Testosterone has now become one of the most widely used medications in the United States.  The beneficial effects of testosterone have been suspected for hundreds of years. However, it was not until 1889 that Charles Brown-Sequard injected himself with an extract of crushed canine and guinea pig testes and reported improvements in his urinary stream, intellect and erectile function. 

 

At approximately age 20 to 30 years, men begin to experience a decline in testosterone and free testosterone levels of 0.4% and 1.3% per year, respectively. 

 

Roughly 39% of men older than 45 years have low testosterone.

 

Physical Signs of Low Testosterone

 

Increased body fat

Reduced muscle bulk and strength 

Low bone density

Loss of body hair 

 

Symptoms 

 

Decreased energy or motivation 

Diminished sex drive
Erectile dysfunction
Diminished work performance

Poor concentration
Sleep disturbance
Depression

 

Causes of low testosterone

 

Medications: Numerous medications have been associated with androgen deficiency, including glucocorticoids, exogenous testosterone, opioids, statins and selective serotonin reuptake inhibitors. 

 

Medical conditions associated with low serum testosterone levels: Numerous medical conditions have been associated with low testosterone.  Roughly 52% of diabetics and 50% of obese patients have low testosterone. Obese patients tend to convert testosterone to estradiol and thus lower their own testosterone levels.  In 1 study approximately 92% of men with low testosterone suffered from some degree of depression, including 17% suffering from severe depression.  Finally, about 36% of men with erectile dysfunction have low testosterone.  A digital rectal examination should be performed on all patients before initiation of testosterone therapy. Men with a prostate nodule or an elevated PSA should be evaluated for prostate cancer before beginning testosterone therapy.  Blood levels should also should be evaluated because it can become too thick with testosterone replacement. 

 

Treatment Contraindications 

 

Testosterone therapy is contraindicated in patients with metastatic prostate cancer, breast cancer, unevaluated prostate nodule or induration, PSA >4 ng/ml (>3 ng/ml in high risk individuals), hematocrit >50%, severe lower urinary tract symptoms associated with enlarged prostate and uncontrolled or poorly controlled congestive heart failure.  

 

Treatment Options

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The primary goal of testosterone replacement is to restore normal physiological concentrations of testosterone. The method of testosterone replacement depends on availability, safety, tolerability, efficacy, patient and physician preference. 

 

Transdermal Testosterone: Options for transdermal androgen replacement include adhesive skin patches or gel applications.   Adverse reactions include skin induration, vesicle formation, allergic contact dermatitis, headaches and depression. Up to 37% of men have reported some type of skin reaction after applying testosterone patches. While gels achieve a physiological steady state with daily application, patches recreate the physiological circadian release of androgens.

The benefits of the gels and solutions are that they can be discontinued at any time and doses can be titrated to meet patient needs. Patients who do not respond to one form of gel therapy may try switching to another gel or solution as this may improve serum testosterone levels.  Currently, all testosterone solutions and gels in the U.S. contain an FDA black box warning of the risk of transference. Thus the gel or solution must be washed off before there is any skin- to-skin contact between the testosterone application site and another person. 

 

Intramuscular Injections:  Peak serum testosterone concentrations are achieved within 72 hours and injections are administered every 7 to 21 days.  Intramuscular injections lack circadian release of testosterone, resulting in transient supraphysiological levels in the first 2 to 3 days after an injection, followed by a steady decline to sub physiological levels just prior to next injection. The sudden decline of testosterone towards the end of the injection cycle is also known as ‘‘testosterone crash’’ and can be associated with a sudden and severe occurrence of low testosterone symptoms. Due to peaks and troughs following testosterone injection, mood swings can occur.  Furthermore, patients receiving injectable testosterone are more susceptible to their blood becoming too thick.  

 

Subcutaneous Testosterone Pellets: Subcutaneous pellets have been available for decades but were approved in 2008 by the FDA.   8 to 12 pellets are usually inserted in the subdermal adipose tissue in the side of the hip. The pellets typically dissolve over 4 to 6 months.  Potential risks of testosterone pellets are bleeding, infection, expulsion of the pellets, pain and bruising. 

Follow-up and monitoring: Patients should be evaluated at 3 months after initiation of TTh and then every 6 to 12 months thereafter to assess serum testosterone levels, symptomatic improvement, and PSA, digital rectal examination and hematocrit changes. If a hematocrit level increases to >54%, TTh should be discontinued until it decreases or the patient should consider a therapeutic phlebotomy. A patient receiving injectable testosterone might consider switching to another TTh formu- lation that has a lower risk of erythrocytosis. Repeat bone scan is indicated after 1 to 2 years of TTh in hypogonadal men with osteoporo- sis or low trauma fractures. 

 

Adverse effects of Testosterone Therapy

 

Serious adverse side effects secondary to administration of exogenous testosterone are relatively uncommon in a medically supervised program. Adverse effects appear to be particularly significant in elderly patients and are often dependent on the method of testosterone supplementation (table 1). Some of the adverse effects reported with TTh are primarily reported with supraphysiological levels of testosterone. Reported adverse effects include polycythemia, prostate enlargement or exacerbation of BPH, gynecomastia, hepatotoxicity (primarily with oral methylated formulations), lipid profile abnormali- ties (primarily at supraphysiological levels), impaired sperm production and fertility, edema, sleep apnea (primarily at supraphysiological levels), acne or oily skin and alopecia. Often these adverse effects can be minimized or negated altogether by dose adjustment, switching to an alternative form of therapy or discontinuation of androgen supplementation. 

 

Potential Benefits of Testosterone Replacement Therapy

 

Testosterone therapy has been shown to improve sugar levels in diabetic patients.  

Cardiovascular disease: Testosterone appears to have a minimal effect on cardiovascular risk factors except for a potential increase in hematocrit. 

Depression: Many studies have also demonstrated improvement in depressive symptoms in hypogonadal men with testosterone supplementation.

Sexual function: Low testosterone has been associated with erectile dysfunction. Testosterone plays a key role in maintaining erectile function.  Testosterone has been shown to reduce erectile dysfunction and decrease its risk in men.

Mortality: Low serum testosterone has been associated with increased mortality.

Other benefits: Increase energy and muscle mass, decrease fat deposition, and improve cognition and bone mineral density in hypogonadal men.

 

Specific considerations during treatment

 

Fertility: TTh can lead to impaired spermatogenesis, and men desiring to initiate a pregnancy in the future should be counseled appropriately before beginning therapy. 

 

Sleep apnea: Although obstructive sleep apnea is listed as a relative contraindication by most testosterone formulations, there is a weak association between sleep apnea and testosterone therapy. Men with OSA are more likely to be hypogondal, and they should be screened for hypogonadism.