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.

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.

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)

Recommendations for the use of testosterone in male transgender / Recomendações para o uso da testosterona em homens transgêneros

Abstract Gender incongruence is defined as a condition in which an individual self-identifies and desires to have physical characteristics and social roles that connote the opposite biological sex. Gender dysphoria is when an individual displays the anxiety and/or depression disorders that result from the incongruity between the gender identity and the biological sex. The gender affirmation process must be performed by a multidisciplinary team. The main goal of the hormone treatment is to start the development of male physical characteristics by means of testosterone administration that may be offered to transgender men who are 18 years old or over. The use of testosterone is usually well tolerated and improves the quality of life. However, there is still lack of evidence regarding the effects and risks of the long-term use of this hormone. Many different pharmacological formulations have been used in the transsexualization process. The most commonly used formulation is the intramuscular testosterone esters in a short-term release injection, followed by testosterone cypionate or testosterone enanthate. In the majority of testosterone therapy protocols, the male physical characteristics can be seen in almost all users after 6 months of therapy, and themaximum virilization effects are usually achieved after 3 to 5 years of regular use of the hormone. To minimize risks, plasmatic testosterone levels should be kept within male physiological ranges (300 to 1,000 ng/dl) during hormonal treatment. It is recommended that transgender men under androgen therapy be monitored every 3 months during the 1st year of treatment and then, every 6 to 12 months.

Resumo Incongruência de gênero é umacondição na qual o indivíduo se identifica, deseja viver e ser aceito como uma pessoa do gênero oposto ao designado por ocasião do nascimento. Na disforia de gênero o indivíduo manifesta ansiedade e sofrimento pelo desejo de viver e ser aceito como uma pessoa do gênero oposto ao designado ao nascimento. O processo transsexualizador requer trabalho em equipe multiprofissional. O objetivo do tratamento hormonal é induzir o aparecimento de características sexuais masculinas secundárias por meio da administração da testosterona em indivíduos com idade igual ou superior a 18 anos. O tratamento de estimulação androgênica costuma ser bem tolerado. Entretanto, ainda não existemevidências sobre os efeitos e riscos do uso da testosterona a longo prazo. Diferentes preparações farmacológicas da testosterona têm sido utilizadas. As mais utilizadas têm sido as injeções intramusculares de administração a curto prazo de ésteres, seguidas do cipionato de testosterona e do enantato de testosterona. Na maioria dos protocolos de tratamento observa-se o aparecimento de características corporais masculinas nos primeiros 6 meses, e a obtenção do máximo efeito da estimulação androgênica, após 3 a 5 anos de uso regular da testosterona. Recomenda-se a manutenção dos níveis plasmáticos de testosterona dentro dos limites fisiológicos para o sexo masculino (300 a 1.000 ng/dl), a fim de minimizar os riscos. A monitorização dos homens transgênero é recomendada a cada 3meses durante o primeiro ano de tratamento e a seguir, a cada 6 a 12 meses.

Avaliação da reserva ovariana na predição do mau prognóstico reprodutivo: quando e como investigar / Ovarian reserve evaluation in the prediction of poor reproductive prognosis: when and how to investigate?

Muitas vezes, torna-se um grande desafio para o ginecologista a identificação daquelas com maior ou menor chance de concepção. Vários marcadores laboratoriais e ultrassonográficos, conhecidos conjuntamente como testes de avaliação da reserva ovariana, são estudados há décadas com a intenção de se buscar uma ferramenta para a predição do potencial reprodutivo. E, embora ainda se busquem os marcadores ideais para aplicação clínica, mais difícil do que os definir é definir quando eles estão indicados. Este artigo de atualização, assinado pela Comissão Nacional Especializada em Ginecologia Endócrina da Febrasgo, pretende oferecer ao leitor as ferramentas necessárias para o uso racional dos testes de avaliação da reserva ovariana no cotidiano.(AU)

Often, it becomes a great challenge for the gynecologist to identify women with a greater or lesser chance of conception. Several laboratory and ultrasound markers, known jointly as ovarian reserve evaluation tests, have been studied for decades with the intention of seeking a tool for the prediction of reproductive potential. And, while the ideal markers for clinical application are still sought, defining them is as harder as defining when they are indicated. This update article, signed by the National Specialized Committee on Gynecologic Endocrinology, Febrasgo, intends to offer the reader the necessary tools for the rational use of ovarian reserve evaluation tests in daily practice.(AU)

Hypothalamic transcriptional expression of the kisspeptin system and sex steroid receptors differs among polycystic ovary syndrome rat models with different endocrine phenotypes

OBJECTIVES: Polycystic ovary syndrome is a heterogeneous endocrine disorder that affects reproductive-age women. The mechanisms underlying the endocrine heterogeneity and neuroendocrinology of polycystic ovary syndrome are still unclear. In this study, we investigated the expression of the kisspeptin system and gonadotropin-releasing hormone pulse regulators in the hypothalamus as well as factors related to luteinizing hormone secretion in the pituitary of polycystic ovary syndrome rat models induced by testosterone or estradiol. METHODS: A single injection of testosterone propionate (1.25 mg) (n=10) or estradiol benzoate (0.5 mg) (n=10) was administered to female rats at 2 days of age to induce experimental polycystic ovary syndrome. Controls were injected with a vehicle (n=10). Animals were euthanized at 90-94 days of age, and the hypothalamus and pituitary gland were used for gene expression analysis. RESULTS: Rats exposed to testosterone exhibited increased transcriptional expression of the androgen receptor and estrogen receptor-β and reduced expression of kisspeptin in the hypothalamus. However, rats exposed to estradiol did not show any significant changes in hormone levels relative to controls but exhibited hypothalamic downregulation of kisspeptin, tachykinin 3 and estrogen receptor-α genes and upregulation of the gene that encodes the kisspeptin receptor. CONCLUSIONS: Testosterone- and estradiol-exposed rats with different endocrine phenotypes showed differential transcriptional expression of members of the kisspeptin system and sex steroid receptors in the hypothalamus. These differences might account for the different endocrine phenotypes found in testosterone- and estradiol-induced polycystic ovary syndrome rats.

A prospective randomized study of the inflammatory responses to multiport and singleport laparoscopic hysterectomies

Abstract Purpose: To evaluate the inflammatory responses induced by laparoscopic hysterectomies with multiport and singleport approaches. Methods: This was a pilot prospective randomized study that included 42 women candidates for hysterectomy at School of Medicine, Hospital das Clínicas, USP. The patients were randomized to two groups: MP-TLH (total laparoscopic hysterectomy with 3 abdominal incisions), and SP-TLH (total laparoscopic hysterectomy with a single umbilical incision).We evaluated the inflammatory response (via CRP, IL-6, IL-10, TNFα, VEGF and leukogram assessments), surgical time, postoperative pain, blood loss and surgical complications in both groups. Results: Both techniques were similar regarding C-reactive protein (p=.666), IL-6 (p=.833), IL-10 (p=.420), TNF-α(p=.098), VEGF (p=.092) and the leukogram (p=.712) measures. The operative time was significantly longer in the SP-TLH group than in the MP-TLH group (p=.001). The pain evaluation was similar in both groups (p=.170). Hemoglobin variation and the aspirated blood volume were similar in both groups (p=.493 and p=.347). There were no major complications. Conclusions: Multiport and singleport laparoscopic approaches are both safe methods for hysterectomy. Although SP-TLH resulted in a significantly longer operative time than MP-TLH, no differences were observed between the groups in inflammatory responses, blood loss and postoperative pain.

Morfologia das células intersticiais de ovários policísticos de ratas: um estudo experimental / Morphology of the interstitial cells of rat polycystic ovaries: an experimental study

OBJETIVOS: Avaliar a histomorfometria das células intersticiais dos ovários, bem como analisar a concentração sanguínea de esteroides sexuais de ratas portadoras de ovários policísticos induzidos pela luz contínua. MÉTODOS: Vinte ratas foram divididas em dois grupos: ratas na fase de estro (GCtrl ) e ratas portadoras de ovários policísticos induzidos pela iluminação contínua (GOP). Os animais do GCtrl permaneceram com período de luz das 7:00 s 19:00 horas, e os animais do GOP, com iluminação contínua (400 Lux), durante um período de 60 dias. Ao final desse período todos os animais foram anestesiados, foi coletado o sangue, para determinação dos níveis séricos de estradiol (E2), progesterona (P4) e testosterona (T), seguido da retirada dos ovários que foram fixados em formol a 10% e processados para inclusão em parafina. Cortes histológicos com 5 µm corados pela hematoxilina e eosina foram utilizados para análise histomorfométrica. As análises morfológicas, contagem de cistos, determinação da concentração e do volume nuclear das células intersticiais foram realizadas com o auxílio de microscópio de luz adaptado a uma câmera de alta resolução (AxioCam), cujas imagens foram transmitidas e analisadas em computador com software AxioVision Rel 4.8 (Carl Zeiss). Os dados obtidos foram submetidos ao teste t de Student (p<0,05). RESULTADOS: A morfologia mostrou a presença de cistos nos ovários pertencentes ao Grupo OP e de corpos lúteos no GCtrl, mostrando ainda evidências da origem das células intersticiais a partir das células da teca interna desses cistos. Com relação aos níveis hormonais o GOP apresentou níveis séricos de estradiol (pg/mL) aumentados em relação ao GCtrl (GOP=124,9±4,2>GCtrl=73,2±6,5; p<0,05), o mesmo ocorrendo com os níveis de testosterona (pg/mL) (GOP=116,9±4,6>GCtrl=80,6±3,9; p<0,05). Entretanto os níveis de progesterona (ng/mL) foram mais elevados no GCtrl em relação ao GOP (GCtrl=16,3±2,0>GOP=4,2±1,5; p<0,05). A morfometria mostrou haver aumento significante do volume nuclear no grupo GOP (GOP=102,1±5,2>GCtrl=63,6±16,5; p<0,05), assim como da área ocupada (%) pelas células intersticiais (GOP=24,4±6,9>GCtrl=6,9±3,2; p<0,05) em relação aos animais do GCtrl. CONCLUSÃO: As células intersticiais do ovário policístico da rata provavelmente provêm dos cistos ovarianos devido degeneração das células da granulosa e diferenciação das células da teca interna. As elevações dos níveis séricos de testosterona e de estradiol provavelmente provêm do aumento significativo da atividade celular e da área ocupada pelas células intersticiais.

PURPOSES: To evaluate the histomorphometry of ovarian interstitial cells, as well as the blood sex steroid concentrations of female rats with polycystic ovaries induced by continuous light. METHODS: Twenty female rats were divided into two groups: Control Group - in the estrous phase (CtrlG), and a group of rats with polycystic ovaries induced by continuous illumination (POG). CtrlG animals were maintained on a light period from 07:00 a.m. to 07:00 p.m., and POG animals with continuous illumination (400 Lux) for 60 days. After this period all animals were anesthetized and blood was collected for the determination of serum estradiol (E2), progesterone (P4), and testosterone (T), followed by removal of the ovaries that were fixed in 10% formalin and processed for paraffin embedding. Five-µm histological sections were stained with hematoxylin and eosin and used for histomorphometric analysis. Morphological analyses, cyst count, determination of concentration and of the nuclear volume of interstitial cells were performed with the aid of a light microscope adapted to a high resolution camera (AxioCam), whose images were transmitted to and analyzed by the computer using AxioVision Rel 4.8 software (Carl Zeiss). Data were analyzed statistically by the Student's t-test (p<0.05). RESULTS: Morphological analysis showed the presence of ovarian cysts in POG animals and corpora lutea in CtrlG animals, as well as evidence of the origin of interstitial cells from the internal theca of these cysts. POG animals presented increased serum estradiol levels (pg/mL) compared to CtrlG animals (POG=124.9±4.2>CtrlG=73.2±6.5, p<0.05), the same occurring with testosterone levels (pg/mL) (POG=116.9±4.6>CtrlG=80.6±3.9, p<0.05). However, progesterone levels (ng/mL) were higher in CtrlG than in POG animals (CtrlG=16.3±2.0>POG=4.2±1.5, p<0.05). Morphometry showed a significant increase in nuclear volume in POG animals (POG=102.1±5.2>CtrlG=63.6±16.5, p<0.05), as well as in the area occupied (%) by interstitial cells (POG=24.4±6.9>CtrlG=6.9±3.2, p<0.05) compared to CtrlG animals. CONCLUSION: The interstitial cells of the rat polycystic ovary probably originate from ovarian cysts due to the degeneration of granulosa cells and differentiation of the internal theca cells. The elevations of serum testosterone and estradiol were probably due to the significant increase in cell activity and in the area occupied by interstitial cells.

A comparison of CA125, HE4, risk ovarian malignancy algorithm (ROMA), and risk malignancy index (RMI) for the classification of ovarian masses

OBJECTIVE: Differentiation between benign and malignant ovarian neoplasms is essential for creating a system for patient referrals. Therefore, the contributions of the tumor markers CA125 and human epididymis protein 4 (HE4) as well as the risk ovarian malignancy algorithm (ROMA) and risk malignancy index (RMI) values were considered individually and in combination to evaluate their utility for establishing this type of patient referral system. METHODS: Patients who had been diagnosed with ovarian masses through imaging analyses (n = 128) were assessed for their expression of the tumor markers CA125 and HE4. The ROMA and RMI values were also determined. The sensitivity and specificity of each parameter were calculated using receiver operating characteristic curves according to the area under the curve (AUC) for each method. RESULTS: The sensitivities associated with the ability of CA125, HE4, ROMA, or RMI to distinguish between malignant versus benign ovarian masses were 70.4%, 79.6%, 74.1%, and 63%, respectively. Among carcinomas, the sensitivities of CA125, HE4, ROMA (pre-and post-menopausal), and RMI were 93.5%, 87.1%, 80%, 95.2%, and 87.1%, respectively. The most accurate numerical values were obtained with RMI, although the four parameters were shown to be statistically equivalent. CONCLUSION: There were no differences in accuracy between CA125, HE4, ROMA, and RMI for differentiating between types of ovarian masses. RMI had the lowest sensitivity but was the most numerically accurate method. HE4 demonstrated the best overall sensitivity for the evaluation of malignant ovarian tumors and the differential diagnosis of endometriosis. All of the parameters demonstrated increased sensitivity when tumors with low malignancy potential were considered low-risk, which may be used as an acceptable assessment method for referring patients to reference centers.

Análise quantitativa dos folículos na síndrome dos ovários policísticos / Folicular quantitative analysis in polycystic ovary syndrome

Na síndrome dos ovários policísticos (SOP) há defeitos no desenvolvimento folicular normal. Propusemo-nos a avaliar se, em virtude da expressão aberrante do fator de crescimento e desenvolvimento - 9 (growth and differentiation factor - 9) no ovário de pacientes com SOP, os estádios iniciais do desenvolvimento folicular estariam alterados. Analisou-se a composição dos folículos ovarianos em mulheres com SOP, comparado-a com a de mulheres normais. Os folículos foram classificados em primordiais, primário de transição, primário clássico, secundário e de DeGraaf. Foram avaliados 2274 folículos. Verificamos que número total de folículos em crescimento foi significantemente maior nas pacientes com SOP quando comparados com o grupo controle; o número de folículos quiescentes não foi diferente entre os grupos. Conseqüentemente, o maior número de folículos primários não pode ser explicado pelo aumento no recrutamento folicular. A contagem seletiva, por tipo de folículo, mostrou que, em todos os estádios de desenvolvimento, as pacientes com SOP apresentaram mais folículos. o número de folículos primários foi 2,7 vezes maior na SOP; o de secundários, 1,8 vezes maior, e o de folículos de DeGraaf, 2 vezes maior. No entanto, o efeito mais proeminente foi notado nos folículos primários clássicos, nos quais o incremento foi de 5 vezes, em comparação aos ovários normais. A ausência de sinais morfológicos de apoptose sugere a possibilidade de haver maior taxa de atresia folicular nas pacientes com SOP Conclui-se, portanto, que o desenvolvimento folicular na SOP é mais lento, promovendo um acúmulo de folículos primários. Tal fato poderia dar origem às anormalidades na dinâmica folicular que se ocorre na síndrome dos ovários policísticos.