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Original Studies |
Department of Obstetrics and Gynecology (L.M.-P., R.K., C.T., H.M.) and Department of Clinical Chemistry (A.R.), University Hospital of Oulu, 90220 Oulu, Finland
Address all correspondence and requests for reprints to: Morin-Papunen Laure, M.D., Department of Obstetrics and Gynecology, University Hospital of Oulu, Kajaanintie 50, 90220 Oulu, Finland.
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Abstract |
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Introduction |
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Several studies (5, 6, 7), but not all (8, 9), have shown that insulin-sensitizing therapy with metformin results in a reduction of hyperinsulinemia and hyperandrogenism in obese and nonobese PCOS women. In our previous study (10), we showed that the administration of metformin partially restored ovarian function in some, but not all, obese PCOS patients with menstrual disturbances, suggesting the therapeutic value of metformin. To further study the mechanism of metformin action in PCOS, we analyzed the serum leptin concentrations during the treatment.
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Subjects and Methods |
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Women with PCOS were recruited from the endocrinology outpatient
clinic at the University Hospital of Oulu, Finland. The criteria for
PCOS were as defined by Homburg (11). All the patients had polycystic
ovaries in vaginal ultrasound (at least 8 subcapsular follicles of 3-
to 8-mm diameter in one plane in one ovary and increased stroma by
transvaginal ultrasound) with at least one of the following symptoms:
oligo/amenorrea (21/26, 81%), hirsutism (score 
7, according to
Ferriman-Gallway; 20/26, 77%) (12), or acne (6/26, 23%). Twenty-two
(85%) of the patients were obese, with a BMI more than 27
kg/m2. The mean age of the patients was 30 ± 6.8 yr
(range 20–41 yr).
Protocol of the study
Serum leptin concentrations were evaluated between 0800 h and 0900 h, after an 12-h overnight fast, before the treatment and in the same conditions after sitting for 20 min at 2 and 4–6 months of metformin therapy (metformin hydrochloride; Diformin, Leiras, Finland; 500 mg x 3 daily).
The study has been approved by the Ethical Committee of the University Hospital of Oulu; and, in the metformin study, informed written consent was obtained from each subject.
Assays
Serum leptin was measured in duplicate with a highly specific human leptin RIA kit (Linco Research, Inc., St. Charles, MO), following the manufacturer’s instructions. The leptin RIA detects immunoreactive human leptin with a sensitivity of 0.5 ng/mL in serum (100-µL sample size). Serum insulin was measured by RIA, following the instructions of the manufacturer (Pharmacia, Uppsala, Sweden).
Statistical analyses
For statistical analysis, we used the Wilcoxon signed-rank test and ANOVA for repeated measurements. A multiple-regression model was used for detecting correlations between continuous variables and detection of covariance.
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Results |
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In the 26 patients treated for 2 months, the mean serum leptin levels
decreased significantly (P = 0.03) from 29.2 (±
12.7) ng/mL to 25.7 (± 10.9) ng/mL, at 2 months metformin therapy
(Fig. 1
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). In comparison with the levels
before treatment, there was a mean decrease in serum leptin
concentrations of 3.53 ng/mL (95% CI, of 0.5 to 6.5 ng/mL;
P = 0.004) after 2 months, and of 4.5 ng/mL (95% CI,
of -0.88 to 9.8; not significant) after 4–6 months of treatment (Fig. 2).
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Before the treatment, there was a significant linear correlation between the BMI and the serum leptin levels (r = 0.8, P = 0.0001). Although there was also a significant correlation between the serum leptin and the fasting insulin levels, this effect disappeared when a multiple-regression analysis, including also BMI, was performed. This indicates that the correlation between insulin and leptin is dependent on BMI.
Before metformin treatment, there were 10 patients with abnormal menstrual cycles. During the 4–6 months of the metformin treatment, 7 patients showed an improvement in their menstrual cycles. In these responsive women, the mean serum leptin concentration decreased at 2 months (from 38.8 ± 8.7 to 27.4 ± 7.9 ng/mL; P = 0.018) but increased slightly at 4–6 months of treatment (31.9 ± 15.0 ng/mL; not significant).
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Discussion |
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In accordance with a recent study (14), we found a positive correlation between fasting serum leptin and insulin levels before therapy, although this correlation disappeared when BMI was included in the analysis. Insulin has been shown to stimulate leptin production in vitro (15) and in vivo (16); and, inversely, leptin could also contribute to an hypersecretion of insulin by the ß-cell islets in obese insulin-resistant subjects (17). However, in our study, the mean serum leptin levels tended to return towards the starting level at 4–6 months treatment; although, in most cases, the serum leptin concentrations remained decreased. We could not find any explanation for this variability between subjects. It is possible that the metformin effect on the leptin secretion may be transitional and that some adaptation may occur during the prolonged therapy (10).
Our data are in contrast to a study in which no change in serum leptin was observed after 3 months therapy with another insulin sensitizing drug, troglitazone, in very obese PCOS women (3). This discrepancy may be caused by the fact that the mechanisms of actions of metformin and troglitazone are different (18, 19). Interestingly, troglitazone was found to inhibit leptin synthesis in vitro (20).
Recent studies have shown that metformin, by decreasing serum insulin level, reduces ovarian cytochrome P450c17a activity and ameliorates the hyperandrogenism of PCOS women (6, 7). In this study, the serum leptin concentrations followed the same pattern as the serum testosterone concentrations during metformin (10), suggesting the possibility that leptin and androgen synthesis are related. This hypothesis gets support from our finding of significant correlation between serum testosterone and leptin concentrations in normal women and women with PCO ovaries (R Koivunen et al., unpublished observation). The direct effect of leptin on ovarian steroidogenesis is possible because, recently, messenger RNA for leptin receptors has been found in both thecal and granulosa cells of the ovaries (21).
In conclusion, metformin therapy, restoring ovarian function in some obese PCOS women, seems to decrease leptin serum concentration in these patients. This suggests that the effects of metformin could, at least partly, be mediated by leptin.
Received December 8, 1997.
Accepted April 2, 1998.
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