Androgen receptor antagonists are compounds that block androgen receptors and antagonize the effect of androgens such as testosterone. Several conditions such as hirsutism, acne and prostate cancer are known to be dependent on androgens and antiandrogens can help alleviate the symptoms of these condition or even improve the outcome in patients with metastatic prostate cancer.
Are you more of a visual learner? Check out our online video lectures and start your pathology course now for free!

human androgen receptor and androgen binding


Definition of Androgen Receptor Antagonists

Androgen receptor antagonists work by blocking androgen receptors, hence diminishing the androgen effects on the target tissue, for instance, a prostate tumor. These antiandrogens resemble natural occurring androgens such as testosterone structurally, but have an opposite effect in that they block the receptor.

Why Androgen Receptor Antagonists are Needed

The role of androgens in the pathophysiology of different conditions such as prostate cancer, acne, hirsutism, or infertility in polycystic ovary syndrome has been extensively studied.

Androgen diminishing techniques such as castration, and the administration of high dosage estrogen were used in the 1950s to improve the prognosis of patients with metastatic prostate cancer.

Additionally, patients with metastatic prostate cancer, with progression of tumor after castration, showed response to docetaxel, prolonging their life by decades. These findings led to the realization that antiandrogens might play an important role in changing the outcome of prostate cancer.

Androgens and Prostate Cancer

Our current understanding of the role of androgens in the normal prostate allows us to anticipate how important it is to modulate androgen receptors in prostate disease, including prostate cancer.

prostate cancer

Image: “Differences between healthy prostate and prostate with a tumor.” by BQmUB2012102 – Own work. License: CC BY-SA 3.0

The binding of androgen to androgen receptors in normal prostate cells activates the pathways responsible for cellular differentiation, rather than proliferation. However, in patients with prostate cancer, the androgen binding to its receptors results in the activation of proliferation pathways rather than differentiation, hence making the tumor more aggressive and more likely to metastasize. Therefore, blocking this cascade by either castration, or by inhibiting androgen receptors, can have a positive effect on the prognosis of patients with advanced and metastatic prostate cancer.

Androgen Deprivation Therapy

One of the easiest ways to diminish the effects of androgen is to simply diminish production of androgen. Surgical or chemical castration are one form of anti-androgen therapy, since the testicles are rendered unable to produce androgens, either chemically or due to surgical removal.

The administration of leuprolide can achieve chemical castration. Leuprolide is a luteinizing hormone releasing hormone (LHRH) analogue that works on LHRH receptors in the hypothalamus and down-regulates them. Down-regulating LHRH receptors in the hypothalamus are thought to adversely affect the hypothalamic-pituitary axis and eventually results in reduction of testosterone production.

Why Do We Need Other Treatments?

In the treatment of prostate cancer, approximately three years after castration, the adrenal glands take over and start producing androgens. Therefore, the disease could progress, unless intracellular synthesis of androgens is inhibited.

Ketoconazole, an anti fungal drug, has one side effect that might be helpful in patients with castration resistant advanced prostate cancer: it can inhibit androgen synthesis in the adrenal glands.

More recently, abiraterone has been approved for the treatment of castration resistant prostate cancer. Abiraterone works by inhibiting androgen synthesis like ketoconazole but it is safer, more potent, and more selective to the adrenal glands.

Antiandrogens in the Treatment of Metastatic Prostate Cancer

Unfortunately, many patients with metastatic prostate cancer are castration-resistant and they still have disease progression even after the administration of ketoconazole or abiraterone. Therefore, other mechanisms of blocking androgen effects on the cancerous prostate cells are needed.

The first antiandrogens used in practice were steroidal in structure. Unfortunately, these antiandrogens had low efficacy, were hepatotoxic and had several other side effects such as decreased libido and increased risk of cardiovascular disease.

The next group of drugs used were nonsteroidal anti androgens. As we have previously explained, androgen binds to its receptors thus activating cellular proliferation instead of differentiation in cancerous cells. This happens due to two important factors: the first, is that androgen will bind to its receptors on the cellular surface by binding to the ligand-binding pocket. Once this happens, a coactivator-binding platform is formed (AF1), which recruits other coactivators, which eventually form an active transcriptional complex. This complex reads several androgen-regulated genes that are thought to play an important role in inducing cellular proliferation.

Therefore, blocking the AF1 coactivator from recruiting other coactivators can play a key role in antagonizing the effects of androgens. The antiandrogen bicalutamide (bic) acts by binding to the ligand-binding pocket at the androgen receptor and forming an inactive coactivator that cannot recruit other coactivators, hence make it impossible to form the active transcription complex. In fact, binding of bic to the ligand-binding pocket results in the formation of a factor that recruits co-repressors, further antagonizing the normal androgenic effects of inducing DNA transcription.

Bic has been studied in different randomized clinical trials where they found it to be effective in altering the prognosis of advanced prostate cancer as first line therapy. Therefore, the American Society of Clinical Oncology currently suggests the use of bic monotherapy as a possible alternative for castration.

structural formula of enzalutamide

Image: “Structural formula of enzalutamide.” by Vaccinationist – Own work. License: Public Domain

Another antiandrogen that was approved in 2009 is enzalutamide. Enzalutamide is superior to bic because it does not only inhibit the formation of an active AF1 but it also inhibits the translocation and binding of the coactivator binding platform to its nuclear target.

This mechanism of action is responsible for the almost complete blockade of DNA transcription of androgen regulated genes that can be achieved with enzalutamide. Enzalutamide and bic are both nonsteroidal antiandrogens and are currently approved only in metastatic prostate cancer that is castration- and chemotherapy-resistant.

While enzalutamide is currently approved for use in chemotherapy-resistant cases of advanced prostatic cancer, a recent clinical trial showed efficacy of enzalutamide in patients with advanced prostate cancer even before attempting chemotherapy. This clinical trial showed clear efficacy of enzalutamide to the extent that it became unethical to continue with the clinical trial and the placebo group was switched to enzalutamide.

Do you want to learn even more?
Start now with 500+ free video lectures
given by award-winning educators!
Yes, let's get started!
No, thanks!

Leave a Reply

Your email address will not be published. Required fields are marked *