Effects of Insulin Sensitizing Drug Metformin on Clinical Features, Endocrine and Metabolic Profiles in Obese Women with Polycystic Ovary Syndrome: A Randomized, Double Blind, Placebo-Controlled Sixteen Weeks Trial

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder that affects approximately 6-10% of women of reproductive age (Franks, 1995). Polycystic ovary syndrome is probably the most prevalent endocrinopathy in women and by far the most common cause for infertility. In fact, polycystic ovaries have been associated with 75% of cases of anovulation (Hull, 1987). The many features of this syndrome can be divided into three categories: clinical, endocrine and metabolic. The clinical features include menstrual abnormalities, hirsutism, acne, alopecia, anovulatory infertility and recurrent miscarriages. The endocrine features are presented with elevated androgens, luteinizing hormone, and oestrogen and prolactin levels. The metabolic aspects of this syndrome are insulin resistance, obesity, lipid abnormalities and an increased risk for impaired glucose tolerance and type 2 diabetes mellitus (type 2 DM). Endocrine Abnormalities The main endocrine features of PCOS are increased androgen production and disordered gonadotropin secretion. Both luteinizing hormone (LH) pulse frequency and amplitude are increased, whereas follicle-stimulating hormone (FSH) levels remain constant in the midfollicular range (Marshall et al., 1999). The frequency of gonadotropin-releasing hormone (GnRH) release is increased secondary to decreased sensitivity of the GnRH pulse generator to the negative feedback effects of estradiol and progesterone. This increased GnRH pulse frequency selectively increases LH release. The raised LH levels enhance thecal androgen production, and these androgens are incompletely aromatised into estrogens by the granulosa cells, because of arrested follicular development as a consequence of low-level cyclic FSH release. The so-called vicious cycle of PCOS is created, in which disordered gonadotropin secretion causes increased ovarian androgen production, which in turn alters gonadal steroid feedback, INTRODUCTION 6 perpetuating disordered gonadotropin release (Dunaif, 1997). Adrenal androgen production is also frequently increased in PCOS (Rosenfield, 1999). This finding might reflect a common defect in ovarian and adrenal androgen biosynthesis because adrenocorticotropin hormone (ACTH) release is not increased. Metabolic Features Insulin resistance is a prominent feature of PCOS, independent of obesity (Dunaif, 1992). Many but not all women with PCOS are insulin resistant. Obesity and PCOS have an additive deleterious effect on insulin sensitivity. The molecular mechanisms of this defect differ from those in other common insulin resistant conditions, such as Type 2 Diabetes mellitus and obesity, suggesting that PCOS-related insulin resistance has an individual genetic aetiology (Dunaif, 1997). Studies of PCOS adipocytes suggest that there is a post-binding defect in insulin receptor-mediated signal transduction, and this observation has recently been confirmed in skeletal muscle, the …