Symptoms Of Cushing's Disease Research Articles

P-57 A case of pituitary carcinoma treated with osilodrostat for severe Cushing's syndrome

Abstract Introduction Pituitary carcinoma is a rare disorder accounting for 0.1–0.2% of pituitary tumors. We present a case of a male subject with ACTH-secreting pituitary carcinoma with metastasis to the spine, achieving eucortisolism on osilodrostat treatment. Clinical Case A 31-year-old male presented with complaints of pain in the rear-left thigh, numbness in the left-hand fingers and shoulder. MRI revealed an invasive pituitary tumor which had spread to the left frontal and temporal lobes with infiltration of the dura mater and compression of the left part of the optic chiasm, multiple formations in the large hemispheres, hemispheres of the cerebellum, in the right internal auditory meatus and at the level of the C1 vertebra compatible with metastasis. Spinal MRI showed a mass at Th6, L1-S2 level compatible with metastasis (Fig.1). The patient was diagnosed with Cushing's disease (CD) at 23 (late-night serum cortisol 1450 nmol/L (64–327), late-night salivary cortisol (LNSC) 66.4 nmol/L (0.5–9.65), 24hUFC 608 nmol/L (100–379), ACTH 107.3 pg/mL (7.2–63.3)) and underwent transsphenoidal pituitary surgery for pituitary macroadenoma 26×18×29 mm with biochemical remission. Two years later his symptoms of CD relapsed and he had a second transsphenoidal surgery. Histological examination showed an atypical corticotroph tumor with Ki67 – 11.6%. Two months after surgery, Kiber knife surgery was performed. However, 2 years later he had gradual deterioration of vision due to loss of lateral margins. A third transcranial adenomectomy was performed with following panhypopituitarism and diabetes insipidus. The tumor was positively stained for ACTH and also contained some atypical features including nuclear pleomorphism. Postoperative chemotherapy adjuvant treatment with Temozolomide and Carboplatin was prescribed. After 6 cycles, proton radiotherapy was done. In order to control hypercortisolism the patient received ketoconazole 800 mg per day, cabergoline 1 mg twice weekly and pasireotide 1.8 mg per day. However, it was not possible to achieve remission of hypercortisolism. As an adverse event of pasireotide, diabetes mellitus developed, which required insulin therapy and finally lead to pasireotide cessation. Ketoconazole and cabergoline were discontinued and osilodrostat treatment was initiated with a final dose of 5 mg daily over 2 years. He also received another course of radiation therapy at the age of 31 years. Over the past 2 years of observation, his ACTH level ranged from 37 pg/mL to 325.1 pg/ml. In spite of tumor progression and raised ACTH, the patient remains in eucortisolism (late-night serum cortisol 163.3 nmol/L, LNSC 5.21 nmol/L, 24hUFC 70.14 nmol/L) on osilodrostat 10 mg daily. Conclusion In this case osilodrostat was effective at controlling hypercortisolism, but its effects on the tumor are unknown. As this patient is the first described case of corticotroph carcinoma tumor treated with Osilodrostat, the results should be taken with caution.Figure 1.Pituitary and spinal MRI of the patientT1-weighted MRI demonstrating (A) chiasmal-sellar region formation, (B) formation in the rigt internal auditory meatus, (C) a highly invasive sacral L1–S2 metastasis

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

Rosella C.

![Figure][1]</img> (Left) Rosella C. before she had any symptoms of Cushing disease. (Right) Rosella C. 2 months before surgery. Photos by Frank C. (left) and Rosella C. (right) My health deteriorated over a period of 6 years. My symptoms escalated from easy bruising, hair loss, high blood

Course of Cushing`s disease and treatment outcomes in correlation with pituitary MRI in children.

Cushing's disease (CD) is a rare disorder of a persistent cortisol excess caused by ACTH-secreting pituitary tumor (corticotropinoma). Transsphenoidal surgery (TSS) is a treatment of choice for СD, which effectiveness range is from 70 to 90%. Recurrence rate after successful treatment is about 25%. If surgical treatment is unsuccessful or recurrence appear, radiation treatment is the next therapeutic option, which effectiveness range is also 90%, but the hypopituitarism rate as side effect of treatment is higher. Preoperative predictors of remission and recurrence are still unexplored what leads to further investigations. Analysis of remission and recurrence rates of pediatric CD after successful treatment according to preoperative MRI and therapeutic option. We conducted a retrospective analysis of 90 pediatric patients with CD who were observed between 1992 and 2020 at the Endocrinology Research Centre. The most common clinical symptoms of CD were weight gain [94%] and growth retardation [72%]. Pituitary tumor was detected on radiological imaging in 53/90 patients [59%], there were no signs of visible adenoma in 37/90 of patients[41%]. 63 of 90 patients underwent TSS (70%), 27 patients underwent radiosurgery (30%). Remission rate after TSS was 71%[45/63], after radiosurgery - 85% [23/27]. There were no significant differences in remission rates after radical treatment according to preoperative MRI results (P=0.21 after TSS and P=0.87 after radiosurgery, х2 analysis). Recurrence after successful treatment was diagnosed in 10 patients. There were no significant differences in time to recurrence according to preoperative MRI results (P=0.055, х2 analysis). Time to recurrence was statistically different after TSS compared to radiosurgery (P=0.007, Kaplan-Meier analysis) and in the group with developed adrenal insufficiency in the early postoperative period (P=0.04, Kaplan-Meier analysis). Analysis of side effect of treatment showed that the frequency of growth hormone and gonadotrophin deficiency was statistically higher after radiosurgery (р&lt;0.01, Kruskel-Wallis ANOVA test). Diabetes insipidus was diagnosed only after TSS. Results of our study didn`t allow to use MRI-results as predictor of effectiveness treatment in pediatric CD. Therapeutic option has an impact on time to recurrence, not on recurrence rates. The frequency of growth hormone and gonadotrophin deficiency was statistically higher after radiosurgery compared to TSS. Further studies are needed to identify predictors of remission and recurrence in CD.&gt;&lt; 0.01, Kruskel-Wallis ANOVA test). Diabetes insipidus was diagnosed only after TSS. Results of our study didn`t allow to use MRI-results as predictor of effectiveness treatment in pediatric CD. Therapeutic option has an impact on time to recurrence, not on recurrence rates. The frequency of growth hormone and gonadotrophin deficiency was statistically higher after radiosurgery compared to TSS. Further studies are needed to identify predictors of remission and recurrence in CD.

Aseptic femur head necrosis revealing Cushing's disease: a rare presentation

Background: Cushing's disease is an endocrine disorder and may be associated with non-traumatic osteonecrosis of the hip. We report the case of avascular necrosis of the femoral heads (AVNFH) as the presenting manifestation of Cushing's disease. Case presentation: A 29-year-old male patient was referred to our department because of non-traumatic bilateral hip pain evolving for two years. The pain was associated with lameness when walking. He noticed a drop in libido since one year with erectile dysfunction. Physical examination revealed facio-truncal obesity, abdominal violaceous striae, dorsal hyper-kyphosis, a pain and limitation of internal rotation of the left hip with a Lequesne index of 16. The standard radiography showed a loss of sphericity of the left femoral head with an aspect of eggshell. The MRI confirmed the diagnosis of a bilateral AVNFH. The baseline cortisol level was 287 ng/ml. AVNFH as the presenting manifestation of Cushing's disease was suspected and confirmed by a pituitary MRI which revealed a pituitary adenoma. A discharge of the hips was indicated. The patient underwent surgical resection of the adenoma and was referred to the endocrinology department. The histopathological examination confirmed the diagnosis of pituitary adenoma (corticotrope adenoma). The patient has also received an intravenous perfusion of 5 mg of Zoledronic acid. The follow up was marked by the regression of the symptoms of Cushing's disease and the hip pain. Conclusion: AVNFH as the presenting manifestation of Cushing's disease is rarely described. Hence, it’s needed to exclude endogenous hypercorticism in any patient with idiopathic osteonecrosis.

Efficacy and safety of pasireotide for Cushing's disease: A protocol for systematic review and meta-analysis.

Background:Cushing's disease (CD) is associated with increased risk of mortality, myocardial infarction, stroke, peptic ulcers, fractures and infections. The prevalence of CD is nearly 40 per million and higher in women than in men. When surgery has failed, is not feasible, or has been refused, pharmacotherapy can be considered a valuable option. Pasireotide is the first medical therapy officially approved for adult patients with CD. We will conduct a comprehensive systematic review and meta-analysis to systematically evaluate the efficacy and safety of pasireotide for CD.Methods:Five English databases (PubMed, Web of Science, Embase, Cochrane Library, and OVID) and 3 Chinese databases (China National Knowledge Infrastructure, China Science and Technology Journal Database, and Chinese Biomedical Literature Database) will be searched from their respective inception of databases to December 2020. Two reviewers will select articles, extract data and assess the risk of bias independently. Any disagreement will be resolved by discussion with the third reviewer. Review Manager 5.3 software will be used for data synthesis. The Cochrane risk of bias assessment tool will be used to evaluate the bias risk.Results:This systematic review and meta-analysis will conduct a comprehensive literature search and provide a systematic synthesis of current published data to explore the efficacy and safety of pasireotide for CD.Conclusions:This systematic review and meta-analysis will provide clinical evidence for the efficacy and safety of pasireotide for CD, and inform our understanding of the value of pasireotide in improving CD clinical signs and symptoms. The conclusions drawn from this study may be beneficial to patients, clinicians, and health-related policy makers.Study registration number:INPLASY2020110070.

Cushing's disease and its impact on quality of life as seen through patients' eyes: a narrative qualitative study

Cushing disease (CD) is a rare and highly debilitating pathology. Its impact on quality of life is significant and the disease puts serious limitations on patients' daily lives. While clinical success in the treatment of CD is measured in terms of hypercortisolism remission, it is important to remember that this should coincide with an improvement in patients' psy-chological resilience and quality of life. The present qualitative study aims to reconstruct the psychological journey the patients embark on in living with the disease and its treatment. This study was designed according to the qualitative method of Narrative Inquiry. The pa-tients enrolled were required to keep a one-week diary on living and coping with the dis-ease. The diaries were designed to elicit the free expression of patients. After filling in their diaries for a week, patients were then interviewed face-to-face in order to deeply investigate insights emerged from the diaries' stories. The study involved 12 CD patients. This study gives emotional images of how patients react and try to give meaning to their CD diagnosis and their disease. Particularly, according to patients' narratives, the several physical symp-toms of CD have a tremendously negative impact on patients' self-image and contribute to psychologically deteriorate their self-esteem and confidence. This study not only confirm previous research regarding the deep impact of CD symptoms on everyday life of patients, but they also open interesting perspectives on the psychological representations of patients regarding their symptoms and on their un met needs.

CLINICAL MANIFESTATIONS OF CUSHING'S DISEASE (RESULTS OF ANALYSIS OF THE CLINICAL DATABASE OF THE MOSCOW REGION)

Background: Cushing's disease (CD) is a severe multimorbid disorder that affects primarily young people in their productive age. In most cases, the diagnosis is delayed and patients with complications of hypercorticism are seen by doctors of various specialties.Aim: To identify the most frequent clinical signs and symptoms of CD at the time of diagnosis, to assess an association between clinical manifestations of hypercorticism and main clinical and laboratory parameters.Materials and methods: We examined 44 CD patients registered in the database of CD patients of the Moscow Regional Research and Clinical Institute (MONIKI).Results: The mean age of patients was 37.9±10.5 years, with most of them (68.2%) being in the age range of 30 to 50 years. The median of disease duration was 35.5 [22; 75] months. Facial plethora, which is the most characteristic sign of hypercorticism, was seen in 97.7% of patients. Striae, thought to be most often associated with hypercorticism, were found only in 38.6% of patients. The most frequent complaints (&gt; 80%) were weight gain, fatigue, headache, and menstrual dysfunction. Some of the symptoms showed a positive correlation with cortisol levels.Conclusion: Clinical manifestations of CD are mostly non-specific. Only facial plethora was highly prevalent of all typical symptoms of hypercorticism. At least one of the "specific" symptoms was found in all patients.

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.

American Association Of Clinical Endocrinologists And American Association Of Endocrine Surgeons Medical Guidelines For The Management Of Adrenal Incidentalomas

American Association Of Clinical Endocrinologists And American Association Of Endocrine Surgeons Medical Guidelines For The Management Of Adrenal Incidentalomas

Improved Quality of Life After Bilateral Laparoscopic Adrenalectomy for Cushing's Disease

To determine long-term quality of life after bilateral adrenalectomy for persistent Cushing's disease after transsphenoidal pituitary tumor resection. Bilateral adrenalectomy for symptomatic relief of persistent hypercortisolism appears to be an effective treatment option. However, few studies have examined long-term outcomes in this patient population. Retrospective review of 39 patients treated by bilateral laparoscopic adrenalectomy for Cushing's disease from 1994 to 2004. Patients completed a follow-up phone survey, including our Cushing-specific questionnaire and the SF-12v2 health survey. Patients then refrained from taking their steroid replacement for 24 hours, and serum cortisol and ACTH levels were measured. Three patients died at 12, 19, and 50 months following surgery from causes unrelated to adrenalectomy. The remaining 36 patients all responded to the study questionnaire (100% response rate). Patients were between 3 months and 10 years post-adrenalectomy. We had zero operative mortalities and a 10.3% morbidity rate. Our incidence of Nelson's syndrome requiring clinical intervention was 8.3%; 89% of patients reported an improvement in their Cushing-related symptoms, and 91.7% would undergo the same treatment again. Twenty of 36 (55%) and 29 of 36 (81%) patients fell within the top two thirds of the national average for physical and mental composite scores, respectively, on the SF-12v2 survey. An undetectable serum cortisol level was found in 79.4% of patients. Laparoscopic bilateral adrenalectomy for symptomatic Cushing's disease is a safe and effective treatment option. The majority of patients experience considerable improvement in their Cushing's disease symptoms, and their quality of life equals that of patients initially cured by transsphenoidal pituitary tumor resection.

Pro-opiomelanocortin gene expression in silent corticotroph-cell adenoma and Cushing's disease

The silent corticotroph-cell adenoma (SCCA) is characterized by the presence of immunoreactive adrenocorticotropic hormone (ACTH) in the tumor tissue in patients without symptoms of Cushing's disease. To elucidate the pathophysiology of SCCA, the expression of pro-opiomelanocortin (a ACTH precursor) genes was studied in a patient with SCCA and in three patients with Cushing's disease. Pro-opiomelanocortin messenger ribonucleic acid (mRNA) was found in the SCCA tissue to a greater degree than in the adenomas of the patients with Cushing's disease. Northern blot analysis revealed that the size of pro-opiomelanocortin mRNA present in the SCCA tissue was indistinguishable from that in the adenomas associated with Cushing's disease. A ribonuclease mapping study indicated that there were no point mutations in the coding sequence of pro-opiomelanocortin mRNA present in the SCCA tissue. Because of the presence of pro-opiomelanocortin mRNA and immunoreactive ACTH in the adenoma tissue, it is proposed that translation of the mRNA and subsequent accumulation of ACTH precursor occurred in the SCCA. Thus, the absence of Cushing's disease symptoms in this SCCA could not be caused by abnormality in the coding sequence of the pro-opiomelanocortin gene or in ribonucleic acid processing. The occurrence of abnormality at or after the translational steps was strongly suggested.