Special Feature
Use of Insulin Sensitizing Agents in the Treatment of Polycystic Ovary Syndrome
By Sarah L. Berga, MD
We recognize that diagnosis determines treatment, but, in aiming to expeditiously care for patients, there is a tendency to become reductionistic about diagnostic categories. In the past, this tendency was fueled by a relative lack of specific treatments for specific conditions. Previously, this was indeed the case for anovulation. Enter now the era of orally active agents that increase insulin action. Should these agents be routinely used for women with polycystic ovary syndrome (PCOS)? If so, what criteria will need to be met to make the diagnosis of PCOS? If not all women with PCOS are to be treated with these agents, what criteria will identify the subset of women with PCOS who should receive these agents? Clearly, there is a burgeoning need to consolidate the diagnosis of PCOS for women with oligomenorrhea and suspected anovulation, so that the appropriate treatment strategies can be considered.
Women with PCOS frequently manifest truncal obesity, hypertriglyceridemia, and cosmetic sequelae in addition to anovulation. While it has been argued that all women with PCOS have insulin resistance, there is clearly a spectrum of severity and thin women with PCOS do not uniformly display insulin resistance (Holte J. Baillieres Clin Endocrinol Metab 1996;10:221-247). The presence of insulin resistance is clinically important, however, as it apparently predisposes to ovarian hyperstimulation syndrome when exogenous gonadotropins are used to induce ovulation (Fulghesu A, et al. J Clin Endocrinol Metab 1997;82:644-648), gestational diabetes when conception occurs (Holte J, et al. J Clin Endocrinol Metab 1998;83:1143-1150), frank diabetes in later life, and an excess risk of cardiovascular disease (Talbott E, et al. Arterioscler Thromb Vasc Biol 1995;15:821-826). Prior to the introduction of oral agents that increase insulin action, the best way to increase insulin action and decrease hyperinsulinemia was to have women with PCOS lose weight through diet and exercise. The difficulty of sustaining lifestyle interventions is legion and compounded in PCOS by a metabolic propensity to gain weight due to calorie efficiency (Robinson S, et al. Clin Endocrinol 1992;36:537-543). It is critical, then, for women with PCOS to do all that they can to maintain an appropriate weight, because losing weight may be particularly difficult. Further, excess weight aggravates insulin resistance, which, in turn, exacerbates androgen secretion, anovulation, and CVD risk. Given these considerations, it is no wonder that the introduction of orally active insulin sensitizing agents has been heralded as a therapeutic breakthrough that may replace or be used concomitantly with weight loss as a strategy for improving outcomes in PCOS. Although the actual efficacy of agents, such as metformin and troglitazone, in the treatment of PCOS remains to be determined in larger clinical trials, early results show promise. For instance, just this month, Nestler and colleagues (N Engl J Med 1998;338:1876-1880) showed that the use of metformin greatly increased the efficacy of clomiphene ovulation induction in women with PCOS.
Given the costs and risks of these agents, however, it is clearly preferable that their use be restricted to those women with PCOS who "need" to use them. At present, we do know what criteria should be used to determine which women with PCOS should take these agents. A fasting blood glucose will certainly be too insensitive and is meant to identify those who are hyperglycemic, not just hyperinsulinemic. An elevated glycosylated hemoglobin would certainly make one want to obtain a three-hour glucose tolerance test, but must criteria for impaired glucose tolerance be met before instituting metformin or troglitazone use? If there is no good and feasible test for detecting the subtle impairments in insulin action characteristic of many women with PCOS, should all women with anovulation and hyperandrogenism be given one of these agents on an empiric basis? If so, what type of monitoring should accompany their use? Furthermore, which agent is best? The current argument focuses on whether metformin or troglitazone is best, or if both should be used because they each have a different mechanism of action. By far, the trickiest question of all is whether thin women with PCOS, without obvious evidence of hyperinsulinemia, should receive these agents on a chronic basis, even when conception is not being sought. Certainly, no one is currently advocating their use during pregnancy, so, as soon a pregnancy occurs, they will have to be stopped. Should these agents be used only when conception is being actively sought, or is it appropriate to institute concurrent use of troglitazone and oral contraceptives, for instance? There are obviously more questions than answers at this moment, but it seems likely that, rapidly, we may begin to have preliminary information to guide our use. One outcome seems certain, however. In the near future, it will be mandatory to make a diagnosis as to the cause of anovulation or oligomenorrhea before starting therapy. In short, women with hyperandrogenic anovulation require special attention and it would be misguided not to be fully aware of their metabolic and endocrine status when deriving a treatment plan and providing advice about well-care.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content