Unit 12 — Endocrine System · Question Bank

The thyroid is the only endocrine gland in the body that stores its hormone outside the cell, and that single peculiarity drives the whole of its histology. Section through the gland and you find thousands of tightly packed spherical units called follicles, each one a hollow ball lined by a single epithelial layer with a pink-staining gel inside. The surrounding stroma is delicate, the capillary supply is dense and fenestrated, and the activity of the gland can be read off directly from the shape of the lining cells.

Capsule and stroma

The thyroid is wrapped in a thin fibrous capsule from which delicate septa run inwards to carry blood vessels, lymphatics and autonomic nerves and to divide the parenchyma into ill-defined lobules. Between the follicles lies a remarkably rich basket of fenestrated capillaries, perfectly placed to deliver TSH to the follicular cells and pick up secreted T₃ and T₄. Scattered lymphocytes are normal in small numbers; heavy lymphocytic infiltration with germinal centres is the hallmark of Hashimoto thyroiditis.

The follicle and its colloid

Each follicle is a sphere lined by a single layer of simple cuboidal epithelium — the follicular cells — enclosing a central lumen filled with colloid. The colloid is gel-like, eosinophilic and PAS-positive because it is essentially pure iodinated thyroglobulin, the pre-made precursor of thyroid hormone. The follicle is therefore a storage vessel: weeks of hormone are kept ready outside the cell, no other endocrine gland does this. The diameter of a follicle ranges from 0.2 to 1.0 mm and the cell height changes with activity, giving the pathologist a direct readout of physiology.

Follicular cells

Follicular cells are classical protein-secreting cells with abundant RER, prominent Golgi and apical microvilli reaching into the colloid. They have a two-way job: synthesise thyroglobulin and oxidise iodide at the apex (iodinating tyrosine residues to form mono- and di-iodotyrosines that couple into T₃/T₄), then re-endocytose colloid back into the cell when TSH signals, digest it in lysosomes, and release free T₃/T₄ across the basal membrane into the capillary. When the gland is hyperactive (Graves disease) the cells go tall columnar and the colloid is scalloped at the edges; when hypoactive the cells flatten and colloid heaps up.

Parafollicular (C) cells

Lying between follicles, or wedged between follicular cells and the basement membrane, sit larger, paler cells with no contact with the colloid — the parafollicular or C cells. They are derived not from endoderm but from the neural crest (via the ultimobranchial body), and they secrete the peptide calcitonin, which lowers blood calcium by inhibiting osteoclasts. Calcitonin is a minor player in adult calcium homeostasis but the C cells are the cell of origin for medullary thyroid carcinoma, a familial cancer that is part of the MEN-2 syndrome.

Clinical link

The histology mirrors disease beautifully. Graves disease: tall columnar cells, scalloped colloid, scattered lymphoid follicles, hyperthyroidism with ophthalmopathy. Hashimoto thyroiditis: lymphocytic infiltrate with germinal centres, follicle destruction, Hurthle-cell change, hypothyroidism. Multinodular goitre: variably distended follicles full of colloid. Papillary carcinoma: branching papillae with Orphan-Annie nuclei and psammoma bodies. Medullary carcinoma: sheets of C-cell-derived cells with amyloid stroma (calcitonin-derived), often part of MEN-2 with phaeochromocytoma and parathyroid hyperplasia.

The adrenal sits like a tricorn hat on top of each kidney and is really two endocrine glands wrapped in one capsule. The yellow outer cortex grows from mesoderm and makes steroid hormones; the brown-grey central medulla migrates in from the neural crest and makes catecholamines. The two embryonic origins explain everything — from the hormones produced, to the cytoplasmic ultrastructure, to the way one organ runs both a slow hormonal shower and a fast neural switch.

Capsule and general organisation

A thick fibrous capsule surrounds the gland and sends fine trabeculae into the cortex, carrying the arterial supply. Beneath the capsule the cortex forms three concentric zones — glomerulosa, fasciculata, reticularis — running from outside in. Inside the cortex sits the medulla, occupying about 10% of the volume but receiving a disproportionately rich venous drainage. The arrangement is so consistent that one low-power look at a slide should let you read off all three cortical layers and the medulla in order.

Zona glomerulosa — salt

The outermost thin band. Cells are small and arranged in rounded clusters or arches, with relatively little cytoplasmic lipid. The glomerulosa is the only cortical zone that expresses aldosterone synthase, so it is the sole adrenal source of the mineralocorticoid aldosterone. Unlike the deeper zones it does not depend on ACTH; instead it responds to angiotensin II (renin-angiotensin system) and to plasma potassium. Aldosterone makes the kidney retain Na⁺ and excrete K⁺/H⁺.

Zona fasciculata — sugar

The broadest middle zone, occupying about 70% of the cortex. Cells are arranged in long straight cords, two cells thick, with sinusoidal capillaries between them. Their cytoplasm is pale and foamy because of abundant lipid droplets full of cholesterol esters, earning the affectionate nickname spongiocytes. They respond to ACTH from anterior-pituitary corticotrophs and secrete the glucocorticoid cortisol, which raises blood glucose, suppresses inflammation, supports vascular tone and, importantly for the medulla, induces the enzyme PNMT.

Zona reticularis — sex

The innermost cortical band, with anastomosing irregular cords of darker, smaller cells holding brown lipofuscin granules from years of steroid turnover. The reticularis is also ACTH-driven and secretes weak androgens, mainly DHEA, which the peripheral tissues convert to testosterone or oestrogen. The mnemonic GFR = Salt, Sugar, Sex captures the whole cortex in five words.

Cortical cell ultrastructure

All three cortical zones share the typical steroid-cell organelle plan: abundant smooth ER for steroid-modifying P450 enzymes, mitochondria with tubular cristae for side-chain cleavage of cholesterol, and prominent lipid droplets storing the cholesterol precursor. There are no secretory granules, because steroids are lipid-soluble and diffuse out of the cell the moment they are made.

Medulla

The central medulla is composed of large basophilic chromaffin cells arranged in clumps around fenestrated capillaries and central veins. They are modified postganglionic sympathetic neurons that have lost their axon and now release into blood instead. Innervated directly by preganglionic sympathetic fibres, they discharge roughly 80% adrenaline and 20% noradrenaline in response to fight-or-flight signals. Scattered ganglion cells and supporting sustentacular cells sit between them.

Blood supply — an integrative trick

The adrenal has a unique cortical-to-medullary portal arrangement. Capsular arteries break into a cortical sinusoidal capillary plexus that flows centripetally through glomerulosa → fasciculata → reticularis and then bathes the medulla in cortisol-rich blood. Cortisol induces phenylethanolamine-N-methyltransferase in chromaffin cells, the enzyme that converts noradrenaline to adrenaline — which is why the medulla makes A > NA. Anatomy and biochemistry reinforce each other.

Clinical link

Conn syndrome (glomerulosa adenoma) → hypertension + hypokalaemia. Cushing syndrome → excess cortisol from pituitary, ectopic ACTH or adrenal source. Addison disease → autoimmune destruction of whole cortex with hyperpigmentation. Congenital adrenal hyperplasia (21-hydroxylase deficiency) → cortisol/aldosterone fall, androgens rise, virilised female infant. Phaeochromocytoma → medullary tumour, “rule of 10s”, paroxysmal hypertension, part of MEN-2.

The pituitary gland is a pea-sized broadcaster sitting in the sella turcica, hanging by a stalk from the floor of the diencephalon. It is the master endocrine gland because almost every other endocrine organ — thyroid, adrenal cortex, ovary, testis — takes its orders from a pituitary tropic hormone. Histologically the gland is a fusion of two organs of completely different embryological origin, and on a single H&E slide you can still see the two halves living side by side.

Development — two parts that never quite merge

The anterior part (adenohypophysis) grows up from the roof of the embryonic mouth as Rathke’s pouch, so it is glandular epithelium. The posterior part (neurohypophysis) grows down from the floor of the diencephalon as a neural-tissue diverticulum. The two meet and become apposed but never blend: the front is epithelial cords, the back is nerve fibres.

Adenohypophysis

The adenohypophysis is subdivided into three parts. The bulky pars distalis is the workhorse and forms most of the anterior lobe. A narrow pars intermedia sits between the two lobes, often containing colloid-filled cysts (the obliterated remnant of Rathke’s pouch lumen). A thin pars tuberalis wraps the upper part of the pituitary stalk.

The pars distalis is arranged in cords and clumps of secretory epithelial cells separated by sinusoidal fenestrated capillaries. Two staining classes are seen: chromophils take up dye and are subdivided into acidophils (pink with eosin) and basophils (purple-blue with haematoxylin); chromophobes are pale and represent either degranulated chromophils or undifferentiated stem cells.

Acidophils — the body-builders

Acidophils make up roughly 40% of the pars distalis and carry only two hormones: somatotrophs secrete growth hormone (GH), which drives body growth via IGF-1; mammotrophs (lactotrophs) secrete prolactin, which drives milk production. Think “pink builds.”

Basophils — the commanders

Basophils make up about 10% and command other endocrine organs (mnemonic B-FLAT): thyrotrophs → TSH drives the thyroid; corticotrophs → ACTH drives the adrenal cortex; gonadotrophs → FSH and LH drive the ovary and testis. Think “blue commands.” A common exam trap is “which hormone can basophils not secrete?” — the answer is GH, an acidophil product.

Neurohypophysis (pars nervosa)

Turn the slide to the posterior lobe and you see no glandular cells at all — just a pale tangle of unmyelinated axons, a few glial nuclei and capillaries. The cell bodies live in the hypothalamus: supraoptic nucleus (mainly ADH) and paraventricular nucleus (mainly oxytocin). They synthesise their hormone with the carrier protein neurophysin and ship granules down the unmyelinated axons. Along the axons sit beaded swellings called Herring bodies — dilated terminals stuffed with neurosecretory granules waiting for an action potential to trigger release into the fenestrated capillaries. Modified glial cells called pituicytes support the axons; they are the only resident cell-body nuclei visible.

Control — the hypothalamus rules both halves

The hypothalamus controls the pars distalis through the hypothalamo-hypophyseal portal system: releasing/inhibiting hormones drip into a primary capillary plexus in the median eminence, pass through portal venules in the stalk, and reach a secondary plexus bathing the pars-distalis cords. The pars nervosa is controlled by direct axonal connection, not portal blood — the same neuron that makes ADH or oxytocin releases it.

Clinical link

Prolactinoma is the commonest pituitary tumour (amenorrhoea/galactorrhoea, low libido). Acromegaly/gigantism from a somatotroph adenoma. Cushing disease from a corticotroph adenoma. Sheehan syndrome: post-partum pituitary necrosis after obstetric haemorrhage → failure to lactate, then panhypopituitarism. Central diabetes insipidus: loss of ADH from posterior pituitary damage. SIADH: inappropriate ADH excess, classically from small-cell lung cancer.

The pars distalis is the bulk of the anterior pituitary — cords of secretory epithelial cells separated by sinusoidal fenestrated capillaries. The entire diagnostic logic of this region is built on a single tinctorial split. When the pathologist stains the slide, some cells pick up dye strongly (chromophils) and some look almost empty (chromophobes). Among the chromophils, those whose granules are protein-rich and acidic-loving go pink (acidophils) and those whose granules are glycoprotein-rich and basic-loving go purple-blue (basophils). From that one split fall all the named cell types and all their hormones.

Acidophils — the body-builders (about 40%)

Acidophils carry only two hormones, both simple proteins, both concerned with building the body rather than commanding other glands. Somatotrophs are the more numerous; their granules contain growth hormone (GH), which acts directly on tissues and indirectly through hepatic IGF-1 to drive longitudinal bone growth, protein synthesis and lipolysis. Mammotrophs (lactotrophs) contain prolactin, which initiates and sustains milk synthesis in the lactating breast and, in non-pregnant women, is held in check by hypothalamic dopamine. A useful mnemonic is “Acidophils Are for Growth & milk.”

Basophils — the commanders (about 10%)

Basophils carry the four glycoprotein and peptide tropic hormones that command the other endocrine organs. The mnemonic B-FLAT covers all of them: thyrotrophs → TSH, driving the thyroid follicular cells to make T₃/T₄; corticotrophs → ACTH, derived from POMC, driving the adrenal zona fasciculata and reticularis; gonadotrophs → FSH and LH, driving the ovary (follicle development, ovulation, corpus luteum) and testis (spermatogenesis, testosterone). Note that gonadotrophs are one cell type making two hormones.

The classical exam trap follows directly: which hormone can basophils not secrete? The answer is GH, because GH is an acidophil product. Think “pink builds, blue commands.”

Chromophobes — the quiet majority

Chromophobes make up about 50% of pars-distalis cells and stain palely because they contain few granules. They are not a separate hormone line; the current consensus is that they are a mix of recently degranulated chromophils (cells that have just discharged their hormone) and undifferentiated stem cells that can replenish the chromophil populations during demand or after injury. Recognising them tells you the gland is alive and turning over, even when individual cells look empty.

Control by the hypothalamus — the portal system

None of these cells could function without the hypothalamus. Hypothalamic neurons in the arcuate, paraventricular and other nuclei secrete releasing hormones (GHRH, TRH, CRH, GnRH) and inhibiting hormones (somatostatin, dopamine) into a primary capillary plexus in the median eminence. The blood then flows through long portal venules running down the pituitary stalk and reopens as a secondary plexus bathing the pars-distalis cords. This hypothalamo-hypophyseal portal system concentrates the hypothalamic hormones a hundred-fold before they touch the pituitary cells; without the portal route, the dilute releasing hormones would never reach effective levels through the systemic circulation.

Clinical link

A prolactinoma — the commonest pituitary adenoma — is a mammotroph (acidophil) tumour. Acromegaly and gigantism come from somatotroph adenomas. A corticotroph adenoma drives ACTH and causes Cushing disease. A non-functioning chromophobe adenoma may present only with mass effect — bitemporal hemianopia from optic-chiasm compression, headache, hypopituitarism. Sheehan syndrome (post-partum pituitary necrosis) typically loses prolactin first, leading to failure of lactation.

The parathyroid glands are four pinhead-sized endocrine organs embedded in or just behind the posterior capsule of the thyroid — usually a superior and an inferior gland on each side, although ectopic glands in the mediastinum are common. Although tiny, they are essential for life: removing them causes fatal hypocalcaemic tetany, because they are the body’s minute-to-minute calcium thermostat. The histology is small in scale but very consistent, and it shows up in TMU finals almost every year.

General structure

Each gland is wrapped in a thin connective-tissue capsule that sends fine septa into the parenchyma, carrying blood vessels and dividing the cells loosely into lobules. Inside, two epithelial cell types are arranged in cords and clusters separated by a rich network of fenestrated capillaries — the typical endocrine plan that lets a small mass of cells dump hormone straight into the bloodstream. With age, adipocytes increasingly infiltrate the stroma until about half the parenchyma may be fat by old age; this is normal involution, not pathology.

Chief (principal) cells — the workforce

Chief cells are the dominant population and the only cells that actually secrete hormone. They are small, polygonal and pale-to-slightly-basophilic on H&E, with central round nuclei and a modest cytoplasm. Ultrastructurally they show all the hallmarks of a peptide-secreting cell: abundant RER, prominent Golgi apparatus, and membrane-bound secretory granules containing pre-formed parathyroid hormone (PTH).

PTH is the principal calcium-raising hormone in adults. It raises blood calcium through three coordinated actions: in bone, it stimulates osteoclast resorption (indirectly, via osteoblast RANKL); in the kidney, it increases distal-tubule calcium reabsorption while phosphate excretion is enhanced; and in the gut, it acts indirectly by stimulating renal 1α-hydroxylase, which converts 25-hydroxy-vitamin D to active 1,25-(OH)₂-vitamin D and so promotes intestinal calcium absorption. Crucially, PTH is released in direct response to a fall in ionised plasma calcium, sensed through the chief-cell calcium-sensing receptor (CaSR).

Oxyphil cells — the puzzle

Oxyphil cells are larger and less numerous than chief cells, appear in small clusters, and stand out by their deeply eosinophilic cytoplasm. The pink colour comes from extraordinarily abundant mitochondria, which fill almost the whole cytoplasm. Despite a century of staring at them no clear function has been agreed; they appear after puberty, increase with age and are inactive on routine hormonal assay. They become important pathologically as the cell of origin for the occasional oxyphil parathyroid adenoma.

Calcium homeostasis — the bigger picture

The parathyroids are one node in a three-hormone calcium loop. PTH raises calcium; calcitonin from thyroid C cells lowers it by inhibiting osteoclasts; and 1,25-(OH)₂-vitamin D made in the kidney drives gut absorption of dietary calcium. In adult humans PTH dominates, calcitonin is minor, and vitamin D sets the long-term gain on calcium absorption. When PTH fails, plasma calcium falls within hours and the patient develops perioral tingling, Trousseau and Chvostek signs, and ultimately laryngospasm.

Clinical link

Primary hyperparathyroidism is usually due to a single chief-cell adenoma; PTH rises, calcium rises and phosphate falls, giving “stones (renal calculi), bones (osteitis fibrosa cystica), abdominal groans (peptic ulcer, constipation), psychic moans (depression, fatigue).” Secondary hyperparathyroidism is the compensatory response to chronic hypocalcaemia, most often from chronic kidney disease — impaired 1α-hydroxylation and phosphate retention drive PTH up, eventually producing renal osteodystrophy. Hypoparathyroidism classically follows accidental excision at thyroid surgery and produces hypocalcaemic tetany. The parathyroids are involved in MEN-1 (parathyroid + pituitary + pancreatic islet tumours) and MEN-2A (parathyroid + medullary thyroid + phaeochromocytoma, RET mutation).