The Ultimate Testosterone Replacement Therapy (TRT) Guide

Most television programs and magazines targeting males 30+ years old show advertisements for medications, supplements, and creams claiming to increase testosterone, enhance libido, build muscle, and reverse aging. Many of these claims are unsubstantiated and made without the United States Food and Drug Administration (FDA) seal of approval.

The focus of this article is Testosterone Replacement Therapy (TRT), a scientifically proven, FDA-approved treatment option for men with hypogonadism, also known as low testosterone (T). TRT is a form of hormone replacement therapy also referred to as androgen replacement therapy (ART).

While testosterone replacement therapy offers a number of benefits for those with low T, it comes with a number of potential risks. 

Natural testosterone levels are highest in males during the late teens and up to age 30. Between 30 and 40 years of age most males see a gradual decline of natural testosterone levels by about 1% per year and an age-related increase in sex hormone-binding globulin (SHBG). ^{[1] [2]}

If you are on the higher end of the normal total testosterone level range (750-1000 ng/dL), this gradual decline should not be a concern. ^[3] If you are natural total testosterone levels are on the lower end (300-500 ng/dL), this decline could quickly push you in to the <300 ng/dL range, which is what the Endocrine Society considers the clinical threshold for a diagnosis of low testosterone. ^[4]

Additionally, some studies suggest diagnosing hypogonadism based on free testosterone levels <7ng/dL (circulating testosterone not bound to albumin or SHBG) or bioavailable testosterone levels <230 ng/dl (circulating testosterone not bound to SHBG) . ^{[5] [6]} 

Some of these symptoms and indications are internal and require lab tests to identify, but many can be noticed by simply looking in the mirror. The list below show common symptoms and indications of hypogonadism: ^{[1] [7]}

• Physical appearance - lack or loss of muscle mass, increased fat accumulation, uneven fat distribution, lack or loss of facial and body hair, and/or swollen or tender breasts (gynecomastia)
• Blood levels – cholesterol level fluctuations, decreased red blood cell production, decreased hemoglobin, and/or mild anemia
• Sexual function – infertility, decreased sex drive, sperm production, and/or lack of spontaneous erections
• Sleep patterns – insomnia, inability to fall asleep, and/or inability to wake up under reasonable circumstances
• Emotions – decreased motivation or self-confidence, sadness, depression, irritability difficulty concentrating, and/or memory troubles
• Decreased bone density and energy levels

Based on these symptoms, it may appear low testosterone is an epidemic affecting a large subset of the male population; and some researchers would agree with you. Abraham Morgentaler, M.D., Associate Clinical Professor of Urology at Harvard Medical School, supports the estimate of 2 to 6 million men in the U.S. with low T, and only about 5% of that population receiving TRT. ^[4]

A second study estimates 39% of all males aged 45 years or older to have low testosterone and 6-12% of all men 40 to 60 years old to have symptomatic hypogonadism. ^[2] The Baltimore Longitudinal Study of Aging believes 20% of all males aged 60+, 40% of all male aged 70+, and 50% of males aged 80+ have hypogonadism.9 Regardless of the exact number of hypogonadal males or males with low T, there is a significant gap between that value and the number of males receiving proper treatment.

Evolution of Testosterone Replacement Therapy

The catalyst for testosterone replacement therapy began over 200 years ago when a man named John Hunter successfully transplanted testes on to a castrated domestic rooster. ^[10] The purpose of Hunter's experiment was not to examine the hormonal and endocrinological impact of adding testes to a castrated male animal.

It was not until 1849 when a man named Arnold Adolph Berthold, now considered the father of endocrinology, hypothesized that testicular transplantation impacted normal growth and development. ^[10] He found that castrating roosters eliminated their fighting, crowing, and mating as well as contributed to the regression of the prominent rest crest on top of their heads. ^[11]

Removing the testes of these roosters had a significant negative effect on both their behavior and sexual function. When he re-implanted testes back on to these roosters, they reverted back to their original behavior of fighting, crowing, and mating as well as experienced crest re-growth. ^[11] With these findings he concluded the testes affect the blood and entire animal.

In 1889, a 72-year old French physician and physiologist named Charles-Edouard Brown-Sequard self-injected the testicular extract from guinea pigs and dogs. He presented his findings to the Parisian Société de biologie, claiming the injections revived and rejuvenated him. ^[11] Unfortunately he did not back-up his claims with clinical evidence such as blood levels. However, it is worth noting technology at that time was not advanced enough to measure testosterone levels.

It was not until the 20th century that TRT was examined on humans. In the 1920's, Sergio Voronoff performed an extremely controversial procedure when he removed the testes from monkeys and transplanted them on to male humans. ^[10] Unfortunately he was unable to prove the efficacy of this treatment and skeptics ridiculed him until his death.

The next big breakthrough occurred in 1927 when Fred Koch isolated testosterone from mashed-up bull testes whilst at the University of Chicago. ^[12] In Amsterdam this finding was re-discovered and confirmed in 1935 when Enrest Lacquer also isolated testosterone from bull testes. ^[10]

That same year two independent research groups chemically synthesized testosterone - Adolf Butenandt in Göttingen, Germany and Leopold Ruzicka in Basel, Switzerland. ^[12] In 1939 these two men shared the Nobel Prize in Chemistry for this momentous discovery. ^[13]

In 1944 two male internists from Detroit named Carl Heller and Gordon Myers published an article in the Journal of the American Medical Association entitled "The Male Climacteric." In this article, they identified symptoms found in aging men attributable to what we now know as hypogonadism/andropause/low T. ^[11]

It is from these findings medical professional were able to diagnose male patients with hypogonadism and prescribe TRT. 

Researchers quickly determined oral testosterone supplements were an inefficient form of TRT since most of it was lost by liver processing. As a result, the first form of testosterone was compressed in to pellets and injected beneath the skin. ^[14]

The next major development of TRT occurred when researchers found a way to inject testosterone using an oily solution. The first injectable TRT, in the form of testosterone enanthate in castor oil, was introduced in 1954. ^[14] Although researchers developed other injectable TRTs, the first form continues to be the most popular. 

In all, there are currently five forms of TRT on the market: injections/implants, gels, skin patches, mouth patches, and pills. Each of with positive and negative associations.

Testosterone Injections/Implants

This is the oldest and cost-efficient treatment option that produces noticeable results. ^{[15] [4]} Testosterone can be directly injected in to the muscles or implanted into soft tissues in pellet-form. ^[16] The body absorbs testosterone over a period of 2-10 weeks (depending on the form used) which means you do not have to worry about daily applications. ^[7]

Some users avoid this issue by self-injecting testosterone in the comfort and convenience of their own home. Another drawback is the peak in testosterone levels immediately after injection followed by a slow decrease back to baseline over time. ^[4] To combat these fluctuations medical professionals lower the per-injection dose, but the number of required visits increases.

Not everyone responds well to the hormonal peaks and valleys that come with injections. Implanted pellets underneath the skin require surgery can provide a steady supply of testosterone for 5 to 7 months, but carry a 1 in 20 to 1 in 10 chance of infection and many users report skin irritation at the injection site. ^{[17] [14]}

Testosterone gels

Gels are the most common form of TRT in the US, typically work on 80+% of patients, and may increase T level after only a few applications. ^[4] However, this treatment option requires a relatively high amount of doctor visits to ensure the proper amount of testosterone is being absorbed; skin absorption rates can vary between individuals. Gels are one of the more expensive testosterone replacement therapy options ($100 to $150 per month). ^[15]

Patients also run the risk of inadvertently transferring the gel to other people if it is is not fully rubbed-in absorbed and contact is made with the application site or hand used to rub in the gel.

Testosterone Skin Patches

Skin patches are applied 1-2x per day and worn on the upper body. ^[16] They can also be applied to the scrotum if traditional skin patches excessively irritate the skin. ^[4] The testosterone in the patch is absorbed by the skin and distributed throughout the bloodstream to raise T levels.

On the upside, skin patches are easy to apply and they mimic the normal daily raise and fall of T levels. However, twice daily applications and reports of skin irritation and redness by 40% of users is enough to dissuade many patients from using this treatment option. ^[4]

Testosterone Mouth Patches

Mouth patches are applied to the upper gums above the incisor twice per day and the testosterone is absorbed through oral tissues. ^[16] This treatment provides a low dose multiple times per day, which minimizes the chance of irregularly high testosterone levels.

There is not much research on mouth patches but preliminary evidence indicates this treatment does not negatively affect the liver, nor does it require frequent doctors visits. does cause peaks and valleys in T-levels.

Testosterone Pills

Pills are the least prescribed option in the United States. These pills are processed by the liver before entering the bloodstream; as result some users experience liver toxicity, increased low-density lipoprotein (LDL), and decreased high-density lipoprotein (HDL). ^[16]

It is not surprising both medical professional and patients would avoid this treatment option given the liver's crucial role in the human body. 

Benefits of Testosterone Replacement Therapy

After numerous clinical studies examining TRT use in males with hypogonadism, researchers identified a number of common benefits, including but not limited to: improved energy levels, blood levels, sex drive, bone density, muscle mass, and insulin sensitivity. ^[16] 

TRT benefits hypogonadal men of all ages with minimal impact on prostate specific antigen (PSA) levels. ^[18] When 44 hypogonadal men were placed on TRT for 6 months, their serum androgen levels improved without negatively affecting prostate androgen levels, tissue biomarkers and/or gene expression. ^[9] When elderly men were placed on TRT protocols with moderate, bi-weekly doses, they experienced a decrease in fat mass as well as increases in muscle mass, arm circumference, grip strength. ^[17]

Over 12 months of TRT on 220 hypogonadal men with Type 2 Diabetes and/or Metabolic Syndrome, 16.4% experienced a decreased in insulin resistance and many patients experience improvements in total and LDL cholesterol, lipoprotein a, body composition, libido, and sexual function. ^[19]

A meta-analysis of 18 studies, examining 3,500+ men, concluded serum androgen levels did not increase the risk of prostate cancer development. ^[9] These findings suggest increasing T levels via TRT would not negatively impact the risk of developing prostate cancer. However, some studies indicate TRT may negatively affect the prostate. Increasing T levels below clinically deficient levels may also decrease risk of cardiovascular disease and increase cognitive function. ^[17]

Testosterone replacement therapy may also benefit anemic males by increasing hemoglobin, the protein in red blood cells that carries oxygen, by 5-7%. ^[9] TRT can also promote weight loss by recalibrating the estrogen to testosterone ratio; excessively high estrogen levels, paired with low T levels, can contribute to visceral obesity. As a result, patients undergoing TRT may see significant decreases in both waist circumference and waist to hip ratio. ^[20]

From psychological perspective, 6 months of TRT decreased symptoms of sexual dysfunction, anxiety, and depression in hypogonadal men. ^[21] TRT offers both physical and physiological benefits which can dramatically improve perceived quality of life.

From the fitness perspective TRT appears to positively impact fat loss, lean body mass gain, and muscle strength increase most noticeably after 12 to 16 weeks of treatment. These changes stabilize around the 6 to 12 month mark but many patients report marginal improvements over the subsequent years of treatment. ^[22]

Two studies further analyze TRT's effect on strength. Hypogonadal and older men with lower T levels were treated with 5mg testosterone patches once per day for 12 months; those undergoing TRT experienced a 38% increase in strength whereas the placebo group experienced a 27% increase in strength. A second study treated older hypogonadal men with 6mg testosterone patches once per day for 36 months; these patients experienced no significant strength increases. ^[2] These findings suggest that TRT may only marginally increase strength, if at all.

In hypogonadal men, TRT also appears to improve exercise and pain tolerance as well as improve vasodilation, which decreases blood pressure and improves blood flow. These two benefits are also not dose dependent; patients experienced these improvements with low dose and high dose supplementation over both short and long-term TRT protocols. ^[2]

Based on these findings, it is not surprising some fitness enthusiasts with normal T levels use TRT to maximize fat loss, improve muscle mass, and boost strength in the off-season, before a meet, competition, or performance. When used on the appropriate populations TRT offers a number life-changing benefits.

Side Effects & Risks of Testosterone Replacement Therapy

Although TRT sounds like a miracle treatment for males with a hormonal imbalance, it does carry a number of risks; some of which are confirmed and some of which are still under investigation.

During TRT treatment the body stops or significantly down regulates the natural testosterone production. ^[23] Once you start TRT and begin feeling better, you simply cannot stop treatment as this sudden change may cause serious health complications. Most patients who start TRT understand they will likely have to continue treatment for the rest of their lives.

Recently the Food and Drug Administration (FDA) announced TRT's potential to increase the risk of cardiovascular complications such as heart attack, stroke, or death in aging men. Some studies supported and other refuted these findings so there is no concrete answer to the potential risk. ^[24] The key takeaway from the FDA's announcement is while we have a good understanding of short-term side effects, the long term are largely unknown and require additional studies to confirm.

In additional to the potential cardiovascular risk, testosterone replacement therapy may also: ^{[1] [16] [7] [4] [17]}

• Lead to prostate complications such as the noncancerous growth of the prostate (benign prostatic hypertrophy) or expedited growth of existing cancerous cells in the prostate.
• Those with preexisting enlarged prostate, prostate cancer, or above normal prostate specific antigen (PSA) levels (>3ng/mL) should avoid testosterone replacement therapy.
• Increase the difficulty and frequency of urination. The prostate growth may place pressure on the urinary tract and decreased the stream rate.
• Cause rash, itching or irritation on or around the application site. This is one of the most common side effects.
• Exacerbate sleep apnea. This is a condition in which breathing repeatedly stops and starts during sleep cycles.
• Cause the enlargement of breasts. This is also known as gynecomastia or gyno and is typically seen in 10-25% of male patients. ^[9]
• Decrease sperm production and potentially lead to infertility. This infertility may not be reversible, but in some instances patients increased their sperm count to pre-TRT baseline 6-18 months after discontinuing TRT use.
• Decrease testicle size.
• Exacerbate skin issues such as acne, pimples, rosacea, or oily skin.
• Increase the likelihood of blood clot(s) forming in the veins. If blood clots form and break loose in a deep vein they may block blood flow in major organs such as the lungs. Those with more than 50% of red blood cells in the bloodstream by volume or those with thick, viscous blood should avoid TRT.
• Cause or worsen preexisting congestive heart failure (class III or IV). This is typically the result of two factors – a weakened heart muscle and conditions like narrowed heart arteries and/or high blood pressure. ^[25]
• Increase the risk of heart attack or stroke.
• Negatively impact blood markers such as red blood cell count, cholesterol (e.g. lower HDL and raise LDL), and lipid levels (e.g. raise triglycerides).
• Cause mild fluid retention, which may result in visually apparent swelling, puffing, or bloating. Most common in frail or ill elderly males, but typically decreases or disappears after a few months of TRT.
• Increase the instances of aggression, anger, and emotional mood swings.
• Increase the likelihood of liver toxicity. This risk is highest with oral dosing, moderate with injections, and lowest/almost nonexistent with topical dosing.

The list above is by no means exhaustive and if you are currently on or a potential candidate for TRT, it should not scare you away. This is merely a list of potential risks and side effects. The positive and negative responses to TRT is largely dependent on the individuals. While person may experience acne, another may experience fluid retention. This list is purely for informative purposes to ensure you understand what may happen if you decide to begin TRT.

Abuse of Exogenous Testosterone in the Fitness Community

Before we delve in to this section, it is worth noting TRT has not been approved for treating men with naturally declining or low testosterone levels due to aging alone. ^[16] For TRT to be legally prescribed there must be additional complications contributing to low testosterone levels, like those mentioned in the introduction of this article.

However, this has not stopped medical professionals from prescribing and patients obtaining testosterone replacement therapy. Since 1993, the prescription sale of testosterone products has increased more than 500% and does not appear to be slowing down. ^[17] Between 1988 and 2002 the industry increased in value by over 2100% and is now estimated to be worth $2 billion. ^[6][3]

With traditional TRT protocols, patients have below normal testosterone levels and as a result they are treated with enough testosterone to bring them up to normal levels. In the fitness community, the goal is different; many user have normal testosterone levels and use much higher doses of exogenous testosterone to increase testosterone levels above the normal range.

Furthermore, many athletes may stack testosterone products with other Anabolic-Androgenic Steroids (AASs), Prohormones (PHs), and Selective Androgen Receptor Modulators (SARMs) to expedite recovery, muscle growth, fat loss, and strength gain.

Researchers examined the Departments of Health Prescription Cost Analysis for community pharmacies in England, Scotland and Wales and found that the number of TRT prescriptions increased ~90% between 2001 and 2010. ^[26] Based on this dramatic increase one would assume doctors are diagnosing more patients with hypogonadism and/or more symptomatic patients are going to their doctors.

Neither of these assumptions appear to be true; researchers found that the diagnosis for hypogonadism increased from 5.2% to 6.3% during this same time period. ^[26] With only a 1.1% increase accounted for, it is safe to assume that these patients are obtaining testosterone replacement therapy to combat aging and/or to improve their physical appearance.

A study by the FDA found that TRT use nearly doubled between 2010 and 2013 in the United States. ^[3] 25% of these 1.5 million male patients had not been tested for or diagnosed with hypogonadism. We can safely deduce a portion of that 25% is taking TRT for its physique and performance-enhancing benefits.

Weightlifters were the first group of athletes to use testosterone and other steroid compounds. ^[12] These substances helped to rapidly increase muscle mass and strength, strip body fat, and improve recovery.

It is estimated that 33% of the U.S. Track and Field team used steroids during the pre-games training camp prior to the 1968 Mexico City Olympics. ^[12] Keep in mind this statistic includes all steroid compounds and not just exogenous testosterone. The International Olympic Committee (IOC) did began testing for testosterone until the 1976 Montreal Olympics. ^[12]

To measure exogenous testosterone usage, the IOC examined the testosterone to epitestosterone ratio. The natural ratio is close to 1:1 with an upper limit of 4:1. In 1982 the IOC set a ratio of 6:1 to be grounds for immediate disqualification. More recently the rule has been amended to require an athlete to provide additional samples if the ratio is above 4:1. ^[12]

After additional analysis, the IOC will determine the appropriate action instead of the previous immediate disqualification. Given the relatively straightforward test for exogenous testosterone, athletes can easily take exogenous epitestosterone to bring down this ratio prior to competition. ^[12]

While athletes and their trainings continue to develop methods to beat the system, the IOC is attempting to keep up by developing advanced tests to detect exogenous versus natural testosterone and epitestosterone. Although the provided research on exogenous testosterone use is a few decades old, it is safe the assume testosterone use is still fairly common amongst high-level athletes, particularly in the off-season when testing is more relaxed or nonexistent.

Conclusion

Testosterone replacement therapy is designed for males diagnosed with hypogonadism, a condition in which the body naturally produces below-normal levels of testosterone. Current treatment options include injections/implants, gels, skin patches, mouth patches, and pills; each of which offering upsides and downsides.

Clinical trials verify TRT's ability increase testosterone, which users find helps to improve cholesterol, sex drive, energy, mood, and body composition. Users report increases in muscle mass and strength as well as fat loss. However TRT is a life-long commitment for most and patients may experience a number of side effects including but not limited to increased cardiovascular risk, infertility, and prostate enlargement.

Both novice and high-level athletes use exogenous testosterone to give them an advantage both on and off the field or platform. One thing is for sure, TRT is a big money business and usage by males without hypogonadism will continue to increase unless government and athletic regulating bodies place stricter regulations on their prescription and use.

References

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