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Nathan Goodyear

Testosterone and the Cardiovascular System: A Comprehensive Review of the Clinical Lite... - 0 views

  • Low endogenous bioavailable testosterone levels have been shown to be associated with higher rates of all‐cause and cardiovascular‐related mortality.39,41,46–47 Patients suffering from CAD,13–18 CHF,137 T2DM,25–26 and obesity27–28
  • have all been shown to have lower levels of endogenous testosterone compared with those in healthy controls. In addition, the severity of CAD15,17,29–30 and CHF137 correlates with the degree of testosterone deficiency
  • In patients with CHF, testosterone replacement therapy has been shown to significantly improve exercise tolerance while having no effect on LVEF
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  • testosterone therapy causes a shift in the skeletal muscle of CHF patients toward a higher concentration of type I muscle fibers
  • Testosterone replacement therapy has also been shown to improve the homeostatic model of insulin resistance and hemoglobin A1c in diabetics26,68–69 and to lower the BMI in obese patients.
  • Lower levels of endogenous testosterone have been associated with longer duration of the QTc interval
  • testosterone replacement has been shown to shorten the QTc interval
  • negative correlation has been demonstrated between endogenous testosterone levels and IMT of the carotid arteries, abdominal aorta, and thoracic aorta
  • These findings suggest that men with lower levels of endogenous testosterone may be at a higher risk of developing atherosclerosis.
  • Current guidelines from the Endocrine Society make no recommendations on whether patients with heart disease should be screened for hypogonadism and do not recommend supplementing patients with heart disease to improve survival.
  • The Massachusetts Male Aging Study also projects ≈481 000 new cases of hypogonadism annually in US men within the same age group
  • since 1993 prescriptions for testosterone, regardless of the formulation, have increased nearly 500%
  • Testosterone levels are lower in patients with chronic illnesses such as end‐stage renal disease, human immunodeficiency virus, chronic obstructive pulmonary disease, type 2 diabetes mellitus (T2DM), obesity, and several genetic conditions such as Klinefelter syndrome
  • A growing body of evidence suggests that men with lower levels of endogenous testosterone are more prone to develop CAD during their lifetimes
  • There are 2 major potential confounding factors that the older studies generally failed to account for. These factors are the subfraction of testosterone used to perform the analysis and the method used to account for subclinical CAD.
  • The biologically inactive form of testosterone is tightly bound to SHBG and is therefore unable to bind to androgen receptors
  • The biologically inactive fraction of testosterone comprises nearly 68% of the total testosterone in human serum
  • The biologically active subfraction of testosterone, also referred to as bioavailable testosterone, is either loosely bound to albumin or circulates freely in the blood, the latter referred to as free testosterone
  • It is estimated that ≈30% of total serum testosterone is bound to albumin, whereas the remaining 1% to 3% circulates as free testosterone
  • it can be argued that using the biologically active form of testosterone to evaluate the association with CAD will produce the most reliable results
  • English et al14 found statistically significant lower levels of bioavailable testosterone, free testosterone, and free androgen index in patients with catheterization‐proven CAD compared with controls with normal coronary arteries
  • patients with catheterization‐proven CAD had statistically significant lower levels of bioavailable testosterone
  • In conclusion, existing evidence suggests that men with CAD have lower levels of endogenous testosterone,13–18 and more specifically lower levels of bioavailable testosterone
  • low testosterone levels are associated with risk factors for CAD such as T2DM25–26 and obesity
  • In a meta‐analysis of these 7 population‐based studies, Araujo et al41 showed a trend toward increased cardiovascular mortality associated with lower levels of total testosterone, but statistical significance was not achieved (RR, 1.25
  • the authors showed that a decrease of 2.1 standard deviations in levels of total testosterone was associated with a 25% increase in the risk of cardiovascular mortality
  • the relative risk of all‐cause mortality in men with lower levels of total testosterone was calculated to be 1.35
  • higher risk of cardiovascular mortality is associated with lower levels of bioavailable testosterone
  • Existing evidence seems to suggest that lower levels of endogenous testosterone are associated with higher rates of all‐cause mortality and cardiovascular mortality
  • studies have shown that lower levels of endogenous bioavailable testosterone are associated with higher rates of all‐cause and cardiovascular mortality
  • It may be possible that using bioavailable testosterone to perform mortality analysis will yield more accurate results because it prevents the biologically inactive subfraction of testosterone from playing a potential confounding role in the analysis
  • The earliest published material on this matter dates to the late 1930s
  • the concept that testosterone replacement therapy improves angina has yet to be proven wrong
  • In more recent studies, 3 randomized, placebo‐controlled trials demonstrated that administration of testosterone improves myocardial ischemia in men with CAD
  • The improvement in myocardial ischemia was shown to occur in response to both acute and chronic testosterone therapy and seemed to be independent of whether an intravenous or transdermal formulation of testosterone was used.
  • testosterone had no effect on endothelial nitric oxide activity
  • There is growing evidence from in vivo animal models and in vitro models that testosterone induces coronary vasodilation by modulating the activity of ion channels, such as potassium and calcium channels, on the surface of vascular smooth muscle cells
  • Experimental studies suggest that the most likely mechanism of action for testosterone on vascular smooth muscle cells is via modulation of action of non‐ATP‐sensitive potassium ion channels, calcium‐activated potassium ion channels, voltage‐sensitive potassium ion channels, and finally L‐type calcium ion channels
  • Corona et al confirmed those results by demonstrating that not only total testosterone levels are lower among diabetics, but also the levels of free testosterone and SHBG are lower in diabetic patients
  • Laaksonen et al65 followed 702 Finnish men for 11 years and demonstrated that men in the lowest quartile of total testosterone, free testosterone, and SHBG were more likely to develop T2DM and metabolic syndrome.
  • Vikan et al followed 1454 Swedish men for 11 years and discovered that men in the highest quartile of total testosterone were significantly less likely to develop T2DM
  • authors demonstrated a statistically significant increase in the incidence of T2DM in subjects receiving gonadotropin‐releasing hormone antagonist therapy. In addition, a significant increase in the rate of myocardial infarction, stroke, sudden cardiac death, and development of cardiovascular disease was noted in patients receiving antiandrogen therapy.67
  • Several authors have demonstrated that the administration of testosterone in diabetic men improves the homeostatic model of insulin resistance, hemoglobin A1c, and fasting plasma glucose
  • Existing evidence strongly suggests that the levels of total and free testosterone are lower among diabetic patients compared with those in nondiabetics
  • insulin seems to be acting as a stimulant for the hypothalamus to secret gonadotropin‐releasing hormone, which consequently results in increased testosterone production. It can be argued that decreased stimulation of the hypothalamus in diabetics secondary to insulin deficiency could result in hypogonadotropic hypogonadism
  • BMI has been shown to be inversely associated with testosterone levels
  • This interaction may be a result of the promotion of lipolysis in abdominal adipose tissue by testosterone, which may in turn cause reduced abdominal adiposity. On the other hand, given that adipose tissue has a higher concentration of the enzyme aromatase, it could be that increased adipose tissue results in more testosterone being converted to estrogen, thereby causing hypogonadism. Third, increased abdominal obesity may cause reduced testosterone secretion by negatively affecting the hypothalamus‐pituitary‐testicular axis. Finally, testosterone may be the key factor in activating the enzyme 11‐hydroxysteroid dehydrogenase in adipose tissue, which transforms glucocorticoids into their inactive form.
  • increasing age may alter the association between testosterone and CRP. Another possible explanation for the association between testosterone level and CRP is central obesity and waist circumference
  • Bai et al have provided convincing evidence that testosterone might be able to shorten the QTc interval by augmenting the activity of slowly activating delayed rectifier potassium channels while simultaneously slowing the activity of L‐type calcium channels
  • consistent evidence that supplemental testosterone shortens the QTc interval.
  • Intima‐media thickness (IMT) of the carotid artery is considered a marker for preclinical atherosclerosis
  • Studies have shown that levels of endogenous testosterone are inversely associated with IMT of the carotid artery,126–128,32,129–130 as well as both the thoracic134 and the abdominal aorta
  • 1 study has demonstrated that lower levels of free testosterone are associated with accelerated progression of carotid artery IMT
  • another study has reported that decreased levels of total and bioavailable testosterone are associated with progression of atherosclerosis in the abdominal aorta
  • These findings suggest that normal physiologic testosterone levels may help to protect men from the development of atherosclerosis
  • Czesla et al successfully demonstrated that the muscle specimens that were exposed to metenolone had a significant shift in their composition toward type I muscle fibers
  • Type I muscle fibers, also known as slow‐twitch or oxidative fibers, are associated with enhanced strength and physical capability
  • It has been shown that those with advanced CHF have a higher percentage of type II muscle fibers, based on muscle biopsy
  • Studies have shown that men with CHF suffer from reduced levels of total and free testosterone.137 It has also been shown that reduced testosterone levels in men with CHF portends a poor prognosis and is associated with increased CHF mortality.138 Reduced testosterone has also been shown to correlate negatively with exercise capacity in CHF patients.
  • Testosterone replacement therapy has been shown to significantly improve exercise capacity, without affecting LVEF
  • the results of the 3 meta‐analyses seem to indicate that testosterone replacement therapy does not cause an increase in the rate of adverse cardiovascular events
  • Data from 3 meta‐analyses seem to contradict the commonly held belief that testosterone administration may increase the risk of developing prostate cancer
  • One meta‐analysis reported an increase in all prostate‐related adverse events with testosterone administration.146 However, when each prostate‐related event, including prostate cancer and a rise in PSA, was analyzed separately, no differences were observed between the testosterone group and the placebo group
  • the existing data from the 3 meta‐analyses seem to indicate that testosterone replacement therapy does not increase the risk of adverse cardiovascular events
  • the authors correctly point out the weaknesses of their study which include retrospective study design and lack of randomization, small sample size at extremes of follow‐up, lack of outcome validation by chart review and poor generalizability of the results given that only male veterans with CAD were included in this study
    • Nathan Goodyear
       
      The authors here present Total Testosterone as a "confounding" value
    • Nathan Goodyear
       
      This would be HSD-II
  • the studies that failed to find an association between testosterone and CRP used an older population group
  • low testosterone may influence the severity of CAD by adversely affecting the mediators of the inflammatory response such as high‐sensitivity C‐reactive protein, interleukin‐6, and tumor necrosis factor–α
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    Good review of Testosterone and CHD.  Low T is associated with increased all cause mortality and cardiovascular mortality, CAD, CHF, type II diabetes, obesity, increased IMT,  increased severity of CAD and CHF.  Testosterone replacement in men with low T has been shown to improve exercise tolerance in CHF, improve insulin resistance, improve HgbA1c and lower BMI in the obese.
Nathan Goodyear

Bioavailable Testosterone and Depressed Mood in Older Men: The Rancho Bernardo Study: T... - 0 views

  • bioavailable testosterone levels decrease much more with age than does total testosterone or estradiol levels
  • The decrease in bioavailable testosterone parallels the increase in sex hormone binding globulin with age, a change that accompanies increasing body fat independent of weight change
  • a graded stepwise decrease in bioavailable testosterone with increasing level of depressed mood
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  • This association was independent of age, weight change, and physical activity, the only three significant confounding covariates of the association between sex hormone levels and BDI scores
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    bioavailable Testosterone is inversely associated with increased depressive symptoms.
Nathan Goodyear

Bioavailability of Curcumin: Problems and Promises - Molecular Pharmaceutics (ACS Publi... - 0 views

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    Just abstract available here, but this article reviews the low bioavailability of curcumin and means to get around the limited bioavailability.
Nathan Goodyear

Association of endogenous sex hormone with C-reactive protein levels in middle-aged and... - 0 views

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    total and bioavailable Estradiol associated with increased hsCRP in men age 40-80.  Bioavailable is calculated with serum calculated free Testosterone and albumin bound Testosterone.
Nathan Goodyear

Nature Clinical Practice Endocrinology & Metabolism | Testosterone and ill-health in ag... - 0 views

  • Levels of total and bioavailable testosterone and SHBG were reported to be inversely correlated with the prevalence of the metabolic syndrome in men aged 40–80 years
  • as were total testosterone and SHBG in men aged 65–96 years
  • and in a cross-sectional analysis of a large cohort of non-diabetic men aged 70–89 years
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  • In longitudinal studies, decreased levels of total testosterone and SHBG predicted an increased incidence of metabolic syndrome in nonobese men
  • Free testosterone level is not associated with the prevalence of metabolic syndrome in middle-aged and older men
  • Levels of free, bioavailable and total testosterone are lower in men with T2DM than in age-matched controls,34, 35 and decreased total testosterone level predicts incident T2DM in middle-aged men.
  • men with T2DM commonly have low total or free testosterone levels
  • Total, bioavailable and free testosterone levels are inversely correlated with fasting insulin level and insulin resistance in middle-aged men without T2DM
  • total testosterone is positively correlated with insulin sensitivity in men with normal or impaired glucose tolerance or T2DM
  • low SHBG level is more strongly associated with metabolic syndrome than low total testosterone in aging men
  • the recognized association between low SHBG level and insulin resistance
  • Low levels of SHBG are also associated with smaller, denser LDL-cholesterol molecules in nondiabetic men,58 and were found to predict increased cardiovascular disease mortality in one study of older men
  • Low levels of SHBG might reflect obesity, insulin resistance and overall poor health
  • Compared with those who have normal testosterone levels, men aged 40 years or more with total testosterone levels <9.8 nmol/l or elevated LH level have greater CIMT
  • In men aged 73–94 years, total testosterone was inversely correlated with CIMT
  • a prospective analysis of men aged 73–91 years, progression of CIMT was not related to total testosterone level, but it was inversely related to free testosterone level
  • A study of men aged 55 years or more found that those with total and bioavailable testosterone levels in the highest tertile had a lower risk of severe aortic atherosclerosis (detected by radiography as abdominal aortic calcification) than those with the lowest testosterone levels.
  • a large study of men aged 69–80 years, those with total or free testosterone in the lowest quartile had increased odds of lower-extremity peripheral arterial disease
  • the possibility of reverse causation has to be considered, as systemic illness can result in decreased testosterone levels
  • previous case–control studies and longitudinal studies have failed to identify low testosterone levels as strong predictors of clinically significant coronary disease
  • Reviews of trials on testosterone therapy in men with either low or low-to-normal testosterone levels have not shown consistent beneficial effects either on lipid profiles or on actual cardiovascular events.24, 54, 55 These trials, however, have not been designed or powered to detect treatment-related differences in cardiovascular outcome
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    Declining Testosterone or low Testosterone is clearly associated with poor health in men.   Very nice review of the association between low Testosterone and metabolic dysfunction.  Low T is associated with increased metabolic syndrome, Diabetes, weight gain, insulin resistance...
Nathan Goodyear

Testosterone and Visceral Fat in Midlife Women: The Study of Women's Health Across the ... - 0 views

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    New study, SWAN study, finds that bioavailable Testosterone was "significantly positively related" to visceral fat.  As bioavailable Testosterone increases in post-menopausal women, visceral fat increases.  The authors conclude that Testosterone increases visceral fat accumulation.  This increased Testosterone is concluded to be from a decrease in SHBG as a result of falling Estradiol.
Nathan Goodyear

Testosterone for the aging male; current evidence and recommended practice - 0 views

  • Total serum testosterone consists of free testosterone (2%–3%), testosterone bound to sex hormone binding globulin (SHBG) (45%) and testosterone bound to other proteins (mainly albumin −50%)
  • Testosterone binds only loosely to albumin and so this testosterone as well as free testosterone is available to tissues and is termed bioavailable testosterone
  • Testosterone bound to SHBG is tightly bound and is biologically inactive
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  • Bioavailable and free testosterone are known to correlate better than total testosterone with clinical sequelae of androgenization such as bone mineral density and muscle strength
  • peak levels seen in the morning following sleep, which can be maintained into the seventh decade
  • Samples should always be taken in the morning before 11 am
  • The reliable measurement of serum free testosterone requires equilibrium dialysis. This is not appropriate for clinical use as it is very time consuming and therefore expensive.
  • With increasing age, a greater number of men have total testosterone levels just below the normal range or in the low-normal range. In these patients total testosterone can be an unreliable indicator of hypogonadal status.
  • It is advised that at least two serum testosterone measurements, taken before 11 am on different mornings, are necessary to confirm the diagnosis.
  • Patients with serum total testosterone consistently below 8 nmol/l invariably demonstrate the clinical syndrome of hypogonadism and are likely to benefit from treatment. Patients with serum total testosterone in the range 8–12 nmol/l often have symptoms attributable to hypogonadism and it may be decided to offer either a clinical trial of testosterone treatment or to make further efforts to define serum bioavailable or free testosterone and then reconsider treatment. Patients with serum total testosterone persistently above 12 nmol/l do not have hypogonadism and symptoms are likely to be due to other disease states or ageing per se so testosterone treatment is not indicated.
  • Total testosterone levels fall at an average of 1.6% per year whilst free and bioavailable levels fall by 2%–3% per year.
  • With advancing age there is also a reduction in androgen receptor concentration in some target tissues and this may contribute to the clinical syndrome of LOH
  • Metabolic clearance declines with age
  • Gonadotrophin levels rise during aging (Feldman et al 2002) and testicular secretory responses to recombinant human chorionic gonadotrophin (hCG) are reduced
  • There are changes in the lutenising hormone (LH) production which consist of decreased LH pulse frequency and amplitude, (Veldhuis et al 1992; Pincus et al 1997) although pituitary production of LH in response to pharmacological stimulation with exogenous GnRH analogues is preserved
  • the decreases in testosterone levels with aging seem to reflect changes at all levels of the hypothalamic-pituitary-testicular axis
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    Leptin inhibits male Testosterone production at the level of the hypothalamus and at the testicle level.
Nathan Goodyear

Relationship of serum sex steroid levels and bone turnover markers with bone mineral de... - 0 views

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    Total Testosterone in men decreased by 30% over the lifetime of men in this study compared to 64% decrease in bioavailable Testosterone in men.  Decreased BMD was associated with this loss.  Similar findings for Estrogen was also noted in men.
Nathan Goodyear

Does vitamin C enhance nitric oxide bioavailability in a tetrahydrobiopterin-dependent ... - 0 views

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    vitamin C increases NO bioavailability.
Nathan Goodyear

Sex Hormones and Age: A Cross-sectional Study of Testosterone and Estradiol and Their B... - 0 views

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    Older men have Estradiol levels that are 3 x that of a post-menopausal women.  The bioavailable levels of Testosterone and Estradiol showed the greatest precipitous decline.
Nathan Goodyear

Transport of Steroid Hormones: Binding of 21 Endogenous Steroids to Both Testosterone-B... - 0 views

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    bioavailable Testosterone found to be approximately 30% of the total circulating Testosterone.  Only 1-3% of that percentage is unbound.  The other is bound to albumin.
Nathan Goodyear

Low serum testosterone and increased mortality in men with coronary heart disease -- Ma... - 0 views

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    men with low bioavailable Testosterone associated with increased mortality in men with CAD.
Nathan Goodyear

Sex Steroid Hormone Concentrations and Risk of Death in US Men - 0 views

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    Prospective cohort finds that "low free and bioavailable testosterone" associated with increased mortality in men.
Nathan Goodyear

Low Serum Testosterone and Mortality in Older Men - 0 views

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    men with the lowest Total and free, bioavailable Testosterone levels associated with the highest mortality rates.  This test looked at serum.
Nathan Goodyear

Endogenous Testosterone and Mortality in Men: A Systematic Review and Meta-Analysis - 0 views

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    low bioavailable "endogenous" Testosterone associated with increased cardiovascular mortality.
Nathan Goodyear

Transport of Steroid Hormones: Binding of 21 Endogenous Steroids to Both Testosterone-B... - 0 views

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    Just the abstract here, but article discusses the various forms of Testosterone.  There is protein bound and inactive at apps 70%.  Free or bioavailable is at 2-4% with the remaining loosely bound to albumin.
Nathan Goodyear

Metabolic syndrome, testosterone, and cardiovascular mortality in men. - PubMed - NCBI - 0 views

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    study of 596 men finds that lower bioavailable Testosterone in those men with Metabolic Syndrome, have an increased cardiovascular mortality in those > 40.
Nathan Goodyear

Both total testosterone and sex hormone-binding globulin are independent risk factors f... - 0 views

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    Study of 2361 Chinese men found that men with MetS had lower TT, bioavailable Testosterone, free Testosterone and SHBG than those men without MetS.  Additionally, Total Testosterone and SHBG were both inversely associated with the risk of MetS.  This inverse association stood for both after adjusting for the other.
Nathan Goodyear

Covariation of change in bioavailable testosterone and adiposity in... - PubMed - NCBI - 0 views

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    Bioavailable Testosterone is positively associated with Visceral adipose tissue and to a lesser degree subcutaneous fat in women.  
Nathan Goodyear

Evidence of male hypogonadism at an early age as a familial risk of type 2 diabetes. - ... - 0 views

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    male children of parents with diabetes found to have significantly lower serum total Testosterone, free Testosterone, and bioavailable Testosterone compared to male children of parents without diabetes.
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