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Highlights • Cushing syndrome (CS) is a rare disorder with a variety of underlying etiologies. • CS is expected to affect 0.2 to 5 people per million per year. • Adrenal-dependent CS is an uncommon variant of CS. • This study reports a rare occurrence of pituitary and adrenal adenoma with CS. Abstract Introduction Cushing syndrome is a rare disorder with a variety of underlying etiologies, that can be exogenous or endogenous (adrenocorticotropic hormone (ACTH)-dependent or ACTH-independent). The current study aims to report a case of ACTH-independent Cushing syndrome with adrenal adenoma and nonfunctioning pituitary adenoma. Case report A 37–year–old female presented with amenorrhea for the last year, associated with weight gain. She had a moon face, buffalo hump, and central obesity. A 24-hour urine collection for cortisol was performed, revealing elevated cortisol. Cortisol level was non-suppressed after administering dexamethasone. MRI of the pituitary revealed a pituitary microadenoma, and the CT scan of the abdomen with adrenal protocol revealed a left adrenal adenoma. Discussion Early diagnosis may be postponed due to the variety of clinical presentations and the referral of patients to different subspecialists based on their dominant symptoms (gynecological, dermatological, cardiovascular, psychiatric); it is, therefore, critical to consider the entire clinical presentation for correct diagnosis. Conclusion Due to the diversity in the presentation of CS, an accurate clinical, physical and endocrine examination is always recommended. Keywords Cushing syndrome Cushing's disease Adrenal adenoma Pituitary adenoma Urine free cortisol 1. Introduction Cushing syndrome (CS) is a collection of clinical manifestations caused by an excess of glucocorticoids [1]. CS is a rare disorder with a variety of underlying etiologies that can be exogenous due to continuous corticosteroid therapy for any underlying inflammatory illness or endogenous due to either adrenocorticotropic hormone (ACTH)-dependent or ACTH-independent [2], [3]. Cushing syndrome is expected to affect 0.2 to 5 people per million per year. Around 10% of such cases involve children [4], [5]. ACTH-dependent glucocorticoid excess owing to pituitary adenoma accounts for the majority (60–70%) of endogenous CS, with primary adrenal causes accounting for only 20–30% and ectopic ACTH-secreting tumors accounting for the remaining 5–10% [6]. Adrenal-dependent CS is an uncommon variant of CS caused mostly by benign (90%) or malignant (8%) adrenal tumors or, less frequently, bilateral micronodular (1%) or macronodular (1%) adrenal hyperplasia [7]. The current study aims to report a case of ACTH-independent Cushing syndrome with adrenal adenoma and nonfunctioning pituitary adenoma. The report has been arranged in line with SCARE guidelines and includes a brief literature review [8]. 2. Case report 2.1. Patient's information A 37–year–old female presented with amenorrhea for the last year, associated with weight gain. She denied having polyuria, polydipsia, headaches, visual changes, dizziness, dryness of the skin, cold intolerance, or constipation. She had no history of chronic disease and denied using steroids. She visited an internist, a general surgeon, and a gynecologist and was treated for hypothyroidism. She was put on Thyroxin 100 μg daily, and oral contraceptive pills were given for her menstrual problems. Last time, the patient was referred to an endocrinology clinic, and they reviewed the clinical and physical examinations. 2.2. Clinical examination She had a moon face, buffalo hump, central obesity, pink striae over her abdomen, and proximal weakness of the upper limbs. After reviewing the history and clinical examination, CS was suspected. 2.3. Diagnostic assessment Because the thyroid function test revealed low thyroid-stimulating hormone (TSH), free T3, and freeT4, the patient was sent for a magnetic resonance imaging (MRI) of the pituitary, which revealed a pituitary microadenoma (7 ∗ 6 ∗ 5) mm (Fig. 1). Since the patient was taking thyroxin and oral contraceptive pills, the investigations were postponed for another six weeks due to the contraceptive pills' influence on the results of the hormonal assessment for CS. After six weeks of no medication, a 24-hour urinary free cortisol (UFC) was performed three times, revealing elevated cortisol levels (1238, 1100, and 1248) nmol (normal range, 100–400) nmol. A dexamethasone suppression test was done (after administering dexamethasone tab 1 mg at 11 p.m., serum cortisol was measured at 9 a.m.). The morning serum cortisol level was 620 nmol (non-suppressed), which normally should be less than 50 nmol. The ACTH level was below 1 pg/mL. Download : Download high-res image (103KB) Download : Download full-size image Fig. 1. Contrast enhanced T1W weighted MRI (coronal section) showing small 7 mm hypo-enhanced microadenoma (yellow arrow) in right side of pituitary gland with mild superior bulge. Based on these findings, ACTH independent CS was suspected. The computerized tomography (CT) scan of the abdomen with adrenal protocol revealed a left adrenal adenoma (33 mm × 25 mm) without features of malignancy (Fig. 2). Download : Download high-res image (168KB) Download : Download full-size image Fig. 2. Computed tomography scan of the abdomen with IV contrast, coronal section, showing 33 mm × 25 mm lobulated enhanced left adrenal tumor (yellow arrow), showing absolute washout on dynamic adrenal CT protocol, consistent with adrenal adenoma. 2.4. Therapeutic intervention The patient was referred to the urologist clinic for left adrenalectomy after preparation for surgery and perioperative hormonal management. She underwent laparoscopic adrenalectomy and remained in the hospital for two days. The histopathology results supported the diagnosis of adrenal adenoma. 2.5. Follow-up She was released home after two days on oral hydrocortisone 20 mg in the morning and 10 mg in the afternoon. After one month of follow-up, serum cortisol was 36 nmol, with the resolution of some features such as weight reduction (3 kg) and skin color (pink striae became white). 3. Discussion Cushing's syndrome is a serious and well-known medical condition that results from persistent exposure of the body to excessive glucocorticoids, either from endogenous or, most frequently, exogenous sources [9]. The average age of diagnosis is 41.4 years, with a female-to-male ratio of 3:1 [10]. ACTH-dependent CS accounts for almost 80% of endogenous CS, while ACTH-independent CS accounts for nearly 20% [10]. This potentially fatal condition is accompanied by several comorbidities, including hypertension, diabetes, coagulopathy, cardiovascular disease, infections, and fractures [11]. Exogenous CS, also known as iatrogenic CS, is more prevalent than endogenous CS and is caused by the injection of supraphysiologic glucocorticoid dosages [12]. ACTH-independent CS is induced by uncontrolled cortisol release from an adrenal gland lesion, most often an adenoma, adrenocortical cancer, or, in rare cases, ACTH-independent macronodular adrenal hyperplasia or primary pigmented nodular adrenal disease [13]. The majority of data suggests that early diagnosis is critical for reducing morbidity and mortality. Detection is based on clinical suspicion initially, followed by biochemical confirmation [14]. The clinical manifestation of CS varies depending on the severity and duration of glucocorticoid excess [14]. Some individuals may manifest varying symptoms and signs because of a rhythmic change in cortisol secretion, resulting in cyclical CS [15]. The classical symptoms of CS include weight gain, hirsutism, striae, plethora, hypertension, ecchymosis, lethargy, monthly irregularities, diminished libido, and proximal myopathy [16]. Neurobehavioral presentations include anxiety, sadness, mood swings, and memory loss [17]. Less commonly presented features include headaches, acne, edema, abdominal pain, backache, recurrent infection, female baldness, dorsal fat pad, frank diabetes, electrocardiographic abnormalities suggestive of cardiac hypertrophy, osteoporotic fractures, and cardiovascular disease from accelerated atherosclerosis [10]. The current case presented with amenorrhea, weight gain, moon face, buffalo hump, and skin discoloration of the abdomen. Similar to the current case, early diagnosis may be postponed due to the variety of clinical presentations and the referral of patients to different subspecialists based on their dominant symptoms (gynecological, dermatological, cardiovascular, psychiatric); it is, therefore, critical to consider the entire clinical presentation for correct diagnosis [18]. Weight gain may be less apparent in children, but there is frequently an arrest in growth with a fall in height percentile and a delay in puberty [19]. The diagnosis and confirmation of the etiology can be difficult and time-consuming, requiring a variety of laboratory testing and imaging studies [20]. According to endocrine society guidelines, the initial assessment of CS must include one or more of the three following tests: 24-hour UFC measurement; evaluation of the diurnal variation of cortisol secretion by assessing the midnight serum or salivary cortisol level; and a low-dose dexamethasone suppression test, typically the 1 mg overnight test [21]. Although UFC has sufficient sensitivity and specificity, it does not function well in milder cases of Cushing's syndrome [22]. In CS patients, the typical circadian rhythm of cortisol secretion is disrupted, and a high late-night cortisol serum level is the earliest and most sensitive diagnostic indicator of the condition [23]. In the current case, the UFC was elevated, and cortisol was unsuppressed after administration of dexamethasone. All patients with CS should have a high-resolution pituitary MRI with a gadolinium-based contrast agent to prove the existence or absence of a pituitary lesion and to identify the source of ACTH between pituitary adenomas and ectopic lesions [24]. Adrenal CT scan is the imaging modality of choice for preoperatively localizing and subtyping adrenocortical lesions in ACTH-independent Cushing's syndrome [9]. MRI of the pituitary gland of the current case showed a microadenoma and a CT scan of the adrenals showed left adrenal adenoma. Surgical resection of the origin of the ACTH or glucocorticoid excess (pituitary adenoma, nonpituitary tumor-secreting ACTH, or adrenal tumor) is still the first-line treatment of all forms of CS because it leaves normal adjacent structures and results in prompt remission and inevitable recovery of regular adrenal function [12], [25]. Laparoscopic (retroperitoneal or transperitoneal) adrenalectomy has become the gold standard technique for adrenal adenomas since it is associated with fewer postoperative morbidity, hospitalization, and expense when compared to open adrenalectomy [17]. In refractory cases, or when a patient is not a good candidate for surgery, cortisol-lowering medication may be employed [26]. The current case underwent left adrenalectomy. Symptoms of CS, such as central obesity, muscular wasting or weakness, acne, hirsutism, and purple striae generally improve first and may subside gradually over a few months or even a year; nevertheless, these symptoms may remain in 10–30% of patients [27]. Glucocorticoid replacement is essential after adrenal-sparing curative surgery until the pituitary-adrenal function returns, which might take up to two years, especially if adrenal adenomas have been resected [25]. Chronic glucocorticoid excess causes lots of new co-morbidities, lowering the quality of life and increasing mortality. The most common causes of mortality in CS are cardiovascular disease and infections [28]. After one month of follow-up, serum cortisol was 36 nmol, and several features, such as weight loss (3 kg) and skin color, were resolved (pink striae became white). In conclusion, the coexistence of adrenal adenoma and pituitary adenoma with CS is a rare possibility. Due to the diversity in the presentation of CS, an accurate clinical, physical and endocrine examination is always recommended. Laparoscopic adrenalectomy is the gold standard for treating adrenal adenoma. Consent Written informed consent was obtained from the patient's family for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Provenance and peer review Not commissioned, externally peer-reviewed. Ethical approval Approval is not necessary for case report (till 3 cases in single report) in our locality. The family gave consent for the publication of the report. Funding None. Guarantor Fahmi Hussein Kakamad, Fahmi.hussein@univsul.edu.iq. Research registration number Not applicable. CRediT authorship contribution statement Abdulwahid M. Salh: major contribution of the idea, literature review, final approval of the manuscript. Rawa Bapir: Surgeon performing the operation, final approval of the manuscript. Fahmi H. Kakamad: Writing the manuscript, literature review, final approval of the manuscript. Soran H. Tahir, Fattah H. Fattah, Aras Gh. Mahmood, Rawezh Q. Salih, Shaho F. Ahmed: literature review, final approval of the manuscript. Declaration of competing interest None to be declared. References [1] S.M. Ahmed, S.F. Ahmed, S. Othman, B.A. Abdulla, S.H. Mohammed, A.M. Salih, et al. Topical corticosteroid-induced iatrogenic Cushing syndrome in an infant; a case report with literature review Ann.Med.Surg., 71 (2021), Article 102978 ArticleDownload PDFView Record in ScopusGoogle Scholar [2] L.H. Broersen, C.D. Andela, O.M. Dekkers, A.M. Pereira, N.R. Biermasz Improvement but no normalization of quality of life and cognitive functioning after treatment of Cushing syndrome J.Clin.Endocrinol.Metab., 104 (11) (2019), pp. 5325-5337 View Record in ScopusGoogle Scholar [3] R.L. Hopkins, M.C. Leinung Exogenous Cushing's syndrome and glucocorticoid withdrawal Endocrinol. Metab. Clin., 34 (2) (2005), pp. 371-384 ArticleDownload PDFView Record in ScopusGoogle Scholar [4] D. Hirsch, G. Tsvetov, Y. Manisterski, N. Aviran-Barak, V. Nadler, S. Alboim, et al. Incidence of Cushing's syndrome in patients with significant hypercortisoluria Eur. J. Endocrinol., 176 (1) (2017), pp. 41-48 View Record in ScopusGoogle Scholar [5] B. Bista, N. Beck Cushing syndrome Indian J.Pediatr., 81 (2) (2014 Feb), pp. 158-164 View PDF CrossRefView Record in ScopusGoogle Scholar [6] M. Lodish, C.A. Stratakis A genetic and molecular update on adrenocortical causes of Cushing syndrome Nat. Rev. Endocrinol., 12 (5) (2016), pp. 255-262 View PDF CrossRefView Record in ScopusGoogle Scholar [7] J.M. Swain, C.S. Grant, R.T. Schlinkert, G.B. Thompson, R.V. Lloyd, W.F. Young Corticotropin-independent macronodular adrenal hyperplasia: a clinicopathologic correlation Arch. Surg., 133 (5) (1998), pp. 541-546 View Record in ScopusGoogle Scholar [8] R.A. Agha, T. Franchi, C. Sohrabi, G. Mathew, for the SCARE Group The SCARE 2020 guideline: updating consensus Surgical CAse REport (SCARE) guidelines Int. J. Surg., 84 (2020), pp. 226-230 ArticleDownload PDFView Record in ScopusGoogle Scholar [9] K. Duan, K.G. Hernandez, O. Mete Republished: clinicopathological correlates of adrenal Cushing's syndrome Postgrad. Med. J., 91 (1076) (2015 Jun 1), pp. 331-342 View PDF CrossRefView Record in ScopusGoogle Scholar [10] A. Lacroix, R.A. Feelders, C.A. Stratakis, L.K. Nieman Cushing's syndrome Lancet, 386 (9996) (2015), pp. 913-927 ArticleDownload PDFView Record in ScopusGoogle Scholar [11] L.K. Nieman, B.M. Biller, J.W. Findling, J. Newell-Price, M.O. Savage, P.M. Stewart, et al. The diagnosis of Cushing's syndrome: an endocrine society clinical practice guideline J.Clin.Endocrinol.Metab., 93 (5) (2008), pp. 1526-1540 View PDF CrossRefView Record in ScopusGoogle Scholar [12] S.T. Sharma, L.K. Nieman, R.A. Feelders Cushing's syndrome: epidemiology and developments in disease management Clin.Epidemiol., 7 (2015), p. 281 Google Scholar [13] J. Newell-Price, X. Bertagna, A.B. Grossman, L.K. Nieman Cushing's syndrome Lancet, 367 (9522) (2006), pp. 1605-1617 ArticleDownload PDFView Record in ScopusGoogle Scholar [14] L.K. Nieman Cushing's syndrome: update on signs, symptoms and biochemical screening Eur. J. Endocrinol., 173 (4) (2015), pp. M33-M38 View Record in ScopusGoogle Scholar [15] B. Atkinson, K.R. Mullan What is the best approach to suspected cyclical Cushing syndrome? Strategies for managing Cushing's syndrome with variable laboratory data Clin. Endocrinol., 75 (1) (2011), pp. 27-30 View PDF CrossRefView Record in ScopusGoogle Scholar [16] F. Ferrau, M. Korbonits Metabolic comorbidities in Cushing's syndrome Eur. J. Endocrinol., 173 (4) (2015), pp. M133-M157 View Record in ScopusGoogle Scholar [17] V. Neychev Cushing syndrome: presentation, diagnosis, and treatment, including subclinical Cushing syndrome Management of Adrenal Masses in Children And Adults, Springer, Cham (2017), pp. 159-178 View PDF CrossRefView Record in ScopusGoogle Scholar [18] L.K. Nieman Diagnosis of Cushing's syndrome in the modern era Endocrinol. Metab. Clin., 47 (2) (2018), pp. 259-273 ArticleDownload PDFView Record in ScopusGoogle Scholar [19] H.L. Storr, L.F. Chan, A.B. Grossman, M.O. Savage Paediatric Cushing's syndrome: epidemiology, investigation and therapeutic advances TrendsEndocrinol.Metab., 18 (4) (2007), pp. 167-174 ArticleDownload PDFView Record in ScopusGoogle Scholar [20] R. Pivonello, A.M. Isidori, M.C. De Martino, J. Newell-Price, B.M. Biller, A. Colao Complications of Cushing's syndrome: state of the art Lancet DiabetesEndocrinol., 4 (7) (2016), pp. 611-629 ArticleDownload PDFView Record in ScopusGoogle Scholar [21] C. Tatsi, C.A. Stratakis Cushing disease: diagnosis and treatment Pituitary Disorders of Childhood, Humana Press, Cham (2019), pp. 89-114 View PDF CrossRefView Record in ScopusGoogle Scholar [22] K.I. Alexandraki, A.B. Grossman Is urinary free cortisol of value in the diagnosis of Cushing's syndrome? Curr.Opin.Endocrinol.DiabetesObes., 18 (4) (2011), pp. 259-263 View Record in ScopusGoogle Scholar [23] E.M. Cardoso, A.L. Arregger, O.R. Tumilasci, L.N. Contreras Diagnostic value of salivary cortisol in Cushing's syndrome (CS) Clin. Endocrinol., 70 (4) (2009), pp. 516-521 View PDF CrossRefView Record in ScopusGoogle Scholar [24] G. Arnaldi, A. Angeli, A.B. Atkinson, X. Bertagna, F. Cavagnini, G.P. Chrousos, et al. Diagnosis and complications of Cushing's syndrome: a consensus statement J.Clin.Endocrinol.Metab., 88 (12) (2003), pp. 5593-5602 View Record in ScopusGoogle Scholar [25] L.K. Nieman, I. Ilias Evaluation and treatment of Cushing's syndrome Am. J. Med., 118 (12) (2005), pp. 1340-1346 ArticleDownload PDFView Record in ScopusGoogle Scholar [26] N.A. Wagner-Bartak, A. Baiomy, M.A. Habra, S.V. Mukhi, A.C. Morani, B.R. Korivi, et al. Cushing syndrome: diagnostic workup and imaging features, with clinical and pathologic correlation Am. J. Roentgenol., 209 (1) (2017), pp. 19-32 View Record in ScopusGoogle Scholar [27] R.A. Feelders, S.J. Pulgar, A. Kempel, A.M. Pereira Management of endocrine disease: the burden of Cushing's disease: clinical and health-related quality of life aspects Eur. J. Endocrinol., 167 (3) (2012), pp. 311-326 View Record in ScopusGoogle Scholar [28] A. Ferriere, A. Tabarin Cushing's syndrome: treatment and new therapeutic approaches Best Pract. Res. Clin. Endocrinol. Metab., 34 (2) (2020), Article 101381 ArticleDownload PDFView Record in ScopusGoogle Scholar From https://www.sciencedirect.com/science/article/pii/S221026122200284X -
This article was originally published here Microvasc Res. 2022 Jan 21:104323. doi: 10.1016/j.mvr.2022.104323. Online ahead of print. ABSTRACT PURPOSE: Macrovascular alterations are prominent in Cushing’s syndrome (CS). Microvascular abnormalities are yet to be established. This cross-sectional observational study aimed to evaluate microvascular changes in nailfold capillaries and their association with disease status and carotid intima-media thickness (CIMT) as a marker of atherosclerosis. METHODS: A total of 70 patients with CS [46 (65.7%) ACTH-dependent pituitary adenoma and 24 (34.3%) adrenocortical adenomas] and 100 healthy controls were enrolled. The microvascular structure was evaluated using nailfold video-capillaroscopy (NVC). RESULTS: The median number of capillaries was less [10 mm (IQR: 2, min-max:7-14) vs. 11 mm (IQR: 2, min-max:9-19) (p < 0.001)], the median limb diameter and capillary width were wider in the CS group than in the controls (p = 0.016 and p = 0.002, respectively). Microhemorrhages within limited areas were more frequent in the CS group than in the controls (p = 0.046). Observed capillary changes were similar among the patients with CS with remission or active disease. CIMT levels were higher in the CS group than in the controls and similar in subjects with active disease and remission. Univariate logistic regression analyses revealed that the number of capillaries and capillary widths were associated with body mass index (BMI), the presence of type 2 diabetes mellitus, HbA1c, and CIMT. CONCLUSION: Morphologic alterations present similarly in nailfold capillaries in subjects with CS regardless of disease status, resembling changes in chronic atherosclerotic diseases. Microvascular changes in nailfold capillaries measured using NVC can be used as a marker in the assessment of cardiovascular risk in patients with CS. PMID:35074338 | DOI:10.1016/j.mvr.2022.104323 From https://www.docwirenews.com/abstracts/rheumatology-abstracts/capillary-microarchitectural-changes-in-cushings-syndrome/
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This article was originally published here J Endocr Soc. 2021 Nov 24;6(1):bvab176. doi: 10.1210/jendso/bvab176. eCollection 2022 Jan 1. ABSTRACT CONTEXT: Acromegaly (ACM) and Cushing’s disease (CD) are caused by functioning pituitary adenomas secreting growth hormone and ACTH respectively. OBJECTIVE: To determine the impact of race on presentation and postoperative outcomes in adults with ACM and CD, which has not yet been evaluated. METHODS: This is a retrospective study of consecutive patients operated at a large-volume pituitary center. We evaluated (1) racial distribution of patients residing in the metropolitan area (Metro, N = 124) vs 2010 US census data, and(2) presentation and postoperative outcomes in Black vs White for patients from the entire catchment area (N = 241). RESULTS: For Metro area (32.4% Black population), Black patients represented 16.75% ACM (P = .006) and 29.2% CD (P = .56). Among the total 112 patients with ACM, presentations with headaches or incidentaloma were more common in Black patients (76.9% vs 31% White, P = .01). Black patients had a higher prevalence of diabetes (54% vs 16% White, P = .005), significantly lower interferon insulin-like growth factor (IGF)-1 deviation from normal (P = .03) and borderline lower median growth hormone levels (P = .09). Mean tumor diameter and proportion of tumors with cavernous sinus invasion were similar. Three-month biochemical remission (46% Black, 55% White, P = .76) and long-term IGF-1 control by multimodality therapy (92.3% Black, 80.5% White, P = .45) were similar. Among the total 129 patients with CD, Black patients had more hypopituitarism (69% vs 45% White, P = .04) and macroadenomas (33% vs 15% White, P = .05). At 3 months, remission rate was borderline higher in White (92% vs 78% Black, P = 0.08), which was attributed to macroadenomas by logistic regression. CONCLUSION: We identified disparities regarding racial distribution, and clinical and biochemical characteristics in ACM, suggesting late or missed diagnosis in Black patients. Large nationwide studies are necessary to confirm our findings. PMID:34934883 | PMC:PMC8677529 | DOI:10.1210/jendso/bvab176 From https://www.docwirenews.com/abstracts/journal-abstracts/racial-disparities-in-acromegaly-and-cushings-disease-a-referral-center-study-in-241-patients/
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This article involves discussion on the use of standard and advanced magnetic resonance imaging (MRI) sequences to diagnose and characterize pituitary adenomas (PAs), including MRI characteristics related to treatment response that could assist in presurgical assessment and planning, and red flags that could suggest an alternative diagnosis. Besides PAs, several other lesions may be found in the sellar region, such as meningiomas, craniopharyngiomas and aneurysms. For assessing lesions in the sella turcica, sellar MRI is preferred. With a systematic MRI approach to the pituitary region, generally the obtained information comprises: the size and shape of the PA, the presence of cysts or hemorrhage within the tumor, its link with the optic pathways and surrounding structures, potential cavernous sinus invasion, sphenoid sinus pneumatization type, and differential diagnosis with other sellar lesions. In the majority of cases, standard protocol serves the purpose; but additional information could be obtained by using some advanced techniques (susceptibility imaging, diffusion-weighted imaging, 3D T2-weighted high-resolution sequences, magnetic resonance elastography, perfusion-weighted imaging) and such information may be important for some cases. Journal Summary Read the full article on Journal of Clinical Endocrinology and Metabolism.
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This article was originally published here J Clin Endocrinol Metab. 2021 Sep 3:dgab659. doi: 10.1210/clinem/dgab659. Online ahead of print. ABSTRACT CONTEXT: Confirming a diagnosis of Cushing’s disease (CD) remains challenging yet is critically important before recommending transsphenoidal surgery for adenoma resection. OBJECTIVE: To describe predictive performance of preoperative biochemical and imaging data relative to post-operative remission and clinical characteristics in patients with presumed CD. DESIGN, SETTING, PATIENTS, INTERVENTIONS: Patients (n=105; 86% female) who underwent surgery from 2007-2020 were classified into 3 groups: Group A (n=84) pathology-proven ACTH adenoma; Group B (n=6) pathology-unproven but with postoperative hypocortisolemia consistent with CD, and Group C (n=15) pathology-unproven, without postoperative hypocortisolemia. Group A+B were combined as Confirmed CD and Group C as Unconfirmed CD. MAIN OUTCOMES: Group A+B was compared to Group C regarding predictive performance of preoperative 24-hour urinary free cortisol (UFC), late night salivary cortisol (LNSC), 1mg dexamethasone suppression test (DST), plasma ACTH, and pituitary MRI. RESULTS: All groups had a similar clinical phenotype. Compared to Group C, Group A+B had higher mean UFC (p<0.001), LNSC(p=0.003), DST(p=0.06), ACTH(p=0.03) and larger MRI-defined lesions (p<0.001). The highest accuracy thresholds were: UFC 72 µg/24hrs; LNSC 0.122 µg/dl, DST 2.70 µg/dl, and ACTH 39.1 pg/ml. Early (3-month) biochemical remission was achieved in 76/105 (72%) patients: 76/90(84%) and 0/15(0%) of Group A+B versus Group C, respectively, p<0.0001. In Group A+B non-remission was strongly associated with adenoma cavernous sinus invasion. CONCLUSIONS: Use of strict biochemical thresholds may help avoid offering transsphenoidal surgery to presumed CD patients with equivocal data and improve surgical remission rates. Patients with Cushingoid phenotype but equivocal biochemical data warrant additional rigorous testing. PMID:34478542 | DOI:10.1210/clinem/dgab659
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Abstract Background: Cushing’s syndrome is a condition caused by excessive glucocorticoid with insomnia as one of its neuropsychiatric manifestation. Cushing’s syndrome may be caused by excessive adrenocorticotropin hormone (ACTH-dependent), for example from ACTH producing pituitary tumors, or by overproduction of cortisol by adrenocortical tumors. In this report, we presented a case with Cushing’s syndrome manifesting as chronic insomnia with adrenal cortical adenoma and pituitary microadenoma. Case presentation: A 30-year-old woman was consulted from the Neurologic Department to the Internal Medicine Department with the chief complaint of insomnia and worsening headache for 6 months prior to the admission. She had undergone head MRI and abdominal CT scan previously and was found to have both pituitary microadenoma and left adrenal mass. From the physical examination she had clinical signs of Cushing’s syndrome like Cushingoid face and purplish striae on her stomach. Midnight cortisol serum examination was done initially and showed high level of cortisol. High dose dexamethasone suppression test or DST (8 mg overnight) was later performed to help determine the main cause of Cushing’s syndrome. The result failed to reach 50% suppression of cortisol serum, suggestive that the Cushing’s syndrome was not ACTH-dependent from the pituitary but potentially from overproduction of cortisol by the left adrenal mass. Therefore, left adrenalectomy was performed and the histopathological study supported the diagnosis of adrenal cortical adenoma. Conclusion: Chronic insomnia is a very important symptoms of Cushing’s syndrome that should not be neglected. The patient had both microadenoma pituitary and left adrenal mass thus high dose DST test (8 mg overnight) needed to be performed to differentiate the source of Cushing’s syndrome. The result showed only little suppression therefore the pituitary microadenoma was not the source of Cushing’s syndrome and more suggestive from the adrenal etiology. Keywords: Cushing’s syndrome; insomnia; adrenal cortical adenoma; pituitary microadenoma; dexamethasone suppression test Permalink/DOI: https://doi.org/10.14710/jbtr.v7i1.9247I Read the entire article here: https://ejournal2.undip.ac.id/index.php/jbtr/article/view/9247/5440
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First published:03 May 2020 Read the entire article at https://doi.org/10.1002/alr.22540 Potential conflict of interest: None disclosed. Presented at the 65th Annual Meeting of the American Rhinologic Society, on September 14, 2019, in New Orleans, LA. Abstract Background Endoscopic transsphenoidal surgery (ETS) for the resection of pituitary adenoma has become more common throughout the past decade. Although most patients have a short postoperative hospitalization, others require a more prolonged stay. We aimed to identify predictors for prolonged hospitalization in the setting of ETS for pituitary adenomas. Methods A retrospective chart review as performed on 658 patients undergoing ETS for pituitary adenoma at a single tertiary care academic center from 2005 to 2019. Length of stay (LoS) was defined as date of surgery to date of discharge. Patients with LoS in the top 10th percentile (prolonged LoS [PLS] >4 days, N = 72) were compared with the remainder (standard LoS [SLS], N = 586). Results The average age was 54 years and 52.5% were male. The mean LoS was 2.1 days vs 7.5 days (SLS vs PLS). On univariate analysis, atrial fibrillation (p = 0.002), hypertension (p = 0.033), partial tumor resection (p < 0.001), apoplexy (p = 0.020), intraoperative cerebrospinal fluid (ioCSF) leak (p = 0.001), nasoseptal flap (p = 0.049), postoperative diabetes insipidus (DI) (p = 0.010), and readmission within 30 days (p = 0.025) were significantly associated with PLS. Preoperative continuous positive airway pressure (CPAP) (odds ratio, 15.144; 95% confidence interval, 2.596‐88.346; p = 0.003) and presence of an ioCSF leak (OR, 10.362; 95% CI, 2.143‐50.104; p = 0.004) remained significant on multivariable analysis. Conclusion For patients undergoing ETS for pituitary adenomas, an ioCSF leak or preoperative use of CPAP predicted PLS. Additional common reasons for PLS included postoperative CSF leak (10 of 72), management of DI or hypopituitarism (15 of 72), or reoperation due to surgical or medical complications (14 of 72). From https://onlinelibrary.wiley.com/doi/abs/10.1002/alr.22540?af=R
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The oral chemotherapy temozolomide might be an effective treatment for Cushing’s disease caused by aggressive tumors in the pituitary gland that continue to grow after surgery and taking other medications, a case report suggests. The study, “Successful reduction of ACTH secretion in a case of intractable Cushing’s disease with pituitary Crooke’s cell adenoma by combined modality therapy including temozolomide,” was published in the journal J-Stage. Cushing’s disease is often caused by a tumor in the pituitary gland that secretes high levels of adrenocorticotropic hormone (ACTH), leading to high levels of cortisol and other symptoms. Macroadenomas are aggressive, fast-growing tumors that reach sizes larger than 10 millimeters. Crooke’s cell adenoma is a type of macroadenoma that does not respond to conventional therapies, but has deficient mechanisms of DNA repair. That is why chemotherapeutic agents that damage the DNA, such as temozolomide, might be potential treatments. Researchers in Japan reported the case of a 56-year-old woman with Cushing’s disease caused by a Crooke’s cell adenoma in the pituitary gland who responded positively to temozolomide. The patient was diagnosed with Cushing’s disease at age 39 when she went to the hospital complaining of continuous weight gain. She also had excessive production of urine and a loss of vision in the right eye. The lab tests showed high levels of cortisol and ACTH, and the MRI detected a tumor of 4.5 centimeters in the pituitary gland. The doctors removed a part of the tumor surgically, which initially reduced the levels of ACTH and cortisol. However, the hormone levels and the size of the residual tumor started to increase gradually after the surgery, despite treatment with several medications. By the time the patient was 56 years old, she went to the hospital complaining of general fatigue, leg edema (swelling from fluid), high blood pressure, and central obesity (belly fat). Further examination showed a 5.7 cm tumor, identified as a Crooke’s cell macroadenoma. The patient underwent a second surgery to remove as much tumor as possible, but the levels of ACTH remained high. She took temozolomide for nine months, which normalized the levels of ACTH and cortisol. After the treatment, the patient no longer had high blood pressure or leg edema. The tumor shrunk considerably in the year following temozolomide treatment. The patient started radiation therapy to control tumor growth. The levels of cortisol and ACHT remained normal, and the tumor did not grow in the seven years following temozolomide treatment. “These clinical findings suggest that [temozolomide] treatment to patients with Crooke’s cell adenoma accompanied with elevated ACTH may be a good indication to induce lowering ACTH levels and tumor shrinkage,” researchers wrote. Other cases of Cushing’s disease caused by aggressive macroadenomas showed positive results, such as reduction of tumor size and decrease in plasma ACTH, after temozolomide treatment. However, more studies are needed to establish the ideal course of chemotherapy to treat these tumors, the researchers noted. From https://cushingsdiseasenews.com/2019/06/18/temozolomide-effective-cushings-disease-aggressive-tumors-case-report/
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Adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome (CS) is mostly due to unilateral tumors, with bilateral tumors rarely reported. Its common causes include primary pigmented nodular adrenocortical disease, ACTH-independent macronodular adrenal hyperplasia, and bilateral adrenocortical adenomas (BAAs) or carcinomas. BAAs causing ACTH-independent CS are rare; up to now, fewer than 40 BAA cases have been reported. The accurate diagnosis and evaluation of BAAs are critical for determining optimal treatment options. Adrenal vein sampling (AVS) is a good way to diagnose ACTH-independent CS. A 31-year-old woman had a typical appearance of CS. The oral glucose tolerance test showed impaired glucose tolerance and obviously increased insulin and C-peptide levels. Her baseline serum cortisol and urine free cortisol were elevated and did not show either a circadian rhythm or suppression with dexamethasone administration. The peripheral 1-deamino-8-D-arginine-vasopressin (DDVAP) stimulation test showed a delay of the peak level, which was 1.05 times as high as the baseline level. Bilateral AVS results suggested the possibility of BAAs. Abdominal computed tomography showed bilateral adrenal adenomas with atrophic adrenal glands (right: 3.1 cm × 2.0 cm × 1.9 cm; left: 2.2 cm × 1.9 cm × 2.1 cm). Magnetic resonance imaging of the pituitary gland demonstrated normal findings. A left adenomectomy by retroperitoneoscopy was performed first, followed by resection of the right-side adrenal mass 3 mo later. Biopsy results of both adenomas showed cortical tumors. Evaluations of ACTH and cortisol showed a significant decrease after left adenomectomy but could still not be suppressed, and the circadian rhythm was absent. Following bilateral adenomectomy, this patient has been administered with prednisone until now, all of her symptoms were alleviated, and she had normal blood pressure without edema in either of her lower extremities. BAAs causing ACTH-independent CS are rare. AVS is of great significance for obtaining information on the functional state of BAAs before surgery. World journal of clinical cases. 2019 Apr 26 [Epub] Yu-Lin Gu, Wei-Jun Gu, Jing-Tao Dou, Zhao-Hui Lv, Jie Li, Sai-Chun Zhang, Guo-Qing Yang, Qing-Hua Guo, Jian-Ming Ba, Li Zang, Nan Jin, Jin Du, Yu Pei, Yi-Ming Mu Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing 100853, China., Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing 100853, China. guweijun301@163.com., Department of Pathology, Chinese People's Liberation Army General Hospital, Beijing 100853, China. PubMed http://www.ncbi.nlm.nih.gov/pubmed/31119141 From https://www.urotoday.com/recent-abstracts/urologic-oncology/adrenal-diseases/112782-bilateral-adrenocortical-adenomas-causing-adrenocorticotropic-hormone-independent-cushing-s-syndrome-a-case-report-and-review-of-the-literature.html
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Huang X, et al. Pituitary. 2019;doi:10.1007/s11102-018-0927-x. March 3, 2019 The use of 3D-printed models could lead to less operation time and blood loss and fewer postoperative complications in adults who undergo endoscopic endonasal transsphenoidal surgery for pituitary adenomas and other conditions, according to findings published in Pituitary. “Several factors influence the outcome of endoscopic endonasal surgery, including the tumor volume, patient age, lesion location and sphenoid pneumatolysis,” Xiaobing Jiang, of the department of neurosurgery at Union Hospital of Tongji Medical College of Huazhong University of Science and Technology in Wuhan, Hubei, China, and colleagues wrote. “An accurate model of the target tumor structure is a major prerequisite for a successful [pituitary adenoma] resection, especially for macroadenomas, as this may avoid disastrous complications due to suboptimal treatment.” Jiang and colleagues conducted a retrospective analysis of 20 adults who underwent endoscopic endonasal transsphenoidal surgery at Union Hospital in Wuhan. Participants were included based on similar tumor sizes, the presence of no other diseases and nonintuitive tumor identification. All surgeries in the cohort occurred between January and August 2017, with 10 participants (mean age, 44.4 years; 50% women) receiving CT and MRI before surgery; the remaining 10 also received an operation with 3D printing (mean age, 41.2 years; 50% women). To create the 3D models, images from CT and MRIs were combined. The 3D printer then used this information to create the model, which took between 2 hours, 10 minutes, and 4 hours, 32 minutes, to design and 10 hours, 12 minutes, and 22 hours, 34 minutes, to print. After surgery, the researchers found that mean operation time was lower in participants who had 3D models compared with participants who did not (127 minutes vs. 143.4 minutes; P = .007). In addition, there was less blood loss in participants with 3D printing compared with participants without (159.9 mL vs. 170 mL; P = .009). The researchers noted that there were postoperative complications in 20% of the 3D-printing group and 40% of the CT and MRI alone group. “As it is highly precise and allows personalization, 3D-printing technology has started to be applied in medicine in recent years. In neurosurgery, 3D-printing technology can provide models for the patients’ disease characteristics, such as skull defects, brain tumors, intracranial aneurysms and intracranial vascular malformations,” the researchers wrote. “We believe that with its continuous development, 3D-printing technology will be applied in clinical practice in the near future.” – by Phil Neuffer Disclosures: The authors report no relevant financial disclosures. From https://www.healio.com/endocrinology/neuroendocrinology/news/online/%7B582c6512-708a-4900-ad20-f0adb5a79390%7D/3d-printing-technology-improves-outcomes-in-pituitary-adenoma-surgery
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TOKYO and LONDON, Feb. 20, 2019 /PRNewswire/ -- Sosei Group Corporation ("the Company"; TSE: 4565), announces that the first healthy subject has been dosed with a novel small molecule HTL0030310 in a Phase I clinical study, marking the start of a new in-house clinical program targeting endocrine disorders, including Cushing's disease. HTL0030310 is a potent and selective agonist of the SSTR5 (somatostatin 5) receptor and the sixth molecule designed by the Company using its GPCR Structure-Based Drug Design (SBDD) platform to enter clinical development. HTL0030310 has been designed to modulate the excess release of hormones from adenomas (benign tumors) of the pituitary gland. Highly elevated plasma levels of pituitary hormones result in a number of serious endocrine disorders, including Cushing's Disease. Cushing's disease is characterized by excessive cortisol release, crucial in regulating metabolism, maintaining cardiovascular function and helping the body respond to stress. A key design feature of HTL0030310 is its significant selectivity for SSTR5 over SSTR2. This selectivity is expected to improve the balance of efficacy vs. dose-limiting side effects and therefore, presents an opportunity to develop a best-in-class medicine for patients with Cushing's disease, in particular. The clinical trial with HTL0030310 is a double-blind, randomised, placebo-controlled first-in-human study in which single ascending subcutaneous doses of HTL0030310 will be administered to healthy male and female adult subjects. The study is being conducted in the UK and will assess the safety, tolerability, pharmacokinetics and pharmacodynamics of HTL0030310 in up to 64 subjects. Preliminary results are expected in the second half of 2019 and will provide a first insight into the effects of HTL0030310 on the control of glucose and other endocrine hormones and the potential to target Cushing's disease and other endocrine disorders. Dr. Malcolm Weir, Executive VP and Chief R&D Officer, said: "HTL0030310 is a novel and highly selective molecule, and is the sixth candidate originating from our SBDD platform to advance into human trials. We are not only pleased to begin this new study but also delighted with the productivity of our unique platform to generate attractive candidates targeting GPCRs involved in multiple diseases. These candidates present new prospects for our emerging proprietary pipeline, as well as unique opportunities for partnering, and provide a solid foundation to execute our strategy." About Cushing's disease Cushing's disease is a debilitating endocrine disorder caused by the overproduction of the hormone cortisol and is often triggered by a pituitary adenoma (benign tumour) secreting excess adrenocorticotropic hormone (ACTH). Cortisol has a crucial role regulating metabolism, maintaining cardiovascular function and helping the body respond to stress. Symptoms may include weight gain, central obesity, a round, red full face, severe fatigue and weakness, striae (purple stretch marks), high blood pressure, depression and anxiety. Cushing's disease affects 10-15 million people per year, most commonly adults between 20 to 50 years and women more often than men. The first line and most common treatment approach for Cushing's disease is surgical removal of the pituitary tumor followed by radiotherapy and drug therapy designed to reduce cortisol production. Ref: American Association of Neurological Surgeons (AANS) About Sosei Heptares We are an international biopharmaceutical group focused on the design and development of new medicines originating from its proprietary GPCR-targeted StaR® technology and structure-based drug design platform capabilities. The Company is advancing a broad and deep pipeline of partnered and wholly owned product candidates in multiple therapeutic areas, including CNS, immuno-oncology, gastroenterology, inflammation and other rare/specialty indications. Its leading clinical programs include partnered candidates aimed at the symptomatic treatment of Alzheimer's disease (with Allergan) and next generation immuno-oncology approaches to treat cancer (with AstraZeneca). Our additional partners and collaborators include Novartis, Pfizer, Daiichi-Sankyo, PeptiDream, Kymab and MorphoSys. The Company is headquartered in Tokyo, Japan with R&D facilities in Cambridge, UK and Zurich, Switzerland. "Sosei Heptares" is the corporate brand of Sosei Group Corporation, which is listed on the Tokyo Stock Exchange (ticker: 4565). For more information, please visit https://www.soseiheptares.com/ LinkedIn: @soseiheptaresco | Twitter: @soseiheptaresco | YouTube: @soseiheptaresco Forward-looking statements This press release contains forward-looking statements, including statements about the discovery, development and commercialization of products. Various risks may cause Sosei Group Corporation's actual results to differ materially from those expressed or implied by the forward-looking statements, including: adverse results in clinical development programs; failure to obtain patent protection for inventions; commercial limitations imposed by patents owned or controlled by third parties; dependence upon strategic alliance partners to develop and commercialize products and services; difficulties or delays in obtaining regulatory approvals to market products and services resulting from development efforts; the requirement for substantial funding to conduct research and development and to expand commercialization activities; and product initiatives by competitors. As a result of these factors, prospective investors are cautioned not to rely on any forward-looking statements. We disclaim any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise. View original content:https://www.prnewswire.com/news-releases/sosei-heptares-starts-new-clinical-development-program-300798591.html SOURCE Sosei Heptares
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The surgical removal of two-thirds of the pituitary gland is associated with high initial remission rates and low operative morbidity in patients with suspected Cushing’s disease, when no tumor is found on the gland during surgical exploration. Cushing’s disease (CD) is caused by increased levels of glucocoticosteroids, such as adrenocorticotropic hormone (ACTH), circulating in the blood. In nearly 70 percent of cases this happens as a result of benign tumors on the pituitary gland, which produce excess ACTH. In these patients, the most effective and first-line treatment is surgical removal of the pituitary gland tumor. During the diagnostic stage, clinicians use several methods to identify and localize the source of excessive ACTH. But these methods can fail, and the presence of a tumor in the pituitary is not always confirmed. If the tumor remains unidentified during surgical exploration, it falls to the surgeon’s discretion about how to manage their patients. Researchers at the University of Colorado Denver School of Medicine provided an overview of their experience on the management of patients with presumed Cushing’s disease who underwent surgical treatment. The study, “Negative surgical exploration in patients with Cushing’s disease: benefit of two-thirds gland resection on remission rate and a review of the literature,” was published in the Journal of Neurosurgery. “The diagnosis and treatment of CD is one of the most challenging entities that pituitary neurosurgeons, endocrinologists, and pathologists face,” the researchers wrote. “The ability to make a correct diagnosis and deliver a high likelihood of remission after surgery relies heavily on the performance of a meticulous workup and rational surgical strategy.” The team retrospectively analyzed all cases that had been referred to the Department of Neurosurgery of CU School of Medicine between 1989 and 2011 for a potential ACTH-secreting pituitary tumor. During this period, 161 cases of Cushing’s patients who underwent surgical tumor resection were reported. In 22 patients, the surgeon was unable to detect a tumor. In these cases the surgical team decided to remove two-thirds of the gland, with resection of the lateral and inferior portions of the pituitary. All 22 patients were treated using a consistent technique performed by a single surgeon. Posterior tissue analysis confirmed that six of these patients had pituitary ACTH-secreting tumors. In the remaining 16 patients, no tumor was identified. In three patients the team believed that overproduction of ACTH could be due to an overgrowth of ACTH-secreting cells rather than expansion. The team believes that these findings underscore the difficulty of accurately diagnosing very small pituitary tumors pre- and post-operatively. The 22 patients were followed for a mean time of 98.9 months, or 8.2 years. No remissions were observed in the six patients who had ACTH-secreting tumors or in 12 of the remaining patients. Blood analysis in follow-up exams confirmed these patients had normal levels of glucocoticosteroids. Four patients continued to show persistent elevated amounts of ACTH. Additional clinical evaluations revealed that two patients had ACTH-secreting lung tumors, and one patient was suspected of having an ACTH-secreting tumor on a brain region close to the pituitary. There was one case where the clinical team was unable to identify the origin of elevated ACTH. Only three patients required hormone replacement after the two-thirds gland removal to overcome a newly detected hormone deficit. The approach used by the surgical team was, overall, found to be safe with no severe side effects reported. “Currently, when the neurosurgeon is faced with the inability to identify a discrete adenoma intraoperatively, there is little uniformity in the literature as to how to proceed,” the team wrote. “We believe this [pituitary resection] approach will be useful to help guide surgeons in the operative treatment of this particularly difficult group of patients.” From https://cushingsdiseasenews.com/2017/12/14/pituitary-gland-resection-may-help-presumed-cushings-disease-patients/
