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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-0287
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 8 3124-3127
Copyright © 2008 by The Endocrine Society

BRIEF REPORT

Extended-Release Metformin Does Not Reduce the Clomiphene Citrate Dose Required to Induce Ovulation in Polycystic Ovary Syndrome

Nicholas A. Cataldo, Huiman X. Barnhart, Richard S. Legro, Evan R. Myers, William D. Schlaff, Bruce R. Carr, Michael P. Diamond, Sandra A. Carson, Michael P. Steinkampf, Christos Coutifaris, Peter G. McGovern, Gabriella Gosman, John E. Nestler, Linda C. Giudice for the Reproductive Medicine Network1

Stanford University School of Medicine (N.A.C., L.C.G.), Stanford, California 94305; Duke University School of Medicine (H.X.B., E.R.M.), Durham, North Carolina 27701; Pennsylvania State University School of Medicine (R.S.L.), Hershey, Pennsylvania 17033; University of Colorado (W.D.S.), Denver, Colorado 80218; University of Texas Southwestern Medical Center (B.R.C.), Dallas, Texas 75235; Wayne State University (M.P.D.), Detroit, Michigan 48202; Baylor College of Medicine (S.A.C.), Houston, Texas 77030; University of Alabama at Birmingham (M.P.S.), Birmingham, Alabama 35294; University of Pennsylvania School of Medicine (C.C.), Philadelphia, Pennsylvania 19104; University of Medicine and Dentistry of New Jersey (P.G.M.), Newark, New Jersey 07101-1709; University of Pittsburgh (G.G.), Pittsburgh, Pennsylvania 15260; and Department of Medicine (J.E.N.), Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298-0565

Address all correspondence and requests for reprints to: Richard S. Legro, M.D., Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033. E-mail: RSL1{at}psu.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: When used for ovulation induction, higher doses of clomiphene may lead to antiestrogenic side effects that reduce fecundity. It has been suggested that metformin in combination with clomiphene can restore ovulation to some clomiphene-resistant anovulators with polycystic ovary syndrome (PCOS).

Objective: Our objective was to determine if cotreatment with extended-release metformin (metformin XR) can lower the threshold dose of clomiphene needed to induce ovulation in women with PCOS.

Design: A secondary analysis of data from the National Institute of Child Health and Human Development Cooperative Multicenter Reproductive Medicine Network prospective, double-blind, placebo-controlled multicenter clinical trial, Pregnancy in Polycystic Ovary Syndrome, was performed.

Setting: Study volunteers at multiple academic medical centers were included.

Participants: Women with PCOS and elevated serum testosterone who were randomized to clomiphene alone or with metformin (n = 209 in each group) were included in the study.

Interventions: Clomiphene citrate, 50 mg daily for 5 d, was increased to 100 and 150 mg in subsequent cycles if ovulation was not achieved; half also received metformin XR, 1000 mg twice daily. Treatment was for up to 30 wk or six cycles, or until first pregnancy.

Main Outcome Measures: Ovulation was confirmed by a serum progesterone more than or equal to 5 ng/ml, drawn prospectively every 1–2 wk.

Results: The overall prevalence of at least one ovulation after clomiphene was 75 and 83% (P = 0.04) for the clomiphene-only and clomiphene plus metformin groups, respectively. Using available data from 314 ovulators, the frequency distribution of the lowest clomiphene dose (50, 100, or 150 mg daily) resulting in ovulation was indistinguishable between the two treatment groups.

Conclusion: Metformin XR does not reduce the lowest dose of clomiphene that induces ovulation in women with PCOS.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Polycystic ovary syndrome (PCOS) affects 7–8% of reproductive-aged women. Classically defined as including both anovulation and hyperandrogenism of ovarian origin (1), PCOS is often associated with insulin resistance and insulin excess. These metabolic abnormalities have been associated with comorbidities such as obesity, prediabetes, and type 2 diabetes (2).

Clomiphene citrate is the conventional first-line agent to induce ovulation in PCOS when pregnancy is desired. For the roughly 25% of women with PCOS resistant to clomiphene ovulation induction (3), the conventional next step is either exogenous gonadotropin injections, or ovarian diathermy or drilling. Both of these modalities bring significant risks as well as increased cost, making an alternative approach desirable. Metformin has been used to promote ovulation in PCOS with considerable, though variable, success (4). Insulin sensitization is an attractive strategy for clomiphene-resistant women, who as a group have greater insulin excess than those who ovulate after clomiphene (5). Whether or not metformin is a similarly attractive therapy for unselected women with PCOS remains a subject of debate.

Not all women with PCOS who ovulate after clomiphene conceive readily, in part because clomiphene may have unfavorable antiestrogenic effects on cervical mucus and endometrium (3). Because these clomiphene effects appear to be dose dependent, a strategy that can induce ovulation at lower clomiphene doses might improve live birth rates. Given reports of successful ovulation in previously clomiphene-resistant women after combined clomiphene and metformin treatment (6), it is reasonable to hypothesize that metformin cotreatment can reduce the threshold clomiphene dose for ovulation in an unselected PCOS population. To test this hypothesis, we determined the lowest clomiphene dose that led to ovulation in a large cohort of women with PCOS seeking fertility who were enrolled in a study of extended-release metformin (metformin XR), taken along with clomiphene in doses that were escalated in standard fashion.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The Pregnancy in Polycystic Ovary Syndrome (PPCOS) study was a multicenter, randomized, double-blind, placebo-controlled trial of metformin XR and clomiphene, with the primary endpoint of live birth rate. The study and its primary outcomes are described in detail elsewhere (7). In brief, women with PCOS by National Institute of Child Health and Human Development criteria (1) (oligo-ovulation and hyperandrogenism, defined by an elevated serum testosterone) were randomized through a central interactive voice system with equal likelihood to treatment with metformin XR, clomiphene citrate, or both drugs together. When only one active agent was assigned, a placebo for the second drug was given. Metformin (or its placebo) was begun shortly after study entry at the beginning of a spontaneous or progestin-withdrawal cycle, with a starting dose of 500 mg daily that was gradually increased over 2 wk to the target dose of 1000 mg twice daily. Clomiphene citrate (or its placebo) was started on the fifth day of this first treatment cycle at 50 mg daily for 5 d. Unless pregnancy occurred, treatment was continued for six total cycles or 30 wk, with the daily clomiphene dose increased to 100 mg, then 150 mg for 5 d in subsequent cycles if ovulation, diagnosed by any weekly serum progesterone more than or equal to 5 ng/ml (15.9 nmol/liter), failed to occur. If ovulation occurred in the previous cycle, the same clomiphene dose was given in the next cycle. No ultrasound monitoring was used, and no ovulatory trigger medications or intrauterine inseminations were permitted.

In a secondary analysis, we determined the clomiphene dose taken in the first ovulatory cycle achieved by each participant enrolled in the clomiphene-only (with placebo for metformin) and the clomiphene plus metformin (no placebo) treatment groups. The number of women and the frequency of first ovulation in response to each clomiphene dose were tabulated for each treatment group, and the outcomes compared by {chi}2 testing. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
We have previously published the baseline characteristics of the women enrolled in the PPCOS study and in each of the treatment groups (7). The women enrolled in the PPCOS study had a mean body mass index of 35 kg/m2; 30% had previously taken clomiphene and were still seeking pregnancy. Preenrollment testing was required to confirm tubal patency and an adequate partner semen analysis. Table 1Go shows subject characteristics at entry. In both study groups receiving clomiphene, there were 209 enrolled subjects, consistent with the study aim to enroll equal numbers in each group.


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  		TABLE 1. Baseline characteristics of the two treatment groups (n = 209 for each group)

 
During the entire time of study participation, at least one ovulation occurred in 157 of 209 subjects (75%) in the clomiphene-only group and 174 of 209 subjects (83%) in the clomiphene plus metformin group (P = 0.04). Data on the clomiphene dose taken during the first cycle exhibiting an ovulatory response were available for 150 of the 157 ovulators (96%) in the clomiphene-only group and 164 of the 174 ovulators (94%) in the clomiphene plus metformin group. The number of women who had their first ovulatory cycle after taking each clomiphene dose is shown in Table 2Go. No significant difference (P = 0.47) was found between the two treatment groups in the distribution of the clomiphene dose that was associated with first study ovulation. To address the possibility that the lack of effect of metformin to improve ovulation rate in the 50-mg clomiphene cycles was the result of the target metformin dose not yet having been reached in the follicular phase of these cycles, we performed an additional analysis comparing the frequencies of first ovulations on the 100 and 150-mg clomiphene doses. Again, there was no statistical difference between the clomiphene-only group and the clomiphene plus metformin group.


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  		TABLE 2. Clomiphene dose leading to first detected ovulation, by treatment group

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Debate has continued regarding the best first-line approach to restore ovulation in women with PCOS seeking fertility: clomiphene, an insulin sensitizer, or both together. Although clomiphene has afforded ovulation rates of 70–80% as monotherapy, pregnancy rates lag significantly behind; this has been attributed to effects on the endometrium, corpus luteum, or both resulting from the dose-dependent antiestrogenic property of clomiphene (3). For this reason a strategy to induce ovulation at the lowest possible clomiphene dose is desirable.

The PPCOS study was designed to find a superior first-line treatment strategy in PCOS for achieving a live birth. The study includes the largest cohort to date of women with PCOS undergoing ovulation induction with clomiphene and metformin alone and in combination. The ovulation rates found after clomiphene 50 mg and cumulatively after up to six cycles of escalating dose treatment are comparable to those reported previously (3). The ovulation rate with the clomiphene-metformin combination was slightly greater than with clomiphene alone.

This secondary analysis found that the distribution of first ovulations occurring with each clomiphene dose was indistinguishable between the group also taking metformin and the group taking placebo for metformin. This finding argues strongly against a significant effect of metformin to reduce the clomiphene dose required to induce ovulation in unselected women with PCOS seeking fertility. Given literature suggesting that metformin can lower the clomiphene dose necessary to achieve ovulation from greater than 150 mg (resistance to this dose or lower doses) to as low as 50 mg (6, 8), the contrasting result found in the PPCOS study population could be the result of the use of the extended-release formulation of metformin, of intrinsic differences in the subject population (in previous studies, requiring previous clomiphene resistance for entry may have produced a more metabolically abnormal and, therefore, more susceptible population), or of insufficient power with the sample size of 314 ovulators to detect significance in the observed small difference in rates of ovulation at each clomiphene dose. A power calculation shows that to detect the observed 6.7% difference in ovulation rate after 50-mg clomiphene with 80% power, nearly 900 subjects would be needed in each treatment group. Alternatively, the previous studies noting a clomiphene-sparing effect of metformin (6, 8) may have been biased by inadequate blinding of treatment allocation and/or study medication, which the double-blind design of PPCOS averted, and by significantly smaller sample sizes.

In regard to the PPCOS study design, the near-simultaneous initiation of metformin and clomiphene and gradual increase in metformin dose during the first 15 d of the first clomiphene cycle may have meant that the full effect of metformin was not achieved in all subjects in the first (50 mg) clomiphene cycle. Subjects failing to ovulate in this first, 50-mg clomiphene cycle would then have been advanced to higher clomiphene doses, and the ability of metformin at full therapeutic doses to synergize with 50-mg clomiphene may not have been adequately assessed. Our own data support a benefit of time on the live birth rate in the metformin plus clomiphene treatment group, but not in the metformin-alone group (7). In contrast, previous reports have found metformin to have effects in PCOS within 2 wk of its start on both ovulation (9, 10) and testosterone excess (11). The lack of difference we found in ovulation rates between the 100 and 150-mg clomiphene doses supports the concept that the negative findings are not the result of the delayed effect of metformin.

In conclusion, metformin appears to have no benefit to decrease the clomiphene dose needed to induce ovulation in anovulatory women with PCOS seeking fertility. For this reason cotreatment with metformin is not an effective strategy to avoid the potential adverse effects on fecundity of higher clomiphene doses in an unselected population of women with PCOS seeking pregnancy.


   Acknowledgments
 
In addition to the authors, other investigators of the National Cooperative Reproductive Medicine Network were as follows: University of Pennsylvania: K. Barnhart, L. Mastroianni Jr, L. Martino, K. Timbers; Duke University: L. Lambe, R. DeWire, H. Yang, C. Bodine, D. Mark; Wayne State University: E. Puscheck, K. Ginsburg, K. Collins, M. Brossoit, R. Leach, F. Yelian, and M. Perez; Baylor College of Medicine: J. Buster, P. Amato, M. Torres; Pennsylvania State University: W.C. Dodson, C. Gnatuk, J. Ober, L. Demers, A Kunselman; University of Medicine and Dentistry of New Jersey: D. Heller, J. Colon, G. Weiss, A. Solnica; University of Colorado: K. Gatlin, S. Hahn; University of Texas, Southwestern: M. Roark; University of Alabama: R. Blackwell, V. Willis, L. Love; University of Pittsburgh: K. Laychak; Virginia Commonwealth University: M. Nazmy, D Stovall; University of Virginia: W. Evans; Stanford University: K. Turner; University of California San Diego: J. Chang, P. Malcolm; Denver Health Medical Center: C. Coddington; Kaiser Permanente: K. Faber.

Glucophage XR and matching placebo were provided by Bristol-Myers Squibb.


   Footnotes
 
This work was supported by: National Institutes of Health/National Institute of Child Health and Human Development Grants U10 HD27049 (to C.C.), U01 HD38997 (to E.R.M.), U10 HD39005 (to M.P.D.), U10 HD27011 (to S.A.C.), U10 HD33172 (to M.P.S.), U10 HD38988 (to B.R.C.), U10 HD38992 (to R.S.L.), U10 HD38998 (to W.D.S.), U10 HD38999 (to P.G.M.), and U54-HD29834 University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core; General Clinical Research Center Grant MO1RR00056 to the University of Pittsburgh; and MO1RR10732 and construction Grant C06 RR016499 to Pennsylvania State University.

Disclosure Statement: R.S.L. served as a consultant to Glaxo Smith Kline and Ferring. He has had paid lecture fees by Serono, meeting support from Abbott, and grant support from Pfizer. J.E.N. has equity ownership/stock options in Bristol Myers Squibb. E.R.M., and H.X.B. report grant support from Tap, and H.X.B. also reports grant support from Ortho Biotech, and E.R.M. has received research support from Merck and is also a consultant. W.D.S. has grant support from Organon and Wyeth. N.A.C. consults for Organon. P.G.M. has grant support from Ferring and Serono. M.P.D. reports grant support from Serono, Tap, Glaxo Smith Klein, and Merck, and has served as a consultant for Tap and Serono. S.A.C., C.C., L.C.G., M.P.S., G.G., and B.R.C. have no disclosures.

First Published Online May 27, 2008

1 For a list of members of the Reproductive Medicine Network, see Acknowledgments. Back

Abbreviations: metformin XR, Extended-release metformin; PCOS, polycystic ovary syndrome; PPCOS, Pregnancy in Polycystic Ovary Syndrome.

Received February 5, 2008.

Accepted May 19, 2008.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Zawadzki JK, Dunaif A 1992 Diagnostic criteria for polycystic ovary syndrome: a rational approach. In: Dunaif A, Givens JR, Haseltine F, Merriam GR, eds. Polycystic ovary syndrome. Cambridge, MA: Blackwell Scientific; 377–384
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  4. Lord JM, Flight IH, Norman RJ 2003 Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 327:951–953[Abstract/Free Full Text]
  5. Mor E, Zograbyan A, Saadat P, Bayrak A, Tourgeman DE, Zhang C, Stanczyk FZ, Paulson RJ 2004 The insulin resistant subphenotype of polycystic ovary syndrome: clinical parameters and pathogenesis. Am J Obstet Gynecol 190:1654–1660[CrossRef][Medline]
  6. Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma SW, Nestler JE 2001 Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril 75:310–315[CrossRef][Medline]
  7. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Giudice LC, Leppert PC, Myers ER 2007 Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 356:551–566[Abstract/Free Full Text]
  8. Palomba S, Orio Jr F, Falbo A, Russo T, Caterina G, Manguso F, Tolino A, Colao A, Zullo F 2005 Metformin administration and laparoscopic ovarian drilling improve ovarian response to clomiphene citrate (clomiphene) in oligo-anovulatory clomiphene-resistant women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 63:631–635[CrossRef][Medline]
  9. Hwu YM, Lin SY, Huang WY, Lin MH, Lee RK 2005 Ultra-short metformin pretreatment for clomiphene citrate-resistant polycystic ovary syndrome. Int J Gynaecol Obstet 90:39–43[CrossRef][Medline]
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  11. Pirwany IR, Yates RW, Cameron IT, Fleming R 1999 Effects of the insulin sensitizing drug metformin on ovarian function, follicular growth and ovulation rate in obese women with oligomenorrhoea. Hum Reprod 14:2963–2968[Abstract/Free Full Text]



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