Learn — Endocrine system

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Growth hormone

Growth hormone (somatotropin) is a peptide of 191 amino acids secreted by the somatotroph cells of the anterior pituitary, and it is the most abundant hormone stored in that gland. It acts partly on its own and largely through insulin-like growth factor 1 made in the liver, lengthening bone at the epiphyseal plates while they are still open and thickening bone and soft tissue after they have fused — which is why the same excess produces gigantism in a child and acromegaly in an adult.

Control is dual and opposite: growth hormone releasing hormone from the hypothalamus stimulates secretion while somatostatin inhibits it, ghrelin from the stomach also stimulates, and insulin-like growth factor 1 feeds back negatively on both the pituitary and the hypothalamus.
Secretion is pulsatile, with the largest surge during the first hours of deep slow-wave sleep — which is why a single random level is uninterpretable, and why sleep, exercise, fasting, hypoglycaemia, stress and a protein-rich meal raise it while hyperglycaemia, obesity, free fatty acids and cortisol suppress it.
Metabolically it is anabolic for protein (increased amino acid uptake, protein synthesis and nitrogen retention), lipolytic and ketogenic for fat, and anti-insulin for carbohydrate — it reduces glucose uptake by tissues so the blood glucose rises, which is why acromegaly so often comes with diabetes.
Its growth action is mediated by insulin-like growth factor 1 (somatomedin C) from the liver, which drives proliferation of cartilage at the epiphyseal growth plates; once those plates fuse after puberty no further increase in height is possible whatever the hormone level.
Excess before epiphyseal fusion causes gigantism with very tall but proportionate stature; excess after fusion causes acromegaly — enlarging hands and feet with rising ring and shoe sizes, coarse features, prognathism, macroglossia, a deepening voice, excessive sweating, carpal tunnel syndrome, hypertension and diabetes — and the usual cause of both is a pituitary somatotroph adenoma.
Deficiency in a child gives proportionate short stature with normal intelligence and a delayed bone age; Laron syndrome is the instructive contrast, with high growth hormone but a defective receptor and therefore a low insulin-like growth factor 1.
Diagnosis exploits the physiology: because glucose normally suppresses growth hormone, failure of the level to suppress during a 75 g oral glucose tolerance test confirms acromegaly, and a raised insulin-like growth factor 1 is the best screening test, while deficiency has to be shown by a stimulation test because random levels are low in everyone.
Treatment of acromegaly is trans-sphenoidal excision of the adenoma first, with somatostatin analogues such as octreotide, the receptor antagonist pegvisomant, dopamine agonists and radiotherapy as second line; deficiency is treated with recombinant growth hormone given subcutaneously at night to imitate the natural sleep pulse.

Pituitary — anterior vs posterior

The pituitary gland (hypophysis cerebri) is a pea-sized gland weighing about 0.5 gram that lies in the hypophyseal fossa of the sella turcica of the sphenoid bone and is joined to the hypothalamus by the pituitary stalk. It is really two glands in one capsule: the anterior lobe (adenohypophysis) is glandular epithelium derived from Rathke's pouch that manufactures its own hormones under hypothalamic releasing factors carried down a portal venous system, while the posterior lobe (neurohypophysis) is nervous tissue growing down from the hypothalamus that manufactures nothing and only stores and releases hormones made in hypothalamic neurons.

The anterior lobe hormones are remembered as FLAT PiG: FSH, LH, ACTH and TSH are the four tropic hormones acting on other glands, and prolactin and growth hormone act directly on tissues; melanocyte stimulating hormone comes from the intermediate zone.
The posterior lobe releases only two hormones — antidiuretic hormone (vasopressin) and oxytocin — and both are synthesised in the supraoptic and paraventricular nuclei of the hypothalamus, carried down the axons of the hypothalamo-hypophyseal tract bound to neurophysin, and stored in the posterior lobe until a nerve impulse releases them.
The two lobes are connected to the hypothalamus in different ways: the anterior lobe has no secretomotor nerve supply and is controlled chemically through the hypophyseal portal veins in the stalk, while the posterior lobe is controlled by direct nerve fibres — so cutting the stalk causes transient diabetes insipidus but raises prolactin, because prolactin alone is held down by tonic inhibition from hypothalamic dopamine.
Antidiuretic hormone acts on V2 receptors in the collecting duct to insert aquaporin-2 water channels: too little gives diabetes insipidus with more than 3 litres of dilute urine a day, a specific gravity below 1.005 and a rising serum sodium, while too much gives the syndrome of inappropriate ADH with concentrated urine, dilutional hyponatraemia and no oedema.
Oxytocin contracts uterine smooth muscle in labour and the myoepithelial cells of the breast for the milk-ejection reflex, and its release by suckling is the standard example of positive feedback in physiology.
The relations of the gland explain its symptoms: the optic chiasma lies immediately above it, so an expanding adenoma presses on the decussating fibres and causes bitemporal hemianopia; the cavernous sinus with the internal carotid artery and cranial nerves III, IV, V1, V2 and VI lies on each side; and the sphenoid air sinus lies below, which is the route used for trans-sphenoidal surgery.
The commonest pituitary tumour is a prolactinoma, presenting in women with amenorrhoea, galactorrhoea and infertility and in men with loss of libido and late visual field loss; it is one of the few tumours treated medically first, with dopamine agonists such as cabergoline or bromocriptine.
Sheehan's syndrome is post-partum necrosis of the enlarged, highly vascular anterior lobe after severe obstetric haemorrhage; the earliest sign is failure of lactation, followed by amenorrhoea, loss of axillary and pubic hair and the full picture of panhypopituitarism.
Blood supply comes from the internal carotid artery through the superior hypophyseal arteries, which supply the median eminence and reach the anterior lobe indirectly through the portal system, and the inferior hypophyseal arteries, which supply the posterior lobe directly.

Thyroid hormones

The thyroid is a butterfly-shaped gland of two lobes joined by an isthmus that lies over the second, third and fourth tracheal rings, weighs about 25 grams and is the only endocrine gland that stores its hormone outside its cells, as colloid within follicles. Its follicular cells make thyroxine (T4) and tri-iodothyronine (T3) from iodine and the tyrosine of thyroglobulin, and these set the basal metabolic rate of every tissue, while its parafollicular C cells make calcitonin, which lowers the plasma calcium.

Synthesis has four steps: iodide is trapped against a gradient by the sodium-iodide symporter, oxidised and organified onto the tyrosine residues of thyroglobulin by thyroid peroxidase, coupled as MIT and DIT into T3 and T4, and finally released by proteolysis — and it is the peroxidase step that carbimazole and propylthiouracil block.
About 90 to 93% of what the gland secretes is T4 and only about 7 to 10% is T3, but T3 is three to four times more potent and is the active hormone at the receptor; roughly 80% of circulating T3 is produced by deiodination of T4 in the liver, kidney and other peripheral tissues.
More than 99% of both hormones circulate bound to thyroxine-binding globulin, transthyretin and albumin, so only the free fraction is active; T4 has a half-life of about 6 to 7 days and T3 of about one day, which is why levothyroxine is a once-daily tablet and why the TSH is rechecked only about 6 weeks after any dose change.
The axis is TRH from the hypothalamus, TSH from the anterior pituitary and negative feedback from free T3 and T4 — so in primary hypothyroidism the TSH is high with a low free T4, and in primary thyrotoxicosis the TSH is suppressed with a high free T4; a low TSH with a low T4 points to the pituitary instead.
Actions: they raise the basal metabolic rate and heat production, increase the number and sensitivity of beta-adrenergic receptors (which is why thyrotoxicosis gives tremor, tachycardia and anxiety and why propranolol relieves it), speed gut motility, and are essential for myelination and brain growth in the fetus and infant — the reason untreated congenital hypothyroidism causes irreversible intellectual disability and newborn screening exists.
The daily iodine requirement is about 150 micrograms, rising to about 250 micrograms in pregnancy and lactation; under India's national programme iodised salt must contain at least 15 parts per million of iodine at the consumer end, and deficiency causes goitre, hypothyroidism, cretinism and stillbirth.
Calcitonin from the parafollicular C cells lowers serum calcium by inhibiting osteoclastic bone resorption, opposing parathyroid hormone; medullary carcinoma of the thyroid arises from these cells and is monitored by serum calcitonin.
Levothyroxine is taken on an empty stomach 30 to 60 minutes before breakfast and separated by at least 4 hours from iron, calcium, antacids and soya products, all of which block its absorption and are a common reason for a TSH that will not settle.
The surgical anatomy that governs post-operative nursing: the recurrent laryngeal nerves run in the tracheo-oesophageal groove close to the inferior thyroid artery, and the four parathyroid glands lie behind the lobes — so hoarseness, stridor and hypocalcaemic tetany are the classic complications of thyroidectomy.

Reproductive hormones

Reproduction is run by the hypothalamic-pituitary-gonadal axis: gonadotropin releasing hormone is secreted in pulses by the hypothalamus, drives FSH and LH from the anterior pituitary, and these act on the ovary to produce oestrogen and progesterone or on the testis to produce testosterone and sperm. The gonadal steroids feed back on the hypothalamus and pituitary — negatively for most of the cycle and, uniquely in physiology, positively just before ovulation — and that switch from negative to positive feedback is what produces the LH surge on which the whole menstrual cycle turns.

Gonadotropin releasing hormone must be pulsatile: pulses every 60 to 90 minutes maintain FSH and LH, whereas a continuous supply from a long-acting agonist paradoxically shuts the axis down — which is exactly how those drugs are used to shrink fibroids and to treat prostate cancer.
In the ovary the two-cell, two-gonadotropin model applies: LH acts on theca cells to make androgens, and FSH acts on granulosa cells whose aromatase converts those androgens into oestradiol; FSH grows the follicle and LH triggers ovulation and then maintains the corpus luteum.
The 28-day cycle has a variable follicular phase and a nearly fixed luteal phase of 14 days — menstruation on days 1 to 5, the follicular phase to about day 13 with rising oestrogen, ovulation at about day 14, and the luteal phase dominated by progesterone; in a longer cycle it is the follicular phase, not the luteal phase, that is longer.
Ovulation follows 24 to 36 hours after the LH surge begins and about 10 to 12 hours after its peak, and the trigger for that surge is oestradiol itself once it has stayed above roughly 200 picograms per millilitre for about two days — the single point at which oestrogen feedback turns positive.
Progesterone from the corpus luteum converts the proliferative endometrium into a secretory one, thickens the cervical mucus into a barrier and raises the basal body temperature by about 0.3 to 0.5 degrees Celsius after ovulation, which is the basis of the temperature method of natural family planning.
If there is no fertilisation the corpus luteum regresses at about day 26, progesterone and oestrogen fall, and menstruation follows; if fertilisation occurs, human chorionic gonadotropin from the syncytiotrophoblast rescues the corpus luteum from about the eighth or ninth day after ovulation, doubles roughly every 48 hours and peaks at about 8 to 10 weeks.
In the male, LH acts on the Leydig cells to produce testosterone and FSH acts on the Sertoli cells to support spermatogenesis; the Sertoli cells also secrete inhibin, which selectively suppresses FSH, and one cycle of spermatogenesis takes about 74 days, which is why a semen analysis is repeated only after about 3 months.
Oestrogen produces the female secondary sexual characters, the proliferative endometrium, thin watery cervical mucus that shows ferning at ovulation, and closure of the epiphyses; it also protects bone, so the fall at menopause accelerates osteoporosis.
Menarche in India occurs at about 12 to 14 years and menopause at about 45 to 50 years; menopause is diagnosed retrospectively after 12 consecutive months of amenorrhoea and is confirmed biochemically by a high FSH with a low oestradiol.

Islets of Langerhans

The islets of Langerhans are the endocrine part of the pancreas — one to two million cell clusters scattered among the exocrine acini, making up only 1 to 2 per cent of the gland by mass but taking a disproportionately rich share of its blood supply. They contain four main cell types whose hormones set the blood glucose between meals and after them, and the destruction or exhaustion of the beta cells is what defines type 1 and type 2 diabetes.

Beta cells are about 60 to 75 per cent of the islet and lie centrally; they secrete insulin, C-peptide and amylin.
Alpha cells are about 20 per cent and lie at the periphery; they secrete glucagon, the hormone of the fasting state, which drives hepatic glycogenolysis and gluconeogenesis.
Delta cells, about 5 to 10 per cent, secrete somatostatin, which inhibits both insulin and glucagon and slows gastric emptying; PP or F cells secrete pancreatic polypeptide and epsilon cells secrete ghrelin.
Insulin is a protein of 51 amino acids in two chains, A of 21 and B of 30, joined by disulphide bonds; it is cut out of proinsulin, so one molecule of C-peptide is released for every molecule of insulin.
C-peptide therefore measures the patient's own insulin output: it is low or absent in type 1 diabetes and in hypoglycaemia caused by injected insulin, and normal or high in an insulinoma.
Glucose enters the beta cell through GLUT2, its metabolism raises ATP, the ATP-sensitive potassium channel closes, the cell depolarises, calcium enters and insulin is released — the same channel that sulphonylureas close.
Insulin acts through a tyrosine kinase receptor and recruits GLUT4 transporters in skeletal muscle and adipose tissue; brain, liver, renal tubule and red cells take up glucose without insulin, which is why the brain starves in hypoglycaemia but not in insulin deficiency.
Insulin drives potassium into cells along with glucose — the basis of insulin-with-dextrose treatment for hyperkalaemia, and the reason serum potassium falls sharply while diabetic ketoacidosis is being corrected.
Islets are more numerous in the tail of the pancreas, so a distal pancreatectomy costs proportionately more endocrine tissue than a resection of the head.

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