Análise do polimorfismo do gene do receptor de melatonina mtnr1b em mulheres com síndrome dos ovários policisticos em uso de metformina e antinconcepcional

• Autor(a) principal: Iwata, Margareth Chiharu [UNIFESP]
• Data de Publicação: 2014
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Repositório Institucional da UNIFESP
• Texto Completo: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=2522018; https://repositorio.unifesp.br/handle/11600/47584
• topic: polycystic ovary syndrome; melatonin; polymorphism; genetic; metformin; contraceptive agents; adolescent; insulin resi; síndrome do ovário policístico; melatonina; polimorfismo genético; metformina / anticoncepcionais / adolescente / resistência à insulina

INTRODUCTION.The polycystic ovary syndrome (PCOS) is the most common endocrine disorder of reproductive age in women. The exact pathophysiological mechanism of the syndrome remains unclear, but it is believed that insulin and its receptor are involved. Hyperinsulinemia and its receptor defect. may contribute to the onset of ovarian and systemic hyperandrogenism as well as chronic anovulation. Melatonin is a hormone that can regulate insulin receptor sensitivity by tyrosine phosphorylation and also act on insulin secretion by pancreatic beta cells by MT2 receptor. Therefore, melatonin may be related to carbohydrate metabolism and thus, with PCOS pathogenesis. Studies have associated genetic alterations in MTNR1B gene encoding MT2 receptor with risk of developing type 2 diabetes. Another point in the PCOS would be the worsening of glucose tolerance with use of contraceptives, and patients with these polymorphisms could have worse outcome. Furthermore, if metformin was given, perhaps its action was not as effective. Therefore, we sought to evaluate the response of adolescents with PCOS using metformin and combined oral contraceptive, and analyze the influence of melatonin receptor gene polymorphisms in these patients. OBJECTIVE. identify four genetic polymorphisms of type 2 melatonin receptor correlating them with plasma glucose, plasma insulin and sex steroids; evaluate the use of insulin sensitizing drug (metformin) and therapy using etnilestradiol and cyproterone in adolescents with PCOS. METHODS. Prospective, randomized, double blind, placebo controlled clinical trial in adolescents with PCOS by Rotterdam criteria (2003), divided into group 1 - contraceptive (35 mcg ethinylestradiol + 2 mg of cyproterone acetate) and metformin 1500 mg / day; Group 2 - contraceptive and placebo. Time use: 6 months. Clinical parameters (BMI, waist-hip ratio, blood pressure, acanthosis nigricans, hirsutism, acne) and laboratory (AST, ALT, creatinine, FSH, LH, estradiol, total testosterone, androstenedione, SHBG, fasting and 2 hours after overload glucose and insulin, total cholesterol, HDL, LDL, triglycerides, melatonin) were evaluated. Polymorphisms rs10830963 C/G, rs12804291 C/T, rs3781638 A/C, 1387153 C/T by PCR and DNA sequencing. RESULTS. Polymorphisms were evaluated in 106 patients and the response to medication in 45 of them. Clinical improvement of hyperandrogenism was higher in the metformin and oral contraceptive group and not determined significant weight gain. Oral contraceptive plus placebo group showed significant increase in body mass index. Metformin and contraceptive determined marked reduction of LH, free testosterone and blood glucose and insulin parameters than in the placebo plus contraceptive after six months of treatment. There was no significant change in melatonin levels during the study. Adverse effects were greater in metformin plus contraceptive group. In the data before treatment, the polymorphism rs10830963 C/G determined higher values of fasting glucose; and rs3781638 polymorphism A/C determined lower insulin levels after glucose overload. During treatment, the polymorphism rs1387153 C/T determined elevated blood glucose levels, while rs12804291C/T and rs3781638 A/C determined increase and decrease, respectively, of total testosterone. CONCLUSIONS. The use of metformin may be safe in adolescents and the association of metformin may provide additional benefit in these patients, particularly in relation to body weight, carbohydrate metabolism and hyperandrogenism. MTNR1B gene polymorphisms are associated with metabolism of glucose and insulin and may influence the response to treatment with metformin and combined oral contraceptive.