Integrated
endocrinology
We can regard the endocrine system as having the following
physiological missions
Regulation of sodium and water balance: preservation of the
volume/pressure reservoir required for tissue perfusion
Regulation of calcium balance: preservation of extracellular
fluid concentrations required for membrane integrity, intracellular signaling,
hemostasis,etc., and preservation of skeletal integrity
Regulation of energy balance: preserving, accessing, and
interconverting metabolic fuels to meet
cellular energy demands
Coordination of processes for coping with a hostile environment
Coordination of growth and development
Coordination of processes associated with reproduction and
lactation
It is clear that at least some aspect of virtually every
physiological system lies within the realm of endocrine control
No single hormone or endocrine gland can accomplish any of
these missions alone, and virtually every hormone participates in fulfilling
multiple missions
Consequently, it is to understand not only how hormones act
but also how they interact.
Control of hormone action
Negative feedback
The essence of negative feedback control of hormone secretion
is that some consequence of secretion blocks or dampens further secretion
Hypothalamic input to
the negative feedback system allows for episodic override and adjustment of the
set point in response to environmental inputs
Positive feedback
In positive feedback
systems, the consequences of hormone secretion feed back is to reinforce the
drive for secretion rather than dampen it.
Rather than maintaining matters stable and unchanging,
positive feedback creates instability and leads to explosive changes .
Consequently, positive feedback is rare in biology
Eg: During parturition
Coagulation
Generation
of action potential
Concepts of Specificity
Because of “internal secretion” of hormones into the blood,
hormones are widely disseminated throughout the body and have access to
virtually all cells. However, only certain cells respond to any particular hormone.
These “target” cells differ from all other cells in the respect that they
express receptors for that hormone.
The information delivered to the target cell is present in
the structure and three-dimensional conformation of the hormone and is
sufficient only to activate the receptor.
It appears that
activation of one particular receptor is an all-or-none phenomenon, with
gradations in response resulting from gradations in the numbers of receptors
that are activated in each cell.
The receptor, by
virtue of the biochemical changes it triggers in transducing the signal,
initiates a particular biochemical change or group of changes. The signals
generated in the target cell are determined by the signal-transducing component
of the receptor.
In many cases, there is more than a single class of
receptors for a particular hormone, and each class usually activates a
different biochemical pathway.
The nature of the final response elicited in a target cell is
not determined by the intracellular signal generated by the receptor but, rather,
by the effective machinery expressed in the cell as a consequence of its differentiated
state
For example,
Receptors for the parathyroid hormone are present in the
basal membranes of cells of both the proximal and distal portions of the
nephron . Binding of the hormone initiates the same signaling cascade in both
cell types,but the proximal tubules respond by decreasing phosphate
reabsorption from the glomerular filtrate and increasing hydroxylation of
vitamin D, while the distal cells respond by increasing reabsorption of calcium
CONCEPTS RELATED TO TARGET CELL RESPONSIVENESS
Responsiveness of target cells to stimulation by their hormones
is not constant but may vary widely in different physiological states and is
often adjusted by the actions of other hormones or local paracrine or autocrine
agents as well as the primary hormone
Factors that govern the magnitude of
the response to a hormone.
1) Concentration of the hormone
which in turn is determined by
a) The
rate of hormone secretion
b) The
rate of delivery by the circulation to the target cell surface, which is slower
if the hormone circulates bound to plasma proteins than if it is unbound
c) The
rate at which the hormone is degraded or excreted
2) Number of
competent target cells that express functional receptors
3) The sensitivity of
each target cell to hormonal stimulation is not constant and depends on
a) The
number of functional receptors that are expressed
b) The
affinity of the receptor for the hormone
c) The
status of postreceptor amplification mechanisms
d) The
status and abundance of effector molecules
The sensitivity to a hormone of target organ is often
defined as the concentration needed to produce a half-maximal response
Target
organ sensitivity is not constant and is often adjusted in accordance with
physiological circumstances.
Can be done by:
a) Changing
the number of receptors expressed.
b) On
the cellular level, upregulation or downregulation of effector molecules such
as enzymes, ion channels
c) On
the tissue/organ level aggregate of the contributions of all of the respond-ing
cells, so that the magnitude of the response to a particular concentration of
hormone is a function of the number of available cells as well as the competence
of each cell.
Factors
that govern the duration of the response to a hormone.
1) The duration of hormone availability, which
is determined by
a) The
duration of secretion
b) The
rate of hormone clearance from the blood, usually described as its half-life
2) Whether the response results from
a) A
rapidly reversible covalent change, i.e., phosphorylation or dephosphorylation
of key enzyme
b) Or
genomic events involving synthesis of proteins and the half-lives of the
proteins
