Clinical tests in endocrinology based on the negative feedback

191) Clinical tests in endocrinology based on the negative
feedback control of hormone secretion?
The endocrine system is one of the body’s two major control systems, the other being
the nervous system.
The endocrine system through secreting hormones regulates the control and integration
in responses to stress and injury, growth and development, absorption of nutrients,
energy metabolism, water and electrolyte balance, reproduction, birth, and lactation.
To keep peripheral hormonal levels and endocrine function normal, the system uses
integrated feedback controls: positive feedback system and more commonly negative
feedback system.
Positive feedback system
Positive feedback is a mechanism in which the output
is enhanced. This mechanisms are designed to push levels
out of normal ranges, not maintaining stable levels.
For example by the hormone oxytocin, which
stimulates and enhances parturition contractions.
As the baby moves through the birth canal,
Pressure receptors within the cervix send
messages to the brain to produce oxytocin.
Oxytocin travels to the uterus through the
bloodstream, stimulating the muscles in the
uterine wall to contract, which in turn increase
the intensity contractions until the baby is out the birth canal.
Negative feedback system
Negative feedback is a mechanism in which the output of a pathway inhibits inputs to
the pathway, reaching homeostasis, that is the maintenance of hormone levels within
appropriate physiological range.
Hypothalamic-pituitary- Adrenocortical axis
Corticotropin-releasing hormone (CRH) is secreted
in the hypothalamus in response to circadian rhythm,
stress and other stimuli. CRH travels down the portal
system to stimulate ACTH release from the anterior
pituitary. Circulating ACTH stimulates cortisol production
in the adrenal gland. The cortisol secreted (or any other
synthetic corticosteroid administered to the patient) causes
negative feedback on the hypothalamus and pituitary to
inhibit further CRH/ACTH release. An important place
to consider negative feedback inhibition is in evaluating
disorders of hypersecretion or hyposecretion of cortisol .
Cushing's syndrome is the name given to hypersecretion of cortisol (or
In primary hypercortisolism, Cushing's syndrome is due to a tumor in the adrenal
cortex, increased negative feedback inhibition has the effect of decreasing secretion of
tropic hormones. Therefore, the level of ACTH will be low.
Alternatively, Cushing's syndrome might result because of hypersecretion of ACTH,
secondary hypercortisolism. Which is caused by a pituitary adenoma (a pituitary
tumor). Cushing's syndrome caused by a pituitary adenoma is known as Cushing's
disease. In Cushing's disease, both ACTH and cortisol levels will be high.
Tests to confirm Cushing's syndrome
Dexamethasone suppression tests
Administration of a synthetic glucocorticoid to a normal subject produces prompt
feedback suppression of CRH and ACTH levels and thus of endogenous cortisol
secretion. Patients with Cushing's syndrome fail to show complete suppression of
plasma cortisol levels.
-24-hour urinary free cortisol measurements. This is simple, but less reliable.
 Disease
Cushing's disease (pituitary tumor)
Adrenal tumor
Hyposecretion of cortisol is known as adrenal insufficiency.
Primary adrenal insufficiency is the disorder originating in the adrenal gland. In
primary adrenal insufficiency, there is a release of the pituitary from negative feedback
inhibition, and consequently, ACTH levels are high. If there is generalized damage to
the adrenal cortex, there will also be hyposecretion of aldosterone. Adrenal
insufficiency involving hyposecretion of both cortisol and aldosterone is known as
Addison's disease.
Secondary adrenal insufficiency (or hypopituitary adrenal insufficiency) describes
the situation where abnormally low ACTH levels lead to hyposecretion of cortisol. This
can occur after the end of high dose glucocorticoid therapy to treat inflammation and
autoimmune diseases.
Clinical tests if Addison's disease is suspected
-Single cortisol measurements are of little value, although a random cortisol below
100 nmol/L during the day is highly suggestive.
- Synthetic ACTH stimulation tests Tetracosactid, is given to stimulate adrenal
cortisol production.
-A 0900 h plasma ACTH level, when high level (> 80 ng/L) with low or low-normal
cortisol confirms primary hypoadrenalism.
-Serum aldosterone is reduced with high plasma renin activity.
 Disease
Addison's disease (adrenal damage)
Parathyroid Hormone negative feedback regulation
If calcium decreases, the parathyroid glands sense the decrease and secrete more
parathyroid hormone. The parathyroid hormone stimulates calcium release from the
bones and increases the calcium uptake into the bloodstream from the collecting tubules
in the kidneys. Conversely, if blood calcium increases too much, the parathyroid glands
reduce parathyroid hormone production. Both responses are examples of negative
feedback because in both cases the effects are opposite to the stimulus.
Clinical tests for hyperparathyroidsm
Several fasting serum calcium and phosphate samples should be performed.
Serum PTH. Primary hyperparathyroidism shows hypercalcaemia and
hypophosphataemia with detectable or elevated intact PTH levels during
There is often a mild hyperchloraemic acidosis.
Renal function is usually normal but should be measured as a baseline.
Hydrocortisone suppression test: hydrocortisone 40 mg three times daily for 10
days leads to suppression of plasma calcium in sarcoidosis, vitamin D-mediated
hypercalcaemia and some malignancies.
Primary hyperparathyroidism appears due to parathyroid adenomas which are
Secondary hyperparathyroidism is physiological compensatory hypertrophy of all
parathyroids because of hypocalcaemia, such as occurs in renal failure or vitamin D
deficiency. PTH levels are raised but calcium levels are low or normal, and PTH falls to
normal after correction of the cause of hypocalcaemia where this is possible.
Tertiary hyperparathyroidism is the development of apparently autonomous
parathyroid hyperplasia after long-standing secondary hyperparathyroidism, most often
in renal failure. Plasma calcium and phosphate are both raised, the latter often grossly.
Clinical tests for hypoparathyroidsm
The clinical history and picture is usually diagnostic and is confirmed by a low serum
calcium (after correction for any albumin abnormality). Additional tests include:
serum and urine creatinine for renal disease
PTH levels in the serum: absent or inappropriately low in hypoparathyroidism,
high in other causes of hypocalcaemia
parathyroid antibodies (present in idiopathic hypoparathyroidism)
25-hydroxy vitamin D serum level (low in vitamin D deficiency)
X-rays of metacarpals, showing short fourth metacarpals which occur in
Deficient Parathyroid Hormone Secretion
Decreased or a complete absence of parathyroid tissue therefore inadequate PTH is
A) Post Surgical: due to injur or removal of parathyroid glands at the time of surgery.
B) Idiopathic: deficient PTH secretion without a defined cause (e.g. surgical injury) is
termed Idiopathic hypoparathyroidism
C) Hypomagnesemia: when magnesium levels are too low, calcium levels may also
Resistance to Parathyroid Hormone (pseudo-hypoparathyroidism).
The diseased individuals are characterized by hypocalcemia, hyperphosphatemia, but
they are distinguished by the fact that they produce PTH in normal values but their
bones and kidneys do not respond to it. Even if PTH is given to them in their veins,
they do not respond to it.
Kumar and Klark., (2008) Clinical Medicine .Elsevier Inc.
James Norman, M.D., F.A.C.S., (1997 – 2008) Endocrinology Overview. (online)
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Colorado State University. (2006) Endocrine system. (online)
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