The Journal of Pediatrics
Volume 148, Issue 5 , Pages 573-574, May 2006

Expanding applications for metformin in polycystic ovarian syndrome

  • James H. Liu, MD

      Affiliations

    • Department of Reproductive Biology, Case School of Medicine, Cleveland, Ohio
    • Corresponding Author InformationReprint requests: Dr. James Liu, University Hospital, Obstetrics and Gynecology, 11100 Euclid Avenue, MAC7105, Cleveland, OH 44106-5034.
    • ,
  • Arthur H. Bill, Prof.

      Affiliations

    • Department of Obstetrics and Gynecology, University MacDonald Women’s Hospital, Cleveland, Ohio

Article Outline

Abbreviations:  PCOS, Polycystic ovarian syndrome

 

Polycystic ovary syndrome (PCOS) is a one of the most common hormonal disorders in women and is estimated to occur in 6–10% of reproductive-aged women.1 Because PCOS may be associated with multiple etiologies, the criteria for the diagnosis of the PCOS phenotype were recently revised by the 2003 International Consensus Conference. The diagnosis of PCOS is made if two of the following three features are present: (1) oligo-ovulation or anovulation (irregular menstrual cycles or amenorrhea); (2) elevated serum androgens or clinical manifestations of androgen excess; and (3) polycystic-appearing ovaries on ultrasonography.2 Other disorders, such as hyperprolactinemia, nonclassic congenital adrenal hyperplasia, Cushing’s syndrome, and androgen-secreting tumors, must be excluded. PCOS can arise during puberty with development of irregular menstrual cycles, but this condition can also develop with increased weight gain later in reproductive life.

See related article, p 628

Although PCOS is a heterogenous disorder, there is strong evidence that it arises from several defined genetic causes. Among the candidate genes with linkage or association with PCOS are genes associated with insulin secretion and action (insulin receptor, PPARγ, IRS-1, and IRS-2) and those associated with androgen biosynthesis and metabolism (SHBG, CYP17, and CYP11α).3

One of the key metabolic defects of this disorder is insulin resistance and compensatory hyperinsulinemia,4 which is found in PCOS individuals with normal or increased adiposity. These increases in insulin levels are associated with hyperandrogenism caused by increased intraovarian production of androgens by theca cells. Reduction in body weight in some cases will lead to decreased circulating insulin levels, reduced androgens, and resumption of ovulatory menstrual cycles. This management approach, however, is challenging and not often successful.

Another option is to use pharmacologic approaches to reduce insulin levels. Metformin is a biguanide compound that is widely used in the treatment of type II diabetes. Its mode of action is the inhibition of hepatic glucose output, which lowers insulin concentrations. One of the first groups to investigate the use of metaformin in PCOS was Glueck et al.5 Metformin treatment at doses between 1,500 and 2,500 mg/d appears to reduce insulin levels and decrease ovarian androgen production, and can induce ovulatory cycles in more than 50% of patients with PCOS. Subsequent randomized trials with metformin have confirmed its efficacy for the treatment of PCOS patients who have failed to ovulate with and without clomiphene citrate.6, 7 Moreover, metformin has also been reported to reduce the incidence of first-trimester pregnancy loss in women with PCOS.8, 9

Once pregnancy has been achieved, PCOS women are at increased risk for gestational diabetes, pre-eclampsia, and preterm delivery. Metformin use during pregnancy in insulin-dependent diabetics did not cause adverse effects.10 Thus, investigators have explored the feasibility of continuing metformin treatment during pregnancy beyond the first trimester. Several small trials and observational studies, including those by Glueck and co-workers, suggest that metformin may reduce pregnancy complications such as gestational diabetes in PCOS women.11, 12 Subsequent analysis in a cohort of 126 infants born to mothers with PCOS while on metformin treatment have found no evidence of teratogenicity or no adverse effects on birth weight and length or on growth and motor-social development in the first 18 months of life.13

In this issue of The Journal, Glueck et al extended their studies to investigate growth, motor, and social development in breast- and formula-fed infants of metformin-treated women with PCOS.14 Although metformin is excreted into breast milk, available studies suggest that the concentrations are probably not clinically significant and are not associated with hypoglycemia in the infants.15 All infants were born to PCOS women taking metformin throughout their pregnancy and lactation. The present findings show no differences among the infants exposed to breast or formula feeding. Glueck et al should be congratulated for their leadership in conducting clinical studies in PCOS treatment with metformin. Collectively, their prospective findings suggest that metformin treatment appears to be safe during pregnancy and lactation. Nevertheless, their studies are limited by relatively modest sample size and the necessity for long-term follow-up that may identify potential developmental issues. Long-term studies of child development are not trivial and require considerable dedication, psychological expertise, and funding to the investigative team(s).

Back to Article Outline

References 

  1. Franks S . Polycystic ovarian syndrome . N Engl J Med . 1995;333:853–861
  2. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS) . Hum Reprod . 2004;19:41–47
  3. Ehrman D . Polycystic ovary syndrome . N Engl J Med . 2005;352:1223–1236
  4. Ehrmann D , 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;96:520–527
  5. Velazquez EM , Menodoza S , Hamer T , Sosa F , Glueck CJ . Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy . Metabolism . 1994;43:647–654
  6. 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;338:1876–1880
  7. Lord JM , Flight IHK , Norman RJ . Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome . Cochrane Database Syst Rev . 2003;3: CD003053
  8. Jakubowicz DJ , Iuorno MJ , Jakubowicz S , Roberts KA , Nestler JE . Effects of metformin on early pregnancy loss in the polycystic ovary syndrome . J Clin Endocrinol Metab . 2002;87:524–529
  9. Glueck CJ , Wang P , Goldenberg N , Sieve-Smith L . Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin . Hum Reprod . 2002;17:2858–2864
  10. Coetzee EJ , Jackson WP . Oral hypoglycaemics in the first trimester and fetal outcome . S Afr Med J . 1984;65:635–637
  11. Glueck CJ , Wang P , Kobayashi S , Phillips H , Sieve-Smith L . Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome . Fertil Steril . 2002;77:520–525
  12. Vanky E , Salvesen KA , Heimstad R , Fougner KJ , Romundstad P , Carlsen SM . Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women (results of a randomized study) . Hum Reprod . 2004;19:1734–1740
  13. Glueck CJ , Goldenberg N , Pranikoff J , Loftspring M , Sieve L , Wang P . Height, weight, and motor-social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy . Hum Reprod . 2004;19:1323–1330
  14. Glueck CJ , Salehi M , Sieve L , Wang P . Growth, motor, and social development in breast and formula fed infants of metformin treated women with polycystic ovary syndrome . J Pediatr . 2006;148:628–632
  15. Briggs GG , Ambrose PJ , Nageotte MP , Padilla G , Wan S . Excretion of metformin into breast milk and the effect on nursing infants . Obstet Gynecol . 2005;105:1437–1441

PII: S0022-3476(06)00200-9

doi:10.1016/j.jpeds.2006.03.016

Refers to article:

  • Growth, motor, and social development in breast- and formula-fed infants of metformin-treated women with polycystic ovary syndrome

    Charles J. Glueck, Marzieh Salehi, Luann Sieve, Ping Wang
    The Journal of Pediatrics May 2006 (Vol. 148, Issue 5, Pages 628-632.e2)

The Journal of Pediatrics
Volume 148, Issue 5 , Pages 573-574, May 2006

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