Androgen receptor blockers, often called antiandrogens, interfere with the body’s natural male sex hormones, known as androgens (testosterone and dihydrotestosterone, or DHT). The primary function of these blockers is to prevent androgens from activating specific proteins, which promotes cell growth in hormone-sensitive tissues. By disrupting this hormonal signaling pathway, these drugs are important tools for treating conditions that rely on androgen activity for their progression.
Understanding Androgen Signaling and Blockade
Androgens, such as testosterone and DHT, exert their effects by binding to the Androgen Receptor (AR), a protein found inside cells. When an androgen binds to the AR, the receptor changes shape and moves into the cell’s nucleus, where it attaches to specific DNA sequences. This binding activates gene transcription, promoting cell growth, division, and survival. In diseases like prostate cancer, cells become dependent on this signaling pathway for proliferation.
Androgen receptor blockers work by competitively occupying the binding site on the AR, acting as a decoy molecule. By binding to the receptor, the blocker prevents natural androgens from attaching and activating the protein. This action alters the receptor’s structure, inhibiting its ability to move into the nucleus and initiate the gene transcription that drives cell growth. This direct receptor blockade mechanism is distinct from other hormone therapies, such as LHRH agonists, which reduce the overall production or level of androgens in the body.
Classification of Androgen Receptor Inhibitors
Androgen receptor blockers are classified into different generations based on their potency, structure, and ability to overcome drug resistance. The earliest versions are first-generation antiandrogens, including non-steroidal agents like bicalutamide, flutamide, and nilutamide. These initial drugs bind to the AR with lower affinity compared to natural androgens, providing incomplete inhibition. A limitation of these older agents is that during prostate cancer resistance, they can sometimes exhibit an unintended agonist effect, activating the receptor instead of blocking it.
The development of second-generation AR blockers marked a significant advance, offering a more robust mechanism of action. Examples include enzalutamide, apalutamide, and darolutamide. These drugs bind the AR with higher affinity and more effectively impede its functions, preventing its movement into the cell nucleus and its binding to DNA. Their enhanced potency allows them to overcome resistance mechanisms that develop with first-generation therapy.
A separate classification distinguishes between steroidal and non-steroidal antiandrogens based on composition. Steroidal agents are structurally similar to natural steroid hormones and often have broader hormonal effects. Non-steroidal agents, which include all first and second-generation drugs, are chemically distinct and are the current standard because they offer more specific targeting of the androgen receptor. The newest agents, such as darolutamide, also exhibit lower penetration into the central nervous system, which reduces certain side effects.
Primary Medical Applications
The most common application for androgen receptor blockers is the treatment of prostate cancer, as this malignancy is frequently driven by androgen signaling. In early-stage or localized disease, AR blockers are sometimes used briefly with Luteinizing Hormone-Releasing Hormone (LHRH) agonists to prevent a temporary surge in testosterone levels, known as a “tumor flare.” For advanced or metastatic castration-sensitive prostate cancer, these blockers are often combined with other forms of androgen deprivation therapy (ADT) to achieve total androgen blockade.
In castration-resistant prostate cancer (CRPC), where the disease progresses despite very low androgen levels, second-generation AR blockers are used. These potent agents suppress residual AR activity that drives cancer growth, offering improved survival outcomes for patients with both non-metastatic and metastatic CRPC. By interfering with the mutated or overactive androgen receptors often seen in CRPC, drugs like enzalutamide or apalutamide slow disease progression.
Beyond oncology, AR blockers manage conditions related to excess androgen activity in women, known as hyperandrogenism. They may be prescribed for severe hirsutism (excessive hair growth) or to manage symptoms associated with Polycystic Ovary Syndrome (PCOS). Spironolactone is a common antiandrogen used for these purposes, though it is primarily a diuretic. Additionally, AR blockers are utilized as a component of hormone replacement therapy (HRT) for transgender women to reduce masculine physical traits and promote feminization.
Common and Severe Adverse Reactions
The side effect profile of androgen receptor blockers stems directly from their mechanism of action, as blocking androgen signaling affects multiple physiological systems. Systemic side effects are frequent and hormonal, including fatigue and hot flashes, which are common to most forms of androgen deprivation. Other typical reactions include decreased libido, erectile dysfunction, and physical changes such as gynecomastia (growth of male breast tissue). Patients may also experience loss of muscle mass, weakness, and changes in body weight.
Some AR blockers carry risks of severe adverse events that require careful monitoring. For instance, first-generation agents like flutamide have been linked to liver toxicity, necessitating regular checks of liver function. Newer agents, such as enzalutamide and apalutamide, have been associated with neurological side effects, including increased risk of seizures and cognitive impairment. Darolutamide was developed to minimize these neurological risks due to its limited ability to cross the blood-brain barrier.
Cardiovascular risks are another important consideration, as some AR blockers are linked to events like hypertension and heart failure. Clinical trials have shown an increased risk of hypertension with enzalutamide use. Because of these potential complications, especially cardiovascular and hepatic risks, patients receiving AR blocker therapy must undergo regular blood work and health assessments. Prior to starting treatment, a patient’s overall cardiovascular risk profile and existing comorbidities are evaluated to determine the safest drug choice.