Division of Endocrinology and Metabolism, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA. E-mail: nestler{at}hsc.vcu.edu
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: metformin/oral contraceptives/polycystic ovarian syndrome/type 2 diabetes
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Reproductive endocrinologists are increasingly adopting metformin for the acute treatment of infertility in PCOS, and with good reason. As Dr Homburg points out, evidence indicates that in women with PCOS metformin improves menstrual cyclicity and increases the frequency of ovulation (Velazquez et al., 1997; Nestler et al., 1998
; Glück et al., 1999
; Moghetti et al., 2000
; Batukan and Baysal, 2001
), enhances the success of induction of ovulation with clomiphene citrate (Nestler et al., 1998
; Ng et al., 2001
; Vandermolen et al., 2001
; Kocak et al., 2002
), improves fertility (Vandermolen et al., 2001
; Kocak et al., 2002
) and may even decrease the high rate of early pregnancy loss (Glück et al., 2001
; Jakubowicz et al., 2002
).
Less well recognized is the rationale for the use of metformin as chronic therapy in PCOS. Basic to an understanding of this issue, is the appreciation that PCOS is more than an infertility disorder or cosmetic annoyance. Insulin resistance is a prominent feature of PCOS in both obese and lean women with the disorder, and this fundamental metabolic abnormality places these women at high risk for other disorders linked to insulin resistance, namely type 2 diabetes (Ehrmann et al., 1999; Legro et al., 1999
; Conn et al., 2000
; Norman et al., 2001
; Peppard et al., 2001
; Solomon et al., 2001
; Weerakiet et al., 2001
), hypertension (Rebuffe-Scrive et al., 1989
; Björntorp, 1996
; Holte et al., 1998
), dyslipidaemia (low serum HDL cholesterol and high triglycerides) (Wild et al., 1992
; Talbott et al., 1995
, 1998
; Wild, 1995
; Legro et al., 2001
) and heart disease (Dahlgren et al., 1992
; Birdsall et al., 1997
; Talbott et al., 1998
, 2000
; Paradisi et al., 2001
). Therefore, PCOS is at its core a metabolic disorder with widespread systemic effects. Considering that up to 610% of women of childbearing age may suffer from PCOS (Knochenhauer et al., 1998
; Asuncion et al., 2000
), it may arguably be the most serious general health issue for young women today.
For the purpose of this debate article, I would like to briefly focus on just one of the co-morbidities of PCOS, i.e. type 2 diabetes, and on how the association between PCOS and diabetes must influence our chronic management of the disorder.
![]() |
PCOS: a prediabetic state |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Consistent with these observations is the reported 27% prevalence of PCOS among premenopausal women with type 2 diabetes in an academic diabetes clinic at the Medical College of Virginia Hospitals in the USA (Peppard et al., 2001), and the striking 82% prevalence of anatomically polycystic ovaries among premenopausal women in the diabetes clinic at Middlesex Hospital in the UK (Conn et al., 2000
).
Collectively, the above observations indicate that women with PCOS constitute one of the groups at highest risk for the development of diabetes. Optimally, chronic treatment of PCOS would decrease this risk.
![]() |
Metformin and prevention of diabetes |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Investigators in Finland reported that improved insulin sensitivity achieved through a combination of diet and exercise reduced progression to type 2 diabetes by 58% in individuals with impaired glucose tolerance (Tuomilehto et al., 2001). In the USA, the NIH studied 3234 individuals at high risk for diabetes, as defined by a history of gestational diabetes or presence of impaired glucose tolerance and first-degree relative with diabetes. Progression to type 2 diabetes was reduced by 58% in individuals treated with an intensive diet and exercise and by 31% in individuals treated with metformin alone (Knowler et al., 2002
).
These findings are supported by a preliminary report by Buchanan et al. in which Hispanic women with recent gestational diabetes treated with the insulin-sensitizing drug troglitazone experienced a 56% decrease in progression to type 2 diabetes compared with women who received placebo (Buchanan et al., 2001). The protective effect of insulin-sensitizing treatment to prevent progression to diabetes persisted for 8 months after drug discontinuation, suggesting preservation of pancreatic ß cell function.
These outcome studies indicate that improving insulin sensitivity, with lifestyle changes or drugs, reduces the risk for developing diabetes in individuals with impaired glucose tolerance (Tuomilehto et al., 2001; Knowler et al., 2002
) or a history of gestational diabetes (Buchanan et al., 2001
; Knowler et al., 2002
). Women with PCOS are an insulin-resistant group with high prevalence of impaired glucose tolerance, who are at a markedly increased risk for type 2 diabetes. Therefore, it seems reasonable to presume that the demonstrated efficacy of insulin sensitizing drugssuch as metforminto stave off type 2 diabetes should apply to them as well.
![]() |
Do oral contraceptive pills promote the development of diabetes? |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
When a low dose (Korytkowski et al., 1995) or high dose (Dahlgren et al., 1998
) oral contraceptive pill was administered to women with PCOS for 36 months, insulin sensitivity decreased significantly, as determined directly either by a hyperglycaemic or hyperinsulinaemiceuglycaemic clamp. In one study (Dahlgren et al., 1998
), the aggravation of insulin resistance in PCOS occurred despite suppression of circulating androgens by the oral contraceptive.
Two other studies assessed the effects of 6 month administration of a low dose oral contraceptive pill on oral glucose tolerance in women with PCOS (Nader et al., 1997; Morin-Papunen et al., 2000
). Both studies demonstrated a deterioration of glucose tolerance with administration of an oral contraceptive, as evidenced by higher plasma glucose levels during the oral glucose tolerance test, with no change in plasma insulin concentrations. Body mass index did not change and circulating androgens decreased. Collectively, these findings suggest that the deterioration in glucose tolerance associated with administration of an oral contraceptive was likely to be due to a decrease in insulin sensitivity.
No cohort studies have been performed to assess the risk of developing type 2 diabetes specifically in women with PCOS who used oral contraceptive pills. Nonetheless, two Nurses Health Study cohort studies (NHSI and NHSII) have assessed the risk of type 2 diabetes associated with the use of oral contraceptive pills in a general population of healthy women (Rimm et al., 1992; Chasan-Taber et al., 1997
). NHSI reported that the relative risk of developing type 2 diabetes associated with past use of oral contraceptive pills was 10% greater than the risk in never-users (Rimm et al., 1992
). NHSII assessed the risk of developing type 2 diabetes associated specifically with use of low dose oral contraceptive pills. The adjusted relative risk (RR) was increased in past and current users of oral contraceptive pills compared with never users (RR = 1.2 and 1.6 respectively). These differences did not attain statistical significance, which may have been related to the studys limitations including: brief period of observation (4 years), young age at follow-up (38 years old), and limited number of cases (170).
Collectively, the above studies strongly suggest that oral contraceptive pill use (i) decreases insulin sensitivity and impairs glucose tolerance in women with PCOS, and (ii) may be associated with an increased risk of type 2 diabetes in healthy women.
Therefore, on balance, evidence suggests that insulin-sensitizing drugs such as metformin may retard or prevent women with PCOS from progressing to type 2 diabetes, whereas oral contraceptive pills may actually increase the risk. This is certainly an important consideration in women with PCOS, who are characterized by baseline insulin resistance and are already at high risk for type 2 diabetes.
![]() |
The metamorphosis of PCOS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Batukan, C. and Baysal, B. (2001) Metformin improves ovulation and pregnancy rates in patients with polycystic ovary syndrome. Arch. Gynecol. Obstet., 265, 124127.[Medline]
Birdsall, M.A., Farquhar, C.M. and White, H.D. (1997) Association between polycystic ovaries and extent of coronary artery disease in women having cardiac catheterization. Ann. Intern. Med., 126, 3235.
Björntorp, P. (1996) The android womana risky condition. J. Intern. Med., 239, 105110.[ISI][Medline]
Buchanan, T.A., Xiang, A.H., Peters, R.K., Kjos, S.L., Marroquin, A., Goico, J., Ochoa, C., Tan, S. and Azen, S.P. (2001) Protection from type 2 diabetes persists in the TRIPOD cohort eight months after stopping troglitazone. Diabetes, 50 (Suppl. 2), A81 (Abstract).
Chasan-Taber, L., Willett, W.C., Stampfer, M.J., Hunter, D.J., Colditz, G.A., Spiegelman, D. and Manson, J.E. (1997) A prospective study of oral contraceptives and NIDDM among U.S. women. Diabetes Care, 20, 330335.[Abstract]
Conn, J.J., Jacobs, H.S. and Conway, G.S. (2000) The prevalence of polycystic ovaries in women with type 2 diabetes mellitus. Clin. Endocrinol. (Oxf.), 52, 8186.[ISI][Medline]
Dahlgren, E., Janson, P.O., Johansson, S., Lapidus, L. and Odén, A. (1992) Polycystic ovary syndrome and risk for myocardial infarction. Evaluated from a risk factor model based on a prospective population study of women. Acta Obstet. Gynecol. Scand., 71, 599604.[ISI][Medline]
Dahlgren, E., Landin, K., Krotkiewski, M., Holm, G. and Janson, P.O. (1998) Effects of two antiandrogen treatments on hirsutism and insulin sensitivity in women with polycystic ovary syndrome. Hum. Reprod., 13, 27062711.
Ehrmann, D.A., Barnes, R.B., Rosenfield, R.L., Cavaghan, M.K. and Imperial, J. (1999) Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care, 22, 141146.[Abstract]
Eriksson, J., Franssila-Kallunki, A., Ekstrand, A., Saloranta, C., Widen, E., Schalin, C. and Groop, L. (1989) Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N. Engl. J. Med., 321, 337343.[Abstract]
Glück, C.J., Wang, P., Fontaine, R., Tracy, T. and Sieve-Smith, L. (1999) Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome. Metabolism, 48, 511519.[ISI][Medline]
Glück, C.J., Phillips, H., Cameron, D., Sieve-Smith, L. and Wang, P. (2001) Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil. Steril., 75, 4652.[ISI][Medline]
Holte, J., Gennarelli, G., Wide, L., Lithell, H. and Berne, C. (1998) High prevalence of polycystic ovaries and associated clinical, endocrine, and metabolic features in women with previous gestational diabetes mellitus. J. Clin. Endocrinol. Metab., 83, 11431150.
Homburg, R. (2002) Should patients with polycystic ovarian syndrome be treated with metformin? A note of cautious optimism. Hum. Reprod., 17, 853856.
Jakubowicz, D.J., Iuorno, M.J., Jakubowicz, S., Roberts, K.A. and Nestler, J.E. (2002) Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J. Clin. Endocrinol. Metab., 87, 524529.
Knochenhauer, E.S., Key, T.J., Kahsar-Miller, M., Waggoner, W., Boots, L.R. and Azziz, R. (1998) Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J. Clin. Endocrinol. Metab., 83, 30783082.
Knowler, W.C., Barrett-Connor, E., Fowler, S.E., Hamman, R.F., Lachin, J.M., Walker, E.A. and Nathan, D.M. (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med., 346, 393403.
Kocak, M., Caliskan, E., Simsir, C. and Haberal, A. (2002) Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome. Fertil. Steril., 77, 101106.[ISI]
Korytkowski, M.T., Mokan, M., Horwitz, M.J. and Berga, S.L. (1995) Metabolic effects of oral contraceptives in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab., 80, 33273334.[Abstract]
Legro, R.S., Kunselman, A.R., Dodson, W.C. and Dunaif, A. (1999) Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J. Clin. Endocrinol. Metab., 84, 165169.
Legro, R.S., Kunselman, A.R. and Dunaif, A. (2001) Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. Am. J. Med., 111, 607613.[ISI][Medline]
Lillioja, S., Mott, D.M., Spraul, M., Ferraro, R., Foley, J.E., Ravussin, E., Knowler, W.C. and Bogardus, C. (1993) Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N. Engl. J. Med., 329, 19881992.
Moghetti, P., Castello, R., Negri, C., Tosi, F., Perrone, F., Caputo, M., Zanolin, E. and Muggeo, M. (2000) Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J. Clin. Endocrinol. Metab., 85, 139146.
Morin-Papunen, L.C., Vauhkonen, I., Koivunen, R.M., Ruokonen, A., Martikainen, H.K. and Tapanainen, J.S. (2000) Endocrine and metabolic effects of metformin versus ethinyl estradiol-cyproterone acetate in obese women with polycystic ovary syndrome: a randomized study. J. Clin. Endocrinol. Metab., 85, 31613168.
Nader, S., Riad-Gabriel, M.G. and Saad, M.F. (1997) The effect of a desogestrel-containing oral contraceptive on glucose tolerance and leptin concentrations in hyperandrogenic women. J. Clin. Endocrinol. Metab., 82, 30743077.
Nestler, J.E., Jakubowicz, D.J., Evans, W.S. and Pasquali, R. (1998) Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N. Engl. J. Med., 338, 18761880.
Nestler, J.E., Stovall, D.W., Akhter, N., Iuorno, M.J. and Jakubowicz, D.J. (2002) Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome. Fertil. Steril., 77, 209215.[ISI][Medline]
Ng, E.H., Wat, N.M. and Ho, P.C. (2001) 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., 16, 16251631.
Norman, R.J., Masters, L., Milner, C.R., Wang, J.X. and Davies, M.J. (2001) Relative risk of conversion from normoglycaemia to impaired glucose tolerance or non-insulin dependent diabetes mellitus in polycystic ovarian syndrome. Hum. Reprod., 16, 19951998.
Paradisi, G., Steinberg, H.O., Hempfling, A., Cronin, J., Hook, G., Shepard, M.K. and Baron, A.D. (2001) Polycystic ovary syndrome is associated with endothelial dysfunction. Circulation, 103, 14101415.
Peppard, H.R., Marfori, J., Iuorno, M.J. and Nestler, J.E. (2001) Prevalence of polycystic ovary syndrome among premenopausal women with type 2 diabetes. Diabetes Care, 24, 10501052.
Rebuffe-Scrive, M., Cullberg, G., Lundberg, P.-A., Lindstedt, G. and Björntorp, P. (1989) Anthropometric variables and metabolism in polycystic ovarian disease. Horm. Metab. Res., 21, 391397.[ISI][Medline]
Rimm, E.B., Manson, J.E., Stampfer, M.J., Colditz, G.A., Willett, W.C., Rosner, B., Hennekens, C.H. and Speizer, F.E. (1992) Oral contraceptive use and the risk of type 2 (non-insulin-dependent) diabetes mellitus in a large prospective study of women. Diabetologia, 35, 967972.[ISI][Medline]
Solomon, C.G., Hu, F.B., Dunaif, A., Rich-Edwards, J., Willett, W.C., Hunter, D.J., Colditz, G.A., Speizer, F.E. and Manson, J.E. (2001) Long or highly irregular menstrual cycles as a marker for risk of type 2 diabetes mellitus. JAMA, 286, 24212426.
Talbott, E., Guzick, D., Clerici, A., Berga, S., Detre, K., Weimer, K. and Kuller, L. (1995) Coronary heart disease risk factors in women with polycystic ovary syndrome. Arterioscler. Thromb. Vasc. Biol., 15, 821826.
Talbott, E., Clerici, A., Berga, S.L., Kuller, L., Guzick, D., Detre, K., Daniels, T. and Engberg, R.A. (1998) Adverse lipid and coronary heart disease risk profiles in young women with polycystic ovary syndrome: results of a casecontrol study. J. Clin. Epidemiol., 51, 415422.[ISI][Medline]
Talbott, E.O., Guzick, D.S., Sutton-Tyrrell, K., McHugh-Pemu, K.P., Zborowski, J.V., Remsberg, K.E. and Kuller, L.H. (2000) Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women. Arterioscler. Thromb. Vasc. Biol., 20, 24142421.
Tuomilehto, J., Lindstrom, J., Eriksson, J.G., Valle, T.T., Hamalainen, H., Ilanne-Parikka, P., Keinanen-Kiukaanniemi, S., Laakso, M., Louheranta, A., Rastas, M. et al. (2001) Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N. Engl. J. Med., 344, 13431350.
Vandermolen, D.T., Ratts, V.S., Evans, W.S., Stovall, D.W., Kauma, S.W. and Nestler, J.E. (2001) 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., 75, 310315.[ISI][Medline]
Velazquez, E., Acosta, A. and Mendoza, S.G. (1997) Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet. Gynecol., 90, 392395.
Warram, J.H., Martin, B.C., Krolewski, A.S., Soeldner, J.S. and Kahn, C.R. (1990) Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann. Intern. Med., 113, 909915.[ISI][Medline]
Weerakiet, S., Srisombut, C., Bunnag, P., Sangtong, S., Chuangsoongnoen, N. and Rojanasakul, A. (2001) Prevalence of type 2 diabetes mellitus and impaired glucose tolerance in Asian women with polycystic ovary syndrome. Int. J. Gynaecol. Obstet., 75, 177184.[ISI][Medline]
Wild, R.A. (1995) Obesity, lipids, cardiovascular risk, and androgen excess. Am. J. Med., 98, 27S32S.[Medline]
Wild, R.A., Alaupovic, P. and Parker, I.J. (1992) Lipid and apolipoprotein abnormalities in hirsute women. I. The association with insulin resistance. Am. J. Obstet. Gynecol., 166, 11911196.[ISI][Medline]