section 30.4
Mechanism of Hormone Action
~ 0.71 /zM, with a cortisol binding capacity of 250 /zg/L
(mean cortisol levels (~ 100 /zg/L); while the plasma
TeBG concentration is ~25 nM in men and ~40 nM in
women (mean testosterone levels in adult men is ~ 22 nM).
An increase in steroid hormone production will result in
an increase in the fraction of the hormone bound by the
protein until all of the sites on the protein are saturated
(i.e., maximal binding capacity); any increase in hormone
production beyond this will result in a pathological situa-
tion of hormone excess because the cells will be exposed to
supraphysiological levels of albumin-bound and unbound
hormone. The concentrations of CBG and TeBG in plasma
have important influences on both the production and bio-
effectiveness of steroid hormones; thus, factors that affect
the plasma levels of these binding proteins will indirectly
affect the physiology of the steroid hormones they bind.
Serum albumin is a quantitatively important binder of
hydrophobic molecules that makes possible the transport
of these otherwise insoluble molecules in blood; how-
ever, it binds very loosely, and this enables the molecules
(ligands) to dissociate very rapidly. This means that the
albumin-bound fraction serves primarily to solubilize
the steroid in plasma and does not oppose tissue uptake
of the steroid. For this reason,
the albumin-bound fraction
should be regarded as being functionally “
plasma steroid hormones can be viewed as existing in
only two fractions: those that are bound to specific binding
protein and those that are not (albumin-bound + unbound).
For the sake of simplicity, when dealing with specific
steroid hormones, the fractions will be designated relative
to the specific binding protein only; for example, when
dealing with testosterone, the two plasma fractions will be
designated “TeBG-bound” and “non-TeBG-bound.” Like-
wise, plasma cortisol fractions will be referred to as “CBG-
bound” and “non-CBG-bound.”
Although the unbound form of steroid hormones is the
“active” form, it is also the form that is more susceptible to
rapid metabolism. The major site of steroid metabolism is
the liver, which inactivates steroids by conjugation and by
structural modification. Hepatic A4-hydrogenase reduces
the double bond at positions 4 and 5; 17-HSD oxidizes
the hydroxyl group at position 17, thereby forming 17-
ketosteroids; 3a-hydroxysteroid dehydrogenase reduces
the 3-keto to a 3a-hydroxy group. The efficacy of this
liver function explains why steroid hormones are ineffec-
tive when taken by mouth: they are transported via the
hepatic portal system to the liver, where they are promptly
metabolized. Minor modifications in the steroid structure,
however, can render the hormone more resistant to liver
inactivation and, hence, orally active. For example, the in-
troduction of a double bond at position
of cortisol yields
prednisolone, of a 17a-ethinyl group in estradiol gives
ethinyl estradiol, and of a 17a-ethinyl group and removal
of the 19-carbon in testosterone yields the orally active
progestin, norethindrone.
The eicosanoids are discussed in Chapter 18.
30.4 Mechanism of Hormone Action
A target cell is equipped with specific receptors that en-
able it to recognize and bind a hormone selectively and
preferentially. Usually there is one type of receptor for a
hormone, but in some cases more than one type of receptor
may exist. For example, oq-,
and /U-adrcnergic
receptors are available for catecholamines. The number of
receptors for a given hormone in a given cell varies from
1 0 , 0 0 0
to more than
1 0 0
0 0 0
Hormone recognition (and binding) by a receptor initi-
ates a chain of intracellular events that ultimately lead to
the effect of the hormone. Binding can be described as a
lock-and-key interaction, with the hormone serving as the
key and the receptor as the lock. The structural attributes
of a hormone allow it to bind to its receptor and to unlock
the expression of receptor function. The receptor, which
frequently is a hormone-dependent regulatory protein, is
functionally coupled to key enzyme systems in the cell,
such that hormone binding initiates a receptor-mediated
activation of enzymatic reactions, or it is functionally cou-
pled to a region on chromatin, such that hormone binding
initiates expression of one or more structural genes. Stated
in another way, a hormone-responsive cell is programmed
to carry out certain functions when a sensor (receptor)
receives the appropriate signal (hormone).
In general, the number of receptors for a hormone deter-
mines how well the cell responds to that hormone. Several
factors influence the number of receptors in a cell.
1. The genotype of the cell determines whether the cell
is capable of receptor synthesis and, if so, how much
and of what type. (Some endocrinopathies involve
receptor deficiency or a defect in receptor function.)
2. The stage of cellular development.
3. Hormones themselves are important regulators of the
number of receptors in a cell; this regulation may be
homologous or heterologous.
Homologous regulation occurs when a hormone affects
the number of its own receptors. “Downregulation” (de-
crease in receptor number) is seen when a target cell is ex-
posed to chronically elevated levels of a hormone. Down-
regulation involves a decrease in receptor synthesis and
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