Estrogen receptor modulators

Molecular mechanism of action

The main therapeutic goal of developing SERMs is to obtain an "ideal" drug that takes only the beneficial properties of estrogens (such as bone protection and improved hepatic lipid metabolism) and cuts off the dangerous ones (cell proliferation in the mammary gland and uterus).

Drugs in this group compete with endogenous estradiol for binding to $\alpha$- and $\beta$-estrogen receptors. When the drug molecule (ligand) binds to the receptor, its spatial structure changes. The final conformation of the receptor complex depends precisely on which ligand has attached.

Next, this modified receptor interacts with intranuclear proteins — coactivators or corepressors. They, in turn, influence the promoters of target genes. The differing effects of drugs in various organs are explained by the unique set of these cofactors in each cell type.

Classification and pharmacological profiles

By chemical structure, modulators are divided into triphenylethylene derivatives (clomifene, tamoxifen, toremifene) and benzothiophene derivatives (raloxifene).

• Clomifene: Acts predominantly at the level of the hypothalamo-pituitary system. By blocking receptors, it deprives the body of the ability to perceive the inhibitory influence of its own estrogens. Negative feedback is removed, gonadotropin secretion (FSH and LH) increases sharply, which stimulates follicle maturation. The main indication is anovulatory infertility. Characteristic side effects include hot flashes, blurred vision, and menstrual cycle irregularities.
• Tamoxifen and Toremifene: Used for postmenopausal breast cancer. They block receptors in tumor tissue, but stimulate them in bones and the endometrium. Due to the agonistic effect on the uterus, long-term administration poses a risk of endometrial hyperplasia and cancer. They also cause hypoestrogenic reactions (sweating, palpitations).
• Raloxifene: A safer analogue for the prevention and treatment of postmenopausal osteoporosis. It retains a protective effect on bones, but acts as a strict antagonist in both the mammary glands and the uterus, without increasing oncological risks.

Alternative: estrogen synthesis inhibitors

If SERMs block the receptors themselves, synthesis inhibitors deprive receptors of their natural ligand. The use of gonadotropin-releasing hormone (GnRH) agonists shuts down ovarian function, but estrogens continue to be synthesized from adrenal androgens in peripheral tissues. The aromatase enzyme is responsible for this process.

Aromatase blockade stops the conversion of androstenedione to estrone and testosterone to estradiol. This creates a pronounced estrogen deficiency, suppressing the growth of hormone-dependent tumors in postmenopausal women.

1. First generation (Aminoglutethimide): Acted non-selectively, simultaneously shutting down the synthesis of glucocorticoids and mineralocorticoids in the adrenal cortex.
2. Modern drugs: Work selectively in the periphery. They are divided into steroidal (formestane, exemestane), which bind to the active center of the enzyme covalently and irreversibly, and non-steroidal (anastrozole, letrozole), which work as competitive inhibitors.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Neurological and vascular side effects of clomifene.
• Hypoestrogenic manifestations during tamoxifen administration.
• Limitations of the use of gonadotropin-releasing hormone (GnRH) analogues.
• Differences in the kinetics of steroidal and non-steroidal aromatase inhibitors.
• Mechanism of development of endometrial hyperplasia against the background of triphenylethylene derivatives.

Other topics in the section "Hormone preparations, their synthetic substitutes, and antagonists"

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