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Testosterone deficiency

Circulating levels of testosterone decline with age in men, and some clinical consequences of hypogonadism resemble those of normal aging with fatigue, weakness, impaired sexual function.

Some studies estimate that up to 25% of men who receive testosterone therapy do not have their testosterone tested prior to initiation of treatment, and nearly half do not have their testosterone levels checked after therapy commences.

 

Up to one third of men treated with testosterone therapy do not meet the criteria to be diagnosed as testosterone deficient.

 

A large percentage of men in need of testosterone therapy fail to receive it due concerns about prostate cancer development and cardiovascular events.

 

A total testosterone level below 300 ng/dL as a reasonable cut-off in support of the diagnosis of low testosterone. 

 

The clinical diagnosis of testosterone deficiency is only made when patients have  low total testosterone levels combined with symptoms and/or signs.

 

A total testosterone level should be sought in patients with a history of unexplained anemia, bone density loss, diabetes, exposure to chemotherapy, exposure to testicular radiation, HIV/AIDS, chronic narcotic use, male infertility, pituitary dysfunction, and chronic corticosteroid use even in the absence of symptoms or signs associated with testosterone deficiency. 

 

With low testosterone, clinicians should measure serum luteinizing hormone levels, serum prolactin levels.

 

Serum estradiol should be measured in testosterone deficient patients who present with breast symptoms or gynecomastia prior to the commencement of testosterone therapy. 

 

Prior to testosterone therapy, one  should measure hemoglobin and hematocrit and inform patients regarding the increased risk of polycythemia.

 

PSA should be measured in men over 40 years of age prior to commencement of testosterone therapy to exclude a prostate cancer diagnosis.

 

 A low testosterone is a risk factor for cardiovascular disease. 

 

Testosterone therapy may result in improvements in erectile function, low sex drive, anemia, bone mineral density, lean body mass, and/or depressive symptoms. 

 

It is inconclusive whether testosterone therapy improves cognitive function, measures of diabetes, energy, fatigue, lipid profiles, and quality of life measures. 

 

There is an absence of evidence linking testosterone therapy to the development of prostate cancer. 

 

No definitive evidence exists linking testosterone therapy to a higher incidence of venothrombolic events. 

 

It cannot be stated definitively whether testosterone therapy increases or decreases the risk of cardiovascular events.

 

Testosterone therapy dosing is aimed at achieving  a total testosterone level in the middle of the normal reference range. 

 

Exogenous testosterone therapy should not be prescribed to men who are currently trying to conceive.

 

Testosterone therapy should not be commenced for a period of three to six months in patients with a history of a cardiovascular events. 

 

The use aromatase inhibitors, human chorionic gonadotropin, selective estrogen receptor modulators, or a combination  in men with testosterone deficiency desiring to maintain fertility can be preserved.

 

Testosterone levels should be measured every 6-12 months while on testosterone therapy. 

 

Cessation of testosterone therapy three to six months after commencement of treatment in patients who experience normalization of total testosterone levels but fail to achieve symptom or sign improvement should be considered.

 

Testosterone deficiency does not imply simply a state of low testosterone production, but rather to be testosterone deficient is to have low testosterone levels combined with symptoms or signs that are associated with low serum total testosterone.

 

Symptoms associated with low testosterone levels are very non-specific and can be manifestations of other conditions, such as chronic fatigue, chronic stress, a depressed state.

 

300 ng/dL level for diagnosis/treatment is based on the mean total testosterone levels cited with a view to maximizing the potential benefit from prescribing testosterone while minimizing the risks of such treatment.

 

The term testosterone therapy refers to all forms of treatment that are aimed at increasing serum testosterone, including exogenous testosterone as well as alternative strategies, such as selective estrogen receptor modulators (SERMs), human chorionic gonadotropin (hCG) or aromatase inhibitors (AIs).

 

Successful therapy is achieved  at therapeutic testosterone levels to the normal physiologic range of 450 -600 ng/dL accompanied by symptom/sign improvement/resolution.

 

Testosterone therapies include the following: oral agents, transdermal agents (gels, creams, patches), buccal agents, trans-nasal agents, intramuscular (IM) agents (short- and long-acting), and subcutaneous (SQ) pellets. 

 

Alternative testosterone therapies included SERMs, hCG, and AIs.

 

Testosterone is the predominant androgen in males.

It has been hypothesize that age related decreases in testosterone level may cause symptoms of weakness, fatigue and impaired sexual function, and that quality of life could be improved by testosterone supplementation.

The number of older men with testosterone levels below the normal range is small.

In a series of placebo controlled trials, symptomatic men 65 years of age or older, and who had a low testosterone level of less than 275 ng/dL, a one year of testosterone supplementation resulted in modest but significant improvements in sexual function, bone mineral density, six minute walking distance, depressive symptoms, and hemoglobin levels, but did not improve vitality or cognitive functions(Snyder PJ).

In  the TRAVERSE trial , transdermal testostosterone  versus placebo in men with low testosterone levels with a total of 5246 men treated for a duration of approximately 22 months there were no apparent differences in the incidence of secondary and most tertiary endpoints for major adverse cardiac events.

In this study, the testosterone replacement therapy was non-inferior to placebo with respect to safety.

However, the incidence of pulmonary embolism, nonfatal arrhythmias, atrial fibrillation, and acute kidney injury were slightly higher.

Major criticisms of the trial is that it had a high population of high cardiovascular risk men , most had obesity, and the majority had diabetes: the increase in testosterone levels during therapy was modest and did not need meey the normal range.

Testosterone is involved in a multitude of physiological and biochemical processes throughout the body. 

 

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.

 

The free and loosely-bound testosterone fractions combined are known as bioavailable testosterone.

 

Testosterone therapy may result in improvements in erectile function, low sex drive, anemia, bone mineral density, lean body mass, and/or depressive symptoms. 

 

Evidence is inconclusive whether testosterone therapy improves cognitive function, measures of diabetes, energy, fatigue, lipid profiles, and quality of life measures. 

 

There is an absence of evidence linking testosterone therapy to the development of prostate cancer. 

 

There is no definitive evidence linking testosterone therapy to a higher incidence of venothrombolic events. 

 

It is not definitively whether testosterone therapy increases or decreases the risk of cardiovascular events-myocardial infarction, stroke, cardiovascular-related death, all-cause mortality.

 

Exogenous testosterone therapy should not be prescribed to men who are currently trying to conceive.

 

Testosterone therapy should not be started  for a period of three to six months in patients with a history of cardiovascular events.

 

Testosterone may be used  use with aromatase inhibitors,  human chorionic gonadotropin, selective estrogen receptor modulators, or a combination  to maintain fertility.

 

 Transdermal drug systemic absorption rates ranging from 13-20%.

 

An occlusive dressing has been shown to increase absorption by approximately 2.5 fold.

 

Topical gels and liquids have less variability in absorption uptake when compared to other therapies, and 

steady state levels are achieved within 24-72 hours.

 

Testosterone levels returning to baseline within 4 days of discontinuation.

 

Topical liquid and gel formulations are able to achieve testosterone levels in the normal range in 74-87% of men.

 

Adverse effects of topical preparations include:  site reactions (3-16% erythema or rash), and risk of transference. 

 

Transference may be mitigated by washing hands, covering the application site with clothing, and washing the region prior to anticipated direct contact with others, such as women and children.

 

Testosterone patches consist of: mixture of testosterone, penetration agents, and a gelatinous matrix.

 

Testosterone patches demonstrate increases in total testosterone from a baseline 167 ng/dL to a peak of 1,154 ng/dL at 5.7 hours, with a decrease to 490 ng/dL over the next 12 hours.

 

The  observed testosterone half-life is 116 minutes.

 

Randomized control trials comparing patches to IM testosterone administration and demonstrate improved maintenance of testosterone values within normal physiologic levels and closer representation of the natural circadian rhythm.

 

With topical patches, the testosterone levels achieved directly relate to the amount of surface area exposed to drug.

 

Patch doses: available in 2 and 4 mg formulations, with a 4mg starting dose recommended and titration to 6

mg permitted.

 

Adverse effects with patches: site reactions, reported in up to 60% of patients, pruritus, application site vesicles, and back pain.

 

Unlike. topical gels and solutions, the rate of transference is likely minimal.

 

A 30 mg sustained-release muco-adhesive buccal pellet applied to the upper gums above the incisor teeth twice daily, is a treatment alternative.

 

Oral absorption is associated with liver deactivation and an oral mucosal agent avoids this problem.

 

In a 12-week study of buccal testosterone in 82 men, 72.6% of patients achieved a total testosterone concentration within the physiological range at steady state.

 

The study showed 92% of buccal versus 83% of gel patients achieved testosterone levels in the physiologic range.

 

Buccal pellets  adverse effects: gum-related disorders: gum or mouth irritation‎ (‎9.2%), gum tenderness‎ (3.1%), gum pain‎ (‎3.1%), and gum edema‎ (2%).

 

An intranasal testosterone gel applied is approved.

 

Intranasal testosterone is absorbed through the nasal mucosa to achieve maximum concentrations in about 40 minutes, with a serum half-life of 10-100 minutes.

 

A metered pump that supplies 5.5 mg of testosterone per dose, and recommended dose is two pumps.one to each nostril, three times daily.

 

90% have an average testosterone concentration within the specified normal range for the study, and  the  mean testosterone concentration reaches 421 ng/dL.436

 

Adverse effects of intranasal  testosterone:  nasopharyngitis, rhinorrhea, and epistaxis occurring in 7-10% of men.

 

Injectable testosterone is available in several forms, including short acting and long-acting preparations. 

 

The SQ route has also been described with short-acting agents.

 

With topical agents there is  a percentage of men that have difficulty achieving therapeutic levels within standard dosing ranges.

 

injectable testosterone preparations can achieve therapeutic levels.

 

Adverse effects with short acting injectable agents:  local site reactions, and abnormally elevated Hb/Hct.

 

Long-acting IM testosterone injection may also result in higher rates of polycythemia.

 

Testosterone pellets have a crystalline structure, dissolving slowly in SQ spaces. 

 

Serum Luteinizing Hormone LH is a a first-line test in conjunction with a repeat testosterone level to determine the etiology of the testosterone deficiency. 

 

A low or low/normal LH level suggests secondary, or central hypothalamic-pituitary defect.

 

An elevated LH indicates a primary testicular defect (hypergonadotropic hypogonadism). 

 

Men with low testosterone and low to low/normal LH, should have a prolactin level measured.   

 

In men with low to low/normal LH levels the use of SERMs in the management of their testosterone deficiency is effective.

 

The presence of an elevated FSH level suggests abnormal spermatogenesis, and such men  should have a semen analysis.   

 

Men with very high FSH levels (without an obvious cause, such as chemotherapy) are at increased risk for Klinefelter’s syndrome.

 

In men  with sustained elevated prolactin levels, very low total testosterone levels and unexplained failure to produce LH/FSH warrant a pituitary MRI to identify pituitary adenoma, prolactinoma, or infiltrative diseases of the pituitary.

 

Men with testosterone deficiency are at increased risk of bone density loss, and dual energy X-ray absorptionometry (DEXA) scan is warranted.

 

Prior to initiation of testosterone therapy, baseline assessment of Hb/Hct should be done.

 

In trials there is not enough data to definitively state that testosterone therapy posed a significant cardiovascular risk.

 

FDA, nonetheless requires testosterone product manufacturers to add information to the labeling about a possible increased risk of myocardial infarction and cerebrovascular accidents in patients using testosterone therapy.

 

Over a mean duration of 27.5 months, 1,223 men received testosterone therapy, and 7,486 were placed on placebo: In the testosterone therapy group, the raw data revealed a 2% myocardial infarction rate and a 3% cerebrovascular accident rate compared to 6% and 6%, respectively, in those patients not receiving testosterone. 

 

Many studies have failed to demonstrate a risk of cardiovascular events in patients on testosterone therapy. 

 

 

In men  with hypogonadism and pre-existing high risk of cardiovascular disease, testosterone replacement therapy is non inferior to placebo with respect to the incidence of major adverse cardiac events TRAVERSE study investigators).

 

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