Physiological rationale and evolution of the drug class
In postmenopausal women, ovarian function declines, and the ovaries cease to be the primary source of sex hormones. During this period, the extraadrenal (peripheral) pathway of estrogen synthesis comes to the forefront. It takes place in the liver, adipose tissue, skin, and the breast tissue itself. The key enzyme of this process is aromatase.
Historically, the first drugs to block this pathway were first-generation inhibitors (aminoglutethimide). Their major drawback was low selectivity: they non-selectively inhibited the synthesis of all steroids, including glucocorticoids and mineralocorticoids. Because of this, patients required mandatory coverage with hydrocortisone. Modern drugs, such as letrozole, were developed specifically to overcome this drawback — they possess high selectivity and do not require concurrent glucocorticoid administration.
Mechanism of action
According to its chemical structure, letrozole is classified as a non-steroidal drug. Its pharmacological target is the aromatase enzyme in peripheral tissues.
Letrozole acts as a competitive inhibitor. It reversibly binds to the active site of the enzyme and blocks the biochemical reactions converting androgens into estrogens. Specifically, the drug disrupts the aromatization of androstenedione to estrone and testosterone to estradiol.
Due to its high selectivity of action, letrozole provides virtually complete suppression of estrogen synthesis without affecting the production of adrenal cortex hormones.
Pharmacological effects and indications
The main pharmacological effect of letrozole is the induction of a pronounced estrogen deficiency in the body. Since the growth of certain tumor cells is directly stimulated by estrogens, the artificial reduction of their levels deprives the tumor of growth stimuli and reliably suppresses the proliferation of estrogen-dependent tissues.
In clinical practice, letrozole is used as an antineoplastic agent. The primary indication for its use is the treatment of estrogen-dependent breast cancer. A critical condition is prescribing the drug exclusively in the postmenopausal period, when peripheral hormone synthesis is dominant.
Side effects
Modern aromatase inhibitors are significantly better tolerated than first-generation drugs. Among the common side effects of letrozole therapy are nausea and fatigue.
It is important to differentiate side effects within the class of modern inhibitors. Unlike steroidal drugs (e.g., exemestane), which bind to the enzyme covalently and irreversibly, letrozole lacks a steroidal structure. Therefore, specific adverse effects such as hot flashes, acne, and alopecia are not characteristic of it.
Dosage form and prescription
The drug is intended for oral administration. It is available as film-coated tablets with a dosage of 0.0025 g (2.5 mg).
Example of a prescription for letrozole: ```latin Rp.: Tab. Letrozoli obductas 0,0025 D.t.d. N. 30 S. Oral, 1 tablet (0.0025 g) once daily. ```
Letrozole — LEgko TORmozit aromatazu (Easily inhibits aromatase). Non-steroidal (no steroid-like side effects such as acne), competitive, prescribed only in postmenopause.
Class and exam questions
Why is letrozole not prescribed to premenopausal women?
Before menopause, the ovaries are the primary source of estrogens, whereas letrozole blocks only peripheral (extraadrenal) estrogen synthesis, which becomes dominant only after menopause.
Is hydrocortisone co-administration necessary with letrozole?
No. Letrozole is a highly selective aromatase inhibitor. Unlike first-generation drugs (aminoglutethimide), it does not suppress adrenal cortex hormone synthesis.
What is the difference between the mechanism of action of letrozole and exemestane?
Letrozole is a non-steroidal drug that causes reversible (competitive) inhibition of aromatase. Exemestane has a steroidal structure, binds covalently, and inhibits the enzyme irreversibly.
What else to study on this topic
- Comparison of non-steroidal (letrozole, anastrozole) and steroidal (exemestane) aromatase inhibitors.
- Biochemistry of peripheral estrogen synthesis in adipose tissue and the liver.
- Differences between aromatase inhibitors and estrogen receptor modulators (tamoxifen, toremifene, raloxifene).
- Evolution of antineoplastic endocrine drugs from aminoglutethimide to modern highly selective agents.
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