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Editorial |
Department of Obstetrics, Gynecology and Reproductive Biology Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Robert Barbieri M.D., Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. E-mail: rbarbieri{at}partners.org.
A 30-yr-old nulligravida woman presents with hirsutism, amenorrhea, obesity, and infertility. She desires to become pregnant as soon as possible. Findings on physical examination include a blood pressure of 120/82 mm Hg, body mass index (BMI) of 41 kg/m2, and waist circumference of 99 cm (39 in.). She has acanthosis nigricans, a Ferriman-Gallwey hirsutism score of 13, and no virilization. Her hysterosalpingogram and her partner’s semen analysis are normal. A diagnosis of polycystic ovary syndrome (PCOS) is made.
Would You Prescribe Clomiphene or Metformin to Treat Her Anovulatory Infertility?
PCOS and infertility are common problems affecting 6 and 8% of women of reproductive age, respectively (1, 2). Anovulation or oligo-ovulation is the cause of infertility in about 25% of cases (3). In turn, PCOS is the most common cause of anovulatory infertility (4).
For women with PCOS and infertility and a normal BMI, the initial approach to induction of ovulation includes the choice of clomiphene or metformin. The ovulation-inducing properties of clomiphene and metformin reflect the underlying pathophysiology of PCOS, in which both reproductive axis abnormalities (increased GnRH pulse frequency and increased LH) (5) and metabolic derangements (insulin resistance, metabolic syndrome, excess visceral fat activity, and endothelial inflammation) (6) contribute to the anovulation and infertility. Clomiphene likely improves ovulation in women with PCOS by partially blocking estradiol negative feedback on FSH secretion, resulting in increased pituitary gonadotropin secretion (7). Metformin probably improves ovulation in women with PCOS by reducing gluconeogenesis, improving insulin sensitivity, and reducing ovarian androgen production (8, 9).
The discovery that metformin is effective in inducing ovulation in women with PCOS represents a major advance in clinical endocrinology (10). Placebo-controlled studies clearly indicate that metformin is superior to placebo for inducing ovulation in infertile women with PCOS (11). A Cochrane review of clinical trials comparing metformin vs. placebo for ovulation induction in women with PCOS reported that metformin is more effective than placebo in achieving ovulation with an odds ratio of 3.9 (confidence interval 2.3–6.7). The authors (11) of the Cochrane review concluded that metformin is an effective treatment for anovulation in women with PCOS, and "Its choice as a first line agent seems justified, ... "
The relative clinical efficacy of clomiphene vs. metformin remains controversial. In the largest head-to-head study of clomiphene vs. metformin, Legro et al. (12) reported that clomiphene treatment resulted in significantly greater live birth rates than metformin (23 vs. 7%) (Table 1
). Positive features of this trial include large sample size, multiple centers, live birth as a primary outcome, and National Institutes of Health sponsorship and coordination. The authors concluded that clomiphene is superior to metformin as first-line therapy for infertility in women with PCOS.
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In contrast to the report by Legro et al. (12), multiple small studies report that clomiphene and metformin treatment is associated with similar ovulation and pregnancy rates (14, 15, 16). For example, in the study reported in this issue, Palomba et al. (14) report that 6-month clomiphene or metformin treatment resulted in cumulative pregnancy rates of 49 and 63%, respectively (P = 0.2). In this study clomiphene was initiated at a standard dose of 50 mg daily for 5 d with increases up to 250 mg daily for 5 d if ovulation did not occur. In contrast, in the study reported by Legro et al. (12), the maximal dose of clomiphene was 150 mg daily for 5 d. In the Palomba et al. (14) study, metformin was administered at a dose of 850 mg twice daily as a rapid release formulation, a dose slightly lower than the target dose of 2000 mg administered as an extended release formulation in the Legro et al. (12) study. In a clinical trial previously reported by Palomba et al. (15), nonobese women with PCOS and infertility treated with metformin had a greater live birth rate than those treated with clomiphene (58 vs. 19%). The different results among these clinical studies have not been adequately explained. Patient heterogeneity, including differences in genotype, BMI, and circulating androgen levels, may account for some of differences. The mean BMI of the subjects in the studies reported by Palomba (14, 15) and Legro (12) et al. were vastly different: 27 and 36 kg/m2, respectively. However, it is unlikely that a difference in BMI is the main cause of the heterogeneity in the reported findings. In the Legro et al. (12) study, when the results were stratified by BMI, clomiphene remained superior to metformin across all BMI strata (Table 1
). Differences in genotype might account for some of the heterogeneity. The Legro et al. (12) study included subjects from a wide range of ethnic and racial backgrounds, whereas the Palomba et al. (14, 15) studies were performed in a largely homogenous Italian population. Another possibility is that there was significant heterogeneity in drug compliance among the subjects in the different trials. The discordant results from these trials remain perplexing, but for the case subject presented previously, is it safe to treat an infertile patient with a BMI of 41 kg/m2 with any ovulation inducing medication?
The obesity epidemic is increasing the prevalence of women with the combination of morbid obesity, anovulation, and infertility. For the young patient with morbid obesity, immediate ovulation induction with clomiphene or metformin may not be the wisest clinical intervention. Obese women are at increased risk for many adverse pregnancy outcomes, including congenital malformations, gestational diabetes, macrosomia, preeclampsia, and increased risk of cesarean delivery (17). The overall health of the woman may be best enhanced by first completing an endocrine evaluation to assess the metabolic status of the patient. After this evaluation, the patient should be guided to achieve a healthier weight before attempting pregnancy.
The endocrine workup should include a glucose tolerance test to assess the patient for the presence of undiagnosed diabetes or impaired glucose tolerance (18). Of obese women with PCOS, 10% have undiagnosed diabetes, and 35% have impaired glucose tolerance (19). A fasting glucose alone is not sufficiently sensitive to detect women with PCOS at risk for impaired glucose tolerance (20). However, a fasting glucose with triglyceride and high-density lipoprotein-cholesterol measurements will help determine if the patient has the metabolic syndrome. If appropriate, TSH, prolactin, and androgens measurements, e.g. testosterone and dehydroepiandrosterone sulfate, may be warranted. Before ovulation induction, genetic counseling may be useful to appraise the patient of the complex genetic testing options available both before and during pregnancy.
For the young morbidly obese patient with anovulation and infertility, 6- to 18-month therapy with a focus on diet and improvement in metabolic condition may be the best approach before inducing ovulation with clomiphene or metformin. Initial pilot studies indicate that lifestyle changes, including diet (21), weight loss medications (22), and, when appropriate, bariatric surgery (23), may all be helpful in achieving a healthy weight and improving metabolic balance. Weight loss in the range of 15% body mass has improved spontaneous ovulation and pregnancy rates in women with PCOS (24). Weight loss also improves the efficacy of drugs that induce ovulation (25). For the patient described previously, the presence of morbid obesity should trigger a concerted effort to achieve a healthy body weight before prescribing any medication to induce ovulation. Rather than instituting ovulation induction therapy with either clomiphene or metformin, the patient should be referred for consultation for a thorough assessment of metabolic status and the development of a weight loss plan.
Footnotes
Abbreviations: BMI, Body mass index; PCOS, polycystic ovary syndrome.
Received June 22, 2007.
Accepted June 27, 2007.
References
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