Inhibition Of Steroidogenesis Research Articles

Medical Therapy of Endogenous Cushing's Syndrome with Steroidogenesis Inhibitors: Treatment Rationale, Available Drugs, and Therapeutic Effects.

Endogenous Cushing's syndrome (CS) is a rare disease characterized by a glucocorticoid excess. If inadequately treated, hypercortisolism can lead to increased morbidity and mortality. Surgical removal of the underlying tumor is the first-line treatment but is sometimes not feasible or even contraindicated. Additionally, in cases with severe CS, rapid control of hypercortisolism may be required. In these scenarios, steroidogenesis inhibitors represent a therapeutic alternative to surgery. Over the last years, the knowledge of the broad therapeutic effects of steroidogenesis inhibitors per se and the number of available drugs have increased. However, large comparative studies are still lacking. Accordingly, the decision on which drug to be used in a certain patient or clinical setting may be difficult. This review aims to summarize the main characteristics of steroidogenesis inhibitors.

Medical treatment of functional pituitary adenomas, trials and tribulations.

Functioning pituitary adenomas (FPAs) include most frequently prolactinomas, somatotroph or corticotroph adenomas, while thyrotroph and gonadotroph adenomas are very rare. Despite their benign histological nature (aggressive tumors are rare and malignant ones exceptional), FPAs could cause significant morbidity and increased mortality due to complications associated with hormonal excess syndromes and/or mass effect leading to compression of adjacent structures. This mini review will focus on the increasing role of medical therapy in the multimodal treatment, which also includes transsphenoidal surgery (TSS) and radiotherapy. Most patients with prolactinomas are treated only with medications, but surgery could be considered for some patients in a specialized pituitary center, if higher chances of cure. Dopamine agonists, especially cabergoline, are efficient in reducing tumor size and normalizing prolactin. TSS is the first-line treatment for all other FPAs, but most patients require complex adjuvant treatment, including a combination of therapeutic approaches. Medical therapy is the cornerstone of treatment in all patients after unsuccessful surgery or when surgery cannot be offered and includes somatostatin receptor ligands and dopamine agonists (almost all FPAs), growth hormone receptor antagonists (acromegaly), adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers (Cushing's disease). Novel medical treatments, especially for acromegaly and Cushing's disease are under research. An enlarged panel of effective drugs available with increased knowledge of predictive factors for response and/or adverse effects will enhance the possibility to offer a more individualized treatment. This would not only improve disease control and prognosis, but also quality of life.

Steroidogenesis inhibitors in mild/subclinical cushing's syndrome: results from a retrospective cohort of patients

Steroidogenesis inhibitors in mild/subclinical cushing's syndrome: results from a retrospective cohort of patients

Abstract 6071: Identification of a molecular glue degrader targeting the full-length AR and AR-V7 splice variant

Abstract Prostate cancer is the most common cancer in males and the fifth leading cause of cancer mortality worldwide. A variety of therapeutic approaches exist including steroid synthesis inhibitors and next-generation ligand binding domain (LBD) antagonists [e.g., enzalutamide (Enza)]. However, these approaches are only effective against tumors bearing the full-length androgen receptor (AR-FL). In the course of their disease, many patients acquire androgen receptor splice variant 7 (AR-V7), a mutant form of the receptor which lacks the LBD and is constitutively activated. To date, no effective therapy has been demonstrated for patients with metastatic prostate cancer bearing the AR-V7 signature. We have recently developed a high throughput platform that allows for the identification of ligands that can bind to a wide variety of protein targets. Using this approach, we screened a diverse chemical library of 100,000 small molecules to identify compounds that are bound to AR-V7. One such molecule, AR-600, directly bound to AR-V7 and moreover, induced proteasomal-mediated targeted protein degradation of both AR-V7 and AR-FL. In prostate cancer cell lines expressing AR-FL, AR-600 induced a gene expression profile similar to cells treated with Enza including a marked reduction in KLK3 (PSA) expression. Moreover, AR-600 inhibited the growth of 22RV1 cells (IC50=23 nM), a cell line that predominantly expresses AR-V7, as well as C4-2 cells that express predominantly full-length AR (IC50=51 nM). In contrast, the compound did not affect the growth of a wide variety of non-tumorigenic cells, non-prostate tumor cell lines or PC3 cells, a prostate cell line that exhibits AR-independent cell growth (IC50>100uM). Preliminary exploration of the mechanism of action of AR-600 (M.W. ~300 Daltons) demonstrates the compound works as a molecular glue. These results thereby identify a small molecule glue degrader that can specifically induce the targeted protein degradation of the AR-V7 splice variant. Given the strong association of this isoform with treatment resistance, this approach would appear to provide an attractive strategy for patients with metastatic castration resistant prostate cancer. Citation Format: Yuan Liu, Mads B. Larsen, Bo Lin, Irene A. Cardenal, Jason Kennerdell, Toren Finkel, Bill B. Chen. Identification of a molecular glue degrader targeting the full-length AR and AR-V7 splice variant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6071.

Intertwined regulators: hypoxia pathway proteins, microRNAs, and phosphodiesterases in the control of steroidogenesis.

Oxygen sensing is of paramount importance for maintaining cellular and systemic homeostasis. In response to diminished oxygen levels, the hypoxia-inducible factors (HIFs) orchestrate various biological processes. These pivotal transcription factors have been identified as key regulators of several biological events. Notably, extensive research from our group and others has demonstrated that HIF1α exerts an inverse regulatory effect on steroidogenesis, leading to the suppression of crucial steroidogenic enzyme expression and a subsequent decrease in steroid levels. These steroid hormones occupy pivotal roles in governing a myriad of physiological processes. Substantial or prolonged fluctuations in steroid levels carry detrimental consequences across multiple organ systems and underlie various pathological conditions, including metabolic and immune disorders. MicroRNAs serve as potent mediators of multifaceted gene regulatory mechanisms, acting as influential epigenetic regulators that modulate a broad spectrum of gene expressions. Concomitantly, phosphodiesterases (PDEs) play a crucial role in governing signal transduction. PDEs meticulously manage intracellular levels of both cAMP and cGMP, along with their respective signaling pathways and downstream targets. Intriguingly, an intricate interplay seems to exist between hypoxia signaling, microRNAs, and PDEs in the regulation of steroidogenesis. This review highlights recent advances in our understanding of the role of microRNAs during hypoxia-driven processes, including steroidogenesis, as well as the possibilities that exist in the application of HIF prolyl hydroxylase (PHD) inhibitors for the modulation of steroidogenesis.

A23 IMPAIRMENT OF INTESTINAL CRYPTAL STEM CELL CYCLE AND PANETH CELL PROLIFERATION BY CHRONIC STRESS

Abstract Background The small intestine’s epithelial barrier is essential for intestinal homeostasis and host defense. It consists of epithelial cells that are constantly renewed by crypt stem cells and their progeny, which have different functions in the gut. Chronic stress can impair the barrier by modulating the gut-brain axis, which involves the hypothalamic-pituitary-adrenal (HPA) axis, the vagus nerve, and the immune system. Chronic stress can also alter the gut microbiota, which can further influence the barrier and immune system. Aims The present study examines how chronic stress affects the crypt stem cell niche and function in the small intestine. Methods Restraint stress was applied to 6-8 weeks old mice in a plastic container for 1 hour daily for 7 days. The dark/light transition box test was used to evaluate the stress-induced behavior change. The Ussing chamber technique was used to assess the paracellular permeability of the small intestine. RNA was extracted from the mucosa and submucosa layers of the small intestine, after removing the muscle layer, and RNA sequencing analysis was performed. Immunofluorescence analysis was also performed on the small intestinal tissues to detect the expression of various markers. To assess the in vivo effect of cortisol, dexamethasone (a synthetic steroid activating same receptors as cortisol), or metyrapone (an 11β-hydroxylation blocker to inhibit cortisol production), was applied to the mice. Results We found that restraint stress induced anxiety-like behavior, increased small intestinal epithelial permeability, and reduced villus and crypt length in mice. RNA sequencing analysis revealed that restraint stress upregulated steroid-driven pathways and downregulated cell cycle and cell mitosis pathways in the small intestinal mucosa, suggesting increased cortisol production and decreased stem cell activity. Immunofluorescence analysis confirmed that restraint stress reduced the expression of stem cell marker Olfm-4 and proliferation markers Ki-67 and p-H3 in the small intestinal crypts. Dexamethasone, a synthetic glucocorticoid, mimicked the effects of restraint stress on crypt stem cell proliferation, while metyrapone, a steroid synthesis inhibitor, attenuated the effects of restraint stress on crypt stem cell proliferation. Restraint stress and dexamethasone also reduced Paneth cell RNA expression and marker in the small intestine. Conclusions Chronic stress induces anxiety, barrier dysfunction, and epithelial shortening. Chronic stress also alters crypt stem cell and Paneth cell expression. These findings show how chronic stress impacts intestinal epithelial renewal and differentiation, which may affect intestinal health and disease. Funding Agencies JSPS

IN SILICO STUDIES FOR ANTI-BREAST CANCER ACMELLA OLERACEA (L.) FLOWERS

The study of the efficacy of Acmella oleracea (L.) flowers on breast cancer is still in its early stages. The molecular interaction mechanisms underlying Acmella oleracea's anti-breast cancer activity will be elucidated using in-silico analysis. For this study, seventeen bioactive compounds were used: spilanthol, alpha- and beta-amyrin ester, stigmasterol, beta-sitosterol, alpha-1-sitosterol, 3-acetylaleuritic acid, scopoletin, vanillic acid, trans-ferulic, (72,9E)-2-oxo-undeca-7,9-dienyl 3-methylbut-2-enoate, beta-caryophyllene, beta-pinene, myrcene, caryophyllene oxide, and limone Canonical smiles were obtained from PubChem and inserted into the PASS server to determine biological activity. Several compounds were docked with protein targets, such as ESR1, MAP2K2, and PGR. We used Pyrx 0.8 software for anchoring molecular interaction and Discovery Studio software to visualize the complex binding. In terms of Antineoplastic, apoptosis agonist, caspase-3, caspase-8 stimulant, ovulation inhibitor, steroid synthesis inhibitor, and TP53 expression enhancer, all the compounds tested positive for anticancer activity. According to Swiss ADME and protox analysis, Acmella oleracea flowers have the potential to modulate apoptosis and cell growth. More research is required to confirm the role of Acmella oleracea bioactive compounds in developing target cancers. The study reveals that Acmella oleracea has numerous bioactive chemicals advantageous for cancer therapy by inducing apoptosis through interaction with ESR1, MAPK2, and PGR protein.

Osilodrostat: A Novel Potent Inhibitor of 11-Beta-Hydroxylase for the Treatment of Cushing's Syndrome.

Osilodrostat is a novel potent oral steroidogenesis inhibitor with a non-steroidal chemical structure, recently approved for the treatment of adult patients with endogenous Cushing's syndrome, and Cushing's disease not cured bytab pituitary surgery or in whom pituitary surgery is not an option. Osilodrostat has been evaluated in different multicentre phase II and III clinical studies, and has shown to have notable effects, such as significant reductions in cortisol secretion, associated with significant improvement in body weight, blood pressure, glucose metabolism, lipid profile, psychological status and quality of life. The favourable safety profile, combined with the relevant efficacy, could make osilodrostat suitable as medical treatment in several phases of the Cushing's syndrome treatment journey: before surgery, as preoperative treatment, or instead of surgery, in cases where surgery is not an option or refused, as first-line treatment; after surgery, in cases of persistent or recurrent disease, as second-line treatment; after second surgery or radiotherapy following pituitary surgery as bridging treatment waiting for the definitive disease control, as third-line treatment. Further real-world clinical experience data are needed to confirm the current knowledge.

Di-(2-ethylhexyl) phthalate exacerbates abnormalities of testicular development in F1 males via inhibition the Wnt/β-catenin signaling pathway

The theory of “Developmental Origins of Health and Disease (DOHaD)” espouses that environmental exposures to toxicants during critical developmental stages can affect health outcomes in adulthood. Di (2-ethylhexyl) phthalate (DEHP) is a plasticizer that can be transferred to developing organisms via the placenta and breast milk as an environmental endocrine disruptor. We herein implemented a cross-fostering model to decipher the contributions of prenatal vs. postnatal exposure to low or high dose DEHP (30 or 500 mg/kg-bw•d) on reproductive outcomes in male offspring and the underlying mechanism of action. Unexpectedly, we observed that postnatal DEHP exposure programmed weight gain in a dose-dependent manner, in-utero exposure to high dose DEHP appeared to constitute a significant factor in the weight loss of male offspring. Moreover, in the low dose group, offspring of control that were suckled by DEHP dams (CC-DE) generated a considerable number of adverse reproductive outcomes compared with the offspring of DEHP that were suckled by control dams (DE-CC), based on histopathologic alterations in the testis, blockage of sex hormone secretion, and transcriptional inhibition of steroid-hormone-related factors in the hypothalamic-pituitary-testicular (HPT) axis. However, DE-CC group affected reproductive dysfunction in male offspring more so than CC-DE in the high dose group. Mechanistically, DEHP contributed to the inhibition of steroidogenesis by perturbing the Wnt/β-catenin-signaling pathway. These studies confirm the sensitivity window in which future reproductive outcomes in offspring are influenced following developmental exposure to DEHP at two different dosages, and reveals a critical role for the Wnt/β-catenin signaling pathway in DEHP-induced male reproductive disorders.

Local Effects of Steroid Hormones within the Bone Microenvironment.

Steroid hormone production via the adrenal cortex, gonads, and placenta (so-called glandular steroidogenesis) is responsible for the endocrine control of the body's homeostasis and is organized by a feedback regulatory mechanism based on the hypothalamus-pituitary-steroidogenic gland axis. On the other hand, recently discovered extraglandular steroidogenesis occurring locally in different tissues is instead linked to paracrine or autocrine signaling, and it is independent of the control by the hypothalamus and pituitary glands. Bone cells, such as bone-forming osteoblasts, osteoblast-derived osteocytes, and bone-resorbing osteoclasts, respond to steroid hormones produced by both glandular and extraglandular steroidogenesis. Recently, new techniques to identify steroid hormones, as well as synthetic steroids and steroidogenesis inhibitors, have been introduced, which greatly empowered steroid hormone research. Based on recent literature and new advances in the field, here we review the local role of steroid hormones in regulating bone homeostasis and skeletal lesion formation. The novel idea of extraglandular steroidogenesis occurring within the skeletal system raises the possibility of the development of new therapies for the treatment of bone diseases.

Cushing's Disease: Long-Term Effectiveness and Safety of Osilodrostat in a Polish Group of Patients with Persistent Hypercortisolemia in the Experience of a Single Center.

Osilodrostat is a potent oral steroidogenesis inhibitor that has emerged as the new medical agent for patients with Cushing's disease (CD) requiring long-term medical therapy for hypercortisolemia control. Its efficacy and safety have been assessed in clinical trials; however, real-world evidence is still scarce. This study aimed to investigate the long-term treatment (156 weeks) clinical and biochemical effect of osilodrostat in six patients with CD at a single center in Poland, initially participating in the LINC4 study. At week 36, all six patients met the key secondary endpoint of the LINC4 trial, achieving normalization of median urinary free cortisol. Osilodrostat treatment allowed for complete disease control in all patients and none of the patients was excluded due to the lack of treatment effectiveness in 156 weeks of follow-up. All patients demonstrated significant improvement from baseline on most metabolic and cardiovascular parameters, which was most evident at week 36 and sustained throughout the study period. This study supports and strengthens the role of osilodrostat as an effective long-term medical treatment in patients with CD. We also present three patient case histories in detail to highlight the clinical situations that endocrinologists might face during osilodrostat therapy.

Epidemiology and Management of Hypertension and Diabetes Mellitus in Patients with Mild Autonomous Cortisol Secretion: A Review.

Mild autonomous cortisol secretion (MACS) is associated with a higher cardiometabolic risk than that observed in patients with nonfunctioning adrenal adenomas and in the general population. In patients with MACS, the excess of glucocorticoids affects various metabolic pathways, leading to different manifestations of metabolic syndrome and other comorbidities. Hypertension and diabetes mellitus are two of the most common cardiometabolic comorbidities associated with MACS, reaching a prevalence of up to 80% and up to 40%, respectively. In addition, they are the comorbidities that experienced a greater improvement after adrenalectomy in patients with MACS. Hypertension pathogenesis is multifactorial, including the coexistence of comorbidities such as obesity or diabetes and the role of the different polymorphisms of the glucocorticoid receptor gene, among others. Glucocorticoid-induced diabetes mellitus is mainly related to the detrimental effects of glucocorticoids on insulin-dependent glucose uptake in peripheral tissues, gluconeogenesis and insulin secretion. There are no specific recommendations for hypertension and diabetes treatment in patients with MACS. Thus, considering the similar underlying pathogenesis of hypertension and diabetes mellitus in overt and mild hypercortisolism, our recommendation is to follow this general stepwise approach: surgically remove the adrenal culprit lesion to induce remission from hypercortisolism; control hypercortisolism with steroidogenesis inhibitors; and treat elevated blood pressure or high glucose levels using carefully selected anti-hypertensives and glucose-lowering medications if blood pressure and glucose levels remain uncontrolled, respectively. In this review, we summarize the epidemiology, physiopathology and management of diabetes mellitus and hypertension in patients with MACS.

Transgenerational inheritance of adrenal steroidogenesis inhibition induced by prenatal dexamethasone exposure and its intrauterine mechanism

BackgroundAdrenal gland is the synthesis and secretion organ of glucocorticoid, which is crucial to fetal development and postnatal fate. Recently, we found that prenatal dexamethasone exposure (PDE) could cause adrenal dysfunction in offspring rats, but its multigenerational genetic effects and related mechanisms have not been reported.MethodsThe PDE rat model was established, and female filial generation 1 (F1) rats mate with wild males to produce the F2, the same way for the F3. Three generation rats were sacrificed for the related detection. SW-13 cells were used to clarify the epigenetic molecular mechanism.ResultsThis study confirmed that PDE could activate fetal adrenal glucocorticoid receptor (GR). The activated GR, on the one hand, up-regulated Let-7b (in human cells) to inhibit steroidogenic acute regulatory protein (StAR) expression directly; on the other hand, down-regulated CCCTC binding factor (CTCF) and up-regulated DNA methyltransferase 3a/3b (Dnmt3a/3b), resulting in H19 hypermethylation and low expression. The decreased interaction of H19 and let-7 can further inhibit adrenal steroidogenesis. Additionally, oocytes transmitted the expression change of H19/let-7c axis to the next generation rats. Due to its genetic stability, F2 generation oocytes indirectly exposed to dexamethasone also inhibited H19 expression, which could be inherited to the F3 generation.ConclusionsThis cascade effect of CTCF/H19/Let-7c ultimately resulted in the transgenerational inheritance of adrenal steroidogenesis inhibition of PDE offspring. This study deepens the understanding of the intrauterine origin of adrenal developmental toxicity, and it will provide evidence for the systematic analysis of the transgenerational inheritance effect of acquired traits induced by PDE.45YfzC5bohQgYTrjifxqYiVideo

THU577 Acth Dependent Cushing Syndrome Identification And Management Challenges

Abstract Disclosure: B.C. Barreto: None. S. Patrick: None. H. Oktaei: None. H.O. Steinberg: None. Endogenous Cushing Syndrome(CS) is rare with an incidence of 0.2-5.0 per million people per year. 70 to 80% of CS is ACTH dependent and subclassified into Cushing Disease, Ectopic ACTH Syndrome and Ectopic CRH Syndrome. Ectopic ACTH secretion(EAS) has a variable clinical presentation. Atypical features like refractory hypokalemia in a patient with a tumoral lesion should raise suspicion. When imaging is inconclusive, differentiating between pituitary or ectopic disease includes invasive and noninvasive methods. We report a case of EAS. Case: A 57-year-old male with history of metastatic small-cell lung-cancer on palliative chemotherapy was admitted for acute coronary syndrome. Endocrinology evaluated the patient’s uncontrolled hypertension, hyperglycemia, and hypokalemia (1.5 mmol/L). He had no suppression with low dose dexamethasone (cortisol>75mcg/dL, ACTH 926pg/mL). Examination was pertinent for an elevated BMI 36.1kg/m2, hyperpigmented anterior thorax but no other stigmata of hypercortisolism. Laboratory analysis showed baseline cortisol 146.1mcg/dL(8.7-22), ACTH 590pg/ml(6-50), 24hr Urine Free Cortisol 736mcg/24h(5-50), which were not suppressed by high dose dexamethasone suppression test(HDDST). Aldosterone and PRA were undetectable. Brain MRI showed an enlarged pituitary gland, but no focal mass. CT abdomen pelvis showed bilateral adrenal hyperplasia, multiple hepatic masses, and bone lesions. Since the patient was a poor surgical candidate, medical therapy was initiated with ketoconazole 200mg TID, aldactone 50mg BID and potassium chloride 40mEq TID. After twelve days cortisol levels decrease to 65.2 mcg/dL, potassium 3.8 mmol/L and glucose 146 mg/dL. Hospitalization was complicated by a small bowel ileus. Medications were held due to poor gastrointestinal absorption and parenteral octreotide 200mcg TID was initiated. Once the ileus resolved, ketoconazole 200mg TID, eplerenone 50mg daily, and dexamethasone 0.5mg daily was started. Despite medical care, the patient eventually expired. Discussion: The HDDST can help distinguish pituitary from an ectopic ACTH overproduction. HDDST with >50% suppression, has been described with sensitivity-specificity of 60 to 100% for pituitary ACTH source. Symptomatic treatment of CS requires rapid normalization of hypercortisolism action. Surgery is the first line approach. When surgery is not an option, medical therapy should be considered. Adrenal steroidogenesis inhibitors, such as ketoconazole, are the first line due to rapid onset of action. Agents such as glucocorticoid receptor antagonists have limited availability in the inpatient setting. Somatostatin analogs and etomidate that inhibit 11-ßhydroxylase are potential options but require close monitoring. Severe hypercortisolism in the critically ill prompts the use of noninvasive evaluation tools and alternative medical approaches. Presentation Date: Thursday, June 15, 2023

SAT313 Therapeutic Dosing Of Steroids In Patients On Mitotane

Abstract Disclosure: C. Pham: None. S.M. Cannon: None. J.S. Lopresti: None. Introduction: Mitotane is a known inhibitor of steroidogenesis with some patients requiring supraphysiologic dosing for steroid replacement. Clinical Case: A 43-year-old female with a history of adrenal cell carcinoma (ACC) on multiagent chemotherapy and mitotane presents with a pruritic rash. Three weeks prior, she had received her first dose of pembrolizumab. Her other home medications included mitotane 500mg QID and hydrocortisone 180mg (40mg-40mg-30mg -20mg QID). Labs on admission were notable for an ALT of 458 (ref 10-35 U/L), AST of 272 (ref 10-35 U/L), and normal alkaline phosphatase and bilirubin with otherwise normal electrolytes. Due to the temporal relation of her transaminitis and rash to recent pembrolizumab infusion with an otherwise negative work-up, the patient was diagnosed with immune-mediated liver injury from checkpoint inhibitors (ILICI). Per National Comprehensive Cancer Network (NCCN) guidelines, high dose methylprednisolone was initiated (1mg/kg) equivalent to approximately 525 mg hydrocortisone total daily. Over five days, the patient’s transaminases continued to rise and methylprednisolone was increased to 3mg/kg/day to account for the known effects of mitotane on steroid metabolism. The patient’s rash subsequently resolved followed by slow improvement of her transaminitis with steroid taper. Mitotane level obtained one week after discontinuation of mitotane was noted to be 21mcg/mL demonstrating persistent therapeutic levels (14-20mcg/mL). Mitotane has a profound inhibitory effect on steroidogenesis through multiple mechanisms, inhibiting glucocorticoid production by the adrenal and increasing hepatic disposal of glucocorticoids leading to subtherapeutic doses1, Furthermore, mitotane can persist in the body for a prolonged period, with a half-life between 18-154 days. As such, patients who develop adrenal insufficiency on mitotane typically require higher doses for physiologic replacement up to three times standard physiologic dose1. In this case, only when the patient’s methylprednisolone dose was tripled did her ILICI begin to improve. Conclusion: This is one of the first cases to describe ILICI in a patient with ACC highlighting unique clinical considerations in management. Higher doses of corticosteroids may be required to overcome the effects of mitotane on steroid metabolism in patients with adverse effects from immune checkpoint inhibitor therapy. 1.)Puglisi, S., Calabrese, A., Basile, V., Pia, A., Reimondo, G., Perotti, P., & Terzolo, M. (2020). New perspectives for mitotane treatment of adrenocortical carcinoma. Best Practice & Research Clinical Endocrinology & Metabolism, 34(3), 101415. https://doi.org/10.1016/j.beem.2020.101415 Presentation: Saturday, June 17, 2023

THU503 An Unusual Case Of Ectopic ACTH Syndrome Secondary To Non-small Cell Lung Cancer

Abstract Disclosure: N. Hernandez: None. E. Askar: None. J.R. Fredrick: None. R.C. Schulman-Rosenbaum: None. Background: Cushing syndrome (CS) is a clinical entity characterized by HTN, DM, peripheral edema, hypokalemia, metabolic alkalosis, and myopathy. CS can be clinically classified into Corticotropin-dependent vs Corticotropin-independent processes. Those categorized as corticotropin dependent can further be subclassified into Eutopic CS (i.e. from the pituitary) vs Ectopic CS (i.e. extra-pituitary). The extra-pituitary source of ACTH most often comes from intra-thoracic neoplasms, of which small cell lung cancer (SCLC) is the most prevalent. However, here we present a case of a patient with Ectopic ACHT Syndrome (EAS) due to non-small cell lung cancer. Clinical Case: 87-year-old woman with pmhx of RA and HTN was admitted for 2-week history of constipation and lower abdominal pain. Physical exam was notable for hypertension and tachycardia, along with lower abdominal tenderness. Laboratory results showed WBCs of 32,000 (3,800-10,500), K of 2.7 mmol/L (3.5-5.5 mmol/L) and HCO3 was 38 mmol/L (22-29 mmol/L). CT chest and abdomen showed a left perihilar necrotic mass 6.6 X 6.0cm, with loco-regional lymphadenopathy with destructive osseous lesion on the right pedicle of L1 and metastatic disease to the liver and adrenal glands. Paraneoplastic ACTH production was suspected in the setting of metastatic lung cancer. Serum ACTH level was 105 pg/mL (7.2-63.6 pg/mL). Initial 8AM cortisol was 41 ug/dL (6.8-18.4 ug/dL) and 24 hr urine cortisol was 2327 mcg/24 h (3.5-45 mcg/24 h) which proved the diagnosis of ACTH-dependent hypercortisolemia. The AM cortisol was 62.3 ug/dL (6.0-18.4 ug/dL) after the 1mg dexamethasone test consistent with hypercortisolemia secondary to ectopic ACTH. IR biopsy of the right axillary LN showed poorly differentiated non-small cell carcinoma with squamous differentiation. The patient was started on chemotherapy, as well as, mifepristone 300 mg daily and ketoconazole 200 TID for hypercortisolism. She was also considered for Metyrapone. However, cortisol levels did not improve despite optimized therapy due to the aggressive nature of the cancer. Later chemotherapy was discontinued and was discharged on hospice with ketoconazole and mifepristone. Conclusion: EAS is associated with neuroendocrine tumors of which up to 50% are caused by SCLC and rarely with adenocarcinoma. However, our case is novel as the source of ACTH was a lung tumor of squamous cell origin. Treatment strategies for ACTH secreting tumors combine chemotherapy as well as medications that target the hormonal imbalance such as steroidogenesis inhibitors and cortisol receptor blockers. Unfortunately, patients with ACTH producing tumors tend to have low median survival rates which limits our ability as clinicians to determine the effectiveness of such interventions. Given the uniqueness of her case, it would be even harder to predict the type of clinical response obtained from such treatment. Presentation: Thursday, June 15, 2023

FRI237 A Fluke Or No? Fluconazole Treatment In A Case Of Ectopic Cushing Syndrome

Abstract Disclosure: M. McDole: None. K. Zemeir: None. M.H. Horani: None. N. Morris: None. Cushing syndrome is characterized by elevated cortisol levels due to iatrogenic causes, pituitary tumors or from an ectopic focus. Ketoconazole has been shown to effectively decrease cortisol levels without a high risk of toxicities. Here we show a case report of a patient with ectopic Cushing syndrome treated with an alternative steroidogenesis inhibitor, fluconazole. We reported a 75-year-old male with a past medical history significant for atrial fibrillation, hypertension and obstructive sleep apnea. He was admitted to the hospital due to severe hypokalemia of 2.6 mmol/L (reference range 3.6-5.2 mmol/L), a blood sugar of 498 mg/dL (reference range 7-99 mg/dL), elevated PM cortisol levels of 66.1 mcg/dL (reference range 3-13 mcg/dL) and AM Cortisol Levels of 112 (reference range 5-25mcg/dL), thus prompting an endocrinology consult. Further examination of 24-hour urine cortisol displayed elevated levels at 11,656 mcg/24hrs (reference range 4-40 mcg/24hrs). The patient failed a 8mg dexamethasone suppression test with AM cortisol levels of 57.8 mcg/dL (5-25 mcg/dL) with a dexamethasone drug level of 2713 ng/dL (reference range >200 ng/dL), excluding elevated metabolism as cause of failed suppression. Pituitary magnetic resonance imaging showed a normal pituitary gland. Patient was started on 400mg of fluconazole daily with plans to switch to 400 mg ketoconazole in outpatient care. Outpatient positron emission tomography failed to identify the source of ACTH. Additionally, petrosal sinus sampling failed to detect altered levels of ACTH secretion. Patient was readmitted to hospital one month after original diagnosis with continued hypokalemia of 2.7 mmol/L (reference range 3.6-5.2 mmol/L) and worsening diabetic symptoms. Patient was taken off ketoconazole two weeks after prior discharge, not knowing it was temporary treatment for his Cushing’s syndrome. He was restarted on 400mg fluconazole and on day three of admission, fluconazole dose was increased to 600 mg daily (Endocrinology Metabolism case reports 2019, July 3) with cortisol levels to be monitored. On day one of admission, his AM cortisol levels were 91.5 mcg/dL (reference range 5-25 mcg/dL) and declined to 76.8 mcg/dL, 72.9 mcg/dL, 69.2 mcg/dL, 66.4 mcg/dL, and 60 mcg/dL the following days with fluconazole treatment. The patient was then discharged to outpatient follow-up with continuation of 600mg fluconazole. Within a week of the latest discharge, the patient presented to the hospital again due to an episode of atrial fibrillation. AM cortisol levels were measured to be 37.2 mcg/dL (reference range 5-25 mcg/dL), showing a 59.3% decrease since his last admission. Patient was then discharged from our care to an outpatient endocrinologist. This case shows that cortisol levels in ectopic Cushing Syndrome can be effectively lowered through fluconazole treatment. This medication has a more favorable side effect profile than other steroidogenesis inhibitors such as metyrapone and mitotane. Fluconazole monotherapy or dual therapy should be investigated further as a viable option for ectopic Cushing Syndrome therapy prior to bilateral adrenalectomy. Presentation: Friday, June 16, 2023

THU019 Osilodrostat As An Emergency Alternative For Hypercortisolism In A Patient With An Impaired Liver Function

Abstract Disclosure: M. Minasyan: None. A. Bogusławska: None. A. Gamrat: None. A. Hubalewska-Dydejczyk: None. A. Gilis-Januszewska: None. Osilodrostat as an emergency alternative for hypercortisolism in a patient with an impaired liver function. A case presents a 34 year old woman with an active Cushing Disease, who underwent non-radical surgery of invasive pituitary adenoma in 2014 and CyberKnife radiotherapy in 2018. Patient demonstrates many complications of long lasting hypercortisolemia- poorly controlled diabetes mellitus, heart failure, hypertension, hypercholesterolemia, mental disturbances and severe hepatic impairment. Challenges in this case are aggravated by very difficult compliance. Due to elevated liver function tests, the patient couldn’t have started ketoconazole and relacorilant treatment. Because of non-controlled DM, pasireotide treatment was contraindicated in her case. She didn’t agree either for metyrapone treatment or for adrenalectomy. Finally osilodrostat has been implemented as the last-chance alternative given at the time of severe hepatic impairment. At the dose of 2x2mg we observe clinical improvement, normalisation of UFC, decrease of Hba1c and spectacular improvement of liver function. However the current data on use of osilodrostat in patients with hepatic impairment are limited, our case shows that osilodrostat can be an emergency alternative for severe hypercortisolism with impaired liver function. The mechanism of improvement of liver function may be indirect through decreasing the level of hypercortisolemia, however potential direct beneficial influence of osilodrostat on liver function seems to be an interesting subject worth further investigation. More studies on the link between hypercortisolemia, liver function and steroidogenesis inhibitors are needed. Presentation: Thursday, June 15, 2023

THU013 A Rare Case of Ectopic Cushing’s Syndrome Caused By Metastatic Parotid Gland Carcinoma

Abstract Disclosure: E. Punni: None. I. Goyal: None. Introduction: Ectopic Cushing’s Syndrome (ECS) is a rare condition that accounts for only a small percentage of all Cushing’s syndrome cases. Although rare, the typical tumors associated with ECS are small cell lung carcinomas, bronchial carcinoids, pancreatic neuroendocrine tumors, medullary thyroid carcinomas, thymic carcinoids and pheochromocytomas. Metastatic acinic cell carcinoma (ACC) of the parotid gland has very rarely been associated with ectopic Cushing’s syndrome. Case Presentation: A 67-year-old Caucasian male with a known diagnosis of high grade metastatic ACC of the parotid gland presented to the hospital with progressively worsening proximal muscle weakness and bilateral lower extremity edema of 6 weeks duration. A month prior to presentation, he developed persistent hypokalemia requiring potassium supplementation and was diagnosed with new onset type 2 diabetes mellitus. Laboratory results on admission were remarkable for low potassium at 2.5 mEq/L (N: 3.5-5.3 meq/L), a random cortisol level of 107 mcg/dL (N: 6 - 30 mcg/dL), and an ACTH level of 485 pg/mL (N: 7.2 - 63.3 pg/mL). Subsequently, a 24-hour urine cortisol was > 1600 ug/24 hours (N 5-64 ug/24 hours). A 1 mg dexamethasone suppression test failed to suppress an 8 a.m. cortisol with level of 110.8 mcg/dl (N < 1.8 mcg/dl). Following, an 8 mg dexamethasone suppression test also failed to suppress 8 a.m. cortisol with a value of 100.8 mcg/dl. A MRI of the pituitary with and without contrast showed mild diffuse enlargement of the pituitary gland concerning for pituitary hyperplasia. At the time, ECS was highly suspected given the rapid course of patient’s presentation, known metastatic malignancy, and failed 8 mg dexamethasone suppression test. An inferior petrosal sinus sampling (IPSS) could not be performed given the patient’s guarded condition. Instead, a PET/CT Ga-68 DOTA-TATE scan obtained showed widespread DOTA-TATE avid malignancy concerning for neuroendocrine type tumor. Patient was a poor surgical candidate, therefore bilateral adrenalectomy could not be performed for the rapid treatment of ECS. Patient was started on a steroidogenesis inhibitor ketoconazole. However, he elected to undergo hospice care and passed away shortly after. Conclusion: This case is particularly interesting given that metastatic ACC of the parotid gland causing ECS is rare with only a few cases reported in the literature. This case highlights the importance of maintaining a high degree of suspicion for diagnosing ECS especially when patients present with rapid onset of signs and symptoms of Cushing’s syndrome and a known underlying malignancy. Recognizing less common causes of ECS may prompt early diagnosis and intervention. Presentation: Thursday, June 15, 2023

SAT316 Severe Cushing’s Syndrome Due To Ectopic ACTH In Newly Diagnosed Small Cell Lung Cancer: The Pivotal Role Of Etomidate In Acute Treatment

Abstract Disclosure: H. Belal: None. G.Y. Gandhi: None. Introduction: Ectopic ACTH syndrome can present as an endocrine emergency. Etomidate, the only parenteral steroidogenesis inhibitor, can rapidly treat critically ill patients with Cushing’s syndrome (CS) and concurrent significant metabolic derangements, severe hypertension, or psychosis. Case Description: A 66-year-old female presented with abdominal pain, vomiting, proximal muscle weakness, and confusion for 6 months. Physical exam revealed hypertension, bilateral supraclavicular fat pads, and abdominal distention, while laboratory evaluation uncovered severe hypokalemia <1.5 mmol/L, metabolic alkalosis, and elevated proBNP. A hilar soft tissue mass with mediastinal lymphadenopathy and bilaterally enlarged adrenal glands were seen on CT imaging. Serum cortisol was high at 114 mcg/dL. ACTH was inappropriately elevated at 111 pg/mL. MRI revealed a normal pituitary gland. She developed hypertensive emergency and status epilepticus, requiring intubation. Due to her life-threatening presentation, a guideline-based hypercortisolism workup was forgone for emergent treatment with continuous etomidate infusion. Serum cortisol normalized after 4 days of etomidate therapy. Due to concerns of reduced seizure threshold with etomidate therapy, it was weaned off after 14 days and replaced by ketoconazole. She subsequently developed recurrent hypercortisolism (serum cortisol 92 mcg/dL). After 14 days of etomidate, 9 days of ketoconazole, and 3 days of chemotherapy for biopsy-proven small-cell lung carcinoma, serum cortisol reached a trough of 22 mcg/dL. At this point, hydrocortisone therapy was initiated (block-and-replace). Recurrent clinical hypercortisolism then developed, and hydrocortisone was discontinued. Hypercortisolism comorbidities were treated appropriately: trimethoprim-sulfamethoxazole for pneumocystis pneumonia prophylaxis, anticoagulation for DVT prophylaxis, antibiotics for acute diverticulitis, and insulin for hyperglycemia. Despite treatment, her condition worsened; she was transitioned to comfort care one month after admission and died 4 days later. Discussion: Etomidate inhibits steroidogenesis through 11 beta-hydroxylate blockade and works rapidly (within 12-24 hours) to decrease cortisol levels versus ketoconazole (several days) and has a reduced risk of hepatic injury. Side effects of etomidate include respiratory depression, myoclonus, and reduced seizure threshold. Several experts have suggested a block-and-replace strategy in severe CS treatment. While effective, this strategy poses risks of etomidate toxicity and makes serum cortisol interpretation unreliable. Etomidate analogs are on the horizon that retain the potent adrenostatic action of etomidate without its sedative-hypnotic activity, offering an alternative treatment option for treating patients with severe CS in non-ICU hospital settings. Presentation: Saturday, June 17, 2023