Bisphenol A and polycystic ovary syndrome in human: A systematic review.

BACKGROUND: Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by anovulation, hyperandrogenism, and polycystic ovarian morphology. Its etiology is uncertain and one of the hypotheses is that environmental factors, such as the bisphenol A (BPA) endocrine disruptor, may be involved. OBJECTIVE: To investigate the association between exposure to BPA and PCOS. SEARCH STRATEGY: Research was conducted focusing on studies published in English, Portuguese, and Spanish from January 2001 to March 2023 and available in Embase, Medline/PubMed, Rima, Lilacs, Scielo, Google academic, and SCI databases. SELECTION CRITERIA: Studies in humans that evaluated the association between exposure to BPA and a diagnosis of PCOS. DATA COLLECTION AND ANALYSIS: Following PRISMA guidelines, study characteristics and relevant data were extracted. MAIN RESULTS: Selection of 15 case-control and 7 cross-sectional studies with a total of 1682 PCOS patients. The studies were carried out in China, Poland, Turkey, Japan, Greece, Italy, the USA, Iran, Iraq, Egypt, India, Czechia, and Slovakia. A positive relationship between exposure to BPA and PCOS was described in19 studies (1391 [82.70%] of the PCOS patients). The fluids used in the studies were serum, urine, plasma, and follicular fluid. BPA was measured by ELISA and by chromatography (HPLC, HPLC-MS/MS, GC-MS, and GC-MS/MS). Diagnosis of PCOS used Rotterdam criteria in 15, NIH 1999 in 3, AE&PCOS Society in 2, similar to the Rotterdam criteria in 1, and criteria not informed in 1. Androgens were measured in 16 studies; in 12, hyperandrogenism was positively associated with BPA. BPA level was related to body mass index (BMI) in studies. In 15 studies independently of BMI, women with PCOS had higher BPA levels. Carbohydrate metabolism disorders were evaluated in 12 studies and in 6 a positive correlation was found with BPA levels. Lipid profile was evaluated in seven studies and in only one the correlation between lipid profile and BPA levels was present. CONCLUSIONS: Exposure to BPA is positively associated with PCOS, mainly with the hyperandrogenism.

Association of intrauterine synechiae with pituitary gonadotrophin pulse patterns: A pilot study.

BACKGROUND: Intrauterine synechiae (IS) is an acquired uterine condition that occurs when scar tissues (adhesions) form within the uterus and/or cervix, causing menstrual disturbance. However, approximately 50% of patients with IS are refractory to treatment. Therefore, other endocrine disturbances, such as gonadotropin disturbance, may affect treatment success. STUDY AIM: To analyze gonadotropin levels in women with and without IS. METHODS: Ten women with refractory IS experiencing amenorrhea since at least 6 months and nine with normal menstrual cycles (control group) were included in this study. Blood sample were collected every 10 minutes during a 4-h period. The serial ultrasound was performed in both groups for evaluating the cycle phase. Blood was collected when the follicles size was between 5-10 mm. Serum LH, FSH, progesterone and estradiol concentrations were measured. To detect LH and FSH pulses, the technique proposed by Santen and Bardin was adopted; therefore, one pulse was defined as a 20% increase in the concentrations as to the preceding point, followed by an important decrease. RESULTS: No differences were observed between the study groups at baseline. Estradiol levels were lower in the IS group than in the control group, but the difference was not statistically significant. During the first hour of monitoring, cumulative FSH pulsatile frequency of IS group was lower than one of control. CONCLUSION: Our data suggest that the estradiol levels of IS participants are lower than those of women with normal menstrual cycle. The role of this finding in the physiology of uterine synechiae requires further investigation.

Does bisphenol A (BPA) participates in the pathogenesis of Polycystic Ovary Syndrome (PCOS)?

PCOS is an endocrine disorder characterized by chronic anovulation, hyperandrogenism, and polycystic ovaries. Its etiology is uncertain. It is debated whether BPA would be a component of the environmental factor in the etiology of PCOS. Contamination by BPA can occur from food packaging (exposure during the diet) and through skin absorption and/or inhalation. It can be transferred to the fetus via the placenta or to the infant via breast milk, and it can be found in follicular fluid, fetal serum, and amniotic fluid. The phenolic structure of BPA allows it to interact with Estrogen Receptors (ERs) through genomic signaling, in which BPA binds to nuclear ERα or Erß, or through nongenomic signaling by binding to membrane ERs, prompting a rapid and intense response. With daily and constant exposure, BPA's tendency to bioaccumulate and its ability to activate nongenomic signaling pathways can alter women's metabolic and reproductive function, leading to hyperandrogenism, insulin resistance, obesity, atherogenic dyslipidemia, chronic inflammatory state, and anovulation and favoring PCOS. The harmful changes caused by BPA can be passed on to future generations without the need for additional exposure because of epigenetic modifications. Not only high BPA levels can produce harmful effects, but at low levels, BPA may be harmful when exposure occurs during the most vulnerable periods, such as the fetal and neonatal periods, as well as during the prepubertal age causing an early accumulation of BPA in the body. Learning how BPA participates in the pathogenesis of PCOS poses a challenge and further studies should be conducted.

Effects of estrogen and raloxifene on synaptic density in the hippocampal CA1 region of ovariectomized rats.

INTRODUCTION: The CA1 region of the hippocampus has an important role in learning and memory. It has been shown that estrogen deficiency may reduce the synaptic density in the region and that hormone replacement therapy may attenuate the reduction. OBJECTIVES: This study aimed to evaluate the effects of estrogen and raloxifene on the synaptic density profile in the CA1 region of the hippocampus in ovariectomized rats. METHODS: Sixty ovariectomized three-month-old virgin rats were randomized into six groups (n = 10). Treatments started either three days (early treatment) or sixty days (late treatment) after ovariectomy. The groups received propylene glycol vehicle (0.5 mL/animal/day), equine conjugated estrogens (50 µg/animal/day), or raloxifene (3 mg/kg/day) either early or late after ovariectomy. The drugs were administered orally by gavage for 30 days. At the end of the treatments, the animals were anesthetized and transcardially perfused with ether and saline solution. The brains were removed and prepared for analysis under transmission electron microscopy and later fixed. RESULTS: Results showed a significant increase in the synaptic density profile of the hippocampal CA1 region in both the early estrogen (0.534 ± 0.026 µ/m2) and the early raloxifene (0.437 ± 0.012 µ/m2) treatment groups compared to the early or late vehicle-treated control groups (0.338 ± 0.038 µ/m2 and 0.277 ± 0.015 µ/m2 respectively). CONCLUSIONS: The present data suggest that the raloxifene effect may be lower than that of estrogen, even early or late treatment, on synaptic density in the hippocampus.

Hormonal and Metabolic Factors Influence the Action of Progesterone on the Endometrium of Women with Polycystic Ovary Syndrome.

Hormonal and metabolic factors may influence endometrial quality and interfere with the action of progesterone. Therefore, the aim of our study was to address this issue. Participants were recruited from an outpatient reproductive endocrinology clinic at an academic tertiary medical care centre. All subjects underwent endometrial biopsy (EB) in the follicular phase of the cycle prior to treatment. Thereafter, they were treated with micronized progesterone (400 mg/day × 10 days intravaginally) from days 14-28 of the next cycle. A second EB was performed between days 21-24 of the cycle (the second phase). The metabolic and hormonal serum levels were evaluated during the implantation window. EB samples were analysed using light microscopy for histomorphometric analysis. The endometrium of women with Polycystic Ovarian Syndrome (PCOS) in the second phase demonstrated a uniform surface epithelium with less leukocyte infiltration and an absence of apoptotic figures compared to the control group. (p < 0.021). The thickness of the surface epithelium in the second phase of the PCOS group correlated positively with free and bioavailable testosterone values. The number of stromal cells increases with increasing insulin levels. Our results suggest that histomorphometric abnormalities of the endometrium persist and are linked to androgen and insulin levels despite progesterone supplementation in PCOS.

Does bisphenol A (BPA) participates in the pathogenesis of Polycystic Ovary Syndrome (PCOS)?

Abstract PCOS is an endocrine disorder characterized by chronic anovulation, hyperandrogenism, and polycystic ovaries. Its etiology is uncertain. It is debated whether BPA would be a component of the environmental factor in the etiology of PCOS. Contamination by BPA can occur from food packaging (exposure during the diet) and through skin absorption and/or inhalation. It can be transferred to the fetus via the placenta or to the infant via breast milk, and it can be found in follicular fluid, fetal serum, and amniotic fluid. The phenolic structure of BPA allows it to interact with Estrogen Receptors (ERs) through genomic signaling, in which BPA binds to nuclear ERα or Erβ, or through nongenomic signaling by binding to membrane ERs, prompting a rapid and intense response. With daily and constant exposure, BPA's tendency to bioaccumulate and its ability to activate nongenomic signaling pathways can alter women's metabolic and reproductive function, leading to hyperandrogenism, insulin resistance, obesity, atherogenic dyslipidemia, chronic inflammatory state, and anovulation and favoring PCOS. The harmful changes caused by BPA can be passed on to future generations without the need for additional exposure because of epigenetic modifications. Not only high BPA levels can produce harmful effects, but at low levels, BPA may be harmful when exposure occurs during the most vulnerable periods, such as the fetal and neonatal periods, as well as during the prepubertal age causing an early accumulation of BPA in the body. Learning how BPA participates in the pathogenesis of PCOS poses a challenge and further studies should be conducted.

Effects of estrogen and raloxifene on synaptic density in the hippocampal CA1 region of ovariectomized rats

Abstract Introduction The CA1 region of the hippocampus has an important role in learning and memory. It has been shown that estrogen deficiency may reduce the synaptic density in the region and that hormone replacement therapy may attenuate the reduction. Objectives This study aimed to evaluate the effects of estrogen and raloxifene on the synaptic density profile in the CA1 region of the hippocampus in ovariectomized rats. Methods Sixty ovariectomized three-month-old virgin rats were randomized into six groups (n = 10). Treatments started either three days (early treatment) or sixty days (late treatment) after ovariectomy. The groups received propylene glycol vehicle (0.5 mL/animal/day), equine conjugated estrogens (50 μg/animal/day), or raloxifene (3 mg/kg/day) either early or late after ovariectomy. The drugs were administered orally by gavage for 30 days. At the end of the treatments, the animals were anesthetized and transcardially perfused with ether and saline solution. The brains were removed and prepared for analysis under transmission electron microscopy and later fixed. Results Results showed a significant increase in the synaptic density profile of the hippocampal CA1 region in both the early estrogen (0.534 ± 0.026 µ/m2) and the early raloxifene (0.437 ± 0.012 µ/m2) treatment groups compared to the early or late vehicle-treated control groups (0.338 ± 0.038 µ/m2 and 0.277 ± 0.015 µ/m2 respectively). Conclusions The present data suggest that the raloxifene effect may be lower than that of estrogen, even early or late treatment, on synaptic density in the hippocampus.

Does temporomandibular disorder correlate with menopausal symptoms?

OBJECTIVE: To assess the correlation between menopausal symptoms and pain caused by temporomandibular disorder (TMD) and the impact of sociodemographic factors on the association. METHODS: In this cross-sectional study, a total of 74 women with TMD symptoms were enrolled and divided into three groups according to the Stages of Reproductive Aging Workshop + 10 (STRAW + 10) criteria: G1 (n = 25, late menopausal transition), G2 (n = 30, early postmenopause), and G3 (n = 19, late postmenopause). Sociodemographic data were collected, along with data on menopausal symptoms (Blatt-Kupperman menopausal index) and TMD-induced pain (craniomandibular index). Statistical analysis was performed using a chi-squared test and linear correlation tests (Spearman and Pearson). RESULTS: Analysis of the three groups showed that TMD-induced pain was more intense in G1 than in G3 (P = 0.0426, r  = 0.2364, r2 = 0.05589), and menopausal symptoms correlated with the intensity of TMD-induced pain (P = 0.0004, r  = 0.4020). This correlation was more significant during the late menopausal transition (G1: P  = 0.0267, r  = 0.4427, r2 = 0.1960). In G2, women with fewer than 4 years of schooling had a higher total Blatt- Kupperman menopausal index score (17.0 ±â€Š85.0) and craniomandibular index (0.29 ±â€Š0.23) than women with more than 4 years of schooling (P  = 0.02 for both indices). CONCLUSIONS: Our results suggest that TMD-induced pain and menopausal symptoms are correlated, and more strongly so in the late menopausal transition. Additionally, sociodemographic factors, such as schooling, have a major influence on symptoms in early postmenopause. Performing the TMD evaluation during the climacteric period may be important.

Effects of clinical and metabolic variables and hormones on the expression of immune protein biomarkers in the endometrium of women with polycystic ovary syndrome and normal-cycling controls.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) are at an elevated risk of endometrial cancer, which may be associated with the continuous proliferative state caused by the interaction between hormones and metabolic factors. OBJECTIVE: To investigate the impact of hormones and metabolic factors in the proliferation and death of endometrium during the proliferative phase. METHODS: Cross-sectional study with 11 women with PCOS and eight normal-cycling non-PCOS controls at the Federal University of the State of Rio de Janeiro from February 2011 to June 2019. Clinical, biochemical, and hormonal data were collected to analyze their influence on the expression of biomarkers related to the endometrial tissue breakdown. Hysteroscopy and endometrial biopsies were conducted, and the endometrial samples underwent immunohistochemistry for markers of apoptosis B-cell lymphoma 2 (BCL2), cleaved caspase-3 (CASP3), fas cell surface death receptor (FAS), FAS ligand (FASLG), BCL2 associated X (BAX), marker of proliferation Ki-67 (MKI67), and cell death using terminal deoxynucleotidyl transferase dUTP nick and labeling (TUNEL). RESULTS: CASP3 and TUNEL expressions were lower in both stroma and endometrium gland of PCOS women than in controls. MKI67 and homeostasis indexes (BCL2/BAX; FASLG/FAS) in the endometrium of the PCOS group were significantly higher. Body mass index (BMI) values were positively correlated with the expression of MKI67 and MKI67/TUNEL ratio in the endometrial stroma compartment. Fasting insulin levels were positively correlated with the expression of BCL2, and DHEA-S levels were negatively correlated with the expression of CASP3 of women with PCOS. CONCLUSION: BMI, insulin, and DHEA-S influence the endometrial homeostasis breakdown in PCOS in the endometrium stroma.

Síndrome dos ovários policísticos e sua relação com a microbiota intestinal / Polycystic ovary syndrome and its relationship with the intestinal microbiota

Objetivo: Revisar a implicação e a relação existente entre a microbiota intestinal e a síndrome do ovário policístico (SOP). Métodos: Trata-se de uma revisão sistemática de artigos das bases de dados PubMed, Cochrane e Science Direct dos últimos cinco anos, nos idiomas inglês, português e espanhol. Resultados: A disbiose da microbiota intestinal ativa o sistema imunológico do hospedeiro. Tal ativação interfere na função do receptor de insulina, causando hiperinsulinemia, o que aumenta a produção de androgênio ovariano e dificulta o desenvolvimento de um folículo saudável. Além disso, pacientes com SOP apresentam o perfil taxonômico alterado, o qual se associou inversamente com excesso de andrógenos e inflamação da SOP. Foi evidenciado que o uso de probióticos pode regular a resposta inflamatória, diminuir os níveis totais de testosterona e contribuir para que a SOP não prejudique uma possível gravidez. Conclusão: Essa revisão sugere que há íntima associação entre a disbiose microbiana e as alterações patológicas que ocorrem na SOP. Assim, a suplementação de probióticos em tais pacientes pode ter grandes benefícios, como melhora dos sintomas e redução das repercussões da doença.(AU)

Objective: To review the implication and the relationship between the intestinal microbiota and polycystic ovary syndrome. Methods: This is a systematic review of articles from the PubMed, Cochrane and Science Direct databases, from the last five years, in English, Portuguese and Spanish. Results: Dysbiosis of the intestinal microbiota activates the host's immune system. Such activation interferes with the function of the insulin receptor, causing hyperinsulinemia, which increases the production of ovarian androgens and hinders the development of a healthy follicle. In addition, patients with PCOS have an altered taxonomic profile, which is inversely associated with excess androgens and PCOS inflammation. It was evidenced that the use of probiotics can regulate the inflammatory response, decrease the total testosterone levels and contribute so that PCOS does not harm a possible pregnancy. Conclusion: This review suggests that there is a close association between microbial dysbiosis and pathological changes that occur in PCOS. Thus, supplementation of probiotics in such patients can have great benefits, such as improving symptoms and reducing the repercussions of the disease.(AU)

Repercussões metabólicas: quais, como e por que investigar? / Metabolic repercussions: which ones, how and why investigate?

A síndrome dos ovários policísticos (SOP) é frequentemente acompanhada de distúrbio metabólico, principalmente dos carboidratos e dos lipídeos, aumentando o risco de síndrome metabólica. Por essa razão, alguns investigadores ainda denominam a SOP de síndrome metabólica-reprodutiva. O objetivo deste capítulo é descrever as principais repercussões metabólicas, bem como como investigá-las e saber como suas consequências podem ser deletérias para a saúde da mulher. Esta é uma revisão narrativa mostrando a implicação do metabolismo dos carboidratos e dos lipídeos nas dislipidemias, bem como da síndrome metabólica sobre o sistema reprodutor, e o risco cardiovascular da mulher com SOP. Conclui-se que o manejo adequado dos distúrbios metabólicos na SOP é benéfico a curto e a longo prazo tanto para o sistema reprodutor quanto para o cardiovascular.(AU)

Evidence that Melatonin Increases Inhibin Beta-A and Follistatin Gene Expression in Ovaries of Pinealectomized Rats.

Melatonin plays an important role in the regulation of ovarian function including oocyte maturation in different mammalian species. Many studies indicate that melatonin has an impact on the ovarian function of a variety of ovarian cells. However, the information on the exact mechanism and involved hormones is low. To evaluate inhibin beta-A (INHBA) and follistatin (FST) expression in the ovaries of pinealectomized rats treated with melatonin, thirty adult female Wistar rats were randomized into three groups of ten animals each: group 1 (GSh), sham-operated controls receiving vehicle; group 2 (GPx), pinealectomized animals receiving vehicle; and group 3 (GPxMe), pinealectomized animals receiving replacement melatonin (1.0 mg/kg body weight. It was assumed that each animal drank 6.5 ± 1.2 ml per night and weighs approximately 300 g.) for 60 consecutive days. The ovaries were collected for mRNA abundance and protein of INHBA and FST by qRT-PCR and immunohistochemical analyses, respectively. Treatment with melatonin resulted in the upregulation of INHBA and FST genes in the ovarian tissue of the melatonin-treated animals (GPxMe), when compared with GPx. These findings were then confirmed by analyzing the expression of protein by immunohistochemical analyses, which revealed higher immunoreactivity of INHBA and FST in GPxMe animals in the follicular cells compared with GSh and GPx rats. Melatonin increases the expression of INHBA and FST in the ovaries of pinealectomized female rats.