Making a case for metformin

By Thomas S. Kosasa, MD

While metformin is certainly no miracle cure for polycystic ovary disease, a wide range of studies support its role in lowering serum androgens, restoring normal menstrual cycles and ovulation, and—perhaps—even improving pregnancy rates.

The realization that insulin resistance is a pivotal defect in polycystic ovary syndrome (PCOS) probably counts as one of the most important advances in the battle to control the disorder. This metabolic "mishap" leads to a compensatory increase in circulating insulin, and evidence suggests that this elevated insulin level directly stimulates the ovary to produce excess androgens.^1,2 Since both obese and lean women with PCOS have insulin resistance, it's safe to assume that women with PCOS are insulin resistant.^3,4

If, as the research strongly suggests, insulin resistance turns out to be one of the primary causes of PCOS, we would expect drugs that reverse insulin resistance to also relieve hyperandrogenism, restore normal menses, and help eliminate the infertility associated with PCOS. At the top of that list of pharmaceutical agents is metformin, which was developed in 1957 to treat type 2 diabetes. Metformin reduces insulin resistance of peripheral tissue and allows muscle and adipose cells to take in glucose at normal insulin levels. The drug also reduces intestinal absorption of glucose and decreases the production of glucose by the liver, without causing hypoglycemia.⁵

The first published experiment that used metformin to treat PCOS patients administered 500 mg three times a day after meals to 26 moderately obese women for 8 weeks.⁶ The drug significantly reduced serum luteinizing hormone (LH) and increased follicle stimulating hormone (FSH) and sex hormone binding globulin (SHBG). It also reduced free testosterone levels by 49% and total testosterone by 52%. None of the women had a normal menstrual cycle before entering the study, but after taking metformin, three became pregnant, and seven out of seven women who took the drug for more than 8 weeks resumed normal menstrual cycles. In a subsequent study, 21 out of 22 women treated with metformin for 6 months resumed normal menstrual cycles and four became pregnant.⁷

The first placebo-controlled clinical trial that looked at metformin for the treatment of PCOS used 500 mg three times daily for 4 to 8 weeks in 24 obese women. The drug caused insulin levels to drop and caused decreases in GnRH-stimulated LH release and free testosterone; it also increased SHBG levels. These improvements occurred in the absence of any change in body weight. An independent placebo-controlled study using metformin 500 mg three times daily in lean women with PCOS yielded similar results: Metformin decreased fasting- and glucose-stimulated insulin levels, decreased basal and GnRH-stimulated LH release, decreased free and total testosterone, and increased SHBG.⁴

Unfortunately, not all the evidence on metformin is so positive. In a placebo-controlled 16-week trial, French investigators concluded that metformin had no additional benefit over diet in improving hyperinsulinemia and hyperandrogenism. This study, however, used 850 mg of metformin twice daily in very obese women (averaging 35.2 kg/m²).⁸ Similarly, a 1997 investigation using 850 mg three times daily in markedly obese women (averaging 39 kg/m²) found that metformin did not significantly reduce hyperinsulinemia or hyperandrogenism.⁹ These studies suggest that the drug will not benefit PCOS patients suffering from morbid obesity. Finally, Turkish researchers conducted a single-blind study using 850 mg of metformin twice daily in 16 patients for 10 weeks and were also unable to detect any improvement in insulin resistance.¹⁰

But despite these negative findings, there have been over 20 subsequent studies that have shown that the drug improves insulin metabolism, hormonal parameters, or both.¹¹

What effect does metformin have on ovulation induction?

What's impressive about the research on ovulation induction (OI) is that every study to date has shown that giving 500 mg of metformin three times daily to lean and moderately obese women restores normal menstrual cycles and improves spontaneous ovulation.^12-18 Although a trial comparing metformin with clomiphene citrate for OI has not been done, there's substantial evidence from randomized controlled trials to indicate that when taken with clomiphene, the drug enhances the likelihood of successful OI.

For instance, in a multinational single-blind, placebo-controlled study, in which metformin or placebo was given for 5 weeks to women with PCOS, 34% (12/35) in the metformin group ovulated, compared to only 4% (1/26) in the placebo group.¹³ The women who did not ovulate were given clomiphene, 50 mg a day for 5 days, while continuing to take metformin or placebo. In the clomiphene/ metformin group, 90% (19/21) ovulated while only 8% (2/25) ovulated in the metformin/placebo group.

In another multicenter double-blind study, patients who didn't ovulate on 150 mg of clomiphene were given metformin or placebo for 7 weeks. In the metformin/clomiphene group, 75% (9/12) of women ovulated, compared to 27% (4/15) in the placebo/clomiphene group. Pregnancies occurred in 55% of women in the metformin/ clomiphene group compared to only 7% in the placebo/clomiphene group.¹⁹ In a similar study, 65.2% (15/23) of patients taking metformin with clomiphene conceived, compared to only 4.2% (1/24) in the placebo/clomiphene group.²⁰ Over 90% of the conceptions occurred after four cycles of metformin and clomiphene.

In contrast to these positive reports are two that failed to show metformin benefits in women with PCOS who have not responded to clomiphene citrate. In one very recent investigation, 20 clomiphene-resistant women with PCOS were initially given either placebo or 500 mg of metformin three times daily for 3 months. The researchers added 100 mg of clomiphene to this regimen for 5 days for one cycle for women who didn't ovulate after taking metformin or placebo alone. During the one cycle on clomiphene and metformin, none of the women ovulated, although researchers did observe significant decreases in serum testosterone, fasting leptin, and body mass index.²¹

The second study, which was randomized and double-blind, involved 3 months of placebo/metformin therapy, 500 mg three times daily, followed by 3 months of placebo/metformin together with clomiphene citrate (50–100 mg for 5 days) for three cycles in clomiphene-resistant women with PCOS. Ovulation was induced in 41% (5/12) of metformin- treated women, and 25% (4/14) in placebo-treated women (P=0.63). Pregnancy occurred in 25% of the women given metformin and 14% of those given placebo (P=0.59). This study suggested that metformin may be beneficial to a subset but not all patients with PCOS.²² Those more likely to benefit from the drug have higher fasting insulin, lower androstenedione, and less severe menstrual irregularities.

When gonadotropins are used to induce ovulation in PCOS patients, they can sometimes overstimulate the ovaries. In one randomized study, for instance, clomiphene-resistant PCOS patients received no medication or metformin, 500 mg three times daily for 1 month prior to OI with follicle-stimulating hormone (FSH). In the group of 19 patients receiving only FSH, six (31.5%) were not given hCG because they developed excessive follicular development and five (26.3%) developed hyperstimulation after receiving hCG. All 18 patients receiving metformin and FSH were given hCG and three (16.6%) developed the hyperstimulation syndrome.²³ These findings suggest that metformin may reduce the rate of hyperstimulation with FSH therapy.

Patients with PCOS undergoing in vitro fertilization (IVF) have a large number of oocytes, but have a lower percentage of quality oocytes and a lower fertilization rate than patients with tubal disease. This is presumably due to the excess androgen in the ovary. In a prospective study of 26 patients undergoing IVF, who were treated with or without metformin, those on 500 mg of metformin took it twice daily starting on day 1 of the cycle prior to leuprolide suppression and continued to the day of the pregnancy test. Metformin significantly increased the number of mature oocytes, fertilization rates, and number of embryos produced. It did not, however, alter the total number of oocytes or peak estradiol levels.²⁴

Metformin and early pregnancy loss

Women with PCOS are at increased risk for miscarriage. First-trimester pregnancy loss in PCOS patients is reported to be 30% to 50% higher than the rates reported for normal women (10%–15%).^21-31 Among women with early pregnancy loss, 36% to 82% are reported to have PCOS.^32,33 Hyperinsulinemia is considered a risk factor for early pregnancy loss as well as increased insulin resistance.³⁴

In one case-control prospective study, investigators have shown that there is an increased frequency of insulin resistance in unselected women with a history of recurrent pregnancy loss. Among 74 women with recurrent pregnancy loss, 27% were insulin resistant, whereas only 9.5% of the matched controls were insulin resistant.³⁵

Plasminogen activator inhibitor (PAI), which apparently causes placental insufficiency by reducing the lysis of thrombi in the placenta, increases as insulin levels rise, and has been found in high levels in PCOS women with early pregnancy loss.³⁶ Since high PAI activity is associated with early miscarriage, and metformin reduces PAI activity, it appears that metformin can reduce the high rate of spontaneous miscarriage in women with PCOS.^6,37,38 Results from a pilot study of pregnant women with PCOS using metformin, 1.5 to 2.55 g per day, reduced the rate of first-trimester miscarriage from 73% to 10%.³⁹ Researchers theorize this was the result of the effect of metformin on insulin resistance and PAI activity. Although these studies suggest that patients treated with metformin have better pregnancy outcomes, we can't come to any definite conclusions until a randomized, placebo-controlled, double-blind clinical study is completed.

Metformin can impact gestational diabetes

We know that women with PCOS are more likely to develop gestational diabetes than normal women: 20% to 41%, compared to 3% to 8.9%.^40,41 Since metformin reduces serum insulin, insulin resistance, and insulin secretion, it should reduce the demands on the pancreatic ß-cells and subsequently decrease the development of gestational diabetes.

Last year, Glueck and associates reported that giving metformin to pregnant women with PCOS reduced the risk of gestational diabetes tenfold (31%–3%).⁴² And preventing gestational diabetes may help prevent type 2 diabetes as well.⁴³ Once again, while metformin appears to safely reduce the incidence of gestational diabetes in PCOS patients, further prospective, randomized clinical trials need to be performed to confirm this observation.

What about adverse reactions?

Metformin has been available worldwide for over 40 years and its side effects are well known. The main adverse effects are transient nausea and diarrhea. As many as 20% of patients experience GI side effects but the symptoms appear to be dose related and can be minimized by gradually increasing the dose and taking the medication with food.^41,44 The sustained-release formulation appears to be better tolerated than the original formula.

Although lactic acidosis is extremely rare (1/33,000) and has not been reported in a single woman with PCOS, it is a life- threatening complication that kills as many as half of all affected patients.^46,47 Contraindications to metformin include liver failure, alcoholism, and active infection because these conditions predispose patients to hypoxia-induced lactic acidosis.⁴⁸ With that in mind, some experts suggest that clinicians document normal hepatic and renal function (serum creatinine <1.4 mg/dL) before starting therapy, but also note that repeat testing is not indicated unless an illness develops that would affect hepatic or renal function.⁴⁸

Summing up the latest research on PCOS

The link between insulin resistance, hyperinsulinemia, and PCOS has been one of the most significant advances in the treatment of PCOS. As I mentioned previously, these increased insulin levels stimulate the ovary to produce excess androgens, which in turn results in the hirsutism and acne found in PCOS patients. Of more significance is the fact that these increased insulin levels impede ovulation.

Metformin reduces insulin resistance and lowers insulin levels in PCOS patients, and that lowers serum androgens, restores normal menstrual cycles and ovulation, and may even improve pregnancy rates. The drug also seems to increase the ovulatory rate and pregnancy rate from clomiphene citrate in patients with PCOS who are resistant to clomiphene alone.

The data also show that metformin significantly reduces first-trimester miscarriages and reduces the development of gestational diabetes in PCOS patients. And finally, long-term treatment may also lower the risk of type 2 diabetes and may even cause weight loss in obese patients.⁴⁸ These are all good reasons to consider using this hypoglycemic agent in your practice.

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14. Glueck CF, Wang P, Fontaine R, et al. Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome. Metabolism. 1999;48:511-519.

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19. Vandermolen DT, Ratts VS, Evans WS, et al. 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. 2001;75:310-315.

20. Batukan C, Baysal B. Metformin improves ovulation and pregnancy rates in patients with polycystic ovary syndrome. Arch Gynecol Obstet. 2001;265:124-127.

21. Ng EH, Wat NM, Ho PC. Effects of metformin on ovulation rate, hormonal and metabolic profiles in women with clomiphene-resistant polycystic ovaries: a randomized, double-blinded placebo-controlled trial. Hum Reprod. 2001;16:1625-1631.

22. Sturrock ND, Lannon B, Fay TN. Metformin does not enhance ovulation induction in clomiphene resistant polycystic ovary syndrome in clinical practice. Br J Clin Pharmacol. 2002;53:469-473.

23. De Leo V, la Marca A, Ditto A, et al. Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome. Fertil Steril. 1999;72:282-285.

24. Stadtmauer LA, Riehl RM, Toma SK, et al. Metformin treatment of patients with polycystic ovarian syndrome undergoing IVF increases the number of mature oocytes, the fertilization rate and the number of embryos with changes in the levels of insulin-like growth factors. 1999;72:S12. Abstract nr 0-031.

25. Balen AH, Tan SL, MacDougall J, et al. Miscarriage rates following in vitro fertilization are increased in women with polycystic ovaries and reduced by pituitary desensitization with buserelin. Hum Reprod. 1993;8:959-964.

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34. Fedorcsak P, Storeng R, Dale PO, et al. Obesity is a risk factor for early pregnancy loss after IVF or ICSI. Acta Obstet Gynecol Scand. 2000;79:43-48.

35. Craig LB, Le RW, Kutteh WH. Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss. Fertil Steril. 2002;78:487-490.

36. Glueck CJ, Wang P, Fontaine RN, et al. Plasminogen activator inhibitor activity: an independent risk factor for the high miscarriage rate during pregnancy in women with polycystic ovary syndrome. Metabolism. 1999;48:1589-1595.

37. Velazquez EM, Mendoza SG, Wang P, et al. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein (a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism. 1997;46:454-457.

38. Glueck CJ, Phillips H, Cameron D, et al. Metformin throughout pregnancy in women with polycystic ovary syndrome reduces first-trimester miscarriage from 45% to 5%. J Invest Med. 2000;48:188A.

39. Glueck CJ, Phillips H, Cameron D, et al. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril. 2001;75:46-52.

40. Radon PA, McMahon MJ, Meyer WR. Impaired glucose tolerance in pregnant women with polycystic ovary syndrome. Obstet Gynecol. 1999;94:194-197.

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42. Glueck CJ, Wang P, Kobayashi S, et al. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertil Steril. 2002;77:520-525.

43. Buchanan TA, Xiang AH, Peters RK, et al. Response of pancreatic beta-cells to improved insulin sensitivity in women at high risk for type 2 diabetes. Diabetes. 2000;49:782-788.

44. Sills ES, Perloe M, Palermo GD. Correction of hyperinsulinemia in oligo-ovulatory women with clomiphene-resistant polycystic ovary syndrome: a review of 18 therapeutic rationale and reproductive outcomes. Eur J Obstet Gynecol Reprod Biol. 2000;91:135-141.

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47. Lalau JD, Race JM. Lactic acidosis in metformin therapy. Drugs. 1999;58:55-60; discussion 75-82.

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Dr. Kosasa is Professor and Chief, Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Hawaii, John A. Burns School of Medicine, Honolulu, Hawaii.

Series editor: Richard Legro, MD, is Associate Professor, Department of Obstetrics and Gynecology, Penn State Hershey Medical Center, Hershey, Pa.

Key points

• Metformin has been shown to decrease fasting- and glucose-stimulated insulin levels, basal and GnRH-stimulated LH release, and free and total testosterone, while increasing SHBG in PCOS patients.

• Every study to date has shown that giving 500 mg of metformin three times daily to lean and moderately obese women restores normal menstrual cycles and improves spontaneous ovulation.

• High plasminogen activator activity has been linked to early miscarriage, and metformin reduces PAI activity, suggesting that metformin may be able to reduce the high rate of spontaneous miscarriage in women with PCOS. A pilot study of pregnant women with PCOS using metformin, 1.5 to 2.55 g per day, reduced the rate of first-trimester miscarriage from 73% to 10%.

Thomas Kosasa. Making a case for metformin.

Contemporary Ob/Gyn

2003;3:69-80.