The pathophysiology of polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder of uncertain aetiology, which affects between 6 and 10% of women of the reproductive age. The heterogeneity of both the ovarian morphology and clinical findings in women with polycystic ovaries has been well recognized since Stein & Leventhal's (1935) first report and gradually led to the establishment of the term polycystic ovary syndrome. The many features of this syndrome can be broadly 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 include elevated androgens, luteinizing hormone, oestrogen and prolactin levels. The metabolic aspects of this syndrome include insulin resistance, obesity, lipid abnormalities and an increased risk for impaired glucose tolerance and type 2 diabetes mellitus (type 2 DM). Controversy persists regarding the criteria used for PCOS diagnosis. Currently, the recommended diagnostic criteria for PCOS are hyperandrogenism and ovulatory dysfunction with the exclusion of specific disorders, such as nonclassic adrenal 21-hydroxylase deficiency, Cushing's syndrome, hyperprolactinaemia and androgen-producing tumours. This clinical definition reflects a 1990 National Institutes of Health–National Institute of Child Health and Development Consensus Conference (Zawadeski & Dunaif, 1992) in which there was poor agreement among the 58 specialists who completed a questionnaire on the diagnostic criteria for PCOS, with no single criterion endorsed as ‘definite or probable’ by more than 64% of respondents. Interestingly, the conclusion of this meeting was that the polycystic ovary morphology is consistent with, but not essential for, the diagnosis of the syndrome. Sonographic criteria for polycystic ovaries have been refined with advances in technology (Fox, 1999; Atiomo et al., 2000) and transvaginal ultrasound is currently the gold standard for diagnosing polycystic ovaries. Using the most conservative criteria based on transabdominal ultrasound, the presence of 10 or more cysts, 2–8 mm in diameter, arranged either peripherally around a dense core of stroma or scattered throughout an increased amount of stroma (Adams et al., 1985), up to 23% of normal volunteer women meet the sonographic criteria for polycystic ovaries (Clayton et al., 1992). On the other hand, many investigators have maintained that ovaries from women with PCOS may be sonographically normal (Hann et al., 1984; Timor-Tritsch & Rottem, 1998). Thus, the ovarian morphological changes must be distinguished from the endocrine syndrome of PCOS and be considered as a sign rather and not a disease. Despite being one of the most common endocrinopathies, a comprehensive explanation of pathophysiology is still lacking. The heterogeneity of PCOS may well reflect multiple pathophysiological mechanisms, but the definition of each contributing mechanism has been slow to emerge. Traditionally, it has been useful to consider the polycystic ovary syndrome as the result of a ‘vicious cycle’, which can be initiated at any one of many entry points. Altered function at any point in the cycle leads to the same result: ovarian androgen excess and anovulation. Several theories have been proposed to explain the pathogenesis of PCOS: A unique defect in insulin action and secretion that leads to hyperinsulinaemia and insulin resistance. A primary neuroendocrine defect leading to an exaggerated LH pulse frequency and amplitude. A defect of androgen synthesis that results in enhanced ovarian androgen production. An alteration in cortisol metabolism resulting in enhanced adrenal androgen production. It must be accepted, however, that each of these are artificial stating points to our understanding of the metabolic–ovarian–pituitary circuitry being closely interrelated. The first recognition of an association between glucose intolerance and hyperandrogenism was made by Achard & Thiers (1921) and was called ‘the diabetes of bearded women’. The association between increased insulin resistance and PCOS is now well recognized. Insulin resistance is defined as a reduced glucose response to a given amount of insulin. There are several mechanisms contributing to the state of insulin resistance: peripheral target tissue resistance, decreased hepatic clearance, or increased pancreatic sensitivity. Studies with the euglycaemic clamp technique indicate that insulin resistance is a common feature of the syndrome, and both obese and nonobese women with the syndrome are more insulin-resistant and hyperinsulinaemic than age- and weight-matched normal women (Chang et al., 1983; Dunaif et al., 1989, 1992). However, obese PCOS women had significantly decreased insulin sensitivity compared with nonobese PCOS women (Dunaif, 1995). For example, Morales et al. (1996) demonstrated reduced insulin sensitivity in lean PCOS compared with lean controls,