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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

In this study, we will investigate the possible side effects of psoriasis patients using long-term topical corticosteroids (TCS) such as adrenal insufficiency, Cushing’s Syndrome (CS) and osteoporosis and determine how these side effects develop. Forty-nine patients were included in the study. The patients were divided into two groups based on the potency of the topical steroid they took and the patients’ ACTH, cortisol and bone densitometer values were evaluated. There was no significant difference between the two groups regarding the development of surrenal insufficiency, CS and osteoporosis. One patient in group 1 and 4 patients in group 2 were evaluated as iatrogenic CS. ACTH stimulation tests of these patients in group 2 showed consistent results with adrenal insufficiency, while no adrenal insufficiency was detected in the patient in Group 1. Patients who used more than 50g of superpotent topical steroids per week compared to patients who used 50g of superpotent topical steroids per week. It was identified that patients who used more than 50g of superpotent topical steroids had significantly lower cortisol levels, with a negatively significant correlation between cortisol level and the amount of topical steroid use ( < .01).Osteoporosis was detected in 3 patients in group 1 and 8 patients in Group 2. Because of the low number of patients between two groups, statistical analysis could not be performed to determine the risk factors. Our study is the first study that we know of that investigated these three side effects. We have shown that the development of CS, adrenal insufficiency and osteoporosis in patients who use topical steroids for a long time depends on the weekly TCS dosage and the risk increases when it exceeds the threshold of 50 grams per week. therefore, our recommendation would be to avoid long-term use of superpotent steroids and to choose from the medium-potent group if it is to be used. ABOUT THE CONTRIBUTORS Betul Erdem Department of Dermatology, Van Training and Research Hospital, Van, Turkey. Muzeyyen Gonul Department of Dermatology, Ministry of Health, Ankara Etlik City Hospital, Ankara, Turkey. Ilknur Ozturk Unsal Department of Endocrine and Metabolic Disease, Ministry of Health, Ankara Etlik City Hospital, Ankara, Turkey. Seyda Ozdemir Sahingoz Department of Biochemistry, Ministry of Health, Ankara Etlik City Hospital, Ankara, Turkey. From https://www.physiciansweekly.com/evaluation-of-psoriasis-patients-with-long-term-topical-corticosteroids-for-their-risk-of-developing-adrenal-insufficiency-cushings-syndrome-and-osteoporosis/

Abstract The most common cause of Cushing syndrome (CS) is exposure to exogenous glucocorticoids. There is an increasing incidence of adulterated over-the-counter (OTC) supplements containing steroids. We present a case of Artri King (AK)-induced CS in a 40-year-old woman who presented with an intertrochanteric fracture of her right femur. Laboratory testing revealed suppressed cortisol and adrenocorticotropic hormone, which was consistent with suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Following the cessation of the AK supplement, the patient’s HPA axis recovered, and the clinical manifestations of CS improved. This case emphasizes the need for better regulation of OTC supplements and the need for cautious use. Introduction Cushing syndrome (CS) is a condition that occurs because of high blood levels of glucocorticoids (GCs). These patients can present with a variety of systemic signs and symptoms, including truncal obesity, easy bruising of the skin, violaceous abdominal striae, resistant hypertension, dysglycemia, as well as osteoporosis. CS can occur because of adrenal etiologies such as adrenal adenoma, adrenal cancer, or adrenal hyperplasia or from an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma or ectopic tumor. However, the most common cause of CS is the exogenous administration of GCs [1]. While exogenous GCs are often medically prescribed for the treatment of inflammatory conditions, some patients may be accidentally exposed to exogenous GCs from over-the-counter (OTC) supplements. We present a case of a young woman who developed exogenous CS and suffered a hip fracture as a result of taking an OTC supplement, Artri King (AK), adulterated with GCs. Case Presentation A 40-year-old obese woman presented to the hospital following a fall at home. She reported a snapping noise and sudden right hip pain while trying to stand up, and subsequently fell to the floor. She had noted right-sided hip pain for several days preceding her fall. She was evaluated in the emergency department where computed tomography (CT) imaging of the right lower extremity showed an intertrochanteric fracture of the right femur (Figure 1). The patient underwent open reduction and internal fixation of her right femur. The patient reported an unexplained weight gain of approximately 40 lbs in the preceding five months with a peak weight of 223 lbs (101 kg) and a body mass index (BMI) of 37 kg/m2. The patient denied taking any medications or supplements at the time of hospitalization. The endocrinology team was consulted to evaluate for causes of secondary osteoporosis in this young woman. Figure 1: A CT scan showing the right intertrochanteric fracture of the right femur (yellow arrows) Diagnostic assessment Her vital signs showed a blood pressure of 142/96 mmHg, heart rate of 68 beats per minute, temperature of 98.1°F (36.7°C), and 98% oxygenation on room air. Physical examination did not reveal abdominal striae or buffalo hump. She did have supraclavicular fat deposition and central obesity. No proximal muscle weakness was present. Laboratory tests were pertinent for decreased 25-hydroxy vitamin D, increased parathyroid hormone (PTH), and normal calcium (Table 1). These findings were consistent with secondary hyperparathyroidism due to vitamin D deficiency. Dual-energy X-ray absorptiometry (DEXA) scan revealed osteoporosis (Figures 2, 3 and Tables 2, 3). Further testing showed normal thyroid-stimulating hormone (TSH), estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), thus ruling out hyperthyroidism and primary ovarian insufficiency as possible causes of reduced bone mineral density (Table 1). Random cortisol was checked as hypercortisolism was suspected but it was found to be decreased along with decreased ACTH as well (Table 4). A cosyntropin stimulation test was performed, which showed decreased baseline cortisol with inappropriately decreased cortisol levels at 30 minutes and 60 minutes (Table 5). Given the discordance between the patient’s presentation and the lab results, assay interference was suspected, and further evaluation of the adrenal function was performed. Repeat labs using liquid chromatography-mass spectrometry (LCMS) assay again confirmed persistently low cortisol (Table 4). A 24-hour free urine cortisol was too low to quantify per assay despite the adequate volume. Further evaluation showed overall low adrenal steroids, including deoxycorticosterone, 17-hydroxyprogesterone, androstenedione, 11-deoxycortisol, pregnenolone, dehydroepiandrosterone sulfate, corticosterone, and progesterone. Lab test Patient's value Reference range 25-hydroxy vitamin D 12.8 ng/ml 30-100 ng/ml Parathyroid hormone (PTH) 86.2 pg/ml 10-66 pg/ml Serum calcium 9.5 ng/dl 8.8-10.5 mg/dl Thyroid-stimulating hormone (TSH) 2.49 mIU/L 0.36-3.74 mIU/L Estradiol 57.1 pg/ml 19.8-144.2 pg/ml Follicle-stimulating hormone (FSH) 5.4 mIU/ml 2.5-10.4 mIU/ml Luteinizing hormone (LH) 6 mIU/ml 1.9-12.5 mIU/ml Table 1: Patient's lab values on admission Figure 2: Dual-energy X-ray absorptiometry (DEXA) scan of the femoral neck showing osteopenia Figure 3: Dual-energy X-ray absorptiometry (DEXA) scan of the lumbar spine showing osteoporosis Region Area (cm2) Bone mineral content (g) Bone mineral density (g/cm2) T-score Peak reference Z-score Age-matched Femoral neck 4.76 3.53 0.742 -1.0 87 -0.7 91 Total 33.39 26.14 0.783 -1.3 83 -1.1 85 Table 2: Summary of dual-energy X-ray absorptiometry (DEXA) scan results of the femoral neck Region Area (cm2) Bone mineral content (g) Bone mineral density (g/cm2) T-score Peak reference Z-score Age-matched L1 10.79 7.56 0.701 -2.6 71 -2.4 73 L2 11.79 9.06 0.768 -2.4 75 -2.1 77 L3 12.70 9.98 0.786 -2.7 73 -2.4 75 L4 15.57 11.42 0.733 -3.0 69 -2.7 71 Total 50.86 38.03 0.748 -2.7 71 -2.5 73 Table 3: Summary of dual-energy X-ray absorptiometry (DEXA) scan results of the lumbar spine Lab test Patient's values while on Artri King Patient's values four weeks off of Artri King Reference range Random cortisol (routine assay) <0.64 μg/dL 7.3 μg/dL 5-25 μg/dL Adrenocorticotropic hormone (ACTH) 1.5 pg/ml 12 pg/ml 7.2-63.3 pg/ml Random cortisol (using liquid chromatography-mass spectrometry (LCMS) assay) 0.526 μg/dL N/A 5-25 μg/dL Table 4: Patient's cortisol and adrenocorticotropic hormone levels before and after stopping Artri King Cosyntropin stimulation test Patient value Reference range Baseline cortisol 1.64 μg/dL 5-25 μg/dL Cortisol after 30 minutes 1.33 μg/dL >18 μg/dL Cortisol after 60 minutes 6.48 μg/dL >18 μg/dL Table 5: Results of cosyntropin test while on Artri King Treatment She was started on teriparatide as well as vitamin D and calcium supplementation for the treatment of osteoporosis. Based on the aforementioned testing and the apparent symptoms of hypercortisolism, the patient was questioned again about the potential intake of steroids. She then recalled that she had been taking AK, an OTC supplement promoted for joint pain and arthritis. She reported that she had been taking two tablets of the supplement three times a day intermittently for the past three years. The patient neglected to bring it to the medical team’s attention before because she was under the impression that it was a multivitamin and did not have implications on her diagnosis. She was asked to stop the supplement and was educated about potential adrenal insufficiency symptoms and GC withdrawal. Outcome and follow up Repeat labs after four weeks off AK showed improved cortisol and ACTH levels indicating recovery of her hypothalamic-pituitary-adrenal (HPA) axis (Table 4). She lost 25 lbs in this time span with lifestyle modification. She continues teriparatide for osteoporosis, and monitoring of her bone mineral density is planned. Discussion This patient initially presented with a pathological fracture of her right femoral head. Given her young age, causes of secondary osteoporosis, including CS, were explored. The prevalence of osteoporosis in CS patients is 50% [2]. The effects of GC on bone health have been well studied. The major mechanism by which GC affects bone mineral density is by impairment of bone formation. GCs increase osteoblast and osteocyte apoptosis and decrease osteoblast function through their catabolic effects, which result in a dramatic decrease in bone formation rate. A prolonged lifespan of osteoclasts is observed with GC. A decrease in bone formation markers such as P1NP and osteocalcin has been observed in patients treated with GC [3]. Long-term GC use is associated with increased risk for fractures with a reported global prevalence of fractures of 30-50%. The risk for vertebral fractures is even higher, particularly in the thoracic and lumbar vertebrae. Interestingly, the risk for fracture with GC use peaks early in the course of treatment, often as early as three months into treatment, and declines rapidly after GC discontinuation [4]. An increased fracture risk has been described even with relatively low doses of GC (2.5-7.5 mg of prednisone or other equivalently dosed GC) and even with short-term use of under 30 days [5]. Our patient’s initial labs confirmed adrenal suppression despite our initial suspicion of CS, given her ongoing weight gain, central obesity, and osteoporosis. However, no obvious source of exogenous GC was identified. In most cases, the source of exogenous GC is easily identified through medication reconciliation; however, in our case, the patient was inadvertently exposed to steroids from an unregulated supplement, AK. The supplement’s ingredients were listed as glucosamine, chondroitin, collagen, vitamin C, curcumin, methylsulfonylmethane, nettle, and omega-3 fatty acids, with no mention of any steroid components. In a letter to the editor of the Internal Medicine magazine, several doctors published their concerns about a recent increase in CS cases associated with the use of AK and other similarly unregulated products [6]. Based on our literature search, three similar cases were published [7,8]. The reported cases developed CS after taking Artri King for several months, but none of them presented with a fracture. A warning by the U.S. Food & Drug Administration (FDA) was issued on April 20, 2022, indicating that FDA laboratory testing of this supplement confirmed the presence of undeclared drug ingredients, including dexamethasone, methocarbamol, and diclofenac. The FDA, however, was unable to confirm the exact amount of dexamethasone that these supplements contained [9]. Adverse events, including liver toxicity and death, were reported by the FDA. One study revealed that between 2007 and 2016, the FDA had issued more than 700 warnings about the sale of dietary supplements that contained unlisted and potentially dangerous ingredients. The majority of these supplements included those marketed for sexual enhancement, weight loss, or muscle building [10]. This case highlights the risks of undisclosed ingredients in OTC supplements. Conclusions In conclusion, we recommend that a thorough reconciliation of medication and supplements be obtained for all patients with CS. Supplements should be stopped and HPA axis testing should be repeated in patients with suspected exogenous GC exposure, even if steroids are not declared in the ingredients. It is also important to monitor such patients for adrenal insufficiency due to GC withdrawal and consider GC tapering if necessary. Our patient showed improvement in cortisol levels with no overt symptoms of adrenal insufficiency without the need for GC therapy. This case demonstrates the first case of AK-induced CS resulting in a pathological fracture. Given the increased use and availability of OTC supplements, this case highlights on the importance of detailed history-taking and the role of supplements in causing CS. This case also stresses the need for further education and counseling of our patients as well as tighter control on the manufacturing and sale of these supplements. References Lacroix A, Feelders RA, Stratakis CA, Nieman LK: Cushing's syndrome. Lancet. 2015, 386:913-27. 10.1016/S0140-6736(14)61375-1 Mancini T, Doga M, Mazziotti G, Giustina A: Cushing's syndrome and bone. Pituitary. 2004, 7:249-52. 10.1007/s11102-005-1051-2 Briot K, Roux 😄 Glucocorticoid-induced osteoporosis. RMD Open. 2015, 1:e000014. 10.1136/rmdopen-2014-000014 Canalis E, Mazziotti G, Giustina A, Bilezikian JP: Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int. 2007, 18:1319-28. 10.1007/s00198-007-0394-0 Waljee AK, Rogers MA, Lin P, et al.: Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ. 2017, 357:j1415. 10.1136/bmj.j1415 Del Carpio-Orantes L, Quintín Barrat-Hernández A, Salas-González A: Iatrogenic Cushing syndrome due to fallacious herbal supplements. The case of Ortiga Ajo Rey and Artri King. Med Int Mex. 2021, 37:599-602. Patel R, Sherf S, Lai NB, Yu R: Exogenous Cushing syndrome caused by a "Herbal" supplement. AACE Clin Case Rep. 2022, 8:239-42. 10.1016/j.aace.2022.08.001 Mikhail N, Kurator K, Martey E, Gaitonde A, Cabrera C, Balingit P: Iatrogenic Cushing’s syndrome caused by adulteration of a health product with dexamethasone. JSM Clin Case Rep. 2022, 3: U.S. Food and Drug Administration. Public notification: Artri King contains hidden drug ingredients. (2022). Accessed: February 25, 2023: https://www.fda.gov/drugs/medication-health-fraud/public-notification-artri-king-contains-hidden-drug-ingredients. Tucker J, Fischer T, Upjohn L, Mazzera D, Kumar M: Unapproved pharmaceutical ingredients included in dietary supplements associated with US Food and Drug Administration warnings. JAMA Netw Open. 2018, 1:e183337. 10.1001/jamanetworkopen.2018.3337 From https://www.cureus.com/articles/153927-exogenous-cushing-syndrome-and-hip-fracture-due-to-over-the-counter-supplement-artri-king#!/

Abstract Importance Cushing syndrome is defined as a prolonged increase in plasma cortisol levels that is not due to a physiological etiology. Although the most frequent cause of Cushing syndrome is exogenous steroid use, the estimated incidence of Cushing syndrome due to endogenous overproduction of cortisol ranges from 2 to 8 per million people annually. Cushing syndrome is associated with hyperglycemia, protein catabolism, immunosuppression, hypertension, weight gain, neurocognitive changes, and mood disorders. Observations Cushing syndrome characteristically presents with skin changes such as facial plethora, easy bruising, and purple striae and with metabolic manifestations such as hyperglycemia, hypertension, and excess fat deposition in the face, back of the neck, and visceral organs. Cushing disease, in which corticotropin excess is produced by a benign pituitary tumor, occurs in approximately 60% to 70% of patients with Cushing syndrome due to endogenous cortisol production. Evaluation of patients with possible Cushing syndrome begins with ruling out exogenous steroid use. Screening for elevated cortisol is performed with a 24-hour urinary free cortisol test or late-night salivary cortisol test or by evaluating whether cortisol is suppressed the morning after an evening dexamethasone dose. Plasma corticotropin levels can help distinguish between adrenal causes of hypercortisolism (suppressed corticotropin) and corticotropin-dependent forms of hypercortisolism (midnormal to elevated corticotropin levels). Pituitary magnetic resonance imaging, bilateral inferior petrosal sinus sampling, and adrenal or whole-body imaging can help identify tumor sources of hypercortisolism. Management of Cushing syndrome begins with surgery to remove the source of excess endogenous cortisol production followed by medication that includes adrenal steroidogenesis inhibitors, pituitary-targeted drugs, or glucocorticoid receptor blockers. For patients not responsive to surgery and medication, radiation therapy and bilateral adrenalectomy may be appropriate. Conclusions and Relevance The incidence of Cushing syndrome due to endogenous overproduction of cortisol is 2 to 8 people per million annually. First-line therapy for Cushing syndrome due to endogenous overproduction of cortisol is surgery to remove the causative tumor. Many patients will require additional treatment with medications, radiation, or bilateral adrenalectomy. From https://jamanetwork.com/journals/jama/article-abstract/2807073

She experienced extreme weight gain, thin skin and a racing heart. It took years to finally solve the medical mystery. Angela Yawn went to a dozen doctors before finally getting a diagnosis for her life-disrupting symptoms.Courtesy Angela Yawn April 27, 2022, 10:52 AM EDT / Source: TODAY By A. Pawlowski When a swarm of seemingly unrelated symptoms disrupted Angela Yawn’s life, she thought she was going crazy. She gained weight — 115 pounds over six years — even as she tried to eat less. Her skin tore easily and bruises would stay on her body for months. Her face would suddenly turn blood red and hot to the touch as if she had a severe sunburn. She suffered from joint swelling and headaches. She felt tired, anxious and depressed. Her hair was falling out. Then, there was the racing heart. “I would put my hand on my chest because it made me feel like that’s what I needed to do to hold my heart in,” Yawn, 49, who lives in Griffin, Georgia, told TODAY. “I noticed it during the day, but at night when I was trying to lie down and sleep, it was worse because I could do nothing but hear it beat, feel it thump." Yawn, seen here before the symptoms began, had no problems with weight before.Courtesy Angela Yawn Yawn was especially frustrated by the weight gain. Even when she ate just 600 calories a day — consuming mostly lettuce leaves — she was still gaining about 2 pounds a day, she recalled. A doctor told her to exercise more. Yawn gained 115 pounds over six years. "When the weight really started to pile on, I stayed away from cameras as I felt horrible about myself and looking back at this picture is still very embarrassing for me but I wanted (people) to see what this disease has the potential to do if not diagnosed," she said.Courtesy Angela Yawn In all, Yawn went to a dozen doctors and was treated for high blood pressure and congestive heart failure, but nothing helped. As a last resort, she sought out an endocrinologist in February of 2021 and broke down in her office. “That was the last hope I had of just not lying down and dying because at that point, that’s what I wanted to do,” Yawn said. “I thought the problem was me. I thought that I’m making up these issues, that maybe I’m bipolar. I was going crazy.” What is Cushing disease? When the endocrinologist suddenly started listing all of her symptoms without being prompted, Yawn stopped crying. Blood tests and an MRI finally confirmed the doctor’s suspicion: Yawn had a tumor in her pituitary gland — a pea-size organ at the base of the brain — that was causing the gland to release too much adrenocorticotropic hormone. That, in turn, flooded her body with cortisol, a steroid hormone that’s normally released in response to stress or danger. The resulting condition is called Cushing disease. Imagine the adrenaline rush you’d get while jumping out of an airplane and skydiving — that’s what Yawn felt all the time, with harmful side-effects. Yawn was making six times the cortisol she needed, said Dr. Nelson Oyesiku, chair of neurosurgery at UNC Health in Chapel Hill, North Carolina, who removed her tumor last fall. “That’s a trailer load of cortisol. Day in, day out, morning, noon and night, whether you need it or not, your body just keeps making this excess cortisol. It can wreak havoc in the body physiology and metabolism,” Oyesiku told TODAY. The steroid regulates blood pressure and heart rate, which is why Yawn's skin was flushed and her heart was racing, he noted. It can regulate how fat is burned and deposited in the body, which is why Yawn was gaining weight. Other effects of the steroid's overproduction include fatigue, thin skin with easy bruising, mental changes and high blood sugar. Cushing disease is rare, affecting about five people per million each year, so most doctors will spend their careers without ever coming across a case, Oyesiku said. That’s why patients often go years without being diagnosed: When they complain of blood sugar problems or a racing heart, they’ll be treated for much more common issues like diabetes or high blood pressure. Pituitary gland is hard to reach Removing Yawn’s tumor in September of 2021 would require careful maneuvering. If you think of the head as a ball, the pituitary gland sits right at the center, between the ears, between the eyes and about 4 inches behind the nose, Oyesiku said. It’s called the “master gland” because it regulates other glands in the body that make hormones, he noted. The location of the pituitary gland makes it heard to reach.janulla / Getty Images It’s a very difficult spot to reach. To get to it, Oyesiku made an incision deep inside Yawn’s nose in a small cavity called the sphenoid sinus. Using a long, thin tube that carried a light and a camera, he reached the tiny tumor — about the size of a rice grain — and removed it using special instruments. The surgery took four hours. The potential risk is high: The area is surrounded by vessels that carry blood to the brain, and it’s right underneath optic nerves necessary for a person to see. If things go wrong, patients can become blind, brain dead, or die. Recovery from surgery Today, Yawn is slowly returning to normal. She has lost 41 pounds and continues to lose weight. Her hair is no longer falling out. But patients sometimes require months or even a few years to adjust to normal cortisol levels. “It takes some time to unwind the effects of chronic exposure to steroids, so your body has to adapt to the new world order as the effects of the steroids recede,” Oyesiku said. "My life was on hold for five years... I'm trying not to be too impatient," Yawn said.Courtesy Angela Yawn Yawn’s body was so used to that higher cortisol level that she’s had to rely on steroid supplements to feel normal after the surgery. It’s like an addict going through withdrawal, she noted. The next step is finishing another cycle of supplements and then slowly tapering off them so that her body figures out how to function without the steroid overload. “I am definitely moving in the right direction,” she said. "I hope that I’ll get back to that woman I used to be — in mind, body and spirit." From https://www.today.com/health/health/cushing-disease-pituitary-gland-tumor

The CAHmelia clinical trials are exploring a new investigational treatment for classic CAH. CAHmelia 203 and CAHmelia 204 are clinical trials to test tildacerfont in adults with classic CAH, which may offer you and your loved ones hope of a brighter future – one where you may not have to choose between symptom management and long-term health. Tildacerfont is a new type of oral, once-daily investigational treatment – one that is not a steroid – that is currently being tested in adults with classic CAH. By reducing the amount of androgens your body makes, tildacerfont may improve your classic CAH symptoms. This investigational treatment will not replace your steroid treatment but may allow you to manage your disease with lower amounts of steroids at normal or near-normal doses. Who can take part in this trial? You may be able to take part if you: Are at least 18 years of age Have a confirmed diagnosis of classic CAH due to 21-OH deficiency Have been on the same daily dose of steroids (GCs and/or mineralocorticoids) for at least 1 month before starting the trial Both trials are now open for enrollment. Tildacerfont is an investigational treatment not authorized for use in people outside the clinical trial. For more information, go to: clarahealth.com/studies/cahmelia