Understanding Testosterone Side Effects: What You Need to Know

Testosterone is a crucial hormone in the human body. It functions in many different parts of the body in both men and women. In men, it is the main sex hormone that causes male secondary sexual traits such as a deeper voice, facial hair, and muscle growth. It makes women's bones stronger and their sex drive stronger. Misuse or improper management of testosterone replacement therapy can lead to short-term and long-term health complications, regardless of the benefits of hormone replacement therapy. This study explores testosterone side effects, causes, diagnosis, clinical evaluations, and when therapy is appropriate or inadvisable.

Key Takeaways

• Testosterone therapy is a powerful tool for men with male hypogonadism, helping improve symptoms like fatigue, low libido, and muscle loss. It must be personalized and medically supervised to avoid complications.
• Receiving testosterone injections can be effective, but without regular monitoring and lab tests, it may cause side effects such as dark urine, mood swings, and can exacerbate sleep apnea.
• Conditions like delayed puberty or low testosterone in adolescents and adults may warrant therapy, but TRT should be avoided in cases of early puberty or certain medical conditions that increase the risk of side effects.
• Adjustments in lifestyle, like weight reduction, getting better sleep, and exercising, can help the treatment work better and lower the chance of problems like blood clots, erectile dysfunction, and liver damage while taking testosterone therapy for a long time.
• Contraindications like breast cancer and untreated sleep apnea can be ruled out through proper diagnosis.
• Lab tests and physical exams can also be used to track TRT’s impact on erectile function, fertility, and metabolic health.

What is Testosterone?

Testosterone is a steroid hormone from the androgen group. In men, the majority of testosterone is produced in the Leydig cells (specialised, polygonal-shaped cells) found in the testes. In women, it originates in the ovaries and adrenal glands. It influences key bodily functions, including:

• Sexual function (libido, erectile strength)
• Muscle and bone density
• Fat distribution
• Red blood cell production
• Mood and cognitive performance

The body's endocrine system (glands that release hormones) tightly regulates these physiological effects. For example, the hypothalamic-pituitary-gonadal (HPG) axis controls testosterone synthesis and release through hormonal signalling involving luteinizing hormone (LH), a hormone produced by the pituitary gland. This hormone plays a crucial role in the reproductive system, especially in regulating the menstrual cycle in women and testosterone production in men.

When the testosterone level reduces, the hypothalamus (the area of the brain that produces hormones) signals the pituitary gland to release LH, which stimulates the testes to produce more testosterone. This feedback loop keeps the level in the right range.

Aging, physical diseases, and the usage of hormones from outside the body can all cause problems in the system, which show up as clinical symptoms and need medical help.

As men grow older, starting at age 30, their testosterone levels may go down, leading to low testosterone. Symptoms of low testosterone include weariness, loss of muscle mass, mood changes, and a diminished sex drive.

Testosterone Injection

Testosterone replacement therapy (TRT) often uses a testosterone injection as the primary method for restoring adequate testosterone levels in men diagnosed with low testosterone.

Low testosterone is a clinical condition characterized by low serum testosterone combined with symptoms such as reduced libido, fatigue, and decreased lean body mass. 

Testosterone injection is popular due to its efficiency in delivering controlled, bioavailable doses directly into the bloodstream. They bypass first-pass metabolism (a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation) by the liver, ensuring a predictable absorption pattern than oral alternatives.

Injectable formulations include:

• Testosterone Enanthate is a widely used short-acting ester (compound derived from an acid) administered every 1 to 2 weeks. It causes a rapid rise in testosterone level within 24–48 hours, followed by a gradual decline. Enanthate is valued for its flexibility in dosing schedules, although some patients experience mood swings or symptom changes as a result of hormonal peaks and troughs.
• Testosterone Cypionate is chemically similar to enanthate; it is a short- to medium-acting ester with a dosage frequency of 1 to 2 weeks. It is one of the most common injectable forms in the United States. Like enanthate, cypionate is oil-based and may produce variable absorption rates, requiring a specified dosage to reduce side effects.
• Testosterone Undecanoate: A long-acting injectable formulation administered less frequently, every 10 to 14 weeks. Due to its extended release profile, it maintains steadier testosterone levels, which may reduce side effects connected to hormonal fluctuations. However, it often requires in-clinic administration due to the risk of allergic reaction, such as pulmonary oil microembolism (POME) — a rare but serious complication. Each formulation is kept in an oil-based solution to allow for slow release into the circulation over time.

TRT through intramuscular testosterone injection helps increase and maintain serum testosterone levels, leading to noticeable improvement in energy, libido, muscle strength, and lean body mass.

A 2018 guideline by the Endocrine Society stated that men with low testosterone enjoy good quality of life and sexual health when treated well with testosterone injection (Bhasin et al., 2018).

However, despite the benefits, fluctuations in hormone levels, particularly with testosterone injection forms like cypionate and enanthate, can lead to a peak-and-trough effect.

Physicians may administer lower-dose injections to achieve stable testosterone levels. Clinical lab tests and monitoring are necessary to design the regimen for each patient’s physiological response.

How the Testosterone Injection is Administered

Testosterone injections are administered intramuscularly, meaning the hormone is injected deep into the muscle tissue. The injection can be administered in the gluteus maximus (buttocks), vastus lateralis (outer thigh), or deltoid (upper arm).

These muscles have a rich blood supply, which allows for efficient absorption of the hormone into the bloodstream.

Depending on the formulation, testosterone injections are given at intervals:

• Cypionate and enanthate: every 1–2 weeks
• Undecanoate: every 10–14 weeks

When administered correctly, testosterone injections result in a gradual release of the hormone over several days or weeks, depending on the ester used. This helps to maintain a stable testosterone level, although some short-acting forms may still cause changes.

Patients may be taught how to administer injections at home using aseptic technique after receiving appropriate training from a healthcare professional. Self-injection involves using a 1-1.5-inch needle and injecting into the muscle at a 90-degree angle. Safety protocols such as hand hygiene, proper needle disposal, and avoiding contaminated injection equipment are important.

It is best to rotate injection sites to reduce the risk of complications like irritation, inflammation, or lipodystrophy (changes in fat distribution at the injection site). Repeated use of the same muscle group can cause tissue scarring or fibrosis, which can affect hormone absorption and increase discomfort.

Injections are usually administered in a clinical setting for long-acting formulations like testosterone undecanoate, due to the potential risk of pulmonary oil microembolism (POME).

It is necessary to monitor injection technique, adverse effects, and ensure that testosterone levels remain within the therapeutic range.

Side Effects of Testosterone

Testosterone treatment changes lives, but it comes with risks. Clinical studies have documented the following side effects"

Acne and Oily Skin

Increased testosterone levels can activate sebaceous (oil) glands in the skin, leading to the overproduction of sebum (an oily substance that protects the skin and hair). This excess oil can clog pores, resulting in acne outbreaks on the face, back, and chest. Though often mild, acne can be stubborn and may require oral dermatologic or topical treatment during testosterone therapy

Fluid Retention

Some men receiving testosterone injections experience water retention, which can manifest as swelling in the lower extremities, like the feet. Hormonal shifts may change sodium balance and kidney function. Edema should be evaluated to rule out underlying heart disease or renal issues.

Erythrocytosis

Testosterone energizes erythropoiesis, otherwise known as the production of red blood cells. Excess production leads to erythrocytosis, a condition marked by increased hematocrit in the blood. This can make the blood thick and increase the risk of clots, stroke, and heart disease. Regular blood test monitoring (CBC) is important.

Sleep Apnea

TRT can worsen existing or reveal undiagnosed obstructive sleep apnea (OSA), a condition where the airway collapses during sleep. Worsening sleep apnea may result from effects on airway muscles or central respiratory drive. Monitor symptoms such as loud snoring or excessive daytime sleepiness before and during testosterone injection use.

Irritability or Aggression

Hormonal changes from testosterone injection may affect neurotransmitters, leading to irritability, mood swings, or aggression, but may improve with dose consistency.

Gynecomastia

Testosterone can convert into estrogen through a process called aromatization (conversion of androgens to estrogens), at higher doses. Increased estrogen levels may lead to gynecomastia, which is the development of breast tissue in men. This condition may cause tenderness and cosmetic concerns. Healthcare providers can use aromatase inhibitors to counteract this effect if it develops.

Testicular Atrophy

Exogenous testosterone reduces testosterone production by inhibiting the hypothalamic-pituitary-gonadal axis. This leads to reduced stimulation and sperm output, which can cause the testicles to contract. While usually reversible, long-term testosterone injections can cause lasting effects.

Infertility

TRT suppresses spermatogenesis by reducing the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), both important for sperm production. Men seeking fertility should avoid TRT or use it under controlled protocols that include gonadotropins to preserve reproductive capacity.

Hair Loss

Testosterone and its potent derivative dihydrotestosterone (DHT) can accelerate androgenic alopecia (male pattern baldness) in genetically predisposed individuals. Hair loss usually affects the frontal hairline and crown. Finasteride and similar medications may reduce this side effect, but they come with their own risks. These risks may include decreased libido, erectile dysfunction (ED), reduced ejaculate volume, delayed ejaculation, depression, cognitive fog, etc.

High Blood Pressure

TRT may increase blood pressure through fluid retention and vasoconstriction. Increased red blood cell mass can cause vascular resistance, contributing to heart disease. Monitoring is also important in hypertensive men.

Chest Pain

Unexplained chest pain during testosterone injection is a concern. It may indicate angina or myocardial infarction. Although a connection between TRT and heart disease is debated and has evolved as more high-quality data have come out, all chest symptoms warrant immediate evaluation.

Blood Clots

As testosterone increases hematocrit and red blood cell production, it also raises the risk of venous thromboembolism (VTE), a condition that includes deep vein thrombosis (DVT) and pulmonary embolism (PE). Symptoms include leg pain, swelling, and sudden shortness of breath. TRT patients should be screened physically, genetically, or historically for clotting risk factors. 

Prostate Risks

There is debate regarding testosterone injection and prostate cancer. While testosterone doesn’t directly cause prostate cancer, it can potentially worsen the condition of benign prostatic hyperplasia (BPH).  Regular PSA checks are necessary before and during testosterone injection therapy.

Allergic Reaction

Men may experience an allergic reaction to components in testosterone injection, such as oil carriers, but this is a rare occurrence. Symptoms include rash, shortness of breath, and chest tightness. They require immediate medical attention.

Testosterone Side Effects: Causes

The causes of the side effects of testosterone include:

Excessive Dosage

Hormonal balances can be affected by dosages that exceed what the body produces, leading to adverse effects. These excessive levels can increase estrogen through aromatization, contribute to erythrocytosis, activate androgen receptors, and result in a range of physiological disturbances, including breast swelling, acne, and increased risk of cardiovascular disease.

Studies have shown that high testosterone doses are related to increased hematocrit and estradiol levels, both associated with heart attack risk (Coviello et al., 2008; Basaria, 2010).

To reduce risks, testosterone therapy must be initiated based on clinical symptoms and regular lab tests

Comorbid Conditions

Men with conditions like sleep apnea, liver disease, cardiovascular disease, or clotting disorders suffer an increased risk of complications from TRT. Sleep apnea may worsen, and patients with a history of thrombosis ( the formation of a blood clot (thrombus) inside a blood vessel, which can block blood flow) are more prone to blood clots..

Improper Delivery

When receiving testosterone injections, inconsistent injection schedules, wrong dosages, or poor technique can lead to unstable testosterone levels and side effects like mood swings, breathing problems, acne, and erectile dysfunction. Switching formulations, such as from testosterone enanthate to transdermal options, can improve stability.

Age

Older men are likely to experience testosterone side effects, especially those affecting the cardiovascular and prostate systems. Age-related decline also affects drug metabolism and clearance. They need frequent lab tests and a cautious approach for managing low testosterone alongside other age-related conditions.

Diagnosis

Testosterone side effects require a comprehensive clinical approach that includes medical history, physical examination, and laboratory diagnostics. The goal is to determine if adverse symptoms are attributable to testosterone therapy or if other underlying conditions are contributing factors.

1. Medical History: The physician will take a detailed history that includes past hormone use, preexisting health issues (e.g., prostate cancer, blood clots), and current medications. The patient's reproductive goals, lifestyle factors, and any symptoms of testosterone deficiency (such as low testosterone, libido, or fatigue) are also examined. It includes assessment for prior hormone therapy, low testosterone symptoms, erectile dysfunction, existing conditions (e.g., heart attack, breast cancer, liver disease), and concurrent medications or dietary supplements.
2. Physical Examination: This involves checking for gynecomastia, acne, testicular atrophy, and important signs like blood pressure. A digital rectal exam (DRE) may be performed to examine the prostate if the patient is at risk for prostate cancer or benign prostatic hyperplasia. The American Urological Association recommends this for all men over 50 starting TRT (AUA, 2018). Signs such as breast swelling, acne, body hair changes, fewer spontaneous erections, and testicular size may be examined.
3. Laboratory Testing: Blood tests are important in confirming side effects and guiding treatment. These may include:
   
   • Total and free testosterone to assess hormonal adequacy
   • Complete blood count (CBC) to monitor for erythrocytosis
   • Prostate-specific antigen (PSA) to screen for prostate abnormalities
   • Liver function tests to ensure safe metabolism
   • Estradiol levels to assess the aromatization effects
   • Lipid profile and glucose to monitor metabolic impact

These diagnostic steps allow clinicians to design therapy, adjust dosages, and intervene early if adverse effects emerge.

Treating the Side Effects

Treatment for testosterone therapy side effects must be individualized, depending on the nature, differences, and underlying cause. Medical supervision is important, and adjustments should be made based on clinical judgment and objective test results.

• Lower the dose: Reducing the testosterone dosage can resolve mild symptoms such as acne, mood changes, or fluid retention. Lowering the dose helps the body maintain a physiological testosterone range, reducing the side effects while preserving therapeutic benefits (Basaria, 2010).
• Discontinue therapy: For patients experiencing severe adverse reactions, such as significant erythrocytosis (hematocrit >54%), uncontrolled hypertension, or confirmed blood clots, testosterone therapy should be stopped immediately. Discontinuation is also considered in patients with new or worsening prostate cancer or other contraindications (Endocrine Society Clinical Guidelines, 2018).
• Switch delivery methods: Patients receiving testosterone injection with unstable hormone levels may benefit from switching to gels or patches. This helps maintain mood, erectile function, and libido. These methods can help reduce peaks and troughs, which are often responsible for mood instability and irritability. Transdermal options are useful in patients who are sensitive to dosing changes or have experienced injection site reactions.
• Medications: Supportive treatments may be used in combination with TRT modifications:
  
  • Aromatase inhibitors (e.g., anastrozole) are prescribed to control estrogen levels and manage gynecomastia. 
  • Antihypertensives help control high blood pressure caused by TRT.
  • Continuous Positive Airway Pressure (CPAP) machines are used in patients with sleep apnea, particularly if TRT has worsened nocturnal breathing patterns (Hoyos et al., 2012).
  • 5-alpha reductase inhibitors may be prescribed to address prostate-related side effects such as benign prostatic hyperplasia.
• Phlebotomy: For patients who develop erythrocytosis (high red blood cell count), regular therapeutic phlebotomy can reduce hematocrit and reduce the risk of blood clots. This intervention is necessary if hematocrit exceeds 52–54%, a common threshold used in clinical practice (Coviello et al., 2008).
• Monitor and reassess: Treatment adjustments should be followed by close monitoring of testosterone levels, PSA, hematocrit, and symptom resolution. In some cases, endocrinologists may collaborate with cardiologists, urologists, or hematologists, depending on the nature of the side effect.
• Lifestyle modification: Addressing modifiable risk factors like obesity, alcohol intake, poor sleep hygiene, and physical inactivity can help reduce side effects. For instance, weight loss and regular exercise improve insulin sensitivity and cardiovascular health, which may counteract TRT-related metabolic shifts.

Managing side effects requires a proactive, multidisciplinary approach that prioritizes patient safety while preserving the intended benefits of testosterone replacement therapy. Continuous education, shared decision-making, and individualized care plans are crucial to maintaining therapeutic efficacy without compromising long-term health outcomes.

When Should You Use Testosterone?

According to the Endocrine Society, you can use TRT when:

• Total testosterone < 300 ng/dL on two separate mornings
• Symptoms of testosterone deficiency are persistent (e.g., low libido, muscle wasting, depression)
• The patient has no contraindications
• You’ve discussed risks and benefits with your doctor

Why Should You Not Use Testosterone?

You should not use TRT in the following conditions:

• The presence of active prostate cancer or suspicious PSA levels
• Breast cancer in males
• Hematocrit > 54% (risk of blood clots)
• Severe sleep apnea
• Recent heart attack or stroke
• Uncontrolled high blood pressure

References

• Bhasin, S., Brito, J. P., Cunningham, G. R., Hayes, F. J., Hodis, H. N., Matsumoto, A. M., ... & Wu, F. C. (2018). Testosterone therapy in men with hypogonadism: An Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism, 103(5), 1715–1744.
• Basaria, S. (2010). Androgen abuse in athletes: Detection and consequences. The Journal of Clinical Endocrinology & Metabolism, 95(4), 1533–1543.
• Coviello, A. D., Kaplan, B., Lakshman, K. M., Chen, T., Singh, A. B., & Bhasin, S. (2008). Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. The Journal of Clinical Endocrinology & Metabolism, 93(3), 914–919. 
• Finkle, W. D., Greenland, S., Ridgeway, G. K., Adams, J. L., Frasco, M. A., Cook, M. B., ... & Hoover, R. N. (2014). Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLOS ONE, 9(1), e85805.
• Vigen, R., O’Donnell, C. I., Baron, A. E., Grunwald, G. K., Maddox, T. M., Bradley, S. M., ... & Rumsfeld, J. S. (2013). Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA, 310(17), 1829–1836.
• Hoyos, C. M., Killick, R., Yee, B. J., Phillips, C. L., & Grunstein, R. R. (2012). Effects of testosterone therapy on sleep and breathing in obese men with severe obstructive sleep apnea: A randomized placebo-controlled trial. Thorax, 67(6), 563–570. 
• Glueck, C. J., Wang, P., Goldenberg, N., & Sieve-Smith, L. (2011). Testosterone therapy, thrombophilia-hypofibrinolysis, and hospitalization for deep venous thrombosis-pulmonary embolus: An exploratory, hypothesis-generating study. Clinical and Applied Thrombosis/Hemostasis, 17(3), 261–266.
• Zitzmann, M., Depenbusch, M., Gromoll, J., & Nieschlag, E. (2001). Androgen receptor CAG repeat length and body mass index modulate the safety and efficacy of testosterone undecanoate treatment in hypogonadal men. The Journal of Clinical Endocrinology & Metabolism, 86(9), 3845–3852. 
• Saad, F., Gooren, L., Haider, A., & Yassin, A. (2016). A dose–response analysis of testosterone on mood and well-being in hypogonadal men. Journal of Endocrinological Investigation, 39(12), 1449–1458.
• American Urological Association (AUA). (2018). Guideline on the Evaluation and Management of Testosterone Deficiency.