What are the guidelines for starting testosterone therapy?

Starting Testosterone Therapy: Evidence-Based Guidelines

Before initiating testosterone therapy, clinicians must complete a comprehensive pre-treatment evaluation including baseline hemoglobin/hematocrit, PSA testing in men over 40, cardiovascular risk assessment, and fertility counseling, while ensuring testosterone levels are measured on two separate fasting morning samples to confirm true deficiency. 1

Pre-Treatment Laboratory Evaluation

Baseline Hematologic Assessment

• Measure baseline hemoglobin and hematocrit in all patients before starting therapy 1
• If hematocrit exceeds 50%, withhold testosterone therapy until the etiology is formally investigated 1
• Injectable testosterone formulations are associated with the greatest treatment-induced increases in hemoglobin/hematocrit 1

Prostate Cancer Screening

• PSA must be measured in all men over 40 years of age prior to commencing testosterone therapy 1
• For patients with elevated baseline PSA, obtain a second PSA test to rule out spurious elevation 1
• If two PSA levels raise suspicion for prostate cancer, perform formal urological evaluation (potentially including reflex testing such as 4K or phi, and prostate biopsy with/without MRI) before initiating therapy 1

Cardiovascular Risk Stratification

• Assess all testosterone deficient patients for atherosclerotic cardiovascular disease (ASCVD) risk factors 1
• Fixed risk factors include older age and male gender 1
• Modifiable risk factors include dyslipidemia, hypertension, diabetes, and current cigarette smoking 1
• Testosterone therapy should not be commenced for 3-6 months in patients with a history of recent cardiovascular events (myocardial infarction or cerebrovascular accident) 1

Fertility Considerations

Pre-Treatment Fertility Assessment

• Men interested in future fertility must have reproductive health evaluation performed prior to treatment 1
• Perform testicular examination to evaluate testicular size, consistency, and descent 1
• Measure serum follicle-stimulating hormone (FSH) to assess underlying reproductive health status 1
• Consider semen analysis in patients with elevated FSH levels (hypergonadotropic hypogonadism) 1

Absolute Contraindication for Fertility

• Exogenous testosterone therapy should NOT be prescribed to men who are currently trying to conceive 1
• Testosterone therapy interrupts normal spermatogenesis and can cause severe oligospermia or azoospermia 1
• Patients must be informed of the highly variable time course to recover sperm in the ejaculate after testosterone cessation 1

Alternative Therapy for Fertility Preservation

• For men with secondary hypogonadism desiring fertility, use aromatase inhibitors, human chorionic gonadotropin (hCG), selective estrogen receptor modulators (SERMs), or combinations thereof instead of testosterone 1
• Only hCG has FDA approval for use in males among these alternatives 1

Contraindications to Therapy

Absolute Contraindications

• Breast or prostate cancer 1, 2, 3
• Men currently trying to conceive 1
• Hematocrit >50% (until etiology investigated) 1
• Recent cardiovascular event within 3-6 months 1

Relative Contraindications Requiring Caution

• Palpable prostate nodule or induration 1
• PSA >4 ng/mL (or >3 ng/mL in high-risk men including African Americans or those with first-degree relatives with prostate cancer) 1
• Severe lower urinary tract symptoms 1
• Untreated severe obstructive sleep apnea 1

Patient Counseling Requirements

Expected Benefits

• Inform patients that testosterone therapy may result in improvements in erectile function, low sex drive, anemia, bone mineral density, lean body mass, and/or depressive symptoms 1

Cardiovascular Risk Discussion

• Counsel patients that current scientific literature does not definitively demonstrate that testosterone therapy increases the risk of major adverse cardiovascular events (MACE) 1
• Advise patients to report cardiovascular symptoms such as chest pain, shortness of breath, dizziness, or transient loss of consciousness during follow-up 1

Prostate Cancer Risk

• Inform patients of the absence of evidence linking testosterone therapy to the development of prostate cancer 1
• For patients with history of treated prostate cancer, inform them there is inadequate evidence to quantify the risk-benefit ratio 1

Lifestyle Modifications

• Counsel all men with testosterone deficiency regarding lifestyle modifications as a treatment strategy 1
• Weight loss and increased physical activity can increase total testosterone levels and reduce symptoms of testosterone deficiency 1
• High body mass index coupled with low testosterone increases cardiovascular event risk 1

Formulation Selection

Avoid Specific Formulations

• Clinicians should NOT prescribe alkylated oral testosterone (17-alpha-alkylated androgens) 1
• Methyl testosterone is associated with liver toxicity, including abnormal liver function tests, cholestasis, and jaundice 1

FDA-Approved Indications

• Testosterone therapy is indicated for replacement therapy in conditions associated with deficiency or absence of endogenous testosterone 2, 3
• Primary hypogonadism (testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, or orchidectomy) 2, 3
• Hypogonadotropic hypogonadism (gonadotropin or LHRH deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation) 2, 3

Target Testosterone Levels

• Adjust testosterone therapy dosing to achieve total testosterone levels in the middle tertile of the normal reference range (450-600 ng/dL) 1
• Use minimal dosing necessary to drive testosterone levels to the normal physiologic range 1
• If patients do not experience symptomatic relief after reaching target testosterone levels, testosterone therapy should be stopped 1

Special Populations

Men with Treated Prostate Cancer

• The decision to commence testosterone therapy in men with in-situ prostate cancer on active surveillance or previously treated prostate cancer should be made with caution 1
• Testosterone therapy can be considered in men post-radical prostatectomy with favorable pathology (negative margins, negative seminal vesicles, negative lymph nodes) and undetectable PSA postoperatively 1
• After radiation therapy, patients do not appear to experience recurrence or progression of prostate cancer 1

Topical Testosterone Precautions

• Women and children are at highest risk for adverse events from topical testosterone transference 1
• Risks include virilization, precocious puberty, and hyperandrogenism 1
• Patients must avoid contact with unwashed or uncovered areas where topical testosterone has been applied 1

Common Pitfalls to Avoid

• Do NOT use testosterone therapy in eugonadal men 1
• Do NOT initiate therapy based on a single testosterone measurement—always confirm with repeat fasting morning measurement 1
• Do NOT start therapy in men actively trying to conceive—this is a critical error that can cause prolonged infertility 1
• Do NOT skip PSA testing in men over 40—this is essential to exclude occult prostate cancer 1
• Do NOT initiate therapy with hematocrit >50% without investigation 1