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Nathan Goodyear

Longitudinal Effects of Aging on Serum Total and Free Testosterone Levels in Healthy Me... - 0 views

  • NUMEROUS CROSS-SECTIONAL INVESTIGATIONS have demonstrated lower concentrations of circulating testosterone (T) and/or free T in older men
  • Two small-scale longitudinal investigations have observed decreases, with aging, in total T
  • T levels decline at a more or less constant rate, with age, in men, with no period of accelerated decline
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  • aging in men is associated with decreases in bone mineral density (BMD) (18, 19), lean body and muscle mass
  • strength (22, 23) and aerobic capacity (24), as well as with increases in total and abdominal body fat, low-density lipoprotein cholesterol, and/or low-density lipoprotein/high-density lipoprotein cholesterol ratios (25, 26, 27, 28), all of which also occur in nonelderly hypogonadal men
  • Most (1, 5, 6, 7, 8, 9), but not all (10, 11, 12), cross-sectional studies have demonstrated a decrease, with age, in total T in men
    • Nathan Goodyear
       
      FAI: 100 x total Testosterone nmol/L/SHBG nmol/L
    • Nathan Goodyear
       
      These numbers do point to an increase in ng/dl decline in Total Testosterone with increasing age (decade group)
  • total T, but not free T index, tended to decrease with greater BMI is consistent with prior studies showing that obesity is associated with decreases in both SHBG and total T, with an unchanged T-to-SHBG ratio
  • The conventional definition for T levels is statistical (values more than 2 sd below the mean), rather than functional. Such a definition does not reflect clinical realities, such as the existence of characteristic individual set points for circulating hormone levels, below which one, but not another, individual may develop metabolic changes of hormone deficiency; nor does it address the concept of reserve capacity, the possibility that persons with hormone levels 2 sd below the population mean still may have adequate hormone concentrations to meet their metabolic needs.
    • Nathan Goodyear
       
      good explanation of problems with just using a number to define low T
  • both T and free T index (a calculated value related to free or bioavailable T) decreased progressively at a rate that did not vary significantly with age, from the third to the ninth decades.
  • contrasts with other studies showing diminished free, as well as total, T in with increasing total (48) or abdominal (49) obesity in men.
  • Our analysis of date-adjusted T and free T index levels, by decade, showed that relatively high numbers of older men in this generally healthy population had at least one hypogonadal value (defined as below the 2.5th percentile for young men)
  • The issue of how properly to define hypogonadism, or indeed any hormone deficiency, remains problematic
  • The decrease in free T index was somewhat steeper than that of total T, owing to a trend for an increase in SHBG with age
  • LH for gonadal function
  • It would clearly be better to define the lower limit of normal for a hormone as: the blood level at which metabolic and/or clinical sequelae of hormone deficiency begin to appear, or the level below which definite benefits can be demonstrated for hormone supplementation for a significant proportion of the population
  • an effect of aging to lower both total and bioavailable circulating T levels at a relatively constant rate, independent of obesity, illness, medications, cigarette smoking, or alcohol intake
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    Article highlights the problems with the definition of low T.  This article finds consistent decline in Total Testosterone and FAI with increasing age groups, with a significant portion of men > 60 meeting the required levels for "low T".  This study found a decrease in total T and FAI at a consistent rate independent of variables, such as BMI.    This study did find a decrease in SHBG and total T with obesity; in contrast to other studies.
Nathan Goodyear

Sex steroids and cardiovascular disease Yeap BB - Asian J Androl - 0 views

  • Levels of SHBG are higher in older men, therefore levels of free T decline more steeply than total T as men's age increases.
  • calculations based on mass action equations may not reflect precisely free T measured using a reference method
  • free T declines more steeply with age than total T in both cross-sectional [35] and longitudinal studies, [36] as does free E2 in comparison to total E2
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  • T may slow development of or progression of atherosclerosis by modulating effects on insulin resistance, inflammation, endothelial function, preclinical atherosclerosis or the vasculature.
  • these cross-sectional and longitudinal studies support a relationship between low circulating T with CIMT and higher E2 with its progression
  • lower levels of T are biomarkers for aortic vascular disease
  • circulating free T was negatively associated with the presence of AAA
  • luteinizing hormone (LH) was positively associated.
  • low levels of total or bioavailable T were associated with aortic atherosclerosis manifested as calcified deposits detected by radiography
  • Men with total or free T in the lowest quartile had increased adjusted ORs for PAD defined as ABI <0.90, as did men with free E2 in the highest quartile of values
  • The apparent association of SHBG with intermittent claudication reflects the correlation of total T with SHBG, while the contribution of E2 to risk of PAD remains unclear
  • men with total T in the lowest quartile of values (<11.7 nmol l−1 ) experienced an increased incidence of stroke or transient ischemic attack
  • lower total T with increased incidence of CVD events
  • cohort studies in mostly older men have supported the association of lower androgen levels with higher mortality
  • lower total or free T levels were associated with mortality in older men, but with discordant results for cause-specific mortality and for associations of E2
  • several large studies identifying lower endogenous levels of total or free T as independent predictors of all-cause or CVD-related deaths in middle-aged and older men
  • T exhibits anti-inflammatory effects, enhances flow-mediated brachial artery reactivity, and reduces arterial stiffness
  • Short-term T therapy had a beneficial effect on exercise-induced myocardial ischemia in middle-aged men with coronary artery disease or chronic stable angina, [95],[96],[97] and reduced angina frequency in older men with diabetes and coronary artery disease
  • T therapy resulted in an increase in treadmill test duration and time to ST segment depression
  • there are interventional studies supporting a protective effect of exogenous T against myocardial ischemia in men with coronary artery disease
  • employ conservative doses
    • Nathan Goodyear
       
      This dosing is 100 fold higher then peak production of a  young man at 20-22.
  • Observational studies indicate that lower levels of endogenous T in older men are associated with the presence of carotid atherosclerosis, aortic and peripheral vascular disease, and incidence of CVD events and mortality
  • Interventional studies have shown beneficial effects of exogenous T on vascular function and on exercise-induced myocardial ischemia in men with coronary artery disease
    • Nathan Goodyear
       
      the therapies employed in these studies were massively overdosed.
  •  
    Nice review of all the sex hormones and their relationship to CVD in men.  
Nathan Goodyear

Testosterone deficiency and cardiovascular mortality Morgentaler A, - Asian J Androl - 0 views

  • overall mortality and CV mortality were inversely associated with serum T concentrations.
  • men with low serum T, defined as < 8.7 nmol l−1 (250 ng dl−1 ), demonstrated significantly greater all-cause mortality than men with higher serum T (hazard ratio [HR]: 2.24; 95% CI: 1.41-3.57), as well as greater CV mortality
  • lower T levels were significantly associated with the presence of any CV disease
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  • more than 30 years of studies suggesting that low levels of T represent an increased risk for CV and overall mortality,
  • lower serum T concentrations also are associated with CV disease, including incident coronary artery disease [17],[18],[19] and atherosclerosis,
  • the actual rate of adverse events was only half as great in the T group (123 events in 1223 men at risk = 10.1%) as in the untreated group (1587 events in 7486 men = 21.2%)
  • The study by Vigen et al. [7] has already undergone two published corrections,
  • 29 medical societies have called for retraction of the article, asserting "gross data mismanagement and contamination," that rendered the study "no longer credible
  • Mortality in T-treated men was reduced by approximately half in treated men compared with untreated men, at 10.3% versus 20.7%, respectively
  • The mortality rate for men who received TTh was 3.4 deaths per 100 person-years, and 5.7 deaths per 100 person-years in untreated men
  • HR of 0.61 (95%CI: 0.42-0.88; P = 0.008), indicating a significant reduction in mortality with TTh
  • men in the highest prognostic MI risk quartile, treatment with TTh was associated with reduced risk
  • tripling in T prescriptions in the US over the last decade
  • a majority of observational studies have found that low endogenous serum T levels are associated with increased mortality.
  • Men who received TTh were able to exercise significantly longer without ischemia compared with men who received placebo
  • In men with congestive heart failure, those who received T demonstrated greater walking distance and other functional endpoints compared with those who received placebo
  • TTh has been shown uniformly and repeatedly to improve several known CV risk factors, including reduced fat mass, body fat percent, and waist circumference, and increased lean mass
  • improved glycemic control
  • reductions in insulin resistance.
  • the evidence strongly points to improved CV status with normal serum T or treatment with TTh in men with TD
  • analysis of health insurance claims data that reported a 36% increased rate of nonfatal MI in the 90d following receipt of a T prescription compared with the 12 prior months.
  • Comparison with men who received a prescription for a phosphodiesterase type 5 inhibitor (PDE5i) revealed no increased rate of MI following the prescription
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    Great review by Morgentaler of Testosterone and CVD.  He highlights the significant flaws in the JAMA and the NEJM articles of Testosterone therapy risks.  Morgentaler highlights the significant evidence that points to low T and increased risk of CVD. On contention I have, is Morgantaler seems to flip aside the massive uptick of Testosterone use in the US as compared to other countries.  The evidence definitely points to Testosterone therapy as being safe in those with low T, but there is definitely a problem of significant Testosterone doping that is taking place as well.
Nathan Goodyear

Exposure to Bisphenol A Prenatally or in Adulthood Promotes TH2 Cytokine Production Ass... - 0 views

  • BPA promotes the development of TH2 cells in adulthood and both TH1 and TH2 cells in prenatal stages by reducing the number of regulatory T cells.
  • Bisphenol A (BPA), an estrogenic endocrine-disrupting chemical (EDC
  • BPA is one of the most widespread EDCs.
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  • BPA antagonizes the actions of thyroid hormone
  • Prenatal exposure to BPA has been shown to alter a variety of reproductive endocrine parameters, such as testosterone and luteinizing hormone levels
  • arly onset of sexual maturation of female mice
  • imbalanced T-helper (TH)1/TH2 immune responses have been demonstrated on exposure to BPA
  • indicating that BPA exerted its effects by reducing the number of Treg cells.
  • Exposure to BPA by subcutaneous injection in adulthood significantly promoted antigen-stimulated production of IL-4, IL-10, and IL-13 in TH2-skewed
  • BPA can leak from the placenta and accumulate in the fetus
  • We showed that prenatal exposure to BPA increased the production of a TH1 cytokine, IFN-γ, and a TH2 cytokine, IL-4, after the offspring developed, suggesting that prenatal exposure to BPA can induce persistent immunologic effects lasting into adulthood.
  • These results are consistent with a previous report that fetal exposure to BPA augmented TH1 and TH2 immune responses
  • our results clearly demonstrate that the production of TH2 cytokines is promoted by BPA in adult mice and in offspring during developmental exposure.
  • The decrease of Treg cells would predispose to immune dysfunction in aged individuals, explaining their higher risk of immune-mediated diseases, cancer, and infections.
  • BPA might cause these diseases. Thus, avoiding exposure to or promoting the excretion of BPA and other EDCs would help in preventing diseases and adverse health effects.
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    BPA as endocrine disruptor and as immune disruptor
Nathan Goodyear

Hypothalamic-Pituitary-Testicular Axis Disruptions in Older Men Are Differentially Link... - 0 views

  • 0.4–2% annual decline
  • the age trend in free T was more substantial (−1.3% per annum)
  • The core hormonal pattern with increasing age is suggestive of incipient primary testicular dysfunction with maintained total T and progressively blunted free T associated with higher LH.
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  • Obesity was associated with progressively lower total and free T independent of the simultaneous decrease in SHBG.
  • our data highlight the fact that LH was unchanged or even lower in older men in the face of lower T in obesity, suggesting that there may be a failure at the hypothalamic-pituitary level.
  • a change in BMI from nonobese to obese may be equivalent to a 15 yr fall in T.
  • This pattern supports the hypothesis that different underlying mechanisms influence the functions of the HPT axis: age predominantly affects testicular function, whereas obesity impairs hypothalamic/pituitary function.
  • the effects of aging on testicular function can be moderated by increased LH compensation for many decades
  • obesity impairs hypothalamic/pituitary function independent of age, arguably an adaptive response for which there should be no compensatory mechanism.
  • the concurrent but opposite (and separate) effects of obesity and age on SHBG
  • SHBG was negatively associated with increasing strata of obesity
  • Obesity is associated with insulin resistance (28), and the increased circulating insulin inhibits hepatic SHBG synthesis
  • the SHBG increase with age may be related to relative IGF-I deficiency (27), although this has not been directly proven.
  • Obesity is associated with peripheral and central insulin resistance (30) and proinflammatory cytokine production (TNFα and IL-6) from adipocytes (31) and central nervous system endocannibinoid release (32), all of which are potential candidates for abrogating hypothalamic endocrine and downstream reproductive axis functions.
    • Nathan Goodyear
       
      The HPA axis effect may be the result of inflammation.
  • The relationship between obesity and T can be bidirectional: low T may be the cause rather than consequence of obesity
  • chronic alcohol abuse is known to suppress LH (40), our data showed no significant association among the three hormones or SHBG and alcohol intake.
  • increase in total T in smokers occurs through a primary increase in SHBG with a compensatory rise in LH
  • the effects of obesity (BMI or waist circumference) was by far the most important determinant of variance in total T, whereas age per se was important for SHBG, LH, and free T with comorbidity and smoking being comparatively minor contributors
  • It is noteworthy that these predisposing lifestyle and health factors are modifiable. This implies that the apparent age-related decline in T may constitute a barometer of health and thus be potentially preventable and/or reversible.
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    Age induced decline in Testosterone is more associated with a decline in leydig cell function and thus elevated LH will be associated.  In contrast, obesity is more of a HPA axis disruption and thus LH may be normal to low.  The pulse amplitude is decrease.  No change in pulse frequency is noted.   With obesity, a decline in TT and fT was independent of SHBG. Aging is associated with a greater decrease in fT versus TT.
Nathan Goodyear

Role of IL-2 in cancer immunotherapy: OncoImmunology: Vol 5, No 6 - 1 views

  • IL-2 is one of the key cytokines with pleiotropic effects on the immune system
  • IL-2 as “T-cell growth factor”
  • approved for the treatment of metastatic renal cell carcinoma (1992) and later for metastatic melanoma (1998) by FDA
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  • It is produced predominately by antigen-simulated CD4+ T cells, while it can also be produced by CD8+ cells, natural killer (NK) cells, and activated dendritic cells (DC)
  • IL-2 is an important factor for the maintenance of CD4+ regulatory T cells
  • plays a critical role in the differentiation of CD4+ T cells into a variety of subsets
  • It can promote CD8+ T-cell and NK cell cytotoxicity activity, and modulate T-cell differentiation programs in response to antigen, promoting naive CD4+ T-cell differentiation into T helper-1 (Th1) and T helper-2 (Th2) cells while inhibiting T helper-17 (Th17) differentiation
  • Of note, Tregs, which act to dampen the immune response, constitutively express high levels of α chain
  • IL-2Rα is unique to IL-2 and is expressed by a number of immune cells including T regulatory cells (Treg), activated CD4+ and CD8+T cells, B cells, mature DCs, endothelial cells
  • some investigators evaluated the efficacy of regimens containing low-dose IL-2
  • IL-2 can promote the activation and cell growth of T and NK cells
  • Unfortunately, not all of patients would benefit from targeted therapy and nearly all patients who initially respond to targeted inhibitors inevitably develop acquired resistance to the treatment
  • IL-2 also stimulates T-regulatory cells that constitutively express CTLA-4 and can suppress immune reactions. Hence, IL-2 might enhance antitumor reactivity in the presence of CTLA-4 blockade
  • both HD and low-dose IL-2 therapy preferentially induce the expansion of CD4+CD25+Foxp3+ Treg and the Treg level remains elevated after each cycle of HD IL-2 therapy
  • Due to rapid elimination and metabolism via the kidney, IL-2 has a short serum half-life of several minutes
  • HD IL-2-induced severe toxicities including vascular leak syndrome (VLS), pulmonary edema, hypotension, and heart toxicities
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    Great historical and functional role of IL-2 in the fight against cancer.
Nathan Goodyear

Metabolic Effects of Liothyronine Therapy in Hypothyroidism: A Randomized, Double-Blind... - 0 views

  • tissue euthyroidism is the net result of multiple steps including conversion of the prohormone T4 into its active metabolite T3, which is ultimately responsible for signaling at the end-organ target level
  • The circulating and intracellular pools of T3 of treated hypothyroid patients (i.e. devoid of endogenous TH production) depend entirely on the conversion of exogenous l-T4 into T3
  • TH is the major regulator of basal metabolic rate
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  • The substitution of l-T3 for l-T4 caused a significant weight loss
  • The substitution of l-T3 for l-T4 caused a significant reduction in lipid parameters
  • TH action is increased in the liver, and the SHBG increase supports this hypothesis
  • The changes in serum lipid metabolism parameters are similar to the effects observed with drugs approved for the treatment of dyslipidemia
  • This differential response appears to be limited to the lipid metabolism and SHBG, whereas no differences in indices of insulin resistance were detected. This is remarkable because hyperthyroid states are associated with an increase in hepatic gluconeogenesis (37), and overt thyrotoxicosis is a known cause of secondary diabetes.
  • Despite the increase in serum T3, the l-T3 treatment did not cause major changes in cardiovascular or musculoskeletal function, as indicated by the echocardiographic and maximal exercise tolerance tests and DXA studies.
  • Similarly, no significant differences were observed in blood pressure, heart rate, or endothelial vascular function
  • In conclusion, the results of this pharmacology, proof-of-concept study indicate that replacement therapy of hypothyroidism with l-T3, compared with l-T4 causes weight loss and favorable changes in the lipid profile without appreciable side effects
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    Crossover study finds T3 versus T4 results in more weight loss, improved lipid management and increased SHBG without any adverse cardiovascular effects.   The T3 was dosed 3 x daily due to its short half life compared to T4.
Nathan Goodyear

Review of health risks of low testosterone and testosterone administration - 0 views

  • Hypogonadism may be defined either as serum concentration of T (either total T, bioavailable T or free T) or as low T plus symptoms of hypogonadism
  • The Baltimore Longitudinal Study on Aging reported the incidence of total serum T < 325 ng/dL to be 20% for men in their 60s, 30% for men in their 70s and 50% for men over 80
  • The Massachusetts Aging Male Study reported that 12.3% of men aged 40 to 70 had a total serum T of < 200 ng/dL with 3 or more symptoms of hypogonadism
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  • The Boston Area Community Health Study reported that 5.6% of men aged 30 to 70 were hypogonadal, as defined by total serum T < 300 ng/dL; or, free serum T < 5 ng/dL plus 3 or more symptoms of hypogonadism
  • In a health screening project among 819 men in Taiwan, the prevalence of hypogonadism (total serum T < 300 ng/dL) ranged from 16.5% for men in their 40s, 23.0% for men in their 50s, 28.9% for men in their 60s, and 37.2% for men older than 70 years of age
  • The prevalence of hypogonadism among men in Taiwan is higher than the prevalence reported in the Massachusetts Male Aging Study
  • CAG repeat sequence, within the androgen receptor (AR). Rajender et al[12] reviewed over 30 studies on the AR trinucleotide repeat and infertility
  • suggestion that CAG repeat length may determine androgen responsiveness, this issue is not clearly settled
  • reported prevalence of low T in older men range from 5.6% to 50%
  • Those in the hypogonadal group (n = 4269) had direct health care costs, that exceeded the eugonadal group (n = 4269) by an average of $7100 over the course of the observation window
  • higher economic burden and presence of co-morbidities for hypogonadism
  • minor to moderate improvements in lean mass and muscle strength
  • increased bone mineral density
  • modest enhancement in sexual function
  • reduced adiposity
  • lessening of depressive symptoms
  • Meta-analyses of clinical TRT trials as of 2010 have identified three major adverse events resulting from TRT: (1) polycythemia; (2) an increase in prostate-related events; and (3) and a slight reduction in serum high-density lipoprotein (HDL) cholesterol
  • polycythemia (> 3.5-fold increase in risk
  • TRT produced a 40% prostate enlargement in older hypogonadal male Veterans over 12 mo
  • no published analysis has reported measurable increases in prostate cancer risk or Gleason score in men undergoing TRT, or in hypogonadal men with a history of prostate cancer undergoing TRT
  • the prostate which highly expresses the type II 5α-reductase enzyme. Inhibition of this enzyme via finasteride (a type II 5α-reductase inhibitor) or dutasteride (a dual type I and II 5α-reductase inhibitor) reduces circulating DHT 50%-75% and > 90%, respectively[47], and reduces prostate mass[48] and prostate cancer risk
  • Normally estradiol partially regulates testosterone levels, at the hypothalamus, blunting LH and FSH release from the pituitary. As a selective estrogen receptor modulator, CC interrupts this pathway, and consequently there is a greater stimulation for the production of testosterone in Leydig cells
    • Nathan Goodyear
       
      this would only apply if E1 and/or E2 levels were elevated, which the authors make no mention of.
  •  
    to be read
Nathan Goodyear

Hormonal Modulation in Aging Patients with Erectile Dysfunction and Metabolic Syndrome - 0 views

  • Hypogonadism and MetS are strongly associated [12, 13, 16], having even been demonstrated that with the increasing number of MetS parameters there is a proportional raise in the incidence of hypogonadism
  • increasing number of MetS components is inversely associated with T levels
  • the presence of MetS did not prove to be a significant determinant of hypogonadism, as it did not lead to a decline in T levels, in MetS patients with already established hypogonadism, the increasing number of MetS features was associated with further decline in T
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  • In the setting of MetS, hypertriglyceridemia and increased WC have been reported as the most important determinants of hypogonadism
  • recent literature consistently associates obesity not only with higher risk of hypogonadism [4, 6, 27] but also with lower T levels
  • Visceral adiposity has been particularly related with reduction of T and SHBG levels (independent of other metabolic disorders)
  • WC was one of the MetS parameters with the greatest influence in T levels decrease, presenting itself as a strong risk factor for hypogonadism development
  • MetS-related T decline was not accompanied by an increase in pituitary LH levels, suggesting impairment in gonadotropin secretion
  • The molecules behind this smoothing compensatory effect of GnRH/LH are still unknown, but estrogens and insulin, as well as leptin, TNF-α, and other adipokines, were proposed candidates
  • fat stores undertake an increase aromatization of androgens, therefore raising estrogen levels [9, 15], which in turn decrease LH secretion
  • our data contradicts the concept that estradiol exerts a negative feedback on hypothalamic GnRH secretion
  • taking into account that high estradiol levels have already been described as the only abnormality in a subset of patients with ED, the hypothesis that the later might not only be caused by androgen deficiency is becoming increasingly evident
  • it has been reported that the chronic exposure to phosphodiesterase type 5 inhibitors (PDE5i), widely used for the treatment of ED, may influence serum estradiol levels
  • thyroid disorders (specially hyperthyroidism) have been related to ED and hypogonadism, and so must be considered in a sexual-dysfunction setting
  • It is clear from the current literature that collecting a more thorough hormonal panel might be a wise approach to further uncover hormonal relations
    • Nathan Goodyear
       
      outstanding point.  This hits to the point that Low T is the effect not the cause.
  • We concluded that in ED patients with hypogonadism and MetS, the attenuated response of HPG axis (normal or low LH levels) might not always be due to an underlying adiposity-dependent estrogen-raising effect.
  • our findings indicate that ED, aging, and estradiol might have a stronger connection than what is currently described in the literature.
  • this study underlines the importance of the collection of a full hormonal panel in ED men
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    low T strongly associated with metabolic syndrome in men.
Nathan Goodyear

Testosterone and Abnormal Glucose Metabolism in an Inner-City Cohort - 0 views

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    This study of inner city men found low T associated with methadone use.  Narcotics are a known risk factor for low T.  The free T was calculated from serum.  This equilibrium dialysis is based on too many variables.  Look at the studies on equilibrium dialysis.  This study also found calculated free T was not associated with insulin resistance.  However, insulin resistance is a peripheral tissue dysfunction not a serum dysfunction.  So, a calculated free T (not reality) in the serum shows me nothing of the peripheral activity.  For example, inflammation has been shown to increase aromatase activity in the prostate tissue only.  The thinking in the conclusions of so many of these studies is soooo flawed.
Nathan Goodyear

Leptin and Androgens in Male Obesity: Evidence for Leptin Contribution to Reduced Andro... - 0 views

  • in male obesity basal and LH-stimulated androgen levels are reduced and inversely correlated with circulating leptin
  • functional leptin receptors are present in rodent Leydig cells
  • it is conceivable that in males high leptin concentrations may have a direct inhibitory effect(s) on Leydig cell function.
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  • insulin is an important inhibitor of the synthesis of SHBG
  • no correlation between leptin and SHBG levels
  • SHBG reduction in obesity is a minor determinant of lowered androgen levels
  • SHBG can explain only up to 3% of the correlation
  • testicular T de novo production is impaired in obese men and that leptin seems to be the best hormonal predictor of this blunted response to LH stimulation
  • The low basal 17-OH-P levels found in massively obese men are consistent with a global impairment of Leydig cell steroidogenic function in this group of subjects.
  • These findings indicate that obese men have a FM-related defect in the enzymatic conversion of 17-OH-P to T, which is revealed by hCG stimulation.
  • Other studies have investigated the adrenal function in male obesity and have shown that basal cortisol and 17-OH-progesterone levels tend to decrease with the increase in the degree of obesity
  • High E2 can inhibit the expression and activity of the 17,20-lyase and may be responsible for this steroidogenic lesion
  • However, stimulated E2 levels were not higher in the obese than in controls, excluding the fact that the lower androgen response was due to an increased aromatization of T to E2 and that estrogens have a major role in the observed defect of 17,20-lyase activity in obese men.
  • the percentage increase in the 17-OH-progesterone to T molar ratio paralleled the increase in leptin levels of obese men
  • Multiple regression analysis indicated that the best hormonal predictor of the obesity-related reduction in T and FT basal levels and androgen changes after hCG stimulation was serum leptin concentration
  • insulin has no negative influences on androgen production in obese men
  • insulin is known to have stimulatory actions on T production that have been demonstrated in obese and normal weight men (57) and in Leydig cells in culture
  • the negative correlation between insulin and basal T can be partly explained by the inhibitory action of insulin on SHBG production
  • hypogonadal men have higher circulating leptin levels compared with hypogonadal patients under effective androgen substitution therapy
  • The impaired androgen response to LH stimulus was due to a defect in the enzymatic conversion of 17-OH-progesterone to T, which was disclosed by a leptin-related increase in 17-OH-progesterone to T ratio
  • Estrogens, which are inhibitory modulators of LH pulsatility and bioactivity
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    Leptin appears to be a good marker of low Testosterone.  This study proposes that the mechanism of action is potentially 2 fold: first, a decrease in LH release by leptin (kisspeptin?) and 2nd, a directed decrease in Testosterone production by the leydig cells in the testes.
Nathan Goodyear

Cutting Edge: IL-12 Induces CD4+CD25− T Cell Activation in the Presence of T ... - 0 views

  • Whereas IL-12 instigates Th1 immune responses, CD4+CD25+ regulatory T cells (Treg)3 actively restrain them
  • Following engagement of their TCR, Treg suppress the proliferation of conventional CD4+CD25− T responder cells in vitro
  • Furthermore, they inhibit the development of CD4+ T cell responses against alloantigens, tumor, microbial, and self-Ags in vivo.
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  • Treg act to prevent spontaneous autoimmunity and to limit collateral damage to healthy tissues during adaptive immunity. However, these cells also have the potential to sabotage protective antimicrobial responses
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    Great T cell activiation review: Il-2 stimulates NK cells primarily release from TH1 cells and T cytotoxic lymphocytes are under the control of IL-12 released primarily from dendritic cells.  Inflammatory cytokines in the presence of Treg to stimulate CD4+CD25- T cell activation.
Nathan Goodyear

How is the Immune System Suppressed by Cancer - 1 views

  • nitric oxide (NO) released by tumor cells
  • Excellent work by Prof de Groot of Essen, indicated by adding exogenous xanthine oxidase ( XO) in hepatoma cells, hydrogen peroxide was produced to destroy the hepatoma cells
  • NO from eNOS in cancer cells can travel through membranes and over long distances in the body
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  • NO also is co linked to VEGF which in turn increases the antiapoptotic gene bcl-2
  • The other important influence of NO is in its inhibition of the proapoptoic caspases cascade. This in turn protects the cells from intracellular preprogrammed death.
  • nitric oxide in immune suppression in relation to oxygen radicals is its inhibitory effect on the binding of leukocytes (PMN) at the endothelial surface
  • Inhibition of inducible Nitric Oxide Synthase (iNOS)
  • NO from the tumor cells actually suppresses the iNOS, and in addition it reduces oxygen radicals to stop the formation of peroxynitrite in these cells. But NO is not the only inhibitor of iNOS in cancer.
  • Spermine and spermidine, from the rate limiting enzyme for DNA synthases, ODC, also inhibit iNOS
  • tolerance in the immune system that decreases the immune response to antigens on the tumors
  • Freund’s adjuvant
  • increase in kinases in these cells which phosphorylate serine, and tyrosine
  • responsible for activation of many growth factors and enzymes
  • phosphorylated amino acids suppress iNOS activity
  • Hexokinase II
  • Prostaglandin E2, released from tumor cells is also an inhibitor of iNOS, as well as suppressing the immune system
  • Th-1 subset of T-cells. These cells are responsible for anti-viral and anti-cancer activities, via their cytokine production including Interleukin-2, (IL-2), and Interleukin-12 which stimulates T-killer cell replication and further activation and release of tumor fighting cytokines.
    • Nathan Goodyear
       
      Th1 cells stimulate NK and other tumor fighting macrophages via IL-2 and IL-12; In contrast, Th2, which is stimulated in allergies and parasitic infections, produce IL-4 and IL-10.  IL-4 and IL-10 inhibit TH-1 activation and the histamine released from mast cell degranulation upregulates T suppressor cells to further immune suppression.
  • Th-2 subset of lymphocytes, on the other hand are activated in allergies and parasitic infections to release Interleukin-4 and Interleukin-10
  • These have respectively inhibitory effects on iNOS and lymphocyte Th-1 activation
  • Mast cells contain histamine which when released increases the T suppressor cells, to lower the immune system and also acts directly on many tumor Histamine receptors to stimulate tumor growth
  • Tumor cells release IL-10, and this is thought to be one of the important areas of Th-1 suppression in cancer patients
  • IL-10 is also increased in cancer causing viral diseases such as HIV, HBV, HCV, and EBV
  • IL-10 is also a central regulator of cyclooxygenase-2 expression and prostaglandin production in tumor cells stimulating their angiogenesis and NO production
  • nitric oxide in tumor cells even prevents the activation of caspases responsible for apoptosis
    • Nathan Goodyear
       
      NO produced by cancer cells inhibits proapoptotic pathways such as the caspases.
  • early stages of carcinogenesis, which we call tumor promotion, one needs a strong immune system, and fewer oxygen radicals to prevent mutations but still enough to destroy the tumor cells should they develop
  • later stages of cancer development, the oxygen radicals are decreased around the tumors and in the tumor cells themselves, and the entire cancer fighting Th-1 cell replication and movement are suppressed. The results are a decrease in direct toxicity and apoptosis, which is prevented by NO, a suppression of the macrophage and leukocyte toxicity and finally, a suppression of the T-cell induced tumor toxicity
  • cGMP is increased by NO
  • NO in cancer is its ability to increase platelet-tumor cell aggregates, which enhances metastases
  • the greater the malignancies and the greater the metastatic potential of these tumors
  • The greater the NO production in many types of tumors,
  • gynecological
  • elevated lactic acid which neutralizes the toxicity and activity of Lymphocyte immune response and mobility
  • The lactic acid is also feeding fungi around tumors and that leads to elevated histamine which increases T-suppressor cells.  Histamine alone stimulates many tumor cells.
    • Nathan Goodyear
       
      The warburg effect in cancer cells results in the increase in local lactic acid production which suppresses lymphocyte activity and toxicity as well as stimulates histamine production with further stimulates tumor cell growth.
  • T-regulatory cells (formerly,T suppressor cells) down regulate the activity of Natural killer cells
  • last but not least, the Lactic acid from tumor cells and acidic diets shifts the lymphocyte activity to reduce its efficacy against cancer cells and pathogens in addition to altering the bacteria of the intestinal tract.
  • intestinal tract bacteria in cancer cells release sterols that suppress the immune system and down regulate anticancer activity from lymphocytes.
  • In addition to the lactic acid, adenosine is also released from tumors. Through IL-10, adenosine and other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state
  • Adenosine up regulates the PD1 receptor in T-1 Lymphocytes and inhibits their activity
  • Adenosine is a purine nucleoside found within the interstitial fluid of solid tumors at concentrations that are able to inhibit cell-mediated immune responses to tumor cells
  • Adenosine appears to up-regulate the PD1 receptor in T-1 Lymphocytes and inhibits the immune system further
  • Mast cells with their release of histamine lower the immune system and also stimulate tumor growth and activate the metalloproteinases involved in angiogenesis and metastases
  • COX 2 inhibitors or all trans-retinoic acid
  • Cimetidine, an antihistamine has been actually shown to increase in apoptosis in MDSC via a separate mechanism than the antihistamine effect
    • Nathan Goodyear
       
      cimetidine is an H2 blocker
  • interleukin-8 (IL-8), a chemokine related to invasion and angiogenesis
  • In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNF-alpha)
  • these data raise the possibility that the majority of CAFs in CLM originate from resident LFs. TNF-alpha-induced up-regulation of IL-8 via nuclear factor-kappaB in CAFs is an inflammatory pathway, potentially permissive for cancer invasion that may represent a novel therapeutic target
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    Great review of the immunosuppression in cancer driven by the likes of NO.
Nathan Goodyear

http://press.endocrine.org/doi/pdf/10.1210/jc.2014-3818 - 0 views

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    Study finds that low free T and low Total T were associated with decline in desire, ED and activity versus none with Estradiol and SHBG in older men.  The difficult issue is the threshold of "low T".  The definition of "low T" is not uniform and varies with age.  Thus baseline evaluations and correlation with symptoms, metabolic dysfunction must be done.
Nathan Goodyear

Acute and short term chronic testost... [J Clin Endocrinol Metab. 2014] - PubMed - NCBI - 0 views

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    Study finds that Testosterone regulates glucose metabolism, in part, through adiponectin production.  Early state of low T will slow the use of fats as a source of fuel and this results in an increased energy balance and results in the increased adiponectin production to increase metabolism.  Testosterone and adiponectin exist in an inverse relationship. This study does not mimic normal physiology.  Men with low T are unhealthy with significant metabolic dysfunction.  These young, "healthy" men were induced to a low T state--that is not a clear picture as the physiology of a "young healthy" man is quite different than that of one with low T.   Testosterone conversion to DHT increases GLUT4 and thus glucose uptake--another mechanism of Testosterone's effect on glucose metabolism.
Nathan Goodyear

The prevalence of prediabetes in population of Polish men with late-onset hypogonadism,... - 0 views

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    Study of late onset of low T in polish men found a significantly increased prevalence of glucose metabolism dysregulation when compared to normal T control group.  In the low T group, Total Testosterone and Free Testosterone levels were decreased. 
Nathan Goodyear

http://onlinelibrary.wiley.com/store/10.1002/tre.178/asset/178_ftp.pdf;jsessionid=F122C... - 0 views

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    A revisit of the saturation model of Testosterone therapy and prostate cancer.  Review finds Testosterone therapy does not "appear to promote prostate cancer growth".  The saturation model is the thought around the AR.  At low concentrations, there is a greater sensitivity of Testosterone to AR binding at very low T levels; but above those very low T levels, prostate cancer becomes insensitive to the Testosterone.
Nathan Goodyear

Essential Role for Estrogen Receptor β in Stromal-Epithelial Regulation of Pr... - 0 views

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    ER beta agonists shown to be anti-proliferative in the prostate and "ablated preexisting prostatic epithelial hyperplasia".  This has important implications: low T conditions increase ER alpha expression, which increases ER alpha production.  Low T is a pro inflammatory state in men, which increases aromatase activity.  Thus increase conversion of T to E2 in the stroma of the prostate results in growth.  ER beta is not activated.
Nathan Goodyear

Androgens and prostate disease Cooper LA, Page ST - Asian J Androl - 0 views

  • intraprostatic androgens are not concomitantly increased when serum androgen levels are raised.
  • The "saturation model" proposes that the prostate is sensitive to very low concentrations of circulating androgens, but that once maximal AR binding is achieved, which occurs at relatively low concentrations of circulating T, further increases in serum T have little impact
  • men with metastatic prostate cancer given T who had been previously treated with castration had worsening of disease, whereas those without prior castration did not
  • ...3 more annotations...
  • There is little data to support the withholding of T therapy on the basis of concern for precipitating prostate cancer.
  • Both intervention data and physiology studies point to minimal effects on the prostate gland when serum T levels are increased to the mid-normal range with T therapy
  • an individualized care plan to assess the possible risks and benefits of T therapy for each patient is critical to optimizing the use of androgens in male health.
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    Nice review of the mixed data on Testosterone and Prostate disease. It is clear that Testosterone does not precipitate prostate cancer.  The intraprostatic hormone milieu likely is different than that present in the serum.  No surprise there.  5alpha reductase decreases prostate volume, PSA, and low-grade prostate cancer, but actually increases aggressive prostate cancer. Supraphysiologic doping in young men associated with no increase in prostate disease. PSA no longer to be followed in men < 55.  Mortality rate not changed.  PSA change of 1.4 ng/ml is appropriate for additional prostate evaluation.  Testosterone therapy on average increased 0.5 ng/ml. Still, no mention of aromatase activity in this article.  Why is it that hormone sensitive disease in men is only with regards to androgens and women estrogen.
Nathan Goodyear

How regulatory T cells work - 0 views

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    T reg  cells are the primary regulators of the immune system signaling.
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