Stress & Fatigue

Stress & Fatigue, Hormone Testing

Cortisol (hydrocortisone) is the most prominent glucocorticosteroid, and it is essential for the maintenance of several body functions. Like other glucocorticosteroids, cortisol is synthesized from the common precursor cholesterol in the zona fasciculata of the cortex of the adrenal gland. For the transport of cortisol in blood, about 90% of cortisol is bound to corticosteroid-binding globulin (CBG) and to albumin. Only a small amount of cortisol circulates unbound in blood and is free to interact with its receptors.3The most important physiological effects of cortisol are the increase of blood glucose levels (enhancement of gluconeogenesis, catabolic action) and its anti-inflammatory and immunosuppressive action.3Synthesis and secretion of cortisol by the adrenal gland are controlled by a negative feedback mechanism within the hypothalamus-pituitary-adrenal cortex-axis. If the cortisol level is low, corticotropin-releasing hormone (CRH) is secreted by the hypothalamus, which causes the pituitary to release adrenocorticotropic hormone (ACTH). This stimulates the synthesis and secretion of cortisol by the adrenal gland. Cortisol itself acts in a negative feedback mechanism on the pituitary gland and the hypothalamus. In addition, stress is followed by increased cortisol secretion.3Serum cortisol concentrations normally show a diurnal variation.3Maximum concentrations are usually reached early in the morning and then concentrations decline throughout the day to an evening level that is about half of the morning concentration; therefore, for interpretation of results, it is important to know the collection time of the serum sample.The cortisol status of a patient is used to diagnose the function or malfunction of the adrenal gland, the pituitary, and the hypothalamus.4,5Thereby, cortisol serum concentrations are used for monitoring several diseases with an overproduction (eg, Cushing syndrome)6,7or underproduction (eg, Addison disease) of cortisol and for monitoring several therapeutic approaches (eg, dexamethasone suppression therapy in Cushing syndrome and hormone replacement therapy in Addison disease).

Stress & Fatigue, Hormone Testing

Offered as part of multiple lab tests

Stress & Fatigue, Hormone Testing

Cortisol is increased in Cushing's Disease and decreased in Addison's Disease (adrenal insufficiency).

Stress & Fatigue, Hormone Testing

Cortisol is increased in Cushing's Disease and decreased in Addison's Disease (adrenal insufficiency).

Stress & Fatigue, Hormone Testing

Cortisol is increased in Cushing's Disease and decreased in Addison's Disease (adrenal insufficiency).

Stress & Fatigue, Hormone Testing

Offered as part of multiple lab tests

Stress & Fatigue, Hormone Testing

Offered as part of multiple lab tests

Hormone Testing, Stress & Fatigue

Determination of ACTH is useful in differentiating between primary and secondary adrenocortical hypo- and hyperfunctional disorders: Addison's Disease, Cushing's Syndrome, Adrenal Carcinoma, Ectopic ACTH Syndrome, Nodular Hyperplasia.

Stress & Fatigue

This test is useful in the initial evaluation of patients with suspected Cushing syndrome (CS).1,2Patients with CS usually have urine free cortisol >100 μg/24 hours, but there is wide variation and no single cutoff can be used safely. If the 24-hour urine free cortisol is elevated, additional testing is indicated to differentiate among pituitary-dependent CS, pituitary-independent CS, and pseudo-Cushing syndrome.2Some patients with an elevated 24-hour urine cortisol do not have Cushing syndrome and are often classified as pseudo-Cushing syndrome. Establishing this diagnosis requires additional testing which includes the low-dose dexamethasone suppression test, the CRH stimulation test, or a protocol that combines them both.3The diagnosis of CS requires a meticulous history and physical examination,2and these should precede a biochemical evaluation.

Stress & Fatigue, Hormone Testing

Offered as part of multiple lab tests

Stress & Fatigue

Metanephrine and normetanephrine (together referred to as metanephrines) are the 3-methoxy metabolites of the catecholamines, epinephrine and norepinephrine, respectively. The methylation of catecholamines is accomplished by catecholamine O-methyltransferase, a membrane-bound enzyme of chromaffin cells.1-8Levels of these metabolites can be increased in both plasma and urine in patients with catecholamine-producing tumors such as pheochromocytomas, paragangliomas and neuroblastomas. Pheochromocytomas, intra-adrenal paraganglioma, and extra-adrenal sympathetic and parasympathetic paragangliomas (PPGLs) are rare neuroendocrine tumors derived from neural crest progenitor cells including adrenal chromaffin cells and similar cells in extra-adrenal sympathetic and parasympathetic paraganglia. Approximately 10% of pheochromocytomas and 35% of paragangliomas are malignant. About a third of these tumors are associated with three specific syndromes; von Hippel-Lindau syndrome, multiple endocrine neoplasia type 2 (MEN 2), and neurofibromatosis type 1. A number of germline mutations responsible for PPGLs have been identified.9,10Neuroblastomas are derived from immature embryonic neuroblast cells that also form tumors at adrenal and extra-adrenal locations, but present almost exclusively in childhood.11Patients with PPGLs can present with episodic hypertension related to excessive catecholamine synthesis and variety of other symptoms that can include tachycardia, headache, palpitations, profuse diaphoresis, and pallor.5,12Less frequently, these tumors can manifest as nausea, vomiting, flushing, and weight loss. In young patients with normal body weight, hypertension with diabetes mellitus may suggest PPGL.13Many patients present with an unidentified mass lesion and no specific clinical symptoms associated with PPGL. Given the relative non-specificity of symptoms and the low prevalence of the condition (less than 1 per 100,000 individuals in the general population),14it is not unusual for the diagnosis of PPGL to be delayed. The critical first step for diagnosis is to recognize the possibility of the tumor.15-17The consequences of delayed detection can be severe as excessive catecholamine secretion can precipitate life-threatening hypertension, intracerebral hemorrhage, and cardiac arrhythmias.18,19When detected early, these tumors are potentially curable.20Diagnosis of pheochromocytoma and paraganglioma relies on biochemical evidence of catecholamine production by the tumor. Guidelines suggest that measurement of plasma free metanephrines or urinary fractionated metanephrines should be performed in symptomatic patients,15,22patients with an adrenal incidentaloma,21and in individuals who have a hereditary risk for developing a pheochromocytoma or paraganglioma.10Metanephrines are produced continuously by the normal adrenal and by tumors via a process that is independent of catecholamine release, which for some tumors occurs at low rates or is episodic in nature.6-8,15While non-chromaffin cells of the sympathetic nervous system are the major sites of norepinephrine metabolism, they do not convert catecholamines to metanephrines because they lack the catecholamine O-methyltransferase enzyme. Consequently, levels of free metanephrines reflect functional chromaffin cell quantity and become elevated in patients with catecholamine producing chromaffin tumors.1,6Since many PPGLs produce and metabolize catecholamines but do not secrete the amines continuously or in amounts sufficient to produce a diagnostic signal, the metanephrines are superior to the parent catecholamines as diagnostic biomarkers.23,24The high diagnostic accuracy of measurements of urine fractionated metanephrines and plasma free metanephrines has been confirmed by a large number of studies.6-8,15,25-26,34Normetanephrine or metanephrine elevated 3-fold or more above upper cutoffs are rarely false positives and should be followed up in most cases by imaging to locate the tumor.15,24,28In cases of borderline elevation (less than 3-fold the upper limit of the reference interval), repeat testing and/or second-line tests such clonidine suppression test with measurements of plasma normetanephrine can be performed prior to proceeding to imaging studies.15,29Chromogranin A levels are elevated in most patients with PPGLs and have been associated with risk of malignancy.34-35However, the test is not specific and is seen in other disorders such as carcinoid.

Stress & Fatigue

This urinary free cortisol (UFC) test, performed with a 24-hour urine specimen, is one of the preferred tests for screening for and diagnosing Cushing syndrome. This test may also be used to monitor for recurrence of Cushing disease [1]. In addition, when used in conjunction with the measurement of 24-hour urine cortisone, this test may help identify disorders caused by impaired activity of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), such as apparent mineralocorticoid excess (AME) syndrome [2].UFC level is independent of corticosteroid-binding globulin and albumin levels; thus, UFC level can demonstrate increased bioavailable cortisol in patients with endogenous Cushing syndrome [1]. A UFC test with 24-hour urine specimen also has the advantage of averaging circadian and ultradian variations of cortisol secretion. An elevated UFC level may provide initial evidence for Cushing syndrome. Two or more positive results of UFC tests may establish the diagnosis of Cushing syndrome if non-neoplastic hypercortisolism (pseudo-Cushing syndrome) is excluded [1].A late-night salivary cortisol (LNSC) test or dexamethasone suppression test (DST) can also be used to diagnose Cushing syndrome or monitor for Cushing disease. Choice of test should be based on clinical scenario [1]. When monitoring for recurrence of Cushing disease, UFC levels usually become abnormal after LNSC tests or DSTs do [1].UFC testing is not recommended for screening for Cushing syndrome in individuals with impaired kidney function or polyuria [1]. Non-neoplastic hypercortisolism caused by obesity, psychiatric disorders, alcohol use disorder, and polycystic ovary syndrome may increase UFC levels.In patients with AME syndrome, deficiency of 11beta-HSD2 impairs the deactivation of cortisol to cortisone. Similarly, ingestion of certain compounds that inhibit 11beta-HSD2 activity, such as glycyrrhetinic acid (in licorice), carbenoxolone, and phthalates, may also reduce the conversion of cortisol to cortisone. Therefore, a high cortisol-to-cortisone ratio measured in 24-hour urine may help identify disorders caused by impaired activity of 11beta-HSD2 [2, 3].The results of this test should be interpreted in the context of pertinent clinical and family history and physical examination findings.Reference1. Fleseriu M, et al.Lancet Diabetes Endocrinol. 2021;9(12):847-875.2. Young WF, Jr., et al.Endocrine Reviews. 2017;38(2):103-122.3. Carvajal CA, et al.J Clin Endocrinol Metab.2020;105(4):dgz315.

Stress & Fatigue, Hormone Testing

Offered as part of multiple lab tests

Stress & Fatigue, Hormone Testing

Offered as part of multiple lab tests

Stress & Fatigue

Test is useful in the evaluation of pheochromocytoma.

Stress & Fatigue

Offered as part of multiple lab tests

Stress & Fatigue, Hormone Testing

Offered as part of multiple lab tests

Stress & Fatigue, Hormone Testing

Offered as part of multiple lab tests

Stress & Fatigue, Hormone Testing

Urinary free cortisol is useful in the detection of patients with Cushing's syndrome for whom free cortisol concentrations are elevated

Stress & Fatigue, Hormone Testing

Cortisol stimulates gluconeogenesis in the liver and reduces insulin secretion while increasing glucagon release by the pancreas. This increases blood glucose levels. Cortisol is also involved in inhibiting inflammatory responses and maintaining blood pressure by potentiating effects on norepinephrine.Most of circulating cortisol is bound to protein, primarily transcortin (corticosteroid-binding globulin [CBG]) and albumin. The free hormone hypothesis suggests that the unbound, or free, cortisol is the active fraction, and that this fraction is the most important clinically. Total serum cortisol may be an adequate measure of cortisol activity except when the levels of the binding proteins are abnormal such as in liver disease or acute illness.A study published in theNew England Journal of Medicinedemonstrates the utility of measurements of free cortisol in critically ill patients. Patients with critical illness increase cortisol secretion; however, this is best observed when free cortisol levels are measured. In the study, 40% of patients with hypoproteinemia had low levels of total cortisol even though their adrenal function was adequate as demonstrated by robust response to ACTH. Similar results were obtained when salivary cortisol was used as a marker for adrenal sufficiency during illness.A number of tests to determine free cortisol have been devised. The free fraction depends on the concentrations of the binding proteins and cortisol, and, thus, may be calculated based on these factors. Free cortisol is best measured by equilibrium dialysis. Structure-function observations favor a direct measure of free cortisol. There are polymorphic forms of transcortin that affect cortisol binding, and glycosylation affects cortisol binding to transcortin. TheCortisol, Free, Equilibrium Dialysis and LC/MS-MSassay provides a specific direct test.

Stress & Fatigue, Hormone Testing

Cortisol stimulates gluconeogenesis in the liver and reduces insulin secretion while increasing glucagon release by the pancreas. This increases blood glucose levels. Cortisol is also involved in inhibiting inflammatory responses and maintaining blood pressure by potentiating effects on norepinephrine.Most of circulating cortisol is bound to protein, primarily transcortin (corticosteroid-binding globulin [CBG]) and albumin. The free hormone hypothesis suggests that the unbound, or free, cortisol is the active fraction, and that this fraction is the most important clinically. Total serum cortisol may be an adequate measure of cortisol activity except when the levels of the binding proteins are abnormal such as in liver disease or acute illness.A study published in theNew England Journal of Medicinedemonstrates the utility of measurements of free cortisol in critically ill patients. Patients with critical illness increase cortisol secretion; however, this is best observed when free cortisol levels are measured. In the study, 40% of patients with hypoproteinemia had low levels of total cortisol even though their adrenal function was adequate as demonstrated by robust response to ACTH. Similar results were obtained when salivary cortisol was used as a marker for adrenal sufficiency during illness.A number of tests to determine free cortisol have been devised. The free fraction depends on the concentrations of the binding proteins and cortisol, and, thus, may be calculated based on these factors. Free cortisol is best measured by equilibrium dialysis. Structure-function observations favor a direct measure of free cortisol. There are polymorphic forms of transcortin that affect cortisol binding, and glycosylation affects cortisol binding to transcortin. TheCortisol, Free, Equilibrium Dialysis and LC/MS-MSassay provides a specific direct test.

Hormone Testing, Stress & Fatigue

11-Deoxycortisol is the immediate precursor of cortisol and follows the same catabolic pathways as cortisol. The conversion of 11-deoxycortisol to cortisol is inhibited by metyrapone, which acts on 11-β-hydroxylase. The metyrapone test (see the online Endocrine Appendix: ACTH Stimulation) serves as a reliable and sensitive indicator of pituitary ACTH secretory reserve. The 11-deoxycortisol levels normally increase to 100 times the control value following metyrapone administration. Reduced response occurs in patients with hypoadrenalism or with hypopituitarism and in some patients with diseases of the hypothalamus. Patients with myxedema, some pregnant patients, and those on oral contraceptives respond poorly.

Hormone Testing, Stress & Fatigue

Offered as part of multiple lab tests

Hormone Testing, Stress & Fatigue

11-Deoxycortisol is the immediate precursor of cortisol and follows the same catabolic pathways as cortisol. The conversion of 11-deoxycortisol to cortisol is inhibited by metyrapone, which acts on 11-β-hydroxylase. The metyrapone test (see the online Endocrine Appendix: ACTH Stimulation) serves as a reliable and sensitive indicator of pituitary ACTH secretory reserve. The 11-deoxycortisol levels normally increase to 100 times the control value following metyrapone administration. Reduced response occurs in patients with hypoadrenalism or with hypopituitarism and in some patients with diseases of the hypothalamus. Patients with myxedema, some pregnant patients, and those on oral contraceptives respond poorly.

Hormone Testing, Stress & Fatigue

11-Deoxycortisol is the immediate precursor of cortisol and follows the same catabolic pathways as cortisol. The conversion of 11-deoxycortisol to cortisol is inhibited by metyrapone, which acts on 11-β-hydroxylase. The metyrapone test (see the online Endocrine Appendix: ACTH Stimulation) serves as a reliable and sensitive indicator of pituitary ACTH secretory reserve. The 11-deoxycortisol levels normally increase to 100 times the control value following metyrapone administration. Reduced response occurs in patients with hypoadrenalism or with hypopituitarism and in some patients with diseases of the hypothalamus. Patients with myxedema, some pregnant patients, and those on oral contraceptives respond poorly.

Hormone Testing, Stress & Fatigue

Offered as part of multiple lab tests

Stress & Fatigue, Hormone Testing

Free cortisol is useful in the detection of patients with Cushing's syndrome for whom free cortisol concentrations are elevated.

Stress & Fatigue, Hormone Testing

Offered as part of multiple lab tests