What are the expected adverse effects of transdermal testosterone treatment?

Expected Adverse Effects of Transdermal Testosterone Treatment

The most common adverse effect of transdermal testosterone gels is skin reactions (erythema and pruritus) occurring in approximately 5% of users, while the most clinically significant adverse effect is erythrocytosis, which can occur in up to 43.8% of patients on testosterone therapy and requires mandatory monitoring. 1

Dermatologic Effects (Most Common)

Skin reactions are the primary distinguishing adverse effect of transdermal formulations:

• Transdermal gels cause local skin reactions in only 5% of users, consisting mainly of erythema or pruritus 2, 1
• Patches cause significantly more skin reactions, occurring in up to 66% of users 2
• Application site reactions are generally mild and resolve with continued use, with discontinuation rates of only 0.9% in clinical trials 3
• Contact dermatitis at non-application sites can occur in rare cases 3
• Minor cosmetic effects include acne, oily skin, increased body hair, and flushing 2

Clinical Pearl: The dramatically lower skin reaction rate with gels (5%) versus patches (66%) makes gels the preferred transdermal formulation for most patients 1.

Hematologic Effects (Most Clinically Significant)

Erythrocytosis represents the most important adverse effect requiring active monitoring:

• Erythrocytosis occurs in 2.8% to 17.9% of patients using transdermal preparations, with rates increasing in a dose-dependent manner 2
• Hematocrit increases of 15-20% are typical as testosterone stimulates erythropoiesis 2, 1
• Most elevations occur within the first three months of therapy 2, 1
• When hematocrit exceeds 54%, immediate intervention is mandatory: dose reduction, temporary discontinuation, therapeutic phlebotomy, or blood donation 1
• Elevation above normal range may aggravate vascular disease in coronary, cerebrovascular, or peripheral circulation, particularly in elderly patients 2

Important Note: Transdermal preparations have significantly lower erythrocytosis rates (2.8-17.9%) compared to intramuscular injections (43.8%) 2.

Prostate-Related Effects

Prostate monitoring is essential despite lack of proven cancer causation:

• Increased PSA is reported in 11.1% of patients and is the most commonly reported adverse reaction in clinical trials 3
• Prostate volume increases significantly during the first six months to levels equivalent to eugonadal men 2, 1
• Prostate biopsy should be performed for PSA increases ≥1.0 ng/mL in one year 2, 1
• The American Urological Association states there is no evidence linking testosterone therapy to prostate cancer development 1
• Benign prostatic hyperplasia exacerbation is rare, with no significant worsening of voiding symptoms in most studies 2

Reproductive/Endocrine Effects

Fertility compromise is universal and predictable:

• Down-regulation of gonadotropins causes testicular atrophy and infertility through suppression of FSH and LH 2, 1
• If fertility is desired, testosterone therapy is contraindicated and alternative treatments should be used 1
• Exogenous testosterone will further suppress gonadotropin secretion 1
• Breast tenderness and gynecomastia occur in a small number of men, as testosterone can be aromatized to estradiol 2, 1

Cardiovascular Considerations

Recent high-quality evidence suggests cardiovascular safety:

• The 2024 American Heart Association/American Stroke Association guideline states that testosterone therapy in men 45-80 years with confirmed hypogonadism does not increase stroke risk based on the TRAVERSE trial 1
• The American Urological Association cannot definitively state whether testosterone increases or decreases cardiovascular event risk, though recent data suggest a neutral or possibly beneficial effect 1
• Fluid retention is uncommon and generally mild, but use cautiously in men with congestive heart failure or renal insufficiency 2
• Hypertension is rarely reported 2

Neuropsychiatric Effects

Sleep apnea risk requires baseline assessment:

• Sleep apnea risk is highest in men receiving higher doses who have other identifiable risk factors 2, 1
• Assessment for sleep apnea history should be performed at baseline 2, 1
• Upper-airway dimensions are unaffected, suggesting androgen replacement contributes to sleep-disordered breathing by central mechanisms 2
• Emotional lability (including mood swings, affective disorder, impatience, anger, and aggression) occurs in 2.6% of patients 3

Metabolic Effects

Lipid profiles remain largely unaffected:

• Transdermal testosterone appears to have minimal effects on lipid profiles, with no significant changes in HDL, LDL, or total cholesterol in most studies 2, 1
• Hyperlipidemia is reported in ≤2% of patients 3

Hepatic Effects

Transdermal preparations are hepatically safe:

• Transdermal preparations do not appear to be associated with hepatic dysfunction, and routine monitoring with liver-function tests is unnecessary 2
• This contrasts sharply with oral testosterone preparations, which are strongly discouraged due to hepatotoxicity 2

Critical Monitoring Algorithm

Mandatory baseline assessments:

• PSA and digital rectal examination 2, 1
• Hematocrit or hemoglobin level 2, 1
• Sleep apnea history 2, 1
• Voiding symptoms 2

Follow-up monitoring schedule:

• First visit at 1-2 months to assess efficacy and check hematocrit 2, 1
• Every 3-6 months for the first year, then yearly thereafter 2, 1
• At each visit: assess symptomatic response, voiding symptoms, sleep apnea, perform digital rectal examination, measure serum testosterone, PSA, and hematocrit 2