24-hour Urinary Free Cortisol Research Articles

Assessment of adrenal function in pediatric cancer survivors.

Oncological therapy can temporarily or permanently disrupt adrenal gland function. The aim of our study was to assess the function of adrenal glands in cancer survivors and to find the best diagnostic tools for it. Sixty patients aged 1.2-14.9 years (mean 8.3 ±3.5) with diagnosed malignancies and 45 healthy children as controls were recruited to the study. Patients were assessed 0-8 years (mean 2.4 ±2.0 years) after the oncological therapy. In all patients fasting blood samples were collected to measure: glucose, sodium, potassium, cortisol, aldosterone, plasma renin activity (PRA), dehydroepiandrostenedione-sulphate (DHEA-S), adrenocorticotropic hormone (ACTH) and antibodies against the adrenal cortex (AAA). Moreover, 24-hour urinary free cortisol (UFC) was assessed. Test with synthetic ACTH was carried out with 250 µg in neuroblastoma and nephroblastoma patients and with 1 µg in other oncological patients. The levels of morning cortisol and sodium were significantly lower and blood glucose were higher in cancer survivors than in controls (p = 0.006, p = 0.043, p = 0.008). Basal laboratory tests confirmed adrenal insufficiency (AI) in 1 patient with neuroblastoma. Low-dose ACTH revealed AI in 3 patients with acute lymphoblastic leukemia. In the study group, UFC correlated with evening and midnight cortisol (p = 0.001, p = 0.006). In the control group UFC correlated with DHEA-S (r = 0.623, p = 0.0001). None of assessed parameters correlated with the time since the completion of oncological therapy. The study confirmed possibility of developing asymptomatic AI in cancer survivors even several years after therapy. Instead of morning cortisol, classical diagnostic low-dose ACTH test seems to be an optimal tool for adrenal function's assessment.

Diagnosis and Management of Cushing's Disease: A Survey of Endocrinologists from the Middle East and North Africa

Abstract Background Cushing's disease is the most prevalent cause of endogenous Cushing's syndrome. This study aimed to scope the current clinical practice pattern in managing Cushing's disease by endocrinologists in the Middle Eastern and North African (MENA) region. Methods A questionnaire dealing with diagnosis, treatment, and follow-up of patients with Cushing's disease was adopted and sent electronically to a convenience sample of endocrinologists from the MENA region. Results Out of 125 responses received, 88 were eligible for inclusion in the analysis. Most respondents selected the overnight dexamethasone suppression test (ONDST) and 24-hour urinary-free cortisol (UFC) as the best screening tests, 58 (66.7%) and 50 (57.5%) respectively, followed by midnight serum cortisol and midnight salivary cortisol. Measurement of serum adrenocorticotropic hormone (ACTH; 86.2%) and classic high-dose dexamethasone suppression test (40.2%) were selected for localization of the primary lesion. The primary choice of treatment was transsphenoidal pituitary surgery (98.8%). For the recurrence of Cushing's disease, medical therapy was the preferred modality followed by repeated pituitary surgery or bilateral adrenalectomy. In case of treatment failure following the first pituitary surgery and ketoconazole treatment, 36.9% selected pasireotide, while 32.1% chose bilateral adrenalectomy. Conclusion ONDST and UFC are the two most common tests used to screen an index case with features of hypercortisolism. Pituitary surgery is the primary choice of treatment in Cushing's disease. However, medical treatment by ketoconazole is preferred for recurrent cases. Bilateral adrenalectomy is followed by pasireotide may be chosen in case of treatment failure after pituitary surgery and ketoconazole.

Annals for Educators - December 2021.

Annals for Educators - December 2021.

Novel threshold value of midnight serum cortisol for diagnosis of hypercortisolism using the Roche Cortisol II assay

BackgroundThe diagnosis of hypercortisolism requires multiple biochemical investigations, due to variations in cortisol production during the 24-hour circadian cycle. Midnight serum cortisol is difficult to interpret since the threshold value is dependent on the analytical method used and is often not provided by the manufacturer. Second-generation assays are more specific than first-generation assays and may have lower threshold values. ObjectivesThe aim of this study was to determine a novel threshold value of midnight serum cortisol for the biochemical diagnosis of hypercortisolism, using the Roche Cobas Cortisol® second-generation assay. MethodsThis study was performed in adult patients hospitalized in the endocrinology unit of a university hospital. Patients had a complete assessment of their 24-hour cortisol cycle, i.e., a serum cortisol test every four hours and at least two first-line tests: late night salivary cortisol, dexamethasone suppression test and/or 24-hour urinary free cortisol. First-line tests were used to identify patients with hypercortisolism. Serum samples were analyzed by second-generation electrochemiluminescence immunoassays (ECLIA) from Roche Cobas Cortisol®. ResultsMidnight serum cortisol samples were obtained from 175 hospitalized patients. The novel threshold value obtained was 157 nmol/L with a sensitivity of 82.9% (68.6 to 94.3%) and a specificity of 90.0% (85.0 to 95.0%). ConclusionOur study confirms that the threshold value of midnight serum cortisol is not comparable between first- and second-generation Roche Cobas Cortisol® assays and that the threshold value is lower with the second-generation assay.

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.

Avascular femoral necrosis as part of Cushing syndrome presentation: a\xa0case report

BackgroundThe clinical characteristics and complications of Cushing syndrome (CS) are well known and described in the literature. Nevertheless, rare, atypical presentations may go unnoticed. Osteonecrosis is a well-documented complication of glucocorticoid therapy. However, endogenous hypercortisolism is a rare, but relevant, cause of bone avascular necrosis. We describe the case of a woman with CS undiagnosed for 2 years after presenting with femoral avascular necrosis.Case presentationA 38-year-old Caucasian woman was referred for evaluation of secondary amenorrhea, associated with oral contraception withdrawal in the context of deep venous thrombosis (DVT). She had a previous right hip arthroplasty for treatment of avascular necrosis of the femoral head, diagnosed after 3 years of progressive right hip pain and limited mobility. She also had high blood pressure (HBP) of 5 years’ duration, and reported weight gain (4 kg in 2 years). There was no history of infertility (gravida 2, para 2). Physical examination revealed buffalo hump, truncal obesity, facial plethora, muscular atrophy and proximal myopathy, and easy bruising (under anticoagulant treatment for DVT). Workup showed abnormal overnight dexamethasone suppression test (DST) (serum cortisol 21.5 µg/dL; normal < 1.8 µg/dL), elevated 24-hour urinary free cortisol (UFC) (728.9 µg/day; reference range 36.0–137.0 µg/day), and suppressed plasma adrenocorticotropic hormone (ACTH) (< 1.0 pg/mL), findings consistent with ACTH-independent CS. Urinary metanephrines and catecholamines were normal, and the remaining analytical study showed no major changes, apart from glycated hemoglobin (HbA1c) of 6.8%. Adrenal computed tomography (CT) scan showed a 25 mm lesion in the left adrenal gland, with density non-suggestive of adenoma. The patient underwent unilateral adrenalectomy and started steroid replacement. Histology revealed an adrenal cortex adenoma. Three months after surgery the patient presented with resolution of HBP and hypercortisolism (UFC 37.4 µg/day; reference range 36.0–137.0 µg/day).ConclusionIn some cases, CS signs may go unnoticed and the diagnosis postponed. Avascular necrosis is a rare presenting feature of endogenous hypercortisolism, and, if left untreated, complete collapse of the femoral head may ensue, rendering the need for hip replacement in up to 70% of patients. Suspicion and recognition of atypical features is therefore important in avoiding complications and delay in treatment of CS.

Cushing’s Syndrome Associated With an Adrenal Cavernous Hemangioma

Introduction: Adrenal cavernous hemangiomas are rare benign tumors that arise from vascular endothelium and are often discovered incidentally on abdominal imaging. The majority are nonfunctioning; however, we present a case of adrenal Cushing’s syndrome in a patient with a cavernous adrenal hemangioma.Case: A 72-year-old woman was referred for an incidental right adrenal mass. On questioning, she endorsed abdominal pain, sixty-pound unintentional weight gain over five years, truncal obesity, and easy bruising. Past medical history was relevant for hypertension. Her surgical history was extremely complicated, having had a perforated peptic ulcer, open cholecystectomy complicated by injury to the right ureter, incisional hernia repair, appendectomy, and hysterectomy with bilateral salpingo-oophorectomy.She was first noted to have a right adrenal mass on a CT done eight years ago, measuring 3.8 x 3.2 cm. A repeat CT abdomen and pelvis now showed this mass to be 6.5 x 6.3 x 8.1 cm with unenhanced Hounsfield units of 29.6. Radiographically, this was a heterogeneous, solid, and cystic appearing mass with peripheral brisk arterial enhancement areas, which appeared to fill in on delayed imaging. The enhancement pattern of the lesion was consistent with an adrenal cavernous hemangioma. An MRI of the abdomen also demonstrated similar peripheral nodular enhancement favoring an adrenal cavernous hemangioma.Functional testing for the adrenal mass was undertaken. Morning cortisol was 23.4 mcg/dl with ACTH low at 5.3 pg/ml, and DHEA-S 3 mcg/dl. She failed to suppress with overnight 1 mg dexamethasone with AM cortisol of 3.6 mcg/dl. Midnight salivary cortisol levels were high at 0.237 mcg/dl and 0.419 mcg/dl while a 24-hour urine free cortisol was normal at 15.2 mcg/d. She tested negative for pheochromocytoma and primary aldosteronism.The patient was deemed a poor surgical candidate due to her history of multiple prior abdominal surgeries and a BMI of 46. Therefore, she underwent an IR angioembolization of the right adrenal mass instead. On follow-up CT, there was no significant change in the size of the lesion; however the degree of rim enhancement was slightly decreased. Post procedurally, her a.m. cortisol remained high-normal at 18.3 mcg/dL.. She is currently enrolled in a study for medical treatment of Cushing’s syndrome.Discussion: Adrenal cavernous hemangiomas usually present incidentally in the 6th-7th decade of life with a female predominance. These lesions are often asymptomatic; however, abdominal pain is the most common presenting symptom. The majority of adrenal cavernous hemangiomas are hormonally quiescent and mineralocorticoid excess and/or subclinical Cushing’s syndrome is exceedingly rare. Our patient is unique in her presentation of adrenal Cushing’s with this lesion and the novel use of angioembolization to decrease the size of this vascular tumor.

Atypical Carcinoid Tumor of the Mediastinum Presenting as Ectopic Cushing’s Syndrome

Introduction: Ectopic Cushing’s syndrome (ECS) refers to Cushing’s syndrome (CS) that results from extra-pituitary secretion of adrenocorticotropic hormone (ACTH). Neuroendocrine tumors (NETs) are a rare cause of ECS, and their presence in the anterior mediastinum only represents 2-4% of all cases. We report a rare case of ECS in a patient with an atypical mediastinal carcinoid tumor.Case Presentation: A 38-year-old male with a history of depression presented with generalized weakness, fatigue, and myalgia for one month. A one-week history of nausea and slight shortness of breath was reported. Physical exam and vital signs were unremarkable. Labs revealed hyperglycemia, hypokalemia, and metabolic alkalosis. A random serum cortisol was 47.7 mcg/dL (normal: 3-21 mcg/dL) and a 24-hour urine free cortisol was 7405 mcg/24 hours (normal: 3.5-45 mcg/24 hours). The morning serum cortisol after 8 mg dexamethasone at midnight, was 58.7 mcg/dL. Serum aldosterone and plasma renin activity were both undetectable. CT of the chest showed an anterior mediastinal mass measuring 9.0 x 10.3 x 6.1 cm accompanied by two large mediastinal lymph nodes. A PET CT confirmed the anterior mediastinal mass, which showed mild heterogeneous uptake and no evidence of metastatic disease. Core biopsy of mediastinal mass showed grade II neuroendocrine tumor/atypical carcinoid. Potassium, Spironolactone, Ketoconazole, and Metyrapone were used to control hypokalemia and hypercortisolemia. Trimethoprim-sulfamethoxazole (TMP-SMX) was started for Pneumocystis pneumonia prophylaxis. The patient underwent complete resection of the anterior mediastinal mass, thymectomy, and mediastinal lymph nodes dissection. Histopathology confirmed an atypical carcinoid in the mediastinal mass with negative margins. The rest of the thymus tissue and lymph nodes were negative for malignancy. ACTH and cortisol levels dropped significantly after surgery and the patient was discharged on oral hydrocortisone and TMP-SMX. At 4 weeks follow-up in the clinic, the patient was feeling much better and reported complete resolution of symptoms.Discussion: ECS caused by an atypical carcinoid tumor is an extremely rare finding. Mediastinal NETs tend to have a poor prognosis due to their metastatic tendency and recurrence rates. Due to limited evidence in the medical literature, there’s much uncertainty and controversy regarding the best treatment of NETs. Standardized guidelines for the management of these atypical tumors are not well established. The primary mode of treatment is surgical resection of the ACTH-secreting tumor. However, in cases of advanced and metastatic tumors, surgical resection might not be sufficient and medical therapy with adrenal enzyme synthesis inhibitors may be needed. The use of neoadjuvant chemotherapy and/or radiotherapy remains unclear.

A Case of Renal Cell Carcinoma and Pheochromocytoma Due to Germline Inactivating Mutation in Fumarate Hydratase (FH)

A 60-year-old female with a history of well-controlled hypertension, prediabetes, status post hysterectomy for fibroids, presented for evaluation of hematuria and unintentional weight loss. She denied palpitations, headaches, tremors, and diaphoresis. Initial CT demonstrated a right renal mass suspicious for renal cell carcinoma and an adrenal mass. Magnetic resonance imaging (MRI) confirmed a hypervascular, right adrenal mass (6.7 x 6 x 5 cm) without loss of signal.Laboratory Testing: elevated 24-hour urine vanillylmandelic acid (VMA) 17.5 mg/24 h (<6), and urine normetanephrines 2276 ug/24 h (122-676) with normal urine metanephrines 158 ug/24 h (90-315). 24-hour urine free cortisol was normal. The patient underwent a right adrenalectomy and partial nephrectomy. Pathology confirmed a low-grade renal cell carcinoma (RCC) and a 6.8 cm pheochromocytoma (PCC). Genetic analysis revealed an inherited mutation in the fumarate hydratase (FH) gene, which is diagnostic of hereditary leiomyomatosis and renal cell cancer (HLRCC). Wildtype FH codes for an enzyme that converts fumarate to malate in the mitochondrial Krebs cycle. Inactivating mutations in FH trigger the hypoxia pathway by activating hypoxia-inducible factor (HIF) thereby promoting tumor growth and angiogenesis.In PCC, 30-40% are hereditary and another 40-50% are found to have somatic mutations in 1 of 20 PCC susceptibility genes. Several autosomal dominant heritable syndromes, including Neurofibromatosis type 1 (NF-1), von Hippel-Lindau (VHL), Multiple Endocrine Neoplasia Type 2 (MEN 2), and Paraganglioma Syndromes Types 1–5, have an increased incidence of PCC, most of which modulate hypoxia pathways. FH mutations are similarly inherited in an autosomal dominant fashion and cause HLRCC.HLRCC is associated with 75-80% risk for cutaneous and uterine leiomyomas, and a 10-16% risk for type II papillary renal cell carcinoma. The risk of RCC in patients with FH mutations is much greater than in the general population, where the prevalence is ~2% in those who lack the mutation. In one study, FH deficiencies attribute between 19-41% of all RCC cases. Rare families with PGL/PCC have also been found to carry this germline FH mutation. This FH mutation is associated with increased risk of metastasis in patients with PGL/PCC by a similar mechanism of carcinogenesis via the hypoxia pathway. Currently, there are no strict guidelines for surveillance in individuals with HLRCC, however, patients should have a yearly abdominal MRI, skin examination every 2 years, and an annual gynecological evaluation for leiomyosarcoma. Each first-degree relative should be offered genetic testing of the FH mutation, as 50% of relatives may carry the gene. This case underscores the importance of genetic workups in patients with PCC, especially if associated with other tumors.

Presentation of ACTH Independent Cushing’s as Severe Insulin Resistance During Pregnancy

Introduction: Cushing’s syndrome is very rare in pregnancy with around 200 cases reported in literature. It remains a diagnostic dilemma as pregnancy itself is a hypercortisolemic state. Several clinical characteristics of Cushing’s syndrome such as insulin resistance and hirsutism may overlap with normal variants of pregnancy and therefore leading to a missed diagnosis. We hereby present a case of a young pregnant woman with severe insulin resistance, with workup consistent with Cushing’s syndrome. Clinical Case: This was a 27-year-old pregnant woman with DM type 2 diagnosed about 7 years ago. During her pregnancy she was started on insulin and was later admitted to the hospital at 32 weeks for inpatient management of pre-eclampsia and uncontrolled hyperglycemia. Endocrine was consulted for severe insulin resistance and persistent hyperglycemia. On exam patient was noted to be obese with facial plethora, frontal balding and significant facial hirsutism. During the pregnancy she had noted significant weight gain with substantial worsening of frontal balding and hirsutism. Her current pregnancy was spontaneous but was after many years of trying to conceive. Prior pregnancy 8 years ago was uncomplicated with no history for GDM at that time. Review of recent pre-pregnancy imaging revealed left adrenal mass measuring 3.5 cm with 40 HU which measured around 2 cm 8 years ago. Biochemical work up revealed elevated 8 am cortisol at 35.4 ug/dL (ref range 6.2 - 19.4) with suppressed ACTH <5 pg/mL (6 – 50). Testosterone was high at 299 ng/dL (8 – 48) and DHEAS was low normal at 37 mcg/dL (18 – 391). Plasma and 24 hour urine metanephrine collection results were normal. 24-hour urine free cortisol was measured and was elevated at 628.5 mcg/24(4.0–50.0). Midnight salivary cortisol was 0.87 mcg/dL (<OR=0.09). Patient was managed conservatively with plan for surgical intervention post-delivery. Pregnancy was complicated by PPROM at 35 weeks with subsequent cesarean section. Baby was of average weight but developed mild hyperbilirubinemia which required short NICU stay. On reevaluation at 4-week postpartum period, repeat biochemical workup revealed elevated cortisol of 22.5 mcg/dL, ACTH <5 pg/ml, elevated 24-hour urine cortisol 163.9 mcg/24h with appropriate urinary creatinine. Testosterone level was improved postpartum to 9 ng/dL. DHEAS was 39 mcg/dL. Repeat imaging with CT with adrenal protocol revealed left adrenal mass measuring 2.3 cm with 20 HU with absolute washout of 79%. She was started on ketoconazole is now awaiting surgical intervention. Conclusion: We suspect that this patient may have had pregestational subclinical Cushing’s syndrome which eventually progressed to Cushing’s syndrome during pregnancy. Although this is a rare finding during pregnancy, workup for Cushing’s should be considered in pregnant women with severe insulin resistance, hirsutism, hypertension and pre-eclampsia.

Severe Cyclical Hypercortisolism Due to Metastatic Neuroendocrine Cancer Initially Diagnosed as Colon Cancer

Case Description: A 65 year-old male with initial diagnosis of metastatic colon cancer based on liver biopsy presented for evaluation of severe hypercortisolism with 24-hour urinary free cortisol (UFC) of 1184 mcg/day after presenting to his Oncologist in December 2019 requesting evaluation for muscle weakness and weight gain. On re-evaluation in March, his cortisol had dramatically improved with 24-hr UFC of 120 mcg/day and ACTH of 84 pg/mL and had resolved with 24-hr UFC of 32.6 mcg/day by May.A 2 cm pancreatic lesion was noted during cancer staging; a second opinion was obtained on the liver biopsy which was interpreted as metastatic neuroendocrine tumor, possibly of pancreatic origin. The patient was started on FOLFINIRNOX in December 2019. This was transitioned to carboplatin and etoposide after the revised diagnosis and was continued through May with regression of liver lesions on followup imaging. A 68 Ga-DOTATATE PET CT confirmed uptake in the pancreas, retroperitoneal lymph nodes, and thyroid. A thyroid ultrasound was obtained which did not meet FNA criteria.Given the chronologic association between cortisol levels and chemotherapy response we were suspicious for ectopic Cushing’s syndrome due to metastatic neuroendocrine cancer and the patient was followed for recurrence. In September, the patient endorsed leg weakness and hyperglycemia and was found to have a 24-hr UFC of 4731 mcg/day and an 8 am cortisol of 102 mcg/dL.The patient developed severe hypokalemia requiring admission and was restarted on chemotherapy with moderate improvement in cortisol levels and symptoms. Given the degree of cortisol elevation, we recommended bilateral adrenalectomy, for which the patient established care at a more specialized center.Discussion: Ectopic Cushing’s syndrome is an uncommon variety of ACTH-dependent Cushing’s syndrome caused by CRH or ACTH-producing tumors. The more aggressive form is associated with small-cell lung cancer while the chronic form is associated with indolent tumors.Cyclical Cushing’s syndrome is a rare cause of hypercortisolism characterized by cyclical variations in cortisol levels. The pathophysiology of the cyclical variation is unclear. About half of cases are caused by pituitary corticotrophs but up to 26% can be attributed to ectopic ACTH production, typically due to indolent tumors rather than aggressive malignancies.We present a case of cyclical hypercortisolism with an initial diagnosis of colon cancer. On further review, the cyclical hypercortisolism was likely associated with chemotherapy response. Reevaluation of surgical pathology was consistent with metastatic neuroendocrine cancer, the likely source of ectopic ACTH.Our case highlights the importance of maintaining a broad differential when considering cases of cyclical cortisol elevation, including consideration of concurrent chemotherapy for seemingly unrelated malignancies.

Taking it with a Grain of Salt: A Woman with ‘PCOS’ and Infertility Diagnosed with Nonclassic Congenital Adrenal Hyperplasia and a Large Renal Mass

Background: Clinical manifestations of Nonclassic CAH (NCCAH) in women may range from asymptomatic to hirsutism, oligo-menorrhea, or infertility. Testicular adrenal rest tumors are common in men with classic CAH though uncommon in NCCAH. In women with classic CAH, ovarian adrenal rest tumors are even rarer. 11–58% of patients with classic CAH will have at least one adrenal nodule but the prevalence is unknown in NCCAH (1).Clinical Case: A 34-year-old Hispanic woman was seen by reproductive endocrinology for evaluation of infertility. She had been unable to conceive for the past 7 years. She was diagnosed with PCOS by her PCP. She was referred to our clinic for further workup. The patient denied galactorrhea. Laboratory evaluation revealed prolactin 49.3 (< 20.0 ng/ml), TSH 2.290 (0.5–5.0 μU/mL), fT4 1.14 (0.9–2.3 ng/dL), total testosterone 92 (15 -70 ng/dL for women), DHEAS 361 (45 -270 µg/dL), 8 AM cortisol 20.0 (5–23 μg/dL), ACTH 59.0 (6–76 pg/ml), 17-hydroxyprogesterone (17OHP) >2000 ng/dL, and A1c 5%. 24-hour urinary free cortisol was 26.4 (3.5–45 mcg/day). MRI of the pituitary did not show any adenoma. Pelvic ultrasound did not reveal any ovarian cysts.Cosyntropin stimulation test showed baseline 17OHP 1076 ng/dL, 30 minutes 8812 ng/dL, and 60 minutes 9452 ng/dL. She was begun on hydrocortisone and cabergoline. CT of the abdomen did not reveal any adrenal masses but showed mildly thickened adrenal limbs suggesting adrenal hyperplasia. A 4.5 cm exophytic enhancing mass on the left kidney was noted representing an adrenal rest tumor versus angiomyolipoma.Given the exophytic nature of the mass and increased risk of hemorrhage with angiomyolipomas greater than 4 cm, the patient was referred to urology and interventional radiology for radioembolization and possible biopsy of the mass. We are unsure if this renal mass is an angiomyolipoma or an adrenal rest tumor, which are uncommon in the kidneys. The patient was also referred for genetic counseling. Patients with CAH typically have CYP21A2 gene mutations, and the chance that a patient with NCCAH will have a child with classic CAH is reported to be 1 to 2% in two large cohort studies (2).Conclusion: This case is a reminder that evaluation of infertility/subfertility includes less common diagnoses, such as NCCAH. This genetic disorder is seen more frequently in certain ethnic groups, including Hispanics; and after diagnosis, patients should be referred to a genetic specialist. Additional abdominopelvic imaging should be considered in both men and women with a new diagnosis of NCCAH to evaluate for rare but clinically significant tumors.Reference: 1. Nordenström, A., Falhammar H. Diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency Eur J Endocrinol. 2019 Mar;180(3):R127-R145.2. Merke, D, Auchus, R Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. NEJM 2020;383:1248–61.

Adrenal Cushing’s in Pregnancy, Managed with Metyrapone to Optimize for Adrenalectomy at 27 Weeks Gestation

Background: Cushing’s syndrome in pregnancy is associated with increased fetal and maternal morbidity and mortality. Prompt diagnosis and management during pregnancy is critical to improving these outcomes. Clinical Case: Patient is a 28-year-old female who presented to our hospital at 25 weeks of pregnancy with severe striae, high blood pressure, mildly elevated blood sugars and hypokalemia. Striae began in the 6th week of her pregnancy but progressed in the 2nd trimester to encompass multiple sections of skin. Blood pressure on presentation was 146/100 mmHg (on labetalol) and fasting glucose 113 mg/dL (goal <95 mg/dL in pregnancy). Labs were consistent with ACTH-independent Cushing’s Syndrome: AM serum cortisol of 42.3 mcg/dL (n < 22.6 mcg/dL), PM serum cortisol of 46 mcg/dL (n < 11.9 mcg/dL), ACTH of <1 pg/mL (normal 7–63 pg/mL), 24-hour urinary free cortisol of 1388 mcg/day (n <45 mcg/day), and salivary midnight cortisol of 2.2 mcg/dL (n <0.3 mcg/dL). An abdominal MRI scan without contrast showed a 3.2 cm fat-containing right adrenal lesion consistent with an adenoma. The fetus was large for gestational age at 98th percentile. Patient was started on metyrapone 250 mg twice daily, which was titrated up to 250 mg three times daily. Her blood pressure and glucose levels, treated with labetalol and insulin respectively, improved on metyrapone. Surgery, Maternal Fetal Medicine, Endocrine, Anesthesia, and Neonatal physicians reviewed her case at an interdisciplinary meeting. She received metyrapone for 1 week pre-operatively. AM serum cortisol improved to 21.4 mcg/dL and 24-hour urinary free cortisol improved to 139 mcg/day. She underwent laparoscopic right adrenalectomy at 27 weeks of pregnancy. Betamethasone was given 2 days prior to ensure fetal lung maturity in case of preterm labor. Stress dose hydrocortisone 100 mg was given intra-operatively. Fetal heart monitoring was normal throughout the surgery and post-operatively. After surgery, metyrapone was stopped and hydrocortisone was tapered to 20 mg and 10 mg. Five weeks after her adrenalectomy, striae decreased in size and glucoses normalized. Remarkably, fetal size is now appropriate for gestational age in the 62th percentile at 34 weeks. However, blood pressure remains elevated and is being treated with labetalol. She is planned for induction of labor at 37 weeks due to her elevated blood pressures and will be given stress dose steroids intraoperatively. Conclusion: Medical management of adrenal Cushing’s in pregnancy with metyrapone followed by adrenalectomy required a multidisciplinary team approach. Patient underwent successful adrenalectomy without complications of severe hypercortisolism, including infection, thromboembolism, pre-eclampsia, preterm labor and pregnancy loss. After surgery, there was normalization of maternal blood sugars as well as fetal size, and persistent, but improved, elevated blood pressure.

Multiple Challenges: An Unusual Case of an Adrenal Mass With Plurihormonal Secretion of Catecholamines and Cortisol in a Patient With Several Neoplasms

Introduction:Simultaneous hypersecretion of both catecholamines and cortisol in one adrenal tumor is rarely seen because cortical cells, which produce cortisol, and medullary cells, which secrete catecholamines, are derived from different germ layers1. Formidable challenges ensue from a tumor with a complex behavior. We demonstrate here the clinical course and multi-modal management of the case of an adrenocortical adenoma which had neuroendocrine differentiation accounting for the excess of both catecholamine and cortisol hormones in a patient with multiple neoplasms.Clinical Case: An adrenal mass was incidentally discovered in a 61-year old female undergoing imaging as part of the metastatic work-up for an esophageal mass. The patient has insulin-requiring diabetes mellitus, hypertension and a history of breast cancer. A right adrenal gland mass, avidly enhancing, measuring 3.8 x 2.7 x 2.7 cm was found on abdominal imaging. The 24-hour urine metanephrine collections were done, and these were more than twice elevated in two instances at 2.516 mg/24 hours and 2.101 mg/24 hours (NV: 0–1 mg/24 hours). An unsuppressed cortisol level at 6.57 μg/dL (NV: ≤ 1.8 μg/dL) was obtained after the 1 mg dexamethasone suppression test. Hypercortisolism was confirmed with an elevated 24-hour urine free cortisol at 312.07 μg/24 hours (NV: 20–90 μg/24 hours). Adrenocorticotrophic hormone (ACTH) was low at 0.90 pg/ml, indicative of the presence of an adrenal form of Cushing’s. Primary aldosteronism was ruled out based on a ratio between plasma aldosterone concentration and plasma renin activity of less than 20.Pre-operative alpha blockade with terazosin was initiated. Right adrenalectomy was done. Histopathology revealed an adrenal mass of cortical origin, atypically staining positively for synaptophysin, which is indicative of neuroendocrine differentiation of the tumor. The patient had better blood pressure and glycemic control after the adrenalectomy.Clinical Lessons: An adrenocortical adenoma very seldom undergoes neuroendocrine differentiation. Pathophysiologic mechanisms include a genetic aberration in cortical cells leading to production of catecholamines2. This case underscores the importance of a comprehensive biochemical evaluation of a patient with an adrenal mass because control of hormonal hypersecretion is essential in reducing cardiovascular risks, morbidity and mortality.

Incidence of Venous Thromboembolic Events in Patients With Endogenous Cushing Syndrome

Background: Hypercortisolemia is a hypercoagulable state associated with increased risk of venous thromboembolic events (VTE). The reported incidence of VTE in patients with ACTH-dependent or independent Cushing Syndrome (CS) is variable, ranging from 3 to 14%. Our aim was to assess the incidence of clinically significant VTE among patients with endogenous CS and to identify risk factors for the development of VTE. Methods: We conducted a single center retrospective longitudinal study of adult patients diagnosed with endogenous CS between 2010 and 2020. Patients with a known prothrombotic disease (e.g. Factor V Leiden), insufficient data, or non-neoplastic hypercortisolism were excluded. Data collected included patient demographics, presenting symptoms, biochemical and radiological workup, treatment details, and incidence of clinically significant VTE. Results: A total of 114 patients (mean age of 45.55 ± 14.78 years, 79.8% women) followed for mean of 3.26 ± 2.9 years were included. Of the 114 patients, 58 (50.9%) had Cushing disease (CD), 40 (35.1%) had CS due to adrenal adenoma/hyperplasia, 6 (3.5%) had adrenocortical carcinoma (ACC), and 10 (8.8%) had ectopic Cushing syndrome (eCS). The overall incidence of VTE at any time point was 14/114 (12.3%); 11 (79%) VTEs were associated with presence of an additional VTE risk factor (8 surgery and 3 malignancy). Prior to any intervention for CS, 3 of 114 (2.6%) patients had a VTE. Surgery for CS (adrenalectomy, transsphenoidal surgery, tumor resection) was performed in 97 patients (85.1%) whereas 17 were treated medically (n=10), died before treatment (n=1) or observed (n=6). VTE occurred in 2 patients receiving medical therapy for CS. The post-operative incidence of VTE was 9 (9.3%; 4 in CD, 1 in adrenal CS, 3 in ACC, and 1 in eCS). VTE occurred ≤ 3-month post-operative in 4 patients (44.4%). Among the 5 patients in whom VTE occurred >3 months post-operative, 3 had recurrent metastatic ACC with hypercortisolemia and 2 were in remission (1 with CS and 1 with eCS). The median time from surgery to VTE occurrence was 315 days (8-1006). Compared to those who did not develop VTE, those who developed VTE had higher mean 24-hour urine free cortisol (4663.6 vs 558.21 mcg/dL; n = 100, P < 0.0001) and mean 1 mg overnight dexamethasone suppression test (36.3 vs 11.8 mcg/dL; n = 69, P = 0.0003), but similar mean late-night salivary cortisol (0.591 vs 0.790 ng/dL, n = 84, P = 0.71) at diagnosis of CS. Discussion: Among those with CS, the overall incidence of VTE was 12.3% and the majority of VTE were provoked (surgery, malignancy). Moreover, VTE was more likely in those with higher UFC and 1 mg overnight dexamethasone suppression test in our cohort. This suggests that in patients with CS who have an active malignancy, severe CS or those undergoing a surgical procedure may be at increased risk of VTE. Future studies should investigate the optimal type and duration of the VTE prophylaxis.

A Case of Iatrogenic Cushing’s Syndrome

Cushing’s syndrome (CS) is considered a rare disease. The most common cause is the exogenous use of glucocorticoids (GCs), which are often given within a controlled medical setting, but their factitious use is rare. Factitious CS is more common in females, young patients, those with psychiatric disorders, and those with contacts within the medical field. The diagnosis of CS is challenging because some features are non-specific and commonly present in the general population, such as obesity, depression, diabetes, hypertension (HTN), and low bone mineral density (BMD). A high suspicion is warranted. We present the case of a 47-year-old man with HTN, obesity, dyslipidemia, obstructive sleep apnea, and low BMD who complained of increased appetite, significant weight gain, fatigue, sleepiness, muscle weakness, and occasional facial flushing. Medications include Hydrochlorothiazide, Furosemide, Losartan, Atorvastatin, and Teriparatide. Vital signs were normal and body mass index was 41.9 kg/m2. He had a round face, central obesity, and wide purple striae in his abdomen. Dual-energy X-ray absorptiometry scan showed low BMD at spine. Laboratories revealed a glycated hemoglobin of 6.1%, late-night salivary cortisol of <0.03 mcg/dL, 24-hour urine free cortisol of 22.5 mcg/24hr, morning cortisol of 0.01 ug/mL, ACTH 23.5pg/mL, and dehydroepiandrosterone sulfate (DHEA-S) 35 mcg/dL. Our patient persistently denied use of exogenous GCs, but a urine synthetic GC screen disclosed a positive result for dexamethasone; levels at 1.1 mcg/dL. After an exhaustive conversation, our patient confessed to using over-the-counter dexamethasone 4mg to treat occasional muscle aches. ACTH is usually suppressed in factitious CS, but this was not our patient’s case, giving the appearance of ACTH-dependent hypercortisolism. This can lead to unnecessary diagnostic and therapeutic approaches. An unsuppressed ACTH could be due to an unreliable ACTH immunoassay or intermittent, instead of continuous, ingestion of GCs. A suppressed DHEA-S level, as seen in our patient, may provide the clue to exogenous GC use as the cause of CS. Our case is also rare because our patient is male, older, and not related to the medical field. Hypercortisolism must be detected and treated early due to its high morbidity and mortality. Several features may be reversed with treatment. The possibility of hypothalamic-pituitary-adrenal (HPA) axis suppression due to prolonged use of GCs, resulting in adrenal insufficiency (AI) should be considered. The prevalence of GC-induced AI ranges from 14–63%, with the highest risk in those with Cushingoid features and those receiving a dose equivalent to prednisone 20mg daily for more than three weeks. Sudden withdrawal of GCs should be avoided to prevent adrenal crisis. A tapering regimen should be adopted with subsequent biochemical testing of the HPA axis once GCs have been reduced to a physiologic dose.

A Case of Acute Psychosis as Manifestation of Ectopic ACTH Producing Pancreatic Neuroendocrine Tumor

Abstract Introduction: Ectopic adrenocorticotrophic hormone (ACTH) producing Pancreatic Neuroendocrine Tumor (p-NET) are extremely rare with incidence of 1.2% and confer a poor prognosis (5-year survival &amp;lt;20%). Case Report: 31-year old female with diabetes mellitus type 2 (DM-2) and hypertension (HTN) was found to be severely hypokalemic on routine labs and was sent to the Emergency Department for potassium replacement. Vitals; BP:139/87 mmHg, HR:108 bpm, RR:18, T:37°C and saturating 98% on ambient air. Examination revealed cushingoid features; hyperpigmented face, bilateral upper extremity pigmented papules, proximal muscle weakness, acanthosis nigricans, violaceous abdominal striae, truncal obesity, ecchymoses, bilateral lower extremity edema, memory impairment and anxiety. Initial labs; BG: 289 mg/dL, HbA1c: 9.5%, K: 2 mmol/L (N 3.5-5.2), WBC: 12.5 k/μL (N 4-10.8), Cortisol &amp;gt;150 mcg/dL (N 5-23), TSH: 0.325 μIU/mL (N 0.45-4.5), and FT4: 0.69 ng/dL (N 0.82-1.77). Diagnosis of Cushing’s syndrome was made based on elevated cortisol level and confirmed with elevated 24-hour urinary free cortisol: 13,294 μg (N&amp;lt;45), midnight salivary cortisol &amp;gt;15 ug/dL (N 0.09-1.5) and 1 mg dexamethasone suppression test (Cortisol &amp;gt;150 mcg/dL, ACTH: 621 pg/ml). Additional labs showed Chromogranin A: 717 ng/mL (N 0-160). She was started on prophylactic Enoxaparin &amp; Trimethoprim/Sulfamethoxazole and treated with Spironolactone, Basal/Bolus insulin, and Ketoconazole for hypercortisolemia. Pituitary MRI was negative for pituitary adenoma. Abdominal/Pelvic CT scan demonstrated a solid 5 cm pancreatic head mass with innumerable haptic metastases consistent with metastatic p-NET which was confirmed on PET-CT Ga68 Dotatate scan. Liver biopsy was positive for a well differentiated p-NET with ki-67 &amp;lt;5% and negative ACTH staining. Hospital course was complicated by fluctuating cortisol levels with intermittent psychotic manifestations despite up-titration of Ketoconazole, addition of Octreotide as well as anti-psychotics. She later developed transaminitis on maximum dose of Ketoconazole and thus underwent laparoscopic total adrenalectomy for treatment of her hypercortisolemia. Post-operatively, she was started on Hydrocortisone &amp; Fludrocortisone and Spironolactone was discontinued. She was transitioned to monthly Lanreotide and treated with Capecitabine and Temozolomide with adequate therapeutic response and subsequent down trending of her Chromogranin A: 188 ng/mL and ACTH: 228 pg/ml levels. Currently, she is doing well with significant improvement of her DM-2, HTN, psychiatric symptoms and overall clinical status. Conclusions: Symptoms of ectopic Cushing’s syndrome may be delayed, however given the rare and aggressive nature of ACTH producing p-NET, timely diagnosis, prophylaxis and individualized treatment approach is crucial in achieving favorable prognosis.

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.

Bedtime Salivary Cortisol as a Screening Test for Cushing Syndrome in Children.

BackgroundDiagnosing Cushing syndrome (CS) can be challenging. The 24-hour urine free cortisol (UFC) measurement is considered gold standard. This is a laborious test, dependent on correct urine collection. Late-night salivary cortisol is easier and is used as a screening test for CS in adults, but has not been validated for use in children.ObjectiveTo define liquid chromatography tandem mass spectrometry (LC-MS/MS)-based cutoff values for bedtime and morning salivary cortisol and cortisone in children, and validate the results in children with and without CS.MethodsBedtime and morning salivary samples were collected from 320 healthy children aged 4 to 16 years. Fifty-four patients from the children’s outpatient obesity clinic and 3 children with pituitary CS were used for validation. Steroid hormones were assayed by LC-MS/MS. Cutoff levels for bedtime salivary cortisol and cortisone were defined by the 97.5% percentile in healthy subjects.ResultsBedtime cutoff levels for cortisol and cortisone were 2.4 and 12.0 nmol/L, respectively. Applying these cutoff levels on the verification cohort, 1 child from the obesity clinic had bedtime salivary cortisol exceeding the defined cutoff level, but normal salivary cortisone. All 3 children with pituitary CS had salivary cortisol and cortisone far above the defined bedtime cutoff levels. Healthy subjects showed a significant decrease in salivary cortisol from early morning to bedtime.ConclusionsWe propose that bedtime salivary cortisol measured by LC-MS/MS with a diagnostic threshold above 2.4 nmol/L can be applied as a screening test for CS in children. Age- and gender-specific cutoff levels are not needed.

Treatment and outcomes of recurrent/persistent Cushing's disease: a single-center experience.

Although transsphenoidal adenomectomy is the first treatment choice for Cushing's disease (CD), tumor recurrence rates are as high as 45%, resulting in a therapeutic challenge for endocrinologists and neurosurgeons. For recurrent/persistent CD (RCD/PCD), Repeat transsphenoidal surgery (RTSS), radiotherapy, gamma knife radiosurgery (GKRS) or bilateral adrenalectomy may be considered. The purpose of the study was to report the treatments and outcomes of RCD/PCD in a single center. A retrospective study was performed on 55 RCD/PCD patients from a single center between 2000 and 2012 at Peking Union Medical College Hospital (PUMCH). Among the 55 RCD/PCD patients, 43 achieved remission (78%), and 11 maintained a PCD status (20%). The average times to recurrence after the initial treatment and Repeated treatment were 43.25±10.3 and 5.13±4.7 months, respectively (P=0.006); 17.6% of the patients experienced recurrence within the first year, and 52.9% of the patients experienced recurrence within 1.1-5.0 years. For the Repeated treatments, surgery was more effective for the biochemical remission of serum cortisol and adrenocorticotrophic hormone (ACTH) levels than radiotherapy. Delayed remission occurred in 28.9% (11/38) of the patients after Repeated surgery. Considering the previous biochemical levels after the initial surgery in RCD patients, 19.75% of patients experienced recurrence when serum cortisol levels were less than <3 µg/dL, and 51.4% of patients experienced recurrence under conditions of hypocortisolism and when 24-hour urinary free cortisol (24 UFC) was undetectable. RTSS remains a recommended treatment option for RCD/PCD patients while radiotherapy is suggested as an adjunctive treatment. Intensive follow-up is recommended, as patients with serum cortisol levels <3 µg/dL or undetectable 24 UFC levels can still experience recurrence after surgical treatment.