Endocrine Physiology
1. What this chapter covers, and how NEET PG actually tests it
Endocrine questions in NEET PG almost always supply a pattern of hormone levels and ask what is wrong.
That pattern is readable, because every endocrine system is a feedback loop with a small number of limbs.
A high trophic hormone with a low target hormone means the gland has failed. A low trophic hormone with a high target hormone means the gland is autonomous.
That single pair of rules answers a surprising fraction of the subject, and everything else is knowing the specific pathway well enough to locate the block.
Steroid synthesis is the clearest example. A blocked enzyme causes deficiency of everything downstream and accumulation of everything upstream, and the clinical picture is simply the sum of those two consequences.
This chapter covers the hypothalamic-pituitary axes, the thyroid, the adrenal cortex, and calcium and glucose regulation.
| In scope here | Deliberately out of scope |
|---|---|
| Pituitary axes, feedback logic, ADH disorders | Pituitary surgery and radiotherapy |
| Thyroid hormone synthesis, conversion and iodide autoregulation | Thyroid malignancy pathology (see Pathology) |
| Adrenal zones, steroid pathway and congenital adrenal hyperplasia | Detailed steroid pharmacokinetics (see Pharmacology) |
| Calcium homeostasis, insulin secretion and counter-regulation | Diabetes management protocols (see Medicine) |
2. The hypothalamic-pituitary axes
2.1 The feedback rule, and how to read a hormone panel
The anterior pituitary secretes growth hormone, prolactin, adrenocorticotropic hormone, thyroid stimulating hormone, luteinising hormone and follicle stimulating hormone.
Each is controlled by a hypothalamic releasing factor and restrained by negative feedback from its target hormone.
So the relationship between the two levels localises the lesion.
| Pattern | Interpretation |
|---|---|
| Low target hormone, high trophic hormone | Primary failure of the target gland |
| Low target hormone, low or inappropriately normal trophic hormone | Secondary failure, at the pituitary or hypothalamus |
| High target hormone, suppressed trophic hormone | Autonomous target gland — an adenoma or exogenous hormone |
| High target hormone, unsuppressed trophic hormone | A trophic-hormone-secreting tumour, or resistance |
An inappropriately normal value counts as abnormal. A thyroid stimulating hormone level in the reference range alongside a clearly low thyroxine indicates pituitary failure, because a healthy pituitary would have raised it.
2.2 Prolactin is the exception that gets tested
Every other anterior pituitary hormone is under net stimulatory hypothalamic control.
Prolactin alone is under tonic inhibition, by dopamine travelling down the pituitary stalk.
That single difference creates a distinctive clinical consequence.
Anything that interrupts the stalk — a mass, trauma, surgery — removes the inhibition, so prolactin rises while every other pituitary hormone falls.
This is the stalk effect, and distinguishing it from a true prolactinoma matters because the management differs.
The magnitude of the rise is the discriminator. Stalk compression typically produces a modest elevation, while a prolactinoma large enough to compress the stalk usually produces a far higher level, broadly proportional to tumour size.
Dopamine antagonists such as antipsychotics and metoclopramide raise prolactin by the same mechanism, blocking the inhibitory signal rather than stimulating secretion.
2.3 Growth hormone works through an intermediary
Growth hormone has some direct metabolic effects — it is diabetogenic, raising blood glucose and promoting lipolysis.
But its growth-promoting actions are mediated by insulin-like growth factor 1, produced mainly by the liver in response to growth hormone.
This two-step arrangement is why growth hormone levels alone are a poor test. Secretion is pulsatile, so a single measurement may be high or low in the same healthy person.
Insulin-like growth factor 1 is stable through the day and therefore the better screening measurement.
The two-step design also explains Laron syndrome, in which the growth hormone receptor is defective.
Growth hormone is therefore high while insulin-like growth factor 1 is low, and the patient has severe short stature despite abundant hormone — a resistance pattern rather than a deficiency.
2.4 Antidiuretic hormone, and the two ways water balance fails
Antidiuretic hormone is synthesised in the hypothalamus and released from the posterior pituitary.
It acts on V2 receptors in the collecting duct, inserting aquaporin-2 channels into the apical membrane so water can be reabsorbed. Its V1 receptors mediate vasoconstriction.
Diabetes insipidus is failure of this system, giving large volumes of dilute urine with a rising plasma osmolality.
The two forms are separated by a single test. Central diabetes insipidus responds to desmopressin with urine concentration; nephrogenic diabetes insipidus does not, because the defect is at the receptor or beyond.
Syndrome of inappropriate antidiuretic hormone secretion is the mirror image: water is retained inappropriately, producing a euvolaemic hyponatraemia.
The diagnostic pattern follows directly from the physiology. Plasma is dilute while urine is inappropriately concentrated, and urine sodium is high because volume expansion suppresses aldosterone and promotes natriuresis.
Euvolaemia is what distinguishes it clinically, since hypovolaemic and hypervolaemic hyponatraemias have their own visible volume signs.
3. The thyroid
3.1 Synthesis, step by step, with the drug that blocks each step
Thyroid hormone synthesis is a sequence, and knowing it locates the action of every relevant drug.
Iodide trapping occurs at the basolateral membrane via the sodium-iodide symporter, which concentrates iodide many-fold. Perchlorate and thiocyanate block it competitively.
Oxidation and organification follow, in which thyroid peroxidase oxidises iodide and attaches it to tyrosine residues on thyroglobulin, forming monoiodotyrosine and diiodotyrosine.
Coupling, also by thyroid peroxidase, joins these to form T3 and T4.
Thionamides — propylthiouracil and methimazole — block thyroid peroxidase, and therefore both organification and coupling.
Propylthiouracil additionally blocks peripheral conversion of T4 to T3, which is why it is preferred in thyroid storm despite methimazole's better general profile.
3.2 T4, T3 and the significance of conversion
The thyroid secretes mainly T4, but T3 is the more potent hormone and most circulating T3 comes from peripheral deiodination of T4.
The enzyme responsible is 5'-deiodinase, and the alternative deiodination pathway produces reverse T3, which is metabolically inactive.
This branch point is where systemic illness intervenes.
In severe illness, 5'-deiodinase activity falls and conversion shifts toward reverse T3, producing the sick euthyroid pattern: low T3, normal or low T4, raised reverse T3, and a normal or low thyroid stimulating hormone.
Recognising this matters because treating it as hypothyroidism is a well-recognised error — the pattern reflects the illness, not thyroid disease.
Note also that most thyroid hormone is protein-bound, chiefly to thyroxine-binding globulin.
Pregnancy and oestrogen raise thyroxine-binding globulin, so total T4 rises while free T4 stays normal and the patient remains euthyroid. Measuring free hormone avoids this trap entirely.
3.3 Iodide autoregulation: two named effects
The thyroid regulates its own response to iodide, and both directions have names.
The Wolff-Chaikoff effect is the transient inhibition of organification by a large iodide load.
This is exploited therapeutically. Iodine given in thyroid storm reduces hormone release rapidly, but it must be given after a thionamide, because iodide would otherwise be used as substrate for new hormone synthesis.
The Jod-Basedow effect is the opposite: iodine exposure precipitating hyperthyroidism, characteristically in a patient with a pre-existing nodular goitre whose autonomous nodules were previously iodine-limited.
The two effects are not contradictory. A normal thyroid escapes the iodide load by autoregulating; an autonomous nodule does not autoregulate and simply makes more hormone.
4. The adrenal cortex
4.1 Three zones, three products, two regulators
The cortex is layered, and the layers are read from outside inward.
| Zone | Product | Regulated by |
|---|---|---|
| Glomerulosa (outer) | Aldosterone | Angiotensin II and potassium, not primarily ACTH |
| Fasciculata (middle) | Cortisol | ACTH |
| Reticularis (inner) | Androgens | ACTH |
The traditional hook is salt, sugar and sex, in that order, and the deeper the layer the sweeter the product.
The important physiological point is that the glomerulosa is largely ACTH-independent.
This is why secondary adrenal insufficiency, from pituitary failure, causes cortisol deficiency without significant aldosterone deficiency — so hyperkalaemia and severe salt wasting are features of primary adrenal failure, not secondary.
It also explains why hyperpigmentation occurs only in primary disease, where the raised ACTH precursor drives melanocyte stimulation.
4.2 Congenital adrenal hyperplasia: read the block
All the congenital adrenal hyperplasias follow one rule. A blocked enzyme means deficiency downstream and accumulation upstream, and the accumulated precursors are shunted into whichever pathway remains open.
| Enzyme deficient | Cortisol | Mineralocorticoid effect | Androgens | Clinical picture |
|---|---|---|---|---|
| 21-hydroxylase (~90% of cases) | Low | Low — salt wasting | High | Virilisation, hypotension, hyperkalaemia, raised 17-hydroxyprogesterone |
| 11-beta-hydroxylase | Low | High — deoxycorticosterone accumulates | High | Virilisation with hypertension |
| 17-alpha-hydroxylase | Low | High | Low | Hypertension with hypokalaemia and sexual infantilism |
Reason through the pattern rather than memorising three lists.
In 21-hydroxylase deficiency both cortisol and aldosterone pathways are blocked, so the only route left is androgens — hence virilisation with salt wasting.
In 11-beta-hydroxylase deficiency the block is one step later, so deoxycorticosterone accumulates. It has mineralocorticoid activity, so the patient is hypertensive instead of salt-wasting, while androgens still accumulate.
In 17-alpha-hydroxylase deficiency the block is early and on the androgen side, so sex steroids are absent while mineralocorticoid precursors pile up — hypertension without virilisation.
Loss of cortisol removes negative feedback in every case, so ACTH rises and drives the hyperplasia that gives the group its name.
4.3 Cortisol's actions, and why they look like the side effects
Cortisol is a stress hormone, and its actions are coherent as a set once that is the frame.
It raises glucose by promoting gluconeogenesis, and supplies the substrate by promoting proteolysis in muscle and lipolysis peripherally.
It is immunosuppressive and anti-inflammatory, and it is permissive for catecholamines — vascular smooth muscle responds poorly to noradrenaline without it, which is why adrenal crisis causes refractory hypotension.
It inhibits fibroblasts and reduces bone formation.
Every feature of Cushing syndrome is one of these actions in excess: central obesity with thin limbs from redistributed fat and muscle wasting, purple striae and thin skin from fibroblast inhibition, hyperglycaemia, osteoporosis, and infection risk.
5. Calcium and glucose
5.1 Parathyroid hormone and vitamin D differ in one crucial way
Parathyroid hormone is released in response to a fall in ionised calcium, sensed by the calcium-sensing receptor.
It acts at three sites. In bone it mobilises calcium and phosphate. In the kidney it increases distal calcium reabsorption and, importantly, inhibits proximal phosphate reabsorption. It also activates 1-alpha-hydroxylase, producing calcitriol.
Calcitriol then increases absorption of both calcium and phosphate from the gut.
So the two hormones differ in their effect on phosphate, and that difference is the diagnostic tool.
Parathyroid hormone raises calcium and lowers phosphate, because renal phosphate wasting outweighs what it mobilises from bone.
Vitamin D raises calcium and raises phosphate, since gut absorption takes up both.
A patient with hypercalcaemia and a low phosphate has primary hyperparathyroidism; one with hypercalcaemia and a high phosphate has vitamin D excess or another non-parathyroid cause.
Calcitonin, from the parafollicular C cells, lowers calcium but has a minor physiological role in humans. Its main clinical importance is as a tumour marker for medullary thyroid carcinoma.
5.2 Insulin secretion is a channel story
The beta cell senses glucose through GLUT2, a low-affinity transporter whose uptake rises in proportion to blood glucose rather than saturating.
Glucose metabolism raises the intracellular ATP to ADP ratio, which closes the ATP-sensitive potassium channel.
Closing that channel depolarises the cell, opening voltage-gated calcium channels, and the resulting calcium influx triggers exocytosis of insulin granules.
Sulfonylureas act by closing the same channel directly, which is why they cause hypoglycaemia — they are independent of the ambient glucose level.
Insulin acts on a tyrosine kinase receptor and recruits GLUT4 to the membrane in muscle and adipose tissue. Liver, brain and red cells do not require insulin for glucose uptake.
Two derived facts are heavily tested.
C-peptide is co-secreted with endogenous insulin but absent from injected insulin, so it separates an insulinoma or sulfonylurea abuse from surreptitious insulin injection.
The incretin effect describes the greater insulin response to oral than to intravenous glucose, mediated by glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide released by the gut.
5.3 The counter-regulatory hormones
Four hormones oppose insulin, and each has a distinct timescale.
Glucagon acts first, within minutes, driving hepatic glycogenolysis and then gluconeogenesis.
Catecholamines act equally fast, adding glycogenolysis and lipolysis.
Cortisol and growth hormone act over hours, sustaining gluconeogenesis and reducing peripheral glucose uptake.
This layered design explains the dawn phenomenon, in which early-morning growth hormone and cortisol surges raise fasting glucose, and it explains why hypoglycaemia is prolonged in adrenal or pituitary failure.
Worked clinical vignettes
Q1. A patient has a free T4 well below the reference range and a thyroid stimulating hormone level in the middle of its reference range. What does this indicate?
Pick an option to check your answer.
Show explanation
Solution. A healthy pituitary responds to a low thyroxine by raising thyroid stimulating hormone substantially.
A value that is merely normal is therefore inappropriately normal, which counts as abnormal and indicates the pituitary is not responding.
(a) would show a clearly raised trophic hormone. Answer: (b).
Q2. A newborn girl has ambiguous genitalia, hypotension, hyponatraemia and hyperkalaemia. Which enzyme is deficient, and why does this combination occur?
Pick an option to check your answer.
Show explanation
Solution. Virilisation indicates androgen excess, and salt wasting with hyperkalaemia indicates aldosterone deficiency.
Only 21-hydroxylase deficiency blocks both the cortisol and aldosterone pathways while leaving the androgen route open, so accumulated precursors are shunted into androgens.
(a) would cause hypertension rather than salt wasting, and (c) would cause absent rather than excess androgens. Answer: (b).
Q3. A patient has hypercalcaemia with a serum phosphate below the reference range. Which cause is most likely?
Pick an option to check your answer.
Show explanation
Solution. Parathyroid hormone raises calcium but inhibits proximal tubular phosphate reabsorption, so renal phosphate wasting lowers serum phosphate.
Vitamin D instead increases gut absorption of both ions, so hypercalcaemia from vitamin D excess is accompanied by a high phosphate.
The phosphate level therefore separates the two most common causes of hypercalcaemia. Answer: (b).
7. Common exam traps
- Accepting a normal trophic hormone as normal. If the target hormone is clearly abnormal, a trophic level within the reference range is inappropriate and localises the lesion to the pituitary.
- Treating prolactin like the other pituitary hormones. It is uniquely under tonic dopaminergic inhibition, so stalk interruption raises it while lowering everything else.
- Measuring random growth hormone. Secretion is pulsatile; insulin-like growth factor 1 is the stable screening test, and a high growth hormone with a low insulin-like growth factor 1 means receptor resistance.
- Giving iodine before a thionamide in thyroid storm. Iodide would be used as substrate; the thionamide must block synthesis first.
- Diagnosing hypothyroidism in critical illness. A low T3 with raised reverse T3 in a sick patient is sick euthyroid syndrome and reflects the illness.
- Expecting hyperkalaemia in secondary adrenal insufficiency. The glomerulosa is not ACTH-dependent, so aldosterone is largely preserved.
- Confusing the phosphate direction in hypercalcaemia. Parathyroid hormone lowers phosphate; vitamin D raises it.
- Forgetting C-peptide in hypoglycaemia work-up. It separates endogenous causes from injected insulin, and a sulfonylurea screen separates the endogenous causes from each other.
Summary
- A low target hormone with a high trophic hormone means primary gland failure; with a low or inappropriately normal trophic hormone it means pituitary or hypothalamic failure.
- Prolactin is unique in being tonically inhibited by dopamine, so stalk compression and dopamine antagonists both raise it while other pituitary hormones fall.
- Growth hormone acts through insulin-like growth factor 1, which is why a high growth hormone with a low insulin-like growth factor 1 indicates receptor resistance, as in Laron syndrome.
- Antidiuretic hormone inserts aquaporin-2 through V2 receptors; central diabetes insipidus responds to desmopressin and nephrogenic does not.
- The syndrome of inappropriate antidiuretic hormone gives euvolaemic hyponatraemia with inappropriately concentrated urine and high urine sodium.
- Thyroid synthesis runs trapping, organification and coupling; thionamides block thyroid peroxidase and propylthiouracil additionally blocks peripheral conversion.
- T4 is the main secretory product but T3 is the active hormone, produced by 5'-deiodinase; illness diverts conversion to inactive reverse T3, giving the sick euthyroid pattern.
- Raised thyroxine-binding globulin in pregnancy raises total T4 while free T4 and clinical status stay normal.
- The Wolff-Chaikoff effect is transient inhibition of organification by iodide; the Jod-Basedow effect is iodine-induced hyperthyroidism in an autonomous nodular gland.
- Adrenal zones run glomerulosa to aldosterone, fasciculata to cortisol, reticularis to androgens, with only the latter two being ACTH-dependent.
- Congenital adrenal hyperplasia is read as deficiency downstream and accumulation upstream: 21-hydroxylase gives virilisation with salt wasting, 11-beta gives virilisation with hypertension, 17-alpha gives hypertension without virilisation.
- Cortisol's actions — gluconeogenesis, proteolysis, lipolysis, immunosuppression and permissiveness for catecholamines — are exactly the features of Cushing syndrome in excess.
- Parathyroid hormone raises calcium and lowers phosphate; vitamin D raises both, so the phosphate level discriminates the causes of hypercalcaemia.
- Insulin secretion depends on ATP-dependent closure of the potassium channel, which sulfonylureas close directly and glucose-independently.
- C-peptide is present with endogenous insulin and absent with injected insulin, and the incretin effect explains the greater response to oral than intravenous glucose.
- Glucagon and catecholamines counter-regulate within minutes while cortisol and growth hormone act over hours, which explains both the dawn phenomenon and prolonged hypoglycaemia in adrenal or pituitary failure.
