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If you are a male 45 years or older, there is a 35% chance you have hypogonadism (testosterone deficiency) with symptoms such as low sex drive, erectile dysfunction, reduced energy, or depression. Late-onset hypogonadism sometimes occurs with age and is a loss in the body's innate ability to produce testosterone. The resulting decrease in testosterone production occurs due to a breakdown in communication between the brain and the testosterone-producing cells in the testes. The rate of testosterone decrease is affected by factors such as the amount of body fat, medications, and chronic disease.
Hypogonadism (testosterone deficiency) is diagnosed by a blood testosterone level below 300 ng/dL in combination with symptoms such as decreased libido and depression. Testosterone replacement therapy (TRT) is the primary treatment for hypogonadism and can reverse symptoms by restoring testosterone levels to a healthy level.
Recently FDA-approved, oral testosterone pills have equal efficacy with other modalities, a mild side-effect profile, and ease of use, increasing patient compliance. As such, oral testosterone pills have the potential to overtake injectables as the modality of choice for prescribers and patients.
Certain patients are not good candidates for testosterone, such as those with high red blood cells or planning to have children. In addition, there are potential risks associated with TRT, such as acne, decreased sperm production, and a high red blood cell count.
Benefits of TRT
The benefits of restoring testosterone levels in hypogonadal men include improvement in:
- Body composition
- Bone density
- Sexual activity
- Mental activity
- Quality of life
- Insulin resistance
There is a strong correlation between low testosterone and type 2 diabetes. A recent study once again found that testosterone levels are significantly lower in men with type-2 diabetes, highlighting the importance of TRT consideration for men presenting in the diabetic clinic.
Side-effects and Risks of TRT
Although uncommon, immediate side effects of testosterone therapy include acne, breast swelling or tenderness, swelling of the ankles, and disturbed breathing while sleeping.
Prostate cancer
The medical community has traditionally believed that TRT increases the risk of prostate cancer. However, studies show TRT is not associated with a higher incidence of prostate cancer. Moreover, studies demonstrate that men with high testosterone levels do not have an increased risk of prostate cancer, and hypogonadal men do not have lower rates of prostate cancer. In addition, TRT in men diagnosed with prostate cancer did not have higher mortality, cancer-specific mortality. Treatment guidelines are beginning to reflect this updated understanding of the relationship between prostate cancer and TRT.
Abundance of red blood cells
A high red blood cell count is an important potential side-effect of TRT. There is a supposed increased risk of vascular events related to abundant red blood cells, though studies on men taking TRT have not demonstrated this risk. Still, all formulations of TRT can cause increases in hemoglobin (a protein in your red blood cells that carries oxygen and carbon dioxide in the body) and hematocrit (proportion of red blood cells in the blood), measures of red blood cell quantity. Of the testosterone treatment modalities, injectables produce the most significant effect.
Obstructive Sleep Apnea
Though studies are contradictory, TRT may increase the risk of obstructive sleep apnea (OSA). Since TRT is feared to worsen sleep apnea, providers should investigate ventilatory capacity before initiating TRT, especially in obese hypogonadal patients with compromised ventilation. Further clarification is needed, and more extensive studies are in progress.
Cardiovascular events
The results of a long-awaited comprehensive study have provided insight into the risks associated with TRT and cardiovascular events. The study showed that TRT did not cause an increase in major cardiac events. However, it did suggest TRT may increase the risk of atrial fibrillation, acute kidney injury, and pulmonary embolism.
Types of Testosterone Medication
There are three primary testosterone injections available: testosterone cypionate (TC), testosterone enanthate (TE), and testosterone undecanoate (TU). They differ in how long they stay in your body, hence, how frequent injections are necessary. TE lasts the shortest time, followed by TC, and TU lasts the longest, requiring fewer injections. Preliminary evidence suggests that long-acting testosterone injections improve treatment adherence.
A large retrospective study compared treatment patterns and health outcomes of men using TC injection with men using TU injection for TRT. Men using TU demonstrated a two-fold higher adherence rate, a two-thirds lower discontinuation rate, five-fold improved maintenance, and more stable testosterone levels at a 1-year follow-up versus men in the TC group.
Testosterone undecanoate is an FDA-approved form of testosterone available as long-acting injectable or oral pills. The injectable form is long-acting, requiring only five injections per year. In contrast, oral tablets are taken twice per day. Testosterone undecanoate are the only available oral testosterone pills. Oral testosterone undecanoate provides a convenient option for many patients and may improve compliance due to the avoidance of needles.
Choosing injectable testosterone depends on safety risks, the best injection site, patient and health care provider preference, and insurance coverage and cost.
Comparison of TRT Formulations
A study compared intramuscular injection, transdermal, and oral testosterone TRT concerning beneficial and undesirable effects. The modalities were similar in their ability to raise testosterone and improve body composition and quality of life in sexual function and mental health measures. Results indicated that oral testosterone administration is as advantageous as the other modalities when assessing bone mineral density, skeletal muscle mass, and libido.
Patients disapproved of the intramuscular modality due to pain at the injection site, which decreased treatment compliance.
- Patients liked the ease of use of the transdermal gel and patch modality; however, the potential for interpersonal patient transfer is problematic.
- Oral testosterone undecanoate is an equal alternative to gel throughout the world. Like transdermal gel, oral TU allows for higher patient compliance due to its ease of use. The study found that oral TU has minimal side effects that can be countered by altering the dosage. In addition, oral TU did not increase PSA levels, unlike transdermal gels.
- Injectable TU has a unique non-life-threatening risk of pulmonary oil micro embolism (POME), an acute onset of cough, flushing, faintness, or anxiety that resolves quickly after the injection.
- Oral testosterone undecanoate has shown small but significant increases in systolic blood pressure, especially in patients with type 2 diabetes and on antihypertensive therapy.
- Studies suggest that patients with chronic conditions such as rheumatoid arthritis and multiple sclerosis that impact mobility prefer oral medications and demonstrate improved compliance compared with other testosterone modalities.
While more research is needed, the equal efficacy of oral TU compared with the other modalities and increased compliance make it a promising TRT option. Also, the potential to increase patient adherence, its recent FDA approval, ease of use, and mild side effects make TU poised to become the preferred choice by patients and healthcare providers for TRT. Since many forms of testosterone are appropriate for TRT, a patient-centered approach focused on treatment goals should guide the selection process.
