THE SIGNAL

Scientific Intelligence for Men's Health & Performance

A FeltovichFit Publication  ·  Collegium of Order & Flow

Each week, The Signal cuts through the noise in health, performance, and science:

• What to watch?
• What to ignore?
• What’s “news” but isn’t new?

The Signal analyzes each topic with the IICE Framework:

• Incentives.  Who is being asked to believe what? Why? And why now?
• Impact.  Does it move the needle?
• Context.  How does it relate to other evidence within the discipline and across disciplines, both currently and historically?
• Epistemic Authority.  Is the argumentation sound and valid?

This week’s deep dive: Testosterone Replacement Therapy—the history, the risks, the real indications, and what the body’s own medicine cabinet can do first.

Testosterone Replacement Therapy: History, Risks, Real Indications, and the Body’s Own Medicine Cabinet

The magic of whatever lay within the testes and its role in male traits and reproduction has been known since humans first castrated animals approximately 10,000 years ago to make them sterile, docile, or alter their bodies, and men were castrated and made eunuchs to guard royal households and harems as early as the Chinese Xia dynasty in 2205 BCE [1].

The magic itself—testosterone—was first isolated, named, and synthesized in 1935 and soon found clinical and non-clinical uses: first in therapeutic doses to treat anemia, depression, angina, peripheral vascular disease, and hypogonadism (then termed “male climacteric” or “male menopause”), then in supratherapeutic doses for physique and performance enhancement [2].

Several beneficial effects of TRT were soon observed, including improved mood, libido, and body composition. One result was also observed—and misinterpreted—which effectively brought a halt to TRT for seven decades. A 1941 experiment treated men with metastatic prostate cancer using castration and high-dose estrogens and observed sharp falls in a tumor marker of the day (acid phosphatase), which they interpreted as evidence that withdrawing androgens shrank prostate cancer. The same paper—with a sample size of just three men—reported an increase in acid phosphatase after short courses of testosterone propionate injections and generalized that observation into the conclusion that exogenous testosterone “activates” prostate cancer in hypogonadal men without cancer [2].

That narrative prevailed until the 1970s when radioimmunoassay made laboratory testing cheap and accurate enough to study large cohorts. The resulting data over the following decades showed that men with chronically low testosterone had higher all-cause mortality, more cardiovascular disease, more low-trauma fractures, and worse cardiometabolic profiles than eugonadal men [2]. The downside risks have since skewed toward not doing TRT in hypogonadal men, but risks remain, and not every symptomatic man is a candidate for TRT.

Real Risks and Real Tradeoffs

Like any powerful drug, there are real risks, costs, and tradeoffs:

• TRT can increase hematocrit (red blood cell count), a potential risk factor for thrombosis (blood clots). Most guidelines recommend checking hematocrit regularly and pausing TRT if it exceeds established thresholds [3]. Men undergoing elective surgery while on TRT should disclose this to their surgical team; cessation prior to surgery—especially if elevated hematocrit is detected—is an effective mitigant.
• TRT can suppress sperm production and cause sterility. Fertility usually returns after cessation, but timing is variable and return is not guaranteed [4, 5].
• Although the “testosterone activates prostate cancer” myth has been debunked for men without known cancer, men with active prostate cancer, suspicious prostate findings, very high PSA, or severe lower urinary tract symptoms are generally advised to avoid TRT or proceed only with urologic evaluation and close monitoring [6].
• TRT is generally avoided or used cautiously in men with severe untreated obstructive sleep apnea [3]. Much of the early data linking TRT with worsening sleep-disordered breathing was based on supratherapeutic doses, but caution remains prudent [7].
• TRT can also cause acne, oily skin, gynecomastia, injection-site reactions, and in some men raise PSA modestly even without cancer—which is why ongoing lab and symptom monitoring is recommended [8].

Unfounded Fears

Along with those real risks, there are unfounded fears—most notably alopecia (male pattern baldness). Alopecia is mostly determined by genetic sensitivity to dihydrotestosterone (DHT), a testosterone byproduct. TRT might accelerate balding but is unlikely to cause it in men who were not already genetically predisposed [9]. The data suggesting accelerated hair loss were based largely on supratherapeutic doses, so therapeutic doses may pose less risk. Drugs to counteract alopecia—dutasteride or finasteride (e.g., Propecia)—work by inhibiting conversion of testosterone to DHT, [10] which could blunt some DHT-mediated processes, including those that TRT is trying to remedy.

The Body’s Own Medicine Cabinet

Before resorting to pharmaceuticals to remedy hypogonadism—or any other pathology—lifestyle and environmental optimization should always be the first line of defense.

Empirically validated factors to promote healthy testosterone production include:

• Sleep, sleep, sleep. Sleep deprivation decreases testosterone approximately 10–15% in short-term studies [7], the functional equivalent of adding a decade of age to a man’s testosterone profile [11].
• Body composition and energy optimization. Excess body fat can decrease testosterone directly and increase estrogen via aromatization of testosterone to estradiol [3]. It can also decrease testosterone indirectly through disrupted sleep [7], but low energy availability through very low body fat or hypocaloric diets can decrease testosterone too [12].
• Nutrition. Suboptimal levels of vitamin D, zinc, or magnesium can limit testosterone production, but benefits plateau once sufficient levels are achieved [12].
• High-volume resistance training with compound movements [13]. The effects are likely more transient and less impactful in total than the previous three drivers, but it is still an effective lever—and something all men should be doing regardless.

Environmental Toxins

The known environmental toxins that impair testosterone production, grouped by type and severity, include [14]:

• Hormone mimetics and blockers (endocrine-disrupting chemicals, EDCs)—mostly BPA and phthalates from plastics and parabens from cosmetics—moderate risk
• Persistent endocrine disruptors—mostly agricultural and industrial chemicals such as herbicides, pesticides, and PCBs—moderate to high risk
• Direct cellular toxins—mostly heavy metals such as lead, mercury, and cadmium—high risk
• Bioaccumulating hormone disruptors (persistent organic pollutants, POPs)—such as dioxins and flame retardants (PBDEs). PCBs also fit here—low risk from acute exposure that accumulates to moderate risk from chronic exposure
• Systemic inflammatory toxins—mostly particulate air pollution such as smoke, exhaust, and urban air pollution—moderate to high risk

To optimize the environment: avoid plastics by filtering water and by not storing or heating food in them. Use paraben-free cosmetics. Buy organic food when practical and economical, especially in the U.S. As Nathan notes on pesticide use in the U.S.:

Twenty-five of these pesticides [used in the U.S.] are banned in more than thirty other countries. Phorate, the most used ‘extremely hazardous’ insecticide in the U.S., is banned in thirty-eight other countries, including China, Brazil, and India. None of the ‘extremely hazardous’ pesticides we use here in the U.S. can be used in the twenty-seven nations of the European Union [15].

Avoid flame retardants by using natural fabrics like wool or cotton instead of synthetic fabrics—including synthetic carpets—or use materials that don’t burn: brick, stone, metal, glass. For air pollutants and particulate matter, a HEPA air filter in the bedroom and a MERV 13+ HVAC system are the biggest levers, as are avoiding burning candles and incense. And of course avoid heavy metals, including by moderating consumption of tuna, shark, swordfish, king mackerel, and tilefish [16].

Optimizing immunity is sufficient for incidental exposure to most common environmental toxins (see LinkedIn post and Substack article). True toxicity in which the body’s detoxification machinery is insufficient for the task is rarer than the “detox” industry would have you believe. When it does occur, the patient is usually very sick and should be treated by a professional.

Myths Worth Dispelling

With environmental toxins, a couple of myths are worth dispelling. The first concerns “female hormones” and their mimetics (xenoestrogens) in soy products and in the water supply from contraceptive pills being flushed down toilets—both of which have been safely exonerated as culprits [17, 18]. The emerging data on microplastics cannot be dismissed as easily. There are credible mechanisms for hormone disruption [19, 20], but the population data remain at the level of correlational epidemiology [21]. It is concerning and worth monitoring, but testosterone decline at the population level is likely better explained by the behavioral and lifestyle factors mentioned above.

Diagnostics: When to Consider TRT

After optimizing lifestyle and environment and ruling out contraindications, the decision to pursue TRT comes down to a combination of lab results, symptoms [3, 8], and personal cost-benefit analysis.

The standard diagnostic criteria begin with two lab tests below 300 ng/dL on two separate mornings. The standard test measures all three forms of testosterone:

• Testosterone bound by Sex Hormone-Binding Globulin (SHBG), a transporter and regulator protein—not immediately bioavailable
• Testosterone bound by albumin—considered loosely bound and bioavailable
• Free testosterone—the most bioavailable form

If total testosterone is borderline or if SHBG levels are abnormal, additional tests may be warranted: free testosterone, luteinizing hormone (LH), or follicular stimulating hormone (FSH)—the latter two being intermediate signaling hormones that precede testosterone synthesis.

The other diagnostic criteria are symptom-based: mood changes, decreased libido, erectile dysfunction, fatigue, reduced muscle mass and strength, or increased body fat.

Forms of TRT

Once the decision to pursue TRT has been made, the next question is which form to use. The most common options, each with its pros and cons, include [22]:

Short-duration intramuscular injectables (testosterone cypionate or enanthate)

• Pros: cost-effective and flexible
• Cons: serum testosterone peaks at 24–72 hours then declines gradually over approximately two weeks, which can lead to fluctuations in mood, performance, and hematocrit

Transdermal gels or creams

• Pros: more consistent, stable delivery
• Cons: require daily application and risks exposing others: children, pets, partners

Transdermal patches

• Pros: consistent delivery, shares the advantages of gels and creams
• Cons: requires daily application and can cause skin irritation—generally not advised

Oral pills

• Pros: convenient
• Cons: must be consumed with fat and has variable bioavailability. Formulations are getting safer but hepatotoxicity (liver toxicity) remains a risk—generally not advised.

Long-duration injectables

• Pros: less frequent injections than short-duration injectables
• Cons: less flexibility than short-duration injectables and small risk of pulmonary oil microembolisms

Pellets (inserted subcutaneously, releasing testosterone over several months)

• Pros: infrequent administration and steady release
• Cons: can be expensive, cause irritation at the insertion site, and occasionally be extruded from the body

Regardless of formulation, TRT suppresses natural testosterone and sperm production, which can reduce fertility and decrease testicular volume. Human chorionic gonadotropin (hCG) can be used in addition to or in lieu of TRT to help preserve natural testosterone production, sperm production, and testicular volume.

The Decision

If you recognize these symptoms and lifestyle and environmental interventions have failed to remedy the problem, talk with your physician. If he dismisses TRT outright, get a second opinion. Dogmatic opposition by ostensible medical professionals not only ignores substantial evidence of TRT’s ability to improve health outcomes—it is contrary to their duty to treat disease. Hypogonadism is a disease state. The hypothalamic-pituitary-gonadal (HPG) axis is damaged or otherwise not producing healthy levels of testosterone for whatever reason: age, injury, etc. The “R” in “TRT” stands for “Replacement”—replacing what is absent in the diseased state to return the patient to health.

Conversely, if your physician reflexively recommends TRT—or worse—immediately farms you out to a TRT clinic (“mills” to use the often-deserved sobriquet)—possibly one in which he has a financial interest—also get a second opinion. TRT offers tremendous potential benefits for the right candidate, but it shouldn’t be entered into lightly—nor should it be done to finance your doctor’s country club membership.

► W. J. G. Hellstrom (Ed.), Androgen Deficiency and Testosterone Replacement: Current Controversies and Strategies. Humana Press, 2013.
This is the single best scientific, academic text on hypogonadism and TRT, the clinical reference for practitioners, dense and authoritative.
Hardcover   Paperback   Kindle

► S. S. Gropper, J. L. Smith, and T. P. Carr, Advanced Nutrition and Human Metabolism, 8th ed. Cengage Learning, 2022.
This is another dense and authoritative advanced text, the go-to reference for general nutrition and metabolism.
Hardcover   Kindle

► M. Greenwood et al., Nutritional Supplements in Sports and Exercise, 2nd ed. Springer International Publishing, 2015.
This is the foundational text for the Certification of the International Society of Sports Nutrition (CISSN), the gold standard in sports nutrition certifications. It focuses on nutrition and ergogenic aids from the standpoint of performance.
Hardcover   Paperback   Kindle

► C. D. Klaassen, Casarett and Doull’s Toxicology: The Basic Science of Poisons, 9th ed. McGraw-Hill Education, 2019.
This is the standard graduate textbook on toxicology.
Hardcover   eTextbook

► N. Nathan, The Sensitive Patient’s Healing Guide, 1st ed. Cypress House, 2024.
Dr. Nathan was the inspiration for adding Environment to the SCREEN Framework: Spirituality, Cognition, Recovery, Environment, Exercise, and Nutrition. He does some of the best work on environmental toxicity and treating toxicity.
Paperback   Kindle   Audible

► N. Nathan, Toxic. Victory Belt Publishing, 2025.
This is Dr. Nathan’s other major work, which focusses more on environmental toxins and their impact and less on treatment.
Paperback   Audible

► M. H. Kryger, T. Roth, and C. A. Goldstein, Kryger’s Principles and Practice of Sleep Medicine, 7th ed. Elsevier, 2022.
This is the standard clinical text on sleep medicine.
Hardcover   Kindle

■ The Signal Podcast with Dr. Arny Ferrando—TRT, protein, and men’s aging. The companion interview to this issue’s Deep Dive.

■ The Signal Podcast with Dr. Muhammad Usama—Sleep as a Superpower. Sleep is the highest-leverage lifestyle intervention for testosterone. This is where to start.

■ Immunity Optimization—LinkedIn. Sufficient for incidental exposure to most common environmental toxins.

■ Pretox: Stronger Immunity and the Body’s Own Detox System—Substack.

■ Peptides and FDA: The Real Story—LinkedIn.

■ FDA/EPA Mercury in Fish Advisory—Full species-by-species mercury concentration table. Updated 2021.

■ Instagram: @FeltovichFit

■ FeltovichFit Podcast—Spotify

■ X: @FeltovichFit

■ Substack: @FeltovichFit

■ LinkedIn: FeltovichFit

■ YouTube: @FeltovichFit

■ Facebook: Andy Feltovich

Collegium of Order & Flow

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THE SIGNAL is produced by Andy Feltovich—CISSN · CSCS · StrongFirst Elite
A FeltovichFit Publication  ·  Collegium of Order & Flow  ·  Not medical advice.