Correspondence

Treatment of Infertility in the Polycystic Ovary Syndrome

N Engl J Med 2007; 356:1999-2001May 10, 2007

Article

To the Editor:

In their report on the treatment of infertility in women with the polycystic ovary syndrome, Legro et al. (Feb. 8 issue)1 do not mention lifestyle interventions, although a significant proportion of the women in their study were obese. Many studies have shown that weight reduction normalizes ovulation, improves hyperandrogenism, and ultimately increases rates of conception among women with the polycystic ovary syndrome.2 In fact, ovulation rates similar to those achieved in the two recent trials with metformin1,3 have been previously reported in association with lifestyle interventions.4

In addition to infertility in anovulatory women, the polycystic ovary syndrome is associated with metabolic disorders that are linked to insulin resistance and central obesity.5 The administration of clomiphene alone does not target these abnormalities, and in the study by Legro et al. it actually led to increases in weight and insulin resistance. In contrast, weight loss has been associated with a significant reduction of visceral fat, leading to an improved metabolic profile.2

On the basis of this evidence, we believe that lifestyle modifications — increased exercise, a properly supervised diet, and smoking cessation — should be the first and are probably the most important steps in the therapeutic approach to the polycystic ovary syndrome in obese women.

Dimitrios Panidis, M.D., Ph.D.
Dimitrios Farmakiotis, M.D.
Aristotle University of Thessaloniki, 54006 Thessaloniki, Greece

5 References

1
Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551-566
Full Text | Web of Science | Medline

2
Norman RJ, Davies MJ, Lord J, Moran L. The role of lifestyle modification in polycystic ovary syndrome. Trends Endocrinol Metab 2002;13:251-257
CrossRef | Web of Science | Medline

3
Palomba S, Orio F Jr, Falbo A, et al. Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:4068-4074
CrossRef | Web of Science | Medline

4
Clark AM, Thornley B, Tomlinson L, Galletley C, Norman RJ. Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Hum Reprod 1998;13:1502-1505
CrossRef | Web of Science | Medline

5
Matalliotakis I, Kourtis A, Koukoura O, Panidis D. Polycystic ovary syndrome: etiology and pathogenesis. Arch Gynecol Obstet 2006;274:187-197
CrossRef | Medline

To the Editor:

Legro et al. assert that the inferiority of metformin in achieving live births is inconsistent with the findings of previous studies, which show the benefits of metformin in stimulating ovulation. However, in the previous studies, subjects received metformin in an immediate-release form, whereas the subjects in the study by Legro et al. received metformin in the extended-release form, which may not be as efficacious in lowering insulin, androgen, and sex hormone–binding globulin levels.

Clinical experience with extended-release metformin suggests that it is not as effective as the immediate-release form for glycemic control. The nonsignificant decreases in the levels of glucose, insulin, proinsulin, and insulin resistance as determined by homeostasis model assessment associated with metformin in the study by Legro and colleagues provide support for this impression. In an initial study of immediate-release metformin, reported by Nestler and Jakubowicz,1 sex hormone–binding globulin levels increased by 187.5% (vs. a 12.0% increase with extended-release metformin in the study by Legro et al.), and free testosterone decreased by 44.1% (vs. a 15.2% decrease in the free androgen index). Thus, the results of the study by Legro et al. further suggest a decreased potency of extended-release metformin. If the subjects in their study had received immediate-release metformin, it might not have been inferior to clomiphene.

David S.H. Bell, M.B.
University of Alabama at Birmingham, Birmingham, AL 35205
dshbell@yahoo.com

1 References

1
Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 1996;335:617-623
Full Text | Web of Science | Medline

To the Editor:

The trial by Legro et al. was well designed and adequately powered, but the results contradict the findings of a meta-analysis of several earlier trials.1 We are concerned about the very high rate of diarrhea in the metformin group as compared with the clomiphene group (64.9% vs. 23.0%, P<0.05). Although diarrhea is a known adverse effect of metformin, the proportion of subjects with this side effect was three times as high as that in previous trials involving metformin.2,3 Even though the number of subjects who discontinued therapy because of adverse events was similar among the three groups in the study by Legro et al., such adverse events affect compliance and, hence, the efficacy of the drug.4 Our experience with patients with type 2 diabetes for whom metformin therapy has been prescribed is that diarrhea is a major cause of poor compliance. In this study, compliance might have diminished the effect of metformin on the primary end point and insulin-sensitivity markers.

Tarekegn Geberhiwot, M.D., Ph.D.
Alan F. Jones, M.D., D.Phil.
Heart of England NHS Foundation Trust, Birmingham B93 9HW, United Kingdom
tgeberhiwot@nhs.net

4 References

1
Lord JM, Flight IHK, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003;327:951-953
CrossRef | Web of Science | Medline

2
Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427-2443
Full Text | Web of Science | Medline

3
Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403
Full Text | Web of Science | Medline

4
Walker EA, Molitch M, Kramer MK, et al. Adherence to preventive medications: predictors and outcomes in the Diabetes Prevention Program. Diabetes Care 2006;29:1997-2002
CrossRef | Web of Science | Medline

Author/Editor Response

We did not conduct a weight-loss intervention either before or during our trial, as Panidis and Farmakiotis recommend. Evidence of the efficacy of weight loss as a therapy for infertility associated with the polycystic ovary syndrome rests primarily on observational studies, most of which focused on ovulation or other surrogate outcomes, not on pregnancy or live birth. The results of our study strongly suggest that successful ovulation alone does not predict fecundity. The most effective therapy for weight loss in this patient population is not known. Randomized trials in other populations suggest that combination therapies with pharmacotherapy and behavioral support are markedly more effective than lifestyle modification alone.1 The risks of these therapies, including lifestyle alterations, must also be identified. In other populations of women with infertility, severe caloric restriction2 and increases in the frequency of exercise3 have been associated with treatment failure. Although weight loss clearly has other short-term and long-term health benefits, we believe that prospective, randomized trials of weight loss as the primary treatment for infertility in the polycystic ovary syndrome are needed rather than blanket recommendations.

Panidis and Farmakiotis also note that the previous finding that insulin resistance is the primary endocrine defect in the polycystic ovary syndrome is inconsistent with our data, which showed worsened insulin sensitivity yet improved rates of ovulation and pregnancy with clomiphene as compared with metformin. Our conclusion from these data is that perhaps other strategies are needed to guide the treatment of infertility in anovulatory women with the polycystic ovary syndrome.

Bell suggests that the extended-release metformin used in our study may be less effective than immediate-release metformin, and Geberhiwot and Jones note a high rate of side effects in our study. The Food and Drug Administration does not routinely approve extended-release preparations that have diminished efficacy, and, indeed, in type 2 diabetes, extended-release preparations have an equal or improved efficacy with respect to glycemic measures.4,5 Improved efficacy with an extended-release version of metformin has been attributed to lower gastrointestinal side effects and better compliance with the medication regimen.5 In our study, the two groups taking metformin had a similarly high rate of compliance with the medication regimen; the mean compliance rate was 79.3% (interquartile range, 70.0 to 92.8) in the metformin group and 79.7% (interquartile range, 71.0 to 92.3) in the group that received metformin and clomiphene. In addition, the combination-therapy group had a rate of diarrhea (60.3%) that was similar to that in the metformin group (64.9%), although dropout, pregnancy, and live-birth rates were significantly higher and similar to those in the clomiphene group. We attribute the higher dropout rates in the metformin group to patients' dissatisfaction with the diminished rates of ovulation and pregnancy.

Richard S. Legro, M.D.
Pennsylvania State University College of Medicine, Hershey, PA 17033
rsl1@psu.edu

Evan R. Myers, M.D., M.P.H.
Duke University School of Medicine, Durham, NC 27710

for the Cooperative Multicenter Reproductive Medicine Network

5 References

1
Wadden TA, Berkowitz RI, Womble LG, et al. Randomized trial of lifestyle modification and pharmacotherapy for obesity. N Engl J Med 2005;353:2111-2120
Full Text | Web of Science | Medline

2
Tsagareli V, Noakes M, Norman RJ. Effect of a very-low-calorie diet on in vitro fertilization outcomes. Fertil Steril 2006;86:227-229
CrossRef | Web of Science | Medline

3
Morris SN, Missmer SA, Cramer DW, Powers RD, McShane PM, Hornstein MD. Effects of lifetime exercise on the outcomes of in vitro fertilization. Obstet Gynecol 2006;108:938-945
CrossRef | Web of Science | Medline

4
Schwartz S, Fonseca V, Berner B, Cramer M, Chiang YK, Lewin A. Efficacy, tolerability, and safety of a novel once-daily extended-release metformin in patients with type 2 diabetes. Diabetes Care 2006;29:759-764
CrossRef | Web of Science | Medline

5
Fujioka K, Brazg RL, Raz I, et al. Efficacy, dose-response relationship and safety of once-daily extended-release metformin (Glucophage XR) in type 2 diabetic patients with inadequate glycaemic control despite prior treatment with diet and exercise: results from two double-blind, placebo-controlled studies. Diabetes Obes Metab 2005;7:28-39
CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1
Stefano Palomba, Renato Pasquali, Francesco Orio, John E. Nestler. (2009) Clomiphene citrate, metformin or both as first-step approach in treating anovulatory infertility in patients with polycystic ovary syndrome (PCOS): a systematic review of head-to-head randomized controlled studies and meta-analysis. Clinical Endocrinology 70:2, 311-321
CrossRef
2
Tarek Shokeir, Ghada El-Kannishy. (2008) Rosiglitazone as Treatment for Clomiphene Citrate-Resistant Polycystic Ovary Syndrome: Factors Associated with Clinical Response. Journal of Women's Health 17:9, 1445-1452
CrossRef