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Clinical Research Center Studies |
Departments of Medicine (D.A.E., M.K.C., J.I., J.S., R.L.R., K.S.P.) and Pediatrics (R.L.R.), University of Chicago, Chicago, Illinois 60637
Address all correspondence and requests for reprints to: David A. Ehrmann, M.D., Department of Medicine, Section of Endocrinology, University of Chicago Pritzker School of Medicine, 5841 South Maryland Avenue, MC 1027, Chicago, Illinois 60637. E-mail: dehrmann{at}medicine.bsd.uchicago.edu
Abstract
Hyperinsulinemia contributes to the ovarian androgen overproduction and glucose intolerance of polycystic ovary syndrome (PCOS). We sought to determine whether metformin would reduce insulin levels in obese, nondiabetic women with PCOS during a period of weight maintenance and thus attenuate the ovarian steroidogenic response to the GnRH agonist leuprolide. All subjects (n = 14) had an oral glucose tolerance test, a GnRH agonist (leuprolide) test, a frequently sampled iv glucose tolerance test, graded and oscillatory glucose infusions, and a dual energy x-ray absorptiometry scan before and after treatment with metformin (850 mg, orally, three times daily for 12 weeks).
With weight maintenance (body mass index: pretreatment, 39.0 ± 7.7 kg/m2; posttreatment, 39.1 ± 7.9 kg/m2), oral glucose tolerance, insulin sensitivity (Si; 0.87 ± 0.82 vs. 0.74 ± 0.63 x 10-5 min-1/pmol·L), and the relationship between Si and first phase insulin secretion (AIRg vs. Si) were not improved by metformin. The insulin secretory response to glucose, administered in both graded and oscillatory fashions, was likewise unaltered in response to metformin. Free testosterone levels remained about 2-fold elevated (pretreatment, 26.6 ± 12.7 pg/mL; posttreatment, 22.4 ± 9.8 pg/mL). Both basal and stimulated LH and FSH levels were unaffected by metformin. The mean responses to leuprolide of 17-hydroxyprogesterone (pretreatment, 387 ± 158 ng/dL; posttreatment, 329 ± 116 ng/dL) as well as those of the other ovarian secretory products (androstenedione, dehydroepiandrosterone, progesterone, and estradiol) were not attenuated by metformin.
We conclude that hyperinsulinemia and androgen excess in obese nondiabetic women with PCOS are not improved by the administration of metformin.
HYPERINSULINEMIA appears to play a key pathogenetic role in the ovarian androgen overproduction (1, 2, 3) and glucose intolerance (4, 5, 6, 7) of polycystic ovary syndrome (PCOS). Thus, interventions that improve insulin resistance and lower the often extreme elevations in circulating insulin should ameliorate the androgen excess of PCOS. In fact, this has been demonstrated in response to weight loss (8), diazoxide (9), and, most recently, metformin (10). Although it has been clear from these studies that a reduction in androgen levels correlated with a reduction in hyperinsulinemia, it has not been possible to determine whether ovarian androgen production per se was reduced or, alternatively, whether free androgen concentrations declined because of the insulin-related decrease in serum levels of sex hormone-binding globulin (SHBG) (10). In addition, controversy has persisted as to whether these salutary effects on insulin and androgen levels in women with PCOS (10) are directly related to the drug itself or result at least in part from the weight loss that often accompanies its use (11).
The present study was thus undertaken in an attempt to resolve these controversies. Specifically, we sought to determine whether metformin, when given to obese nondiabetic women with PCOS, results in a reduction of hyperinsulinemia while body weight is maintained. In addition, we sought to determine whether the reduction in insulin levels would attenuate the 17-hydroxyprogesterone (17-PROG) hyperresponsiveness to a GnRH agonist challenge that characterizes the ovarian dysfunction of women with PCOS (12, 13, 14).
Materials and Methods
Selection and definition of study subjects
Twenty women with hyperandrogenemia [plasma free testosterone,
>10 pg/mL (34.6 pmol/L)] (12) were recruited. All subjects were
anovulatory (cycle lengths >35 days) and had a history of infertility,
hirsutism, or acne. To avoid sample bias, the results of GnRH agonist
testing were not used to identify or select subjects. The ovarian
source of androgen excess was established in all subjects by a
dexamethasone androgen-suppression test, as previously described (12).
Dexamethasone suppression of androgen levels was considered abnormal if
the plasma free testosterone concentration remained elevated [
8
pg/mL (27.7 pmol/L)] after administration of dexamethasone (2 mg daily
for 4 days) (12). Although ultrasound evidence of polycystic ovaries
was not used as a diagnostic or inclusion criterion, all but one
subject had polycystic ovaries by transvaginal ultrasonography using a
5-megahertz/900 phased array sector vaginal probe (GE RT
3000, General Electric Corp., Milwaukee, WI) (15).
Exclusion criteria included the use of medications known to alter insulin secretion or action, endocrinopathies, including nonclassic 21-hydroxylase deficiency congenital adrenal hyperplasia, Cushing’s syndrome, hyperprolactinemia, or thyroid dysfunction. Women with a prior history of glucose intolerance (including gestational diabetes) or noninsulin-dependent diabetes mellitus (NIDDM) (16) were excluded. A negative screening pregnancy test was required.
The racial/ethnic composition of the study subjects was representative of that of women attending the clinics: 65% were Caucasian, and 35% were African-American. All protocols were approved by the institutional review board of the University of Chicago. Written informed consent was obtained from each subject.
Because of the possible effect of variations in insulin secretion (17, 18) and ovarian function at different phases of the menstrual cycle, women were studied in the follicular phase (days 1–8) of the cycle or after 2 or more months of amenorrhea. After completion of the studies at baseline, subjects met with the Clinical Research Center nutritionist for a detailed dietary history. Throughout the course of the study, caloric intake was monitored and adjusted with the aim of maintaining the subject’s body weight. After baseline studies (see below) were completed, metformin was administered at an initial dose of one 850-mg tablet orally per day, with weekly escalation by 850-mg increments to a maximum daily dosage of 2550 mg (three tablets) per day. Subjects received metformin for 12 weeks, at which time the pretreatment studies were repeated.
Because of the impact of body fat distribution on androgen levels, glucose tolerance, and possibly insulin secretion (19), waist/hip ratios were measured, and body composition and fat distribution were assessed by dual energy x-ray absorptiometry scan (20) before and after treatment.
Experimental protocols
Studies were performed after an overnight fast. Intravenous catheters were placed into antecubital veins. Where appropriate, one catheter was used for administration of iv glucose or other secretagogues, and the catheter in the contralateral forearm was used for blood sampling. The blood sampling arm was heated to obtain arterialized venous samples.
GnRH agonist test. Blood samples were obtained before (i.e. at baseline; 20-min intervals, four times) and 0.5, 1, 16, 20, and 24 h after the administration of 10 µg/kg leuprolide acetate (TAP Pharmaceuticals, Deerfield, IL). Serum LH and FSH were measured at baseline, 0.5 h, and 1 h, and steroid hormones were measured at 0, 16, 20, and 24 h. The plasma steroids assayed included total testosterone, estradiol, 17-PROG, dehydroepiandrosterone (DHEA), androstenedione, and progesterone.
Oral glucose tolerance test. Blood samples were obtained at baseline and at 30-min intervals for 3 h for measurement of glucose and insulin after ingestion of a 75-g glucose load. Glucose tolerance was evaluated using the criteria of the WHO (16).
Frequently sampled iv glucose tolerance test (IVGTT). A frequently sampled IVGTT was performed as previously described by Bergman et al. (21). Blood samples for glucose and insulin determinations were obtained every 5 min for 20 min, at which time 0.3 g/kg glucose was administered as an iv bolus. At 20 min, iv tolbutamide (125 mg/m2; Orinase, Upjohn, Kalamazoo, MI) was administered.
Graded iv glucose infusion. A low dose graded glucose infusion protocol designed to determine ß-cell responsiveness over the physiological range of plasma glucose concentrations was performed as previously described (22). Blood samples were drawn at 10-min intervals for 30 min to define baseline levels of glucose, insulin, and C peptide. A graded iv infusion of 20% dextrose was then started at a rate of 1 mg/kg·min for 40 min, followed by 2, 3, 4, 6, and 8 mg/kg·min each for 40 min. Blood samples were drawn at 10, 20, 30, and 40 min of each period for measurement of glucose, insulin, and C peptide.
Insulin secretory responses to oscillatory glucose administration. To determine whether the ability of the ß-cell to be entrained (i.e. respond to repetitive increases and decreases in glucose with parallel changes in insulin secretion) is affected by metformin, a 20% glucose solution was administered in an oscillatory pattern with a period of 144 min, as previously described (23, 24). This period most effectively brings out defective entrainment of pulsatile insulin secretion by glucose (23). Samples were drawn every 15 min for the remaining 12 h for the measurement of glucose, insulin, and C peptide.
Assay methods
Plasma glucose was measured immediately using a glucose analyzer (YSI model 2300 STAT, Yellow Springs Instruments Co., Yellow Springs, OH). The coefficient of variation of this method is less than 2%. Serum insulin was assayed by a double antibody technique (25), with a lower limit of sensitivity of 20 pmol/L and an average intraassay coefficient of variation of 6%. The cross-reactivity of proinsulin in the RIA for insulin is approximately 40%. Plasma C peptide was measured as previously described (26). The lower limit of sensitivity of the assay is 0.02 pmol/mL, and the intraassay coefficient of variation averaged 6%. Serum LH and FSH concentrations were measured by polyclonal RIAs developed to optimize their specificity for bioactive molecular species (14, 27). LH and FSH were measured in terms of the National Human Pituitary Program primary standards I-2 and I-3, respectively. Results are expressed in terms of the Second International Reference Preparations, which yielded parallel dose-response curves with these standards: 1.0 ng LH I-2 is equivalent to 4.8 mIU WHO 80/552, and 1.0 ng FSH I-3 is equivalent to 4.0 mIU WHO 78/549 in these assays. The minimal detectable concentrations of LH and FSH were 0.48 IU/L (0.1 ng/mL) and 0.6 IU/L (0.15 ng/mL), respectively. The intraassay midrange coefficient of variation averaged 5%; the interassay coefficient of variation was 12%. Plasma concentrations of testosterone, estradiol, and DHEAS were measured using kits obtained from Diagnostic Products Corp. (Los Angeles, CA), Pantex (Santa Monica, CA), and Diagnostic Systems (Webster, TX). The free fraction of plasma testosterone and the concentration of SHBG were measured by a competitive protein binding assay as previously described (28). The intra- and interassay coefficients of variation were 3.8% and 8.7%, respectively. Plasma levels of 17-PROG, androstenedione, and DHEA were determined by RIA after these steroids had been chromatographically purified as previously reported (14). The precision of these assays averaged 7% (intraassay coefficient of variation) and 12% (interassay coefficient). Serum levels of metformin were analyzed by HPLC at Hazelton Laboratories (Madison, WI).
Data analysis and statistical methods
Summary measures derived from IVGTT. Summary measures
derived from the IVGTT included 1) the area under the insulin response
curve from 0–10 min (AUCinsulin); 2) the insulin response to glucose,
expressed as the percent rise (AUCinsulin from 0–10 min divided by
half the AUCinsulin from -20 to 0 min); 3) the first phase insulin
secretion (AIRg) in response to glucose calculated as the mean
increment above basal of insulin values measured at 2, 3, 4, 5, 6, 8,
and 10 min; 4) insulin sensitivity index (Si), calculated using the
MINMOD program provided by Dr. R. N. Bergman (21, 29); the Si
represents the increase in net fractional glucose clearance rate per
unit change in plasma insulin concentration after the iv glucose load;
and 5) the relationship between the AIRg relative to the degree of
insulin resistance (Si). This relationship is calculated from the
equation Z
= (ln [(Si x 10-5) x AIRg)] +
3.802)/0.5613, which defines the relationship for these parameters in
normal subjects (30). The percentile ranking based on the value for
Z is obtained from the table of the standard normal
distribution.
Determination of insulin secretion rates. Standard kinetic parameters for C peptide clearance were used to derive insulin secretory rates (ISRs). These standard parameters were calculated from 200 decay curves of biosynthetic C peptide obtained in normal, obese, and NIDDM subjects (31). Age, sex, and body surface area were accounted for. These parameters were derived by application of a two-compartment model of C peptide distribution as proposed by Eaton et al. (32). These parameters were used to derive, in each 15-min interval between blood sampling, the ISR from the plasma C peptide concentrations by deconvolution as previously described (33). The C peptide profiles were smoothed with a two-point moving average before calculation of the ISRs.
Relationship between glucose and ISR derived from graded glucose infusion. Baseline glucose, insulin, C peptide, and ISR were calculated as the average of the four baseline samples, the first of which was drawn 20 min after insulin administration. During each glucose infusion period, average glucose and ISR were calculated. The mean ISR for each period was then plotted against the corresponding mean glucose level, thereby establishing a dose-response relationship.
Spectral analysis. Each individual ISR and glucose profile from the oscillatory glucose infusion protocol was submitted to spectral analysis to determine whether the insulin oscillations were entrainable as previously reported (34, 35). Each spectrum was normalized, assuming the total variance of each series to be 100%, and is expressed as the normalized spectral power. Slow trends were removed by the first difference filter before each spectrum was calculated with the window closing procedure using a Tukey window with a width of 24 data points as described by Jenkins and Watts (35).
Statistical analysis. The significance of differences between pretreatment and posttreatment measures was determined using the paired t test. Analysis of covariance was performed as appropriate. For all analyses, a two-tailed P < 0.05 was considered to indicate statistical significance. Unless otherwise noted, all results are expressed as the mean ± SD. Data analysis was performed using StatView 4.5 and SuperANOVA for the Macintosh (Abacus Concepts, Berkeley, CA).
Results
Complete data from 14 of the 20 subjects could be analyzed. Two subjects withdrew from the study for reasons unrelated to the use of metformin. One subject was pregnant after 2 weeks of metformin treatment and was withdrawn from the study. Because 17-PROG levels are highest in the luteal phase of the menstrual cycle, three subjects’ data were excluded from analysis when it became apparent from their progesterone levels (serum progesterone >150 ng/dL) at the time of leuprolide testing that they had ovulated and were studied in the luteal phase. Eleven of the 14 subjects tolerated the maximum metformin dose of 850 mg, three times daily; modest gastrointestinal symptoms were experienced by three subjects that necessitated a reduction in dosage to 850 mg, twice daily. Compliance with the medication was confirmed by pill count at weekly visits during treatment as well as by measurement of metformin levels (769 ± 507 ng/mL) during the treatment phase.
Clinical characteristics of study subjects
All study subjects were obese, and most were markedly so (mean
BMI, 39.9 ± 7.7 kg/m2; range, 27.3–52.5
kg/m2; Table 1
). Because alterations in body
fat distribution can affect insulin sensitivity independently of body
weight (36), precise assessment of regional fat distribution was made
by dual energy x-ray absorptiometry scan, in addition to the standard
waist/hip ratio measure. With the exception of one subject who had a
waist/hip ratio below 0.80, all subjects had the characteristic central
obesity of PCOS. Body weight, BMI, and body fat distribution remained
stable over the course of the study.
|
Glucose tolerance. By design, no subject had NIDDM. For the
entire cohort of 14 subjects, the mean glucose concentrations at 0 and
120 min postglucose challenge were within the normal range both before
and after treatment (Fig. 1). Although glucose tolerance
was normal in 9 (64%) of the 14 subjects, 5 (36%) met criteria for
impaired glucose tolerance. This prevalence of impaired glucose
tolerance is representative of that observed in other populations of
women with PCOS (4, 7).
|
).
The insulinogenic index, calculated by dividing the AUCinsulin by the
AUCglucose, did not differ significantly posttreatment (8.3 ±
3.2) from the pretreatment value (9.1 ± 3.9). There was no
significant difference in any outcome measure (below) when data were
dichotomized by glucose tolerance status. Responses during the frequently sampled IVGTT
Insulin sensitivity and first phase insulin secretory responses to
iv glucose. Insulin resistance was profound at baseline and did
not improve in response to metformin, as reflected in an unchanged mean
Si. This finding held true even in subjects who experienced weight loss
(Fig. 2). There was no significant effect of weight
change on change in Si, as assessed by analysis of
covariance. As expected, there was a significant negative correlation
between BMI and Si (r = -0.64; P < 0.02).
|
).
|
Responses to graded glucose infusion
The relationship between glucose and ISR obtained during the
graded glucose infusion protocol is depicted in Fig. 4.
Metformin administration did not alter the ISR to glucose over the
entire range of achieved glucose concentrations. Over the physiological
glucose range (5–9 mmol/L), the insulin secretion rate pretreatment
did not differ from that after treatment (712 ± 279
vs. 682 ± 244 pmol/min).
|
The ability of the oscillatory infusion of exogenous glucose to entrain insulin secretion was modestly impaired at baseline, as reflected in a mean value for normalized spectral power similar to that previously reported in subjects with modest glucose intolerance (5). There was a significant negative correlation between the degree of glucose intolerance, as reflected in the plasma glucose concentration 120 min postglucose challenge, and the normalized spectral power for ISR (r = -0.59; P = 0.04). The impairment in the ability of the ß-cell to detect and respond to alterations in plasma glucose concentration did not improve after metformin treatment; the mean normalized spectral power for ISR posttreatment (9.2 ± 5.1) was not significantly different from the baseline (8.3 ± 5.3).
Androgen and gonadotropin levels
Total testosterone levels were elevated at baseline and declined modestly (18%) after metformin treatment. A modest, but significant, reduction in the total testosterone response to leuprolide was observed after metformin administration (pretreatment, 102 ± 45 ng/dL; posttreatment, 84 ± 34 ng/dL; P < 0.05). However, the level of free testosterone, the biologically active fraction, which was approximately 2.5-fold elevated above normal at baseline (12), did not change in response to metformin. These findings can be accounted for at least in part by the significant decline in serum SHBG levels posttreatment.
The LH and FSH levels as well as the ratio of LH to FSH were within the normal range at baseline and did not change after treatment. Likewise, the early LH response to leuprolide was not altered after metformin treatment. There were slight, but statistically insignificant, reductions in the responses of 17-hydroxyprogesterone (15%) and androstenedione (12%) posttreatment. There was no reduction in DHEA or estradiol responses to leuprolide after metformin administration.
Discussion
The present study was undertaken to assess the impact of metformin on measures of insulin secretion, insulin action, and ovarian steroid production in obese nondiabetic women with PCOS. We postulated that metformin would attenuate the steroidogenic response to ovarian stimulation by the GnRH agonist, leuprolide acetate. This postulate is based upon the finding that metformin treatment ameliorated the hyperinsulinemia and hyperandrogenemia of PCOS (10) and that insulin appears to modulate the 17-hydroxylase and 17,20-lyase activities of the ovarian steroid-forming P450c17 (13, 37). This enzyme is characteristically abnormally regulated in women with the ovarian androgen excess of PCOS (13, 37) as reflected in the 17-hydroxyprogesterone response to GnRH agonists, including nafarelin, buserelin, and leuprolide (12, 14, 38, 39, 40, 41). By studying metformin-treated obese women during a period of weight maintenance, we have avoided the confounding effects of weight reduction on both insulin secretion and androgen levels (8). In addition, since defects in both insulin secretion and action are demonstrable once NIDDM is established (23), we limited our study to nondiabetic subjects.
We found that the profound insulin resistance in obese women with PCOS was not improved by metformin, as assessed by the Si derived from a frequently sampled IVGTT. Similar conclusions were reached in this population when insulin sensitivity was assessed by an iv insulin tolerance test (42) or the hyperinsulinemic-euglycemic clamp technique (43). Our data are also consistent with the finding that there is no effect of metformin on hyperinsulinemia or hyperandrogenemia that is independent of weight loss in obese normal (44) and obese hirsute (11) women. In fact, we found that even in those women who lost weight during metformin treatment, there was no significant improvement in insulin sensitivity. These results contrast with the recently reported findings of Velazquez (10). What could account for this difference? Firstly, Velazquez used the insulin response to an oral glucose challenge as the measure of insulin action. Conclusions from oral glucose tolerance test results must be made cautiously given the test’s poor reproducibility and high coefficient of variation (45, 46). Another explanation for our divergent findings may be that our study group comprised women with moderate to extreme obesity. The ability of metformin to alter insulin sensitivity in individuals with obesity of this magnitude appears to be limited. Kahn, et al. (30) reported that substantial reductions in BMI are necessary to improve Si in individuals whose BMI exceeds 30 kg/m2. Thus, even in the subset of women who experienced a modest weight reduction, Si remained unchanged. Alternative explanations for our findings include the possibilities that metformin was administered in a dose or for a duration that was insufficient or that nondiabetic women with PCOS may respond in a unique manner to the drug.
We have previously shown that subtle alterations in ß-cell function are demonstrable in nondiabetic women with PCOS, as assessed by the insulin secretory response to mixed meals (47) and to graded and oscillatory infusions of glucose (5). In the present study, these alterations in insulin secretion were again demonstrable, even in subjects whose glucose tolerance was normal. The magnitude of the defect, as assessed by the ability to entrain insulin secretion in response to an oscillatory glucose infusion, correlated with the degree of glucose intolerance. Nonetheless, ß-cell dysfunction was not improved by metformin treatment, presumably because glucose tolerance was unchanged.
Of interest, we found that the disposition index derived from the IVGTT is approximately constant within any given individual. That is, there appears to be a compensatory alteration in first phase insulin secretion in response to the change in insulin sensitivity, albeit modest, after metformin treatment. This is reflected in the lack of change in Z score/percentile rank and is readily appreciated when the relationship between these measures is plotted. The slope describing this relationship is virtually identical pre- and posttreatment.
Finally, metformin did not alter the baseline or stimulated levels of gonadotropins or ovarian steroids in women with PCOS. In light of the fact that there was persistent hyperinsulinemia in the subjects, the lack of an androgen response remains consistent with the initial hypothesis. This is corroborated by in vitro data demonstrating that metformin has no effect on insulin-stimulated thecal cell androgen production in culture (48). We thus conclude that there is no direct effect of metformin on gonadotropin or ovarian steroid production that is independent of weight loss.
In summary, we have shown that metformin does not significantly reduce the hyperinsulinemia or excess androgen secretion in obese nondiabetic women with PCOS. Development of an agent capable of achieving these effects should prove useful in treating the metabolic complications of this syndrome.
Acknowledgments
The authors thank Jody Dushay and Eunice Yim for their assistance in coordinating this study. Dr. Zubie Sheikh kindly performed and evaluated the transvaginal ultrasonography. The nursing staff of the Clinical Research Center provided expert care of the subjects who participated in the study.
Footnotes
1 This work was supported in part by Grants DK-02315, HD-06308, and
DK-07011-17; General Clinical Research Center Grant MO1-RR-00055, and
in part by LIPHA Pharmaceuticals. 
2 Supported by a Research Career Development Award from the Juvenile
Diabetes Foundation International.
Received July 31, 1996.
Revised September 9, 1996.
Accepted October 3, 1996.
References
as the cause of polycystic ovary
syndrome. Fertil Steril. 53:785–791.[Medline]
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L. A. Stadtmauer, B. C. Wong, and S. Oehninger Should patients with polycystic ovary syndrome be treated with metformin?: Benefits of insulin sensitizing drugs in polycystic ovary syndrome--beyond ovulation induction Hum. Reprod., December 1, 2002; 17(12): 3016 - 3026. [Abstract] [Full Text] [PDF]
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 R. Murray Recognizing the Signs of Metabolic Syndrome and Polycystic Ovary Syndrome in a Caucasian Adolescent Girl: Differentiating Type 2 From Type 1 Diabetes Diabetes Spectr, October 1, 2002; 15(4): 227 - 231. [Full Text] [PDF]
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E. Seli and A. J. Duleba Should patients with polycystic ovarian syndrome be treated with metformin? Hum. Reprod., September 1, 2002; 17(9): 2230 - 2236. [Abstract] [Full Text] [PDF]
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V. De Leo and A. la Marca Metformin and FSH for induction of ovulation in women with polycystic ovarian syndrome Hum. Reprod., September 1, 2002; 17(9): 2481 - 2482. [Full Text] [PDF]
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K. Elter, G. Imir, and F. Durmusoglu Clinical, endocrine and metabolic effects of metformin added to ethinyl estradiol-cyproterone acetate in non-obese women with polycystic ovarian syndrome: a randomized controlled study Hum. Reprod., July 1, 2002; 17(7): 1729 - 1737. [Abstract] [Full Text] [PDF]
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S. A. Arslanian, V. Lewy, K. Danadian, and R. Saad Metformin Therapy in Obese Adolescents with Polycystic Ovary Syndrome and Impaired Glucose Tolerance: Amelioration of Exaggerated Adrenal Response to Adrenocorticotropin with Reduction of Insulinemia/Insulin Resistance J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1555 - 1559. [Abstract] [Full Text] [PDF]
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