Giovana De Nardo Maffazioli’s research while affiliated with University of São Paulo and other places

Objective This study aims to evaluate antimullerian hormone (AMH) levels across Polycystic Ovary Syndrome (PCOS) phenotypes (A, B, C, D) based on the Rotterdam diagnostic criteria. Data Sources A systematic review and meta-analysis were conducted following PRISMA guidelines. PubMed, Embase, ScienceDirect, and Web of Science were searched for studies published between January 2009 and June 2024. Study Eligibility Criteria Studies reporting AMH levels stratified by PCOS phenotypes based on the Rotterdam criteria, along with population characteristics and AMH measurement methods, were included. Animal studies, reviews, case reports, opinion articles, letters to the editor, other non-original research. and those lacking complete phenotype stratification were excluded. Study Appraisal and Synthesis Methods Study quality was assessed using the ROBINS-E tool. Primary outcomes included mean AMH levels across phenotypes, analyzed as tAMH (without assay differentiation) and bcAMH (Beckman Coulter Gen II assay). Secondary outcomes included age and BMI by phenotype. Random-effects meta-analysis was used to calculate mean levels and standardized mean differences (SMD) with 95% confidence intervals (CI). Heterogeneity was assessed using the I2 statistic. Results Forty-nine studies involving 15,535 subjects revealed that AMH levels vary significantly by phenotype, being highest in A, followed by D, C, and B. For phenotype A: tAMH=9.87 ng/mL (SMD 2.97, CI 9.29-10.48); bcAMH=11.49 ng/mL (SMD 3.06, CI 10.47-12.61). For phenotype B: tAMH=5.71 ng/mL (SMD 0.98, CI 4.96-6.57); bcAMH=6.25 ng/mL (SMD 1.36, CI 5.20-7.51). There were no significant differences in age or BMI among phenotypes. High heterogeneity suggests additional factors influence AMH levels beyond phenotypic categories. Conclusions AMH levels are elevated in PCOS and vary across phenotypes, underscoring their potential to improve PCOS subtype characterization and guide management strategies. The findings highlight the need for standardizing AMH measurement techniques for consistent clinical application.

[This corrects the article DOI: 10.1371/journal.pone.0275031.].

Background: We followed polycystic ovary syndrome (PCOS) women with metabolic syndrome (MS) over a six-year treatment period and evaluated the influence of PCOS phenotypes on MS and on the risk for type 2 diabetes mellitus (T2DM). Methods: This was an observational study of 457 PCOS women, whose demographic, clinical, hormonal, and metabolic data underwent analysis. The PCOS women were divided into four groups per NIH recommendations. Results: After a follow-up of a mean of six years (1-20 years), 310 patients were selected to assess the development of T2DM and MS. The clinical and biochemical parameters, along with the Rotterdam phenotypes, were evaluated. Data were analyzed using Student's t- and the Pearson chi-square tests for data variation and group proportions, respectively. Additionally, multivariate analysis was applied to evaluate the effect of PCOS phenotypes on the risk for MS and T2DM. Patients of the four PCOS phenotypes did not differ in age, body mass index, total testosterone, insulin resistance, and dyslipidemia, but phenotype A patients showed the highest risk for T2DM. A decrease in androgen levels was not followed by an improved metabolic profile; instead, there was a significant increase in the number of T2DM cases. Conclusion: Phenotype A women are at the highest risk for type 2 diabetes mellitus.

Objective Polycystic ovary syndrome (PCOS) is a heterogeneous endocrinopathy, which etiology encompasses complex genetic traits associated with epigenetic factors, including differences in microRNA (miRNA) expression in a variety of tissues. The circulating form of these molecules is raising attention in the syndrome not only as potential biomarkers of PCOS but also as possible therapeutic targets. The aim of this study was to explore the circulating miRNA profiles present in a cohort of Brazilian women with and without PCOS and to evaluate the potential role of miRNAs in the pathophysiology of the syndrome. Methods Cross-sectional study of 36 well-characterized PCOS women and 16 healthy controls. Clinical, hormone and metabolic data were recorded and evaluated. The expression profile of the 201 circulating miRNA selected were analyzed by taqman quantitative real time polymerase chain reactions (RT-PCR) using a customized Open Array platform. Statistical and bioinformatic analyzed were performed. Results Circulating miR-21-5p, miR-23a-3p and miR-26a-5p were upregulated, and miR-103a-3p, miR-376a-3p, miR-19b-3p and miR-222-3p were downregulated in women with PCOS compared to healthy normo-ovulatory controls. miR-21-5p, miR-103a-3p and miR-376a-3p levels correlated positively with androgen levels. These miRNAs, in combination, were related to pathways involved in insulin signaling, steroids biosynthesis and endothelial regulation as well as in folliculogenesis. Conclusion In this study, we identified a specific circulating miRNA signature in Brazilian women with PCOS. According to our data, circulating miR-21-5p, miR-23a-3p, miR-26a-5p, miR-103a-3p, miR-376a-3p, miR-19b-3p and miR-222-3p may represent potential candidates for differential diagnosis of PCOS in the future.

Introduction Relative Energy Deficiency in Sport (RED-S) is a clinical syndrome that includes the many complex health and performance consequences of low energy availability (EA) in athletes, when there is insufficient caloric intake to meet exercise-related energy expenditure and to support basic physiologic functions. There is a high prevalence of urinary incontinence (UI) in female athletes and it is more common in female athletes than non-athletes. The objective of this study was to determine if low EA is associated with UI in a population of adolescent and young adult female athletes and to evaluate for an association between sport categories and UI. Material and methods 1,000 nulliparous female patients, ages 15–30 years, presenting to a sports medicine subspecialty clinic, provided informed consent/assent to participate in a cross-sectional study involving a comprehensive survey, anthropomorphic measurements, and medical record review. Low EA was defined as meeting ≥ 1 criterion: self-reported history of eating disorder/disordered eating (ED/DE), and/or a high score on the Brief Eating Disorder in Athletes Questionnaire (BEDA-Q), and/or a high score on the Eating Disorder Screen for Primary Care (ESP). UI was assessed using questions adapted from the International Consultation on Incontinence-Urinary Incontinence Short Form (ICIQ-UI-SF), questions regarding timing of UI onset/duration, and a binary question regarding UI during sport activities. A total of 36 sport types were included in the survey and sub-divided into categories. Results and Discussion Of the 1,000 female athletes surveyed, 165 (16.5%) reported a history of experiencing UI during athletic activities. ICIQ- UI-SF responses indicated that 14% (137/1000) of the cohort experienced slight incontinence, 4% (35/1000) moderate incontinence, and 2 athletes experienced severe incontinence. There was a significant difference between UI categories in age (p=0.01), low EA (p<0.001), and sport category (p<0.001). Females who had low EA had twice the likelihood (OR=1.97; 95% CI=1.39 to 2.81; p<0.001) of UI compared to those with adequate EA, controlling for sports category and menstrual dysfunction. Females who participated in high impact sports were 4.5 times more likely (OR=4.47; 95% CI=2.29 to 8.74; p<0.001) to have had UI compared to females who participated in ball sports, controlling for EA and menstrual dysfunction. Conclusions UI during athletic activities is a common problem among nulliparous adolescent and young adult female athletes, occurring in 16.5% of female athletes surveyed. UI was significantly associated with low EA across all sport categories. Sport type was significantly associated with UI, with the highest impact sport group demonstrating a higher prevalence and symptom severity compared to other sport categories.

Objective To describe the prevalence of metabolic disturbances in a large cohort of women with polycystic ovary syndrome (PCOS) in southeastern Brazil and to compare the findings with other cohorts of Brazilian women with PCOS. Methods A retrospective study analyzing clinical and laboratory data of 462 women with PCOS treated at an outpatient clinic in a tertiary hospital in southeastern Brazil. Prevalence of insulin resistance, glucose intolerance, type 2 diabetes, dyslipidemia, central obesity, hypertension, and metabolic syndrome was compared to that of other cohorts of age and body mass index‐matched Brazilian women with PCOS. Results Women with PCOS had a median age of 25.0 (21.0–29.0) years and BMI of 28.7 (23.9–34.0) kg/m². Prevalence of insulin resistance, glucose intolerance, and type 2 diabetes varied from 39.6% to 55.0%, 7.2% to 28.1%, and 2.0% to 4.1%, respectively. Prevalence of central obesity, dyslipidemia due to decreased high‐density lipoprotein cholesterol, hypertriglyceridemia, and metabolic syndrome ranged from 57.8% to 66.4%, 54.1% to 70.4%, 22.9% to 35.1%, and 27.4% to 38.3%, respectively, which did not differ among regions in Brazil. Conclusion Prevalence of metabolic disturbances was high among Brazilian women with PCOS. This study suggests that, from a public health perspective, authorities in Brazil should be aware of and encourage screening for metabolic dysfunction in women with PCOS in all regions of the country.

Polycystic Ovary Syndrome (PCOS) is a complex endocrine disorder, which affects 5-17% of reproductive age women and is often associated with obesity and metabolic impairment. Common treatment strategies are based on exercise, diet and nutrient supplementation since PCOS is often linked with obesity and metabolic impairment. Studies have recommended that nutrition is a key factor in the health maintenance of women with PCOS, however, little is known about the subject in the context of such a disease. This narrative review aims to identify dietary and nutritional aspects of PCOS and discuss the role of nutrients in management of polycystic ovary syndrome in view of clinical trials.

Background: miRNAs act as regulatory molecules at the post-transcriptional level. Their expression can influence in carcinogenesis, leading to alterations in the genetic and the epigenetic processes that contribute to tumors heterogeneous behaviors. miRNAs represent new potential biomarkers and promising translational targets in neoplasms therapy. These molecules expression has a crucial role in smooth muscle differentiation from mesenchymal stem cells. Leiomyoma (LM) is the most frequent benign uterine smooth muscle tumors (USMT), occurring in up to 80% of reproductive-age women. Leiomyosarcoma (LMS) is a malignant USMT that represents 40-60% of all gynecological sarcomas. This study aims to evaluate the expression profile and the role of miR-34a and in LM and LMS cells. Methods: LM (THESCs CRL-4003) and LMS (SK-UT-1) cell lines were grown in specific mediums and conditions (ATCC recommendations). Cell lines were transfected with synthetic miRNA mimics and inhibitors of miR-34a and and evaluated for proliferation, migration and gene expression (qPCR) assays. For gene expression analysis in patients' samples, 10 myometrium (MM), 10 LM and 15 LMS were selected and compared to cell lines expression profile. In silico analysis was performed to identify miR-34a and 181b main genetic interactions network of (MirtarBase database). Results: LM cells depicted higher basal expression levels of miR-34a and , while the LMS presented a lower expression, both compared to MM. The same profile was observed for patients' samples. The 34a mimic showed great efficiency in expression induction at 24 h, in LM and LMS cells. Its inhibitor showed better efficacy at 72h in LM and 24 - 48h in LMS. For 181b, higher mimics efficiency was obtained at 72 and 96h in LM, and 24 and 48h in LMS. Its higher inhibition was observed at 24h, both for LM and LMS. LM cell proliferation showed a significant reduction for both mimics miRNAs at 72 and 96h, while inhibitory miRNAs decreased its proliferative capacity at 48 and 72h for 34a and only at 48h for 181b. Proliferation of LMS cells was lower only for 34a mimics at 72 and 96h and trended lower at 120h. Cell proliferation was lower when 181b was inhibited, at 72 and 96h, but a tendency was also observed at 48 and 120h. These preliminary results demonstrate a decreasing migratory rate in LM and LMS cells for 34a mimic and 181b inhibitor. In silico analysis depicted a strong interaction of the 34a, TP53 and BCL2 genes, and of the 181b, BCL2 and TIMP3. In conclusion, the upregulation of miR-34a and induced cell proliferation and migration decrease in LM. For LMS cells, 34a upregulation was associated with the inhibition of cell proliferation and migration, while its downregulation induces the reduction of only the cell proliferation. inhibition had an inductor effect over the LMS cells proliferation, but diminished in the cell migration. Citation Format: Bruna C. de Almeida, Isabela S. Faria, Laura G. Dos Anjos, Giovana N. Maffazioli, Edmund C. Baracat, Katia C. Carvalho. miRNAs with potential application for diagnosis, prognosis and treatment response prediction in uterine smooth muscle tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2520.

p>Leiomyoma (LM) and leiomyosarcoma (LMS) are uterine mesenchymal tumors that present variable clinical and biological behavior. They are associated with infertility, pelvic pain and abnormal uterine bleeding.. LM is a benign tumor commonly affecting women at reproductive age whereas LMS represents 40% of all uterine sarcomas. These tumors do not have specific therapy and their origin is still uncertain. Some researchers believe that degenerated LM may to turn to LMS. FOXO3a, a transcriptional factor, has been associated to regulation of several cellular functions as well as tumors development. Previously, we detected that FOXO3a gene and protein expression present different expression profiles in LM and LMS. In this current study, our aim was to investigate the in vitro effects of metformin and genistein, both inhibitors of AKT-mediated FOXO3a phosphorylation, treatment in LM and LMS cells behavior. LM (THESCs CRL-4003) and LMS (SK-UT-1) cell lines were grown in specific mediums and conditions (ATCC recommendations), and treated with different drugs concentrations (0.1 - 200 uM and 0.1 - 200 nM, for metformin and genistein, respectively) at several time points (0, 24, 48, 72, 96 and 120 h). After treatment, cells were evaluated for gene and protein expression, cell proliferation, migration and apoptosis. Gene expression was assessed by quantitative Real Time PCR and proteins were evaluated by immunocitochemical analysis. Genistein depicted high toxicity for the cells, due to its vehicle (DMSO), in all tested dose and times. Metformin presented higher efficiency in cell proliferation and migration inhibition for both cell lines, as well as in the apoptosis induction. Prominent effects were observed in LMS cells after treatment with 25 uM for 72h. Gene expression analysis showed a slight decrease in FOXO3a expression after treatment with these drugs. Our results suggest that treatment with metformin induces the FOXO3a function restoration in the cells, by inhibition of the AKT/PI3K pathway, and can represent a future alternative target therapy for these neoplasias. Citation Format: Anamaria R. Ricci, Giovana D. Maffazioli, Edmund C. Baracat, Kátia C. Carvalho. Metformin treatment inhibits uterine leiomyoma and leiomyosarcoma cells growth and migration in vitro [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4027.</p

Uterine leiomyomas (LM) are the most frequent benign tumors in women of reproductive age. They are associated with infertility, pelvic pain, abnormal uterine bleeding and represent a public health challenge. LM are over 4 times more common in African-descendent women. Additionally, this tumor constitutes a major health and financial burden in several countries. Similar to many pathologies, environmental exposure contributes to their origin and development. Air pollution acts as a disruptor in the hormonal activity and in other key pathways leading to enhanced tumor progression and making possible pregnancies difficult. In this study, we evaluated LM samples from women resident in urban (high exposure area) and no-urban areas (low or negative exposure area) for the expression of genes related to endometrial receptivity. We selected a total of 100 patients and among them twenty fill the specific profile of those exposed or not exposed to air pollution. mRNA expression analysis was performed using an array composed by 84 receptivity-related genes (Array Code: CLAH27251A, Qiagen, USA). Gene expression analyses showed PRLR, LITAF, COL6A3, HOXA11, KLRC1, UBE2A e IGFBP5 with higher fold expression (fold >2) in the exposed group. On the other hand, PENK, CALB2, DUOX1, COMP, CXCL14, CTNNA2, TCN1, S100P, WNT5A, ERBB2, MTNR1B and were dowregulated in these samples (fold < - 4). Several other genes exhibited differential regulation between exposed and non-exposed group of patients, but with lower significance. Our results corroborate the expected for these populations, since it is known that women resident in areas with high air pollution have reproductive complications and higher tendency to tumors development. However, this work is the first evidence of the impairment of endometrial receptivity in uterine LM patients associated to air pollution in Brazil. Further studies are ongoing to validate and elucidate the specific roles of these genes in uterine LM origin and development, as well as their reproductive function in this population. Citation Format: Dara O. Ferreira, Giovana D. Maffazioli, Edmund C. Baracat, Katia C. Carvalho. Endometrial receptivity markers in patients with uterine fibroids and their correlation with air pollution exposure [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4696.