Sex Steroid Mechanism of Action and Nuclear Receptors

Sex steroids — androgens, estrogens and progestogens — are lipid-soluble hormones that act mainly by entering target cells and binding intracellular nuclear receptors. The hormone-receptor complex regulates gene transcription, so a circulating steroid is translated into tissue-specific changes in which genes a cell expresses.

Definition

Sex-steroid mechanism of action is the process by which gonadal steroid hormones, largely through binding to nuclear hormone receptors, regulate gene transcription in target cells, producing tissue-specific physiological effects.

Scope

This topic covers how gonadal steroid hormones exert their effects: the family of nuclear steroid receptors, the classical genomic mechanism of transcriptional regulation, the existence of more than one estrogen receptor, and the concept of tissue-selective receptor modulation. It is a reference account of molecular physiology, not clinical guidance.

Key concepts

• Nuclear hormone receptor superfamily
• Ligand-activated transcription factors
• Hormone-response elements in DNA
• Coactivators and corepressors
• Estrogen receptors alpha and beta
• Androgen and progesterone receptors
• Tissue-selective receptor modulation (SERMs)

Key theories

Genomic (nuclear-receptor) model of steroid action

Steroid hormones bind intracellular nuclear receptors that act as ligand-activated transcription factors, binding hormone-response elements in DNA and recruiting coregulators to switch target genes on or off.

Mechanisms

Because they are lipophilic, sex steroids cross the cell membrane and bind receptors of the nuclear hormone receptor superfamily. As reviewed by Beato and colleagues, the activated receptor functions as a transcription factor: it binds specific hormone-response elements in DNA and recruits coactivator or corepressor proteins that increase or decrease transcription of target genes. Estrogen signalling is more complex than a single receptor, because Kuiper and colleagues cloned a second estrogen receptor (ER-beta) alongside the long-known ER-alpha, and the two receptors differ in tissue distribution and effects, as synthesised in subsequent reviews of estrogen action. The tissue-dependent balance of receptor subtypes and coregulators explains how selective estrogen-receptor modulators can act as agonists in some tissues and antagonists in others. Some rapid steroid effects involve membrane-associated signalling that complements the genomic pathway.

Clinical relevance

The nuclear-receptor mechanism explains why a single circulating sex steroid produces different effects in different tissues and why pharmacological agents can be designed to be tissue-selective. Understanding receptor subtypes and coregulators is central to interpreting how sex steroids shape physiology. This entry describes molecular physiology and the basis of evidence and is not a basis for diagnostic or treatment decisions.

History

The recognition that steroid hormones act through intracellular receptors that regulate gene transcription was a major advance of late-twentieth-century molecular endocrinology, consolidated in the nuclear-receptor superfamily concept. The cloning of a second estrogen receptor, ER-beta, in 1996 revised the long-held single-receptor view of estrogen action and prompted reassessment of how estrogens and selective modulators work in different tissues.

Key figures

• Miguel Beato
• Jan-Ake Gustafsson
• George Kuiper
• Pierre Chambon

Seminal works

• beato-1995
• kuiper-1996
• nilsson-2001

Frequently asked questions

How do sex steroid hormones change cell behaviour?

They enter target cells and bind nuclear receptors that act as transcription factors, turning specific genes on or off, which produces the cell's response.

Why are there two estrogen receptors?

After the original estrogen receptor (ER-alpha) was known, a second receptor, ER-beta, was cloned in 1996; the two have different tissue distributions and roles, which helps explain the varied effects of estrogens.