Metabolic abnormalities in polycystic ovary syndrome women: obese and non obese

OBJETIVO: Comparar as características metabólicas de mulheres jovens do sudeste brasileiro, obesas e não obesas com síndrome dos ovários policísticos (SOP). MÉTODOS: Estudo transversal que incluiu 218 mulheres de idade reprodutiva com diagnóstico de SOP - 90 mulheres não obesas (IMC entre 18,5 e 29,9 kg/m²) e 128 pacientes obesas (IMC &gt;30 kg/m²), selecionadas no momento do diagnóstico. Foram comparadas as frequências de resistência insulínica (RI), intolerância à glicose (IG), síndrome metabólica (MetS) e diabetes mellitus tipo 2 (DM2) e os valores médios de colesterol total (CT), triglicérides (TG), lipoproteínas de alta (LDL) e baixa densidade (HDL), entre as pacientes obesas e não obesas com SOP. Foram comparadas também as características clínicas e hormonais (hormônio folículo estimulante, luteinizante, prolactina, hormônio tireoestimulante, testosterona total, sulfato de dehidroepiandrostenediona e 17-hidroxiprogesterona) nos dois grupos. A análise estatística foi realizada com o auxílio do software SAS 9.0. Para análise das variáveis com distribuição normal, utilizou-se o teste t de Student não pareado; na ausência desta característica, o teste utilizado foi Mann-Whitney bicaudal. Para as variáveis qualitativas utilizou-se o teste Exato de Fisher. Em todas as análises, foi considerado o nível de significância de 5% (p<0,05). RESULTADOS: As frequências de RI, IG e MetS foram significativamente mais elevadas em pacientes com SOP obesas do que não obesas (66,7, 29,9 e 63% versus 24,7, 12,2 e 16.4%, respectivamente). As pacientes obesas apresentaram maiores níveis de CT e TG (189,8±35.8 mg/dL e 145.4±71.1 mg/dL, respectivamente) do que as não obesas (172,1±38.4 mg/dL e 99,3±54 mg/dL, respectivamente). Ambos os grupos apresentaram níveis médios de HDL abaixo de 50 mg/dL. CONCLUSÕES: Mulheres obesas jovens com SOP apresentam maior frequência de RI, IG e SM do que as não obesas. Todavia, a ocorrência dos distúrbios metabólicos é elevada também na pacientes não obesas, sugerindo que a presença da síndrome favoreça o desenvolvimento de comorbidades metabólicas, com potenciais repercussões a médio e longo prazos.PURPOSE: To compare the metabolic characteristics of obese and non-obese young women with polycystic ovary syndrome (POS) from the Brazilian Southeast. METHODS: This was a cross-sectional study conducted on 218 women of reproductive age with a diagnosis of POS - 90 non-obese women (BMI between 18.5 and 29.9 kg/m²), and 128 obese patients (BMI &gt;30 kg/m²) selected at the time of diagnosis. The frequency of insulin resistance (IR), glucose intolerance (GI), metabolic syndrome (MetS) and type 2 diabetes mellitus (DM2) and mean values of total cholesterol (TC), triglycerides (TG), high-density (HDL) and low-density lipoproteins (LDL), were compared between obese and non-obese patients with POS. The two groups were also compared in terms of clinical and hormonal characteristics (follicle stimulating hormone, prolactin, thyroid stimulating hormone, total testosterone, dihydroepiandrostenedione sulfate, and 17-hydroxyprogesterone). Statistical analysis was performed using the SAS 9.0 software. Quantitative variables were compared by the Student´s t-test (data with normal distribution) or by the Mann-Whitney test (non-parametric distribution). Qualitative variables were compared by the Fisher test. The level of significance was set at 5% (p<0.05) in all analyses. RESULTS: The frequency of IR, GI and MetS was significantly higher in obese than non-obese patients with POS (66.7, 29.9, and 63% versus 24.7, 12.2, and 16.4%, respectively). Obese patients had higher TC and TG levels (189.8±35.8 mg/dL and 145.4±71.1 mg/dL, respectively) than non-obese patients (172.1±38.4 mg/dL and 99.3±54 mg/dL, respectively). Both groups had mean HDL levels below 50 mg/dL. CONCLUSIONS: Young obese women with POS have a higher frequency of IR, GI and MS than non-obese. However, the occurrence of metabolic disorders is elevated also in the non-obese patients, suggesting that the presence of the syndrome may favor the development of metabolic comorbidities with potential medium- and long-term repercussions

The impact of adjuvant breast cancer chemotherapy on ovarian reserve and menses

Parte das mulheres com câncer de mama na menacme gostariam de tentar preservar sua fertilidade após o tratamento oncológico. Entretanto, as informações disponíveis sobre a extensão do dano aos ovários após o tratamento quimioterápico são insuficientes para estimar o risco de comprometimento da reserva ovariana. Dessa forma, como objetivo primário deste estudo propusemos caracterizar o impacto dos regimes quimioterápicos mais comumente utilizados no tratamento do câncer de mama em mulheres na menacme sobre a reserva ovariana avaliada por meio da aferição das concentrações séricas de hormônio antiMulleriano (HAM) e calendário menstrual, analisados antes e um ano após o término da quimioterapia. Cento e trinta e quatro pacientes foram analisadas para o objetivo primário do estudo. As concentrações séricas de HAM foram dosadas por meio do teste ELISA e foram representadas pela mediana e intervalo interquartil. Os testes não paramétricos de MannWhitney e de Kruskal-Wallis foram utilizados para comparar as medidas de HAM em relação as variáveis categóricas. A idade média foi de 36,67 anos (DP 3,95), sendo que 104 mulheres realizaram quimioterapia com regime antracíclico (AC-T), 13 regime não antracíclico (CMF) e 17 outros regimes quimioterápicos. Os níveis de HAM após 1 ano do término da quimioterapia reduziram de maneira significativa (mediana 0,13 ng/ml, intervalo interquartil 0,02; 0,35 ng/ml) quando comparados aos níveis basais (mediana 2,84 ng/ml, intervalo interquartil 1,26; 4,65 ng/ml; p<0,0001). Apesar da redução significativa dos níveis de HAM, 74,7% das mulheres apresentavam ciclos menstruais um ano após o término da quimioterapia. O tipo de regime quimioterápico influenciou de maneira significativa a redução dos níveis do HAM após 1 ano do término da quimioterapia. O grupo de tratamento que utilizou CMF apresentou maior redução da reserva ovariana quando comparado com o grupo de tratamento que utilizou outros regimes quimioterápicos. O uso adjuvante de tamoxifeno não alterou os níveis de HAM aferidos após 1 ano do término do tratamento quimioterápico. As concentrações séricas de HAM basais (p<0,0001), a idade (p=0,0438) e o regime de tratamento realizado (p=0,0259) foram relacionados com a redução dos níveis de HAM após um ano do término da quimioterapia. Mulheres com mutações BRCA apresentam menores concentrações basais de HAM e menores taxas de recuperação ovariana após otérmino do tratamento quimioterápico quando comparadas a mulheres sem a mutação e mulheres não testadas por apresentarem baixo risco de mutação. Esse estudo longitudinal demonstrou que o tratamento quimioterápico promoveu redução significativa das concentrações séricas de HAM um ano após o término do tratamento. O fato da maioria das pacientes apresentar ciclos menstruais, apesar dos baixos níveis de HAM, sugere que a presença de menstruação não é um marcador acurado de reserva ovariana. O tipo de regime quimioterápico utilizado no tratamento oncológico demonstrou influenciar o comprometimento da reserva ovariana. O tratamento adjuvante com tamoxifeno parece não exacerbar o comprometimento da reserva ovariana. Demonstramos que a idade, os níveis basais de HAM e o tipo de regime quimioterápico são os fatores de predição mais importantes da reserva ovariana após o tratamento citotóxico. Sendo assim, geramos o primeiro nomograma para predizer o impacto da quimioterapia na reserva ovariana. O nomograma descrito deve ser validado prospectivamente em novos estudos. Além disso, a presença de mutações BRCA pode colocar as mulheres em desvantagem reprodutiva quando expostas ao estresse genotóxico. Essas informações podem ser utilizadas para aconselhamento individual de mulheres em idade reprodutiva em relação a necessidade de tratamentos para tentativa de preservação da fertilidade.Some women of reproductive age diagnosed with breast cancer wish to preserve their fertility and ovarian function after their oncological treatment. However, information available on the likelihood and extent of ovarian damage from chemotherapy is insufficient to predict the risk of ovarian reserve damage for individual women. Thus, the primary goal of this study is to delineate the extent of ovarian damage from chemotherapeutic treatment regimens by using serum AMH and menstrual calendars analyzed before and one year after the end of chemotherapy treatment. A prospective longitudinal IRB-approved study was performed. One hundred and thirty-four patients fulfilled the eligibility criteria and accepted to participate in the study, presenting blood samples with AMH measurement before and after one year of chemotherapy treatment. Serum AMH concentrations were measured by ELISA and were represented by median and interquartile range. The nonparametric tests of MannWhitney and Kruskal-Wallis were used to compare AMH concentrations in relation to the categorical variables. The mean age was 36.67 years (SD 3.95), and 104 women underwent chemotherapeutic regimen with anthracyclic regimen (AC-T), 13 non-anthracyclic regimen (CMF) and 17 other chemotherapeutic regimens. In the 134 women analyzed, the AMH levels after 1 year of chemotherapy were significantly reduced (median 0.13 ng/ml, interquartile range 0.02; 0.35 ng/ml) when compared to levels before chemotherapy (median 2.84 ng/ml, interquartile range 1.26; 4.65 ng/ml; p<0.0001). Despite the significant reduction in AMH levels, 74.7% of the women had return of menses by 1-year post treatment. The treatment regimen significantly influenced the reduction of AMH levels after 1-year post chemotherapy treatment. The CMF treatment group demonstrated a greater ovarian reserve reduction when compared to other chemotherapeutic regimens treatment group. Our study did not show statistical difference when other comparisons were made between the treatment groups. In addition, adjuvant tamoxifen use did not alter AMH levels 1-year post chemotherapy. Mixed effect model analysis confirmed that, for all the analyzed women (N=134), baseline serum AMH levels (p<0.0001), age (p=0.0438), and regimen (p=0.0259) were related to the reduction in AMH levels 1-year after chemotherapy treatment. Women treated for breast cancer with BRCA mutations have lower baseline serum AMH levels and lower rates of ovarian recovery after chemotherapy treatment compared to non-mutatedwomen and untested women with low risk of mutation. This longitudinal study demonstrated that chemotherapy regimens commonly used in the treatment of breast cancer in postmenopausal women significantly reduced serum concentrations of AMH 1-year after the end of treatment, suggesting a significant impairment of the ovarian reserve. The fact that most of the patients present menstrual cycles, despite the low levels of AMH, suggests that the presence of menstruation is not an accurate marker of ovarian reserve. The type of chemotherapy regimen used in oncological treatment has been shown to influence the ovarian reserve impairment. Adjuvant treatment with tamoxifen does not exacerbate the impairment of the chemotherapy-induced damage to ovarian reserve. We have shown that age, baseline AMH levels, and type of chemotherapy regimen are the most important predictors of ovarian reserve after cytotoxic treatment. In addition, we generated the first nomogram to predict the impact of chemotherapy on ovarian reserve in women diagnosed with breast cancer at reproductive age who will undergo chemotherapy. The nomogram described should be prospectively validated in new studies. In addition, the presence of mutations in BRCA may place women at reproductive disadvantage when exposed to genotoxic stress. These findings have significant bearing both on fertility preservation counseling as well as reproductive aging research and treatment

History, Evolution and Current State of Ovarian Tissue Auto-Transplantation with Cryopreserved Tissue: a Successful Translational Research Journey from 1999 to 2020

The loss of fertility and early menopause are common after gonadotoxic therapies and radical pelvic surgery. The strategy of ovarian tissue cryopreservation and auto-transplantation was introduced to prevent this significant quality of health issue. Ovarian transplantation with cryopreserved tissue has gone through remarkable evolution in the last 20\ua0years. In this review, we detail the history and evolution of ovarian transplantation with cryopreserved tissue from its origins to the present. Ovarian cryopreservation and transplantation approach was first tested with animal models. The approach was then validated in human ovarian xenografting models before being applied to patients in pioneering clinical studies. The first orthotopic and heterotopic approaches to ovarian transplantation was developed by Oktay et al. who reported the first successful restoration of ovarian function with these approaches beginning in 2000 with first embryo development in 2004. Controversy remains on when the first live birth occurred after orthotopic ovarian transplantation with cryopreserved tissue as the patient was ovulating with elevated progesterone levels in the case reported in 2004; first live birth is likely to be the one reported by Meirow et al. in 2005. Nevertheless, the technique has evolved to reach a level where most recent live birth rates are exceeding 35% and the procedure is no longer considered experimental by many

Fresh versus frozen blastocyst transfer

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A prospective longitudinal analysis of the predictors of amenorrhea after breast cancer chemotherapy: Impact of BRCA pathogenic variants.

BACKGROUND: Better tools for post-chemotherapy amenorrhea risk assessment are needed for fertility preservation decision-making. Our aim was to determine the predictors of amenorrhea risk at 12 and 18 months post-chemotherapy in women with breast cancer. METHODS: 142 women with breast cancer were longitudinally followed for their menstrual changes at 6, 12, and 18 months after the completion of adjuvant chemotherapy with an Anthracycline-Cyclophosphamide-based (AC-based) or Cyclophosphamide-Methotrexate +5-Fluorouracil regimen. Pre- and/or post-chemo AMH levels, age, BMI, tamoxifen use, regimen type, and germline BRCA pathogenic variant (gBRCApv) status were evaluated for the prediction of amenorrhea at 6-18 months. RESULTS: In multivariable-adjusted logistic regression, age (p = 0.03) and AMH (p = 0.03) at 12 months, and gBRCApv status (p = 0.03) at 18 months were significant predictors of amenorrhea (areas under the ROC curve of 0.77 and 0.76, for 12 and 18 months, respectively) among 102 evaluable subjects. An undetectable AMH immediately post-chemotherapy was predictive of amenorrhea with &lt;18 month follow-up. In longitudinal analysis estimating time trends, baseline AMH and gBRCApv status was associated with the risk of amenorrhea over 6-18 months; the AMH &gt;2.0 ng/mL group showed attenuated time-trend risk of amenorrhea versus AMH ≤2.0 group (ratio of ORs = 0.91, 95% CI = 0.86-0.97, p = 0.002), while the gBRCApv + showed a steeper time trend, versus the controls (ratio of ORs = 1.12, 95% CI = 1.04-1.20, p = 0.003). CONCLUSIONS: In addition to the pre- and post-treatment AMH levels, gBRCApv status is a novel potential predictor of amenorrhea at 12 and 18 months after chemotherapy. The higher likelihood of amenorrhea in women gBRCApv suggests that they are more prone to losing their fertility post-chemotherapy

Risk of ovarian hyperstimulation syndrome in women with malignancies undergoing treatment with long-acting gonadotropin-releasing hormone agonist after controlled ovarian hyperstimulation for fertility preservation: a systematic review

Background: Fertility preservation is an important quality of life issue for women of reproductive age undergoing gonadotoxic treatment. The possibility of administering an adjuvant long-acting gonadotropin-releasing hormone agonist (GnRHa) with the aim of reducing the number of follicles susceptible to the effects of chemotherapy and thus reducing the risk of ovarian damage is considered in some international society guidelines, particularly in certain cancers such as breast cancer. Nowadays, the administration of long-acting GnRHa after controlled ovarian hyperstimulation (COH) for fertility preservation by cryopreservation of oocytes or embryos is increasingly used. However, cases of ovarian hyperstimulation syndrome (OHSS) have been reported following the use of long-acting GnRHa after COH for fertility preservation, indicating that the potential adverse effects of this treatment need to be further investigated. Objectives: The aim of this systematic review was to comprehensively characterize patients who developed OHSS after treatment with long-acting GnRHa following COH for fertility preservation. Methods: A comprehensive search of major electronic databases through January 2023 was performed. Studies reporting the use of long-acting GnRHa after COH for fertility preservation and the development of OHSS were included. Risk of bias was assessed using a modified version of the Newcastle-Ottawa scale. Results were synthesized qualitatively. Results: Three studies with five patients met the eligibility criteria. The majority of patients were diagnosed with breast cancer and all patients underwent COH for oocyte cryopreservation. OHSS occurred in all patients after administration of long-acting GnRHa. The interval between ovulation induction and administration of long-acting GnRHa thereafter ranged from 3 to 5 days. All patients were treated conservatively and recovered without complications. Conclusion: Current evidence suggests that the use of long-acting GnRHa after COH for fertility preservation may be associated with OHSS. Healthcare providers should thoroughly discuss the benefits and risks of this intervention with their patients before making a decision. Further studies are needed to fully elucidate the causal relationship between long-acting GnRHa and OHSS in this population

A prospective longitudinal analysis of the predictors of amenorrhea after breast cancer chemotherapy: Impact of BRCA pathogenic variants

Abstract Background Better tools for post‐chemotherapy amenorrhea risk assessment are needed for fertility preservation decision‐making. Our aim was to determine the predictors of amenorrhea risk at 12 and 18 months post‐chemotherapy in women with breast cancer. Methods 142 women with breast cancer were longitudinally followed for their menstrual changes at 6, 12, and 18 months after the completion of adjuvant chemotherapy with an Anthracycline‐Cyclophosphamide‐based (AC‐based) or Cyclophosphamide‐Methotrexate +5‐Fluorouracil regimen. Pre‐ and/or post‐chemo AMH levels, age, BMI, tamoxifen use, regimen type, and germline BRCA pathogenic variant (gBRCApv) status were evaluated for the prediction of amenorrhea at 6–18 months. Results In multivariable‐adjusted logistic regression, age (p = 0.03) and AMH (p = 0.03) at 12 months, and gBRCApv status (p = 0.03) at 18 months were significant predictors of amenorrhea (areas under the ROC curve of 0.77 and 0.76, for 12 and 18 months, respectively) among 102 evaluable subjects. An undetectable AMH immediately post‐chemotherapy was predictive of amenorrhea with 2.0 ng/mL group showed attenuated time‐trend risk of amenorrhea versus AMH ≤2.0 group (ratio of ORs = 0.91, 95% CI = 0.86–0.97, p = 0.002), while the gBRCApv + showed a steeper time trend, versus the controls (ratio of ORs = 1.12, 95% CI = 1.04–1.20, p = 0.003). Conclusions In addition to the pre‐ and post‐treatment AMH levels, gBRCApv status is a novel potential predictor of amenorrhea at 12 and 18 months after chemotherapy. The higher likelihood of amenorrhea in women gBRCApv suggests that they are more prone to losing their fertility post‐chemotherapy