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Background The polycystic ovary syndrome is a common cause of infertility. Clomiphene and insulin sensitizers are used alone and in combination to induce ovulation, but it is unknown whether one approach is superior.
Methods We randomly assigned 626 infertile women with the polycystic ovary syndrome to receive clomiphene citrate plus placebo, extended-release metformin plus placebo, or a combination of metformin and clomiphene for up to 6 months. Medication was discontinued when pregnancy was confirmed, and subjects were followed until delivery.
Results The live-birth rate was 22.5% (47 of 209 subjects) in the clomiphene group, 7.2% (15 of 208) in the metformin group, and 26.8% (56 of 209) in the combination-therapy group (P<0.001 for metformin vs. both clomiphene and combination therapy; P=0.31 for clomiphene vs. combination therapy). Among pregnancies, the rate of multiple pregnancy was 6.0% in the clomiphene group, 0% in the metformin group, and 3.1% in the combination-therapy group. The rates of first-trimester pregnancy loss did not differ significantly among the groups. However, the conception rate among subjects who ovulated was significantly lower in the metformin group (21.7%) than in either the clomiphene group (39.5%, P=0.002) or the combination-therapy group (46.0%, P<0.001). With the exception of pregnancy complications, adverse-event rates were similar in all groups, though gastrointestinal side effects were more frequent, and vasomotor and ovulatory symptoms less frequent, in the metformin group than in the clomiphene group.
Conclusions Clomiphene is superior to metformin in achieving live birth in infertile women with the polycystic ovary syndrome, although multiple birth is a complication. (ClinicalTrials.gov number, NCT00068861
[ClinicalTrials.gov]
.)
Women with this syndrome have hyperandrogenism,10 morphologic changes in the ovary (polycystic),10 inappropriate gonadotropin secretion (elevated levels of circulating luteinizing hormone),11 and insulin resistance with accompanying compensatory hyperinsulinemia.12 Targeting these metabolic abnormalities has been noted to improve ovulation and fertility in women with this syndrome.13,14,15,16,17 Results from small head-to-head trials have suggested that the efficacy of treatment with insulin sensitizers such as metformin (alone or in combination with clomiphene citrate) is equal or superior to that of clomiphene alone for infertility.13,16,17
We designed a trial to test the hypothesis that treatment of women with the polycystic ovary syndrome with extended-release metformin is more likely to result in a live birth than is treatment with clomiphene citrate and that the combination of the two therapies will result in the highest live-birth rate.
Methods
Study Design
We have previously described the rationale for choosing live birth as the primary outcome,18 the power analysis and main statistical methods,19 the use of infertility screening in the study,20 and the study design and baseline characteristics of the subjects.21
The institutional review board at each center approved the protocol, and all subjects gave written informed consent. All subjects had received the diagnosis of the polycystic ovary syndrome, which was defined as oligomenorrhea (with a history of no more than eight spontaneous menses per year) and hyperandrogenemia (with an elevated testosterone level documented within the previous year in an outpatient setting on the basis of local laboratory results, with a predetermined cutoff level set by the principal investigator at each study site). Subjects were excluded if they had hyperprolactinemia, congenital adrenal hyperplasia, thyroid disease, or other causes of amenorrhea, including premature ovarian failure. Clinically suspected Cushing's syndrome and androgen-secreting neoplasm were additional exclusion criteria.21
We randomly assigned 626 infertile women with the polycystic ovary syndrome to one of three study groups by means of an interactive voice system. The assignments were stratified according to the study site and the presence or absence of previous exposure to either of the study drugs.21 Subjects with other causes of infertility were excluded on the basis of documentation of a normal uterine cavity and at least one patent fallopian tube; analysis of the semen of each woman's current partner was performed within 1 year before participation in the study, and a sperm concentration of at least 20 million per milliliter was required.21 All subjects were in good health with no major medical disorders.21
Study Drugs
We used extended-release metformin because of its increased tolerability and proven efficacy in the treatment of type 2 diabetes.22,23 Extended-release metformin (Glucophage XR) plus identical placebo were provided by Bristol-Myers Squibb. Overencapsulated clomiphene citrate tablets (purchased from Teva Pharmaceuticals) and matching placebo capsules were packaged and tested by a commercial pharmacy supply company (CTS) specifically for the study. Neither manufacturer had any other role in the study.
Baseline laboratory testing was performed after the subjects had fasted overnight. All specimens were analyzed in a core laboratory.21 In subjects without recent menses, withdrawal bleeding was induced with a course of oral medroxyprogesterone acetate before the initiation of study medication. Each subject received a monthly medication package consisting of bottle M (metformin in 500-mg tablets or matching placebo) and blister pack C (clomiphene in 50-mg tablets or matching placebo). The two drugs were begun concurrently. Subjects gradually increased the dose of the study drug in bottle M until reaching the maximum dose of four tablets (two tablets twice a day). Subjects took one tablet a day from blister pack C for 5 days, beginning on day 3 of menses; this dose was maintained if adequate ovulation was documented. However, in subjects who had no response or a poor response, the dose was increased by one tablet a day on a treatment-cycle basis (either after 5 weeks of anovulation or after a menses until the maximum dose of three tablets per day was reached).
After the baseline visit, subjects returned each month for a visit with a limited physical examination, urine pregnancy test, and repeated fasting blood tests.21 Subjects were instructed to have regular intercourse every 2 to 3 days and to keep a diary recording intercourse, vaginal bleeding, and symptoms. The progesterone levels in all subjects were measured weekly or every other week in local laboratories in order to document ovulation.21 If two consecutive measurements showed elevated levels of progesterone (above 5 ng per milliliter [16 nmol per liter]), a weekly pregnancy test was administered until a positive result or menses occurred. Induction of withdrawal bleeding with progestin was scheduled at the discretion of the principal investigator at each site. Ultrasonography for follicular and endometrial response was not included in the protocol, and ovulation triggering with human chorionic gonadotropin and intrauterine insemination were not permitted.
Subjects were treated for up to six cycles, or 30 weeks. All study medication was discontinued if a pregnancy test was positive. Pregnant subjects were followed until ultrasonography documented fetal viability and were then referred for prenatal care. Investigators reviewed all obstetrical records to obtain data on birth outcomes. We did not collect data on the use of other medications during pregnancy.
Outcomes
The primary outcome of the trial was the rate of live births. Secondary outcomes included the rate of pregnancy loss, singleton birth, and ovulation (a serum progesterone level above 5 ng per milliliter during a cycle). A serious adverse event was defined as any event that was fatal, immediately life-threatening, or severely or permanently disabling; an event that required or prolonged hospitalization; an overdose (intentional or accidental); a congenital anomaly; pregnancy loss after 12 weeks of gestation; or an event that was deemed to be serious by the principal investigator at each site.
Data Management
All data entry, data management, and analyses were performed at the Data Coordinating Center at the Duke Clinical Research Institute. Subjects were enrolled in the study from November 2002 to December 2004. The last conception was in June 2005, the last subject finished medication in August 2005, and the last birth was reported in February 2006. Data were analyzed according to the intention-to-treat principle.
Statistical Analysis
We assumed a dropout rate of 15% and the following rates of live birth: 45% in the combination-therapy group, 30% in the metformin group, and 25% in the clomiphene group. On the basis of these assumptions, we needed to enroll 678 subjects19 for the study to have a power of 80% with a type I error rate of 0.05 to detect a 15% absolute difference in live-birth rates for the following two primary comparisons: the combination-therapy group versus the next best group and the metformin group versus the clomiphene group.
Because of limitations in the supply of metformin and matching placebo, the number of subjects was reduced to 626 after the data safety and monitoring board reviewed blinded data in November 2004. Because the live-birth rate was lower than projected, the final number of subjects provided adequate power (
80%) to detect the same 15% absolute difference in live-birth rates for the original two primary comparisons because of the increased power for detecting the same difference in proportions when the magnitude of the proportion was decreased.
Either a chi-square test or Fisher's exact test was used for testing differences among the three study groups for categorical variables. A Wilcoxon rank-sum test was used for testing differences between two groups, and a Kruskal–Wallis test was used for testing differences among groups of three or more. Kaplan–Meier curves were used for time-to-event analyses. Generalized estimating equations were used for analysis of the ovulation rate to account for correlation of multiple ovulation cycles for each subject. Post hoc stratification of outcomes was performed on the basis of the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) and presence or absence of previous exposure to medication. All analyses were performed with SAS software, version 8.2 (SAS Institute).
Results
Study Population
There were no significant differences in baseline variables among the study groups (Table 1).21 The numbers of subjects who dropped out of the study were 55 of 209 (26.3%) in the clomiphene group, 72 of 208 (34.6%) in the metformin group, and 49 of 209 (23.4%) in the combination-therapy group (P=0.07 for the metformin group vs. the clomiphene group, and P=0.01 for the metformin group vs. the combination-therapy group) (Figure 1). The reasons for dropout were similar among the three groups, except that the metformin group had a higher rate of loss to follow-up than did the other two groups (P=0.03 for the comparison with the clomiphene group, and P=0.01 for the comparison with the combination-therapy group).
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The rate of live birth was significantly lower in the metformin group than in the clomiphene group and the combination-therapy group (P<0.001 for both comparisons), and there was no significant advantage of the combination therapy over clomiphene (Table 2 and Figure 2A). However, independently of treatment, subjects with a BMI below 30 had a significantly higher rate of live births than did women whose BMI was 30 or more (P<0.001 by univariate analysis) (Figure 2B). The relationship between treatment and live birth was similar in post hoc analyses of subgroups stratified according to BMI (<30, 30 to 34, and 35) (see Table 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org) and according to previous treatment (Table 2 of the Supplementary Appendix).
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The rate of ovulation was significantly higher in the combination group than in either of the single-agent groups (Table 2). Over the course of the study, the mean (±SD) number of ovulations per subject was 2.22±1.87 in the clomiphene group, 1.43±1.72 in the metformin group, and 2.80±2.04 in the combination-therapy group (P<0.001 for the comparisons of the clomiphene and combination-therapy groups with the metformin group). However, as previously noted, the differences in ovulation rates did not translate into an increase in the live-birth rate among subjects receiving combination therapy. Rates of conception and live birth per cycle in which ovulation occurred and per subject who ovulated were significantly higher in the clomiphene group and the combination-therapy group than in the metformin group. All multiple pregnancies occurred in either the clomiphene group or the combination-therapy group, although rates were low, and the differences among the three groups were not significant (P=0.56 for the metformin group vs. the clomiphene group, and P=1.0 for the metformin group vs. the combination-therapy group).
Over the course of the study, there were no documented ovulations in 52 of 209 women (24.9%) in the clomiphene group, 93 of 208 (44.7%) in the metformin group, and 35 of 209 (16.7%) in the combination-therapy group (P<0.001 for both comparisons with the metformin group). There was no significant linear effect of time on the rate of ovulation in the metformin group and the clomiphene group, but there was such an effect on ovulation and live birth in the combination-therapy group (P=0.002 and P=0.05, respectively).
Other Treatment Effects
We analyzed metabolic and hormonal effects associated with the medications by comparing baseline data with data recorded at the last study visit before pregnancy was documented or at the final study visit, whichever came first (Table 3). As compared with the baseline values, the clomiphene group had a significant increase in BMI (P=0.05), levels of insulin (P=0.01), insulin resistance as determined by homeostasis model assessment (HOMA) (P=0.01), and levels of sex hormone–binding globulin (P<0.001) and a corresponding decrease in the free androgen index (P<0.001). Conversely, the metformin group had a significant decrease in BMI and total testosterone and a significant increase in sex hormone–binding globulin levels, with a corresponding decrease in the free androgen index (P<0.001 for all comparisons). The combination-therapy group had changes similar to those in the metformin group, including a significant decrease in BMI, levels of testosterone, and the free androgen index and a significant increase in sex hormone–binding globulin levels (P<0.001 for all comparisons), and a significant decrease in waist circumference (P=0.004).
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Adverse Events and Pregnancy Complications
Serious adverse events, most of which were complications of pregnancy, were more common among subjects in the clomiphene group and the combination-therapy group than among those in the metformin group: 7 of 209 (3.3%), 11 of 209 (5.3%; 1 subject had two events), and 2 of 208 (1.0%), respectively (P=0.12 for metformin vs. clomiphene, and P=0.02 for metformin vs. combination therapy) (Table 4). Gastrointestinal symptoms were more frequent in the groups receiving metformin, whereas hot flashes and symptoms associated with ovarian enlargement and ovulation were more common in the groups receiving clomiphene.
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Discussion
Our findings do not support the hypothesis that extended-release metformin, either alone or in combination with clomiphene citrate, improves the rate of live birth in women with the polycystic ovary syndrome. Conception, pregnancy, and live birth were significantly more likely to occur after treatment with clomiphene alone than after metformin alone. Adverse-event rates were similar among the study groups, although serious adverse events, primarily related to pregnancy, tended to occur in the groups receiving clomiphene (either alone or in combination therapy); these groups had correspondingly higher rates of pregnancy than did the metformin group.
These results are inconsistent with data from several other studies reporting benefits of metformin, especially in combination with clomiphene, in stimulating ovulation in women with the polycystic ovary syndrome.16,17,24,25,26 Previous data have generally come from small, primarily single-center trials18,26,27 that did not assess pregnancy rates but rather focused on metabolic and hormonal measures, rates of ovulation, or both.26 As in the earlier studies, we found that the groups receiving metformin (both the metformin group and the combination-therapy group) had improved insulin sensitivity (including effects on BMI, proinsulin and insulin levels, and insulin resistance as determined by HOMA), as compared with the clomiphene group. However, these effects did not translate into increased live-birth rates. Instead, increases in sex hormone–binding globulin levels were associated with improved live-birth rates.
Our results also differed from those of a previous randomized trial by Palomba et al.,17 which included 100 subjects and used a design similar to ours. In that study, the live-birth rate was 52% after 6 months of metformin, as compared with 18% after clomiphene. In contrast to our results, levels of fecundity improved over time among subjects receiving metformin, as compared with clomiphene. Unlike our trial, the study by Palomba et al. excluded subjects whose BMI was greater than 30. However, our post hoc analysis of women with a BMI of less than 30 also showed an increased live-birth rate with clomiphene, as compared with metformin.
Our findings regarding the effects of the combination of metformin and clomiphene are consistent with those of another large, multicenter, randomized trial, reported by Moll et al.,28 in which the rate of ovulation was the primary outcome. Among 228 subjects with the polycystic ovary syndrome who were randomly assigned to receive either clomiphene alone or a combination of metformin and clomiphene for up to six ovulatory cycles, there were no significant differences in ovulation rates or pregnancy rates between the combination-therapy group and the group that received clomiphene alone, with a cumulative pregnancy rate of 40% in the combination-therapy group and 46% in the clomiphene group (absolute change in the combination-therapy group, –6%; 95% confidence interval [CI], –20 to 7).28
Although we found no significant benefit of the combination of metformin and clomiphene, as compared with clomiphene alone, the possibility of some benefit cannot be excluded. On the basis of the 95% CIs, plausible differences in the live-birth rate between groups range from a 12.6% absolute increase to a 4.2% absolute decrease in the combination-therapy group. Furthermore, when ovulation is used as the outcome, the combination of metformin and clomiphene was superior to either clomiphene alone or metformin alone.13 The pregnancy rates in our trial were lower than those reported by others,16,17,28,29 perhaps reflecting the inclusion of obese women and the fact that many of the subjects had a long-standing history of infertility. These factors may also have contributed to a high rate of pregnancy complications.6,7,30 Our selection criteria were consistent with both National Institutes of Health criteria and the revised Rotterdam diagnostic criteria8,9 for the polycystic ovary syndrome, and more than 90% of our subjects had polycystic ovaries on baseline ultrasonography.21 Our cohort was similar in age and BMI to the cohort in a large, multicenter trial that showed a benefit of the insulin sensitizer troglitazone on ovulatory frequency in the polycystic ovary syndrome.15
Our study demonstrates the limitations of relying on ovulation rates as a surrogate for live-birth rates.18,27 We found that pregnancy was approximately twice as likely when ovulation was induced by clomiphene as when it was induced by metformin. Our study did not address mechanisms for improved fecundity per ovulation with clomiphene, as compared with metformin. Multiple follicular recruitment, which is characteristic of the induction of ovulation with clomiphene,31 may have resulted in an increased opportunity for fertilization and successful implantation (as evidenced by multiple pregnancies only in the groups receiving clomiphene), as compared with the presumed monofollicular ovulation rate with metformin. We did not perform routine ultrasonography to monitor follicular development because the addition of such a procedure exceeds the normal standard of care in this setting and because it might have led to unblinding in the presence of multiple follicles.31
Early pregnancy loss may be another mechanism for subfecundity in women with the polycystic ovary syndrome. The observed rate of loss of intrauterine pregnancies in our study was similar to or lower than that observed after in vitro fertilization among women of a similar age range using their own eggs (approximately 13%) on the basis of 2003 data from the Society for Assisted Reproductive Technology.32 Our study was not adequately powered to detect a difference in the first-trimester loss rate between the clomiphene group (22.6%) and the metformin group (40.0%), but our results appear to be inconsistent with those of Palomba et al.,17,29 in which study medication was likewise discontinued after a positive pregnancy test. These investigators reported significantly lower first-trimester loss rates with metformin than with clomiphene (9.7% vs. 37.5%)17 or fertility treatment with laparoscopic ovarian diathermy (9.3% vs. 29%),29 although these results were based on small numbers (six events17 and four events,29 respectively). Another group reported no significant difference in rates of spontaneous abortion between groups treated with clomiphene (11%) and combination therapy (12%).27
Our study cannot address the effects of continuing metformin throughout pregnancy,33 though our findings raise concern and highlight the need for randomized trials for this indication.34 Our results, however, support other studies suggesting an increased rate of pregnancy complications in women with the polycystic ovary syndrome,4 such as gestational diabetes (12% among subjects in our study, as compared with 2 to 5% in the U.S. population35) and preeclampsia (12% in our study, as compared with 3 to 8% in the U.S. population36), although obesity clearly contributes to these risks.7,30
Subjects in our study received extended-release metformin, and this form of the drug may be less efficacious in women with the polycystic ovary syndrome than is immediate-release metformin.37 Our study demonstrates that the tolerability of extended-release metformin is similar to that of clomiphene, although metformin had more gastrointestinal side effects and fewer vascular side effects and ovulation-related symptoms.
In summary, our study supports the use of clomiphene citrate alone as first-line therapy for infertility in women with the polycystic ovary syndrome. We did not find a significant benefit of combination therapy with clomiphene and metformin over clomiphene alone with respect to the live-birth rate. In addition, the results of our study underscore the limitations of the use of ovulation as a surrogate marker for live birth in infertility trials.
Supported by grants from the National Institutes of Health (U10 HD27049, to Dr. Coutifaris; U01 HD38997, to Dr. Myers; U10 HD39005, to Dr. Diamond; U10 HD27011, to Dr. Carson; U10 HD33172, to Dr. Steinkampf; U10 HD38988, to Dr. Carr; U10 HD38992, to Dr. Legro; U10 HD38998, to Dr. Schlaff; U10 HD38999, to Dr. McGovern; U54-HD29834, to the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core; GCRC MO1RR00056, to the University of Pittsburgh; and MO1RR10732 and C06 RR016499, to Pennsylvania State University). Glucophage XR and matching placebo were provided by Bristol-Myers Squibb.
Dr. Legro reports receiving consulting fees from GlaxoSmithKline, Ferring, and Abbott, lecture fees from Serono, and grant support from Pfizer; Dr. Barnhart, consulting fees from TAP and grant support from Ortho Biotech; Dr. Schlaff, grant support from Organon and Wyeth; Dr. Diamond, consulting fees from TAP and Serono and grant support from Serono, TAP, GlaxoSmithKline, and Merck; Dr. McGovern, grant support from Ferring and Serono; and Dr. Cataldo, consulting fees from Organon. Dr. Nestler reports holding an equity interest in Bristol-Myers Squibb. Dr. Leppert reports receiving grant support from TAP; and Dr. Myers, consulting fees from Merck and TAP and grant support from Merck. No other potential conflict of interest relevant to this article was reported.
We thank the staff at the Ligand Assay and Analysis Core Laboratory at the University of Virginia Center for Research and Reproduction, under the direction of D. Hasenleider, for their contributions.
Source Information
From Pennsylvania State University College of Medicine, Hershey (R.S.L.); Duke University Medical Center, Durham, NC (H.X.B., E.R.M.); University of Colorado, Denver (W.D.S.); University of Texas Southwestern Medical Center, Dallas (B.R.C.); Wayne State University, Detroit (M.P.D.); Baylor College of Medicine, Houston (S.A.C.); University of Alabama, Birmingham (M.P.S.); University of Pennsylvania School of Medicine, Philadelphia (C.C.); University of Medicine and Dentistry of New Jersey, Newark (P.G.M.); Stanford University, Stanford, CA (N.A.C.); University of Pittsburgh, Pittsburgh (G.G.G.); Virginia Commonwealth University School of Medicine, Richmond (J.E.N.); University of California at San Francisco, San Francisco (L.C.G.); and the National Institute of Child Health and Human Development, Bethesda, MD (P.C.L.).
Address reprint requests to Dr. Legro at the Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, M.S. Hershey Medical Center, 500 University Dr., H103, Hershey, PA 17033, or at rsl1{at}psu.edu.
References
In addition to the authors, other members of the Cooperative Multicenter Reproductive Medicine Network were as follows: University of Pennsylvania, Philadelphia: K. Barnhart, L. Mastroianni, L. Martino, K. Timbers; Duke University, Durham, NC: L. Lambe, R. DeWire, H. Yang, C. Bodine, D. Mark; Wayne State University, Detroit: E. Puscheck, K. Ginsburg, K. Collins, M. Brossoit, R. Leach, F. Yelian, M. Perez; Baylor College of Medicine, Houston: J. Buster, P. Amato, M. Torres; Pennsylvania State University College of Medicine, Hershey: W.C. Dodson, C. Gnatuk, J. Ober, L. Demers, A. Kunselman; University of Medicine and Dentistry of New Jersey, Newark: D. Heller, J. Colon, G. Weiss, A. Solnica; University of Colorado, Denver: K. Gatlin, S. Hahn; University of Texas Southwestern, Dallas: M. Roark; University of Alabama, Birmingham: R. Blackwell, V. Willis, L. Love; University of Pittsburgh, Pittsburgh: K. Laychak; Virginia Commonwealth University, Richmond: M. Nazmy, D. Stovall; University of Virginia, Charlottesville: W. Evans; Stanford University, Palo Alto, CA: K. Turner; University of California San Diego, San Diego: J. Chang, P. Malcolm; Denver Health Medical Center, Denver: C. Coddington; and Kaiser Permanente, Denver: K. Faber. Advisory Board: J. Hogan, F. Howard, M. Schiff, J. Wactawski-Wende, N. Santoro (chair). Data and Safety Monitoring Committee: E. Thom, J. Peipert, J. Zhang, P. Cato, C. Henderson, R. Rebar (chair).
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