European Journal of Endocrinology (2006) 154 763–775 ISSN 0804-4643 INVITED REVIEW Insulin-sensitizing agents in polycystic ovary syndrome Renato Pasquali and Alessandra Gambineri Unite´ Operativa di Endocrinologia, Dipartimento di Medicina Interna, Universita` Alma Mater Studiorum, Azienda Policlinico S. Orsola-Malpighi, Via Massarenti 9, 40138 Bologna, Italy (Correspondence should be addressed to R Pasquali; Email: [email protected]) Abstract Insulin-sensitizing agents have been recently proposed as the therapy of choice for polycystic ovary syndrome (PCOS), since insulin resistance and associated hyperinsulinemia are recognized as important pathogenetic factors of the syndrome. Moreover, since almost all obese PCOS women and more than half of those of normal weight are insulin resistant, and therefore present some degree of hyperinsulinemia, the use of insulin sensitizers should be suggested in most patients with PCOS. Insulin sensitizer treatment has been associated with a reduction in serum androgen levels and gonadotropins, and with an improvement in serum lipids and in prothrombotic factor plasminogen- activator inhibitor type 1, whatever the insulin sensitizer used. This therapy has also been associated with a decrease in hirsutism and acne, and with a regulation of menses and an improvement of ovulation and fertility. Notable improvements in all these parameters have also been described after a change in lifestyle approach, particularly in the presence of obesity. Lifestyle interventions should therefore be combined with insulin sensitizers in PCOS when obesity is present. European Journal of Endocrinology 154 763–775 Introduction hyperandrogenism in the majority of PCOS women, particularly when obesity is present (5, 6). On the other Polycystic ovary syndrome (PCOS), one of the most hand, obesity by itself may favor ovarian hyperandro- common causes of ovulatory infertility, affects 4–7% of genism in a subset of PCOS women, by mechanisms that women (1). Since the first description by Stein and may be partly independent of the primary role of excess Leventhal in 1935 (2), this syndrome has, over the years, circulating insulin (7, 8), provided that genetic or other been defined in different ways. In 1990 the National still undefined factors are present (9). In most PCOS Institutes of Health (NIH) established new diagnostic patients, however, obesity probably represents a second- criteria for this disorder, which were based on the ary additional pathogenetic condition, capably of presence of hyperandrogenism and chronic oligo- amplifying primary factors leading to exaggerated anovulation, with the exclusion of other causes of ovarian androgen secretion, such as an increased hyperandrogenism such as adult-onset congenital luteinizing hormone (LH) stimulation (5, 7, 10). adrenal hyperplasia, hyperprolactinemia, and andro- Regardless of the causative factors, there is no doubt gen-secreting neoplasms (3). More recently, a consensus that the phenotype of a woman affected by PCOS is conference held in Rotterdam in 2003 re-examined the fundamentally related to two main factors, namely the 1990 criteria and agreed to the appropriateness of hyperandrogenic and the insulin-resistant hyperinsuli- including ultrasound morphology of the ovaries as a nemic states (Fig. 1). further potential criteria to define PCOS (4). On the other Treatment of androgen excess can be pursued by hand, it was also established that at least two of the reducing androgen production rates from the ovaries following criteria are sufficient for diagnosis: oligo and/or and the adrenals or, conversely, by counteracting anovulation, clinical and/or biochemical signs of androgen function at receptor levels. An alternative is hyperandrogenism and polycystic ovaries at ultrasound. represented by therapeutic procedures aimed at improv- Despite this effort, however, the definition still appears to ing insulin resistance and, consequently, hyperinsuli- be incomplete, since it does not consider characteristics nemia. As reported above, this method exploits the frequently present in PCOS, particularly insulin resist- pathophysiological role of excess insulin in determining ance, hyperinsulinemia and obesity, the key features of increased androgen secretion and activity. The improve- the metabolic syndrome (5). Insulin resistance and ment of insulin resistance and the decrease of insulin associated hyperinsulinemia are also now recognized concentration and action can be achieved in different as important pathogenetic factors in determining ways: (i) by reducing body weight with lifestyle q 2006 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.02156 Online version via www.eje-online.org Downloaded from Bioscientifica.com at 09/30/2021 12:05:43PM via free access 764 R Pasquali and A Gambineri EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 154 Figure 1 Pathophysiological role of hyperan- drogenism and the insulin resistance-hyper- insulinemic state in determining the PCOS phenotype. modifications, if overweight or if obesity is present; (ii) whilst it is uncommon in their normal-weight counter- by using insulin-sensitizing agents; (iii) by using parts (5, 12). In any case, the prevalence rate for antiandrogens. It has in fact been demonstrated that impaired glucose tolerance in the population of obese long-term treatment with antiandrogens may improve PCOS subjects appears to be higher than that reported insulin sensitivity in both normal weight and obese in population-based studies on the incidence of glucose PCOS women presenting an insulin-resistant state (6). intolerance in women of similar ages (13), although In addition, there is increasing evidence that ovulation epidemiological studies are lacking. These findings and fertility rate can also be significantly improved by indicate that obesity may contribute to determining insulin sensitizers, often regardless of changes in the insulin-resistant state and may impair glucose circulating insulin levels. This opens up the intriguing tolerance in PCOS. Although insulin resistance seems possibility that these compounds can exert a direct to play a determining role in the development of action at ovarian level, and introduces new routes in the diabetes, the presence of insulin resistance does not treatment of infertility in PCOS. immediately imply a concomitant alteration of glucose This short review is focused on the role of insulin tolerance. In fact, most obese insulin-resistant PCOS sensitizers, given alone or combined with other women still have normal glucose tolerance. However, it therapies, on hyperandrogenism, metabolism, body has recently been found that PCOS women with composition, menses abnormalities and spontaneous impaired glucose tolerance or type 2 diabetes are and stimulated ovulation in PCOS. significantly more insulin resistant and hyperinsuline- mic than those with normal glucose tolerance, regardless of the presence of obesity (11). It has also PCOS, obesity, insulin resistance and the been reported that the development of states of glucose metabolic syndrome intolerance can be predicted to a certain extent, since there are early markers such as low birth weight and This metabolic syndrome is a consistent feature of the early menarche age in PCOS, as in the general majority of obese women with PCOS, although it can population (14, 15). Prospective studies in which also be detected in many normal-weight affected women PCOS women were followed for approximately 10 (5, 6). Obese women with PCOS, particularly those with years have also found that insulin resistance tends to the abdominal obesity phenotype, are usually more worsen over time, together with an increment of insulin insulin resistant and more hyperinsulinemic than and c-peptide response to an oral glucose challenge, and their normal-weight counterparts (5, 7). Both fasting that, in several cases, glucose intolerance appears (16). and glucose-stimulated insulin concentrations are in Taken together, these findings strongly support the role fact significantly higher in obese than in non-obese of insulin resistance in the development of altered PCOS subgroups. Accordingly, studies examining insu- glucose tolerance states in PCOS women. lin sensitivity by using different methods, such as the Studies examining the extent of insulin secretion in euglycemic hyperinsulinemic clamp technique, the relation to insulin sensitivity have demonstrated that a frequent-sample intravenous glucose test and the insulin b-cell dysfunction may coexist with insulin resistance in test have further demonstrated that obese PCOS women obese PCOS women. In particular, a defective early have significantly lower insulin sensitivity than their phase b-cell insulin secretion and a reduced insulin non-obese PCOS counterparts and, therefore, a more secretory response to boluses or graded intravenous severe insulin-resistant state (see extensive reviews in infusion of glucose, when expressed in relation to the refs 5, 7, 8). degree of insulin resistance, have been reported in these Glucose intolerance is present in as many as 30–40% women (16, 17). Notably, these findings have been of obese PCOS women in the United States (5) and described in Hispanic-American insulin-resistant obese probably to a lower extent in those living in Europe (11), PCOS women, but not in PCOS women living in Europe www.eje-online.org Downloaded from Bioscientifica.com at 09/30/2021 12:05:43PM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 154 Insulin-sensitizing agents in PCOS