What is the role of androgen (testosterone) in the body and its potential uses and risks in clinical settings?

Androgen (Testosterone): Role, Clinical Uses, and Risks

What Androgens Are

Yes, androgens refer primarily to testosterone and its derivatives, which are steroid hormones responsible for male sexual characteristics and multiple physiological functions throughout the body. 1, 2

Testosterone is the principal androgen secreted by the testes in males, with additional contributions from the adrenal glands. 1, 3 The hormone exists in multiple forms:

• Free testosterone (2% of total, biologically active) 1
• Testosterone bound to sex hormone-binding globulin (SHBG) (98% of total) 1
• Dihydrotestosterone (DHT), a more potent metabolite formed through 5α-reductase conversion in target tissues 4, 3

Physiological Roles

Androgens regulate critical functions across multiple organ systems:

Reproductive system development and function:

• Growth and maturation of prostate, seminal vesicles, penis, and scrotum 1
• Maintenance of spermatogenesis (requires high intratesticular testosterone levels) 5
• Male sexual function and libido 4

Musculoskeletal effects:

• Increased protein synthesis and muscle mass 4, 1
• Decreased protein catabolism 1
• Bone density maintenance and growth plate fusion 1

Metabolic functions:

• Retention of nitrogen, sodium, potassium, and phosphorus 1
• Stimulation of red blood cell production through erythropoietin 1
• Regulation of body fat distribution 1

Central nervous system:

• Mood regulation and sense of well-being 4
• Cognitive function 4
• Energy and vitality 4

Clinical Indications for Testosterone Replacement Therapy

Testosterone replacement therapy should be prescribed for men with confirmed hypogonadism, defined as low serum testosterone levels (below 250-350 ng/dL) combined with specific symptoms. 6

Diagnostic criteria for hypogonadism:

• Sexual symptoms: Diminished libido, erectile dysfunction 4, 6
• Physical symptoms: Decreased muscle mass and strength, reduced bone density, anemia 4
• Psychological symptoms: Diminished energy, depressed mood, impaired cognition, increased fatigue 4

Established benefits of testosterone replacement:

• Improved sexual function and libido 6
• Increased bone density and muscle mass 6
• Enhanced mood and reduced depressive symptoms 6
• Improved overall sense of well-being and energy 6

Formulations and Administration

For adult male hypogonadism, long-acting testosterone esters administered intramuscularly are the preferred first-line treatment. 7

Recommended dosing:

• Testosterone enanthate or cypionate: 200 mg intramuscularly every 2 weeks or 300 mg every 3 weeks 7
• Peak serum levels occur 2-5 days after injection, with return to baseline at 10-14 days 4
• Half-life of testosterone cypionate is approximately 8 days 1

Alternative formulations:

• Transdermal patches: High skin reaction rate (up to 66%) 4, 8
• Transdermal gels: Lower skin reaction rate (5%) 4, 8
• Oral preparations: Strongly discouraged due to hepatotoxicity risk (except testosterone undecanoate) 8, 1

Contraindications

Testosterone therapy is absolutely contraindicated in men with prostate or breast cancer, and in those with uncontrolled heart failure. 6

Additional contraindications include:

• Active plans for fertility within the next year (testosterone suppresses spermatogenesis) 1, 5
• Severe benign prostatic hyperplasia with urinary obstruction risk 1

Risks and Adverse Effects

Hematologic complications:

Erythrocytosis is the most common serious side effect, occurring in 3-18% with transdermal formulations and up to 44% with intramuscular injections. 4, 6, 8

• Most elevations occur within the first 3 months 8
• When hematocrit exceeds 54%, immediate intervention is mandatory: dose reduction, temporary discontinuation, therapeutic phlebotomy, or blood donation 8

Cardiovascular risks:

The relationship between testosterone therapy and cardiovascular events remains controversial, with conflicting evidence. 4, 6, 8

• One high-risk trial was stopped early due to excess cardiovascular events (7% testosterone vs 1% placebo) 8
• A Veterans Affairs study found increased risk for combined endpoint of mortality, MI, and stroke (hazard ratio 1.29) 8
• However, pooled analysis of 14 trials showed no statistically significant difference in cardiovascular events 8
• Current evidence suggests a neutral or possibly beneficial effect, but long-term safety data remains limited 4, 6

Prostate-related effects:

• There is no definitive evidence linking testosterone therapy to prostate cancer development 6, 8
• Prostate volume increases during first 6 months to levels equivalent to eugonadal men 8
• Lower urinary tract symptoms occur in 6.5% of treated men 8

Reproductive effects:

• Testicular atrophy and infertility are common, especially in young men, but usually reversible with cessation 4, 8
• Exogenous testosterone suppresses LH and FSH through feedback inhibition 1
• Oligospermia develops after prolonged administration 1

Other adverse effects:

• Fluid retention (rarely clinically significant) 4
• Sleep apnea (highest risk with high-dose parenteral testosterone) 4, 8
• Gynecomastia (rare, usually reversible) 4
• Acne or oily skin (infrequent) 4

Monitoring Requirements

Baseline assessments must include PSA, digital rectal examination, and hematocrit/hemoglobin. 6, 8

Monitoring schedule:

• First follow-up at 1-2 months to assess efficacy and early side effects 8
• Every 3-6 months for the first year 8
• Annual monitoring thereafter 8

Specific monitoring parameters:

• Hematocrit/hemoglobin: More frequent monitoring in high-risk patients 6, 8
• PSA: Perform prostate biopsy for increases ≥1.0 ng/mL in one year 8
• Blood pressure 6
• Sleep apnea assessment at baseline 6, 8
• Voiding symptoms evaluation 8

Special Clinical Contexts

Cancer cachexia:

There is insufficient consistent clinical data to recommend currently approved androgenic steroids to increase muscle mass in cancer patients. 4

• Nandrolone decanoate (200 mg/week) showed only a trend toward smaller weight loss in NSCLC patients 4
• Fluoxymesterone (20 mg/day) resulted in less appetite stimulation compared to megestrol acetate, with similar toxicity rates 4
• Selective androgen receptor modulators (SARMs) remain experimental and are not approved for cancer treatment 4

Androgen deprivation therapy in prostate cancer:

• Bilateral orchiectomy or LHRH agonists rapidly reduce testosterone to castrate levels (<10 ng/mL) 4
• Early treatment confers small but statistically significant survival advantage with durable progression-free survival improvements up to 10 years 4
• Cognitive effects of androgen deprivation remain controversial, with mixed results in systematic reviews 4

Common Pitfalls to Avoid

• Do not use testosterone interchangeably between formulations (cypionate vs propionate) due to differences in duration of action 1
• Never administer testosterone cypionate intravenously 1
• Do not prescribe testosterone for muscle building in non-hypogonadal individuals or cancer cachexia 4
• Avoid oral alkylated testosterone derivatives for adult male hypogonadism due to insufficient androgenic potency and hepatotoxicity risk 8, 1, 7
• Do not overlook fertility counseling in young men, as suppression of spermatogenesis is common and may take months to reverse 1, 5