Background
A syndrome with extensive variability
PCOS (also known as Stein-Leventhal syndrome) is associated with features of insulin resistance (obesity, acanthosis nigricans); hyperandrogenism (hirsutism, elevated androgen levels), and oligomenorrhea leading to anovulatory bleeding and infertility. PCOS has a prevalence of approximately 5% to 10% in women of reproductive age. Patients may have high serum concentrations of androgenic hormones, such as testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEAS). However, much variation exists clinically and a specific patient may have normal androgen levels.3 In addition, despite the syndrome’s name, not all women with PCOS have ovarian cysts.
The features of peripheral insulin resistance, hyperinsulinemia, oligomenorrhea, and infertility can be magnified in the presence of obesity. Insulin resistance is not due to defects in insulin binding to the insulin receptors; rather, it involves post-binding signaling pathways. The elevated insulin levels may have gonadotropin-augmenting effects on ovarian function.3
Numerous comorbidities play a role
There is a great deal of frustration for both physicians and patients regarding the various comorbidities associated with this syndrome. For patients, the problems include androgenic features, menstrual irregularities, and infertility. For clinicians, however, the concerns include cardiovascular risks4 (obesity, lipid abnormalities, elevated C-reactive protein and leptin levels, blood pressure changes), hyperinsulinemia, insulin resistance, and the theoretical risks for endometrial hyperplasia due to a hyperestrogenic state.
NIH criteria is used for diagnosis in trials
Although there are no definitive consensus criteria for the diagnosis of PCOS, the 1990 National Institutes of Health (NIH) criteria and its revision in 2003, the Rotterdam Criteria, have been used to make the diagnosis in clinical trials. Most trials however use the NIH criteria as there is disagreement regarding the Rotterdam Criteria.
The NIH criteria use the following for the diagnosis of PCOS:
- oligomenorrhea
- hyperandrogenism (clinical or laboratory evidence), and
- absence of other endocrine disorders (congenital adrenal hyperplasia, hyperprolactinemia, thyroid dysfunction, and androgen secreting tumors).
In reviewing the literature, most clinicians and researchers have noted that PCOS has been associated with various outcomes such as elevated body mass index (BMI),5 waist-to-hip ratio,5,6 fasting blood glucose,7 insulin levels,7 testosterone levels,8 androstenedione levels,8 DHEAS levels,9 hirsutism scores,9 lipids,5 blood pressure,9 luteinizing hormone to follicle-stimulating hormone ratio (LH/FSH),9 C-peptide,5 and leptin,6 as well as decreased ovulatory and pregnancy rates.4,5,10
Metformin/TZDs are used, but what about the evidence?
Both metformin and the TZDs (glitazones) including troglitazone—which was withdrawn from the market—pioglitazone, and rosiglitazone, are antidiabetic agents that also work as insulin sensitizers. These agents—especially metformin—are widely used by primary care physicians and specialists to treat the clinical and biochemical features of PCOS. However, the evidence-based data supporting this use is lacking. Although much research has been done on this topic, most published trials are of less than ideal quality and involve methodological issues. Often times they are nonrandomized, not controlled, involve a low number of subjects, provide no long-term follow up, and use nonstudy agents or ancillary treatments that were not randomized and could yield confounding results.
Objectives
Our primary objective was to assess whether there is evidence to support the use of metformin or TZDs, as well as to suggest any differences among the drugs. The secondary objective was to ascertain if, and to what extent, the studied drugs affected the studied parameters.
Methods
Search Strategy
We searched MD Consult, PubMed, Medline, Ovid, and Google Scholar through January 2007 with the following terms: “PCOS and metformin,” “PCOS and Glucophage,” “PCOS and troglitazone,” “PCOS and pioglitazone,” “PCOS and rosiglitazone,” “PCOS and thiazolidenediones.” These searches were also done by substituting “+” instead of the word “and,” as well as by using full form of the abbreviation PCOS—polycystic ovarian syndrome.
The following limits were placed on the search: randomized controlled trials, English language, human, and female subjects. We also searched articles from reference lists and made additional efforts to contact clinicians and researchers in this field.
Selection criteria
Our search resulted in 115 articles. From these articles, we included only those trials that:
- Used the NIH 1990 criteria for the diagnosis of PCOS
- Studied the effect of any of the following drugs: metformin, troglitazone, rosiglitazone, or pioglitazone
- Did not use or advocate adjunctive therapy—ie, diet or exercise
- Were randomized and controlled (based on a review of the methods section).
We also excluded studies that permitted confounding or concomitant treatments if it made it difficult to estimate the true effect of the medications studied.
This criteria resulted in 33 trials and ultimately 31 trials were included in the analysis (23 metformin, 2 rosiglitazone, 1 pioglitazone, 5 troglitazone) with a total of 1892 patients. Two metformin trials were unobtainable.