Correspondence
Metformin in Polycystic Ovary Syndrome
N Engl J Med 2008; 358:1866-1868April 24, 2008
- Article
To the Editor:
The article by Nestler (Jan. 3 issue)1 on the use of metformin for the treatment of the polycystic ovary syndrome provides a very good review of the concerns about future diabetes and cardiovascular disease associated with this disorder and with the metabolic syndrome. However, many are unaware of the potential for endometrial disease in patients with the polycystic ovary syndrome.
Since the patient in the vignette shows signs of estrogen breakthrough bleeding, regular progesterone withdrawal bleeding will be required to prevent the development of endometrial disease, including complex hyperplasia and cancer.2 Therefore, use of a contraceptive agent would be desirable.
It is important to use a contraceptive with low estrogen content and progesterone with minimal androgen side effects or even antiandrogen effects. Intolerance of oral contraceptives in patients with the polycystic ovary syndrome is most often due to either severe androgen side effects or high estrogen content. Another option is a progesterone-containing intrauterine device. If there has been evidence of chronic anovulation or oligo-ovulation for 10 to 15 years, endometrial biopsy should be considered.
2 ReferencesThomas A. Raskauskas, M.D.
Michigan State University College of Human Medicine, Brighton, MI 481161
Nestler JE . Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med 2008;358:47-54
Full Text | Web of Science | Medline2
Hardiman P ,Pillay OC ,Atiomo W . Polycystic ovary syndrome and endometrial carcinoma. Lancet 2003;361:1810-1812[Erratum, Lancet 2003;362:1082.]
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To the Editor:
Nestler unfortunately perpetuates the misconception that metformin enhances insulin sensitivity. To most readers, this would imply that there is a direct interaction, at the cellular level, between insulin and metformin at either the receptor or postreceptor stage in insulin. However, the evidence that we have on this issue1 shows that although metformin enhances the disposal of glucose by peripheral tissues, this action is unrelated to the action of insulin. It is largely for this reason that metformin monotherapy does not cause weight gain or hypoglycemia. Thus, metformin causes an apparent, but not a true, increase in insulin sensitivity. Understanding the pharmacology in this way is important for planning combination therapies and also for explaining treatments to patients.
1 ReferencesRoger A. Fisken, F.R.C.P.
South Tees Hospitals NHS Trust, Northallerton DL6 1JG, United Kingdom
roger.fisken@stees. nhs. uk 1
Natali A ,Ferrannini E . Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review. Diabetologia 2006;49:434-441
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To the Editor:
In the review of metformin in the polycystic ovary syndrome, more emphasis could have been given to the emerging role of nonalcoholic fatty liver disease in the development and progression of the syndrome. About half of patients with the polycystic ovary syndrome also have nonalcoholic fatty liver disease, and these patients have greater insulin resistance and are more likely to have the metabolic syndrome than patients with the polycystic ovary syndrome who do not have nonalcoholic fatty liver disease.1-3 The latter disorder also appears to be involved in the pathogenesis of cardiovascular disease.4
In our preliminary study, insulin sensitivity, as measured by euglycemic clamp, was decreased in young women with both the polycystic ovary syndrome and nonalcoholic fatty liver disease, whereas it was similar between women with the polycystic ovary syndrome alone and healthy controls, who were matched for age and body weight. Moreover, nonalcoholic fatty liver disease strongly predicted the response (i.e., ovulation rate) to a 6-month course of treatment with metformin in patients with the polycystic ovary syndrome.
Thus, nonalcoholic fatty liver disease may help to explain why some but not all patients with the polycystic ovary syndrome have insulin resistance. It may also help to determine in which of these patients metformin might be effectively used.
4 ReferencesGiovanni Targher, M.D.
Giuseppe Lippi, M.D.
Paolo Moghetti, M.D.
University of Verona, 37126 Verona, Italy
giovanni.targher@univr. it 1
Setji TL ,Holland ND ,Sanders LL ,Pereira KC ,Diehl AM ,Brown AJ . Nonalcoholic steatohepatitis and nonalcoholic fatty liver disease in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91:1741-1747
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Gambarin-Gelwan M ,Kinkhabwala SV ,Schiano TD ,Bodian C ,Yeh HC ,Futterweit W . Prevalence of nonalcoholic fatty liver disease in women with polycystic ovary syndrome. Clin Gastroenterol Hepatol 2007;5:496-501
CrossRef | Web of Science | Medline3
Cerda C ,Perez-Ayuso RM ,Riquelme A , et al. Nonalcoholic fatty liver disease in women with polycystic ovary syndrome. J Hepatol 2007;47:412-417
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Targher G ,Arcaro G . Nonalcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis 2007;191:235-240
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To the Editor:
Predictors of the response to metformin therapy in women with the polycystic ovary syndrome have not been clearly identified. We suggest that part of the metformin effect might be related to the higher body iron stores often found in such patients.
It has been reported that women with the polycystic ovary syndrome have an increase in serum ferritin levels that is unrelated to chronic inflammation, indicating that body iron stores are increased in these women.1 This finding is in agreement with the accumulating evidence suggesting a pathogenic role of iron in other insulin-resistant conditions.2 Increased iron stores may contribute to insulin resistance by reducing hepatic insulin extraction and metabolism3 and by decreasing glucose uptake in muscle.4 Insulin can stimulate intestinal iron absorption.1 Therefore, it is possible that metformin decreases iron absorption in patients with the polycystic ovary syndrome, thus breaking the vicious cycle of insulin resistance, increased intestinal iron absorption, and further worsening of insulin sensitivity.1
Increased body iron stores might be considered as an important component of the metabolic derangements seen in the polycystic ovary syndrome. They may also be a potential target of metformin therapy.
4 ReferencesLuca Mascitelli, M.D.
Comando Brigata Alpina Julia, 33100 Udine, Italy
lumasci@libero.it Francesca Pezzetta, M.D.
Ospedale di Tolmezzo, 33028 Tolmezzo, ItalyMark R. Goldstein, M.D.
Fountain Medical Court, Bonita Springs, FL 341351
Luque-Ramirez M ,Alvarez-Blasco F ,Botella-Carretero JI ,Sanchon R ,San Millan JL ,Escobar-Morreale HF . Increased body iron stores of obese women with polycystic ovary syndrome are a consequence of insulin resistance and hyperinsulinism and are not a result of reduced menstrual losses. Diabetes Care 2007;30:2309-2313
CrossRef | Web of Science | Medline2
Swaminathan S ,Fonseca VA ,Alam MG ,Shah SV . The role of iron in diabetes and its complications. Diabetes Care 2007;30:1926-1933
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Niederau C ,Berger M ,Stremmel W , et al. Hyperinsulinaemia in non-cirrhotic haemochromatosis: impaired hepatic insulin degradation? Diabetologia 1984;26:441-444
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Merkel PA ,Simonson DC ,Amiel SA , et al. Insulin resistance and hyperinsulinemia in patients with thalassemia major treated by hypertransfusion. N Engl J Med 1988;318:809-814
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Author/Editor Response
In response to the comments by Raskauskas, the degree to which the polycystic ovary syndrome is associated with an increased risk of endometrial cancer is controversial.1 Nonetheless, I agree that it is prudent to provide treatment to prevent endometrial disease.
Standard practice to prevent endometrial cancer in anovulatory women is either to induce withdrawal bleeding with a progestin every 1 to 3 months or to provide treatment with an oral contraceptive pill. Treatment with metformin is associated with an increased frequency of ovulation, resulting in at least six ovulatory menses per year in 55 to 85% of treated women.2 This frequency of ovulatory menses is consistent with the current standard of care for the prevention of endometrial cancer. My review emphasizes that once an improvement in menstrual cyclicity is achieved with metformin, it is important to document that the menses are ovulatory. If ovulation followed by menstrual bleeding occurs at least every 2 to 3 months, then additional treatment with a progestin or an oral contraceptive pill should not be necessary. If ovulation is not satisfactorily improved, I recommend treatment with periodic progestin or an oral contraceptive pill while treatment with metformin is continued.
In response to Fisken's comments, metformin's primary action is to inhibit hepatic glucose production. However, using the hyperinsulinemic–euglycemic clamp, Diamanti-Kandarakis and colleagues showed that metformin increases insulin-stimulated glucose disposal in normoglycemic women with the polycystic ovary syndrome.3 If we define an insulin sensitizer by its ability to enhance glucose disposal during treatment with insulin, then this observation supports the idea that metformin is an insulin-sensitizing drug, albeit a weak one.
Space limitations precluded a discussion of all coexisting conditions related to insulin resistance in patients with the polycystic ovary syndrome, including nonalcoholic fatty liver disease, discussed by Targher et al., and sleep apnea. Although nonalcoholic fatty liver disease is associated with the polycystic ovary syndrome, it is not known to have a role “in the development and progression” of the disorder. Many women with the polycystic ovary syndrome present with mild elevations in serum hepatic aminotransferase levels, and it is my experience that these values often revert to the normal range during treatment with metformin. This is not surprising, given the literature linking insulin resistance to nonalcoholic fatty liver disease and the reported amelioration of the signs and symptoms of nonalcoholic fatty liver disease after treatment with insulin-sensitizing drugs.4
Mascitelli and colleagues raise the interesting possibility that metformin may enhance insulin sensitivity by inhibiting intestinal absorption of iron. This is not a known effect of metformin, and the hypothesis warrants testing.
4 ReferencesJohn E. Nestler, M.D.
Virginia Commonwealth University, Richmond, VA 23298-0111
jnestler@mcvh-vcu.edu 1
Hardiman P ,Pillay OC ,Atiomo W . Polycystic ovary syndrome and endometrial carcinoma. Lancet 2003;361:1810-1812[Erratum, Lancet 2003;362:1082.]
CrossRef | Web of Science | Medline2
Essah PA ,Apridonidze T ,Iuorno MJ ,Nestler JE . Effects of short-term and long-term metformin treatment on menstrual cyclicity in women with polycystic ovary syndrome. Fertil Steril 2006;86:230-232
CrossRef | Web of Science | Medline3
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 1998;138:269-274
CrossRef | Web of Science | Medline4
Duseja A ,Das A ,Dhiman RK , et al. Metformin is effective in achieving biochemical response in patients with nonalcoholic fatty liver disease (NAFLD) not responding to lifestyle interventions. Ann Hepatol 2007;6:222-226
Web of Science | Medline
