Aromatase Inhibitors

Mechanism

Mechanism of Action

Letrozole and Anastrozole are third-generation reversible non-steroidal inhibitors of the aromatase enzyme (cytochrome P450 monooxygenase complex, CYP19 gene).

Physiology of Estrogen Biosynthesis Blockade

1. Aromatase catalyzes the final limiting enzymatic step of estrogen biosynthesis in the body: the conversion of androgens of adrenal or ovarian origin (androstenedione and testosterone) into estrogens (estrone and estradiol, respectively).
2. In postmenopausal women, the main source of estrogen is peripheral synthesis in adipose, liver, muscle tissue and in the malignant breast tumor tissue itself.
3. Letrozole and Anastrozole bind competitively and highly selectively to the heme group of aromatase, preventing the oxidation of androgens.
4. This blockade reduces circulating estrogen levels by more than 95-98% in postmenopausal women, depriving breast cancer cells of their main mitogenic trophic stimulus.
5. In premenopausal women (Ovulation induction): The acute decrease in circulating estrogens in the late luteal or early follicular phase frees the hypothalamus and pituitary from negative estrogenic feedback. This stimulates pituitary FSH secretion, inducing the recruitment of multiple ovarian ovarian follicles.

Pharmacokinetics

Pharmacokinetics

• Route of administration: Oral.
• Absorption: Rapid and complete, with 100% bioavailability that is not affected by concomitant food intake.
• Distribution: Large apparent distribution volume of approx. 1.9L/kg. Moderate binding to serum albumin (60%).
• Metabolism: Mainly hepatic. Letrozole is slowly metabolized by the isoenzymes CYP3A4 and CYP2A6 to an inactive carbinol metabolite; Anastrozole is purified by N-dealkylation and minor hydroxylation.
• Half-life (t_1/2): Prolonged, approx. 2 to 4 days, which allows dosing in a single daily dose.
• Excretion: Renal 90% in the form of inactive metabolites conjugated with glucuronide.

Indicators and dose

Indications

• First-line adjuvant treatment of ER+ invasive breast cancer in postmenopausal women.
• First-line treatment of ER+ advanced breast cancer in postmenopausal women on a palliative basis.
• Off-label use in Reproductive Medicine (Letrozole): Induction of ovulation in the treatment of infertility due to chronic anovulation in women with Polycystic Ovary Syndrome (PCOS) (clinical studies demonstrate higher live birth rates compared to clomiphene citrate, with less endometrial thinning and a lower rate of multiple pregnancy).

Dosage and Schemes

• Postmenopausal breast cancer: Letrozole 2.5 mg orally once a day uninterrupted for 5 years; Anastrozole 1 mg orally once daily identically.
• Ovulation induction in PCOS (Letrozole): 2.5 mg to 5 mg orally once a day for 5 consecutive days (starting the cycle between day 3 and day 5 of spontaneous or induced menstruation).

Pregnancy and Breastfeeding

FDA Category