MG: ENDOCRINE SYSTEM AND DIGESTIVE AND
RESPIRATORY TRACT
PITUITARY AND ADRENAL CORTEX
The endocrine system plays an important
role in autonomic body functions, which
are aimed at the continued existence of the
individual and the species. Communication
between organs and cell systems is
important for this. This communication
occurs by autonomic nervous system,
hormones, and neuroendocrine cells.
Examples of endocrine regulation are:
metabolic functions, immune system, internal environment, and reproduction.
The structure of the bioactive compounds are either peptide or protein hormones. These
are produced in the hypothalamus, pituitary gland, pancreas, thyroid and parathyroid
gland. They act on membrane receptors, like G-protein
coupled receptors (adenylyl cyclase, PI metabolism) and
tyrosine kinases.
Other hormones are steroid hormones, sterols, and
thyroxine derivatives. These are produced in the
adrenal gland, reproductive organs, calcitriol (vit. D
derivative), and tyroid gland. These act on intracellular
receptors and are involved in the regulation of protein
synthesis (ligand-gated transcription factors).
The hormones are often stable (ant)agonists and they
have the ability to act as ‘trophic
hormones’, which induce growths.
The hypothalamus and pituitary gland
together regulate a major part of the endocrine system. The
hypothalamus converts nerve impulses from the brain into a hormonal
impulse. The pituitary gland is made up of three parts:
1. Anterior pituitary (anterior lobe)
2. Pars intermedia (barely present in humans)
3. Posterior pituitary (posterior lobe)
Hormones from the hypothalamus regulate the release of hormones by
the anterior pituitary.
The majority of the hormones released by the anterior pituitary gland
are part of a negative feedback system. Therefore, the release of the
hormones in the blood will decrease the release of hormonal release in
the pituitary and hypothalamus.
Hypothalamic-posterior pituitary system contains the hormones
vasopressin which has an effect on the kidneys and oxytocin.
,Hypothalamic hormones are transported to the anterior pituitary via the bloodstream and
they regulate the release of anterior pituitary hormones. These hormones are also referred
to as neurohormones because their release is regulated by neurones. The synthesis of
other hormones by the anterior pituitary is either stimulated (RF, RH) or inhibited (IF, IH).
The posterior pituitary releases oxytocin and vasopressin (ADH) directly into the
bloodstream.
All hypothalamic hormones are peptides, except from the hormone dopamine. These are
generally small peptides, whereas the pituitary hormones are generally large
peptides/proteins.
Anterior pituitary hormones can be divided in three groups:
1. Somatotrophic hormones: growth hormone, prolactin
2. Glycoproteins: LH, FSH, TSH, and CG
These consist of an alpha and beta subunit. Alpha subunits are virtually identical
and these contain 2 oligosaccharide chains bound together via asparagine. The
beta subunits have the specific biological effect and these contain either 1 or 2
oligosaccharide chains.
3. Derived from precursor protein: ACTH, α-MSH, and β-LPH
Multiple hormones that are produced form a large precursor molecule by
enzymatic cleavage in various tissues.
The synthesis of peptide analogues is of interest because endogenous peptides are often
metabolized quickly. The knowledge of the amino acid sequence and characteristics of a
peptide creates opportunities to develop new analogues with increased stability,
improved activity, and fewer side effects. Possible changes are:
- Shortening the chain (elision)
- Lengthening the chain (intercalation)
- Changing an amino acid
- Replacing an L-amino acid by a D-amino acid
- Blocking an end group
- Replacing S-S bridges by ethylene bridges or by CH2 bonds
THE GROWTH HORMONE
This hormone is also related to the
hypothalamus and the pituitary gland. The
hypothalamus releases GRH, which results in
the release of GH by the pituitary gland. This is
a negative feedback system.
Effects of the growth hormone
- Growth: almost all body cells, in
particular chondrocytes in epiphyseal
plates of long bones (longitudinal
growth), skeletal muscle
- Metabolism: protein anabolic, glucose-
sparing, lipolytic
Regulation of growth hormone release
,The hypothalamus centre can transduce information from the brain into the production of
either GHRF or somatostatin. GHRF has a positive effect on the anterior pituitary, whereas
somatostatin has an inhibitory effect. The growth hormone has a profound effect on the
liver and on the growth of peripheral tissue. In the peripheral tissue the anabolic effect of
the growth hormone is visible.
GHRH (GHRF) is a polypeptide. It activates adenylyl cyclase and the effect is enhanced by
T3. T3 promotes GH synthesis, synergism of metabolism and growth.
Somatostatin is also a polypeptide and inhibits adenylyl cyclase. It lead to suppression of
GH and TSH secretion by the pituitary gland. In the pancreas it leads to suppression of
insulin and glucagon secretion.
Somatomedins (insulin-like growth factors, mainly IGF-1) is a peptide, which is in
homology with insulin. It acts via a tyrosine kinase receptor.
GHRH and somatostatin work as a so-called
functional antagonism, in which one stimulates
the conversion of ATP to cAMP, whereas the
other inhibits this process. This takes place in the
anterior pituitary gland.
Signal transductions
The growth hormone works with cytokines,
which act on a receptor. This causes
dimerization and conformation change of
the receptors and activation of JAK. After
that there is phosphorylation of both the
receptor and JAK.
IFG-1 signal transduction
This works with a tyrosine kinase receptor.
Pathophysiology
- Gigantism
These are adolescents with have excessive growth
leading to a body length above 210 cm.
- Acromegaly
In this disease there is deformation of bones, skull,
hand, and feet. There is growth of soft tissue,
roughening of the skin and it can lead to
hypophyseal diabetes. This is mainly occurring in
adults.
- Dwarfism
There is a deficiency in the growth hormone release.
Possible causes are:
o Abnormalities in the hypothalamus (GHRF) or pituitary gland, including
genetic abnormalities
o GH receptor defect, reduced IGF-1 production
o Abnormal IGF-1 receptor
, Pharmacotherapy
- Somatostatin, octreotide, lanreotide
These medicines are used for
gigantism and acromegaly. These are
somatostatin analogues, which are
synthetic peptides with a prolonged
duration of action compared to
somatostatin. Applications are:
o Acromegaly preceding and, if
necessary, following
hypophysectomy
o Tumours: pituitary adenomas (TSH), pancreas (insulin, glucagon),
gastrointestinal tract (VIP)
o Bleeding oesophageal varices:
vasoconstriction, restriction of motility
- Pegvisomant is a GH hormone receptor
antagonist. It binds to the growth hormone
receptor and block the binding site.
- Somatropin, mecasermin, sermorelin
Somatropin is used in growth disorders (once
daily), but it might be linked to osteoporosis.
Mecasermin is used in IGF-1 deficiency and
sermorelin is applied in diagnostics of GH
secretion.
CALCIUM HOMEOSTATIS AND BONE
METABOLISM
This system consists mainly of the thyroid and 4 parathyroid glands. The calcium
regulation is very closely regulated with limits from 2.3 – 2.7 mM. It is regulated by the
endocrine system, by hormones like parathyrioid hormone (PTH), 1,2,5-
dihydrocholecalciferol (calcitriol, vitamin D deficiency), and calcitonin. The regulation is
closely linked to the phosphate regulation. The phosphate regulation is as follows:
phosphate ↑ → Ca2+ phosphate ↑ → [Ca2+] ↓.
Biosynthesis of parathyroid hormone
PTH is synthesized from precursors. It
strats with pre-pro-PTH wich is
changed into pro-PTH, which will
eventually become PTH.
