Hormonal therapies

Hormone-Receptor Hijinks - The Basic Premise

• Core Principle: Certain cancers are hormone-sensitive; their growth is driven by hormone binding to intracellular receptors, which then act as transcription factors.
• Key Examples:
  • Breast Cancer: Estrogen Receptor (ER), Progesterone Receptor (PR)
  • Prostate Cancer: Androgen Receptor (AR)
  • Thyroid Cancer: TSH Receptor
• Therapeutic Goal: Disrupt this signaling pathway.
  • Strategy 1: ↓ Hormone Synthesis (e.g., Aromatase Inhibitors)
  • Strategy 2: Block Hormone Receptors (e.g., Tamoxifen)

⭐ Exam Favorite: Some agents (SERMs like Tamoxifen) have mixed agonist/antagonist profiles. They can block estrogen's effects in breast tissue (therapeutic) while mimicking its effects in bone and endometrium (side effects).

Estrogen Blockers - SERMs & Aromatase Inhibitors

• Selective Estrogen Receptor Modulators (SERMs)

  • MoA: Mixed agonist/antagonist action on estrogen receptors.
  • Tamoxifen, Raloxifene
  • Use: ER+ breast cancer. Raloxifene also for osteoporosis.
  • ADRs: Hot flashes, venous thromboembolism (VTE).
    • Tamoxifen: ⚠️ ↑ risk of endometrial cancer.
    • Raloxifene: No ↑ endometrial risk.

• Aromatase Inhibitors

  • MoA: Block peripheral conversion of androgens to estrogen. Effective only when ovarian estrogen production is low.
  • Anastrozole, Letrozole, Exemestane
  • Use: ER+ breast cancer in postmenopausal women.
  • ADRs: ↑ risk of osteoporosis & fractures, arthralgias.

⭐ For ER+ breast cancer, Tamoxifen is preferred in premenopausal women, while Aromatase Inhibitors are first-line for postmenopausal women.

Androgen Antagonists - Prostate Power Plays

• GnRH Analogs: Pituitary Manipulation

  • Agonists (Leuprolide, Goserelin): Continuous stimulation → initial testosterone surge, then receptor downregulation → ↓FSH/LH & ↓testosterone.
  • Antagonists (Degarelix): Directly block GnRH receptors. No initial surge, faster testosterone suppression.

• Androgen Receptor Inhibitors: Direct Blockade

  • -lutamides (Flutamide, Bicalutamide, Enzalutamide): Competitively inhibit androgen receptors, blocking testosterone/DHT binding.
  • Used for prostate carcinoma, often with GnRH agonists.

• Androgen Synthesis Inhibitors: Source Control

  • Abiraterone: Irreversibly inhibits CYP17A1, blocking androgen production in testes, adrenals, and the tumor itself. Used in castration-resistant prostate cancer (CRPC).

⭐ The initial testosterone surge from a GnRH agonist (Leuprolide) can cause a painful tumor flare and bone pain. Prevent this by co-administering an androgen receptor blocker (Bicalutamide) for the first few weeks.

GnRH Agonists - The Master Switch

• Drugs: Leuprolide, Goserelin, Triptorelin.
• Mechanism: Biphasic action.
  • Transient Agonist: Initially ↑ LH/FSH, causing a potential "tumor flare."
  • Sustained Antagonist: Continuous use downregulates GnRH receptors, leading to ↓ LH/FSH and ↓ testosterone/estrogen.
• Uses: Prostate cancer, endometriosis, uterine fibroids, precocious puberty.
• Adverse Effects: Symptoms of hypogonadism (hot flashes, ↓ libido, osteoporosis), gynecomastia.

⭐ To prevent tumor flare in prostate cancer, co-administer with an androgen receptor antagonist (e.g., flutamide) for the first few weeks.

📌 Mnemonic: Leuprolide can be used in lieu of GnRH.

High‑Yield Points - ⚡ Biggest Takeaways

• Tamoxifen (SERM), for ER+ breast cancer, paradoxically increases the risk of endometrial cancer and VTE.
• Aromatase inhibitors (e.g., Anastrozole) are first-line for ER+ breast cancer in postmenopausal women; major side effect is osteoporosis.
• Leuprolide (GnRH agonist) given continuously treats prostate cancer but causes an initial testosterone flare.
• Flutamide, an androgen receptor antagonist, is co-administered with GnRH agonists to prevent this flare.
• Trastuzumab targets HER2+ breast cancer but carries a significant risk of cardiotoxicity.