Low and High-Normal FMR1 Triplet Cytosine, Guanine Guanine Repeats Affect Ovarian Reserve and Fertility in Women Who Underwent In Vitro Fertilization Treatment? Results from a Cross-Sectional Study.

Dynamic mutations in the 5' untranslated region of FMR1 are associated with infertility. Premutation alleles interfere with prenatal development and increase infertility risks. The number of CGG repeats that causes the highest decrease in ovarian reserves remains unclear. We evaluated the effect of FMR1 CGG repeat lengths on ovarian reserves and in vitro fertilization (IVF) treatment outcomes in 272 women with alleles within the normal range. FMR1 CGG repeat length was investigated via PCR and capillary electrophoresis. Alleles were classified as low-normal, normal, and high-normal. Serum levels of follicle-stimulating hormone and anti-Mullerian hormone (AMH) in the follicular phase of the menstrual cycle were measured, and antral follicles (AFC) were counted. IVF outcomes were collected from medical records. Regarding FMR1 CGG repeat length alleles, 63.2% of women presented at least one low-normal allele. Those carrying low-normal alleles had significantly lower AMH levels than women carrying normal or high-normal alleles. Low-normal/low-normal genotype was the most frequent, followed by low-normal/normal and normal/normal. A comparison of ovarian reserve markers and reproductive outcomes of the three most frequent genotypes revealed that AFC in the low-normal/normal genotype was significantly lower than the low-normal/low-normal genotype. The low number of FMR1 CGG repeats affected AMH levels and AFC but not IVF outcomes per cycle of treatment.

Implication of FSHB rs10835638 variant in endometriosis in Brazilian women.

OBJECTIVE: The follicle-stimulating hormone subunit beta gene rs10835638 variant (c.-211G>T) may have detrimental effects on fertility and protective effects against endometriosis. A case-control analysis was performed, aiming to investigate the possible relationship between this variant and the development and/or progression of endometriosis. METHODS: This study included 326 women with endometriosis and 482 controls without endometriosis, both confirmed by inspection of the pelvic cavity during surgery. Genotyping was performed using a TaqMan real-time polymerase chain reaction assay. Genotype and allele frequencies and genetic models were compared between the groups. RESULTS: The genotype and allele frequencies of the rs10835638 variant did not differ between women with and those without endometriosis. Subdividing the endometriosis group into fertile and infertile groups did not result in a significant difference in these frequencies. However, the subgroup with minimal/mild endometriosis had a higher frequency of the GT genotype than the Control Group, regardless of fertility. The T allele was significantly more common in women with minimal/mild endometriosis than in the Control Group in the recessive model. CONCLUSION: The T allele is associated with the development of minimal/mild endometriosis in Brazilian women.

Involvement of SYCP2L and TDRD3 gene variants on ovarian reserve and reproductive outcomes: a cross-sectional study.

OBJECTIVE: Single nucleotide variants have been implicated in the response to fertility treatment and a pharmacogenomic approach may help to customize therapy based on patient genome. We aimed to evaluate the effect, individual and combined, of SYCP2L (rs2153157:G>A) and TDRD3 (rs4886238:G>A) variants on ovarian reserve, response to controlled ovarian stimulation (COS) and reproductive outcomes of women undergoing in vitro fertilization (IVF) treatment. METHODS: This cross-sectional study included 149 normoovulatory women undergoing IVF. Genotyping was performed using the TaqMan real-time polymerase chain reaction method. Clinical parameters and reproductive outcomes were compared according to the genotypes of the variants studied. RESULTS: Considering ovarian reserve, there were no significant differences among SYCP2L or TDRD3 genotypes in terms of FSH levels or AFC; however, AMH levels were significantly different in carriers of both variants. Regarding the SYCP2L rs2153157:G>A variant, lower AMH levels were observed in women carrying an AA genotype compared to women carrying a heterozygous genotype (p=0.01). Considering the TDRD3 rs4886238:G>A variant, women carrying an AA genotype presented higher AMH levels than carriers of GG and GA genotypes (p=0.025). Nevertheless, no difference was found regarding response to COS or reproductive outcomes. Considering the combined effect of the variants, women carrying the heterozygous genotype of both variants presented statistically increased AMH levels compared to SYCP2L rs2153157 AA genotype carriers and TDRD3 rs4886238 GG genotype carriers (p=0.042). CONCLUSIONS: Individually and combined, the SYCP2L rs2153157 and TDRD3 rs4886238 variants have an effect on AMH level.

Spatial, spatio-temporal, and origin-destination flow analyses of patients with severe acute respiratory syndrome hospitalized for COVID-19 in Southeastern Brazil, 2020-2021.

Brazil experienced one of the fastest increasing numbers of coronavirus disease (COVID-19) cases worldwide. The Sao Paulo State (SPS) reported a high incidence, particularly in Sao Paulo municipality. This study aimed to identify clusters of incidence and mortality of hospitalized patients with severe acute respiratory syndrome for COVID-19 in the SPS, in 2020-2021, and describe the origin flow pattern of the cases. Cases and mortality risk area clusters were identified through different analyses (spatial clusters, spatio-temporal clusters, and spatial variation in temporal trends) by weighting areas. Ripley's K12-function verified the spatial dependence between the cases and infrastructure. There were 517,935 reported cases, with 152,128 cases resulting in death. Of the 470,441 patients hospitalized and residing in the SPS, 357,526 remained in the original municipality, while 112,915 did not. Cases and death clusters were identified in the Sao Paulo metropolitan region (SPMR) and Baixada Santista region in the first study period, and in the SPMR and the Campinas, Sao Jose do Rio Preto, Barretos, and Sorocaba municipalities during the second period. We highlight the priority areas for control and surveillance actions for COVID-19, which could lead to better outcomes in future outbreaks.

Implication of FSHB rs10835638 variant in endometriosis in Brazilian women

ABSTRACT Objective The follicle-stimulating hormone subunit beta gene rs10835638 variant (c.-211G>T) may have detrimental effects on fertility and protective effects against endometriosis. A case-control analysis was performed, aiming to investigate the possible relationship between this variant and the development and/or progression of endometriosis. Methods This study included 326 women with endometriosis and 482 controls without endometriosis, both confirmed by inspection of the pelvic cavity during surgery. Genotyping was performed using a TaqMan real-time polymerase chain reaction assay. Genotype and allele frequencies and genetic models were compared between the groups. Results The genotype and allele frequencies of the rs10835638 variant did not differ between women with and those without endometriosis. Subdividing the endometriosis group into fertile and infertile groups did not result in a significant difference in these frequencies. However, the subgroup with minimal/mild endometriosis had a higher frequency of the GT genotype than the Control Group, regardless of fertility. The T allele was significantly more common in women with minimal/mild endometriosis than in the Control Group in the recessive model. Conclusion The T allele is associated with the development of minimal/mild endometriosis in Brazilian women.

Spatial, spatio-temporal, and origin-destination flow analyses of patients with severe acute respiratory syndrome hospitalized for COVID-19 in Southeastern Brazil, 2020-2021

ABSTRACT Brazil experienced one of the fastest increasing numbers of coronavirus disease (COVID-19) cases worldwide. The Sao Paulo State (SPS) reported a high incidence, particularly in Sao Paulo municipality. This study aimed to identify clusters of incidence and mortality of hospitalized patients with severe acute respiratory syndrome for COVID-19 in the SPS, in 2020-2021, and describe the origin flow pattern of the cases. Cases and mortality risk area clusters were identified through different analyses (spatial clusters, spatio-temporal clusters, and spatial variation in temporal trends) by weighting areas. Ripley's K12-function verified the spatial dependence between the cases and infrastructure. There were 517,935 reported cases, with 152,128 cases resulting in death. Of the 470,441 patients hospitalized and residing in the SPS, 357,526 remained in the original municipality, while 112,915 did not. Cases and death clusters were identified in the Sao Paulo metropolitan region (SPMR) and Baixada Santista region in the first study period, and in the SPMR and the Campinas, Sao Jose do Rio Preto, Barretos, and Sorocaba municipalities during the second period. We highlight the priority areas for control and surveillance actions for COVID-19, which could lead to better outcomes in future outbreaks.

Effects of FSHR and FSHB Variants on Hormonal Profile and Reproductive Outcomes of Infertile Women With Endometriosis.

Background: Single nucleotide variants (SNVs) FSHB:c.-211G>T, FSHR:c.919G>A, and FSHR:c.2039G>A were reported to be associated with the variability in FSH and LH levels, and in vitro fertilization (IVF) outcomes. In this study, we aimed to evaluate the effects of FSHB:c.-211G>T, FSHR:c.919G>A, and FSHR:c.2039G>A variants, alone and combined, on the hormonal profile and reproduction outcomes of women with endometriosis. Methods: A cross-sectional study was performed comprising 213 infertile Brazilian women with endometriosis who underwent IVF treatment. Genotyping was performed using TaqMan real-time PCR. Variables were compared according to the genotypes of each variant and genetic models, and the combined effects of the SNVs were evaluated using the multifactorial dimensionality reduction method. Results: FSHB:c.-211G>T affected LH levels in women with overall endometriosis and minimal/mild disease. FSHR:c.919G>A affected FSH levels in women with overall endometriosis and the number of oocytes retrieved in those with moderate/severe endometriosis. Moreover, the FSHR:c.2039G>A affected FSH levels in women with overall endometriosis, LH levels and total amount of rFSH in those with minimal/mild disease, and number of follicles and number of oocytes retrieved in those with moderate/severe endometriosis. No effect on hormone profile or reproductive outcomes was observed when the genotypes were combined. Conclusions: Variants of the FSHB and FSHR genes separately interfered with the hormonal profiles and IVF outcomes of women with endometriosis.

COVID-19 in the state of São Paulo: the evolution of a pandemic. / COVID-19 no estado de São Paulo: a evolução de uma pandemia.

OBJECTIVES: To retrospectively describe severe cases of hospitalized patients and deaths related to the COVID-19 epidemic in the state of São Paulo, starting from the date of the first record, with symptoms onset on 02/10/2020 up to 05/20/2021. METHODS: This is a descriptive study carried out using the Influenza Epidemiological Surveillance System (Sistema de Vigilância Epidemiológica da Gripe - SIVEP-Gripe) database. The rates of incidence, mortality, and accumulated incidence in the period were calculated, stratified by age group and Regional Health Department (RHD). In addition, severe cases were geocoded to analyze their spread across the state; and the Effective R, which determines the spread potential of a virus within a population, was calculated. RESULTS: There was a significant increase in severe cases and deaths recorded in the period of one year, with incidence and mortality rates being heterogeneous within the state. The most critical periods regarding the incidence of severe cases occurred between May and July 2020 and between March and April 2021. The RHD in São José do Rio Preto, Expanded São Paulo, and Araçatuba concentrated the highest incidence and mortality rates. Severe cases and deaths were more frequent in men and in the population over 60 years, while the main risk conditions related to deaths were heart disease (59%) and diabetes (42,8%). CONCLUSIONS: These results not only provide a detailed profile for more efficient control action plan, but will also allow the historical understanding of the COVID-19 evolution within the state of São Paulo.

OBJETIVO: Descrever, de forma retrospectiva, os casos graves de pacientes hospitalizados e os óbitos relacionados à epidemia de COVID-19 no estado de São Paulo, desde a data do primeiro registro, com início de sintomas em 10 de fevereiro de 2020 até registros disponíveis em 20 de maio de 2021. MÉTODOS: Trata-se de um estudo descritivo realizado por meio da base de dados do Sistema de Vigilância Epidemiológica da Gripe. Foram calculadas as taxas de incidência, mortalidade e incidência acumulada no período, estratificadas por faixa etária e agrupadas de acordo com cada Departamento Regional de Saúde. Os casos graves foram geocodificados para a análise de seu espalhamento pelo estado e foi calculado o R efetivo, que estima o potencial de propagação de um vírus em uma população. RESULTADOS: Houve aumento significativo dos casos graves e óbitos registrados no período de um ano, e as taxas de incidência e mortalidade foram heterogêneas no estado. Os períodos mais críticos em relação à incidência de casos graves ocorreram entre maio e julho de 2020 e entre março e abril de 2021. Os Departamentos Regionais de Saúde de São José do Rio Preto, Grande São Paulo e Araçatuba concentraram as maiores taxas de incidência e mortalidade. Os casos graves e óbitos foram mais frequentes nos homens e na população acima de 60 anos, e as principais condições de risco relacionadas aos óbitos foram cardiopatia (59%) e diabetes (42,8%). CONCLUSÕES: Espera-se que esses resultados ofereçam embasamento e possam contribuir para uma ação de controle mais eficiente da COVID-19, além de permitir o entendimento histórico de sua evolução no estado.

SARS-CoV-2 reinfection: report of two cases in Southeast Brazil.

From February 26, 2020 to March 11, 2021, coronavirus disease 2019 (COVID-19) pandemic resulted in 11,439,558 cases and 277,102 deaths in Brazil. Among them, 2,195,130 cases and 63,965 deaths occurred in Sao Paulo State, Southeast Brazil. The recent emergence and rise of new variants of SARS-CoV-2 is of concern because of their higher transmissibility and possible association with more severe disease. Cases of SARS-CoV-2 reinfections have been described since December 2020 in Brazil. This report describes two cases of COVID-19 reinfection, that occurred five and six months after the first infection, during the second wave of the pandemic in Sao Paulo State. Both patients presented mild symptoms in the two COVID-19 episodes and different lineages of SARS-CoV-2 were identified: B.1.1.33 and B.1.1.28 lineages in case 1 and B1.1.128 and P. 2 lineages in case 2.

COVID-19 in the state of São Paulo: the evolution of a pandemic / COVID-19 no estado de São Paulo: a evolução de uma pandemia

OBJECTIVES: To describe retrospectively severe hospitalized cases and deaths related to the COVID-19 epidemic in the state of São Paulo, starting from the date of the first record with symptoms onset on 02/10/2020 up to 05/20/2021 records. METHODS: This is a descriptive study. The data source used was from the Influenza Epidemiological Surveillance System (SIVEP-Gripe). The rates of incidence, mortality and accumulated incidence in the period were calculated, stratified by age group and Regional Health Department (DRS). In addition, severe cases were geocoded to analyze their spread across the state; and the Effective R, which determines the spread potential of a virus within a population, was calculated. RESULTS: There was a significant increase in severe cases and deaths recorded in the period of one year, with incidence and mortality rates being heterogeneous within the state. The most critical periods regarding the incidence of severe cases occurred between May and July 2020 and between March and April 2021. The DRSs in São José do Rio Preto, Grande São Paulo and Araçatuba concentrated the highest incidence and mortality rates. Severe cases and deaths were more frequent in men and in the population over 60 years, while the main risk conditions related to deaths were heart disease (59%) and diabetes (42,8%). CONCLUSIONS: These results not only provide a detailed profile for more efficient control action plan, but will also allow the historical understanding of the COVID-19 evolution within the state of São Paulo.

OBJETIVOS: Descrever, de forma retrospectiva, os casos graves hospitalizados e óbitos relacionados à epidemia de COVID-19 no estado de São Paulo, desde a data do primeiro registro com início de sintomas em 10/02/2020 até registros disponíveis em 20/05/2021. MÉTODOS: Trata-se de um estudo descritivo realizado por meio da base de dados do Sistema de Vigilância Epidemiológica da Gripe (SIVEP-Gripe). Foram calculadas as taxas de incidência, mortalidade e incidência acumulada no período, estratificadas por faixa etária e Departamento Regional de Saúde (DRS). Os casos graves foram geocodificados para análise de seu espalhamento pelo estado e foi calculado o R Efetivo, que estima o potencial de propagação de um vírus dentro de uma população. RESULTADOS: Houve um aumento significativo dos casos graves e óbitos registrados no período de um ano, sendo que as taxas de incidência e mortalidade foram heterogêneas dentro do estado. Os períodos mais críticos em relação à incidência de casos graves ocorreram entre maio e julho de 2020 e entre março e abril de 2021. Os DRS de São José do Rio Preto, Grande São Paulo e Araçatuba concentraram as maiores taxas de incidência e mortalidade. Os casos graves e óbitos foram mais frequentes nos homens e na população acima de 60 anos, e as principais condições de risco relacionadas aos óbitos foram cardiopatia (59%) e diabetes (42,8%). CONCLUSÕES: Espera-se que esses resultados ofereçam embasamento e possam contribuir para uma ação de controle mais eficiente, além de permitir o entendimento histórico da evolução da COVID-19 no estado.

Epidemiological characteristics of influenza-like illness outbreaks in long-term care facilities of the state of São Paulo, Brazil / Características epidemiológicas dos surtos de síndrome gripal em instituições de longa permanência para idosos no estado de São Paulo, Brasil

Long-term care facilities for older adults present a high risk of outbreaks since they concentrate often more frail and vulnerable individuals. OBJECTIVE: To describe the epidemiological characteristics of influenza-like illness outbreaks and cases among older people in long-term care facilities in the state of São Paulo, Brazil. METODS: The analysis was performed through an exploratory and descriptive approach, with records from the outbreak module of the National System of Notifiable Diseases between January 2020 and June 2021. RESULTS: Outbreaks of influenza-like illness in this department represented 24.93% of all notifications. The highest concentration was seen in the state capital and metropolitan area. A total of 1 018 confirmed outbreaks were observed, involving 6 110 cases and 1 240 deaths among older people. Of these cases, 71.67% were confirmed for coronavirus disease 19 (COVID-19), 12.77% for the influenza virus, and 15.56% for other respiratory viruses. The percentages regarding death outcomes were similar, with a 20.29% lethality of influenza-like illness. Within the studied group, the older adults were the most affected. A statistical difference was observed between cases and deaths. CONCLUSIONS: Owing to the current scenario and the known vulnerabilities of these facilities, there is an urgent need for joint and articulated action by various administrative levels in order to minimize the devastating effects of influenza-like illness outbreaks (especially of COVID19) in older adults at long-term care homes. The strengthening of information systems and their interoperability are considered of utmost importance in order to improve the quality of information on outbreaks, which is essential during a pandemic.

Instituições de longa permanência para idosos são locais que apresentam um alto risco de surtos epidêmicos, visto que concentram indivíduos, frequentemente mais frágeis e vulneráveis. OBJETIVO: Descrever as características epidemiológicas de surtos de síndrome gripal entre idosos em instituições de longa permanência no estado de São Paulo. MÉTODOS: A análise foi realizada através de uma abordagem exploratória e descritiva, utilizando-se de registros do Sistema de Informações de Agravos de Notificação, módulo surto, entre janeiro de 2020 e junho de 2021. RESULTADOS: Surtos de síndrome gripal neste departamento representaram 24,93% do total de notificações. A maior concentração de surtos ocorreu na capital e região metropolitana. Foram observados 1018 surtos confirmados, envolvendo 6110 casos e 1240 óbitos em idosos. Entre estes casos, 71,67% foram confirmados para COVID-19, 12,77% para o vírus Influenza e 15,56%, para outros vírus respiratórios. Óbitos apresentaram porcentagens semelhantes, com a letalidade de síndrome gripal sendo de 20,29%. No grupo estudado, idosos mais longevos foram os mais acometidos. Houve diferença estatística entre casos e óbitos. CONCLUSÕES: Devido ao cenário atual e às conhecidas vulnerabilidades destas instituições, há a necessidade urgente de uma ação conjunta e articulada por parte de diversas esferas administrativas para minimizar os efeitos devastadores de surtos de síndrome gripal, especialmente os de COVID-19, em instituições de longa permanência. O fortalecimento de sistemas de informação e sua interoperabilidade são considerados de vital importância para melhorar a qualidade da informação sobre surtos institucionais, a qual é essencial durante uma pandemia.

COVID-19 no estado de São Paulo: a evolução de uma pandemia / COVID-19 in the state of São Paulo: the evolution of a pandemic

RESUMO: Objetivo: Descrever, de forma retrospectiva, os casos graves de pacientes hospitalizados e os óbitos relacionados à epidemia de COVID-19 no estado de São Paulo, desde a data do primeiro registro, com início de sintomas em 10 de fevereiro de 2020 até registros disponíveis em 20 de maio de 2021. Métodos: Trata-se de um estudo descritivo realizado por meio da base de dados do Sistema de Vigilância Epidemiológica da Gripe. Foram calculadas as taxas de incidência, mortalidade e incidência acumulada no período, estratificadas por faixa etária e agrupadas de acordo com cada Departamento Regional de Saúde. Os casos graves foram geocodificados para a análise de seu espalhamento pelo estado e foi calculado o R efetivo, que estima o potencial de propagação de um vírus em uma população. Resultados: Houve aumento significativo dos casos graves e óbitos registrados no período de um ano, e as taxas de incidência e mortalidade foram heterogêneas no estado. Os períodos mais críticos em relação à incidência de casos graves ocorreram entre maio e julho de 2020 e entre março e abril de 2021. Os Departamentos Regionais de Saúde de São José do Rio Preto, Grande São Paulo e Araçatuba concentraram as maiores taxas de incidência e mortalidade. Os casos graves e óbitos foram mais frequentes nos homens e na população acima de 60 anos, e as principais condições de risco relacionadas aos óbitos foram cardiopatia (59%) e diabetes (42,8%). Conclusões: Espera-se que esses resultados ofereçam embasamento e possam contribuir para uma ação de controle mais eficiente da COVID-19, além de permitir o entendimento histórico de sua evolução no estado.

ABSTRACT: Objectives: To retrospectively describe severe cases of hospitalized patients and deaths related to the COVID-19 epidemic in the state of São Paulo, starting from the date of the first record, with symptoms onset on 02/10/2020 up to 05/20/2021. Methods: This is a descriptive study carried out using the Influenza Epidemiological Surveillance System (Sistema de Vigilância Epidemiológica da Gripe - SIVEP-Gripe) database. The rates of incidence, mortality, and accumulated incidence in the period were calculated, stratified by age group and Regional Health Department (RHD). In addition, severe cases were geocoded to analyze their spread across the state; and the Effective R, which determines the spread potential of a virus within a population, was calculated. Results: There was a significant increase in severe cases and deaths recorded in the period of one year, with incidence and mortality rates being heterogeneous within the state. The most critical periods regarding the incidence of severe cases occurred between May and July 2020 and between March and April 2021. The RHD in São José do Rio Preto, Expanded São Paulo, and Araçatuba concentrated the highest incidence and mortality rates. Severe cases and deaths were more frequent in men and in the population over 60 years, while the main risk conditions related to deaths were heart disease (59%) and diabetes (42,8%). Conclusions: These results not only provide a detailed profile for more efficient control action plan, but will also allow the historical understanding of the COVID-19 evolution within the state of São Paulo.

SARS-CoV-2 reinfection: report of two cases in Southeast Brazil

From February 26, 2020 to March 11, 2021, coronavirus disease 2019 (COVID-19) pandemic resulted in 11,439,558 cases and 277,102 deaths in Brazil. Among them, 2,195,130 cases and 63,965 deaths occurred in Sao Paulo State, Southeast Brazil. The recent emergence and rise of new variants of SARS-CoV-2 is of concern because of their higher transmissibility and possible association with more severe disease. Cases of SARS-CoV-2 reinfections have been described since December 2020 in Brazil. This report describes two cases of COVID-19 reinfection, that occurred five and six months after the first infection, during the second wave of the pandemic in Sao Paulo State. Both patients presented mild symptoms in the two COVID-19 episodes and different lineages of SARS-CoV-2 were identified: B.1.1.33 and B.1.1.28 lineages in case 1 and B1.1.128 and P. 2 lineages in case 2.

Endometrial cancer: a genetic point of view.

BACKGROUND: Endometrial cancer is the fourth most frequent gynecological cancer and the most frequent type of uterine cancer. There is an increase in the incidence and mortality of uterine cancers in the past few decades, and there are no well-established screening programs for endometrial cancer currently. Most endometrial cancers arise through the interplay of familial, genetic, and lifestyle factors. Although a number of genetic factors modify endometrial cancer susceptibility, they are not of standard use in the clinical assessment of prognosis. We conducted a comprehensive systematic literature review to provide an overview of the relationship between genetic factors and risk for endometrial cancer. METHODS: MEDLINE and EMBASE databases were searched for studies between January 2010 to March 2020 reporting the genes associated with endometrial cancer. RESULTS: Through the selection process, we retrieved 186 studies comprising 329 genes identified using several molecular methodologies in all human chromosomes and in mitochondrial DNA. Endometrial cancer exhibits a molecular complexity and heterogeneity coherent with its clinical and histologic variability. Improved characterization of molecular alterations of each histological type provides relevant information about the prognosis and potential response to new therapies. CONCLUSIONS: The current challenge is the integration of clinicopathologic and molecular factors to improve the diagnosis, prognosis, and treatment of endometrial cancer.

Kisspeptin Levels in Girls with Precocious Puberty: A Systematic Review and Meta-Analysis.

BACKGROUND/AIMS: Kisspeptin (KP) is a key player in the regulation of the release of gonadotropin-releasing hormone (GnRH), which increases the secretion of gonadotropin during puberty to establish reproductive function and regulate the hypothalamic-pituitary-gonadal axis. Premature activation of GnRH secretion leads to idiopathic/central gonadotropin-dependent precocious puberty (CPP). We aimed to compare the blood KP concentrations in girls with CPP and healthy controls. METHODS: A systematic review and meta-analysis was performed. We searched MEDLINE, EMBASE, The Cochrane Library, and SciELO. Random-effects model and standardized mean difference (SMD) were used. Heterogeneity was assessed through I2. Meta-regression considered patient age, KP fraction, and analytical method for KP measurement. RESULTS: The 11 studies included comprised 316 CPP patients and 251 controls. Higher KP levels in the CPP group were found (SMD 1.53; CI 95% = 0.56-2.51). Subgroup analysis revealed association with patient age (p = 0.048), indicating a positive correlation between elevation in KP concentration and age in CPP group. A group of patients with precocious thelarche (PT) from 5 of the included studies comprising 121 patients showed higher levels of KP (1.10; -0.25-2.45: CI 95%) and high heterogeneity (I2 = 91%). The CPP/PT ratio for KP level indicates KP 36% higher on CPP than PT patients. CONCLUSIONS: A consistent difference in KP levels between girls with CPP and controls was identified. While there are important limitations in KP assays which argue against its use as a diagnostic tool, the KP levels in CPP versus control and PT children are consistent with the predicted mechanisms and pathophysiology of CPP.

The role of Kisspeptin levels in polycystic ovary syndrome: a systematic review and meta-analysis.

PURPOSE: Polycystic ovarian syndrome (PCOS) is a complex and not fully elucidated pathology. This prevalent endocrinopathy affects patients in reproductive age, impacts on estrogen-dependent diseases, as well as in infertility. In this context, Kisspeptin (KP) may be considered a potential biomarker for PCOS diagnosis and follow-up. Here, we aimed to verify the levels of KP in obese and non-obese patients with PCOS, their relationship with other hormones, in comparison to healthy controls. METHODS: A systematic review and meta-analysis were performed according to the PRISMA guidelines. We searched MEDLINE, EMBASE, PsycINFO, Global Health, The Cochrane Library, Health Technology Assessment Database, and Web of Science for eligible studies. A random effects model meta-analysis of standardized mean difference (SMD) was conducted and the I2 was used to assess heterogeneity. Meta-regression was conducted through mixed-effects model. RESULTS: A total of 12 studies were included, comprising 660 PCOS patients and 600 controls. The KP levels were lower in the control group (0.76: 0.17-1.35; 95% CI). In the subgroup analyses, patients were divided in non-overweight/obese (BMI < 25) and overweight/obese (BMI ≥ 25) groups. The meta-regression revealed a difference between the obese and non-obese groups (z = 2.81; p = 0.0050). CONCLUSIONS: PCOS patients showed higher KP levels than control, and obese non-PCOS patients also showed altered KP levels. All studies had poor descriptions of sample collection, pre-analytical and analytical procedures, which is critical considering structural characteristics of the KP molecule.

Influence of STAT4 gene polymorphisms in the pathogenesis of endometriosis.

The STAT4 gene is vital to signaling pathways in the immune response. Immunological alterations are involved in the pathogenesis of endometriosis, and STAT4 polymorphisms may be linked to disease development. This study's aim is to evaluate the possible association between four STAT4 polymorphisms (rs7601754/G > A, rs11889341/C > T, rs7574865/T > G, and rs7582694/C > G) and the pathogenesis of endometriosis in Brazilian women. This case-control study's sample comprised 238 women with endometriosis and 201 healthy, fertile women without endometriosis (which was surgically confirmed). Genotyping was performed using the TaqMan system with a real-time polymerase chain reaction; the genotype, allele, and haplotype frequencies were then compared between groups. A single-polymorphism analysis revealed that the TT genotype of the rs7574865/T > G polymorphism was significantly more frequent in women with minimal or mild endometriosis than in the controls (10% vs. 5%, p = 0.047). The CGAC, GTAT, and GTAC haplotypes were significantly more frequent in the women with endometriosis-related infertility (5.8%, 4.1%, and 2.9%, respectively) than in the controls (2.4%, 1.1%, and 0.8%, respectively; p = 0.020, p = 0.011, and p = 0.032, respectively), but the GGGC and CTAT haplotypes were significantly more prevalent in the control group (34.7% and 13.9%, respectively) than among the infertile group (26.2% and 9.1%, respectively). In addition, the CGAC haplotype was more frequently found in those with minimal or mild endometriosis (6.8%) than in the controls (2.4%, p = 0.009), and the GTAT haplotype was more commonly found in those with moderate or severe disease (3.6%) than in the controls (1.1%, p = 0.028). These findings suggest that STAT4 polymorphisms can influence the pathogenesis of endometriosis.

Effects of a Polymorphism in the Promoter Region of the Follicle-Stimulating Hormone Subunit Beta (FSHB) Gene on Female Reproductive Outcomes.

BACKGROUND: Follicle-stimulating hormone (FSH) is essential to the hypothalamic-pituitary-gonadal axis, playing a key role in human reproduction. It is a heterodimer comprised of a hormone-specific ß-chain (FSH-ß) that is associated with an α-chain. It exerts its biological activities by binding to the FSH receptor (FSHR). The ß-subunit, which is encoded by the FSHB gene, is responsible for ensuring binding specificity to the FSHR. There is a promoter polymorphism in this gene, c.-211G>T (rs10835638), upstream of the transcription start site; and in vitro studies have reported that the T allele decreases FSHB transcription in gonadotrophic cells. AIMS: Investigate the possible effects of the FSHB c.-211G/T polymorphism on hormonal profile and in in vitro fertilization (IVF)/intracytoplasmic sperm injection outcomes in normoovulatory Brazilian women. METHODS: A cross-sectional study of 140 women (median age = 33 years [CI: 32-34]) with infertility mainly caused by male (n = 85) or tuboperitoneal (n = 55) factors. In this study we evaluated FSH, estradiol, luteinizing hormone (LH), progesterone, prolactin and anti-Mullerian hormone levels, and antral follicle counting (AFC). Genotyping was performed using the TaqMan real-time polymerase chain reaction methodology. RESULTS: The wild-type allele G was found in 86.4% and the polymorphic allele T in 13.6% of the women respectively. The TT genotype was not found in any women. Women carrying the GT genotype had a poorer response more frequently to controlled ovarian hyperstimulation when compared to individuals with the GG genotype (47.4% vs. 26.5%, p = 0.010), higher LH levels (3.1 IU/mL vs. 2.4 IU/mL, p = <0.001), lower AFC (8.0 vs. 10.0, p = 0.03), oocytes retrieved (3.0 vs. 5.0, p = 0.03), MII (3.0 vs. 4.0, p = 0.02), and embryos (2.0 vs. 3.0, p = 0.02). Despite these findings, no difference was observed in pregnancy rate. CONCLUSION: Our findings suggest that the FSHB c.-211G/T polymorphism may modestly alter some aspects of the female reproductive system, but they are not associated with significantly different IVF outcomes.

Use of Bone Morphogenetic Protein 15 Polymorphisms to Predict Ovarian Stimulation Outcomes in Infertile Brazilian Women.

AIMS: Polymorphisms in the gene encoding bone morphogenetic protein 15 (BMP15) can result in inhibited secretion or lowered bioactivity of the BMP15 protein. BMP15 levels are associated with follicle-stimulating hormone receptor (FSHR) action on granulosa cells, wherein FSHR increases the sensitivity of ovarian follicles to follicle-stimulating hormone (FSH). In this study we evaluated the BMP15 polymorphisms A905 > G/rs3897937, C901 > T/rs17003221, and C-9 > G/rs3810682 in infertile Brazilian women in terms of anti-Mullerian hormone (AMH), FSH, and estradiol serum levels, as well as controlled ovarian hyperstimulation response and assisted reproduction outcomes. METHODS: A cross-sectional study comprising 186 infertile women who underwent the first cycle of high complexity assisted reproduction treatment was conducted using the TaqMan assay for quantitative polymerase chain reaction genotyping. Serum AMH, FSH, and estradiol levels were measured by enzyme-linked immunosorbent assay. RESULTS: For C901 > T (rs17003221) carriers, there was a statistically significant difference among carriers of a polymorphic BMP15 genotype (TT) and the estradiol concentration. These women had higher estradiol levels than women who had homozygous wild type or heterozygous genotypes. There was also a positive correlation between serum AMH and the C-9 > G (rs3810682) polymorphism, wherein women carrying both polymorphic alleles (homozygous, GG) had higher average AMH levels than heterozygous women. However, none of the three polymorphisms studied showed a statistically significant correlation with assisted reproduction outcome. DISCUSSION: Oocytes are known to secrete factors that regulate follicular development and oocyte maturation. Abnormal expression of these factors may thus be involved in follicular development disorders. A recent study highlighted the importance of BMP15 in regulating ovulation rates in sheep and that heterozygous deletions in the -9C > G polymorphism reduced BMP15 concentrations, increased granulosa cell FHSR mRNA levels, elevated estrogen secretion, and activated production of stem cell factors. In this study we found that BMP15 polymorphisms affected estrogen and AMH levels. CONCLUSION: BMP15 polymorphisms are not correlated with ovarian stimulation and assisted reproduction outcomes in infertile Brazilian women.