Harmone act via intracellular pathway

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Here is a complete explanation of hormones acting via the intracellular pathway, sourced from Guyton & Hall and Costanzo Physiology.

Hormones Acting via Intracellular Receptors

Which Hormones Use This Pathway?

Hormones that are lipid-soluble (lipophilic) readily cross the phospholipid cell membrane and bind to receptors inside the cell rather than on its surface. These include:

Hormone Class	Examples
Glucocorticoids	Cortisol
Mineralocorticoids	Aldosterone
Sex steroids	Testosterone, Estrogen, Progesterone
Thyroid hormones	T3, T4
Vitamin D (active form)	1,25-dihydroxycholecalciferol
Retinoids	Retinoic acid

The Intracellular Receptor (Structure)

These receptors are monomeric phosphoproteins belonging to a gene superfamily of nuclear receptors. Each receptor has six domains (A-F):

Steroid hormone receptor structure showing six domains A/B (N-terminus), C (DNA-binding domain with two zinc fingers), D (hinge), E (hormone-binding and dimerization), and F (C-terminus)

Domain C (central): highly conserved, contains two zinc fingers, responsible for DNA binding
Domain E (near C-terminus): the hormone-binding and dimerization site
Receptor may be located in the cytosol (most steroid hormones) or already in the nucleus (thyroid hormones, retinoids)

Step-by-Step Mechanism

Full diagram showing steroid hormone diffusing across cell membrane, binding cytoplasmic receptor, dimerizing, entering nucleus, binding SREs, triggering transcription, mRNA production, translation, new proteins, and physiologic actions

Step 1 - Diffusion across the cell membrane Because the hormone is lipophilic, it freely diffuses across the plasma membrane into the target cell.

Step 2 - Receptor binding Inside the cell, the hormone binds to a specific receptor protein located in the cytosol or nucleus. This binding causes a conformational change in the receptor, activating it.

Step 3 - Dimerization and nuclear entry The activated hormone-receptor complex dimerizes (pairs with another complex) and translocates into the nucleus if it was in the cytosol.

Step 4 - Binding to DNA (Hormone Response Element) The dimer binds via its zinc fingers (C domain) to specific DNA sequences called Steroid-Responsive Elements (SREs) or Hormone Response Elements (HREs) located in the 5' regulatory region of target genes.

Step 5 - Transcription The hormone-receptor complex now acts as a transcription factor, either activating or repressing gene transcription.

Step 6 - mRNA formation and export New mRNA is transcribed, leaves the nucleus through nuclear pores.

Step 7 - Translation mRNA is translated at ribosomes into new specific proteins.

Step 8 - Physiologic effects The new proteins produce the hormone's physiologic actions.

The Pathway Illustrated (Guyton & Hall)

Lipophilic hormone diffusing into target cell, binding cytoplasmic or nuclear receptor, forming hormone-receptor complex, binding hormone response element on DNA, triggering mRNA and protein synthesis

Key Examples of Proteins Induced

Hormone	New Protein Synthesized	Effect
1,25-(OH)2 Vitamin D	Ca2+-binding protein (calbindin)	Promotes Ca2+ absorption from intestine
Aldosterone	Na+ channels (ENaC)	Promotes Na+ reabsorption in kidney
Testosterone	Skeletal muscle proteins	Muscle growth
Cortisol	Gluconeogenic enzymes	Increases blood glucose

Key Characteristics - Comparison with Membrane Receptor Pathway

Feature	Intracellular Receptor Pathway	Membrane Receptor (e.g., cAMP) Pathway
Hormone type	Lipophilic (steroids, thyroid, vitamin D)	Hydrophilic (peptides, catecholamines)
Receptor location	Cytosol or nucleus	Cell surface
Second messenger	None - acts directly on DNA	Yes (cAMP, IP3, Ca2+)
Speed of action	Slow (hours to days)	Rapid (seconds to minutes)
Effect	New protein synthesis	Enzyme activation/inhibition
Duration	Long-lasting	Short-lived

Tissue Specificity

An important point: many tissues have identical intracellular receptors, but the genes regulated differ between tissues. The response depends not just on the receptor but on which gene regulatory proteins are expressed in that particular tissue. This explains why the same hormone (e.g., cortisol) can have different effects in liver vs. immune cells.

Guyton and Hall Textbook of Medical Physiology, p. 910-912
Costanzo Physiology 7th Edition, p. 410

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