Hormonal Agents

Intro & MoA Principles - Hormone Hijackers

Targets hormone-sensitive cancers by disrupting endocrine pathways vital for their growth.

• Goal: Interfere with hormone synthesis, release, or receptor binding.
• Key Mechanisms:
  • Receptor Antagonism: Block Estrogen Receptors (ER) in breast cancer, Androgen Receptors (AR) in prostate cancer.
  • Synthesis Inhibition: ↓ hormone production (e.g., aromatase inhibitors ↓ estrogen; GnRH analogues: pituitary desensitization → ↓ sex hormones).
  • Hormone Deprivation: Overall ↓ in circulating or local active hormones available to cancer cells.
• Common Targets: Hormone Receptor-positive (HR+) Breast, Prostate, Endometrial, and Ovarian cancers.

⭐ Many hormonal therapies are cytostatic (arrest cell growth) rather than cytotoxic, controlling tumor progression, often used for long-term or adjuvant treatment strategies to prevent recurrence.

Anti-Estrogens & AIs - Estro-Stoppers

• Anti-Estrogens (Target ER):
  • SERMs (Selective Estrogen Receptor Modulators):
    • Tamoxifen: ER antagonist (breast); agonist (bone, endometrium). Use: ER+ breast Ca (pre/postmeno). SE: Hot flashes, ↑ endometrial Ca, DVT/PE. 📌 TAM: Tummy, Thrombo.
    • Raloxifene: ER antag (breast, endometrium); agonist (bone). Use: Osteoporosis, breast Ca prevention (postmeno). No ↑ endometrial Ca.
    • Fulvestrant (SERD): Pure ER antagonist, degrades ER. Use: Tamoxifen-resistant ER+ breast Ca.
• Aromatase Inhibitors (AIs) (Block Estrogen Synthesis):
  • MOA: Inhibit aromatase.
  • Types: Non-steroidal (Anastrozole, Letrozole); Steroidal (Exemestane - irreversible).
  • Use: ER+ breast Ca (POSTMENOPAUSAL).
  • SE: Arthralgia, bone loss (↑ fracture risk), hot flashes.

⭐ AIs are often first-line for adjuvant ER+ breast Ca in postmenopausal women.

Anti-Androgens & GnRH Agents - Testo-Terminators

• Anti-Androgens: Block Androgen Receptor (AR) or inhibit androgen synthesis.
  • AR Antagonists (Non-steroidal):
    • "-lutamides": Flutamide (hepatotoxic), Bicalutamide, Nilutamide.
    • Newer: Enzalutamide (seizure risk), Apalutamide, Darolutamide (improved CNS safety).
    • SE: Gynecomastia, hot flashes, ↓libido.
  • Androgen Synthesis Inhibitor:
    • Abiraterone (CYP17A1 inhibitor): Give with prednisone. SE: Mineralocorticoid excess (HTN, ↓K+).
• GnRH (LHRH) Agents: Achieve medical castration.
  • Agonists: Leuprolide, Goserelin. Initial flare (use anti-androgen cover), then ↓testosterone.
  • Antagonists: Degarelix, Relugolix (oral). No flare, rapid ↓testosterone.
• Primary Use: Prostate cancer.
• 📌 CAB (Combined Androgen Blockade): GnRH agonist + Anti-androgen.

⭐ Degarelix, a GnRH antagonist, provides rapid testosterone suppression without the initial tumor flare characteristic of GnRH agonists (e.g., Leuprolide).

Other Hormonal Agents - Hormone Helpers

• Progestins:
  • Examples: Megestrol acetate, Medroxyprogesterone acetate.
  • Key Uses:
    • Endometrial, breast, prostate Ca (palliative).
    • Cancer cachexia (↑appetite).
  • Mechanism: Downregulate estrogen receptors; high-dose direct cytotoxicity.
• Corticosteroids: (e.g., Prednisone, Dexamethasone)
  • Malignancies: Lymphomas, leukemias (ALL, CLL), multiple myeloma.
  • Palliative roles: ↓inflammation, ↓pain, ↓cerebral edema, anti-emetic, ↑appetite, ↑well-being.
  • Mechanism: Bind glucocorticoid receptors; induce lymphoid cell apoptosis.

  ⭐ Dexamethasone is commonly used to reduce peritumoral edema in brain metastases.

High‑Yield Points - ⚡ Biggest Takeaways

• Tamoxifen (SERM): ER antagonist (breast), agonist (endometrium); Risks: endometrial Ca, DVT.
• Aromatase inhibitors (Anastrozole): Block estrogen synthesis; For postmenopausal ER+ breast Ca; Risk: osteoporosis.
• GnRH agonists (Leuprolide): Continuous use ↓FSH/LH; For prostate Ca; Initial tumor flare.
• GnRH antagonists (Degarelix): Directly block GnRH receptors, no tumor flare; For prostate Ca.
• Antiandrogens (Flutamide): Block androgen receptor; With GnRH agonists for prostate Ca.
• Fulvestrant (SERD): Pure ER antagonist; For tamoxifen-resistant breast Ca.