24 results on '"Mendonça, BB"'
Search Results
2. Neonatal Hydrocolpos in Bardet-Biedl syndrome due to a novel frameshift indel in the BBS10 gene.
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Sircili MH, Batista RL, Barreto EQS, Bueno SP, Figueredo Benedetti AF, Craveiro FL, Ramos RM, Monteiro Filho MP, Domenice S, de Mendonça BB, and Denes FT
- Abstract
Introduction: Hydrocolpos, a rare condition characterized by cystic dilatation of the vagina, can arise from various etiologies, including isolated imperforate hymen and vaginal atresia. Genetic conditions, such as Bardet-Biedl syndrome (BBS), may also manifest with hydrocolpos as part of urogenital malformations., Methods: We present a case of neonatal hydrocolpos associated with BBS. Sequencing of 19 BBS genes was performed to elucidate the genetic basis of the syndrome., Results: Genetic analysis revealed a novel frameshift indel variant (c.1546_1547insGATA p.Thr516Argfs*7) in the BBS10 gene. This finding expands the spectrum of BBS mutations and underscores the importance of genetic evaluation in patients with hydrocolpos, particularly when associated with additional clinical features suggestive of syndromic etiology., Conclusion: Pediatric urologists should maintain a high index of suspicion for underlying genetic conditions, including BBS, in neonates presenting with hydrocolpos, given the potential for more severe associated complications such as renal and retinal diseases, obesity, and polydactyly., (S. Karger AG, Basel.)
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- 2024
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3. Renal Function Evolution and Hypoaldosteronism Risk After Unilateral Adrenalectomy for Primary Aldosteronism.
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Queiroz NL, Stumpf MAM, Souza VCM, Maciel AAW, Fagundes GFC, Okubo J, Srougi V, Tanno FY, Chambo JL, Pereira MAA, Pio-Abreu A, Bortolotto LA, Latronico AC, Barisson Villares Fragoso MC, Drager LF, Mendonça BB, and Almeida MQ
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- Humans, Female, Male, Middle Aged, Aldosterone blood, Adult, Risk Factors, Adrenalectomy adverse effects, Hyperaldosteronism surgery, Hyperaldosteronism etiology, Hyperaldosteronism physiopathology, Glomerular Filtration Rate, Hypoaldosteronism etiology, Hypoaldosteronism physiopathology, Kidney physiopathology
- Abstract
Few studies demonstrated a percentage decrease in the estimated glomerular filtration rate (eGFR) at a single time and the rate of hypoaldosteronism after adrenalectomy for primary aldosteronism (PA). Our aim was to investigate the evolution of renal function and the hypoaldosteronism risk after adrenalectomy for PA. Aldosterone, renin, eGFR, and electrolyte levels were determined before and at 1 week, 1, 3 and 6 months after unilateral adrenalectomy in 94 PA patients (40 men and 54 women). The main outcome was the postoperative eGFR decline using analysis of covariance with the preoperative eGFR as a covariate. eGFR decreased during first postoperative week compared to 3 months before surgery. During the first 6 months, eGFR remained stable at similar levels to the first week after surgery. Age (p=0.001), aldosterone levels (p=0.021) and eGFR 3 months before surgery (p+<+0.0001) had a significant correlation with eGFR during first postoperative week. High aldosterone levels at diagnosis were correlated with decline in renal function in the univariate model (p=0.033). In the multivariate analysis, aldosterone levels at diagnosis had a tendency to be an independent predictor of renal function after surgery (p=0.059). Postoperative biochemical hypoaldosteronism was diagnosed in 48% of the cases after adrenalectomy, but prolonged hyperkalemia occurred in only 4 cases (4.5%). Our findings showed a decrease of eGFR after unilateral adrenalectomy for PA. Additionally, aldosterone levels at diagnosis correlated with postoperative renal function. Postoperative biochemical hypoaldosteronism occurred in almost half of the patients, but prolonged hyperkalemia with fludrocortisone replacement was less frequent., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)
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- 2024
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4. Homozygous CDH2 variant may be associated with hypopituitarism without neurological disorders.
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Ferreira NGBP, Madeira JLO, Gergics P, Kertsz R, Marques JM, Trigueiro NSS, Benedetti AFF, Azevedo BV, Fernandes BHV, Bissegatto DD, Biscotto IP, Fang Q, Ma Q, Ozel AB, Li J, Camper SA, Jorge AAL, Mendonça BB, Arnhold IJP, and Carvalho LR
- Abstract
Context: Congenital hypopituitarism is a genetically heterogeneous condition. Whole exome sequencing (WES) is a promising approach for molecular diagnosis of patients with this condition., Objectives: The aim of this study is to conduct WES in a patient with congenital hypopituitarism born to consanguineous parents, CDH2 screening in a cohort of patients with congenital hypopituitarism, and functional testing of a novel CDH2 variant., Design: Genomic DNA from a proband and her consanguineous parents was analyzed by WES. Copy number variants were evaluated. The genetic variants were filtered for population frequency (ExAC, 1000 genomes, gnomAD, and ABraOM), in silico prediction of pathogenicity, and gene expression in the pituitary and/or hypothalamus. Genomic DNA from 145 patients was screened for CDH2 by Sanger sequencing., Results: One female patient with deficiencies in growth hormone, thyroid-stimulating hormone, adrenocorticotropic hormone, luteinizing hormone, and follicle-stimulating hormone and ectopic posterior pituitary gland contained a rare homozygous c.865G>A (p.Val289Ile) variant in CDH2. To determine whether the p.Val289Ile variant in CDH2 affects cell adhesion properties, we stably transfected L1 fibroblast lines, labeled the cells with lipophilic dyes, and quantified aggregation. Large aggregates formed in cells expressing wildtype CDH2, but aggregation was impaired in cells transfected with variant CDH2 or non-transfected., Conclusion: A homozygous CDH2 allelic variant was found in one hypopituitarism patient, and the variant impaired cell aggregation function in vitro. No disease-causing variants were found in 145 other patients screened for CDH2 variants. Thus, CDH2 is a candidate gene for hypopituitarism that needs to be tested in different populations., Significance Statement: A female patient with hypopituitarism was born from consanguineous parents and had a homozygous, likely pathogenic, CDH2 variant that impairs cell aggregation in vitro. No other likely pathogenic variants in CDH2 were identified in 145 hypopituitarism patients.
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- 2023
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5. Arterial Stiffness in Transgender Men Receiving Long-term Testosterone Therapy.
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Cunha FS, Bachega TASS, Costa EMF, Brito VN, Alvares LA, Costa-Hong VA, Verardino RGS, Sircili MHP, de Mendonça BB, Bortolotto LA, and Domenice S
- Abstract
Context: The effects of androgen therapy on arterial function in transgender men (TM) are not fully understood, particularly concerning long-term androgen treatment., Objective: To evaluate arterial stiffness in TM receiving long-term gender-affirming hormone therapy by carotid-femoral pulse wave velocity (cf-PWV)., Methods: A cross-sectional case-control study at the Gender Dysphoria Unit of the Division of Endocrinology, HC-FMUSP, Sao Paulo, Brazil. Thirty-three TM receiving intramuscular testosterone esters as regular treatment for an average time of 14 ± 8 years were compared with 111 healthy cisgender men and women controls matched for age and body mass index. Aortic stiffness was evaluated by cf-PWV measurements using Complior device post-testosterone therapy. The main outcome measure was aortic stiffness by cf-PWV as a cardiovascular risk marker in TM and control group., Results: The cf-PWV after long-term testosterone therapy was significantly higher in TM (7.4 ± 0.9 m/s; range 5.8-8.9 m/s) than in cisgender men (6.6 ± 1.0 m/s; range 3.8-9.0 m/s, P < .01) and cisgender women controls (6.9 ± .9 m/s; range 4.8-9.1 m/s, P = .02). The cf-PWV was significantly and positively correlated with age. Analysis using blood pressure as a covariate showed a significant relationship between TM systolic blood pressure (SBP) and cf-PWV in relation to cisgender women but not to cisgender men. Age, SBP, and diagnosis of hypertension were independently associated with cf-PWV in the TM group., Conclusion: The TM group on long-term treatment with testosterone had higher aging-related aortic stiffening than the control groups. These findings indicate that aortic stiffness might be accelerated in the TM group receiving gender-affirming hormone treatment, and suggest a potential deleterious effect of testosterone on arterial function. Preventive measures in TM individuals receiving testosterone treatment, who are at higher risk for cardiovascular events, are highly recommended., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2023
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6. Cardiopulmonary capacity and muscle strength in transgender women on long-term gender-affirming hormone therapy: a cross-sectional study.
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Alvares LAM, Santos MR, Souza FR, Santos LM, Mendonça BB, Costa EMF, Alves MJNN, and Domenice S
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- Male, Female, Humans, Adult, Cross-Sectional Studies, Hand Strength, Muscle Strength, Hormones, Transgender Persons
- Abstract
Objective: For transgender women (TW) on oestrogen therapy, the effects of prior exposure to testosterone during puberty on their performance, mainly cardiopulmonary capacity (CPC), while exerting physical effort are unknown. Our objective was to evaluate CPC and muscle strength in TW undergoing long-term gender-affirming hormone therapy., Methods: A cross-sectional study was carried out with 15 TW (34.2±5.2 years old), 13 cisgender men (CM) and 14 cisgender women (CW). The TW received hormone therapy for 14.4±3.5 years. Bioimpedance, the hand grip test and cardiopulmonary exercise testing on a treadmill with an incremental effort were performed., Results: The mean VO2peak (L/min) was 2606±416.9 in TW, 2167±408.8 in CW and 3358±436.3 in CM (TW vs CW, p<0.05; TW vs CM, p<0.0001; CW vs CM, p<0.0001). The O2 pulse in TW was between that in CW and CM (TW vs CW, p<0.05, TW vs CM, p<0.0001). There was a high correlation between VO2peak and fat-free mass/height
2 among TW (r=0.7388; p<0.01), which was not observed in the other groups. The mean strength (kg) was 35.3±5.4 in TW, 29.7±3.6 in CW and 48.4±6.7 in CM (TW vs CW, p<0.05; TW vs CM, p<0.0001)., Conclusion: CPC in non-athlete TW showed an intermediate pattern between that in CW and CM. The mean strength and VO2 peak in non-athlete TW while performing physical exertion were higher than those in non-athlete CW and lower than those in CM., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2022
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7. Impact of schooling in the HIV/AIDS prevalence among Brazilian transgender women.
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Batista RL, Verduguez EDR, Inacio M, Cunha FS, Marques MD, Gomes NLRA, Faria JAD Jr, Sircili MHP, Mendonça BB, Costa EMF, and Domenice S
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- Adolescent, Brazil, Cross-Sectional Studies, Female, HIV, Humans, Male, Prevalence, Young Adult, HIV Infections, Transgender Persons
- Abstract
Objective Discrimination and bullying are common conditions among LGBT people. During schooling, these practices compromising education. The aim of this study is to evaluate educational attainment among Brazilian transgender women (TW) and how their education level affects the risk of HIV infection. Study design a cross-sectional population-based study. Subjects and methods 95 adult TW were selected. Information concerning verbal and physical aggression, school dropout, school years (SY), and educational level were assessed. HIV status was screened using a fourth-generation immunoassay followed by western blot testing. Results The mean of SY was 9.1 ± 3.8 ys. The mean age at school dropout was 16.3 ± 3.4 ys old. Verbal aggression was reported by 83%, physical by 48%, and 18% of the TW dropped out school immediately after being physically assaulted. Participants who suffered physical aggression attended school for almost 4 years less than those participants who did not suffer this abuse (OR = -3.96, p < 0.0001). A similar result was found for verbal aggression (OR = -4.35; p < 0.0001). HIV/AIDS prevalence was 18% (n = 17). The mean of SY among HIV/AIDS positive and negative individuals were 6.8 ± 43 versus 9.7 ± 3, respectively (p = 0.004). Lower education was associated with higher frequency of HIV/AIDS among TW and this relationship was sustained after adjustment for injectable drug use and sex work (OR = 0.79, p = 0.04). Conclusion Among Brazilian TW, lower education level was a risk factor associated with HIV. The reasons for low schooling among TW are multifactorial, but verbal and physical harassment strongly contribute for it.
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- 2020
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8. Real-world impact of glucocorticoid replacement therapy on bone mineral density: retrospective experience of a large single-center CAH cohort spanning 24 years.
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Iervolino LL, Ferraz-de-Souza B, Martin RM, Costa FC, Miranda MC, Mendonça BB, and Bachega TS
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- Absorptiometry, Photon, Adult, Child, Glucocorticoids adverse effects, Humans, Retrospective Studies, Young Adult, Adrenal Hyperplasia, Congenital drug therapy, Bone Density
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The congenital adrenal hyperplasia population seems to have an intrinsic tendency to a high frequency of low bone mass. However in this single-center and long-term evaluated cohort, the simplified corticoid regimen, with exclusive dexamethasone single dose reposition during adulthood, did not represent a risk factor for decrease in bone health., Introduction: The impact of long-term and supposedly physiological doses of gluco and mineralocorticoid (GC/MC) on bone mineral density (BMD) in congenital adrenal hyperplasia (CAH) remains discordant among studies, which contain different clinical forms and corticoid regimens. Our aim was to evaluate the BMD in CAH adults receiving similar GC regimen since childhood and to correlate it with GC/MC cumulative doses., Methods: Only patients with good compliance, who used cortisone acetate (CA) during childhood and dexamethasone after the final height achievement. Cumulative GC/MC doses were calculated from diagnosis until last evaluation. BMD was analyzed by the first and last energy X-ray absorptiometry (DXA) scans performed., Results: Twenty simple virilizing (SV) and 14 salt wasting (WS) whose mean age was 26 ± 6 years, mean CA, dexamethasone, and fludrocortisone cumulative doses were 63,813 ± 32,767, 812 ± 558, and 319 ± 325 mg/m
2 , respectively. Based on the last DXA, low BMD was observed in 11% of patients, total hip Z-score was lower in the SW than SV form (p = 0.04). Cumulative CA dose had an inverse correlation with femoral neck Z-score (p < 0.01). Total cumulative GC and MC doses had an inverse correlation with total hip Z-score (p < 0.01). In the analysis of sequential BMD during dexamethasone therapy, no association was observed among cumulative GC/MC doses, clinical forms, sex, and lumbar Z-score delta., Conclusions: Even though a low CA regimen during growth periods in addition to MC replacement appears to have an influence on BMD at femoral sites, interestingly a low dexamethasone one does not seem to be deleterious for bone health in adulthood.- Published
- 2020
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9. A Bayesian Approach to Diagnose Growth Hormone Deficiency in Children: Insulin-Like Growth Factor Type 1 Is Valuable for Screening and IGF-Binding Protein Type 3 for Confirmation.
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Inoue-Lima TH, Vasques GA, Nakaguma M, Brito LP, Mendonça BB, Arnhold IJP, and Jorge AAL
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- Adolescent, Child, Child, Preschool, Cross-Sectional Studies, Female, Humans, Infant, Male, Retrospective Studies, Growth Disorders blood, Growth Disorders diagnosis, Human Growth Hormone deficiency, Insulin-Like Growth Factor Binding Protein 3 blood, Insulin-Like Growth Factor I metabolism
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Background: The utility of insulin-like growth factor type 1 (IGF-1) is well established in the diagnosis of growth hormone deficiency (GHD), whereas IGF-binding protein type 3 (IGFBP-3) has a more controversial role. Most studies evaluated the value of these peptides by assessing their sensitivity and specificity but not considering the low prevalence of GHD among short children (<2%)., Objective: To evaluate the utility of basal IGF-1 and IGFBP-3 values in the GHD diagnosis process with a Bayesian approach, based on pre- and post-test probability., Methods: We determined ROC curves, sensitivity, specificity, and positive and negative predictive values for IGF-1 and IGFBP-3 obtained from patients with GHD (n = 48) and GH-sufficient children (n = 175). The data were also analyzed by classifying the children into early childhood and late childhood (girls and boys younger and older than 8 and 9 years, respectively)., Results: The area under the curve (AUC) of the receiver operating characteristic curve of IGF-1-SDS (standard deviation score) was greater than that of IGFBP-3-SDS (AUC 0.886 and 0.786, respectively, p = 0.001). In early childhood, the AUC of IGFBP-3-SDS was significantly improved (0.866) and similar to IGF-1-SDS (0.898). IGF-1-SDS, in comparison to IGFBP-3-SDS, had a greater sensitivity (92 vs. 45.8%, respectively), lower specificity (69 vs. 93.8%, respectively), and lower positive predictive value (5.7 vs. 13.1%, respectively), with similar negative predictive values., Conclusion: IGF-1-SDS is a useful screening tool in the diagnosis of GHD. Although IGFBP-3-SDS lacks sensitivity, its high specificity supports the role to confirm GHD in short children, especially in early childhood. This strategy could simplify and reduce the necessity of a second laborious and expensive GH stimulation test to confirm the diagnosis of GHD., (© 2020 S. Karger AG, Basel.)
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- 2020
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10. Combined pituitary hormone deficiency caused by PROP1 mutations: update 20 years post-discovery.
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Correa FA, Nakaguma M, Madeira JLO, Nishi MY, Abrão MG, Jorge AAL, Carvalho LR, Arnhold IJP, and Mendonça BB
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- Female, Humans, Hypopituitarism diagnosis, Male, Phenotype, Septo-Optic Dysplasia genetics, Homeodomain Proteins genetics, Hypopituitarism genetics, Mutation genetics
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The first description of patients with combined pituitary hormone deficiencies (CPHD) caused by PROP1 mutations was made 20 years ago. Here we updated the clinical and genetic characteristics of patients with PROP1 mutations and summarized the phenotypes of 14 patients with 7 different pathogenic PROP1 mutations followed at the Hospital das Clínicas of the University of Sao Paulo. In addition to deficiencies in GH, TSH, PRL and gonadotropins some patients develop late ACTH deficiency. Therefore, patients with PROP1 mutations require permanent surveillance. On magnetic resonance imaging, the pituitary stalk is normal, and the posterior lobe is in the normal position. The anterior lobe in patients with PROP1 mutations is usually hypoplastic but may be normal or even enlarged. Bi-allelic PROP1 mutations are currently the most frequently recognized genetic cause of CPHD worldwide. PROP1 defects occur more frequently among offspring of consanguineous parents and familial cases, but they also occur in sporadic cases, especially in countries in which the prevalence of PROP1 mutations is relatively high. We classified all reported PROP1 variants described to date according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines: 29 were pathogenic, 2 were likely pathogenic, and 2 were of unknown significance. An expansion of the phenotype of patients with PROP1 mutations was observed since the first description 20 years ago: variable anterior pituitary size, different pathogenic mutations, and late development of ACTH deficiency. PROP1 mutations are the most common cause of autosomal recessive CPHD with a topic posterior pituitary lobe. Arch Endocrinol Metab. 2019;63(2):167-74.
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- 2019
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11. Primary malignant tumors of the adrenal glands.
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Almeida MQ, Bezerra-Neto JE, Mendonça BB, Latronico AC, and Fragoso MCBV
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- Adrenal Cortex Neoplasms diagnosis, Adrenal Cortex Neoplasms pathology, Adrenal Gland Neoplasms diagnosis, Adrenal Gland Neoplasms pathology, Adrenocortical Carcinoma diagnosis, Adrenocortical Carcinoma pathology, Antineoplastic Agents, Hormonal therapeutic use, Humans, Mitotane therapeutic use, Paraganglioma diagnosis, Paraganglioma pathology, Pheochromocytoma diagnosis, Pheochromocytoma pathology, Adrenal Cortex Neoplasms therapy, Adrenal Gland Neoplasms therapy, Adrenocortical Carcinoma therapy, Paraganglioma therapy, Pheochromocytoma therapy
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Malignancy must be considered in the management of adrenal lesions, including those incidentally identified on imaging studies. Adrenocortical carcinomas (ACCs) are rare tumors with an estimated annual incidence of 0.7-2 cases per year and a worldwide prevalence of 4-12 cases per million/year. However, a much higher incidence of these tumors (>15 times) has been demonstrated in south and southeastern Brazil. Most ACCs cause hypersecretion of steroids including glucocorticoids and androgens. ACC patients have a very poor prognosis with a 5-year overall survival (OS) below 30% in most series. Pheochromocytoma or paraganglioma (PPGL) is a metabolically active tumor originating from the chromaffin cells of the adrenal medulla. The incidence of PPGL is 0.2 to 0.9 cases per 100,000 individuals per year. Pheochromocytomas are present in approximately 4-7% of patients with adrenal incidentalomas. Classically, PPGL manifests as paroxysmal attacks of the following 4 symptoms: headaches, diaphoresis, palpitations, and severe hypertensive episodes. The diagnosis of malignant PPGL relies on the presence of local invasion or metastasis. In this review, we present the clinical and biochemical characteristics and pathogenesis of malignant primary lesions that affect the cortex and medulla of human adrenal glands.
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- 2018
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12. An update of genetic basis of PCOS pathogenesis.
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Crespo RP, Bachega TASS, Mendonça BB, and Gomes LG
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- Female, Humans, Phenotype, Polycystic Ovary Syndrome genetics
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Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder that affects 5-20% of reproductive age women. PCOS clinical symptoms include hirsutism, menstrual dysfunction, infertility, obesity and metabolic syndrome. There is a wide heterogeneity in clinical manifestations and metabolic complications. The pathogenesis of PCOS is not fully elucidated, but four aspects seem to contribute to the syndrome to different degrees: increased ovarian and/or adrenal androgen secretion, partial folliculogenesis arrest, insulin resistance and neuroendocrine axis dysfunction. A definitive etiology remains to be elucidated, but PCOS has a strong heritable component indicated by familial clustering and twin studies. Genome Wide Association Studies (GWAS) have identified several new risk loci and candidate genes for PCOS. Despite these findings, the association studies have explained less than 10% of heritability. Therefore, we could speculate that different phenotypes and subphenotypes are caused by rare private genetic variants. Modern genetic studies, such as whole exome and genome sequencing, will help to clarify the contribution of these rare genetic variants on different PCOS phenotypes. Arch Endocrinol Metab. 2018;62(3):352-61.
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- 2018
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13. Adjuvant radiotherapy for the primary treatment of adrenocortical carcinoma: Are we offering the best?
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Srougi V, de Bessa J Jr, Tanno FY, Ferreira AM, Hoff AO, Bezerra JE, Almeida CM, Almeida MQ, Mendonça BB, Nahas WC, Chambô JL, Srougi M, and Fragoso MCBV
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- Adrenal Cortex Neoplasms surgery, Adrenalectomy, Adrenocortical Carcinoma surgery, Adult, Aged, Aged, 80 and over, Case-Control Studies, Disease-Free Survival, Female, Follow-Up Studies, Humans, Male, Middle Aged, Radiotherapy, Adjuvant methods, Retrospective Studies, Young Adult, Adrenal Cortex Neoplasms radiotherapy, Adrenocortical Carcinoma radiotherapy
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Purpose: To evaluate the role of ARDT after surgical resection of ACC., Materials and Methods: Records of patients from our institutional ACC database were retrospectively assessed. A paired comparison analysis was used to evaluate the oncological outcomes between patients treated with surgery followed by ARDT or surgery only (control). The endpoints were LRFS, RFS, and OS. A systematic review of the literature and meta-analysis was also performed to evaluate local recurrence of ACC when ARDT was used., Results: Ten patients were included in each Group. The median follow-up times were 32 months and 35 months for the ARDT and control Groups, respectively. The results for LRFS (p=0.11), RFS (p=0.92), and OS (p=0.47) were similar among subsets. The mean time to present with local recurrence was significantly longer in the ARDT group compared with the control Group (419±206 days vs. 181±86 days, respectively; p=0.03). ARDT was well tolerated by the patients; there were no reports of late toxicity. The meta-analysis, which included four retrospective series, revealed that ARDT had a protective effect on LRFS (HR=0.4; CI=0.17-0.94)., Conclusions: ARDT may reduce the chance and prolong the time to ACC local recurrence. However, there were no benefits for disease recurrence control or overall survival for patients who underwent this complementary therapy., Competing Interests: Conflict of interest: None declared., (Copyright® by the International Brazilian Journal of Urology.)
- Published
- 2017
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14. Non-coding variation in disorders of sex development.
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Baetens D, Mendonça BB, Verdin H, Cools M, and De Baere E
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- Animals, Disorders of Sex Development diagnosis, Disorders of Sex Development pathology, Forkhead Box Protein L2, Forkhead Transcription Factors genetics, Gene Expression Regulation, Developmental, Gonads growth & development, Gonads pathology, Humans, Mutation, SOX9 Transcription Factor genetics, Sex-Determining Region Y Protein genetics, Steroidogenic Factor 1 genetics, Chromatin genetics, Disorders of Sex Development genetics, Pathology, Molecular, Regulatory Sequences, Nucleic Acid genetics
- Abstract
Genetic studies in Disorders of Sex Development (DSD), representing a wide spectrum of developmental or functional conditions of the gonad, have mainly been oriented towards the coding genome. Application of genomic technologies, such as whole-exome sequencing, result in a molecular genetic diagnosis in ∼50% of cases with DSD. Many of the genes mutated in DSD encode transcription factors such as SRY, SOX9, NR5A1, and FOXL2, characterized by a strictly regulated spatiotemporal expression. Hence, it can be hypothesized that at least part of the missing genetic variation in DSD can be explained by non-coding mutations in regulatory elements that alter gene expression, either by reduced, mis- or overexpression of their target genes. In addition, structural variations such as translocations, deletions, duplications or inversions can affect the normal chromatin conformation by different mechanisms. Here, we review non-coding defects in human DSD phenotypes and in animal models. The wide variety of non-coding defects found in DSD emphasizes that the regulatory landscape of known and to be discovered DSD genes has to be taken into consideration when investigating the molecular pathogenesis of DSD., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2017
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15. Heterozygous Nonsense Mutation in the Androgen Receptor Gene Associated with Partial Androgen Insensitivity Syndrome in an Individual with 47,XXY Karyotype.
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Batista RL, Rodrigues AS, Nishi MY, Feitosa ACR, Gomes NLRA, Junior JAF, Domenice S, Costa EMF, and de Mendonça BB
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- Base Sequence, Exons genetics, Female, Heterozygote, Homozygote, Humans, Male, Microsatellite Repeats genetics, Young Adult, Androgen-Insensitivity Syndrome genetics, Codon, Nonsense genetics, Genetic Predisposition to Disease, Karyotype, Mutation genetics, Receptors, Androgen genetics
- Abstract
There are only 2 patients with 47,XXY karyotype and androgen receptor (AR) gene mutation reported in the literature, and both are diagnosed as complete androgen insensitivity syndrome (CAIS). We report a 22-year-old female with 47,XXY karyotype and atypical external genitalia. Sequencing of AR revealed the heterozygous p.Asn849Lys*32 mutation, and extensive X chromosome microsatellite analysis showed homozygosity for Xp and heterozygosity for Xq, suggesting partial X maternal isodisomy. Partial androgen insensitivity syndrome (PAIS) developed in this case, probably because of the presence of the heterozygous AR mutation and random X- inactivation of the healthy allele. This is the first report of a female patient with 47,XXY karyotype and PAIS phenotype., (© 2017 S. Karger AG, Basel.)
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- 2017
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16. A Novel Homozygous Missense FSHR Variant Associated with Hypergonadotropic Hypogonadism in Two Siblings from a Brazilian Family.
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França MM, Lerario AM, Funari MFA, Nishi MY, Narcizo AM, de Mello MP, Guerra-Junior G, Maciel-Guerra AT, and Mendonça BB
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- Adolescent, Adult, Base Sequence, Brazil, Family, Female, Homozygote, Humans, Male, Pedigree, Exome Sequencing, Hypogonadism genetics, Mutation, Missense genetics, Receptors, FSH genetics, Siblings
- Abstract
Hypergonadotropic hypogonadism (HH) is defined by increased gonadotropin levels in men and women. Primary ovarian failure (POF) is a form of female infertility characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels in women under the age of 40 years. Although several genes have been associated with POF, its causative genes remain to be identified. Here, we used whole-exome sequencing (WES) to study a consanguineous family with a 46,XX girl and a 46,XY man affected by HH. All exons of both siblings and their parents were captured and massively sequenced by WES, and the candidate variant was confirmed by Sanger sequencing. A novel c.1298C>A;p.Ala433Asp missense variant of the follicle-stimulating hormone receptor (FSHR) gene was found in both affected siblings in a homozygous state and in their parents in a heterozygous state. This FSHR variant is not present in available databases (1000 Genomes and NHLBI/EVS) and Brazilian exome controls. Moreover, it is highly conserved and predicted as deleterious in all prediction sites analyzed. In conclusion, the novel homozygous FSHR variant observed in 2 siblings with HH can expand the spectrum of FSHR mutations in humans., (© 2017 S. Karger AG, Basel.)
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- 2017
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17. Negative correlation between tumour size and cortisol/ACTH ratios in patients with Cushing's disease harbouring microadenomas or macroadenomas.
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Machado MC, Alcantara AE, Pereira AC, Cescato VA, Castro Musolino NR, de Mendonça BB, Bronstein MD, and Fragoso MC
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- Adenoma etiology, Adenoma pathology, Adolescent, Adult, Aged, Child, Enzyme-Linked Immunosorbent Assay, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neoplasm Recurrence, Local, Pituitary ACTH Hypersecretion physiopathology, Pituitary Neoplasms etiology, Pituitary Neoplasms pathology, Retrospective Studies, Young Adult, Adenoma blood, Adrenocorticotropic Hormone blood, Hydrocortisone blood, Pituitary ACTH Hypersecretion complications, Pituitary Neoplasms blood
- Abstract
Purpose: Pituitary macroadenomas (MACs) represent 10-30 % of Cushing's disease (CD) cases. The aim of this study was to report the clinical, laboratorial and imaging features and postsurgical outcomes of microadenoma (MIC) and MAC patients., Methods: Retrospective study with 317 CD patients (median 32 years old, range 9-71 years) admitted between 1990 and 2014, 74 (23.3 %) of whom had MAC., Results: Hirsutism, plethora facial, muscular weakness and muscular atrophy were more frequent in the MIC patients. Nephrolithiasis, osteopenia, hyperprolactinaemia and galactorrhoea were more prevalent in MAC patients. The morning serum cortisol (Fs), nocturnal salivary cortisol (NSC), nocturnal Fs (Fs 2400 h), low- and high-dose dexamethasone suppression test results and CRH and desmopressin test results were similar between the subgroups. MIC patients showed higher urinary cortisol at 24 h (UC), and MAC patients presented higher ACTH levels but lower Fs/ACTH, Fs 2400 h/ACTH, NSC/ACTH and UC/ACTH ratios. There were negative correlations of tumour size with Fs/ACTH, Fs 2400 h/ACTH, NSC/ACTH and UC/ACTH ratios. Overall, the postsurgical remission and recurrence rates were similar between MIC and MAC. However, patients in remission (MIC + MAC) showed smaller tumour diameters and a lower prevalence of invasion and extension on MRI., Conclusions: Despite exhibiting higher plasma ACTH levels, CD patients with MAC presented lower cortisol/ACTH ratios than did patients with MIC, with a negative correlation between tumour size and cortisol/ACTH ratios. The overall postsurgical remission and recurrence rates were similar between MIC and MAC patients, with those with larger and/or invasive tumours showing a lower remission rate.
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- 2016
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18. The Use of Three-dimensional Printers for Partial Adrenalectomy: Estimating the Resection Limits.
- Author
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Srougi V, Rocha BA, Tanno FY, Almeida MQ, Baroni RH, Mendonça BB, Srougi M, Fragoso MC, and Chambô JL
- Subjects
- Aged, Humans, Hyperplasia surgery, Male, Organ Size, Adrenal Gland Diseases surgery, Adrenal Glands pathology, Adrenalectomy methods, Printing, Three-Dimensional
- Abstract
Objective: To avoid hormonal replacement after partial adrenalectomy (PA), establishing the precise limit of an adrenal gland resection is essential. Herein, we evaluated the use of three-dimensional (3D) adrenal gland printing and volumetry measurement before PA to improve the determination of the remnant gland volume., Methods: Concomitant total adrenalectomy and a contralateral PA were performed in a patient with primary macronodular adrenal hyperplasia that exhibited mild hypercortisolism, arterial hypertension, and diabetes. Before surgery, a 3D replica of the adrenal gland to be partially resected was printed and given to the surgeon. The volumetry of the gland was measured by computed tomography 3D image reconstruction., Results: No postoperative complications were noted. Immediately after the surgery, the patient initiated corticosteroid replacement, which was interrupted 52 days later. At the 6-month follow-up, the patient stopped using medications for diabetes and reduced the number of antihypertensive medications from 5 to 1. The pre- and postoperative serum cortisol levels were, respectively, 28 and 8.7 mcg/dl (n 5-25 mcg/dl). The pre- and postoperative adrenocorticotropic hormone levels were, respectively, <5 and 88 pg/ml (n 7.2-63 pg/ml). The postoperative adrenal volume was 12% of the total preoperative adrenal volume., Conclusion: The use of 3D printing associated with adrenal volumetry might be a useful tool for the surgeon when performing PA, enabling an estimation of the remnant gland volume., (Copyright © 2016 Elsevier Inc. All rights reserved.)
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- 2016
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19. Retraction Note: Fatal factitious Cushing syndrome (Münchhausen's syndrome) in a patient with macroprolactinoma and silent corticotrophinoma: case report and literature review.
- Author
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Minanni CA, Cardoso ALA, Albuquerque EVA, Brito LP, Lopes LML, Glezer A, Verduguez EDRU, De Mendonça BB, Bronstein MD, Machado MC, and Fragoso MCBV
- Abstract
[This retracts the article DOI: 10.1186/s40842-015-0002-8.].
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- 2016
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20. Malignant paraganglioma in children treated with embolization prior to surgical excision.
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de Paula Miranda E, Lopes RI, Padovani GP, Moscardi PR, Nishimura FG, de Mendonça BB, Carnevale FC, Cristofani LM, Duarte RJ, Srougi M, and Denes FT
- Subjects
- Adolescent, Adult, Child, Humans, Male, Paraganglioma pathology, Preoperative Care, Prognosis, Embolization, Therapeutic adverse effects, Paraganglioma etiology, Pelvic Neoplasms therapy
- Abstract
Background: Paragangliomas (PGL) are rare tumors derived from neural crest cells, whose origins may vary along the chain of the sympathetic nervous system. Such tumors are often characterized by secretion of catecholamines, but sometimes they are biochemically inactive, which makes diagnosis often challenging. Malignant paraganglioma is defined by the presence of this tumor at sites where chromaffin cells are usually not found or by local invasion of the primary tumor. Recurrence, either regional or metastatic, usually occurs within 5 years of the initial complete resection but long-term recurrence is also described. Malignancy is often linked to a SDHB mutation. Preoperative embolization has been applied in the surgical management of PGLs with the objective to decrease intra-operative blood loss and surgery length without complications., Case Presentation: We report two cases of patients with abdominal or pelvic malignant PGLs who have been treated surgically at our center after preoperative embolization. Surgery was a very challenging procedure with multiple surgical teams involved and embolization did not prevent major blood loss and intraoperative complications. Patients required adjuvant treatment with either chemotherapy or radiotherapy., Conclusions: Many studies in the adult population have established recommendations for the diagnosis and therapeutic management of PGL, but few studies concern the pediatric population. Because malignant PGL is more important in the pediatric population, screening and early diagnosis of PGL is advisable in children with genetic predisposing. Surgical resection is the mainstay of treatment, but a multimodal approach is often required due to the complexity of cases. The role of preoperative embolization is not established and in our experience it has provided little benefit and major complications.
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- 2016
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21. Diagnosis of prolactinoma in two male-to-female transsexual subjects following high-dose cross-sex hormone therapy.
- Author
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Cunha FS, Domenice S, Câmara VL, Sircili MH, Gooren LJ, Mendonça BB, and Costa EM
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- Adult, Antineoplastic Agents therapeutic use, Cabergoline, Ergolines therapeutic use, Estrogens therapeutic use, Female, Humans, Magnetic Resonance Imaging, Male, Pituitary Neoplasms chemically induced, Pituitary Neoplasms drug therapy, Prolactin blood, Prolactinoma chemically induced, Prolactinoma drug therapy, Estrogens adverse effects, Pituitary Neoplasms diagnosis, Prolactinoma diagnosis, Transgender Persons
- Abstract
Male-to-female transsexual persons use oestrogens + antiandrogens to adapt their physical bodies to the female sex. Doses are usually somewhat higher than those used by hypogonadal women receiving oestrogen replacement. Particularly in cases of self-administration of cross-sex hormones, doses may be very high. Oestrogens are powerful stimulators of synthesis and release of prolactin and serum prolactin levels are usually somewhat increased following oestrogen treatment. Prolactinomas have been reported in male-to-female transsexual persons, both after use of high and conventional doses of oestrogens but remain rare events. We report two new cases of prolactinomas in male-to-female transsexual persons, one in a 41-year-old subject who had used nonsupervised high-dose oestrogen treatment since the age of 23 years and another one in a 42 year old who had initiated oestrogen treatment at the age of 17 years. Their serum prolactin levels were strongly increased, and the diagnosis of a pituitary tumour was confirmed by imaging techniques. Both cases responded well to treatment with cabergoline treatment whereupon serum prolactin normalised. Our two cases are added to the three cases of prolactinomas in the literature in persons who had used supraphysiological doses of oestrogens., (© 2014 Blackwell Verlag GmbH.)
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- 2015
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22. RETRACTED ARTICLE: Fatal factitious Cushing syndrome (Münchhausen's syndrome) in a patient with macroprolactinoma and silent corticotrophinoma: case report and literature review.
- Author
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Minanni CA, De Almeida Cardoso AL, de Albuquerque Albuquerque EV, Brito LP, Lopes LML, Glezer A, Verduguez EDRU, De Mendonça BB, Bronstein MD, Machado MC, and Fragoso MCBV
- Abstract
Münchhausen's syndrome (MS) is a chronic factitious disorder characterized by the intentional production of clinical symptoms without external incentive. One type of MS is factitious Cushing syndrome, an extremely rare clinical situation in which the diagnosis is challenging mainly due to interference of the exogenous medication in cortisol immunoassays. We described a 26-year-old woman who was originally diagnosed with a macroprolactinoma and during follow-up developed clinical and laboratorial hypercortisolism. A transsphenoidal surgery was performed and immunohistochemistry revealed positive and diffuse staining for both hormones. Four years later, her hypercortisolism recurred and the confirmation of factitious Cushing syndrome was delayed due to conflicting laboratorial results. There are few cases in the literature of factitious Cushing syndrome, and only one had a fatal outcome. The diagnosis of this condition is complex and includes cyclic Cushing syndrome in the differential diagnosis. These patients have high morbidity and increased mortality risk and are likely to have other psychiatric disorders. Prednisone was identified as the culprit in the majority of the cases.
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- 2015
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23. Pitfalls in hormonal diagnosis of 17-beta hydroxysteroid dehydrogenase III deficiency.
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Khattab A, Yuen T, Yau M, Domenice S, Frade Costa EM, Diya K, Muhuri D, Pina CE, Nishi MY, Yang AC, de Mendonça BB, and New MI
- Subjects
- 17-Hydroxysteroid Dehydrogenases chemistry, 17-Hydroxysteroid Dehydrogenases genetics, Amino Acid Sequence, Child, Chromatography, High Pressure Liquid, Female, Humans, Male, Molecular Sequence Data, Pedigree, Polymorphism, Single Nucleotide, Sequence Homology, Amino Acid, Tandem Mass Spectrometry, 17-Hydroxysteroid Dehydrogenases deficiency, Disorder of Sex Development, 46,XY diagnosis, Gynecomastia diagnosis, Steroid Metabolism, Inborn Errors diagnosis
- Abstract
Steroid 17β-hydroxysteroid dehydrogenase III (17β-HSD3) deficiency is a rare autosomal recessive disorder that usually presents in patients with a 46,XY karyotype with ambiguous genitalia at birth. The 17β-HSD3 enzyme, which is encoded by the HSD17B3 gene, converts gonadal delta-4 androstenedione (Δ4) to testosterone (T). Such 17β-HSD3 enzyme deficiency is expected to lead to an increased ratio of D4 to T when the patient undergoes a human chorionic gonadotropin stimulation (hCG) test. Two patients with 46,XY disorders of sexual differentiation were studied. Serum D4 and T levels were measured by HPLC tandem mass spectrometry. As one of the patients was born to consanguineous parents, we performed single nucleotide polymorphism (SNP) microarray to analyze regions of homozygosity (ROH). The HSD17B3 gene was sequenced using the Sanger method. Contrary to expectations, both patients demonstrated decreased D4/T ratio after hCG stimulation. Initial sequencing results for the androgen receptor or 5α-reductase were negative for mutations. ROH analysis identified HSD17B3 as a candidate gene that might cause the disease. Sanger sequencing of the HSD17B3 gene confirmed 17β-HSD3 deficiency in both patients. Serum D4/T ratios are not reliable parameters for the diagnosis of 17β-HSD3 deficiency. Molecular genetic analysis provides accurate diagnosis.
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- 2015
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24. The clinical, structural, and biological features of neovaginas: a comparison of the Frank and the McIndoe techniques.
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Hayashida SA, Soares JM Jr, Costa EM, da Fonseca AM, Maciel GA, Mendonça BB, and Baracat EC
- Subjects
- 46, XX Disorders of Sex Development surgery, Adolescent, Adult, Color, Congenital Abnormalities surgery, Dyspareunia etiology, Estrogens analysis, Female, Gynecologic Surgical Procedures adverse effects, Humans, Hydrogen-Ion Concentration, Mucous Membrane pathology, Mucous Membrane physiopathology, Mullerian Ducts abnormalities, Mullerian Ducts surgery, Retrospective Studies, Sexuality, Skin Transplantation, Vagina abnormalities, Vagina microbiology, Young Adult, Gynecologic Surgical Procedures methods, Mucous Membrane surgery, Surgically-Created Structures microbiology, Surgically-Created Structures physiology, Vagina anatomy & histology, Vagina surgery
- Abstract
Objective: To compare two methods of neovagina construction, the Frank and McIndoe techniques, in terms of structural and biological aspects., Study Design: A total of 55 subjects were included in this retrospective study: 43 underwent the Frank technique (FT) and 12 underwent the McIndoe technique (MT). A clinical evaluation and a comparison of the structural (color, shine, presence of hair, and histology) and biological (bacteriological, pH, and hormonal determinations) features were performed. Statistical analysis was performed using the Fisher and Mann-Whitney tests., Results: The time to achieve a functional neovagina using the FT was longer than when using the MT (9.8±5.3 versus 5.8±2.9 months) (p=0.01). The neovaginal wall of the MT skin grafts was more rigid and drier, and it did not exhibit a shine in the way that the FT skin grafts did. The lining of the cavity formed by the FT in all subjects was similar to that of vaginal mucosa, whereas the lining formed by the MT persisted as a skin graft in 83.3% of the cases. The pH was lower for the FT (p<0.01), and Döderlein bacilli were present in 90% of the FT neovaginas but absent from the MT neovaginas. In the latter, flora with anaerobic bacteria was present. Hormonal cytology showed estrogen activity in 100% of the FT neovaginas, but there was no such activity in the MT neovaginas., Conclusions: Our data suggest that the FT may be clinically, structurally, and biologically superior to the MT for the creation of neovaginas and is also less costly., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2015
- Full Text
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