Injectable testosterone suppresses natural production, causing infertility. New protocols use shorter-half-life oral/topical testosterone combined with enclomiphene (which blocks estrogen feedback) to increase T-levels while maintaining the body's own production, making it a viable option for younger men concerned about fertility.

Despite showing a metastasis-free survival benefit in the EMBARC trial, enzalutamide monotherapy is being used less. The significant risk of gynecomastia, persistent fatigue, and most importantly, the lack of an overall survival advantage compared to ADT, have made it a less attractive option for patients and clinicians.

ADT monotherapy is an obsolete strategy for metastatic prostate cancer. For patients too frail for standard ADT+ARPI combination therapy, enzalutamide monotherapy is a superior alternative. It offers effective treatment that can be quickly stopped to reverse side effects if tolerance issues arise, unlike injectable ADT.

The EMBARK trial showed that enzalutamide monotherapy was superior to standard ADT monotherapy for metastasis-free survival. This suggests potent AR antagonism may be a more effective strategy than simply depleting the testosterone ligand, challenging the long-held dogma of ADT being the fundamental building block for systemic prostate cancer therapy.

A common mistake in testosterone replacement therapy is to suppress estrogen. For optimal libido, cardiovascular health, and bone density, men should aim to have estrogen levels as high as possible without side effects. High testosterone works best in concert with high estrogen.

Transdermal estradiol is gaining renewed attention as an ADT option. Recent trials show it is non-inferior to standard LHRH analogs, offering a different side effect profile. This allows clinicians to trade side effects like hot flashes for gynecomastia, enabling more personalized treatment decisions.

The body has different estrogens: E1 (pro-inflammatory) and E2 (protective). Current breast cancer therapies are blunt instruments, blocking both types. This indiscriminate blocking contributes to negative side effects like cardiometabolic dysfunction, highlighting a need for more targeted future treatments.

Some men strongly resist continuous androgen deprivation due to its impact on identity and quality of life. Intermittent therapy, pausing treatment after a good response, offers a compromise, allowing for testosterone recovery and a break from side effects.

When using intermittent androgen deprivation, GnRH antagonists like relugolix are preferred over LHRH agonists like leuprolide. Antagonists allow for a much faster recovery of testosterone during off-treatment periods, which is a significant quality-of-life benefit for patients. With agonists, testosterone recovery can sometimes take years.