ACTH-dependent Cushing's Disease Research Articles

SAT330 Recurrence of Acth Independent Cushing Syndrome In Patient With Previously Operated On For Primary Bilateral Macronodular Adrenal Hyperplasia And Co-existence Of Papillary Thyroid Carcinoma

Abstract Disclosure: N. Vashakmadze: None. D. Nikoleishvili: None. Background: Cushing syndrome is a rare and usually sporadic endocrine disorder. Herein we describe a case of ACTH-independent Cushing syndrome and ACTH-dependent Cushing disease in non-identical twins. Moreover, recurrence of Cushing syndrome after 25 years of non-complete resection of adrenal glands and co-existence of papillary thyroid cancer. Clinical Case: A 57-year woman presented with hypertension, depression, easy bruising, proximal muscle weakness, fatigue, and facial plethora. According to the patient, Cushing’s syndrome caused by bilateral macronodular adrenal hyperplasia was diagnosed in 1997. Surgical treatment - left adrenalectomy and right adrenal gland resection was performed. She was receiving HRT during the first 6 months, since then she was not receiving HRT and her cortisol was normal. It is extremely interesting that her nonidentical twin sister was diagnosed with ACTH-dependent Cushing disease in 2006 and was successfully treated with transsphenoidal surgery. In 2019 patient was diagnosed with papillary thyroid cancer (PTC), thyroidectomy was performed and multifocal PTC pT1b(m)N0M0 was diagnosed. Patient received adjuvant therapy with 80 mCi of RAI. In 2019 cortisol and ACTH levels were routinely evaluated, ACTH was undetectable <3 ng/dl (N: 7.2-63); 1 mg dexamethasone suppression test showed no suppression of cortisol 116 ng/ml (N: <1.8 ng/ml). However, patient did not consult an endocrinologist with the results of the mentioned investigations. She admitted to our clinic in December 2022 with above-mentioned complains to determine the tactics of further investigation/treatment. The data obtained during our consultation was consistent to recurrence of Cushing syndrome: midnight salivary cortisol– 0.46 mcg/dl (0.02-0.34), ACTH– 4.2 ng/l (7.2-63), 1 mg of dexamethasone suppression test – 217 nmol/l (<50). CT showed right adrenal noduls (2.5 cm and 1.2 cm). These data confirmed the diagnosis of recurrence of Cushing’s syndrome and right adrenalectomy with steroid coverage and postoperative hormone replacement therapy was recommended. Other data showed normal OGTT, moderate hypercholesterolemia, taking into account Cushing’s syndrome and smoking, statins were initiated. DXA showed osteoporosis (forearm T-score = -3.9 SD). 25(OH)D3 – 22.35 ng/ml, Ca – 1.09 mmol/l (1.1-1.3). Denosumab, calcium and vitamin D supplements were started to the patient. In addition, TSH was markedly suppressed on 125 mcg LT4 therapy, TSH – 0.005 mIU/l (0.4-3.8); Tg <0.17 g/l, anti-Tg - N and neck ultrasound was normal, that is consistent with excellent response and the target TSH was established 0.5-2.0 mIU/l. The dose of LT4 was reduced to 100 mcg. Conclusion: To our knowledge existence of Cushing syndrome and Cushing disease in non-identical twins has not been reported yet. Also, co-existence of Cushing syndrome and thyroid cancer is rare, and no connection is established yet. Presentation: Saturday, June 17, 2023

THU647 Patient With Successful Conception During Treatment For Cushing Disease: Case Report

Abstract Disclosure: C. Iweha: None. E.K. Babler: None. M. Castillo: None. Introduction Cushing Disease (CD) is an endocrine disorder that predominantly affects women of childbearing age and is characterized by excess secretion of adrenocorticotropic hormone (ACTH) with hypercortisolism. We report a case of a woman with ACTH-dependent hypercortisolism treated with pasireotide who had a successful pregnancy while on treatment. Clinical Case A 27-year-old woman presented to the initial consult on 9/01/2011 with a 4-year history of ongoing symptoms of hirsutism, diaphoresis, oligomenorrhea, myalgia, and acne. A physical exam revealed an overweight female with mild facial acne and hirsutism. Family history included autoimmune disease in mother (lupus and multiple sclerosis). She was frustrated by the lack of a definitive diagnosis over 4 years; she was anxious and using multiple medications, including anxiolytics and analgesics, without relief of symptoms. Patient did not use alcohol and never smoked. Labs revealed initial morning (AM) cortisol = 26.9 µg/dL (normal range: 5-23 µg/dL) and ACTH = 14 pg/mL (normal: 6-58 pg/mL); 24-hour urinary cortisol was 110.6 µg/24 h (normal:<100 µg/dL) and serum ACTH =8 pg/mL. Low-dose (1 mg) dexamethasone suppression test reduced AM cortisol to 1.7 µg/dL and ACTH of 8 pg/mL. No evidence of adrenal adenoma on abdominal CT or pituitary adenoma on brain MRI, and IPSS confirmed diagnosis. Based on hypercortisolism and normal ACTH level, diagnosis was ACTH-dependent CD. We advised the patient to join a clinical trial for pasireotide, and she began treatment on 1/3/2013. She presented for follow-up on 6/17/2014 and reported improvement of some symptoms on 0.6 mg pasireotide twice daily, the highest dose she could tolerate. She reported experiencing chronic pain; medications included prescription analgesics, muscle relaxants, and anxiolytics. On 6/23/2015, our patient returned for a follow-up when she was 5.5 months pregnant. While on pasireotide, she became pregnant and subsequently left the study and discontinued treatment. She reported recurrence of hirsutism, acne, fatigue, and hyperemesis with discontinuation of pasireotide. Patient returned twice more during pregnancy and had a successful delivery and healthy infant. Clinical Conclusions Successful conception and pregnancy are unusual with CD due to fertility-inhibiting hormonal effects of excess cortisol. Some medications for CD impede pregnancy through their mechanism (eg, mifepristone). Our patient conceiving while on treatment is promising for women with CD. Although her CD symptoms returned when pasireotide was discontinued, she delivered a healthy infant; limited pasireotide data in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Our case underscores the potential for successful conception for women with CD when cortisol levels are normalized with treatment that avoids suppressing menstruation. Presentation: Thursday, June 15, 2023

What is the role of 11C Methionine PET-CT in the clinical evaluation of ACTH-dependent Cushing's disease?

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract #1407012: ACTH Producing Pituitary Adenoma Found After Transsphenoidal Resection of Meningioma

ACTH-dependent Cushing's disease (CD) is a condition characterized by pituitary hypersecretion of ACTH, leading to adrenal cortisol upregulation. Hypercortisolism has long-term complications, notably metabolic syndrome, cardiovascular disease, and osteoporosis, to name a few. The incidence of CD is approximately 1-2 cases per million. ACTH can be secreted by pituitary macroadenomas and microadenomas, and in some cases, ectopic sources. This case report describes a case of ACTH-dependent CD caused by a pituitary microadenoma with a history of planum sphenoidal meningioma. 48-year-old female with a past medical history of planum sphenoidal meningioma s/p transsphenoidal partial resection, central hypothyroidism on levothyroxine, and hypogonadotropic hypogonadism presented with worsening truncal obesity and prediabetes. The physical exam was remarkable for obesity and hyperpigmentation of knuckles. Labs were significant for elevated AM cortisol at 27.2 mcg/dL with a significantly elevated ACTH level of 81.8 pg/L. Saliva cortisol at 11pm was also mildly elevated at 0.154 ug/dL. The cortisol level was not suppressed with the low-dose dexamethasone suppression test at 8.5 mcg/dL, while High-dose dexamethasone suppressed cortisol to 2.0 mcg/dL, indicating a possible pituitary source. Other biochemical tests such as Prolactin, TSH, and HGH levels were normal. MRI of the pituitary was performed to locate the potential source and was significant for hypo-enhancing lesions suspicious for bilateral synchronous pituitary microadenomas (9x5 mm right and 4x4 mm left). To confirm that there are no ectopic sources for the ACTH, a PET Dotatate scan was done and showed hypermetabolic meningioma corresponding to the findings of the pituitary MRI and confirmed no other abnormal focal radiotracer uptake. Non-functioning pituitary tumors are common, hence, to confirm the pituitary source of ACTH prior to surgery, she underwent inferior petrosal sinus sampling (IPSS). This revealed a significantly elevated ACTH secretion from the right microadenoma. Transsphenoidal resection of the pituitary tumor was performed. Post-procedure, AM cortisol levels were undetectable and ACTH level was low at 5.8 pg/mL. She was then started on hydrocortisone for presumed adrenal insufficiency post pituitary lesion resection. No signs of diabetes insipidus were shown after surgery—the patient will follow up with endocrinology for eventual weaning off hydrocortisone. Simultaneous occurrence of pituitary adenoma and meningioma without a history of radiotherapy is extremely rare, with only 49 cases described before 2019. Even more rare, is an ACTH secreting pituitary adenoma coexisting with a meningioma. IPSS procedure was performed after MRI in this case to get even more accurate localization of the source before surgical excision, as it is the best test to differentiate pituitary from ectopic ACTH-dependent Cushing’s. In approximately 1 out of 3 patients, remission is not achieved with surgical excision alone. For this reason, patients need post-operative monitoring and secondary medications to control their symptoms.

Abstract #1316957: Ectopic ACTH-Dependent Cushing Disease Due to Poorly Differentiated Thymic Carcinoma: Case Report

Ectopic ACTH secretion due to malignant tumors is Cushing syndrome’s most frequently underdiagnosed form. Thymic carcinoma is a rare but aggressive tumor and is infrequently encountered in the etiopathogenesis of intermittent ectopic ACTH secretion with a cyclical clinical presentation.

PSAT002 Unilateral Adrenalectomy as a Treatment Option in Patient with Cyclical Cushing's Syndrome

Abstract Background Patients with Cyclical Cushing`s Syndrome (CSS) are at risk for a lengthy timeline of living with the untreated disease. Continual increased amounts of cortisol can lead to increased morbidity and mortality in these patients and finding effective treatments is of the utmost importance. Here we present a treatment course of the patient with CCS who eventually underwent unilateral adrenalectomy, resulting in marked improvements in excessive cortisol- mediated metabolic derangements. Clinical Case In 2014, a 51-yo female with hypertension (HTN), hyperlipidemia (HLD), and type 2 diabetes (T2D) presented to VA endocrinology clinic for the evaluation of incidentally found bilateral adrenal nodules. Based on the extensive biochemical evaluation, the patient was diagnosed with ACTH-dependent Cushing's disease (CD). In the setting of newly diagnosed CD and complex metabolic co-morbidities, in 09/2016 she underwent pituitary resection. However, she remained hypercortisolemic and in 12/2016 she had a second hypophysectomy. Despite surgical efforts, hypercortisolemia persisted. Neuroendocrine imaging studies and chest computed tomography excluded non-pituitary etiology of CD. She was subsequently started on ketoconazole but it was stopped due to side effects. Other CD-directed agents were not approved, so we continued routine management of T2D, HTN, and HLD. In 2018, the patient developed acute coronary syndrome and received percutaneous intervention despite therapy with statin and ezetimibe. Further, since her second hypophysectomy she required sequential addition of hypoglycemic agents and by the end of 2020, exenatide weekly, empagliflozin, and pioglitazone were added to her escalating basal-bolus insulin therapy due to persistent A1C elevation >10%. Continuous evaluation of her hypercortisolemia post-hypophysectomy suggested presence of CCS. To alleviate the metabolic burden of hypercortisolemia, the patient was offered unilateral adrenalectomy which she underwent in 03/2021. Within 6 months after the surgery, she has had unintentional 22-lb weight loss and we stopped both of her anti-HTN medications, discontinued weekly exenatide, and gradually de-escalated her initial daily insulin regimen of approximately 1.0 u/kg to an only basal insulin at 0.15 u/kg dose achieving A1C of 6.5%. There was no biochemical evidence of adrenal insufficiency since adrenalectomy was performed. Conclusion The patient with initial diagnosis of CD, which we later proved being CCS, underwent a unilateral adrenalectomy with the goal of reduction of cortisol burden. This decision was taken with the consideration that this would likely not be curative but intended to improve the course of her metabolic conditions. The 6-month observation following adrenalectomy has proven that we were able to in large extend achieve our goals. Therefore, this treatment approach should be considered for patients with CSS or CD. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

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.

PMON157 Evidence For Locally Produced Cortisol in Pituitary Tissue

Abstract Double or multiple pituitary adenomas are rare and account for only 1.6-3.3% of all corticotroph tumors. We describe 2 distinct pituitary corticotroph adenomas in a 43-year-old female presenting with ACTH-dependent Cushing disease (CD). Although pre-operative pituitary MRI noted a single 8×6mm left sided pituitary microadenoma, which was confirmed at trans-nasal trans-sphenoidal surgery, she was found to an additional 7mm right sided microadenoma. Histopathology confirmed 2 separate corticotroph adenomas and she exhibited immediate remission of her CD with nadir cortisol of 1mcg/dL. Whole exome sequencing demonstrated a somatic mutation in the 21-alpha-hydroxylase (CYP21A2) gene in both tumors. CYP21A2 transcript and protein expression were absent in the index case but both CYP21A2 transcript and protein were demonstrated in a series of 9 other pituitary corticotroph adenomas and 12 normal pituitary tissues. This unusual case which prompted us to examine CYP21A2 expression in the pituitary allows us to describe for the first time evidence of locally generated pituitary-derived cortisol and indicate this could play a paracrine role on the corticotroph and may contribute to growth of ACTH pituitary adenomas in some instances. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

A noninvasive scoring model for the differential diagnosis of ACTH-dependent Cushing's syndrome: a retrospective analysis of 311 patients based on easy-to-use parameters.

The differential diagnosis of ACTH-dependent Cushing's disease (CS) is challenging. The gold standard approach bilateral inferior petrosal sinus sampling (BIPSS) is expensive and invasive, while other noninvasive tests, like the high-dose dexamethasone suppression test (HDDST), provide unsatisfactory diagnostic accuracy. This study aimed to find a new noninvasive practical approach with higher diagnostic accuracy to differently diagnose ACTH-dependent CS, which can be used in centers where BIPSS cannot be applied. 264 Cushing's disease (CD) patients and 47 ectopic ACTH secretion syndrome (EAS) patients were analyzed in this single-center retrospective study (2011-2021). The multivariate logistic model was used to construct the scoring model. Female (adjusted OR 3.030, 95%CI 1.229-7.471), hypokalemia (0.209, 0.076-0.576), ACTH (0.988, 0.982-0.994), MRI pituitary lesion positive (8.671, 3.521-21.352), and HDDST positive (2.768, 1.139-6.726) have a strong association with the differential diagnosis of ACTH-dependent CS and were included in the final multivariable logistic regression model. A -14-to-14-point noninvasive scoring model was built on the model. The AUC of the noninvasive scoring model was 0.915 (95% CI 0.869-0.960), significantly higher than the AUC of HDDST (0.756, 95% CI 0.685-0.825, P = 0.004). The optimal cutoff of the model was ≥0 to diagnose CD. The sensitivity of the noninvasive scoring model was 91.3% (95% CI 87.3%-94.1%), and the specificity was 80.9% (95% CI 67.5%-89.6%). When the model's sensitivity was 100.0%, the cutoff was ≥ -10 with a specificity of 19.2%; when the model's specificity was 100.0%, the cutoff was ≥ 13 with a sensitivity of 22.7%. We developed a noninvasive scoring model to distinguish CD and EAS in ACTH-dependent CS patients with higher diagnostic utility than HDDST in the same cohort. The noninvasive scoring model might be applied in areas where BIPSS is unavailable, the CRH is hard to obtain, or the desmopressin stimulation is not widely applied. It also provided a triage tool for selecting patients that might benefit the most from a further BIPSS test.

SUN-197 Giant Adrenal Myelolipoma Associated with Prolonged ACTH Elevation in a Patient with Congenital Adrenal Hyperplasia (CAH)

Background: Myelolipomas are rare benign tumours which consist of adipose tissue and mature hematopoietic tissue. The incidence ranges from 0.08 to 0.4% and they constitute 15% of adrenal incidentalomas. We report the case of a massive adrenal myelolipoma in a patient with CAH. Clinical Case: A 51year old man with salt losing CAH due to 21 hydroxylase deficiency presented to the emergency department with abdominal pain. CT scan of the abdomen revealed a 15 x 16 x 19cm mass in the left adrenal gland. There were concerns about malignancy, however expert radiology review diagnosed a massive adrenal myelolipoma. The patient was diagnosed to have salt losing CAH during infancy and managed with cortisone acetate and fludrocortisone during childhood, then dexamethasone 0.5mg nocte, 0,25mg mane as an adult. At 27 years he was reviewed and found to be Cushingoid with abdominal striae, obesity and hypertension. A CT scan of the abdomen done at that time showed a normal left adrenal gland with nodular right adrenal gland. While he was on dexamethasone, his 17-OHP was 14 nmol/l (NR: 0–6.0 nmol/l). His dexamethasone was reduced, then he was transferred on to prednisolone and then to hydrocortisone. 17-OHP level and ACTH levels have risen with each change in medication. At the time of referral with abdominal pain, he was on hydrocortisone 10 mg mane, 10 mg midday and 5mg at 1700h and his biochemistry showed: ACTH 486ng/l (NR 7.2–63.3), 17-OHP 101.1nmol/l (0–6.0nmol/l), renin 5.5 nmol/l/hr (NR 0.2–3.3) and androstenedione 26.6 nmol/l (NR 0–7.8). He underwent laparoscopic hand-assisted left adrenalectomy with the removal of a 2030 gram adrenal myelolipoma. He made an uneventful recovery with remarkable clinical improvement in general wellbeing. Histology confirmed adrenal myelolipoma. Conclusion: Chronic exposure to high ACTH levels causes metaplasia of adrenocortical cells, but a direct causal relationship for myelolipomas is not established. The role of ACTH in development of myelolipomas is supported by the increased incidence in patients with Addison’s disease, Nelson’s syndrome and ACTH dependent Cushing Disease. Our case supports the role of ACTH as the myelipoma developed after the reduction of patient’s glucocorticoid treatment and ACTH levels were high for years. Myelolipomas are usually asymptomatic but can present with abdominal pain, spontaneous rupture, and spontaneous retroperitoneal haemorrhage. There are no set guidelines but for large and rapidly growing tumours, surgery may be considered..

EGFR Induces E2F1-Mediated Corticotroph Tumorigenesis.

The epidermal growth factor receptor (EGFR), expressed in adrenocorticotrophic hormone (ACTH)–secreting pituitary adenomas causing Cushing disease, regulates ACTH production and corticotroph proliferation. To elucidate the utility of EGFR as a therapeutic target for Cushing disease, we generated transgenic (Tg) mice with corticotroph-specific human EGFR expression (corti-EGFR-Tg) using a newly constructed corticotroph-specific promoter. Pituitary-specific EGFR expression was observed by 2.5 months, and aggressive ACTH-secreting pituitary adenomas with features of Crooke’s cells developed by 8 months with 65% penetrance observed. Features consistent with the Cushing phenotype included elevated plasma ACTH and corticosterone levels, increased body weight, glucose intolerance, and enlarged adrenal cortex. Gefitinib, an EGFR tyrosine kinase inhibitor, suppressed tumor POMC expression and downstream EGFR tumor signaling, and ACTH and corticosterone levels were attenuated by 80% and 78%, respectively. Both E2F1 and phosphorylated Ser-337 E2F1 were increased in corti-EGFR-Tg mice and also colocalized with human POMC (hPOMC) in human pituitary corticotroph tumor samples. EGFR inhibition reversed E2F1 activity in vivo, whereas E2F1 inhibition suppressed POMC and ACTH in cultured human pituitary tumor cells. The corti-EGFR-Tg phenotype recapitulates ACTH-secreting pituitary adenomas and Cushing disease, validating the relevance of EGFR to corticotroph tumorigenesis. E2F1 is identified as a promising corticotroph-specific target for ACTH-dependent Cushing disease.

From first symptoms to final diagnosis of Cushing's disease: experiences of 176 patients.

To obtain structured information on the diagnostic delay in patients with Cushing's disease (CD) from the patients perspective to provide leverage points for earlier diagnosis. The study includes 176 patients with ACTH-dependent CD who had received pituitary surgery completed a self-developed questionnaire on their symptomatology before the illness was diagnosed, the course and length of the diagnostic process, and the role of the involved health care professionals. Data were analyzed statistically. Answers in free text options were categorized and counted. The overall diagnostic process took 3.8±4.8 years (median 2 years), during which 4.6±3.8 (1-30) physicians were consulted, most frequently the family physician (FP; 83.0%). The presented symptoms were various and often vague, e.g. 'poor general condition' (at FPs), or very common in the field of the visited specialist (i.e. 'skin changes' at dermatologists). Women recognized the first CD symptoms themselves significantly more frequently than men, whereas physicians recognized CD symptoms significantly more frequently in males. A clear difficulty of diagnosing CD seems that patients describe isolated symptoms to the FP or the respective specialists according to their fields of specialization. As FPs are contacted most frequently, they should be trained to recognize the broad spectrum of CD symptoms, especially in female patients with weight gain, and initiate endocrinological referral.

From first symptoms to final diagnosis of Cushing's disease: experiences of 176 patients

OBJECTIVE To obtain structured information on the diagnostic delay in patients with Cushing's disease (CD) from the patients perspective to provide leverage points for earlier diagnosis. DESIGN The study includes 176 patients with ACTH-dependent CD who had received pituitary surgery completed a self-developed questionnaire on their symptomatology before the illness was diagnosed, the course and length of the diagnostic process, and the role of the involved health care professionals. METHODS Data were analyzed statistically. Answers in free text options were categorized and counted. RESULTS The overall diagnostic process took 3.8±4.8 years (median 2 years), during which 4.6±3.8 (1-30) physicians were consulted, most frequently the family physician (FP; 83.0%). The presented symptoms were various and often vague, e.g. 'poor general condition' (at FPs), or very common in the field of the visited specialist (i.e. 'skin changes' at dermatologists). Women recognized the first CD symptoms themselves significantly more frequently than men, whereas physicians recognized CD symptoms significantly more frequently in males. CONCLUSION A clear difficulty of diagnosing CD seems that patients describe isolated symptoms to the FP or the respective specialists according to their fields of specialization. As FPs are contacted most frequently, they should be trained to recognize the broad spectrum of CD symptoms, especially in female patients with weight gain, and initiate endocrinological referral.

Transsphenoidal Surgery for Cushing Disease After Nondiagnostic Inferior Petrosal Sinus Sampling

Inferior petrosal sinus sampling (IPSS) is a useful technique for confirming a pituitary source of adrenocorticotropic hormone (ACTH) overproduction in Cushing disease. Uncertainty remains regarding the appropriate course of therapy when an ectopic tumor is predicted by IPSS but none can be found and in circumstances when the procedure cannot be successfully completed owing to technical or anatomic limitations. To determine an appropriate course of action after nondiagnostic IPSS. We reviewed 288 IPSS procedures in 283 patients between 1986 and 2010 at our center. An IPS:peripheral ACTH ratio ≥ 2 at baseline or ≥ 3 after corticotrophin-releasing hormone was considered predictive of a pituitary source of ACTH. A procedure was considered nondiagnostic if the procedure was successfully performed and the results predicted an ectopic source but none could be found despite extensive imaging or if the IPS could not be bilaterally cannulated because of technical difficulties or anatomic variants. The sensitivity, specificity, positive predictive value, and negative predictive value of IPSS for detecting a pituitary source in Cushing disease were 94%, 50%, 98%, and 29%, respectively. We identified 3 categories of nondiagnostic IPSS comprising 44 of the total procedures. These patients underwent exploratory transsphenoidal surgery, and in 42 of these patients (95%), a pituitary source was surgically proven, with a remission rate of 83%. Transsphenoidal surgery should be considered in cases of ACTH-dependent Cushing disease and noncentralized or technically unsuccessful IPSS without evidence of ectopic tumor.

Mortality and Morbidity in Cushing's Disease over 50 Years in Stoke-on-Trent, UK: Audit and Meta-Analysis of Literature

Pituitary ACTH-dependent Cushing's disease (CD) is uncommon, and there are very limited data on long-term mortality. The aim was to summarize what is known about mortality in ACTH-dependent CD, to report on our own data, and to provide a meta-analysis of six other reports that addressed mortality of CD. Vital status of 60 CD patients was recorded as of December 31, 2009, and the standardized mortality ratio (SMR) was calculated and compared with the general population of England and Wales, United Kingdom. A meta-analysis of SMRs from seven studies (including ours) was performed for overall mortality in CD. Where reported (four studies), a similar meta-analysis was performed for those patients whose hypercortisolism was in remission after treatment compared to those patients from the same center with persistent disease. 1. From Stoke-on-Trent, 51 of 60 patients were female, median age at diagnosis was in the range of 36-46 yr, and median follow-up was 15 yr. There were 13 deaths, nine due to cardiovascular disease. Overall SMR for the whole cohort was 4.8 (95% confidence interval, 2.8-8.3) (P < 0001). SMR for vascular disease was 13.8 (7.2-36.5) (P < 0001). For persistent disease (n = 6), SMR was 16 (6.7-38.4) vs. remission (n = 54) SMR of 3.3 (1.7-6.7); after adjustment for age and sex, relative risk of death for persistent disease was 10.7 (2.3-48.6) (P = 0.002). Hypertension and diabetes mellitus were associated with significantly worse survival. 2. Using a random effects model meta-analysis revealed an overall (remission plus persistent disease) SMR of 2.2 (1.45-3.41) (P < 0.001). Pooled SMR was 1.2 (0.45-3.2) (P = not significant) for patients in remission and 5.5 (2.7-11.3) (P = 0.001) for patients with persistent disease. Persistence of disease, older age at diagnosis, and presence of hypertension and diabetes are the main determinants of mortality. Overall mortality in CD is double that of the general population. However, patients with CD in remission fare much better than those with persistence of hypercortisolism, and they appear not to have an increased mortality rate. Hypertension and diabetes mellitus are risk factors for worse outcome. Because diagnosis and treatment of patients are at a young age, much longer follow-up of patients in remission is required before one can be confident that their mortality outcome is no different from that of the general population, especially because cardiovascular risk factors may persist after successful biochemical control of the disease.

An Unusual Presentation of Pediatric Cushing Disease: Recurrent Corticotropinoma of the Posterior Pituitary Lobe

Cushing's syndrome (CS) is rare in childhood and adolescence and its diagnosis and work up are often challenging. We report the case of a 15-year-old girl with a recurrent corticotrophin (ACTH)-secreting adenoma, located in the posterior lobe of the pituitary gland. At the age of 11, she presented with classic CS symptoms; biochemical investigation was compatible with ACTH-dependent Cushing disease, although pituitary gland imaging did not show any tumor. Following transsphenoidal surgery (TSS), histopathological analysis identified an ACTH-secreting pituitary microadenoma arising from the posterior gland. The patient went into remission but 4 years later she presented with recurrent CS; this time, pituitary gland imaging showed a microadenoma located in the posterior lobe, which was resected after TSS. Posterior lobe pituitary adenomas are very rare and often hard to diagnose and treat; this is the first case of such a tumor causing recurrent Cushing's disease in a child.

Síndrome de Cushing: situaciones especiales

The present article reviews: Corticotrophin (ACTH) independent bilateral macronodular adrenal hyperplasia, which is characterized by aberrant adrenal receptors due to either ectopic expression or to overexpression (eutopic expression). Micronodular adrenal hyperplasia, which provokes small pigmented nodules in the adrenal gland with atrophy of the internodal tissue. These nodules may not be visible on imaging tests. The term subclinical Cushing's syndrome, coined in 1981, should be used in patients with clinically non-functioning adrenal adenomas but who show autonomous cortisol production that is insufficient to generate overt Cushing's syndrome. This entity must be distinguished from preclinical Cushing's syndrome, given that the subclinical form does not necessarily herald the development of symptoms of hypercortisolism. Cushing's syndrome is uncommon in children and adolescents. Regarding the general incidence of the disease, only 10% of cases are diagnosed in this age group. The most common cause of endogenous Cushing's disease in children older than 7 years is ACTH-dependent Cushing's disease (85%). The association of Cushing's syndrome and pregnancy is highly uncommon, since hypercortisolism usually causes amenorrhea, oligomenorrhea and infertility due to inhibition of gonadotropin secretion. One hundred thirty-six pregnancies have been described in 122 women, with a gestational age at diagnosis of 18.4+/-1 weeks.

Late-night Salivary Cortisol as A Screening Test for the Diagnosis of Cushing's Syndrome in Japan

Measurement of late-night and/or midnight salivary cortisol currently used in US and European countries is a simple and convenient screening test for the initial diagnosis of Cushing's syndrome (CS). Unfortunately, this test has not been widely used in Japan. The purpose of this study was to evaluate the usefulness of the measurement of late-night salivary cortisol as a screening test for the diagnosis of CS in Japan. We studied 27 patients with various causes of CS, consisting of ACTH-dependent Cushing's disease [5] and ectopic ACTH syndrome [4] and ACTH-independent adrenal CS [11] and subclinical CS [7]. Eleven patients with type 2 diabetes and obesity and 16 normal subjects served as control group. Saliva samples were collected at late-night (23:00) in a commercially available device and assayed for cortisol by radioimmunoassay. There were highly significant correlations (P<0.0001) between late-night serum and salivary cortisol levels in normal subjects (r = 0.861) and in patients with CS (r = 0.788). Late-night salivary cortisol levels in CS patients (0.975 +/- 1.56 microg/dl) were significantly higher than those in normal subjects (0.124 +/- 0.031 microg/dl) and in obese diabetic patients (0.146 +/- 0.043 microg/dl), respectively. Twenty-five out of 27 CS patients had late-night salivary cortisol concentrations greater than 0.21 microg/dl, whereas those in control group were less than 0.2 microg/dl. Receiver operating characteristic curve (ROC) analysis showed that the cut-off point of 0.21 microg/dl provides a sensitivity of 93% and a specificity of 100%. Therefore, it is concluded that the measurement of late-night salivary cortisol is an easy and reliable noninvasive screening test for the initial diagnosis of CS, especially useful for large high-risk populations, such as diabetes and obesity.

Undetectable inferior petrosal sinus levels of PTH-related peptide (PTHrP) in patients with ACTH-dependent Cushing’s disease

PTH-related peptide (PTHrP), a member of the PTH family, is widely expressed in foetal and adult tissues, and it has been found in benign and malignant tumors, including GH and PRL-secreting adenomas. Conflicting data are reported in literature on serum PTHrP concentrations in patients with Cushing's disease. The aim of the present study was to further evaluate peripheral and inferior petrosal sinus (IPS) serum PTHrP concentrations before and after CRH, in a group of consecutive patients with ACTH-dependent Cushing's disease. Nine patients with active ACTH-dependent Cushing's disease (8 women and 1 man, age +/- SD 41 +/- 13 yr) were submitted to peripheral and IPS sampling under fluoroscopic control before and after iv administration of CRH. All patients were subsequently submitted to transsphenoidal surgery and an ACTH-secreting microadenoma was found in all cases. In all patients, serum IPS and peripheral ACTH measurement were in keeping with the diagnosis of ACTH-dependent Cushing's disease. Serum PTHrP concentrations before and after CRH stimulation were below the sensitivity limit of the assay in all samples, and no gradient between IPS and peripheral sampling was observed. Our data, combined with others reported in literature, indicate that PTHrP release by ACTH-secreting tumors is not a common occurrence. Therefore, we conclude that IPS and peripheral PTHrP are of little clinical usefulness.

Multimodal management of a patient with corticotrophic adenoma: a new aspect for medical treatment with rosiglitazone?

Objective: To demonstrate a multimodal treatment of a patient with corticotroph pituitary adenoma causing Cushing's disease and developing a Nelson-tumor: surgery, medical treatment, radiotherapy. Patient history: We report on a 42 year old female patient who originally developed central ACTH-dependent Cushing's disease in 1982. Within a MRI scan no sellar tumor was visible. Peripheral ACTH-level were elevated and adequately stimulated by administering CRH from 105 to 151 pg/ml. Sinus petrosus sampling revealed a gradient for Plasma-ACTH to the right side, measuring 3121 pg/ml respectively 246 pg/ml. Selective catheterization of the central venous system revealed no ectopic ACTH or cortisol secretion. Treatment modalities: 1. Severe metabolic disturbances improved under medical pre-treatment with ketoconazol. 2. Transsphenoidal surgery: no clear adenoma could be detected after meticulous sectioning of the normal appearing anterior pituitary gland. 3. Bilateral adrenalectomy: after resecting both hyperplastic adrenal glands, serum cortisol levels decreased to <2µg/dl. However plasma ACTH increased from 235 to 5250 pg/ml. Hyperpigmentation increased. 4. Medical treatment: Rosiglitazone (a PPAG γ-receptor antagonist – Avandia®) for 6 weeks. ACTH decreased to 1120 pg/ml. 5. 2nd transsphenoidal surgery: resection of a invasive macroadenoma, pituitary function pre-/ post-operative not disturbed. 6. Shaped beam radiosurgery (Novalis®). Conclusion: Corticotroph adenomas may present a complex biological behaviour, requiring difficult interdisciplinary diagnostic and therapeutic procedures such as surgery (transsphenoidal, abdominal), radiotherapy and medical treatment (traditional ketocanazol, novel agent Rosiglitazone).