European Journal of Obstetrics & Gynecology and Reproductive Biology 91 (2000) 135–141 www.elsevier.com / locate / ejogrb Review Correction of hyperinsulinemia in oligoovulatory women with clomiphene-resistant polycystic ovary syndrome: a review of therapeutic rationale and reproductive outcomes a, a b * E. Scott Sills M.D. , Mark Perloe M.D. , Gianpiero D. Palermo M.D. a Georgia Reproductive Specialists, Atlanta, GA, USA b Center For Reproductive Medicine and Infertility, Weill Medical College of Cornell University, New York, NY, USA Accepted 27 November 1999 Abstract Polycystic ovary syndrome (PCOS) describes a convergence of chronic multisystem endocrine derangements, including irregular menses, hirsutism, obesity, hyperlipidemia, androgenization, large and cystic-appearing ovaries, insulin resistance and subfertility. Few PCOS patients exhibit all of these features, and often only one sign or symptom is evident. The sequelae of PCOS reach beyond reproductive health, as women affected with PCOS have increased relative risks for myocardial infarction, hypertension, ischemic heart disease, thromboembolic disease and diabetes. Although the adverse health consequences associated with PCOS are substantial, unfortunately most women are not aware of these risks. Indeed, in infertility practice such concerns are secondary as most patients are referred for treatment specifically to achieve a pregnancy. Impairments in insulin metabolism appear central to the physiologic cascade of PCOS, yet clomiphene therapy fails to remedy this defect. Several investigators have described satisfactory reproductive outcomes for PCOS patients treated with oral insulin-lowering agents. In this report, we outline a diagnostic and therapeutic approach for women with PCOS refractory to clomiphene with attention to the underlying insulin imbalance associated with impaired fertility.  2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Polycystic ovary; Infertility; Metformin; Insulin resistance 1. Introduction: clomiphene resistance defined treatment cycles [2]. Continued clomiphene administration beyond this time, even at high dosage levels, is associated While a formal classification system for PCOS patient with only marginal enhancement of the cumulative preg- response following clomiphene therapy has not been nancy rate. Therefore, a patient who has failed to conceive developed, a thorough review of a patient’s prior despite three to four ovulatory clomiphene cycles is clomiphene treatment outcomes is needed to recognize unlikely to respond to this medication and should be ineffective therapy. Ovulation induction with clomiphene considered refractory to clomiphene. has been extensively studied; clinical experience has Since close relationships have been demonstrated among demonstrated this agent will elicit a safe, ovulatory re- hyperinsulinemia, dysfunctional carbohydrate metabolism sponse in an impressive proportion of women who use it and PCOS [3], the proportion of PCOS patients benefitting [1]. Importantly, over 80% of women who successfully from initial fasting insulin screening may be considerable. achieve a pregnancy with clomiphene do so within three Such screening could identify a subset of women with a predisposition to clomiphene resistance. In this setting, the application of pre-diabetic management principles directly *Corresponding author. Suite 270, 5445 Meridian Mark Rd, Atlanta, addresses insulin resistance and can restore normal ovula- GA 30342, USA. E-mail address: dr.sills@ivf.com (E.S. Sills) tion for many women [4]. 0301-2115 / 00 / $ – see front matter  2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0301-2115(99)00287-0