Principles Of Feedback Control
Clinical scenario
Glucocorticoid therapy is widely used to treat a variety of chronic
inflammatory disorders. Mrs A.A. is a 69-year-old lady with long-standing
rheumatoid arthritis. For the last 5 years she has taken oral prednisolone in a
dose of 10 mg daily. She has developed some thinning of the skin and bruises
easily, features which her doctor tells her are side-effects of the treatment. She
knows that if she develops a minor illness she should increase the dose of her
prednisolone for a couple of days and she carries a steroid card with her at
all times (Fig. 7a). She also knows that if she starts vomiting for any reason
she needs to seek urgent medical attention.
In the normal state, glucocorticoids are released in response to stress,
such as illness. Therapeutic doses of glucocorticoids inhibit the normal
hypothalamo pituitary adrenal feedback axis so that this stress response cannot
occur. A patient such as Mrs A.A. relies entirely upon her fixed daily dose of
prednisolone to supply her glucocorticoid requirements. If she develops a minor
illness she needs to increase the dose of the tablets and if she is vomiting,
needs to seek medical help so that glucocorticoids can be given intravenously.
In the event that she stops taking glucocorticoids, she has to taper off the
treatment gradually so as to allow the suppressed hypothalamo pituitary adrenal
axis to recover normal function.
Homeostasis
Living systems possess their own internal environment, which has to
survive within an external environment. Survival involves the maintenance of a
fluid and salt balance, a tight control over temperature in the case of
homoeotherms, and also over the regulation of chemical availability and
utilization within the cell. Poikilotherms, for example some reptiles, whose
temperature is set by the external environment, are more dependent on their
external environment for maintenance of an adequate metabolism.
Internal control is achieved through integration of the different
systems: neural, biochemical and physical. In all cases, the fundamental
components of these systems are: (i) signals; (ii) transducers; (iii) sensors;
and (iv) responders. The signals may be electrical impulses, or
chemicals such as neurotransmitters, hormones or antigens. The transducers are
poorly understood coupling systems which transform one form of energy into
another, for example the conversion of an electrical impulse into a quantum of
chemical neurotransmitter. Sensors are almost always receptors or
enzymes or combined receptor– enzyme systems, which recognize specifically the
signals which bind them. Transducers then convert the binding reaction into
another electrical or chemical response. Responders are the apparatus of
the cell that produce the final response, for example release or inhibition of
hormone or neurotransmitter release, vasodilation, vasoconstriction or changes
in heart rate.
Integration of endocrine systems is achieved through a complex interplay
of regulatory feedback mechanisms operated through both hormonal and neural
communication networks. The most important mechanisms are those commonly called
feedback, whereby systems limit each other’s activity around a preset
oscillator.
For example system 1 (Fig. 7b) releases a hormone, hormone 1, which
causes system 2, another gland, to release another hormone, hormone 2, which
travels in the bloodstream. It is sensed by system l, which somehow compares
the concentration of the hormone with a comparator, and responds by altering
the output of hormone 1. If system 1 responds by reducing the output of hormone
1, this is called a negative-feedback system. An example is the effect
of thyroid hormone (hormone 2) from the thyroid gland (system 2), in reducing
the output of thyroid- stimulating hormone (TSH; hormone 1) from the anterior
pituitary gland (system 1; see Chapter 14).
If system 1 responds by increasing the output of hormone 1, this is
called a positive-feedback system. An example is the effect of estrogen
(hormone 2) from the ovary (system 2) on the release of luteinizing hormone
(LH; hormone 1) from the anterior pituitary gland (system 1) just before
ovulation (see Chapter 25).
In endocrinology, the brain–pituitary–target gland axes provide examples
of feedback mechanisms in action (Fig. 7c). For virtually every anterior
pituitary hormone, a corresponding hypothalamic releasing hormone has been
discovered, and in some cases a corresponding inhibitory hypothalamic hormone
has been found (Fig. 7d).
Feedback systems may involve more than two hormones, for example the
control of thyroid hormone secretion. The brain releases thyrotrophin-releasing
hormone, which travels down the portal blood system to the anterior pituitary
thyrotroph cell, where it stimulates the release of TSH. TSH travels in the
blood- stream to the thyroid gland, where it stimulates the release of T3 and T4.
T3 in turn inhibits TRH and TSH release. It will be readily apparent that this
sort of system provides a means of testing the proper functioning of the
feedback systems in health and disease. One hypothalamic releasing hormone may
release more than one anterior pituitary hormone. Gonadotrophin-releasing
hormone (GnRH), releases both LH and FSH, which control gonadal
steroidogenesis, ovarian follicular growth and ovulation in females and
spermatogenesis in males.
Understanding basic feedback mechanisms is vital in clinical
endocrinology where it forms the basis of diagnostic testing. For example the
adrenal gland may develop a tumour which releases large amounts of cortisol.
This feeds back to the brain and anterior pituitary gland suppressing the
release of ACTH. In this case elevated serum cortisol levels in the presence of
undetectable ACTH points to the adrenal as the source of the cortisol excess.
If the diagnosis is a pituitary tumour secreting ACTH and
therefore excess glucocorticoids, serum
cortisol concentrations will be elevated in the presence of an inappropriately
elevated ACTH concentration. Relatively large doses of glucocorticoids, for
example prednisolone, prescribed for the patients with inflammatory or malignant
diseases will also suppress the hypothalamo pituitary adrenal axis such that
the patient switches off their endogenous cortisol production (see Clinical
scenario; Fig. 7e). Ignorance of this feedback mechanism is potentially
dangerous for the patient, whose stress response system is completely suppressed
while on glucocorticoid therapy. This must be withdrawn gradually to allow the system to restore normal cortisol
secretion.
