RESUMO
Polycystic ovary syndrome (PCOS) is one of the most frequent endocrinopathology affecting women in their reproductive ages. However, PCOS is also related to metabolic abnormalities such as metabolic syndrome (MS), insulin resistance (IR), and type 2 diabetes, among others. Consequently, an inflammatory and pro-oxidative status is also present in these patients, aggravating the syndrome's symptoms. This work aims to discuss some late treatments that focus on oxidative stress (OS) as a central feature related to primary PCOS abnormalities. Therefore, this review focuses on the evidence of anti-oxidant diets, natural compounds, mineralocorticoids, and combined therapies for PCOS management. Oxidative stress (OS) is important in PCOS pathogenesis. In this regard, increased levels of oxidative oxygen species and decreased levels of anti-oxidant agents' impact PCOS's reproductive and metabolic features. In the last years, non-pharmacological therapies have been considered a first line of treatment. For these reasons, several natural compounds such as Kelult honey (KH), Foeniculum Vulgare, Calendula officinalis Linn, Eugenia caryophyllus and Myristicafragrans, vitamin C, vitamin E, selenium, zinc, beta-carotene, magnesium, curcumin, mineralocorticoids and melatonin alone or in combination are powerful anti-oxidant agents being used for PCOS management. Data presented here suggest that natural therapies are essential in managing both reproductive and metabolic features in PCOS patients. Due to the results obtained, these incipient therapies deserve further investigation.
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Background: It is still unelucidated how hormonal alterations affect developing organisms and their descendants. Particularly, the effects of androgen levels are of clinical relevance as they are usually high in women with Polycystic Ovary Syndrome (PCOS). Moreover, it is still unknown how androgens may affect males' health and their descendants. Objectives: We aimed to evaluate the multigenerational effect of prenatal androgen excess until a second generation at early developmental stages considering both maternal and paternal effects. Design And Methods: This is an animal model study. Female rats (F0) were exposed to androgens during pregnancy by injections of 1 mg of testosterone to obtain prenatally hyperandrogenized (PH) animals (F1), leading to a well-known animal model that resembles PCOS features. A control (C) group was obtained by vehicle injections. The PH-F1 animals were crossed with C males (m) or females (f) and C animals were also mated, thus obtaining 3 different mating groups: Cf × Cm, PHf × Cm, Cf × PHm and their offspring (F2). Results: F1-PHf presented altered glucose metabolism and lipid profile compared to F1-C females. In addition, F1-PHf showed an increased time to mating with control males compared to the C group. At gestational day 14, we found alterations in glucose and total cholesterol serum levels and in the placental size of the pregnant F1-PHf and Cf mated to F1-PHm. The F2 offspring resulting from F1-PH mothers or fathers showed alterations in their growth, size, and glucose metabolism up to early post-natal development in a sex-dependent manner, being the females born to F1-PHf the most affected ones. Conclusion: androgen exposure during intrauterine life leads to programing effects in females and males that affect offspring health in a sex-dependent manner, at least up-to a second generation. In addition, this study suggests paternally mediated effects on the F2 offspring development.
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Accumulating evidence suggests that an altered maternal milieu and environmental insults during the intrauterine and perinatal periods of life affect the developing organism, leading to detrimental long-term outcomes and often to adult pathologies through programming effects. Hormones, together with growth factors, play critical roles in the regulation of maternal-fetal and maternal-neonate interfaces, and alterations in any of them may lead to programming effects on the developing organism. In this chapter, we will review the role of sex steroids, thyroid hormones, and insulin-like growth factors, as crucial factors involved in physiological processes during pregnancy and lactation, and their role in developmental programming effects during fetal and early neonatal life. Also, we will consider epidemiological evidence and data from animal models of altered maternal hormonal environments and focus on the role of different tissues in the establishment of maternal and fetus/infant interaction. Finally, we will identify unresolved questions and discuss potential future research directions.
Assuntos
Desenvolvimento Fetal , Hormônios Tireóideos , Gravidez , Animais , Feminino , Desenvolvimento Fetal/fisiologia , FetoRESUMO
Prenatal androgen exposure induces fetal programming leading to alterations in offspring health and phenotypes that resemble those seen in women with Polycystic Ovary Syndrome. It has been described that prenatal androgenization affects the reproductive axis and leads to metabolic and endocrine disorders. Adipose tissue plays a crucial role in all these functions and is susceptible to programming effects. Particularly, gonadal adipose tissue is involved in reproductive functions, so dysfunctions in this tissue could be related to fertility alterations. We aimed to investigate the extent to which prenatal hyperandrogenization is able to alter the functionality of gonadal adipose tissue in female adult rats, including lipid metabolism, adipokines expression, and de novo synthesis of steroids. Pregnant rats were treated with 1 mg of testosterone from day 16 to day 19 of pregnancy, and female offspring were followed until 90 days of age, when they were euthanized. The prenatally hyperandrogenized (PH) female offspring displayed two phenotypes: irregular ovulatory (PHiov) and anovulatory (PHanov). Regarding lipid metabolism, both PH groups displayed disruptions in the main lipid pathways with altered levels of triglyceride and increased lipid peroxidation levels. In addition, we found that Peroxisome Proliferator-Activated Receptors (PPARs) alpha protein expression was decreased in both PH phenotypes (p < 0.05), but no changes were found in PPARγ protein levels. Furthermore, regarding adipokines, no changes were found in Leptin and Adiponectin protein levels, but Chemerin protein levels were decreased in the PHiov group (p < 0.05). Regarding de novo synthesis of steroids, the PHanov group showed increased protein levels of Cyp17a1 and Cyp19, while the PHiov group only showed decreased protein levels of Cyp19 (p < 0.05). These results suggest that prenatal androgen exposure affects females' gonadal adipose tissue in adulthood, disturbing different lipid pathways, Chemerin expression, and de novo synthesis of steroids.
Assuntos
Síndrome do Ovário Policístico , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Ratos , Feminino , Animais , Androgênios , Aromatase , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/veterinária , Esteroides , Adipocinas , Triglicerídeos , Tecido Adiposo , Efeitos Tardios da Exposição Pré-Natal/veterináriaRESUMO
It is known that prenatal hyperandrogenization induces alterations since early stages of life, contributing to the development of polycystic ovary syndrome affecting the reproductive axis and the metabolic status, thus promoting others associated disorders, such as dyslipidemia, insulin resistance, liver dysfunction, and even steatosis. In this study, we aimed to evaluate the effect of fetal programming by androgen excess on the hepatic lipid content and metabolic mediators at adult life. Pregnant rats were hyperandrogenized with daily subcutaneous injections of 1 mg of free testosterone from days 16 to 19 of pregnancy. The prenatally hyperandrogenized (PH) female offspring displayed two phenotypes: irregular ovulatory phenotype (PHiov) and anovulatory phenotype (PHanov), with different metabolic and endocrine features. We evaluated the liver lipid content and the main aspect of the balance between fatty acid (FA) synthesis and oxidation. We investigated the status of the peroxisomal proliferator-activated receptors (PPARs) alpha and gamma, which act as lipid mediators, and the adipokine chemerin, one marker of liver alterations. We found that prenatal hyperandrogenization altered the liver lipid profile with increased FAs levels in the PHanov phenotype and decreased cholesterol content in the PHiov phenotype. FA metabolism was also disturbed, including decreased mRNA and protein PPARgamma levels and impaired gene expression of the main enzymes involved in lipid metabolism. Moreover, we found low chemerin protein levels in both PH phenotypes. In conclusion, these data suggest that prenatal hyperandrogenization exerts a negative effect on the liver and alters lipid content and metabolic mediators' expression at adult age.
Assuntos
PPAR gama , Efeitos Tardios da Exposição Pré-Natal , Androgênios/metabolismo , Animais , Feminino , Desenvolvimento Fetal , Humanos , Metabolismo dos Lipídeos , Lipídeos , Fígado/metabolismo , PPAR gama/metabolismo , PPAR gama/farmacologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Background: Polycystic Ovary Syndrome (PCOS) often present metabolic disorders and hyperandrogenism (HA), facts that may influence the telomere length (TL). Aims: To compare the absolute TL (aTL) between women with PCOS and control women, and their association with the presence of obesity and HA parameters. Materials and methods: The PCOS group included 170 unrelated women outpatients and the control group, 64 unrelated donor women. Anthropometric, biochemical-clinical parameters and androgen profile were determined. The PCOS patients were divided accordingly to the presence of obesity and androgenic condition. The aTL was determined from peripheral blood leukocytes by Real Time quantitative PCR. Results: Women with PCOS exhibited a significantly longer aTL than controls after age adjustment (p=0.001). A stepwise multivariate linear regression in PCOS women, showed that WC (waist circumference) contributed negatively (b=-0.17) while testosterone levels contributed positively (b=7.24) to aTL. The non-Obese PCOS (noOB-PCOS) presented the longest aTL when compared to controls (p=0.001). Meanwhile, the aTL was significantly higher in the hyperandrogenic PCOS phenotype (HA-PCOS) than in the controls (p=0.001) and non hyperandrogenic PCOS phenotype (NHA-PCOS) (p=0.04). Interestingly, when considering obesity and HA parameters in PCOS, HA exerts the major effect over the aTL as non-obese HA exhibited the lengthiest aTL (23.9 ± 13.13 Kbp). Conversely, the obese NHA patients showed the shortest aTL (16.5 ± 10.59 Kbp). Conclusions: Whilst a shorter aTL could be related to the presence of obesity, a longer aTL would be associated with HA phenotype. These findings suggest a balance between the effect produced by the different metabolic and hormonal components, in PCOS women.
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Hiperandrogenismo/genética , Obesidade/genética , Síndrome do Ovário Policístico/genética , Telômero/metabolismo , Adulto , Argentina/epidemiologia , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Humanos , Hiperandrogenismo/complicações , Hiperandrogenismo/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/epidemiologia , Estudos Retrospectivos , Telômero/química , Homeostase do Telômero/fisiologia , Testosterona/sangueRESUMO
BACKGROUND: Lipids are essential components of cells that participate in metabolic and endocrine regulation and reproductive functions. The main organs where lipid regulation takes place are the liver and adipose tissue. Besides, when each tissue- specific action cannot be exerted, it could lead to several endocrine-metabolic disorders closely related to PCOS, such as non-alcoholic fatty liver disease (NAFLD) and obesity. OBJECTIVE: This work aims to discuss the impact of lipid alterations on metabolic and reproductive health. Therefore, this review focus on the importance of carrying out an integrated study of the molecular pathways affected in PCOS for developing target therapies. RESULTS: Lipids play a major role in PCOS pathogenesis. In this regard, failures in lipid regulation, synthesis, and/or homeostasis contribute to metabolic and reproductive abnormalities, such as those seen in PCOS. Several lipid pathways and regulators are altered in this pathology, leading to dysfunctions that worsen reproductive functions. Therefore, there are several treatments to manage dyslipidemias. Non-pharmacological therapies are considered a first-line treatment being the pharmacological treatments a second-line option. CONCLUSION: The best treatment to improve the lipid profile is lifestyle intervention, a combination of hypocaloric diet and exercise. Regarding pharmacological therapies, a combination of fibrate and statins would be the most recommended drugs. Still, in PCOS women, treatment with metformin or TZDs not only modulates the lipid metabolism, but also improves ovulation. In addition, metformin with lifestyle interventions has positive effects on the metabolic and reproductive features of PCOS patients.
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Resistência à Insulina , Metformina , Síndrome do Ovário Policístico , Dieta Redutora , Feminino , Humanos , Metabolismo dos Lipídeos , Obesidade/terapia , Síndrome do Ovário Policístico/terapia , Saúde ReprodutivaRESUMO
Prenatal androgen exposure affects reproductive functions and has been proposed as an underlying cause of polycystic ovary syndrome (PCOS). In this study, we aimed to investigate the impact of prenatal androgen exposure on ovarian lipid metabolism and to deepen our understanding of steroidogenesis regulation during adulthood. Pregnant rats were hyperandrogenized with testosterone and female offspring were studied when adult. This treatment leads to two different phenotypes: irregular ovulatory and anovulatory animals. Our results showed that prenatally hyperandrogenized (PH) animals displayed altered lipid and hormonal profile together with alterations in steroidogenesis and ovarian lipid metabolism. Moreover, PH animals showed alterations in the PPARg system, impaired mRNA levels of cholesterol receptors (Ldlr and Srb1) and decreased expression of the rate-limiting enzyme of de novo cholesterol production (Hmgcr). Anovulatory PH animals presented an increase of ovarian cholesteryl esters levels and lipid peroxidation index. Together with alterations in cholesterol metabolism, we found an impairment of the steroidogenic pathway in PH animals in a phenotype-specific manner. Regarding fatty acid metabolism, our results showed, in PH animals, an altered expression of Srebp1 and Atgl, which are involved in fatty acid metabolism and triglycerides hydrolysis, respectively. In conclusion, fatty acid and cholesterol metabolism, which are key players in steroidogenesis acting as a source of energy and substrate for steroid production, were affected in animals exposed to androgens during gestation. These results suggest that prenatal androgen exposure leads to long-term effects that affect ovary lipid metabolism and ovarian steroid formation from the very first steps.
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Hormônios Esteroides Gonadais/biossíntese , Metabolismo dos Lipídeos/fisiologia , Ovário/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Testosterona/administração & dosagem , Animais , Colesterol/metabolismo , Feminino , Metabolismo dos Lipídeos/efeitos dos fármacos , Ovário/efeitos dos fármacos , Gravidez , RatosRESUMO
Polycystic Ovary Syndrome (PCOS) is a common endocrine and metabolic disorder that affects women in their reproductive age. Recent studies have shown that genes have an important role in the etiology of PCOS. However, the precise way in which these genes are transcriptionally and post-transcriptionally regulated is poorly understood. The aim of the present review is to provide updated information on miRNAs and DNA methylation as epigenetic marks of PCOS. The data presented here allow concluding that both microRNAs and DNA methylation can be considered as possible useful biomarkers when choosing the treatment for a specific PCOS phenotype and thus represent two important tools for the diagnosis and treatment of PCOS patients.
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Síndrome do Ovário Policístico , Metilação de DNA , Epigênese Genética , Epigenômica , Feminino , Humanos , MicroRNAs/genética , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/genéticaRESUMO
Fetal programming by androgen excess is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). PCOS is more than a reproductive disorder, as women with PCOS also show metabolic and other endocrine alterations. Since both ovarian and reproductive functions depend on energy balance, the alterations in metabolism may be related to reproductive alterations. The present study aimed to evaluate the effect of androgen excess during prenatal life on ovarian fuel sensors and its consequences on steroidogenesis. To this end, pregnant rats were hyperandrogenized with testosterone and the following parameters were evaluated in their female offspring: follicular development, PPARG levels, adipokines (including leptin, adiponectin, and chemerin as ovarian fuel sensors), serum gonadotropins (LH and FSH), the mRNA of their ovarian receptors, and the expression of steroidogenic mediators. At 60 days of age, the prenatally hyperandrogenized (PH) female offspring displayed both an irregular ovulatory phenotype and an anovulatory phenotype with altered follicular development and the presence of cysts. Both PH groups showed altered levels of both proteins and mRNA of PPARG and a different expression pattern of the adipokines studied. Although serum gonadotropins were not impaired, there were alterations in the mRNA levels of their ovarian receptors. The steroidogenic mediators Star, Cyp11a1, Cyp17a1, and Cyp19a1 were altered differently in each of the PH groups. We concluded that androgen excess during prenatal life leads to developmental programming effects that affect ovarian fuel sensors and steroidogenesis in a phenotype-specific way.
Assuntos
Androgênios/farmacologia , Desenvolvimento Fetal/efeitos dos fármacos , Ovário/efeitos dos fármacos , Síndrome do Ovário Policístico/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Esteroides/biossíntese , Animais , Feminino , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
This study aimed to evaluate the role of prenatal hyperandrogenization in liver functions and the extent of metformin as treatment. Pregnant rats were hyperandrogenized with subcutaneous testosterone (1mg/rat) between 16 and 19 of pregnancy. Prenatally hyperandrogenized (PH) female offspring displayed, at the adult life, two phenotypes; a PH irregular ovulatory phenotype (PHiov) and a PH anovulatory (PHanov) phenotype. From day 70 to the moment of sacrifice (90 days of age), 50% of the animals of each group received a daily oral dose of 50â¯mg/kg of metformin. We found that both PH phenotypes displayed a hepatic disruptions of insulin and glucose pathway and that metformin treatment reversed some of these alterations in a specific-phenotype manner. Our findings show, for the first time, that androgen excess in utero promotes hepatic dysfunctions and that metformin treatment is able to specifically reverse those hepatic alterations and sheds light on the possible mechanisms of metformin action.
Assuntos
Hiperandrogenismo/complicações , Hipoglicemiantes/farmacologia , Hepatopatias/tratamento farmacológico , Fígado/fisiologia , Metformina/farmacologia , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Animais , Feminino , Resistência à Insulina , Lipídeos/sangue , Fígado/efeitos dos fármacos , Hepatopatias/etiologia , Hepatopatias/patologia , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
Prenatal hyperandrogenism is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). PCOS patients have high risk of developing fatty liver and steatosis. This study aimed to evaluate the role of prenatal hyperandrogenism in liver lipid metabolism and fatty liver development. Pregnant rats were hyperandrogenized with testosterone. At pubertal age, the prenatally hyperandrogenized (PH) female offspring displayed both ovulatory (PHov) and anovulatory (PHanov) phenotypes that mimic human PCOS features. We evaluated hepatic transferases, liver lipid content, the balance between lipogenesis and fatty acid oxidation pathway, oxidant/antioxidant balance and proinflammatory status. We also evaluated the general metabolic status through growth rate curve, basal glucose and insulin levels, glucose tolerance test, HOMA-IR index and serum lipid profile. Although neither PH group showed signs of liver lipid content, the lipogenesis and fatty oxidation pathways were altered. The PH groups also showed impaired oxidant/antioxidant balance, a decrease in the proinflammatory pathway (measured by prostaglandin E2 and cyclooxygenase-2 levels), decreased glucose tolerance, imbalance of circulating lipids and increased risk of metabolic syndrome. We conclude that prenatal hyperandrogenism generates both PHov and PHanov phenotypes with signs of liver alterations, imbalance in lipid metabolism and increased risk of developing metabolic syndrome. The anovulatory phenotype showed more alterations in liver lipogenesis and a more impaired balance of insulin and glucose metabolism, being more susceptible to the development of steatosis.
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Hiperandrogenismo/metabolismo , Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Ciclo-Oxigenase 2/metabolismo , Feminino , Teste de Tolerância a Glucose , Inflamação/metabolismo , Insulina/sangue , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Fígado/efeitos dos fármacos , Síndrome Metabólica/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Testosterona/farmacologiaRESUMO
Fuel sensors such as glucose, insulin or leptin, are known to be directly involved in the regulation of fertility at each level of the hypothalamic-pituitary-gonadal axis. The discovery of the peroxisome proliferator-activated receptor (PPAR) family of transcription factors has revealed the link between lipid/glucose availability and long-term metabolic adaptation. By binding to specific regions of DNA in heterodimers with the retinoid X receptors (RXRs), the members of the PPAR family (α, ß/δ, γ) are able to regulate the gene expressions of several key regulators of energy homeostasis including several glucose regulators (glucose transporters, insulin receptor, substrate insulin receptor, etc), and also metabolic and endocrine pathways like lipogenesis, steroidogenesis, ovulation, oocyte maturation, maintenance of the corpus luteum, nitric oxide system, several proteases and plasminogen activator among others. All the three PPAR isoforms are expressed in different tissues of the female reproductive tract and regulate gametogenesis, ovulation, corpus luteum regression and the implantation process among others. The present review discusses the mechanisms involved in PPAR activation focusing on endogenous and synthetic ligands of PPAR not only in physiological but also in pathological conditions (such as polycystic ovary syndrome, pathologies of implantation process, chronic anovulation, etc).
Assuntos
Genitália Feminina/fisiologia , Receptores Ativados por Proliferador de Peroxissomo/fisiologia , Feminino , Humanos , Ligantes , Receptores Ativados por Proliferador de Peroxissomo/metabolismoRESUMO
Prenatal hyperandrogenism is able to induce polycystic ovary syndrome (PCOS) in rats. The aim of the present study was to establish if the levels of prenatal testosterone may determine the extent of metabolic and endocrine alterations during the adult life. Pregnant Sprague Dawley rats were prenatally injected with either 2 or 5 mg free testosterone (groups T2 and T5 respectively) from day 16 to day 19 day of gestation. Female offspring from T2 and T5 displayed different phenotype of PCOS during adult life. Offspring from T2 showed hyperandrogenism, ovarian cysts and ovulatory cycles whereas those from T5 displayed hyperandrogenism, ovarian cysts and anovulatory cycles. Both group showed increased circulating glucose levels after the intraperitoneal glucose tolerance test (IPGTT; an evaluation of insulin resistance). IPGTT was higher in T5 rats and directly correlated with body weight at prepubertal age. However, the decrease in the body weight at prepubertal age was compensated during adult life. Although both groups showed enhanced ovarian steroidogenesis, it appears that the molecular mechanisms involved were different. The higher dose of testosterone enhanced the expression of both the protein that regulates cholesterol availability (the steroidogenic acute regulatory protein (StAR)) and the protein expression of the transcriptional factor: peroxisome proliferator-activated receptor gamma (PPAR gamma). Prenatal hyperandrogenization induced an anti-oxidant response that prevented a possible pro-oxidant status. The higher dose of testosterone induced a pro-inflammatory state in ovarian tissue mediated by increased levels of prostaglandin E (PG) and the protein expression of cyclooxygenase 2 (COX2, the limiting enzyme of PGs synthesis). In summary, our data show that the levels of testosterone prenatally injected modulate the uterine environment and that this, in turn, would be responsible for the endocrine and metabolic abnormalities and the phenotype of PCOS during the adult life.
Assuntos
Hiperandrogenismo/complicações , Ovário/metabolismo , Síndrome do Ovário Policístico/etiologia , Síndrome do Ovário Policístico/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Testosterona/metabolismo , Animais , Glicemia/metabolismo , Peso Corporal , Feminino , Hiperandrogenismo/metabolismo , Injeções , Ovário/patologia , Síndrome do Ovário Policístico/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Esteroides/metabolismo , Testosterona/administração & dosagemRESUMO
Polycystic Ovary Syndrome (PCOS) is one of the common endocrine diseases that affects women in their reproductive age. PCOS has diverse clinical implications that include reproductive (infertility, hyperandrogenism, hirsutism), metabolic (insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, cardiovascular diseases) and psychological features (increased anxiety, depression and worsened quality of life). The exact patho-physiology of PCOS is complex and remains largely unclear. The prevalence of PCOS is estimated at 4-18%, depending on diverse factors discussed ahead. The phenotype varies widely depending on life stage, genotype, ethnicity and environmental factors including lifestyle and body weight. During the last decades, obesity and excess weight are major chronic diseases all around the word. Obesity increases some features of PCOS such as hyperandrogenism, hirsutism, infertility and pregnancy complications. Both obesity and insulin resistance increase diabetes mellitus type 2 and cardiovascular diseases. Moreover, obesity impairs insulin resistance and exacerbates reproductive and metabolic features of PCOS. It is well known that obesity is associated with anovulation, pregnancy loss and late pregnancy complications (pre-eclampsia, gestational diabetes). Obesity in PCOS is also linked to failure or delayed response to the various treatments including clomiphene citrate, gonadotropins and laparoscopic ovarian diathermy. It has been reported that, after losing as little as 5 % of initial body weight obese women with PCOS improved spontaneous ovulation rates and spontaneous pregnancy. Therefore, the weight loss prior to conception improves live birth rate in obese women with or without PCOS. The treatment of obesity may include lifestyle therapy (diet and exercise), pharmacological treatment and bariatric surgery. In summary, weight loss is considered the first-line therapy in obese women with PCOS. In the present review, the consequence and treatment of obesity in women with PCOS are discussed.
Assuntos
Obesidade/complicações , Síndrome do Ovário Policístico/complicações , Animais , Feminino , Regulação da Expressão Gênica , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos , Obesidade/metabolismo , Obesidade/fisiopatologia , Obesidade/terapia , Sobrepeso/complicações , Sobrepeso/metabolismo , Sobrepeso/fisiopatologia , Sobrepeso/terapia , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/fisiopatologiaRESUMO
Chronic hyperandrogenism alters the peroxisome proliferator-activated receptor γ (PPARγ) pathway in the uterine tissue of prepubertal mice. The gene and protein expression of PPARγ is not modified, but the gene and protein expression of 12-lipoxygenase (12-LOX), an enzyme that synthesizes PPARγ ligands, is decreased. The antihyperglycemic drug metformin can prevent this adverse effect.
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Hiperandrogenismo/metabolismo , Hipoglicemiantes/farmacologia , Metformina/farmacologia , PPAR gama/agonistas , Desenvolvimento Sexual , Útero/efeitos dos fármacos , Animais , Araquidonato 12-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/metabolismo , Desidroepiandrosterona , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Hiperandrogenismo/induzido quimicamente , Hiperandrogenismo/genética , Hiperandrogenismo/fisiopatologia , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , PPAR gama/genética , PPAR gama/metabolismo , RNA Mensageiro/metabolismo , Útero/metabolismo , Útero/fisiopatologiaRESUMO
The objective of the present study was to examine some factors involved in follicular development of women with polycystic ovary syndrome (PCOS). Women with PCOS showed increased levels of serum luteinizing hormone (LH) but decreased follicular production of progesterone and estradiol by pre-ovulatory follicles. The mRNA expression corresponding to steroidogenic acute regulatory protein (StAR), and 20alpha-hydroxysteroid dehydrogenase (20α-HSD) was increased, while that corresponding to cytochrome P450 aromatase (P450arom) was decreased in PCOS follicles as compared to controls. No changes in the mRNA expression for 3beta-hydroxysteroid dehydrogenase 2 (3ß-HSD2), cytochrome P450 side-chain cleavage (P450scc), cytochrome P450 17 alpha hydroxylase/lyase (P450c17), cyclooxygenase 2 (COX2), and transcription factors (GATA-4 and GATA-6) were found. We conclude that despite the hyper-luteinized environment of PCOS follicles, these follicles produce lower levels of progesterone and estradiol, and that this is characterized by increased degradation of progesterone and decreased estradiol synthesis. Our data demonstrate that the synthesis of prostaglandin F2α (PGF2α) may be affected in PCOS-follicles and that the transcription factors GATA-4 and GATA-6 are present in PCOS-follicles but they are not involved in the abnormal transcription observed in the steroidogenic enzymes.
Assuntos
Folículo Ovariano/patologia , Síndrome do Ovário Policístico/patologia , 20-alfa-Hidroxiesteroide Desidrogenase/biossíntese , 20-alfa-Hidroxiesteroide Desidrogenase/genética , 3-Hidroxiesteroide Desidrogenases/biossíntese , 3-Hidroxiesteroide Desidrogenases/genética , Aromatase/biossíntese , Aromatase/genética , Ciclo-Oxigenase 2/biossíntese , Ciclo-Oxigenase 2/genética , Estradiol/biossíntese , Feminino , Fator de Transcrição GATA4/genética , Fator de Transcrição GATA4/fisiologia , Fator de Transcrição GATA6/genética , Fator de Transcrição GATA6/fisiologia , Humanos , Hormônio Luteinizante/sangue , Folículo Ovariano/metabolismo , Fosfoproteínas/biossíntese , Fosfoproteínas/genética , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/enzimologia , Síndrome do Ovário Policístico/metabolismo , Progesterona/biossíntese , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esteroide 17-alfa-Hidroxilase/biossíntese , Esteroide 17-alfa-Hidroxilase/genéticaRESUMO
Acute hyperandrogenism decreases serum P levels and induces early apoptosis of antral follicles by a mechanism mediated by the peroxisome proliferator-activated receptor gamma system and independent of the steroidogenic acute regulator protein.
Assuntos
Gonadotropina Coriônica/farmacologia , Hiperandrogenismo/fisiopatologia , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/fisiologia , PPAR gama/metabolismo , Doença Aguda , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Desidroepiandrosterona/farmacologia , Feminino , Expressão Gênica/efeitos dos fármacos , Hiperandrogenismo/metabolismo , Hiperandrogenismo/patologia , Folículo Ovariano/patologia , PPAR gama/genética , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Substâncias para o Controle da Reprodução/farmacologiaRESUMO
The present study investigated the role of the N, N'-dimethylbiguanide metformin (50 mg/kg body weight in 0.05 ml water, given orally with a canulla) in preventing the adverse effects generated by hyperandrogenism on uterine function. Daily injection of dehydroepiandrosterone (DHEA: 6 mg/100 g body weight in 0.1 ml oil) for 20 consecutive days induces polycystic ovaries in BALB/c mice. In this model we found that DHEA produced alterations on uterine histology closely related to the development of pre-cancerous structures concomitantly with increased incidence of uterine apoptosis. The injection of DHEA induced a pro-inflammatory status since uterine prostaglandin (PG) F2 alpha levels and cyclooxygenase 2 were increased although PGE levels were decreased. Furthermore, DHEA promoted a pro-oxidant status since it increased nitric oxide synthase (NOS) activity and decreased superoxide dismutase and catalase activities and the antioxidant metabolite glutathione levels. DHEA also regulated the percentages of CD4+ and CD8+ T lymphocyte that infiltrate uterine tissue. When metformin was administered together with DHEA uterine histology and apoptosis did not differ when compared with controls. Therefore, metformin prevented the pro-inflammatory and pro-oxidative status generated by DHEA and restores the ratios of CD4+ and CD8+ T cells to those observed in controls. We conclude that metformin is able to restore either directly or indirectly uterine function by preventing some inflammatory and oxidative alterations produced by hyperandrogenism.