Mechanism of hormone action

Two families of hormone

• Steroid-making cells such as the corpus luteum take most of their cholesterol from plasma LDL by receptor-mediated endocytosis through the LDL receptor.
• hCG lasts much longer than LH, though both bind the same LH/hCG receptor, because its beta subunit carries a carboxy-terminal extension rich in sialic acid; sialylated sugars delay hepatic clearance. One injection acts for days (the IVF trigger), which also raises the risk of ovarian hyperstimulation.

G protein-coupled receptors (seven transmembrane)

• The receptor makes the alpha subunit swap GDP for GTP; the active alpha subunit acts on its enzyme until its own GTPase hydrolyses GTP back to GDP, which switches it off.

• cAMP acts through protein kinase A. cAMP binds the regulatory subunits of PKA (two regulatory, two catalytic), freeing the catalytic subunits to phosphorylate enzymes within minutes.
• cAMP also acts slowly on genes: PKA phosphorylates CREB (cAMP response element-binding protein), which switches on genes such as aromatase in granulosa cells within hours of FSH. Phosphodiesterase degrades cAMP and ends the signal.
• Each step activates many molecules, so tiny hormone concentrations give large responses (amplification).
• Gq pathway: IP3 opens the IP3 receptor calcium channel on the endoplasmic (sarcoplasmic) reticulum; DAG with calcium activates protein kinase C.
• ADH: V2 receptors (Gs, cAMP) in the collecting duct cause PKA to insert aquaporin-2 channels into the luminal membrane; V1 receptors (Gq) on vessels cause vasoconstriction.

Myometrium as a worked example

• Calcium binds calmodulin, which activates myosin light-chain kinase: contraction. Adrenaline acts on both alpha-1 and beta-2, so its effect depends on dose.

Errors in G protein signalling

• Desensitisation: prolonged agonist exposure uncouples and internalises receptors. After many hours of oxytocin augmentation the uterus responds poorly, risking atonic PPH.
• GnRH must be pulsatile (every 60–90 minutes) to keep pituitary receptors responsive. A pump giving pulses induces ovulation in hypothalamic amenorrhoea; it cannot work if the pituitary is destroyed (Sheehan syndrome). Continuous agonist first causes a flare, then down-regulation. GnRH antagonists block without a flare.

Cyclic GMP

• Membrane guanylyl cyclase: ANP and BNP.
• Soluble guanylyl cyclase: nitric oxide. cGMP activates protein kinase G, which relaxes smooth muscle. Penile and clitoral erection uses parasympathetic NO and cGMP; PDE5 inhibitors prolong it.

Enzyme-linked receptors

• Receptor tyrosine kinase: insulin, IGF-1, growth factors. Autophosphorylation then IRS, PI3K and Akt, moving GLUT4 to the membrane. In gestational diabetes placental hormones blunt post-receptor steps; chronic hyperinsulinaemia down-regulates receptors.
• Cytokine receptors with JAK–STAT: GH, prolactin, erythropoietin, leptin (low leptin in very lean athletes suppresses GnRH).

Intracellular receptors

• Structure: ligand-binding domain, DNA-binding domain (zinc fingers), transactivation domain. Cortisol is the classic hormone whose receptor binds DNA directly at hormone response elements. Thyroid hormone is an amine but behaves like a steroid.
• Glucocorticoid receptor waits in the cytoplasm bound to heat shock protein 90; hormone releases it and the complex enters the nucleus. Oestrogen receptor is mainly nuclear.
• Thyroid hormone and vitamin D receptors sit on DNA as heterodimers with the retinoid X receptor. Calcitriol raises duodenal calcium absorption by inducing calbindin, so the effect takes days.
• Antenatal betamethasone works best after about 24 hours because new transcription is needed: alveolar type II pneumocytes increase surfactant.
• Tissue-selective modulators: the same receptor recruits different co-activators and co-repressors in each tissue. Tamoxifen is an antagonist in breast but an agonist in endometrium; raloxifene does not stimulate the endometrium; fulvestrant causes receptor degradation.

Receptor disorders

Obstetric drugs and their receptors

• Some drugs act without any receptor: antacids, osmotic diuretics (mannitol), chelating agents and bulk laxatives work by chemical or physical properties.

Remember Peptides are stored and act at the surface; steroids are made on demand and act in the nucleus.

Exam trap FSH and LH use cAMP; GnRH and oxytocin use IP3 and DAG. Do not mix the two levels of the axis.

Exam trap Insulin, GH and prolactin do not use cAMP: insulin uses a tyrosine kinase, GH and prolactin use JAK–STAT.

How FCPS asks about this

• cAMP acts through: protein kinase A; on genes via phosphorylated CREB.
• Phospholipase C is the messenger route of: GnRH, oxytocin, TRH, alpha-1 and V1 receptors.
• cGMP is the second messenger of: nitric oxide and ANP.
• Hormone acting through an intracellular receptor that binds DNA: cortisol (also other steroids, thyroid hormone, vitamin D).
• Why GnRH is given in pulses: pulses keep pituitary GnRH receptors responsive; continuous exposure down-regulates them.
• Why hCG lasts longer than LH: high sialic acid content of its beta-subunit tail.
• McCune–Albright defect: Gs-alpha that cannot hydrolyse GTP.