Antiandrogens

Antiandrogens are drugs that inhibit the action of the male sex hormones (androgens). In the treatment of hormone-dependent prostate carcinoma or benign prostatic hyperplasia, a number of antiandrogenic substances are used. For example, drugs such as cyproterone acetate and flutamide block androgen receptors and thus cancel out the effect of androgens on the prostate tissue. Androgen biosynthesis inhibitors such as abiraterone selectively inhibit CYP17, the key enzyme in testicular and extratesticular drug production. Gonadorelin agonists and antagonists suppress testosterosynthesis by intervening in the hormonal control loop.

Possible side effects of antiandrogens are male breast growth (gynecomastia), loss of libido and potency.

Classification of (oncologically used) drugs with antiandrogenic effect

5alpha-reductase inhibitors: 5alpha-reductase inhibitors are steroid-like drugs that competitively inhibit the enzyme 5alpha-reductase without being enzymatically converted themselves. Finasteride inhibits type II 5alpha reductase, which is expressed mainly in the prostate, other urogenital tissues and genital skin. Dutasteride inhibits 5alpha type II reductase as well as 5alpha type I reductase. This isoform of the enzyme is mainly found in the skin, hair follicles and liver. The inhibition of 5alpha reductase massively reduces the concentration of dihydrotestosterone (DHT) in the plasma. Both drugs are used orally and are approved for the treatment of benign prostatic hyperplasia. Active ingredients:

• Finasteride
• Dutasteride

Antiandrogenic substances with the indication prostate carcinoma

Inhibitors of androgen biosynthesis (inhibition of 17-alpha steroid hydroxylase): Inhibitors of androgen biosynthesis such as the active ingredient abiaterone acetate are pre-systemically converted by esterases into the steroidal active ingredient abiaterone. Abiaterone inhibits 17-alpha steroid hydroxylase and thus suppresses the formation of androstenedione and dehydroepiandrosterone (DHEA). This suppresses the biosynthesis of testosterone and cortisol. Abiraterone acetate is used to treat metastatic prostate cancer. Active ingredients:

• Abiraterone acetate

Androgen receptor antagonists: Androgen receptor antagonists block the androgen receptors. The androgen receptor antagonists are divided into:

• steroidal androgen receptor antagonists (like the androgens themselves)
• and
• non-steroidal androgen receptor antagonist

differentiated.

The steroidal androgen receptor antagonists are derived from progesterone and are less selective than the newer non-steroidal drugs. Cyproterone acetate (CPA), is the typical representative of this group. Cyproterone acetate is an antiandrogen, which is chemically a progesterone derivative. The active ingredient acts as a competitive antagonist at the androgen receptor. Indications are: hirsutism, severe acne vulgaris, sexual dysfunction and palliative treatment of prostate cancer.

The non-steroidal androgen receptor antagonists have common structural elements with the exception of darolutamide. The representatives of the family of non-steroidal androgen receptor antagonists are potent antagonists at the androgen receptor. The androgen receptor antagonists of the 2nd generation(enzalutamide and apalutamide) have the highest affinity to the androgen receptor. Androgen receptor antagonists lead to an increase in the release of gonadotropin and must therefore be used together with GnrH analogues. Various relevant study results support the importance of the androgen receptor signaling pathway in the treatment of prostate cancer. The non-steroidal antiandrogens can be divided into:

• 1st generation non-steroidal androgen receptor antagonists
  • Nilutamide
  • Flutamid
  • Bicalutamide
• 2nd generation non-steroidal androgen receptor antagonists
  • Darolutamide
  • Enzalutamide
  • Apalutamide

Gonadorelin receptor agonists (GnrH agonists, GnrH or LHRH analogs = obsolete term): Gonadorelin receptor agonists are synthetic analogs of the neurohormone gonadotropin-releasing hormone (GnRH), which are used as drugs to artificially lower the blood testosterone or estrogen levels. The substances are mainly used for forms of prostate cancer, breast cancer and endometriosis that are no longer treatable by surgery. They are also used in idiopathic pubertas praecox, where they act as so-called super-agonists to reduce the release of gonadotropins. In in vitro fertilisation they are used to determine the time of ovulation. Gonadorelin receptor agonists are also used in veterinary reproductive medicine. Active ingredients:

• Busrelin
• Leuprorelin
• Triptorelin

Gonadorelin receptor antagonists (GnRH blockers): Gonadorelin receptor antagonists block the GnRH receptors. With the new GnRH antagonists, also called GnRH blockers, alternative therapeutic options to the GnrH agonists are available. GnRH blockers competitively block the GnRH receptors in the pituitary gland, which secrete LH and FSH. Since the blockers block the receptors in contrast to the agonists and do not initially stimulate them, the effect of the GnRH blockers is immediate. Gonadotropin secretion is thus immediately and directly blocked and the testosterone level in the serum drops significantly and continuously within a few days after the start of therapy without an initial testosterone surge - similar to what is known from orchiectomy. Active ingredients:

• Abarelix
• Degarelix

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2. Davies ID et al(2019) Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med 381: 121-131
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