L2 Endocrine Anatomy _ histology of the thyroid, para-thyroid and adrenal glands

Overview

This lecture works through the gross anatomy, histology and embryology of the thyroid, parathyroid and adrenal glands, opening with a recap of the pituitary and its posterior lobe. The organising idea is that endocrine tissues look nothing like one another structurally, and that in each case the structure is explained by the function it serves: the posterior pituitary is neural because its hormones are released from nerve terminals, the thyroid follicle is a fluid-filled sac because hormone synthesis and storage happen outside the cell, and the adrenal is two unrelated tissues sharing a capsule. The lecture closes by showing that endocrine tissue derives from all three germ layers, so endocrine organs are a group defined by function rather than by origin or morphology.

Pituitary gland: structure and embryology

The pituitary (hypophysis) sits below the hypothalamus, attached by the stalk, with an anterior and a posterior lobe.

Vascular arrangement (the hypothalamo-hypophyseal portal system):

• The superior hypophyseal artery supplies a capillary bed at the base of the hypothalamus, where neuroendocrine cell axons terminate.
• Long portal vessels carry blood down the stalk to a second capillary bed in the anterior pituitary, surrounding the trophic hormone secreting cells.
• Those cells secrete their hormones into the blood leaving the anterior pituitary.
• The posterior pituitary is supplied separately by the inferior hypophyseal artery and drains via short portal vessels.

Embryology, in six steps:

1. Neural ectoderm grows down from the brain (this becomes the posterior, “neural” lobe).
2. Rathke’s pouch forms by pinching off from the pharynx.
3. The anterior lobe grows and expands, wrapping around the base of the neural stalk.
4. Epithelial type tissue wraps around the stalk, forming the pars tuberalis.
5. The intermediate lobe is markedly reduced, leaving only a thin remnant between anterior and posterior tissue.
6. The vascular connection (the portal system) is established, with vessels descending the stalk into both lobes.

Posterior lobe (neurohypophysis) and neurosecretion

The posterior lobe is not glandular tissue at all; it is the terminal field of hypothalamic neurons.

Neurosecretory neurons:

• Cell bodies lie in the supraoptic and paraventricular nuclei of the hypothalamus, and are called magnocellular neurons.
• Their axons run in the hypothalamo-hypophyseal tract through the infundibulum to the neurohypophysis.
• Terminals end on fenestrated capillaries rather than on other neurons: this is neurosecretion.
• They secrete 9 amino acid peptides, either oxytocin or vasopressin (anti-diuretic hormone, ADH).

Immunofluorescence of the paraventricular and supraoptic nuclei (rat, coronal section) separates oxytocin-containing from vasopressin-containing cells, and separates two populations by cell body size and location: magnocellular (larger, forming the upper cluster) and parvicellular (lower cluster).

Structural features of the posterior lobe, all of which differ from typical glandular tissue:

• Unmyelinated axons.
• Nerve terminals of neurosecretory neurons.
• An extensive network of fenestrated capillaries.

It is a neural structure, linked to the other endocrine tissues by function rather than by form.

Chemical classification of hormones

• Peptides: anything from three amino acids up to large proteins.
• Amines: derivatives of the amino acid tyrosine.
• Steroids: synthesised from cholesterol.

These different chemical properties give rise to different tissue structure, different modes of transport in plasma (for example whether binding proteins are needed), and different cellular modes of action (intracellular versus cell surface receptors).

Thyroid gland: anatomy and the follicle

The thyroid lies in the anterior neck over the trachea, below the larynx and medial to the common carotid arteries. Its arterial supply is from the superior thyroid artery above and the inferior thyroid artery below.

The thyroid hormones are iodinated derivatives of tyrosine, built from two phenyl rings joined by an ether oxygen with an alanine side chain:

• T4, thyroxine, is 3,5,3’,5’-tetraiodothyronine: four iodines.
• T3 is 3,5,3’-triiodothyronine: the same molecule lacking the iodine at the 5’ position.

The functional unit is the thyroid follicle. On H&E histology a follicle is a large space filled with pink eosinophilic colloid, which contains thyroglobulin, enclosed by a single layer of follicular epithelial cells with dark nuclei.

Thyroid hormone synthesis, storage and secretion

Synthesis and storage, following the follicular cell from blood (basal side) to follicle lumen (apical side):

1. Thyroglobulin is synthesised in the rough endoplasmic reticulum, packaged in the Golgi, and exocytosed into the follicle lumen.
2. Iodide is taken up from the blood and concentrated by the epithelial cells, then released into the lumen.
3. In the lumen the iodide is oxidised to free iodine.
4. Iodine combines with thyroglobulin at tyrosine residues, so hormone synthesis is extracellular, and the iodinated product (TG-I) is stored in the lumen as colloid.

The follicular cells concentrate iodine up to 50 times the blood concentration. This is exploited clinically: iodine isotopes are used to visualise the thyroid and to treat thyroid cancer.

Secretion of T4 and T3:

1. Under stimulation of TSH, the epithelial cells take up droplets of iodinated thyroglobulin from the lumen into the cytoplasm.
2. Lysosomes break down the thyroglobulin.
3. The released iodinated hormones T4 and T3 pass into the bloodstream, with T4 the larger output and T3 the smaller.

Why such an elaborate process? The distinctive features are extracellular storage of the precursor, extracellular synthesis of the hormone by iodination of that precursor, and then mobilisation and degradation of the precursor to produce the hormones. The likely explanation given is that the chemical conditions required for iodination of tyrosine residues are incompatible with intracellular pH. Structure is defined by function.

Feedback regulation and iodine-deficiency goitre

The normal loop:

1. The hypothalamus releases TRH, which stimulates the anterior pituitary.
2. The anterior pituitary releases TSH, which stimulates the thyroid.
3. Thyroxine from the thyroid feeds back negatively on both the anterior pituitary and the hypothalamus.

Iodine-deficiency goitre is presented as the classic example of an endocrine feedback mechanism, and clinically as a visibly enlarged neck:

1. Without iodine the thyroid cannot make thyroxine.
2. With no thyroxine, the negative feedback signal to the pituitary and hypothalamus is absent.
3. TSH stimulation of the thyroid therefore continues unopposed.
4. Continued TSH drive causes massive growth of the thyroid gland, producing the goitre.

Parafollicular (C) cells

• C cells lie between or adjacent to the follicular cells, outside the follicle lumen and close to blood capillaries. Immunohistochemistry for calcitonin stains them brown, scattered singly through the lighter follicular tissue.
• They synthesise the polypeptide hormone calcitonin.
• Ultrastructurally they contain dense-core secretory granules, characteristic of peptide hormone secreting cells.
• Calcitonin inhibits bone resorption and increases urinary calcium excretion, both of which decrease plasma calcium.
• It is released when calcium levels are high, and this release is independent of the pituitary.

Parathyroid glands

• Small oval glands on the posterior surface of the thyroid gland, 2 to 4 pairs, lying anterior to the oesophagus and lateral to the trachea in posterior view.
• Histology shows two cell types: chief cells, which are smaller, more numerous and have darker cytoplasm, and oxyphil cells, which are larger with more eosinophilic cytoplasm and occur in nests.

Embryology of the thyroid and parathyroid glands

Thyroid, around the 4th week of development:

• The thyroid gland forms as a down-growth from the pharyngeal endoderm, budding from the floor of the pharynx as the thyroid primordium.
• It descends from the foramen cecum at the base of the tongue to its final position in the neck.
• Neural crest cells (ectoderm) invade the ventral part of pharyngeal pouch 4 and then enter the thyroid to form the C-cells, so the C-cells have a different origin from the follicular tissue around them.

Parathyroid, around the 6th week of development:

• The parathyroid glands develop as cells bud off the pharyngeal pouches (endoderm).
• Pharyngeal pouches I to IV give rise to the inferior parathyroid, superior parathyroid, ultimobranchial body and thymus [slide labels the pouch of origin for each but the pairing is not recorded in the transcript].
• Several different cell types are present, of different embryonic origin.
• Surgically relevant relations of the parathyroids: thyroid cartilage and cricoid cartilage, the recurrent laryngeal nerve, and the inferior thyroid artery.

Why such a complex tissue arrangement in this region? Within roughly the same capsule and location there are three completely different endocrine tissues: thyroid follicles producing thyroid hormones, parafollicular calcitonin-secreting cells, and the parathyroid glands. They have different embryological origins and different control mechanisms but share an anatomical location, likely taking advantage of a common dense vasculature. Structure is defined by function.

Adrenal gland: anatomy and cortex

• Small encapsulated glands sitting at the superior pole of each kidney, hence “suprarenal”, one on the right and one on the left, related to the inferior vena cava, aorta, spleen and descending colon.
• Each gland contains two functionally different endocrine tissues: the cortex, which secretes steroid hormones under the control of the anterior pituitary (glucocorticoids, cortisol), and the medulla, which secretes catecholamines (adrenaline/epinephrine and noradrenaline/norepinephrine) under the control of the sympathetic nervous system.

In cross-section, from outside inwards: capsule, zona glomerulosa, zona fasciculata, zona reticularis (these three making up the cortex), then the medulla.

Zone	Secretes	Controlled by
Zona glomerulosa	Mineralocorticoids (aldosterone)	Plasma sodium
Zona fasciculata	Glucocorticoids (cortisol)	ACTH
Zona reticularis	Glucocorticoids and androgens	ACTH

Warning

The slide writes the middle zone as “Zona fasiculata”, missing a “c” [transcript flag].

Adrenal medulla

• Originates from neural ectoderm and is closely related to the sympathetic nervous system: its cells are the equivalent of postganglionic sympathetic neurons.
• It secretes catecholamines, adrenaline (epinephrine) and nor-adrenaline (norepinephrine), under direct regulation of preganglionic sympathetic neurons.

Comparison with the standard sympathetic pathway:

• Standard pathway: a CNS neuron releases ACh onto a ganglion neuron, and the ganglionic neuron releases NE directly onto the effector organ.
• Adrenal pathway: a CNS neuron travels in the splanchnic nerve and releases ACh directly onto the adrenal medullary (chromaffin) cells, which release catecholamines into the bloodstream to reach the effector organ. The chromaffin cells are therefore the equivalent of postganglionic sympathetic neurons, but they secrete into the blood instead of synapsing on the target organ.

Histology and regulation:

• Closely packed secretory cells.
• Secretory products are stored in cytoplasmic granules and released in response to nervous stimulation.
• Oxidation of noradrenaline by fixatives containing chrome salts produces a brown stain, which is where the name “chromaffin cells” comes from.
• The medulla is also regulated by glucocorticoids, which reach it in high concentration from the cortex.

Embryology of the adrenal gland:

• Cortex: mesoderm origin, from cells located at the cranial ends of the mesonephros. It is very large in the fetus and plays an important role in fetal development.
• Medulla: neural crest cells migrate out to form the sympathetic ganglia, and some invade the developing adrenal gland. These cells are effectively postganglionic sympathetic neurons but do not develop neuronal processes.

Embryonic origins and structure/function summary

Endocrine tissue derives from multiple different embryonic sources:

1. Ectoderm: pituitary, adrenal medulla, thyroid C-cells.
2. Mesoderm: adrenal cortex, gonad.
3. Endoderm: thyroid, parathyroid.

Different tissues, different origins, different structures, grouped by function.

Summary of structure/function relationships in endocrine tissue: there is a wide variety of morphology grouped by a common function, and the question to ask of any endocrine tissue is what structure is required to serve that function. Five requirements are listed:

1. Hormone synthesis.
2. Hormone storage.
3. No ducts.
4. High vascularisation.
5. A homeostatic mechanism, meaning receptors.

Self-test

1. Describe the six steps of pituitary development, from neural ectoderm down-growth to the vascular connection.
2. Trace the route blood takes through the hypothalamo-hypophyseal portal system to reach the trophic hormone secreting cells of the anterior pituitary, and say how the posterior lobe’s supply differs.
3. Define neurosecretion as it applies to the magnocellular neurons of the posterior pituitary.
4. Name the two hormones released by magnocellular neurons, where their cell bodies lie, and the chemical description they share.
5. List the three structural features of the posterior lobe that distinguish it from typical glandular tissue.
6. List the three chemical classes of hormone and state what each is derived from.
7. Explain why the chemical class of a hormone matters for how it is transported and how it acts on a target cell.
8. Describe the arterial supply of the thyroid gland and its immediate anatomical relations.
9. Distinguish T4 from T3 by their iodination.
10. Describe what is seen histologically in a thyroid follicle, and state what the colloid contains.
11. Describe the steps by which thyroglobulin is synthesised, iodinated and stored.
12. By what factor can the thyroid concentrate iodine relative to blood, and what two clinical uses follow from this property?
13. Describe the steps by which T4 and T3 are released into the bloodstream under TSH stimulation.
14. Explain the reason proposed in the lecture for why thyroid hormone is synthesised outside the follicular cell rather than inside it.
15. Predict what happens to thyroid gland size when dietary iodine is absent, and explain the feedback steps that produce it.
16. State the effects of calcitonin on plasma calcium, the two mechanisms by which it achieves them, and what triggers its release.
17. Describe where the parafollicular cells sit relative to the follicle, and what ultrastructural feature marks them as peptide-secreting.
18. State where the parathyroid glands lie and how many there are, and distinguish their two cell types histologically.
19. Describe the embryological origin and descent of the thyroid gland, and explain how its C-cells come to have a different origin.
20. Describe the embryological origin of the parathyroid glands and list the structures a surgeon must consider when approaching them.
21. Explain why three different endocrine tissues are found together in the thyroid region despite having different origins and controls.
22. List the layers of the adrenal gland from the capsule inwards.
23. For each zone of the adrenal cortex, state what it secretes and what controls it.
24. Explain why adrenal chromaffin cells are regarded as the equivalent of postganglionic sympathetic neurons, and how their output differs from an ordinary postganglionic neuron’s.
25. Explain where the term “chromaffin cell” comes from, and name the non-neural influence that also regulates the medulla.
26. Describe the embryological origins of the adrenal cortex and the adrenal medulla.
27. Match each of the three germ layers to the endocrine tissues derived from it.
28. List the five structural requirements of endocrine tissue given in the summary, and explain how the thyroid follicle meets the first two.

Answers

Reveal answers

1. (i) Neural ectoderm grows down from the brain, forming the posterior “neural” lobe; (ii) Rathke’s pouch forms by pinching off from the pharynx; (iii) the anterior lobe grows and expands; (iv) epithelial type tissue wraps around the stalk to form the pars tuberalis; (v) the intermediate lobe is markedly reduced to a thin remnant; (vi) the vascular connection is established.
2. The superior hypophyseal artery supplies a capillary bed at the base of the hypothalamus; long portal vessels carry blood down the stalk to a second capillary bed in the anterior pituitary around the trophic hormone secreting cells, which then secrete into the blood leaving the gland. The posterior lobe is supplied separately by the inferior hypophyseal artery and drains via short portal vessels.
3. Neurosecretion is the release of hormone from a neuron’s terminals onto fenestrated capillaries rather than onto other neurons, so the neuron’s output enters the bloodstream instead of a synapse.
4. Oxytocin or vasopressin (anti-diuretic hormone, ADH). Cell bodies lie in the supraoptic and paraventricular nuclei of the hypothalamus. Both are 9 amino acid peptides.
5. Unmyelinated axons; nerve terminals of neurosecretory neurons; an extensive network of fenestrated capillaries.
6. Peptides, from three amino acids up to large proteins; amines, derivatives of the amino acid tyrosine; steroids, synthesised from cholesterol.
7. Different chemical properties produce different tissue structure, different modes of transport in plasma such as whether binding proteins are needed, and different cellular modes of action through intracellular versus cell surface receptors.
8. Superior thyroid artery above and inferior thyroid artery below. The gland lies over the trachea, below the larynx, with the common carotid arteries laterally.
9. T4 (thyroxine) is 3,5,3’,5’-tetraiodothyronine with four iodines; T3 is 3,5,3’-triiodothyronine, the same structure without the iodine at the 5’ position.
10. A large space filled with pink eosinophilic colloid, surrounded by a single layer of follicular epithelial cells with dark-stained nuclei. The colloid contains thyroglobulin.
11. Thyroglobulin is synthesised in the rough ER, packaged in the Golgi and exocytosed into the follicle lumen; iodide is taken up from blood and concentrated by the epithelial cells and released into the lumen; in the lumen it is oxidised to free iodine; the iodine combines with thyroglobulin at tyrosine residues extracellularly, and the iodinated thyroglobulin is stored in the lumen.
12. Up to 50 times the blood concentration. Iodine isotopes are used to visualise the thyroid and to treat thyroid cancer.
13. Under TSH stimulation the epithelial cells take up droplets of iodinated thyroglobulin into the cytoplasm; lysosomes break down the thyroglobulin; the released iodinated T4 and T3 pass into the bloodstream, T4 in greater amount than T3.
14. The chemical conditions required for iodination of tyrosine residues are likely incompatible with intracellular pH, so the precursor is stored and iodinated extracellularly and then mobilised and degraded to produce the hormones.
15. The gland enlarges massively, producing a goitre. Without iodine no thyroxine is made; with no thyroxine there is no negative feedback onto the anterior pituitary or hypothalamus; TSH stimulation therefore continues unopposed; continued TSH drive causes growth of the thyroid gland.
16. Calcitonin decreases plasma calcium, by inhibiting bone resorption and by increasing urinary calcium excretion. It is released when calcium levels are high, independently of the pituitary.
17. Parafollicular (C) cells sit between or adjacent to the follicular cells, outside the follicle lumen and close to blood capillaries. They contain dense-core secretory granules, characteristic of peptide hormone secreting cells.
18. Small oval glands on the posterior surface of the thyroid gland, 2 to 4 pairs. Chief cells are smaller, more numerous and have darker cytoplasm; oxyphil cells are larger with more eosinophilic cytoplasm and occur in nests.
19. Around the 4th week the thyroid forms as a down-growth from the pharyngeal endoderm at the floor of the pharynx and descends from the foramen cecum at the tongue base to the neck. The C-cells instead come from neural crest cells (ectoderm) that invade the ventral part of pharyngeal pouch 4 and then enter the thyroid.
20. Around the 6th week the parathyroid glands develop as cells budding off the pharyngeal pouches (endoderm), pouches I to IV also giving the ultimobranchial body and thymus, with several cell types of different embryonic origin. Relations to consider: thyroid cartilage, cricoid cartilage, the recurrent laryngeal nerve and the inferior thyroid artery.
21. Thyroid follicles, parafollicular calcitonin-secreting cells and the parathyroid glands sit within the same capsule and location despite different embryological origins and different control mechanisms, likely so they can take advantage of a common dense vasculature.
22. Capsule, zona glomerulosa, zona fasciculata, zona reticularis (those three forming the cortex), then the medulla.
23. Zona glomerulosa: mineralocorticoids (aldosterone), controlled by plasma sodium. Zona fasciculata: glucocorticoids (cortisol), controlled by ACTH. Zona reticularis: glucocorticoids and androgens, controlled by ACTH.
24. They arise from neural ectoderm and receive ACh directly from preganglionic sympathetic neurons travelling in the splanchnic nerve, occupying the position a postganglionic neuron would; embryologically they are neural crest cells that failed to develop neuronal processes. Unlike a postganglionic neuron, which releases NE onto an effector organ at a synapse, they release catecholamines into the bloodstream to reach effector organs.
25. Oxidation of noradrenaline by fixatives containing chrome salts produces a brown stain, giving the name. The medulla is also regulated by glucocorticoids, which reach it in high concentration from the cortex.
26. Cortex: mesoderm, from cells at the cranial ends of the mesonephros; it is very large in the fetus and important in fetal development. Medulla: neural crest cells that migrate out to form the sympathetic ganglia, some of which invade the developing adrenal gland.
27. Ectoderm: pituitary, adrenal medulla, thyroid C-cells. Mesoderm: adrenal cortex, gonad. Endoderm: thyroid, parathyroid.
28. Hormone synthesis, hormone storage, no ducts, high vascularisation, and a homeostatic mechanism (receptors). The follicular cell synthesises thyroglobulin in the rough ER and iodinates it in the lumen (synthesis), and the iodinated thyroglobulin is held extracellularly as colloid until needed (storage).