Testosterone

It is bound to albumin (50%, loosely-bound), sex hormone-binding globulin ([SHBG], 44%, tightly-bound), corticotropin-binding globulin (4%, loosely-bound), and approximately 2% circulates as free testosterone.

 

Approximately 50% of total testosterone in the circulation is tightly bound to sex hormone binding globulin (SHBG).

Sex hormone binding globulin is a glycoprotein produced in the liver. 

There is an inverse association of SHBG with obesity, insulin resistance and type 2 diabetes.

SHBG polymorphisms that predict higher levels of SHBG are protective against type 2 diabetes in both males and females.

Obesity is associated with lower SHBG concentrations, and there is a physiological lowering of total testosterone concentrations in obese men. 

DHEA can be converted in 2-3 enzymatic steps to dihydrotestosterone or testosterone.

The initial compound in the biosynthesis of estrogen.

Testosterone, is known to regulate sexual function, including sexual performance, erectile function and libido.

 

Testosterone also regulates muscle mass and muscle strength. 

 

Testosterone deficiency leads to anemia and testosterone therapy increases haemoglobin concentrations.

 

Males with hypogonadism suffer from osteoporosis, which also improves with testosterone treatment.

 

Hypogonadism in the male is associated with osteoporosis.

 

The response to testosterone replacement is dramatic in adolescents and young men, as reflected in bone mineral density (BMD). 

 

Testosterone suppresses the increase in bone breakdown that occurs after caloric restriction induced weight loss.

 

Men with type 2 diabetes have a higher risk of hip and non-vertebral fractures than non-diabetic men.

 

The  BMD is higher by ~5% in men with type 2 diabetes compared with men without diabetes: suspect higher body weight.

 

A low bone turnover state exists in type 2 diabetes contributing  to the high fracture risk.

 

Testosterone therapy induces a dramatic increase in plasma osteocalcin concentrations, consistent with an increase in osteoblastic activity in patients with hypogonadism and type 2 diabetes.

 

The beneficial action of testosterone on the bone may be caused by a combination of osteoblastic and osteoclastic activity. 

 

These actions are potentially useful in reducing fracture risk in men with type 2 diabetes.

 

Then hypogonadal state in males is associated with insulin resistance and that testosterone replacement restores insulin sensitivity.

 

Associated with these testosterone changes in hypogonadal patients are reductions in the occurrence of acute myocardial infarction, stroke and death.

 

Insulin resistant states such as obesity, type 2 diabetes and metabolic syndrome in males are associated with lower free and bioavailable testosterone concentrations.

 

A quarter of obese men and a third of men with type 2 diabetes have subnormal free testosterone concentrations.

 

The insulin sensitizing effect of testosterone therapy is, therefore, especially pertinent to this metabolic and diabetic population.

 

Males with diabetes have a diminished expression of estrogen receptor and aromatase, both of which are restored following testosterone replacement.

Estradiol concentrations are low in men with hypogonadism and type 2 diabetes, and increase after testosterone administration.

 

The effects of testosterone therapy on glycemic control in men with type 2 diabetes:  decrease in fasting glucose (28?mg/dL) and HbA1c (0.37%) compared with placebo with 3 months of testosterone therapy in a small trial.

 

In men with new onset type 2 diabetes treated with transdermal testosterone also showed a decrease in HbA1c from 7.5% to 6.3% over a period of 1 year.

 

A randomized placebo controlled trial in men with type 2 diabetes showed a placebo subtracted decrease of 0.7% in HbA1c.

 

By contrast, HbA1c does not change significantly after short?term testosterone therapy in men with well controlled diabetes.

 

Long-term testosterone therapy in patients with hypogonadism may reverse prediabetes altogether and normalize glucose homeostasis. 

 

Long-term testosterone therapy in men can prevent the progression of prediabetes to overt diabetes and reverse the prediabetes state into a normoglycaemic state.

 

Testosterone has an inhibitory effect on the incorporation of dietary fat into adipose tissue, especially intra?abdominal fat, both omental and retroperitoneal. 

Testosterone clearly has an inhibitory effect on fat deposition in visceral adipose tissue. 

 

Patients  treated with testosterone for 6 months, total body and truncal subcutaneous fat were reduced while lean body mass increased by a similar amount. 

In an observation study of obese men with hypogonadism, 8?years of testosterone therapy reduced body weight by about 20% and waist circumference by 10%.

 

Hypogonadal men injected  with depot gonadotropin?releasing hormone agonist lose fat when given testosterone, but they do not lose body fat if they are treated with an aromatase inhibitor, which is responsible for converting testosterone to estradiol.

At a cellular level, testosterone suppresses adipocytic differentiation.

There is an inverse relationship between body mass index and plasma testosterone concentrations: there is relationship of insulin resistance, obesity and low testosterone concentrations.

 

Treatment with testosterone in hypogonadal patients leads to weight loss that was proportional to the weight at baseline, being greatest in the obese (20%), intermediate in the overweight (10%) and least in those with normal weight (5%) compared with those not treated with testosterone over a follow?up period of 11?years: there was a proportionate reduction in waist circumference, systolic, diastolic and pulse blood pressures and plasma lipids. 

The anti?inflammatory action of testosterone may contribute not only to the reversal of insulin resistance, but also to the preservation of the ??cell and insulinogenesis. 

 

Insulin?sensitizing effect of testosterone has been consistently observed in obese insulin?resistant men, studies in non?obese men or in those with low normal testosterone concentrations sometimes fail to show an impact on insulin sensitivity.

 

Testosterone combination of actions potentially has a comprehensive antidiabetic effect.

 

Testosterone therapy diminishes subcutaneous fat mass, but long duration of treatment may be needed to show a decrease in hepatic or visceral fat in obese men.

Levels are quantitatively linked to libido in women, decrease by 50% between age 20 and 40 and undergo little change during menopause.

A potent ligand for androgen receptors in skeletal and myocardial tissue and modulates transcription, translation and enzyme function in a variety of other tissues.

Testosterone increases skeletal muscle  activator, fibroblast growth factor and decreases expression of the muscle growth suppressors.

 

Testosterone increases the number of muscle stem cells and net protein balance.

Testosterone supports muscle hyperplasia and hypertrophy.

 

Testosterone increases in the cross sectional area of myofibers and the number of myonuclei, suggesting that hypertrophy is accompanied by the addition of new nuclei from satellite cells. 

 

Testosterone increases fibroblast growth factor receptors, insulin growth factor and promoting muscle growth.

 

Testosterone also increases serum osteocalcin concentrations, which may account for its anabolic actions on bone. 

 

Key circulating androgen.

Normal levels range from 300 to 1000 ng per deciliter.

Initial test for androgen deficiency is serum total testosterone.

Low levels of androgens in men are associated with obesity and cardiovascular disease, while in women, elevated levels cause polycystic ovarian syndrome that is characterized by increased body weight and cardiovascular disease.

All chronic diseases, such as chronic kidney disease, malignancies, atherosclerosis, are associated with a reduced androgen levels in men.

A reduction in androgens is associated with decreased longevity, risk of fatal cardiovascular events, sarcopenis, osteoporosis, frailty, cognitive impairment, depression, sleep apnea, and atrial fibrillation.

Total serum testosterone levels may not be reliable in patients with altered serum sex hormone binding globulin (SHBG).

Increased SHBG seen with aging, hyperthyroidism, liver disease, elevated estrogen, HIV disease, and anticonvulsants.

Decreased SHBG associated with insulin resistance, obesity,diabetes, hypothyroidism, excess growth hormone, glucocorticoids,androgens, progestins, and nephrotic syndrome.

Where SHBG abnormalities exist measuring free testosterone levels is helpful.

Levels can drop by as much as 13% during the day (Crawford DE et al).

Secreted in a circadian fashion with peak levels in early am.

Levels should be measured in morning.

Levels usually measured by mass spectrometry.

A single result is inadequate to make diagnosis of testosterone deficiency, as repeat analysis may be normal.

The  measurement of total testosterone with sex hormone-binding globulin  allows calculation of free testosterone.

Circulates in plasma mostly bound to plasma proteins , primarily albumin and sex hormone binding globulin.

1-2% of testosterone circulates in free form, the biologically active form.

More than 80% of circulating estradiol in men is derived from aromitization of testosterone.

As serum testosterone levels fall, there is a concomitant decline in serum estradiol levels.

5 mg of testosterone manufactured daily by the testicles.

Testosterone levels that are at least 2 SD below the mean value for healthy young adults are considered low.

Approximately 6-8% of testosterone is metabolized by 5Alpha-reductase to make a 0.3 mg of dihydroxytestosterone ( DHT).

Local conversion of testosterone to DHT by 5alpha-reductase in the skin and prostate can create high concentrations at those sites.

Findings in male hypogonadism are routinely attributed to androgen deficiency.

Low testosterone or androgen deficiency is commonly associated with opioid use.

Estrogen deficiency and male hypogonadism may have some role in pathogenesis of consequences, including bone loss.

Half-life is approximately 45 minutes.

When administered exogenously plasma levels of testosterone, DHT and estradiol increase.

The administration of DHT decreases plasma testosterone levels.

Cardiovascular mortality and incident coronary artery disease are associated with lower levels of total testosterone, free testosterone and bioavailable testosterone (Morgentaler A et al).

Men with serum total testosterone concentration of 550 ng/dL or more have a 30% lower risk of cardiovascular events than does men in the lower 3 quantiles.

The above data are paradoxical.

Multiple studies have shown that having normal blood testosterone concentrations helps promote normal cardiovascular health.

Testosterone therapy is associated with decreased obesity and waist circumference and improved glycemic control.

Testosterone enhances insulin sensitivity in obese men with hypogonadism by decreasing fat mass, increasing lean mass, decreasing free fatty acids and suppressing inflammation. 

 

Testosterone plays an important role in several metabolic functions in males. 

 

Testosterone therapy does not improve fatigue or enhance routine physical activity in elderly men.

 

Testosterone increases the expression of insulin receptors in adipose tissue and activity in skeletal muscle. 

Testosterone therapy not associated with increased venous thromboembolism risk in men (Baillargeon).

In a meta-analysis involving 75 studies and 5004 and 64 patients reported that testosterone therapy did not increase cardiovascular risk but instead decrease cardiovascular risk among those with metabolic syndrome(Corona G et al).

Testosterone Effects on Atherosclerosis Progression in Aging Men (TEAAM) a randomized double blind study among older men with low or low normal testosterone levels the administration of testosterone for three years versus placebo did not result in a significant difference in rates of change the common carotid artery intima-media thickness or coronary artery calcium nor did it improve overall sexual function or health-related quality of life.

In women arises as a by-product of adrenal and ovarian function by secretion or by the metabolism of prohormones (androstenedione or dehydroepiandrosterone sulfate) in peripheral tissues such as fat.

Testosterone increases hematocrit by suppressing hepcidin and increasing expression of ferroportin along with that of transferrin receptor and plasma transferrin concentrations. 

 

Hepcidin concentration is suppressed by testosterone, and it suppresses the expression of ferroportin, the membrane protein responsible for the absorption of iron by the enterocyte and the release of iron stored in the monocytes and macrophages of the reticuloendothelial system.

 

Ferroportin has a key role in increasing the bioavailability of iron. 

With the suppression of hepcidin, testosterone therapy increases the expression of ferroportin along with that of transferrin receptor and plasma transferrin concentrations,and plasma iron and ferritin concentrations decrease. 

Testosterone findings are consistent with the release of iron from the stores with increase in ferroportin and the transport of iron to erythropoietic cells through transferrin and the uptake of iron by erythropoietic tissues through the transferrin receptor. 

Testosterone effects on erythropoietin production, enhance haemoglobin production, along with ferroportin effects.

The stimulatory effect of testosterone on hematocrit has been attributed to an increase in erythropoietin synthesis in the kidney. 

 

Erythrocytosis is a known adverse effect of testosterone administration. 

A randomized placebo‐controlled trial of transdermal testosterone therapy for 1 year in elderly men found a 2% incidence of polycythaemia,which is dose‐dependent.

Hematocrit above 55% increases blood viscosity and could exacerbate vascular disease in coronary, cerebrovascular or peripheral vascular circulation. 

Periodic hematological assessment is therefore indicated in patients on testosterone therapy.

Age related decline in serum levels associated with reduced muscle mass and decreased strength in the lower extremities,decreased lower extremity function and poor mobility.

In elderly, testosterone supplementation increases muscle mass, strength, and leg power, which are important determinants of mobility.

This testosterone replacement therapy increases functional capacity and leg muscle strength.

Androgens and estrogens contribute to maintenance of normal libido and erectile function.

Effects include bone accrual, building and maintaining muscle mass, promoting erectile function and libido.

Testosterone treatment in men with hypogonadism improves bone density, quality and  topological measures of trabecular architecture.

Among middle-aged and older men with hypogonadism, testosterone treatment did not result in lower incidence of clinical fracture than placebo: fracture incidence was numerically higher among men who received testosterone than among those who received placebo (Snyder PJ).

Marked anabolic effects occur at supra physiologic testosterone levels of greater than 1000 mg/dL and requires weekly doses of 300 mg or more.

Prescribing information indicates that testosterone is appropriate for replacement only an adult men with low testosterone levels because of damage or trauma to the testes, because of a gonadatropin or LHRH deficiency or because of damage to the pituitary or the hypothalamus.

Testosterone treatment is not recommended for men who do not fall into the above categories-adult onset hypogonadism.

Testosterone in Older Men with Mobility Limitations a placebo controlled randomized study demonstrated increased risk of cardiovascular adverse events, and manifested greater improvements in leg press, chess press strength and stair climbing while carrying a load (Basaria S)

Levels during midfollicular phase of menstruation vary from 25% above and below the mean and are at the highest levels in the early mornings.

Levels in premenopausal women are slightly lower in premenstrual phase and slightly higher in midcycle.

When released from the testicle it is converted by 5-alpha reductase to dihydrotestosterone, which is a more active activator of the androgen receptor than is testosterone.

Converted by 5-alpha reductase to 5-alpha dihydrotesterone (DHT).

5-alpha dihydrotestosterone is a potent metabolite of dihydrotestosterone.

Exerts its virilizing effects on androgen receptor directly and indirectly via reduction to 5 alpha-dihydrotestosterone.

At least 2 isoenzymes of steroid 5alpha -reductase convert testosterone into DHT in humans.

5alpha-reductase inhibitors are used to treat benign prostatic hyperplasia, and androgenic alopecia.

2 isoforms type 1 and type 2 of alpha-reductase exist with the former type converting testosterone in the skin and liver and the latter is most active in reproductive tissues.

Free testosterone is the main bioactive portion of plasma testosterone and may be elevated in hirsute women with normal total testosterone levels.

Majority of elderly men have a modest reduction in bioavailable testosterone levels, that is the fraction of circulating testosterone not bound to sex hormone binding globulin.

Aging associated with progressive decline in free and total testosterone.

Decrease in hormone levels in men not as steep or sudden as that associated with hormone declines during menopause in women.

Hypogonadism in men not defined by a specific level of serum testosterone because levels associated with dysfunction vary widely among individuals.

Approximately 1% per year reduction in levels after age 30, termed andropause.

Rate of decline of total testosterone level is 3.2ng/dL per year, regardless of age.

Illnesses such as diabetes, cardiovascular disease, hypertension and tobacco use, alcohol abuse, and malnutrition can accentuate decline of androgen levels associated with aging.

There is an high prevalence of hypogonadotropic hypogonadism in type 2 diabetes: insulin resistance tends to decrease after testosterone replacement in this group of patients. 

 

 

Patients with hypogonadotropic hypogonadism and type 2 diabetes have an increase of 35% in insulin resistance compared with eugonadal patients with type 2 diabetes.

 

Testosterone treatment in men with hypogonadotropic hypogonadism and diabetes leads to weight loss and an increase in lean body mass.

 

Testosterone treatment in men with hypogonadotropic hypogonadism and diabetes leads to a decline in circulating free fatty acids.

A decline in circulating free fatty acids enhances insulin signalling because free fatty acids are known to induce oxidative and inflammatory stress and to interfere with insulin signal transduction.

Testosterone administration restores insulin sensitivity.

Serum levels decline with age and may be associated with depression, sexual dysfunction, decreased lean body mass, decreased muscle strength, reduced bone density in aged men.

Deficiency associated with increased body fat mass, central obesity, insulin resistance, emotional irritability and dysphoria.

Lean mass and strength are reduced in men with low testosterone and fat mass is increased.

With hypogonadism men report less sexual activity, fewer sexual thoughts., fewer spontaneous erections than individuals with normal testosterone levels.

Low serum levels associated with increased mortality with 35% mortality over 8 years of follow-up in a low testosterone group compared to a 20% mortality in a group of men with normal testosterone level.

Changes in lean mass, thigh muscle area, and leg press strength are attributable changes in testosterone levels, while changes in fat measures are primarily related to changes in estradiol levels.

Decreased serum levels in elderly men with associated symptoms referred to as the male menopause or other terminology as male climacteric, andropause, androgen deficiency of the aging male and late hypogonadism.

Use in elderly men may be associated with prostate cancer and progression of benign prostatic hypertrophy.

Concerns regarding testosterone replacement therapy in elderly men include: prostate hypertrophy, prostate cancer, cardiovascular events, erythropoiesis leading to polycythemia, lowering of HDL cholesterol and fluid retention.

 

Men with low testosterone concentrations have a smaller prostate and lower prostate‐specific antigen (PSA) concentrations in the blood than men with normal testosterone concentrations.

 

Men with obesity or type 2 diabetes are known to have ~20% lower concentrations of testosterone than lean men without diabetes

 

Testosterone therapy has not been found to increase the incidence of benign prostatic hyperplasia (BPH) or a significant exacerbation of voiding symptoms attributable to BPH.

 

Avoiding testosterone therapy in men with severe urinary symptoms until the BPH has been successfully treated.

 

Testosterone therapy is an absolute contraindication in men with prostate cancer.

 

There is no evidence that testosterone has a causative role in prostate cancer. 

Hypogonadal men do not have a lower incidence of prostate cancer than eugonadal men.

The prevalence of prostate cancer in patients receiving testosterone therapy was similar to that in the general population.

Administration has been associated with the development of the acne, gynecomastia,

peripheral edema and polycythemia

Indiscriminate use may cause coagulation disorders resulting in cerebral vascular injury, dyslipidemia, and infertility.

Side effects include acne, gynecomastia, aggravation of sleep apnea, and reduced HDL levels.

A risk of gynecomastia in the first few months after initiation of testosterone therapy exists.

 

A decrease in testicular size, spermatogenesis and compromised fertility can occur during testosterone therapy because of the downregulation of gonadotropins.

 

With transdermal gel usage for testosterone therapy, there is a possibility of transferring the drug to others after skin‐to‐skin contact. 

 

Testosterone is anabolic and it can cause retention of sodium and water, worsening edema in patients with pre‐existing cardiac, renal or hepatic disease. 

 

Testosterone therapy should be avoided in men with decompensated congestive heart failure.

Baltimore Longitudinal Study of Aging revealed percentage of men with total testosterone concentration in the hypogonadal range (less than 325mg/dL) was 20%, 30%, and 50% for men older than 60, 70 and 80 years, respectively.

Both type 2 diabetes and the metabolic syndrome strongly associated with below normal levels of testosterone.

Long?term therapy with testosterone prevents progression from prediabetes to diabetes and improves HbA1c. 

 

Testosterone replacement leads to an increase in adenosine 5??monophosphate?activated protein kinase (AMPK) expression and phosphorylation.

AMPK is known to mediate glucose transport effects of metformin and exercise, actions  additive to that of the improvement in insulin signal transduction following testosterone replacement.

The insulin?sensitizing effect of testosterone is comparable with other well?known interventions that increase insulin sensitivity including: as weight loss, exercise or treatment with thiazolidinediones. 

Similar to testosterone, pioglitazone reduces circulating free fatty acids and increases AMPK phosphorylation in skeletal muscle.

Estimated between 2-4 million men in the U.S. have low levels.

In a double blind randomized controlled study of 237 healthy men between the ages of 60 and 80 years with a low normal testosterone levels, given testosterone supplementation for 6 months, resulted in increased lean body mass and decreased fat mass, but without improvement in mobility, muscle strength, bone mineral density or cognition (Emmelot-Vonk).

In the above study decreased fat mass accompanied by decreased total and HDL cholesterol and increased insulin sensitivity.

Use has not been found to have a higher risk of prostate cancer .

The dose of testosterone required to prevent adverse changes varies considerably among individuals.

Fat accumulation begins with mild gonadal steroid deficiency, with testosterone levels approximating 300-350 ng/dL.

Lean mass, thigh muscle area, and muscle strength are preserved with gonadal steroid deficiency levels 200 ng/dL or less.

The use of testosterone replacement in patients with hypogonadism increases lean mass, decreases fat mass and can improve sexual function.

The use of testosterone therapy in men is associated with a 30% increased risk of death, MI, or ischemic stroke (Ho M et al).

Reduction in testosterone overtime is thought to contribute to cognitive impairment.

The Testosterone in Older Men with Mobility Limitations Trial (TOM) conducted in older frail men with a high prevalence of cardiovascular disease was stopped prematurely because of cardiovascular events.

Among VA patients who underwent coronary angiography and had a low serum testosterone level, testosterone use was associated with increased risk of adverse outcomes (Vigen R et al).

Older men with high or low testosterone levels have higher mortality risk as compared to men who have mid-range testosterone levels.

Optimal androgen levels should be considered a biomarker for survival in older men.

In the US, nearly 3% of men over 40 years of age are prescribed testosterone therapy.

Testosterone prescriptions reached 5.3 million/year with a market of $1.6 billion in 2011.

Guidelines recommend testosterone therapy for patients with symptomatic testosterone deficiency.

Treatment in testosterone deficiency improves sexual function, bone mineral density, increases free-fat mass, increases strength, and improves lipid profile and insulin resistance, and increases the time to ST depression during stress testing.

Venous thromboembolism, including DVT,and pulmonry embolism reported in patients with use of testosterone gels.

In the evaluation of 73,196 men with prostate cancer treated with androgen deprivation therapy there is a significant increase risk of diabetes, coronary heart disease, myocardial infarction and sudden cardiovascular death (Keating NL et al).

Testosterone induces adverse cardiac remodelling in the male heart.

 

Studies suggest men with low testosterone are more probable to die from a major cardiovascular event.   

There are no randomized controlled trials that has examine cardiovascular outcomes following testosterone therapy. 

Increased cardiovascular‐related events’ were noticed in a trial of 209 elderly frail men, who had been randomly assigned a placebo gel or testosterone gel for 6 months.

Other studies in the elderly have not shown an increase in cardiac events after testosterone replacement.

Major adverse cardiovascular events were similar in the testosterone and placebo groups in a randomized controlled trial of transdermal testosterone replacement in 790 elderly men for 1 year, as well as in another RCT of 308 elderly men for 3 years. 

RCTs performed in men with obesity or metabolic syndrome also do not show an increased cardiovascular event rate after testosterone therapy.

Most retrospective epidemiological studies have indicate  a benefit on cardiovascular events from long‐term testosterone use in elderly men: 

56% reduction in total mortality and a 24% reduction in myocardial infarction with the use of testosterone therapy.

An observational study with a mean follow‐up of 8 years in men with type 2 diabetes showed that testosterone therapy was associated with a reduction in acute myocardial infarction (0% vs. 31%), stroke (0% vs. 25%) and mortality (7% vs. 29%) compared with untreated controls.

 

Testosterone therapy indicated in the presence of the low serum testosterone level in men documented to have associated symptoms and signs of hypogonadism. 

Testosterone therapy is not indicated only when men have low serum testosterone levels without signs and symptoms of hypogonadism.

In prepubertal patients with hypogonadism, treatment is directed at initiating pubertal development at the appropriate age with hormonal replacement therapy.

Hormonal replacement therapy does not confer fertility or stimulate testicular growth.

For review of testosterone treatments: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5182226/

A nasal testosterone replacement therapy has been approved for adult males with conditions such as primary hypogonadism, and hypogonadotropic hypogonadism.

All testosterone preparations are regulated as Schedule III controlled substances according to the Anabolic Steroids Control Act.

Several testosterone salts are available in long-acting oil-based preparations.

Promote and maintain secondary sex characteristics in androgen-deficient males.

Several preparations are available as topical gels or transdermal patches.

Patches are changed daily.

Gels, injections, and patches all effectively raise testosterone levels but their pharmacokinetics differ.

Testosterone injections create spikes of elevated testosterone levels that slowly decrease until a subsequent injection, and this cycling results in less time within the normal range than with transdermal systems.

Gels provide longer lasting increases in testosterone levels than patches.

Testosterone levels may influence short term clotting and polycythemia, and differing PharmaKinetics may result in varying safety profiles.

Testosterone injections may increase the short term risk of cardiovascular events, stroke, death, and hospitalization compared with gels (Layton JB et al.).

Cardiovascular risks associated with patches and gels appear to be similar and lower than the risk with testosterone injections.

In a systemic review and meta-analysis there was no significant association between exogenous

testosterone treatment and myocardial infarction, stroke, or mortality in randomized control trials (Alexander GC).

Complications of untreated hypogonadism include loss of libido, failure to achieve physical strength, the social implications of failing to go through puberty, and osteoporosis.

If hypogonadism occurs before epiphyseal closure, may result in a person becoming usually tall with a eunuchoid body habitus.

Treated males with primary hypogonadism are infertile.

Men who have hypogonadism due to hypothalamic or pituitary dysfunction can potentially become fertile with administration of gonadotropins.

Illicit use of anabolic-androgenic steroids is estimated to be between 1 and 3 million users of in the US.

Most uses of anabolic-androgenc steroids are elite athletes, bodybuilders and weightlifters.

 

It Increases erythropoietin and transferrin, decreases hepcidin.

Increasingly prescribes to relieve non-specific symptoms of aging, such as fatigue and declining sexual function.Testosterone is not indicated for aging, but otherwise healthy man.

Testosterone may increase the risk of cardiovascular events in aging men with low testosterone levels particularly in the first two years of administration.

In the absence of identifiable causes of hypogonadism. testosterone should be initiated with caution among aging men with low testosterone levels (Loo SY).

Testosterone is required for healthy  skeletal system in men and sufficient exposure is necessary to achieve peak bone mass and strength during early adult and later to prevent accelerated bone resorption during aging.

Testosterone induces increased bone mineral density, leading to improved bone strength and micro architecture, which are surrogates for fracture prevention.

The TRAVERSE trial of testosterone in patients with hypogonadism found an increased risk of bone fractures in older men, contrary to what was expected.

Androgens in general, and testosterone in particular have been linked to immunosuppression, perhaps explaining the increased prevalence of autoimmune disorders in women.

Testosterone appears to blunt responses to influenza vaccine and other vaccines as well.