Lipid-soluble (hydrophobic) hormones can cross the phospholipid bilayer unaided.
Major subclasses: steroids (e.g., cortisol, aldosterone, sex steroids) and thyroid hormones (T3, T4).
Their receptors are intracellular (cytosolic, nuclear, or mitochondrial), in contrast to peptide & catecholamine receptors that are membrane-bound.
Canonical Steroid Hormone Mechanism
Entry & Binding
• Hormone diffuses through plasma membrane.
• In cytosol it binds to a steroid hormone receptor (SHR).
• Each receptor has two key domains:
– Hormone-binding site.
– DNA-binding site (zinc-finger motif) that recognizes specific DNA sequences (Hormone Response Elements, HREs).
Chaperone Proteins (Heat-Shock Proteins, HSPs)
• In absence of hormone, HSPs mask the DNA-binding domain & stabilize receptor conformation.
• Hormone binding → conformational change → HSP dissociation → receptor activation.
Dimerization
• Activated receptors usually form homodimers (some form heterodimers). Dimerization increases DNA-binding affinity & specificity.
Nuclear Translocation
• If not already nuclear, the hormone–receptor complex is imported into the nucleus via nuclear-localization signals (NLS) exposed after HSP release.
Transcriptional Regulation
• Complex binds HREs ≈ 6–10 bp palindromic sequences upstream or downstream of target genes.
• Usually activates transcription (↑ mRNA synthesis) but can also repress genes.
• Resultant mRNA exits nucleus → ribosomes translate it → new proteins (often metabolic enzymes) → cellular response.
Key Point on Versatility
• One transcription factor can regulate multiple genes.
• Multiple hormone receptors can share identical HREs, but each controls a characteristic gene ensemble.
Cortisol: A Prototypical Steroid
Source: Zona fasciculata of adrenal cortex; synthesized from cholesterol.
Receptor: Glucocorticoid receptor (GR), present in nearly all nucleated cells.
Major Cellular Responses
• Gluconeogenesis – generation of glucose from non-carbohydrates.
• Glycogenolysis – breakdown of glycogen.
• Lipolysis – triglyceride → glycerol + FAs.
• Protein catabolism (especially skeletal muscle).
• Enhanced vasoconstriction (↑ sensitivity to catecholamines).
• Anti-inflammatory & immunosuppressive (↓ cytokines, ↓ leukocyte migration).
Physiological Role: Maintains fuel availability, sustains blood pressure, modulates immunity during stress — core to the “stress response” (detailed in a later lecture).
Thyroid Hormones (T3 & T4)
Transport into Cells
• Primarily passive diffusion; facilitated by carrier-mediated transporters (e.g., MCT8, OATP1C1).
Intracellular Conversion
• T45′deiodinationDeiodinaseTypeI/IIT3 – T3 is ≈10× more active.
Receptor Distribution & Configuration
• Nuclear thyroid hormone receptors (TRα, TRβ) are pre-bound to HREs, keeping target genes in a repressed or low-basal state.
• T3 binding triggers:
– Release of corepressors.
– Recruitment of coactivators.
– Gene activation (or de-repression).
• A minor fraction of T4 can bind but is less potent.
• Additional TRs identified in cytosol & mitochondria; functions remain incompletely defined.
Systemic Effects
• ↑ Basal Metabolic Rate (BMR).
• Modulates carbohydrate, lipid & protein metabolism.
• Essential for normal growth (synergistic with GH).
• Crucial for CNS development & ongoing neuronal function.
• Regarded as the primary metabolic rate regulator of the body.
Complexity Beyond the Core Pathway
Multiple upstream stimulants or pathways can converge on shared downstream targets ("multiple stimulants → same actions").
• Example given: All steroid pathways begin with cholesterol.
Calcium Homeostasis Reference
• Low blood [Ca2+] triggers compensatory endocrine reflexes (e.g., parathyroid hormone release), though details were only alluded to.
LH Surge Illustration
• Mid-cycle gonadotropin dynamics: Estrogen buildup → positive feedback → surge of LH → ovulation (release of mature oocyte into pelvic cavity).
Autoimmune Intersection
• Thyroid disorders can co-occur with other autoimmune diseases (e.g., Hashimoto’s thyroiditis), highlighting shared immune dysregulation.
Conceptual & Practical Connections
Fundamental Principle: Lipid-soluble hormones regulate gene expression by directly interacting with DNA. This bypasses the need for second-messenger cascades characteristic of membrane receptors.
Pharmacology: Synthetic glucocorticoids (e.g., prednisone) exploit the anti-inflammatory pathways outlined above but carry risks (immunosuppression, osteoporosis).
Clinical Diagnostics:
• Plasma cortisol rhythm (circadian) critical for diagnosing Cushing’s vs Addison’s.
• Serum TSH/T4/T3 panels assess thyroid axis integrity; autoantibodies screen for Hashimoto’s or Graves’.
Bioethics: Chronic steroid therapy necessitates balancing inflammatory control against long-term metabolic & immune consequences.
Research Corner: Intracellular thyroid receptors in mitochondria may link thyroid hormone to direct modulation of oxidative phosphorylation – an active area of investigation.