Pregnancies following use of metformin for ovulation induction in patients with polycystic ovary syndrome

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1 FERTILITY AND STERILITY VOL. 77, NO. 4, APRIL 2002 Copyright 2002 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. Pregnancies following use of metformin for ovulation induction in patients with polycystic ovary syndrome Michael J. Heard, M.D., Anita Pierce, M.D., Sandra A. Carson, M.D., and John E. Buster, M.D. Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Baylor College of Medicine, Houston, Texas Objective: To assess pregnancy outcome in anovulatory infertility patients diagnosed with polycystic ovary syndrome (PCOS) who were treated with metformin. Design: Case series. Setting: Outpatient. Patient(s): Anovulatory patients (n 48) with a diagnosis of PCOS based on clinical, diagnostic, and laboratory evaluations were enrolled in the study over a 15-month period. Intervention(s): Metformin was started at 500 mg b.i.d. for 6 weeks and then increased to 500 mg t.i.d. if no ovulation occurred. Clomiphene citrate (CC; 50 mg) was added if no ovulatory response occurred after 6 weeks. Main Outcome Measure(s): Resumption of menses, presumptive ovulation, and pregnancy. Result(s): Nineteen of 48 (40%) patients resumed spontaneous menses following treatment and showed presumptive evidence of ovulation with metformin alone; 15/48 (31%) required CC (50 mg) in conjunction with metformin therapy, and 10 of these 15 (67%) had evidence of ovulation; 20/48 (42%) conceived with a median time to conception of 3 months, and 7 of these 20 (35%) had spontaneous abortions (SAB); 19/48 (40%) had gastrointestinal-related side effects, and 5 of 48 patients (10%) had to decrease the dosage of metformin. Only 1 patient discontinued therapy. Conclusion(s): Metformin alone in patients with PCOS results in a substantial number of pregnancies, with 69% (20/29) of those who ovulated conceiving in less than 6 months. (Fertil Steril 2002;77: by American Society for Reproductive Medicine.) Key Words: Metformin, polycystic ovary syndrome, infertility, ovulation induction Received May 30, 2001; revised and accepted October 22, Reprint requests: John E Buster, M.D., Baylor College of Medicine, 6550 Fannin S801A, Houston, Texas (FAX: ; jbuster@bcm.tmc.edu) /02/$22.00 PII S (01) Polycystic ovary syndrome (PCOS) is a condition associated with chronic anovulation and hyperandrogenemia. Considered a common cause of infertility, it affects up to 6% of reproductive age women. Many women with PCOS have insulin resistance with elevated insulin levels and are predisposed to non-insulin-dependent diabetes mellitus (NIDDM) and its comorbidities (1 5). Hyperinsulinemia is believed to play a role in the pathogenesis of PCOS. Meformin (Glucophage; Bristol-Myers Squibb, Princeton, NJ) is a biguanide, antihyperglycemic drug that improves tissue sensitivity to insulin while decreasing insulin levels and inhibiting hepatic glucose production. When used in patients with PCOS, metformin reduces LH, sex hormone-binding globulin, and ovarian androgens and corrects hyperinsulinemia (6 10). Metformin also induces the resumption of regular menses and ovulation (10, 11). In addition, Nestler et al. showed that the ovulatory response to clomiphene citrate (CC) can be increased in obese PCOS women when used in conjunction with metformin (12). Vandermolen recently confirmed this finding in a randomized study of PCOS patients and found that metformin also increased the pregnancy rate in those patients who were anovulatory and resistant to CC (15). One small series has been published to date that has evaluated metformin alone for the treatment of infertility (14). Except for a small, preliminary study conducted by Vandermolen 669

2 et al. (15), no reports have evaluated metformin or metformin in conjunction with CC to improve ovulation with the purpose of achieving pregnancy. This study is the first to assess pregnancy outcome in a larger group of anovulatory infertile women diagnosed with PCOS who were treated with metformin. MATERIALS AND METHODS We studied infertile PCOS patients who were treated with metformin with or without CC at Baylor College of Medicine (Division of Reproductive Endocrinology and Infertility) from December 1, 1999, through February 15, This study was approved by the institutional review board at the Baylor College of Medicine. Diagnostic evaluations included a hysterosalpingogram, a semen analysis, and laboratory evaluations for thyroid dysfunction and hyperprolactinemia. The clinical diagnosis of PCOS was based on a history of hyperandrogenemia with menstrual irregularity and anovulation ranging from oligomenorrhea (a bleeding interval greater than 35 days but less than 6 months) to secondary amenorrhea (bleeding interval 6 months or greater). Patients diagnosed with PCOS were considered a subgroup of the World Health Organization (WHO) 2 classification according to Rowe et al. (16). Patients with a history of CC failure had been treated with at least three increasing doses of CC and had no response to therapy. Of the 48 patients enrolled, 31 had a normal semen analysis (count 20 million/ml, motility and morphology 50%), 7 had oligospermia (count 20 million/ml), and 10 patients did not have a semen analysis recorded (Table 1). Treatment Protocol Metformin was initially administered at 500 mg two times daily for 6 weeks. Dosing was varied during the initial start of therapy in order to accommodate side effects. Menstrual calendars with basal body temperature (BBT) charts were recorded initially. Luteinizing hormone monitoring to time intercourse was initiated once menstrual cycles became regular. After 6 weeks of therapy, the patients returned to the clinic. If the patient had resumed regular menses and was showing an ovulatory response based on BBT charts, metformin was continued at 500 mg b.i.d. with follow-up over the next 6 months. If the patient did not conceive during this time, metformin therapy was discontinued and other therapies were considered. If the patient did not respond to the initial dose of 500 mg b.i.d., metformin was increased to 500 mg t.i.d. If there was no response in 6 more weeks, CC (50 mg per day for 5 days) was started in conjunction with metformin for a maximum of 6 cycles. Clomiphene citrate was administered regardless of whether there was a history of CC failure. Patients who conceived while receiving metformin therapy continued to take this medication through 12 weeks of gestation. RESULTS Forty-eight patients who were entered into the study took metformin for at least 3 months unless they became pregnant earlier. The mean age was 29.9 years (range, 20 38), and the body mass index (BMI) was 28.7 hg/m 2 (range, ). Following the treatment protocol, 19/48 (40%) resumed spontaneous menses and showed evidence of ovulation with metformin alone. Ten of 28 (36%) used CC (50 mg) in conjunction with metformin therapy. The median time to onset of spontaneous menses was 30 days after starting metformin. Thus, 19/48 (40%) did not resume regular menses or show an ovulatory response. There were no differences in the clinical characteristics of the patients (i.e., age, parity, BMI, or the use of CC) between responders and nonresponders; 20/48 (42%) conceived with a median time to conception of 3 months, and 7 of these 20 (35%) patients who became pregnant had spontaneous abortions. The pregnancy rate in couples with oligospermia was 2/8 (25%) and 3/9 (33%) in those with unknown semen analysis results; 19/49 (39%) had gastrointestinal-related side effects, including diarrhea, abdominal cramping, and nausea; 5/49 (10%) had to decrease the dosage of metformin due to side effects. Only 1 patient discontinued therapy due to side effects. No patients developed ovarian hyperstimulation syndrome, and no multiple gestations were noted (see Table 1). DISCUSSION No sizable study to date has evaluated metformin alone for use in patients who have PCOS who would like to get pregnant. This is the second and largest study to date that focuses on use of metformin in conjunction with CC to increase the ovulatory and pregnancy rates when treating infertility. The initial studies of the effects of metformin on hyperinsulinemia and hyperandogenemia in PCOS revealed spontaneous resumption of menses and several incidental pregnancies (8, 11, 15, 17). Velazquez studied a small group of patients who received metformin therapy (500 mg t.i.d.) for 6 months; most of them resumed regular menses, spontaneously ovulated, and 19% of them became pregnant (15, 18). Recently, Seale et al. reported three cases of pregnancy in PCOS patients with long-standing infertility who were treated with metformin (14). This case series evaluated the effect of metformin therapy on the incidence of pregnancy in PCOS patients with a known history of infertility. Previous studies have shown benefit with resumption of menses and spontaneous ovulation with the use of insulin-sensitizing agents. The clinical use of metformin alone in this study population resulted in resumption of menses and an ovulatory response in 40%. This rate increased to 60% with the addition of a low dose of CC (50 mg). Ovulation was determined based on urinary midcycle LH monitoring. Median time to resumption of menses was 30 days. These results are consistent with cur- 670 Heard et al. Pregnancies with Metformin in PCOS Vol. 77, No. 4, April 2002

3 FERTILITY & STERILITY 671 TABLE 1 Data for 48 anovulatory patients with polycystic ovary syndrome who were treated with metformin. Patient Age (y) Gravida/ Parity BMI (hg/m 2 ) Semen analysis HSG findings Metformin dose used Resumed normal menses Pregnancy Time to pregnancy Pregnancy outcome viable delivered Side effects 1 32 G2,P0,A WNL Normal 500 b.i.d. Yes Yes 1 month None No 2 37 G1,P0,A WNL Normal HSG 500 b.i.d. Yes No None No 3 26 G1,P0,A WNL Not done 250 b.i.d. Yes Yes 2 months SAB None No 4 32 G Oligospermia Normal 500 b.i.d. Yes Yes 2 months Ongoing None No 5 30 G Oligospermia Not done 500 t.i.d. Yes No Diarrhea Yes 6 27 G1,P0,A1 22 WNL Endometrial polyp with bilateral tubal fill/spill 500 b.i.d. Yes Yes 5 months SAB Fainting No 7 30 G Oligospermia Not done 500 t.i.d. Yes No Diarrhea 8 38 G1,P0,A WNL Normal HSG 500 t.i.d. Yes Yes 3 months Ongoing Nausea Yes 9 29 G1P WNL Not done 500 b.i.d. No No GI diarrhea Yes G0 24 WNL Adhesions at L/S 500 b.i.d. Yes No G WNL Not done 500 t.i.d. No No None Yes G WNL Not done 500 t.i.d. Yes Yes 3 months Ongoing GI cramping No G0,P Not done Not done 500 b.i.d. No No None G Not found Normal HSG 500 b.i.d. Yes No None No G6,P3,A Not done Normal HSG 500 b.i.d. Yes Yes 1 month Biochemical None No G WNL Not done 500 t.i.d. Yes Yes 3 months Viable None No G WNL Not done 500 b.i.d. Yes Yes 1 month Viable Serious GI cramping/ No cramping G0,P WNL Normal HSG 500 t.i.d. Yes Yes 4 months Biochemical None No G0,P WNL Normal HSG 500 t.i.d. Yes Yes 5 months Ongoing None Yes G3,P0,A WNL No, but IUA noted 500 b.i.d. Yes Yes 2 months Missed abortion None No on HSG G0,P0 21 Done elsewhere no Not done 500 b.i.d. Yes Yes 1 month Ongoing None No report G WNL Left tubal 500 t.i.d. No No None No occlusion G0,P0 48 Oligospermia Not done 500 b.i.d. No No Severe GI Yes discontinued 10 days later G1,P WNL Not done 500 b.i.d. NA intolerant No No G WNL Not done 500 t.i.d. Yes Yes 6 months Ongoing None G0,P Oligospermia Normal HSG 500 b.i.d. No No None Yes G0 21 WNL Not done 500 b.i.d. No Yes 3 months Ongoing Diarrhea Yes G0 20 Asthenospermia Normal HSG 500 b.i.d. Yes Yes 1 month Ongoing Cramping/diarrhea No G Oligoasthenospermia Not done 500 t.i.d. Yes No None No G0,P Patient refused/normal postcoital test One open tube/nl UTX 500 b.i.d. No No Nausea/vomiting/ lightheadedness Clomiphene citrate used Yes

4 672 Heard et al. Pregnancies with Metformin in PCOS Vol. 77, No. 4, April 2002 TABLE Patient Age (y) 1 Continued. Gravida/ Parity BMI Semen analysis HSG findings Metformin dose used Resumed normal menses Pregnancy Time to pregnancy Pregnancy outcome viable delivered Side effects G1,P0,A WNL Not done 500 t.i.d. Yes No Lightheadedness/ dizziness No G1,P Not done Not done 500 b.i.d. Yes No None G WNL Not done 500 b.i.d. No No Lethargy No G WNL Unilateral obstruction 500 b.i.d. Yes No Abdominal cramping G3,P1,A Done elsewhere Normal HSG 500 b.i.d. No Yes 11 months Ongoing None Yes saw urologistno report G1,P0,A WNL Normal HSG 500 b.i.d. Yes Yes 2 months Biochemical Diarrhea/vomiting Yes G WNL Not done 500 b.i.d. No Yes 1 month Viable Abdominal cramping No G2,P WNL Not done 500 b.i.d. No No None G2,P1,A Azoospermia Not done 500 b.i.d. Yes No None G2,P1,A WNL Not done 500 b.i.d. Yes No None No G0,P Not done Normal HSG 500 b.i.d. No No None Yes G WNL Not done 500 t.i.d. No No Abdominal cramping Yes G6,P0,A6 36 WNL Normal HSG 500 b.i.d. Yes No None Yes G1,P Normal Not done 500 b.i.d. Yes Yes 2 months Ongoing None No G1,P WNL Not done 500 b.i.d. Yes No None G1,P0,A1 24 Not done Normal HSG 500 t.i.d. Yes No None Yes G0 48 Oligoasthenospermia No HSG done 500 b.i.d. No No None Yes G1,P0,A WNL Normal HSG 500 b.i.d. Yes No Abdominal cramping Yes Note: BMI body mass index; HSG hysterosalpingography; WNL normal; L/S laparoscopy; nl normal; SAB spontaneous abortion; GI gastrointestinal; IUA intrauterine adhesions; UTX uterus. Heard. Pregnancies with metformin in PCOS. Fertil Steril Clomid used

5 rently published data regarding the success of metformin on spontaneous ovulation in PCOS (12, 15). Metformin can cause gastrointestinal side effects that include nausea, abdominal pain, and diarrhea; these side effects occurred in 19/49 (39%) patients, but usually they were self-limiting and presented in the first 2 weeks of therapy. In order to tolerate side effects, 11% of patients had to decrease the dose of metformin. Some of these patients conceived while receiving lower initial doses of metformin. Only 1 patient discontinued the therapy due to an inability to tolerate side effects. Some variations in the treatment protocol included lower dosages of metformin or adding CC to reduce side effects and maximize therapy. The average dosage of metformin was lower than that in other reports, but the ovulatory response rate was still similar. The appropriate dosage to maximize clinical benefit in PCOS patients has not been examined closely and needs further study. Metformin use in pregnancy has not been studied extensively for the treatment of PCOS. One study that examined metformin use in pregnancy found no significant adverse outcomes (19). A pilot study done by Glueck et al. showed that giving metformin in pregnancy might reduce the firsttrimester spontaneous abortion (SAB) rate (13). The patients in this study continued to receive metformin for the first 12 weeks of pregnancy. The SAB rate was 7/20 (35%), which is no lower than the usual SAB rate for PCOS patients. Metformin has been classified as a category B drug in pregnancy, and there have been no teratogenic effects reported in animal studies (20). Although some studies have shown a decreased miscarriage rate during the first trimester (13), this study did not. In addition, the use of this drug during pregnancy is not considered standard of care and cannot be recommended in pregnancy at this time. In conclusion, this preliminary case series is the first to demonstrate that use of metformin alone or with the addition of CC (29 [60%] of 48) in patients with PCOS results in a substantial number of pregnancies, with 20/48 (42%) of those who ovulated achieving conception in less than 6 months of therapy. Gastrointestinal side effects limit its use. Reproductive efficiency with metformin may be superior to traditional therapy with CC but needs to be further tested in comparative trials. References 1. Dunaif A, Futterweit W, Segal KR, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 1989;38: Ehrmann DA, Sturis J, Byrne MM, Karrison T, Rosenfield RL, Polonsky KS. Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus. J Clin Invest 1995;96: Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 1992;41: Sills ES, Perloe M, Palermo GD. Correction of hyperinsulinemia in oligoovulatory women with clomiphene-resistant polycystic ovary syndrome: a review of therapeutic rationale and reproductive outcomes. Eur J Obstet Gynecol Reprod Biol 2000;91: Kolodziejczyk B, Duleba AJ, Spaczynski RZ, Pawelezyk L. Metformin therapy dereases hyperandrogenism and hyperinsulinemia in women with polycystic ovary syndrome. Fertil Steril 2000;73: De Leo V, la Marca A, Ditto A, Morgante G, Cianci A. Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome. Fertil Steril 1999;72: Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M, et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 2000;85: Diamanti-Kandarakis E, Kouli C, Tsianateli T, Bergiele A. Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome. Eur J Endocrinol Metab 1997;82: Ehrmann DA, Cavaghan MK, Imperial J, Sturis J, Rosenfield RL, Polonsky KS. Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997;82: Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L. Metformininduced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome. Metabolism 1999;48: Morin-Papunen C, Koivunen RM, Ruokonen A, Martikainen HK. Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertil Steril 1998;69: Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998;338: Glueck CJ, Phillips H, Cameron D, Sieve-Smith L, Wang P. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril 2001;75: Seale FG, Robinson RD, Neal GS. Association of metformin and pregnancy in the polycystic ovary syndrome. J Reprod Med 2000;45: Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma SW, Nestler JE. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene alone. Fertil Steril 2001;75: Rowe R, Comhaire F, Hargreave T. WHO Manual for the Standardized Investigation and Diagnosis of the Infertile Couple. Female Partner. Cambridge: Press Syndicate of the University of Cambridge. 2000: Velazquez E, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol 1997; 90: Murafawa H, Hasegawa I, Kurabayashi T, Tanaka K. Polycystic ovary syndrome. Insulin resistance and ovulatory responses to clomiphene citrate. J Reprod Med 1999;44: Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic pressure, while facilitating normal menses and pregnancy. Metabolism 1999;43: Elkind-Hirsch K, Chang J. Use of Insulin Sensitizing Agents in the Treatment of Polycystic Ovary Syndrome. American Society for Reproductive Medicine Committee Opinion. April FERTILITY & STERILITY 673

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