Hormone biochemistry

Hormone classes

• A hormone's chemistry decides where its receptor sits. Water-soluble hormones cannot cross the lipid membrane, so they bind surface receptors and act through second messengers within seconds to minutes. Lipid-soluble hormones cross it and bind intracellular receptors that change gene transcription over hours.

• Glycoprotein hormones (TSH, LH, FSH, hCG) share an α subunit; the β subunit gives specificity, which is why very high hCG can stimulate the TSH receptor.
• Neurosecretory hormones are made by neurons and released into blood: ADH and oxytocin (hypothalamic supraoptic and paraventricular nuclei, released from the posterior pituitary) and hypothalamic releasing hormones.
• Prohormones: preproinsulin gives proinsulin, then insulin plus C-peptide in equal amounts (low C-peptide with high insulin means injected insulin). POMC gives ACTH, MSH and β-endorphin, which is why ACTH excess darkens the skin.

Receptors and second messengers

• TSH binds a Gs-coupled receptor on follicular cells: Gs, adenylate cyclase, cAMP (the same receptor that TSH receptor antibodies stimulate in Graves disease).
• ADH is a classic double-pathway hormone: V2 receptors in the collecting duct use cAMP to insert aquaporin-2; V1 receptors in vessels use IP3 to constrict.

Remember Most anterior pituitary hormones (FSH, LH, ACTH, TSH) use cAMP; the hypothalamic GnRH and TRH use IP3; GH and prolactin use JAK–STAT.

Exam trap Insulin acts through a receptor tyrosine kinase, not JAK–STAT; GH and prolactin use JAK–STAT.

Metabolic hormones

• GH is released in pulses, mostly in deep sleep; it rises with hypoglycaemia, fasting, exercise and stress, and falls with hyperglycaemia and obesity. Full growth needs thyroid hormone and insulin as well as IGF-1. Prolactin also rises in sleep.
• Leptin, made by fat cells, acts on the hypothalamus (arcuate nucleus) to reduce appetite and raise energy use; obese people are leptin resistant. Ghrelin from the stomach is the main orexigenic (appetite-stimulating) hormone and peaks before meals.

Steroid synthesis and the adrenal cortex

• All steroids come from cholesterol. The rate-limiting step is its transport into mitochondria by StAR protein and cleavage by side-chain cleavage enzyme (desmolase, CYP11A1) to pregnenolone; ACTH drives it in the adrenal, LH in the gonads.
• Zones: glomerulosa makes aldosterone under the primary control of angiotensin II (and potassium); fasciculata, the largest zone, makes cortisol under ACTH; reticularis makes androgens (DHEA).
• Other enzymes: 21-hydroxylase, 11β-hydroxylase, 17α-hydroxylase, 3β-HSD, aromatase (androgens to oestrogens), 5α-reductase (testosterone to DHT).

Congenital adrenal hyperplasia

• Low cortisol removes feedback, ACTH rises, the adrenals enlarge and precursors are diverted to whatever pathway is still open.

• Treatment: glucocorticoid replacement (suppresses ACTH), plus fludrocortisone if salt wasting.

Hormone binding proteins

• Only the free fraction is active and controls feedback. Oestrogen (pregnancy, the pill) raises TBG and CBG, so total hormone rises while free levels stay normal.

Thyroid hormone and catecholamine synthesis

• Thyroid: iodide trapping by the sodium–iodide symporter; oxidation and organification by thyroid peroxidase (blocked by carbimazole and propylthiouracil); coupling of MIT and DIT (T3) or DIT and DIT (T4) on thyroglobulin; release, mostly as T4; peripheral 5′-deiodination to active T3 (blocked by propylthiouracil, propranolol, steroids, amiodarone). Reverse T3 is inactive. Thyroid hormone raises BMR partly by increasing Na⁺/K⁺-ATPase.
• Catecholamines: tyrosine to L-DOPA (tyrosine hydroxylase, rate-limiting), to dopamine, to noradrenaline (dopamine β-hydroxylase, needs vitamin C and copper), to adrenaline (PNMT, induced by cortisol from the cortex, so mainly in the adrenal medulla). Broken down by MAO and COMT to metanephrines and VMA: metanephrines diagnose phaeochromocytoma.

Feedback and rhythms

• Negative feedback dominates (cortisol suppresses CRH and ACTH). Positive feedback drives the mid-cycle LH surge and oxytocin in labour.
• Cortisol peaks in the early morning and is lowest at midnight; melatonin rises at night; GnRH must be pulsatile to release LH and FSH, and continuous GnRH agonists suppress them.

How FCPS asks about this

• Second messenger of NO and ANP: cGMP via guanylate cyclase.
• Hormones acting through IP3: GnRH, TRH, oxytocin, ADH on V1, angiotensin II (Gq and phospholipase C).
• Second messenger of the TSH receptor: Gs, adenylate cyclase and cAMP.
• Pathway used by GH, prolactin and erythropoietin: JAK–STAT; insulin uses a receptor tyrosine kinase.
• Main metabolic effect of insulin: storage of glycogen, fat and protein; cortisol's main action is gluconeogenesis, glucagon's glycogenolysis.
• Fat-cell hormone reducing appetite: leptin; ghrelin is orexigenic.
• Virilised girl with salt wasting and high 17-hydroxyprogesterone: 21-hydroxylase deficiency; virilisation with hypertension is 11β-hydroxylase deficiency.