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Departments of Endocrinology (M.L.-R., F.A.-B., J.I.B.-C., E.M.-B., H.F.E.-M.) and Biochemistry-Research (M.A.L.), Hospital Universitario Ramón y Cajal and Universidad de Alcalá, E-28034 Madrid, Spain; and Centro de Investigación Biomédica en Red (CIBER) Fisiopatologia Obesidad y Nutrición (CB06/03) (M.A.L.), Instituto de Salud Carlos III, E-28029 Madrid, Spain
Address all correspondence and requests for reprints to: Héctor F. Escobar-Morreale, M.D., Ph.D., Department of Endocrinology, Hospital Universitario Ramón y Cajal and Universidad de Alcalá, Carretera de Colmenar Viejo Km 9,1. 28034 Madrid, Spain. E-mail: hescobarm.hrc{at}salud.madrid.org.
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Abstract |
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Objective: The aim of the study was to compare the effects of a contraceptive pill on metabolic classic cardiovascular risk factors with those of the insulin sensitizer metformin.
Design: We conducted a randomized, parallel, open-label clinical trial.
Setting: The study was conducted at an academic hospital.
Patients: Thirty-four consecutive PCOS patients were studied.
Interventions: Patients were randomized to oral treatment with metformin (850 mg twice daily) or with the Diane35 Diario pill (35 µg of ethinyl-estradiol plus 2 mg of cyproterone acetate) for 24 wk.
Main Outcome Measures: Hyperandrogenism, lipid profiles, and indexes of glucose tolerance and insulin sensitivity were measured at baseline and after 12 and 24 wk of treatment.
Results: Diane35 Diario resulted in higher reductions in hirsutism score and serum androgen levels compared with metformin. Menstrual regularity was restored in all the patients treated with Diane35 Diario compared with only 50% of those receiving metformin. Plasma apolipoprotein A-I and HDL-phospholipid levels increased with Diane35 Diario, whereas metformin did not induce any change in the lipid profile. On the contrary, the insulin sensitivity index increased with metformin but did not change with Diane35 Diario. No differences in the frequencies of abnormalities of glucose tolerance and dyslipidemia were found between both treatments.
Conclusions: Diane35 Diario appears to be superior to metformin for the control of hyperandrogenism and for the restoration of menstrual regularity in PCOS patients, and it is not associated with any clinically relevant worsening in the classic metabolic cardiovascular risk profile of these women.
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Introduction |
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Although the primary defect in PCOS appears to be an exaggerated androgen synthesis and secretion (4), particularly by ovarian theca cells (5), insulin resistance and obesity may act as triggers of this primary defect (6), explaining the frequent association of PCOS with obesity (6, 7) and with insulin resistance (8).
Cardiovascular risk factors cluster in patients with PCOS and their families, although the demonstration of an increase in cardiovascular morbidity or mortality in these patients is still lacking (9). PCOS patients present increased frequencies of glucose intolerance (up to 30–35%) and type 2 diabetes (7 to 10%) (10, 11), gestational diabetes (12, 13), an unfavorable lipid profile characterized by decreased high-density lipoprotein (HDL)-cholesterol and increased triglycerides levels (14, 15), and even increased low-density lipoprotein (LDL)-cholesterol (16, 17) and an increased risk for hypertension (18). In conceptual agreement, the prevalence of the metabolic syndrome is increased in PCOS patients (19, 20), although this finding may result from the frequent association with obesity (7).
In recent years, the clustering of cardiovascular risk factors in PCOS patients raised concern about the optimal drug therapy for this disorder. Aside from essential lifestyle recommendations and diet in women with weight excess (21) and from therapeutic strategies directed toward restoration of fertility, the chronic pharmacological treatment of PCOS is based on the use of two families of drugs, namely oral contraceptives containing a progestin of low androgenicity or even antiandrogenic properties, or insulin sensitizers.
Oral contraceptives have been the mainstay of PCOS pharmacological therapy for decades (22). However, in nonhyperandrogenic women oral contraceptives might adversely influence insulin resistance and glucose tolerance, raising concern about a possible worsening of the unfavorable metabolic cardiovascular risk profile of PCOS patients and favoring the use of the metabolically safer insulin-sensitizer drugs (23).
Yet at present there is not enough scientifically sound evidence supporting this recommendation (24). The present study summarizes the results of a randomized clinical trial comparing the effects of an antiandrogenic low-dose oral contraceptive pill with those of the insulin sensitizer metformin on the classic metabolic cardiovascular risk factors of PCOS patients.
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Patients and Methods |
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The present study is the first report of a broader project aiming to compare systematically the effects of an oral contraceptive and metformin on classic and nonclassic cardiovascular risk factors and on several indexes of cardiovascular function and performance, by using a randomized, open-label, parallel clinical trial comparing both treatments (www.clinicaltrials.gov; NLM Identifier NCT00428311).
Thirty-four consecutive PCOS patients were recruited. The diagnosis of PCOS was based on the presence of clinical and/or biochemical hyperandrogenism, oligoovulation, and exclusion of secondary etiologies (3, 25). Hirsutism was defined by a modified Ferriman-Gallwey score above 7 (26) and oligomenorrhea (more than six cycles longer than 36 d in the previous year) or amenorrhea (absence of menstruation for 3 consecutive months) (27), or luteal phase progesterone measurements less than 4 ng/ml (12.72 nmol/liter) in women with regular menstrual cycles were considered indicative of oligoovulation. Secondary etiologies, including hyperprolactinemia, thyroid dysfunction, Cushing’s syndrome, congenital adrenal hyperplasia, and virilizing tumors, were actively ruled out in all the patients.
None of the patients had a personal history of hypertension, diabetes mellitus, or cardiovascular events, or received treatment with oral contraceptives, antiandrogens, insulin sensitizers, or drugs that might interfere with blood pressure regulation, lipid profile, or carbohydrate metabolism for the previous 6 months. Written informed consent was obtained from all the participants or their legal representatives, and the study was approved by the local ethics committee and by the Spanish Agency of Medicines.
Interventions
After providing informed consent, patients were randomized to receive an antiandrogenic low-dose oral contraceptive pill in cycles of 28 d (21 pills containing 35 µg of ethinyl-estradiol plus 2 mg of cyproterone acetate followed by 7 placebo pills, Diane35 Diario; Schering España S.A., Madrid, Spain), or 850 mg of metformin (Dianben; Merck Farma y Química S.A., Mollet del Vallés, Barcelona, Spain) twice daily for 24 wk. Simple randomization was conducted using blocks of 10 sealed opaque envelopes assigning five patients to receive Diane35 Diario and five patients to receive metformin. One investigator generated the randomization envelopes, whereas another enrolled and assigned the participants to their arm of treatment. No masking method was used after randomization.
Treatment was started the first day of a spontaneous menstrual cycle or, in women with amenorrhea, after excluding pregnancy by proper testing. Metformin was started at a 425-mg dose twice daily during the first week of treatment with the aim of minimizing gastrointestinal side effects. Women randomized to metformin were advised to use barrier contraception throughout the study. All the patients were instructed to maintain a diet containing 25–30 kcal per kg of body weight per day and moderate physical activity throughout the trial, although these measures were not stressed thereafter.
Main outcome measurements
A single investigator (M.L.-R.) was responsible for clinical, anthropometric, and physical evaluations at baseline and after 12 and 24 wk of treatment. Clinical and anthropometrical variables included the above-mentioned hirsutism score, body mass index (BMI), waist circumference, and waist to-hip ratio. The latter was calculated by dividing the minimal waist circumference by the hip circumference at the level of greater trochanters, using a nonstretchable measuring tape. The percentage of body fat with respect to total body weight was estimated using a body fat monitor (Omron BF 300; Omron Corp., Kyoto, Japan).
Serum and plasma samples were obtained between d 5 and 10 of a spontaneous menstrual bleeding or after excluding pregnancy in amenorrheic patients. After a 3-d 300-g carbohydrate diet and 12-h overnight fasting, basal samples were obtained for measurement of an androgenic profile consisting in serum free testosterone, androstenedione, and dehydroepiandrosterone sulfate concentrations (3). Then, a 75-g oral glucose tolerance test (oGTT) was performed, and samples were obtained for measurement of serum insulin and plasma glucose at 0, 30, 60, 90, and 120 min. Samples were immediately centrifuged, and serum was separated and frozen at – 30 C until assayed.
The technical characteristics of the assays employed for plasma glucose and serum hormone measurements have been described elsewhere (28, 29). Free testosterone levels were calculated from total testosterone and SHBG concentrations (30). The composite insulin sensitivity index was calculated from the circulating glucose and insulin concentrations during the oGTT (31). The areas under the curve (AUC) for glucose and insulin during the oGTT were determined according to the mathematical method described by Tai (32).
Disorders of glucose tolerance were defined from the circulating glucose concentrations at 0 and 120 min during oGTT according to the criteria of the American Diabetes Association (33). Circulating HDL-cholesterol and phospholipid levels were measured by enzymatic methods after precipitation of plasma with phosphotungstic acid and Mg2+ (Roche Molecular Biochemicals GmbH, Mannheim, Germany). Total cholesterol and triglyceride levels were determined by enzymatic methods (Menarini Diagnostica, Florence, Italy). LDL-cholesterol concentrations were estimated by Friedewald’s equation (34). Circulating apolipoprotein (Apo) AI, Apo B100, and lipoprotein (a) levels were determined by kinetic immunonephelometry (Dade Behring, Deerfield, IL). The diagnosis of dyslipidemia was established according to the criteria of the National Cholesterol Education Program Adult Treatment Panel III guidelines (35).
Statistical analysis
Data are shown as means ± SD and raw numbers (percentages) unless otherwise stated. The differences in frequencies among groups were analyzed by 
2 or Fisher’s exact tests as appropriate. The changes in the frequencies of metabolic disorders during the study were analyzed by McNemar’s test, applying a Bonferroni correction to the level of significance to correct for multiple comparisons.
For continuous variables, normality was assessed by the Kolmogorov-Smirnov test, and logarithmic or square root transformations were applied as needed to ensure normality. The baseline characteristics of the patients randomized to receive Diane35 Diario or metformin were compared by unpaired t test. Data were submitted to a repeated-measures general lineal model including the arm of treatment as the between-subjects effect, and the visit (baseline, 12 and 24 wk) as the within-subjects effect. To evaluate the differences in the response to each treatment, the interaction between the between-subjects and within-subjects effect was calculated.
A priori sample size analysis was performed using the online calculator provided by the Massachusetts General Hospital Mallinckrodt General Clinical Research Center (http://hedwig.mgh.harvard.edu/sample_size/size.html). Because the possible advantages of metformin over Diane35 Diario rely on the presumed opposite effects of both drugs on insulin resistance, we used the difference in surrogate markers of insulin resistance as the primary outcome for sample size analysis. An experimental design including a total of 22 patients would have power above 0.80 to detect differences in fasting insulin levels between treatments such as those previously reported using a similar experimental design (36, 37).
Because seven patients discontinued metformin for different reasons (Fig. 1
), results obtained when considering only the patients completing the three visits of the protocol were also confirmed by intention-to-treat analysis assuming, for patients who did not complete the study, that the dependent variables had not changed at the missing visits with respect to the values observed in the previous visit. P < 0.05 was considered statistically significant. Other than sample size calculations, analyses were performed using SPSS 10.0 for Macintosh (SPSS Inc., Chicago, IL).
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Results |
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The study was conducted from April 2004 to December 2006. Thirty-four PCOS patients (age 24 ± 6 yr; BMI 30.0 ± 6.3 kg/m2; nine had a BMI < 25 kg/m2, 10 had a BMI 25–29.9 kg/m2, and 15 had a BMI 
30 kg/m2) agreed to participate and, after giving written informed consent, were randomized to receive Diane35 Diario or metformin. The baseline characteristics of each group are summarized in Table 1, showing no differences among the patients randomized to each drug. All the patients treated with Diane35 Diario completed the study, whereas seven of the 19 patients assigned to metformin (37%) did not complete the study for the reasons detailed in Fig. 1
. Of those, mild to moderate gastrointestinal side effects of metformin were responsible for the dropout in two women, whereas Diane35 Diario was well tolerated by all the women.
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There were no differences with respect to baseline in BMI, waist circumference, waist to hip ratio, and fat mass expressed as percentage of body weight (Fig. 2). When considering PCOS patients as a whole, the hirsutism score and serum free testosterone and androstenedione levels decreased with treatment (Fig. 2), yet detailed analysis of the interaction between the within- and between-subjects effects of the general linear model revealed that these differences resulted mostly from the decrease observed in the patients treated with Diane35 Diario, which was much more marked than those observed with metformin (Fig. 2). Similarly, only treatment with Diane35 Diario induced a decrease in serum dehydroepiandrosterone sulfate levels (Fig. 2). Finally, at the end of the study, menstrual regularity was restored as expected in all the patients on Diane35 Diario but only in six patients (50%) on metformin.
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As occurred with clinical and biochemical hyperandrogenism, the changes observed in the lipid profile were mainly related to the effects of Diane35 Diario. In the women treated with this drug, plasma Apo A-I and HDL-phospholipid concentrations increased significantly, explaining the increase observed in these lipids, and in plasma HDL-cholesterol concentrations, in the whole group of patients when compared with baseline values (Fig. 3). On the contrary, no statistically significant changes were observed in plasma total and LDL-cholesterol, triglycerides, Apo B100, and lipoprotein (a) levels compared with baseline concentrations (Fig. 3).
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Indexes of insulin sensitivity improved in the whole series of PCOS patients, as the insulin sensitivity index increased, and fasting insulin and the insulin AUC during the oGTT decreased, compared with baseline (Fig. 4). Of these changes, only the increase in the insulin sensitivity index was specifically related to the metformin arm (Fig. 4), as suggested by a statistically significant interaction in the general linear model in the analysis of patients completing the study (although this particular interaction was not confirmed by the intention-to-treat analysis). On the contrary, fasting glucose and the glucose AUC during the oGTT showed no changes with respect to baseline values in the whole series of PCOS patients, although fasting glucose increased slightly in the patients treated with Diane35 Diario at the end of the study, compared with the evaluations performed at baseline and after 12 wk of treatment (Fig. 4).
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There were no statistically significant differences in the frequencies of disorders of glucose tolerance and dyslipidemia between the arms of treatment, or at baseline and after 12 or 24 wk of treatment either when considering PCOS patients as a whole or when considering each arm of treatment separately (Table 2).
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Discussion |
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On the other hand, although metformin clearly outperforms Diane35 Diario in improving insulin resistance, our present data indicate that Diane35 Diario is a safe drug when considering classic metabolic cardiovascular risk factors, and might even have favorable effects on the lipid profile of PCOS patients. To this regard, whereas the improvement in insulin resistance found with metformin was not related to any change in the lipid profile of PCOS patients, Diane35 Diario actually induced an increase in plasma Apo A-I and HDL-phospholipid levels, explaining the increase in plasma HDL-cholesterol concentrations observed in the whole group of PCOS patients. This finding is especially important considering that decreased HDL-cholesterol levels are among the commonest lipid abnormalities associated with PCOS (14, 15) and are a recognized cardiovascular risk factor (38). Furthermore, similar results have been reported earlier in the few studies actually comparing metformin with the particular oral contraceptive formulation used here (39, 40).
Considering our present finding with those reported by others, it appears that Diane35 Diario has an effect on the regulation of HDL-cholesterol metabolism. This possibly involves the activity of plasma hepatic lipase activity, an enzyme that is remarkably sex steroid sensitive: estrogens decrease its activity, whereas androgens and androgenic progestins increase it (41). In conceptual agreement, and although certain oral contraceptives may worsen the lipid profile in the general population (42, 43), the amelioration of hyperandrogenism in PCOS women, combined with the antiandrogenic properties of cyproterone acetate and the estrogen component of Diane35 Diario might overcome this undesirable effect, explaining its beneficial effect in PCOS patients (44).
Moreover, Diane35 Diario had a minor impact on glucose tolerance because only a minimal increase in fasting glucose, which was not accompanied by a simultaneous increase in the AUC for plasma glucose during the oGTT, was observed between wk 12 and 24 of treatment. Furthermore, fasting insulin and the AUC for insulin during the oGTT decreased during treatment irrespective of the drug administered, and the frequencies of abnormalities in glucose tolerance did not change significantly during treatment with Diane35 Diario. Therefore, our present results are in agreement with previous reports showing minor effects, if any, of Diane35 Diario on glucose tolerance in PCOS patients (37, 39). Of note, the amelioration of insulin resistance observed during the 24 wk of our study in the patients treated with metformin was not accompanied by an actual reduction in the frequencies of abnormalities in glucose tolerance in these women.
Importantly, treatment with metformin was associated with a high dropout rate in our trial, in the range of the 38% (39) and 45% (40) of patients treated with this drug in previous clinical trials comparing Diane35 Diario with metformin, respectively. Aside from the gastrointestinal side effects characteristic of metformin (45), which were directly related to the dropout of two of our patients, the usually suboptimal response of hirsutism with metformin (46) might have contributed to the loss of patients in our study considering that hirsutism is a frequent referral complaint in young PCOS patients such as ours (47). Nevertheless, the confirmation by intention-to-treat analysis of almost all the results obtained analyzing the patients who completed the study rules out a significant impact of the high dropout rate observed in the metformin arm of our trial. On the contrary, tolerance of Diane35 Diario was excellent, and no patient dropped out of this arm of treatment.
However, our study is not free from limitations, especially the relatively short duration of treatment considering that PCOS is a chronic condition that requires long-term interventions. Yet also, it must be noted that our present results were obtained in a relatively small sample of PCOS patients from Spain in whom overweight and obesity were frequent findings and who presented with the classic hyperandrogenic and oligoovulatory PCOS phenotype. Therefore any extrapolation of these results to PCOS patients of different race, ethnicity, and grade of obesity or presenting with different PCOS phenotypes should be made with prudence.
In summary, Diane35 Diario and metformin are safe and effective single drugs for the treatment of PCOS. However, in unselected patients presenting with this disorder, Diane35 Diario appears to be superior in terms of control of clinical and biochemical hyperandrogenism and restoration of menstrual regularity. Furthermore, this superior efficacy is not obtained at the expense of any clinically significant worsening in the metabolic cardiovascular risk profile of these women, yet, much on the contrary, use of Diane35 Diario might even result in an increase in plasma Apo A-I and HDL-phospholipid levels that is not observed with metformin. Also, and although only metformin improved insulin resistance, this drug did not have a uniform beneficial impact on the disorders of glucose tolerance present in PCOS patients that could justify by itself its routine use in all PCOS cases.
We conclude that Diane35 Diario and metformin should be considered for the treatment of PCOS patients, yet the choice for each drug requires careful consideration of the patient’s clinical characteristics and preference. Furthermore, our present results stress that a putative deterioration of the metabolic cardiovascular risk profile of PCOS patients during administration of Diane35 Diario is not supported by current scientific evidence and therefore should not be weighed against the use of this drug in any treatment decision making.
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Acknowledgments |
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Footnotes |
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Present address for M.L.-R.: Department of Endocrinology, Hospital Universitario de La Princesa, Madrid, Spain.
Disclosure Information: All authors have nothing to declare.
First Published Online April 10, 2007
Abbreviations: Apo, Apolipoprotein; AUC, area(s) under the curve; BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; oGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome.
Received February 7, 2007.
Accepted March 30, 2007.
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, P < 0.05 for the differences in the changes of each variable depending on the arm of treatment, only in the intention-to-treat analysis. 
, P < 0.05 for the differences in the changes of each variable depending on the arm of treatment, both by analysis of patients who completed the study and by intention-to-treat analysis.
