Abnormal Cortisol Secretion Research Articles

7822 Mild Autonomous Cortisol Secretion In High Suspicious Adrenal Incidentaloma

Abstract Disclosure: N. Zavrashvili: None. N. Margvelashvili: None. K. Chanturishvili: None. Mild Autonomous Cortisol Secretion in High Suspicious Adrenal IncidentalomaIntroduction: Incidentally discovered adrenal masses are common and mostly benign and non-functioning adenomas. However, evolving evidence suggests that a notable proportion of these adrenal adenomas may demonstrate mild autonomous cortisol secretion (MACS), which has been associated with an increased risk for hypertension, hyperglycemia, obesity, dyslipidemia, vertebral fractures, adverse cardiovascular events, and mortality. 55-year-old women with 5-year history of hypertension and hyperlipidemia. She was treated with a three-drug program: verapamil 250 mg daily, combined B-blocker, atenolol 100 mg and chlorthalidone 25 mg daily. Blood pressure control remained suboptimal. Her body mass index was 29,5 kg/m2. She had no signs or symptoms of overt Cushing syndrome.She was referred to CT coronary angiogram by her cardiologist, which revealed adrenal incidentaloma.Adrenal dedicated CT showed left-sided 3,4 cm high density node (41HU), with absolute washout <60. She was consulted by oncologist to exclude adrenal metastasis. The baseline laboratory test results excluded PA and Pheochromocytoma. The diagnosis of glucocorticoid secretory autonomy was based on positive low-dose dexamethasone suppression test (DST), low serum ACTH concentration, low-normal DHEA-S and lack of complete suppression of serum cortisol with an overnight 8-mg DST. Patient was referred to left-sided laparoscopic adrenalectomy with perioperative glucocorticoid coverage (100 mg hydrocortisone administered IV and again 8 hours later). Conclusion: Mild autonomous cortisol secretion is a term used to describe biochemical evidence of abnormal cortisol secretion in patients with adrenal incidentaloma, but without the classical external manifestations of overt CS, such as central muscle weakness, adipose tissue redistribution, and skin fragility. The management of patients with an incidentally discovered adrenal adenoma who do not have overt Cushing’s syndrome but who have MACS is more controversial as the available studies comparing outcomes of adrenalectomy vs conservative management have been generally small. It is associated with an increased risk of Type 2 diabetes mellitus, HBP, obesity, dyslipidemia, and global cardiovascular risk. Therefore, it is of great importance to correctly identify these patients. There are different tests for the screening of hypercortisolism. However, in the absence of a single test considered as the gold standard, it is necessary to combine the different tests to reach an adequate diagnostic capacity. The indication of surgery in ACS patients should be based mainly on the hormonal evaluation and the comorbidities potentially mediated by cortisol. Presentation: 6/1/2024

Cognitive functions and the brain-derived neurotrophic factor in patients with mild autonomous cortisol secretion.

The impact of abnormal cortisol secretion on cognitive functions in patients with mild autonomous cortisol secretion (MACS) remains uncertain. To assess cognitive functions, determine serum brain-derived neurotrophic factor (BDNF) concentration in patients with MACS, and investigate the association between cognitive subdomains and BDNF. We prospectively recruited 84 participants-28 patients with MACS, 28 patients with nonfunctional adrenal adenoma (NFAA), and 28 control subjects matched for age, gender, body mass index (BMI), visceral adiposity, and educational level. The serum BDNF concentration of participants was measured. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition-focused interviews and Montreal Cognitive Assessments (MoCA) were carried out by an experienced psychiatrist. Patients with MACS had a higher serum BDNF concentration than the NFAA (P = .001), while that of patients with NFAA was lower than the controls (P = .044). Linear regression analysis revealed BMI and morning cortisol after overnight 1 mg dexamethasone (DST) were mostly associated with BDNF (P < .05). No significant difference was found in MoCA scores between MACS and NFAA groups (P = .967), whereas those were lower than the control group (P = .004). When the cognitive subdomains were examined separately, MACS group performed higher memory score than NFAA (P = .045), but lower language scores than both the NFAA (P = .024) and control groups (P < .001). In the whole group, BDNF concentration was positively correlated with memory score (r = 0.337, P = .002), whereas DST was negatively correlated with language score (r = -0.355, P = .008). Low-grade hypercortisolism is associated with elevated BDNF concentrations, which may be a protective factor for memory function in patients with MACS relative to those with NFAA.

Case Report: Management of Mild Autonomous Cortisol Secretion

Mild autonomous cortisol secretion is a term used to describe biochemical evidence of abnormal cortisol secretion in patients with ACA, but without the classical external manifestations of overt CS, such as central muscle weakness, adipose tissue redistribution, and skin fragility. Materials and methods: In this study, we report a case of patient who presents mild autonomous cortisol secretion among incidentally discovered adrenal masses; followed in unit of the endocrinology, diabetology, metabolic diseases and nutrition department of the Mohammed VI University Hospital of Marrakesh. Case report: A 68-year-old woman with a history of well-controlled hypertension and diabete presents to our department for etiological assessment of an adrenal incidentaloma. adrenal scan confirms a diagnosis of an incidental right adrenal nodule measuring 27x26mm is also identified having an density of 33UH and washout &gt; 50%, the patient’s physical examination is unremarkable and she does not have any overt Cushingoid features or midline back pain or paroxysmal attacks. Biochemical investigations revealed a morning cortisol following 1 mg of dexamethasone is 2 ug/dL. A normal serum potassium and methoxylated derivatives in urine are normal. A diagnosis of a mild autonomous cortisol secretion was made and given the relatively mild degree of cortisol excess and well-controlled Comorbidities a conservative management is chosen, she should undergo annual clinical reassessments. If she develops new or worsening cortisol-related comorbidities, she should undergo further biochemical testing and reconsideration of adrenalectomy. Conclusion: Future studies with adequate randomization and follow-up to assess adverse clinical endpoints are needed to determine the optimal management and follow-up of patients with MACS.

Pathophysiology of Mild Hypercortisolism: From the Bench to the Bedside.

Mild hypercortisolism is defined as biochemical evidence of abnormal cortisol secretion without the classical detectable manifestations of overt Cushing’s syndrome and, above all, lacking catabolic characteristics such as central muscle weakness, adipose tissue redistribution, skin fragility and unusual infections. Mild hypercortisolism is frequently discovered in patients with adrenal incidentalomas, with a prevalence ranging between 5 and 50%. This high variability is mainly due to the different criteria used for defining this condition. This subtle cortisol excess has also been described in patients with incidentally discovered pituitary tumors with an estimated prevalence of 5%. To date, the mechanisms responsible for the pathogenesis of mild hypercortisolism of pituitary origin are still not well clarified. At variance, recent advances have been made in understanding the genetic background of bilateral and unilateral adrenal adenomas causing mild hypercortisolism. Some recent data suggest that the clinical effects of glucocorticoid (GC) exposure on peripheral tissues are determined not only by the amount of the adrenal GC production but also by the peripheral GC metabolism and by the GC sensitivity. Indeed, in subjects with normal cortisol secretion, the combined estimate of cortisol secretion, cortisone-to-cortisol peripheral activation by the 11 beta-hydroxysteroid dehydrogenase enzyme and GC receptor sensitizing variants have been suggested to be associated with the presence of hypertension, diabetes and bone fragility, which are three well-known consequences of hypercortisolism. This review focuses on the pathophysiologic mechanism underlying both the different sources of mild hypercortisolism and their clinical consequences (bone fragility, arterial hypertension, subclinical atherosclerosis, cardiovascular remodeling, dyslipidemia, glucose metabolism impairment, visceral adiposity, infections, muscle damage, mood disorders and coagulation).

Predisposing factors for increased cortisol levels in oral cancer patients

Cancer patients may have a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and abnormal secretion of cortisol. Increased cortisol levels have been associated with worse prognosis in patients with different types of tumors. Although anxiety and depression can trigger an abnormal cortisol secretion, little is known regarding the influence of these emotional disorders on HPA axis dysregulation in cancer patients when evaluating together with demographic, clinicopathological and biobehavioral variables. This cross-sectional study analyzed the pre-treatment plasma cortisol levels of 133 patients with oral squamous cell carcinoma (OSCC) and its association with demographic, clinicopathological, biobehavioral and psychological variables. Plasma cortisol levels were measured by electrochemiluminescence, and anxiety and depression symptoms were assessed using Beck Anxiety Inventory (BAI) and Depression (BDI), respectively. Demographic, clinicopathological and biobehavioral data were collected from patients' medical records. Results from multivariate analysis showed that the occurrence of cancer-induced pain was predictive for higher cortisol levels (OR = 5.388, p = 0.003). Men with OSCC were 4.5 times more likely to have higher plasma cortisol levels than women (OR = 4.472, p = 0.018). The effect of sex on cortisol concentrations was lost in the adjusted model for clinical staging (OR = 2.945, p = 0.116). The absence of chronic alcohol consumption history was a protective factor for highest hormone concentrations in oral cancer patients (OR = 0.104, p = 0.004). Anxiety symptoms measured by BAI as “hands trembling” (OR = 0.192, p = 0.016) and being “nervous” (OR = 0.207, p = 0.0004) were associated with lower cortisol levels. In contrast, the feeling of “fear of losing control” was a risk factor for highest hormone concentrations (OR = 6.508, p = 0.0004). The global score and specific symptoms of depression measured by the BDI were not predictive for plasma hormone levels (p > 0.05). Together, our results show that pain, alcohol consumption and feeling fear are independent factors for increased systemic cortisol levels in patients with oral cancer. Therefore, psychological intervention, as well as control of pain and alcohol consumption, should be considered to prevent the negative effects of cortisol secretion dysregulation in cancer patients.

Autonomous cortisol secretion : Laboratory artifact or disease?

Autonomous cortisol secretion was mentioned for the first time in 2016 in the European Guideline on the management of adrenal incidentalomas. Review of the state of knowledge on diagnosis, epidemiology, co-morbidities, mortality and treatment of autonomous cortisol secretion in comparison to non-hormone producing adenomas. Recommendation for clinical practice based on the current European guideline. Analysis of relevant clinical studies, discussion of basic literature and expert opinions. Autonomous cortisol secretion is aterm used to describe abnormal cortisol secretion diagnosed by apathological 1‑mg dexamethasone suppression test in patients with adrenal incidentaloma, but without clinical manifestation of overt Cushing's syndrome. It is associated with increased mortality and morbidity, especially hypertension, diabetes mellitus typeII, dyslipidemia and obesity. Adrenalectomy, as the only specific therapy option, should be considered in an interdisciplinary tumour board.

ARMC5 variants in PRKAR1A-mutated patients modify cortisol levels and Cushing’s syndrome

Mutations in the protein kinase A (PKA) regulatory subunit type 1A (PRKAR1A) and armadillo repeat-containing 5 (ARMC5) genes cause Cushing's syndrome (CS) due to primary pigmented nodular adrenocortical disease (PPNAD) and primary bilateral macronodular adrenocortical hyperplasia (PBMAH), respectively. Between the two genes, ARMC5 is highly polymorphic with several variants in the population, whereas PRKAR1A has very little, if any, non-pathogenic variation in its coding sequence. We tested the hypothesis that ARMC5 variants may affect the clinical presentation of PPNAD and CS among patients with PRKAR1A mutations. In this study, 91 patients with PPNAD due to PRKAR1A mutations were tested for abnormal cortisol secretion or CS and for ARMC5 sequence variants. Abnormal cortisol secretion was present in 71 of 74 patients with ARMC5 variants, whereas 11 of 17 patients negative for ARMC5 variants did not have hypercortisolemia. The presence of ARMC5 variants was a statistically strong predictor of CS among patients with PRKAR1A mutations (P < 0.001). Among patients with CS due to PPNAD, ARMC5 variants were associated with lower cortisol levels at baseline (P = 0.04) and after high dose dexamethasone administration (P = 0.02). The ARMC5 p.I170V variant increased ARMC5 protein accumulation in vitro and decreased viability of NCI-H295 cells (but not HEK 293T cells). PPNAD tissues with ARMC5 variants showed stronger ARMC5 protein expression than those that carried a normal ARMC5 sequence. Taken together, our results suggest that ARMC5 variants among patients with PPNAD due to PRKAR1A defects may play the role of a genetic modifier for the presence and severity of hypercortisolemia.

MON-219 Prevalence and Incidence of Fractures in Patients with Adrenal Adenomas: A Population-Based Study of 1003 Patients

Background: Adrenal adenoma is reported in around 5% of adults undergoing cross-sectional imaging. Although most adenomas are considered non-functioning (NFAT), up to 48% present with mild autonomous cortisol secretion (MACS). Several studies reported increased prevalence and incidence of vertebral fractures in MACS; however conclusions are limited by small sample size, selection bias, inadequate reference population and length of follow up. Objective: To determine the prevalence and incidence of site-specific fragility fractures in a population-based cohort of patients with adrenal adenomas. Methods: Residents of local community with a radiographic diagnosis of adrenal adenoma between 1995 and 2017 were identified using a centralized epidemiologic database and matched with reference subjects for sex and age. All subjects were followed through 2017, until death or migration from the community. MACS was diagnosed based on cortisol level ≥1.8 mcg/dl after overnight 1mg dexamethasone suppression, NFAT based on cortisol level <1.8 mcg/dl, and patients not tested with dexamethasone were considered as adenoma with unknown cortisol secretion (AUCS). Results: Of 1003 patients with adrenal adenomas (581 women (58%), median age of diagnosis 63 years (20–96)), 136 (14%) were diagnosed with NFAT, 86 (9%) with MACS, and 781(78%) with AUCS. At the time of diagnosis, patients had higher BMI (median 30 vs 28 kg/m2, p<0.001), and higher prevalence of tobacco use (70% vs 54%, p<0.001) than reference subjects. Of 154 patients and 113 reference subjects with BMD available at baseline, patients had a higher median BMD at the total hips (0.93 vs 0.89, p=0.02) but similar median BMD at lumbar spine (1.05 vs 1.03, p=0.49) when compared to reference subjects. However, patients had a higher prevalence of fractures than reference subjects (any fracture: 50% vs 42%, p<0.001, vertebral fracture: 6.5% vs 3.7%, P=0.004). When adjusted for age, sex, and prior history of fracture, patients with adenoma had HR of 1.24 (CI 95% 1.04–1.48) for developing a new fracture and HR of 1.18 (CI 95% 0.97–1.44) when also adjusted for BMI and smoking. Subgroup analysis demonstrated that the prevalence of fractures at the time of diagnosis was higher in all 3 subgroups at any fragility fracture site when compared to reference subjects (NFAT: 44% vs 37%, MACS: 48% vs 43%, AUCS: 51% vs 43%); patients with MACS had the highest incidence of new fracture after 5 years of follow up when compared to AUCS and NFAT (cumulative incidence: MACS 25% vs NFAT 19% vs AUCS 16%), though the differences were not significant. Conclusions: Patients with adrenal adenomas have higher prevalence of fractures at the time of diagnosis. During follow up, patients with adenoma have a higher incidence of fractures even when adjusted for sex, age, and prior history of fracture, possibly due to underlying undiagnosed abnormal cortisol secretion.

MON-222 Cardiovascular Risk Factors, Morbidity, and Overall Mortality in Patients with Adrenal Adenomas: A Population-Based Study of 1,003 Patients

Background: Benign adrenal tumors are frequently diagnosed on imaging and may pose health risks to patients regardless of functional status. Both non-functioning adrenal tumors (NFAT) and tumors with mild autonomous cortisol secretion (MACS) have been associated with increased cardiovascular events and risk factors. However, limited data exist on the association of adrenal adenomas with cardiometabolic outcomes in the population-based setting. Aim: 1) To determine the prevalence of cardiovascular co-morbidities and events and 2) to assess mortality in a population-based cohort of patients with adrenal adenomas. Methods: We identified adult patients living in the community diagnosed with an adrenal tumor from 1995-2017 using a medical records linkage system. Adrenal tumors were classified as MACS if cortisol was ≥1.8mcg/dL after 1 mg dexamethasone suppression test, NFAT if cortisol was <1.8 mcg/dL, and adenoma with unknown cortisol secretion (AUCS) if dexamethasone suppression test was not performed. Cardiovascular co-morbidities and events were assessed at baseline. Patients were then followed until death, migration out of the community, or through December 31, 2018. Results were compared to age and sex matched reference subjects without adrenal tumors and adjusted for tobacco use and BMI. Results: A total of 1,003 patients had adrenal adenomas with 136 (14%) NFAT, 86 (9%) MACS, and 781 (78%) AUCS. The median age of diagnosis was 63 years (range, 20-96) and 581 (58%) were women. At baseline, patients with adrenal adenomas were more likely to have hypertension (92% vs 81%, p<0.001), overweight/obesity (89% vs 82%, p<0.001), pre-diabetes/diabetes (82% vs 70%, p<0.001), dyslipidemia (89% vs 82%, p<0.001), and chronic kidney disease (11% vs 7%, p=0.004) than age and sex matched reference subjects. Myocardial infarctions (13% vs 8%, p <0.001), coronary intervention (9% vs 6%, p= 0.007), heart failure (12% vs 6%, p<0.001), peripheral vascular disease (26% vs 15%, p<0.001), and thromboembolic disease (7% vs 3%, p<0.001) were more prevalent in patients with adrenal adenomas, whereas overall survival was lower compared to reference subjects (60% vs 65%, p value = 0.013). Subgroup analysis (adjusted for age, sex, BMI, and smoking) demonstrated prevalence of cardiovascular events including peripheral vascular disease was highest in those with MACS (44.7%), followed by AUCS (40.1%), and then NFAT (36.6%), although differences between groups were not significant. Overall survival was lower in patients with MACS (62%) and AUCS (59%) compared to NFAT (71%), p<0.001. Conclusions: Adrenal adenomas are associated with significantly higher prevalence of cardiovascular risk factors and morbidity at the time of diagnosis and with increased morality during follow-up. Results are potentially related to abnormal cortisol secretion but are limited by suboptimal evaluation for hormone excess.

Pediatric Cushing Syndrome; an Overview.

Endogenous Cushing syndrome (CS) is a rare entity in the pediatric population. Patients usually present with height deceleration and continuous weight gain, along with other classic stigmata of CS, such as acne, striae, hirsutism and others. The diagnosis of CS involves documentation of abnormal cortisol secretion with measurement of urinary free cortisol and midnight serum or salivary cortisol, and the use of the 1mg dexamethasone suppression test. After confirmation of CS, localization of the source of hypercortisolemia, involves differentiation of ACTH-dependent versus ACTH-independent causes of CS. Surgical resection of the identified source of CS is the preferred method of treatment whenever possible.

Modern Management of Mild Autonomous Cortisol Secretion.

Incidentally discovered adrenal tumors are reported in ~ 5% of adults undergoing cross-sectional imaging. Mild autonomous cortisol secretion (MACS) from the adrenal mass is demonstrated in 5-48% of patients with adrenal tumors. The diagnosis of MACS represents a challenge due to limitations of the currently used diagnostic tests, differences in the definitions of the clinically relevant MACS, and heterogeneity in an individual's susceptibility to abnormal cortisol secretion from the adrenal mass. Patients with MACS present with increased risk of cardiovascular risk factors, cardiovascular events, metabolic bone disease, and mortality. Adrenalectomy improves or reverses MACS-associated comorbidities in selected patients. The current review will address diagnostic and management challenges in the care of patients with MACS, discuss data on emerging biomarkers, and suggest future directions in the field of MACS.

A Method for Quantification of Tetrahydroglucocorticoid Glucuronides in Human Urine by LC/MS/MS with Isotope-coded Derivatization.

The determination of urinary tetrahydroglucocorticoid (THGC) glucuronides might prove helpful in the diagnosis, pathophysiological analysis and assessment of the therapeutic efficacy of the diseases caused by abnormal cortisol secretion. We developed and validated a method for the determination of the THGC glucuronides in human urine using liquid chromatography/electrospray ionization (ESI)-tandem mass spectrometry not requiring enzymatic hydrolysis. The method employed a derivatization using an ESI-enhancing reagent for carboxylic acids, 1-[(4-dimethylaminophenyl)carbonyl]piperazine (DAPPZ), and its isotopologue, 2H4-DAPPZ. The deproteinized urine samples were derivatized with DAPPZ. The 2H4-DAPPZ-derivatized standards of known amounts were then added to the DAPPZ-derivatized urine samples and served as the internal standards. The DAPPZ-derivatization enhanced the assay sensitivity and reduced the sample volume, and the use of 2H4-DAPPZ significantly improved the assay accuracy. The developed method enabled the separate quantification and profiling of the urinary THGC glucuronides and had a satisfactory application for the real sample analysis.

Hypothalamic Dysfunction and Multiple Sclerosis: Implications for Fatigue and Weight Dysregulation.

Signs and symptoms of multiple sclerosis are usually attributed to demyelinating lesions in the spinal cord or cerebral cortex. The hypothalamus is a region that is often overlooked yet controls many important homeostatic functions, including those that are perturbed in multiple sclerosis. In this review we discuss how hypothalamic dysfunction may contribute to signs and symptoms in people with multiple sclerosis. While dysfunction of the hypothalamic-pituitary-adrenal axis is common in multiple sclerosis, the effects and mechanisms of this dysfunction are not well understood. We discuss three hypothalamic mechanisms of fatigue in multiple sclerosis: (1) general hypothalamic-pituitary-adrenal axis hyperactivity, (2) disordered orexin neurotransmission, (3) abnormal cortisol secretion. We then review potential mechanisms of weight dysregulation caused by hypothalamic dysfunction. Lastly, we propose future studies and therapeutics to better understand and treat hypothalamic dysfunction in multiple sclerosis. Hypothalamic dysfunction appears to be common in multiple sclerosis, yet current studies are underpowered and contradictory. Future studies should contain larger sample sizes and standardize hormone and neuropeptide measurements.

2. Dysregulation of psychoneuroimmune function in women symptomatic of postpartum depression

500,000 U.S. women develop postpartum depression (PPD) annually. Although psychosocial risks are known, the underlying biology remains unclear. We hypothesized that exaggerated inflammation early after childbirth would increase PPD risk, alone or synergistically with abnormal cortisol secretion, indicating dysregulation of psychoneuroimmune function. Plasma pro- and anti-inflammatory cytokines were measured on Days 7 and 14, and Months 1, 2, 3, and 6 after childbirth. Saliva was collected 5 times the day preceding blood draws for cortisol area under the curve (AUC). Depressive symptoms were measured using the Edinburgh Postpartum Depression Survey (EPDS) and evaluated in light of cytokines and cortisol, independently and together. 152 women completed the EPDS; 18% scored symptomatic of depression (EPDS > 10) by 6-months. Cortisol AUC was higher in symptomatic women on Day 14 ( p = .017). Bivariate analysis indicated change in IFNγ/IL10 (pro- to anti-inflammatory cytokine) ratio on Day 14 from Day 7 and Day 14 cortisol AUC were important predictors of depressive symptoms. Multiple logistic regression indicated joint effects of cortisol AUC and change in IFN/IL10 ratio were highly significant in predicting symptoms. A unit increase in Day 14 IFN/IL10 was associated with 91% increase in odds (OR: 1.91, p = 0.036) of depressive symptoms while a 20-min increase in AUC was associated with a 33% increase in odds (cortisol AUC OR: 1.333, p = 0.012). Findings suggest dysregulation of psychoneuroimmune function is a biological risk for PPD.

The Use of Positron Emission Tomography-Computed Tomography Scan in the Evaluation of a Patient with Carney Complex

A 32-yr-old woman presented with clinical hypercortisolism, including a 30-lb weight gain, central obesity, oligomenorrhea, hirsutism, and hypertension with hypokalemia. The patient reported easy bruisability, and her surgical history included bilateral breast fibrous adenomas within a myxoid stroma. Labs: K+ 2.9 mmol/liter, 0800-h cortisol 33 μg/dl; 1600-h cortisol 35 μg/dl; and 24-h urine-free cortisol 175 μg. An adrenal computed tomography (CT) revealed bilateral nodularity; a positron emission tomography (PET)-CT demonstrated F18-fluorodeoxyglucose uptake in both adrenals (Fig. 1​1 and 2​2).). The patient underwent a two-stage laparoscopic adrenal resection. Pathology revealed primary pigmented nodular adrenocortical disease (PPNAD) (Fig. 3​3). Figure 1 F18 fluorodeoxyglucose avid adrenal glands, transverse section, adrenal glands at white arrows. Standardized Uptake Values (SUV):Liver-3.0(range 2.75–3.4), left adrenal-4.45, right adrenal-3.54. Figure 2 F18 fluorodeoxyglucose avid adrenal glands, coronal section, adrenal glands at white arrows. Standardized Uptake Values (SUV):Liver-3.0(range 2.75–3.4), left adrenal-4.45, right adrenal-3.54. Figure 3 Left adrenal gland; the white arrows point to pigmented areas of the nodular cells (lipofuscin granules). Magnification 40×. Carney complex (CNC) is an autosomal dominant multiple neoplasia syndrome associated with hyperfunctioning pituitary, gonads and/or adrenals with hypercortisolism being the most common endocrine finding (1). The diagnosis of Cushing’s syndrome may be elusive: sometimes, abnormal cortisol secretion can only be demonstrated after a dexamethasone-induced stimulation (2), and adrenal CT can be equivocal (3). PET scan of the adrenals has been used to detect cancers, but PET imaging alone may be ambiguous, and the diagnostic capability is increased with PET-CT, allowing for simultaneous anatomical and functional evaluation of adrenal lesions (4). The presence of breast myxomas, PPNAD, and a PRKAR1A mutation confirmed the diagnosis of CNC in our patient; genetic analysis demonstrated a mutation of the PRKAR1A gene (IVS1–2 A>G), which has been shown before to cause PPNAD and CNC (5). The patient’s only child, a daughter, carries the same PRKAR1A mutation. This is, to our knowledge, the first report of PET-CT imaging of the adrenal glands in PPNAD. PET-CT imaging may be useful in the evaluation of patients with ACTH-independent hypercortisolism. Apparently, not all F18-fluorodeoxyglucose-avid adrenal glands contain malignancies.

Mindfulness-based stress reduction in relation to quality of life, mood, symptoms of stress and levels of cortisol, dehydroepiandrosterone sulfate (DHEAS) and melatonin in breast and prostate cancer outpatients

Objectives: This study investigated the relationships between a mindfulness-based stress reduction meditation program for early stage breast and prostate cancer patients and quality of life, mood states, stress symptoms, and levels of cortisol, dehydroepiandrosterone-sulfate (DHEAS) and melatonin. Methods: Fifty-nine patients with breast cancer and 10 with prostate cancer enrolled in an eight-week Mindfulness-Based Stress Reduction (MBSR) program that incorporated relaxation, meditation, gentle yoga, and daily home practice. Demographic and health behavior variables, quality of life, mood, stress, and the hormone measures of salivary cortisol (assessed three times/day), plasma DHEAS, and salivary melatonin were assessed pre- and post-intervention. Results: Fifty-eight and 42 patients were assessed pre- and post-intervention, respectively. Significant improvements were seen in overall quality of life, symptoms of stress, and sleep quality, but these improvements were not significantly correlated with the degree of program attendance or minutes of home practice. No significant improvements were seen in mood disturbance. Improvements in quality of life were associated with decreases in afternoon cortisol levels, but not with morning or evening levels. Changes in stress symptoms or mood were not related to changes in hormone levels. Approximately 40% of the sample demonstrated abnormal cortisol secretion patterns both pre- and post-intervention, but within that group patterns shifted from “inverted-V-shaped” patterns towards more “V-shaped” patterns of secretion. No overall changes in DHEAS or melatonin were found, but nonsignificant shifts in DHEAS patterns were consistent with healthier profiles for both men and women. Conclusions: MBSR program enrollment was associated with enhanced quality of life and decreased stress symptoms in breast and prostate cancer patients, and resulted in possibly beneficial changes in hypothalamic-pituitary-adrenal (HPA) axis functioning. These pilot data represent a preliminary investigation of the relationships between MBSR program participation and hormone levels, highlighting the need for better-controlled studies in this area.

Abnormal Cortisol Secretion and Responses to Corticotropin-Releasing Hormone in Women with Hypothalamic Amenorrhea

Hypothalamic amenorrhea (HA) is a common disorder associated with hypoestrogenemia and has adverse effects. The mechanism of GnRH deficiency in these women is not yet known. To investigate the role of the hypothalamic-pituitary-adrenal axis in HA, we studied 10 women [mean age, 29 +/- 7 (+/- SD) yr] with 0.5-13 yr of amenorrhea (mean, 4.3 +/- 3.7 yr) related to simple weight loss or psychological stress. We investigated cortisol and ACTH responses to a bolus of ovine CRH, 24-h plasma cortisol levels obtained every 10 min, and urinary free cortisol levels in these patients. Results were compared with those obtained in normal women during all phases of the menstrual cycle. We found that mean basal concentrations of cortisol were significantly higher (P = 0.03) in the HA patients (mean, 210 +/- 130 nmol/L) than in the normal women (100 +/- 30 nmol/L). The delta (peak - basal) cortisol was significantly lower (P = 0.004) in the HA patients than in the normal women (320 +/- 100 vs. 440 +/- 90 nmol/L, respectively). ACTH responses to CRH did not differ between HA patients and normal women. The 24-h mean cortisol was significantly higher (P = 0.006) in the HA patients than in the normal controls (280 +/- 50 and 220 +/- 50 nmol/L, respectively), due to higher cortisol levels at night. The urinary free cortisol level was significantly higher (P = 0.005) in the HA patients (230 +/- 70 nmol/day) than in normal women (150 +/- 40 nmol/day). We conclude that women with HA have a blunted cortisol response to CRH administration. In addition, they have hypercortisolism, as demonstrated by elevated 24-h mean serum cortisol levels and urinary free cortisol values. This hypothalamic-pituitary-adrenal axis activation in patients with stress or weight loss may be a mechanism in the development of amenorrhea and may relate to other potential adverse effects of HA.

Abnormal Cortisol Secretion and Responses to Corticotropin-Releasing Hormone in Women with Hypothalamic Amenorrhea*

Hypothalamic amenorrhea (HA) is a common disorder associated with hypoestrogenemia and has adverse effects. The mechanism of GnRH deficiency in these women is not yet known. To investigate the role of the hypothalamic-pituitary-adrenal axis in HA, we studied 10 women [mean age, 29 +/- 7 (+/- SD) yr] with 0.5-13 yr of amenorrhea (mean, 4.3 +/- 3.7 yr) related to simple weight loss or psychological stress. We investigated cortisol and ACTH responses to a bolus of ovine CRH, 24-h plasma cortisol levels obtained every 10 min, and urinary free cortisol levels in these patients. Results were compared with those obtained in normal women during all phases of the menstrual cycle. We found that mean basal concentrations of cortisol were significantly higher (P = 0.03) in the HA patients (mean, 210 +/- 130 nmol/L) than in the normal women (100 +/- 30 nmol/L). The delta (peak - basal) cortisol was significantly lower (P = 0.004) in the HA patients than in the normal women (320 +/- 100 vs. 440 +/- 90 nmol/L, respectively). ACTH responses to CRH did not differ between HA patients and normal women. The 24-h mean cortisol was significantly higher (P = 0.006) in the HA patients than in the normal controls (280 +/- 50 and 220 +/- 50 nmol/L, respectively), due to higher cortisol levels at night. The urinary free cortisol level was significantly higher (P = 0.005) in the HA patients (230 +/- 70 nmol/day) than in normal women (150 +/- 40 nmol/day). We conclude that women with HA have a blunted cortisol response to CRH administration. In addition, they have hypercortisolism, as demonstrated by elevated 24-h mean serum cortisol levels and urinary free cortisol values. This hypothalamic-pituitary-adrenal axis activation in patients with stress or weight loss may be a mechanism in the development of amenorrhea and may relate to other potential adverse effects of HA.

Cortisol secretion in endogenous depression. II. Time-related functions.

Plasma levels of cortisol were sampled for 24 hours in 32 endogenously depressed (ED) patients and 72 controls to examine mean 24-hour plasma levels of cortisol, intervention in the feedback mechanism of the hypothalamic-pituitary-adrenal system (the dexamethasone suppression test), the circadian rhythm of cortisol secretion and its magnitude, and the ultradian rhythm of cortisol secretion. The main difference in the pattern of cortisol secretion in ED patients, as compared with controls, was in the ultradian rhythm. No acrophase or nadir advance of cortisol secretion in endogenous depression was found when age was controlled, but there was an earlier timing of first secretory episode of cortisol (during night). Only some ED patients have abnormalities in each of the functions studied, and they only partially overlap each other. The results suggest that abnormal cortisol secretion in depression should not be viewed as a monolithic malfunction characteristic of endogenous depression.