24-hour Urinary Free Cortisol Levels Research Articles

Intensity-Modulated Radiotherapy (IMRT) for the Treatment of Cushing's Disease

Aim to investigate the efficacy and toxicity of IMRT in treating Cushing's Disease (CD). A total of 78 of 115 patients with CD treated with IMRT at our institute from April 2012 to August 2021 were included in the study. The radiation doses were usually 45-50 Gy in 25 fractions. After IMRT, endocrine evaluations were performed every 6 months and magnetic resonance imaging (MRI) annually. Endocrine remission was defined as suppression of 1 mg dexamethasone test (DST) or normal 24-hour urinary free cortisol level (24hUFC). Endocrine recurrence was considered when patients who have reached hormonal remission showed no suppression of 1 mg DST and relapse of clinical features. The outcome of endocrine remission, tumor control and complications were retrieved from medical record. At a median follow-up time of 36.8 months, the endocrine remission rate at 1, 2, 3 and 5 years were 28.5%, 50.2%, 62.5% and 74.0%, respectively. The median time to remission was 24 months (95% CI: 14.0-34.0). Endocrine recurrence was found in 5 patients (13.5%) till the last follow-up. The recurrence-free rate at 1, 2, 3 and 5 years after endocrine remission was 98.2%, 93.9%, 88.7% and 88.7%, respectively. The tumor control rate was 98%. The overall incidence of new onset hypopituitarism was 23.1%, with hypothyroidism serving as the most common individual axis deficiency. Univariate analysis indicated that only higher Ki-67 index (P = 0.044) was significant favorable factors for endocrine remission. But no prognostic factors for endocrine remission were found in the multivariate analysis. IMRT was a highly effective second-line therapy with low side effect profile for CD patients. Endocrine remission, tumor control and recurrence rates were comparable to previous reports on FRT and SRS.

Intensity-modulated radiotherapy for cushing's disease: single-center experience in 70 patients.

Intensity-modulated radiotherapy (IMRT) is a modern precision radiotherapy technique for the treatment of the pituitary adenoma. Aim to investigate the efficacy and toxicity of IMRT in treating Cushing's Disease (CD). 70 of 115 patients with CD treated with IMRT at our institute from April 2012 to August 2021 were included in the study. The radiation doses were usually 45-50 Gy in 25 fractions. After IMRT, endocrine evaluations were performed every 6 months and magnetic resonance imaging (MRI) annually. Endocrine remission was defined as suppression of 1 mg dexamethasone test (DST) or normal 24-hour urinary free cortisol level (24hUFC). The outcome of endocrine remission, endocrine recurrence, tumor control and complications were retrieved from medical record. At a median follow-up time of 36.8 months, the endocrine remission rate at 1, 2, 3 and 5 years were 28.5%, 50.2%, 62.5% and 74.0%, respectively. The median time to remission was 24 months (95%CI: 14.0-34.0). Endocrine recurrence was found in 5 patients (13.5%) till the last follow-up. The recurrence-free rate at 1, 2, 3 and 5 years after endocrine remission was 98.2%, 93.9%, 88.7% and 88.7%, respectively. The tumor control rate was 98%. The overall incidence of new onset hypopituitarism was 22.9%, with hypothyroidism serving as the most common individual axis deficiency. Univariate analysis indicated that only higher Ki-67 index (P=0.044) was significant favorable factors for endocrine remission. IMRT was a highly effective second-line therapy with low side effect profile for CD patients. Endocrine remission, tumor control and recurrence rates were comparable to previous reports on FRT and SRS.

PMON98 High-dose dexamethasone suppression test in ACTH-dependent Cushing's syndrome: Lessons learned on the lack of cortisol suppression

Abstract Background The overnight 8-mg high-dose dexamethasone suppression test (HDDST) has been used to discern Cushing's disease from ectopic ACTH production. However, because of its reported low diagnostic accuracy, its use is limited to the assessment of ACTH-dependent Cushing's disease when combined with a corticotropin releasing hormone (CRH) or a desmopressin stimulation test. We evaluated a patient with Cushing's disease in whom the HDDST failed to identify the pituitary source. We point to limitations in test interpretation and highlight the need of future studies to enhance understanding of the clinical utility of this non-invasive test. Clinical Case A 42-year-old male presented with lower extremity cellulitis and hypertensive emergency. He reported increased abdominal girth, easy bruising, severe back pain and proximal muscle weakness and noted headache and blurred vision. Exam was pertinent for obesity (body mass index 31.5 kg/m2), moon facies, dorso-cervical hump and prominent abdominal striae. Lumbar and thoracic compression fractures were noted on imaging. The elevated 24-hour urinary free cortisol level (198 ug/dL; reference: 10-100 ug/24hr) and lack of suppression on the overnight 1-mg dexamethasone suppression test (morning cortisol 23.7 ug/dL) confirmed Cushing's syndrome; a high ACTH level of 92 pg/dL defined it as ACTH-dependent. The 8-mg HDDST resulted in only a 9.7% reduction of his baseline morning cortisol. The patient was not on any medications that enhanced dexamethasone clearance. Serum dexamethasone levels were measured to aid in test interpretation and, although a level was provided, reference values for the single overnight 8-mg dose of dexamethasone were lacking. A CRH stimulation test was performed and resulted in a 60% increase in ACTH levels from baseline, supporting the diagnosis of Cushing's disease. Additionally, a pituitary MRI revealed a suprasellar 2.5×1.5×1.3 cm mass. Due to ambiguity posed by the HDDST result, despite tumor size, neurosurgery requested inferior petrosal sinus sampling (IPSS). Prior to this procedure, the patient underwent an overnight 16-mg HDDST. While limited information remains on the diagnostic performance of this test, we observed that the baseline morning cortisol decreased by 53.9%. IPSS confirmed the diagnosis of Cushing's disease and pathology identified a corticotroph adenoma. Conclusion The diagnosis of Cushing's disease is complex and recommendations continue to evolve. Th role of the HDDST in combination with another dynamic test remains clinically relevant. It is important that when considering a HDDST, clinicians review medication history to exclude agents that may interfere with dexamethasone metabolism. Our case highlights the need of studies that determine an appropriate reference range for dexamethasone plasma levels after a single 8-mg overnight dose and that evaluate the diagnostic performance of the HDDST in this context. It also brings attention to the need of further elucidating the diagnostic utility of a higher dexamethasone dose in the evaluation of ACTH-dependent Cushing's syndrome. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

ODP408 Elevated DHEAS and Acute Hair Loss in an Adult Male with Trichorhinophalangeal Syndrome Type 1: a Case of Male PCOS

Abstract Background Male androgenic alopecia is a common cause of hair loss in both men and women. Although genetic and hormonal factors likely play a role, the etiology is mostly unknown. PCOS is a highly heritable disease with elevated prevalence of reproductive abnormalities in first-degree relatives (FDRs) of patients with PCOS, which may be due to an underlying genetic defect in steroidogenesis. A recent meta-analysis revealed that male FDRs of patients with PCOS had significantly increased levels of DHEAS compared with controls. We present a young adult male who developed acute hair loss with biochemical evidence of hyperandrogenism. Clinical Case A 21-year-old man presented for evaluation of hyperandrogenism after experiencing progressive loss of posterior patch of hair over 3 weeks. He also endorsed acne, intermittent headaches, striae, and difficulty losing weight for the past 2 years. He denied facial rounding, vision changes, and use of glucocorticoids or supplements. Physical examination was notable for height of 67 inches, BMI 30.5 mg/m 2, BP 120/78, recession of the frontotemporal and occipital hairline, sparse posterior scalp hair, bulbous nose, long philtrum, mild facial acne, 2, 3 toe syndactyly, and thin purple striae on bilateral flanks and axillae. Labs revealed elevated DHEAS 1065.7 mcg/dL (ref. 238.4-539.3) and normal 8 AM total testosterone of 382 ng/dL (240-871). Cosyntropin stimulation test revealed baseline cortisol level of 10.6 mcg/dL with ACTH of 22.2 pg/mL (5-46) and 60-minute cortisol level of 24.8 mcg/dL, 17-OH progesterone level 81 ng/dL (18-164), and 17-OH pregnenolone 1040 ng/dL (55-455). Workup for Cushing's revealed multiple normal midnight salivary cortisol levels and mild intermittent elevation of 24-hour urinary free cortisol levels. CT scan of the adrenals was negative for a mass. Exome sequencing revealed a heterozygous de novo pathogenic variant (c.1614_1615delTCinsAT: p. C538X) in the TRPS1 gene (NM_0141112.2). Family history was significant for a 20-year-old sister with PCOS and elevated DHEAS of 443 ug/dL (51-321). Mid-parental height was 69.6 inches. Conclusion Trichorhinophalangeal syndrome Type 1 (TRPS1) is a rare genetic disorder characterized by hair, craniofacial, and skeletal abnormalities such as androgenetic alopecia, bulbous nasal tip, and cone-shaped epiphyses. To our knowledge, the hair findings in TRPS are not associated with hyperandrogenism which prompted further investigation. Evaluation for endocrine causes of hyperandrogenism such as Cushing's disease, congenital adrenal hyperplasia, and adrenal tumor were negative. However, our patient's elevated DHEAS is likely due to male PCOS, as previously described in male FDRs of patients with PCOS. Thus, genetic susceptibility to PCOS and rare genetic syndromes should be considered in the differential diagnosis of young men with clinical and biochemical evidence of hyperandrogenism. Reference: Shan D et al. Reproductive Health in First-degree relatives of Patients with Polycystic Ovarian Syndrome: a Review and Meta-analysis. JCEM. 2022 Jan;107(1); 273-295. Presentation: No date and time listed

Histopathologic Differences Between Adrenocorticotropic Hormone–Dependent and Adrenocorticotropic Hormone–Independent Adrenal Hyperplasia Causing Cushing Syndrome

A 64-year-old man with cushingoid features was found to have bilateral nodular adrenal masses (left > right). Laboratory studies showed elevated 24-hour urinary free cortisol level at 64 μg (reference range, 0-50 μg), abnormal levels for the 1-mg dexamethasone suppression test (cortisol, 4.8 μg/dL; dexamethasone level, 665 ng/dL), and suppressed adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone levels. ACTH-independent Cushing syndrome was diagnosed. He was treated with ketoconazole for 6 years, but owing to worsening symptoms including uncontrolled type 2 diabetes mellitus, bilateral adrenalectomy was performed.

Effects of Ketoconazole on the Clinical Recovery in Central Serous Chorioretinopathy.

PurposePatients with hypercortisolism have been associated with a higher prevalence of the pachychoroid spectrum including central serous chorioretinopathy (CSCR), which may explain the inconsistency of therapeutic responses of the mineralocorticoid receptor antagonist because hyperaldosteronism has rarely been detected in patients with CSCR. Therefore, this study aimed to evaluate the effects of ketoconazole, the first-line cortisol inhibitor, on the resolution of subretinal fluid (SRF) in CSCR and to analyze correlations between choroidal thickness and steroid hormones.Patients and MethodsThis retrospective cohort study included 41 naïve CSCR eyes of 41 patients categorized into control (20 eyes) and treatment (21 eyes) groups. Patients in the treatment group were administered oral ketoconazole at a daily dose of 400 or 600 mg for 3–6 weeks. At week 12, rescue laser therapy was applied to patients exhibiting persistent SRF. Thus, a survival analysis was performed to determine the time interval from presentation to clinical resolution of SRF. Secondary outcomes consisted of eyes with persistent SRF and factors affecting the therapeutic response.ResultsThe mean 24-hour urinary free cortisol (UFC) levels were elevated at 181 ± 70 and 150 ± 68 µg/day (range: 20–150) in the treatment and control groups, respectively (p = 0.21). After controlling for age and gender, baseline UFC levels were significantly associated with choroidal thickness in both eyes (p < 0.05). Ketoconazole significantly increased the CSCR resolution with the median time to resolution of 7 vs 16 weeks (p < 0.01) and decreased the proportion of eyes receiving rescue therapy at 12 weeks (23.8% vs 50%; p = 0.01). Prolonged CSCR durations were likely found in elderly patients with thick choroids in fellow eyes.ConclusionPatients with CSCR showed elevated glucocorticoids, which further correlated with their choroidal thickness. Using cortisol blockers may shorten the duration of existing SRF.

The Relationship Between Baseline Cortisol Levels and Surgery Method of Primary Bilateral Macronodular Adrenal Hyperplasia.

Aim was to explore the associations between baseline cortisol levels and surgery method of primary bilateral macronodular adrenal hyperplasia (PBMAH). We retrospectively reviewed the clinical features and management of 30 patients (18 females and 12 males) who were diagnosed with PBMAH in our center between 2005 and 2019. Based on surgery method, we divided the patients into two groups: unilateral adrenalectomy (UA) group; and bilateral adrenalectomy (BA) group. Serum cortisol rhythm and 24-hour urinary free cortisol (UFC/24 h) levels were assayed using chemiluminescence method. Associations between baseline cortisol levels and BA were assessed using logistic regression. The predictive value of baseline cortisol levels for BA was calculated using receiver operating characteristic (ROC) curves. Twenty patients (66.7%) underwent UAs and ten patients (33.3%) underwent BAs. After adjusting for age, sex, BMI, SBP, and adrenal volume, the concentrations of baseline serum cortisol (8 AM, 4 PM, and 0 AM) and UFC/24 h were associated with bilateral adrenalectomy (all p<0.05). The area under the ROC curve based on 8 AM serum cortisol level model was larger than that in models based on 4 PM, 0 AM serum cortisol levels and UFC/24 h, but the differences were non-significant (all p>0.05). According to maximum Youden index criteria, the optimal cutoffs of 8 AM serum cortisol level and UFC were 26.89 μg/dl and 406.65 μg/24 h, respectively, for BA. The baseline cortisol levels are positively associated with BA. Increased levels of baseline cortisol levels may predict higher possibility of BA, which should be confirmed by prospective studies.

A 30-Year, Single-Center Experience of Unilateral Adrenalectomy for Primary Bilateral Macronodular Adrenal Hyperplasia

ObjectiveThe aim was to assess the short- and long-term outcomes of unilateral adrenalectomy (UA) in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH). MethodsWe conducted a retrospective study of 124 patients with PBMAH who underwent UA. ResultsOne hundred sixteen patients were available for follow-up (median, 28.5 months). Cushingoid features remitted in 43 of 65 patients (70.8%) with overt Cushing syndrome (CS). Hypertension and diabetes mellitus improved in 79 of 96 (82.3%) and 29 of 42 patients (69.0%), respectively. Glucocorticoid insufficiency developed in 7 of 116 patients (6.0%) after the surgery, and it resolved in all the patients during follow-up. The mean 24-hour urinary free cortisol level decreased gradually from 456.02 ± 422.33 mg/24 h at baseline to 84.47 ± 70.06 mg/24 h within 3 months and then increased progressively in some patients. Sixty-four of the 116 patients (55.2%) had biochemical recurrence and 43 patients (67.2%) underwent contralateral adrenalectomy. The median time interval between the second operation and the first UA was 24 months. Patients with overt CS had a larger surgical-side or contralateral adrenal volume than patients without overt CS. Patients with a contralateral adrenal volume of >33.54 mL or with a preoperative urinary free cortisol level of >216.08 mg/24 h were more likely to have recurrence. ConclusionThe efficiency of UA is transient for the majority of patients, and the indications should be strictly limited to those with subclinical or milder CS. Patients who undergo successful UA still require close life-time follow-up for the recurrence of hypercortisolism.

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

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. We examined HPA axis function in perimenopausal women with and without depression using the combined dexamethasone-corticotropin-releasing hormone (Dex/CRH) test. 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. 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. 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.

Silent Pituitary Adenoma in Nasal Cavity

Introduction: Silent corticotroph adenomas (SCA) represent 3-6% of all pituitary adenomas. SCA are confirmed on post-surgical histological tumour staining and can either have no prior clinical or biochemical evidence of excess ACTH or alternatively only biochemical (not clinical) evidence of Cushing’s disease. SCA are potentially large and aggressive tumours with a greater tendency to post-surgical recurrence. We present a case of a giant SCA which pre-operatively didn’t exhibit any clinical signs of cortisol excess but showed signs of early recurrence on follow up imaging. Case: A 40-year-old man presented with frontal and maxillary sinus pain and nasal stuffiness. Nasal endoscopy revealed a mass in the nasal cavity and sphenoid sinus. Subsequent CT scan of his sinuses and MRI Pituitary reported a 4 x 3.5 x 2.5 cm sellar mass extending through the floor of sella into the sphenoid sinus and nasal cavity. Despite no clinical features of any pituitary hormone excess (including Cushing’s) or deficiency, his biochemical parameters were consistent with hypercortisolaemia. Post-low dose dexamethasone (2 mg over 48 hours) suppression cortisol was inadequate: 106 nmol/L (<50nmol/L). His corresponding serum dexamethasone level was 8.6 nmol/L (>3nmol/L), ACTH 46 ng/L (0-46 ng/L) and 24-hour urinary free cortisol levels were 502 and 260 nmol/24 hours (<165 nmol/24 hours)) on 2 separate occasions. The remainder of his pituitary profile was normal. He therefore underwent expanded endonasal endoscopic resection of tumour without significant complication. His post-operative cortisol was <50nmol/L (other pituitary hormone measurements normal) so hydrocortisone replacement therapy was commenced. A 3-month post-operative MRI pituitary scan revealed near total resection of the tumour with peripheral enhancement within the tumour resection site representing post-surgical changes. Histopathology showed sparsely granulated, diffuse cytokeratin immunostaining and immunopositivity for ACTH and T-pit consistent with a corticotroph PitNet of the sparsely granulated variety with low Ki 67 index. His six month post-operative scan showed recurrent sellar mass of 2.2 x 0.9 x 1.4 cm. Again there was an absence of clinical features of Cushing’s syndrome. After multidisciplinary discussion clinical, biochemical and radiological surveillance was continued with a view to further transsphenoidal surgery and/or radiotherapy depending on the progress of the tumour. Conclusion: Our patient solely had biochemical (not clinical) evidence of Cushing’s disease despite a large pituitary tumour in keeping with an SCA, which are aggressive, have high recurrence rate and shorter time to recurrence after surgery. Close and frequent post-operative clinical, biochemical and radiological surveillance is critical to detect and manage early recurrence that may require multimodal therapy.

The usefulness of the combined high-dose dexamethasone suppression test and desmopressin stimulation test in establishing the source of ACTH secretion in ACTH-dependent Cushing's syndrome.

Bilateral inferior petrosal sinus sampling (BIPSS) is the current gold standard test for differentially diagnosing ACTH-dependent Cushing's syndrome (CS). However, BIPSS is an invasive procedure, and its availability is limited. We retrospectively analysed the 24-hour urinary free cortisol (UFC) level during the high-dose dexamethasone suppression test (HDDST) and plasma ACTH/cortisol levels after the desmopressin stimulation test (DDAVP test) in subjects with confirmed Cushing's disease (CD) (n = 92) and ectopic ACTH-dependent CS (EAS) (n = 16), and evaluated the positive predictive value (PPV) of the two combined-tests in the aetiological diagnosis of ACTH-dependent CS. The percent changes in UFC levels after the HDDST and in ACTH/cortisol levels after DDAVP administration relative to the corresponding basal levels and the area under the receiver operating characteristic (ROC) curve (AUC) were analysed. UFC suppression below 62.7% suggested a pituitary origin with a sensitivity (SE) of 80% (95% CI: 70-88) and a specificity (SP) of 80% (95% CI: 52-96). A threshold increase in the ACTH level after DDAVP stimulation of 44.6% identified CD with an SE of 91% (95% CI: 83-97) and an SP of 75% (95% CI: 48-93). The combination of both tests yielded an SE of 95.5% and PPV of 98.4% for CD, and significantly improved the efficiency of the differential diagnosis between CD and EAS. These dual non-invasive endocrine tests may substantially reduce the need for BIPSS in the etiological investigation of ACTH-dependent CS.

Hypercoagulability in Cushing Syndrome, Prevalence of Thrombotic Events: A Large, Single-Center, Retrospective Study.

BackgroundThe risk of Cushing syndrome (CS) patients experiencing a thrombotic event (TE) is significantly higher (odds ratio; OR 18%) than that of the general population. However, there are currently no anticoagulation guidelines.MethodsA retrospective, single-center, longitudinal study of patients undergoing all types of treatment—surgical (pituitary, unilateral, and bilateral adrenalectomy) and medical treatment—was undertaken. TEs were recorded at any point up until last patient follow-up; myocardial infarction (MI), deep venous thrombosis (DVT), and pulmonary embolism (PE) or stroke. Patients’ doses and complications of anticoagulation were recorded.ResultsIncluded were 208 patients; a total of 165 (79.3%) were women, and mean age at presentation was 44 ± 14.7 years. Thirty-nine (18.2%) patients had a TE; extremity DVT (38%), cerebrovascular accident (27%), MI (21%), and PE (14%). Of 56 TEs, 27 (48%) were arterial and 29 (52%) were venous. Patients who underwent bilateral adrenalectomy (BLA) had an odds ratio of 3.74 (95% CI 1.69-8.27) of developing a TE. Of patients with TEs, 40.5% experienced the event within the first 60 days after surgery. Baseline 24-hour urinary free cortisol levels did not differ in patients with or without TE after BLA. Of 197 patients who underwent surgery, 50 (25.38%) received anticoagulation after surgery, with 2% having bleeding complications.ConclusionsThe risk of TEs in patients with CS was approximately 20%. Many patients had more than 1 event, with higher risk 30 to 60 days postoperatively. The optimal prophylactic anticoagulation duration is unknown, but most likely needs to continue up to 60 days postoperatively, particularly after BLA.

Spontaneous Aneurysmal Subarachnoid Hemorrhage and Related Cortisol and Immunologic Alterations: Impact on Patients' Health-related Quality of Life

To highlight the impact of aneurysmal subarachnoid hemorrhage (SAH) on surviving patients' health-related quality of life (HRQoL) with respect to cortisol and interleukin (IL)-6 alterations and also to identify possible clinical predictors for a better HRQoL. Fifty surviving patients treated in our hospital for aneurysmal SAH in a 2-year period with sufficient HRQoL data were enrolled. A good clinical outcome was represented by the modified Rankin Scale (mRS) 0 to 2. The patient's HRQoL was assessed using the Short Form health survey questionnaire, the Beck Depression Inventory, and the Daily Fatigue Impact Scale at 6 and 12 months. The results were analyzed regarding possible correlation to 24-hour urinary free cortisol, serum, and cerebrospinal fluid IL-6 levels. A reduction of HRQoL in up to 35% of survivors was observed at 6 months and in a high proportion of patients (47.2%) with an assumable good outcome (mRS 0-2). Reduced HRQoL in survivors was found in terms of SF-36 (34.9%), depression (26.8%), and fatigue (14%) at 6 months and 18.4%, 39.4%, and 18.9% at 12 months, respectively. Improvement was recorded at 12 months, mainly in SF-36. Early elevated 24-hour urinary free cortisol and IL-6 levels showed a significant positive impact on HRQoL. Early cortisol and IL-6 levels may predict patients' HRQoL after SAH. Twelve months after SAH, a considerable percentage of patients with a presumably good outcome (mRS 0-2) had a lower HRQoL compared with the general population. Implementing corresponding tests at discharge and 12-month follow-up is recommended.

SAT-221 False-Positive Urinary Free Cortisol with Oral Contraceptive Use

Introduction It is well-established that estrogen-containing oral contraceptives can raise serum cortisol levels and yield false-positive results on dexamethasone suppression testing, however it is less known that they can raise urinary free cortisol levels by an unknown mechanism. Case presentation A 47-year old woman taking microgestin 1/20 oral contraceptive (OC) was found incidentally to have osteopenia on chest X-ray. Subsequent DEXA scan demonstrated osteoporosis. During the work-up to determine the underlying etiology of her osteoporosis, she underwent a 24-hour urinary free cortisol, which was 207 ug/24 hours (0-50 ug/24 hours). Serum cortisol was 40.1 (6.2-19.4 ug/dL) and overnight 1mg dexamethasone suppression test yielded a cortisol of 2.7. After one week off her OC, serum cortisol was 24.6. After five weeks off her OC, urinary free cortisol was 19 and 1mg dexamethasone suppression test yielded a cortisol of 0.8. On exam, the patient did not have any cushingoid features. MRI of the brain showed a small hypoenhancing lesion, which was determined by neurosurgery to be insignificant. Ultimately, the cause of her osteoporosis was thought to be likely secondary to vitamin D deficiency and calcium malabsorption due to celiac disease. Discussion The biochemical diagnosis of hypercortisolism during treatment with estrogen-containing OCs remains a challenge. Prior studies have demonstrated that serum cortisol levels are typically elevated during OC use and that 1mg dexamethasone suppression testing may yield false-positive results in more than 50% of cases. This is thought to be due to an increase in the major binding protein for cortisol, corticosteroid-binding globulin. Although it is commonly thought that OCs do not affect urinary free cortisol measurements, a recent study showed that more than one-third of women taking OCs had a mild elevation of urinary free cortisol. There are a few hypotheses for the mechanism by which OC use leads to elevated urinary free cortisol, including direct effect on steroidogenesis in the adrenal glands. Our patient had a significantly elevated 24-hour urinary free cortisol and an equivocal 1mg dexamethasone suppression test while on OCs that normalized with OC discontinuation. Further, serum cortisol decreased with OC discontinuation. Conclusion The 24-hour urinary free cortisol level may be altered by oral contraceptive use and is therefore not a valid tool to evaluate for hypercortisolism in women on OCs. References Nickelsen T, et al. (1989). The dexamethasone suppression test and long-term contraceptive treatment. Experimental and Clinical Endocrinology, 94, 275–280. Paschali M, et al. (2013). False positives on both dexamethasone testing and urinary free cortisol in women on oral contraception. Clin Endocrinol, 79, 443-445. Trainer PJ. (2002). Corticosteroids and pregnancy. Seminars in Reproductive Medicine, 20, 375–280.

Five years follow up of patients with Сushing’s disease with and without visualized pituitary adenoma on MRI, who underwent transsphenoidal adenomectomy

The remission rate of Cushing’s disease in patients after neurosurgery varies from 59 to 94%, while the recurrence rate is 3 to 46%.&#x0D; Aim — to evaluate the five-year outcome in neurosurgery patients with Cushing’s disease (CD), depending on preoperative MRI-based identification of pituitary adenoma.&#x0D; Material and methods. The study included 105 neurosurgery patients with histologically confirmed CD. CD remission was confirmed by the development of adrenal insufficiency and/or normalization of serum cortisol and 24-hour urinary free cortisol (24h UFC) levels, as well as by clinical remission.&#x0D; Results. Pituitary adenoma was not visualized by gadolinium MRI in 35 cases. The size of visualized pituitary adenoma varied from 0.3 to 29 mm. After first neurosurgery, remission was achieved in 87 (82.8%) patients. After second neurosurgery, remission occurred in 12 patients. Radiation therapy was conducted in 24 patients. Six patients had bilateral adrenalectomy. Two patients died during remission: one patient died from stroke two years after neurosurgery, and the other patient died due to surgery complications. During five-year follow-up after neurosurgery, remission continued in 76 (72.8%) patients, including 27 (77%) of 35 patients without MRI-detected adenoma and 49 (70%) of 70 patients with MRI-detected pituitary adenoma, p=0.15. Sixty-six patients developed recurrence, and 14 patients had active hypercortisolism.&#x0D; Conclusion. There was no correlation between the rate of preoperative MRI-based detection of pituitary adenoma and the rate of remission in neurosurgery patients with Cushing’s disease during the five year follow-up. The size of pituitary adenoma was a risk factor for adenoma recurrence.

The diagnostic value of late-night salivary cortisol for diagnosis of subclinical Cushing's syndrome.

Late-night salivary cortisol is a frequently used and easily implemented diagnostically valuable test for the diagnosis of overt Cushing's syndrome. The use of late-night salivary cortisol in the diagnosis of subclinical Cushing's syndrome is somewhat controversial. In this study, we aimed to determine the diagnostic value of late-night salivary cortisol in diagnosing subclinical Cushing's syndrome and compare it with 24-hour urinary free cortisol levels (UFC). The study consisted of 33 cases of subclinical Cushing's syndrome, 59 cases of non-functioning adrenal adenoma, and 41 control subjects. Late-night salivary cortisol and UFC were measured in all the cases. The diagnosis of subclinical Cushing's syndrome was based on combined results of 1 mg dexamethasone suppression test > 1.8 μg/dL and ACTH < 10 pg/mL. Mean late-night salivary cortisol levels in subjects with subclinical Cushing's syndrome were significantly higher than in subjects with non-functioning adrenal adenoma and the control group (p < 0.001). Using a cut-off value of 0.18 μg/dL, the sensitivity and specificity of late-night salivary cortisol for diagnosing subclinical Cushing's syndrome were determined as 82% and 60%, respectively. Using a cut-off value of 137 μg/day, the sensitivity and specificity of UFC was determined as 18% and 90%, respectively. Because the sensitivity of late-night salivary cortisol for the diagnosis of subclinical Cushing's syndrome is limited, using it as the sole screening test for subclinical Cushing's syndrome may lead to false negative results. However, using it as an adjunct test to other tests may be beneficial in the diagnosis of subclinical Cushing's syndrome. (Endokrynol Pol 2016; 67 (5): 487-492).

Coagulation Profile Dynamics in Pediatric Patients with Cushing Syndrome: A Prospective, Observational Comparative Study

To evaluate the association between Cushing syndrome and hypercoagulability in children. A prospective, observational study was performed of 54 patients with Cushing syndrome, 15.1 ± 3.9 years, treated at the National Institutes of Health Clinical Center. Coagulation profiles were taken before and 6-12 months after surgery and compared with18 normocortisolemic children, 13.7 ± 3.6 years. At baseline, patients with Cushing syndrome had greater levels of the procoagulant factor VIII (FVIII) vs controls (145 IU/dL ± 84 vs 99 ± 47, P = .04); 6-12 months after surgery, FVIII levels decreased to 111 ± 47, P = .05. Patients with Cushing syndrome had greater levels of the antifibrinolytic α2-antiplasmin, 96 ± 17% vs 82 ± 26%, P = .015. After surgery, antifibrinolytic α2-antiplasmin levels decreased to 82 ± 24%, P < .001. Anticoagulants were greater in patients with Cushing syndrome vs controls at baseline, including protein C (138 ± 41% vs 84 ± 25%, P < .001), protein S (94 ± 19% vs 74 ± 19%, P = .001), and antithrombin III (96 ± 18% vs 77 ± 13%, P < .0001). The 24-hour urinary free cortisol levels correlated positively with FVIII levels, r = 0.43, P = .004. Children with Cushing syndrome had elevated procoagulants, antifibrinolytics, and anticoagulants at baseline compared with controls; normalization of coagulation measures was seen after surgical cure. Despite the increase in anticoagulants, hypercortisolemia is associated with a hypercoagulable state in children, as is the case in adults. This finding has potential implications for prevention of venous thromboembolism in children with Cushing syndrome. ClinicalTrials.gov:NCT00001595.

Surgical treatment of ectopic adrenocorticotropic hormone syndrome with intra-thoracic tumor.

The study was to review the clinical manifestations and laboratory examinations of ectopic adrenocorticotropic hormone (ACTH) syndrome, and to analyze the efficacy of surgical treatment. The clinical data, surgical therapy, and outcome of 23 cases of ectopic ACTH syndrome accompanied by intra-thoracic tumors were reviewed. The tumors were removed from all the patients according to the principles of radical resection. The tumors were confirmed as associated with ectopic ACTH secretion in 19 cases. Hyperglycemia and hypokalemia were recovered, while plasma cortisol, plasma ACTH and 24-hour urinary free cortisol (UFC) levels were significantly reduced after surgery in these 19 cases. Recurrences of the disease were found in six cases during following-up, and five of them died. The thoracic cavity should be a focus in routine examinations of patients with symptoms of Cushing's syndrome (CS), because ectopic ACTH-producing tumors are commonly found in bronchus/lung and mediastinum. Despite the incidence of the pulmonary nodule secondary to opportunistic infection in some cases, surgery is still the first choice if the tumor is localized. The surgical procedure should be performed according to the principles in resection of lung cancer and mediastinal tumor. The surgical efficacy is significant for short-term periods; however, the recurrence of the disease in long-term periods is in great part related to distal metastasis or relapse of the tumor.

Subclinical Hypercortisolism: How to Deal with It?

Subclinical hypercortisolism (SH) is a condition of mild cortisol excess, found in the 5-30% of patients with adrenal incidentalomas, defined as silent adrenal masses diagnosed throughout radiological examinations performed for unrelated diseases. Generally, the diagnosis of SH is supported by the presence of high cortisol levels after a 1-mg dexamethasone suppression test, low adrenocorticotropic hormone levels, altered cortisol circadian rhythm and 24-hour urinary free cortisol levels higher than the upper reference value. Less frequently, diagnosis is made by other tests. Unfortunately, up to now a consensus on SH diagnostic criteria is lacking. Although SH is characterized by the absence of the classical features of Cushing's syndrome by definition, it has been associated with the presence of different metabolic complications (mainly type 2 diabetes mellitus, arterial hypertension, central obesity and dyslipidemia), cardiovascular diseases, osteoporosis and vertebral fractures, altered coagulation parameters, worsening of quality of life, and increased mortality. The management of SH, as well as the improvement of metabolic parameters and other complications after surgical treatment, is still a matter of debate.

An Unusual Cause of Cushing’s Syndrome and Virilization

Question: A 12-year-old girl had suffered a disease for 2 years. Physical examination showed the central obesity with a body mass index of 22.68 kg/m2, and clinical features with facial redness, thinning of the skin, growth of fat pads along the collarbone, on the back of the neck, and on the face, and purple striae on her arms and legs. Moreover, other symptoms including deepening of her voice, acne, scalp hair loss, development of pubic hair, and excessive facial and body hair were also found. Basal plasma cortisol levels (8 am, 29.16 μg/dL; normal range, 4.0–22.3) and 24-hour urinary free cortisol levels (1628.00 μg/24 h; normal range, 12.3–103.5) were elevated. The plasma adrenocorticotrophic hormone level (17.0 pg/mL; normal range, 0–46) was not increased, and there was no cortisol suppression after high dexamethasone. Plasma levels of testosterone (2541.6 ng/dL; normal range, 6.1–55), dehydroepiandrosterone sulfate (579.9 μg/dL; normal range, 17–343), and 17-hydroxyprogesterone (73.82 ng/mL; normal range, <2.9) were also elevated, although estradiol was not significantly increased (47.8 pg/mL; normal range, <460). Abdominal imaging showed a retroperitoneal mass, which was 7.9 cm in the longest axis, below the left kidney, and contrast agent and octreotide rapidly entered the mass. Bilateral adrenal glands were atrophied (Figure A–C). PET showed that the mass was below the left kidney with uneven increased metabolism (standardized uptake value max, 6.7). Surgery was performed to resect the retroperitoneal mass (Figure D, E). Postoperative plasma cortisol (0.13 μg/dL) and testosterone levels (13.6 ng/dL) decreased immediately. Did the mass cause the symptoms? What is the exact diagnosis of the girl? See the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. Histologically, the neoplasm was diagnosed as an adrenocortical oxyphilic adenoma with myelolipoma. The histologic results are shown in Figure F. Immunohistochemistry showed that the neoplasm was positive for calretinin (Figure G), Melan-A, and Syn, but negative for adrenocorticotrophic hormone, AE1/AE3, CgA, HMB45, hepatocyte, chromogranin A, S-100, CD10, and smooth muscle actin. Ki67 was expressed in the nucleus of 1% of the tumor cells. Adrenal oncocytic adenomas are rarely found outside the adrenal gland, in sites presumed to arise from ectopic adrenal tissue. Our present case of an oncocytic adenoma was thought to be adrenocortical origin because of positive immunohistochemical staining for calretinin and Melan-A (adrenocortical markers), and negative staining for S-100 and chromogranin (adrenomedullary markers). Myelolipomas are rare tumors, with an incidence of 0.4% in extra-adrenal locations at autopsy. Only 10 cases of perirenal and 4 cases of renal myelolipomas have been described in the medical literature.1Brandler T.C. Reder I. Kahn L. Perirenal myelolipoma diagnosed on imprint: case report and review of the literature.Diagn Cytopathol. 2015; 43: 230-233Crossref PubMed Scopus (4) Google Scholar Sections of myelolipomas typically showing a variegated appearance with areas of yellow lipid-appearing tissue alternating with areas of dark brown friable tissue could be used to exclude the diagnosis of liposarcoma. Myelolipomas and ectopic oncocytic adenomas are rarely functional, but positive Syn staining in our case indicated that the mass had neuroendocrine function, which could explain the elevated levels of glucocorticoid and androgen. Some reports have described oncocytic adenomas or myelolipomas with secretory function.2Corpas Jimenez M.S. Ortega Salas R. Tenorio Jimenez C. et al.Myelolipoma associated with adrenocortical adenoma: an unusual cause of Cushing's syndrome.Endocrinol Nutr. 2014; 61: e7-9Crossref PubMed Scopus (7) Google Scholar, 3Surrey L.F. Thaker A.A. Zhang P.J. et al.Ectopic functioning adrenocortical oncocytic adenoma (oncocytoma) with myelolipoma causing virilization.Case Rep Pathol. 2012; 2012: 326418PubMed Google Scholar To the best of our knowledge, ectopic adrenocortical adenoma with myelolipoma, which causes Cushing’s syndrome and hyperandrogenism, has not been described before the current case. Therefore, the functional capacity that these tumors might sometimes have can easily be overlooked and create a diagnostic challenge. Correlation with histology, immunohistochemistry, and serum endocrine studies can be helpful in making a correct diagnosis.