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Background and Aims: Superior imaging techniques have increased the recognition of adrenal pathology. Distinguishing benign from malignant adrenocortical tumors is not always easy. Several criteria and immunohistochemical markers have been discovered which help to differentiate between adrenocortical adenoma (ACA) and adrenocortical carcinoma (ACC). Our aim here was to evaluate the diagnostic and prognostic role of steroidogenic factor-1 (SF-1) in adult adrenocortical tumors (ACT) diagnosed using the Weiss criteria. In this cohort, we have also analyzed Ki67 and p53 expression and the extent of agreement between SF-1 and Ki-67. Methodology: This was a retrospective, observational study comprising 24 cases of adult ACT over 10 years. Immunohistochemical staining for SF-1, Ki67, and p53 was done in all the cases, and the results correlated with the morphological diagnosis made using Weiss criteria. Results: SF-1 was 100% sensitive and 80% specific as a marker of malignancy. Increased SF-1 expression correlated with worse survival. There was a moderate degree of agreement between Ki-67 labeling-index and SF-1 as a marker of malignancy with the kappa coefficient being 0.75. The sensitivity of p53 was lower than Ki67 in diagnosing ACC. Conclusion: In adult ACTs, SF-1 has diagnostic significance and prognostic implication. SF-1 is a crucial, dosage-dependent survival factor in ACC. There is a moderate extent of agreement between Ki-67 and SF-1 as a marker of malignancy.
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Steroidogenic factor-1 (SF-1, NR5A1) is a transcription factor that plays a key role in the development of gonad and adrenal gland. NR5A1 gene mutation is one of the common causes of disorders of sex development(DSD). Heterozygous mutations of NR5A1 gene accounts for the majority of reported cases with various phenotyre. Early reported cases manifested with varying degrees of 46, XY gonadal dysplasia, whereas NR5A1 mutation was revealed to be related with the phenotypes of azoospermia in men and premature ovarian insufficiency in women recently. Adrenocortical insufficiency is absent in most cases. The heterogeneity of the clinical phenotype is considered resulting from the functional impact of different gene mutations on transcriptional activity, dose effect of downstream target gene(such as SOX9)and the genetic background of oligogenic mutation, etc. The process and regulation of gonadal development might be understood comprehensively by investigating the genotype and related phenotype of NR5A1.
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Objective To summarize the clinical manifestations of 46, XX ovotesticular disorder of sex development (DSD) caused by a NR5A1 heterozygous mutation. Methods The first case of 46,XX ovotesticular DSD was caused by a NR5A1 heterozygous mutation in China and was reported with a review of 11 similar cases in the literatures since July 2016. Results A 5. 6-year-old child raised as female was born with ambiguous genitalia. The left gonad was palpable in the inguinal region while the right one was located in abdomen. Gonadal histology showed both ovotestis. Vaginoscopy revealed a short, blind-ending vagina. No uterine was detected by laparoscopy. Repeated karyotype results were 46, XX with SRY gene negative. A heterozygous de novo mutation ( p. Arg92Trp) in the accessory DNA-binding region of NR5A1 gene was found in that child. Conclusions We reported for the first time in China a new phenotype caused by a NR5A1 heterozygous mutation-46,XX ovotesticular DSD. According to the review of literatures, such mutation seemed with incomplete penetrance. It could cause both 46, XX DSD and 46, XY DSD with varied manifestations. The possible underlying mechanism might relate to the impairment of the binding between the mutant protein and target DNA which might lead to a decreased inhibition of the male developmental pathway through downregulation of female antitestis genes.
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Objective To summarize the clinical manifestations of 46, XX ovotesticular disorder of sex development (DSD) caused by a NR5A1 heterozygous mutation. Methods The first case of 46,XX ovotesticular DSD was caused by a NR5A1 heterozygous mutation in China and was reported with a review of 11 similar cases in the literatures since July 2016. Results A 5. 6-year-old child raised as female was born with ambiguous genitalia. The left gonad was palpable in the inguinal region while the right one was located in abdomen. Gonadal histology showed both ovotestis. Vaginoscopy revealed a short, blind-ending vagina. No uterine was detected by laparoscopy. Repeated karyotype results were 46, XX with SRY gene negative. A heterozygous de novo mutation ( p. Arg92Trp) in the accessory DNA-binding region of NR5A1 gene was found in that child. Conclusions We reported for the first time in China a new phenotype caused by a NR5A1 heterozygous mutation-46,XX ovotesticular DSD. According to the review of literatures, such mutation seemed with incomplete penetrance. It could cause both 46, XX DSD and 46, XY DSD with varied manifestations. The possible underlying mechanism might relate to the impairment of the binding between the mutant protein and target DNA which might lead to a decreased inhibition of the male developmental pathway through downregulation of female antitestis genes.
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[Summary] Adrenocortical carcinoma is a rare disease with poor prognosis, and its pathogenesis is mainly related to genetic mutations, abnormal expressions of steroidogenic factor-1, insulin-like growth factor 2,cell growth factors including vascular endothelial growth factor, dysfunction of Wnt pathway, as well as dysregulation of microRNA and DNA methylation. In recent years, the intensive molecular studies provide a brand-new methodology to distinguish adrenocortical carcinomas from benign tumors in early stage.
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Objective To investigate the expression and signification of p63,aromatase P450 (P450arom) and steroidogenic factor-1 (SF-1) in endometrial polyp,and to explore its role in the pathogenesis of endometrial polyp.Methods Specimen were collected from hysteroscopic resection,pathologically confirmed endometrial polyp specimens of 30 cases of endometrial polyp and the adjoining endometrium around endometrial polyp in 20 cases,endometrial tissue of normal control group of 25 patients.Immunohistochemistry SP method and real-time PCR technology were used to detect the three groups in the expression of p63,P450arom and SF-1 protein and gene.Results P450arom gene (0.274±0.082) and protein (1.2± 1.1) expression in endometrial polyp was significantly higher than the adjoining endometrium and normal endometrium (P＜0.05); the expression of SF-1 protein (1.1 ±0.8) and p63 protein (0.8±0.5) were also higher in the endometrial polyp than the other two control groups (P＜0.05); while the expression of SF-1 mRNA (0.105±0.049 versus 0.053±0.043) and p63 mRNA (0.261±0.052 versus 0.180± 0.018) in endometrial polyp had no significant difference between endometrial polyp and the adjoining endometrial (P＞0.05).Conclusion p63,P450arom and SF-1 may play a role in the formation of endometrial polyp.
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This article reviews the major advances of basal and clinical research on the adrenal diseases at home and abroad from 2010 to 2012.There are many advances including the diagnostic value of steroidogenic factor-1 in adrenal tumors,the pathogenesis and new diagnostic methods of aldosterone-producing adenoma,the treatment for severe ACTH-dependent Cushing's syndrome,approach to the patient with an adrenal incidentaloma and subclinical hypercortisolism,screening test for subclinical hypercortisolism in the patients with diabetes or osteoporosis,the characterization of macronodular adrenocortical hyperplasia of the zona reticularis,as well as genetic testing for pheochromocytoma and paragangliomas,etc.
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ObjectiveTo detect mRNA and protein expression of steroidogenic factor-1 ( SF-1 ) and DAX-1 in human adrenocortical tumors and normal adrenal cortex,and to investigate the effect of SF-1 and DAX-1 on the steroidogenesis and development of adrenocortical tumors.Methods Total RNA and protein was extracted from angiotensin Ⅱ unresponsive aldoterone-producing adenomas ( A Ⅱ -U-APA,n =12 ),angiotensin Ⅱ responsive aldoterone-producing adenomas ( AⅡ -R-APA,n =5 ),cortisol-producing adenomas ( CPA,n =10 ),adrenal nonfunctional adenomas ( NFA,n =10 ),aldosterone-producing carcinoma ( APC,n =2 ) and normal adrenal cortex ( NAC,n =8).To analyze gene expression of SF-1,DAX-1,ACTH receptor(ACTHR),and β-actin by real-time quantitative PCR in different tissues.The protein expression of SF-1,DAX-1,and β-actin in the same tissues by Western blot.To study the relationship of ACTHR,SF-1,and DAX-1 with clinical data in adrenocortical tumors.ResultsThe expression of SF-1,DAX-1 mRNA and protein was different in NAC,AⅡ -U-APA,A Ⅱ -R- APA,APC,CPA,and NFA tissues [ relative expression of SF-1 mRNA:24.58±2.45,23.89±3.17,21.59±3.00,(38.75,44.16),14.17±2.80,and 36.38±3.50; DAX-1 mRNA:0.57±0.06,0.37±0.05,0.43±0.05,( 1.52,1.21 ),0.39 ±0.04,and 0.83 ±0.08 ; SF-1 protein:0.76 ±0.11,0.76 ±0.10,0.73 ±0.07,(1.24,1.40),0.55±0.04,and0.98±0.10; DAX-1 protein:0.65±0.14,0.39±0.13,0.43±0.14,(1.18,1.02),0.56±0.04,and 1.03±0.13 ; all P＜0.05 or P＜0.01 ].There was negative correlation by higher SF-1/DAX-1 ratio and tumor size in AⅡ -U-APA tissues.The mRNA and protein expression of SF-1 was lower in CPA and there was the positive correlation with tumor size.Conclusion SF-1 and DAX-1 might play a key role in the development of the adrenocortical tumorigenesis and steroidogenic tissues.
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Disorders of sex development (DSD) involve several conditions that result from abnormalities during gonadal determination and differentiation. Some of these disorders may manifest at birth by ambiguous genitalia; others are diagnosed only at puberty, by the delayed onset of secondary sexual characteristics. Sex determination and differentiation in humans are processes that involve the interaction of several genes such as WT1, NR5A1, NR0B1, SOX9, among others, in the testicular pathway, and WNT4, DAX1, FOXL2 and RSPO1, in the ovarian pathway. One of the major proteins in mammalian gonadal differentiation is the steroidogenic nuclear receptor factor 1 (SF1). This review will cover some of the most recent data on SF1 functional roles and findings related to mutations in its coding gene, NR5A1.
Os distúrbios do desenvolvimento sexual (DDS) envolvem várias condições que resultam de anormalidades que podem acontecer tanto na determinação como durante a diferenciação gonadal. Algumas dessas doenças podem se manifestar ao nascimento principalmente por genitália ambígua, outras são diagnosticadas apenas na puberdade por atraso no aparecimento de características sexuais secundárias. A determinação e a diferenciação do sexo em seres humanos são processos que envolvem interações entre vários genes nas vias testicular, tais como NR5A1, NR0B1, WT1, SOX9, entre outros, e ovariana, tais como WNT4, DAX1, FOXL2 e RSPO1. Uma das principais proteínas na diferenciação gonadal de mamíferos é o fator esteroidogênico e receptor nuclear 1 (SF1). Esta revisão cobrirá alguns dos dados mais recentes sobre os papéis funcionais de SF1 e as últimas descobertas relacionadas a mutações em seu gene, NR5A1.
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Child , Female , Humans , Male , Disorders of Sex Development/genetics , Mutation/genetics , Steroidogenic Factor 1/genetics , Disorders of Sex Development/classificationABSTRACT
Objective To investigate the expression of steroidogenic factor 1 ( SF-1 ) in eutopic endometrium,ovarian endometriosis (EM) and adenomyosis.Methods From Jan.2008 to Dec.2010,30 patients with both ovarian endometriotic cysts and adenomyosis underwent hysterectomy,cystectomy or adenxectomy in Peking University First Hospital.The combination of ovarian EM and denomyosis were confirmed in 17 cases.In the mean time,endometria form 10 patients with cervical intraepithelial neoplasm ( CIN ) Ⅲ underwent hysterectomy were selected as controls.The expression of SF-l in eutopic endometrium,ovarian EM and adenomyosis was detected by immunohistochemistry staining.Results No immunoreactivity of SF-l was observed glandular cell and stromal cell in eutopic endometrium of both groups.14/17 of positive rate of SF-l were observed in lesions of ovarian endometriosis.SF-l protein was not expressed in the endometrial glandular cells of ovarian EM and in adenomyosis foci.Conclusion The differences of SF-l expression in ovarian endometrioma and adenomyosis foci might mediate the development of the disease.
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Objective To study the influence of inhibited steroidogenic factor-1 on human adrenocortical H295R cells, and explore its role in the pathogenesis of adrenal tumors. Methods The plasmids pGenesil1-SF-1-shRNA which containing U6 promoter and SF-1-specific short hairpin RNA (shRNA) and pGenesil1-negative-shRNA containing unspecific shRNA were transfected into H295R cell. The expression of SF-1 was measured by Western blot and real-time polymerase chain reaction(RT-PCR). Cell proliferation was analyzed by WST-1 assay and cell count. Ki-67 expression was detected by immunohistochemistry and cell apoptosis was examined by TUNEL assay. Results Compared with those in control cells, the protein and mRNA level of SF-1- transfected cells were reduced by 69.7% and 71.2% (P＜0. 01). WST-1 and cell count method showed that SF-1 gene silencing obviously inhibited cell proliferation(P＜0. 01). By contrast, there was a 3. 7-fold increase in the percentage of apoptotic H295R cells in SF-1-inhibited group than that of control group (P＜0. 01). Immunohistochemistry showed that Ki-67 positive cells in SF-1-inhibited cells were lower than the negative control cells (16.90±2.17) % and (33. 48±3.16)%,(P＜0. 01). Conclusion SF-1 gene silencing can inhibit the proliferation of adrenocortical cells, and it is expected to become a key protein in understanding pathogenesis of adrenal tumors or treating them.