BERENICE BILHARINHO DE MENDONCA
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
13 resultados
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- Adverse Outcomes and Economic Burden of Congenital Adrenal Hyperplasia Late Diagnosis in the Newborn Screening Absence(2020) MIRANDA, Mirela Costa de; HADDAD, Luciana Bertocco de Paiva; MADUREIRA, Guiomar; MENDONCA, Berenice Bilharinho de; BACHEGA, Tania A. S. S.Objective: To establish short- and long-term adverse outcome frequencies related to a late diagnosis of congenital adrenal hyperplasia (CAH) in the absence of newborn screening (NBS) and to determine respective treatment costs, which have never been reported. Design: A retrospective analysis of a CAH cohort diagnosed without NBS. Methods: We evaluated medical record data concerning 195 patients (141 females) diagnosed with CAH through clinical suspicion and confirmed using hormonal and CYP21A2 analysis, who were followed from 1980 to 2016 at Sao Paulo University. We measured mortality, dehydration, mental impairment frequencies, and hospitalization length outcomes in the salt-wasting form; the frequency of genetic females raised as males in both forms, frequency of depot GnRh analog (GnRha) and GH therapies in the simple virilizing form, and related outcome costs were calculated. Results: Mortality rates and associated costs, varying from 10% to 26% and from $2,239,744.76 to $10,271,591.25, respectively, were calculated using the Brazilian yearly live-births rate, estimated productive life years, and gross domestic product. In the salt-wasting form, 76% of patients were hospitalized, 8.6% were mentally impaired, and 3% of females were raised as males (total cost, $86,230/salt-wasting patient). GnRha and growth hormone were used for 28% and 14% of simple virilizing patients, respectively, and 18% of females were raised as males (preventable cost, $4232.74/simple virilizing patient). Conclusions: A late CAH diagnosis leads to high mortality and morbidity rates, notably increasing public health costs, and may result in physical and psychological damage that is not easily measurable. (C) Endocrine Society 2019.
- High-throughput Sequencing to Identify Monogenic Etiologies in a Preselected Polycystic Ovary Syndrome Cohort(2022) CRESPO, Raiane P.; ROCHA, Thais P.; MONTENEGRO, Luciana R.; NISHI, Mirian Y.; JORGE, Alexander A. L.; MACIEL, Gustavo A. R.; BARACAT, Edmund; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; GOMES, Larissa G.Context: Polycystic ovary syndrome (PCOS) etiology remains to be elucidated, but familial clustering and twin studies have shown a strong heritable component. Objective: The purpose of this study was to identify rare genetic variants that are associated with the etiology of PCOS in a preselected cohort. Methods: This prospective study was conducted among a selected group of women with PCOS. The study's inclusion criteria were patients with PCOS diagnosed by the Rotterdam criteria with the following phenotypes: severe insulin resistance (IR), normoandrogenic-normometabolic phenotype, adrenal hyperandrogenism, primary amenorrhea, and familial PCOS. Forty-five patients were studied by target sequencing, while 8 familial cases were studied by whole exome sequencing. Results: Patients were grouped according to the inclusion criteria with the following distribution: 22 (41.5%) with severe IR, 13 (24.5%) with adrenal hyperandrogenism, 7 (13.2%) with normoandrogenic phenotype, 3 (5.7%) with primary amenorrhea, and 8 (15.1%) familial cases. DNA sequencing analysis identified 1 pathogenic variant in LMNA, 3 likely pathogenic variants in INSR, PIK3R1, and DLK1, and 6 variants of uncertain significance level with interesting biologic rationale in 5 genes (LMNA, GATA4, NR5A1, BMP15, and FSHR). LMNA was the most prevalent affected gene in this cohort (3 variants). Conclusion: Several rare variants in genes related to IR were identified in women with PCOS. Although IR is a common feature of PCOS, patients with extreme or atypical phenotype should be carefully evaluated to rule out monogenic conditions.
- Successful Pregnancies After Adequate Hormonal Replacement in Patients With Combined Pituitary Hormone Deficiencies(2017) CORREA, Fernanda A.; BIANCHI, Paulo H. M.; FRANCA, Marcela M.; OTTO, Aline P.; RODRIGUES, Rodrigo J. M.; EJZENBERG, Dani; SERAFINI, Paulo C.; BARACAT, Edmundo Chada; FRANCISCO, Rossana P. V.; BRITO, Vinicius N.; ARNHOLD, Ivo J. P.; MENDONCA, Berenice B.; CARVALHO, Luciani R.Context: Women with hypopituitarism have lower pregnancy rates after ovulation induction. Associated pituitary hormone deficiencies might play a role in this poorer outcome. Objective: We evaluated fertility treatment and pregnancy outcomes in five women with childhoodonset combined pituitary hormone deficiencies (CPHD). Patients and Methods: Five women with CPHD were referred for fertility treatment after adequacy of hormone replacement was determined. Patients were subjected to controlled ovarian stimulation (COS) for timed intercourse, intrauterine insemination, or in vitro fertilization, according to the presence or absence of other infertility factors (male or tubal). Results: All women became pregnant. The number of COS attempts until pregnancy was achieved varied between 1 and 5. The duration of COS resulting in at least one dominant follicle varied between 9 and 28 days, and total gonadotropin consumed varied between 1200 and 3450 IU. Two patients with severely suppressed basal gonadotropin levels since an early age had a cancelled COS cycle. All pregnancies were singleton except one (monochorionic twin gestation). The gestational ages at birth ranged from 35 weeks to 39 weeks and 4 days; three patients underwent cesarean section, and two had vaginal deliveries. Only one newborn was small for gestational age (delivered at 35 weeks). Conclusion: Adequate hormonal replacement prior to ovarian stimulation resulted in successful pregnancies in patients with childhood-onset CPHD, indicating that hormone replacement, including growth hormone, is an important step prior to fertility treatments in these patients.
- A New Insight into the Surgical Treatment of Primary Macronodular Adrenal Hyperplasia(2020) TANNO, Fabio Yoshiaki; SROUGI, Victor; ALMEIDA, Madson Q.; YAMAUCHI, Fernando Ide; COELHO, Fernando Morbeck Almeida; NISHI, Mirian Yumie; ZERBINI, Maria Claudia Nogueira; SOARES, Iracy Silvia Correa; PEREIRA, Maria Adelaide Albergaria; CHARCHAR, Helaine Laiz Silva; LACOMBE, Amanda Meneses Ferreira; BRONDANI, Vania Balderrama; SROUGI, Miguel; NAHAS, Willian Carlos; MENDONCA, Berenice B.; CHAMBO, Jose Luis; FRAGOSO, Maria Candida Barisson VillaresPurpose: This prospective study presents the results of a new approach in the treatment of primary macronodular adrenal hyperplasia (PMAII), with simultaneous total adrenalectomy of the larger adrenal gland and partial adrenalectomy of the contralateral adrenal gland (adrenal-sparing surgery). Materials and Methods: We performed a prospective study including 17 patients with PMAH treated surgically with adrenal-sparing surgery in a tertiary referral hospital, with a median follow-up of 41 months. Clinical, hormonal, and genetic parameters were evaluated before surgery and during follow-up. All patients had at least 1 radiological examination before and after the procedure. Results: Among the 17 patients, all but 1 patient had complete hypercortisolism control, and 12 recovered normal adrenal function after surgery. Significant improvement in clinical parameters was observed: weight loss (P = .004); reduction of both systolic (P = .001) and diastolic (P = .001) blood pressure; and reduction in the number of antihypertensive drugs (P < .001). Intra-, peri-, and postoperative complications were not observed. Conclusion: Adrenal-sparing surgery is a safe and feasible procedure to treat patients with PMAH, providing a substantial chance of hypercortisolism control without the disadvantages of lifetime corticosteroid replacement. (C) Endocrine Society 2020.
- Genetics of Primary Ovarian Insufficiency in the Next-Generation Sequencing Era(2020) FRANCA, Monica Malheiros; MENDONCA, Berenice BilharinhoPrimary ovarian insufficiency (POI) is characterized by amenorrhea, increased follicle-stimulating hormone (FSH) levels, and hypoestrogenism, leading to infertility before the age of 40 years. Elucidating the cause of POI is a key point for diagnosing and treating affected women. Here, we review the genetic etiology of POI, highlighting new genes identified in the last few years using next-generation sequencing (NGS) approaches. We searched the MEDLINE/PubMed, Cochrane, and Web of Science databases for articles published in or translated to English. Several genes were found to be associated with POI genetic etiology in humans and animal models (SPIDR, BMPR2, MSH4, MSH5, GJA4, FANCM, POLR2C, MRPS22, KHDRBS1, BNC1, WDR62, ATG7/ATG9, BRCA2, NOTCH2, POLR3H, and TP63). The heterogeneity of POI etiology has been revealed to be remarkable in the NGS era, and discoveries have indicated that meiosis and DNA repair play key roles in POI development. (C) Endocrine Society 2019.
- Persistent Poor Metabolic Profile in Postmenopausal Women With Ovarian Hyperandrogenism After Testosterone Level Normalization(2019) ROCHA, Thais; CRESPO, Raiane P.; YANCE, Viviane V. R.; HAYASHIDA, Sylvia A.; BARACAT, Edmund C.; CARVALHO, Filomena; DOMENICE, Sorahia; MENDONCA, Berenice B.; GOMES, Larissa G.Context: Data on prevalence of metabolic risk factors in hyperandrogenic postmenopausal women are limited. Also, the correlation between metabolic disorders and androgen excess in this scenario is poorly understood. Objectives: We aimed to assess the prevalence of obesity, hypertension, type 2 diabetes (T2D), and dyslipidemia (DLP) in postmenopausal women with hyperandrogenism of ovarian origin before and after surgical normalization of testosterone (T) levels, as well as the impact of androgen normalization on body mass index (BMI), glucose, and lipid metabolism. Design: Retrospective study. Setting: Tertiary health center. Participants: Twenty-four Brazilian women with postmenopausal hyperandrogenism who underwent bilateral oophorectomy between 2004 and 2014 and had histologically confirmed virilizing ovarian tumor (VOT) or ovarian hyperthecosis (OH) and T-level normalization after surgery were selected. Main Outcome Measures: FSH, LH, total and calculated free T, BMI, fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) serum levels were accessed before (n = 24) and 24 months after (n 5 19) bilateral oophorectomy. Results: At baseline, the overall prevalence rates of obesity, T2D, DLP, and hypertension were 58.3%, 83.3%, 66.7%, and 87.5%, respectively. No significant difference in prevalence was found between patients with OH and VOTs. At follow-up, FSH, LH, and total and free T levels had returned to menopausal physiologic levels, but mean BMI and mean FPG, HbA1c, LDL-C, HDL-C, and TG levels did not differ from baseline. Conclusions: Postmenopausal hyperandrogenism is associated with adverse metabolic risk. Longterm normalization of testosterone levels did not improve BMI, glucose, or lipid metabolism.
- New Insights Into Pheochromocytoma Surveillance of Young Patients With VHL Missense Mutations(2019) FAGUNDES, Gustavo F. C.; PETENUCI, Janaina; JR, Delmar M. Lourenco; TRARBACH, Ericka B.; PEREIRA, Maria Adelaide A.; D'EUR, Joya Emilie Correa; HOFF, Ana O.; LERARIO, Antonio M.; ZERBINI, Maria Claudia N.; SIQUEIRA, Sheila; YAMAUCHI, Fernando; SROUGI, Victor; TANNO, Fabio Y.; CHAMBO, Jose Luis; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; V, Maria Candida B. Fragoso; ALMEIDA, Madson Q.Context: Von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome caused by germline mutations in the VHL gene. Guidelines recommend pheochromocytoma (PHEO) biochemical screening should start at age 5 years. Objective: Genotype-phenotype correlations in VHL, focusing on PHEO penetrance in children, were studied. Design: We retrospectively evaluated 31 individuals (median age at diagnosis was 26 years) with diagnosed VHL disease. Results: PHEO was diagnosed in six children with VHL. A large PHEO (5 cm) was detected in a 4-yearold boy with p.Gly114Ser mutation. PHEO penetrance was 55% starting at age 4 years. VHL missense mutations were identified in 11 of 22 families (50%), frameshift mutations in four (18.2%), stop codon in three (13.6%), splicing site in two (9.1%), and large gene deletion in two (9.1%). The codon 167 (n = 10) was a hotspot for VHL mutations and was significantly associated with PHEO (90% vs. 38%; P = 0.007). PHEOs and pancreatic neuroendocrine tumors (PNETs) were strongly associated with VHL missense mutations compared with other mutations (89.5% vs. 0% and 73.7% vs. 16.7%; P = 0.0001 and 0.002, respectively). In contrast, pancreatic cysts (91.7% vs. 26.3%; P = 0.0001), renal cysts (66.7% vs. 26.3%; P = 0.027), and central nervous system hemangioblastomas (91.7% vs. 47.3%; P = 0.012) were more frequent in VHL with nonmissense mutations. Conclusion: VHL missense mutations were highly associated with PHEO and PNETs. Our data support that in children with VHL harboring missense mutations, biochemical screening for PHEO should be initiated at diagnosis.
- Arterial Stiffness in Transgender Men Receiving Long-term Testosterone Therapy(2023) CUNHA, Flavia Siqueira; BACHEGA, Tania Aparecida Sanchez; COSTA, Elaine Maria Frade; BRITO, Vinicius Nahime; ALVARES, Leonardo Azevedo; COSTA-HONG, Valeria Aparecida; VERARDINO, Renata Gomes Sanches; SIRCILI, Maria Helena Palma; MENDONCA, Berenice Bilharinho de; BORTOLOTTO, Luiz Aparecido; DOMENICE, SorahiaContext: 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.
- Comprehensive Genetic Analysis of 128 Candidate Genes in a Cohort With Idiopathic, Severe, or Familial Osteoporosis(2020) ROCHA-BRAZ, Manuela G. M.; FRANCA, Monica M.; FERNANDES, Adriana M.; LERARIO, Antonio M.; ZANARDO, Evelin A.; SANTANA, Lucas S. de; KULIKOWSKI, Leslie D.; MARTIN, Regina M.; MENDONCA, Berenice B.; FERRAZ-DE-SOUZA, BrunoContext: The genetic bases of osteoporosis (OP), a disorder with high heritability, are poorly understood at an individual level. Cases of idiopathic or familial OP have long puzzled clinicians as to whether an actionable genetic cause could be identified. Objective: We performed a genetic analysis of 28 cases of idiopathic, severe, or familial osteoporosis using targeted massively parallel sequencing. Design: Targeted sequencing of 128 candidate genes was performed using Illumina NextSeq. Variants of interest were confirmed by Sanger sequencing or SNP array. Patients and Setting: Thirty-seven patients in an academic tertiary hospital participated (54% male; median age, 44 years; 86% with fractures), corresponding to 28 sporadic or familial cases. Main Outcome Measure: The identification of rare stop-gain, indel, splice site, copy-number, or nonsynonymous variants altering protein function. Results: Altogether, we identified 28 variants of interest, but only 3 were classified as pathogenic or likely pathogenic variants: COL1A2 p.(Arg708Gln), WNT1 p.(Gly169Asp), and IDUA p.(His82Gln). An association of variants in different genes was found in 21% of cases, including a young woman with severe OP bearing WNT1, PLS3, and NOTCH2 variants. Among genes of uncertain significance analyzed, a potential additional line of evidence has arisen for GWAS candidates GPR68 and NBR1, warranting further studies. Conclusions: While we hope that continuing efforts to identify genetic predisposition to OP will lead to improved and personalized care in the future, the likelihood of identifying actionable pathogenic variants in intriguing cases of idiopathic or familial osteoporosis is seemingly low.
- Clinical and Pathological Predictors of Death for Adrenocortical Carcinoma(2024) PATO, Eduardo; SROUGI, Victor; ZERBINI, Claudia; LEDESMA, Felipe L.; TANNO, Fabio; ALMEIDA, Madson Q.; NAHAS, William; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; CHAMBO, Jose L.; V, Maria Candida B. FragosoAdrenocortical carcinoma (ACC) is a rare and lethal disease with a poor prognosis. This study aims to share our 41-year experience as a referral center, focusing on identifying risk factors associated with ACC mortality. Our retrospective analysis included a cohort of 150 adult patients with ACC in all stage categories, treated between 1981 and 2022. Tumor hormonal hypersecretion was observed in 78.6% of the patients, and the median age of diagnosis was 40 years. The majority presented as European Network for the Study of Adrenal Tumors (ENSAT) III or IV (22.9% and 31.2%, respectively), and the overall mortality rate was 54.6%. Independent predictors of death were elevated secretion of cortisol (HR = 2.0), androstenedione (HR = 2.2), estradiol (HR = 2.8), 17-OH progesterone (HR = 2.0), and 11-deoxycortisol (HR = 5.1), higher Weiss (HR = 4.3), modified Weiss (HR = 4.4), and Helsinki scores (HR = 12.0), advanced ENSAT stage (HR = 27.1), larger tumor size (HR = 2.7), higher Ki-67 percentage (HR = 2.3), and incomplete surgical resection (HR = 2.5). Mitosis greater than 5/50 high-power field (HR = 5.6), atypical mitosis (HR = 2.3), confluent necrosis (HR = 15.4), venous invasion (HR = 2.8), and capsular invasion (HR = 2.4) were also identified as independent predictors of death. Knowing the risk factors for ACC's mortality may help determine the best treatment option.