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Increased Insulin-Like Growth Factor-I Levels in Women With Polycystic Ovary Syndrome, and Beneficial Effects of Metformin Therapy

November 26, 2004

Key words: INSULIN, INSULIN-LIKE GROWTH FACTOR-I, METFORMIN, POLYCYSTIC OVARY SYNDROME, REGULAR MENSES

ABSTRACT

We aimed to investigate whether metformin would reverse the endocrinopathy of polycystic ovary syndrome (PCOS), allowing resumption of cyclic ovulation and regular menses, and whether metformin causes any change in the serum concentration of insulin- like growth factor-I (IGF-I) in patients with PCOS. Fifty-eight women with PCOS participated in the study and received metformin at a dose of 850 mg three times a day (total 2550 mg)for 16 weeks. Serum concentrations of luteinizing hormone, follicle stimulating hormone, estradiol, free testosterone, total testosterone, 17- hydroxyprogesterone, dehydroepiandrosterone sulfate, fasting insulin, IGF-I, sex hormone binding globulin and insulin-like growth factor binding protein-1 (IGFBP-1) were evaluated before and after metformin treatment. Patients were divided into two groups as responders and non-responders according to the achievement of regular menstrual periods. The mean IGFI levels decreased significantly on metformin therapy. After 16 weeks of metformin treatment, 55.17% of PCOS patients achieved regular menses. Only the change in serum levels of progesterone and IGF-I on metformin were statistically significant between responders and nonresponders; metformin-induced decremental change in IGF-I levels were greater in responders. In conclusion, we observed that elevated IGF-I levels may have a crucial role in many consequences of PCOS in addition to hyperinsulinemia. By decreasing insulin and IGF-I levels, metformin therapy offers additional beneficial effects in resumption of regular menses. Thus, in PCOS patients with elevated levels of IGF- I, metformin may be considered as an appropriate agent to be used for the regulation of menstrual cycles.

INTRODUCTION

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies, affecting approximately 5-10% of women of reproductive age . This syndrome, in addition to chronic anovulation and hyperandrogenemia, is also characterized by several metabolic aberrations, including insulin resistance and compensatory hyperinsulinemia, as well as possible dysregulations of the insulin- like growth factor-I (IGF-I) system. Because the majority of women with PCOS are obese, it seemed initially that their insulin resistance could be accounted for on this basis alone; however, the studies of Dunaif and colleagues2-4 firmly established that the magnitude of insulin resistance is greater in women with PCOS than in their controls, matched for total and fat-free body mass. The current consensus is that both lean and obese women with PCOS may show evidence of decreased insulin sensitivity5. The resultant hyperinsulinemia enhances androgen levels by stimulating ovarian androgen synthesis and by lowering circulating concentrations of sex hormone binding globulin (SHBG).

The discovery that insulin resistance has a key role in the pathophysiology of PCOS has led to a novel and promising therapy in the form of insulinsensitizing drugs. Among the various agents, metfbrmin is the most widely tested. Metfbrmin has several mechanisms of action that tend to result in improvements in hyperinsulinemia in women with PCOS. The major effect is seen in the liver, where it suppresses hepatic glucose output. Metformin may also improve peripheral insulin resistance6. For many patients, metfbrmin therapy results in measurable weight loss, presumably secondary to the induction of sufficient abdominal discomfort to decrease appetite. The results of various studies of metfbrmin in patients with PCOS are variable. Not all studies have demonstrated a beneficial effect that could be clearly separated from that of weight loss7-9.

Several studies have suggested that IGF-I may play an important role in the regulation of ovarian follicular maturation and steroidogenesis10-12. It has been postulated that elevated levels of insulin and IGF-I along with elevated levels of luteinizing hormone (LH), acting on the thecal component m vivo, contribute to the hyperandrogenemia observed clinically in PCOS patients. While it is evident that IGF-I plays a role in PCOS, only a few studies have focused on the effects of metfbrmin therapy on IGF-I levels in PCOS patients13,14. The present study aimed to investigate whether metfbrmin would reverse the endocrinopathy of PCOS, allowing resumption of cyclic ovulation and regular normal menses. The second aim was to investigate whether metfbrmin causes any change in the serum concentration of IGF-I in patients with PCOS.

SUBJECTS AND METHODS

Fifty-eight women with clinical and biochemical evidence of PCOS were enrolled into this study. Mean age of the patients was 24.9 2.3 (range 19-31 years). The study protocol was approved by the Institutional Review Board of the Department of Obstetrics and Gynecology, and informed consent was obtained from each woman before starting the study. Subjects were recruited consecutively between February 2001 and June 2002 from our out-patient clinic. Diagnosis of PCOS was based on the presence of oligomenorrhea or amenorrhea and hyperandrogenemia. Free testosterone (FT) concentrations were determined in the local laboratory using radioimmunoassay. We considered that a patient had elevated FT if the concentration exceeded 3.2 pg/ml. Oligomenorrhea was defined as fewer than six cycles per year and amenorrhea as the absence of periods for ≥ 6 months. A baseline ultrasound scan was applied to all patients to evaluate the uterus and the ovaries. However, the polycystic ovarian morphology detected by ultrasound was not considered an essential criterion for the diagnosis of the syndrome, since abnormal ovarian appearance is a prevalent but not a universal feature of PCOS15.

Thyroid dysfunction, hyperprolactinemia, hypercortisolism and late-onset congenital adrenal hyperplasia were all excluded, using the appropriate tests. In order to exclude diabetes mellitus, a standard 2-h, 75-g oral glucose tolerance test (OGTT) was performed in all women, with normal results. None of the patients had taken oral contraceptives or any other steroid medication during the preceding 3 months. To gain entry to the study, body weight had to remain stable for at least 2 months before the study, and subjects participating in a dietary or exercise program for weight reduction were excluded.

Study design

All patients were evaluated between days 3 and 6 of spontaneous menstruation or at any time if amenorrhea was present. At the initial visit, a medical history was obtained and a physical examination was conducted with measurement of height and weight for the calculation of body mass index (UMI). Before the metfbmiin treatment, patients were screened for blood count, serum electrolytes, liver and renal functions, and lipid profile; basal blood samples for LH, follicle stimulating hormone (FSH), estradiol, FT, total testosterone (TT), 17-hydroxyprogcsterone (17OHP), dehydroepiandrosterone sulfate (DHEAS), fasting insulin (FI), IGF- I, SHBG and insulin-like growth factor binding protein-1 (IGFBP-I) were obtained at 08.00 after an overnight rest and fast.

After baseline study, all patients received metformin (metformin hydrochloride, Glucophage retard tablet; Merck, Germany) at a dose of 850 mg three times a day (total 2550 mg), 1 h after meals. All the patients were instructed to continue taking the medication for 16 weeks without modifying their physical activity and usual diet. At the end of the 16 weeks, the baseline protocol was repeated, and changes in the BMI and menstrual pattern were also recorded. We divided the patients into two groups as responders and non- responders according to the achievement of regular menstrual periods defined as two or more sequential menstrual cycles encompassing 21- 35 days. Spontaneous ovulation was detected by blood sampling between days 20 and 24 of the last menstruation. A progesterone serum level of ≥ 5 ng/ml was considered an ovulatory level. Since it is accepted that metformin treatment is not associated with episodes of hypoglycemia, glucose serum levels were not monitored during treatment16.

Hormonal assays

Serum glucose level was determined enzymatically using the glucose oxidase method on a Hitachi 747 autoanalyzer (Hitachi, Tokyo). Serum DHEAS level was measured by electrochemiluminescence immunoassay (Elecsys Systems 1010/2010/ Modular Analytics E170, Roche Diagnostics GmbH, Mannheim, Germany; normal range 70-300 g/dl in females). 17-OHP and FT were measured by radioimmunoassay (RIA), using ^sup 125^I RIA kits (17OHP kit: ICN Biomedicals, Inc., Diagnostic Division, Costa Mesa, CA, USA; normal range 0.1-0.8 ng/ ml in the fbllicular phase; FT kit: DSL-4900, Diagnostic System Laboratories, TX, USA; normal range 0.45-3.2 pg/ml). Serum LH and FSH levels were measured by immunometric assay (IMMULITE 2000, Diagnostic Products Corporation, Los Angeles, CA, USA; normal range in fbllicular phase 2.5-12.00 mIU/ml and 1.98-11.60 mIU/ml, respectively). Estradiol, progesterone and TT were measured by competitive immunoassays using available kits (IMMULITE 2000, Diagnostic Products Corporation; normal range 26-161 pg/ml, 0.12- 1.7 ng/ml in fbllicular phase, and 5.76-77 ng/ml, respectively). Insulin was measured by R\IA using a Coat-A-Count kit (Diagnostic Products Corporation, Los Angeles, CA, USA). For the insulin measurement, intraassay coefficients of variation (CVs) were 9.3% and 5%, and interassay CVs were 10% and 4.9% for low and high values, respectively. IGF-I was measured by using an immunoradiometric assay kit (Immunotech, Marseille, France; normal range 232-385 ng/ml, for 20-30 years of age). Intraassay CVs were 7.4% and 4.1% for the low and high values, and interassay CVs were 15.5% and 12.9% for the low and high values of IGF-I, respectively. SHBG was measured by RIA by using the BC 1020 kit (Biocode, Schlessin, Germany). For SHBG, the intra-assay CVs were 5.6% and 4.9%, and interassay CVs were 7.6% and 6.9% for the low and high values, respectively. IGFBP-1 was measured by RIA (Bio-Source, Nivelles, Belgium). Intra-assay and interassay CVs were less than 10%.

Statistical analysis

The pre- and post-treatment data were evaluated using the Wilcoxon rank sum test. The results between the responders and non- responders were analyzed using the Mann-Whitney U test. Correlations were estimated using simple regression analysis. A value of p

RESULTS

The effects of metformin on endocrine and clinical indices are presented in Table 1. The mean BMI of the patients did not change significantly during the study period. After 16 weeks of metformin therapy, there was a significant reduction of LH levels (11.15 3.02 vs 8.67 2.92 miIU/ml; p

Table 1 Clinical and hormonal data of 58 women with polycystic ovary syndrome before and after 16-week metformin treatment

After 16 weeks of metformin treatment, 32 of 58 PCOS patients achieved regular menses (55.17%) To determine the effects of metformin on menstrual regularity, we divided the patients into two groups according to menstrual changes: responders (n = 32) and non- responders (n = 26) (Table 2). These two groups did not differ from each other in terms of mean age and BMI. Twenty-one out of 32 (65.6%) patients with regular menses had a serum progesterone level within the ovulatory range (3.0-28 ng/ ml) which was statistically significant (p

The baseline study showed statistically significant correlations between insulin and TT, FT, IGF-I, HOMA-R index and BMI (Table 3). We failed to find any correlation between insulin and other studied hormonal parameters. Unlike insulin, IGF-I was not statistically related to testosterone levels. After 16 weeks of metformin therapy, we did not find any significant correlation between decrease in serum fasting insulin level and the changes in other studied hormonal and clinical parameters. As shown in Table 4, the change in IGF-I on metformin therapy was inversely correlated with the change in progesterone level (r=-0.41; p = 0.002), and was positively correlated with the change in LH level (r = 0.29;p = 0.023). The relationships of the change in IGF-I to the change in other variables were examined also, but no statistically significant correlations were observed.

Table 2 Comparison of the differences of the clinical and hormonal data between responders and nonresponders to metformin treatment in 58 women with polycystic ovary syndrome

Table 3 Significant correlations between insulin and other parameters at study entry in 58 patients with polycystic ovary syndrome

Table 4 Significant correlations between changes on metformin in 58 patients with polycystic ovary syndrome

After starting on metformin treatment, 22 of 58 women reported minor gastrointestinal problems including abdominal discomfort, meteorism, nausea and diarrhea that did not necessitate discontinuation of the treatment. These side-effects resolved spontaneously within a few weeks when the drug was taken at mealtime.

DISCUSSION

Although PCOS is the most common pathological cause of anovulation, the pathogenesis of this syndrome has not been AUIy defined. Current studies suggest that abnormalities of the insulin and IGF systems, including hyperinsulinemia, insulin resistance and increased IGF-I, may be involved18-20. These findings prompted the testing of insulinsensitizing agents, such as metfbrmin or troglitazone, for the treatment of both the metabolic and the endocrine abnormalities of women with PCOS ” .

In this respect, there were two main findings of the present study: first, 16 weeks of metfbrmin administration reduced IGF-I levels and ameliorated insulin resistance and hyperandrogenemia, with no significant changes in BMI; and second, metfbrniininduced decrements in IGF-I levels were greater in women with PCOS who achieved regular menstruation after metfbrmin therapy.

In our study, we observed higher insulin concentrations in all PCOS women, in agreement with the literature21,22. After metfbrmin therapy, we observed a significant reduction in FI, TT and FT concentrations together with decreased insulin resistance (decreased HOMA-R), whereas change in BMI did not reach statistical significance. There are several studies on metfbrmin therapy in patients with PCOS, but the results are inconsistent5,7,9,19. Currently, it is still not clear whether the reduction in FI concentration is a direct effect of metfbrmin action or an indirect result of the weight loss in the group of PCOS patients. Ehrmann and colleagues did not observe any beneficial effect of metfbrmin treatment on body weight . Additionally, they reported that hyperinsulinemia and hyperandrogenism did not improve after metfbrmin treatment, which is in constrast to our findings. They concluded that there was no direct effect of nictfbrmin on gonadotropin or ovarian steroid production that could be independent of weight loss9. However, contrary to the results of Ehrmann et al., Morin-Papunen and colleagues did not observe a significant change in BMI after 4-6 months of metformin treatment, and they also observed a statistically significant decrease in fasting insulin concentrations and free testosterone levels23. These data are in agreement with the results obtained in our study. Thus, it was demonstrated that the effects of metfbrmin on PCOS were due to actions independent of weight loss, and BMI should not be the sole predictor of the success of mctformin therapy.

In the present study, metfbrmin treatment was associated with a reduction in androgen serum levels, partly due to a reduction in insulin levels. Hyperinsulinemia enhances androgen concentration by direct stimulation of ovarian androgen synthesis, or by enhancing LH secretion and by lowering the concentration of SHUG14. Since the serum levels of SHBG were within normal limits at the beginning of the study and did not change significantly after metfbrmin treatment, the last factor is most probably not the major responsible mechanism for insulin-mediated hyperandrogenism observed in our study. In the current study, insulin was more strongly correlated with TT and FT than with LH. Supporting the finding of our study, m i//(m studies have shown that thecal cells from polycystic ovaries were more sensitive to insulin; the same concentrations only slightly affected testosterone production in controls” .

More recent studies have focused on the ability of metformin to improve menstrual regularity and documented ovulation ^ “” . Morin- Papunen and colleagues reported that 69% of Finnish PCOS women with menstrual disturbances developed regular menstrual cyclicity on metfbrmin 1500 mg/day for 6 months “. Diamanti-Kandarakis cf a/, reported that seven of 16 (44%) Greek women with PCOS resumed normal menstruation on metfbrmin, 1700 mg/day for 6 months”". Nestler ff a/ , reported that 12 of 35 obese women (34%) ovulated after 35 days on nietfbrmin 1500 mg/day, versus one of 26 (4%) given placebo” . In the present study, parallel to the previous reports, with metfbrmin of 2550 mg/day, 32 of 58 (55.17%) previously oligomenorrheic/ amenorrheic PCOS women resumed normal menstrual cyclicity, labeled as responders. It was demonstrated that, in subjects experiencing regular menses after metfbrmin treatment, improvement was observed within 4 months” ” . In our opinion, a dose of metfbrmin 850 nig three times per day is important in the achievement of regular menses. Although we could not assess how many of the cycles were ovulatory during therapy, after 16 weeks of treatment, 21 of 32 (65.6%) women who resumed regular menses had a serum progesterone level within the ovulatory range. As a result, consistent with the novel theoretical models of PCOS, we can state that hyperinsulinism and resultant hypcrandrogenism chronically alter gonadotropin secretion, increasing LH, disrupting the normal pituitary-ovarian axis, leading to oligomenorrhea and amenorrhea26,32. Thus, when metfbrmin reduces insulin levels, this leads directly to consequent decrements inandrogens with restoration of the normal pituitaryovarian feedback system23,25,28-30,33. However, in the current study, we demonstrated that only the change in scrum levels of progesterone and IGF-I on metfbrmin were statistically significant between responders and non-respondcrs; metfbrmin- induced decrements in IGF-I levels were greater in responders. Therefore, whether all of the therapeutic effects of metfbrmin in women with PCOS are mediated solely by its insulin-lowering effects remains to be determined. Hence, we can speculate that the decrements in IGF-I on metfbrmin therapy may also play a part in achievement of a normal pituitary-ovarian axis; i.e. resumption of ovulatory menses.

There is evidence suggesting that PCOS is associated with an increase in the level of IGF-I, possibly because of a decrease in IGFBP-I, a hepatic product the synthesis of which is inhibited by insulin13,34,35. We showed a significant correlation between IGF-I and insulin and insulin resistance, supporting the suggestion that IGF-I could play a role in the pathogenesis of PCOS. However, the situation is likely to be complex, and the physiology of how IGF-I contributes to hyperandrogenemia is not fully defined. While it is evident that IGF-I plays a role in PCOS, there are a limited number of studies showing the precise effect of metfbrmin therapy on IGF-I levels. Kowalska and colleagues reported that the IGF-I level remained unchanged, and the IGFBP-1 concentration showed a tendency to increase, which did not reach statistical significance after 4-5 months of metfbrmin treatment in the PCOS group14. Similarly, De Leo and colleagues observed that IGF-I concentrations did not change after 30-32 days of metfbrmin treatment, with a significant increase in serum IGFBP-1 levels in patients with PCOS13. In our study, we observed a statistically significant decrease in IGF-I levels after 16 weeks of metfbrmin treatment. Additionally, as we expected, the IGFBP-I level showed a tendency to increase. However, it did not reach statistical significance. This finding may be explained by the fact that the response to metfbrmin in PCOS patients is not entirely uniform. The decrement in IGF-I levels was significantly greater in women who resumed regular menses. We also found a significant correlation between change in IGF-I concentrations and changes in progesterone and LH levels. We can speculate that, despite the significant decrease in serum insulin levels in both responders and nonresponders, improvement in menstrual cyclicity following metfbrmin treatment in the responder group may be primarily related to the overwhelming decrease in the IGF-I levels in this group of PCOS women. In agreement with our data, in a recent study, Duleba and colleagues showed that IGF-I increased the number of thecal- interstitial cells more potently than insulin35. This important finding offers another, complementary, explanation of hyperandrogenism seen in PCOS patients.

In summary, we observed that elevated IGF-I levels may have a crucial role in many consequences of PCOS in addition to hyperinsulinemia. By decreasing insulin and IGF-I levels, metfbrmin therapy offers additional beneficial effects in resumption of regular menses. Thus, in PCOS patients with elevated levels of IGF- I, metfbrmin may be considered as an appropriate agent that could be used for the regulation of menstrual cycles, but large randomized trials are needed. With increasing understanding of the IGF system and its roles in ovarian physiology, future therapeutic modalities will be developed to treat such disturbances in ovarian physiology as anovulation and disorders of androgen excess, and treatment modalities for the infertile couple will be expanded.

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B. Berker, R. Emmi*, C. Demirel, D. Corapcioglu*, C. Unlu and K. Kose[dagger]

Department of Obstetrics and Gynecology; * Department of Endocrinology; [dagger] Department of Biostatistics, Ankara University School of Medicine, Ankara, Turkey

Correspondence: Dr B. Berker, Hseyinonat Sokak 10/6 Sahinbey Ap. Asagi ayranci , 06540-Ankara, Turkey

Tel: +90-312-466 28 70 Fax: +90-312-3203553 e-mail: bulentberker@hotmail.com

Copyright CRC Press Sep 2004




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