Adrenal Hormones Research Articles

SAT267 BMP4, GDF11 And TGFβ2 Repress Adrenal Cell Cortisol Production By Blocking CYP17A1 And CYP11B1 Expression

Abstract Disclosure: E.C. Fischbach: None. A. Lopez: None. M. Ullenbruch: None. J. Rege: None. W.E. Rainey: None. Introduction: The adrenal cortex is responsible for the biosynthesis of multiple steroid hormones that regulate electrolyte and carbohydrate balance. Cortisol, the principal glucocorticoid in humans, is primarily produced in the middle zone of the cortex known as the zona fasciculata (ZF). The enzymes responsible for cortisol biosynthesis include cytochrome P450c17 (17α-hydroxylase), encoded by CYP17A1 and cytochrome P450c11 (11β-hydroxylase), encoded by CYP11B1. Several paracrine/autocrine regulators, including members of the transforming growth factor beta (TGFβ) superfamily, have been implicated in controlling adrenocortical cell homeostasis and steroid hormone production. Previously, we reported a bone morphogenetic protein 4 (BMP4) expression gradient in the adrenal cortex with higher levels in the zona glomerulosa (ZG) and outer ZF compared to the zona reticularis (ZR). In this study, we sought to compare adrenal expression of members of the TGFβ family including BMP4, growth differentiation factor 11 (GDF11), and transforming growth factor beta 2 (TGFβ2), and determine their effect on adrenal cell cortisol biosynthesis. Methods: Growth factor mRNA levels were studied using microarray analysis of laser captured ZG, ZF and ZR from human adrenals. The adrenal cell line, HAC15 was used to determine the effects of the TGFβ family members alone and in combination. Output measures included cell cortisol production and mRNA levels of steroidogenic enzymes using ELISA and quantitative RT-PCR, respectively. Results: Microarray analysis indicated higher mRNA levels of BMP4, GDF11 and TGFβ2 in the ZG compared with the ZF and ZR regions of the adrenal. Treatment of HAC15 cells with either BMP4 (50 ng/mL), GDF11 (50 ng/mL) or TGFβ2 (10 ng/mL) significantly inhibited cortisol production, as well as CYP11B1 and CYP17A1 mRNA levels. The inhibition was observed under basal and forskolin-stimulated conditions. Furthermore, the inhibitory effects on cortisol production and enzyme expression were additive when factors were added together. Summary: Overall, our findings suggest that the human adrenal has a gradient of multiple members of the TGFβ family. The additive action of these growth factors on adrenal cell differentiation may explain, in part, the inability of the ZG to produce cortisol and its low expression of CYP11B1 and CYP17A1. Presentation: Saturday, June 17, 2023

THU116 Characteristics Of Sleep Disturbance And The Related Hormonal Changes In Patients With Long COVID

Abstract Disclosure: N. Sunada: None. Y. Nakano: None. Y. Otsuka: None. K. Tokumasu: None. H. Honda: None. Y. Sakurada: None. Y. Matsuda: None. T. Hasegawa: None. D. Omura: None. K. Ochi: None. H. Hagiya: None. K. Ueda: None. H. Kataoka: None. F. Otsuka: None. COVID-19 causes prolonged symptoms called either long COVID or post COVID-19 condition (PCC). Such prolonged conditions have been experienced in approximately one-third of COVID-19 patients even a few months after the acute phase of infection. In Japan, we have recently reported clinical characteristics of long COVID patients who visited our COVID-19 aftercare outpatient clinic (CAC). The major complaints in the early period of the COVID-19 pandemic were fatigue and anxiety and that the severity of the infection status affected the number and duration of persistent symptoms. We have also shown that endocrine factors including anterior pituitary, adrenal and thyroid hormones and male androgen levels might be related to the fatigue symptoms of long COVID. However, the characteristics of long COVID patients with sleep disturbance have yet to be elucidated. The aim of this study was to determine the characteristics of sleep disturbance in patients with long COVID by focusing on the clinical manifestations and the related endocrine data. This study was a single-center retrospective observational study for patients who visited the CAC established in Okayama University Hospital in Japan during the period from Feb. 2021 to Jul. 2022. Out of 363 patients with long COVID after excluding 6 patients, 60 patients (16.5%) (55% males, median age of 38 years) complaining of sleep disturbance were compared with 303 patients (83.5%) (43% males, median age of 40 years) without sleep-related symptoms. Although there were no significant differences in clinical backgrounds and severities of COVID-19 between the two groups, the percentage of long COVID patients with sleep disturbance was significantly increased (50%) among patients infected in the Omicron-dominant phase. Also, the prevalence rate of sleep disturbance in patients when infected in the Omicron phase (24.8%) was two-times higher than that in patients infected in the Delta phase (12.8%). Of note, the percentages of patients with sleep disturbance who also complained of general fatigue, headache, concentration loss, anxiety, low-grade fever and brain-fog symptoms were higher than the percentages of patients without sleep disturbance who had the same complaints. Among the types of sleep disturbance, the percentage of patients who complained of loss of sleep induction (75%) was much higher than the percentage of patients with early-awaking sleep disturbance (6.7%). Endocrine examinations revealed that long COVID patients with sleep disturbance had significantly higher levels of plasma ACTH and lower levels of serum GH, suggesting the presence of hypothalamo-pituitary stress. Collectively, we uncovered that 16.5% of total patients with long COVID, reaching up to half of those in Omicron-dominant phase, complained of sleep disturbance. Endocrine workup also indicated that these manifestations could be associated with increased stress of the hypothalamo-pituitary axis. Presentation: Thursday, June 15, 2023

OR08-01 Expression of Gonadal Differentiation Markers in Bilateral Macronodular Adrenocortical Disease

Abstract Disclosure: K. De Sousa: None. V. Pautasso: None. C. Duparc: None. S. Renouf: None. B. Ragazzon: None. F. Violon: None. L. Bouys: None. F. Bonnet-Serrano: None. M. Sibony: None. N. Driessens: None. S. Espiard: None. G. Raverot: None. J.Y. Bertherat: None. E. Louiset: None. H. Lefebvre: None. Context: Bilateral macronodular adrenocortical disease (BMAD) is a rare cause of primary Cushing syndrome, occurring mostly in women. ARMC5 and KDM1A mutations are responsible for distinct forms of BMAD. In particular, KDM1A mutations are associated with food-dependent Cushing syndrome. In addition, BMAD tissues can express illegitimate receptors, including LH receptor, that lead to aberrant control of cortisol secretion by various factors. Moreover, steroidogenic cells are able to abnormally produce bioactive factors, such as ACTH and the Leydig cell hormone INSL3. Since LH receptor, ACTH and INSL3 are known to be produced in gonads, we speculated on a gonadal-like differentiation of adrenocortical cells in BMAD tissues. Aim: The aim of our study was to investigate the presence of different gonadal markers in a series of BMAD tissues, and to search for secretion of adrenal and gonadal hormones by BMAD cells. Methodology: Gene expression of gonadal markers were evaluated by RNAseq. Immunohistochemical studies were performed on 41 BMAD and 9 normal adrenal samples to examine the presence of hormones (ACTH, INSL3, anti-Mullerian hormone [AMH]), the estrogen synthetizing enzyme aromatase, and transcription factors (GATA4, SOX9, FOXL2, MAGEA4) known to be expressed in testis or ovary. Perifusion experiments, coupled to immunoassays or liquid chromatography/mass spectrometry, were conducted to quantify hormone secretion by 2 adrenal explants. Results: BMAD tissues were collected from patients (60% women) without or with ARMC5 (32%) or KDM1A (13%) mutations. ARMC5-mutated tissues overexpressed FOXL2 and CYP19A1 (encoding aromatase) in comparison with other BMAD samples. In normal adrenals, cortisol-producing cells, located in the zona fasciculata, were immunonegative for INSL3, AMH, aromatase, GATA4 and SOX9, whereas FOXL2 and MAGEA4 immunostainings were detected in the cortex. In BMAH tissues, the presence of positive cells for ACTH (100% of BMAD), INSL3 (90%), AMH (50%), aromatase (77%), SOX9 (92%), GATA4 (97%), FOXL2 (100%) and MAGEA4 (100%) were observed in most of the samples regardless of the gender or mutational status. FOXL2 and MAGEA4 immunostainings were detected throughout BMAD tissues. Distribution of other gonadal markers was heterogenous in tissue sections with clusters of cells positive for ACTH, aromatase and GATA4 or ACTH and SOX9. Functional studies revealed pulsatile secretion of different glucocorticoids and INSL3 by BMAD explants. ACTH and hCG stimulated steroid production but were without effect on INSL3 release. Conclusion: These data show that steroidogenic cells in BMAD tissues exhibit a gonadal-type phenotype and abnormally secrete INSL3. They suggest that BMAD may result from a genetically driven defect occurring during early embryogenesis and affecting differentiation and development of adrenal tissues. Presentation: Friday, June 16, 2023

FRI317 Simultaneous Occurrence Of A Pineal Germ Cell Tumor And Pituitary Macroprolactinoma In A Young Male

Abstract Disclosure: E.P. Monsour: None. S. Badour: None. J.M. Munoz Pena: None. W.T. Donahoo: None. Background: Germ Cell Tumors (GCTs) are a group of heterogeneous tumors that derive from pluripotent germ cells and originate in the yolk sac of the embryo in early gestation. They account for 10% of all central nervous system (CNS) GCTs, primarily occurring in the pediatric and adolescent populations. The co-existence of macroprolactinoma and a mixed CNS GCT is extremely rare, with an unknown worldwide prevalence. Here we report a case of a pituitary macroprolactinoma occurring with a separate primary CNS mixed GCT. Clinical Case: A 19-year-old male presented with a 2-month history of headaches associated with nausea and vomiting. Relevant physical exam findings included decreased visual acuity, absent facial and axillary hair, and prominence of the left testis. Brain MRI demonstrated a pituitary adenoma measuring 3.5 x 2.3 x 3.2 cm extending into the cavernous sinus and an enhancing necrotic lesion in the third ventricle measuring 5.0 x 3.7 x 4.9 cm. Testicular ultrasound revealed two sub-centimeter ill-defined masses in the left testis. Pre-operative labs showed intact thyroid, adrenal, and growth hormone axis. He had a low total testosterone [14.2 ng/dl, reference range (RR): 230-800 ng/dL] with inappropriately normal gonadotrophins and markedly elevated prolactin (PRL) level (2,517 ng/mL, RR <14 ng/mL). Testicular tumor marker, alpha-fetoprotein, was elevated (15.3 ng/dL, RR <9 ng/dL). He was started on glucocorticoids for vasogenic edema and cabergoline twice weekly. He underwent left orchiectomy and subsequent pineal tumor resection. Testicular tumor pathology was consistent with teratoma and a well-differential neuroendocrine tumor with negative margins. Pineal tumor pathology was diagnostic of a mixed GCT. Despite optimal medical therapy, the patient ultimately opted to pursue transsphenoidal tumor resection. Pituitary mass pathology was compatible with a pituitary adenoma, immunoreactive for PRL. Post-operative PRL levels decreased to 6 ng/dL. He achieved a surgical cure without the need to restart dopamine agonist therapy. Conclusion: Simultaneous occurrence of primary brain tumors with different pathologies is estimated to be ∼0.9% of all brain tumors. To our knowledge, only one other case report described an adolescent with a craniopharyngioma and intracranial GCT. This is the first report in the literature of a pituitary macroprolactinoma synchronous with a mixed CNS GCT, and testicular well-differential neuroendocrine tumor with teratoma. Presentation: Friday, June 16, 2023

FRI222 Large Non-functional Adrenocortical Carcinoma In A Patient With History Of Occupational Radiation Exposure

Abstract Disclosure: A. Makawi: None. G. Elshimy: None. N. Martinez de Andino: None. A. Bolduc: None. Introduction: Adrenocortical carcinoma (ACC) is a rare malignancy with an incidence of 0.1-2.0 cases/per million per year. Up to 70% of tumors present with biochemically apparent adrenocortical hormone production. Diagnosis requires investigation of clinical, biological, and imaging features with measurement of steroid hormones key for evaluation. Anderson’s syndrome is commonly seen. Research has shown ACC is driven by several molecular changes that include the inactivation of tumor suppressor genes and activation of different oncogenes, DNA mutations, and epigenetic changes. The widely used staging of ACC is by the European Network of Study of Adrenal Tumors (ENSAT) as it is correlated with clinical outcomes. Here we present a case of a non-secretory ACC noted for 10 years with growth up to 7.5 cm in a patient with history of occupational radiation exposure. Case Presentation: Patient is a 57-year-old white male with history of colon polyps, basal and squamous cell carcinoma, and hypertension diagnosed 10 years prior, on amlodipine 5 mg and lisinopril 20 mg daily who presented to adrenal clinic for evaluation of a 7cm left adrenal mass that had grown from 1.8cm 10 years prior, to 5.7cm 7 years later to 7.5cm at time of surgery. He had symptoms of fatigue and occasional lightheadedness with no other signs or symptoms of Cushing's or pheochromocytoma. Family history noncontributory. He has a history of occupational exposure to radiation working at a nuclear reactor. Workup for adrenal incidentaloma included assays of serum normetanephrine which was increased at 1.2 nmol/L (reference <0.9 nmol/L) with normal metanephrine less than 0.20 nmol/L, normal DHEA-S of 52 mcg/dL, normal ACTH of 16 pg/mL and negative 1mg dexamethasone suppression test with serum cortisol suppressed to 0.78 mcg/dL. CT scan adrenal protocol showed a heterogeneous 7.7x6.6 cm left adrenal mass with 30 HU, with an absolute adrenal washout of 39% and relative washout of 31.4%. He then underwent left adrenalectomy on 12/16/2022. The tumor measured 7.5cm with pathology of low-grade ACC with staging of pT3. Margins were negative for carcinoma but microscopic angioinvasion and capsular invasion were noted. Postoperatively, the patient had resolution of his symptoms with marked improvement in BP. We continue to follow him in clinic for postoperative management. He has been referred for genetic testing with results pending. Discussion: The prognosis of ACC has been believed to be poor due to the low prevalence and sample size of ACC patients, but recent studies have shown that ACC presentation, survival, and prognosis are heterogeneous. Only 20-30% of ACC are nonfunctional. It is important to note that only 30% of ACC cases are curable at early stages, further impacting the poor prognosis. The goal of this report is to bring further attention to the timely assessment and personalized management of ACC given the evolving knowledge base. Presentation: Friday, June 16, 2023

SAT315 A Case Of PAI "Do Not Miss This Rare Cause"

Abstract Disclosure: R. Alshantti: None. C. Musurakis: None. U. Rafat: None. W. Akhter: None. J.L. Gilden: None. A. Moid: None. Background: Adrenoleukodystrophy (ALD) is an X-linked disorder caused by a mutation in the ABCD1 gene, located at Xq28. This impairs beta-oxidation and breakdown of very long chain fatty acids (VLCFAs) which then accumulate in the CNS, adrenal cortex, and Leydig cells of the testes, leading to three main phenotypes of X-ALD: childhood cerebral ALD, adrenomyeloneuropathy AMN, and adrenal insufficiency (AI). AI presents in 47% of X-ALD cases by age 10 years. X-ALD represents a spectrum of phenotypes that vary in age of onset, severity, and clinical characteristic. AI may predate, occur simultaneously with, or follow the onset of the neurologic deterioration. While in the majority, it is inherited in an X-linked manner, at least 4.1% of individuals with X-ALD have a de novo pathogenic variant of ABCD1. Case Description: A 30-year-old male, previously healthy, was found to have adrenal nodule on CT renal during the evaluation of a transient episode of acute abdominal pain. Further evaluation of the adrenal nodule with a CT adrenal protocol showed a 1.5 cm x 1.0 cm right adrenal nodule, HU 22, washout of 66.7% consistent with an adrenal adenoma. Evaluation of adrenal hormones failed to show abnormal hypersecretion, but rather suggested insufficiency. Lab tests: RENIN FRZ PLS 45.76 ng/mL/h (0.25 - 5.82), ALDOSTERONE <1 ng/dL, ACTH >1250 pg/mL (0 - 47), SALIV CORT 0.06 mcg/dL, DHEAS 28.19 ug/dL (34.5 - 568.9). The patient was referred to endocrinology. Only reported symptom was poor exercise tolerance. Diagnosis of primary adrenal insufficiency was confirmed by low AM cortisol of 7.91 ug/dL, and very high ACTH of >1250 H pg/mL. He was started on glucocorticoid & mineralocorticoid replacements. An evaluation to determine the etiology of PAI was conducted. The patient was not taking any medications or drugs. Family history was noncontributory. 21 OH Ab was negative. Quantiferron was negative. Our patient had no risk factors or clinical manifestations to suggest TB or fungal infections. No bleeding disorders. CT adrenal findings did not suggest infiltrative, infectious, hemorrhage, or malignant etiologies. Blood tests for VLCFAs showed elevations in phytanic, C22:0, C24:0, C26:0, C24/C22, & C26/C22. These are consistent with X-linked adrenomyeloneuropathy. Genetic testing has confirmed the diagnosis; POSITIVE for a hemizygous pathogenic variant in ABCD1, consistent with a diagnosis of X-linked adrenoleukodystrophy/adrenomyeloneuropathy (ALD/AMN). Conclusion: Our case highlights the importance of a comprehensive evaluation to determine the cause of PAI. When autoimmunity and infectious etiologies are ruled out in male patients, it is crucial to consider X- ALD regardless of age at presentation, family history, or presence/absence of neurologic symptoms. This diagnosis is particularly important not to miss, since X-ALD can have devastating implications not only for the patient but also the family. Presentation: Saturday, June 17, 2023

FRI228 Primary Adrenal T-cell Lymphoma: A Case Report

Abstract Disclosure: H. Tabassum: None. S. Xu: None. A. Manavalan: None. Introduction: Primary T-cell adrenal lymphoma (PAL) is exceedingly rare. Adrenal insufficiency (AI) is common in these cases. Here we describe a patient with bilateral, large, T-cell PAL with rapid progression, without adrenal insufficiency. Clinical Case: A 62-year-old male, with coronary artery disease and recent coronary intervention, hyperlipidemia and hypertension presented to the hospital with abdominal pain, fever, night sweats and weight loss for a month. Work up revealed a 5.8 cm left adrenal mass with 14% absolute washout, measuring 34 Hounsfield Units (HU) pre-contrast, 68 HU postcontrast, and 63 HU on delayed images, and a 5.2 cm right adrenal mass with 42% absolute washout, measuring 35 HU pre-contrast, 81 HU postcontrast, and 62 HU on the delayed images with no other suspicious lesions or lymphadenopathy. The patient demonstrated no clinical symptoms or signs of adrenal hormone excess or deficiency. Levels of renin, aldosterone, serum cortisol, ACTH, 24-hour urine free cortisol, serum metanephrines, and thyroid function were normal. Additional tests to rule out adrenal cortical carcinoma (ACC) revealed normal levels of androstenedione, 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, and estradiol. Persistent non-significant elevation of 11-deoxycortisol was observed at 51 ng/dL and 63ng/dL (Ref < 42 ng/dL). Adrenal biopsy was suggested but deferred due to the increased risk of hemorrhage given recent coronary revascularization and use of dual antiplatelet therapy. Follow up imaging in a few weeks revealed diffuse, retroperitoneal lymphadenopathy with unchanged adrenal masses. A lymph node biopsy confirmed a diagnosis of peripheral T-cell lymphoma. The left adrenal gland demonstrated an uptake SUV of 22.7 and the right, 19.17 on FDG PET. The patient was initiated on chemotherapy with etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin. Imaging three months later revealed a marked decrease in FDG activity SUV 6.98 g/mL on the left and SUV up to 3.32 g/mL on the right. Adrenal function remained intact on follow up. Conclusion: Peripheral T-cell lymphoma with adrenal involvement is an extremely rare and aggressive disease with rapid progression. Mostly seen in males over the age of 50, it may present with abdominal pain, B symptoms or both. While ACC is usually unilateral, lymphoma and metastatic disease may present bilaterally, however, other imaging features can be similar. AI is expected when 90% of the adrenal glands are destroyed by tumor infiltration, however, this does not always correlate with tumor size. In our patient, AI was not observed on presentation or follow up. As adrenal insufficiency can occur at any time in the disease course and may mimic symptoms of cancer or chemotherapy, the clinician should always be vigilant for its development in these cases. Presentation: Friday, June 16, 2023

THU038 Osilodrostat Dosing In Cushing’s Disease: A Pooled Analysis Of The LINC Program

Abstract Disclosure: J. Newell-Price: Consulting Fee; Self; HRA Pharmaceuticals, Diurnal, Novartis Pharmaceuticals, Recordati Rare Diseases, Crinetics. Grant Recipient; Self; Crinetics, Diurnal, HRA Pharmaceuticals, Novartis Pharmaceuticals, Recordati Rare Diseases. R. Pivonello: Consulting Fee; Self; Novartis Pharmaceuticals, Recordati, Corcept Therapeutics, Pfizer, Inc., Bresmed Health Solutions, Damor farmaceutici, S&R Farmaceutici SpA, Organon Italia Srl, Siunergos Pharma, Biohealth Italia Srl. Grant Recipient; Self; Novartis Pharmaceuticals, Recordati, Xeris Pharmaceuticals (Strongbridge), Corcept Therapeutics, Takeda, Neurocrine Biosciences, Camurus AB, Pfizer, Inc., Merk Serono, Ibsa. A. Lacroix: Consulting Fee; Self; Novartis Pharmaceuticals, Recordati, Corcept Therapeutics, Ipsen, Novo Nordisk. Grant Recipient; Self; Novartis Pharmaceuticals, Recordati, Corcept Therapeutics, Ipsen, Novo Nordisk. B.M. Biller: Consulting Fee; Self; HRA Pharmaceuticals, Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Research Investigator; Self; served on the LINC 3 steering committee. R. Feelders: Consulting Fee; Self; HRA Pharmaceuticals, Recordati. Grant Recipient; Self; Corcept Therapeutics. M. Gadelha: Advisory Board Member; Self; Novo Nordisk, Recordati, Crinetics Pharmaceuticals. Speaker; Self; Recordati, Ipsen, Crinetics, Novo Nordisk. J. Bertherat: Consulting Fee; Self; Atterocor, Shire, HRA Pharmaceuticals, Novartis Pharmaceuticals, Corcept Therapeutics, Recordati. Grant Recipient; Self; Novartis Pharmaceuticals, Pfizer, Inc., HRA Pharmaceuticals. Z. Belaya: None. A. Piacentini: Employee; Self; Recordati. A.M. Pedroncelli: Employee; Self; Recordati. M. Fleseriu: Consulting Fee; Self; HRA Pharmaceuticals, Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Grant Recipient; Self; Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Research Investigator; Self; served on the LINC 3 steering committee. Introduction: Phase II (LINC 2, NCT01331239) and Phase III (LINC 3, NCT02180217; LINC 4, NCT02697734) studies showed that osilodrostat, a potent oral 11β-hydroxylase inhibitor, was an effective long-term therapy for Cushing’s disease (CD) patients (pts). Objective: This pooled analysis of the LINC program examined how dosing, including dose uptitration and adjustments during long-term maintenance, can provide rapid, sustained mUFC control, minimize AEs and improve treatment outcomes. Methods: Individual pt data from LINC 2, LINC 3 and LINC 4 were pooled and analyzed. Given differences in study designs across trials, placebo treatment periods were excluded. Pts with mUFC >1.5 times the upper limit of normal (ULN) (LINC 2 and LINC 3) or mUFC >1.3 x ULN (LINC 4) were enrolled. In LINC 2, pts started open-label osilodrostat 2 mg twice daily (bid), with dose increases every 2 weeks (W) if mUFC >ULN. In LINC 3, pts started open-label osilodrostat 2 mg bid, with dose increases every 2W until W12 if mUFC >ULN, then every 4W after W12. In LINC 4, pts were randomized to osilodrostat 2 mg bid or placebo for the first 12W. Dose was increased every 3W until W12 if mUFC >ULN and every 3W after W12. Maximum dose was 30 mg bid in all studies (reduced from 50 mg bid in LINC 2 core phase). Dose adjustments were permitted during the extensions based on efficacy and tolerability. Results: This analysis included 229 pts. Median (min-max) osilodrostat exposure was 100.1 weeks (1–351). Median (min–max) daily osilodrostat dose was 6.8 mg/day (1–47); dose needed to achieve mUFC control varied widely between pts. Median time to first mUFC control was 35 days (D; 95% confidence interval [CI] 34–41) in all pts; according to baseline (BL) mUFC severity: mUFC <2 x ULN, 28D (95% CI 17–34); mUFC 2–5 x ULN, 40D (95% CI 34–42); mUFC >5 x ULN, 52D (95% CI 41–56). Median time to first AE of special interest (AESI) was 12W (95% CI 10–15); AESIs occurred at different osilodrostat doses. AEs related to hypocortisolism (BL to W12, 23%; W12–48, 24%; W48–72, 8%; W72 onwards, 20%) and accumulation of adrenal hormone precursors (BL to W12, 36%; W12–48, 37%; W48–72, 14%; W72 onwards, 18%) were less frequent during long-term maintenance than dose titration. AESIs were mostly manageable with dose interruption and/or additional therapy; few patients discontinued treatment as a result (hypocortisolism-related AEs, n=8; adrenal hormone precursor accumulation-related AEs, n=3). Conclusions: Osilodrostat led to sustained mUFC control in all 3 studies; time to control was shorter in pts with lower BL mUFC values. Median daily osilodrostat dose was low but varied widely. Dose titration regimens differed for each study, but AESIs were less frequent during long-term treatment than dose uptitration and were manageable in most pts without stopping treatment. Personalized therapy during dose titration and lifelong monitoring are needed to optimize clinical outcomes in CD pts. Presentation: Thursday, June 15, 2023

Urinary Glyphosate, 2,4-D and DEET Biomarkers in Relation to Neurobehavioral Performance in Ecuadorian Adolescents in the ESPINA Cohort.

Herbicides are the most used class of pesticides worldwide, and insect repellents are widely used globally. Yet, there is a dearth of studies characterizing the associations between these chemical groups and human neurobehavior. Experimental studies suggest that glyphosate and 2,4-dichlorophenoxyacetic acid (2,4-D) herbicides can affect neurobehavior and the cholinergic and glutamatergic pathways in the brain. We aim to assess whether herbicides and insect repellents are associated with neurobehavioral performance in adolescents. We assessed 519 participants (11-17 years of age) living in agricultural communities in Ecuador. We quantified urinary concentrations of glyphosate, 2,4-D, and two N,N-diethyl-meta-toluamide (DEET) insect repellent metabolites [3-(diethylcarbamoyl)benzoic acid (DCBA) and 3-(ethylcarbamoyl)benzoic acid (ECBA)] using isotope-dilution mass spectrometry. We assessed neurobehavioral performance using 9 subtests across 5 domains (attention/inhibitory control, memory/learning, language, visuospatial processing, and social perception). We characterized the associations using generalized estimating equations and multiple imputation for metabolites below detection limits. Models were adjusted for demographic and anthropometric characteristics, urinary creatinine, and sexual maturation. Mediation by salivary cortisol, dehydroepiandrosterone, , and testosterone was assessed using structural equation modeling. The mean of each neurobehavioral domain score was between 7.0 and 8.7 [standard deviation (SD) range: 2.0-2.3]. Glyphosate was detected in 98.3% of participants, 2,4-D in 66.2%, DCBA in 63.3%, and ECBA in 33.4%. 2,4-D was negatively associated with all neurobehavioral domains, but statistically significant associations were observed with attention/inhibition [score difference per 50% higher metabolite concentration 95% confidence interval (CI): , ], language [ (95% CI: , )], and memory/learning [ (95% CI: , 0.01)]. Glyphosate had a statistically significant negative association only with social perception [ (95% CI: , )]. DEET metabolites were not associated with neurobehavioral performance. Mediation by gender and adrenal hormones was not observed. This study describes worse neurobehavioral performance associated with herbicide exposures in adolescents, particularly with 2,4-D. Replication of these findings among other pediatric and adult populations is needed. https://doi.org/10.1289/EHP11383.

Phytocompositions of ayurvedic medicine in the restoration of menstrual health in women of early reproductive age who have survived moderate and severe form of COVID-19

Research objectives: to evaluate the effectiveness of phytotherapy in the treatment of menstrual health disorders in women of early reproductive age after a moderate and severe form of the coronavirus disease.Material and methods. 104 women of early reproductive age with menstrual health disorders that occurred 3 months later after moderate or severe COVID-19 were under observation and 34 gynecologically and somatically healthy women of the control group who did not suffer from COVID-19. Female patients with COVID-19 were randomly divided into two groups: the main group (n=53) and the comparison group (n=51). The performed examination included: study of complaints, general and gynecological anamnesis, physical and gynecological examination, ultrasound examination of pelvic organs, determination of hormonal profile. All patients with COVID-19 received a comprehensive rehabilitation program, which included diet therapy, vitamin and mineral complexes, psychotherapy. In addition to the complex rehabilitation program patients of the main group received ayurvedic phytocompositions Femicycle or Femimens for 6 months.Results. It has been established that the moderate and severe course of the coronavirus infection affects the reproductive system of early reproductive aged women and leads to menstrual health disorders, among which irregular menstruation, premenstrual syndrome and dysmenorrhea dominate. Levels of pituitary, adrenal, ovarian and thyroid serum hormones were within the reference norm in most cases, but have statistically significant deviations from similar indicators of healthy control women who did not have COVID-19. One-third of women of early reproductive age after moderate to severe COVID-19 had elevated prolactin levels. Ayurvedic phytocompositions Femicycle and Femimens in a comprehensive rehabilitation program for post-COVID menstrual health disorders led to a faster recovery of menstrual health and a full hormonal recovery.Conclusions. Ayurvedic phytocompositions Femicycle and Femimens are effective and safe naturopathic drugs for restoring menstrual health in women of early reproductive age after experiencing moderate to severe COVID-19.

Adrenal limb thickness is associated with metabolism profiles in patients with diabetes: A cross-sectional study.

The association between adrenal size and metabolic profiles in patients with diabetes mellitus (DM) is unclear. This study was conducted to determine whether the adrenal thickness measured by computed tomography (CT) is correlated with the metabolic profiles of patients with DM. This was a cross-sectional study including 588 Chinese hospitalized patients with DM without comorbidities or medications known to affect adrenal morphology or hormone secretion. Adrenal limb thickness was measured on unenhanced chest CT. Participants were stratified into tertiles according to their total adrenal limb thickness. Linear and logistic regression models were used to estimate the correlations. After adjustment for sex and age, the adrenal thickness was positively associated with body mass index (BMI), waist circumference (WC), urinary albumin/creatinine ratio, and 24-h urinary free cortisol (UFC) and negatively correlated with high-density lipoprotein cholesterol. The sequential equation model (SEM) suggested UFC partially mediated the effect of adrenal limb thickness on WC by 12%. Adrenal thickness, but not UFC, was associated with a higher risk of existing hypertension (odds ratio [OR] = 3.78, 95% confidence interval [CI] 1.58, 9.02) and hyperlipidemia (OR = 2.76, 95% CI 1.03, 7.38), independent of age, gender, BMI, and WC. The adrenal thickness is independently associated with BMI, WC, cortisol levels, urinary albumin/creatinine ratio, hypertension, and dyslipidemia but not glycemic parameters in patients with diabetes. Our study encourages further studies to investigate the role of adrenal physiology in patients with diabetes.

Urinary Organophosphate and Neonicotinoid Metabolites in relation to Sex and Adrenal Hormones among Adolescents living in Ecuador

Urinary Organophosphate and Neonicotinoid Metabolites in relation to Sex and Adrenal Hormones among Adolescents living in Ecuador

Myopathies of endocrine origin: A review for physicians

Myopathies are a common manifestation of endocrine disorders. Endocrine myopathies are often overlooked while considering differential diagnoses in patients with musculoskeletal symptoms. The hindrance to mobility and the musculoskeletal discomfort owing to these myopathies are important causes of disability and depreciated quality of life in these patients. Endocrine myopathies occur due to the effects of endogenous or iatrogenic hormonal imbalance on skeletal muscle protein and glucose metabolism, disrupting the excitation-contraction coupling. Abnormalities of the pituitary, thyroid, parathyroid, adrenal, and gonadal hormones have all been associated with myopathies and musculoskeletal symptoms. Endocrine myopathies can either be the complication of a secondary endocrine disorder or a presenting symptom of a missed underlying disorder. Therefore, an underlying endocrine abnormality must always be excluded in all patients with musculoskeletal symptoms. This review presents a compilation of various endocrine myopathies, their etiopathogenesis, clinical presentation, diagnostic modalities, and treatment protocols.

Treatment with dexamethasone's effects on pregnant women and their fetuses Guinea pigs' Thyroid and Adrenal Hormones

Among the common small laboratory animals, the guinea pig has a thyroid and adrenal hormone pattern most similar to that in humans. Daily administration of 10mg Dexamethasone s/c from 55 days of pregnancy for 6 days resulted in a depression of fetal body and organ weight and depression of maternal and fetal plasma T4, T3, and cortisol concentration. However, an increase in fetal plasma T4 and T3 concentration rates suggests enhanced de-iodination of T4. In human fetuses, late in gestation, a rise in plasma cortisol may not be necessary for organ maturation. Considerable species differences have been observed concerning the type of hormone secreted by the adrenal cortex. Keywords: Dexamethasone, fetal cortisol, Thyroxin, Triiodothyronine, Guinea pigs.

Clinical Characteristics and Long-Term Outcomes of Adrenal Tumors in Children and Adolescents.

Adrenal tumors are generally rare in children and can be a part of familial cancer syndrome. This research was conducted to examine the clinical outcomes, histopathological results, and genetic etiologies of adrenal tumors in children and adolescents. Thirty-one children and adolescents with adrenal tumors were included. Data on clinical outcomes and endocrine and radiologic results were retrospectively analyzed. Molecular analysis was conducted in select patients according to their phenotype and family history. The median age at diagnosis was 7.9 years (range: 0.8-17.8 years) with 5.1±1.8 cm of maximum tumor diameter. Adrenal adenoma (n=7), carcinoma (n=5), borderline (n=2), isolated micronodular adrenocortical disease (n=2), pheochromocytoma (n=8), paraganglioma (n=3), and ganglioneuroma (n=4) are all pathological diagnoses. The most common presenting symptom was excess production of adrenocortical hormones (n=15), including virilization and Cushing syndrome. Non-functioning adrenocortical tumors were found in a patient with congenital adrenal hyperplasia. Genetic etiologies were identified in TP53 (n=5), VHL (n=4), and PRKACA (n=1). Patients with mutations in TP53 were young (1.5±0.5 years) and had large masses (6.1±2.3 cm). This study describes clinical outcomes and the pathological spectrum of adrenal tumors in children and adolescents. Adrenocortical tumors mostly presented with an excess of the adrenocortical hormone. Patients with genetic defects presented at a young age and large size of tumors, necessitating genetic testing in patients at a young age.

Anorexia nervosa and adrenal hormones: a systematic review and meta-analysis.

Anorexia nervosa is a primary psychiatric disorder characterized by self-induced negative energy balance. A number of hormonal responses and adaptations occur in response to starvation and low body weight including changes in adrenocortical hormones. Our objective was to systematically review adrenocortical hormone levels in anorexia nervosa. We searched MEDLINE and EMBASE for studies that reported at least one adrenocortical hormone, including dehydroepiandrosterone (DHEA), DHEA-sulphate (DHEA-S), progesterone, 17-hydroxyprogesterone, pregnenolone, cortisol (serum, urine, cerebrospinal fluid, and hair sample), aldosterone, androstenedione, and testosterone in patients with anorexia nervosa and normal-weight healthy controls from inception until October 2021. Means and standard deviations for each hormone were extracted from the studies to calculate a mean difference (MD). A pooled MD was then calculated by combining MDs of each study using the random-effects model. We included a total of 101 studies with over 2500 females with anorexia nervosa. Mean cortisol levels were significantly higher in anorexia nervosa as compared to normal-weight controls for multiple forms of measurement, including morning cortisol, 12-hour and 24-hour pooled serum cortisol, 24-hour urine cortisol, and after an overnight dexamethasone suppression test. In contrast, mean serum total testosterone and DHEA-S levels were significantly lower among patients with anorexia nervosa. Women with anorexia nervosa have higher cortisol levels and lower DHEA-S and testosterone levels compared to women without anorexia nervosa. This finding is important to consider when evaluating low-weight women for disorders involving the adrenal axis, especially Cushing's syndrome.

Dehydroepiandrosterone (DHEA) Supplementation in Rheumatic Diseases: A Systematic Review.

Dehydroepiandrosterone (DHEA) is an adrenal hormone used to treat rheumatic conditions such as systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), rheumatoid arthritis (RA) with controversial results. To review the results of DHEA use in rheumatic diseases. PubMed, Scielo, Scopus, and Embase databases were systematically searched for articles on the treatment of rheumatic diseases with DHEA between 1966 and April 2023. Twenty-one studies were identified: 13 in SLE, 5 in SS, 2 in RA, and 1 in fibromyalgia. DHEA use in SLE has shown a mild to moderate effect on disease activity, a positive effect on bone mineral density (BMD), and improved fatigue. The studies on SS showed a decrease in symptoms of dry mouth, but its performance did not differ from placebo in disease activity. In RA, a questionable effect on disease activity was noted. The only study on fibromyalgia failed to show any improvement. The drug was well tolerated; mild androgenic effects were the most common complaints. DHEA seems to have a place in SLE treatment, where it improves BMD and disease activity. The use in RA, SS, and FM is questionable.

Genethormonal Outlook of Epilepsy: A Case Report Associated with Catamenial Epilepsy

Epilepsy can be considered as unprovoked seizures within 24 hours. From decades, seizures shrouded even when CNS was not studied. With the help of case study, we have tried to point out a hypothetical point correlating genetically acquired epilepsy and catamenial epilepsy. So far, studies have been conducted on the influence of female sex hormones upon differently oriented electrical charges in the brain and related complications. The present article describes genetic variations and hormonal changes as two sides of the disease condition. We have tried to explain the mechanism of QARS gene mutation from previously researched data and an evidence-based study of the same has been done for a better understanding of the reader. The article has aimed discussion upon etiological factors including female sex hormones, thyroid hormones, insulin, prolactin, alteration in bone metabolism, adrenal hormones, and genetic epilepsy for better apprehension of pathological conditions. Keywords: Catamenial epilepsy, genetic epilepsy, adrenal hormones, unprovoked seizures

How do eating disorders can affect the endocrine system? - literature review

Introduction: Eating disorders (ED) are complex psychological disorders with low rates of detection and early intervention. High rates of morbidity and mortality in eating disorders, especially anorexia nervosa (AN), is still continued. ED mostly refers to adolescent and lead to many significant complications, including many changes in endocrine system. Hormonal disorders in AN occur among sex hormones, thyroid hormones, adrenal hormones, growth hormones, as well as the entire hypothalamic-pituitary axis. 
 Purpose of the study: The aim of this study is to collect and summarize the latest views on endocrine dysregulation in anorexia nervosa and highlights the complications associated with it.
 Material and method: Literature review was performed in English different databases, using keywords: eating disorders, anorexia nervosa, menstruation, menses, irregular menstruation, estrogen, bone mineral density, cortisol, hipercortisolemia, insulin, leptin, ghrelin, growth hormone, thyroid, tyrosine.
 Results and conclusions: In our systematic review we would like to present the most significant hormone dysregulation in anorexia nervosa and how they can affect the whole organism, such as gonadal axis disregulation, menstrual disorders, bone mineral density, hipercortisolemia, hypoglycemia and other that anorexia nervosa may cause. The phenomenon of eating disorder is becoming more and more frequent – for this reason it is important to put attention to that and be aware of many complication ED can lead to, including hormonal changes.

Transplantation of porcine adrenal spheroids for the treatment of adrenal insufficiency.

Primary adrenal insufficiency is a life-threatening disorder, which requires lifelong hormone replacement therapy. Transplantation of xenogeneic adrenal cells is a potential alternative approach for the treatment of adrenal insufficiency. For a successful outcome of this replacement therapy, transplanted cells should provide adequate hormone secretion and respond to adrenal physiological stimuli. Here, we describe the generation and characterization of primary porcine adrenal spheroids capable of replacing the function of adrenal glands in vivo. Cells within the spheroids morphologically resembled adult adrenocortical cells and synthesized and secreted adrenal steroid hormones in a regulated manner. Moreover, the embedding of the spheroids in alginate led to the formation of cellular elongations of steroidogenic cells migrating centripetally towards the inner part of the slab, similar to zona Fasciculata cells in the intact organ. Finally, transplantation of adrenal spheroids in adrenalectomized SCID mice reversed the adrenal insufficiency phenotype, which significantly improved animals' survival. Overall, such adrenal models could be employed for disease modeling and drug testing, and represent the first step toward potential clinical trials in the future.