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Original Studies |
Division of Endocrinology and Metabolic Diseases (P.M., R.C., C.N., F.T., F.P., M.M.), and Division of Medical Statistics (E.Z.), University of Verona, Verona; Laboratory of Clinical Chemistry (M.C.), Ospedale Maggiore, Verona, Italy
Address correspondence and requests for reprints to: Dr. Paolo Moghetti, Divisione di Endocrinologia e Malattie del Metabolismo, Ospedale Maggiore, P.le Stefani, 1 I-37126 Verona, Italy. E-mail: moghetti{at}iol.it
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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These observations suggested that insulin sensitizing agents, such as metformin or troglitazone, should be tested for the treatment of PCOS. These drugs improve insulin sensitivity by different mechanisms, thus determining a subsequent reduction in plasma insulin levels (8, 9). Recently, some short-term studies supported this hypothesis, reporting significant reductions of serum androgens in women with PCOS given either metformin (10, 11, 12, 13) or troglitazone (14, 15). Interestingly, improvements in reproductive abnormalities of these patients have also been reported in some of these studies (13, 16). On the other hand, other authors failed to observe any clinical or biochemical changes after metformin (17, 18). These discrepancies are not easily explained. In addition, controlled long-term studies assessing the clinical effects of these treatments are still lacking.
The present study was designed to assess, with a randomized, double-blind, placebo-controlled protocol, the effects on menstrual abnormalities of a 6-month course of metformin in a group of 23 subjects with PCOS with normal glucose tolerance. Subsequently, 18 of these subjects and 14 additional women with PCOS were included in an open trial to evaluate the long-term effects of metformin on clinical features of the syndrome and to determine any baseline predictors of the treatment’s efficacy.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Protocol A (double-blind study). Twenty-three caucasian women with PCOS, ages between 18–35 yr and with normal glucose tolerance by the criteria of the World Health Organization (19), were recruited for the double-blind, placebo-controlled study. All these subjects were referred to our division for menstrual abnormalities, with or without hirsutism.
Diagnosis of PCOS was based on the presence of hyperandrogenic chronic anovulation, after exclusion of Cushing’s syndrome, late-onset 21-hydroxylase deficiency, thyroid dysfunction, hyperprolactinemia, or androgen secreting tumors, according to recommendations of the NICHHD consensus conference on PCOS (2). No subject had other diseases or was taking medications.
All these women had an abnormal response of serum 17-hydroxyprogesterone to GnRH-agonist stimulation (20). Twenty of them had severe oligoamenorrhea (6 or fewer menses per year), whereas 3 women had less severe irregularities in menstrual cycles. In these 3 subjects, anovulation was confirmed by serum progesterone assessment in the luteal phase of the cycle.
The large majority of these subjects were overweight (mean body mass index 30.0 ± 1.1, range 19.0–38.7 kg/m2). Sixteen of them (70%) showed increased plasma insulin response to oral glucose, a rough parameter of insulin resistance.
Women were randomly assigned to double-blind oral metformin or placebo for 6 months. The dose of the study drug was increased stepwise, from 500 mg (1 capsule) once daily for the first week to 500 mg bid for the next week, and to 500 mg tid for a further 24 weeks. Patients were instructed not to modify their usual eating habits throughout the study.
Metformin effects on menstrual abnormalities of women with PCOS were evaluated by assessing post-treatment changes in frequency of cycles. Furthermore, changes in several endocrine and metabolic features of the syndrome were also assessed.
Thus, before and at the end of study, the following were carried out:
All baseline evaluations were carried out in the early follicular phase of the menstrual cycle, or after at least 3 months of amenorrhea.
Each woman was asked to report any side-effect during the treatment. In addition, safety parameters (hematology, liver and renal function, serum electrolytes and uric acid) were assessed before and at 2-month intervals during the study.
All subjects gave their informed written consent before entering the study, which was conducted in accordance with the Declaration of Helsinki and approved by the institutional ethical committee.
Protocol B (open, long-term study). Eighteen out of the 23 women included in protocol A received metformin in an open design providing treatment for an unscheduled duration after the completion of the double-blind study, to assess long-term effects of treatment and to determine any predictors of the efficacy of metformin. Fourteen additional, previously untreated, severely oligoamenorrheic women with PCOS were also included in this protocol. Thus, the total number of subjects participating in the open study was 32, 21 overweight and 11 lean. These additional women with PCOS were evaluated at baseline by the procedures indicated in protocol A, except for the glucose clamp. Subjects participating in this protocol also gave their informed consent before entering the study. A placebo group was not included in this long-term protocol, as it was considered unethical after results of the double-blind study. Moreover, a control group is irrelevant to assessment of therapeutic efficacy predictors.
In all patients, metformin dosage was increased stepwise as indicated above, and the following were assessed at 4-month intervals: changes in menstrual history (main outcome), side effects, body weight, hirsutism score, blood pressure, fasting plasma insulin, serum testosterone, gonadotropins, sex hormone-binding globulin, and lipids. GnRH-agonist challenge was repeated after 4–6 months of metformin in 19 subjects.
To assess the effects of treatment on ovulatory function, serum progesterone levels were repeatedly measured in the luteal phases of subjects experiencing regular menses after metformin treatment. Ten women accepted these additional assessments, which were carried out in an overall total of 39 cycles. Ovulation was presumed to have occurred when serum progesterone exceeded 18 nmol/L.
Insulin sensitivity
Insulin sensitivity was measured by the euglycemic hyperinsulinemic glucose clamp, as previously described (5). Briefly, after overnight fasting, a primed, continuous insulin infusion (Humulin R, Eli Lilly & Co., Indianapolis, IN) was started; this was maintained for 120 min, at a constant rate of 80 mU/m2 x min, which makes it possible to reach steady-state plasma insulin levels in the high in vivo range. Euglycemia was maintained throughout the test with a variable infusion of 20% dextrose, adjusted by monitoring plasma glucose levels in arterialized venous blood, approximately every 10 min. We previously found that in nondiabetic hyperandrogenic subjects endogenous glucose production was negligible at this insulin infusion rate (22). Therefore, the amount of glucose infused into each subject may be considered equivalent to the whole body insulin-induced glucose uptake.
Assays
Plasma insulin was measured by a specific immunoradiometric assay (cross-reactivity with proinsulin <5%), using a kit from Biosource Technologies, Inc. (Fleurus, Belgium). Serum gonadotropins, androgens, progesterone, 17-hydroxyprogesterone, estradiol, sex hormone-binding globulin and lipoproteins were measured by commercial kits, as previously described (22).
Statistical analysis
Differences in baseline characteristics between the two groups (metformin and placebo) were analyzed by Student’s t test (two-tailed). The Mann-Whitney U test and Wilcoxon matched pairs signed rank sum test were used for hirsutism score data.
The difference in frequency of menstruation before and after the trial, a normally distributed variable, was studied by analysis of covariance, so that the effect of intergroup differences in basal body mass index and androgens could be accounted for.
Free testosterone levels and other relevant clinical, endocrine and metabolic features were analyzed by repeated measures analysis of variance. SPSS, Inc. Release 6.0 (SPSS, Inc., Chicago, IL) was used for these analyses.
For the open long-term study, Student’s t test was used to analyze differences in main baseline characteristics of responders and nonresponders. Predictors of response to metformin were identified by logistic regression, by the EGRET program (Statistics and Epidemiology Research Corp., EGRET, Seattle, WA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Clinical and endocrine features. Table 1
shows the main characteristics of women
given metformin or placebo, at baseline and after
treatment. At baseline, the placebo group had significantly higher body
mass index, whereas serum androgens tended to be higher in the
metformin group.
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Five subjects given metformin and two subjects given placebo reported the following mild to moderate side effects: nausea (n = 5), heartburn (n = 1), and mild abdominal pain (n = 1) in the metformin group; nausea (n = 2), vertigo (n = 1), and headache (n = 1) in the placebo group. These resolved within 4 weeks in all patients except one, receiving metformin, who required a stable reduction of the study drug dose to 1 capsule bid.
Menstrual abnormalities. Figure 1 shows the median and interquartile
range of the changes after treatment in frequency of menstruation, in
both groups. After treatment, the metformin group showed a
significant improvement in frequency of menstruation, whereas no change
was observed in subjects receiving placebo (P = 0.002
between groups, controlling for baseline body mass index and
androstenedione). Five women in the metformin group
vs. none in the placebo group had their menstrual pattern
substantially improved during treatment. In subjects experiencing
regular menses after metformin, improvement was observed
within 3 months.
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GnRH-agonist challenge. Before treatment, serum 17-hydroxyprogesterone levels at basal evaluation and after GnRH-agonist stimulation were similar between the two groups, as were serum gonadotropins. After treatment, 17-hydroxyprogesterone response to buserelin was significantly lowered in women given metformin (10.4 ± 1.6 vs. 14.2 ± 3.4 nmol/l), but not in those receiving placebo (12.0 ± 2.0 vs. 9.9 ± 1.3 nmol/l) (P < 0.05 between groups). In both groups, GnRH-agonist-induced increases in serum gonadotropins did not change significantly (data not shown).
Metabolic parameters. Before treatment, plasma glucose and
insulin at fasting and after oral glucose were not significantly
different between the two groups, though there was a tendency to higher
fasting insulin levels in the placebo group. The baseline serum lipid
profile was also similar between groups (Table 2).
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Insulin sensitivity. Before treatment, women in both the metformin and placebo groups had similar steady-state insulin levels during the clamp studies (273 ± 21 vs. 274 ± 23 µU/mL, respectively). After treatment, these values were reduced in women receiving metformin (226 ± 19 µU/mL, P < 0.01 vs. baseline), whereas they were unchanged in subjects receiving placebo (271 ± 22 µU/mL, P = NS vs. baseline) (by ANOVA, P < 0.05 between groups). As insulin infusion rates were similar before and after treatment, these findings suggest raised metabolic clearance of the hormone after metformin.
To allow comparison of insulin sensitivity changes in the two groups,
measures of insulin-induced glucose metabolism were corrected for
ambient plasma insulin (M/I ratio). Whole body
insulin-stimulated glucose uptake was significantly increased after
metformin, indicating improved insulin sensitivity (Table 2
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Open, long-term study
Long-term tolerability. The women already given metformin in the double-blind study did not report any additional side-effect during the open, long-term trial. Among the remaining PCOS patients (those from the placebo group and the newly treated subjects), one woman complained of persistent abdominal pain, diarrhea and nausea; she continued to receive 1 capsule per day of metformin for 3 weeks, after which the treatment was discontinued. This patient was considered in the evaluation of tolerability, but not of clinical efficacy. Seven subjects complained of transient nausea, diarrhea and/or heartburn, which disappeared within 1 month.
Considering the side-effects reported by women given metformin in both protocols as a whole, 13 subjects (40.6%) had some discomfort during treatment (mild and transient in 11 and severe or persistent in 2).
Reproductive abnormalities. In the overall population of
oligoamenorrheic women with PCOS given metformin in the
open, long-term study (mean duration of metformin therapy
11.0 ± 1.3 months, median 8, range 4–26; figures inclusive of
the previous 6 months of treatment for those subjects previously given
the active drug in the double-blind protocol), the frequency of menses
improved from 0.22 ± 0.04 to 0.59 ± 0.07 cycles per month
per patient (P < 0.001). Thirteen of these subjects
experienced complete regularization (i.e. uterine bleeding
every 25–33 days, with normal duration and amount of blood loss), and
another 4 reported striking amelioration of menstrual cycle
abnormalities. These 17 women (54.8%) were considered as
"responders." Fifteen of them were overweight and 2 lean. In
another 14 women (5 overweight and 9 lean), there was no appreciable
clinical improvement, or there was a slight amelioration of their
menstrual history (in 3 of these subjects), possibly attributable to
spontaneous fluctuations of menstrual abnormalities, after
metformin. These subjects were considered as
"nonresponders" (Fig. 2).
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). After
treatment, responders showed significantly greater reductions in serum
LH (-22.2 ± 11.4 vs. +39.7 ± 24.7%,
P = 0.025). Changes in body weight were similar between
responders and nonresponders (-4.5 ± 1.1 vs.
-1.5 ± 1.4%; P = NS).
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shows
unadjusted and adjusted odds ratios of the three variables, which also
retained their significance when included together in the model: higher
plasma insulin, less severe menstrual abnormalities, and lower serum
androstenedione predicted clinical improvement. As a whole, this model
accounted for 54.8% of total deviance in the clinical outcome. Body
mass index was not included in the analysis, in spite of its
significance, as this parameter is closely related to plasma insulin;
moreover, when introduced in the model instead of insulin, it showed a
lower predictive power.
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In women with excessive hair growth, hirsutism scores were not improved after metformin (10.3 ± 2.5 vs. 12.6 ± 1.7, before and after treatment respectively, P = NS), independently of any change in menstrual cycle abnormalities.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the last few years, a number of mostly uncontrolled short-term studies assessed the effects of these drugs in nondiabetic hyperandrogenic women, with varying results (23). Nestler and Jakubowicz (11) reported a controlled study in 25 obese women with PCOS, many with acanthosis nigricans–a marker of severe insulin resistance. After 4–8 weeks of metformin, there were significant reductions in serum insulin, free testosterone, and LH, and an increase in serum sex hormone-binding globulin. The women also showed an attenuation in serum 17-hydroxyprogesterone hyperresponse to GnRH-agonist stimulation, a hallmark of ovarian hyperandrogenism (20). These effects were independent of changes in body weight. Subsequently, the authors fully replicated their results in nonobese women with PCOS (12), indirectly confirming that effects of metformin were not dependent on weight loss. Neither of these studies directly measured insulin sensitivity, but reductions in insulin levels suggest improved insulin resistance. More recently, a short-term single-blind study from the same group showed that clomifene-induced ovulatory capacity is strikingly improved in obese women with PCOS given metformin for 2 months (16). In this study, a significant increase in spontaneous ovulation rate in the first month of treatment suggested potential early reversal of reproductive abnormalities in PCOS treated with metformin alone.
Two groups have examined the effects of troglitazone, given for 3 months, in massively obese women with PCOS (14, 15). These studies reported improvements in insulin sensitivity and reductions in serum testosterone (14, 15) and LH levels (14). After treatment, these women also showed an attenuation of abnormalities in glucose tolerance and insulin secretion and an increase in fibrinolytic capacity (15).
These short-term studies suggest that insulin sensitizers may affect the entire spectrum of endocrine, metabolic and reproductive abnormalities found in women with PCOS. On the other hand, other studies that assessed metformin effects in hyperandrogenic subjects did not confirm these findings (17, 18). The reasons for the striking discrepancies among these studies are not readily explained. Interestingly, where insulin levels were reduced by treatment, serum androgens were lowered as well.
A similar relationship was found in studies in which attenuation of hyperinsulinemia was obtained in obese subjects by weight loss (24, 25, 26). In this regard, Crave et al. (27) did not observe any additional benefit of metformin over the effects of diet alone, in a double-blind study comparing the effects of a 4-month low calorie diet vs. diet plus metformin in obese hirsute women. Unfortunately, this study was not specifically designed to recruit women with PCOS and actually the large majority of patients had regular menses. This weakens any conclusion, as hyperinsulinemia likely plays a major role in the pathogenesis of hyperandrogenism only in PCOS subjects (2).
The present controlled study was conducted in women with PCOS with normal glucose tolerance, mostly overweight. In these subjects metformin treatment for 6 months determined significant reductions in baseline serum free testosterone, as well as in the serum 17-hydroxyprogesterone response to GnRH-agonist testing. These data are consistent with the results obtained in short-term studies by the Nestler and Jakubovicz group (11, 12) and indicate that in PCOS subjects attenuation of ovarian hyperandrogenism after metformin treatment is sustained. In these women, insulin sensitivity, measured by the glucose clamp–the gold standard method to assess in vivo insulin action (28)–was improved, and consistent with this finding, plasma insulin levels were lowered. Furthermore, serum HDL cholesterol was increased, consistent with attenuation of both hyperinsulinemia and hyperandrogenemia (29, 30).
Interestingly, although improvements of insulin sensitivity in these women were not dramatic, effects of metformin on menstrual abnormalities were striking. About 50% of these subjects, most with severe oligoamenorrhea at baseline, had their cycles normalized. These effects of treatment were independent of changes in body weight and were shown to be sustained up to 2 years in the open, long-term protocol. In addition, consistent with the short-term findings of Nestler et al. (16), serum progesterone assessment in women who experienced regular menses after metformin showed that most cycles became ovulatory.
At baseline, women randomized to metformin and those randomized to placebo were not entirely similar. In particular, body mass index was significantly lower and androgens tended to be higher in subjects given the active drug. These counfounding factors were taken into account in the analysis. Noticeably, the open long-term study shows that responders had higher body mass index and lower serum androstenedione than nonresponders. Thus, baseline differences between groups in the double-blind study could actually have reduced evidence of benefits of metformin vs placebo.
Low calorie diet should be the first choice of treatment for obese PCOS subjects (24, 25, 26). Nevertheless, insulin sensitizing agents may offer greater scope for practical application in these women, whose compliance with diet is often poor. Hyperinsulinemia and insulin resistance are also characteristic features of many lean PCOS patients (2), in whom weight loss would be undesirable. In these subjects as well insulin sensitizers may be a feasible choice (12), although our data indicate that the expected response rate is lower in lean patients.
In the present study, almost half of the women given the active drug had no improvement in their menstrual history. The reasons for the striking differences in clinical response to metformin among the individual PCOS subjects are not easily explained. We hypothesize that this phenomenon might reflect the heterogeneity in the pathogenesis of the syndrome. While insulin resistance is a common but not universal feature in women with PCOS, it likely plays a pathogenetic role only in a subset of women (2). Only these subjects would benefit substantially from improved insulin sensitivity. This hypothesis could also account for the discordant results among previous studies that considered metformin for the treatment of women with PCOS.
It should be borne in mind that the mechanisms of insulin resistance in PCOS and the ways by which both metformin and troglitazone may improve insulin action in these women are still largely unknown. These drugs seem to act at different levels, at least as far as glucose metabolism is concerned (31). Thus, intersubject differences in efficacy might be observed according to the specific defect responsible for the impairment in insulin action and the specific effects of each drug. On the other hand, the universal clinical efficacy of reductions in insulin levels (whether obtained by metformin, troglitazone, diet, diazoxide, somatostatin, or the putative mediator of insulin action D-chiro-inositol) (6, 7, 10, 11, 12, 14, 15, 16, 24, 25, 26, 32) in PCOS suggests that reproductive abnormalities in these patients may be directly related to hyperinsulinemia and not to any specific mechanism of insulin resistance.
An original aspect of our study was analysis of baseline predictors of clinical response to metformin. Actually, responders differed from nonresponders in several characteristics. Logistic regression analysis showed that higher plasma insulin, lower serum androstenedione, and less severe menstrual abnormalities were independent predictors of clinical efficacy of metformin. These data further strengthen the hypothesis that insulin sensitizers may be effective only in the insulin-resistant subset of this heterogeneous syndrome. On the other hand, the unfavorable predictive effect of higher baseline serum androstenedione levels may indicate poor efficacy of metformin in women with either a different pathogenesis of the syndrome or more advanced disease.
An intriguing finding of this study was the significant post-treatment reduction of serum LH, in responders only. Reductions in serum LH after treatment with metformin were previously found in the other studies, which likewise reported improvements in biochemical and/or clinical features of PCOS (10, 11, 12, 13). Furthermore, Dunaif et al. (14), but not Ehrmann et al. (15), reported similar concurrent changes after troglitazone. Interestingly, insulin stimulates gonadotropin release in vitro, at least in the rat (33). As a whole, these data suggest that changes in insulin levels might also contribute to changes in ovarian androgen secretion through effects at the pituitary level. However, current knowledge of these aspects is too limited to encourage the formulation of precise hypotheses.
In our study, while reproductive abnormalities strikingly improved after treatment, hirsutism was unaffected both in the 6-month controlled trial and in the long-term follow-up, despite substantial reductions in serum testosterone. These findings resemble those of other authors in hirsute subjects with congenital adrenal hyperplasia, in whom adrenal androgen suppression by glucocorticoid therapy has limited efficacy on established hair excess (34). In these women, a course of antiandrogen drugs is needed to improve their hirsutism, whereas corticosteroid therapy is sufficient for clinical maintenance. Whether this would also be true for hirsute PCOS subjects given metformin should be investigated by further research. Further studies should also establish whether metformin and troglitazone might have synergic effects in improving reproductive and endocrine abnormalities of women with PCOS, as recently shown for glucose metabolism abnormalities in type 2 diabetic subjects (31).
In conclusion, treatment with the insulin sensitizing agent metformin is effective in many women with PCOS, independently of changes in body weight, in attenuating insulin resistance and hyperandrogenemia and in reversing menstrual abnormalities and chronic anovulation. Insulin sensitizing agents may prove an efficacious therapeutic tool in a large subset of subjects with this common disease.
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Acknowledgments |
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Footnotes |
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Received July 29, 1999.
Revised September 27, 1999.
Accepted October 4, 1999.
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