FOXO3a deregulation in uterine smooth muscle tumors.

OBJECTIVE: The present study aimed to investigate FOXO3a deregulation in Uterine Smooth Muscle Tumors (USMT) and its potential association with cancer development and prognosis. METHODS: The authors analyzed gene and protein expression profiles of FOXO3a in 56 uterine Leiomyosarcomas (LMS), 119 leiomyomas (comprising conventional and unusual leiomyomas), and 20 Myometrium (MM) samples. The authors used techniques such as Immunohistochemistry (IHC), FISH/CISH, and qRT-PCR for the present analyses. Additionally, the authors conducted an in-silico analysis to understand the interaction network involving FOXO3a and its correlated genes. RESULTS: This investigation revealed distinct expression patterns of the FOXO3a gene and protein, including both normal and phosphorylated forms. Expression levels were notably elevated in LMS, and Unusual Leiomyomas (ULM) compared to conventional Leiomyomas (LM) and Myometrium (MM) samples. This upregulation was significantly associated with metastasis and Overall Survival (OS) in LMS patients. Intriguingly, FOXO3a deregulation did not seem to be influenced by EGF/HER-2 signaling, as there were minimal levels of EGF and VEGF expression detected, and HER-2 and EGFR were negative in the analyzed samples. In the examination of miRNAs, the authors observed upregulation of miR-96-5p and miR-155-5p, which are known negative regulators of FOXO3a, in LMS samples. Conversely, the tumor suppressor miR-let7c-5p was downregulated. CONCLUSIONS: In summary, the outcomes of the present study suggest that the imbalance in FOXO3a within Uterine Smooth Muscle Tumors might arise from both protein phosphorylation and miRNA activity. FOXO3a could emerge as a promising therapeutic target for individuals with Unusual Leiomyomas and Leiomyosarcomas (ULM and LMS), offering novel directions for treatment strategies.

Diagnosis of hyperprolactinemia in women: A Position Statement from the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and the Brazilian Society of Endocrinology and Metabolism (SBEM).

Hyperprolactinemia is a frequent cause of menstrual irregularity, galactorrhea, hypogonadism, and infertility. The most common etiologies of hyperprolactinemia can be classified as physiological, pharmacological, and pathological. Among pathological conditions, it is essential to distinguish prolactinomas from other tumors and pituitary lesions presenting with hyperprolactinemia due to pituitary stalk disconnection. Proper investigation considering clinical data, laboratory tests, and, if necessary, imaging evaluation, is important to identify the correctcause of hyperprolactinemia and manage the patient properly. This position statement by the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and Brazilian Societyof Endocrinology and Metabolism (SBEM) addresses the recommendations for measurement of serum prolactin levels and the investigations of symptomatic and asymptomatic hyperprolactinemia and medication-induced hyperprolactinemia in women.

Treatment of hyperprolactinemia in women: A Position Statement from the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and the Brazilian Society of Endocrinology and Metabolism (SBEM).

Dopamine agonists are the first line of treatment for patients with symptomatic hyperprolactinemia due to prolactinomas and in those with idiopathic hyperprolactinemia. Treatment with these agents is effective in 80%-90% of the cases. Infertility treatment of patients with hyperprolactinemia is also carried out with dopamine agonists, aiming for the normalization of prolactin levels. The risk of symptomatic growth of prolactinomas during pregnancy is dependent on the tumor's size, duration of previous treatments, and prolactin levels. Notably, the corresponding risk is relatively low in cases of microprolactinomas (<5%). Remission of hyperprolactinemia occurs in about 30% of the patients after drug treatment and may also occur after pregnancy and menopause. The use of some drugs, such as antidepressants and antipsychotics, is a frequent cause of hyperprolactinemia, and managing this occurrence involves unique considerations. This position statement by the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and Brazilian Society of Endocrinology and Metabolism (SBEM) addresses the recommendations for measurement of serum prolactin levels and the investigations of symptomatic and asymptomatic hyperprolactinemia and drug-induced hyperprolactinemia in women.

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.

PRL-R Variants Are Not Only Associated With Prolactinomas But Also With Dopamine Agonist Resistance.

CONTEXT: Knockout prolactin receptor gene (PRL-R) mice are animal models for prolactinomas and PRL acts via autocrine/paracrine inhibiting lactotroph proliferation. Recently, variants of the PRL-R were identified in prolactinoma patients and their frequency was higher compared to individuals from the genomic database. OBJECTIVE: We analyzed PRL-R variants frequency in an extensive cohort of prolactinoma patients and evaluated their association with clinical, laboratorial, and imaging characteristics and hormonal response to cabergoline. DESIGN: Observational, retrospective, and cross-sectional study. SETTING: This study took place at the Neuroendocrinology Unit of Clinics Hospital, Medical School of University of São Paulo, Brazil, a tertiary referral center. PATIENTS AND METHODS: Study participants included adults with sporadic prolactinomas treated with cabergoline, where response to therapy was defined by prolactin normalization with up to 3 mg/week doses. DNA was extracted from blood samples and the PRL-R was analyzed by polymerase chain reaction techniques and automatic sequencing. The association of PRL-R variants with serum prolactin levels, maximal tumor diameter, tumor parasellar invasiveness, and response to cabergoline was analyzed. RESULTS: We found 6 PRL-R variants: p.Ile100(76)Val, p.Ile170(146)Leu, p.Glu400(376)Gln/p.Asn516(492)Ile, p.Glu470Asp e p.Ala591Pro; the last 2 are newly described in prolactinomas' patients. The variants p.Glu400(376)Gln/p.Asn516(492)Ile and p.Ala591Pro were more frequent amongst patients compared to genomic databases, and the p.Asn516(492)Ile showed pathogenic potential using in silico analysis as previously described. PRL-R variants were associated with male sex (P = 0.015), higher serum PRL levels (P = 0.007), larger tumors (P = 0.001), and cabergoline resistance (P < 0.001). CONCLUSIONS: The prolactin/prolactin receptor system seems to be related to prolactinoma tumorigenesis and cabergoline resistance. Additional studies are needed to better understand the PRL-R variants' role and their potential as therapeutic targets.

Impact of hormone therapy on the bone density of women with premature ovarian insufficiency: A systematic review.

INTRODUCTION: Women with premature ovarian insufficiency (POI) are exposed to a long period of estrogenic deficiency, which potentially brings higher health risks, especially regarding bone health. We performed a systematic review of the literature to evaluate the effect of hormone therapy (HT) on bone mineral density (BMD) in women with POI. MATERIALS AND METHODS: A systematic search was performed of the MEDLINE and EMBASE databases up to September 2021. We included studies that analyzed women with idiopathic (spontaneous) POI treated with HT, and those who had BMD evaluated. Analysis of risk of bias of studies selected was performed. RESULTS: We found 335 articles and selected 16 studies according to the inclusion criteria. Most of the studies revealed lower bone density in both the femoral neck and lumbar spine of women with POI compared with healthy women. Bone mass had the tendency to remain stable in women treated with estrogen + progestin therapy. However, in women already with bone mass loss, the therapy - in the doses most frequently used - was not able to revert the loss. Higher doses of estrogen seem to have a positive impact on BMD, as did combined oral contraceptives used continuously. Also, the interruption of HT for longer than one year was linked to significant bone loss. CONCLUSION: Although HT brings clear benefits, further studies are needed to establish its long-term effects, as well as doses and formulations with better protective effects on the bone mass of these women.

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.

Evaluation of circulating microRNA profiles in Brazilian women with polycystic ovary syndrome: A preliminary study.

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.

Comparison of metabolic and obesity biomarkers between adolescent and adult women with polycystic ovary syndrome.

PURPOSE: Knowledge of adolescent and adult phenotypes of women with polycystic ovary syndrome (PCOS) might drive opportune management. The aim of this study was to compare metabolic and obesity biomarkers between adolescent and adult women with PCOS. METHODS: This observational study compared biomarkers of obesity and metabolism derangements between adolescent (n = 62) and adult (n = 248) women with PCOS. Predictors of metabolic syndrome (MS) were investigated using univariate and multivariate binary logistic regression analysis. RESULTS: The postmenarcheal age of adolescents was 4.9 ± 0.03 years. Systolic blood pressure was lower in adolescents than in adults (112.3 mmHg vs 117.0 mmHg, p = 0.001) Diastolic blood pressure was also lower in adolescents (70.7 mmHg vs 75.8 mmHg, p < 0.001). Glucose intolerance (12.0% vs 19.3%) and insulin resistance (18.2% vs 17.7%) were similar in both groups (p > 0.05, for comparisons). Impaired fasting glucose was lower in adolescents (1.8% vs 11.6%, p = 0.015). Total cholesterol and low-density lipoprotein cholesterol were lower in adolescents (p < 0.001). MS in adolescents and adults were found in 10.3% and 27.8%, respectively (p = 0.005). Visceral adiposity index (VAI) was a good predictor of MS in both adolescents (OR = 12.2), and adults (OR = 9.7). CONCLUSIONS: Most biomarkers of glucose metabolism abnormalities were similar in adolescents and adults with PCOS. The prevalence of MS was lower in adolescents. VAI was a strong predictor of metabolic syndrome, both in adolescent and adult women with PCOS.

Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases.

Rare diseases comprise a diverse group of conditions, most of which involve genetic causes. We describe the variable spectrum of findings and clinical impacts of exome sequencing (ES) in a cohort of 500 patients with rare diseases. In total, 164 primary findings were reported in 158 patients, representing an overall diagnostic yield of 31.6%. Most of the findings (61.6%) corresponded to autosomal dominant conditions, followed by autosomal recessive (25.6%) and X-linked (12.8%) conditions. These patients harbored 195 variants, among which 43.6% are novel in the literature. The rate of molecular diagnosis was considerably higher for prenatal samples (67%; 4/6), younger children (44%; 24/55), consanguinity (50%; 3/6), gastrointestinal/liver disease (44%; 16/36) and syndromic/malformative conditions (41%; 72/175). For 15.6% of the cohort patients, we observed a direct potential for the redirection of care with targeted therapy, tumor screening, medication adjustment and monitoring for disease-specific complications. Secondary findings were reported in 37 patients (7.4%). Based on cost-effectiveness studies in the literature, we speculate that the reports of secondary findings may influence an increase of 123.2 years in the life expectancy for our cohort, or 0.246 years/cohort patient. ES is a powerful method to identify the molecular bases of monogenic disorders and redirect clinical care.

Reproductive outcomes in cases of subclinical hypothyroidism and thyroid autoimmunity: a narrative review / Resultados reprodutivos nos casos de hipotireoidismo subclínico e autoimunidade tireoidiana: Uma revisão narrativa

Abstract Thyroid diseases are relatively common in women in the reproductive period. It is currently understood that clinically-evident thyroid disorders may impair ovulation and, consequently, fertility. However, to date it has not been proven that high serum levels of thyroid-stimulating hormone and/or positivity for antithyroid antibodies are associated to a reduction in fertility, mainly in the absence of altered thyroxine levels. The present comprehensive review aims to present current data on the association between subclinical hypothyroidism and/or thyroid autoimmunity and reproductive outcomes.

Resumo As doenças da tireoide são relativamente comuns em mulheres no período reprodutivo. Atualmente, entende-se que distúrbios da tireoide clinicamente evidentes podem prejudicar a ovulação e, consequentemente, a fertilidade. No entanto, não se provou até o presente que níveis séricos altos do hormônio estimulador da tireoide e/ou positividade para anticorpos antitireoidianos estão associados a uma redução na fertilidade, sobretudo na ausência de níveis alterados de tiroxina. Esta revisão narrativa tem como objetivo apresentar dados atuais sobre a associação entre hipotireoidismo subclínico e/ou autoimunidade tireoidiana e resultados reprodutivos.

Nutritional and dietary aspects in polycystic ovary syndrome: insights into the biology of nutritional interventions.

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.

Kisspeptin Influence on Polycystic Ovary Syndrome-a Mini Review.

Polycystic ovary syndrome (PCOS) affects 6% to 20% of reproductive age women and is the most frequent cause of anovulatory infertility. Its physiopathology may result in part from hypothalamic alterations in the pulsatile secretion of gonadotropin-releasing hormone (GnRH). The neuropeptide kisspeptin participates in the mechanism through stimulation of the hormone's production. The purpose of this study was to review the articles which compared kisspeptin levels in women with PCOS with those of controls. A systematic review of observational studies was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) recommendations. The selected studies encompassed a population of patients with PCOS and controls, whose serum kisspeptin levels were evaluated. The studies were retrieved from the Medline, Cochrane, and Embase databases, and four of them were chosen for the review. In most studies, the serum kisspeptin levels were higher in women with PCOS than in controls notwithstanding the BMI. One of the articles showed that circulating plasma levels of kisspeptin were significantly higher in women with PCOS whose BMI was lower than 25 than in obese and overweight women. Our data suggest a higher concentration of serum kisspeptin in women with PCOS irrespective of their BMI. Further experimental and clinical studies are needed to ascertain the role of kisspeptin in PCOS.

Repercussões metabólicas e uso dos medicamentos sensibilizadores da insulina em mulheres com síndrome dos ovários policísticos / Metabolic repercussions and use of insulin-sensitizing drugs in women with polycystic ovary syndrome

A síndrome dos ovários policísticos (SOP) é um distúrbio endócrino-metabólico muito frequente no período reprodutivo. Quando associado ao distúrbio metabólico, as mulheres com SOP podem ter ainda risco acrescido para doença cardiovascular. O objetivo deste manuscrito é descrever as repercussões metabólicas, incluindo quais as principais, como investigar e as consequências desse distúrbio sobre a saúde da mulher. É uma revisão narrativa mostrando a implicação da resistência insulínica, das dislipidemias e da síndrome metabólica sobre o sistema reprodutor e sobre o risco cardiovascular da mulher com SOP, bem como do uso de sensibilizadores de insulina no seu tratamento. Conclui-se que a correção dos distúrbios metabólicos na SOP é benéfica tanto para o sistema reprodutor quanto para o cardiovascular. A primeira linha de tratamento é a mudança de estilo de vida e a perda de peso. Na resposta inadequada, o tratamento medicamentoso está recomendado. Nas mulheres com obesidade mórbida que não tiveram bons resultados com o tratamento clínico, a cirurgia bariátrica é uma opção.(AU)

Sexual Dysfunction in Women With Polycystic Ovary Syndrome: Systematic Review and Meta-Analysis.

INTRODUCTION: Sexual dysfunction occurs in any phase of sexual performance or any period of the sexual response cycle, and polycystic ovary syndrome (PCOS) affects self-image with repercussions on sexuality. AIM: To evaluate sexual dysfunction in women with PCOS. METHODS: A systematic review was undertaken following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. The primary databases MEDLINE, EMBASE, Cochrane, and Lilacs were accessed using specific terms. There was no constraint against year of publication. The meta-analysis was conducted with RevMan program version 5.3. MAIN OUTCOME MEASURE: We evaluated the relationship between sexual dysfunction and PCOS. RESULTS: The systematic review encompassed 19 studies. The analysis indicated that 11 specific and 6 general instruments were used to measure the sexual function in PCOS women. Of these, the Female Sexual Function Index scale was used most frequently. All studies assessed different aspects of sexual performance in PCOS women, and no difference was found in between women with PCOS and control subjects. CLINICAL IMPLICATIONS: Although there were disparities regarding ethnicity, culture, religion, and economy among studies, the available evidence failed to prove a significant link between PCOS and sexual dysfunction. STRENGTH & LIMITATIONS: This systematic review addressed a multidimensional theme with many variables and with a wide diversity of measurement tools. Studies were small, and populations were not homogeneous. CONCLUSION: Despite potential risk of bias, such as inhomogeneity of study population, sexual function of both PCOS patients and women with regular menstrual cycles might, in general, be similar. Firmino Murgel AC, Santos Simões R, Maciel GAR, et al. Sexual Dysfunction in Women With Polycystic Ovary Syndrome: Systematic Review and Meta-Analysis. J Sex Med 2019;16:542-550.