Cushing’s Syndrome - Endotext - NCBI Bookshelf
An elevated midnight serum cortisol and no suppression of cortisol during a Plasma h ACTH measurement guides imaging and further investigations. to excessive circulating cortisol levels and that gives rise to the clinical state studies have cast doubt on the utility of prolactin for this purpose. The correlation coefficient between h/h cortisol by h serum cortisol levels ACTH levels >13pmol/L in the absence of . A major goal of the present study was to assess whether a single cortisol. An ACTH test measures the levels of ACTH and cortisol in the blood. Here's why it's done and what your results may mean.
The anterior lobe of the pituitary gland. ACTH in turn acts on: CRH and vasopressin are released from neurosecretory nerve terminals at the median eminence. CRH is transported to the anterior pituitary through the portal blood vessel system of the hypophyseal stalk and vasopressin is transported by axonal transport to the posterior pituitary gland.
ACTH is transported by the blood to the adrenal cortex of the adrenal glandwhere it rapidly stimulates biosynthesis of corticosteroids such as cortisol from cholesterol. Cortisol is a major stress hormone and has effects on many tissues in the body, including the brain. In the brain, cortisol acts on two types of receptor — mineralocorticoid receptors and glucocorticoid receptors, and these are expressed by many different types of neurons. One important target of glucocorticoids is the hypothalamuswhich is a major controlling centre of the HPA axis.
Vasopressin can be thought of as "water conservation hormone" and is also known as "antidiuretic hormone. It is also a potent vasoconstrictor. Important to the function of the HPA axis are some of the feedback loops: Cortisol produced in the adrenal cortex will negatively feedback to inhibit both the hypothalamus and the pituitary gland. In healthy individuals, cortisol rises rapidly after wakening, reaching a peak within 30—45 minutes.
It then gradually falls over the day, rising again in late afternoon. Cortisol levels then fall in late evening, reaching a trough during the middle of the night. This corresponds to the rest-activity cycle of the organism. The HPA axis integrates physical and psychosocial influences in order to allow an organism to adapt effectively to its environment, use resources, and optimize survival. At the hypothalamus, fear-signaling impulses activate both the sympathetic nervous system and the modulating systems of the HPA axis.
Increased production of cortisol during stress results in an increased availability of glucose in order to facilitate fighting or fleeing. As well as directly increasing glucose availability, cortisol also suppresses the highly demanding metabolic processes of the immune system, resulting in further availability of glucose.
Atrophy of the hippocampus in humans and animals exposed to severe stress is believed to be caused by prolonged exposure to high concentrations of glucocorticoids.
Deficiencies of the hippocampus may reduce the memory resources available to help a body formulate appropriate reactions to stress. Immune system[ edit ] There is bi-directional communication and feedback between the HPA axis and immune system.
The HPA axis in turn modulates the immune response, with high levels of cortisol resulting in a suppression of immune and inflammatory reactions. This helps to protect the organism from a lethal overactivation of the immune system, and minimizes tissue damage from inflammation. The HPA axis is responsible for modulating inflammatory responses that occur throughout the body. IL-1 are released into the peripheral circulation system and can pass through the blood brain barrier where they can interact with the brain and activate the HPA axis.
Because subcutaneous fat is also diminished, patients suffer easy bruising, which often can be misinterpreted as senile purpura or even a coagulation disorder. Purple-coloured "violaceous" striae greater than 1 cm in diameter are almost pathognomonic of Cushing's syndrome.
Adrenocorticotropic hormone | You and Your Hormones from the Society for Endocrinology
Typically seen on the abdomen, they can also occur in other areas, such as the thighs, breasts and arms. Narrow and coloured striae are more commonly present, and should be differentiated from the typical healed silvery striae seen most commonly post-partum. Cutaneous fungal infections as truncal tinea versicolor and onychomicosis are often found.
It is also associated with the rapid onset of profound weakness, often with little or no weight gain, and an absence of a gross Cushingoid appearance. However, other forms of the ectopic ACTH syndrome, particularly associated with neuroendocrine tumours, may be clinically indistinguishable from patients with other forms of hypercortisolism Severe hirsutism and virilisation strongly suggest an adrenal carcinoma Hypercortisolism may suppress other pituitary hormones.
In both men and women, hypogonadotrophic hypogonadism is common and correlates with the degree of hypercortisolaemia 55; Glucocorticoids inhibit gonadotrophin—releasing hormone pulsatility and the release of luteinising LH and follicle-stimulating hormone FSH. Women experience menstrual irregularity, while both sexes have decreased libido. Gonadal dysfunction is reversible after correction of the hypercortisolaemia 55; There is reduced GH secretion during sleep and blunted GH responses to dynamic stimulation tests Thyrotropin-releasing hormone and thyroid-stimulating hormone release has been shown to be disturbed, and in particular the nocturnal surge of thyroid-stimulating hormone is lost Hypokalaemic metabolic alkalosis is related to the degree of hypercortisolaemia and represents a mineralocorticoid action of cortisol at the renal tubule due to saturation of the enzyme 11b-hydroxysteroid dehydrogenase type 2, which inactivates cortisol to cortisone and allows selective binding of aldosterone to mineralocorticoid receptor In terms of hypersaturation, cortisol can now access the mineralocorticoid receptor and act as a mineralocorticoid.
It occurs when urine free cortisol excretion is greater than about nmol per day Glucocorticoids stimulate glycogen deposition, promote gluconeogenesis, inhibit glucose uptake in peripheral tissues, activate lipolysis and have a permissive effect on contra-regulatory hormones, glucagon and catecholamines. However, in the absence of clinical suspicion the percentage is probably lower 68; 69and therefore it is probably not justified to screen for Cushing in poorly-controlled diabetic patients unless other suggestive features are present Hyperglycaemia becomes easier to control after treatment There is an increase in total cholesterol and triglyceride levels, and a variable effect on high-density lipoprotein HDL.
These changes are multifactorial, including cortisol effects on increased hepatic synthesis of very low density lipoprotein VLDLlipolysis, and free fatty acid metabolism Overall, hypertension is common in patients with Cushing syndrome, Severe hypertension with additional hypokalaemia is more prevalent in ectopic Cushing syndrome, usually best controlled with spironolactone Cardiovascular risk markers continue to be present long after cure of the hypercortisolaemia 76 and cardiovascular risk remains increased 77; Sympathetic autonomic function is also abnormal in patients with Cushing's syndrome 79and the ECG abnormalities of a prolonged QTc dispersion QTcd and left ventricular hypertrophy have been identified as characteristic features in patients with Cushing's disease 80 Hypercortisolaemia increases clotting factors including factor VIII, fibrinogen, and von Willebrand factor, and reduces fibrinolytic activity.
This along with other risk factors such as obesity, surgery and invasive investigative procedures, results in a significantly increased risk of thrombotic events in patients with Cushing's syndrome Ophthalmic complications include glaucoma and exopthalmus due to retroorbital fat deposition 83; Cataract is rare, mostly a complication of diabetes Cognitive defects as learning, cognition and impairment of short-term memory may be prominent 89; These changes are not always reversible with treatment.
In patients there is a greater frequency of infections because of inhibition of immune function by glucocorticoids by decreasing the number of CD4 cells, NK cells and inhibition in cytokine synthesiswith predominant effects on cell-mediated immunity TH1 responses.
The most common are bacterial infections, and special attention should be pointed at a possibility of opportunistic pathogens, especially in cases of severe hypercortisolism 94; Some cases of ACTH-dependent Cushing's syndrome occur in a periodic or cyclical form, with intermittent and variable cortisol secretion, the symptoms and signs waxing and waning according to the active periods of the disease. These patients can cause particular diagnostic difficulty, as it is imperative that the diagnostic tests are performed in the presence of hypercortisolaemia to allow accurate interpretation.
Patients may 'cycle in' or 'cycle out' over periods of months or years; if at presentation they are eucortisolaemic, they will need regular re-evaluation usually with urinary free cortisol or late-night salivary cortisol to allow full investigation at the appropriate time. Hypercortisolaemia together with the loss of the normal circadian rhythm of cortisol secretion, and disturbed feedback of the HPA axis, are the cardinal biochemical features of Cushing's syndrome.
Almost all tests to confirm the diagnosis are based upon these principles. Furthermore, to screen for Cushing's syndrome, tests of high sensitivity should be used initially so as to avoid missing milder cases. Tests of high specificity can then be employed to exclude false positives. It is important to realise that the validation of the published test criteria employed have been on specific assays, and thus test responses should ideally be validated on the local assay used before the results can be interpreted in particular patients.
This is aided by supra-regional and nationwide inter-assay quality control assurance 1. However, most of the patients still maintain their morning values within the normal range, but have raised nocturnal levels, rendering midnight levels most useful diagnostically. The measurement of free serum cortisol is very challenging, so either levels of salivary cortisol or total serum cortisol are being used.
However, exogenous oestrogens and some medical conditions see below will increase cortisol-binding globulin and therefore total cortisol levels. Hence, in all investigations relying on a serum cortisol assay that measures total cortisol, hormone replacement therapy or the oral contraceptive pill should be stopped weeks prior to investigation, although it is likely that a shorter time off treatment may still be effective.
Late Night Salivary Cortisol Late-night salivary cortisol LSC measurement accurately reflects the plasma free cortisol concentration, because cortisol-binding globulin CBG is absent from saliva. Assays using a modification of the plasma cortisol radioimmunoassay, enzyme-linked immunosorbent assay, or liquid chromatography tandem mass spectrometry are now widely available. It has been evaluated at a large number of centres worldwide. However, it should be noted that the diagnostic value cut-off varies between studies because of different assays and the comparison groups studied.
Normal values also differ between adults and paediatric populations, and may be affected by other comorbidities such as diabetes 98and the method by which the saliva is collected Not surprisingly, this test performs less well in patients with subclinical Cushing's syndrome Salivary rather than serum cortisol has been evaluated as the endpoint for the low-dose dexamethasone suppression test LDDST.
This has the potential benefit in terms of convenience but requires further evaluation ; Salivary cortisol has also been advocated as a sensitive tool to detect recurrence or treatment failure in patients post-pituitary surgery for Cushing's disease ; In summary, late-night salivary cortisol appears to be a useful and convenient screening test for Cushing's syndrome, particularly in the outpatient setting.
However, local normal ranges need to be validated based on the assay used and population studied.
Unbound cortisol is filtered by the kidney, with the majority being reabsorbed in the tubules, and the remainder excreted unchanged.
Thus, hour UFC collection produces an integrated measure of serum cortisol, smoothing out the variations in cortisol during the day and night. Furthermore, this sensitivity figure is based on the more florid cases, and is likely to be much less for the more common subtle cases now being seen. The major drawback of the test is the potential for an inadequate hour urine collection, and written instructions must be given to the patient. Also, multiple collections reduce the possibility of overlooking in episodic cortisol secretion, sometimes seen in adrenal adenomas.
The 24 hour UFC is of little value in the differentiation from pseudo-Cushing's states ;although obesity per se does not appear to confound the results High-performance liquid chromatography or tandem mass spectrometry are now used to measure UFC, which overcomes the previous problem with conventional radioimmunoassays of cross-reactivity of some exogenous glucocorticoids and other structurally similar steroids Drugs such as carbamazepine, digoxin and fenofibrate may co-elute with cortisol during high-performance liquid chromatography and cause falsely elevated results ; In summary, UFC measurements have a high sensitivity if collected correctly, and several completely normal collections make the diagnosis of Cushing's syndrome very unlikely.
Values greater than fourfold normal are rare except in Cushing's syndrome. For intermediate values the specificity is somewhat lower, and thus patients with marginally elevated levels require further investigation 1.
HPA Axis & Stress Response: Hypothalamic Pituitary Adrenal Axis | Integrative Therapeutics
It is our opinion that the test is of little use for screening, and in general we rarely utilise it nowadays. Low-dose Dexamethasone Suppression Test LDDST This test works on the principle that in normal individuals administration of an exogenous glucocorticoid results in suppression of the HPA axis, whilst patients with Cushing's syndrome are resistant, at least partially, to negative feedback.
Dexamethasone is a synthetic glucocorticoid that is 30 times more potent than cortisol, and with an extremely long duration of action. It does not cross-react with most cortisol assays. Since then, various doses have been suggested for the overnight test, between 0. There appears to be no advantage in discrimination between 1mg and 1. Although higher doses have been tried, the increased suppression in some patients with Cushing's syndrome significantly decreases the sensitivity of the test It should be noted that patients with PPNAD may show a paradoxical rise in cortisol levels to dexamethasone Second Line Tests In some patients with equivocal results other tests may be needed.
The most useful of these are a midnight serum cortisol, and the dexamethasone-CRH test. Less reliable tests such as the insulin tolerance testthe loperamide testand the desmopressin test 47 are not in widespread use.
Midnight Serum Cortisol Before the introduction of salivary cortisol, measurement a midnight serum cortisol was the only reliable method used to determine loss of the circadian rhythm of cortisol secretion. However, it is a burdensome test that requires that the patient should have been an in-patient for at least 48 hours to allow acclimatisation to the hospital environment.
The patient should not be forewarned of the test, and should be asleep prior to venepuncture, which must be performed within minutes of waking the patient. The theory is that a small number of patients with Cushing's disease as well as normal individuals will show suppression to dexamethasone, but those with Cushing's disease should still respond to CRH with a rise in ACTH and cortisol. In the original description of the test, dexamethasone 0. Importantly, in these two studies although eight of 59 patients with proven Cushing's disease showed suppression to dexamethasone, all were correctly characterised after CRH.
However, the results from a number of other smaller studies have challenged the diagnostic utility of this test over the standard LDDST.
It is perhaps not surprising that the diagnostic utility of the Dex-CRH has altered with further studies at more centres. There are a number of reasons why there might be the case: It is recommended that if this test is used, a dexamethasone level is measured at the time of CRH administration and the serum cortisol assay is accurate down to these low levels Modern two-site immunoradiometric assays are more sensitive than the older radioimmunoassays and therefore provide the best discrimination.
This is called a negative feedback loop. Stress, both physical and psychologicalalso stimulates adrenocorticotropic hormone production and hence increases cortisol levels. What happens if I have too much adrenocorticotropic hormone?
The HPA Axis
The effects of too much adrenocorticotropic hormone are mainly due to the increase in cortisol levels which result. Higher than normal levels of adrenocorticotropic hormone may be due to: Cushing's disease — this is the most common cause of increased adrenocorticotropic hormone. It is caused by a non-cancerous tumour called an adenoma located in the pituitary gland, which produces excess amounts of adrenocorticotropic hormone.
A tumour, outside the pituitary gland, producing adrenocorticotropic hormone also called ectopic adrenocorticotropic hormone tumour. Addison's disease although cortisol levels are low, adrenocorticotropic hormone levels are raised. Congenital adrenal hyperplasia a genetic disorder with inadequate production of cortisol, aldosterone or both.
What happens if I have too little adrenocorticotropic hormone?