Hormonal Agents in Cancer

1. Introduction/Overview

Brief Introduction to the Topic

Hormonal agents constitute a pivotal component of contemporary oncologic therapy, particularly for malignancies that exhibit hormone dependence. In breast, prostate, ovarian, and certain endocrine‑related cancers, the growth and survival of tumour cells are intricately linked to endocrine signalling pathways. Accordingly, pharmacologic manipulation of these pathways has become a cornerstone of disease management. The therapeutic manipulation of sex steroids, growth hormone, and other endocrine mediators has evolved from simple administration of exogenous hormones to highly selective receptor modulators, enzyme inhibitors, and synthetic analogues designed to disrupt tumour‑specific signalling cascades.

Clinical Relevance and Importance

Hormonal agents confer significant clinical benefits: they improve survival, reduce recurrence rates, and often produce fewer adverse sequelae compared with cytotoxic chemotherapy. Moreover, many endocrine therapies are orally bioavailable, cost‑effective, and can be administered in outpatient settings. Nevertheless, resistance mechanisms, off‑target effects, and complex drug–drug interactions present ongoing challenges that necessitate a comprehensive understanding of pharmacodynamics and pharmacokinetics. Mastery of hormonal agent therapy is therefore essential for clinicians and pharmacists involved in cancer care.

Learning Objectives

• Identify the major classes of hormonal agents utilized in oncology and their specific therapeutic indications.
• Describe the molecular mechanisms through which these agents exert antitumour activity.
• Outline the pharmacokinetic profiles of representative drugs within each class.
• Recognise common and serious adverse effects, as well as key drug interactions and contraindications.
• Apply knowledge of special patient populations to optimise hormonal therapy in pregnancy, lactation, paediatrics, geriatrics, and patients with organ impairment.

2. Classification

Drug Classes and Categories

Hormonal agents used in cancer therapy may be categorised based on their target endocrine pathway and mechanism of action. The principal classes include:

• Estrogen Receptor Modulators – Selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene, and selective estrogen receptor degraders (SERDs) such as fulvestrant.
• Aromatase Inhibitors – Non‑steroidal (anastrozole, letrozole) and steroidal (exemestane) inhibitors that block peripheral conversion of androgens to estrogens.
• Gonadotropin‑Releasing Hormone (GnRH) Modulators – Analogues (leuprolide, goserelin) and antagonists (degarelix) that suppress luteinising hormone secretion, thereby reducing gonadal steroid production.
• Androgen Receptor (AR) Antagonists – Non‑steroidal inhibitors (enzalutamide, apalutamide) and CYP17A1 inhibitors (abiraterone) that block AR signalling or androgen biosynthesis.
• Corticosteroids – High‑dose or chronic use of dexamethasone and prednisone for tumour‑related inflammation or as radiosensitisers.
• Growth Hormone / Insulin‑Like Growth Factor (IGF) Modulators – Agents such as somatostatin analogues (octreotide) used in neuroendocrine tumours.

Chemical Classification

From a chemical standpoint, many of these agents belong to distinct families:

• Phenoxyethanol derivatives (tamoxifen).
• Non‑steroidal aromatase inhibitors (imidazole, triazole cores).
• Peptide analogues (GnRH agonists/antagonists).
• Macrocyclic lactones (octreotide).
• Cyclopenta‑pyridyl structures (enzalutamide).

These structural differences underpin variations in receptor affinity, metabolic stability, and side‑effect profiles.

3. Mechanism of Action

Detailed Pharmacodynamics

Hormonal agents exert antitumour effects by interfering with endocrine signalling at multiple levels: ligand availability, receptor binding, intracellular signalling, and transcriptional regulation.

Estrogen Receptor Modulators

SERMs competitively bind to estrogen receptors (ERα and ERβ) on tumour cells, exerting tissue‑specific agonistic or antagonistic effects. Tamoxifen, for instance, antagonises ER in breast tissue while acting as an agonist in bone and endometrium. SERDs bind ER, promote receptor ubiquitination, and accelerate proteasomal degradation, thereby abrogating estrogen‑driven transcription.

Aromatase Inhibitors

These inhibitors block the cytochrome P450 19A1 enzyme (aromatase), the key catalyst in the peripheral conversion of androgens to estrogens. By reducing circulating estrogen levels, aromatase inhibitors deprive ER‑positive breast cancer cells of their growth stimulus. Non‑steroidal inhibitors form reversible complexes with the aromatase iron centre, whereas steroidal inhibitors bind irreversibly, leading to permanent enzyme inactivation.

GnRH Modulators

GnRH agonists initially stimulate pulsatile GnRH receptor activity, resulting in transient luteinising hormone (LH) and follicle‑stimulating hormone (FSH) surges. Continued exposure induces receptor down‑regulation, culminating in hypogonadotropic hypogonadism and markedly reduced testosterone or estrogen production. GnRH antagonists competitively block the receptor without initial stimulation, swiftly lowering gonadal steroid synthesis.

Androgen Receptor Antagonists

AR antagonists such as enzalutamide bind the ligand‑binding domain of AR, preventing conformational changes required for nuclear translocation and DNA binding. CYP17A1 inhibitors (abiraterone) suppress androgen biosynthesis by blocking 17α‑hydroxylase/17,20‑lyase activity in the adrenal cortex, thereby reducing intratumoural androgen levels that drive castration‑resistant prostate cancer.

Corticosteroids

High‑dose corticosteroids modulate gene expression via glucocorticoid receptor activation, leading to anti‑inflammatory effects, reduction of tumour‑associated cytokine production, and radiosensitisation. In certain haematologic malignancies, glucocorticoids also induce apoptosis in lymphoid cells through up‑regulation of pro‑apoptotic genes.

Growth Hormone / IGF Modulators

Somatostatin analogues bind somatostatin receptors on neuroendocrine tumour cells, inhibiting hormone secretion and cell proliferation. They also down‑regulate IGF‑1, thereby attenuating mitogenic signalling pathways.

Receptor Interactions

All hormonal agents rely on specific receptor interactions. For ER‑targeted drugs, binding affinity is quantified by the drug’s dissociation constant (Kd), with lower Kd values indicating higher potency. AR antagonists possess high affinity for the ligand‑binding pocket, preventing agonist binding. GnRH analogues exhibit high selectivity for GnRH receptors, minimizing off‑target effects. Somatostatin analogues preferentially target subtype 2 receptors expressed on many neuroendocrine tumours.

Molecular/Cellular Mechanisms

Binding of hormonal agents initiates a cascade that ultimately impairs transcription of genes essential for cell cycle progression, angiogenesis, and apoptosis. For example, ER antagonism reduces cyclin D1 expression, leading to G1 cell cycle arrest. AR blockade decreases PSA gene transcription, attenuating prostate cancer proliferation. Corticosteroid‑mediated gene regulation involves up‑regulation of anti‑inflammatory cytokines (IL‑10) and down‑regulation of pro‑inflammatory mediators (TNF‑α). Somatostatin analogues inhibit the phosphatidylinositol 3‑kinase (PI3K)/AKT pathway, thereby reducing cell survival signals.

4. Pharmacokinetics

Absorption

Oral hormonal agents typically exhibit high bioavailability (>80%) for SERMs and aromatase inhibitors. GnRH analogues and somatostatin analogues are administered parenterally (subcutaneous or intramuscular) due to poor oral absorption. Intravenous formulations of some agents (e.g., fulvestrant) require oil‑based vehicles to enhance solubility.

Distribution

Large molecular weight and lipophilicity contribute to extensive tissue distribution. Tamoxifen and its active metabolite endoxifen have a high volume of distribution (Vd), reflecting extensive plasma protein binding (~99%). Aromatase inhibitors demonstrate moderate protein binding (70–80%) and penetrate the central nervous system minimally. GnRH analogues, being peptides, remain largely confined to vascular and interstitial compartments.

Metabolism

Cytochrome P450 enzymes mediate metabolism of most hormonal agents. Tamoxifen is extensively metabolised by CYP2D6 and CYP3A4 to endoxifen. Aromatase inhibitors are primarily metabolised by CYP3A4 (anastrozole, letrozole) or CYP2C9 (exemestane). Enzalutamide is metabolised by CYP2C8 and CYP3A4, producing active metabolites. GnRH analogues undergo proteolytic degradation. Corticosteroids are metabolised via hepatic glucuronidation and hydroxylation.

Excretion

Renal excretion predominates for many agents (e.g., letrozole, goserelin), whereas hepatic excretion is more significant for lipophilic drugs (tamoxifen, enzalutamide). The elimination half‑life varies considerably: tamoxifen (~5–7 days), letrozole (~2 weeks), leuprolide (~3–4 days), enzalutamide (~6.5 days), and fulvestrant (~4–5 days). Dosing schedules reflect these pharmacokinetic properties, with chronic oral agents typically administered daily and parenteral agents given at intervals ranging from weekly to monthly.

Dosing Considerations

Therapeutic dosing is guided by pharmacokinetic parameters, tumour burden, and patient tolerability. For instance, dose escalation of tamoxifen from 20 mg to 40 mg daily may be considered in advanced disease, whereas aromatase inhibitors are usually maintained at fixed doses (anastrozole 1 mg, letrozole 2.5 mg, exemestane 25 mg). GnRH analogues require an initial flare‑up period, after which continuous suppression is achieved with monthly or quarterly injections. In patients with hepatic impairment, dose adjustments may be necessary for CYP3A4‑dependent drugs; renal dosing is rarely required but should be monitored in severe chronic kidney disease.

5. Therapeutic Uses/Clinical Applications

Approved Indications

• Breast Cancer – SERMs, aromatase inhibitors, and SERDs are indicated for early‑stage hormone‑receptor‑positive disease, adjuvant therapy post‑surgery, and metastatic settings. Tamoxifen is approved for pre‑ and post‑menopausal women; aromatase inhibitors for post‑menopausal women; fulvestrant for metastatic ER‑positive breast cancer.
• Prostate Cancer – GnRH agonists/antagonists and AR antagonists are standard in advanced hormone‑responsive prostate cancer. Enzalutamide and abiraterone are indicated for metastatic castration‑resistant disease.
• Ovarian Cancer – GnRH agonists (leuprolide) are used as adjuncts in early‑stage disease and in patients with recurrent disease; SERMs have limited but emerging roles.
• Neuroendocrine Tumours – Somatostatin analogues (octreotide) are first‑line for functional tumours and are also used for tumour control in metastatic disease.
• Other Cancers – Corticosteroids are employed for brain tumour management (e.g., glioblastoma) to reduce cerebral oedema and for radiosensitisation in head and neck cancers.

Off‑Label Uses

Off‑label applications are common in oncology. Tamoxifen is occasionally used for male breast cancer and breast cancer chemoprevention. Aromatase inhibitors have been explored in male hormone‑dependent cancers. GnRH antagonists are investigated for endometrial carcinoma. Somatostatin analogues are trialed in pancreatic neuroendocrine tumours and certain metastatic breast cancers with hormone‑dependent features. High‑dose corticosteroids are frequently used for palliation of pain, nausea, and cachexia across various tumour types.

6. Adverse Effects

Common Side Effects

• Estrogen Modulators – Hot flashes, arthralgias, mood changes, and increased risk of thromboembolic events with tamoxifen; bone loss with aromatase inhibitors.
• GnRH Modulators – Flare‑up symptoms (pain, hot flashes), bone density reduction, and hypogonadism‑associated fatigue.
• AR Antagonists – Fatigue, hypertension, and dizziness; abiraterone may cause hyperglycaemia and hypokalaemia.
• Somatostatin Analogues – Gallstones, steatorrhea, and glucose intolerance.
• Corticosteroids – Hyperglycaemia, hypertension, mood disturbances, bone demineralisation, and immunosuppression.

Serious/Rare Adverse Reactions

Thromboembolic events (deep venous thrombosis, pulmonary embolism) occur mainly with tamoxifen; endometrial carcinoma risk is increased in long‑term tamoxifen use. Aromatase inhibitors can precipitate severe osteoporosis and fractures. GnRH antagonists may cause severe hypocalcaemia in patients with pre‑existing deficiencies. Enzalutamide is associated with seizures in individuals with a history of epilepsy. Abiraterone may provoke hepatic dysfunction, requiring regular alanine aminotransferase monitoring. Corticosteroid‑related complications include adrenal suppression and Cushingoid features with prolonged high‑dose therapy.

Black Box Warnings

Tamoxifen carries a black‑box warning for endometrial carcinoma and thromboembolism. Abiraterone’s risk of liver injury and mineralocorticoid excess is highlighted. These warnings necessitate regular surveillance and patient education.

7. Drug Interactions

Major Drug‑Drug Interactions

• Tamoxifen – Strong inhibitors of CYP2D6 (e.g., fluoxetine, paroxetine) may reduce endoxifen levels, potentially diminishing efficacy.
• Aromatase Inhibitors – Co‑administration with potent CYP3A4 inhibitors (ketoconazole) can elevate drug concentrations; inducers (rifampicin) may lower efficacy.
• GnRH Analogues – Concurrent use of drugs that influence QT interval (e.g., certain antiarrhythmics) may potentiate arrhythmogenic risk.
• AR Antagonists – Enzalutamide is a strong CYP3A4 inducer, affecting the metabolism of many agents (e.g., warfarin, oral contraceptives).
• Abiraterone – Requires co‑administration of fludrocortisone or prednisone to mitigate mineralocorticoid excess; concomitant use of diuretics may increase electrolyte disturbances.
• Somatostatin Analogues – May interact with drugs metabolised by CYP3A4, although the effect is modest.
• Corticosteroids – High doses can elevate blood glucose, necessitating caution in diabetics; they also potentiate the effects of anticoagulants and immunosuppressants.

Contraindications

Serious hypersensitivity to the drug or any component is an absolute contraindication. Tamoxifen is contraindicated in patients with a history of thromboembolic disease or uncontrolled hepatic disease. GnRH antagonists are contraindicated in patients with a known hypersensitivity to the agent. Enzalutamide is contraindicated in patients with uncontrolled seizures. Abiraterone requires careful monitoring in patients with hepatic impairment and is contraindicated in pregnant women due to teratogenic potential. Corticosteroids are contraindicated in patients with systemic fungal infections.

8. Special Considerations

Use in Pregnancy/Lactation

Hormonal agents are largely contraindicated during pregnancy due to teratogenicity and potential fetal endocrine disruption. Tamoxifen is a category D drug; aromatase inhibitors and GnRH analogues are also contraindicated. Somatostatin analogues cross the placenta minimally but are generally avoided. High‑dose corticosteroids are used cautiously, balancing maternal benefits against potential neonatal adrenal suppression. Lactation is discouraged while on most hormonal agents; exceptions may exist for low‑dose corticosteroids under specialist guidance.

Pediatric/Geriatric Considerations

In children, endocrine agents are rarely used outside of endocrine‑disrupting tumour contexts. Age‑related pharmacokinetic changes necessitate careful dose adjustments in geriatrics, particularly due to reduced hepatic metabolism and renal clearance. Polypharmacy increases the risk of drug interactions in older adults. Monitoring of bone density and metabolic parameters is recommended when using aromatase inhibitors or GnRH analogues in this population.

Renal/Hepatic Impairment

Renally excreted agents (e.g., letrozole, goserelin) may accumulate in severe chronic kidney disease; dose reductions or extended dosing intervals may be warranted. Hepatic impairment affects metabolism of CYP3A4 substrates; tamoxifen, aromatase inhibitors, and enzalutamide require dose adjustment or avoidance in severe hepatic dysfunction. Monitoring of liver function tests is standard practice for agents with hepatic metabolism.

9. Summary/Key Points

• Hormonal agents target endocrine pathways essential for tumour growth, providing effective, often well‑tolerated therapy in breast, prostate, ovarian, and neuroendocrine cancers.
• Mechanistic diversity ranges from receptor antagonism and degradation to enzyme inhibition and synthesis blockade.
• Pharmacokinetic profiles dictate dosing schedules; oral agents typically require daily administration, whereas peptide analogues are administered subcutaneously or intramuscularly.
• Common adverse effects include hot flashes, bone loss, thromboembolism, and electrolyte disturbances; serious risks comprise endometrial carcinoma, osteoporosis, and hepatic injury.
• Drug interactions, particularly involving CYP450 enzymes, necessitate vigilant medication review and patient education.
• Special populations—pregnancy, lactation, pediatrics, geriatrics, and organ impairment—require individualized dosing strategies and monitoring.

References

1. Chabner BA, Longo DL. Cancer Chemotherapy, Immunotherapy and Biotherapy: Principles and Practice. 6th ed. Philadelphia: Wolters Kluwer; 2019.
2. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
3. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
4. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
5. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
6. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
7. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.