Secretion, transport, and feedback control of hormones
Hormone classes determine everything downstream
| Class | Examples | Receptor | Transport | Half-life |
|---|---|---|---|---|
| Peptide/protein | Insulin, GH, PTH, ACTH, LH/FSH, TSH | Cell surface (GPCR, RTK) | Free in plasma | Minutes |
| Steroid | Cortisol, aldosterone, sex steroids, vitamin D | Nuclear | Carrier protein bound | Hours |
| Amine - thyroid | T4, T3 | Nuclear | TBG, albumin, transthyretin | Days (T4 ~7d) |
| Amine - catecholamine | Adrenaline, noradrenaline | Cell surface | Free | Seconds |
- Peptide hormones are stored in granules and released on demand; steroid hormones are synthesised on demand and cannot be stored
- Only the free fraction is biologically active - anything that changes binding protein changes the total but not the free level
Pituitary output
- Anterior (6): GH, prolactin, TSH, ACTH (from POMC), and the glycoproteins LH and FSH (shared alpha subunit with TSH and hCG - the basis of hCG-mediated thyrotoxicosis)
- Posterior (2): ADH and oxytocin - synthesised in supraoptic/paraventricular hypothalamic nuclei and transported down axons; the posterior lobe is neural tissue, not glandular
Practical numbers
- Pituitary adenoma present in ~10% of autopsy and incidental MRI series
- Thyroid function tests, cortisol and HbA1c are among the most-ordered pathology tests - most abnormal results are non-thyroidal illness or assay artefact rather than disease
- Biotin supplementation (high-dose, in hair/nail products) is now a common and under-recognised cause of spurious results
Hypothalamic control of the anterior pituitary
| Axis | Stimulates | Inhibits |
|---|---|---|
| GH | GHRH, ghrelin | Somatostatin, IGF-1 feedback |
| Prolactin | TRH | *Dopamine (tonic)* |
| TSH | TRH | Somatostatin, dopamine, glucocorticoid, T3/T4 |
| ACTH | CRH (augmented by ADH) | Cortisol |
| LH/FSH | Pulsatile GnRH | Sex steroids, inhibin (FSH) |
- *Prolactin is the only anterior pituitary hormone under net inhibitory control* - stalk section raises it, everything else falls
- *GnRH must be pulsatile - continuous exposure desensitises the gonadotroph. This is exactly how GnRH agonists are used to suppress puberty and prostate cancer*
Signalling
- TSH, ACTH, LH/FSH all act via Gs -> cAMP -> PKA
- -> why an activating GNAS mutation (McCune-Albright) produces autonomy in several glands at once
- ACTH controls the rate-limiting step of steroidogenesis: StAR-mediated cholesterol transport across the mitochondrial membrane
- TSH stimulates every step of thyroid hormone synthesis - iodide trapping (NIS), organification (TPO), coupling, endocytosis, release
Individual axes
- GH
- Stimulated by GHRH, ghrelin, fasting/hypoglycaemia, high-protein meal, oestrogen, dopamine and alpha-agonists, beta blockade, sleep, exercise
- Inhibited by somatostatin, IGF-1 feedback, hyperglycaemia, glucocorticoid, leptin, obesity
- Acts on liver -> IGF-1, which mediates the mitogenic effects; direct GH effects are lipolysis and insulin antagonism
- GH is pulsatile -> IGF-1 is the stable marker. This is why acromegaly is screened with IGF-1 and confirmed by failure of GH to suppress below 1 microg/L after 75 g glucose
- Gonadotrophins
- FSH -> granulosa (follicle development) and Sertoli (spermatogenesis)
- LH -> theca (androgen, luteinisation) and Leydig (testosterone)
- ADH - released by inc plasma osmolality (hypothalamic osmoreceptors, threshold ~280-285 mOsm/kg) and by falling volume/pressure (baroreceptors, a less sensitive but more powerful stimulus)
- V2 receptor -> cAMP -> aquaporin-2 insertion in the collecting duct
- Volume defends itself at the expense of tonicity - the mechanism of hypovolaemic hyponatraemia
- Aldosterone - regulated by angiotensin II and potassium (via zona glomerulosa intracellular calcium); ACTH only weakly and transiently
- Which is why ACTH deficiency causes hyponatraemia but not hyperkalaemia
Calcium handling - the transport detail that gets examined
- Gut: active transcellular via TRPV6 (duodenum/proximal jejunum, calcitriol-dependent) + paracellular throughout
- Kidney: ~70% proximal tubule (passive, with sodium), ~20% thick ascending limb (paracellular, lumen-positive potential), ~10-15% distal via TRPV5 - the site of PTH regulation
- Loop diuretics abolish the lumen-positive potential -> calciuresis; thiazides act distally -> calcium retention
The universal rule of dynamic testing
- *Suspected deficiency -> stimulate. Suspected excess -> suppress.*
| Suspicion | Test |
|---|---|
| GH excess | 75 g OGTT - failure of GH to suppress <=1 microg/L |
| GH deficiency | Insulin tolerance test, glucagon test |
| Cortisol excess | 1 mg overnight dexamethasone, 24h urine free cortisol, late-night salivary cortisol |
| Cortisol deficiency | Short Synacthen, insulin tolerance test |
| Aldosterone excess | Saline suppression, fludrocortisone suppression |
| Phaeochromocytoma | Clonidine suppression (only if metanephrines equivocal) |
- Always measure the trophic and target hormone as a pair - the pair localises the lesion
- Low T4 + high TSH = primary; low T4 + low/normal TSH = central
- High Ca + non-suppressed PTH = inappropriate = primary hyperparathyroidism
Assay pitfalls to check before believing a result
Assay pitfalls she should look for before believing a result
- Biotin - competes in streptavidin-biotin immunoassays -> falsely high fT4/fT3 and falsely low TSH (a "Graves" pattern). Stop 48h before testing
- Hook effect - grossly elevated analyte saturates the assay -> falsely low result (prolactin, hCG). Dilute the sample
- Macroprolactin - inert prolactin-IgG complex; asymptomatic hyperprolactinaemia
- Heterophile/anti-animal antibodies - falsely high or low, usually a single discordant result
- Binding protein changes - pregnancy and oestrogen raise TBG, CBG and SHBG -> total hormone rises with normal free hormone
- Non-thyroidal illness (sick euthyroid) - low T3 first, then low T4, TSH normal or low then rebounds high in recovery. Do not test thyroid function in the acutely unwell without a reason
- Pulsatility and diurnal rhythm - a single random GH, LH, testosterone or cortisol is often uninterpretable; time the sample
Physiological replacement
- Physiological replacement mimics the natural rhythm where it matters
- Hydrocortisone in divided doses with the largest on waking; modified-release preparations for a more physiological profile
- Pulsatile GnRH to induce fertility; continuous GnRH agonist to suppress
- Monitor the axis that is still intact, never the one you have replaced
- Primary hypothyroidism -> TSH. Central hypothyroidism -> fT4 only (TSH is meaningless)
- Glucocorticoid replacement -> clinical assessment; no useful biochemical marker
- Pegvisomant (GH-receptor blockade) -> IGF-1, not GH (GH rises on treatment)
- Replace glucocorticoid before thyroxine in combined deficiency - thyroxine accelerates cortisol clearance and precipitates crisis
Cross-reactivity and axis interactions
- Shared glycoprotein alpha subunit - hCG cross-stimulates the TSH receptor (molar pregnancy, hyperemesis)
- Very high TSH cross-stimulates the FSH receptor - Van Wyk-Grumbach precocious puberty in profound hypothyroidism
- Primary hypothyroidism -> inc TRH -> hyperprolactinaemia and pituitary hyperplasia (both reverse with thyroxine)
- Gs/cAMP pathway - GNAS activating mutation (McCune-Albright, gsp somatotroph adenoma); inactivating (pseudohypoparathyroidism)
- Dopamine infusion in ICU suppresses TSH and prolactin; glucocorticoids suppress TSH
- MEN1, MEN2, MEN4 - multiple axes affected by a single germline defect
Feedback in disease
- Feedback loops make most endocrine disease self-declaring on a paired sample - the trophic hormone tells you where the lesion is
- Chronic understimulation causes atrophy (exogenous glucocorticoid -> adrenal atrophy; months to recover)
- Chronic overstimulation causes hyperplasia then autonomy (long-standing secondary hyperparathyroidism -> tertiary; iodine deficiency -> toxic MNG)
- Receptor downregulation follows sustained ligand excess - why phaeochromocytoma patients are volume-contracted and paradoxically postural
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