Why are aromatase inhibitors given with testosterone in patients with male hypogonadism or transgender men?

Why Aromatase Inhibitors Are Given With Testosterone

Aromatase inhibitors are combined with testosterone therapy primarily to prevent excessive conversion of testosterone to estradiol (estrogen), which can cause problematic elevations in estrogen levels, leading to gynecomastia, sexual dysfunction, and other adverse effects. 1, 2

Mechanism of Action

• Testosterone undergoes aromatization to estradiol via the cytochrome P450 aromatase enzyme, and when exogenous testosterone is administered at therapeutic doses, this conversion can result in supraphysiologic estradiol levels. 2

• Aromatase inhibitors like anastrozole reversibly block this enzymatic conversion, reducing estradiol production while maintaining or even increasing testosterone levels through reduced negative feedback on the hypothalamic-pituitary-gonadal axis. 1, 2

• In men receiving testosterone replacement, aromatase inhibitors decrease estradiol from a median of 65 pg/mL to 22 pg/mL (P < 0.001) while maintaining stable testosterone levels (616 ng/dL pre-treatment vs 596 ng/dL post-treatment). 1

Clinical Indications for Combined Therapy

When to Add an Aromatase Inhibitor

• Consider anastrozole 0.5 mg three times weekly when estradiol levels exceed 60 pg/mL regardless of symptoms, or when estradiol levels are 40-60 pg/mL with subjective symptoms such as gynecomastia, sexual dysfunction, or mood changes. 2

• Before adding an aromatase inhibitor, first optimize testosterone dosing to achieve mid-normal range levels (400-600 ng/dL) to minimize aromatization and avoid unnecessary polypharmacy. 1

Special Populations

• For fertility preservation, aromatase inhibitors may be preferable to exogenous testosterone alone because they increase endogenous testosterone production while reducing estradiol, resulting in significant improvements in sperm concentration (5.5 vs 15.6 million/mL, p<0.001) and motility. 1, 3

• In men with excess aromatase activity (abnormal testosterone/estradiol ratios), aromatase inhibitors can restore normal hormonal balance and improve spermatogenesis in cases of non-obstructive azoospermia. 3

Critical Safety Requirements Before Prescribing

Mandatory Baseline Assessment

• Before initiating anastrozole, baseline bone mineral density via DEXA scan and fracture risk assessment are absolute requirements, regardless of the indication. 1, 2

• Severe osteoporosis (T-score < -4 or >2 vertebral fractures) is an absolute contraindication to anastrozole use. 1, 2

• Moderate bone density loss (T-score -1.0 to -2.5) requires extreme caution and consideration of concurrent bone-protective agents like bisphosphonates or RANKL inhibitors. 1, 2

Mandatory Bone Protection

• All patients on anastrozole require calcium supplementation (1200 mg daily), vitamin D supplementation (400-600 IU daily minimum), and regular weight-bearing exercise. 1, 2

• Annual bone mineral density monitoring is necessary if continuing long-term therapy. 1

Expected Adverse Effects and Counseling

• Joint stiffness and arthralgias are very common side effects that patients must be counseled about before starting therapy. 1

• Vasomotor symptoms including hot flashes occur frequently and may require management with agents like venlafaxine. 1

• Hypertension and potential cardiovascular effects are possible, requiring monitoring of cardiovascular parameters. 1

Dosing Protocol

• The most commonly studied and recommended regimen is anastrozole 0.5 mg three times weekly, which appears safer than daily dosing by limiting excessive estradiol suppression. 1, 2

• Monitor testosterone levels every 6-12 months while on combined therapy to ensure appropriate hormonal balance. 1

Important Contraindications and Warnings

Specific to Hormone-Sensitive Cancers

• In men with hormone receptor-positive breast cancer, testosterone conversion to estrogen by aromatase raises serious concern about cancer recurrence. 4

• Testosterone/androgen supplementation should not be used by men with breast cancer according to ASCO guidelines (moderate strength recommendation). 4

• If testosterone is considered for hypogonadism in men with a history of hormone receptor-positive breast cancer, this requires an informed discussion about potential benefits and risks, considering the patient's residual risk of recurrence. 4

Transgender Medicine Context

• In transgender men receiving gender-affirming testosterone therapy, early preclinical studies suggest that high concentrations of testosterone may increase risk for estrogen-dependent cancer progression through aromatization. 4

• Implanted testosterone pellets for vasomotor or sexual symptoms may be combined with aromatase inhibitors without increased cancer risk, but the doses in these preparations are much lower than those used in gender-affirming hormone therapy. 4

Common Pitfalls to Avoid

• Never skip baseline bone density assessment before initiating aromatase inhibitor therapy, as this is a critical safety requirement. 1, 2

• Avoid daily dosing of anastrozole in men on testosterone therapy, as three-times-weekly dosing (0.5 mg) provides adequate estradiol suppression with better safety profile. 1, 2

• Do not use aromatase inhibitors as monotherapy in premenopausal women, as they are ineffective without ovarian suppression and are contraindicated in this population. 5

• Recognize that aromatase inhibitors alone do not address the underlying cause of hypogonadism and should be reserved for specific situations where estradiol elevation is problematic. 6