/content/early/2011/11/17/jc.2011-0601.abstract

Background: Accumulating evidence suggests that hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA axis) is involved in depression. 11?-Hydroxysteroid dehydrogenase type 1 (11?-HSD1) converts inert cortisone to active cortisol and is implicated in HPA axis regulation in animal studies. The aim of our study was to identify polymorphisms in 11?-HSD1 gene (HSD11B1) with consistent associations with increased HPA axis activity and relate those polymorphisms to depression.

Methods: Twelve single-nucleotide polymorphisms (SNPs), including 11 tagging SNPs, were selected using the HapMap database and genotyped in 4228 participants of the population-based Rotterdam Study. The outcome measures were salivary cortisol levels after awakening, 30 min later, at 1700 h, at bedtime, and plasma levels of androstenedione (in women only). SNPs that were significantly associated with cortisol as well as androstenedione levels were also related to incident depression.

Results: rs11119328 was associated with higher cortisol saliva samples collected at bedtime as well as higher androstenedione levels (P value after correction for multiple testing: 0.01 and 0.04, respectively). Carriers of this polymorphism had an increased risk of an incident depression (hazard ratio 1.28, 95% confidence interval 1.03–1.59). Two other SNPs, which were in high linkage disequilibrium with rs11119328, were related to higher cortisol levels but not with androstenedione levels.

Conclusions: We identified one SNP, which was associated with increased salivary cortisol levels at nadir as well as higher androstenedione levels. Moreover, this SNP was also associated with a higher risk of an incident depression. This suggests that 11?-HSD1 is implicated in human HPA axis regulation and susceptibility to depression.

 

[Michael Scally MD]

Viguerie N, Picard F, Hul G, et al. Multiple effects of a short term dexamethasone treatment in human skeletal muscle and adipose tissue. Physiological Genomics. Multiple effects of a short term dexamethasone treatment in human skeletal muscle and adipose tissue.

Glucocorticoids are frequently prescribed drugs with important side-effects such as glucose intolerance and tissue remodelling. The goal was to explore the molecular basis of the response of skeletal muscle and adipose tissue during a short term dexamethasone treatment to better understand the induction of side-effects of glucocorticoids on these metabolic tissues.

Fifteen healthy male subjects were assigned to a 4-d treatment with dexamethasone at 4mg/d. The primary outcome measures were changes in gene expression profiling of subcutaneous skeletal muscle and adipose tissue. Urinary cortisol, plasma and metabolic biochemistry were also assessed.

In both tissues, the prominent observation was a response to stress and increased inflammatory responses. An upregulation of the serum amyloid A was detected in skeletal muscle, adipose tissue and plasma whereas circulating levels of C reactive protein, another acute phase protein, decreased along with a worsened insulin sensitivity index. As tissue specific features, tissue remodelling was shown in skeletal muscle while the adipose tissue exhibited a decreased energy metabolism.

Several limitations might be raised due to the small number of subjects investigated, a possible crosstalk with the mineralocorticoid receptor, and because a single time point may not identify regulations occurring during longitudinal treatment. In line with the known physiological effect of glucocorticoids the early modulation of stress response genes was observed. An unexpected feature was the upregulation of the inflammatory and immune pathways. The identification of novel impact on two glucocorticoid target tissues provide molecular basis for the design of more specific glucocorticoids devoid of adverse effects.

 

[Michael Scally MD]

Faulds MH, Zhao C, Dahlman-Wright K, Gustafsson J-Ã. The diversity of sex steroid action: regulation of metabolism by estrogen signaling. Journal of Endocrinology 2011;212(1):3-12. The diversity of sex steroid action: regulation of metabolism by estrogen signaling

The metabolic syndrome is a complex condition characterized by obesity, insulin resistance, decreased high-density lipoproteins, and hypertension associated with high risk of developing type 2 diabetes and cardiovascular disease. A major increase in the incidence of developing metabolic syndrome and related diseases is observed worldwide in association with a change toward a less active lifestyle and increased food consumption. Estrogen and the estrogen receptors (ERs) are well-known regulators of several aspects of metabolism, including glucose and lipid metabolism, and impaired estrogen signaling is associated with the development of metabolic diseases. This review will describe the key effects of estrogen signaling in metabolic and glucose sensing tissues, including the liver, pancreatic ? cells, adipose tissue, and skeletal muscle. The impact on metabolic processes of impaired estrogen signaling and knock out of each ER subtype will also be discussed.



Summary of the effects on metabolism observed in ER?, ER?, and aromatase knockout (ArKO) female and male mice. Reported effects in different metabolic tissues, i.e. central nervous system (CNS), pancreatic ? cell, skeletal muscle, liver, and white adipose tissue (WAT), are indicated. ND, no difference; HFD, high-fat diet; TG, triglycerides.