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Monday, August 11, 2025

Hormones / antineoplastics


1. Definition and Overview

  • Hormones/antineoplastics are a pharmacological category comprising agents that exert anticancer effects through modulation of endocrine pathways.

  • They are not traditional cytotoxic chemotherapy agents; instead, they alter the hormonal environment or block hormone receptor activity to inhibit tumor growth.

  • Primarily used for hormone-dependent cancers such as breast cancer, prostate cancer, endometrial cancer, and certain adrenal malignancies.

  • Include natural hormones, synthetic analogs, and hormone antagonists, as well as drugs that inhibit hormone synthesis.

2. Rationale for Use in Oncology

  • Certain tumors require specific hormones for growth (e.g., estrogen in breast cancer, androgens in prostate cancer).

  • By reducing hormone levels or blocking their receptors, tumor proliferation can be slowed or halted.

  • Often used as adjuvant therapy (post-surgery/radiation) or for metastatic disease to prolong survival and manage symptoms.

3. Main Classes and Examples

A. Anti-estrogens

  • Selective Estrogen Receptor Modulators (SERMs): tamoxifen, toremifene.

  • Selective Estrogen Receptor Downregulators (SERDs): fulvestrant.

  • Mechanism: Block estrogen binding to estrogen receptors in breast tissue; SERDs degrade the receptor.

  • Indications: ER-positive breast cancer (adjuvant and metastatic settings).

B. Aromatase Inhibitors

  • Non-steroidal: anastrozole, letrozole.

  • Steroidal: exemestane.

  • Mechanism: Inhibit aromatase enzyme, preventing conversion of androgens to estrogens in postmenopausal women.

  • Indications: Hormone receptor–positive breast cancer in postmenopausal patients.

C. Anti-androgens

  • Non-steroidal: bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide.

  • Mechanism: Block androgen receptors in prostate cancer cells.

  • Indications: Prostate cancer, often combined with androgen deprivation therapy (ADT).

D. Androgen Synthesis Inhibitors

  • Abiraterone acetate.

  • Mechanism: Inhibits CYP17A1 enzyme, blocking androgen biosynthesis in testes, adrenal glands, and tumor cells.

E. Gonadotropin-Releasing Hormone (GnRH) Agonists and Antagonists

  • Agonists: leuprolide, goserelin, triptorelin.

  • Antagonists: degarelix, relugolix.

  • Mechanism: Suppress gonadal steroid hormone production via pituitary downregulation (agonists) or direct blockade (antagonists).

  • Indications: Prostate cancer, premenopausal breast cancer, certain gynecologic cancers.

F. Progestins

  • Megestrol acetate, medroxyprogesterone acetate.

  • Mechanism: Modulate estrogen activity and exert direct antiproliferative effects on some tumors.

  • Indications: Endometrial carcinoma, palliative care in advanced breast cancer, appetite stimulation.

G. Corticosteroids

  • Prednisone, dexamethasone.

  • Mechanism: Lympholytic activity against hematologic malignancies; reduce edema and inflammation from brain metastases.

  • Indications: Leukemias, lymphomas, multiple myeloma, supportive care in oncology.

4. Mechanisms of Action

  • Hormone receptor blockade: Prevents hormones from activating growth-promoting pathways in cancer cells.

  • Hormone synthesis inhibition: Reduces circulating hormone levels, depriving cancer cells of growth stimuli.

  • Cytotoxic effects on hormone-sensitive tissues: Certain hormones can directly cause tumor regression in hormone-dependent cancers.

5. Pharmacokinetics

  • Variable oral bioavailability depending on agent.

  • Most metabolized in the liver (CYP450 system involvement common).

  • Many have long half-lives allowing once-daily dosing.

  • High protein binding for many agents, leading to potential drug–drug interactions.

6. Clinical Indications

  • Breast cancer: ER/PR-positive in pre- and postmenopausal women.

  • Prostate cancer: Localized, advanced, and metastatic androgen-sensitive disease.

  • Endometrial carcinoma: Advanced or recurrent cases.

  • Adrenal cancers: Agents such as mitotane.

  • Other cancers: Ovarian, testicular, pituitary adenomas (selected cases).

7. Adverse Effects

Anti-estrogens/SERMs/SERDs:

  • Hot flushes, night sweats.

  • Increased risk of thromboembolism (SERMs).

  • Endometrial cancer risk (tamoxifen).

Aromatase Inhibitors:

  • Arthralgia, myalgia.

  • Osteoporosis and fracture risk.

  • Hot flushes.

Anti-androgens:

  • Gynecomastia, hot flushes.

  • Fatigue, diarrhea.

  • Hepatotoxicity (flutamide).

Androgen synthesis inhibitors:

  • Mineralocorticoid excess: hypertension, hypokalemia, fluid retention.

GnRH agonists:

  • Initial tumor flare (agonists only).

  • Hot flushes, decreased libido, erectile dysfunction.

  • Bone mineral density loss.

Corticosteroids:

  • Immunosuppression, hyperglycemia, muscle wasting, osteoporosis, mood changes.

8. Contraindications and Precautions

  • Pregnancy and lactation (many are teratogenic).

  • History of thromboembolism (for SERMs).

  • Severe hepatic impairment for certain agents.

  • Osteoporosis risk with aromatase inhibitors or androgen deprivation therapy.

9. Drug Interactions

  • CYP450-mediated interactions:

    • CYP3A4 substrates/inhibitors/inducers affect levels of many agents (e.g., abiraterone, enzalutamide).

  • Anticoagulants: Warfarin effects potentiated by tamoxifen.

  • QT prolongation risk with some agents when combined with other QT-prolonging drugs.

10. Advantages and Limitations

Advantages:

  • Targeted mechanism for hormone-dependent tumors.

  • Generally less myelosuppressive than cytotoxic chemotherapy.

  • Oral administration possible for most agents.

Limitations:

  • Only effective in hormone receptor–positive tumors.

  • Resistance develops over time (via receptor mutation, alternative signaling pathways).

  • Endocrine and metabolic side effects can be significant in long-term use.



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