Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Marmara University School of Medicine, Istanbul, Turkey
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: cyproterone acetate/insulin resistance/metformin/oral contraceptive/polycystic ovarian syndrome
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Metformin is an oral biguanide antihyperglycaemic drug used for decades for the treatment of type 2 diabetes mellitus. Recent studies have indicated that this drug improves metabolic abnormalities, results in decreased androgen levels, and improves menstrual pattern and ovulatory function in women with PCOS (Velazquez et al., 1994, 1997
; Nestler and Jakubowicz, 1996
, 1997
; Diamanti-Kandarakis et al., 1998
; Morin-Papunen et al., 1998
; Nestler et al., 1998
; Moghetti et al., 2000
). Furthermore, it has been suggested that metformin improves the dyslipidaemia which is commonly associated with PCOS (Wild et al., 1985
; Talbott et al., 1995
; Moghetti et al., 2000
). There is not enough evidence to suggest the insulin-reducing medications as first-line therapy for women with PCOS. First, not all women with PCOS are insulin resistant, and it is not clear that insulin resistance is the primary defect of the heterogeneous disorder of PCOS (Taylor, 2000
). More important, none of the drugs has been administered for long enough periods of time or to a sufficient number of patients to prove superiority over other established therapies (Taylor, 2000
).
In hyperandrogenic women, who do not require fertility, oral contraceptive pills (OC) are usually the first choice of treatment. They typically suppress ovarian and adrenal androgen production, increase sex hormone-binding globulin (SHBG) levels, and improve clinical hirsutism scores in 80% of patients (Erenus et al., 1996
; Taylor, 2000
). However, suppression of ovarian and/or adrenal androgenism does not diminish insulin resistance (Geffner et al., 1986
; Singer et al., 1989
) and, in addition, OC may induce impairment of glucose tolerance, and elevate insulin levels in women with PCOS as well as in healthy women (Wynn et al., 1979
; Godsland et al., 1990
; Korytkowski et al., 1995
). They also do not improve, or may even worsen, the dyslipidaemia associated with PCOS (Prelevic et al., 1990
; Korytkowski et al., 1995
). Therefore, addition of an insulin-lowering drug to the OC treatment may have metabolic benefits in women with PCOS. In addition, it may further improve hyperandrogenaemia since it has been shown that insulin, in synergy with LH, has a direct ovarian effect to modulate ovarian androgen secretion (Taylor, 2000
; Attia et al., 2001
).
Therefore, we designed the present study to compare the clinical, endocrine and metabolic effects of the two treatment modalities: (i) the commonly used ethinyl estradiol (EE)cyproterone acetate (CA) OC; and (ii) metformin added to this OC, in non-obese women with PCOS.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
All the women were euthyroid (serum TSH level, 0.355.5 mU/l) and had normal prolactin levels (serum prolactin level, 3.424 µg/l). Their serum testosterone levels were <7 nmol/l, and dehydroepiandrosterone sulphate (DHEA-S) levels were <19 µmol/l. If the basal serum 17OH-progesterone level was >6 nmol/l, an adrenocorticotrophic hormone (ACTH) stimulation test was done to exclude patients with late-onset congenital adrenal hyperplasia (Speroff et al., 1994). Serum 17OH-progesterone levels were determined before and 30 min after an i.v. injection of 0.25 mg of synthetic ACTH (Synacthen; Ciba, Basel, Switzerland). Women who had an increase of >10 nmol/l in the serum 17OH-progesterone level after ACTH stimulation were excluded from the study (Elter et al., 1999
). A serum cortisol level of >140 nmol/l after an overnight dexamethasone suppression test was also an exclusion criterion (Elter et al., 1999
). Women were excluded from the study if an adnexal mass was noted on pelvic sonography.
After 3 days on a high carbohydrate diet (300 g/day) and an overnight fast of 1012 h, all subjects underwent an oral glucose tolerance test (OGTT; a load of 75 g glucose in 300 ml water). Venous blood samples were drawn at 0, 30, 60 and 120 min for plasma glucose determination. Women who were found to have diabetes according to published criteria (American Diabetes Association, 1997) were excluded from the study. Women who had any other known endocrinological disease, and those taking drugs known to affect carbohydrate or lipid metabolism and OGTT results during the 6 months preceding the study, were also excluded.
Medical histories were taken, and all subjects underwent gynaecological examination and pelvic ultrasonography. Weight and height were obtained and BMI [weight (kg)/height (m)2] was calculated. Waist and hip circumferences were measured to the nearest centimeter with a soft tape at the narrowest part of the torso and at the widest part of the gluteal region, and waist:hip ratio (WHR) was calculated.
All laboratory investigations and ultrasound examinations were performed in the early follicular phase (days 35) of spontaneous bleeding or withdrawal bleeding induced with medroxyprogesterone acetate at baseline or with the OC after the follow-up period. All ultrasound examinations were performed by one operator (G.I.), either transabdominally or transvaginally (3.5 and 5 MHz sector probes respectively; GE Logiq 200 Pro, GE Medical Systems, Milwaukee, WI, USA). Polycystic-appearing ovaries were defined sonographically as the presence of multiple (>10), small (28 mm in diameter) follicles in the periphery (in one plane) and increased stromal echogenicity as described (Adams et al., 1986). Ovarian volumes were also measured, and volume determinations were carried out using the formula for the volume of an ellipsoid: 0.523xlength (cm)xwidth (cm)xthickness (cm) (Robert et al., 1995
). The study was approved by the Institutional Review Board at Marmara University, and written informed consent was obtained from each subject.
Protocol
After baseline clinical (BMI, WHR, FerrimanGallwey score and ovarian volume), endocrinological (FSH, LH, testosterone, free testosterone, androstenedione, 17OH-progesterone, DHEA-S and SHBG) and metabolic [fasting glucose and insulin, total cholesterol, triglycerides, high density lipoprotein (HDL)-cholesterol and low density lipoprotein (LDL)-cholesterol] work-ups, the subjects were randomized to either the OC group or to the OC + metformin group. Women in the OC group were prescribed EE, 35 µg, and CA, 2 mg (Diane 35; Schering AG, Berlin, Germany) for 21 days per month followed by a 7 day pill-free period. Women in the OC + metformin group were prescribed metformin 500 mg three times per day orally (for the first 15 days, 500 mg twice daily for adequate compliance (Glucophage; Ilsan and Iltas Pharmaceuticals, Istanbul, Turkey) in addition to the above-mentioned pill. The women were prospectively followed for 4 months, and at the end of this follow-up period, the baseline evaluation was repeated. Glucose:insulin ratio [GIR; glucose (mmol/l)/insulin (pmol/l)] was calculated for each subject at baseline and after treatment.
Assignment
Randomization was produced from a computer-generated random list, where even and odd numbers were allocated OC and OC + metformin treatments respectively.
Masking
Clinical parameters (BMI, WHR, FerrimanGallwey score and ovarian volume) of the subjects were evaluated by the same person, who was blind to the type of treatment. No attempt was made to mask the treatments from the subjects, and placebo was not used.
Assays
Blood samples were obtained through venepuncture, and centrifuged within 2 h after withdrawal. Serum was stored at 20°C; it was assayed for FSH, LH, testosterone, SHBG and DHEA-S with chemiluminescent immunoassay kits (FSH, LH and testosterone kits were provided by Roche Diagnostics Corporation, Indianapolis, IN, USA; SHBG and DHEA-S kits were provided by Diagnostic Products Corporation, Los Angeles, CA, USA), and for free testosterone, androstenedione and 17OH-progesterone with commercially available radioimmunoassay kits (17OH-progesterone kit was provided by Diagnostic Systems Laboratories, Inc., Webster, TX, USA; free testosterone and androstenedione kits were provided by Diagnostic Products Corporation).
The average intra-assay coefficients of variation (CV) were 1.5% for FSH, 0.7% for LH, 1.4% for testosterone, 9% for free testosterone, 6.1% for SHBG, 9.5% for DHEA-S, 6.5% for androstenedione, and 4.1% for 17OH-progesterone. The average total CV were 3.8% for FSH and 1.6% for LH. The average inter-assay CV were 2.2% for testosterone, 8.5% for free testosterone, 8% for SHBG, 13% for DHEA-S, 10% for androstenedione, and 6.8% for 17OH-progesterone.
Plasma glucose concentrations were measured with the glucose oxidase technique using an auto-analyser (BM/Hitachi 917; Boehringer Mannheim GmbH, Mannheim, Germany). Serum insulin concentrations were measured by chemiluminescent enzyme immunoassay (Diagnostic Products Corporation). Intra-assay and total CV for different values of insulin were between 3.8 and 4.8%, and 4.2 and 7.6% respectively. Fasting serum triglyceride, total cholesterol, HDL- and LDL-cholesterol concentrations were determined by using the BM/Hitachi 917 auto-analyser utilizing enzymatic calorimetric assays with intra- and inter-assay CV of <10% (Roche Diagnostics Corporation).
Sample size calculation and statistical analysis
A power calculation showed that a sample size of 20 in each group has a power of 80% to detect a 0.56 kg/m2 difference in BMI change during treatment, between groups at the 5% level of significance. The corresponding values were 0.03 for the WHR and 0.04 mmol/pmol for the GIR. Randomization and power analysis were made by using StatMate version 1.01 (GraphPad Software, San Diego, CA, USA).
Differences in baseline characteristics between the two groups were analysed by Student's t-test. Clinical, endocrine and metabolic features were analysed by repeated measures analysis of variance (ANOVA). In this repeated measures model, simple contrasts were used to test differences between baseline and after-treatment values. While evaluating the effect of treatment on hirsutism, analysing hirsute and non-hirsute subjects together may not be conclusive. Therefore, in addition to analysis of the FerrimanGallwey scores in all subjects, we also analysed only hirsute subjects in each group.
To analyse the role of weight loss in metformin's effect on insulin sensitivity, we calculated percentage changes in BMI, WHR and GIR during treatment, for each subject. After the median value for the percentage change in BMI was determined, subjects in the OC + metformin group were divided into two groups by using this median as the cut-off value. GIR in each group was compared by using repeated measures ANOVA. Correlations between changes in BMI, WHR and GIR were also analysed in the OC + metformin group by using the Pearson's correlation test. SPSS Release 10.0 (SPSS, Inc., Chicago, IL, USA) was used for these analyses. Values are expressed as mean ± SD, and P < 0.05 was considered statistically significant.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
After treatment, women in the OC group had a slight, but insignificant, increase in BMI compared with those in the OC + metformin group, who had a significant decrease (P = 0.003; Table I; Figure 2
). WHR also decreased significantly in the OC + metformin group (P = 0.001), while there was no change in the OC group (Table I
; Figure 3
). Fasting GIR improved significantly, mainly due to the decreased insulin levels, in the OC + metformin group (P = 0.006 and 0.001 for GIR and fasting insulin respectively), while OC treatment alone did not cause any significant change in the other group (Table II
; Figure 4
). Treatment caused no change in serum lipids in the two groups, except total cholesterol levels in the OC group. Total cholesterol levels increased significantly in the OC group (P = 0.002), but insignificantly in the OC + metformin group (Table II
). However, these differences between groups did not reach significance (Tables I and II
).
|
|
|
When percentage changes during treatment were analysed in the OC + metformin group, there was no correlation between BMI, WHR and GIR (P > 0.05). The median value for the percentage change in BMI in the OC + metformin group was 2.5%. Mean (± SD) percentage increase in the GIR for the subjects, who lost more weight than 2.5%, was 47.20 ± 24.25% (95% CI, 24.7769.62). The corresponding value for the subjects who lost less weight than 2.5% was 14.79 ± 45.26% (41.41 to 70.99). The change in the GIR was comparable between these groups (P = NS).
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
There is considerable evidence that OC can cause deterioration of glucose tolerance in normal women (Wynn et al., 1979; Godsland et al., 1990
; Watanabe et al., 1994
) as well as in women with PCOS (Korytkowski et al., 1995
; Nader et al., 1997
). However, it has been recently reported that insulin sensitivity did not decrease during OC treatment in non-obese women with PCOS (Cibula et al., 2002
). The results of studies involving CA have been controversial. One study has shown a significant decrease in insulin sensitivity, as measured by using the euglycaemic clamp in women with PCOS before and after 6 months of EECA OC treatment (Dahlgren et al., 1998
). However, in other studies, either no effects on insulin sensitivity (Pasquali et al., 1986
; Morin-Papunen et al., 2000a
) or impairment of carbohydrate metabolism (Prelevic et al., 1990
) have been observed. In the present study, fasting GIR, which is a reliable indicator of insulin sensitivity in women with PCOS (Legro et al., 1998
), did not change significantly in the OC group. However, it increased significantly in the OC + metformin group. Therefore, EECA OC treatment does not improve, or may even adversely affect insulin sensitivity in women with PCOS (Dahlgren et al., 1998
), and glucose tolerance should be monitored during the OC treatment. Adding metformin to the OC treatment may have beneficial effects in terms of carbohydrate metabolism, and may be considered especially in those subjects with a familial predisposition to type 2 diabetes mellitus.
Metformin either decreases or causes no change in BMI and WHR, when used alone in women with PCOS (Velazquez et al., 1994, 1997
; Nestler and Jakubowicz, 1996
; Acbay and Gundogdu, 1996
; Ehrmann et al., 1997
; Morin-Papunen et al., 1998
; Kolodziejczyk et al., 2000
; la Marca et al., 2000
). However, in most of these studies, metformin has not been administered specifically to non-obese women with PCOS, or non-obese subjects have not been analysed separately. To our knowledge, the present study is the second in which metformin has been administered to non-obese women with PCOS. Only one study (Nestler and Jakubowicz, 1997
) has given metformin to normal weight or thin women in a randomized, placebo-controlled study, and reported no change in BMI but a decrease in the WHR after metformin treatment. In the present study, metformin, in combination with the OC, resulted in significant decreases in BMI and WHR among non-obese women. The EECA OC treatment alone did not cause any change in BMI and WHR, as it has been reported previously (Morin-Papunen et al., 2000
).
It has been suggested that insulin resistance in PCOS women is, at least partly, related to obesity and fat distribution and not entirely to PCOS itself (Morin-Papunen et al., 2000b). Whether metformin improves insulin sensitivity independently of weight loss remains to be determined (Ehrmann, 1999
). One way to address this question would be the separate analysis of the subjects who maintained, and those who lost, their weight during the treatment. To our knowledge, no investigators have analysed the study subjects in this manner. In most of the studies, metformin administration either improved or had no effect on insulin sensitivity, in parallel with changes in BMI (Velazquez et al., 1994
; Acbay and Gundogdu, 1996
; Ehrmann et al., 1997
; Pasquali et al., 2000
). This may support the idea that metformin improves insulin sensitivity through weight loss. However, correlations between changes in BMI, WHR and insulin sensitivity have not been analysed in these studies. In addition, there are studies in which improvement of insulin sensitivity has been observed without a significant change in BMI (Diamanti-Kandarakis et al., 1998
; Morin-Papunen et al., 1998
). In the present study, we divided the subjects in the OC + metformin group into two groups by using the median percentage change in BMI as the cut-off value. `Higher weight loss' patients had more improvement in insulin sensitivity than `lesser weight loss' patients. However, the difference was not significant, possibly due to a type II error. Another way to address the question of the role of weight loss is to analyse the correlations between changes in BMI and insulin sensitivity. In the present study, we could not observe any correlation between percentage changes in BMI, WHR and insulin sensitivity.
In the present study, adding metformin to the OC treatment resulted in a greater reduction in androstenedione and a higher increase in SHBG. Similar changes in serum androgens and SHBG levels have been reported previously with metformin treatment in women with PCOS (Velazquez et al., 1994; Diamanti-Kandarakis et al., 1998
). The increase in SHBG in the present study may be partly explained by the weight loss observed in the OC + metformin group (Guzick et al., 1994
; Jakubowicz and Nestler, 1997
). This further improvement of hyperandrogenaemia after adding an insulin-lowering drug to the OC supports the idea that insulin, in synergy with LH, has a direct effect to modulate serum androgen levels (Taylor, 2000
; Attia et al., 2001
).
PCOS is commonly associated with low HDL and high triglyceride levels (Wild et al., 1985; Talbott et al., 1995
). It has been previously reported that the OC containing EE and CA induced additional adverse effects on lipids in women with PCOS (Dahlgren et al., 1998
). In the present study, we observed a significant increase in total cholesterol levels in the OC group, but not in the OC + metformin group. Data on the effects of metformin on lipids in women with PCOS suggest either no effect or an improvement of the lipid profile (Velazquez et al., 1994
; Crave et al., 1995
; Morin-Papunen et al., 1998
; Ibanez et al., 2000
; Moghetti et al., 2000
). A well-controlled trial (Moghetti et al., 2000
) reported a 10% increase in serum HDL levels after 12 months of metformin treatment with only a minor change in BMI. According to one group (Crave et al., 1995
), diet, neither alone nor combined with metformin, caused any significant change in serum HDL, triglyceride and total cholesterol levels, despite a favourable change in BMI. Surprisingly, the impact of weight loss on lipids has not been well studied in subjects with PCOS (Hoeger, 2001
). One study reported a 15% decrease in total cholesterol and a 10% increase in HDL-cholesterol levels after 6 months of very-low-calorie diet in obese PCOS women (Andersen et al., 1995
).
Recent findings regarding the long-term metabolic consequences of PCOS show that the optimal treatment should correct the hyperandrogenaemia, yet at the same time improve insulin sensitivity and dyslipidaemia. Given that there is not enough evidence to suggest metformin as first-line therapy for women with PCOS, especially for those whose chief complaints are cosmetic problems, e.g. hirsutism and acne, adding metformin to the OC treatment may result in additional benefits. This combination may be suggested for the treatment of women with PCOS, especially those who are at high risk for diabetes. In addition, the present study supports the suggestion that metformin has some benefits in non-obese women with PCOS. However, long-term clinical consequences of these mostly hormonal benefits need to be investigated.
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Adams, J., Polson, D.W. and Franks, S. (1986) Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br. Med. J., 293, 355359.[ISI][Medline]
American Diabetes Association (1997) Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care, 20, 11831197.[ISI][Medline]
Andersen, P., Seljeflot, I., Abdelnoor, M., Arnesen, H., Dale, P.O., Lovik, A. and Birkeland, K. (1995) Increased insulin sensitivity and fibrinolytic capacity after dietary intervention in obese women with polycystic ovary syndrome. Metabolism, 44, 611616.[ISI][Medline]
Attia, G.R., Rainey, W.E. and Carr, B.R. (2001) Metformin directly inhibits androgen production in human thecal cells. Fertil. Steril., 76, 517524.[ISI][Medline]
Chang, R.J., Nakamura, R.M., Judd, H.L. and Kaplan, S.A. (1983) Insulin resistance in nonobese patients with polycystic ovarian disease. J. Clin. Endocrinol. Metab., 57, 356359.[Abstract]
Cibula, D., Fanta, M., Hill, M., Fanta, M., Skrha, J. and Zivny, J. (2002) Insulin sensitivity in non-obese women with polycystic ovary syndrome during treatment with oral contraceptives containing low-androgenic progestin. Hum. Reprod., 17, 7682.
Crave, J.C., Fimbel, S., Lejeune, H., Cugnardey, N., Dechaud, H. and Pugeat, M. (1995) Effects of diet and metformin administration on sex hormone-binding globulin, androgens, and insulin in hirsute and obese women. J. Clin. Endocrinol. Metab., 80, 20572062.[Abstract]
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.
Diamanti-Kandarakis, E., Kouli, C., Tsianateli, T. and Bergiele, A. (1998) Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome. Eur. J. Endocrinol., 138, 269274.[ISI][Medline]
Dunaif, A., Graf, M., Mandeli, J., Laumas, V. and Dobrjansky, A. (1987) Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J. Clin. Endocrinol. Metab., 65, 499507.[Abstract]
Dunaif, A., Segal, K.R., Futterweit, W. and Dobrjansky, A. (1989) Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes, 38, 11651174.[Abstract]
Ehrmann, D.A. (1999) Insulin-lowering therapeutic modalities for polycystic ovary syndrome. Endocrinol. Metab. Clin. North Am., 28, 423438.[ISI][Medline]
Ehrmann, D.A., Cavaghan, M.K., Imperial, J., Sturis, J., Rosenfield, R.L. and Polonsky, K.S. (1997) Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab., 82, 524530.
Elter, K., Erel, C.T., Cine, N., Ozbek, U., Hacihanefioglu, B. and Ertungealp, E. (1999) Role of the mutations Trp8 « Arg and Ile15 « Thr of the human luteinizing hormone ß-subunit in women with polycystic ovary syndrome. Fertil. Steril., 71, 425430.[ISI][Medline]
Erenus, M., Yucelten, D., Gurbuz, O., Durmusoglu, F. and Pekin, S. (1996) Comparison of spironolactone-oral contraceptive versus cyproterone acetate-estrogen regimens in the treatment of hirsutism. Fertil. Steril., 66, 216219.[ISI][Medline]
Ferriman, D. and Gallwey, J.D. (1961) Clinical assessment of body hair growth in women. J. Clin. Endocrinol. Metab., 21, 14401447.[ISI]
Geffner, M.E., Kaplan, S.A., Bersch, N., Golde, D.W., Landaw, E.M. and Chang, R.J. (1986) Persistence of insulin resistance in polycystic ovarian disease after inhibition of ovarian steroid secretion. Fertil. Steril., 45, 327333.[ISI][Medline]
Godsland, I.F., Crook, D., Simpson, R., Proudler, T., Felton, C., Lees, B., Anyaoku, V., Devenport, M. and Wynn, V. (1990) The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N. Engl. J. Med., 323, 13751381.[Abstract]
Guzick, D.S., Wing, R., Smith, D., Berga, S.L. and Winters, S.J. (1994) Endocrine consequences of weight loss in obese, hyperandrogenic, anovulatory women. Fertil. Steril., 61, 598604.[ISI][Medline]
Hacihanefioglu, B., Seyisoglu, H., Karsidag, K., Elter, K., Aksu, F., Yilmaz, T. and Gurol, A.O. (2000) Influence of insulin resistance on total renin level in normotensive women with polycystic ovary syndrome. Fertil. Steril., 73, 261265.[ISI][Medline]
Hoeger, K. (2001) Obesity and weight loss in polycystic ovary syndrome. Obstet. Gynecol. Clin. North Am., 28, 8597.[ISI][Medline]
Ibanez, L., Valls, C., Potau, N., Marcos, M.V. and de Zegher, F. (2000) Sensitization to insulin in adolescent girls to normalize hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia, and hyperinsulinism after precocious pubarche. J. Clin. Endocrinol. Metab., 85, 35263530.
Jakubowicz, D.J. and Nestler, J.E. (1997) 17 alpha-Hydroxyprogesterone responses to leuprolide and serum androgens in obese women with and without polycystic ovary syndrome offer dietary weight loss. J. Clin. Endocrinol. Metab., 82, 556560.
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.
Kolodziejczyk, B., Duleba, A.J., Spaczynski, R.Z. and Pawelczyk, L. (2000) Metformin therapy decreases hyperandrogenism and hyperinsulinemia in women with polycystic ovary syndrome. Fertil. Steril., 73, 11491154.[ISI][Medline]
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]
la Marca, A., Egbe, T.O., Morgante, G., Paglia, T., Cianci, A., De Leo, V. and Ciani, A. (2000) Metformin treatment reduces ovarian cytochrome P-450c17alpha response to human chorionic gonadotrophin in women with insulin resistance-related polycystic ovary syndrome. Hum. Reprod., 15, 2123.
Legro, R.S., Finegood, D. and Dunaif, A. (1998) A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab., 83, 26942698.
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.
Morales, A.J., Laughlin, G.A., Butzow, T., Maheshwari, H., Baumann, G. and Yen, S.S. (1996) Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features. J. Clin. Endocrinol. Metab., 81, 28542864.[Abstract]
Morin-Papunen, L.C., Koivunen, R.M., Ruokonen, A. and Martikainen, H.K. (1998) Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertil. Steril., 69, 691696.[ISI][Medline]
Morin-Papunen, L.C., Vauhkonen, I., Koivunen, R.M., Ruokonen, A., Martikainen, H.K. and Tapanainen, J.S. (2000a) Endocrine and metabolic effects of metformin versus ethinyl estradiolcyproterone acetate in obese women with polycystic ovary syndrome: a randomized study. J. Clin. Endocrinol. Metab., 85, 31613168.
Morin-Papunen, L.C., Vauhkonen, I., Koivunen, R.M., Ruokonen, A. and Tapanainen, J.S. (2000b) Insulin sensitivity, insulin secretion, and metabolic and hormonal parameters in healthy women and women with polycystic ovarian syndrome. Hum. Reprod., 15, 12661274.
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. and Jakubowicz, D.J. (1996) Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N. Engl. J. Med., 335, 617623.
Nestler, J.E. and Jakubowicz, D.J. (1997) Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens. J. Clin. Endocrinol. Metab., 82, 40754079.
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.
Pasquali, R., Fabbri, R., Venturoli, S., Paradisi, R., Antenucci, D. and Melchionda, N. (1986) Effect of weight loss and antiandrogenic therapy on sex hormone blood levels and insulin resistance in obese patients with polycystic ovaries. Am. J. Obstet. Gynecol., 154, 139144.[ISI][Medline]
Pasquali, R., Gambineri, A., Biscotti, D., Vicennati, V., Gagliardi, L., Colitta, D., Fiorini, S., Cognigni, G.E., Filicori, M. and Morselli-Labate, A.M. (2000) Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J. Clin. Endocrinol. Metab., 85, 27672774.
Prelevic, G.M., Wurzburger, M.I., Trpkovic, D. and Balint-Peric, L. (1990) Effects of a low-dose estrogenantiandrogen combination (Diane-35) on lipid and carbohydrate metabolism in patients with polycystic ovary syndrome. Gynecol. Endocrinol., 4, 157168.[ISI][Medline]
Robert, Y., Dubrulle, F., Gaillandre, L., Ardaens, Y., Thomas-Desrousseaux, P., Lemaitre L. and Dewailly, D. (1995) Ultrasound assessment of ovarian stroma hypertrophy in hyperandrogenism and ovulation disorders: visual analysis versus computerized quantification. Fertil. Steril., 64, 307312.[ISI][Medline]
Singer, F., Bhargava, G. and Poretsky, L. (1989) Persistent insulin resistance after normalization of androgen levels in a woman with congenital adrenal hyperplasia. A case report. J. Reprod. Med., 34, 921922.[ISI][Medline]
Speroff, L., Glass, R.H. and Kase, N.G. (1994) Hirsutism. In Speroff, L., Glass, R.H. and Kase, N.G. (eds), Clinical Gynecologic Endocrinology and Infertility. Williams & Wilkins, Baltimore, 483513.
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.
Taylor, A.E. (2000) Insulin-lowering medications in polycystic ovary syndrome. Obstet. Gynecol. Clin. North Am., 27, 583595.[ISI][Medline]
Velazquez, E.M., Mendoza, S., Hamer, T., Sosa, F. and Glueck, C.J. (1994) Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism, 43, 647654.[ISI][Medline]
Velazquez, E., Acosta, A. and Mendoza, S.G. (1997) Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet. Gynecol., 90, 392395.
Watanabe, R.M., Azen, C.G., Roy, S., Perlman, J.A. and Bergman, R.N. (1994) Defects in carbohydrate metabolism in oral contraceptive users without apparent metabolic risk factors. J. Clin. Endocrinol. Metab., 79, 12771283.[Abstract]
Wild, R.A., Painter, P.C., Coulson, P.B., Carruth, K.B. and Ranney, G.B. (1985) Lipoprotein lipid concentrations and cardiovascular risk in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab., 61, 946951.[Abstract]
Wynn, V., Adams, P.W., Godsland, I., Melrose, J., Niththyananthan, R., Oakley, N.W. and Seed, M. (1979) Comparison of effects of different combined oral-contraceptive formulations on carbohydrate and lipid metabolism. Lancet, i, 10451049.
Submitted on November 5, 2001; resubmitted on January 16, 2002; accepted on March 15, 2002.