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Indication - Endocrine disorders
Cortisol (total)
Facility level:
2. Laboratory
Assay formats
Immunoassay
Status history
First added in 2020
Purpose type
Diagnosis
Purpose
To diagnose central (pituitary) or primary (adrenal, Addison’'s disease) cortisol deficiency ; To diagnose central (pituitary) or primary (adrenal) hypercortisolism (Cushing’s Syndrome).
Specimen types
Serum, Plasma
WHO prequalified or recommended products
N/A
WHO supporting documents
N/A
Codes
ICD11 code: 5B3Z

Summary of evidence evaluation

Cortisol levels are directly related to the presence or absence of hypo- or hyper-adrenal function disorders such as Cushing’s syndrome and Addison’s disease. Diagnostic accuracy for these conditions appears to be very good (90% sensitivity and specificity). It should be noted that cortisol testing is a test that, if positive, might warrant further testing to specify the cause of loss of adrenal function that will guide options for treatment. There are no direct comparisons for impact on health outcomes, though it seems likely that early detection of loss of function of the adrenal glands will facilitate early detection, diagnosis and treatment. This is supported by guidelines, as it is not recommended to postpone treatment until cortisol measurement has been performed, but to start immediately and adjust later based on the results. Cost–effectiveness cannot be established based on the current literature. But there is sufficient evidence in the submission to recommend serum cortisol measurement based on the analytic and diagnostic accuracy and likely benefits of early detection and treatment. Diagnostic accuracy measures depend on the indication for the test (intended role of the test) and cut-off points used. The full evidence review for this test category is available online at: https://www.who.int/medical_devices/diagnostics/selection_in-vitro/selection_in-vitro-meetings/new-prod-categories_3

Summary of SAGE IVD deliberations

Adrenal insufficiency and Cushing’s disease are two conditions with high morbidity and mortality. Primary diagnosis of both conditions can usually be done by determining cortisol levels, with very good accuracy. Serum/plasma cortisol concentrations are useful both as a single measurement (morning sample for adrenal insufficiency and midnight cortisol for Cushing’s syndrome) or as a dynamic test (cosyntropin stimulation test for adrenal insufficiency and overnight dexamethasone test for Cushing’s syndrome). Early detection of both conditions can lead to early treatment and reversal. And treatment for adrenal insufficiency is also included in the EML, including corticosteroids and fludrocortisone. Cortisol testing is included in the guidelines of many professional societies and is widely used in clinical practice across the world to both diagnose and follow up adrenal insufficiency and Cushing’s disease. SAGE IVD noted that interpretation of cortisol levels varies depending on whether you are measuring total or free cortisol; and also emphasized that the cost–effectiveness of the test cannot be established based on the data submitted. The group also raised concerns about the potential for misuse of the test if it is introduced in the absence of specialized centres. This is not just about having a specialized laboratory but also about having specialist staff available to interpret results and guide treatment. SAGE IVD also noted that cortisol testing, if positive, may warrant further testing to specify the cause of loss of adrenal function to guide treatment options. The group further noted that different autoanalysers and assays may give different results, although it acknowledged that this is typical of hormone determinations. Importantly, SAGE IVD highlighted a number of interpretive issues with cortisol testing and raised concerns about the potential for it to be inappropriately ordered or inaccurately interpreted without guidance. In particular, the timing of sample collection and the need for cosyntropin stimulation (or dexamethasone suppression) is often critical for cortisol testing to work effectively.

SAGE IVD recommendation

SAGE IVD recommended including the cortisol (total) test category in the third EDL: • as a disease-specific IVD for use in clinical laboratories (EDL 3, Section II.b, within a new subsection for endocrine disorders); • using an immunoassay format; • to diagnose central (pituitary) or primary (adrenal, Addison’s disease) cortisol deficiency;* and • to diagnose central (pituitary) or primary (adrenal) hypercortisolism (Cushing’s syndrome).** *Often used with timed collection and stimulation with cosyntropin. ** Often used with timed collection and suppression with dexamethasone. The group further requested the addition of a note to the test category entry in the EDL stating that it is only recommended for use in specialized health care settings.

Details of submission from 2020

Background

Disease condition and impact on patients Cortisol is an essential hormone; it helps the body respond to stress, such as surgery and illness, and recover from infections. Cortisol also helps maintain blood pressure and cardiovascular functions and regulates the metabolism of proteins, carbohydrates and fatty acids. Aldosterone plays a key role in sodium and potassium balance. Cortisol is the main glucocorticoid hormone produced by the adrenal gland. It is secreted in response to stimulation of the adrenal gland by adrenocorticotropic hormone (ACTH), produced by the pituitary. Adrenal hypofunction describes central and primary adrenal insufficiency and is characterized by insufficient secretion of cortisol. It is caused either by insufficient secretion of ACTH (central adrenal insufficiency, usually associated with deficiency in other pituitary hormones) or by a non-functional adrenal gland (primary adrenal insufficiency, most commonly because of autoimmune destruction of the gland or Addison’s disease). Patients with adrenal insufficiency, both central and primary, often present with hypotension, anorexia, vomiting, weight loss, fatigue and recurrent abdominal pain. Reproductive complaints typically occur in women (amenorrhoea, loss of libido, decreased axillary and pubic hair). In primary adrenal insufficiency, hyperpigmentation and salt craving are also usually present. Patients may also manifest neuropsychiatric signs and symptoms. In children, weight loss with failure to thrive as well as hypoglycaemic crisis with seizures can be seen. Biochemical findings include hyponatraemia, hyperkalaemia (for primary adrenal insufficiency) and hypoglycaemia. Adrenal insufficiency is a life-threatening disorder, which, if not recognized, leads to high morbidity and mortality. Any type of stress in patients with adrenal insufficiency can precipitate an adrenal crisis; the most frequent precipitating factors are gastrointestinal and other infectious diseases. Patients with adrenal crisis usually present with unexplained shock refractory to vasopressors and fluids. Early identification and treatment of adrenal crisis significantly decrease mortality rates during these episodes (1). Treatment of adrenal insufficiency is relatively easy and affordable, using medicines included in the EML. Although treatment improves quality of life and markedly decreases morbidity, there are still challenges. Adrenal hyperfunction, or Cushing’s syndrome, is characterized by excess production of ACTH by the pituitary or by excess production of cortisol directly by the adrenal gland. Although Cushing’s syndrome is clinically unmistakable when fully blown, the spectrum of clinical presentation is broad. It affects numerous systems, such as reproductive, dermatologic, metabolic, cardiovascular, musculoskeletal, neuropsychiatric and infectious. Few, if any, features of Cushing’s syndrome are unique, but some are more discriminatory than others, including reddish-purple striae, plethora, proximal muscle weakness, easy bruising and unexplained osteoporosis. Other symptoms, such as fatigue, weight gain, depression, diabetes, hypertension and menstrual irregularity are also common in individuals without the disorder, which makes the diagnosis very challenging. In children, weight gain with decreasing growth velocity is noticeable (2). This potentially lethal disorder is associated with significant comorbidities and significantly impaired quality of life. This seems to improve after remission and appears to be significantly correlated with the degree of disease control (3, 4). Untreated, Cushing’s syndrome causes severe illness and death. The earliest reports of mortality documented a median survival of 5 years, with most deaths caused by vascular or infectious complications. With modern-day treatments, however, the standard mortality ratio after normalizing cortisol is similar to that of an age-matched population (5, 6). Does the test meet a medical need? Determining serum cortisol is required to diagnose both adrenal hypofunction and hyperfunction. It is also useful in screening for adrenal hypofunction in asymptomatic patients at high risk of developing adrenal insufficiency, including previous long-term exposure to exogenous corticosteroids, as well as pituitary tumours, pituitary surgery, and history of cranial or total body irradiation. Recommendations for testing for adrenal insufficiency and Cushing’s syndrome are based on observational evidence of a large treatment effect on morbidity and mortality in patients diagnosed with the condition. Adrenal hypofunction. In patients with adrenal insufficiency, any type of infection or stress can precipitate an adrenal crisis, leading to unexplained refractory shock with a high mortality rate (7, 8). Treatment consists of glucocorticoid replacement, with hydrocortisone being the first choice, in two to three daily doses. Prednisone can also be used. Once-daily fludrocortisone is also given to patients with primary adrenal insufficiency (9). Generally, appropriately diagnosed and treated patients have a good prognosis and can have a normal lifespan, compared with the high mortality rate seen in untreated patients (10). The benefits of using steroids to treat patients with adrenal insufficiency have long been proven. In the 1930s, many case reports documented miraculous recovery in patients with Addison’s disease who were treated with hydrocortisone. When congenital adrenal hyperplasia was discovered, chronic administration of hydrocortisone to these infants was found to dramatically reverse hypotension, hypoglycaemia and salt wasting (11). Current research is focused on finding different steroid formulations that can mimic the physiological circadian pattern of cortisol secretion, with less frequent dosing, in order to improve quality of life as well as compliance (12). Preventing adrenal crisis, which has a mortality rate of 0.5 per 100 patient years, is important (13). It requires timely diagnosis of at-risk patients as well as education of both patients and health professionals (1, 14). Early treatment with parenteral hydrocortisone is life-saving and is recommended for any patient with even suspected adrenal crisis by all expert guidelines (9). Adrenal hyperfunction. Patients with active Cushing’s syndrome have a mortality rate that is 1.7–4.8 times greater than the general population. It is associated with significant comorbidities, including hypertension, diabetes, coagulopathy, cardiovascular disease, infections and fractures (15, 16). Treating patients with moderate to severe Cushing’s syndrome clearly reduces illness and death. Because Cushing’s syndrome tends to progress and severe hypercortisolism is probably associated with a worse outcome, it is likely that early recognition and treatment of mild disease would also reduce the risk of residual morbidity (17). Even though morbidity and mortality rates decrease with treatment, these may still be higher than the general population, even after hypercortisolism is cured. A recent meta-analysis of seven studies showed that patients with Cushing’s disease in whom initial surgical cure was not obtained had higher death rates than the general population, while patients with initial remission did not (6). But a multicentre, retrospective cohort study showed that patients in remission for more than 10 years still had a higher risk of overall mortality compared with the general population, particularly from circulatory disease; median survival from cure was still found to be excellent at about 40 years of remission (5). How the test is used Adrenal hypofunction. A morning cortisol 140 nmol/L is used as a preliminary test suggestive of adrenal insufficiency. A morning cortisol > 400–500 nmol/L rules out adrenal insufficiency. When corticotropin is available (uncommon in many low-resource settings), intravenous (IV) administration of high dose (250 mcg of cosyntropin in adults, 125 mcg in children > 2 years and 15 mcg/kg of body weight in infants and children < 2 years) or low dose (1 mcg of cosyntropin), followed by determination of serum cortisol 30 or 60 min after the injection should be performed. A peak cortisol level of less than 500 nmol/L (or 250 nmol/L in infants) at this time is commonly used to diagnose adrenal insufficiency (assay dependent) (9). In HICs, the ACTH stimulation test is commonly used because it is independent of the time of the day, cosyntropin is usually readily available and there is no limit on the number of cortisol samples to be assessed. In LMICs, early morning cortisol determination is preferred. Adrenal hyperfunction. The first step in evaluating patients for hypercortisolism is to exclude any exogenous causes, such as administration of corticosteroid medications. After ruling these out, the two most common options for screening are: • The so-called low-dose dexamethasone test, which can be performed as an outpatient test. 1 mg dexamethasone per os is administered between 23:00 and 24:00 h, and serum cortisol is then determined between 08:00 and 09:00 h the next morning. A post-dexamethasone serum cortisol of less than 50 nmol/L rules out Cushing’s syndrome with a sensitivity rate of greater than 95%. This test is easy to perform and is not expensive; dexamethasone is also listed in the EML, albeit for use in palliative care. • Midnight cortisol (2). Overall, the evidence in adults indicates that both tests have similar performance, so choosing which one to use depends on feasibility and technical aspects (2). This application includes cortisol to diagnose both adrenal hypo- and hyperfunction. In low-resource settings, implementing one test for both conditions will be beneficial in terms of training, quality control, etc. Given the low incidence of Cushing’s disease and the fact that it can be properly diagnosed by measuring cortisol after a dexamethasone suppression test or overnight, we would not recommend including other tests to the EDL at the present time. Urinary free and salivary cortisol are also mentioned as alternative tests to diagnose Cushing’s; but these are not usually readily available in LMICs.

Public health relevance

Prevalence and socioeconomic impact Adrenal hypofunction. The prevalence of central adrenal insufficiency is reported to be 150–280 per million population, but is probably underestimated (7). It can be permanent (pituitary tumours, cranial injury from irradiation, surgery, trauma, infections) or transient (for weeks, months or even years, secondary to exogenous glucocorticoid withdrawal). This latter etiology has dramatically increased over the past decades. Glucocorticoids are largely used in the general population worldwide (up to 2%), and adrenal insufficiency after discontinuation is not only common but usually unrecognized. There is no glucocorticoid administration form, dosing, treatment duration or underlying disease that could exclude the risk of transient adrenal insufficiency, although higher doses and longer use give the highest risk (18). In a meta-analysis evaluating 3753 participants treated with corticosteroids for various conditions (19), the proportion of patients with adrenal insufficiency ranged from 4% for nasal administration to more than 50% for intra-articular administration. Stratified by disease, percentages ranged from slightly below 7% for asthma to 60% for haematological malignancies. The risk also varied according to dose and treatment duration. The prevalence of Addison’s disease is 82–144 cases per million (7). Autoimmunity is the most common cause in adults; other insults to the adrenal gland that lead to Addison’s disease include adrenal haemorrhage, cancer, infections (HIV, syphilis, TB, bacteria) and some medicines. Genetic causes, especially enzyme defects, are the most common cause in children. About half of paediatric cases can be attributed to congenital adrenal hyperplasia (8). These diverse causes mean no distinct group of individuals is at increased risk of disease. Well-informed patients with Addison’s disease undergoing currently accepted replacement therapy are considered to have a normal survival rate. But studies still show that mortality of patients with adrenal insufficiency is 1.5–2 times higher than the general population, particularly for patients diagnosed at a young age. Increased mortality in primary adrenal insufficiency is linked to adrenal crisis and sudden death, as well as cardiovascular, malignant, and infectious diseases (10). There is also significant morbidity and impact on quality of life. A model for measuring health burden in patients with congenital adrenal hyperplasia estimated that adrenal crisis results in an average loss of 7.3 years of life, or 9 QALYs (20). Adrenal hyperfunction. The reported total incidence of endogenous Cushing’s syndrome varies from 3 to 7 cases per million each year (21–23). But these figures likely underestimate the incidence of iatrogenic Cushing’s, undiagnosed mild hypercortisolism, and ectopic ACTH syndrome; the actual incidence of Cushing’s disease may be as high as 5–25 per million per year. The gender distribution of Cushing’s syndrome varies with the cause. Men used to have a three times greater incidence of the ectopic ACTH syndrome, but the increasing incidence of lung cancer in cigarette-smoking women has narrowed that margin (24). Women are more likely than men to develop Cushing’s disease, as well as either benign or malignant adrenal tumours. Age at presentation varies depending upon the cause of hypercortisolism (16). Incidence of ectopic ACTH syndrome increases rapidly after 50 years of age, as does lung cancer. Cushing’s disease occurs mainly in women 25–45 years of age (25). Adrenal tumours have a bimodal age distribution, with small peaks in the first decade of life and major peaks at approximately 40–50 years of age (26). Adrenal carcinoma accounts for half of all cases of childhood Cushing’s syndrome.

WHO or other clinical guidelines relevant to the test

Adrenal hypofunction. The Endocrine Society clinical practice guidelines for diagnosing and treating primary adrenal insufficiency (9) recommends the standard dose IV corticotropin stimulation test over other existing diagnostics tests to establish the diagnosis of adrenal insufficiency. If a corticotropin stimulation test is not feasible, they suggest using a morning cortisol < 140 nmol/L until confirmatory testing with corticotropin stimulation is available. The Society for Endocrinology Clinical Committee guidelines on emergency management of adrenal crisis in adults (27) recommends that, provided the patient is haemodynamically stable, a short ACTH test (serum cortisol at baseline and 30 min after IV injection of 250 mg of cortrosyn) should be done (27). The American Association of Family Physicians (28) similarly recommends using the ACTH stimulation test to diagnose primary adrenal insufficiency, which is also suggested as the best diagnostic test for children (29). A consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency (30) recommends measuring cortisol and ACTH levels as initial tests to diagnose adrenal insufficiency; but it also states that the cosyntropin test should be used to confirm the diagnosis (30). Adrenal hyperfunction. The Endocrine Society clinical practice guidelines for diagnosing Cushing’s syndrome (2) recommend various options depending on the patient suitability, including measuring urinary free cortisol (UFC) (at least two measurements) or late-night salivary cortisol (two measurements), or using the 1 mg overnight dexamethasone suppression test or the longer low-dose test (2 mg per day for 48 h). Confirmation of any abnormal results should be made by doing another of these recommended tests. In cases with a high pretest probability of Cushing’s syndrome but a normal initial test, an additional alternative test has the potential benefit of identifying those with milder disease. Midnight serum cortisol, though not recommended as an initial test, can be used for further confirmation after performing an initial dexamethasone suppression test. The Mexican Society consensus (31) is to perform two tests, such as the dexamethasone suppression test and UFC measurement; followed by midnight serum cortisol if there is a discrepancy between the two (31).

Evidence for diagnostic accuracy

No systematic reviews of serum/plasma cortisol assays were identified. The following summarizes accuracy reviews, test comparisons and relevant non-systematic reviews. Like all immunoassays, serum cortisol assays have some limitations. Recognition of these has led to some re-formulation of assays, and publications of inter-assay comparisons (32, 33). Inter-assay variation can be somewhat mitigated by using laboratory- or method-specific cut-offs and through appropriate interpretative support of cortisol test results (34, 35). Despite these limitations, serum cortisol measurement remains a key component of hypothalamic pituitary adrenal (HPA) axis assessment and management of patients with adrenal dysfunction. Adrenal hypofunction. For the ACTH stimulation tests, a meta-analysis by Kazlauskaite et al. (36) evaluating the diagnostic accuracy of cortisol measurement in ambulatory subjects with presumed normal sleep–wake cycle following high-dose corticotropin stimulation (250 mcg dose) to identify HPA insufficiency (defined relative to results of an insulin tolerance test or overnight metyrapone suppression test) showed that 30 min post-dose cortisol values of > 833 nmol/L ruled out adrenal insufficiency, while results of < 440 nmol/L were highly predictive of it, with an area under the curve (AUC) of 0.82 (95% CI: 0.78–0.86). Similarly, cortisol levels 30 min after a low-dose corticotropin stimulation (1 mcg dose) of < 440 nmol/L and > 600 nmol/L predicted adrenal insufficiency or a normal reference test, respectively, with an AUC of 0.94 (95% CI: 0.90–0.94). Using the low-dose protocol in low-resource settings may not prove a disadvantage, as it showed higher AUC or similar performance characteristics when compared with the high-dose protocol (36, 37). For screening, basal, fasting morning cortisol levels collected between 08:00 and 10:00 h of 365 nmol/L predicted normal HPA axis function with an AUC of 0.79 (95% CI: 0.75–82) (36). Adrenal hyperfunction. Chiondini et al. (38) reported that measuring serum cortisol after overnight suppression with 1 mg of dexamethasone had sensitivities of > 95% and specificities of 85–90%. Elamin et al. (39) did a meta-analysis comparing outcomes of an overnight dexamethasone suppression test with a reference standard for diagnosing Cushing’s syndrome and yielded a pooled positive likelihood ratio of 11.6 (95% CI: 5.8–23.1) and a negative likelihood ratio of 0.09 (95% CI: 0.05–0.14). Among the tests evaluated, the authors concluded that UFC and the overnight dexamethasone suppression test have the most evidence supporting their use for detection of Cushing’s syndrome. Hawley et al. (40) identify several limitations to immunoassays. These include heterogeneity between assays made by different vendors and cross-reactivity with structurally similar compounds, in the presence of altered serum components or acute illness, and with altered protein binding (e.g. in pregnancy). While reference materials for cortisol exist, there are well documented differences between methods of analysis and immunoassay vendors themselves, attributed to differences in antibodies used as well as the means of dissociating cortisol from its binding. Ortiz-Flores et al. (41) find that sex-specific and assay-specific serum cortisol cut-off values may improve the diagnostic accuracy but are not commonly used in practice. And Kline et al. (42) suggest that recalibration and reformulation of assay leads by vendors require evaluation of performance of new methods; as experienced with the recent release of an improved Cortisol II assay, stimulation test cut-offs in the literature may warrant closer examination in the context of new assays and specific patient populations. Struja et al. (43) evaluated patients who underwent ACTH stimulation tests and found basal cortisol levels of ≤ 100 and ≥ 450 nmol/L in almost half of patients tested for possible adrenal insufficiency, with high diagnostic accuracy, abolishing the need for formal ACTH testing. This supports measurement of basal cortisol as the first-line test, particularly in low-resource settings. Lopez Schmidt et al. (44) similarly found that using basal cortisol upper (285 nmol/L) and lower (98 nmol/L) cut-off points with high sensitivity and specificity can reduce the number of individuals who need provocative tests. Montes et al. (45) present similar results. A subnormal serum cortisol response 30 min after an ACTH stimulation test is a reliable marker of adrenal dysfunction for primary disease. But Ortiz-Flores et al. show that when central adrenal insufficiency is suspected, 60 min serum cortisol measurement improves the diagnostic accuracy of the test. Peechakara et al. (46) found no difference between low- and high-dose ACTH tests performance. As for Cushing’s syndrome, Barrou et al. (47) used a cut-off point of 1.9 nmol/L and found that the sensitivity remained at 100% and the specificity was 94%. They clearly recommended it as one of the screening tests for Cushing’s syndrome. Tang et al. (48) conclude that overnight low-dose dexamethasone suppression test and late-night plasma total cortisol have similar values in the initial diagnosis of Cushing’s syndrome, but the dexamethasone suppression test is more convenient in an outpatient environment.

Evidence for clinical usefulness and impact

Adrenal hypofunction. There are no modern studies comparing replacing therapy with no treatment, due to the proven life-threatening consequences of the latter. Treatment is guided by experts’ recommendations, aiming to mimic physiological secretion, both on a usual basis and in times of stress. There are also no randomized controlled studies evaluating glucocorticoid dose requirements in patients with adrenal insufficiency during times of increased cortisol need, and so the doses recommended to treat adrenal crisis are largely set on an empirical basis. Glucocorticoid dose is typically based on the severity and duration of the stressor. Current recommendations place a higher value on preventing underdosage than on reducing potential negative effects of short-term overdosage, as there are no clear data on the potential consequences of the latter, and undertreatment can have significant deleterious effects. Ho and Druce (49) did a systematic review involving patients with either primary or adrenal insufficiency and Cushing’s syndrome from any cause; and showed that quality of life is reduced in both groups and that while it improves with treatment, it is not completely reversed. Al Nofal et al. (12) did a systematic review of different glucocorticoids regimens, which showed some preliminary low-quality evidence of improved quality of life with new forms such as extended-/dual-release, and continuous subcutaneous forms. But studies could not show any relationship between glucocorticoid type and dose and bone loss or rates of adrenal crisis. Non-systematic reviews on the treatment of adrenal insufficiency address the benefits of treatment with steroids; but these reviews also identify the challenges, including finding the right dosing and frequency of administration (50), lack of complete resolution of morbidity (51), the need for education and availability of emergency treatment for adrenal crisis (52), and issues affecting (53). There are few studies evaluating the impact of treatment for adrenal insufficiency and adrenal crisis. It is considered standard practice and recommended by every clinical guideline. Current studies focus on dosage and pharmacological forms that could be associated with fewer adverse effects and improve compliance. A small study by Wichers et al. (54) on hydrocortisone doses for the treatment of secondary adrenal insufficiency showed that lower doses (15–20 mg/day) had similar effects on well-being as higher doses, avoiding the risk of adverse bone health effects. Another study by Laureti et al. (55) showed benefits of thrice-daily administrations of cortisone acetate in patients with primary adrenal insufficiency compared with twice-daily dosing, with increased total UFC excretion and reduced plasma ACTH levels. Mah et al. (56) studied steroid dose adjustment by weight or body surface area in patients with primary adrenal insufficiency and showed benefits in terms of more physiological cortisol levels compared to fixed-dose regimens. Johansson et al. (57) studied oral dual-release hydrocortisone, and showed benefits including more circadian-based serum cortisol profile and metabolic improvements in body weight, blood pressure and glucose metabolism. Adrenal hyperfunction. Broersen et al. (58) did a systematic review of endoscopic vs microscopic surgery for Cushing’s disease and found remission rates of 80% with either technique (with a tendency towards better results for macroadenomas with endoscopic procedure), and short-term mortality below 0.5%. Another study by Petersen et al. (59) showed-low quality evidence for benefits of microscopic transsphenoidal surgery, which provided remission rates of 42–96% (median 77.9%); recurrence was 0–47.4% with a median of 11.5%. Ritzel et al. (60) did a review on bilateral adrenalectomy showing adequate success with residual cortisol secretion from 3% to 34% and less than 2% relapse. Surgical morbidity was 18% and mortality 3%, but the latter increased to 17% on the first year after surgery, suggesting the need to improve postoperative care . A systematic review and meta-analysis by Broersen et al. (61) on medical treatment for Cushing’s showed effective cortisol normalization in a large percentage of patients, supporting medical treatment as a reasonable option when surgery is not available or is non-curative. Therapy with multiple agents led to normal cortisol levels in up to 65% of patients. Another review by Fleseriu and Castinetti (62) focused on new drugs and showed promising results for efficacy and safety of current and emerging adrenal steroidogenesis inhibitors, although these still have to be confirmed in larger-scale phase 3 studies. Finally, van Haalen et al. (63) showed that mortality in patients with Cushing’s disease remains increased even after initial biochemical cure remission. The hypothesis is that this is because of the metabolic consequences of long-term overexposure to cortisol, which may provide support for early diagnosis and treatment. Clayton et al. (64) did a study on mortality and morbidity in Cushing’s disease, which also included a meta-analysis of previous reports, and showed a twofold increase in mortality compared with the general population. Patients in remission, however, fare much better and appear not to have a higher death rate; hypertension and diabetes mellitus are risk factors for worse outcomes. Similarly, Hammer et al. (65) studied transsphenoidal surgery for Cushing’s disease and showed that successful treatment of Cushing’s disease is associated with normal long-term survival, as opposed to initial persistent disease, supporting the need for early and aggressive intervention. Another study by Faggiano et al. (66) on cardiovascular risk factors in patients with Cushing’s showed improvement of various parameters one year after remission, although these were still abnormal compared with healthy controls. And a small study by Davies et al. (67) on children with Cushing disease, all of whom were cured with surgery (with or without radiotherapy), found that most achieved an adult height within target. Excess adiposity improved with treatment but was still greater than in the general population.

Evidence for economic impact and/or cost–effectiveness

None provided.

Ethical issues, equity and human rights issues

The availability of laboratory studies to diagnose adrenal insufficiency should not prevent prompt therapy in an acutely ill patient with possible adrenal crisis, which is a life-threatening condition. If cortisol levels are measured and ACTH stimulation testing is not available, providing steroid replacement therapy and stress dosing to all patients with low or borderline-normal morning cortisol levels is the safest and recommended approach. Given the low prevalence of Cushing’s disease, testing should not be performed unless it is based on reasonable clinical suspicion. Wider availability of the cortisol levels test should not lead to unnecessary testing; false-positive results, with their attendant costs, are reduced if case detection is limited to individuals with an increased pretest probability of having the disorder. Adrenal hypofunction. If the cortisol levels test becomes available, it should reduce inequity, especially in resource-limited settings, by helping diagnose adrenal insufficiency and providing steroid replacement therapy and stress dosing in a timely manner to those who need them, and by preventing their misuse in patients with preserved adrenal function. Adrenal hyperfunction. Cosyntropin is currently not available in many low-income settings. Should the cortisol levels test be added to the EDL, an application for including cosyntropin in the next EML might need to be considered.
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