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Blockade of testicular and adrenal androgens in prostate cancer treatment

Nature Reviews Urology volume 8, pages 73–80 (2011)Cite this article

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Abstract

Prostate cancer is the most hormone sensitive of all cancers. However, any hormonal therapeutic strategy must take into account the fact that two almost equivalent sources of androgens act in the prostate, namely testosterone of testicular origin, and the locally produced androgens testosterone and dihydrotestosterone (DHT) derived from dehydroepiandrosterone of adrenal origin. Combined androgen blockade—medical or surgical castration plus a pure antiandrogen—would, therefore, be the logical first-line treatment for prostate cancer, although castration or an antiandrogen alone is still chosen in the majority of cases. Although long-term control, or even cure, is possible when combined androgen blockade is used when the tumor is localized, resistance to treatment invariably develops in patients when start of treatment is delayed until the disease has become metastatic. This observation can be explained either by elevated levels of the androgen receptor, which can increase the response to low levels of androgens and also modify the response to antiandrogens; or by local biosynthesis of androgens. Research to identify new and more potent antiandrogens, as well as blockers of peripheral and adrenal androgen biosynthesis—such as abiraterone—could be of great importance.

Key Points

  • Testicular androgens account for only 50–60% of total testosterone in the prostate, with the remainder produced by intraprostatic conversion of adrenal steroids

  • Prostate cancer is most frequently treated with medical or surgical castration alone, but this treatment does not ablate androgens of extratesticular origin, and castration resistance usually develops

  • Castration resistance could be caused by increased levels of the androgen receptor or by intraprostatic synthesis of androgens from adrenal steroids or, possibly, from cholesterol

  • Combined androgen blockade with a pure antiandrogen in addition to surgical or medical castration seems, therefore, to be a scientifically sound approach to managing patients with prostate cancer

  • Novel agents such as abiraterone, which blocks androgen biosynthesis, have shown promise in patients with prostate cancer, especially when combined with glucocorticoid treatment

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Figure 1: Sources of androgens in the human prostate.
Figure 2: Effect of castration on androgen levels.
Figure 3: The human steroidogenesis pathways in peripheral target tissues.
Figure 4: The effect of medical or surgical castration alone (monotherapy) versus CAB (castration plus an antiandrogen, such as flutamide, nilutamide or bicalutamide) on prostate-cancer-specific survival, expressed as a percentage of responses to placebo.
Figure 5: Potential sites of action for hormonal therapies in prostate cancer.

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Labrie, F. Blockade of testicular and adrenal androgens in prostate cancer treatment. Nat Rev Urol 8, 73–80 (2011). https://doi.org/10.1038/nrurol.2010.231

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