The hypothalamo-pituitary system and ectopic hormones

· The hypothalamo-pituitary system controls the function of the adrenal, thyroid, and reproductive
glands, as well as regulating growth, lactation, milk secretion and water excretion.

· Protein and peptide hormone synthesis starts with processing of a primary gene transcript (code)
called a prohormone. The processing includes proteolysis, glycosylation and phosphorylation.

· Catecholamines, peptide and protein hormones are stored in secretory granules and discharged
by exocytosis.

· Catecholamines, peptide and protein hormones are water-soluble and cannot pass the cell
membrane. They act on the surface of target cells via membrane receptors. The hormone-receptor-
complex activates second messengers in the cell (cAMP, Ca2+, DAG, IP3) via stimulatory or inhibitory
G-proteins.

· Thyroid and steroid hormones are lipid-soluble and act through specific nuclear receptors. The
hormone-receptor-complex modulates elements in DNA molecules in order to change the expression
of target genes.

· Peptide hormones produced in the cell bodies of hypothalamic neurons pass down their axons
inside secretory granules to be stored in the terminals of the neurohypophysis.

· Releasing and inhibiting peptides from the hypothalamus are released in pulses in the
adenohypophysis and act via second messengers. They modulate transcription, translation and
secretion of tropic hormones.

· Vasopressin or antidiuretic hormone is a vasopressor with a strong antidiuretic effect as the

names imply. Vasopressin (ADH) is normally synthesized as a big pre-prohormone in the ribosomes of
neurons in the supraoptic and paraventricular nuclei of the hypothalamus. The pre-prohormone
consists of a signal peptide, ADH, neurophysin and a glycopeptide.

· POMC peptides are neuroregulatory hormones: ACTH, endogenous opiates, b-endorphin, b-

lipoprotein, a-MSH and b-MSH.

· Stimulation of tactile receptors in the mammary nipple causes the neurosecretory neurons to
release oxytocin through a neuroendocrine reflex. Oxytocin stimulates the myoepithelial cells in the
milk ducts of the lactating breast. Oxytocin also stimulates the myoepithelial (myometrial) cells of the
uterus. Oxytocin can perhaps start labour.

· The true form of diabetes insipidus is caused by deficiency of vasopressin (ADH deficiency). There
are two types of diabetes insipidus. The primary or idiopathic type, which is due to a genetic defect
that blocks the hormone production, and the secondary type, where the hypothalamo-hypophysary
system is damaged by disease or surgery.
· ADH producing tumours in the hypophysis or in the lungs causes the Syndrome of inappropriate
ADH secretion. Water retention, concentrated urine, hyposmolar plasma, and muscle cramps
characterise this syndrome.

· Panhypopituitarism is due to total destruction (lesions or tumour invasion) of all hormones in the
hypothalamo-hypophysary system. Lack of GH and somatomedins result in a dwarf without normal
sex development (lack of LH and FSH). This dwarf has also hypothyroidism (lack of TSH), and a
Cushing-like hypercorticism (wothout ACTH secretion).

· Hyperpituitarism is often caused by prolactin producing microadenomata, which cause abnormal

milk production. This leads to disturbance of the menstrual cycle and infertility. Other pituitary
adenomas produce large amounts of GH leading to gigantismus in childhood and to acromegaly in
adults.

Blood glucose and diabetes

· Glucose is absorbed through the luminal membrane of the intestinal cells in glucose-Na+
transporter proteins. The two substances pass through the basolateral membrane via separate
routes: Glucose passes in a special glucose-transporter, and Na+ is transferred by the Na+-K+-pump.

· Somatotropin - human growth hormone (GH) - is an insulin-antagonist, but together with

insulin probably the most important anabolic hormone.

· Glucose sensitive neurons in the hypothalamus (the glucostatic centre) react to hypoglycaemia
by releasing glucagon from the pancreatic a-cells and catecholamines from the adrenal medulla by
action of the sympathetic system.

· Since the hypophysis hormones ACTH and GH are insulin-antagonists the net effect of the
hypophysis, when not balanced by a normal pancreatic insulin secretion, is a reduced glucose
tolerance.

· The endocrine pancreas or the pancreatic islets are synonyms for the production site of four
polypeptide hormones: Glucagon, insulin, somatostatin, and pancreatic polypeptide (PP).

· Insulin is synthesized as proinsulin, which is stored in granules close to the cell membrane of the
b-cells of the pancreatic islets. When the secretory granules release proinsulin to the portal blood
and later the extracellular fluid volume, connecting peptide (C-peptide) and two amino acids breaks
off.

· A poorly controlled diabetic condition leads to extracellular hyperglycaemia, glucosuria,

metabolic acidosis, polyuria (osmotic diuresis), dehydration and polydipsia. The osmotic diuresis
leads to the excretion of Na+ and water, which results in Na+ and ECV depletion.
 · Intracellular lack of glucose activates glycogenolysis in the liver and muscles, and accelerates
muscular proteolysis and lipolysis. This liberates free fatty acids, which are converted to ketone
bodies.

· A patient with hyperglycaemia above 25 mM loses consciousness to such a degree that contact
is impossible (ie, coma).

· The increased rate of cholesterol production increases the occurrence of atherosclerosis and of
diabetic nephropathy.

· Albuminuria, hypertension and low glomerular filtration rate characterise diabetic nephropathy.

Thyroid hormones and disorders

· T4 is likely to be a prohormone, which is deiodinised by monodeiodinase to the more potent T3

just before it is used in the cells. Thus T3 is probably the final hormone, although it is present only in
a very low concentration (10-9 mol per l).

· Thyroid hormones are synthesised in adult persons as long as the dietary iodine (I2) supersedes
75 mg daily. This is an adequate supply to prevent goitre formation.

· The endoplasmic reticulum synthesises a large storage molecule called thyroglobulin. This
compound is build up by a long peptide chain with tyrosine units and a carbohydrate unit completed
by the Golgi apparatus. Iodine-free thyroglobulin is transported in vesicles to the apical membrane,
where they fuse with the membrane and finally release thyroglobulin at the apical membrane.

· Thyroid hormones stimulate oxygen consumption in almost all cells. They stimulate the rate of 1)
hepatic glucose output and peripheral glucose utilisation, 2) hepatic metabolism of fatty acids,
cholesterol and triglycerides, and 3) the synthesis of important proteins. The many rate-stimulating
effects are summarized in an overall increase in oxygen consumption. This slow - but long lasting -
calorigenic and thermogenic effect is confined to the mitochondria.

· The thyroid hormones and the catecholamines work together in metabolic acceleration. Thyroid
hormones increase the number of b-adrenergic receptors. Thyroid hormones modulate the secretion
of sex hormones (sex development), growth hormone (growth), and nerve growth factors (CNS
development).

· The high basal metabolic rate raises the core and shell temperature, so that the peripheral
vessels dilatate. This vasodilatation forces the cardiac output to increase. A circulatory shock
develops, if the rise in cardiac output is insufficient - so-called high output failure.

· Calcitonin is produced by the parafollicular C-cells of the thyroid. Calcitonin inhibits bone
resorption by blocking the PTH receptors on the osteoclasts. The result is an extremely effective
lowering of plasma [Ca2+ ] and [phosphate]. Calcitonin is important in bone remodelling and in
treatment of osteoporosis.

· The classical hyperthyroidism or thyrotoxicosis (Graves thyroiditis, Basedows disease) is a

condition characterized by an abnormal rise in basal metabolic rate, struma and eye signs (thyroid
eye disease). The eyes of the patient typically bulge (ie, exophtalmus). Patients with thyrotoxicosis
have overwhelmingly high metabolic rates.

· Primary hypothyroidism is abnormally low activity of the thyroid gland with low circulating
thyroid hormone levels caused by thyroid disease. Secondary hypothyroidism results from
hypothalamic-pituitary disease.

· Primary hypothyroidism is caused by microsomal autoantibodies precipitated in the glandular

tissue. Lymphoid infiltration of the thyroid may eventually lead to atrophy with abnormally low
production of T4. Another clinical form starts out as Hashimotos thyroiditis, often with
hyperthyroidism and goitre. Following atrophy caused by microsomal autoantibodies, the condition
ends as hypothyroidism, or the patient is euthyroid. When hypothyroidism is congenital both
physical and mental development is impaired and cretinism is the result. Also iodide deficiency in
childhood may result in a hypothyroid dwarf or cretin.

· Myxoedema in the adult is severe thyroid gland hypothyroidism with a puffy swollen face due to
a hard, non-pitting oedema (tortoise skin called myxoedema). The skin is dry and cold; there is
bradycardia, often cardiomegaly (ie, myxoedema heart), hair loss, constipation, muscle weakness and
anovulatory cycles in females.

· Struma is a visible or palpable enlargement of the thyroid. Struma is due to iodine deficiency,
increased iodine demand or strumagens. Any prolonged TSH stimulation results in an enlarged
thyroid.

Sexual satisfaction, reproduction and disorders

· The presence of normal ovaries or testes determines the gonadal sex. Without normal ovaries or
testes any genetic sex will develop into an apparent female.

· The brain is an important sex organ. The sex desire (libido) is stimulated by a multitude of sense
impressions (visual, auditive, olfactory, and psychological). Potency refers to the ability to engage in
intercourse.

· On the first day of the menstrual bleeding, the low progesterone and high prostaglandin level
probably releases enough Ca2+ to start spontaneous contractions of the myometrial cells. Ca2+ -ions
enters myometrial cells and stimulates their activity in the secretory (progesterone) phase.

· At certain high plasma level of oestradiol can increase FSH output. This is called the positive
feedback release ovulation. At lower levels oestradiol is a potent inhibitor of Gonadotropin-RH
secretion and thus of FSH output (negative feedback). The negative feedback forms the basis for the
ovulation-inhibition by contraceptives.

· The primary inhibitor of FSH secretion is the peptide, inhibin that is secreted by the ovary and
testis, and blocks the effect of Gonadotropin-RH.

· The plasma [oestradiol] increases sharply in the last part of the follicular phase, while the [LH]
also increases. The sharp rise in LH and a modest rise in FSH coincide with ovulation. The LH not only
causes rupture of the follicle; it continues to act on the follicular cells, turning them into a yellow
endocrine organ, the corpus luteum.

· The spermatozoa can keep their vitality for more than 4 days if they reach the tube. They lose
their protection cover in the uterine tube. The head of the spermatozoa swell and liberates
proteolytic enzymes. These enzymes dissolve the corona radiata around the egg (oocyte). The oocyte
can only live 14 hours without conception.

· Due to the priming effect of oestrogen on progesterone receptors, both hormones stimulate the
growth of the endometrial glands, so that they curl like a helix. The progesterone effect in particular
provides the endometrial/myometrial tissues with their high secretion and blood perfusion, so the
uterus is prepared to receive the fertilised ovum.

· The b-group of hCG is specific and found in the blood by specific antibody methods even before
the first menstrual bleeding fails to appear. The hCG is detectable in the urine 8-12 days after the
first missing vaginal bleeding.

· During puberty FSH, LH, growth hormone, and insulin are important for the breast development.
The thyroid hormones (T3/T4) are permissive. At the end of pregnancy there are other hormonal
events. Progesterone secretion reaches a peak and then falls. This fall in progesterone allows the
pituitary to release prolactin (LTH).

· Relaxin is a pro-insulin-like polypeptide produced by the corpus luteum. The hormone relaxes
pelvis articulations and softens the uterine cervix in order to facilitate passage of the foetus. These
and several other factors are involved in human labour, but the exact trigger mechanism remains
unclear.

· Turner described a syndrome in small apparent females, retarded in growth and in sexual
development, and with small or no ovaries. Since they have only one sex chromosome (X), their total
chromosome number is 45. They have no sex chromatin and no drumstick.

· Klinefelter described a syndrome in persons appearing as males. They are tall, have small testes,
some have female breasts (gynaecomastia), and they are sterile. Their cells contain XXY
chromosomes (47 instead of the normal 46).

· Amenorrhoea or oligomenorrhoea are terms used for absence or irregularity of menstrual

periods. Causes are ovarian disease or absence (Turners syndrome, XO), hypothalamic deficiencies,
congenital adrenal hyperplasia (adrenogenital syndrome), starvation amenorrhoea such as in
anorexia nervosa and excessive exercise, hypothyroid amenorrhoea with increased TRH, and
withdrawal amenorrhoea (following oral contraception).
Other hormones and disorders

· Growth hormone (GH) produced in the placenta differs from the pituitary GH by a few amino
acid residues. Placental GH suppresses release of maternal, pituitary GH during pregnancy. Placental
GH stimulates maternal metabolism and foetal cell proliferation and hypertrophia.

· Foetal thyroid hormones stimulate brain development, and foetal insulin stimulates foetal
growth, cellular glucose uptake and glucose utilisation. Paracrine and autocrine growth factors are
also important for foetal growth: Insulin-like growth factor-II (IGF-II), nerve growth factors (NGF),
epidermal growth factor (EGF), and platelet derived growth factor (PDGF).

· Growth hormone and insulin are the most important anabolic hormones in the human body.

· PTH binds to membrane receptors on target cells in bone, kidney and gut. The PTH actions result
in hypercalcaemia and hypophosphataemia. The bone resorption is illustrated by a high basic
phosphatase concentration in blood.

· Cortisol stimulates hepatic glucose production, both glycogenolysis and gluconeogenesis,

lipolysis, formation of FFA and of ketone bodies. Cortisol inhibits the glucose uptake in target cells
(GLUT 4 in muscle cells, heart cells and adipocytes).

· Therapeutic doses of glucocorticoids are used for a multitude of diseases such as inflammations,
allergy, malignancy and aplastic anaemia. The negative effects are delayed healing of wounds and
increased gluconeogenesis with destruction of tissue proteins.

· Aldosterone is the major mineralocorticoid with corticosterone contributing only little.

Aldosterone promotes the reabsorption of Na+ and increases the secretion of K+ and H+ in the distal
tubular system (ie the cortical collecting ducts and the connecting segment). A rise in serum - [K+]
from normal or a fall in serum- [Na+] releases aldosterone. The renin-angiotensin-aldosterone
cascade controls the adrenal aldosterone secretion, not ACTH.

· Sex steroids are mainly weak adrenal androgens, which are metabolised to testosterone and
dihydrotestosterone. Also a small oestrogen production is present in healthy persons.

· Catecholamines increase the heart rate and the cardiac output by stimulation of the adrenergic
b1-receptors in the myocardium.

· Noradrenergic nerve fibres innervate vessels all over the body, and this system usually has some
tonic, vasoconstrictor activity. The a1-receptors are located on the surface of vascular smooth
muscles.

· Catecholamines dilatate the bronchial airways by stimulation of their adrenergic b2-receptors.

Catecholamines increase both tidal volume and respiratory frequency. The result is an increase in
ventilation together with an increase in cardiac output.

· Catecholamines relax the smooth muscles of the digestive tract (b2-receptors), but contract the
sphincters just like the sympathetic nerve system.
· Catecholamines stimulate metabolism (T3). Adrenaline stimulates hepatic glycogenolysis and
lipolysis in adipose tissue. Adrenaline increases the plasma concentrations of glucose, FFA and
ketoacids.

· Adrenaline stimulates the ascending reticular system (ie, the reticular activating system or RAS)
in the brain stem, keeping us alert and causing arousal reactions with desynchronisation of the EEG.

· Pituitary acidophilic adenomas that secrete excess growth hormone (GH) causes gigantism in
children and acromegaly in adults. Rare cases are caused by GHRH excess release from the
hypothalamus. Since pituitary acidophilic adenomas often contain both somatotropic and
mammotropic cells, the combined adenomas secrete an excess of both GH and prolactin (causing
galactorrhoea in males).

· Primary parathyroid hyperfunction is almost inevitably due to parathyroid adenomas or

hyperplasia that secrete an excess of parathyroid hormone, PTH. Ectopic tumours have been found in
the mediastinum and elsewhere. Excessive secretion of PTH leads to: bone resorption, high [Ca2+] in
plasma, high Ca2+ -excretion in the kidneys with renal stone formation, bone lesions, and metastatic
calcification.

· Chronic hypoadrenalism (ie, Addison’s disease) is hypocorticism due to destruction with atrophy
of the entire adrenal cortex by autoimmune processes, malignancy, infarction or infection. Most
cases develop organ-specific autoantibodies; these cases are associated with many other
autoimmune disorders (eg diabetes mellitus, hypoparathyroidism, pernicious anaemia, vitiligo and
thyroiditis).