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Abstract Cushing syndrome (CS) is a rare endocrinological disorder resulting from chronic exposure to excessive cortisol. The term Cushing disease is used specifically when this is caused by excessive secretion of adrenocorticotropic hormone (ACTH) by a pituitary tumor, usually an adenoma. This disease is associated with a poor prognosis, and if left untreated, it has an estimated 5-year survival rate of 50%. We present the case of a 66-year-old female patient who received a referral to endocrinology for an evaluation of obesity due to right knee arthropathy. Taking into consideration her age, she was screened for osteoporosis, with results that showed diminished bone density. Considering this, combined with other clinical features of the patient, suspicion turned toward hypercortisolism. Laboratory findings suggested that the CS was ACTH-dependent and originated in the pituitary gland. After a second look at the magnetic resonance imaging results, a 4-mm lesion was identified on the pituitary gland, prompting a transsphenoidal resection of the pituitary adenoma. case report, pituitary ACTH hypersecretion, Cushing syndrome, obesity Issue Section: Case Report Introduction Chronic excessive exposure to glucocorticoids leads to the diverse clinical manifestations of Cushing syndrome (CS), which has an annual incidence ranging from 1.8 to 3.2 cases per million individuals [1]. The syndrome's signs and symptoms are not pathognomonic, and some of its primary manifestations, such as obesity, hypertension, and glucose metabolism alterations, are prevalent in the general population [2], making diagnosis challenging. Endogenous CS falls into 2 categories: adrenocorticotropic hormone (ACTH)-dependent (80%-85% of cases), mostly due to a pituitary adenoma, or ACTH-independent (15%-20% of cases), typically caused by adrenal adenomas or hyperplasia [3]. Cushing disease (CD) represents a specific form of CS, characterized by the presence of an ACTH-secreting pituitary tumor [1]. Untreated CD is associated with high morbidity and mortality compared to the general population [1], with a 50% survival rate at 5 years [2]. However, surgical removal of a pituitary adenoma can result in complete remission, with mortality rates similar to those of the general population [2]. This article aims to highlight the challenges of suspecting and diagnosing CD and to discuss the current management options for this rare condition. Case Presentation A 66-year-old woman received a referral to endocrinology for an evaluation of obesity due to right knee arthropathy. During physical examination, she exhibited a body mass index of 34.3 kg/m2, blood pressure of 180/100, a history of non-insulin-requiring type 2 diabetes mellitus with glycated hemoglobin (HbA1c) of 6.9% (nondiabetic: < 5.7%; prediabetic: 5.7% to 6.4%; diabetic: ≥ 6.5%) and hypertension. Additionally, the patient complained of proximal weakness in all 4 limbs. Diagnostic Assessment Upon admission, densitometry revealed osteoporosis with T scores of −2.7 in the lumbar spine and −2.8 in the femoral neck. Hypercortisolism was suspected due to concomitant arterial hypertension, central obesity, muscle weakness, and osteoporosis. Physical examination did not reveal characteristic signs of hypercortisolism, such as skin bruises, flushing, or reddish-purple striae. Late-night salivary cortisol (LNSC) screening yielded a value of 8.98 nmol/L (0.3255 mcg/dL) (reference value [RV] 0.8-2.7 nmol/L [0.029-0.101 mcg/dL]) and ACTH of 38.1 pg/mL (8.4 pmol/L) (RV 2-11 pmol/L [9-52 pg/mL]). A low-dose dexamethasone suppression test (LDDST) was performed (cutoff value 1.8 mcg/dL [49 nmol/L]), with cortisol levels of 7.98 mcg/dL (220 nmol/L) at 24 hours and 20.31 mcg/dL (560 nmol/L) at 48 hours. Subsequently, a high-dose dexamethasone suppression test (HDDST) was conducted using a dose of 2 mg every 6 hours for 2 days, for a total dose of 16 mg, revealing cortisol levels of 0.0220 nmol/L (0.08 ng/mL) at 24 hours and 0.0560 nmol/L (0.0203 ng/mL) at 48 hours, alongside 24-hour urine cortisol of 0.8745 nmol/L (0.317 ng/mL) (RV 30-145 nmol/24 hours [approximately 11-53 μg/24 hours]) [4]. These findings indicated the presence of endogenous ACTH-dependent hypercortisolism of pituitary origin. Consequently, magnetic resonance imaging (MRI) was requested, but the results showed no abnormalities. Considering ectopic ACTH production often occurs in the lung, a high-resolution chest computed tomography scan was performed, revealing no lesions. Treatment Upon reassessment, the MRI revealed a 4-mm adenoma, prompting the decision to proceed with transsphenoidal resection of the pituitary adenoma. Outcome and Follow-Up The histological analysis revealed positive staining for CAM5.2, chromogranin, synaptophysin, and ACTH, with Ki67 staining at 1%. At the 1-month follow-up assessment, ACTH levels were 3.8 pmol/L (17.2 pg/mL) and morning cortisol was 115.8621 nmol/L (4.2 mcg/dL) (RV 5-25 mcg/dL or 140-690 nmol/L). Somatomedin C was measured at 85 ng/mL (RV 70-267 ng/mL) and prolactin at 3.5 ng/mL (RV 4-25 ng/mL). At the 1-year follow-up, the patient exhibited a satisfactory postoperative recovery. However, she developed diabetes insipidus and secondary hypothyroidism. Arterial hypertension persisted. Recent laboratory results indicated a glycated hemoglobin (HbA1c) level of 5.4%. Medications at the time of follow-up included prednisolone 5 milligrams a day, desmopressin 60 to 120 micrograms every 12 hours, losartan potassium 50 milligrams every 12 hours, and levothyroxine 88 micrograms a day. Discussion CD is associated with high mortality, primarily attributable to cardiovascular outcomes and comorbidities such as metabolic and skeletal disorders, infections, and psychiatric disorders [1]. The low incidence of CD in the context of the high prevalence of chronic noncommunicable diseases makes early diagnosis a challenge [2]. This case is relevant for reviewing the diagnostic approach process and highlighting the impact of the availability bias, which tends to prioritize more common diagnoses over rare diseases. Despite the absence of typical symptoms, a timely diagnosis was achieved. Once exogenous CS is ruled out, laboratory testing must focus on detecting endogenous hypercortisolism to prevent misdiagnosis and inappropriate treatment [5]. Screening methods include 24-hour urinary free cortisol (UFC) for total cortisol load, while circadian rhythm and hypothalamic-pituitary-adrenal (HPA) axis function may be evaluated using midnight serum cortisol and LNSC [5]. An early hallmark of endogenous CS is the disruption of physiological circadian cortisol patterns, characterized by a constant cortisol level throughout the day or no significant decrease [2]. Measuring LNSC has proven to be useful in identifying these patients. The LNSC performed on the patient yielded a high result. To assess HPA axis suppressibility, tests such as the overnight and the standard 2-day LDDST [5] use dexamethasone, a potent synthetic corticosteroid with high glucocorticoid receptor affinity and prolonged action, with minimal interference with cortisol measurement [6]. In a normal HPA axis, cortisol exerts negative feedback, inhibiting the secretion of corticotropin-releasing-hormone (CRH) and ACTH. Exogenous corticosteroids suppress CRH and ACTH secretion, resulting in decreased synthesis and secretion of cortisol. In pathological hypercortisolism, the HPA axis becomes partially or entirely resistant to feedback inhibition by exogenous steroids [5, 6]. The LDDST involves the administration of 0.5 mg of dexamethasone orally every 6 hours for 2 days, with a total dose of 4 mg. A blood sample is drawn 6 hours after the last administered dose [6]. Following the LDDST, the patient did not demonstrate suppression of endogenous corticosteroid production. After diagnosing CS, the next step in the diagnostic pathway involves categorizing it as ACTH-independent vs ACTH-dependent. ACTH-independent cases exhibit low or undetectable ACTH levels, pointing to adrenal origin. The underlying principle is that excess ACTH production in CD can be partially or completely suppressed by high doses of dexamethasone, a response not observed in ectopic tumors [6]. In this case, the patient presented with an ACTH of 38.1 pg/mL (8.4 pmol/L), indicative of ACTH-dependent CD. Traditionally, measuring cortisol levels and conducting pituitary imaging are standard practices for diagnosis. Recent advances propose alternative diagnostic methods such as positron emission tomography (PET) scans and corticotropin-releasing factor (CRF) tests [7]. PET scans, utilizing radioactive tracers, offer a view of metabolic activity in the adrenal glands and pituitary region, aiding in the identification of abnormalities associated with CD. Unfortunately, the availability of the aforementioned tests in the country is limited. Once ACTH-dependent hypercortisolism is confirmed, identifying the source becomes crucial. A HDDST is instrumental in distinguishing between a pituitary and an ectopic source of ACTH overproduction [2, 6]. The HDDST involves administering 8 mg of dexamethasone either overnight or as a 2-day test. In this case, the patient received 2 mg of dexamethasone orally every 6 hours for 2 days, totaling a dose of 16 mg. Simultaneously, a urine sample for UFC is collected during dexamethasone administration. The HDDST suppressed endogenous cortisol production in the patient, suggesting a pituitary origin. In ACTH-dependent hypercortisolism, CD is the predominant cause, followed by ectopic ACTH syndrome and, less frequently, an ectopic CRH-secreting tumor [3, 5]. With the pretest probability for pituitary origin exceeding 80%, the next diagnostic step is typically an MRI of the pituitary region. However, the visualization of microadenomas on MRI ranges from 50% to 70%, requiring further testing if results are negative or inconclusive [5]. Initial testing of our patient revealed no pituitary lesions. Following a pituitary location, ACTH-secreting tumors may be found in the lungs. Thus, a high-resolution chest computed tomography scan was performed, which yielded negative findings. Healthcare professionals must keep these detection rates in mind. In instances of high clinical suspicion, repeating or reassessing tests and imaging may be warranted [3], as in our case, ultimately leading to the discovery of a 4-mm pituitary adenoma. It is fundamental to mention that the Endocrine Society Clinical Practice Guideline on Treatment of CS recommends that, when possible, all patients presenting with ACTH-dependent CS and lacking an evident causal neoplasm should be directed to an experienced center capable of conducting inferior petrosal sinus sampling to differentiate between pituitary and nonpituitary or ectopic cause [8]. However, in this instance, such a referral was regrettably hindered by logistical constraints. Regarding patient outcomes and monitoring in CD, there is no consensus on defining remission criteria following tumor resection. Prolonged hypercortisolism results in suppression of corticotropes, resulting in low levels of ACTH and cortisol after surgical intervention. Typically, remission is identified by morning serum cortisol values below 5 µg/dL (138 nmol/L) or UFC levels between 28 and 56 nmol/d (10-20 µg/d) within 7 days after surgical intervention. In our case, the patient's morning serum cortisol was 115.8621 nmol/L (4.2 µg/dL), indicating remission. Remission rates in adults are reported at 73% to 76% in selectively resected microadenomas and at 43% in macroadenomas [8], highlighting the need for regular follow-up visits to detect recurrence. Following the surgery, the patient experienced diabetes insipidus, a relatively common postoperative occurrence, albeit usually transient [8]. It is recommended to monitor serum sodium levels during the first 5 to 14 days postsurgery for early detection and management. Additionally, pituitary deficiencies may manifest following surgery. In this patient, prolactin levels were compromised, potentially impacting sexual response. However, postoperative somatomedin levels were normal, and gonadotropins were not measured due to the patient's age group, as no additional clinical decisions were anticipated based on those results. Secondary hypothyroidism was diagnosed postoperatively. Moving forward, it is important to emphasize certain clinical signs and symptoms for diagnosing CD. The combination of low bone mineral density (Likelihood Ratio [LR] +21.33), central obesity (LR +3.10), and arterial hypertension (LR + 2.29) [9] has a higher positive LR than some symptoms considered “characteristic,” such as reddish-purple striae, plethora, proximal muscle weakness, and unexplained bruising [2, 10]. It is essential to give relevance to the signs the patient may present, emphasizing signs that have been proven to have an increased odds ratio (OR) such as osteoporosis (OR 3.8), myopathies (OR 6.0), metabolic syndrome (OR 2.7) and adrenal adenoma (OR 2.4) [9‐11]. The simultaneous development and worsening of these conditions should raise suspicion for underlying issues. Understanding the evolving nature of CD signs highlights the importance of vigilance during medical examinations, prioritizing the diagnostic focus, and enabling prompt initiation of treatment. Recognizing the overlap of certain clinical features in CS is fundamental to achieving a timely diagnosis. Learning Points CS diagnosis is challenging due to the absence of pathognomonic signs and symptoms and the overlap of features present in many pathologies, such as metabolic syndrome. Early detection of CS is crucial, given its association with high morbidity and mortality resulting from chronic exposure to glucocorticoids. Recognizing the combination of low bone mineral density, obesity, hypertension, and diabetes as valuable clinical indicators is key in identifying CS. Interdisciplinary collaboration is essential to achieve a comprehensive diagnostic approach. Acknowledgments We extend our gratitude to Pontificia Universidad Javeriana in Bogotá for providing essential resources and facilities that contributed to the successful completion of this case report. Special acknowledgment is reserved for the anonymous reviewers, whose insightful feedback significantly enhanced the quality of this manuscript during the peer-review process. Their contributions are sincerely appreciated. Contributors All authors made individual contributions to authorship. A.B.O. was involved in the diagnosis and management of this patient. M.A.G., J.M.H., and A.B.O. were involved in manuscript drafting and editing. All authors reviewed and approved the final draft. Funding This research received no public or commercial funding. Disclosures The authors declare that they have no conflicts of interest related to the current study. Informed Patient Consent for Publication Signed informed consent could not be obtained from the patient or a proxy but has been approved by the treating institution. Data Availability Statement Restrictions apply to the availability of some or all data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided. References 1 Hakami OA , Ahmed S , Karavitaki N . Epidemiology and mortality of Cushing's syndrome . Best Pract Res Clin Endocrinol Metab . 2021 ; 35 ( 1 😞 101521 . Google Scholar Crossref PubMed WorldCat 2 Nieman LK , Biller BMK , Findling JW , et al. The diagnosis of Cushing's syndrome: an endocrine society clinical practice guideline . J Clin Endocrinol Metab . 2008 ; 93 ( 5 😞 1526 ‐ 1540 . Google Scholar Crossref PubMed WorldCat 3 Gutiérrez Restrepo J , Latorre Sierra G , Campuzano Maya G . Síndrome de cushing . Med Lab . 2009 ; 15 : 411 ‐ 430 . Google Scholar WorldCat 4 Petersenn S , Newell-Price J , Findling JW , et al. High variability in baseline urinary free cortisol values in patients with Cushing's disease . Clin Endocrinol (Oxf) . 2014 ; 80 ( 2 😞 261 ‐ 269 . Google Scholar Crossref PubMed WorldCat 5 Lila AR , Sarathi V , Jagtap VS , Bandgar T , Menon P , Shah NS . Cushing's syndrome: stepwise approach to diagnosis . Indian J Endocrinol Metab . 2011 ; 15 ( Suppl4 😞 S317 ‐ S321 . Google Scholar PubMed WorldCat 6 Dogra P , Vijayashankar NP . Dexamethasone suppression test. In: StatPearls StatPearls Publishing; 2024 . Accessed January 29, 2024. http://www.ncbi.nlm.nih.gov/books/NBK542317/ 7 Müller OA , Dörr HG , Hagen B , Stalla GK , von Werder K . Corticotropin releasing factor (CRF)-stimulation test in normal controls and patients with disturbances of the hypothalamo-pituitary-adrenal axis . Klin Wochenschr . 1982 ; 60 ( 24 😞 1485 ‐ 1491 . Google Scholar Crossref PubMed WorldCat 8 Nieman LK , Biller BMK , Findling JW , et al. Treatment of Cushing's syndrome: an endocrine society clinical practice guideline . J Clin Endocrinol Metab . 2015 ; 100 ( 8 😞 2807 ‐ 2831 . Google Scholar Crossref PubMed WorldCat 9 Aron DC . Cushing's syndrome: why is diagnosis so difficult? Rev Endocr Metab Disord . 2010 ; 11 ( 2 😞 105 ‐ 116 . Google Scholar Crossref PubMed WorldCat 10 Braun LT , Vogel F , Zopp S , et al. Whom should we screen for cushing syndrome? the Endocrine Society practice guideline recommendations 2008 revisited . J Clin Endocrinol Metab . 2022 ; 107 ( 9 😞 e3723 ‐ e3730 . Google Scholar Crossref PubMed WorldCat 11 Schneider HJ , Dimopoulou C , Stalla GK , Reincke M , Schopohl J . Discriminatory value of signs and symptoms in Cushing's syndrome revisited: what has changed in 30 years? Clin Endocrinol (Oxf) . 2013 ; 78 ( 1 😞 153 ‐ 154 . Google Scholar Crossref PubMed WorldCat Abbreviations ACTH adrenocorticotropic hormone CD Cushing disease CRH corticotropin-releasing hormone CS Cushing syndrome HDDST high-dose dexamethasone suppression test HPA hypothalamic-pituitary-adrenal LDDST low-dose dexamethasone suppression test LNSC late-night salivary cortisol MRI magnetic resonance imaging OR odds ratio RV reference value UFC urinary free cortisol © The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. From https://academic.oup.com/jcemcr/article/2/4/luae048/7643486?login=false

And today, we talk about pink jeeps and ziplines... How in the world did we get here in a Cushing's Challenge? I'm sliding these in because earlier I linked (possibly!) my growth hormone use as a cause of my cancer - and I took the GH due to Cushing's issues. Clear? LOL http://cushieblog.files.wordpress.com/2012/04/pink-jeep.jpg?w=300&h=225 I had found out that I had my kidney cancer on Friday, April 28, 2006 and my surgery on May 9, 2006. I was supposed to go on a Cushie Cruise to Bermuda on May 14, 2006. My surgeon said that there was no way I could go on that cruise and I could not postpone my surgery until after that cruise. I got out of the hospital on the day that the other Cushies left for the cruise and realized that I wouldn't have been much (ANY!) fun and I wouldn't have had any. An especially amusing thread from that cruise is The Adventures of Penelopee Cruise (on the Cushing's Help message boards). Someone had brought a UFC jug and decorated her and had her pose around the ship. The beginning text reads: Penelopee had a lovely time on Explorer of the Seas which was a five day cruise to Bermuda. She needed something to cheer her up since her brother, Tom, went off the deep end, but that's another story! Penelopee wanted to take in all of the sights and sounds of this lovely vessel. Every day she needed to do at least one special thing. Being a Cushie, she didn't have enough spoons to do too much every day. On the first day, she went sunning on the Libido deck......she didn't last too long, only about 10 minutes. Goodness, look at her color! Do you think maybe her ACTH is too high? Although I missed this trip, I was feeling well enough to go to Sedona, Arizona in August 2006. I convinced everyone that I was well enough to go off-road in a pink jeep, DH wanted to report me to my surgeon but I survived without too much pain and posed for the header image. In 2009, I figured I had “extra years” since I survived cancer and I wanted to do something kinda scary, yet fun. So, somehow, I decided on ziplining. Tom wouldn’t go with me but Michael would so I set this up almost as soon as we booked a Caribbean cruise to replace the Cushie Cruise to Bermuda. Each person had a harness around their legs with attached pulleys and carabiners. Women had them on their chests as well. In addition, we had leather construction gloves and hard hats. We climbed to the top of the first platform and were given brief instructions and off we went. Because of the heavy gloves, I couldn’t get any pictures. I had thought that they would take some of us on the hardest line to sell to us later but they didn't. They also didn’t have cave pictures or T-Shirts. What a missed opportunity! This was so cool, so much fun. I thought I might be afraid at first but I wasn’t. I just followed instructions and went. Sometimes they told us to brake. We did that with the right hand, which was always on the upper cable. After the second line, I must have braked too soon because I stopped before I got to the platform. Michael was headed toward me. The guide on the end of the platform wanted me to do some hand over hand maneuver but I couldn’t figure out what he was saying so he came and got me by wrapping his legs around me and pulling me to the platform. After that, no more problems with braking! The next platform was very high – over 70 feet in the air – and the climb up was difficult. It was very hot and the rocks were very uneven. I don’t know that I would have gotten to the next platform if Michael hadn’t cheered me on all the way. We zipped down the next six lines up to 250-feet between platforms and 85-feet high in the trees, at canopy level. It seemed like it was all over too soon. But, I did it! No fear, just fun. Enough of adventures - fun ones like these, and scary ones like transsphenoidal surgery and radical nephrectomy!

ABSTRACT Objective Onset and exacerbation of autoimmune, inflammatory or steroid-responsive conditions have been reported following the remission of Cushing syndrome, leading to challenges in distinguishing a new condition versus expected symptomatology following remission. We describe a case of a 42-year-old man presenting with new-onset sarcoidosis diagnosed 12 months following the surgical cure of Cushing syndrome and synthesise existing literature reporting on de novo conditions presenting after Cushing syndrome remission. Methods A scoping review was conducted in Medline, Epub, Ovid and PubMed. Case reports and case series detailing adult patients presenting with new-onset conditions following Cushing syndrome remission were included. Results In total, 1641 articles were screened, 138 full-text studies were assessed for eligibility, and 43 studies were included, of which 84 cases (including our case) were identified. Most patients were female (85.7%), and the median reported age was 39.5 years old (IQR = 13). Thyroid diseases were the most commonly reported conditions (48.8%), followed by sarcoidosis (15.5%). Psoriasis, lymphocytic hypophysitis, idiopathic intracranial hypertension, multiple sclerosis, rheumatoid arthritis, lupus and seronegative arthritis were reported in more than one case. The median duration between Cushing remission and de novo condition diagnosis was 4.1 months (IQR = 3.75). Of those patients, 59.5% were receiving corticosteroid therapy at the time of onset. Conclusion Our scoping review identified several cases of de novo conditions emerging following the remission of Cushing syndrome. They occurred mostly in women and within the year following remission. Clinicians should remain aware that new symptoms, particularly in the first year following the treatment of Cushing syndrome, may be manifestations of a wide range of conditions aside from adrenal insufficiency or glucocorticoid withdrawal syndrome. 1 Introduction Cushing syndrome (CS) is caused by chronic exposure to excessive glucocorticoids, from either endogenous or exogenous sources [1]. Endogenous Cushing syndrome can be classified as either adrenocorticotropic hormone (ACTH) dependent or independent. ACTH-dependent causes comprise 80% of cases, most of which are pituitary corticotroph adenomas. Unilateral adrenal adenomas are the most common ACTH-independent cause, comprising 20% of total cases [2]. Treatment focuses on controlling tissue exposure to cortisol and treating the source of cortisol overproduction, which can be achieved through surgical resection, radiation or medical therapy depending on the underlying aetiology [2]. Following the biochemical remission of Cushing syndrome, patients commonly feel unwell due to adrenal insufficiency (AI) and/or glucocorticoid withdrawal syndrome (GWS). AI is an expected consequence of remission due to the chronic suppression of the hypothalamic-pituitary-adrenal (HPA) axis from glucocorticoid excess and can manifest with heterogeneous symptoms including myalgias, muscle weakness, fatigue, hypersomnolence, anorexia, nausea and abdominal discomfort [3-5]. GWS is due to the dependence on supraphysiologic glucocorticoid levels and has overlapping symptoms with AI, but occurs even with physiologic or supraphysiologic glucocorticoid replacement [5]. Both AI and GWS can persist for 1 year or longer following the remission of Cushing syndrome [5]. Due to immunosuppression induced by glucocorticoid excess [1, 6, 7], the remission of Cushing syndrome has the potential to unmask or aggravate an underlying autoimmune, inflammatory or steroid-responsive condition. Reports of such conditions include thyroiditis, psoriasis, sarcoidosis and systemic lupus erythematosus (SLE) [8-11]. Therefore, persisting symptoms following the remission of Cushing syndrome can be due to AI, GWS or presentation of a new condition. The latter situation may evade timely diagnosis since AI and GWS are expected consequences in this clinical setting. We report a case of a 42-year-old patient with Cushing syndrome secondary to an adrenal adenoma with first presentation of sarcoidosis 12 months after adrenalectomy. We performed a scoping review to synthesise previous reports of de novo autoimmune, inflammatory or steroid-responsive conditions following the remission of Cushing syndrome. Our aim was to characterise these presentations to provide guidance to clinicians in making this diagnosis challenging. 2 Case Report A 42-year-old white man was referred to endocrinology with a 1-year history of insomnia and rapid weight gain of 18 kg. Past medical history was significant for a pituitary lesion presumed to be a Rathke's cleft cyst, which had been stable on neuroimaging for over two decades. He was otherwise healthy with no prescribed medications. On physical examination, blood pressure was 159/99 mmHg. Pertinent findings included facial plethora, dorsal and supraclavicular fat pads, reduced skin thickness and multiple violaceous striae on the abdomen. Biochemistry showed elevated 24-h urine cortisol on two occasions (3067.5 nmol/day, 2704.0 nmol/day; reference range, 100.0–380.0 nmol/day) and elevated late-night salivary cortisol (54.2 nmol/L; reference range, ≤ 3.6 nmol/L). Plasma ACTH level was suppressed (< 1.1 pmol/L; reference range, 2.0–11.5 pmol/L). Serum-free thyroxine (fT4), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinising hormone (LH) and free testosterone were all within normal limits. Serum random glucose level was normal (4.6 mmol/L; reference range, 3.3–11.0 mmol/L), and haemoglobin A1c (HbA1c) was within the pre-diabetes range at 6.2% (6.0%–6.4%). His serum complete blood count, sodium, potassium and creatinine levels were all within normal limits. His body surface area was 2.53 m2. The patient was diagnosed with ACTH-independent Cushing syndrome. Computed tomography of the abdomen and pelvis revealed a 4.8-cm mass in the left adrenal gland. The patient was referred to endocrine surgery, and in the interim, medical treatment with ketoconazole 200 mg p.o. twice daily and spironolactone 50 mg p.o. daily was initiated, which resulted in normalisation of his 24-h urine cortisol. Shortly after initiating these medications, the patient noticed paraesthesia in his extremities. There was no objective evidence of neuropathy on physical examination, and laboratory investigations including vitamin B12 (329 pmol/L; reference range, 155–700 pmol/L), TSH (2.14 mIU/L) and follow-up HbA1c (5.7%) were within normal range. Three months following his initial presentation, the patient underwent left adrenalectomy. Postoperatively, supraphysiologic glucocorticoids were initiated and he was discharged home on oral hydrocortisone 40 mg in the morning and 20 mg in the afternoon. Pathology was consistent with an adrenal cortical adenoma with Ki-67 < 1%. The patient was highly motivated to wean his glucocorticoid doses to ameliorate symptoms of cortisol excess. He tapered his hydrocortisone to 20 mg in the morning and 10 mg in the late afternoon within 2 weeks postoperatively. He developed significant muscle stiffness to his shoulders, with diffuse myalgias and arthralgias, along with worsening of his pre-existing paraesthesia. Four months after the surgery, he had further reduced his hydrocortisone to 15 mg in the morning and 5 mg in the late afternoon with improvement in his Cushingoid features (reduced supraclavicular fullness, reduced abdominal adiposity, fading of abdominal striae and seven-kilogram weight loss). He was assessed by neurology for his paraesthesia, but no organic cause was identified. Twelve months after surgery, he had weaned off his hydrocortisone to 5 mg twice daily and continued to feel unwell with headaches, muscle weakness and morning stiffness. Morning cortisol after withholding glucocorticoids for 24 h was 35 nmol/L (170–500 nmol/L), demonstrating ongoing HPA axis suppression. The patient's family physician ordered a chest X-ray for a prominent sternoclavicular joint, and the patient was incidentally found to have bilateral hilar lymphadenopathy. The patient was referred to respirology and underwent bronchoscopic sampling of his mediastinal lymph nodes (see Figure 1), which demonstrated well-formed non-necrotising granulomas from lymph node Stations 7 and 11L. Cultures for fungi, AFB and flow cytometry were all negative, confirming Stage 2 pulmonary sarcoidosis. There was no indication for sarcoidosis-specific treatment with glucocorticoids, cytotoxic agents or biologics based on his normal pulmonary function testing and lack of active extra-pulmonary sarcoidosis. However, given the ongoing HPA axis suppression, hydrocortisone was empirically increased to 20 mg total daily dose, which led to improvement in the patient's symptoms. FIGURE 1 Open in figure viewerPowerPoint Enhanced CT scan of the chest demonstrating bilateral hilar and mediastinal lymphadenopathy (indicated by arrows). Due to the ongoing symptoms of headaches and known pituitary lesion potentially concerning for neurosarcoidosis, the patient was referred to neuroimmunology. MRI brain, and cervical, thoracic and lumbar spine showed a reduction in the size of the known cystic pituitary lesion, with no findings suggestive of intracranial or spinal sarcoidosis, and no abnormal leptomeningeal enhancement. Electromyography demonstrated normal nerve conduction studies. Two years following adrenalectomy, the patient has weaned off all glucocorticoid replacement with resolution of his symptoms of adrenal insufficiency. His sarcoidosis remains in remission. 3 Methods A scoping review protocol was developed using the Joanna Briggs Institute methodology [12]. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for Scoping Reviews guidelines in reporting our protocol and results [13]. 3.1 Systematic Literature Search A preliminary search strategy was developed with the aid of a medical librarian. The full search strategy and terms are presented in Appendix 1. Ovid MEDLINE and Epub Ahead of Print, In-Process, In-Data-Review & Other Non-Indexed Citations and Daily and PubMed databases were searched from inception to 8 September 2022. Additional articles were identified by searching the reference lists of all included articles. 3.2 Eligibility Criteria We considered descriptive observational studies including case series and case reviews, as well as systematic reviews. Articles from all years and locations were included; however, articles written in another language than in English or French were excluded given the limitations in conducting review and data extraction from these sources. Full inclusion and exclusion criteria are shown in Table 1. We included the reports of adults ≥ 18 years of age with endogenous Cushing syndrome with a de novo presentation of an autoimmune, inflammatory or steroid-responsive condition following remission, which could be induced by surgery, radiotherapy, medical therapy or a combination of these treatments. Cases of Cushing syndrome secondary to exogenous corticosteroids were excluded due to the high likelihood of pre-existing steroid-responsive conditions in this population. Flares or recurrences of previously diagnosed inflammatory, autoimmune or steroid-responsive conditions were also excluded. Patients with Cushing syndrome secondary to metastatic cancer (i.e. metastatic corticotroph adenoma or metastatic adrenocortical carcinoma) were excluded. Remission was defined as clinical and/or biochemical evidence of AI following treatment of CS by any modality. TABLE 1. Scoping review inclusion and exclusion criteria. Inclusion criteria Exclusion criteria Studies published in any year and location Studies published in English and French Studies published in another language than in English or French All adults ≥ 18 years old at the time of Cushing syndrome cure Children < 18 years old Endogenous Cushing syndrome Exogenous Cushing syndrome De novo conditions post-remission Pre-existing conditions with flare post-remission Cushing syndrome caused by metastatic cancer 3.3 Study Selection All identified studies were uploaded to Covidence, and duplicate articles were removed. Titles and abstracts were screened for eligibility by one reviewer, and articles without abstracts were screened in totality for eligibility. Selected articles underwent a full-text review by two reviewers for inclusion. Disagreements about eligibility of an article were resolved by a third reviewer. 3.4 Data Extraction Two members of the study team created a data extraction tool to collect patient characteristics from the studies that met eligibility criteria following a full-text review. The data extraction tool was piloted with all study team members, and adjustments were made as needed. Patients' age, gender, aetiology of Cushing syndrome, treatment modality and de novo condition were recorded. Characteristics of de novo conditions were collected including clinical presentation, timing of onset, presence of exogenous steroids at the time of presentation and resolution. Data from all included studies were extracted independently by two study team members and reconciled. Any discrepancies were resolved by referring to the primary article. 3.5 Statistical Analysis In this descriptive study, categorical variables are expressed as percentages and non-normally distributed continuous variables as median and interquartile range (IQR). Median and IQR were preferred over mean and standard deviation given the small sample size. 4 Results The search strategy identified 3123 total citations: 3099 abstracts from database searching and 24 from hand-searching (Figure 2). There were 1641 citations remaining after duplicates were removed. After title and abstract screening, 138 studies underwent full-text review, and 43 studies were included in data extraction and analysis (see Appendix 1 for a full list of included citations). FIGURE 2 Open in figure viewerPowerPoint PRISMA flow diagram of included studies. All included studies were either case reports (n = 34) or case series (n = 9). Five articles [8, 9, 14-16] also included a literature review and four [8, 10, 11, 17] included cohort studies in addition to the case report/series. Included articles were published from 1981 to 2021 inclusively. These 43 studies identified 83 unique patient cases of new-onset conditions following the remission of Cushing syndrome (see Table 2 for full patient characteristics). In addition to our case, this review includes 84 cases. Most patients were female (n = 72, 85.7%), and the median reported age was 39.5 years old (IQR = 13 years old, range, 16–80 years old). TABLE 2. Patients' characteristics. Total cases (n = 84) (% [n]) Age (median [IQR]), years 39.5 (13) Sex Women 85.7 (72) Men 14.3 (12) Aetiology of Cushing syndrome ACTH dependant 71.4 (60) Pituitary source 70.2 (59) Ectopic source 1.2% (1) ACTH independent 28.6 (24) Adrenal adenoma 23.8 (20) Adrenal hyperplasia 4.8 (4) Treatment of Cushing syndromea Surgical resection 97.6 (82) Medical therapy 19.0 (16) Radiation therapy 8.3 (7) Biochemical remission reported 79.8 (67) a Adds up to more than 100% as multiple reasons could be documented. The most common aetiology of CS was pituitary adenoma (n = 59), followed by adrenal adenoma (n = 20) and adrenal hyperplasia (n = 4). One patient had a pulmonary neuroendocrine tumour secreting ACTH [8]. All patients but two underwent surgical resection for definitive management of CS. One patient underwent medical management alone with pasireotide [18], and the other had resolution of CS secondary to an adrenal adenoma following adrenal haemorrhage after a motorcycle collision [14]. All patients included in our analysis had documented clinical remission of hypercortisolism, and biochemical remission was reported in 67 cases (79.8%). The most commonly reported de novo conditions following CS remission were thyroid disorders (n = 41, 48.8%), including 34 cases of thyroiditis [9-11, 17-23] and seven cases of Graves disease [8, 9, 21, 24-26]. Rheumatological disorders were the second most commonly reported conditions (n = 22, 26.2%) with cases of sarcoidosis (n = 13) [8, 14, 27-35], systemic lupus erythematosus (n = 2) [9, 36], rheumatoid arthritis (n = 2) [37, 38], seronegative arthritis (n = 2) [37, 39], polymyalgia rheumatica (n = 1) [40], giant cell arteritis (n = 1) [9] and retinal vasculitis (n = 1) [39] (see Figure 3 and Table 3). Further characterisation of thyroid disorders and sarcoidosis is detailed below. FIGURE 3 Open in figure viewerPowerPoint De novo conditions, by system. TABLE 3. Characteristics of de novo conditions. De novo conditions, by system (n = 84) (% [n]) Thyroid disorder 48.8 (41) Silent thyroiditis 23.8 (20) Hashimoto thyroiditis 13.1 (11) Graves disease 8.3 (7) De Quervain thyroiditis 3.6 (3) Rheumatologic disorder 26.2 (22) Sarcoidosis 15.5 (13) Systemic lupus erythematous 2.4 (2) Rheumatoid arthritis 2.4 (2) Seronegative arthritis 2.4 (2) Polymyalgia rheumatica 1.2 (1) Giant cell arteritis 1.2 (1) Retinal vasculitis 1.2 (1) Neurological disorder 13.1 (11) Idiopathic intracranial hypertension 6.0 (5) Multiple sclerosis 2.4 (2) Lymphocytic hypophysitis 2.4 (2) Myasthenia gravis 1.2 (1) Acute disseminated encephalitis 1.2 (1) Dermatological disorder 8.3 (7) Psoriasis 3.6 (3) Rash 3.6 (3) Generalised rash 1.2 (1) Rosacea-like rash 1.2 (1) Eczematous rash 1.2 (1) Angioedema 1.2 (1) Gastrointestinal disorder 3.6 (3) Celiac disease 1.2 (1) Primary biliary cirrhosis 1.2 (1) Sclerosing pancreatocholangitis 1.2 (1) We identified 11 cases of neurological disorders, including idiopathic intracranial hypertension (IIH) (n = 5) [15, 16, 41-43], multiple sclerosis (n = 2) [44, 45], lymphocytic hypophysitis (n = 2) [46, 47], acute disseminated encephalomyelitis (n = 1) [48] and myasthenia gravis (n = 1) [49]. IIH has been associated with both primary adrenal insufficiency and steroid withdrawal [15]. Glucocorticoids are not routinely used as first-line treatment of IIH (due to the risk of rebound intracranial hypertension upon withdrawal); however, three of the five cases included in this review were successfully treated with higher doses of steroids [15, 16, 41]. Given this association, IIH was considered a steroid-responsive condition for the purpose of this review. Acute disseminated encephalomyelitis is a rare autoimmune disease, causing widespread inflammation of the brain and spinal cord, often associated with preceding viral infection or vaccination. However, as first-line treatment for this condition is high dose corticosteroids, we considered it a steroid-responsive condition and was included in this review [50]. Seven dermatological cases were identified in our scoping review including psoriasis (n = 3) [8, 9], rash (n = 3) [8] and angioedema (n = 1) [51]. Gastrointestinal conditions were the least reported (n = 3) with one case of celiac disease [52], one case of primary biliary cirrhosis [8] and one case of sclerosing pancreatocholangitis [53]. The median reported time between the treatment of CS and the onset of symptoms of de novo condition was 4.1 months (IQR = 3.75 months, range, 10 days to 27 years). Most patients (n = 50, 59.5%) were receiving corticosteroids at the time of onset. Only 22 cases (26.2%) explicitly reported a timeline from discontinuation (n = 6) or tapering (n = 16) of corticosteroid dose to the onset of symptoms, with a median time of 1.75 months (IQR = 3 months, range 7 days-7 months). Thirty-nine patients (46.4%) were subsequently treated with corticosteroids (either re-initiated or at an increased dose). Remission or clinical stability of the de novo condition was reported in 66 cases (78.6%), while seven cases (8.3%) remained uncontrolled, and in 11 cases (13.1%), the outcome was not reported. Of the 44 cases where time to remission was reported, the median time was 3 months (IQR = 4.2 months, range 1–24 months). 4.1 Thyroid Disorder Cases Amongst the seven cases of Graves disease, six patients were women and the median age at onset was 44 years old (IQR = 10.5 years old, range, 33–58 years old). Four patients had a pituitary adenoma, two had an adrenal adenoma and one had unilateral adrenal hyperplasia. They all presented with classical signs and symptoms of this condition such as weight loss, tachycardia, goitre and/or orbitopathy. The median time to onset was 5 months (IQR = 3.55 months, range 2–27 months). The majority (5/7) were not on steroids at the onset of Graves disease, and six required additional treatment with antithyroid medications. Of the 34 cases of thyroiditis, 30 patients were women and the median age at onset was 35.5 years old (IQR = 15.5 years old, range 16–80 years old). Twenty-three patients had a pituitary adenoma, eight had an adrenal nodule and three had adrenal hyperplasia. Twenty patients presented with silent thyroiditis, 11 patients presented with Hashimoto thyroiditis and three patients presented with De Quervain (subacute) thyroiditis with fever, neck pain and malaise. Time to onset ranged from 1 to 9 months, with a median of 4.85 months (IQR = 3 months). Twenty-three patients were on steroids at the time of onset, and all patients with De Quervain thyroiditis (n = 3) and most patients with transient thyrotoxicosis (n = 13) were managed with increased corticosteroid doses. 4.2 Sarcoidosis Cases Amongst the 13 identified sarcoidosis cases, 10 patients were women and the median age at onset was 41 years old (IQR = 9, range 27–45 years old). Eight patients had Cushing disease while five had an adrenal adenoma, and all had undergone surgical resection, except for the patient with adrenal haemorrhage. The time between CS remission and onset ranged from 2 weeks to 17 months, with a median time of 3 months (IQR = 3). Twelve patients had skin manifestations with either painless subcutaneous nodules or erythema nodosum, while our case did not have any skin manifestations. Twelve patients had pulmonary involvement with bilateral mediastinal and/or hilar lymphadenopathy (n = 11) or abnormal pulmonary function test (n = 1). Eleven patients were on corticosteroids at the time of onset, of which four required increased doses, while the other seven patients did not require additional steroids. The remaining two patients who were not receiving corticosteroids were started on them for the management of sarcoidosis. 5 Discussion Our scoping review identified 20 conditions following the remission of CS, suggesting that the resolution of glucocorticoid excess and its associated immunosuppressive effect can unmask these diseases. The majority of cases were female, which is in keeping with the epidemiology of Cushing syndrome [2] as well as of autoimmune disease in the general population [54, 55]. Thyroiditis, sarcoidosis and Graves disease were the most commonly reported conditions. The prevalence of de novo thyroid disorders in our review may reflect that autoimmune and inflammatory thyroid diseases are common in the general population [55-57]. However, detection and publication bias may also play a role, as we presume endocrinologists are more likely to diagnose and report thyroid disorders versus non-endocrine conditions. Though most de novo conditions presented within 1 year of CS remission, the reported timing of onset was variable, ranging from 10 days to 27 years. This may reflect differences in post-remission glucocorticoid doses, weaning schedules and responsiveness of various conditions to glucocorticoids. We emphasise that we cannot prove a causative link between CS remission and the emergence of the de novo condition in our case or the other reported cases. Due to the heterogeneity in glucocorticoid requirements and tapering schedules post-CS remission [58, 59], as well as our aim characterising this clinical presentation, we chose not to specify the timing of the onset of de novo conditions in our inclusion criteria. However, we suggest that the emergence of a condition further out from the withdrawal of supraphysiologic glucocorticoids is less likely to be related to the previous state of hypercortisolism. We are dubious about one case in particular [46] that reported a patient with the onset of lymphocytic hypophysitis 27 years post subtotal adrenalectomy for CS, despite tapering off glucocorticoids within a month of surgery. The second case of lymphocytic hypophysitis occurred 7 years after the remission of Cushing disease, but there is no mention of whether the patient was still on exogenous glucocorticoids at the time of onset [47]. With the exclusion of these two cases, the onset of de novo conditions ranged from 10 days to 60 months, the latter case [8] being the emergence of psoriasis following the delayed normalisation of hypercortisolism with medical therapy and radiotherapy, which is more clinically plausible. Our case highlights the challenge of diagnosing a new systemic disorder when features of AI and/or GWS are concurrently present. To avoid diagnostic delay in this setting, we emphasise that clinicians should have a low threshold to investigate symptoms atypical for AI or GWS including (but not limited to) skin changes, neurological symptoms, pulmonary symptoms and symptoms of thyroid disease, particularly if symptoms present or worsen as supraphysiologic glucocorticoids are weaned. 5.1 Strengths and Limitations To our knowledge, this is the first scoping review to synthesise the existing literature on autoimmune, inflammatory and steroid-responsive conditions following Cushing syndrome remission. We adhered to PRISMA scoping review methodology and developed a comprehensive literature search strategy. However, we limited our review to publications in English and French, which resulted in the exclusion of 17 articles. The reported cases are subject to diagnostic and publication bias; therefore, our review may not encompass all de novo conditions that can present in this setting. As outlined above, we cannot establish a causative link between the remission of CS and the emergence of the reported de novo conditions. 6 Conclusion Our scoping review identified several cases of distinct autoimmune, inflammatory or steroid-responsive conditions emerging following the remission of Cushing syndrome, amongst which thyroid disorders and sarcoidosis were the most commonly reported. Delineating such conditions from the expected clinical course of GWS and/or AI can be a challenge; therefore, clinicians should have a low threshold to investigate any atypical symptoms following the remission of Cushing syndrome. Author Contributions Noémie Desgagnés: Conceptualization (equal); data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); project administration (equal); visualization (equal); writing – original draft (equal). Laura Senior: Data curation (equal); formal analysis (equal); investigation (equal); writing – original draft (equal). Daniel Vis: Writing – review and editing (equal). Katayoun Alikhani: Writing – review and editing (equal). Kirstie Lithgow: Conceptualization (equal); data curation (equal); investigation (equal); methodology (equal); project administration (equal); supervision (lead); writing – review and editing (lead). Acknowledgements The authors thank Dr. Kevin Baird for his feedback and contributions to the manuscript. Conflicts of Interest The authors have declared no conflicts of interest. Appendix 1: MEDLINE search strategy # Query Results 1 exp Cushing Syndrome/ 12,803 2 cushing* syndrome.tw,kf. 10,669 3 cushing* disease.tw,kf. 5341 4 1 or 2 or 3 18,042 5 (de novo adj2 steroid*).tw,kf. 160 6 exp Sarcoidosis/ 26,609 7 sarcoid*.tw,kf. 29,517 8 exp Polymyalgia Rheumatica/ 2725 9 PMR.tw,kf. 3328 10 polymyalgia rheumatica.tw,kf. 2890 11 exp Multiple Sclerosis/ 67,479 12 MS.tw,kf. 395,579 13 multiple sclerosis.tw,kf. 87,101 14 exp Autoimmune diseases/ 527,961 15 autoimmun*.tw,kf. 199,531 16 exp Systemic lupus erythematosus/ 65,187 17 SLE.tw,kf. 38,508 18 systemic lupus erythematosus.tw,kf. 56,501 19 exp Rheumatoid arthritis/ 122,521 20 RA.tw,kf. 86,402 21 rheumatoid arthritis.tw,kf. 117,236 22 arthritis*.tw,kf. 201,619 23 exp Sjogren syndrome/ 14,144 24 sjogren syndrome.tw,kf. 3325 25 exp celiac disease/ 21,506 26 celiac disease.tw,kf. 13,896 27 exp myasthenia gravis/ 16,576 28 myasthenia gravis.tw,kf. 16,140 29 exp Crohn disease/ 43,066 30 crohn disease.tw,kf. 5001 31 crohn*.tw,kf. 54,352 32 exp Ulcerative colitis/ 39,053 33 ulcerative colitis.tw,kf. 46,316 34 UC.tw,kf. 25,420 35 colitis*.tw,kf. 77,427 36 exp dermatitis/ 112,602 37 dermatitis.tw,kf. 68,667 38 exp vasculitis/ 102,088 39 vasculitis.kw,kf. 6283 40 exp myositis/ 21,858 41 exp thyroiditis/ 15,345 42 thyroid*.tw,kf. 216,663 43 exp IgG4/ 154,671 44 igg4.tw,kf. 10,905 45 exp encephalopathy/ 1,361,632 46 encephalopathy.tw,kf. 53,011 47 steroid responsive.tw,kf. 1576 48 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 3,122,540 49 4 and 48 5865 50 exp Case Reports/ 2,289,770 51 case report*.tw,kf. 466,902 52 exp Observational Study/ 132,022 53 observational stud*.tw,kf. 147,088 54 case series.tw,kf. 96,054 55 50 or 51 or 52 or 53 or 54 2,676,537 56 4 and 48 and 55 1479 From https://onlinelibrary.wiley.com/doi/10.1002/edm2.476

I first saw a similar image to this one with the saying Life. Be in it at a recreation center when my son was little. At the time, it was "Duh, of course, I'm in it". The original image was a couple of males, a couple of females, and a dog walking/running. No folks in wheelchairs, no older folks, and certainly no zebras. It would be nice to have everyone out there walking or running but that's not real life, at least in the Cushie world. It's been a long time since I've really been In My Life - maybe it's time to get back. A dear friend who had not one, but two forms of cancer was traveling throughout Europe for the first time after her husband's death wrote: Some final words before I turn in for the night. If there is a spark of desire within you to do something which is not contrary to God's Holy Law, find a way to make it happen. All things are possible and blessings abound for those who love Him. Life is such an adventure. Don't be a spectator - live every single moment for Him and with Him. Somedays, it's hard even getting up in the morning but I'm trying. Pre-COVID I took Water Aerobics for People with Arthritis and I actually went to class three times a week. After COVID, I took the stuff I learned there and did it 3 times a week as part of "water walking" by myself or with my DH. I got a "part-time" job several years ago and I'm teaching piano online. We had plans for a cruise to Norway which COVID made us reschedule for Alaska, which wass to be rescheduled...again. I've recently started playing the balalaika with an orchestra even though I never even touched one before. This is the one and only life I'll ever have and I want to make the most of it!

So often during the diagnosis phase of Cushing's I felt lost like this picture - I was walking alone to an unknown place with an unknown future. My diagnosis was pre-Internet which meant that any information had to be gotten from libraries, bookstores, magazines...or doctors. In 1983 to 1986 I knew something was terribly wrong but there was no backup from doctors, family or friends. My first hope was from a magazine (see Day Six) After I got that first glimmer of hope, it was off to the library to try to understand medical texts. I would pick out words I did understand - and it was more words each trip. I made Xerox copies of my findings to read at home and try to digest. (I still have all those old pages!) All my research led me to Cushing's. Unfortunately, the research didn't lead me to doctors who could help for several years. That contributed greatly to the loneliness. If a doctor says you're not sick, friends and family are going to believe the doctor, not you. After all, he's the one trained to know what's wrong or find out. I was so grateful when I finally got into a clinical trial at NIH and was so nice not to be alone with this mystery illness. I was also surprised to learn, awful as I felt, there were Cushies much worse off than I was. I am so glad that the Internet is here now helping us all know that we're not alone anymore. We're all in this together with help, support, research, just being there. I love this quote from Catherine at http://wheniwasyou.wordpress.com/2012/03/31/wheniwasyou/ Mary, I am delighted to see you here. Cushings - because of the persistent central obesity caused by (we know now) the lack of growth hormone plus the hypothyroidism I was diagnosed with (but for which treatment was ineffective due to my lack of cortisol) - was one of the things I considered as an explanation for my symptoms. Your site was enormously educational and helpful to me in figuring out what might be happening to me. Those other patient testimonies I referred to? Many of them were the bios you posted. Thank you so much for commenting. I am so grateful for the support and encouragement. I really hope that my experiences will help other undiagnosed hypopituitary patients find their way to a diagnosis. I often used to dream that one day I'd get to say to others what was so often said to me: don't give up, there will be an answer. I kept believing in myself because people I hadn't even met believed in me. Now I am finally here and I do hope my story will help others to have faith in their own instincts. Thanks again. Please do keep in touch. Catherine http://cushieblog.files.wordpress.com/2012/04/maryo-colorful-zebra.gif

Over the years, we went on several Windjammer Barefoot Cruises. We liked them because they were small, casual and were fairly easy on the wallet. They sailed around the Caribbean to a variety of islands, although they sometimes changed itineraries depending on weather, crew, whatever. One trip we were supposed to go to Saba but couldn't make port. A lot of people got off at the next port and flew home. The captains were prone to "Bedtime Stories" which were often more fiction than true but they added to the appeal of the trip. We didn't care if we missed islands or not - we were just there to sail over the waves and enjoy the ride. The last trip we took with them was about two years before I started having Cushing's problems. (You wondered how I was going to tie this together, right?) The cruise was uneventful, other than the usual mishaps like hitting docks, missing islands and so on. Until it was a particularly rough sea one day. I was walking somewhere on deck and suddenly a wave came up over the deck making it very slippery. I fell and cracked the back of my head on the curved edge of a table in the dining area. I had the next-to-the-worse headache I have ever had, the worst being after my pituitary surgery. At least after the surgery, I got some morphine. We asked several doctors later if that hit could have contributed to my Cushing's but doctors didn't want to get involved in that at all. The Windjammer folks didn't fare much better, either. In October 1998, Hurricane Mitch was responsible for the loss of the s/v Fantome (the last one we were on). All 31 crew members aboard perished; passengers and other crew members had earlier been offloaded in Belize. The story was recorded in the book The Ship and the Storm: Hurricane Mitch and the Loss of the Fantome by Jim Carrier. The ship, which was sailing in the center of the hurricane, experienced up to 50-foot (15 m) waves and over 100 mph (160 km/h) winds, causing the Fantome to founder off the coast of Honduras. "In October 1998, the majestic schooner Fantome came face-to-face with one of the most savage storms in Atlantic history. The last days of the Fantome are reconstructed in vivid and heartbreaking detail through Jim Carrier's extensive research and hundreds of personal interviews. What emerges is a story of courage, hubris, the agony of command, the weight of lives versus wealth, and the advances of science versus the terrible power and unpredictability of nature." This event was similar to the Perfect Storm in that the weather people were more interested in watching the hurricane change directions than they were in people who were dealing with its effects. I read this book and I was really moved by the plight of those crew members. I'll never know if that hit on my head contributed to my Cushing's but I have seen several people mention on the message boards that they had a traumatic head injury of some type in their earlier lives.

In 2021, I had the bestest ever day... and, surpassing that:

A couple years later and "My Dream Day" is substantially the same but now it would include playing with my grandchildren and, instead of practicing the aerophone, practicing the balalaika. Today is already not "My Dream Day" since I'm posting this at 4:26 in the morning! Maybe next year...

Another picture that weirdly turned into a link. Here's the pink jeep: http://cushieblog.files.wordpress.com/2012/04/pink-jeep.jpg?w=300&h=225

Abstract Background: Cushing’s disease (CD) is associated with a specific form of metabolic syndrome that includes visceral obesity, which may affect cardiovascular hemodynamics by stimulating hypercortisolism-related metabolic activity. The purpose of this study was to evaluate the relationship between obesity and the hemodynamic profile of patients with CD. Methods: This prospective clinical study involved a hemodynamic status assessment of 54 patients newly diagnosed with CD with no significant comorbidities (mean age of 41 years). The assessments included impedance cardiography (ICG) to assess such parameters as stroke index (SI), cardiac index (CI), velocity index (VI), acceleration index (ACI), Heather index (HI), systemic vascular resistance index (SVRI), and total arterial compliance index (TACI) as well as applanation tonometry to assess such parameters as central pulse pressure (CPP) and augmentation index (AI). These assessments were complemented by echocardiography to assess cardiac structure and function. Results: Compared with CD patients without obesity, individuals with CD and obesity (defined as a body mass index ≥ 30 kg/m2) exhibited significantly lower values of ICG parameters characterizing the pumping function of the heart (VI: 37.0 ± 9.5 vs. 47.2 ± 14.3 × 1*1000−1*s−1, p = 0.006; ACI: 58.7 ± 23.5 vs. 76.0 ± 23.5 × 1/100/s2, p = 0.005; HI: 11.1 ± 3.5 vs. 14.6 ± 5.5 × Ohm/s2, p = 0.01), whereas echocardiography in obese patients showed larger heart chamber sizes and a higher left ventricular mass index. No significant intergroup differences in blood pressure, heart rate, LVEF, GLS, TACI, CPP, or AI were noted. Conclusions: Hemodynamic changes associated with obesity already occur at an early stage of CD and manifest via significantly lower values of the ICG parameters illustrating the heart’s function as a pump, despite the normal function of the left ventricle in echocardiography. Keywords: Cushing’s disease; global longitudinal strain; impedance cardiography; metabolic syndrome; obesity; hemodynamic profile; cardiovascular complications Graphical Abstract 1. Introduction Cushing’s disease (CD), caused by a pituitary neuroendocrine tumor, leads to a specific type of metabolic syndrome that includes hypertension, obesity, impaired glucose metabolism, and dyslipidemia [1,2,3]. Chronic hypercortisolemia in patients with CD results in the excessive accumulation of visceral fat due to abnormal adipokine production [4]. Visceral obesity plays an important role in hypercortisolism-induced metabolic abnormalities and increased activity of the renin–angiotensin–aldosterone system activity in patients with CD [1,2,3,4,5]. Visceral obesity in patients with CD not only contributes to metabolic syndrome, but it is also an independent risk factor for cardiovascular disease [1,3,6,7]. Importantly, the structure and function of adipose tissue in patients with CD differ from those of healthy individuals [1,8,9]. The various hypercortisolism-induced metabolic abnormalities occurring in obese patients with CD may affect cardiovascular hemodynamics. There are no data on the effect of obesity on the hemodynamic profile of patients with CD and also few data are known on the association between obesity and hemodynamic disturbances in people without CD [10,11]. It was shown that the hemodynamic profile of a person with obesity is characterized by increased cardiac output and thoracic fluid content and decreased vascular resistance in comparison with these parameters in healthy individuals [12]. More studies are needed to enhance our understanding of the pathophysiology of CD-related obesity as a modifiable cardiovascular risk factor, in order to develop effective preventive and therapeutic strategies. Unfortunately, subclinical consequences of hypercortisolism in newly diagnosed patients with early CD, particularly with comorbid obesity, may be undetectable with standard methods. Therefore, novel and easy-to-use diagnostic methods would be of additive value to the standard methods of assessing cardiovascular structure and function in patients with CD. A detailed evaluation of the nature of obesity in patients with CD by innovative noninvasive diagnostic methods, such as impedance cardiography (ICG), applanation tonometry (AT), and echocardiographic assessment of global longitudinal strain (GLS), may provide additional data on cardiovascular hemodynamics, particularly the heart’s pumping function, preload, and afterload [13,14,15,16,17,18]. Our previous studies demonstrated the usefulness of ICG in identifying subclinical cardiovascular complications in patients with CD [19,20]. The purpose of this analysis was to assess the relationship between obesity and the hemodynamic profile of patients newly diagnosed with CD with no significant comorbidities. 2. Materials and Methods 2.1. Study Population This was a prospective observational cohort study involving a comprehensive assessment of 54 patients (mean age of 41 years) newly diagnosed with CD with no significant comorbidities (although 64.8% were diagnosed with hypertension). These patients were admitted to the Military Institute of Medicine—National Research Institute between 2016 and 2021 in order to undergo a thorough cardiovascular assessment prior to transsphenoidal pituitary neuroendocrine tumor resection surgery. This study was approved by the ethics committee at the Military Institute of Medicine—National Research Institute (approval No. 76/WIM/2016) and compliant with the Declaration of Helsinki and Good Clinical Practice guidelines. Each patient received detailed information on the purpose of this study and signed an informed consent form. This study was financed by the Polish Ministry of Research and Higher Education/Military Institute of Medicine—National Research Institute in Warsaw (grant No. 453/WIM). 2.2. Inclusion Criteria The diagnosis of CD was established based on the presence of the typical (clinical and hormonal) evidence of hypercortisolism with no adrenocorticotropic hormone (ACTH) response to corticotropin-releasing hormone (CRH) stimulation, which meets the current guidelines for the diagnosis and treatment of CD [21,22,23]. Physical examination findings consistent with the signs and symptoms of CD, including central obesity with the characteristic altered body fat distribution (a moon face and a short, thick neck); muscle atrophy in the torso and limbs; purplish stretch marks on the abdomen, hips, and thighs; thinned skin; ecchymoses; signs and symptoms of hyperandrogenism; bone pain; frequent infections; erectile dysfunction in men; and secondary amenorrhea and infertility in women. Hormone test results included elevated 24 h urinary free cortisol levels, increased morning serum cortisol levels, altered circadian rhythmicity of ACTH and cortisol secretion, elevated or detectable morning serum ACTH, and a lack of overnight serum cortisol suppression to <1.8 mg/dL during a low-dose dexamethasone suppression test (1 mg or 2 mg of dexamethasone administered at midnight). In order to ensure a pituitary etiology of CD, all patients underwent a two-day high-dose (2 mg every 6 h = a total of 8 mg) dexamethasone suppression test (HDDST), which was expected to show low serum cortisol or a >50% decrease in urinary-free cortisol levels. Moreover, each patient was shown to have no ACTH secretion response to a CRH stimulation test (with 100 μg intravenous CRH), and the presence of a pituitary neuroendocrine tumor was confirmed via contrast magnetic resonance imaging of the pituitary. Patients with inconclusive hormone tests or imaging studies additionally underwent bilateral inferior petrosal sinus sampling (used to determine ACTH levels in the venous blood before and after CRH stimulation) [21,22,23]. 2.3. Exclusion Criteria The following comorbidities, which might considerably affect hemodynamic profiles, constituted our study exclusion criteria: (1) heart failure with mildly reduced or reduced left ventricular ejection fraction (LVEF) (i.e., LVEF of <50%); (2) cardiomyopathy; (3) clinically significant valvular heart disease or arrhythmia; (4) coronary artery disease, including a history of acute coronary syndrome; (5) a poor acoustic window on echocardiography; (6) a history of pulmonary embolism; (7) a history of a stroke or transient ischemic attack; (8) renal failure (estimated glomerular filtration rate < 60 mL/min/1.73 m2); (9) peripheral vascular disease and polyneuropathy; (10) chronic obstructive pulmonary disease; (11) respiratory failure (decreased partial pressure of arterial oxygen [PaO2] < 60 mmHg and/or increased partial pressure of carbon dioxide [PaCO2] > 45 mmHg); (12) a history of head trauma; (13) pregnancy; (14) age < 18 years; (15) no written informed consent. 2.4. Additional Hormone Tests Due to the fact that hypercortisolemia inhibits gonadotropin release, hormone testing was expanded to include follicle-stimulating hormone and luteinizing hormone levels. The patients also had their serum thyroid-stimulating hormone levels tested to determine possible hypothyroidism, associated with reduced CRH and thyroid-stimulating hormone secretion and hypercortisolism-induced alterations in thyroid function. The patients with CD included in this study were not receiving any medications affecting the hypothalamus–pituitary–adrenal axis. None of the female patients with CD were pregnant at the time of the study or had given birth within the previous five years. 2.5. Laboratory Tests In order to detect possible metabolic conditions, such as impaired fasting glucose, type 2 diabetes mellitus, or dyslipidemia, all patients underwent fasting blood tests from venous blood samples collected in the morning (at 6:00 a.m.). The tests evaluated the levels of fasting glucose, creatinine, eGFR, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides, as well as a complete blood count. 2.6. Anamnesis and Physical Examination The patients were thoroughly evaluated for cardiovascular risk factors, cardiovascular signs and symptoms, a family history of cardiovascular disease, comorbidities, prescription medications and other drugs, and smoking. The body mass index (BMI) was calculated, and obesity was determined based on the International Diabetes Federation and European Society of Cardiology guidelines, which define it as a BMI of ≥30 kg/m2 [24,25]. In the study, patients were divided into two groups: patients with CD and obesity (defined as high body mass index ≥ 30 kg/m2) and patients with CD without obesity (defined as normal BMI < 30 kg/m2). Physical examination included the resting heart rate (HR), systolic and diastolic blood pressure, and anthropometric parameters. Office blood pressure measurements were taken by a trained nurse in seated patients in the morning, after a 5 min rest. The blood pressure monitor used was Omron M4 Plus (Omron Healthcare Co. Ltd., Kyoto, Japan), which meets the European Society of Cardiology criteria [26]. 2.7. Echocardiography Two-dimensional echocardiography included standard parasternal, apical, and subcostal views with a 2.5 MHz transducer (VIVID E95, GE Medical System, Wauwatosa, WI, USA) in accordance with the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) guidelines [27]. The parasternal long-axis view was used to measure the left ventricular end-diastolic diameter (LVEDd), right ventricular end-diastolic diameter (RVEDd), interventricular septal thickness, and left atrial (LA) diameter. Linear 2-dimensional left ventricular measurements were used to calculate the left ventricular mass index (LVMI), which is the left ventricular mass divided by the body surface area (LVMI cut-off values of >115 g/m2 for men and >95 g/m2 for women meet ASE and EACVI criteria for the diagnosis of left ventricular hypertrophy). The LVEF was calculated with the biplane Simpson method, based on 2-dimensional views of the left ventricle during systole and diastole in four- and two-chamber apical views. The ascending aortic diameter, valvular structure and function, and pericardium were assessed. The patients were assessed for left ventricular diastolic dysfunction according to current guidelines. Pulse wave Doppler in an apical four-chamber view aligned with mitral valve tips was used to visualize mitral inflow, including the early passive blood inflow (E) and the later atrial (A) contribution to the mitral inflow, E/A ratio, and early mitral inflow deceleration time. Apical four-chamber views were used to determine the septal and lateral early diastolic mitral annular velocities (e′ avg), and the E/e′ avg ratio was calculated [27,28]. Global longitudinal strain (GLS) was assessed via electrocardiography-gated automated function imaging in two-, three-, and four-chamber views. The rates of >60 frames per second were used for optimal speckle-tracking strain assessment. Patients with a poor acoustic window were excluded from the study. Semiautomated endocardial border detection was initiated by manually selecting two points identifying the mitral annulus and one point at the apex. Segmental and whole-chamber strain was assessed. The results have been presented in the form of a “bull’s eye” graph. The data were analyzed for four-, three-, and two-chamber views, and average GLS was calculated [29]. 2.8. Impedance Cardiography Based on the phenomenon of impedance variability in individual body segments associated with regional arterial blood flow, ICG is a noninvasive tool for assessing cardiovascular hemodynamics. ICG assessments were conducted by a trained nurse with a Niccomo device (Medis, Ilmenau, Germany) in patients who had been resting for 10 min in a supine position. ICG data were recorded during a 10 min assessment and processed with dedicated software (Niccomo Software, Medis). We analyzed the mean values of the following hemodynamic parameters reflecting the pumping function of the heart: (1) stroke volume (SV [mL]) and stroke index (SI [mL/m2]), based on the following formula: SV = VEPT × (dZmax/Z0) × LVET, where VEPT is tissue volume calculated from body weight, height, and patient sex, Z0 is the initial thoracic impedance, dZmax is the maximum change in thoracic impedance, and LVET is the left ventricular ejection time; (2) cardiac output (CO [mL] = SV × HR), and cardiac index (CI [mL*m−2*min−1]); (3) velocity index (VI [1*1000−1*s−1]); (4) acceleration index (ACI [1/100/s2], which is the peak acceleration of blood flow in the aorta; and (5) Heather index (HI [Ohm/s2] = dZmax × TRC, where TRC the time interval between the R-peak in the electrocardiogram and the C-point on the impedance wave). We also conducted a detailed analysis of the following afterload parameters: (1) systemic vascular resistance (SVR [dyn*s*cm−5]) together with SVR index (SVRI [dyn*s*cm−5*m2]) and (2) total arterial compliance (TAC) and TAC index (TACI [mL/mmHg] = SV/pulse pressure [mL/mmHg*m2]). Preload was assessed based on thoracic fluid content (TFC [1/kOhm], based on the formula TFC = 1000/Z0, where Z0 is the initial thoracic impedance [30,31,32]. 2.9. Applanation Tonometry Applanation tonometry is a novel method of indirectly illustrating arterial pressure waveform in the aorta and arterial stiffness, which reflect left ventricular afterload. AT parameters were assessed noninvasively with a SphygmoCor system (AtCor Medical, Sydney, NSW, Australia). The measurements were taken in supine patients by a qualified nurse immediately after ICG. Radial artery pressure curves were recorded via AT with a micromanometer (Millar Instruments, Houston, TX, USA) strapped onto the left wrist. We selected high-quality recordings for our analysis. Radial pulse was calibrated against the latest brachial systolic and diastolic blood pressure measurement with an oscillometric module of the Niccomo device. SphygmoCor software (version 9.0; AtCor Medical Inc. Pty Ltd., Sydney, NSW, Australia) was used to process the arterial waveform and generate an appropriate aortic blood pressure curve from the radial pulse curve. The analyzed waveforms were composed of the pulse wave generated by the aorta and were augmented by an overlapping reflected wave. Our analyses yielded the following parameters: central systolic blood pressure; central diastolic blood pressure; central pulse pressure (CPP); augmentation pressure, which is the absolute increase in aortic systolic pressure (directly generated by left ventricular contraction) resulting from the reflection wave; and the augmentation index, calculated as AP × 100/CPP, which is a quotient of the augmentation pressure and the blood pressure in the aorta [33]. 2.10. Statistical Analysis For the statistical analysis of the results, we used MS Office Excel 2023 and Statistica 12.0 (StatSof Inc., Tulsa, OK, USA). Data distribution and normality were assessed visually on histograms and with the use of the Kolmogorov–Smirnov test. Continuous variables were expressed as mean ± standard deviation (SD) or median (interquartile range, IQR), and categorical variables were expressed as absolute and relative (percentage) values. In order to evaluate differences between the subgroups of CD patients with and without comorbid obesity, we used Student’s t-test for normally distributed data, and the Mann–Whitney U test for non-normally distributed data. A comparative analysis with the use of the Mann–Whitney U test was conducted on the data from patients stratified into two subgroups: patients with CD and obesity (BMI ≥ 30 kg/m2, n = 22) and patients with CD without obesity (BMI < 30 kg/m2, n = 32). The relationship between selected indices of cardiovascular function and obesity (represented as BMI) was analyzed separately for each one in a multivariable regression model, adjusting for age and hypertension as potential covariates related to hemodynamics. The threshold of statistical significance was adopted at p < 0.05. 3. Results 3.1. Baseline Characteristics Nearly half of the patients with CD were found to be obese (n = 22, 40.7%). Overall, 20 of the 54 patients with Cushing’s disease (37%) were diagnosed with type 2 diabetes mellitus, 5 (9.3%) had prediabetes, and 29 (46.3%) had normal glucose tolerance. Of the patients with Cushing’s disease and type 2 diabetes, 14 received metformin, 5 received metformin with insulin, and 1 received insulin. The mean age, HR, hemoglobin, creatinine, and sex distribution were similar in the subgroup with and without obesity (Table 1). Table 1. Clinical, echocardiographic, hemodynamic, and applanation tonometry variables in patients with Cushing’s disease (CD) and with or without obesity. 3.2. Echocardiographic Assessment Patients with CD and obesity (BMI ≥ 30 kg/m2) showed larger dimensions of heart chambers and ascending aorta (RVEDd, p < 0.001; LVEDd, p = 0.028; LA diameter, p < 0.001; aortic arch, p = 0.005) and higher rates of left ventricular mass index (LVMI, p = 0.028). We observed no significant differences between the subgroups in terms of the systolic (LVEF or GLS) or diastolic function of the left ventricle (Table 1). 3.3. ICG and AT Assessment The most noticeable differences in ICG were observed for parameters of the left ventricular function as a pump. In obese individuals, VI (p = 0.006), ACI (p = 0.005), and HI (p = 0.012) were lower, whereas the systolic time ratio (STR) was higher (p = 0.038) than those in non-obese individuals, with SI and CI comparable in both subgroups. We observed no significant differences in afterload (TACI, SVRI, CPP, or augmentation index) or preload (TFC) parameters (Table 1). 3.4. Correlation Analysis Analyzing the relationships between BMI and ICG hemodynamic parameters, we observed significant correlations, independent of sex and hypertension, between BMI and CI (R = 0.46; p < 0.001), SI (R = 0.29; p = 0.043), SVRI (−0.31; 0.028), and VI (R = −0.37; p = 0.0006)—see Table 2. Table 2. Correlations between hemodynamic parameters assessed with impedance cardiography and body mass index, adjusted for sex and hypertension in multivariable regression models. 4. Discussion The results of our study revealed a relationship between obesity and hemodynamic profile assessed via ICG in patients newly diagnosed with active CD. The use of novel diagnostic modalities demonstrated that excessive fat accumulation in young and middle-aged patients with CD, already at the early stages of the disease, is associated with some hemodynamic changes in the cardiovascular system, which—at that stage—may still be undetectable in routine assessments. These findings support the need for the early detection of subclinical heart dysfunction in patients with CD to enable early treatment and help prevent cardiovascular complications [1,34,35,36]. Occurring in 25%–100% of patients with CD, visceral obesity is one of the most common components of metabolic syndrome, often being the first sign of the disease. The duration of hypercortisolism correlates with obesity development [1,7,37,38], with chronic excessive cortisol levels being responsible for the abnormal distribution of adipose tissue [39]. The mechanisms behind this phenomenon may be due to the tissue overexpression of the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which affects the pattern of excessive fat distribution in the torso, face, and neck [1,6]. Visceral obesity found in patients with CD is not only a component of metabolic syndrome but is in itself associated with increased metabolic activity, which makes it an independent cardiovascular risk factor, leading to the development of cardiovascular disease [1,4,9]. The tendency to accumulate visceral fat in patients with CD is also associated with abnormal adipokine production [4,6,40,41]. Our study included patients newly diagnosed with active CD with no clinically significant cardiovascular disease. Males were underrepresented in both subgroups. The proportion of patients with hypertension was 64.8%, which is comparable with that reported by other authors [38,42,43,44] and similarly distributed between subgroups. However, the patients in our study presented well-controlled hypertension (mean blood pressure was 126/83 mmHg), usually with one or two medications. Considering both sex and hypertension as potential confounders, these variables were included in regression models evaluating correlations between hemodynamics and BMI. Similar to reports by other authors, our study showed higher SV and CO values in obese patients with CD; however, the respective indexed values (SI and CI) were comparable in obese and non-obese patients [12,45]. A more detailed ICG assessment demonstrated significant impairment of the pumping function of the heart as evidenced by lower HI, VI, and ACI values, and a higher STR value. The analysis of correlations revealed the independence of age and sex interrelation between some hemodynamic indices (CI, SI, SVRI, VI) and BMI. The paradox of the positive relation of obesity with volume indices of left ventricular function (CI and SI), which is negative with the marker of both its outflow and myocardial contractility (VI) encourages further studies investigating the (patho)physiological background of this phenomenon. These findings were detected despite the lack of echocardiographic evidence of left ventricular systolic or diastolic dysfunction. Moreover, our study showed larger heart chamber diameters and significantly higher LVMI in patients with CD and obesity, which is consistent with numerous earlier reports by other authors [46,47,48]. Nonetheless, it seems that in this case, increased heart chamber size and left ventricular hypertrophy should not be considered as only secondary to an increase in body weight. Hypercortisolism in patients with CD worsens the structural and functional condition of the heart muscle and may lead to myocardial fibrosis [48]. This results in myocardial remodeling associated with concentric left ventricular hypertrophy, which may impair left ventricular hemodynamic function, subsequently leading to myocardial dysfunction and symptomatic heart failure [49,50,51]. The effective treatment of patients with CD has been shown to normalize their serum cortisol levels and ultimately stop myocardial remodeling [47]. Therefore, the ICG-evidenced impaired pumping function of the heart may result from myocardial remodeling associated with complex metabolic and neuroendocrine changes in obese patients with CD [52]. These findings are consistent with previous reports on the adverse effect of obesity on left ventricular contractility [53,54,55,56]. The potential mechanisms underlying the results of our study remain to be elucidated. An interesting perspective is represented by the cross-talk between glucocorticoid (GR) and mineralocorticoid receptors (MR) and their impact on metabolic syndrome. Excessive activation of the MR in extra-renal tissues by aldosterone or glucocorticoids depending on the expression of 11beta-hydroxysteroid dehydrogenase type 2 has been shown to be associated with the development of vascular dysfunction and metabolic abnormalities, leading to obesity and metabolic syndrome. High concentrations of aldosterone may also activate the transcriptional function of the GR. These mechanisms result in an interaction between GR and MR in the regulation of adipogenesis [57]. The novelty of our approach is due to the use of noninvasive tools (ICG, AT) for hemodynamic assessment of the cardiovascular system in patients with CD to detect subclinical changes associated with obesity. On the one hand, our findings support earlier observations in other patient groups; on the other hand, they cast a new light on the relationship between obesity and an impaired hemodynamic profile in CD, which may result in the early development of cardiovascular complications. 4.1. Clinical Implications We determined that a dysfunctional pumping action of the heart is the key marker of impaired cardiovascular hemodynamics in obese patients newly diagnosed with CD. The use of noninvasive diagnostic methods in this study revealed a complex relationship between obesity-related hemodynamic changes and the efficiency of left ventricular contractions. An early assessment of a patient’s hemodynamic profile may help detect subclinical cardiovascular dysfunction. Such a personalized approach may facilitate early therapeutic intervention and monitoring of treatment effectiveness focused on preventing myocardial remodeling and heart dysfunction. 4.2. Limitations One limitation of our study was the small sample size. This was a result of the relatively low incidence of pituitary neuroendocrine tumors secreting ACTH. The exclusion of patients with clinically significant comorbidities further diminished the study population. However, this helped to eliminate the effect of additional factors on hemodynamic profiles. The patients assessed in our study were mostly young and middle-aged individuals with CD; therefore, our conclusions should not be extrapolated to older subjects. Although we conducted neither cardiac stress tests nor coronary angiography to exclude asymptomatic ischemic heart disease, other thorough assessments showed no physical, electrocardiographic, or echocardiographic evidence suggesting myocardial ischemia. Another potential limitation of our study is the fact that some patients had hypertension; however, it was well controlled with medications. The hemodynamic assessments involved the use of noninvasive methods as an alternative to the more expensive and less readily available invasive techniques. Nonetheless, we acknowledge the fact that noninvasive measurements can only provide indirect measurements and depend on the patient’s condition, which may vary over time. 5. Conclusions The results of our study support the usefulness of ICG in diagnosing early heart dysfunction associated with obesity in patients with CD. Asymptomatic impairment of the heart’s pumping function seems to be the earliest clinical sign of cardiovascular hemodynamic abnormalities, which at this stage are still undetectable with standard echocardiography. Individual hemodynamic profile assessment with novel noninvasive diagnostic methods encourages further studies on cardiovascular system function in obese individuals with CD and on the use of personalized therapies, which aim at preventing adverse cardiovascular events. Author Contributions Conceptualization, A.J. and P.K.; methodology, A.J., P.K., G.G., B.U.-Ż., P.W. and G.Z.; software, P.K.; validation, A.J., P.K., B.U.-Ż., P.W. and G.Z.; formal analysis, P.K., P.W., G.G. and G.Z.; investigation, A.J., P.K., B.U.-Ż., P.W. and G.Z.; resources, A.J., P.K., B.U.-Ż., P.W. and G.Z.; data curation, A.J., P.K., B.U.-Ż., P.W., G.Z., A.K., R.W. and M.B.; writing—original draft preparation, A.J. and P.K.; writing—review and editing, G.G., B.U.-Ż., P.W. and G.Z.; visualization, A.J.; supervision, G.G. and G.Z.; project administration, G.Z.; funding acquisition, G.Z. All authors have read and agreed to the published version of the manuscript. Funding This research was funded by the Polish Ministry of Research and Higher Education/Military Institute of Medicine—National Research Institute in Warsaw (grant No. 453/WIM). Institutional Review Board Statement The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines and approved by the Bioethics Committee at the Military Institute of Medicine—National Research Institute in Warsaw, Poland (approval No. 76/WIM/2016; 21 December 2016). Informed Consent Statement Informed consent was obtained from all subjects involved in the study. Data Availability Statement The data presented in this study are available upon request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Acknowledgments We would like to thank the medical personnel of the Military Institute of Medicine—National Research Institute in Warsaw for the provided patient care. 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