Endocrinology
Introduction
Lecture 4
Regulation of Hormone Secretion
• For hormones to function as carriers of critical
information, their secretion must be turned
on and off at precisely the right times
• The organism must have some way of knowing
when there is:
– a need for a hormone to be secreted,
– how much is needed,
– and when that need has passed
Necessary
Components of
Endocrine Regulatory
Systems
• It is important to identify
and understand the
components of the
regulation of each hormonal
secretion because:
– Derangements in any of the
components are the bases
of endocrine disease
– and manipulation of any
component provides an
opportunity for therapeutic
intervention
Negative Feedback
• Secretion of most hormones is regulated by negative
feedback
• This means that some consequence of hormone
secretion acts directly or indirectly on the secretory cell
in a negative way to inhibit further secretion
• A simple example from everyday experience is the
thermostat
– When the temp. in a room falls below some preset level,
the thermostat signals the heater to produce heat
– When room temperature rises to the preset level, the
signal from the thermostat to the heater is shut off , and
heat production ceases until the temperature falls again
• This is a simple closed-loop feedback system and is
analogous to the regulation of glucagon secretion
Negative Feedback of Hepatic Glucose
Production by Glucagon
• A fall in blood glucose detected by the alpha cells of the islets
of Langerhans causes them to release glucagon, which
stimulates the liver to release glucose and thereby increase
blood glucose concentrations
• With restoration of blood glucose to normal level or set point ,
further secretion of glucagon is inhibited
• This mechanism is seen in some endocrine control
systems
• A problem that emerges with this system of control is
that the thermostat maintains room temperature
constant only if the natural tendency of the
temperature is to fall
• If the temperature were to rise, it could not be
controlled by simply turning off the heater
• Regulation is more efficient and precise, however,
with a second, opposing loop, which is activated
when the controlled variable deviates in the opposite
direction
Negative Feedback Regulation of Blood Glucose
Concentration by Insulin and Glucagon
• For the example with regulation of blood glucose,
that second loop is provided by insulin
• Insulin inhibits glucose production by the liver
and is secreted in response to an elevated blood
glucose level
• Closed loop negative feedback control as just
described can maintain conditions only in a
state of constancy
• Such systems are effective in guarding against
upward or downward deviations from some
predetermined set point
• But changing environmental demands often
require temporary deviation from constancy
• This can be accomplished in some cases by
adjusting the set point and in other cases by a
signal that overrides the set point
• For example, epinephrine secreted by the
adrenal medulla in response to some
emergency inhibits insulin secretion and
increases glucagon secretion even though the
concentration of glucose in the blood may
already be high
• Whether the set point is changed or
overridden, deviation from constancy is
achieved by the intervention of some
additional signal from outside the negative
feedback system
Positive Feedback
• Some consequence of hormonal secretion acts on the
secretory cells to provide an augmented drive for
secretion
• A good example of a positive feedback system involves
oxytocin causing contraction of uterine muscle during
childbirth
• In this case the stimulus for oxytocin secretion is
dilation of the uterine cervix
• Upon receipt of this information through sensory
nerves, the brain signals the release of oxytocin from
nerve endings in the posterior pituitary gland
• Enhanced uterine contraction in response to oxytocin
results in greater dilation of the cervix, which
strengthens the signal for oxytocin release and so on
until the infant is expelled from the uterine cavity
Positive Feedback Regulation of
Oxytocin Secretion
1.
2.
Uterine contractions at the
onset of parturition apply
mild stretch to the cervix
In response to sensory
input from the cervix (blue
arrows),
oxytocin is secreted from the
posterior pituitary gland, and
stimulates (green arrows)
further contraction of the
uterus, which, in turn
stimulates secretion of more
oxytocin
3.
4.
This lead to further
stretching of the cervix, and
even more oxytocin
secretion
& 5. until the fetus is
expelled
Measurement of Hormones
• It is often necessary to measure how much
hormone is present in some biological fluid
for:
– for the purpose of diagnosing a patient’s disease
– or research to gain understanding of normal
physiology
• Chemical detection of hormones in blood is
difficult
• Their minute concentrations further
complicates the problem of their detection
Immunoassays
• As knowledge of hormone structure increased, it
became evident that peptide hormones are not
identical in all species
• Hormones isolated from one species were
recognized as foreign substances in recipient
animals of another species, which often
produced antibodies to the foreign hormone
• Antibodies are exquisitely sensitive and can
recognize and react with tiny amounts of the
antigens that evoked their production, even in
the presence of large amounts of other
substances that may be similar or different
Radioimmunoassay
• A typical radioimmunoassay takes advantage
of the fact that iodine of high specific
radioactivity can be incorporated readily into
tyrosine residues of peptides and proteins
• This permits detection and quantitation of tiny
amounts of hormone
• Hormones present in biological fluids are not
radioactive, but can compete with radioactive
hormone for a limited number of antibody
binding sites
Radioimmunoassay
• Labeled hormone ( H, in red) competes
with the hormone in a biological sample
(green H) for a limited amount of
antibodies ( Ab)
• As the concentration of hormone in the
biological sample rises (rows 1,2, and 3)
decreasing amounts of the labeled
hormone appear in the hormone-antibody
(H-Ab) complex and the ratio of
bound/free labeled hormone (B/F)
decreases
• A typical standard curve used to estimate
the amount of hormone in the biological
sample
• A B/F ratio of 50% corresponds to 12
ng/ml in this example
Radioimmunoassay
• Although this procedure originally was devised for protein
hormones, radioimmunoassays are now available for all the
known hormones
• Production of specific antibodies to non-protein hormones
can be induced by first attaching these compounds to some
protein, like serum albumin
• For hormones that lack a site capable of incorporating
iodine such as the steroids, another radioactive label can
be used or a chemical tail containing tyrosine can be added
• Methods are even available to replace the radioactive
iodine with fluorescent tags or other labels that can be
detected with great sensitivity
Immunometric Assays
• Two different antibodies that recognize different
immunological determinants in the hormone are
used
• One antibody is coupled to a solid support such as
an agarose bead or adsorbed onto the plastic of a
multiwell plate
• The biological sample containing an unknown
amount of hormone then is added under conditions
in which there is a large excess of antibody so that
essentially all the hormone can be bound by the
antibody
• The second antibody, linked to a fluorescent probe
or an enzyme that can generate a colored product,
then is added and allowed to bind to the hormone
that is held in place by the first antibody so that the
hormone is sandwiched between the two
antibodies and acts to link them together
Hormone Levels in Blood
• It is evident now that hormone
concentrations in plasma fluctuate from
minute to minute and may vary widely in
the normal individual over the course of a
day
• Hormone secretion may be episodic,
pulsatile, or follow a daily rhythm
• Endocrine disease occurs when the
concentration of hormone in blood is
inappropriate for the physiological
situation rather than because the
absolute amounts of hormone in blood
are high or low
Disorders of the
Endocrine System
• Classic disorders of the
endocrine system arise
from states of excess or
deficiency of hormones,
but resistance to
hormones also plays a
major role in disease