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Endocrine system & Digestive and Respiratory tractLecture 1: Introduction to the endocrine system & the growth hormone, Martina
Schmidt 06-09-2021
The endocrine system plays an important role in autonomic body functions. These are functions that
are aimed at the continued existence of the individual and the species. Communication between
organs and cell systems is important for this such as the autonomic nervous system, hormones and
interaction between these systems. Endocrine regulation are for example: metabolic functions,
functioning of the immune system, reproduction and regulation of the water homeostasis.
The neuroendocrine hormone is produced in the
neuroendocrine cells which are in the
hypothalamus. These hormones maintain the
communication between the organs in the body.
The endocrine system is located in the brain in the
hypothalamus and pituitary gland. Hormone-
releasing hormones are TSH, ACTH, FSH, LH and
GH. Effector hormones are prolactin, MSH, ADH
and oxytocin.
The chemical structure and signal transduction mechanisms are peptide hormones and protein
hormones and also steroid hormones, sterols, thyroxine derivatives. They are produced in the
hypothalamus, pituitary gland, pancreas, thyroid and parathyroid glands. Membrane receptors
(relatively quick) are G-protein couples receptors (couple to adenylyl cyclase and PI metabolism) and
tyrosine kinases. Steroid hormones, sterols, thyroxine derivatives are produced in the adrenal gland,
reproductive organs, calcitriol and thyroid gland. They use intracellular receptors (relatively slow)
such as the regulation of protein synthesis (ligand-gated transcription factors).
Hormones are often analogues like stable agonists or antagonists, with protein hormones they are
often more stable effector hormones that can be administered orally. Pharmaceuticals used are
pharmaceuticals that affect hormone synthesis, hormone release or hormone metabolism.
The hypothalamic-pituitary system contains special hormones that
are able to produce hormones by transducing the signal from the
brain to the pituitary and thereby activating hormone production.
Hypothalamus converts nerve impulses from the brain into a
hormonal impulse. Pituitary gland is made up of 3 parts: anterior
pituitary, pars intermedia and the posterior pituitary. Hormones from
the hypothalamus regulate the release of hormones by the anterior
pituitary.
In the hypothalamus a lot of hormones are produced and act in the anterior
pituitary. When hormones are produced they give a negative feedback on
the upper centres where the hormones are produced. The majority of the
hormones produced by the anterior pituitary have a negative feedback on
the anterior pituitary or hypothalamus (negative feedback mechanism).
Hypothalamic-posterior pituitary system will start in the hypothalamus and
the hormones will then travel down the blood stream.
,Hypothalamic hormones are
transported to the anterior
pituitary via the bloodstream.
They regulate the release of
anterior pituitary hormones. They
are also referred to as
neurohormones because their
release is regulated by neurones.
The synthesis of other hormones
by the anterior pituitary is
stimulated by releasing factors
(RF) or hormones (RH). Whilst the
synthesis is inhibited by inhibiting factors (IF) or hormones (IH). The posterior pituitary releases
oxytocin and vasopressin (ADH) directly into the bloodstream. All hypothalamic hormones are
peptides (expect dopamine).
The different groups of hormones are the somatotropic hormones, glycoproteins and derived from
precursor protein:
- The glycoproteins are made up of a peptide chain with an α-subunit and a β-subunit.
- Pro-opiomelanocortin are multiple hormones that are produced from a large precursor
molecule by enzymatic cleavage in various tissues. ACTH and opioids will be formed by the
activity of proteases.
- Synthesis of peptide analogues is important because the 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. pharmacological activity of analogues provide insight into the
structure-activity relationship. Possible structural changes are:
- Shortening the chain by removing an amino acid
- Lengthening the chain by inserting an amino acid
- 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
Growth hormone
The growth hormone affects all cells in the body. In particular chondrocytes in epiphyseal plates of
long bones (longitudinal growth) and also in skeletal muscle. The
metabolism is also influenced, this is done by protein anabolic, glucose-
sparing and lipolytic activity.
The hypothalamic centre transduces information of other brain areas
into the production of different factors. The GHRF has a positive effect
on the anterior pituitary, somatostatin will have a negative effect on
the anterior pituitary. Since most of the hormones are produced in the
anterior pituitary there will either be an upregulation of the production
of the growth hormone or there will be a downregulation. The
hypothalamus can be influenced by amino acids, stress and by deep
sleep, this will cause either GHRF or somatostatin to be produced and
thereby produce the growth hormone or make the production stop.
,The growth hormone has a profound effect on both the liver and the growth of peripheral tissue. In
the liver IGF-1 will be produced which will result in a decrease in the production of the growth
hormone and it has a positive effect on the production of somatostatin resulting in less production
by the anterior pituitary. The production of the growth hormone will lead to negative feedback on
the production of the GHRF by the hypothalamus. T3 is the active hormone of the thyroid and this
hormone will have a positive effect on the growth hormone.
- GHRH (GHRF) is a polypeptide that activates the adenylyl cyclase and its effect is
enhanced by T3.
- Somatostatins is a polypeptide that inhibits the adenylyl cyclase and have an effect on
the growth hormone release and the thyroid stimulation hormone release. They have an
influence on the activity of insulin and glucagon secretion in the pancreas.
- Somatomedins are peptides that act like insulin and act via the tyrosine kinase receptor.
Growth hormone-releasing hormone (GHRH), it has a short half-life of 5 minutes and is used for
diagnostics. Somatostatin has a short half-life of about 2 minutes. The growth hormone
(somatotropin) can be used in substitution regimes and has a longer half-life of about 20 minutes.
Insulin-like growth factor-1 (IGF-1) is somatomedin C, are polypeptides and have a half-life of 60
minutes.
There are receptors for GHRH and
somatostatin and both of these receptors
will have an opposing effect on the cAMP
levels. The GHRH is an G-protein coupled
receptor and will when stimulated the
concentration of cAMP. This will activate
PKA and eventually the growth hormone.
When the somatostatin receptor is
activated the adenylyl cyclase will be
inhibited and no cAMP will form and therefore no PKA will be produced and the release of the
growth hormone will be inhibited.
The growth hormone transduces its signal via
cytokine like receptors that need a dimerization
with 2 receptors. Then phosphorylation of the
receptor will take place which will activate it and
a signal will be transduced via Jak-Stat. Stat will
be phosphorylated and will be dimerised
whereafter it will enter the nucleus where gene
transcription will be started.
The metabolic effects of the growth hormone are:
- In the liver (performed by IGF-1): cartilage and bone growth and muscle and other organ
growth.
- Adipose tissue: stimulating lipolysis and releases fatty acids.
- Most tissues: decreased glucose utilization leading to gluconeogenesis -> glucose
intolerance with overproduction, hypophyseal diabetes.
, IGF-1 signal transduction happens via the tyrosine kinase
receptor. Binding of IGF-1 will cause dimerization and this will
use Grb2 to SOS and a signalling cascade to take place and a
kinase cascade to take place and cause cell proliferation.
The pathophysiology can be excessive production of growth
hormone. In adolescents this can be gigantism and in adults
this can cause acromegaly which is deformation of bones, skull,
hands and feet. Growth of soft tissues, roughening of the skin
and hypophyseal diabetes.
This can be treated by using stable somatostatin analogues.
Octreotide, lanreotide are synthetic peptides with a prolonged
duration of action compared to somatostatin. These analogues
are made by replacing one of the amino acids making it more stable making
it useful for treatment.
Pegvisomant is a growth hormone receptor antagonist. However this time
it will make dimerization impossible and therefore will block signal
transduction.
In case of a growth hormone deficiency (dwarfism) can be caused by
abnormalities in the hypothalamus or pituitary gland, including genetic
abnormalities or a GH receptor defect, reduced IGF-1 production and
abnormal IGF-1 receptor.
This can be treated by somatropin (recombinant hGH),
mecasermin (recombinant IGF-1) and sermorelin
(GHRF) analogue.
The effect of the different substances are depicted in
the system of the growth hormone.
Calcium homeostasis & Bone metabolism
The calcium regulation is very closely regulated in the
serum concentration in the range 2.3 – 2.7 mM. In the
endocrine the parathyroid hormone, 1,25-
dihydrocholecalciferol and calcitonin are produced.
Regulation is closely linked to phosphate regulation,
when phosphate goes up calcium phosphate goes up
as well resulting in a lower calcium concentration.
There are four parathyroid glands which will produce the parathyroid hormones. The biosynthesis of
parathyroid hormone is produced from precursors and is then released in the extracellular fluid.
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