PCOS Endocrine–metabolic effects of the treatment with pioglitazone in obese patients with polycystic ovary syndrome HERALDO M. GARMES, MARCOS A. TAMBASCIA, & DENISE E. ZANTUT-WITTMANN Division of Endocrinology, Department of Internal Medicine, School of Medical Sciences, State University of Campinas, Campinas, Sa ˜ o Paulo, Brazil (Received 10 March 2005; revised 12 August 2005; accepted 24 October 2005) Abstract The hyperandrogenism found in polycystic ovary syndrome (PCOS) can be a consequence of hyperinsulinemia as a result of peripheral insulin resistance. Metformin and insulin sensitizers have become a potential therapeutic tool for treating these patients; however, there are few studies with pioglitazone in PCOS. Elevated luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratios and LH hyper-responsivity to stimulation with gonadotropin-releasing hormone (GnRH) are common findings in PCOS. The reason why hyperinsulinemia produces hyperandrogenism and whether insulin action on the pituitary alters gonadotropin liberation remain unknown. In the present study, we evaluated the effect of pioglitazone (30 mg/day for 2 months) on insulin response to an oral glucose tolerance test (OGTT), serum levels of androgens and sex hormone-binding globulin (SHBG), and pituitary gonadotropin response to GnRH stimulation in 15 obese PCOS women. We found a significant decrease in insulin response to the OGTT and also in total and free testosterone levels, an increase in SHBG and a reduction in the LH response to GnRH stimulation after pioglitazone treatment. In conclusion, this short-term treatment with pioglitazone decreased hyperinsulinemia and hyperandrogenemia in obese PCOS patients, and there was a significant reduction in LH response to GnRH stimulation. Further research should be carried out to establish the risks and benefits of pioglitazone, which would assist in the physiopathologic comprehension of PCOS. Keywords: Insulin resistance, polycystic ovary syndrome, pioglitazone, hyperandrogenism, luteinizing hormone Introduction The increased androgen levels seen in polycystic ovary syndrome (PCOS) may result from the hyperinsuli- nemia caused by the resistance of peripheral tissues to insulin [1]. Obesity contributes to insulin resistance [2], but the phenomenon may also be found in non- obese women with PCOS [3]. The use of drugs that reduce hyperinsulinemia may correct hyperandrogen- emia [4,5]. Based on this assumption, metformin, an insulin-sensitizing agent, has been used to decrease serum levels of insulin and to improve the clinical and laboratory findings in these patients [6]. Pioglitazone, troglitazone and rosiglitazone belong to the thiazolidinedione class of drugs that increases sensitivity to insulin [7]. Although usually indicated to control blood glucose levels in patients with type 2 diabetes mellitus, thiazolidinediones have an effect in reducing hyperinsulinemia and hyperandrogenemia in patients with PCOS. Troglitazone reverses the hormonal changes in PCOS [8], but has been with- drawn from the market because of severe liver toxicity, a condition not reported so far with pioglitazone. However, previous studies on the effect of pioglita- zone in PCOS patients are limited. Apoptosis is considered a major cause of the loss of b-cells in diabetes [9], and pioglitazone can protect human pancreatic b-cells against apoptosis and loss of function [10], an effect not reported with metformin. Any such beneficial effects of pioglitazone on b-cell function would synergize with the positive impact on insulin sensitivity and could prevent the cardiovas- cular events associated with diabetes in PCOS patients. Elevated luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio is a common finding in patients with PCOS, and the increased serum levels of LH are an important factor in the etiopathogenesis of hyperandrogenism in these patients [11,12]. In PCOS, inappropriate gonadotropin secretion is char- acterized by increased pulse frequency and amplitude, and in some patients there is a hyper-response of LH after a stimulation test with gonadotropin-releasing hormone (GnRH) [13,14]. The insulin receptor Correspondence: H. M. Garmes, Faculdade de Cie ˆncias Me ´dicas, Departamento de Clı ´nica Me ´dica, Disciplina de Endocrinologia, Universidade Estadual de Campinas, PO Box 6111, Rua Tessa ´lia Vieira de Camargo 126, Bara ˜o Geraldo, 13084-971 Campinas SP, Brazil. Tel/Fax: 55 19 3289 4107. E-mail: heraldmg@uol.com.br Gynecological Endocrinology, December 2005; 21(6): 317–323 ISSN 0951-3590 print/ISSN 1473-0766 online ª 2005 Taylor & Francis DOI: 10.1080/09513590500430575