Endocrinology
History
- Function of glands was for a long time unknown, until Berthold’s experiment with roosters –
roosters wherein testis were removed had less aggressive behaviour, no interest in hens. He
suggested that the testis produced something that conditions the blood in a way that it
changes the male’s behaviour. Later on this was confirmed to be testosterone – the hormone
produced by the testis.
- Discovery of secretin – a hormone produced by the small intestine
that stimulates food digestion.
- Discovery of insulin – removal of pancreas (particularly the small
islets of Langerhans) causes diabetes-like symptoms.
- Discovery of neurotransmitters.
- Discovery of the role of the hypothalamus on the pituitary gland –
particularly seen in the regulation of thyroid releasing hormone
TRH, which is produced in the hypothalamus and stimulates
release of prolactin and TSH in the anterior pituitary.
Techniques used in endocrinology
- Radioimmunoassay – measuring the hormone concentration in the
plasma without very expensive/unethical methods. Nowadays ELISAs are used to determine
hormone concentration.
- Molecular biology – overexpress/knockout hormones or detect the genes that encode for
specific hormones.
Endocrine system
- Endocrine cell produces hormone in the bloodstream → travels to tissues in a distance
where it can bind to its receptor where it sets an action in motion.
- Exocrine gland: delivers product to a duct that leads to the lumen of another organ, for
example the intestines. Exocrine products do not enter the bloodstream.
- Types of hormone release can be autocrine, paracrine, neuro-endocrine etc.
- Also communicates with the nervous system – many organs respond to both endocrine and
nervous system and are therefore tightly interconnected.
Homeostasis – important in physiology and endocrinology
- The regulation and maintenance of a balance, so that the state of the
internal environment in the body (blood and tissue fluids) remain stable.
- As soon as a certain value (eg blood glucose level/body temperature)
deviates from the norm, the body takes action.
- Almost all endocrine systems work through a negative feedback loop
For example: insulin
Due to food intake, blood glucose levels go up. This change in glucose level is sensed by a pancreatic
B-cell of the islets of Langerhans. This stimulates the production of insulin which decreased blood
glucose again because it is taken up by the liver.
,Negative feedback can also regulate homeostasis by two hormone systems
- Decreased metabolite is sensed by endocrine tissue A → producing hormone A
- Hormone A affects the targets tissue so that this target tissue will increase the metabolite
again.
- But this increased metabolite is then sensed in endocrine tissue B → produces hormone B
- Hormone B affects the target tissue in a way that the metabolite is decreased again.
Example: blood calcium levels
- Blood calcium levels are increased by dietary intake,
and the thyroid follicle (thyroid gland), containing
parafollicular cells, releases calcitonin.
- Calcitonin makes sure that blood calcium is taken up
by the bone thereby decreasing blood calcium level
- These decreased levels of blood calcium (due to
kidney/intestinal loss) are sensed and activated by the
parathyroid glands that secrete parathormone.
- Parathormone increases blood calcium level again by
release of calcium into the bloodstream from the bones.
As said, most hormones are regulated by negative feedback loops, but not all. Positive feedback
loops are seen in estrogens.
- Increased metabolite → endocrine releases hormone → metabolite increases even more
Estrogens → FSH/LH are released → increased estrogens
- Can only take place if there are certain events that eventually stop this vicious circle, because
otherwise the metabolite level would increase unstoppable. This occurs during ovulation,
only stops when certain levels of estrogens are reached and ovulation is induced.
Hormone categories
1. Protein hormones
- Linear/ring structure, they can form dimers.
- There are isoforms that regulate gene levels at a post-transcriptional level.
- They are hydrophilic – cannot diffuse into the cell, so these hormones always have an
extracellular receptor to bind to.
- Synthesis: prehormone → prohormone → hormone following normal DNA transcription and
mRNA translation. After this process, which takes place in the ER and golgi, the hormone is
secreted into secretory granules where they can be stored for a long time in the cell, so the
cell has a pool of hormones present.
- Stimulus → intracellular Ca → fusion of secretory granules with cell membrane → exocytosis
and release of hormone into the circulation.
,- After stimulus, protein hormones can be released in very high concentrations into the
circulation. Protein hormones are broken down by proteinases into inactive metabolites:
usually short half-life.
- Mechanisms of hormone effects → intracellular signalling once the hormone is bound to its
cognate receptor. One receptor only binds one specific hormone – ligand binding specificity.
There are receptor isoforms that induce different cell responses, for instance the estrogen
receptor (ERα and ERβ, estrogen can bind to both receptor and thereby induce different cell
responses).
Receptor agonist – binds to receptor, mimics a hormone
Receptor antagonist – occupies a receptor and prevents activation of the receptor by the
hormone.
- As said, all protein-hormones have extracellular receptors
o Channel-bound receptors
o Enzyme-linked receptors/enzyme receptors
o G-protein coupled receptors – they have a extracellular part (N-terminal NH2) where
the hormone binds, a transmembrane part (7 barrels) and an
intracellular part to which the G-protein attaches (this is the C-terminal
COOH)
▪ G-protein activates effector enzyme Gs
▪ G-protein inhibits effector enzyme Gi
▪ Hormone binds to receptor → GDP → GTP
▪ GTP leaves the receptor, binds to effector enzyme.
▪ Effector enzyme is often adenyl cyclase/guanyl cyclase that activates
the second messenger cAMP/cGMP that is formed from ATP/GTP.
▪ Leads to effects on cellular functioning
- Different protein hormones
o Neurotransmitters – synthesized by neurons, released and influences directly
neighbouring cells (nerve cell, muscle cell, secretory cell). They can act as hormones,
such as dopamin/serotonin.
o Neuropeptides – peptide hormones that are produced by nerve cells (oxytocin, CRH,
GnRH)
o Growth factors – peptide hormones that regulate growth activity (NGF, TGF-β, EGF)
2. Steroid hormones
- Derived from steroids: lipids with 4 characteristic ring structures with different side chains
- Sex hormones – estradiol, testosterone and progesterone
- Hormones of the adrenal cortex – cortisol, corticosterone and aldosterone
- They are lipophilic – able to diffuse through the membrane
- They are almost not stored in cell because they cannot be stored into vesicles due to their
lipophilic property (although there is some storage in fat droplets). Once needed, they
excess the cell by passive diffusion. The speed of production is controlled and very slow,
they need to be made first because they are not stored.
- All derived from cholesterol
Cholesterol → diffuse into cell → intracellular receptor
Mechanism of hormone effects
- Since the receptor is always intracellular, the steroid hormone diffuses through the
membrane and forms a complex with the receptor.
- This complex travels to the nucleus, able to bind to a binding domain of a promotor,
resulting in gene expression.
, - Hormone circulation and metabolism
They are not able to dissolve in the watery plasma, but bound to transport proteins to able
to travel in the circulation. They are not cut into inactive forms such as protein hormones
are, instead, they are transported to the liver where they are sulphated or converted to
glucuronic acid which makes them inactive.
So these steroid hormones are made inactive in the liver, while protein hormones are cut by
proteinases everywhere to become inactive.
- Steroid hormones have a longer half-life.
3. Amines – hormones made from tryptophan or tyrosine
- Tryptophan → 5-hydroxytryptophan → serotonin (5-HT) → … → melatonin
- Phenylalanine → tyrosine → L-Dopa → dopamin → norepinephrin → epinephrin
- Catecholamines are made from one tyrosine molecules
- Thyroid hormones require two tyrosine molecules
o Unique: they need iodine for its functioning
o Just like steroid hormones: intracellular receptor
Other hormone categories
a. Eicosanoids and fatty acid derivatives: prostaglandins, thromboxanes, leukotrienes.
They have hormone-like actions.
b. Pheromones – organic structures with carbon and hydrogen atoms, released by an
animal and causes a behavioural change in another animal.
c. Electrolytes and metabolites – induce hormone actions. For instance Na, binds to
osmoreceptors and can induce intracellular signalling.
Pancreatic hormones
- Pancreas is located between the liver and intestine and consists of two parts: an endocrine
and exocrine part.
o Exocrine: cells secrete pancreatic enzymes into the pancreatic duct that help to
digest food.
o Endocrine: cells secrete hormones into blood vessels. This endocrine part is also
called the islets of Langerhans – these cells cannot be regenerated!
▪ Function is to control glucose homeostasis, facilitating glucose storage and
release of glucose when needed.
▪ By food intake, the islets of Langerhans (β-cells) produce insulin, that
decreases blood glucose level because the liver absorbs it.
The islets of Langerhans consist of 5 endocrine cell types
1. β-cell – most present, often in the middle of the islets, produces insulin
2. α-cell – produces glucagon
3. δ-cell – produces somatostatin
4. PP-cell – produces pancreatic polypeptides
5. ε-cell – produces ghrelin (hunger hormone)
between these cells, there are complex paracrine interactions.
▪ the islets are highly vascularized – blood vessels are structured in a way that
the blood first goes to the endocrine cells, so to the islets, and then to the
exocrine cells. This indicates how important these islets are, although they
