The conundrum of differentiating Cushing's syndrome from non-neoplastic hypercortisolism: a systematic review and meta-analysis.

CONTEXT: Once hypercortisolemia is confirmed, differential diagnosis between Cushing's syndrome (CS) due to neoplastic endogenous hypercortisolism and non-neoplastic hypercortisolism (NNH, pseudo-Cushing's syndrome) is crucial. Due to worldwide corticotropin-releasing hormone (CRH) unavailability, accuracy of alternative tests to dexamethasone (Dex)-CRH, is clearly needed. OBJECTIVE: Assess the diagnostic accuracy of Dex-CRH test, desmopressin stimulation test, midnight serum cortisol (MSC), and late-night salivary cortisol (LNSC) levels to distinguish CS from NNH. METHODS: Articles through March 2022 were identified from Scopus, Web of Science, MEDLINE, EMBASE, and PubMed. All steps through the systematic review were performed independently and in duplicate and strictly adhered to the updated PRISMA-DTA checklist. DATA SYNTHESIS: A total of 24 articles (1900 patients) were included. Dex-CRH had a pooled sensitivity and specificity of 91% (95%CI 87-94%; I2 0%) and 82% (73-88%; I2 50%), desmopressin test 86% (81-90%; I2 28%) and 90% (84-94%; I2 15%), MSC 91% (85-94%; I2 66%) and 81% (70-89%; I2 71%), and LNSC 80% (67-89%; I2 57%) and 90% (84-93%; I2 21%), respectively. Summary receiver operating characteristics areas under the curve were Dex-CRH 0.949, desmopressin test 0.936, MSC 0.942, and LNSC 0.950 without visual or statistical significance. The overall risk of studies bias was moderate. CONCLUSION: Dex-CRH, the desmopressin stimulation test, and MSC have similar diagnostic accuracy, with Dex-CRH and MSC having slightly higher sensitivity, and the desmopressin test being more specific. LNSC was the least accurate, probably due to high heterogeneity, intrinsic variability, different assays, and lack of consistent reported cutoffs. When facing this challenging differential diagnosis, the results presented here should increase clinicians' confidence when deciding which test to perform.

Second-line tests in the differential diagnosis of neoplastic and non-neoplastic hypercortisolism: a systematic review and meta-analysis.

PURPOSE: The clinical and hormonal overlap between neoplastic (CS) and non-neoplastic (NNH/pCS) hypercortisolism is a challenge. Various dynamic tests have been proposed to allow an early discrimination between these conditions, but to date there is no agreement on which of them should be used. AIM: To provide an overview of the available tests and to obtain a quantitative synthesis of their diagnostic performance in discriminating NNH/pCS from CS. METHODS: The included articles, published between 1990 and 2022, applied one or more second line tests to differentiate NNH/pCS from CS patients. For the NNH/pCS group, we admitted the inclusion of patients presenting clinical features and/or biochemical findings suggestive of hypercortisolism despite apparent lack of a pCS-related condition. RESULTS: The electronic search identified 339 articles. After references analysis and study selection, we identified 9 studies on combined dexamethasone-corticotropin releasing hormone (Dex-CRH) test, 4 on Desmopressin test and 3 on CRH test; no study on Dex-Desmopressin met the inclusion criteria. Dex-CRH test provided the highest sensitivity (97%, 95 CI% [88%; 99%]). CRH tests showed excellent specificity (99%, 95% CI [0%; 100%]), with low sensitivity. Although metaregression analysis based on diagnostic odds ratio failed to provide a gold standard, CRH test (64.77, 95% CI [0.15; 27,174.73]) seemed to lack in performance compared to the others (Dex-CRH 138.83, 95% CI [49.38; 390.32] and Desmopressin 110.44, 95% CI [32.13; 379.63]). DISCUSSION: Both Dex-CRH and Desmopressin tests can be valid tools in helping discrimination between NNH/pCS and CS. Further studies are needed on this topic, possibly focusing on mild Cushing's Disease and well-characterized NNH/pCS patients. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022359774 , identifier CRD42022359774.

The addition of corticotropin-releasing hormone to 2-day low dose dexamethasone suppression test provides additional case detection.

ABSTARCT: PURPOSE: The diagnostic value of adding a Corticotropin-Releasing Hormone (CRH) Stimulation Test to the 2-day Low Dose Dexamethasone Suppression Test (Dex-CRH Test) has been debated in the literature. METHODS: We identified 65 patients with Cushing disease (CD) and 42 patients in whom a diagnosis of Cushing disease could not be confirmed (NCD) after a minimum follow-up of 14 months who underwent the Dex-CRH test. RESULTS: The female sex ratio, median (range) age, and BMI were similar between the two groups. The follow-up for patients with CD and NCD was 74 (4-233) and 52 (14-146) months, respectively. Among 65 patients with CD, 5 (7.7%) had a cortisol level ≤1.4 µg/dl after LDDST but were appropriately classified as CD with a cortisol level >1.4 µg/dL at 15-min post CRH stimulation. In contrast, 3/42 patients (7.1%) in NCD had an abnormal Dex-CRH test. In only one of three patients, the LDDST was marginally normal (cortisol was 1.4 µg/dL and increased to 3.1 µg/dL 15-min post CRH). A cortisol cutoff value of >1.4 µg/dL during the Dex-CRH test provided a sensitivity of 100%, specificity of 93%, and diagnostic accuracy of 97% to diagnose CD. When patients without a Dex level were excluded (n = 74), the sensitivity did not change, but the specificity and accuracy of the Dex-CRH test increased to 97 and 99%, respectively. CONCLUSION: The Dex-CRH Test provided additional case detection in 5/65 (7.7%) patients with CD. It resulted in one false-positive case compared to LDDST. Measurement of dexamethasone improved diagnostic accuracy of the test.

Dynamic Testing for Differential Diagnosis of ACTH-Dependent Cushing Syndrome: A Systematic Review and Meta-analysis.

CONTEXT: Diagnostic accuracy of testing currently used for the differential diagnosis of Cushing disease (CD) vs ectopic adrenocorticotropic hormone secretion (EAS) is difficult to interpret. OBJECTIVE: The present study aimed to identify and evaluate the diagnostic accuracy of the corticotropin-releasing hormone (CRH) test, the desmopressin test, and the high-dose dexamethasone suppression test (HDDST) when used to establish a CD or EAS diagnosis. METHODS: This study is a systematic review of the literature and meta-analysis. MEDLINE, OVID, and Web of Science databases were searched for articles published between 1990 and 2021. Articles included described at least 1 test(s) (CRH, desmopressin, or HDDST) and the diagnostic reference standard(s) (histopathology, petrosal sinus sampling, surgical remission, imaging, and long-term follow-up) used to establish a CD or EAS diagnosis. RESULTS: Sixty-two studies were included: 43 reported the use of the HDDST; 32, the CRH test; and the 21, the desmopressin test. The CRH test was found to have the highest sensitivity in detecting CD (ACTH 86.9%, 95% CI 82.1-90.6, cortisol 86.2%, 95% CI 78.3-91.5) and the highest specificity in detecting EAS (ACTH 93.9%, 95% CI 87-98.3, cortisol 89.4%, 95% CI 82.8-93.7). This resulted in a high diagnostic odds ratio (58, 95% CI 43.25-77.47), large area under the curve, and a receiver operating characteristic of 0.934. The diagnostic accuracy of the HDDST and desmopressin test was lower than that of the CRH test. CONCLUSION: The meta-analysis indicates that a patient with a positive ACTH response after a CRH test is highly likely to have CD. Further studies analyzing role of dynamic testing in addition to imaging are needed.

Pediatric Cushing's disease: Case reports and retrospective review.

BACKGROUND: We report four pediatric subjects with Cushing's disease (CD) diagnosed in the Czech Republic. We focus on initial symptoms of Cushing's syndrome (CS) which can lead to early diagnosis, on typical symptoms of CS in children, their age and sex distribution, the mean length of symptoms prior to diagnosis, indication for examination, post-cure growth, sexual development and pituitary function in our four CD patients after transsphenoidal pituitary surgery (TSS). We describe the diagnostic process leading to confirmation of CD and we emphasize the biochemical and radiological diagnostic difficulties. CONCLUSIONS: Pediatric CD has a number of features distinct from adult CD. Our retrospective analysis confirmed the presence of growth retardation and change in facial appearance with development of moon face as the first symptoms of CS. According to our observation, growth retardation is prior to development of moon face. The other typical symptoms frequently seen in pediatric patients are pseudo-precocious puberty in both sexes, hirsutism in pubertal girls due to excessive adrenal androgen secretion and pubertal delay. A corticotropin-releasing hormone (CRH) test and especially bilateral inferior petrosal sinus sampling for ACTH (BIPSS) contribute to confirming the diagnosis of CD and excluding ectopic ACTH syndrome in children with unvisible adenoma on pituitary magnetic resonance imaging (MRI).

An attempt to create a treatment algorithm of central adrenal insufficiency using CRH test, DHEA-S and clinical evaluation.

Objective : To examine diagnostic performance of corticotropin-releasing hormone (CRH) test combined with baseline dehydroepiandrosterone sulfate (DHEA-S) in patients with a suspect of central adrenal insufficiency. Methods : Patients (n=215) requiring daily or intermittent hydrocortisone replacement, or no replacement were retrospectively checked with their peak cortisol after CRH test and baseline DHEA-S. Results :  None of 106 patients with the peak cortisol ≥ 17.5 µg / dL after CRH test required replacement, and all 64 patients with the peak cortisol < 10.0 µg / dL required daily replacement. Among 8 patients with 10.0 µg / dL ≤ the peak cortisol < 17.5 µg / dL and baseline DHEA-S below the reference range, 6 patients required daily replacement and 1 patient was under intermittent replacement. Among 37 patients with 10.0 µg / dL ≤ the peak cortisol < 17.5 µg / dL and baseline DHEA-S within the reference range, 10 and 6 patients were under intermittent and daily replacement, respectively. Conclusions : No patients with the peak cortisol ≥ 17.5 µg / dL required hydrocortisone replacement, and all patients with the peak cortisol below 10.0 µg / dL required daily replacement. Careful clinical evaluation was required to determine requirement for replacement in patients with 10.0 µg / dL ≤ the peak cortisol < 17.5 µg / dL even in combination with baseline DHEA-S. J. Med. Invest. 69 : 287-293, August, 2022.

Biochemical testing to differentiate Cushing's disease from ectopic ACTH syndrome.

The differential diagnosis of ACTH-dependent Cushing's syndrome is often a diagnostic challenge that has been debated in numerous studies. In this short article, we will discuss the performance and main drawbacks of the biochemical tests used for this diagnosis.

The co-chaperone FKBP51 modulates HPA axis activity and age-related maladaptation of the stress system in pituitary proopiomelanocortin cells.

Glucocorticoid (GC)-mediated negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, the body's physiological stress response system, is tightly regulated and essential for appropriate termination of this hormonal cascade. Disturbed regulation and maladaptive response of this axis are fundamental components of multiple stress-induced psychiatric and metabolic diseases and aging. The co-chaperone FK506 binding protein 51 (FKBP51) is a negative regulator of the GC receptor (GR), is highly stress responsive, and its polymorphisms have been repeatedly associated with stress-related disorders and dysfunctions in humans and rodents. Proopiomelanocortin (Pomc)-expressing corticotropes in the anterior pituitary gland are one of the key cell populations of this closed-loop GC-dependent negative feedback regulation of the HPA axis in the periphery. However, the cell type-specific role of FKBP51 in anterior pituitary corticotrope POMC cells and its impact on age-related HPA axis disturbances are yet to be elucidated. Here, using a combination of endogenous knockout and viral rescue, we show that male mice lacking FKBP51 in Pomc-expressing cells exhibit enhanced GR-mediated negative feedback and are protected from age-related disruption of their diurnal corticosterone (CORT) rhythm. Our study highlights the complexity of tissue- and cell type-specific, but also cross-tissue effects of FKBP51 in the rodent stress response at different ages and extends our understanding of potential targets for pharmacological intervention in stress- and age-related disorders.

The Cortisol and ACTH Response to Dex/CRH Testing in Women With and Without Perimenopausal Depression.

CONTEXT: Abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are frequent accompaniments of depression, and studies have documented the role of stress and stressful life events in the ontogeny of perimenopausal depressions (PMD). Because HPA axis function in women is further modulated both by aging and ovarian steroids, it is possible that a dysregulated HPA axis contributes to the increased risk of PMD. OBJECTIVE: We examined HPA axis function in perimenopausal women with and without depression using the combined dexamethasone-corticotropin-releasing hormone (Dex/CRH) test. METHODS: Dex/CRH tests were performed on 20 women with PMD and 20 women who were also perimenopausal but without current or past depression (control women). Main outcome measures were plasma levels of cortisol and adrenocorticotropin (ACTH) and 24-hour urinary free cortisol (UFC). Five women took chronic stable medications, otherwise all women were medically healthy, and both groups were comparable with respect to reproductive stage and age. Standardized symptom rating scales were administered to each woman prior to Dex/CRH testing. RESULTS: No group differences were present in either baseline or stimulated ACTH and cortisol secretion. Baseline plasma measures of estradiol, progesterone, and 24-hour UFC levels similarly did not differ in PMD and control women. CONCLUSION: Despite reports of increased stress responsiveness in PMD, we observed no abnormalities of HPA axis activity associated with PMD compared with women without depression. These findings suggest that PMD is not uniformly associated with HPA dysregulation and could reflect underlying pathophysiologic processes that are distinct from women with nonreproductive-related depressions.

Hormonal responsiveness in the Trier Social Stress Test and the dexamethasone-corticotropin releasing hormone test in healthy individuals.

A number of different laboratory procedures investigate the hormonal response in a standardized pharmacological challenge test (dexamethasone-corticotropin releasing hormone; DEX-CRH) or in a psychosocial stress induction on the hypothalamic-pituitary-adrenocortical axis by the Trier Social Stress Test (TSST). However, the magnitude of the response related to the different stressors and the interaction of the responsiveness between the two tests is still unclear. Fifty-two participants underwent both the DEX-CRH test and the TSST on two separate days. The cortisol and the plasma adrenocorticotropic hormone (ACTH) release were assessed before and after the stress tests. For a specification of the cortisol response to both conditions, subgroups of high- and low-cortisol responders to the TSST and the DEX-CRH test were formed. The healthy participants showed a substantial increase in the ACTH and the cortisol concentration after the two tests. This increase was 3 times greater in the TSST than the DEX-CRH test. High responders in both tests demonstrated a higher factor of the cortisol reactivity ratio (TSST/DEX-CRH test). Psychosocial stress as induced by the TSST was associated with a significantly greater increase in cortisol compared to the DEX-CRH test, even though the ACTH response displayed no differences. Our findings indicate an interaction of the hormonal responsiveness between the two tests with regard to the cortisol patterns.

Non-invasive Diagnostic Strategy in ACTH-dependent Cushing's Syndrome.

CONTEXT: Inferior petrosal sinus sampling (IPSS) is used to diagnose Cushing's disease (CD) when dexamethasone-suppression and CRH tests, and pituitary magnetic resonance imaging (MRI), are negative or give discordant results. However, IPSS is an invasive procedure and its availability is limited. OBJECTIVE: To test a noninvasive diagnostic strategy associated with 100% positive predictive value (PPV) for CD. DESIGN: Retrospective study. SETTING: Two university hospitals. PATIENTS: A total of 167 patients with CD and 27 patients with ectopic ACTH-syndrome investigated between 2001 and 2016. MAIN OUTCOME MEASURE(S): Performance of a strategy involving the CRH and desmopressin tests with pituitary MRI followed by thin-slice whole-body computed tomography (CT) scan in patients with inconclusive results. RESULTS: Using thresholds of a cortisol increase > 17% with an ACTH increase > 37% during the CRH test and a cortisol increase > 18% with an ACTH increase > 33% during the desmopressin test, the combination of both tests gave 73% sensitivity and 98% PPV of CD. The sensitivity and PPV for pituitary MRI were 71% and 99%, respectively. CT scan identified 67% EAS at presentation with no false-positives. The PPV for CD was 100% in patients with positive responses to both tests, with negative pituitary MRI and CT scan. The Negative Predictive Value was 100% in patients with negative responses to both tests, with negative pituitary MRI and positive CT scan. Using this strategy, IPPS could have been avoided in 47% of patients in whom it is currently recommended. CONCLUSIONS: In conjunction with expert radiologic interpretation, the non-invasive algorithm studied significantly reduces the need for IPSS in the investigation of ACTH-dependent Cushing's syndrome.

Accuracy of Laboratory Tests for the Diagnosis of Cushing Syndrome.

CONTEXT: The diagnosis of Cushing syndrome (CS) can be challenging. It remains to be determined which diagnostic tests are the most accurate. OBJECTIVE: To summarize the accuracy of diagnostic tests for CS using contemporary meta-analytic techniques (hierarchical models). DATA SOURCES: PubMed, Embase, Scopus, Web of Science, and the Cochrane Database of Systemic Reviews (inception until August 3, 2018). STUDY SELECTION: Studies performed in adults that determined the accuracy of one or more diagnostic tests: overnight 1-mg dexamethasone suppression test (DST), 2-day low-dose DST (2d DST), 24-hour urinary free cortisol (UFC), late-night salivary cortisol (LNSC), midnight serum cortisol (MSC), and the dexamethasone-suppressed CRH (dex-CRH) and desmopressin (dex-DDAVP) tests. DATA EXTRACTION: Two authors independently extracted data and performed methodological assessments. DATA SYNTHESIS: One hundred thirty-nine studies (14 140 participants) were included in the analysis. The respective sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio (95% confidence interval [CI]) estimates include the following: DST 98.6% (96.9%-99.4%), 90.6% (86.4%-93.6%), 10.5 (7.2-15.3), and 0.016 (0.007-0.035); 2d DST 95.3% (91.3%-97.5%), 92.8% (85.7%-96.5%), 13.2 (6.47-27.1), and 0.051 (0.027-0.095); UFC 94.0% (91.6%-95.7%), 93.0% (89.0%-95.5%), 13.3 (8.47-21.0), and 0.065 (0.046-0.092); LNSC 95.8% (93.%-97.2%), 93.4% (90.7%-95.4%), 14.6 (10.3-20.7), and 0.045 (0.030-0.066); MSC 96.1% (93.5%-97.6%), 93.2% (88.1%-96.3%), 14.2 (7.96-25.2), and 0.042 (0.026-0.069); and dex-CRH 98.6% (90.4%-99.8%), 85.9% (67.6%-94.7%), 7.0 (2.80-17.6), and 0.016 (0.002-0.118). A single study evaluated dex-DDAVP. Meta-regression and a novel network meta-analytic approach suggest that DST is the most sensitive while UFC is the least sensitive. CONCLUSIONS: All of the included diagnostic tests for CS are highly sensitive and specific. It appears that the DST is the most sensitive while the UFC is less sensitive. The specificity of all first-line tests appears comparable.

Central noradrenaline transporter availability is linked with HPA axis responsiveness and copeptin in human obesity and non-obese controls.

The central noradrenaline (NA) stress-response network co-mediates hypothalamic-pituitary-adrenal (HPA) axis activation and arginine-vasopressin (AVP) release. Dysregulation of these systems contributes to stress-related diseases such as human obesity, but their interrelation remains unclear. The study was aimed to test for the first time in vivo whether central noradrenergic activity quantitatively indexed by the availability of the presynaptic NA transporter (NAT) is associated with HPA axis responsiveness as measured with the combined dexamethasone suppression/corticotropin releasing hormone stimulation (dex/CRH) test and copeptin as a surrogate marker of the serum AVP tone in highly obese, otherwise, healthy individuals compared to age- and sex-matched non-obese, healthy controls. In order to assess central NAT availability, positron emission tomography (PET) was applied using the NAT-selective radiotracer S,S-[11C]O-methylreboxetine (MRB) and correlated with curve indicators derived from the dex/CRH test (maximum, MAX, and area under the curve, AUC, for cortisol and adrenocorticotropic hormone, ACTH) as well as with copeptin. In non-obese controls, positive correlations were found between the NAT distribution volume ratios (DVR) of the orbitofrontal cortex (OFC) and the amygdala with the HPA response (OFC: ACTHMAX r = 0.87, p = .001; cortisolMAX r = 0.86, p = .002; amygdala: ACTHMAX r = 0.86, p = .002; cortisolMAX r = 0.79, p = .006), while in obesity, the hypothalamic DVR correlated inversely with the HPA axis response (cortisolMAX, r = -0.66, p = .04) and with copeptin (r = -0.71, p = .02). This association of central NAT availability with HPA axis responsiveness and copeptin suggests a mechanistic interaction between noradrenergic transmission with HPA axis activity and the serum AVP system that differs between non-obese individuals with prefrontal-limbic involvement and obesity with a hypothalamic-centered relationship. Whether the latter finding contributes to obesogenic behavior needs to be further explored.

The difficulties of pseudo-Cushing's syndrome (or "non-neoplastic hypercortisolism").

Pseudo-Cushing's syndrome covers different pathological conditions responsible for mild-to-moderate ACTH-dependent hypercortisolism, related not to an ACTH-secreting tumor but rather to CRH and/or AVP hypothalamic secretion through activation of various neural pathways, in patients generally displaying excess central adiposity. It is better termed "non-neoplastic hypercortisolism" (NNH). The main conditions implicated in NNH comprise: neuropsychiatric disorder, alcohol abuse, insulin-resistant obesity, polycystic ovary syndrome, and end-stage kidney disease. Glucocorticoid resistance is one differential diagnosis, as are some cases of primary adrenal disease with incompletely suppressed ACTH. Differentiating between NNH and mild-to-moderate Cushing's disease can be a real challenge. Clinical analysis, based on thorough history taking and screening for catabolic signs is essential; useful explorations include midnight serum or salivary cortisol and Dex/CRH and ddAVP stimulation response. Pituitary MRI suffers from limitations regarding both sensitivity and specificity, while bilateral inferior petrosal sinus sampling cannot distinguish between pituitary ACTH secretion by a tumor or by normal cells stimulated by endogenous CRH. Definitive diagnosis of functional etiology requires demonstrating that treatment of the underlying condition restores normal secretion of ACTH and cortisol, but this is not always possible. Lingering diagnostic uncertainty has to be accepted in certain patients, who will have to be followed up for some time before diagnosis can be considered more or less definitive.

How to measure glucocorticoid receptor's sensitivity in patients with stress-related psychiatric disorders.

Stress is a state of derailed homeostasis and a main environmental risk factor for psychiatric diseases. Chronic or uncontrollable stress may lead to a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which is a common feature of stress-related psychiatric disorders. One of the key mechanisms underlying a disturbed HPA axis is an impaired function of the glucocorticoid receptor (GR) with an enhanced or reduced feedback sensitivity for glucocorticoids and subsequently altered concentrations of peripheral cortisol. GR function is regulated by a multiprotein complex including the different expression of the hsp90 co-chaperone FK 506 binding protein 51 (FKBP5) that may be genetically determined or acquired in response to stressful stimuli. Specific patterns of a dysregulation of the HPA axis and GR function are found in different stress-related psychiatric entities e.g. major depression, job-related exhaustion or posttraumatic stress disorder. GR challenge tests like the dexamethasone-suppression test (DST), the dexamethasone-corticotropin-releasing hormone (dex-CRH) test or most recently the analysis of the dexamethasone-induced gene expression are employed to sensitively measure HPA axis activity in these disorders. They provide information for a stratification of phenotypic similar but neurobiological diverse psychiatric disorders. In this review we present a synopsis of GR challenge tests with a focus on the application of the DST, the CRH test and the dex-CRH test as well as the dexamethasone-induced gene expression in stress-related psychiatric entities.

Sex-related differential response to dexamethasone in endocrine and immune measures in depressed in-patients and healthy controls.

Although sex differences in major depression have been reported repeatedly, the underlying mechanisms are still disputed. The rapidly changing gonadal steroid concentrations of the postpartum period or during menopause have been shown to be associated with depressive symptoms and to modulate the hypothalamic-pituitary-adrenal (HPA)-axis, which is implicated in depression. The sample comprised of 128 depressed in-patients (36.7% women) and 166 healthy controls (30.0% women). Blood was collected at baseline (at 6pm) and then 3 h as well as 21 h after ingestion of 1.5 mg dexamethasone for measurement of cortisol, ACTH and blood count. To further assess the function of the HPA-axis the dexamethasone/corticotrophin releasing hormone (Dex-CRH) test was performed in a subsample of 115 patients and 116 controls the following day. A significant interaction effect between sex, disease and ACTH concentrations over time after dexamethasone stimulation was observed, with men showing increased ACTH concentrations at baseline and after 21 h, while there was no difference after 3 h (p = .007). After separating for disease status this significant interaction effect was only observed in controls (p = .005). The cortisol response in the dex-CRH test was enhanced in female compared to male controls (p = .002). Leucocytes showed a stronger increase upon dexamethasone administration only in female compared to male controls (p = .023). These findings suggest a higher glucocorticoid receptor sensitivity following in-vivo glucocorticoid stimulation in healthy women that was absent in depressed patients. The sex-related differences in HPA-axis regulation and immune system function may contribute to the vulnerability of female sex to the development of depression.

The dexamethasone corticotropin releasing hormone test in healthy and depressed women with and without childhood adversity.

BACKGROUND: Alterations of the hypothalamic-pituitary-adrenal (HPA) axis are a prominent finding in patients with major depressive disorder (MDD). Inconsistencies regarding a hyper- or hypoactive HPA axis may be explained by the moderating effect of childhood adverse experiences (ACE) which are associated with both HPA axis dysfunction and MDD in adulthood. We aimed to systematically disentangle the effects of ACE and MDD on HPA axis by comparing healthy women with and without childhood adversity and women with MDD with and without ACE. METHODS: The dexamethasone/corticotropin-releasing hormone (DEX/CRH) test was administered in 35 women with MDD and ACE as determined by a clinical interview (SCID, Early Trauma Inventory), 51 women with MDD without ACE, 21 women with ACE but no current or lifetime MDD and 37 healthy women without either MDD or ACE. RESULTS: There were no group differences in age, smoking, body mass index, and intake of oral contraceptives. Free salivary cortisol responses were not significantly different between the four groups. CONCLUSIONS: This study shows no evidence for a dysregulation of the HPA axis as measured by the DEX/CRH test in depressed women with and without childhood adversity as compared to mentally healthy women with or without early life stress. Our results do not support the assumption of distinct neuroendocrine endophenotypes in MDD with regard to ACE.

Copeptin as a marker of an altered CRH axis in pituitary disease.

BACKGROUND: Copeptin (pre-proAVP) secreted in equimolar amounts with vasopressin closely reflects vasopressin release. Copeptin has been shown to subtly mirror stress potentially mediated via corticotrophin-releasing hormone. To further test a potential direct interaction of corticotrophin-releasing hormone with copeptin release, which could augment vasopressin effects on pituitary function, we investigated copeptin response to corticotrophin-releasing hormone. PATIENTS AND METHODS: Cortisol, adrenocorticotropin and copeptin were measured in 18 healthy controls and 29 subjects with a history of pituitary disease during standard corticotrophin-releasing hormone test. RESULTS: Patients with previous pituitary disease were subdivided in a group passing the test (P1, n = 20) and failing (P2, n = 9). The overall copeptin response was higher in controls than in subjects with pituitary disease (area under the curve, p = 0.04 for P1 + P2) with a maximum increase in controls from 3.84 ± 2.86 to 12.65 ± 24.87 pmol/L at 30 min, p < 0.05. In contrast, both groups of pituitary patients lacked a significant copeptin response to corticotrophin-releasing hormone, and even in P1, where adrenocorticotropin concentrations increased fourfold (mean, 21.48 vs. 91.53 pg/mL, p < 0.01), copeptin did not respond (e.g., 4.35 ± 5.81 vs. 5.36 ± 6.79 pmol/L, at 30 min, p = ns). CONCLUSIONS: Corticotrophin-releasing hormone is able to stimulate copeptin release in healthy controls suggesting a direct interaction of corticotrophin-releasing hormone and vasopressin/vasopressin. Interestingly, this relation is altered already in the group of pituitary patients who pass the standard corticotrophin-releasing hormone test indicating (1) the corticotrophin-releasing hormone-adrenocorticotropin-cortisol response is largely independent from the vasopressin system, but (2) the corticotrophin-releasing hormone-vasopressin interaction reflected by copeptin may be much more sensitive to reveal subtle alterations in the regulation of pituitary function.