Summary MG: Endocrine system and digestive
and respiratory tract
Lecture 1: Introduction, hypothalamus pituitary system, growth hormone and
calcium homeostasis – Endocrine system 06-09-2021
The endocrine system is very important in autonomic body functions, assisted by communication between
organs and cells. Communication occurs through the ANS and hormones, or a combination of both: the
neuroendocrine system. Endocrine regulation is important in a lot of bodily functions, such as metabolism,
homeostasis of the internal environment and reproduction.
Mechanisms of signaling
Signaling can be autocrine (same cell), paracrine (different cell), endocrine (from one cell through the
bloodstream to another cell) or neuroendocrine (from a neuron through the bloodstream to another cell).
Hormones and glands in the endocrine system
Important players in the endocrine system are the hypothalamus, the pituitary gland, the thyroid gland,
the parathyroid glands, the adrenal glands, the pancreas, the ovaries, and the testes. All of them produce
their own hormones. Hormones can be peptide/protein hormones, mainly from the hypothalamus,
pituitary, pancreas, and thyroid. Such hormones bind to membrane receptors (like G-protein coupled
receptors or tyrosine kinases) quickly. Steroid hormones, thyroxine derivatives and sterols come from the
adrenal gland, reproductive organs and thyroid gland, and act via intracellular ligand-gated transcription
factors receptors slowly (regulation of protein synthesis).
Treatment of the endocrine system
When something is wrong in the endocrine system, hormones are used to reverse what is wrong. This can
be using analogues, either agonists (creating similar response to original hormone) or antagonists
(inhibiting the effect of the original hormone). Such analogues are created using knowledge of amino acid
sequences and the characteristics of a peptide, to increase stability, improve activity and reduce side
effects (by changing the chain, replacing L-AA for D-AA, blocking groups, or replacing S-S bridges).
Pharmacological activity of analogues provides insight into the structure-activity relationship (SAR). Tropic
protein hormones from the anterior pituitary can be also used, by oral administration. Another way of
treating the endocrine system is use of pharmaceuticals that affect hormone synthesis, release, or
metabolism.
Hypothalamus – pituitary system
The hypothalamus and the pituitary together regulate a big part of the endocrine system. Hypothalamus
receives information from the brain and turns it into hormones. These hormones go to the pituitary to
stimulate (RF, RH) or inhibit (IF, IH) the release of different hormones. All hypothalamic hormones, except
for dopamine, are small peptides. Most hormones from the pituitary are large peptides. Hormones from
the pituitary are transported to different parts of the body where they serve various functions.
Anterior pituitary hormones:
• Somatotropic hormones: GH (somatotropin) and prolactin
• Glycoproteins: LH, FSH, TSH (thyrotropin). They are made of an alpha and beta subunit. The alpha
subunits contain 2 oligosaccharide chains that are bound via asparagine, serine or threonine,
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, whereas the beta subunits have the specific biological effect and contain 1 or 2 oligosaccharide
chains.
• Hormone derived from precursor protein pro-opiomelanocortin with the help of proteases: ACTH,
but also alpha-MSH. ACTH is formed in the anterior pituitary, but alpha-MSH is split off in the
pituitary pars intermedia.
Posterior pituitary hormones: vasopressin and oxytocin.
Growth hormone
The growth hormone causes growth in all body cells, in
particular chondrocytes in epiphyseal plates of long bones
and in skeletal muscle. It is also important in metabolism,
since it acts anabolic, and is important in glucose-sparing
and lipolysis. GH is released from the anterior pituitary
when GHRH (somatoliberin) is released from the
hypothalamus. This process can be influenced by stress,
amino acids, and deep sleep. The hypothalamus can also
produce somatostatin, which reduces GH (and TSH)
production and release. Somatostatin also suppresses
insulin and glucagon. GH causes peripheral tissue growth,
but also acts on the liver to create IGF-1 (somatomedin),
which increases somatostatin release and represses GH
release. The growth hormone itself also uses negative
feedback on the hypothalamus, by inhibiting GHRH. T3 (produced by thyroid gland) stimulates GH release.
Mechanism GHRH and somatostatin
G-protein coupled receptors bind to the hormones
in the anterior pituitary. GHRH binds to Gs to
stimulate adenylyl cyclase, causing conversion of
ATP to cAMP, phosphorylation by PKA and
eventually release of GH. Somatostatin binds Gi to
inhibit adenylyl cyclase. No cAMP is produced, and
no GH is released.
The signal transduction of the growth hormone
itself acts via cytokine like receptors that dimerize and
phosphorylate upon binding, activating the JAK-STAT pathway
and causing gene transcription (like IGF-1). IGF-1 also leads to
growth of bone and muscles, by binding to tyrosine kinase
receptors and activating the RAS pathway. When the GH acts
on tissues to decrease glucose utilization and increase
gluconeogenesis, glucose intolerance can occur due to
overproduction. This is called hypophyseal diabetes.
Pathophysiology: excessive production of the growth
hormone
In adolescents, excessive GH production leads to gigantism. In
adults, it leads to acromegaly, characterized by deformation
of the bones, skull hand and feet, growth of soft tissue and
roughening of the skin, and hypophyseal diabetes.
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,Treatment: use of octreotide and lanreotide, which are somatostatin analogues (with prolonged activity).
Another treatment can be pegvisomant, which is a growth hormone receptor antagonist.
Pathophysiology: deficient production of the growth hormone
Dwarfism and proportional dwarfism can be caused by a deficiency in growth hormone production. This
can be caused by abnormalities in the hypothalamus (GHRH) or the pituitary itself (GH), a GH receptor
defect, reduction in IGF-1 production or an abnormal IGF-1 receptor.
Treatment: somatropin (recombinant hGH), mecasermin (recombinant hIGF-1) or sermorelin (GHRF
analog), depending on where in the pathway lies the problem.
Calcium homeostasis
Thyroid and parathyroid glands are important in calcium homeostasis and bone metabolism. Most calcium
is found in the bones and teeth, but some of the calcium is intracellular, either soluble or insoluble, or
found in the extracellular fluid. The storage form is hydroxyapatite. For the regulation of calcium
concentrations, the parathyroid hormone (PTH, produced by the parathyroid glands) is very important, just
like 1,25-dihyfrocholecalciferol (calcitriol) and calcitonin (produced by the thyroid glands). Calcium
regulation is linked to phosphate regulation. If calcium concentration is low, PTH is secreted. High
concentration in calcium leads to the reduction in PTH release. Parathyroid cells have a calcium receptor,
CaSR, a G-protein coupled receptor. When the receptor is activated, PTH secretion is inhibited. When CaSR
is inactive, PTH is secreted. When PTH is secreted, there are 3 things
that happen to increase calcium:
• reabsorption of calcium in the kidneys
• dissolution of CaPO4 crystals in the bone by differentiation of
osteoclast precursor cells and mobilization of crystalline calcium
phosphate by protease and acid secretion
• increased calcium absorption in the intestine by increased
conversion of vitamin D3 (cholecalciferol) into 1,25-
dihyfrocholecalciferol (calcitriol), which stimulates the uptake of
calcium
Negative feedback is used to prevent excessive amounts of calcium.
Cholesterol is turned into cholecalciferol (vitamin D3) in the skin
under the influence of UV light. The liver then produces calcifediol
from the cholecalciferol. In the kidney, calcifediol is turned into
calcitriol with the help of PTH. Calcitriol leads to differentiation
and activation of osteoblasts. Calcitonin, which is produced by
parafollicular cells (C-cells) in the thyroid gland, inhibits
resorption of calcium in the kidneys and promotes calcium
deposition in the bone through osteoclast suppression.
Instead of cholecalciferol (vitamin D3), also ergocalciferol (vitamin
D2, with an additional CH2 group) can be used to produce
calcitriol. Alfacalcedol is a vitamin D3 analogue, which can also be
used to create calcitriol. Cinacalcet is a pharmaceutical compound
that increases the sensitivity of CaSR, which leads to less PTH secretion.
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, Lecture 2: Bone metabolism and thyroid hormones – Endocrine system
07-09-2021
Bone remodeling
Both osteoblasts (OBs) and osteoclasts (OCs) have
precursor cells. Osteoclast precursors are recruited by
calcitriol, PTH and cytokines and the precursors can
differentiate to mature osteoclasts with the help of
osteoblasts. Osteoblasts can differentiate after signals
like cytokines, hormones or teriparatide. Mature
osteoclasts secrete protease and build up an acidic
environment, causing bone degradation and the release
of both calcium and growth factors, which influence
osteoblast activation. Osteoblasts drive the repair and fill
up the new matrix. OCs are inhibited by OBs and
calcitonin. Glucocorticoids stimulate osteoclasts but
inhibit the differentiation to osteoblasts (destroyed bone
matrix after long time inflammation). Oestrogens inhibit
OCs, therefore, in the menopause, when there are less
oestrogens, the occurrence of osteoporosis increases.
Oestrogen-like drugs, for example raloxifene can reduce
osteoporosis. Bisphosphonates (found in the bone
matrix) also inhibit OCs and its differentiation.
Communication between OBs and OCs
OCs have the RANK receptor (NFkB signaling) and OBs have the ligand: RANKL. The rank ligand also exists in
soluble form, which is called osteoprotegerine (OPG). A recombinant drug of this is r-OPG, which avoids
the binding of RANK to RANKL and therefore prevents differentiation of osteoclasts. Another drug to
prevent OC differentiation is denosumab, which is an
anti-RANKL antibody. Bisphosphonates inhibit
activation of osteoclasts. Under the influence of
calcitriol and PTH, M-CSF is released from the
osteoblast and RANKL is expressed, which are both
important for the differentiation of OCs. M-CSF is
inhibited by oestrogen and glucocorticoids. Low
intermittent dosage of rhPTH 1-34 stimulates
osteoblast differentiation (paradoxical effect).
Calcitonin inhibits osteoclasts via the calcitonin
receptor. Oestrogens suppress osteoclast
differentiation and stimulate osteoblast proliferation.
Glucocorticosteroids stimulate osteoclast differentiation and suppress osteoblast differentiation.
So:
stimulation of OBs: oestrogens, low intermittent dosage of rhPTH 1-34
stimulation of OCs: RANK/RANKL, calcitriol, PTH, M-CSF, glucocorticoids
inhibition of OCs: OPG, r-OPG, denosumab, bisphosphonates, oestrogen, calcitonin, raloxifene (oestrogen-
like drug)
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