A P T E R
Basic Concepts of
Endocrine Regulation
1 6
O B J E C T I V E S
After studying this chapter,
you should be able to:
o Describe hormones and their contribution to whole body homeostatic
mechanisms.Secretion rats may peak and ebb "trough" relative to
circadian rhythms (day and nigh times) in response to meal
timing, other periodically changed regulators which may
range from millisecond to years - according to the age and
development)
? The oscillator in the hypothalamus regulates the membrane
potential of hypothalamic neurons and thus determine the
pulsatile secretion of trophic factors into hypophysial blood
supplies the pituitary gland hormones and hence the
pulsatile manner of pituitary hormone secretion. ? These hormone pulses convey different information to target
tissues on which they act compared to a steady state
secretion rate. ? Factors influencing the circulating level of hormones:
1. Rate of secretion
2. 3. 4. 5. Nature of secretion (steady vs pulsatile)
Rate of degradation and uptake
Affinity of binding to receptor and receptors availability
Affinity to carrier plasma proteins
? Hormone stability (resistance to degradation or loss) influence
the half-life of a hormone and offer a therapeutic implications
for hormone replacement therapy (by synthesizing more
stable analogues):
? Keep in mind: Only the FREE hormone is biologically active in target tissue and the only can mediate the feedback
regulation (since it is the only form able to access the extravascular compartment)
? Plasma carriers which ultimately modulate the level of free hormone in plasma. Their functions are below:
1. 2. 3. They serve as a reservoir of inactive hormone and thus provide a hormonal reserve. They prevent degradation or uptake of bound hormone and allow for smoothed hormonal level over time. They restrict the access of hormone to some sites. ? Adrenaline & most peptide are soluble in plasma
and do not require a transport. ? Estradiol & testosterone bind to SBG
? Progesterone, cortisol and glucocorticoids bind to
Transcortin. ? The SBP-hormone complex and the free
hormone are in equilibrium in the plasma, and
only the free hormone can diffuse across cell
membranes
SBP have 3 main functions:
(1) They increase the solubility of lipid-based
hormones in the blood;
(2) They reduce the rate of hormone loss in the
urine by preventing the hormones from being
altered in the kidney
(3) They provide a source of hormone in the
bloodstream that can release free hormone as
the equilibrium changes (reservoir). Additional way to regulate the availability of
hormones is to regulate the expression and
secretion of the carrier proteins themselves. This is
a critical mechanism that regulates the
bioavailability of thyroid hormones, for example. Finally, several hormones are destroyed by passage
through the pulmonary circulation or the liver . This
may markedly curtail the temporal window (peak and
trough plasma level) within which a given hormone
can act. ? Peptides and catecholamines (Hydrophilic
hormones), exert their acute effects by binding to
cell surface receptors (most are of the GPCR
family). ? Steroids and thyroxine (Hydrophobic hormones),
predominantly exert their actions via nuclear
receptors. ? Two classes of nuclear receptors are important in
endocrine physiology when a hormone bind them:
1. Those directly stimulate the transcription via
induction of the binding of a transcriptional co-
activator . 2. Those indirectly stimulate the transcription via
dislodging of a transcriptional co-repressor and
recruitment of a co-activator . The latter class of receptor allows for a wider dynamic
range of regulation of the genes targeted by the
hormone in question
? Feedback loops are either negative or
positive. ? Positive feedback loop: involves the
enhancement or continued stimulation of
the original release mechanism/stimulus
(this seen in parturition "delivery").Example: T4 bind nuclear genes on suppressor regulatory
sites of the TSH dictating gene in the pituitary gland ended
with suppression of TSH synthesis.Since the regulatory regions of many peptide hormone
genes contain binding sites for nuclear receptors, other
hormones can control the synthesis of the peptide
hormones
?Synthesis involved entry of cholesterol across the inner
membrane of mitochondria by a specific carrier (StAR)- a
first limiting step in the synthesis of the hormone
precursor (pregnenolone).o Define how hormones are synthesized and secreted by cells of endocrine
glands, including how peptide hormones are cleaved from longer precursors.o Explain the relevance of protein carriers in the blood for hydrophobic
hormones, and the mechanisms that determine the level of free circulating
hormones.It operates as a distributed network comprising glands and circulating
messengers, often under the influence of the CNS, the autonomic
nervous system, or both
?The hormone-receptor complex form dimer with a distinct ligand nuclear
receptor that in turn bind DNA and cause gene transcription
Control of synthesis:
?Amine and steroids: by regulating enzyme and
substrates availability involved in the synthesis of the
hormone.The endocrine system differs from other physiological systems in that it
cannot be distinctly defined based on anatomical boundaries.Example of co-evolution: co-evolution of surface GPCR and tyrosine
kinases for peptide and amine hormones. Steroid and T4 hormones have intracellular cytoplasmic receptors (they
freely cross cell membrane).Thus multiple hormones my be derived from the same
initial precursor (pre-pro-hormone).High glucose level increase the interaction of insulin-
mRNA with specific RNA binding proteins.Peptide hormones are stored in secretory vesicles
(granules) of secreting cells.A specific signal (neurotransmitter, hormone, peptide)
activate the exocytosis of stored granules.Trophic hormones and cytokines bind their receptors on
steroid secreting cells.Hormones grouped into families according to their structural similarities
according to their similarities of the receptors they activate.These vesicles will contain the hormone and its inactive
fragments and designed to export the hormone out of the
cell
?These
interactions increase stability and translation of insulin-
mRNA and hence high level of insulin in blood after meal.o Understand the principles of feedback control for hormone release and its
relevance for homeostasis.Hormones comprises of: steroids, amines, and peptides.Example in hormone diversity: several peptide hormones are
heterodimers with a common ?Depending on the specific enzyme the cleavage may occur
at different site of the peptide chain
?All peptide hormones synthesis is subjected to
translational control.Complexity of hemostasis increase with increase life form; this need an
increase in the number of hormones and increase in their diversity
?chain and the different ?-chain arise from
a common duplicated ancestral gene (evolution).The evolution in hormone structure need evolution in its receptor for
actions/ specificity spread.This provide a way
for measuring regulatory control or the site of highest
hormone availability.Steroid hormones are not stored in secreting cells.Synthesis is in the mitochondria of secreting cells from
cholesterol.Some hormones are secreted in a pulsatile manner
(pulses).o Understand the chemical nature of different classes of hormones and how this
determines their mechanism of action on target cells.o Understand the principles governing disease states that result from over- or
under-production of key hormones.TSH, FSH and LH: have same ?Synthesized initially as pre-pro-hormone
?The pre-pro-hormone cleave by specific proteases into
pre-hormone
?The pre-hormone again cleave by specific proteases into
the final hormone
?The hormone precursors are inactive.Activation of these receptors ended with expression of
StAR protein.StAR traffics cholesterol enter into the mitochondria
?Peptides are the most numerous.Peptides: by gene transcription
?Peptide hormones:
?The precursor is process inside a specific vesicles.The abundance of insulin level during meal can be
explained.....They secreted by diffusion.The carrier expression is regulated by a gene.chain, with differ and specific ?-chain.This provide a genetic
economy.??????????????????????????