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Full summary advanced endocrinology
Full summary for the course advanced endocrinology (NWI-BM032C) given in 2024 - Radboud University, Nijmegen
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Advanced Endocrinology: Lecture 1Introduction: The Emergence and History of Endocrinology
12-04-2024
Key Concepts
• Endocrinology is a young field of research, with already a rich history
• Endocrine, neural and feedback mechanisms modulate endocrine axis output
• Modern strategies to identify new ligands (e.g. hormones) of receptors
o Discovery of ghrelin: an example of contemporary hormone discovery
o Orphan receptor in pituitary gland: growth hormone secretagogue-R
• Endocrine axes interact (e.g. stress axis and glucose homeostasis) with each other and
with other systems (e.g. the immune system)
• Different modes of communication: endocrine and/or paracrine. Local communication
in the Islets of Langerhans key to understanding and curing diabetes?
• “Old” hormones may be assigned “new” roles
History of Endocrinology
Back in Ancient Egypt (<1000 BC), they gained an understanding of the role of gonads (ovaries
and testes) in sexual reproduction. They performed the first excision experiments in which they
found that removal of ovaries resulting in no pregnancy and removal of testes resulted in a
distinct phenotype, often seen in eunuchs that served the pharaoh’s harem. They were able to
diagnose pregnancies through morning sickness. We now know that morning sickness is related
to high plasma levels of estrogen. They also detected diabetes through “the passing of too much
urine”.
,The Romans performed organoectomy and organotherapy (e.g. eating brain to treat epilepsy and
testes to treat impotence). Claudius Galenus described the thyroid gland and the pituitary
gland. He believed that substances from the brain were being carried into the blood and that the
pituitary gland served to store waste products from the brain. They found that castration results
in a decreased libido, changed fat deposition and changes in the body hair. Their conclusion
was that a substance from the testes affected physical characteristics.
Not a lot of information is known about the development of endocrinology in the west during the
Middle Ages. However, in China, they discovered a cure for goitre: the consumption of seaweed
and shellfish (rich sources of iodine). They correlated the disease with a dysfunction of the
thyroid gland and treated it with dried thyroid glands as well. They gained an insight into the
cause of diabetes (correlation with carbohydrate metabolism) and performed testicular
organotherapy. They were also able to extract bioactive compounds (steroids and their
metabolites) from urine, without knowing the nature of these compounds.
Thyroid
There were some early misconceptions regarding the thyroid gland, such as that it served a
cosmetic role or served to lubricate the trachea. Others believed that it served as a reservoir to
diverge blood from the brain or that the swelling was a danger signal from their wives.
In 1600 BC in China and during the Roman period, people figured out that eating marine
sponges and algae (both rich in iodine) were methods to treat goitre. Goitre epidemics in the
Alps were treated with seaweed therapy. Wang Hei wrote down an anatomical description of the
thyroid gland in 1475 and treated goitre with dried thyroid glands. In 1811, Prout described
iodide for goitre treatment. Magnus-Levy constated that the thyroid gland regulates
metamorphosis in amphibia in 1911. Kendall (1915) and Harington (1926) were able to isolate
and synthesize thyroxine (T4), the prohormone of active thyroid hormone; Gross and Pitt-Rivers
were able to isolate and synthesize triiodothyronine (T3) – the bioactive thyroid hormone – in
1952.
One of the first known functions of thyroid hormone was the induction of metamorphosis in
amphibians (1911. We now know that thyroid hormone also plays a role in physiological and
behavioural metamorphoses (e.g. in salmon).
The Rise of Clinical Endocrinology
The first endocrine disease described in modern history is Addison’s
disease. Symptoms include, but are not limited to, hyperpigmentation,
salt craving, fatigue, mood swings, etc. The wide variety of symptoms
often overlap between diseases, making it harder to diagnose. Addison
was a diagnostic and discovered that TB patients had failure of the
adrenals (back then called suprarenal capsules). This was the start of the
field of clinical endocrinology.
Due to the lack of negative feedback, an
excess of pro-opiomelanocortin (POMC) is
created, which is broken down into ACTH and
subsequently α-MSH. In high concentrations,
ACTH can also activate MC1R immediately,
resulting in pigmentation as well.
,The Discovery of the First Hormones
Brown-Séquard sold extracts of animal organs, claiming it would help with certain issues, such
as constipation. He first wrote down “… by some substance or substances which our blood
owes to the testicles”, indicating that something from the testicles enters the blood flow.
Pavlov studied the secretory activity of the exocrine pancreas in 1898. He noticed that
administration of diluted hydrochloric acid stimulated pancreatic secretion. However, due to
him being a dogmatic nervist, he believed that there was a local neural network causing the
pancreatic secretion when the duodenum contained acid.
Bayliss and Starling also
studied this phenomenon. They
used dogs with severed spinal
cords and noticed that 2
minutes after the
administration of 50 ml HCl in
the duodenum, pancreatic
secretion starts. They had
similar observations after administration of acid in a denervated duodenal segment.
Intravenous administration of an extract from the duodenal mucosa showed pancreatic
secretion after 70 seconds, causing them to believe a substance in the duodenal mucosa
caused the pancreatic secretion, rather than the acid itself. They suggested the name secretin
for it.
“We soon found, however, that the secretion of the pancreas is normally called into play (…) by a
chemical substance (hormone) which is formed (…) in the upper parts of the small intestine
(gland or gland cells) under the influence of acid (stimulus), and is carried thence by the
bloodstream (transport via blood) to the gland-cells of the pancreas (target cells/organ).”
The first mention of the term “hormone” was in 1905.
Secretin has an important role. Stomach acid in the duodenal lumen
causes the pH to increase, leading to secretion
of secretin from the duodenal mucosa (done
by 5 cells). This stimulates the pancreatic duct
cells, causing secretion of aqueous NaHCO3
solution in the duodenum. This neutralizes the
stomach acid in the duodenal lumen, causing
a pH decrease (negative feedback loop).
, Modern-day Discovery of a “New” Hormone: Ghrelin
(1999)
The discovery of ghrelin is an example of contemporary hormone
discovery. The pituitary contains an orphan receptor in the pituitary
gland called growth hormone secretagogue receptor (GHS-R). We
know that synthetic growth hormone secretagogue binds to it, but
we don’t know which natural ligand binds to it. Using the FLIPR
(fluorescent imaging plate reader) cell system, scientists
discovered that stimulation of the GHS-R leads to an increase in
calcium within the cell. This stimulates the pituitary to release growth hormone (GH).
The search for an endogenous ligand originally started in the brain, but no signals were to be
found. They moved on to the whole body, and found the endogenous ligand in the stomach,
where the motilin receptor can be found. The motilin receptor is closely related to the GHS-R.
Isolation of the hormone and amino acid sequencing lead to the discovery of an unknown 3rd
amino acid. DNA analysis showed that this aa should have been a serine residue and the
recombinant protein was not bioactive. Mass spectrophotometry showed that the synthetic
ghrelin was 125 m.u (daltons) lighter than natural ghrelin, indicating a missing modification of
126 m.u. (1 proton of Ser replaced with a modification). In the end, they came up with the
following modification:
Ghrelin is a hormone that is predominantly
produced in the stomach. Ghrelin increases in
non-fed states, meaning that it is orexigenic.
Ghrelin, which is released by the stomach,
stimulates the GHSR in the brain, leading to the
secretion of growth hormone in the pituitary.
This stimulates liver glucose production
(glycolysis, gluconeogenesis) via growth
hormone and IGF-1. This causes an increase in
blood glucose. In a fed state, the stomach will
not secrete as much ghrelin, and LEAP2 is
secreted, which inhibits ghrelin. This means
that GHSR is not stimulated, leading to no
secretion of growth hormone and therefore a
decrease in glucose production in the liver.
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