Jesse Mills, MD, explains the complications of multi-drug TRT

In this video, Jesse N. Mills, MD, director of the Men's Clinic at UCLA, fellowship director of the UCLA male reproductive medicine and surgery program, and director of UCLA Urology Santa Monica, discusses how the landscape of testosterone replacement therapy (TRT) has shifted, especially with the rise of online and direct-to-consumer platforms.

He explains that medications such as anastrozole, hCG, clomiphene, and enclomiphene—tools used thoughtfully in academic urology for specific indications—are now often bundled automatically with TRT, even when they are unnecessary or inappropriate. This trend, he argues, stems from widespread misinterpretation of medical literature and a lack of individualized clinical judgment.

Mills emphasizes that adjunct medications are not benign. Anastrozole, for example, is frequently prescribed by telehealth providers to “prevent” estrogen-related symptoms, yet long-term use can reduce bone density and lower HDL cholesterol. Its legitimate role is narrow: It may modestly raise intratesticular testosterone to support sperm production, but only in specific fertility-related contexts. When patients on high doses of testosterone develop estrogen-related adverse events—such as gynecomastia or hair loss—he stresses that the first step should be adjusting the testosterone dose, not reflexively adding estrogen blockers.

He notes that hCG is widely used by commercial TRT clinics, often appropriately, because exogenous testosterone suppresses pituitary FSH and LH, leading to reduced sperm production and smaller testicular volume. Though off-label, hCG can help maintain some testicular function and preserve sperm output in men who want fertility protection. In contrast, pairing clomiphene with testosterone rarely makes physiological or clinical sense; combining a selective estrogen receptor modulator with exogenous testosterone amounts to redundant therapy with unclear long-term effects.

Mills warns that such poorly justified combination regimens complicate downstream management for urologists, who must untangle unnecessary medications, address avoidable adverse events, and reset expectations for patients who were led to believe these multi-drug protocols are standard. He concludes by urging caution, evidence-based dosing, and awareness that most of these combination approaches remain off-label despite years of empirical use.