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Hormone therapy typically is effective for only a few years. After this time, the hormone-independent cells eventually become strong enough that hormone therapies will have less and less of an effect on the growth of the tumor. However, because the hormone sensitive cells aren’t actually eradicated, a number of "secondary" hormone approaches can be used to keep the tumor from spreading.

For many men who were using an antiandrogen in combination with an LHRH agonist, stopping the antiandrogen, or antiandrogen withdrawal, is the most common first step in secondary hormone therapy. Switching to a different antiandrogen might also be able to offer an extra few months of benefit before other therapeutic approaches are required. About 10-30% of men will experience this anti-androgen withdrawal, which lasts on average 3-5 months, during which time additional therapies are not needed. However, inevitably, additional therapies will be needed even if this withdrawal response occurs.

Another option is to block the release of testosterone from the adrenal glands, small organs that sit on top of the kidneys. Only about 10% of the circulating testosterone is produced by these two glands, so few therapeutic interventions focus on them until it becomes important that every last bit of the hormone is removed. The two most commonly used drugs used for this purpose, ketoconazole or aminoglutethimide, are typically administered in conjunction with steroids to avoid the effects seen when the adrenal glands are shut down. Newer second generation hormonal drugs (like abiraterone acetate) also work to lower testosterone in this fashion, and are in clinical trials currently.

As a final option, estrogen therapy can be added to the mix. A synthetic form of estrogen known as diethylstilbestrol (DES) was the first hormone therapy used in lieu of surgical castration, but was removed from the market because of safety issues in women who were taking it to prevent miscarriage. Nevertheless, it continues to be used for men with prostate cancer, and can be obtained from non-US pharmacies or can be synthesized from other estrogens. Although the drug has proved to be effective in counteracting the effects of testosterone and in slowing the growth of prostate cancer, continuous estrogen therapy has been associated with increased cardiovascular side effects including blood clots and strokes, and is therefore often administered along with an anticoagulant drug.

Other estrogens might be used when DES is unavailable, but all have the same side effects. Because estrogen is one of the main hormones that affect female characteristics, signs of demasculinization such as increased breast size and tenderness, are commonly seen. Importantly, many plant-based and complementary medicines can have estrogen-like properties and can interfere with the effectiveness of your hormone therapy, so be sure that your doctor has a complete list of all drugs—including the "non-traditional" ones—so that he or she can better monitor the effects of your therapy on the progression of your disease.

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