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malnutrition progressing to cachexia is another common manifestation of cirrhosis

Malnutrition can be mitigated with BCAA supplementation

Studies show that administration of amino acid formulas enriched with BCAAs can reduce protein loss, support protein synthesis, and improve nutritional status of patients with chronic liver disease

Leucine has been shown to be the most effective of the BCAAs because it acts via multiple pathways to stimulate protein synthesis

BCAAs metabolites inhibit proteolysis

Patients with cirrhosis have both insulin deficiency and insulin resistance

BCAAs (particularly leucine) help to reverse the catabolic, hyperglucagonemic state of cirrhosis both by stimulating insulin release from the pancreatic β cells and by decreasing insulin resistance allowing for better glucose utilization

Coadministration of BCAAs and glucose has been found to be particularly useful

BCAA supplementation improves protein-energy malnutrition by improving utilization of glucose, thereby diminishing the drive for proteolysis, inhibiting protein breakdown, and stimulating protein synthesis

Cirrhotic patients have impaired immune defense, characterized by defective phagocytic activity and impaired intracellular killing activity

another effect of BCAA supplementation is improvement of phagocytic function of neutrophils and possibly improvement in natural killer T (NKT) cell lymphocyte activity

BCAA supplementation may reduce the risk of infection in patients with advanced cirrhosis not only through improvement in protein-energy malnutrition but also by directly improving the function of the immune cells themselves

BCAA administration has also been shown to have a positive effect on liver regeneration

A proposed mechanism for improved liver regeneration is the stimulatory effect of BCAAs (particularly leucine) on the secretion of hepatocyte growth factor by hepatic stellate cells

BCAAs activate rapamycin signaling pathways which promotes albumin synthesis in the liver as well as protein and glycogen synthesis in muscle tissue

Chemical improvement with BCAA treatment is demonstrated by recovery of serum albumin and lowering of serum bilirubin levels

long-term oral BCAA supplementation was useful in staving off malnutrition and improving survival by preventing end-stage fatal complications of cirrhosis such as hepatic failure and gastrointestinal bleeding

The incidence of death by any cause, development of liver cancer, rupture of esophageal varices, or progression to hepatic failure was decreased in the group that received BCAA supplementation

Patients receiving BCAA supplementation also have a lower average hospital admission rate, better nutritional status, and better liver function tests

patients taking BCAA supplementation report improved quality of life

BCAAs have been shown to mitigate hepatic encephalopathy, cachexia, and infection rates, complications associated with the progression of hepatic cirrhosis

BCAAs make up 20-25% of the protein content of most foods

Highest levels are found in casein whey protein of dairy products and vegetables, such as corn and mushrooms. Other sources include egg albumin, beans, peanuts and brown rice bran

In addition to BCAAs from diet, oral supplements of BCAAs can be used

Oral supplementation tends to provide a better hepatic supply of BCAAs for patients able to tolerate PO nutrition as compared with IV supplementation, especially when treating symptoms of hepatic encephalopathy

Coadministration of BCAAs with carnitine and zinc has also been shown to increase ammonia metabolism further reducing the encephalopathic symptoms

Cirrhotic patients benefit from eating frequent, small meals that prevent long fasts which place the patient in a catabolic state

the best time for BCAA supplementation is at bedtime to improve the catabolic state during starvation in early morning fasting

A late night nutritional snack reduces symptoms of weakness and fatigability, lowers postprandial hyperglycemia, increases skeletal muscle mass,[25] improves nitrogen balance, and increases serum albumin levels.[26] Nocturnal BCAAs even improve serum albumin in cirrhotic patients who show no improvement with daytime BCAAs

Protein-energy malnutrition (PEM), with low serum albumin and low muscle mass, occurs in 65-90% of cases of advanced cirrhosis

hyperglucagonemia results in a catabolic state eventually producing anorexia and cachexia

BCAAs are further depleted from the circulation due to increased uptake by skeletal muscles that use the BCAAs in the synthesis of glutamine, which is produced in order to clear the ammonia that is not cleared by the failing liver

patients with chronic liver disease, particularly cirrhosis, routinely have decreased BCAAs and increased aromatic amino acids (AAAs) in their circulation

Maintaining a higher serum albumin in patients with cirrhosis is associated with decreased mortality and improved quality of life

the serum BCAA concentration is strongly correlated with the serum albumin level

may result in part from the destruction of lymphocytes by the tumor and/or an impaired differentiation of lymphocytes progenitors

presence of liver metastasis (HR of, 2.27; P = .0003) and hypoalbuminemia were the 2 most powerful adverse prognostic factors

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

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 Table​T

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

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

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

BCAA supplementation was shown to delay the progression of CCl4-induced chronic liver injury in a rat model by reducing hepatic apoptosis

BCAAs promoted hepatocyte regeneration in a rat model of hepatectomy

BCAA supplementation for advanced cirrhotic patients improves nutritional status and quality of life

BCAAs activate mTOR and subsequently increase the production of eukaryotic initiation factor 4E-binding protein-1 and ribosomal protein S6 kinase, which upregulate the synthesis of albumin

BCAAs were shown to improve homeostasis model assessment scores for insulin resistance (HOMA-IR) and beta cell function (HOMA-%B) in patients with chronic liver disease, indicating that BCAAs can ameliorate insulin resistance

Several clinical trials have suggested that BCAA supplementation improves the prognosis of cirrhotic patients

A low Fischer ratio has been associated with hepatic encephalopathy

Treatment with BCAAs may therefore have a beneficial effect on patients with hepatic encephalopathy mainly by compensating decreased ratio of BCAAs to AAAs, but not by reducing serum ammonia levels

Two randomized studies also showed that BCAAs did not clearly prevent HE in patients with advanced cirrhosis, although BCAAs prevented the progression of hepatic failure

a systematic review with meta-analyses on the effect of oral BCAAs for the treatment of HE was published[66]. The review has revealed that supplementation of oral BCAAs in cirrhotic patients inhibits the manifestation of HE, especially in patients with overt HE rather than those with minimal HE, but showed no effect on the survival of those patients[66]. Thus, oral administration of BCAAs is the treatment of choice in cirrhotic patients with HE

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

SHBG decreases in response to androgens, and in the presence of hypothyroidism, and insulin resistance.

Plasma SHBG levels tend to increase with increasing age

The apparent metabolic clearance rate of testosterone is decreased in elderly as compared to younger men

Testosterone circulates predominantly bound to the plasma proteins SHBG and albumin, with high and low affinity respectively

Testosterone is secreted in a pulsatile fashion

Current clinical guidelines suggest at least two measurements

In adult men, there is a well-documented diurnal variation (particularly in younger subjects) in testosterone levels, which are highest in the early morning and progressively decline throughout the day to a nadir in the evening

In older men, the diurnal variation is blunted

it is standard practice for samples to be obtained between 0800 and 1100 h.

Testosterone and DHEA decline, whereas LH, FSH, and SHBG rise

DHT remains constant despite the decline of its precursor testosterone

Longitudinal studies show an average annual decline of 1–2% total testosterone levels, with decline in free testosterone more rapid because of increases in SHBG with aging

Massachusetts Male Aging Study (MMAS) data show DHEA, DHEAS, and Ae declining at 2–3% per year

DHT showed no cross-sectional age trend

Androstanediol glucuronide (AAG) declined cross-sectionally with age in the MMAS sample, at 0.6% per year

The EMAS data show that, consistent with the longitudinal findings of MMAS (Figure 1), the core hormonal pattern with increasing age is suggestive of incipient primary testicular dysfunction with maintained total testosterone and progressively blunted free testosterone associated with higher LH

obesity impairs hypothalamic/pituitary function

Androgen deprivation in men with prostate cancer has been associated with increased insulin resistance, worse glycemic control, and a significant increase in risk of incident diabetes

Low serum testosterone is associated with the development of metabolic syndrome 116, 117 and type 2 diabetes. 118 SHBG has been inversely correlated with type 2 diabetes

Improvement in insulin sensitivity with testosterone treatment has been reported in healthy 121 and diabetic 122 adult men

In studies conducted in men with central adiposity, testosterone has been shown to inhibit lipoprotein lipase activity in abdominal adipose tissue leading to decreased triglyceride uptake in central fat depots. 123

highest concentration occurring at about 8:00 a.m. and the lowest at about 8:00 p.m.

Average serum concentrations and diurnal variation in testosterone diminish as men age

40% is sequestered with high affinity to sex hormone-binding globulin (SHBG)

almost 60% is bound with low affinity to albumin

2% as free, unbound hormone

5α-DHT has even greater binding affinity to sex hormone-binding globulin than does testosterone

5α-DHT is only about 5% as abundant in the blood as testosterone and is largely derived from peripheral metabolism of testosterone

Both 5α-reduction and aromatization are irreversible processes

Approximately 90% of an oral dose of testosterone is metabolized before it reaches the systemic circulation

there are three modes of action of testosterone. It may directly act through AR in target tissues where 5α-reductase is not expressed, be converted to 5α-DHT (5–10%) by 5α-reductase before binding to AR, or be aromatized to estrogen (0.2%) and act through the estrogen receptor

5α-DHT is a more potent AR ligand than testosterone

has 2–10-fold higher potency than testosterone in androgen-responsive tissues

estrogen plays a major role in regulating metabolic process,74,75 mood and cognition,76 cardiovascular disease,77,78 sexual function including libido,79 and bone turnover in men

Free testosterone is considered the most “biologically active” form

testosterone is the major androgen that acts in the “DHT-independent” tissues, such as skeletal muscle, where 5α-reductase is not expressed or is expressed at a very low level

Testosterone has a known age-related decline, and total levels typically drop by approximately 1.6% per year beginning for most men in their 30s

As estrogen levels rise, they prompt the body to produce more SHBG, which in turn has a higher binding affinity for testosterone, and drives the unbound fraction of the testosterone pool down even further

When the increase in SHBG is taken into account, the age-related decline in the level of hormone that can be used by the body is closer to 2% to 3% per year.

Stinging nettle (Urtica dioica), an herb commonly used for allergies, can also be employed to bind to SHBG, which leaves more testosterone available to tissues

Leptin, an adipose-derived peptide hormone that regulates appetite and metabolism, has been shown to directly inhibit testosterone production in animal models

tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) further inhibit Leydig cell testosterone production

Natural aromatase inhibitors include the bioflavonoids chrysin and luteolin

Zinc deficiency causes an upregulation of the aromatase enzyme

Testosterone reduces lipoprotein lipase (LPL) activity

there are several herbs that can work to boost testosterone levels, including longjack (Eurycoma longifolia), horny goat weed (Epimedium grandiflorum), and tribulus (Tribulus terrestris).

the majority of the hormone is bound to carrier proteins including sex hormone binding globulin (SHBG) and albumin

Activation of NF-κB can also be blocked by several other thiol-containing antioxidants including N-acetyl-l-cysteine (NAC)

Other clinically available antioxidants reported to have antiinflammatory, antioncogenic, and/or antiatherogenic properties that have been shown to block the activation of NF-κB include resveratrol (115, 116), (-)-epicatechin-3-gallate (117), pycnogenol (118), silymarin (119), and curcumin (120)

the amount of BCAAs supplied in the various studies is extremely variable