Studies have shown that ED may be an early biomarker of general endothelial dysfunction, atherosclerosis and CVD
testosterone treatment of hypogonadal young and older men improves sexual function, increases lean mass and decreases fat mass
In men with low serum testosterone (for example, <8 or 230 nmol l−1) with obesity, metabolic syndrome and diabetes mellitus, treatment with testosterone is warranted
In obese middle-aged men, testosterone treatment reduced visceral adipocity, insulin resistance, serum cholesterol and glucose levels
testosterone replacement has a favorable impact on body mass, insulin secretion and sensitivity, lipid profile and blood pressure in hypogonadal men with the metabolic syndrome as well as type 2 diabetes mellitus
Testosterone significantly inhibits lipoprotein lipase activity, which reduces triglycerides uptake into adipocytes in the abdominal adipose tissue
testosterone treatment decreased endogenous inflammatory cytokines (tumor necrosis factor-α and IL-1β) and lipids (total cholesterol) and increased IL-10 in hypogonadal men
Testosterone treatment reduced leptin and adiponectin levels in hypogonadal type 2 diabetic men after 3 months of testosterone replacement
available data clearly show a relationship between obesity, low testosterone levels and ED
Obesity adversely affects endothelial function and lowers serum testosterone levels through the development of insulin resistance and metabolic syndrome
Metabolic disturbances as well as production of cytokines and adipokines by inflamed fat cells may be causal factors in the development of ED
The onset of ED and the associated risk of CVD may be delayed through lifestyle modifications that affect obesity, such as diet and exercise
Very low testosterone levels contribute to the development of ED in obesity, metabolic syndrome and type 2 diabetes mellitus
Obesity is associated with low total testosterone levels that can be explained at least partially by lower sex hormone-binding globulin (SHBG) in obese men
epidemiological studies have shown a negative correlation between BMI and total testosterone and to a lesser extent with free and bioavailable (biologically active) testosterone levels
For so many, lifestyles are seen as unobtainable and of limited benefit. This study proves otherwise. This study found that lifestyle changes made in middd-life were associated with a decrease in cardiovascular disease. Equally important, many were found to be able to implement said lifestyle changes--this flies in the face of what a lot of physicians believe.
Oxidative stress generated by breast cancer cells activates HIF-1α and NFκB in fibroblasts, leading to autophagy and lysosomal degradation of Cav-1
increased levels of hydrogen peroxide in exhaled breath condensate from patients with localized breast malignancy, associated with increased clinical severity
Comparing mitochondrial metabolic activity revealed a difference between stroma and epithelial cells
Overexpression of NOX4 in normal breast epithelial cells results in cellular senescence, resistance to apoptosis, and tumorigenic transformation, as well as increased aggressiveness of breast cancer cells
metalloproteinases (MMP) such as MMP-2, MMP-3, and MMP-9 increase extracellular matrix turnover and are themselves activated by oxidative stress
Lowered expression of Cav-1 not only leads to myofibroblast conversion and inflammation but also seems to impact aerobic glycolysis, leading to secretion of high energy metabolites such as pyruvate and lactate that drive mitochondrial oxidative phosphorylation in cancer cells
Reverse Warburg Effect
secreted transforming growth factor β (TGFβ), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), fibroblast growth factor 2, and stromal-derived factor 1 (SDF1) are able to activate fibroblasts and increase cancer cell proliferation
oxidative stress has an important role in the initiation and preservation of breast cancer progression
cancer preventive role of healthy mitochondria
the cancer cells produce hydrogen peroxide and by driving the “Reverse Warburg Effect” initiate oxidative stress in fibroblasts. As a result of this process, fibroblasts exhibited reduced mitochondrial activity, increased glucose uptake, ROS, and metabolite production.
Oxidative stress results from an imbalance between unstable reactive species lacking one or more unpaired electrons (superoxide anion, hydrogen peroxide, hydroxyl radical, reactive nitrogen species) and antioxidants
cancer cells are able to induce drivers of oxidative stress, autophagy and mitophagy: HIF-1α and NFκB in surrounding stroma fibro-blasts
Studies show that loss of Cav-1 in adjacent breast cancer stroma fibroblasts can be prevented by treatment with N-acetyl cysteine, quercetin, or metformin
However, diets rich in antioxidants have fallen short in sufficiently preventing cancer
hydrogen peroxide is one of the main factors that can push fibroblasts and cancer cells into senescence
It is widely held that HIF-1α function is dependent upon its location within the tumor microenvironment. It acts as a tumor promoter in CAFs and as a tumor suppressor in cancer cells
It was reported that overexpression of recombinant (SOD2) (Trimmer et al., 2011) or injection of SOD, catalase, or their pegylated counterparts can block recurrence and metastasis in mice
obstructing oxidative stress in the tumor microenvironment can lead to mitophagy and promote breast cancer shutdown is a promising discovery for the development of future therapeutic interventions.
Recent studies show that in the breast cancer microenvironment, oxidative stress causes mitochondrial dysfunction
Really fascinating article on tumor signaling. The article points to a complex signaling between cancer cells and stromal fibroblasts that results in myofibroblast transformation that increases the microenvironment favorability of cancer. This article points to oxidative stress as the primary driving force.
defined by consistent symptoms and signs of androgen deficiency, and an unequivocally low serum testosterone level
the threshold serum testosterone level below which adverse clinical outcomes occur in the general population is not known
most population-based studies use the serum testosterone level corresponding to the lower limit, quoted from 8.7 to 12.7 nmol/L, of the normal range for young Caucasian men as the threshold
Researchers tried to examine whether serum total or free testosterone would be a better/more reliable choice when studying the effect of testosterone. The results were mixed. Some reported significant associations of both serum total and free testosterone level with clinical parameters25, whereas others reported that only serum free testosterone26 or only serum total testosterone6 showed significant associations.
−0.124 nmol/L/year in serum total testosterone
this equates to a 4 ng/dl decline annually in total Testosterone.
In experimental studies, androgen receptor knockout mice developed significant insulin resistance rapidly
In mouse models, testosterone promoted differentiation of pluripotent stem cells to the myogenic lineage
testosterone decreased insulin resistance by enhancing catecholamine induced lipolysis in vitro, and reducing lipoprotein lipase activity and triglyceride uptake in human abdominal tissue in vivo
by promoting lipolysis and myogenesis, testosterone might lead to improved insulin resistance
testosterone regulated skeletal muscle genes involved in glucose metabolism that led to decreased systemic insulin resistance
In the liver, hepatic androgen receptor signaling inhibited development of insulin resistance in mice
independent and inverse association of testosterone with hepatic steatosis shown in a cross-sectional study carried out in humans
In short, androgen improves insulin resistance by changing body composition and reducing body fat.
Although a low serum testosterone level could contribute to the development of obesity and type 2 diabetes through changes in body composition, obesity might also alter the metabolism of testosterone
In obese men, the peripheral conversion from testosterone to estrogen could attenuate the amplitude of luteinizing hormone pulses and centrally inhibit testosterone production
leptin, an adipokine, has been shown to be inversely correlated with serum testosterone level in men
Leydig cells expressed leptin receptors and leptin has been shown to inhibit testosterone secretion, suggesting a role of obesity and leptin in the pathogenesis of low testosterone
Baltimore Longitudinal Study of Aging (BLSA) cohort made up of 3,565 middle-class, mostly Caucasian men from the USA, the incidence of low serum total testosterone increased from approximately 20% of men aged over 60 years, 30% over 70 years, to 50% over 80 years-of-age
30–44% sex hormone binding globulin (SHBG)-bound testosterone and 54–68% albumin-bound testosterone
As the binding of testosterone to albumin is non-specific and therefore not tight, the sum of free and albumin-bound testosterone is named bioavailable testosterone, which reflects the hormone available at the cellular level
Serum total testosterone is composed of 0.5–3.0% of free testosterone unbound to plasma proteins
alterations in SHBG concentration might affect total serum testosterone level without altering free or bioavailable testosterone
listed in TableT
A significant, independent and longitudinal effect of age on testosterone has been observed with an average change of −0.124 nmol/L/year in serum total testosterone28. The same trend has been shown in Europe and Australia
Asian men residing in HK and Japan, but not those living in the USA, had 20% higher serum total testosterone than in Caucasians living in the USA, as shown in a large multinational observational prospective cohort of the Osteoporotic Fractures in Men Study
subjects with chronic diseases consistently had a 10–15% lower level compared with age-matched healthy subjects
In Caucasians, the mean serum total testosterone level for men in large epidemiological studies has been reported to range from 15.1 to 16.6 nmol/L
Asians, higher values, ranging from 18.1 to 19.1 nmol/L, were seen in Korea and Japan
Chinese middle-aged men reported a similar mean serum testosterone level of 17.1 nmol/L in 179 men who had a family history of type 2 diabetes and 17.8 nmol/L in 128 men who had no family history of type 2 diabetes
The reduction of total testosterone was 0.4% per year in both groups
HK involving a cohort of 1,489 community-dwelling men with a mean age of 72 years, a mean serum total testosterone of 19.0 nmol/L was reported
pro-inflammatory factors, such as tumor necrosis factor-α in the testes, could locally inhibit testosterone biosynthesis in Leydig cells47, and testosterone treatment in men was shown to reduce the level of tumor necrosis factor-α
In Asians, a genetic deletion polymorphism of uridine diphosphate-glucuronosyltransferase UGT2B17 was associated with reduced androgen glucuronidation. This resulted in higher level of active androgen in Asians as compared to Caucasians, as Caucasians' androgen would be glucuronidated into inactive forms faster.
Compared with Caucasians, the frequency of this deletion polymorphism of UGT2B17 was 22-fold higher in Asian subjects
Other researchers have suggested that environmental, but not genetic, factors influenced serum total testosterone
The basal and ligand-induced activity of the AR is inversely associated with the length of the CAG repeat chain
In the European Male Aging Study, increased estrogen/androgen ratio in association with longer AR CAG repeat was observed
a smaller number of AR CAG repeat had been shown to be associated with benign prostate hypertrophy and faster prostate growth during testosterone treatment
In India, men with CAG ≤19 had increased risk of prostate cancer
the odds of having a short CAG repeat (≤17) were substantially higher in patients with lymph node-positive prostate cancer than in those with lymph node-negative disease or in the general population
assessing the polymorphism at the AR level could be a potential tool towards individualized assessment and treatment of hypogonadism.
In elderly men, there was reduced testicular response to gonadotropins with suppressed and altered pulsatility of the hypothalamic pulse generator
a significant, independent and longitudinal effect of age on serum total testosterone level had been observed
A significant graded inverse association between serum testosterone level and insulin levels independent of age has also been reported in Caucasian men
Low testosterone is commonly associated with a high prevalence of MES
most studies showed that changes in serum testosterone level led to changes in body composition, insulin resistance and the presence of MES, the reverse might also be possible
MES predicted a 2.6-fold increased risk of development of low serum testosterone level independent of age, smoking and other potential confounders
Other prospective studies have shown that development of MES accelerated the age-related decline in serum testosterone level
In men with type 2 diabetes, changes in serum testosterone level over time correlated inversely with changes in insulin resistance
weight loss by either diet control or bariatric surgery led to a substantial increase in total testosterone, especially in morbidly obese men, and the rise in serum testosterone level was proportional to the amount of weight lost
To date, published clinical trials are small, of short duration and often used pharmacological, not physiological, doses of testosterone
In the population-based Osteoporotic Fractures in Men Study cohort from Sweden, men in the highest quartile of serum testosterone level had the lowest risk of cardiovascular events compared with men in the other three quartiles (hazard ratio [HR] 0.70
low serum total testosterone was associated with a significant fourfold higher risk of cardiovascular events when comparing men from the lowest testosterone tertile with those in the highest tertile
Shores et al. were the first to report that low serum testosterone level, including both serum total and free testosterone, was associated with increased mortality
low serum total testosterone predicted increased risk of cardiovascular mortality with a HR of 1.38
low serum total testosterone increased all-cause (HR 1.35, 95% CI 1.13–1.62, P < 0.001) and cardiovascular mortality (HR 1.25
European Association for the Study of Diabetes 2013 suggested there was an inverse relationship between serum testosterone level and acute myocardial infarction
Diabetic men in the highest quartile of serum total testosterone had a significantly reduced risk of acute MI when compared with those in the lower quartiles
serum total testosterone level in the middle two quartiles at baseline predicted reduced incidence of death compared with having the highest and lowest levels
Nice review of Testosterone levels and some of the evidence linking Diabetes with low T. However, the conclusion by the authors regarding what is causing the low T in men with Diabetes is baffling. The literature does not point to one cause, it is clearly multifactorial--obesity, inflammation, high aromatase activity...I would suggest the authors continue their readings in the manner.
Current recommendations for dietary protein intake during pregnancy is to low. New study points to 1.22 g/kg and 1.52 g/kg requirements for first and third trimester.
Current protein recommendations for women > 65 are inadequate. New study finds daily requirements range from 0.96 g/kg and 1.29 g/kg per day for women > 65. What does the RDA get right?
Para ser franco,el nivel de creatinina es mucho mayor que el nivel normal de creatinnia ,es la etapa 4 de la enfermedad renal .Sin un buen control,puede caer en la ultima etapa rendidamente ,es decir la uremia .Así como un paciente de la insuficiencia renal con alta creatinina ,debe tomar los tratamientos oportunos y efectivos.
Hypercalcemia of malignancy occurs as the result of direct bone metastasis and via humoral mechanisms such as parathyroid hormone-related protein (PTHrP) or 1,25-dihydroxyvitamin D mediated pathways
ectopic secretion of parathyroid hormone (PTH) has been implicated
Hypercalcemia due to osteolytic bone lesions is common in multiple myeloma, leukemia, and breast cancer
Humoral hypercalcemia is predominant in squamous cell, renal cell and ovarian cancers, and lymphomas are associated with 1,25-dihydroxyvitamin D mediated hypercalcemia
20% of cases of hypercalcemia of malignancy and is frequently encountered in multiple myeloma, metastatic breast cancer, and to a lesser extent in leukemia and lymphoma
Physiologic bone turnover requires the complementary activity of osteoblasts – mesenchymal stem cell-derived bone-forming cells – and bone-resorbing cells of monocyte and macrophage lineage known as osteoclasts
In local osteolytic hypercalcemia, the RANKL/RANK interaction results in excessive osteoclast activation leading to enhanced bone resorption and thus hypercalcemia
In addition, osteoclast activation is also mediated by malignancy secreted cytokines, including interleukin-1, initially termed “osteoclast stimulating factor”
Macrophage inflammation protein 1-alpha (MIP 1-alpha)
hypercalcemia is through extra-renal 1,25-dihydroxyvitamin D (calcitriol) production
1% of cases
increased production of 1,25-dihydroxyvitamin D occurs nearly exclusively in Hodgkin and non-Hodgkin lymphoma with case reports of the same in ovarian dysgerminoma
1-α-hydroxylase in the kidney, a process regulated by PTH
in 1,25-dihydroxyvitamin D induced hypercalcemia, malignant cells likely recruit and induce adjacent macrophages to express 1-α-hydroxylase, converting endogenous calcidiol into calcitriol.31 Calcitriol then binds to receptors in the intestine leading to heightened enteric calcium reabsorption with resultant hypercalcemia
this mechanism of disease is best conceptualized as an absorptive form of hypercalcemia
Ectopic production of PTH by malignant cells has been described in a handful of cases involving cancer of the ovary and lung, as well as neuroendocrine tumors and sarcoma
primary hyperparathyroidism and malignancy comprising nearly 90% of cases of hypercalcemia
an initial panel consisting of PTH, PTHrP, phosphorus, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D should be obtained
Lymphoma, a hypercalcemia due to 1,25-dihydroxyvitamin D mediated pathways, is implied by elevations in 1,25-dihydroxyvitamin D without concomitant elevations in 25-hydroxyvitamin D. In such cases, PTH is low and PTHrP undetectable
Treatment of hypercalcemia of malignancy is aimed at lowering the serum calcium concentration by targeting the underlying disease, specifically by inhibiting bone resorption, increasing urinary calcium excretion, and to a lesser extent by decreasing intestinal calcium absorption
mildly symptomatic disease
marked symptoms
hydration with isotonic fluid (if admitted), avoidance of thiazide diuretics, and a low-calcium diet
denosumab
Denosumab is an RANKL antibody that inhibits osteoclast maturation, activation, and function
Serine, glycine, glutamine, glutamate, asparagine upregulated in cancer. Most glutamine is converted to glutamate to drive alpha-ketoglutarate production to drive energy production. It also upregulates mTOR signaling.