Adrenocortical Research Articles

Electron Microscopic Studies of the Adrenal Gland during Seasonal Cycle of Fruit Eating Bat Pteropus Giganteus giganteus

The fine structure of the adrenal gland is testified in many mammals; whereas, very diminutive information is available on the fine structure of the bat’s adrenal gland. The present work is constrained to the ultrastructural studies of the adrenal gland of Pteropus giganteus giganteus. The adrenal gland of the male bat has two distinct perceptible zonations viz., cortex and medulla. The cortex is divided into three illustrious zones namely, zona glomerulosa, zona fasciculata and zona reticularis. The differences in the zonation under the electron microscope becomes more acute when the studied bat is sexually active. Histoarchitectural study of the adrenal gland designate prominent structures and striking differences in the adrenocortical zone during the sexually active period than the sexually quiescent period. The zona fasciculata is well developed during the sexually active period than that of the sexually quiescent period. Likewise, zona fasciculata is well developed as compared to zona glomerulosa and zona reticularis of the adrenal cortex in both active and quiescent stages. Light microscopic studies on adrenal gland are confirmed by the ultrastructural studies.

Adrenocortical Carcinoma about One Case and Literature Review

Introduction: Adrenocortical carcinoma (ACC) is a rare malignant tumor that develops in the layers of the adrenal cortex with an incidence of 0.5–2 per million per year. Case report: A 40-year-old female patient, admitted for left flank heaviness, evaluation was in favour of a suspicious left adrenal tumour, the non-functional caracater was retained after a negative secretory workup. The patient was operated on with a histological appearance of metastatic ACC. Discussion and conclusion: The prognosis for these tumors is poor, since at the time of diagnosis the majority of cases are already metastatic, especially when the tumour is non-functional. The management of ACC is complex, representing a real diagnostic and therapeutic challenge.

Analysis of associations of personality traits and stress with the level of serum cortisol in Sakha (Yakut) men

The purpose of this study is to test the hypothesis that personality traits and stressful situations experienced in childhood could be associated with the level of serum cortisol. The sample included 121 healthy adult men of Yakut (Sakha) ethnicity aged 18 to 27 years. To assess personality traits, the TCI temperament and character questionnaire by R. Cloninger was used. Serum cortisol levels were assessed by enzyme-linked immunosorbent assay (ELISA). It was found that such a temperament trait as “reward dependence” is associated with higher level of cortisol in the blood (p = 0.04). Experienced stressful situations are associated with the character trait “self-transcendence” (p = 0.049) but do not significantly affect cortisol levels. In individuals with high levels of stress, significant correlations were found between the “novelty seeking” (r = 0.33) and “self-directedness” (r = 0.36) with serum cortisol levels, which may reflect the prolonged effect of stress on increasing the sensitivity of the adrenal cortex. The results indicate a possible connection between one of the human temperament traits “reward dependence” and higher levels of cortisol in the blood. A high level of experienced stress situations reduces scores on the character trait “self-transcendence.”

Evolutionary Characteristics in Primary Aldosteronism Patients.

Primary aldosteronism is predominantly caused by excessive aldosterone production from the adrenal cortex, and the aldosterone-producing structures could take many forms, like adenomas, nodules, micronodules, and so on. Most studies of primary aldosteronism were limited to the hotspot driver genes responsible for autonomous aldosterone production; however, the panoramic genetic architecture and genomic alterations of aldosterone-producing structures and their adjacent hyperplasia glands remain unknown. In this study, whole-exome sequencing and transcriptome sequencing (RNA-seq) analyses were performed using functional nodules and matched hyperplasia tissues, which were microdissected guided by aldosterone synthase immunohistochemistry. Phylogenetic trees were constructed based on the shared and unique mutations, gene mutation spectrums, and clonal characteristics. The rates of mutations represented higher means of functional nodules than hyperplasia samples, and the little mutational overlap was shown between the 2 groups on phylogenetic trees. The mutations of the aldosterone driver gene (KCNJ5 or CACNA1D) were only observed in functional nodules and indicated almost the largest values of cancer cell fraction. Moreover, the functional nodules also harbored some potential variants related to cell proliferation, which were not detected in hyperplasia tissues. Transcriptome analysis suggested that only 25.5% upregulated and 23.3% downregulated genes overlapped between functional nodules and hyperplasia tissues. This study demonstrated a genetic and transcriptome landscape of aldosterone-producing structures and adjacent hyperplasia glands in primary aldosteronism. The results indicated independent clonal origins on functional nodules and hyperplasia tissues, and little mutual evolutionary relationship was found on their phylogenetic trees.

The Application and Pharmaceutical Development of Etomidate: Challenges and Strategies.

Etomidate is a synthetic imidazole anesthetic that exerts hypnotic effects by potentiating the action of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) or directly activating the anionic GABA (GABAA) receptor. It stands out among many anesthetics because of its multiple advantages, such as good hemodynamic stability and minimal inhibition of spontaneous respiration. However, its low water solubility and side effects, such as adrenal cortex inhibition and myoclonus, have limited the clinical application of this drug. To address these issues, extensive research has been conducted on the drug delivery of etomidate in recent decades, which has led to the emergence of different etomidate preparations. Despite so many etomidate preparations, so far some of the toxic side effects have not yet been effectively addressed. Herein we discuss the pharmaceutical design of etomidate that may resolve the above problem. We also propose targeted strategies for future research on etomidate preparations and discuss the feasibility of different administration routes and dosage forms to expand the application of this drug. Through this review, we hope to draw more attention to the potential of etomidate and its application challenges and provide valuable insights into the development of new etomidate preparations.

Clinical and Genetic Mechanisms in Patients with MC2R Deficiency Presenting with Early Puberty.

Melanocortin receptor 2 (MC2R) in the adrenal cortex controls the hypothalamic-pituitary-adrenal axis. The melanocortin system, influenced by leptin, regulates GnRH neurons, crucial for puberty onset and fertility. This study evaluates early puberty in primary adrenal insufficiency (PAI) patients due to MC2R gene alterations. Seven patients with PAI (P1-P7) from five unrelated families, all presenting with early or precocious puberty, were included. MC2R deficiency diagnosis ranged from 1 day to 11 months. MKRN3, DLK1, KISS1, and KISS1R genes were analyzed using Sanger sequencing in four cases (P2,P4,P6 and P7). All clinical data were obtained retrospectively. Puberty onset mean age was 8.6 years (7.4-9.5) in boys (P1, P2, P3, P7) and 8.5 years (7.4-9.5) in girls (P4, P5, P6). Tumor markers were negative; no adrenal rest or tumors were found. GnRH analogs were used for rapid puberty in P2, P3, P6. Final height in P1 and P2 was below target (-2.6 SDS, -0.7 SDS). Menarche occurred at 11 and 11.3 years in P4 and P5. No pathogenic variants were found. Genetic causes of early puberty were not identified. Elevated ACTH may stimulate kisspeptin neurons, triggering puberty. Close monitoring of these patients for pubertal development is recommended.

Subunit-Specific Developmental Roles of PI3K in SF1-Expressing Cells.

Phosphatidylinositol 3-kinase (PI3K) regulates cellular development and energy homeostasis. However, the roles of its subunits in organ development remain largely unknown. We explored the roles of PI3K catalytic subunits in steroidogenic factor 1 (SF1)-expressing cells through knockout (KO) of the p110α and p110β subunits. We examined mice with a double KO of p110α and p110β in SF1-expressing cells (p110αβ KOSF1). Although these animals exhibited no significant changes in the development of the ventromedial hypothalamus, we noted pronounced hypotrophy in the adrenal cortex, testis, and ovary. Additionally, corticosterone and aldosterone levels were significantly reduced. The absence of these subunits also resulted in decreased body weight and survival rate, along with impaired glucose homeostasis, in p110αβ KOSF1 mice. The data demonstrate the specific roles of PI3K catalytic subunits in the development and function of SF1-expressing organs.

Historical Control Background Incidence of Spontaneous Nonneoplastic Lesions of Sprague Dawley Rats in 104-Week Carcinogenicity Studies.

Microscopic observation data collected from approximately 1800 male and female Sprague Dawley (SD) control rats used on 104-week carcinogenicity studies performed at North American Labcorp Early Development, Inc, Madison, WI, were retrospectively evaluated for spontaneous nonneoplastic findings. This study provides incidence of the most common spontaneous nonneoplastic microscopic findings in each organ system of SD rats encountered during 104-week carcinogenicity studies. Some of the most common spontaneous background findings were cardiomyopathy; chronic progressive nephropathy; uterine cystic endometrial hyperplasia; prostate inflammation; pulmonary alveolar macrophage infiltrates; hepatocyte vacuolation, bile duct hyperplasia, and basophilic foci in the liver; pancreatic fibrosis; splenic extramedullary hematopoiesis and pigment; decreased lymphocytes and epithelial hyperplasia in the thymus; ventral brain compression; cystic degeneration and hyperplasia of the adrenal cortex; and mammary gland hyperplasia. The most common nonneoplastic findings in male SD rats were chronic progressive nephropathy (80.9%) and rodent progressive cardiomyopathy (73.2%). The most common nonnenoplastic findings in female SD rats were cystic degeneration of the adrenal cortex (64.7%) and ventral compression of the brain due to pituitary neoplasms (62.7%).

A case of X-Linked adrenoleukodystrophy caused by a novel mutation with singular clinical manifestation: unilateral lower limb weakness.

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene, leading to the accumulation of very long-chain fatty acids (VLCFAs) in plasma and tissues. It primarily affects the central nervous system white matter and the adrenal cortex. Clinical manifestations include myeloneuropathy, leukodystrophy, and adrenal insufficiency. Reliable methods for diagnosis include VLCFAs and genetic testing. We report the case of a 31-year-old male X-ALD patient who mainly presented with unilateral lower limb weakness. Adrenal insufficiency was not observed, and there was no evidence of peripheral nerve involvement in nerve conduction studies. MRI revealed only mild atrophy of thoracic spinal cord without other relevant abnormalities. Ultimately, Next-Generation Sequencing (NGS) and VLCFAs testing confirmed the diagnosis of X-ALD, and the NGS indicated a novel missense mutation.

Respiratory failure and rhabdomyolysis caused by severe hypokalemia in a young female with hypertension: a rare critical condition in primary aldosteronism

BackgroundThe two classic manifestations of primary aldosteronism are hypertension and hypokalemia. However, acute respiratory failure due to hypokalemia in primary hyperaldosteronism is rare.Case presentationThe patient was a 27-year-old female who presented with drowsiness and weakness in all extremities. She had been diagnosed with hypertension three years prior, with irregular follow-up, and had a history of preeclampsia one year later. She exhibited high blood pressure and severe hypokalemia (2 mEq/L), leading to respiratory depression and impending respiratory arrest. Consequently, the patient was intubated and transferred to the intensive care unit (ICU). She also developed rhabdomyolysis. Blood pressure tests, including hormonal tests (aldosterone: 13.2 ng/dL, plasma renin activity: 0.32 ng/mL/h), were conducted. Due to the high aldosterone-renin ratio, an abdominopelvic computed tomography (CT) scan was performed. The CT scan revealed a 14 × 12 mm round mass with a washout value above 60%, consistent with an adrenal adenoma, leading to a diagnosis of primary aldosteronism. The patient was discharged after stabilization, and one and a half months after ICU admission, a laparoscopic left adrenalectomy was successfully performed without post-operative complications. Histopathology showed encapsulated hypertrophy of the adrenal cortex with a predominance of large clear cells, confirming the diagnosis of adrenal adenoma. At the most recent follow-up, the patient had normal potassium levels, was normotensive without any medications, and exhibited no alarming signs or symptoms.ConclusionRespiratory depression to the extent of impending respiratory failure and rhabdomyolysis as a result of hypokalemia in primary aldosteronism are extremely rare. In this patient, who developed respiratory depression due to resistant hypokalemia, timely investigation of secondary causes and diagnosis of adrenal adenoma were crucial. The surgery provided definitive treatment for the patient’s blood pressure and prevented the recurrence of life-threatening complications.

Texture analysis can predict response to etoposide-doxorubicin-cisplatin in patients with adrenocortical carcinoma.

The adrenocortical carcinoma (ACC) is a rare and highly aggressive malignancy originating from the adrenal cortex. These patients usually undergo chemotherapy with etoposide, doxorubicin, cisplatin and mitotane (EDP-M) in case of locally advanced or metastatic ACC. Computed tomography (CT) radiomics showed to be useful in adrenal pathologies. The study aimed to analyze the association between response to EDP-M treatment and CT textural features at diagnosis in patients with locally advanced or metastatic ACCs. We enrolled 17 patients with advanced or metastatic ACC who underwent CT before and after EDP-M therapy. The response to treatment was evaluated according to RECIST 1.1, Choi, and volumetric criteria. Based on the aforementioned criteria, the patients were classified as responders and not responders. Textural features were extracted from the biggest lesion in contrast-enhanced CT images with LifeX software. ROC curves were drawn for the variables that were significantly different (p < 0.05) between the two groups. Long-run high grey level emphasis (LRHGLE_GLRLM) and histogram kurtosis were significantly different between responder and not responder groups (p = 0.04) and the multivariate ROC curve combining the two features showed a very good AUC (0.900; 95%IC: 0.724-1.000) in discriminating responders from not responders. More heterogeneous tissue texture of initial staging CT in locally advanced or metastatic ACC could predict the positive response to EDP-M treatment. Adrenal texture is able to predict the response to EDP-M therapy in patients with advanced ACC.

Role of Gonadal Steroid Hormones in the Eye: Therapeutic Implications.

Gonadal steroid hormones are critical regulatory substances involved in various developmental and physiological processes from fetal development through adulthood. These hormones, derived from cholesterol, are synthesized primarily by the gonads, adrenal cortex, and placenta. The synthesis of these hormones involves a series of enzymatic steps starting in the mitochondria and includes enzymes such as cytochrome P450 and aromatase. Beyond their genomic actions, which involve altering gene transcription over hours, gonadal steroids also exhibit rapid, nongenomic effects through receptors located on the cell membrane. Additionally, recent research has highlighted the role of these hormones in the central nervous system (CNS). However, the interactions between gonadal steroid hormones and the retina have received limited attention, though it has been suggested that they may play a protective role in retinal diseases. This review explores the synthesis of gonadal hormones, their mechanisms of action, and their potential implications in various retinal and optic nerve diseases, such as glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), or retinitis pigmentosa (RP), discussing both protective and risk factors associated with hormone levels and their therapeutic potential.

Gut microbiota causally impacts adrenal function: a two-sample mendelian randomization study

Some studies have reported that the gut microbiota can influence adrenal-related hormone levels. However, the causal effects of the gut microbiota on adrenal function remain unknown. Therefore, we employed a two-sample Mendelian randomization (MR) study to systematically investigate the impact of gut microbiota on the function of different regions of the adrenal gland. The summary statistics for gut microbiota and adrenal-related hormones used in the two-sample MR analysis were derived from publicly available genome-wide association studies (GWAS). In the MR analysis, inverse variance weighting (IVW) was used as the primary method, with MR-Egger, weighted median, and cML-MA serving as supplementary methods for causal inference. Sensitivity analyses such as the MR-Egger intercept test, Cochran’s Q test, and leave-one-out analysis were used to assess pleiotropy and heterogeneity. We identified 27 causal relationships between 23 gut microbiota and adrenal function using the IVW method. Among these, Sellimonas enhanced the function of the adrenal cortex reticularis zone (beta = 0.008, 95% CI: 0.002–0.013, P = 0.0057). The cML-MA method supported our estimate (beta = 0.009, 95% CI: 0.004–0.013, P = 2 × 10− 4). Parasutterella, Sutterella, and Anaerofilum affect the functioning of different regions of the adrenal gland. Notably, pleiotropy was not observed. Our findings revealed that the gut microbiota is causally associated with adrenal function. This enhances our understanding of the gut-microbiota-brain axis and provides assistance in the early diagnosis and treatment of adrenal-related diseases in clinical practice.

Adrenal insufficiency - causes and laboratory diagnosis.

Adrenal insufficiency (AI) manifests as a clinical syndrome arising from either the direct impairment of adrenal glands, leading to primary AI characterized by deficiencies in glucocorticoids and mineralocorticoids, or adrenal cortex atrophy due to diminished adrenocorticotropic hormone (ACTH) stimulation, a consequence of hypothalamic and/or pituitary damage, resulting in secondary AI. The diagnosis of AI is based on clinical assessment and biochemical tests, including basal hormone level measurements and stimulation tests. In evaluating the results of laboratory tests, it is necessary to consider factors that may influence both pre-analytical and analytical phases, as well as the chosen methodology. Correct diagnosis of adrenal insufficiency and timely initiation of suitable replacement therapy are paramount. These steps are crucial not only for managing the condition but also to avert potentially life-threatening adrenal crises.

7290 Hippo Signaling Regulates Zona Glomerulosa Cell Fate In The Adrenal Cortex Of Mice

Abstract Disclosure: N. Abou Nader: None. N. Jakuc: None. M. Meinsohn: None. L. Charrier: None. M. Paquet: None. G. St-Jean: None. J. Brind’Amour: None. D. Boerboom: None. J. Mao: None. D. Pepin: None. G. Zamberlam: None. D.T. Breault: None. A. Boyer: None. The Hippo signaling is a major signaling pathway that regulates processes such as cell proliferation and differentiation during both embryogenesis and postnatal homeostatic maintenance in several tissues. Our recent findings, using the Nr5a1-cre model, have highlighted the essential role of Lats1 and Lats2 (large tumor suppressor homolog kinases 1/2), the main kinases of the Hippo signaling cascade, in maintaining proper differentiation of mouse developing adrenocortical cells by suppressing their differentiation into myofibroblast-like cells. However, since the abnormal transdifferentiation of Lats1/2-negative adrenocortical cells occurs before the establishment of zonation when using the Nr5a1-cre model, the role of Hippo signaling in zona glomerulosa (zG) cells could not be assessed with this model. To overcome this limitation, we inactivated Lats1/2 in aldosterone-producing zG cells using the zG cell-specific AS-cre strain (Lats1flox/flox; Lats2flox/flox; AScre/+). We report here that specific loss of Lats1/2 in steroidogenic zG cells results in the accumulation of an important extracellular matrix (ECM) in the zG an outer zona fasciculata (zF) by 4 weeks of age; a phenotype that does not seem to progress with aging. In addition, tracing experiments demonstrate that the inactivation of Lats1/2 leads to the ectopic transdifferentiation of the zG cells into the ECM-producing cells rather than into zF cells. We then performed RNAseq experiments on whole adrenals which further suggested that the ECM producing cells derived from zG cells share characteristics with chondroblast/osteoblast mesenchymal progenitors among other cell lineages and, that the ectopic transdifferentiation of zG cells triggers a significant inflammation/immune response in the adrenal cortex. Our study also demonstrates that the increased activity of the Hippo pathway effectors YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) is responsible for the ectopic transdifferentiation of the zG cells as their concomitant inactivation with Lats1/2 (Yapflox/flox; Tazflox/flox; Lats1flox/flox; Lats2flox/flox; AScre/+) rescues the observed phenotype. Finally, we also demonstrate that the expression of a constitutively active form of YAP (YAP5SA) in zG cells (Rosa26YAP5SA/+; AScre/+) does not alter their identity as severely as the loss of Lats1/2 but leads to adrenal hyperplasia. Together, these novel findings underscore the crucial role of Hippo signaling in maintaining the identity of zG cells in the adrenal cortex. Presentation: 6/2/2024

7427 Cellular Senescence As A Pro-Tumorigenic Process And Therapeutic Target In Adrenocortical Carcinoma

Abstract Disclosure: L. Smith: None. K. Warde: None. S. Haston: None. J. Martinez-Barbera: None. K. Basham: None. Adrenocortical carcinoma (ACC) is a rare, yet highly aggressive malignancy that arises in the adrenal cortex. Advanced age is a major risk factor for ACC, with the peak age incidence between 50 and 60 years old. Older individuals above age 50 also have significantly worse survival outcomes. A better understanding of how aging contributes to the development and progression of ACC will uncover new treatment strategies. A major hallmark of aging is the systemic accumulation of senescent cells. While senescent cells have been implicated in various age-related diseases, including cancer, their role in ACC remains poorly understood. ACC tumors from older patients have an enrichment of senescence-associated gene signatures. Moreover, advanced ACC patients are treated with etoposide, doxorubicin, and cisplatin (EDP), which are chemotherapies that induce senescence. While EDP offers short-term benefit in some patients, more than half will progress within 6-months. We hypothesize that the accumulation of senescent cells that arise after EDP treatment are ultimately tumor-supportive long-term. As a result, we postulate that the use of senolytic compounds that clear away senescent cells after EDP treatment will lead to improved survival outcomes for ACC patients. We developed a new ACC mouse model that provides a window to study the role of senescence in ACC tumor progression and treatment. Our model is based on adrenal specific loss of ZNRF3, which is a Wnt inhibitor that is frequently inactivated in human ACC tumors. Despite early adrenal hyperplasia, we showed that Znrf3 conditional knockout (cKO) mice do not develop adrenal tumors until 18-months of age, which corresponds to the peak age incidence in humans. Additionally, the adrenals of Znrf3 cKO mice show a robust senescence activation phenotype that precedes adrenal tumorigenesis. We hypothesize that the accumulation of senescent cells is pro-tumorigenic long-term. To test our hypothesis, we combined Znrf3 cKO mice with a newly established mouse model that enables selective ablation of senescent cells (ZKO-FDR mice). Ongoing aging studies will determine whether the removal of early and late senescent cells in ZKO-FDR mice reduces adrenal tumorigenesis. Further, we established new primary tumor cell lines from aged ZKO-FDR mice. These cell lines will facilitate testing of the pro-tumor mechanisms of senescence. Additionally, they will permit the removal of senescent cells, both genetically and pharmacologically with senolytics, as a new treatment strategy in ACC. Overall, this project aims to investigate the pro-tumor biology of age- and therapy-induced senescence in ACC. Results from these studies will advance our understanding of senescence in cancer and aid in the development of new therapeutic strategies for ACC, including senolytics. Presentation: 6/2/2024

6371 Conditional Deletion Of Nr5a1 In Sox9-cre Mice Impairs Adrenal Development

Abstract Disclosure: Y. Ikeda: None. A. Tagami: None. K. Ishizuka: None. M. Maekawa: None. The adrenal cortex is a major tissue that produces steroidogenic hormones necessary for regulating body homeostasis. Nuclear receptor subfamily 5, group A, member 1 (Nr5a1, SF-1, or Ad4BP) plays a crucial role in the regulation of adrenal and gonadal development, function and maintenance. SRY-related HMG-box gene 9 (Sox9) is upregulated by interaction of SRY with NR5A1, and leads the supporting cell precursors in XY gonads to differentiate into Sertoli-lineage cells at the initiation of testis differentiation. We previously generated Sox9-cre-Nr5a1flox/flox conditional knockout (cKO) mice, and showed that the loss of Nr5a1 in the gonads of XY Sox9-cre-Nr5a1flox/flox cKO mice abrogated the testicular pathway at embryonic day (E) 12.5–E13.5 to result in postnatal male-to-female gonadal sex reversal (1). Here, we investigated adrenal development of the Sox9-cre-Nr5a1flox/flox cKO mice. In mammals, after separation from the common adrenogonadal primordium, the adrenal primordium, which is formed dorsomedial to the gonadal primordium, begins to develop around E11.5. Double-immunostaining for NR5A1 and SOX9 revealed the presence of cells expressing both NR5A1 and SOX9 in the adrenal primordium of both sexes at E11.5 but not at E12.5. At E12.5, the number of NR5A1+ adrenocortical cells in Sox9-cre-Nr5a1flox/flox cKO mice markedly decreased compared with Nr5a1+/+ mice, and apoptotic cells, which were immunolabelled for active caspase 3, were detected in the area of the adrenal primordium in Sox9-cre-Nr5a1flox/flox cKO mice but not in Nr5a1+/+ mice, indicating that NR5A1- and SOX9-immunoreactive adrenocortical cells in Sox9-cre-Nr5a1flox/flox cKO mice were extinguished by apoptosis due to the activation of the Sox9-cre transgene. At E13.5–postnatal day 20, Sox9-cre-Nr5a1flox/flox cKO adrenals were hypoplastic associated with reduced number of NR5A1-immunoreactive adrenocortical cells, and only a few medullary cells immunolabelled for tyrosine hydroxylase, a marker of chromaffin cell precursors, were infiltrated into the adrenal primordium. Our findings suggest that sufficient number of adrenal cortical progenitors at the earliest stage of adrenal development are required for the subsequent adrenal development. In 8-week-old, Sox9-cre-Nr5a1flox/flox cKO adrenals were smaller in size compared with Nr5a1+/+ adrenals, but showed relatively normal organization with the medulla surrounded by the cortex. However, unlike XY Nr5a1+/+ adrenals, cells immunolabelled for the X-zone marker 20αHSD were observed at the junction between the cortex and medulla in XY Sox9-cre-Nr5a1flox/flox cKO adrenals, probably due to the sex reversal of the XY gonads, since androgen induces regression of the X-zone. Reference: (1) Ikeda et al., Sci Rep. 2021 Feb 24;11(1):4486. Presentation: 6/2/2024

6768 A Rare Presentation of Primary Adrenal Insufficiency with Hypertension &amp; Hypokalemia

Abstract Disclosure: A.M. San Hernandez: None. R. Alshantti: None. G. Espinoza Mercado: None. J.L. San Hernandez: None. Introduction: Adrenal Insufficiency is caused by the failure of the adrenal cortex to produce glucocorticoids +/- mineralocorticoids. This can be due to a defect in the adrenal cortex, or in the hypothalamic pituitary axis. The clinical manifestations are usually non-specific, ranging from mild vague symptoms to life threatening crisis. Therefore, diagnosis requires a high level of suspicion by providers. Unusual presentations of primary adrenal insufficiency (PAI) with hypertension and hypokalemia have been rarely described in the literature. We present a rare case of PAI with hypertension and hypokalemia. Case Presentation: A 68 years old female with a medical history of rheumatoid arthritis, hypothyroidism on Levothyroxine, chronic transaminitis, and bicytopenia presented to the hospital with a 6 weeks history of generalized weakness, loss of appetite, weight loss, and dizziness. Patient denied any diuretic or steroid use within the last 2 years. On arrival, she was afebrile, hypertensive (168/84mmHg), with normal oxygenation and pulse. Physical examination was unremarkable with normal volume status. Initial laboratory results showed low sodium 116 mEq/L, low serum osmolality 247 MEQ/kg, normal potassium 3.6 mEq/L, Creatinine 0.3 mg/dL &amp; BUN 9 mg/dL. She was initially started on IVF normal saline. Further workup revealed normal TSH &amp; FT4 levels. Urine study showed urine osmolality (477 MOSM/KG), &amp; urine sodium (127 mEq/L). Given these findings, SIADH was suspected and fluid restriction was started. Sodium level continued to be low with minimal improvement to 120 mEq/L, potassium levels also dropped (3.3-3.2 mEq/L), requiring daily replacement. BP remained elevated ranging from 150s to 160s systolic and 80s to 90s diastolic. Hypertension was controlled with her home medication Amlodipine. Although atypical presentation with hypertension &amp; hypokalemia, the diagnosis of adrenal insufficiency was considered. Laboratory evaluation showed low morning cortisol 5.2 ug/dL, with album level 3.5 g/dL. Cosyntropin stimulation test showed 1.3 ug/dL (at baseline), 9.9 (30 min post administration), and 14.4 (1 hour post administration); results confirming PAI. ACTH, Renin, Aldosterone, &amp; DHEAS levels were normal. CT adrenal was normal. Patient was started on hydrocortisone; some of her symptoms &amp; Na level improved. Further investigation of the etiology of PAI and possible hyperaldosteronism is pending outpatient follow up. Conclusion: Adrenal insufficiency is a life threatening condition with serious consequences if diagnosis is missed. It manifests by a wide spectrum of symptoms and signs, some can be masked by the presence of other comorbid conditions leading to atypical presentations. Our case highlights the importance of maintaining a high level of suspicion of adrenal insufficiency in patients with atypical presentation, including those with hypertension &amp; hypokalemia. Presentation: 6/3/2024

7438 DAX1/NR0B1 Related Adrenal Hypoplasia Congenita Without Hypogonadotropic Hypogonadism

Abstract Disclosure: R.L. Figueiredo: None. J.B. Drummond: None. A. Meireles: None. J.L. Machado: None. G. Vidigal: None. B.S. Rocha: None. Background: X-linked congenital adrenal hypoplasia (AHC) is a rare disease caused by genetic mutations in DXA1/NRB01 gene, which encodes a nuclear hormone receptor expressed in the adrenal cortex, gonads, hypothalamus and anterior pituitary gland, occurring in less than 1:12,500 live births (1,2). AHC is characterized by primary adrenal insufficiency (PAI) associated with hypogonadotropic hypogonadism (HH) and impaired spermatogenesis (oligospermia or azoospermia). Although DAX1/NR0B1 mutations can manifest with different phenotypes, HH is mostly present, which makes this present case a diagnostic challenge. Clinical case: A 23-year-old man presented with typical symptoms of adrenal insufficiency at the age of 7 (abdominal pain, dehydration, nausea, vomiting and cutaneous hyperpigmentation). Initial testing was consistent with primary adrenal failure: elevated ACTH levels (1250pg/mL, RR&amp;lt;46pg/mL) and very low serum cortisol (0.8mcg/dL, RR 3-20mcg/dL). Etiological investigation excluded autoimmune etiology (negative anti-adrenal and anti-21-hydroxylase antibodies) as well as adrenoleukodystrophy (normal very long chain fatty acid levels). Physical exam revealed normal virilization, testicular volume and penile length. The patient reported normal libido and sexual function. Hormonal evaluation showed normal total testosterone (424 and 713ng/dL, RR 165 to 753ng/dL) as well as calculated free testosterone (7.2 and 11.4ng/mL, RR&amp;gt;3.8ng/mL) levels. Abdominal CT showed signs of bilateral adrenal hypoplasia. We then proceeded to genetic testing that revealed a pathological variant c.625C&amp;gt;T:p (Gln 209*) in hemizygosity in exon 1 of the DAX 1/NR0B1 gene. This is a nonsense mutation that introduces a premature stop codon. This variant is not present on the global and Brazilian genetic databases (gnomAD and ABraOM) and has not been previously described in the literature. The patient is currently being treated for adrenal insufficiency with the lowest tolerated dose of prednisone (7.5mg/day) and fludrocortisone 0.1mg/day. Conclusion: Etiological investigation of patients with PAI is essential to understand the evolution of the disease, monitoring extra-adrenal manifestations and the possibility of genetic counseling for the family. An intact hypothalamic-pituitary gonadal axis should not preclude genetic evaluation for a DAX/NR0B1 mutation in patients with PAI and suspected AHC. Further studies will clarify if this specific mutation carries a genotype-phenotype correlation in patients with AHC without HH.

8774 An Uncommon Presentation Of A Large Silent Pheochromocytoma

Abstract Disclosure: M. Lozano: None. A. Pinero-Pilona: None. Background: The reported estimated incidence of pheochromocytoma is approximately 2-8 cases per 1 million people per year. Of those, silent pheochromocytomas will make up about 8%. Thus, biochemically silent and non-secreting pheochromocytomas are a very rare phenomenon. Clinical Case: A 74-year-old Caucasian female with significant past medical history of primary hypothyroidism, hypercholesterolemia, and nasal sinus carcinoma s/p surgery (in remission) presented to the clinic for endocrine evaluation of a right adrenal mass. The patient was asymptomatic and denied headaches, tachycardia, sweating, severe hypertension, diabetes, muscle weakness, easy bruising, or striae. The mass was initially diagnosed as an incidental finding after a contrast CT scan of the abdomen was performed for diverticulitis. The right adrenal enhancing mass was 2.3 x 3.9 x 4.1 cm in diameter. Subsequent MRI abdomen with and without contrast ordered by the referring physician showed that the adrenal mass had grown to 4.9 x 3.8 x 5.4 cm and was hyperenhancing in nature with central T2 hyperintense signal. Notably, multiple “parasitized and arborealized” vessels were detected within the mass. Such findings led us to suspect metastatic versus primary adrenal neoplasm such as cortical carcinoma as a working diagnosis. Other laboratory studies including plasma free metanephrines (&amp;lt;10 pg/mL, normal 0-88 pg/mL), plasma normetanephrines (29.2 pg/mL, normal 0-285.2 pg/mL) and 24-hour urine collections (24 hr urine epinephrine - 3 ug/24 hr [normal 0-20 ug/24 hr]; 24 hr urine norepinephrine - 75 ug/24 hr [normal 0-135 ug/24 hr]; 24 hr urine VMA - 3 mg/24 hr [normal 0-7.5 mg/24 hr]) were negative for pheochromocytoma. As her mass was greater than 4 cm in diameter, surgical referral was then recommended to the patient. Right adrenalectomy was performed. Pathology report was consistent with pheochromocytoma as supported by immunohistochemistry. Ki-67 proliferation index was 0-10% (average 3-4%, rare hotspots 10%). Atrophy and vascular ectasia were present in residual non-neoplastic adrenal cortex and medulla. Histology showed a nested growth pattern, absence of composite tumor elements, absence of necrosis, and no atypical mitoses. The incidence of non-secreting pheochromocytomas has been quoted to be 0.000064% (1). Conclusion: The case illustrates an uncommon presentation of a large, silent pheochromocytoma with negative plasma metanephrines accompanied by negative urine studies, which have a negative predictive value close to 100% in ruling out a pheochromocytoma. Our case emphasizes the importance of considering pheochromocytoma on the differential of adrenal masses with high attenuation or high enhancement even when biochemical studies suggest otherwise. Reference: (1) Radojkovic, D., et al. "CLINICALLY" SILENT GIANT PHEOCHROMOCYTOMA. CASE REPORT." Acta Endocrinologica (1841-0987) 9.1 (2013). Presentation: 6/1/2024