Testosterone Testing and Treatment Guidelines

Diagnostic Criteria

• The American Urological Association recommends that testosterone deficiency requires both consistently low testosterone levels (<300 ng/dL on two separate morning measurements) AND the presence of clinical symptoms/signs of hypogonadism 1, 2

Laboratory Testing Requirements

• The Endocrine Society suggests measuring total testosterone on two separate mornings between 8-10 AM using the same laboratory and methodology to confirm diagnosis 1, 2
• The diagnostic threshold is <300 ng/dL on both measurements, as recommended by the American Urological Association 1, 2

Clinical Symptoms to Assess

• Patients must have symptoms consistent with testosterone deficiency, including reduced energy, endurance, and physical performance, as noted by the American Urological Association 1
• The American Urological Association also recommends assessing for fatigue and diminished work performance 1
• Depression, reduced motivation, poor concentration, and impaired memory are also symptoms of testosterone deficiency, according to the Endocrine Society 3

Physical Examination Findings

• A targeted examination evaluating body habitus and BMI/waist circumference is recommended by the American Urological Association 1
• The American Urological Association also suggests evaluating virilization status (body hair patterns in androgen-dependent areas) 1

High-Risk Populations Requiring Testing

• The American Urological Association recommends measuring testosterone in all patients with unexplained anemia, even without symptoms 1
• The Endocrine Society suggests measuring testosterone in patients with bone density loss, diabetes, and HIV/AIDS 2, 3

Adjunctive Laboratory Testing

• The American Urological Association recommends measuring serum LH in all patients with confirmed low testosterone to establish etiology (primary vs. secondary hypogonadism) 1, 3
• The Endocrine Society suggests measuring serum prolactin if testosterone is low AND LH is low or low-normal to screen for hyperprolactinemia 1, 3

Treatment Initiation

• The American Urological Association recommends aiming for testosterone levels in the mid-normal range (350-750 ng/dL) during treatment 1, 3

Monitoring During Treatment

• The Endocrine Society recommends monitoring PSA in men over 40 years 3
• The American Urological Association suggests measuring serum estradiol if breast symptoms or gynecomastia develop 1, 3

Special Considerations for Fertility Preservation

• The American Urological Association recommends considering selective estrogen receptor modulators instead of testosterone therapy for patients wishing to preserve fertility with low/normal LH levels 3
• The Endocrine Society suggests considering gonadotropin therapy (combination of hCG and FSH) as an alternative 3

Lifestyle Modifications

• The Endocrine Society recommends weight loss through low-calorie diets to improve testosterone levels in obese patients with secondary hypogonadism 3
• Regular physical activity provides similar benefits, though testosterone increases are typically modest (1-2 nmol/L), as noted by the Endocrine Society 3

Diagnosis of Low Testosterone

Diagnostic Criteria

• The morning timing of testosterone measurement is critical due to diurnal variation in testosterone production 4
• Decreased libido and erectile dysfunction are key symptoms to assess in patients with low testosterone 4
• Loss of muscle mass and body hair are also symptoms associated with low testosterone 4
• Hot flashes, gynecomastia, or infertility can be symptoms of low testosterone 4

Laboratory Evaluation

• In patients with obesity, measure free testosterone by equilibrium dialysis and sex hormone-binding globulin 4
• Obesity-related low total testosterone may be due solely to low sex hormone-binding globulin with normal free testosterone 4
• If free testosterone is also low on at least 2 separate assessments, consider testosterone replacement after completing the hypogonadism workup 4

Etiology Determination

• Measure serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to distinguish primary (testicular) from secondary (pituitary-hypothalamic) hypogonadism 4
• Consider further evaluation including iron saturation, pituitary function testing, and MRI of the sella turcica if secondary hypogonadism is confirmed 4

Critical Considerations

• Never measure testosterone at random times of day, as afternoon or evening measurements will be physiologically lower and lead to false-positive diagnoses 4

Monitoring Blood Tests for Patients on Testosterone Therapy

Baseline Testing (Before Starting Therapy)

• The American Urological Association recommends that hemoglobin and hematocrit must be measured before initiating testosterone therapy; if hematocrit exceeds 50%, withhold therapy until the etiology is investigated 5, 6
• The American Urological Association recommends that PSA testing is required in all men over 40 years of age to exclude occult prostate cancer; if elevated, obtain a second PSA to rule out spurious elevation 5, 6
• Serum estradiol should be measured in patients presenting with breast symptoms or gynecomastia prior to starting therapy 5
• Cardiovascular risk factors including lipid profile, blood pressure, and assessment for diabetes must be evaluated, as these represent modifiable ASCVD risk factors 5, 6
• Fertility evaluation including testicular exam and FSH measurement should be performed in men interested in preserving fertility 5

Monitoring During Treatment

• Hematocrit >54% warrants immediate intervention such as dose reduction or temporary discontinuation of therapy 5, 6
• Injectable testosterone formulations carry the highest risk of erythrocytosis (43.8% of patients had elevated hematocrit >52% in one study), compared to transdermal patches (15.4%) and gels (2.8-17.9% depending on dose) 7, 8
• Most hematocrit changes occur within the first 3 months of therapy, making early monitoring particularly important 7, 8
• Erythrocytosis increases blood viscosity and can aggravate coronary, cerebrovascular, or peripheral vascular disease, particularly in elderly patients or those with chronic obstructive pulmonary disease 8
• For patients over 40 who maintain on-treatment testosterone levels in the normal range, PSA testing frequency should follow a shared decision-making approach in accordance with AUA Early Detection of Prostate Cancer Guidelines 5, 6
• Testosterone levels should be monitored to ensure therapeutic efficacy and avoid supraphysiologic levels, which are associated with higher rates of erythrocytosis 7, 8

Frequency of Monitoring

• Most intensive monitoring should occur in the first 3-6 months, when hematocrit changes are most pronounced and prostate volume increases stabilize 5, 7, 8
• Hematocrit monitoring should be more frequent with injectable testosterone (every 3-6 months initially) given the 43.8% incidence of elevated values, compared to less frequent monitoring with transdermal preparations 7, 8

Management of Abnormal Values

• Implement dose reduction, temporarily discontinue testosterone, perform therapeutic phlebotomy, or arrange blood donation for elevated hematocrit (>54%) 7, 8
• Two elevated baseline PSA levels warrant formal evaluation including reflex testing (4K or phi) and consideration of prostate biopsy with/without MRI before continuing therapy 5, 6
• Although no testosterone-associated thromboembolic events had been reported in the literature as of 2004, the theoretical risk remains significant given the documented increases in blood viscosity, particularly in patients with pre-existing cardiovascular disease 7, 8