Understanding testosterone replacement therapy: potential risks and benefits

Testosterone therapy can restore drive, mood, and muscle for some men, but it is a powerful hormone drug with real trade-offs. Here is a clear, evidence-based guide to understanding testosterone potential risks and benefits so you can decide, with your doctor, if it is worth it for you.

“Testosterone therapy is neither a magic youth potion nor a guaranteed heart attack in a vial. The men who do best are the ones who confirm low levels, treat specific symptoms, and stay on top of labs and side effects.”

Susan Carter, MD: Endocrinologist & Longevity expert

The relationship

Testosterone is a sex hormone that helps regulate muscle mass, red blood cell production, sex drive, mood, bone density, and energy. In men, it is mainly made in the testicles under control from the brain. Levels peak in the late teens and early 20s, then fall by about 1% to 2% per year after age 30.

When levels drop too low, a condition called hypogonadism can appear. Hypogonadism means the body does not produce enough testosterone for normal function. Men may notice fatigue, low libido, difficulty with erections, muscle loss, and depressed mood. Meta-analyses suggest that men with total testosterone below about 350 ng/dL, or free testosterone below 100 pg/mL, and clear symptoms are most likely to benefit from therapy.^[1]

Understanding testosterone potential risks and benefits means separating age-related, mild decline from true hormone deficiency. It also means knowing that treatment is usually long term. Once you start testosterone replacement therapy, or TRT, your body’s own production often drops, so stopping is not always simple. Clear goals, realistic expectations, and close medical follow-up are essential.

How it works

To make sense of understanding testosterone potential risks and benefits, it helps to see how the hormone system is wired and how treatment changes that system.

Brain–testicle feedback loop

The hypothalamic–pituitary–gonadal axis is the hormone feedback loop that links the brain and testicles. The hypothalamus in the brain releases GnRH, a signal hormone. GnRH tells the pituitary gland to release LH and FSH, hormones that drive the testicles to make testosterone and sperm. Rising testosterone then feeds back to the brain to dial down further production.

When you take external testosterone, blood levels rise and the brain senses “enough.” GnRH and LH drop, the testicles make less hormone, and sperm production can fall sharply. This is why TRT often causes testicular shrinkage and lower fertility, even when men feel stronger and more energetic.

Delivery methods and absorption

Most men receive testosterone as injections, skin gels, patches, or long-acting pellets. Injections place the hormone into muscle or under the skin. Gels and patches deliver it across the skin. Pellets are tiny cylinders placed under the skin that release hormone over months. These routes differ in how steady the hormone level is, how convenient they feel, and which side effects they tend to trigger.^[2]

Short-acting injections can cause sharp peaks and valleys in blood levels. Peaks may bring acne, mood swings, or high red blood cell counts. Gels and patches usually give smoother levels but can irritate skin and require daily use. Pellets reduce daily hassle but make it harder to adjust the dose if problems appear.

What “low” testosterone really means

Testosterone in the blood travels mostly bound to proteins called SHBG and albumin. Only a small fraction is free testosterone, which can enter cells and do the work. Total testosterone measures everything; free testosterone measures only the active portion. Conditions like obesity and thyroid disease can change SHBG, hiding true low or normal levels if you only check total testosterone.^[1]

Current evidence suggests that symptomatic men with total testosterone below about 350 ng/dL, or free testosterone below 100 pg/mL, are the clearest candidates for TRT after repeating tests in the early morning and ruling out other illnesses.^[1],[3]

How benefits appear over time

TRT tends to improve different systems on different timelines. Studies show that libido and sexual thoughts may improve within 3 to 4 weeks. Erections and ejaculation can take up to 6 months. Mood, energy, and depressive symptoms often ease by 3 months, while increases in muscle mass, strength, and bone density may require 6 to 12 months of stable therapy.^[3]

Understanding testosterone potential risks and benefits means noting that not all symptoms respond. For example, severe erectile dysfunction from vascular disease alone may not improve much with TRT unless testosterone was very low to begin with.

Cardio‑metabolic ripple effects

Low testosterone is linked with higher body fat, insulin resistance, and metabolic syndrome, a cluster of risk factors including large waistline, high blood pressure, abnormal cholesterol, and high blood sugar. Some trials show TRT can modestly reduce fat mass, improve insulin sensitivity, and lower fasting glucose in men with hypogonadism, especially when combined with lifestyle changes.

At the same time, TRT can raise hematocrit, the proportion of red blood cells in blood. Very high hematocrit thickens the blood and might raise clot and stroke risk if not monitored. Good programs track these numbers closely and adjust doses or pause therapy when hematocrit climbs.

Conditions linked to it

Understanding testosterone potential risks and benefits means looking at both the health problems caused by low testosterone and the conditions that might be worsened by TRT.

Conditions linked to low testosterone:

Sexual dysfunction: Decreased sex drive and difficulty with erections are classic signs. Up to 20% of men with erectile dysfunction have clinically low testosterone.^[4]
Osteoporosis: Low testosterone accelerates bone loss and raises fracture risk, especially in older men.^[3]
Depressed mood and fatigue: Men with hypogonadism report more depressive symptoms and lower vitality scores on validated questionnaires.^[3]
Metabolic syndrome and type 2 diabetes: Low testosterone is common in these conditions and predicts higher future risk of cardiovascular events.

Conditions that can be worsened by TRT:

Polycythemia: An abnormally high red blood cell count. TRT increases hematocrit in 5% to 20% of men, depending on dose and route, and may require dose reductions or therapeutic blood removal.^[2]
Prostate issues: TRT is generally avoided in men with active prostate cancer. It can worsen urinary symptoms from benign prostatic hyperplasia in some men, especially if doses are high.^[5]
Sleep apnea: TRT may aggravate undiagnosed or poorly treated obstructive sleep apnea by promoting fluid shifts around the airway and weight gain.^[2]
Cardiovascular disease: Evidence is mixed. Some studies suggest increased cardiovascular events in older, frail men on high-dose TRT, while others show neutral or modestly protective effects when therapy is well monitored.

Limitations note: Much of the risk data comes from observational studies and trials that used different doses, forms of testosterone, and follow-up times. That means some risk estimates may not apply to carefully dosed, guideline-based TRT today.

Symptoms and signals

The signs of low testosterone and TRT-related side effects often overlap with normal aging and other diseases. That is why understanding testosterone potential risks and benefits requires paying attention to patterns and clusters of symptoms, not single red flags.

Common symptoms of low testosterone include:

Low sex drive or less interest in sex than usual
Difficulty getting or keeping erections, especially morning erections
Reduced energy, stamina, or “get up and go”
Persistent tiredness even after sleep
Loss of muscle mass or strength despite exercise
Increased belly fat or difficulty losing weight
Low mood, irritability, or a “flat” emotional state
Reduced shaving frequency or less body hair
Decreased motivation, competitiveness, or confidence
More fragile bones or fractures after minor falls

Possible side effects or signals to watch for during TRT:

Acne, oily skin, or increased body hair
Swelling in the ankles or sudden weight gain from fluid retention
Breast tenderness or enlargement
Shortness of breath, chest discomfort, or headaches that are new or worse
Dark, thick blood on lab results or rising hematocrit and hemoglobin
Worsening snoring or pauses in breathing during sleep
More frequent urination at night or weaker urine stream
Noticeable shrinkage of testicles or changes in fertility

Many of these signals are not emergencies but should prompt a call to your doctor. Sudden chest pain, face or arm weakness, trouble speaking, or severe shortness of breath require emergency care whether you are using TRT or not.

What to do about it

Understanding testosterone potential risks and benefits is only useful if it leads to a clear action plan. Here is a simple 3‑step roadmap to follow with your clinician.

Get properly tested

Ask for at least two early‑morning total testosterone tests, ideally between 7 and 10 a.m. Avoid heavy exercise, illness, or heavy drinking right before testing because these can skew results. If your total testosterone is borderline, usually between about 300 and 400 ng/dL, ask for free testosterone, SHBG, and related labs such as LH, FSH, estradiol, prolactin, thyroid function, and fasting glucose.

Meta-analyses and guidelines suggest using about 350 ng/dL for total testosterone or 100 pg/mL for free testosterone as practical decision points when significant symptoms are present.^[1],[3] Your doctor should also review medications, sleep, stress, and alcohol use, all of which can drive testosterone down.

Start with lifestyle and targeted therapy

Before or alongside TRT, tackle factors that suppress natural testosterone production:

Weight management: Losing 5% to 10% of body weight through diet and exercise can raise testosterone by 100 to 200 ng/dL in many overweight men.
Resistance training: Strength training 2 to 3 times per week boosts muscle mass and supports higher testosterone.
Sleep: Aim for 7 to 9 hours nightly. Sleep apnea and chronic sleep debt blunt hormone production.
Stress and alcohol: High cortisol from chronic stress and heavy drinking both lower testosterone. Stress management and moderating alcohol can help.

If low levels and symptoms persist despite these steps, discuss TRT options. Ask about:

Injection versus gel versus patch versus pellet
Impact on fertility and plans for children
Baseline PSA, digital rectal exam, and hematocrit before starting

Men hoping to maintain fertility can ask about alternative strategies like clomiphene citrate or hCG, medications that stimulate the body’s own hormone production rather than replacing testosterone outright.^[4]

Monitor and adjust over time

Guidelines recommend checking testosterone, hematocrit, PSA, and symptom scores about 3 months after starting TRT, again at 6 months, and then at least yearly if stable.^[3],[5] Your dose may need fine‑tuning. If hematocrit climbs above about 54%, most clinicians lower the dose, pause therapy, switch routes, or arrange therapeutic phlebotomy, a controlled blood removal.

Any new chest pain, neurological symptoms, or suspected prostate or sleep apnea issues should trigger an earlier reassessment. In some men, the risks will eventually outweigh the benefits, and tapering off or switching strategies can be the safest choice.

Myth vs Fact: testosterone therapy

Myth: “TRT is a fountain of youth for any tired middle‑aged man.”
Fact: TRT helps most when you have clear symptoms and confirmed low levels. If your testosterone is normal, pushing it higher mainly adds risks.
Myth: “Testosterone therapy always causes prostate cancer.”
Fact: Large reviews do not show a clear increase in prostate cancer in men carefully treated and monitored, but TRT is not used in men with known active prostate cancer.^[5]
Myth: “Once you start TRT, you can never stop.”
Fact: Stopping can be hard because the body’s own production slows, but under medical supervision, men can taper or transition off in some cases.
Myth: “Natural boosters are always safer than prescription testosterone.”
Fact: Many “boosters” are unregulated, under‑tested, and sometimes spiked with steroids. Guideline‑based TRT with labs is usually safer than unknown powders.
Myth: “TRT always harms the heart.”
Fact: Heart risks depend on age, dose, health status, and monitoring. Some data show higher events in frail older men on high doses, while other data show neutral or even improved risk markers when therapy is optimized.

Bottom line

Understanding testosterone potential risks and benefits starts with honest lab testing and a clear look at your broader health. TRT can meaningfully improve libido, mood, and muscle in men with true hypogonadism. It can also raise hematocrit, affect the prostate, worsen sleep apnea, and, in some men, may tilt cardiovascular risk. The safest path is to treat testosterone as a potent tool, not a lifestyle supplement: confirm the diagnosis, individualize the dose and delivery, and stay on top of monitoring. Done that way, TRT becomes a shared, data‑driven decision rather than a gamble.

References

Hudson J, Cruickshank M, Quinton R, et al. Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis. The lancet. Healthy longevity. 2022;3:e381-e393. PMID: 35711614
Corona G, Isidori AM, Buvat J, et al. Testosterone supplementation and sexual function: a meta-analysis study. The journal of sexual medicine. 2014;11:1577-92. PMID: 24697970
Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. The Journal of clinical endocrinology and metabolism. 2018;103:1715-1744. PMID: 29562364
Khera M, Adaikan G, Buvat J, et al. Diagnosis and Treatment of Testosterone Deficiency: Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015). The journal of sexual medicine. 2016;13:1787-1804. PMID: 27914560
Salonia A, Bettocchi C, Boeri L, et al. European Association of Urology Guidelines on Sexual and Reproductive Health-2021 Update: Male Sexual Dysfunction. European urology. 2021;80:333-357. PMID: 34183196