CAROLINA DE OLIVEIRA RAMOS
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
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- Applicability of a novel mathematical model for the prediction of adult height and age at menarche in girls with idiopathic central precocious puberty(2018) LOPES, Mateus Cavarzan; RAMOS, Carolina Oliveira; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; BRITO, Vinicius N.OBJECTIVES: Unfavorable predicted adult height and psychosocial inadequacy represent parameters used to guide therapeutic intervention in girls with central precocious puberty. Gonadotropin-releasing hormone analog is the first-line treatment. The aim of this study was to compare two methods used to predict adult height and assess a validated tool for predicting the age at menarche in girls with central precocious puberty. METHODS: The predicted adult height of 48 girls with central precocious puberty was calculated at diagnosis using the Bayley-Pinneau method based on average and advanced bone age tables and compared with the predicted adult height calculated using a mathematical model. In addition, the age at spontaneous menarche was predicted using the new formulae. After Gonadotropin-releasing hormone analog treatment, the predicted adult height was calculated using only the Bayley-Pinneau tables. RESULTS: The achieved adult height was within the target height range in all treated girls with central precocious puberty. At diagnosis, the predicted adult height using the Bayley-Pinneau tables was lower than that using the mathematical model. After the Gonadotropin-releasing hormone analog treatment, the predicted adult height using the Bayley-Pinneau method with the average bone age tables was the closest to the achieved adult height. Using the formulae, the predicted age at spontaneous menarche was 10.1 +/- 0.5 yr. The Gonadotropin-releasing hormone analog treatment significantly postponed this event until 11.9 +/- 0.7 yr in these ""idiopathic"" central precocious puberty girls, highlighting the beneficial effect of this treatment. CONCLUSION: Both initial adult height prediction methods are limited and must be used with caution. The prediction of the age at spontaneous menarche represents an innovative tool that can help in clinical decisions regarding pubertal suppression.
- DLK1 Is a Novel Link Between Reproduction and Metabolism(2019) GAMES, Larissa G.; CUNHA-SILVA, Marina; CRESPO, Raiane P.; RAMOS, Carolina O.; MONTENEGRO, Luciana R.; CANTON, Ana; LEES, Melissa; SPOUDEAS, Helen; DAUBER, Andrew; MACEDO, Delanie B.; BESSA, Danielle S.; MACIEL, Gustavo A.; BARACAT, Edmund C.; JORGE, Alexander A. L.; MENDONCA, Berenice B.; BRITO, Vinicius N.; LATRONICO, Ana ClaudiaBackground: Delta-like homolog 1 (DLK1), also called preadipocyte factor 1, prevents adipocyte differentiation and has been considered a molecular gatekeeper of adipogenesis. A DLK1 complex genomic defect was identified in five women from a single family with central precocious puberty (CPP) and increased body fat percentage. Methods: We studied 60 female patients with a diagnosis of CPP or history of precocious menarche. Thirty-one of them reported a family history of precocious puberty. DLK1 DNA sequencing was performed in all patients. Serum DLK1 concentrations were measured using an ELISA assay in selected cases. Metabolic and reproductive profiles of adult women with CPP caused by DLK1 defects were compared with those of 20 women with idiopathic CPP. Results: We identified three frameshift mutations of DLK1 (p.Gly199Alafs*11, p.Va1271Cysfs*14, and p.Pro160Leufs*50) in five women from three families with CPP. Segregation analysis was consistent with the maternal imprinting of DLK1. Serum DLK1 concentrations were undetectable in three affected women. Metabolic abnormalities, such as overweight/obesity, early-onset glucose intolerance/type 2 diabetes mellitus, and hyperlipidemia, were more prevalent in women with the DLK1 mutation than in the idiopathic CPP group. Notably, the human metabolic alterations were similar to the previously described dlk1-null mice phenotype. Two sisters who carried the p.Gly199Alafs*11 mutation also exhibited polycystic ovary syndrome and infertility. Conclusions: Loss-of-function mutations of DLK1 are a definitive cause of familial CPP. The high prevalence of metabolic alterations in adult women who experienced CPP due to DLK1 defects suggests that this antiadipogenic factor represents a link between reproduction and metabolism.
- Anthropometric, metabolic, and reproductive outcomes of patients with central precocious puberty treated with leuprorelin acetate 3-month depot (11.25 mg)(2021) RAMOS, Carolina O.; CANTON, Ana P. M.; SERAPHIM, Carlos Eduardo; FARIA, Aline Guimaraes; TINANO, Flavia Rezende; MENDONCA, Berenice B.; LATRONICO, Ana C.; BRITO, Vinicius N.Objectives: Longer-acting gonadotropin-releasing hormone analogs (GnRHa) have been widely used for central precocious puberty (CPP) treatment. However, the followup of patients after this treatment are still scarce. Our aim was to describe anthropometric, metabolic, and reproductive follow-up of CPP patients after treatment with leuprorelin acetate 3-month depot (11.25 mg). Methods: Twenty-two female patients with idiopathic CPP were treated with leuprorelin acetate 3-month depot (11.25 mg). Their medical records were retrospectively evaluated regarding clinical, hormonal, and imaging aspects before, during, and after GnRHa treatment until adult height (AH). Results: At the diagnosis of CPP, the mean chronological age (CA) was 8.2 +/- 1.13 year, and mean bone age (BA) was 10.4 +/- 1.4 year. Mean height SDS at the start and the end of GnRHa treatment was 1.6 +/- 0.8 and 1.3 +/- 0.9, respectively. The mean duration of GnRHa treatment was 2.8 +/- 0.8 year. Mean predicted adult heights (PAH) at the start and the end of GnRH treatment was 153.2 +/- 8.6 and 164.4 +/- 7.3 cm, respectively (p<0.05). The mean AH was 163.2 +/- 6.2 cm (mean SDS: 0.1 +/- 1). All patients were within their target height (TH) range. There was a decrease in the percentage of overweight and obesity from the diagnosis until AH (39-19% p>0.05). At the AH, the insulin resistance and high LDL levels were identified in 3/17 patients (17.6%) and 2/21 patients (9.5%), respectively. The mean CA of menarche was 12.2 +/- 0.5 years. At the AH, PCOS was diagnosed in one patient (4.8%). Conclusions: Long-term anthropometric, metabolic, and reproductive follow-up of patients with CPP treated with longer-acting GnRHa revealed effectivity, safety, and favorable outcomes.
- Long-Term Outcomes of Patients with Central Precocious Puberty due to Hypothalamic Hamartoma after GnRHa Treatment: Anthropometric, Metabolic, and Reproductive Aspects(2018) RAMOS, Carolina O.; LATRONICO, Ana C.; CUKIER, Priscilla; MACEDO, Delanie B.; BESSA, Danielle S.; CUNHA-SILVA, Marina; ARNHOLD, Ivo J.; MENDONCA, Berenice B.; BRITO, Vinicius N.Background: Hypothalamic hamartoma (HH) represents the commonest cause of organic central precocious puberty (CPP). Follow-up of these patients in adulthood is scarce. Objective: To describe the anthropometric, metabolic, and reproductive parameters of patients with CPP due to HH before and after treatment with gonadotropin-releasing hormone analog (GnRHa). Methods: We performed a retrospective and cross-sectional study in a single tertiary center including 14 patients (7 females) with CPP due to HH. Results: The mean duration of GnRHa treatment was 7.7 +/- 2.4 years in boys and 7.9 +/- 2.1 years in girls. GnRHa treatment was interrupted at the mean chronological age (CA) of 12.1 +/- 1.1 years in boys and 10.7 +/- 0.5 years in girls. At the last visit, the mean CA of the male and female patients was 21.5 +/- 3.2 and 24 +/- 3.9 years, respectively. Eleven of the 14 patients reached normal final height (FH) (standard deviation score -0.6 +/- 0.9 for males and -0.6 +/- 0.5 for females), all of them within the target height (TH) range. The remaining 3 patients had predicted height within the TH range. The mean body mass index and the percentage of body fat mass was significantly higher in females, with a higher prevalence of metabolic disorders. All patients presented normal gonadal function in adulthood, and 3 males fathered a child. Conclusion: All patients with CPP due to HH reached normal FH or near-FH. A higher prevalence of overweight/obesity and hypercholes-terolemia was observed in the female patients. Finally, no reproductive disorder was identified in both sexes, indicating that HH per se has no deleterious effect on the gonadotropic axis in adulthood. (c) 2017 S. Karger AG, Basel
- Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations(2021) SERAPHIM, Carlos Eduardo; CANTON, Ana Pinheiro Machado; MONTENEGRO, Luciana; PIOVESAN, Maiara Ribeiro; MACEDO, Delanie B.; CUNHA, Marina; GUIMARAES, Aline; RAMOS, Carolina Oliveira; BENEDETTI, Anna Flavia Figueiredo; LEAL, Andrea de Castro; GAGLIARDI, Priscila C.; ANTONINI, Sonir R.; GRYNGARTEN, Mirta; ARCARI, Andrea J.; ABREU, Ana Paula; KAISER, Ursula B.; SORIANO-GUILLEN, Leandro; ESCRIBANO-MUNOZ, Arancha; CORRIPIO, Raquel; I, Jose Labarta; TRAVIESO-SUAREZ, Lourdes; ORTIZ-CABRERA, Nelmar Valentina; ARGENTE, Jesus; MENDONCA, Berenice B.; BRITO, Vinicius N.; LATRONICO, Ana ClaudiaContext: Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP). Objective: To describe the clinical and hormonal features of a large cohort of patients with CPP due to MKRN3 mutations and compare the characteristics of different types of genetic defects. Methods: Multiethnic cohort of 716 patients with familial or idiopathic CPP screened for MKRN3 mutations using Sanger sequencing. A group of 156 Brazilian girls with idiopathic CPP (ICPP) was used as control group. Results: Seventy-one patients (45 girls and 26 boys from 36 families) had 18 different loss-of-function MKRN3 mutations. Eight mutations were classified as severe (70% of patients). Among the 71 patients, first pubertal signs occurred at 6.2 +/- 1.2 years in girls and 7.1 +/- 1.5 years in boys. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation and higher follicle-stimulating hormone levels than ICPP. Patients with severe MKRN3 mutations had a greater bone age advancement than patients with missense mutations (2.3 +/- 1.6 vs 1.6 +/- 1.4 years, P =.048), and had higher basal luteinizing hormone levels (2.2 +/- 1.8 vs 1.1 +/- 1.1 UI/L, P =.018) at the time of presentation. Computational protein modeling revealed that 60% of the missense mutations were predicted to cause protein destabilization. Conclusion: Inherited premature activation of the reproductive axis caused by loss-of-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels.
conferenceObject ANTHROPOMETRIC, METABOLIC AND REPRODUCTIVE OUTCOME OF PATIENTS WITH CENTRAL PRECOCIOUS PUBERTY DUE TO HYPOTHALAMIC HAMARTOMA IN ADULT LIFE(2017) RAMOS, Carolina O.; LATRONICO, Ana Claudia; CUKIER, Priscila; MACEDO, Delanie; BESSA, Danielle S.; SILVA, Marina C.; ARNHOLD, Ivo J.; MENDONCA, Berenice B.; BRITO, Vinicius N.conferenceObject PREMATURE PUBARCHE CAN BE CAUSED BY EXOGENOUS TESTOSTERONE GEL OR DIAPER RASH PREVENTION CREAM(2017) RAMOS, Carolina O.; MACEDO, Delanie; BACHEGA, Tania S. S.; LEE, Juliana C.; NASCIMENTO, Marilza L.; MADUREIA, Guiomar; BRITO, Vinicius N.; LATRONICO, Ana Claudia; MENDONCA, Berenice B.conferenceObject OUTCOMES OF GIRLS WITH IDIOPATHIC CENTRAL PRECOCIOUS PUBERTY TREATED WITH 1-AND 3-MONTH GONADOTROPIN-RELEASING HORMONE ANALOG FORMULATIONS(2017) RAMOS, Carolina O.; SILVA, Marina C.; SALLES, Priscila; MENDONCA, Berenice B.; LATRONICO, Ana Claudia; BRITO, Vinicius N.