cortisol control loop

bnhpct · June 14, 2004, 3:37am

[From Bruce Nevin (2004.06.13 23:37 EDT)]
I have been reading Principles of Biological Control by David
Horrobin (1970), a copy of which Marc kindly sent me.

On p. 7 is a diagram of the unusual relationship between the hypothalamus
and the anterior pituitary. An artery entering the hypothalamus
subdivides into a network of capillaries. These then reunite into a
single blood vessel, termed the pituitary stalk vessel, which travels to
the anterior pituitary. There it subdivides again into a network of
capillaries, which again rejoin into a single blood vessel, which leads
blood thence to a vein.

The posterior pituitary secretes hormones that act directly on major
effector organs. An example is Adrenocorticotrophic hormone (ACTH), which
controls the output of cortisol from the adrenal gland.

The diagram of this relationship which appears on p. 19 is recreated
below.

The adrenal cortex secretes cortisol (hydrocortisone) into the blood
stream. The hypothalamus senses the level of cortisol in the blood
passing through its capillary net and compares it with a reference value
for blood level of cortisol. This is part of the nervous system. As part
of the endocrine system, the hypothalamus secretes Cortotrophin Releasing
Factor (CRF) into the blood travelling down the pituitary stalk to the
anterior pituitary. There, the level of CRF in the blood determines the
rate at which the anterior pituitary produces ACTH. I do not know how
direct or complex the path of blood from the anterior pituitary to the
adrenal cortex may be, but it is decidedly farther. The level of ACTH in
the blood when it reaches the adrenal cortex determines the rate at which
that organ produces cortisol, closing the loop (through the open flow of
the blood stream) to the hypothalamus.

During that return journey, cortisol does a number of things which in
turn affect the level in the blood stream. Cortisol stimulates production
of glycogen in the liver while decreasing the rate at which cells utilize
glucose. It causes all body cells to reduce their reserves of protein,
except for cells of the liver and the gastrointestinal tract. It makes
fatty acids available for metabolic use.

One thing that is unclear to me is whether the pituitary and adrenal
cortex function as control systems or as effectors in this loop. The
hypothalamus is clearly a control system that outputs CRF into its
environment as means of controlling its perception of cortisol in its
environment. Its proximal environment is the blood stream within its
capillary net, but beyond that its environment includes the complete
blood stream and the pituitary and the adrenal cortex through which the
blood also flows. Beyond that, it includes the organs and cells affected
by the level of cortisol in the ways summarized above. Beyond that, it
includes the environment in which the organism as a whole is controlling
its perceptual input, as its control activities affect the level of (and
need for) glycogen, etc.

It appears that the anterior pituitary is simply a kind of chemical
transponder, producing ACTH in quantities chemically determined by the
quantity of CRF entering it. If it were a control system with the level
of CRF as its reference and the level of ACTH as its output, what is its
perceptual input? CRF cannot be both perceptual input and reference
input. Similarly for the adrenal cortex with respect to ACTH and
cortisol.

But I could be wrong. All of these organs are doing many things
simultaneously, so to refer to the hypothalamus as a control system
controlling cortisol level by means of CRF level is a simplification;
that is one of its functions, one control system of many within it, and
the pituitary and the adrenal cortex are likewise complex in function. So
the appearance of simplicity in the above loop may be due to
oversimplification and may yet turn out to be an interrelationship of
control systems. As it is, it appears to be one control system (the
hypothalamus) acting either through a chain of effectors or through a
chain of predictably affected systems in its environment. It is not at
all clear to me how you distinguish these interpretations, much less
decide which is correct, or indeed if some other interpretation is
correct, such as interconnected control systems.

    /Bruce

Nevin

At the date of writing this (1970), Horrobin was able to say that most of
the endocrine system was under neurological control in the manner
exemplified above, and that the few exceptions were suspected to be under
as yet undetermined neurological control.

Bill_Powers1 · June 14, 2004, 1:48pm

[From Bill Powers (2004.06.14.0730 MDT)]

Bruce Nevin (2004.06.13 23:37 EDT) --

The adrenal cortex secretes cortisol (hydrocortisone) into the blood
stream. The hypothalamus senses the level of cortisol in the blood passing
through its capillary net and compares it with a reference value for blood
level of cortisol.

I'm surprised by seeing the "cortisol" feedback arrow drawn so it goes
directly into the hypothalamus. In most of the pituitary systems I have
heard of, the feedback signals go into the pituitary, so the signals
entering from the hypothalamus function as reference signals, with the
comparator then being in the pituitary. This is how the thyroxin control
system works.

As the figure is drawn, it suggests that there is a higher-order loop
involving the hypothalamus. I seem to recall that the cortisol itself has a
negative feedback effect on the pituitary, so it is the controlled variable
of a pituitary loop. This would not preclude cortisol from also
contributing to a perception in the hypothalamus as part of a higher-order
loop; we would then expect that loop to produce outputs setting reference
levels for several of the loops involving the pituitary.

This is part of the nervous system. As part of the endocrine system, the
hypothalamus secretes Cortotrophin Releasing Factor (CRF) into the blood
travelling down the pituitary stalk to the anterior pituitary. There, the
level of CRF in the blood determines the rate at which the anterior
pituitary produces ACTH. I do not know how direct or complex the path of
blood from the anterior pituitary to the adrenal cortex may be, but it is
decidedly farther. The level of ACTH in the blood when it reaches the
adrenal cortex determines the rate at which that organ produces cortisol,
closing the loop (through the open flow of the blood stream) to the
hypothalamus.

Yes, that is how I have understood it, with the exception of the feedback
effects directly on the pituitary omitted from this description. I recall
reading somewhere that _every_ output of the pituitary feeds back via the
bloodstream to inhibit production of that same output product, which is all
we need to establish the presence of a negative feedback loop. Perhaps
cortisol is an exception to this generalization, although perhaps there is
a lower-order pathway that was simply omitted, or overlooked.

At the date of writing this (1970), Horrobin was able to say that most of
the endocrine system was under neurological control in the manner
exemplified above, and that the few exceptions were suspected to be under
as yet undetermined neurological control.

Yes, that has been my understanding as well. I was never confident enough
of my grasp of biochemistry to include these matters in B:CP, but they are,
implicitly at least, part of my theory of emotion. The pathway from
hypothalamus to pituitary is part of the "preparation for action" branch of
the emotion model.

Best,

Bill P.

bnhpct · June 14, 2004, 3:38pm

[From Bruce Nevin (2004.06.14 11:38 EDT)]

Bill Powers (2004.06.14.0730 MDT) –

In most of the pituitary systems I have

heard of, the feedback signals go into the pituitary, so the
signals

entering from the hypothalamus function as reference signals, with
the

comparator then being in the pituitary. This is how the thyroxin
control

system works.

Is it possible that this is a simplification, talking of direct influence
rather than influence mediated by releasing factors that travel down the
pituitary stalk? If not these releasing factors, what inputs determine
rate of release of hormones by the pituitary? Is the pituitary directly
under neural control?
Horrobin is unequivocal:
It is now known that the nerve cells of the hypothalamus secrete into the
blood capillaries substances known as releasing factors. There seems to
be a separate releasing factor for each of the anterior pituitary
hormones. These releasing factors travel in the blood down the
[pituitary] stalk and then escape from the capillaries in the anterior
pituitary. There they control the output of the pituitary hormones. …
Most of the endocrine glands are therefore not independent of the nervous
system. The output of their hormones is ultimately determined by the
behaviour of control centres in the brain. As yet a few endocrine glands,
notably the parathyroids which control the level of blood calcium, seem
to be independent of the nervous system. A final decision as to whether
they are truly entirely free of its influence must await further
research. (Principles of Biological Control, pp. 7-8)

The pathway from

hypothalamus to pituitary is part of the “preparation for
action” branch of

the emotion model.

The pituitary stalk seems to me an extraordinary structure – a blood
vessel connecting the capillary net in the hypothalamus to the capillary
net a very short distance away in the anterior pituitary. Are you saying
that chemicals produced by the hypothalamus are only one factor among
several that compose the reference signals for release of hormones by the
pituitary? That they merely jigger the release rate (and the level in the
blood) for the sake of “preparation for action”?

It is either true or not that releasing factors travel secreted by nerve
cells in the hypothalamus travel down the pituitary stalk and determine
the rate of release of every pituitary hormone. Horrobin might be wrong.
After all, he was writing at the same time you were writing B:CP, and I
assume you are referring to more recent findings.

    /Bruce

Nevin

···

At 07:48 AM 6/14/2004 -0600, Bill Powers wrote:

Bill_Powers1 · June 14, 2004, 7:20pm

[From Bill Powers (2004.06.14.1240 MDT)]

Bruce Nevin (2004.06.14 11:38 EDT) –

In
most of the pituitary systems I have

heard of, the feedback signals go into the pituitary, so the
signals

entering from the hypothalamus function as reference signals, with
the

comparator then being in the pituitary. This is how the thyroxin
control

system works.

Is it possible that this is a simplification, talking of direct influence
rather than influence mediated by releasing factors that travel down the
pituitary stalk?

I don’t know about the system involving cortisone, but the thyroxin
control system works as I’ve described. The pituitary generates TSH, or
Thyroid-Stimulating Hormone, which travels to the thyroid gland via the
bloodstream where it causes the release of thyroxin. The thyroxin enters
the pituitary via the bloodstream, whnere it strongly inhibits the rate
of production of TSH. So TSH is the error signal and thyroxin is the
controlled variable.

The reference signal is in the “partly-neural, partly chemical”
path you mention that descends from the hypothalamus ( as I’ve seen it
described); I don’t recall the name of the substance, but its action is
to increase the rate of release of TSH. At the same place it acts, the
thyroxin (or maybe some messenger molecule produced by it) inhibits the
release of TSH, so the rate of release of TSH depends positively on the
signal from the hypothalamus and negatively on the concentration of
thyroxin: that’s all we need in order to say there is a comparator
function in the pituitary. The difference between excitation and feedback
inhibition is what drives TSH output.

If not these releasing
factors, what inputs determine rate of release of hormones by the
pituitary? Is the pituitary directly under neural control?

The releasing factors are probably the output signals of control systems
in the hypothalamus, and for at least some components of the endocrine
system they serve as reference signals for control systems in the
pituitary. That interpretation fits all that I have read about the
endocrine system.

Horrobin is unequivocal:

It is now known that the nerve cells of the hypothalamus secrete into the
blood capillaries substances known as releasing factors. There seems to
be a separate releasing factor for each of the anterior pituitary
hormones. These releasing factors travel in the blood down the
[pituitary] stalk and then escape from the capillaries in the anterior
pituitary. There they control the output of the pituitary hormones.
…

I would guess that this is in part a misinterpretation. My fairly strong
impression is that the difference between the releasing-factor
concentration and the concentration of the relevant output substance is
what drives the output. Of course if you trace only the path from the
hypothalamus to the output of the pituitary, you don’t pick up on the
inhibitory feedback signal that intervenes. This would be like tracing
the path from the reference signal in our standard diagram, through a
combined comparator and output function to the output signal, a pathway
that certain exists but is not the whole story.

Most of the endocrine glands are
therefore not independent of the nervous system. The output of their
hormones is ultimately determined by the behaviour of control centres in
the brain. As yet a few endocrine glands, notably the parathyroids which
control the level of blood calcium, seem to be independent of the nervous
system. A final decision as to whether they are truly entirely free of
its influence must await further research. (Principles of Biological
Control, pp. 7-8)

This is quite in line with what I learned at about the same time
Horrobin’s book was written. This is why I have proposed a biochemical
hierarchy that branches off from the behavioral hierarchy at about the
level of the thalamus. I’m not 100% confident of my impression that EVERY
output of the pituitary feeds back negatively through the bloodstream to
the pituitary, creating a negative feedback loop with its comparator
inside the pituitary. I know this is true for some of the
products.

The
pathway from

hypothalamus to pituitary is part of the “preparation for
action” branch of

the emotion model.

The pituitary stalk seems to me an extraordinary structure – a blood
vessel connecting the capillary net in the hypothalamus to the capillary
net a very short distance away in the anterior pituitary. Are you saying
that chemicals produced by the hypothalamus are only one factor among
several that compose the reference signals for release of hormones by the
pituitary?

No, I’m proposing that they are reference signals for control systems
inside the pituitary, where the pituitary contains sensors, comparators,
and output functions for each product.

That they merely jigger the
release rate (and the level in the blood) for the sake of
“preparation for action”?

Not that. The effect of adjusting the reference signals entering the
pituitary is adjust the levels of hormonal outputs, and thus to prepare
the biophysical system for a different state of activity, higher or lower
as the case may be. That’s my proposal, anyway. It’s like the engineer of
a steam locomotive signalling the fireman to throw more coal into the
firebox as the train approaches an upgrade and the throttle is being
opened wider – and to slow down the feed of coal on the
downgrade.

It is either true or not that
releasing factors travel secreted by nerve cells in the hypothalamus
travel down the pituitary stalk and determine the rate of release of
every pituitary hormone.

I think “affect” is more appropriate than
“determine,” but I agree with this description as far as it
goes. What’s left out is that every pituitary hormone, again within the
limits of my memory, has a strong negative feedback effect on the
pituitary, tending to shut down its own production. This is true, I
believe, of the chemical products of every organ in the body. I would
consider this strong evidence of a set of control systems within the
pituitary, and of several levels of biochemical control
systems.

Horrobin might be wrong.
After all, he was writing at the same time you were writing B:CP, and I
assume you are referring to more recent findings.

No, I wrote that editor-excised chapter on emotion at about the same time
Horrobin was writing his book, and probably read some of the same
sources. I don’t think he was wrong; he probably read the same things I
read about the negative feedback effects of hormones on the pituitary,
but didn’t recognize them as significant.

It would be good to have a review article on the modern state of
knowledge in this field, by someone who understands control theory. I
notice that doctors stopped recommending thyroid pills some time ago, on
the basis that their main effect was to cause atrophy of the thyroid
gland without materially raising the circulating throxine level (I can’t
decide between thyroxine and thyroxin).

Best,

Bill P.

Marc_Abrams1 · June 14, 2004, 8:38pm

From [Marc Abrams
(2004.06.14.1623)]

Bruce, I told you some of things from
Horrobin were dated. Much water has passed under the bridge.

If you really have some interest in this
area I would strongly recommend the following for starters.

Rethinking
Homeostasis: Allostatic Regulation in Physiology and Pathophysiology
, 2003, MIT Press, Jay Schulkin

The work of A.D.’Bud’ Craig.
I have a couple of his research papers that are extremely interesting. Let me
know if you have any interest.

Marc

Considering how often throughout history even intelligent
people have been proved to be wrong, it is amazing that there are still people
who are convinced that the only reason anyone could possibly say something
different from what they believe is stupidity or dishonesty.

Being smart is what keeps some people from being intelligent.

Thomas Sowell

Don’t argue with an idiot; people watching may not be able to
tell the difference.

Anon

I don’t
approve of political jokes. I’ve seen too many of them get elected

Anon

···

Bill_Powers1 · June 14, 2004, 9:14pm

[From Bill Powersn (2004.06.14.1503 MDT)]

Bruce Nevin (2004.06.14 11:38 EDT)

Try this URL for an online book about the endocrine system.

http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/index.html

Following links to “Hypothalamus and Pituitary Gland” and
“Thyroide Stimulating Hormone” we find this diagram, described
as a “classical negative feedback loop.”

This is just as I remember it except for the second negative feedback
link up to the hypothalamus, which suggests the possibility of two levels
of control.

The web page implies that there are similar discussions of many hormone
control systems organized the same way. I haven’t followed them through
– maybe you could do that. I’m somewhat relieved to find that not much
has changed since the late 60s and early 70s when I was learning about
these things. Good to see negative feedback being given a semi-official
mention.

Best,

Bill P.

Marc_Abrams1 · June 15, 2004, 3:19am

From [Marc Abrams (2004.06.14.2304)]

Nice find Bill. Now all you have to do is
actually read the site. I took the liberty of copying a part of it. Did you notice
the ‘positive’ feedback? I italicized it, underlined it and put it
in bold just so you don’t miss it a second time.

**Control

of Endocrine Activity**

···

The physiologic effects of hormones depend largely on their
concentration in blood and extracellular fluid. Almost
inevitably, disease results when hormone concentrations are either too high or
too low, and precise control over circulating concentrations of hormones is
therefore crucial.

The concentration of hormone as seen by target cells is
determined by three factors:

Rate of production:
Synthesis and secretion of hormones are the most highly regulated aspect
of endocrine control. Such control is mediated by positive and
negative feedback circuits, as described below in more detail.

None-the-
less, it’s wonderful to see you doing some ‘research’ Bill,
but Bruce, I still maintain the two cites I gave you would provide a very nice foundation
for any exploring you might want to do in this area.

You
might also have noticed that the site was last updated in 2001. It’s a wonderful site and again, much kudo’s
to Bill for bringing it to our attention. Every PCT’er should take this
stuff very seriously. It is the
basis for our emotional system and understanding how and why it works is an essential
part of understanding human behavior.

Marc

Considering how often throughout history even intelligent
people have been proved to be wrong, it is amazing that there are still people
who are convinced that the only reason anyone could possibly say something
different from what they believe is stupidity or dishonesty.

Being smart is what keeps some people from being intelligent.

Thomas Sowell

Don’t argue with an idiot; people watching may not be able to
tell the difference.

Anon

I don’t
approve of political jokes. I’ve seen too many of them get elected

Anon

BJORN_SIMONSEN · June 15, 2004, 11:48am

[From Bjorn Simonsen (2004.06.15,13:45 EuST)]

From [Marc Abrams (2004.06.14.2304)]

Nice find Bill. Now all you
have to do is actually read the site. I took

the liberty of copying a part of it. Did you notice the ‘positive’ feedback?

I italicized it, underlined it and put it in bold just so you don’t miss it
a second time.

Then you
copied:

```
        **     Rate of
```
production:** Synthesis and secretion of hormones are the most highly re-
gulated aspect of endocrine control. Such control is mediated by positive and
negative
```
 feedback circuits, as described below in more detail.
```

Why didn’t you
copy the next section?

Feedback circuits
are at the root of most control mechanisms in physiology, and
are particularly prominent in the endocrine system. Instances of positive

feedback certainly occur, but negative feedback is much more common.

Instances of positive feedback certainly occur, ……

I know just about one cited example and that is oxytocin
during childbirth. May you help me
with other examples?

bjorn

Marc_Abrams1 · June 15, 2004, 12:12pm

From [Marc Abrams (2004.06.15.0755)]

[From Bjorn Simonsen (2004.06.15,13:45 EuST)]

Why
didn’t you copy the next section?

Because my point was and is that
positive feedback or ‘feedforward’ processes play a role in ‘regulating’
our endocrine system. It was not my intention to discredit negative feedback. It
seems the devil is always in the details.

Instances of positive feedback
certainly occur, ……

I know just about one cited example
and that is oxytocin during childbirth. May you help me with other examples?

This is why I provided
the references I did.

Angiotensin-II, which
is largely responsible for water and sodium cravings. There are many others.

The key here is that
these feedforward systems are nested in larger regulatory or feedback loops.

Again, I refer you to
Rethinking Homeostasis, 2003. MIT
Press, Jay Schulkin, for an excellent treatment of this subject.

Marc

Considering how often throughout history even intelligent
people have been proved to be wrong, it is amazing that there are still people
who are convinced that the only reason anyone could possibly say something
different from what they believe is stupidity or dishonesty.

Being smart is what keeps some people from being intelligent.

Thomas Sowell

Don’t argue with an idiot; people watching may not be able to
tell the difference.

Anon

I don’t
approve of political jokes. I’ve seen too many of them get elected

Anon

···

Marc_Abrams1 · June 15, 2004, 3:03pm

From [Marc Abrams (2004.06.15.1000)]

[From Bjorn Simonsen (2004.06.15,13:45 EuST)]

Bjorn, if positive feedback is in
fact a reality physiologically, than the possibility of it being present in PCT
becomes real.

Things like ‘anger’, ‘stress’,
and ‘frustration’, seem to act, at times this way before being
brought back into line. Positive feedback can never exist in an infinite state.
So, if positive feedback does in fact exist, it must exist within a larger negative feedback system. Of course,
something like cancer provides the other side of positive feedback, unchecked
growth and the eventual implosion of the system.

The book by Schulkin, introduces a
new term, ‘Allostatic regulation’. This represents a new notion and
concept (not to PCTer’s) of variable reference levels being set by
positive feedback processes for the larger physiological negative feedback systems.
The term ‘homeostasis’ always had fixed ‘set points’
(reference levels) associated with the systems and they have found that this is
simply not true.

Marc

Considering how often throughout history even intelligent
people have been proved to be wrong, it is amazing that there are still people
who are convinced that the only reason anyone could possibly say something
different from what they believe is stupidity or dishonesty.

Being smart is what keeps some people from being intelligent.

Thomas Sowell

Don’t argue with an idiot; people watching may not be able to
tell the difference.

Anon

I don’t
approve of political jokes. I’ve seen too many of them get elected

Anon

···

bnhpct · June 15, 2004, 6:10pm

[From Bruce Nevin (2004.06.15 14:02)]

Marc Abrams (2004.06.15.1000) --

In Bruce Nevin (2004.04.19 12:49 EDT) I described a positive feedback loop
in which body sensations and associative memory escalate until they obtrude
on awareness as a feeling or emotion. That description was based on
subjective observation. These mechanisms that you mention perhaps provide a
more elegant account that is based on physiology and anatomy.

A major project just heated up fast. I have a reply to something else near
completion, but other than that will be less communicative for a while again.

/Bruce Nevin