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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0441
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 8 3128-3135
Copyright © 2007 by The Endocrine Society

Insulin Sensitivity after Metformin Suspension in Normal-Weight Women with Polycystic Ovary Syndrome

Stefano Palomba, Angela Falbo, Tiziana Russo, Francesco Manguso, Achille Tolino, Fulvio Zullo, Pierpaolo De Feo and Francesco Orio, Jr.

Department of Obstetrics and Gynecology (S.P., A.F., T.R., F.Z.), University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy; Departments of Clinical and Experimental Medicine (F.M.) and Obstetrics and Gynecology (A.T.), University "Federico II" of Naples, 80131 Naples, Italy; Department of Internal Medicine (P.D.F.), Section of Internal Medicine and Metabolic and Endocrine Diseases, University of Perugia, 06100 Perugia, Italy; and Endocrinology (F.O.), University "Parthenope" of Naples, 80133 Naples, Italy

Address all correspondence and requests for reprints to: Stefano Palomba, M.D., Department of Gynecology and Obstetrics, University "Magna Graecia" of Catanzaro, Via Pio X, 88100 Catanzaro, Italy. E-mail: stefanopalomba{at}tin.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: To date, the metabolic effects of the long-term metformin administration in anovulatory patients with polycystic ovary syndrome (PCOS) are known, whereas few data are available on the effects of its suspension.

Objective: The objective of the study was to evaluate the effects of metformin suspension on insulin sensitivity in PCOS patients.

Design: This was a prospective, randomized, placebo-controlled study.

Setting: The study was conducted at the University "Magna Graecia" of Catanzaro, Italy.

Patients: Patients included 30 normal-weight anovulatory PCOS women and 10 age- and body mass index-matched healthy controls.

Intervention: PCOS patients were randomized to receive 1700 mg daily metformin (metformin group) or placebo tables (placebo group) for 12 months, whereas no treatment was administered in healthy women (control group).

Main Outcome Measures: Clinical, endocrine, and metabolic profile and clamp insulin sensitivity index were evaluated at study entry and after 6, 12, 18, and 24 months.

Results: At baseline, the clamp insulin sensitivity index resulted significantly different (P < 0.05) in PCOS patients in comparison with healthy controls, without difference between metformin and placebo groups. During treatment, the clamp insulin sensitivity index was significantly improved (P < 0.05) in the metformin group in comparison with baseline and placebo group, without significant differences between the 6- and 12-month assessments. At 6 and 12 months after treatment suspension, in the metformin group, insulin sensitivity index significantly (P < 0.05) worsened in comparison with that observed at baseline and during treatment and with that observed in the placebo and control groups.

Conclusion: In normal-weight anovulatory PCOS patients, long-term metformin administration exerts beneficial effects on peripheral insulin sensitivity. Furthermore, this effect disappears at treatment suspension.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
POLYCYSTIC OVARY SYNDROME (PCOS) is a common and complex endocrine-metabolic disorder characterized by chronic anovulation and/or clinical/biochemical hyperandrogenism and/or polycystic ovaries (PCOs) at ultrasonography (1). Many patients with PCOS have insulin resistance and hyperinsulinemia (2); obesity (3); impaired glucose tolerance and/or type 2 diabetes mellitus (4); dyslipidemia (5); arterial hypertension (6); metabolic syndrome (7); and coagulation disorders (8). All these features seem to increase the long-term risk for cardiovascular diseases even if, to date, no prospective controlled data are available regarding the mortality in PCOS population.

In the last decade, several reports have shown that metformin, an oral biguanide used in type 2 diabetes mellitus, is a safe and effective treatment for women with PCOS (9). Metformin administration restores ovulatory menstrual cycles and improves fertility in anovulatory PCOS women (9, 10), exerting beneficial effects on insulin sensitivity (9) and androgen and lipoprotein metabolism (9). For these reasons, some researchers and practitioners have advocated the administration of metformin in PCOS patients to reduce the long-term metabolic and cardiovascular sequelae related to this syndrome (11).

Even though metformin plays a consolidated role in the treatment of clinical and endocrinological PCOS-related abnormalities and it has a promising position in the prevention of the long-term PCOS-related sequelae, to date it is not known for how long a time metformin administration should be continued and whether its benefits are maintained after its suspension. Based on these considerations, the aim of this experimental randomized, controlled study was to evaluate the effects on insulin sensitivity of the suspension of a long-term metformin treatment in a well-selected sample of normal-weight PCOS patients.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
The procedures used were in accordance with the guidelines of the Helsinki Declaration on human experimentation. The study was approved by the Institutional Review Board of the University "Magna Graecia" of Catanzaro. The purpose of the protocol was carefully explained to each woman, and written consent was obtained from them before beginning the study.

Protocol and treatment

Between December 2003 and April 2004, 30 young normal-weight anovulatory PCOS women were enrolled.

The diagnosis of PCOS was based on the presence of clinical [Ferriman-Gallwey score ≥ 8 (12)] and/or biochemical hyperandrogenism [serum testosterone levels (>2 SD above our reference mean values] and chronic anovulation [serum luteal progesterone (P) < 2 ng/ml)]. A body mass index (BMI; kilograms per square meter) between 18 and 25 was considered as index of normal weight (13).

Another 10 healthy, normal-weight volunteers were successively enrolled and considered as controls. The controls were midwifes not genetically related to PCOS patients. Control women were matched two to one with PCOS patients for age and BMI. The controls and cases (PCOS patients) were defined as age and BMI matched when the differences between them were less than 1 yr and 0.5 kg/m2 for age and BMI, respectively.

The state of health of the controls was determined by medical history, physical and pelvic examination, and blood chemistry tests. Their normal ovulatory state was confirmed by transvaginal ultrasonography and plasma P levels assessed 7 d before the expected menses (serum P higher than 10 ng/ml). Women with clinical and/or biochemical hyperandrogenism as well as PCOs at transvaginal ultrasonography were excluded from the control group.

We considered the following as exclusion criteria for all subjects (cases and controls): age younger than 20 or older than 30 yr; BMI higher than 25 and lower than 18; neoplastic, metabolic, hepatic, and cardiovascular disorder or other concurrent medical illness; hypothyroidism, hyperprolactinemia, Cushing’s syndrome, nonclassical congenital adrenal hyperplasia, and androgen-secreting tumors; current or previous (within the last 6 months from study enrollment) use of hormonal drugs and use of alcoholic beverages. In addition, women with a fasting glucose to insulin ratio (GIR) less than 4.5 mg per 10–4U (SI: <582 mmol/pmol) were excluded (14, 15). Impaired glucose tolerance (IGT) was also excluded by use of a fasting glucose level greater than 100 mg/dl (SI: > 5.6 mmol/liter) and/or a 2-h oral glucose tolerance test (OGTT) value greater than 140.5 mg/dl (SI > 7.8 mmol/liter) (16).

Neither cases nor controls intended to start a diet or a specific program of physical activity or achieve a pregnancy.

No treatment was administered in control women, whereas PCOS patients were randomly allocated into two treatment groups (metformin and placebo group). The randomization was carried out using computer software (University of Catanzaro) to generate a random allocation sequence in single blocks as method of restriction. The random allocation sequence was concealed until the interventions were assigned.

Fifteen PCOS patients received metformin at a dosage of 1700 mg daily (one tablet of 850 mg twice daily; metformin group), whereas another 15 PCOS women received placebo tablets (one tablet twice daily; placebo group). The duration of the treatment was 12 months. The patients were instructed to take the tablets with their meals. The drug and placebo were packaged in the Department of Obstetrics and Gynecology of the University of Catanzaro and labeled according to subject number. For the overall 24-month study period, operators and patients were blind to the treatment allocation.

Both cases (PCOS patients) and controls (healthy women) subjects were instructed to follow their usual diet and physical activity and use barrier contraception throughout the study. Each enrolled subject was also instructed to avoid any drugs with possible hormonal and metabolic effects throughout the study. In particular, neither natural P nor progestogens were administrated to induce a withdrawal bleeding (17, 18).

Each subject underwent complete follow-up visits after 6, 12, 18, and 24 months from the start of the study. In particular, PCOS patients were studied at 6 and 12 months from treatment start and at 6 and 12 months from treatment withdrawal. At each follow-up visit, all subjects underwent clinical, hormonal, metabolic, and insulin sensitivity assessments as detailed below by the same operator. PCOS patients alone underwent weekly blood drawn to assay P levels.

Clinical assessments

Clinical evaluation consisted of anthropometric measurements [including height, weight, BMI, and waist to hip ratio (WHR)] (19) and the Ferriman-Gallwey score by the standard method (12); evaluation of the daily physical activity, job, and daily activities using a semiquantitative questionnaire (20); and the diet and caloric intake assessment. Specifically, the food consumption was assessed using a self-administered, semiquantitative, validated food frequency questionnaire, which was used as a cross-check of the dietary history. Daily diet was evaluated by an experienced clinical dietitian (F.M.) with the aid of a software specific for the analysis of food habits and the estimation of nutrient and caloric intake (WinFood, release 1.5; Medimatica, Martinsicuro, Te, Italy).

The length and frequency (defined as percentage of observed menses/number of expected menses) of the menstrual cycles, and the adverse experiences (AEs) were reported on a personal daily diary by all subjects (cases and controls).

The quantity of the uterine bleedings was evaluated subjectively by each woman using a rank analog scale ranging from 0 to 10. A value of 0 was given arbitrary in absence of menses, a value of 5 was given for uterine bleedings defined normal, and a value of 10 for uterine bleeding defined severe. Restoration of normal menstrual cycles was defined as menstrual bleeding having a score of at least 5 and a cycle length less than 35 d. A menstrual cycle was defined ovulatory after the confirmation of ovulatory plasma P levels (>10 ng/ml; SI: 32 nmol/liter) retrospectively assayed in normally cycled PCOS patients.

For each AE reported on the personal diary, the severity, duration, and a possible cause-effect relationship with the drug administrations were noted.

To evaluate the compliance with the treatment and protocol, the number of tablets forgotten, changes in diet, physical activity, and weight were also recorded.

Biochemical assays

All blood samples were obtained in the morning between 0800 and 0900 h after an overnight fast and resting in bed. In particular, at baseline blood samples were obtained during the early proliferative phase (second through third day) of the P-induced withdrawal uterine bleeding (for the cases) or the spontaneous uterine bleeding (for the controls), whereas throughout the study, they were obtained randomly in anovulatory PCOS patients and during the early proliferative phase of the spontaneous uterine bleeding in both controls and ovulatory PCOS patients. Blood samples (5 ml) were collected into tubes containing EDTA after a 12-h fast and a 30-min resting period in the supine position and immediately centrifuged at 4 C for 20 min at 1600 x g, and plasma samples were stored at –20 C.

FSH, LH, TSH, prolactin (PRL), 17-ßestradiol (E2), P, 17-hydroxyprogesterone (17-OHP), and the OGTT were assessed at baseline alone, whereas total testosterone (T), androstenedione (A), dehydroepiandrosterone sulfate (DHEAS), and SHBG were assayed at baseline and at each follow-up visit (21).

At baseline and at different follow-up visits, total cholesterol (TC), high-density lipoprotein (HDL)- and low-density lipoprotein (LDL)-cholesterol (C), and triglycerides (TGs) were assessed (21). The glucose and insulin values were also detected both at fasting and after 2 h-OGTT. In particular, glucose and insulin concentrations were measured 30 min after insertion of the iv catheter to detect the fasting levels (time 0) before OGTT. Then each subject received orally a 75-g glucose load, and further blood samples (10 ml each) were obtained at 30-min intervals for the following 2 h during the infusion period, and glucose and insulin concentrations were determined. Glucose tolerance was assessed by World Health Organization criteria (22). In both groups the glucose and insulin response to OGTT was analyzed by calculating the area under curve (AUC). The AUC for glucose (AUCglucose) and insulin (AUCinsulin) were determined according to the mathematical method described by Tai (23) for the metabolic curves. The AUCglucose to AUCinsulin ratio was also calculated in each subject. Finally, the GIR (14, 15) and free androgen index [FAI: T (nanomoles per liter)/SHBG x 100] (24) were also calculated in each subject.

Euglycemic hyperinsulinemic clamp

Throughout the study, each woman underwent serial insulin sensitivity assessments using a standard euglycemic hyperinsulinemic clamp.

After a 3-d standard carbohydrate diet (300 g/d) and an overnight fast, a 2-h euglycemic hyperinsulinemic clamp was performed on random days as previously described (25).

Continuous insulin infusion (Humulin R; Eli Lilly, Sesto Fiorentino, Italy) was started at a rate of 40 mU/m2 per minute and maintained for 120 min. During the last 30 min of the basal equilibration period, plasma samples were taken at 10-min intervals for the determination of plasma glucose and insulin concentrations. During the insulin infusion, plasma glucose concentration was measured every 5 min, and a variable infusion of 20% glucose was adjusted, based on the negative feedback principle, to maintain the plasma glucose concentration at each subject’s fasting plasma glucose level with a coefficient of variation less than 5%.

Plasma samples were collected every 15 min from 0 to 90 min and every 10 min from 90 to 120 min for the determination of plasma glucose and insulin concentrations. Insulin sensitivity was determined from the values obtained during the steady-state period (100th to 120th min). The glucose disposal rate (M; micromole per kilogram x minutes), defined as amount of glucose supplied by the infusion to maintain the desired blood glucose level, was calculated on clamp results and used as index of insulin sensitivity.

Statistical analysis

Data were expressed as mean ± SD. Continuous variables were analyzed with the one-way ANOVA and ANOVA for repeated measures with Bonferroni test for the post hoc analysis. For categorical variables, the Fisher’s exact test or the {chi}2 square test was applied as required.

In addition, our data were analyzed with the use of general linear model (GLM) univariate procedure that provides regression analysis and ANOVA for one independent variable (M values) by one or more factors and/or variables.

In the current study P ≤ 0.05 was considered significant, and the Statistics Package for Social Science (SPSS 15.0.0; SPSS Inc., Chicago, IL) was used for all statistical analyses.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The flow diagram of the clinical trial according to the Consolidated Standards of Reporting Trials guidelines (26) is shown in Fig. 1Go.


Figure 1
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  		FIG. 1. Trial profile according to Consolidated Standards of Reporting Trials guidelines (26 ).

 
Final analysis was performed on a population of 14 and 13 women taking metformin or placebo, respectively, and a sample of 10 healthy controls. In particular, one patient was excluded because she became pregnant after 7 months of metformin administration in the metformin group, whereas two patients (one for poor compliance to the treatment and one for poor compliance to the study protocol) were excluded in the placebo group. On the other hand, no subject was excluded in the control group.

In all cases criteria for the European Society for Human Reproduction, American Society of Reproductive Medicine (1), and National Institutes of Health (27) were satisfied. At study entry, all PCOS patients had PCOs at transvaginal ultrasonography (28).

No significant difference was observed between metformin and placebo groups, in clinical, hormonal, and metabolic parameters after randomization (Table 1Go). In the metformin and placebo groups, the Ferriman-Gallwey score, P, 17-OHP, T, A, DHEAS, FAI, fasting insulin, AUCinsulin, and AUCglucose to AUCinsulin ratio had significantly higher (P < 0.05) results than in the control group. On the contrary, SHBG and GIR were significantly lower (P < 0.05) in both the metformin and placebo groups in comparison with the control group.


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  		TABLE 1. Clinical, hormonal, and metabolic data in PCOS patients (metformin and placebo group) and healthy controls at study entry

 
Throughout the study, no change in physical activity score, diet, and caloric intake was observed in any group. No significant variation in BMI, weight, and WHR was noted in any patient.

Metformin treatment was generally well tolerated (no dropout for drug-related AEs) and no serious AE was reported.

Tables 2Go and 3Go summarize the most significant clinical, hormonal, and metabolic data of the PCOS patients (metformin and placebo group) and healthy controls throughout the study.


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  		TABLE 2. Glucose disposal rate (micromoles per kilogram x min) in PCOS patients (metformin and placebo group) and healthy controls

 

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  		TABLE 3. The most significant clinical, hormonal, and metabolic data in PCOS patients (metformin and placebo group) and healthy controls

 
At study entry, M value was significantly lower (P < 0.05) in both the metformin and placebo groups than in the control group. After 6 and 12 months of treatment, a significant improvement (P < 0.05) in M values was observed in the metformin group in comparison with baseline and the placebo group, without difference between 6 and 12 months of treatment, and they resulted similar to those observed in the control group (Table 2Go).

Under metformin administration and without difference between 6- and 12-month visits, a significant reduction (P < 0.001) in AUCinsulin and in AUCglucose-insulin was observed in comparison with baseline. Serum T, SHBG, FAI, and LDL-C levels resulted also significantly reduced (P < 0.05) from baseline. A significant improvement (P < 0.05) was finally detected in Ferriman-Gallway score (Table 3Go).

At 6-month assessment, nine and no women taking metformin or placebo, respectively, had ovulatory cycles [nine of 14 (64.4%) vs. none of 13 (0%); P < 0.001]. No further improvement in clinical response to treatment was observed at the 12-month follow-up.

Subanalyzing our data, distinguishing PCOS patients who ovulated from those who did not ovulate after 12 months of metformin administration, significant differences were observed in M (49.0 ± 4.2 vs. 40.8 ± 3.8, P = 0.003), plasma T (1.2 ± 0.3 vs. 1.8 ± 0.4, P = 0.008), SHBG (44.4 ± 7.7 vs. 34.2 ± 2.3, P = 0.015), FAI (14.1 ± 5.4 vs. 21.6 ± 3.1, P = 0.023), AUCinsulin (2848.5 ± 344.5 vs. 3255.8 ± 218.8, P = 0.036), AUCglucose-insulin (0.38 ± 0.03 vs. 0.34 ± 0.03, P = 0.021), and Ferriman-Gallway score (10.2 ± 1.9 vs. 12.8 ± 1.6, P = 0.024). All other clinical and biochemical data were similar in both groups.

On the other hand, at 6 and 12 months after treatment suspension, in the metformin group, M values were significantly worse (P < 0.05) in comparison with those observed during treatment. In addition, results also significantly worsened (P < 0.05) in comparison with the placebo group (Table 2Go). During the 2-yr follow-up, no significant change in M values was observed in both the placebo and control groups (Table 2Go).

At 6 months from metformin suspension, all clinical and biochemical parameters were not significantly different from baseline, and no further change was observed at the 12-month visit (Table 3Go).

After 12 months from treatment suspension, none of the nine PCOS patients who had ovulated under metformin still had ovulatory cycles (none of 14; 0%), whereas four of 13 (30.8%) were ovulating in the placebo group (P = 0.025).

Throughout the study, no other change in any clinical, hormonal and metabolic data were observed within the placebo and control groups.

Subanalyzing our data, distinguishing again PCOS patients (placebo group) who spontaneously ovulated from those who did not ovulate after 12 months from treatment suspension, significant differences were observed in M (47.0 ± 3.8 vs. 41.6 ± 2.5, P = 0.010), plasma T (1.4 ± 0.1 vs. 1.8 ± 0.3, P = 0.010), SHBG (30.5 ± 2.9 vs. 24.4 ± 3.0, P = 0.006), FAI (14.2 ± 4.7 vs. 21.6 ± 5.5, P = 0.041), AUCinsulin (4367.1 ± 425.6 vs. 5334.8 ± 695.6, P = 0.027), AUCglucose-insulin (0.29 ± 0.07 vs. 0.20 ± 0.02, P = 0.002), and Ferriman-Gallway score (9.0 ± 1.4 vs. 11.6 ± 1.3, P = 0.009). All other clinical and biochemical data were similar in both groups.

During the study, no subject in any group developed IGT or diabetes.

GLM univariate procedure showed no significant influence of M on any clinical and/or biochemical parameter assessed.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Metformin has been recently proposed as therapeutic option to improve reproductive and metabolic functions in PCOS women (9). The efficacy of metformin in these patients is probably related to the effects on insulin resistance that, independently of body weight, plays a crucial role in the pathogenesis of hyperandrogenism and anovulation, and, probably, in the long-term sequelae related to the PCOS (29). Metformin seems to act by several mechanisms. Specifically, metformin exerts its action principally on the liver inhibiting gluconeogenesis, and reducing hepatic glucose output (30, 31). In addition, in vitro (32, 33, 34) and in vivo (34), data suggest that metformin restores peripheral insulin sensitivity augmenting insulin-mediate glucose uptake in skeletal muscle. Furthermore, the exact mechanism for explaining these actions remains still partially understood. Metformin seems to increase the translocation of glucose transporters from intracellular pool to plasma membranes in rat adipocytes (32) and the binding of insulin to its receptor (33). In this regard, metformin has shown to regulate the phosphorylations of insulin receptor ß-subunit and phosphoinositol 3-kinase and Akt activities in adipocytes exposed for a long time to hyperinsulinemic environment (34).

Although several evidences (9) support the efficacy at metabolic level of metformin treatment for a limited time in insulin-resistant PCOS women, it is still unknown whether metformin administration should be considered as a symptomatic treatment or as a curative and definitive therapy. Thus, it is not clear for how long a time metformin should be administrated and what its effects are on insulin sensitivity at treatment suspension.

Based on these considerations, our study was specifically conducted to evaluate the effects of metformin on peripheral insulin sensitivity after 12 months of therapy suspension in a sample of normal-weight anovulatory PCOS women. Specifically, we studied, in a randomized, controlled fashion, a small group of well-selected PCOS patients analyzing the data of patients compliant to treatment and/or protocol alone. In fact, given the characteristics of high homogeneity of our population, we decided to not use the intention-to-treat principle because there was no necessity to avoid some selection bias. Thus, our data did not reflect the findings of patients allocated in the metformin arm but those of subjects who regularly receive metformin.

The rationale for considering metformin as chronic therapy in PCOS should be related not only to the effects of the treatment for improving infertility and cosmetic disorders but also and especially to the efficacy on peripheral insulin resistance linked to the risk of other long-term disorders, i.e. diabetes and cardiovascular disease (35, 36).

Several data (37, 38, 39) are available regarding the effects of long-term metformin administration in PCOS women. Specifically, the beneficial effects of 16-wk metformin administration on menstrual cyclicity was demonstrated by Fleming et al. (37) in an oligomenorrheic population of obese patients. Furthermore, no hormonal change was detected under treatment (37). On the contrary, some authors (38) showed that long-term treatment with metformin induced a reduction of insulin and androgen levels, and improved ovulation, and these results were maintained up to 2 yr. A significant improvement in clinical and biochemical features of PCOS after 6-month of metformin plus hypocaloric diet combination was also confirmed by Pasquali et al. (39). In particular, a population of obese PCOS patients showed an improvement of menstrual cyclicity and hirsutism contemporary with a reduction in fasting glucose, AUCinsulin, and T under treatment (39).

Our study confirmed (38, 39) a significant hormonal and metabolic improvement after metformin in a sample of normal-weight PCOS women. In particular, we observed a significant improvement of the insulin sensitivity index measured by euglycemic hyperinsulinemic clamp after metformin administration and a significant change in T, SHBG, FAI, AUCglucose to AUCinsulin ratio, and LDL-C, in comparison with baseline assessment and placebo group. In our sample, these biochemical responses seem to translate into clinical improvements. In fact, hirsutism resulted significantly reduced from baseline, and more than half of the PCOS patients had ovulatory menstrual cycles after 6 months of metformin administration.

An important point to be highlighted is the absence of further improvements in any clinical, hormonal, and metabolic feature after 12 months of metformin administration.

To eliminate any confounding factor due to ovulation on the clinical response to metformin, we compared clinical and biochemical characteristics of responders and nonresponders, considering as responders patients who ovulated under treatment (metformin or placebo). Our subanalysis showed lower biochemical hyperandrogenism and insulin resistance in responder than nonresponder patients. In addition, also the subanalysis of the spontaneously ovulatory PCOS patients (under placebo) showed a significant influence of ovulation on several biochemical and clinical PCOS features.

No specific predictor for peripheral insulin sensitivity change was detected in the current study by use of GLM analysis. Furthermore, our results were obtained on a very small and homogeneous sample population.

Moreover, the aim of our study was to assess the biochemical and clinical long-term effects of metformin suspension. In fact, the current is the first study aimed to evaluate whether and how long the increased peripheral insulin sensitivity, induced by or related to metformin, is sustained after treatment suspension and which are the potential clinical implications.

Our data show that, at treatment suspension, metformin quickly stops its beneficial effect on peripheral insulin sensitivity. In fact, a slightly but significant worsening of the insulin-resistant state was observed in comparison with baseline and with patients who received placebo. However, no PCOS patient developed IGT or diabetes at 12 months from metformin suspension, even if a comeback to baseline values was observed for T, SHBG, FAI, AUCglucose to AUCinsulin ratio, and LDL-C.

Our findings seem to suggest that the quick loss of beneficial effects due to metformin on insulin resistance and thus on hyperandrogenism after its suspension is related to a comeback of the clinical features of the PCOS. In particular, no PCOS patient resulted normally cycled at the end of the study.

In agreement with these findings, a recent study (40) has shown that the withdrawal of metformin treatment was followed within 3 months by a significant reversal toward pretreatment hyperandrogenic hyperinsulinemic state in 10 nonobese adolescents with hirsutism, oligomenorrhea, dyslipidemia, and history of precocious pubarche.

A secondary, even if relevant, observation is the spontaneous restoration of the ovulatory menstrual cycles in approximately 30% of PCOS patients throughout 2 yr of study (12 months of placebo plus 12 months of follow-up). These responder patients, as discussed before, were less hyperandrogenic and insulin resistant than nonresponders. These findings suggest that a percentage of anovulatory patients with PCOS could gain ovulatory cycles spontaneously and shift in a milder PCOS phenotype.

Because the time could be considered as a confounding factor on the clinical evolution of PCOS, further data on a wide sample and on a long-time follow-up, and having as a primary aim the evaluation of the effect of the time on the ovarian function and the clinical features in PCOS patients, are necessary to draw definitive conclusions in this regard. The necessity to clarify this issue is pivotal, considering that metformin administered for long times could interfere with the potential beneficial evolution of the syndrome.

In conclusion, normal-weight anovulatory PCOS patients treated with metformin for long periods did not maintain the beneficial biochemical and clinical effects of metformin after treatment suspension. On the contrary, they showed a slight but significant worsening of the basal peripheral insulin sensitivity. Further studies on the clinical and metabolic effects of metformin suspension are needed before the use of this drug becomes common in clinical practice.


   Acknowledgments
 
No financial support was provided by any pharmaceutical company to realize the present research. The authors thank all the gynecological units of the Calabria and Campania Regions that have given their help in subject enrollment.


   Footnotes
 
Disclosure Summary: The authors have nothing to declare.

First Published Online May 22, 2007

Abbreviations: A, Androstenedione; AE, adverse experience; AUC, area under curve; BMI, body mass index; C, cholesterol; DHEAS, dehydroepiandrosterone sulfate; E2, 17-ß estradiol; FAI, free androgen index; GIR, glucose to insulin ratio; GLM, general linear model; HDL, high-density lipoprotein; IGT, impaired glucose tolerance; LDL, low-density lipoprotein; M, glucose disposal rate; OGTT, oral glucose tolerance test; 17-OHP, 17-hydroxyprogesterone; P, progesterone; PCO, polycystic ovary; PCOS, polycystic ovary syndrome; PRL, prolactin; T, testosterone; TC, total cholesterol; TG, triglyceride; WHR, waist to hip ratio.

Received February 26, 2007.

Accepted May 15, 2007.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group 2004 Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 81:19–25[Medline]
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