Human-like adrenal features in Chinese tree shrews revealed by multi-omics analysis of adrenal cell populations and steroid synthesis

The Chinese tree shrew(Tupaia belangeri chinensis)has emerged as a promising model for investigating adrenal steroid synthesis,but it is unclear whether the same cells produce steroid hormones and whether their production is regulated in the same way as in humans.Here,we comprehensively mapped the cell types and pathways of steroid metabolism in the adrenal gland of Chinese tree shrews using single-cell RNA sequencing,spatial transcriptome analysis,mass spectrometry,and immunohistochemistry.We compared the transcriptomes of various adrenal cell types across tree shrews,humans,macaques,and mice.Results showed that tree shrew adrenal glands expressed many of the same key enzymes for steroid synthesis as humans,including CYP11B2,CYP11B1,CYB5A,and CHGA.Biochemical analysis confirmed the production of aldosterone,cortisol,and dehydroepiandrosterone but not dehydroepiandrosterone sulfate in the tree shrew adrenal glands.Furthermore,genes in adrenal cell types in tree shrews were correlated with genetic risk factors for polycystic ovary syndrome,primary aldosteronism,hypertension,and related disorders in humans based on genome-wide association studies.Overall,this study suggests that the adrenal glands of Chinese tree shrews may consist of closely related cell populations with functional similarity to those of the human adrenal gland.Our comprehensive results(publicly available at http://gxmujyzmolab.cn:16245/scAGMap/)should facilitate the advancement of this animal model for the investigation of adrenal gland disorders.

Expression of Angiotensin Ⅱ Receptors in Aldosterone-producing Adenoma of the Adrenal Gland and Their Clinical Significance

The expression of angiotensin Ⅱ type 1 receptor (AT1R) and angiotensin Ⅱ type 2 receptor (AT2R) in aldosterone-producing adenoma (APA) of the adrenal gland was detected, and their relationship with clinical indexes of APA was analyzed. The mRNA expression of AT1R and AT2R in 50 cases of APA and tissues adjacent to tumors and 12 cases of normal adrenal tissues was detected by using reverse transcriptase polymerase chain reaction (RT-PCR). The expression of AT1R and AT2R proteins in paraffin-embedded slices of tissue was detected by immunohistochemistry. The expression of AT1R in adenoma, tissues adjacent to tumor, and normal tissues of the adrenal gland showed no significant differences. The expression of AT2R in APA tissue was lower than that in normal adrenal gland tissues (P<0.05). Correlation analysis of the mRNA expression level of AT2R and clinical data from patients demonstrated that AT2R expression was negatively related to plasma aldosterone concentration (PAC) (r=-0.467, P<0.05), but positively related with plasma renin activity (PRA) (r=0.604, P<0.05). It is concluded that down-regulation of the AT2R expression is possibly related with the tumorigenesis of APA.

Evaluation of Normal Adrenal Gland Volume by 64-slice CT

Objective To measure volume and other parameters of normal adrenal glands in Chinese adults with 64-slice multidetector CT, to evaluate the relationship of volume result with age, sex and body size, and to explore the correlations between adrenal volume and other measurements. Methods This study was based on 125 acquired contrast-enhanced upper abdominal CT scans performed with a 64-slice CT. The final study group consisted of 81 patients (49 males, 32 females). Portal venous phase images were studied for the measurements. Both the reconstruction interval and thickness were 1.5 mm. Each adrenal gland was outlined manually with computer-assistant technology to calculate its volume. The maximal sectional area, length, width and thickness of each adrenal gland were also measured. Results The mean age of total population was 47.9±13.0 (range: 20-76) years. The left, right, and total adrenal gland volumes were 4.23±0.74 (range: 2.85-5.83) cm 3 , 4.26±0.86 (2.59-6.56) cm 3 , and 8.50±1.40 (5.80-11.39) cm 3 , respectively. These volumes increased with weight (r=0.381, 0.389, and 0.437 respectively, all P<0.001), height (r=0.386, P<0.001; r=0.297, P=0.007; r=0.384, P<0.001) and body surface area (r=0.406, 0.392, and 0.452, all P<0.001). There was no significant difference in left, right or total adrenal volume with regard to sex after applying General Linear Model procedure to reduce the impact of weight (F=1.304, 0.064, and 0.597, all P>0.05), nor did volume change significantly with age (r=-0.033, -0.014, and -0.026, all P>0.05). Nearly all descriptors of bilateral adrenal glands correlated with ipsilateral volume except thickness (r=-0.027, P=0.814) and width (r=0.166, P=0.138) in the left side. Among these parameters, length had a stronger correlation with volume than others in the both left (r=0.412, P<0.001) and right (r=0.516, P<0.001) adrenal glands. Conclusion Our study has defined the volume distribution and other parameters of normal adrenal glands in Chinese adults, which provide a baseline for future studies.

Role of endoscopic ultrasound fine-needle aspiration evaluating adrenal gland enlargement or mass

AIM:To report the clinical impact of adrenal endoscopic ultrasound fine-needle aspiration(EUS-FNA)in the evaluation of patients with adrenal gland enlargement or mass.METHODS:In a retrospective single-center caseseries,patients undergoing EUS-FNA of either adrenal gland from 1997-2011 in our tertiary care center were included.Medical records were reviewed and results of EUS,cytology,adrenal size change on follow-up imaging≥6 mo after EUS and any repeat EUS or surgery were abstracted.A lesion was considered benign if:(1)EUS-FNA cytology was benign and the lesion remained<1 cm from its original size on follow-up computed tomography(CT),magnetic resonance imaging or repeat EUS≥6 mo after EUS-FNA;or(2)subsequent adrenalectomy and surgical pathology was benign.RESULTS:Ninety-four patients had left(n=90)and/or right(n=5)adrenal EUS-FNA without adverse events.EUS indications included:cancer staging or sus-pected recurrence(n=31),pancreatic(n=20),mediastinal(n=10),adrenal(n=7),lung(n=7)mass or other indication(n=19).Diagnoses after adrenal EUSFNA included metastatic lung(n=10),esophageal(n=5),colon(n=2),or other cancer(n=8);benign primary adrenal mass or benign tissue(n=60);or was non-diagnostic(n=9).Available follow-up confirmed a benign lesion in 5/9 non-diagnostic aspirates and 32/60benign aspirates.Four of the 60 benign aspirates were later confirmed as malignant by repeat biopsy,followup CT,or adrenalectomy.Adrenal EUS-FNA diagnosed metastatic cancer in 24,and ruled out metastasis in 10patients.For the diagnosis of malignancy,EUS-FNA of either adrenal had sensitivity,specificity,positive predictive value and negative predictive value of 86%,97%,96%and 89%,respectively.CONCLUSION:Adrenal gland EUS-FNA is safe,minimally invasive and a sensitive technique with significant impact in the management of adrenal gland mass or enlargement.

Incidentally detected hydatid cyst of the adrenal gland:A case report

Hydatid cysts are a zoonotic disease that can involve many organs and tissues in the human body but primarily involve the liver and lungs. Of the main organs, adrenal glands are those seldom affected by hydatid cysts. The purpose of this study was to present a case with an incidentally detected hydatid cyst of the right adrenal gland on computed tomography, and a positive echincoccus Ig G enzyme-linked immunosorbent assay test on top of a toxic multinodular thyroid goiter for which thyroidectomy was indicated.

Ovarian thecal metaplasia of the adrenal gland in association with Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome(BWS) is an overgrowth syndrome associated with increased risk to develop malignancies including adrenocortical carcinoma. Ovarian thecal metaplasia of the adrenal gland is a rare tumorlike mesenchymal lesion in BWS patients that lacks detailed radiological description. We report a 17-yearold female patient with BWS, associated with bilateral Wilms tumor, hepatic hemangiomatosis, pancreatic neuroendocrine tumor, and a phyllodes tumor of the right breast. Surveillance abdominal ultrasound identified a right adrenal mass that was further characterized by computed tomography and magnetic resonance imaging. Radiologically, this mass displayed features that overlap with adrenocortical carcinoma and pheochromocytoma but after pathological examination this proved to be an ovarian thecal metaplasia of the adrenal gland. Adrenal masses in BWS should raise the suspicion for adrenocortical carcinoma though other adrenal tumors including ovarian thecal metaplasia can be seen in these patients.

Establishment of rat model of combined kidney-adrenal gland allotransplantation

Objective： To establish a rat model of combined kidney-adrenal gland and allotransplantation, and to explore the immunoprotecive effect of the transplanted adrenal gland on the transplanted kidney in the combined transplantation. Methods. SD rats 160 served as donors and recipients. The combined kidney-adrenal gland allotransplantation was performed. Infusion was conducted and prepared at prime position ,and the kidney and adrenal gland were at the left side. Direct vascular anastomosis and operation of connecting ureter attached part of bladder with the bladder were conducted. The kidney pedicle of the right side was ligated. Results： A stable and mature rat model of combined transplantation was established. The warm ischemia time was 30 seconds, and the cold ischemia time was 90-120min.The average time was 100 min. The operation time was 150 min. The survival time of the recipients was 21 days. The successful rate of the operation was 75%. Conclusion： The model of the combined kidney-adrenal gland allotransplantation can be established with higher successful rate. The model can be used to explore that transplanted adrenal gland may have immunoprotecive effect on the transplanted kidney in the combined transplantation.

Ultrasonographic Changes of Adrenal Glands Size under Trilostane Therapy, Their Correlation with Clinical Signs and Endocrine Tests and Possibility of Introducing Ultrasound as Additional Monitoring Modality of Cushing’s Syndrome

A prospective study of 15 dogs with diagnosed Cushing’s syndrome was made to find a correlation between adrenal size enlargement, clinical signs and results of an ACTH stimulation test. To our knowledge, no study was made trying to correlate changes in adrenal size, response to therapy and ACTH stimulation test results. Ultrasonographic evaluation and an endocrine test (ACTH stimulation test/“pre pill”) were performed in each dog two weeks after initiating the therapy, two to four weeks after changing the dosage of trilostane and ideally 10 weeks after establishing the right dosage of trilostane (two owners showed up later on date due pandemic of COVID-19). The results indicate that there is correlation between adrenal size enlargement and response to trilostane therapy. In this study, all dogs that had increase in adrenal gland size of more than 7% showed as well clinical improvement of HAC (hyperadrenocorticism) signs under trilostane therapy. Further, possible multicentric, studies should be performed to verify assumed correlation between adrenal size enlargement and positive response to trilostane therapy.

A Case Report of Two Primary Cancers, Breast Cancer with Adrenal Gland Metastatic and Second Primary Neuroendocrine Tumor in Colon, a Rare Case in Al-Bashir Hospital

A 68 years old female, was diagnosed as a case of right breast cancer in 2013;grade II/III according to Bloom Richardson grading, Modify radical mastectomy (MRM) was done and the pathology report showed moderately differentiated invasive ductal carcinoma (IDC), stage T3N3M0. Immunohisrochemisty (IHC) findings revealed a tumor with Triple positive. Patient refused to treat by chemotherapy. Patient was given adjuvant trastuzumab (first dose 8 mg/kg, followed by 6 mg/kg every three weeks) for the period of one year (16) cycles after which she went on regular follow up. Exemestane tab for 5 years and radiotherapy (50 gray in 25 fractions) was applying on right breast. One year and half after diagnosed primary breast cancer, patient complained from severe diarrhea 8 times per day watery contents, vomiting and suffered from lower abdominal pain. PET scan for whole body in October 2014 was done;the results showed ascending colon is highly suspicious for malignancy and moderately hypermetabolic left adrenal mass. Subtotal colectomy surgery was done, the pathology report of biopsy revealed low grade malignant neuroendocrine neoplastic lesion stage of T3N1Mo. Physician prescribed octreotide acetate 20 mg I. M monthly due to neuroendocrine lesion. In January 2016, cancer recurrence in the same right breast, IHC revealed ER+, PR&minus;, Her 2+, physician decided to change exemestane to fulvestrant 250 mg s. c for 6 cycles. Radiation therapy was applied 20 gray in 10 fractions on scar. In May 2016, CAP-CT scan result revealed two enlarged left axillary L.N and left soft tissue density adrenal mass (3.0 × 2.3). Excisional lymph node was done which revealed IDC, ER+, PR&minus;, Her 2+. Physician decided to discontinue fulvestrant and switch to exemestane 20 mg monthly. CAP-CT was done in Feb 2017;single left axillary L.N 1 cm, small hypodense lesion (spleen 4 cm), left adrenal lesion (2.2 × 2.6 cm) and osteolytic lesion were noted in iliac areas, so the physician considered those results a metastatic area from breast and prescribed lapatinib 84 tablets. Patient now onoctreotide acetate 20 mg I. M, trastuzumab 440 m, exemestane and lapatinib tablets) monthly, zoledronic acid 4 mg q 3 months, patient now still on follow up with a good condition. Conclusion: Breast cancer metastatic to left adrenal gland which is extremely rare especially when they originate from IDCs. The present case is the seventh breast cancer metastatic to the adrenal gland in the literature up to our search. Neuroendocrine tumor was happened in colon after one year and half which was a rare second primary malignancy (SPM) among female breast cancer.

Adrenal gland

950265 The rapid ACTH stimulation test and the ini-tial clinical application.PENG Jun-ying(彭俊英),etai.Dept Endocrinol,PUMC Hosp,Bejing,100730.Bei-jing Med J 1994;6(6):323-327.The response to rapid ACTH stimulation test (250μg β1-24ACTH,iv bolus) was measured with indicesof serum F in normals and patients with primary andsecondary adrenal insufficiency,and Cushing’s syn-drome.In 20 normais,serum F level was increased.After β1-24ACTH iv 3-day rapid ACTH test wasperformed in patients with primary and secondary a-drenal insufficiency,the results showed that had no re-

Case of metachronous bilateral isolated adrenal metastasis from colorectal adenocarcinoma and review of the literature

rarely has a solitary, metachronous bilateral adrenal metastasis of colorectal cancer been reported. We depict a 41-year-old man who underwent sigmoid colon cancer radical surgery followed by adjuvant chemotherapy for alocally ulcerative sigmoid adenocarcinoma with metachronous bilateral adrenal metastasis revealed by a computed tomography scan. histopathological examination showed adenocarcinoma, compatible with metastasis from the rectal cancer. the level of serum carcinoembryonic antigen had indicative significance for the presence of adrenal metastasis in the reported series. We performed a literature analysis related to this pathological characteristic and attach importance to consistent, vigilant radiological surveillance of the adrenal glands in the patients' follow up for colorectal cancer with or without subsequent adrenal metastasis.

Adrenal lymphangioma masquerading as a pancreatic tail cyst

Cystic lymphangiomas of the adrenal gland are rare. A 79-year-old female presented in the emergency room with epigastric discomfort, and an immovable mass was palpated in her abdomen upon physical examination. Imaging studies revealed a large cystic lesion in the pancreatic tail. The radiologic impression ruled out the possibility of a mucinous cystic neoplasm, or a pseudocyst in the pancreas. The operative findings demonstrated that the cystic mass originated in the left adrenal gland. A laparoscopic excision of the cystic mass was performed, and immunohistochemistry confirmed that this mass was a lymphangioma of the adrenal gland. Several prior reports have suggested that lymphangioma can mimic renal or splenic cysts. However, lymphangioma cases mimicking pancreatic cysts are very rare.

Laparoscopic resection of an adrenal pseudocyst mimicking a retroperitoneal mucinous cystic neoplasm

Adrenal pseudocysts are rare cystic masses that arise within the adrenal gland and are usually non-functional and asymptomatic. Adrenal pseudocysts consist of a fibrous wall without a cellular lining. We report a patient with a 9 cm, left-sided suprarenal cystic mass who presented with abdominal discomfort of 2 years' duration. A 38-year-old woman was referred to our service for evaluation of abdominal discomfort and gastrointestinal symptoms. Routine laboratory tests were within normal limits. An abdominal computed tomography scan showed a 9 cm × 8 cm × 8 cm well-defined cystic lesion displacing the left kidney. Magnetic resonance imaging showed a cystic lesion with low signal intensity on the T1-weighted image and high signal intensity on the T2-weighted image. A laparoscopic left adrenalectomy was performed to diagnose the lesion. The final pathology showed an adrenal pseudocyst without a cellular lining. The patient had no postoperative complications and she was discharged four days after surgery.

Maternal betaine suppresses adrenal expression of cholesterol trafficking genes and decreases plasma corticosterone concentration in offspring pullets

Background:Laying hens supplemented with betaine demonstrate activated adrenal steroidogenesis and deposit higher corticosterone(CORT)in the egg yolk.Here we further investigate the effect of maternal betaine on the plasma CORT concentration and adrenal expression of steroidogenic genes in offspring pullets.Results:Maternal betaine significantly reduced(P<0.05)plasma CORT concentration and the adrenal expression of vimentin that is involved in trafficking cholesterol to the mitochondria for utilization in offspring pullets.Concurrently,voltage-dependent anion channel 1 and steroidogenic acute regulatory protein,the two mitochondrial proteins involved in cholesterol influx,were both down-regulated at m RNA and protein levels.However,enzymes responsible for steroid syntheses,such as cytochrome P450 family 11 subfamily A member 1 and cytochrome P450 family 21 subfamily A member 2,were significantly(P<0.05)up-regulated at m RNA or protein levels in the adrenal gland of pullets derived from betaine-supplemented hens.Furthermore,expression of transcription factors,such as steroidogenic factor-1,sterol regulatory element-binding protein 1 and c AMP response element-binding protein,was significantly(P<0.05)enhanced,together with their downstream target genes,such as 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase,LDL receptor and sterol regulatory element-binding protein cleavage-activating protein.The promoter regions of most steroidogenic genes were significantly(P<0.05)hypomethylated,although methyl transfer enzymes,such as AHCYL,GNMT1 and BHMT were up-regulated.Conclusions:These results indicate that the reduced plasma CORT in betaine-supplemented offspring pullets is linked to suppressed cholesterol trafficking into the mitochondria,despite the activation of cholesterol and corticosteroid synthetic genes associated with promoter hypomethylation.

Long-term survival of a patient with a large adrenal primitive neuroectodermal tumor: A case report

BACKGROUND Adrenal primitive neuroectodermal tumor(PNET) is an extremely rare malignant tumor with poor prognosis and of neural crest origin. Herein, we report a case of adrenal PNET and summarized its clinical and pathological characteristics on the basis of 16 patients reported recently.CASE SUMMARY A female patient aged 25 years presented with right lumbago for 12 mo, and preoperative computed tomography showed a huge right adrenal mass. She received tumorectomy, and post-operative pathological examination showed adrenal PNET. After surgery, she underwent adjuvant chemotherapy and was followed up 31 mo after surgery. She received brachytherapy for right paracolic and hepatic metastases. She was alive and followed up for 60 mo. In available studies, only 57.14%(4/7) and 44.44%(4/9) were positive for the expression of neuron-specific enolase and synaptophysin, respectively, although CD99 expression was found in all the patients(100%; 10/10).CONCLUSION It is concluded that adrenal PNET is very rare and highly malignant, and histology is a golden standard in its diagnosis. Surgery and adjuvant therapy is the main treatment.

Adrenal myelolipoma within myxoid cortical adenoma associated with Conn's syndrome

The coexistence of myelolipoma within adrenal cortical adenoma is extremely rare,for both tumors present usually as separate entities.There are only 16 such cases reported worldwide.To the best of our knowledge,the case we reported here is the first one of myxoid adrenal cortical adenoma associated with myelolipoma reported.A 32-year-old Chinese woman with 4-year history of hypertension was presented in our study.Computed tomography(CT)of the abdomen showed a large heterogene- ously-enhancing mass(4.5 cm in diameter)in the left suprarenal region.Clinical history and laboratory results suggest a metabolic disorder as Conn's syndrome.The patient underwent a left adrenalectomy,and a histopathological study confirmed the mass to be a myxoid adrenal cortical adenoma containing myelolipoma.The patient was postoperatively well and discharged uneventfully.In the present case report,we also discuss the etiology of simultaneous myelolipoma and adrenal adenoma associated with Conn's syndrome,and the methods of the diagnosis and differential diagnosis.

Diffuse large B cell lymphoma with bilateral adrenal and hypothalamic involvement: A case report and literature review

BACKGROUND Non-Hodgkin’s lymphoma(NHL)can involve extralymphatic organs,resulting in diverse clinical manifestations,especially if the endocrine organs are affected.This type of involvement can often be difficult to detect accurately.Until now,no patients with NHL and concomitant bilateral adrenal and hypothalamic involvement have been reported.The purpose of this article is to discuss the diagnosis and treatment of lymphoma with bilateral adrenal gland and hypothalamic involvement so as to help physicians avoid misdiagnosis and missed diagnosis.CASE SUMMARY We describe a case of a 52-years-old male patient with bilateral adrenal masses,who presented with a fever of unknown origin on admission.Subsequently,hypopituitarism of the anterior pituitary followed by posterior pituitary developed.18fluorine-fluorodeoxyglucose positron emission tomography/computed tomography(PET/CT)showed lesions with a high metabolism in both adrenal glands,hypothalamus,left supraclavicular lymph nodes,and other organs.The etiological diagnosis was determined based on a left supraclavicular lymph node biopsy.The patient,who eventually present with panhypopituitarism,was finally diagnosed with diffuse large B cell lymphoma with bilateral adrenal gland and hypothalamic involvement.After immunochemotherapy,glucocorticoids administration and desmopressin acetate replacement therapy,the symptoms of fever and panhypopituitarism improved,and all the lesions reduced in size.CONCLUSION This report demonstrates that,although synchronous involvement of two endocrine organs is rare in NHL,extra caution should be taken when dysfunction occurs in multiple endocrine organs.

Myxoid adrenal cortical adenoma—the first case reported in China

Myxoid adrenal cortical adenoma is a rare tumor and till now only 9 cases have been presented in the world. We here report another case of myxoid adenoma of the adrenal gland in a 45-year-old Chinese man who was admitted to hospital because of the right adrenal mass and mild hypertension. At surgery, the mass was well-circumscribed, measured 3.3 cm in diameter. Light-microscopic findings showed most of the tumor region with myxoid stroma, and the tumor cells were benign-look- ing. Immunohistochemical study showed the tumor had the positivity for vimentin, synaptophysin, neuron specific endolase but negative with cytokeratin and epithelial membrane antigen. Moreover, it was negative with alpha-inhibin that is not in accordance with those reported. There was no finding corresponding to malignancy.

Adrenal metastasis from endometrial cancer: A case report

BACKGROUND Metastases to adrenal glands originate principally from lung, breast, or gastrointestinal cancers, followed by malignant melanoma and thyroid neoplasms. We present an unusual case of uterine cancer metastasizing to the adrenal glands with a review of the English literature on the management of this rare disease. CASE SUMMARY A 53-year-old Caucasian woman with a history of endometrial cancer (grade 2;International Federation of Gynecology and Obstetrics III A) was hospitalized in November 2017 for a left adrenal mass found on a follow-up computed tomography scan 3 years after her gynecological surgery. Laboratory test results were normal. A laparoscopic left adrenalectomy was performed. The postoperative course was uneventful, and no chemotherapy was administered. The pathological report confirmed an adrenal endometrioid metastasis. At 36 mo of follow-up, the patient is alive and well, with no evidence of recurrent disease. A literature review identified only 11 previously-published cases of adrenal metastases from uterine cancer. CONCLUSION Adrenal metastasis from uterine cancer is very rare. Laparoscopic adrenalectomy may be an effective treatment in selected cases of localized adrenal metastasis.