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Monday, August 11, 2025

Aromatase inhibitors


Introduction

  • Aromatase inhibitors (AIs) are drugs that block the aromatase enzyme, responsible for converting androgens into estrogens.

  • They are primarily used in hormone receptor-positive breast cancer, especially in postmenopausal women.

  • By reducing estrogen levels, they help prevent the stimulation of estrogen-dependent tumor growth.

  • AIs have replaced or supplemented tamoxifen in many treatment protocols due to superior disease-free survival benefits.

Physiological Role of Aromatase

  • Aromatase (CYP19A1) is a cytochrome P450 enzyme complex.

  • Catalyzes conversion of androstenedione to estrone and testosterone to estradiol.

  • Located in various tissues: adipose, liver, skin, muscle, brain, gonads.

  • In premenopausal women: primary estrogen production occurs in the ovaries.

  • In postmenopausal women: estrogen production is mainly from peripheral aromatization in adipose and other tissues.

  • Even low postmenopausal estrogen levels can promote ER-positive breast cancer growth.

Mechanism of Action

  • AIs inhibit aromatase enzyme activity, reducing conversion of androgens to estrogens.

  • Cause a reduction of circulating estrogen by over 90% in postmenopausal women.

  • Two main classes:

    • Nonsteroidal (Type II): bind reversibly to the heme group of aromatase (e.g., anastrozole, letrozole).

    • Steroidal (Type I): bind irreversibly to the aromatase enzyme, causing permanent inactivation (e.g., exemestane).

Pharmacokinetics

  • Absorption:

    • Rapid oral absorption.

    • Peak plasma levels within 1–2 hours for most agents.

    • Food has minimal effect on anastrozole and letrozole; exemestane absorption may increase with food.

  • Distribution:

    • Moderate plasma protein binding (40–60%).

    • Wide tissue distribution, including adipose-rich tissues.

  • Metabolism:

    • Anastrozole and letrozole: hepatic metabolism via CYP450 enzymes (CYP3A4, CYP2A6).

    • Exemestane: hepatic metabolism via oxidation/reduction followed by conjugation.

  • Elimination:

    • Half-life: anastrozole (~24 h), letrozole (30–40 h), exemestane (~24 h).

    • Excretion: urine and feces.

Clinical Indications

Breast Cancer

  • Adjuvant therapy for hormone receptor-positive early breast cancer in postmenopausal women.

  • Extended adjuvant therapy after completion of tamoxifen to reduce recurrence.

  • First-line therapy in advanced/metastatic hormone receptor-positive breast cancer.

  • Neoadjuvant therapy to reduce tumor size before surgery.

Prevention

  • Chemoprevention in high-risk postmenopausal women.

Other Indications (off-label in many cases)

  • Male breast cancer.

  • Gynecomastia (especially in prostate cancer patients receiving antiandrogens).

  • Precocious puberty in boys (with other agents).

  • Infertility in women with ovulatory dysfunction (particularly letrozole).

  • Estrogen-dependent tumors outside the breast.

Advantages Over Tamoxifen

  • Greater reduction in recurrence risk in postmenopausal ER+ breast cancer.

  • Lower incidence of contralateral breast cancer.

  • No increased risk of endometrial cancer.

  • No partial estrogen agonist activity.

Adverse Effects

Common

  • Arthralgia and myalgia.

  • Hot flushes.

  • Fatigue.

  • Headache.

  • Mild gastrointestinal upset (nausea, diarrhea).

Bone Health

  • Increased risk of osteoporosis and fractures due to estrogen depletion.

  • Requires bone density monitoring and preventive strategies.

Cardiovascular and Metabolic Effects

  • Possible adverse changes in lipid profiles.

  • Potential increased cardiovascular risk in predisposed patients.

Other

  • Vaginal dryness, sexual dysfunction.

  • Mild mood changes.

  • Carpal tunnel syndrome.

  • Hair thinning.

Contraindications

  • Premenopausal women without ovarian suppression.

  • Known hypersensitivity to the drug or its excipients.

  • Pregnancy and lactation.

  • Severe hepatic impairment (relative contraindication, use with caution).

Precautions

  • Monitor bone mineral density at baseline and periodically during therapy.

  • Monitor cardiovascular status in patients with risk factors.

  • Use caution in hepatic impairment.

  • Avoid concomitant use with estrogen-containing products.

Drug Interactions

  • Estrogens: antagonize the therapeutic effect.

  • Tamoxifen: reduces plasma concentration of some AIs when co-administered.

  • CYP450 modulators: may alter metabolism, especially for exemestane (CYP3A4 substrate).

Individual Agents

Anastrozole

  • Nonsteroidal, reversible AI.

  • Usual dose: 1 mg orally once daily.

  • Half-life: ~24 h.

  • Minimal effect on lipid profile.

Letrozole

  • Nonsteroidal, reversible AI.

  • Usual dose: 2.5 mg orally once daily.

  • Half-life: 30–40 h.

  • Potent estrogen suppression; effective in early and metastatic settings.

Exemestane

  • Steroidal, irreversible AI.

  • Usual dose: 25 mg orally once daily after food.

  • Structurally similar to androstenedione.

  • May cause slightly less bone density loss in some patients.

Treatment Strategies

Sequential Therapy

  • Tamoxifen for 2–3 years followed by AI for 2–3 years.

  • AI for initial years followed by tamoxifen (less common).

Extended Therapy

  • Up to 10 years of endocrine therapy (AI ± tamoxifen) in high-risk patients.

Combination with Ovarian Suppression

  • In premenopausal women, combine with GnRH agonists to suppress ovarian estrogen production.

Efficacy Highlights

  • Large trials (ATAC, BIG 1-98, MA.17) show AIs reduce recurrence more effectively than tamoxifen in postmenopausal ER+ breast cancer.

  • Survival benefit more pronounced in high-risk subgroups.

Bone Health Management

  • Baseline DEXA scan before therapy.

  • Calcium and vitamin D supplementation.

  • Weight-bearing exercises.

  • Bisphosphonates or denosumab in patients with osteoporosis or high fracture risk.

  • Repeat DEXA scan every 1–2 years.

Special Populations

  • Elderly: generally well tolerated; monitor comorbidities.

  • Renal impairment: no major dose adjustment for anastrozole or letrozole; use caution with exemestane in severe cases.

  • Hepatic impairment: caution with all; exemestane clearance may be significantly reduced.

Future Directions

  • Development of biomarkers to predict AI response and resistance.

  • Combination therapy with targeted agents (CDK4/6 inhibitors, PI3K inhibitors).

  • Improved strategies to reduce musculoskeletal symptoms and preserve bone health.



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