Metformin—Comparison with Other Therapies in Ovulation Induction in Polycystic Ovary Syndrome

R. J. Norman

Research Centre for Reproductive Health and Repromed, Department of Obstetrics and Gynaecology, University of Adelaide, The Queen Elizabeth Hospital, Woodville SA 5011, Australia

Address all correspondence and requests for reprints to: Dr. R. J. Norman, Research Centre for Reproductive Health and Repromed, Department of Obstetrics and Gynaecology, University of Adelaide, The Queen Elizabeth Hospital, Woodville SA 5011, Australia. E-mail: robert.norman{at}adelaide.edu.au.

Polycystic ovary syndrome (PCOS) is a common hormonal condition in women and is associated with insulin resistance, disorders of weight and metabolism, hyperandrogenism, anovulation, infertility, and menstrual irregularities. Its etiology is uncertain, but current theories emphasize genetic and intrauterine origins coupled with environmental factors such as diet and altered lifestyle patterns. Effective treatment of PCOS remains controversial but needs to be divided into the main requirements of the patient, depending on whether they are seeking cosmetic improvement, restoration of menstrual function, fertility, weight loss, or amelioration of metabolic changes. In recent years, so-called insulin-sensitizing agents such as metformin have found wide usage in PCOS based on the relationship between hyperinsulinism and ovarian hyperandrogenism. The introduction of these agents has led to questioning of established therapeutic pathways for ovulation induction, which have been based on clomiphene citrate and gonadotropins such as FSH. Much has been written about the value of laparoscopic ovarian drilling whereby diathermy or application of laser surgery to the ovary leads to enhanced ovulation, reduction in testosterone, and increased live birth rates. Although the procedure is less damaging to the ovary than wedge resection, concern has been expressed that adhesions may form that convert anovulatory infertility into tubal obstruction. Nevertheless, there is widespread use of this procedure by gynecologists who either plan a laparoscopy to perform ovarian drilling or operate on polycystic ovaries that are discovered incidentally at laparoscopic surgery.

In this issue, Palomba et al. (1) address the optimal intervention in cases of PCOS in which fertility is the major problem. Patients who had PCOS and were resistant to clomiphene citrate were enrolled and randomized into one of two groups. Both groups underwent laparoscopy with one having a diagnostic procedure only, followed by metformin 850 mg twice per day for 6 months. The second group also underwent laparoscopy but had additional ovarian drilling. The latter group was then given placebo for the next 6 months. At the end of the study, the total ovulation rate was not significantly different between the two groups but the pregnancy rate was higher in the metformin group, whereas the miscarriage rate was lower. As a consequence, the live birth rates were significantly different between the two groups in favor of metformin treatment. Economic analysis of the two therapies strongly favored the metformin group. This well-conducted study indicates that metformin is extremely effective in inducing ovulation and pregnancy and is also justified in terms of cost benefits compared with ovarian surgery.

Women with anovulatory PCOS respond well to weight loss and lifestyle modification as shown by a number of studies in which approximately 5% weight loss will restore ovulation and reduce miscarriage rates (2, 3). Intervention therapies have varied but generally include a hypocaloric diet, exercise, and the use of group therapy. There is no doubting the efficacy of lifestyle intervention, but there has been great difficulty in instituting appropriate weight loss programs. There have been few randomized controlled trials looking at the effect of weight loss in PCOS, although Pasquali et al. (4) have shown that the addition of metformin is more effective than that of placebo alone when dietary intervention is attempted in women with PCOS. More weight loss, greater reduction in waist circumference, more decrease in visceral fat mass, and lower levels of testosterone were found in women who took metformin rather than placebo. Unfortunately, many women with PCOS find lifestyle intervention difficult to institute and maintain or are in the normal weight range and may not benefit from weight loss. In these women with PCOS, medical or surgical therapies have been widely used to induce ovulation and pregnancy.

Clomiphene citrate is a first-line drug that has been available for many years and significantly increases ovulation by interfering with feedback mechanisms in the hypothalamic pituitary ovarian axis (5). It is a safe oral therapy and has relatively few side effects other than an increase in multiple pregnancy rates. It should be used with effective monitoring by blood tests and ultrasound. Rates of ovulation are reported at approximately 70% after the first cycle, although pregnancy rates are much lower. Women who fail to ovulate on low doses of clomiphene are exposed to higher doses of the drug, and those who still do not ovulate are described as clomiphene resistant. Clomiphene resistance is more common in women who are heavier, have higher androgen concentrations, and have excess LH. The recent introduction of aromatase inhibitors instead of clomiphene citrate opens a new avenue in oral therapy for ovulation induction, but more information is required before aromatase inhibitors are used widely to treat symptoms of PCOS.

Laparoscopic ovarian drilling has been introduced as an alternative therapy for women with PCOS who are resistant to clomiphene citrate (6). This procedure has potential side effects of its own, including serious surgical complications and anesthetic risks. The advantage of laparoscopy is that tubal patency can be checked at the same time in a single procedure, and ovarian drilling of either one or both ovaries appears to restore ovulation in a substantial number of patients. Serum concentrations of LH and testosterone decrease rapidly after ovarian drilling with a sustained mid- and long-term effect. The proportion of women with regular menstrual cycles increases substantially after drilling and is sustained at long-term follow-up. Ovulation and pregnancy rates are substantially increased in the period after the operation and appear to be maintained. Resistance to the effects of ovarian drilling include marked obesity, very elevated levels of androgens, and long duration of infertility. Addition of other ovulating agents such as clomiphene citrate or FSH appears to improve the effectiveness of laparoscopic ovarian drilling (7).

Injection of FSH has been very effective over the years but requires a high degree of skill, extensive hormone and ultrasound monitoring, a low tolerance of multiple follicles, and a high cost. Multiple cycles of gonadotropins may be required. A randomized controlled trial of ovarian drilling vs. FSH ovulation induction recently showed that the cumulative rate of pregnancy was 67% with FSH and 34% with ovarian drilling (7). The latter figure was increased to 67% after an additional period of FSH injections. Gonadotropin therapy is inevitably associated with increased multiple births, although skilled use can minimize this to less than 10% per pregnancy by low-dose, step-up procedures. Oral and surgical therapies for PCOS are considerably more cost effective than gonadotropins (8), and the quest for treatments that do not rely on gonadotropins must be encouraged. It is in this environment that metformin has been introduced as an effective treatment of anovulatory PCOS (Fig. 1Go).



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FIG. 1. A cost-effective and evidence-based approach to the anovulatory woman with PCOS who is seeking to become pregnant. The use of metformin alone before clomiphene citrate is controversial and depends upon the facilities available, i.e. specialist reproductive unit or office practice. Similar caution applies to the use of FSH injection, which should be carried out and monitored by experienced staff.

 
The initial use of metformin in the treatment of PCOS by Nestler et al. (9) was initially received with some skepticism but is now accepted to be a valuable and inexpensive therapeutic modality. Insulin resistance is a common feature of PCOS, and there is a documented association between high insulin concentrations and anovulatory infertility. In vitro evidence of the synergistic interaction between LH and insulin in promoting androgen secretion from theca lutein cells in patients with and without PCOS suggested that reduction of insulin action would improve clinical symptoms. Recent systematic reviews have indicated that metformin is highly effective in inducing ovulation and increasing pregnancy rates (10). The numbers needed to treat for ovulation are around 4; there is an improvement in serum insulin levels and a reduction in free testosterone in response to metformin. The drug appears to be safe in early pregnancy with respect to congenital abnormalities, although there are few prospective studies. There are claims that metformin use during pregnancy reduces miscarriage rates and that neonatal and infant outcomes are equivalent to those of the general population, although widespread use of metformin in early pregnancy should be discouraged until more data are available.

The predictors of success of metformin have not been established, although there is some evidence that patients who are substantially overweight do not respond as well. Side effects to metformin include nausea, vomiting, diarrhea, and other forms of gastrointestinal intolerance. Serious side effects such as lactic acidosis are rarely seen in younger patients, but patients should be warned about the interaction between metformin and alcohol. Metformin and lifestyle modification seem to work effectively together and the addition of clomiphene citrate to metformin also appears to be more effective than clomiphene alone (4, 11).

What is the most effective therapy for an anovulatory patient with PCOS who wishes to become pregnant? It is clear that lifestyle modification with caloric restriction and exercise is extremely important in the first stage of any intervention. This should be considered active medical therapy and not as an alternative to other medical intervention. Once the patient has established adequate lifestyle change, ovulations will either occur spontaneously with subsequent pregnancy or additional intervention will be required. Clomiphene citrate is still considered to be a cheap, safe, and easy alternative and would probably be the first-line therapy for anovulatory PCOS. It could be argued, however, that at this stage metformin is equally effective and is introduced initially at a low dose and subsequently building up to 1500–2500 mg/d. Metformin alone can be considered an effective form of therapy (Fig. 2Go). Failure to respond to clomiphene citrate offers the options of laparoscopic drilling, addition of metformin, or the use of gonadotropins. The paper by Palomba et al. (1) suggests that metformin should be the first line of therapy for a clomiphene-resistant patient. It appears to be as effective as laparoscopic drilling in inducing ovulation and may increase the number of pregnancies and reduce the prevalence of miscarriage, giving higher live birth rate. Metformin is free from the side effects and cost of surgery and requires minimal monitoring, thereby further saving expense. If, after several months, ovulation is not occurring, laparoscopic ovarian drilling may be considered to be an effective option or the addition of gonadotropins in a specialized unit where only one or two mature follicles are the objective. The use of in vitro fertilization, although advocated by some practitioners to reduce multiple births, is a last option for anyone with PCOS who is unable to ovulate effectively.



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FIG. 2. Evidence for the effectiveness of metformin alone for ovulation induction vs. placebo [J. M. Lord, I. H. Flight, and R. J. Norman: Cochrane Database Syst Rev, CD003053, 2003 (10 ). Copyright Cochrane Library, reproduced with permission.]

 
The long-term metabolic effects of metformin and of laparoscopic ovarian drilling have yet to be determined. Laparoscopic ovarian drilling is associated with lower androgen and LH concentrations several years later, but, building on the experience of the Diabetes Prevention Program, it would be expected that metformin would have superior long-term effects. The combination of long-term lifestyle modification and metformin may restore menstrual cyclicity, improve fertility, reduce metabolic syndrome, and lower the risk for diabetes. Papers such as those by Palomba et al. (1), which are well-designed randomized, controlled trials with built-in economic analysis, indicate that these new therapies are likely to prove effective in treating PCOS and in supplanting some of the more expensive and risky interventions.

Footnotes

This work was supported by the National Health and Medical Research Council of Australia through a Program Grant to R.J.N.

Abbreviation: PCOS, Polycystic ovary syndrome.

Received August 23, 2004.

Accepted August 24, 2004.

References

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