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Effect of Metformin on the Clinical and Metabolic Assessment of Women With Polycystic Ovary Syndrome

Posted on: Thursday, 28 October 2004, 03:00 CDT

Key words: METITOKMIN, INSULIN RESISTANCE, POLYCYSTIC OVAKY SYNDROME, PCOS, CHKONIC ANOVULATION, HYPEKANDKOGRNISM

ABSTRACT

A longitudinal prospective study was conducted in 21 women until polycistic ovary syndrome (PCOS), aged 27.20 5.02 years and treated with metformin (1500 mg/day) for 8 weeks. The patients were assessed for spontaneous menstruation, weight, body mass index (BMI), waist circumference, waist/hip ratio (WHR), glucose and insulin concentrations under fasting conditions and after a 75-g glucose tolerance test, lipid profile, testosterone, androstenedione, deity droepiandrosterone snljate, sex-hormone binding globulin (SHBG), and insulin-like growth factor (IGb')-L Spontaneous menstruation was observed in 81% of the women treated with nietformin, unth no changes in weight or BMI. Waist measurement and the WHR were reduced. The quantitative insulin sensitivity check index (QLJICKI) improved from 0.33 0.03 to 0.35+0.04 (p < 0.005), and serum total cholesterol and low-density lipoproiein-cholesterol were reduced, while high-density lipoprotein-clioleslerol was increased. Serum testosterone concentrations were also reduced. There were no differences in serum triglycerides, SHBG or IGF-I. The occurrence of spontaneous menstruation and changes in the pattern oj body fat distribution, the reduction in serum testosterone concentrations, the improvement in lipid profile and the reduction of insulinemia with the use of metformin permit us to conclude that treatment with this drug is of benefit to women with PCOS.

INTRODUCTION

Polycystic ovary syndrome (PCOS) is the gynecological endocrine disease most frequently occurring during mcnarche, affecting (S-10% of women during this phase of life .The physiopathological mechanisms of P(JUS are complex, and are characterized by hyperandrogenic chronic anovulation. Insulin resistance and compensatory hyperinsulincmia are currently considered to be the major factors involved in its etiopathogenesis.

The molecular mechanisms of insulin resistance in PCOS have not been fully clarified. Dunaif", in a study of fibroblast cultures from women with PCOS, detected alterations in serine phosphorylation in 50% of cases. An important point in the pathogenesis of PCOS is the evidence that serine phosphorylation may modulate the activity of the enzyme P450c17α responsible for the regulation of androgen biosynthesis . In ovarian thecal cells, insulin may directly stimulate P450c17α, with a consequent increase in the activity of the enzymes 17α-hydroxylase and 17,20-lyase, an increase in androstenedione production, and a consequent increase in testosterone4. Thus, a single defect may induce insulin resistance and hyperandrogenism in PCOS5.

The use of drugs such as metformin that improve the sensitivity to insulin in the treatment of PCOS has been extensively studied6. The objective of the present investigation was to analyze the effects of metformin treatment on women with PCOS in terms of clinical, endocrinological and metabolic aspects.

MATERIALS AND METHODS

A prospective longitudinal study was conducted to assess the effects of the use of metformin (Glucoformin, Biobrs, Montes Claros, MG, Brazil) at a dose of 1500 mg/day for 8 weeks on 21 women with PCOS attending the Sector of Human Reproduction, Department of Gynecology and Obstetrics, University Hospital, Faculty of Medicine of Ribeiro Preto, University of So Paulo, from January 2000 to December 2001. The study was approved by the Ethics Committee of the institution and the patients gave written informed consent to participate.

Inclusion criteria were: patient consent to participate in the study; age from 18 to 38 years; and no use of any hormonal medication during a period of 90 days before the study. The criteria considered for the diagnosis of PCOS were a clinical history of oligomenorrhea since menarche and the presence of clinical and/or laboratory hyperandrogenism2. An additional criterion for the diagnosis of PCOS was a luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio of 2 or more, this being the pathognomonic indication for PCOS.

Exclusion criteria were: presence of metabolic disease such as Gushing syndrome, congenital adrenal hyperplasia, hyperprolactinemia, hyper- or hypothyroidism, and diabetes mellitus; significant changes in hepatic and renal function determined by laboratory tests; or any other clinically significant abnormal results during the pretreatment period.

The clinical parameters assessed before and after treatment were: presence of spontaneous menstruation, weight, body mass index (BMI), waist (W) and hip (H) circumference, waist/hip ratio (WHR), hirsutism (Ferriman index), acanthosis nigricans and side-effects and tolerability of the drug.

The metabolic parameters assessed before and after treatment were fasting glycemia and insulin level determined under fasting conditions and after the glucose tolerance test (GTT with 75 g dextrose); serum determinations of androgens: testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS); lipid profile determined by serum measurement of total cholesterol, low- density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides, and serum measurement of insulin-like growth factor I (IGF-I) and sex-hormone binding globulin (SHBG).

Plasma glucose was determined by the hexokinase method using a Cobas Miras apparatus, with a coefRient of variation of 9%. The glycemia values obtained during the GTT (75 g dextrose) were analyzed according to the 1997 criteria of the American Diabetes Association (ADA) and the World Health Organization (WHO)7, i.e. normal, fasting glycemia of= 110 mg/dl and glycemia after 2 h of < 140 mg/dl; diabetes, fasting glycemia of= 126 mg/dl and glycemia after 2 h of= 200 mg/dl; glucose intolerance, intermediate values between normal and diabetes. The area under the glucose curve was calculated by the trapezoidal method and is expressed as mg/dl.2 h. Serum insulin was measured in duplicate by radioimmunoassay (PJA) by the solid technique according to the protocol of the DPC kit (Diagnostic Product Corporation, Los Angeles, CA, USA). The intra- and interassay coefficients of variation were 7.9% and 6.1%, respectively. Insulin resistance was assessed according to two parameters: the quantitative insulin-sensitivity index (QUICKI), which considers a normal value to be = 0.34 , and the fasting insulinemia/glycemia index (I/G index), which considers a normal value to be < 0.19 . The area under the insulin curve was calculated by the trapezoidal method and is expressed as IUml.2 h.

Serum androgens were determined by RIA. The coefficients of variation for the determinations of testosterone, androstenedione and DHEAS were 4%, 2.29% and 4.77%, respectively. Serum total cholesterol, triglycerides and HDL-cholesterol were determined by an enzymatic colorimetric method, with respective coefficients of variation of 1.9%, 5.5% and 1.12%. SHBG was determined by chemoluminescence with a DPC kit, with a coefficient of variation of 5.2% and IGF-I was determined by double-antibody RIA after extraction, with a coefficient of variation of 3.87%.

The patients were divided into two groups: group I consisted of women with a family history of diabetes mellitus (n = 10) and group II consisted of women with no family history of diabetes mellitus (n=11).

Data were analyzed statistically by the non-parametric Kolmogorov- Smirnov test to determine the normality of the sample values and by the paired t test for data comparison, with the level of significance set at 5%. To compare the patients with respect to a family history of diabetes mellitus we used the Mann-Whitney test, with the level of significance set at 5%. All statistical procedures were carried out using the GraphPad Prism software version 3.00 for Windows (GraphPad Software, San Diego, CA, USA (wwAv.graphpad.com)10

RESULTS

The age of the women ranged from 18 to 37 years, with a mean of 27.20 years. The mean age at menarche was 12.5 years. Twenty women had a complaint of infertility. A family history of diabetes mellitus was detected in ten cases (47.6%). With respect to the menstrual cycle, ten women were amenorrheic and 11 had oligomenorrheic cycles at the beginning of treatment. After treatment, spontaneous menstruation occurred in 81% (17) of the women studied (Table 1) A Ferriman index of = 9 was detected in 16 patients, with no change in the index before or after the use of metformin. Acanthosis nigncans was detected in seven patients, an alteration that remained unchanged during treatment.

Obesity was observed in 66.7% of cases (14) and was graded according to WHO criteria. Five women showed grade I obesity (BMI 25- 29.9 kg/ m^sup 2^), seven showed grade II obesity (BMI 30-39.9 kg/ m^sup 2^), and only two women showed grade III obesity (BMI > 40 kg/ m^sup 2^). No changes in weight or BMI occurred before or after treatment. There was a change in the pattern of distribution of body fat indirectly assessed by waist measurement and by the WHR. At the beginning of treatment, the waist measurement was more than 80 cm in 15 women, with a mean value of 89.36 15.23 cm. After treatment, this measurement was reduced to 87.71 15.35 (p = 0.0337). WHRs of ≥ 0.85 were detected in 13 women be\fore treatment, but in only eight at the end of the study. A significant alteration in WHR was observed, with a mean reduction from 0.85 to 0.82 cm (p = 0.0017) (Table 1).

Table 1 Clinical characteristics of 21 women with poycystic ovary syndrome before and after treatment with metformin at a dose of 1500 mg/day for 8 weeks

Glucose intolerance was detected in four women (19%). Analysis of mean glucose levels before and after metformin treatment revealed a significant decrease in fasting glycemia from 80.67 10.67 to 71.19 7.71 mg/dl. No significant differences in mean glucose values occurred at the remaining times of the GTT before or after the use of metformin, nor did differences occur in the mean values of the area under the glucose curve with treatment (Table 2).

Evaluation of scrum androgen levels showed a significant change only in testosterone, which was reduced on average from 63.19 + 18.94 ng/dl to 50.32 13.98 ng/dl. Twelve women (57.1%) showed serum SHBG levels of < 37 nmol/l, with no changes occurring after the use of metformin for 8 weeks. The normal range is considered to be 18- 114 nmol/l, with a median of 51 nmol/1 (Table 2).

Treatment with metformin for 8 weeks was effective in reducing serum levels of total cholesterol, which decreased from 181.70 38.09 mg/dl to 167.70 30.06 mg/dl, and also in promoting a better equilibrium in the distribution of cholesterol levels, with a mean increase in HDL-cholesterol from 39 8.05 mg/dl to 50.43 10.81 mg/ dl, and a decrease in LDL-cholesterol levels from 119.80 33.06 mg/ dl to 94.71 23.94 mg/dl. No changes in triglyceride levels were observed (Table 2).

Table 2 Serum levels of testosterone, androstenedione, DHEAS, SHBG, total cholesterol, triglycerides, HDL-cholesterol, and LDL- cholesterol, fasting glycemia, AUC for glucose, fasting insulinemia, I/G index, the QUICKI, AUC for insulin and IGF-I before and after treatment with metformin at a dose of 1500 mg for 8 weeks in 21 women with PCOS

There was a significant change in fasting insulin levels, which decreased from 19.32 18.48 IU/ ml to 12.49 8.19 IU/ml (p = 0.02). The I/G index was significantly reduced by metformin treatment from 0.25 0.19 to 0.18 0.11 (p = 0.0064). The results of the QUICKI before therapy showed the presence of insulin resistance in 61.91% of women, whereas after treatment only 28.57% of the women were considered to have insulin resistance. The QUICKI increased from 0.33 0.03 to 0.35 0.04. Evaluation of the area under the insulin curve showed a decrease, with mean values of 15.840 10.330 IU/ml.2 h and 13.190 7.454 IU/ml.2 h (p = 0.0606) before and after treatment, respectively, although the difference was not significant (Table 2).

No significant difference in serum IGF-I levels was observed when the results obtained before and after treatment were compared. (Table 2)

When we analyzed the patients separately with respect to the presence (n = 10) or absence (n = 11) of a family history of diabetes mellitus, we observed no differences between groups in the basal values or between the pre- and post-treatment values of the following variables: weight, BMI, waist circumference, WHR, mean levels of testosterone, androstenedione, total cholesterol, and triglycerides, area under the curve for glucose, fasting insulin, I/ G ratio, QUICKI, area under the curve for insulin, IGF-I, or SHBG.

A significant difference in mean testosterone values occurred after treatment with metformin only in the group of women with no history of diabetes mellitus, with mean values before and after treatment of 67.38% 18,96 ng/dl and 48.04 12.04 ng/dl, respectively (p = 0.0048). The same occurred regarding the mean values of LDL-cholesterol, which were reduced significantly from 121.5 30.58 mg/dl before treatment to 92.64 22.17 mg/dl after treatment (p = 0.0302) only in the group with no family history of diabetes mellitus. The mean testosterone values for the group of women with a family history of diabetes mellitus were 58.57% 18.78 ng/dl before treatment and 52.83 10.13 ng/dl after treatment. The mean LDL-cholesterol values for the group of women with a family history of diabetes mellitus were 117.90% 37.18 ng/dl before treatment and 97.00 20.77 ng/dl after treatment.

A significant improvement in HDL-cholesterol levels occurred in both groups after treatment with metformin, with an increase from 39.50 10.30 mg/dl to 51.50 12.86 mg/dl (p = 0.0355) in the group of women with a family history of diabetes mellitus and from 38.55 5.80 to 49.55 9.11 mg/dl (p = 0.0043) in the group of women with no family history of diabetes mellitus.

A significant decrease in mean fasting glycemia from 81.20 13.09 mg/dl before treatment with metformin to 69.00 6.77 mg/dl after treatment occurred only in the group with a family history of diabetes mellitus, whereas in the group of women without a family history of diabetes mellitus there was no significant difference, with mean values of 80.18 8.55 mg/dl before treatment and 73.18 8.28 mg/dl after treatment.

DISCUSSION

The mechanisms by which metformin improves insulin resistance in women with PCOS have not been fully elucidated. It has been established that the antihyperglycemic efiects of metformin are due to a reduction of hepatic glucose production, to improved tissue sensitivity to insulin, facilitating glucose utilization by skeletal muscle and adipocytes, and reduced intestinal glucose absorption6,12.

It has been demonstrated that metformin reduces hepatic gluconeogenesis, interfering with the oxidative respiratory process of mitochondria, and suppressing gluconeogenesis in various substrates including lactate, pyruvate, glycerol and amino acids. In addition, metformin increases intramitochondrial calcium levels ". With the improved tissue sensitivity to insulin, metformin facilitates glucose transport with increased tyrosine kinase activity on insulin receptors ". It has been demonstrated that metfbrmin has no direct effect on insulin secretion by pancreatic β cells14.

The presence of glucose intolerance (19.04%) observed here agrees with literature reports. Women with PCOS are susceptible to the development of glucose intolerance and non-insulin-dependent diabetes mellitus, usually during the third or fourth decade of life6 at a rate ranging from 20 to 40% of cases15,16. In this study, the presence of a family history of diabetes mellitus was a factor that contributed to the efficiency of treatment with metformin only with respect to the improvement of fasting glycemia, having no effect on any other clinical and/or laboratory factors analyzed. In our patient series, after the use of metformin we observed a reduction in fasting plasma glucose levels, possibly as a consequence of the reduction in hepatic glucose production and a better tissue consumption of glucose.

The choice of the method for insulin resistance assessment is a matter of extensive debate in the literature. In the present study, the values of the area under the insulin curve were decreased after treatment with metformin, although the difference was not significant. The current suggestion is to use indices based on fasting insulin and glycemia determinations such as the homeostasis model assessment method (HOMA)17 the QUICKI, and the I/G index9. Among these indices, the one showing the best correlation with the hyperinsulincmic euglycemic clamp is the QUICKI . The improved QUICKI and the reduced fasting insulinemia and I/G index and the tendency towards a decrease in the area under the insulin curve observed in the present study permit us to conclude that metformin was effective in the treatment of insulin resistance in women with PCOS. Our data agree with those reported by others, regardless of the diagnostic method used to determine insulin sensitivity6,19. The present results are consistent with the possible mechanisms of action of metformin such as the improved peripheral tissue sensitivity promoted by an increase in tyrosine kinase activity on insulin receptors, promoting a better tissue glucose consumption. The state of chronic anovulation present in women with PCOS causes changes in the menstrual cycle ranging from amenorrhea and oligomenorrhea to situations of dysfunctional uterine hemorrhage, with PCOS being one of the most frequent causes of secondary amenorrhea20 and female infertility21.

The main mechanisms by which hyperinsulinemia can contribute to inadequate follicular development are changes in LH secretion, action of insulin via the IGF-I receptor stimulating LH, reduced intrafollicular IGF binding protein (IGFBP)-1, reduced SHBG secretion, and insulin action through its own receptors. All of these factors contribute to intraovarian androgen production4,22. In the present study, treatment with metformin was effective in producing spontaneous/regular menses and a significant improvement in testosterone levels and insulin resistance. Thus, even though we did not assess the presence of ovulatory cycles, these data lead us to suggest that most of these patients would be in a condition to ovulate. Investigators who assessed the use of metformin for 6 months reported regular cycles for 58-95% of cases23,24. In the treatment of hyperandrogenism, metformin probably acts by reducing P450c17α, a fact possibly mediated by the improved action of tyrosine kinase. Nestler and Jakubowicz25 demonstrated a reduction of P450c17α activity after the use of metformin in women with PCOS. In the present study we observed a significant reduction in mean total serum testosterone levels before and after treatment with metformin, in agreement with other studies in which metformin was used1, although not all investigators agree about this point26. The clinical manifestations of hyperandrogenism in women with PCOS are hirsutism and acne. The conversion of testosterone to dihydrotestosterone (DHT) by the act\ion of the enzyme 5α- reductase is an essential prerequisite for the cellular action of androgens on the pilosebaceous follicles. It has been demonstrated that the enzymatic action of 5α-reductase is mediated by IGF- I27. Thus, the elevated bioactivity of IGF-I in hyperandrogenic and hyperinsulinemic women with PCOS may act by amplifying the manifestations of hirsutism28. In the present study, there were no changes in hirsutism after treatment with metformin. It is important to point out that the duration of the hair growth cycle is about 6 months29. Reduction of hirsutism can be considered effective only in prolonged treatments lasting 6 months or more. Insulin affects the hyperandrogenic status of women with PCOS by both a direct and an indirect action, regulating the concentrations of SHBG in the circulation . Low SHBG levels are usually found in hyperandrogenic states, especially in association with PCOS, regardless of obesity30, although they are more clearly reduced in obese women30,31. Since insulin is a probable regulator of SHBG synthesis, we expected SHBG levels to increase with the improvement in insulinemia, a fact that did not occur in the present study. Our data support those of Vandermolen et al.26 who did not find differences in SHBG levels after the use of metformin. However, other investigators19,32 observed a significant improvement in SHBG values after treatment with metformin. We detected no difference in serum IGF levels. It should be pointed out that the simple serum determination of IGF-I is not sufficient to reflect, per se, the autocrine/ paracrine activity of the IGFBP-IGF-I complex. The association of obesity with PCOS in 66.67% of the women studied agrees with literature data, which show this association in 35-80% of cases of PCOS15. The use of the QUICKI revealed the association between obesity and insulin resistance in 84.62% of cases, indicating a probable correlation between these parameters.

When present in patients with PCOS, obesity acts by potentiating the effects of insulin resistance. Reduction of insulin with the use of metformin33 and weight loss34 reduce the ovarian activity of the enzyme P450c17α, with a consequent reduction in serum testosterone concentrations in women with PCOS. A weight reduction of more than 5% in obese women with PCOS has been shown to have an important effect in reducing the concentration of estrone, with a tendency towards a decrease in total and free testosterone levels and to a normalization of gonadotropin secretion, especially LH. This promotes a regularization of the menstrual cycle, with improved fertility accompanied by a fall in insulin levels . In the present study we did not detect changes in body weight or BMI after treatment. Thus, the clinical and laboratory changes observed can be attributed to the action of metformin. Patients with PCOS tend to present an android pattern of fat distribution and this type of obesity shows a higher correlation with cardiovascular and metabolic complications11. WHRs higher than 0.80 are correlated with a larger amount of visceral or portal fat measured by tomography or magnetic resonance. More recently, the measurement of waist circumference alone proved to be sufficient to establish risks, with a value of < 80 cm being considered the normal limit. The risk for the presence of at least one classic factor of coronary risk increases when the measurements exceed 88 cm in women (odds ratio: 2.6)11. We observed that the use of metformin was effective in promoting a reduction of waist circumference and of the WHR, reducing the risk for cardiovascular disease in women with PCOS.

Hyperinsulinemia has been associated with an increased incidence of diseases such as diabetes mellitus type 2 and arterial hypertension and with metabolic defects, with frequent changes in lipid profile represented by increased serum concentrations of the LDL-cholestcrol fraction and decreased concentrations of the HDL- cholesterol fraction. All of these factors represent risks for cardiovascular disease35. The lipoprotein profile of PCOS is accompanied by insulin resistance and involves increased very low- density lipoprotein (VLDL), reduced HDL and increased triglycerides. Androgens, estrogens and insulin affect lipase activity, with a consequent altered pattern of lipid circulation36. Insulin resistance acts on antilipolysis activation, on changes in lipoprotein lipase activity, on the cholesterol ester carrier protein and on hepatic lipase36. Metformin inhibits the production and oxidation of free fatty acids by 10-30%, reducing the formation of fatty acids induced by insulin resistance and reducing hepatic glucose production13. In our study, treatment with metformin promoted a significant increase in the lipid profile of women with PCOS, and serum HDL-cholesterol levels were significantly increased, probably inducing a protective cardiovascular effect. Our results agree with those reported in several other studies6, although there is no consensus in the literature37.

The main side-effects of metformin reported in this study were nausea and diarrhea, which disappeared after 2 weeks of use of the medication. These changes are probably due to the accumulation of metformin in the intestinal lumen, with the consequent elevation in local lactic acid production. However, histological analysis of the intestinal mucosa of animals treated with metformin did not reveal histological changes13. Similar data were reported by Pasquah et al.12, and interruption of metformin treatment due to side effects has been observed in only 5% of cases13.

Considering that the occurrence of ovulatory cycles depends on a perfect and harmonious interaction among all the elements involved in the hypothalamic-pituitary-ovarian axis, as well as on the action of other endocrinological systems, and considering that metformin can have a favorable action on insulin resistance, we conclude, on the basis of literature data and the present results, that metformin may play the role of a conductor by regulating several parts of the orchestra, improving androgenism, acting on IGF-I and carrier proteins, favoring the lipid profile, and exerting many other, still unknown, effects. Thus, this drug could have very valuable effects on a short-term basis by improving symptoms, regulating the menses, promoting ovulation and contributing to the treatment of infertility, but may also produce long-term effects such as reducing the risk of developing diabetes mellitus type 2 and cardiovascular disease.

ACKNOWLEDGEMENTS

We are grateful to Maria Albina Verceze Bortolieiro, Sebastio Lzaro Brando Filho, Ndia Bittar, Adriana Rossi, Lucimara Bueno, Jos Roberto Silva and Sonia Cambrea for valuable technical assistance, and to Mrs Elettra Greene for translating the Portuguese original.

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L. Fendra Santana, M. F. Silva de S, R. A. Feniani, M. D. de Moura, M. C. Foss* and R. M. dos Reis

Sector of Human Reproduction, Department of Gynecology and Obstetrics; *Departrnent of Internal Medicine, Faculty of Medicine of Ribeiro Preto, University of So Paulo, Ribeirao Preto, Brazil

Correspondence: Dr R.M. dos Reis, Department of Gynecology and Obstetrics, Faculty of Medicine of Ribeiro Preto, University of So Paulo, Avenida Bandeirantes 3900, 14049-900 Ribeiro Preto, SP, Brazil

Copyright CRC Press Aug 2004

Source: Gynecological Endocrinology

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