CentralBringing Excellence in Open Access

Journal of Endocrinology, Diabetes & Obesity

Cite this article: Yela DA, Crispim Marquez GG, Benetti-Pinto CL (2016) Evaluation of Metabolic Parameters in Women with Polycystic Ovary Syndrome after Treatment with Metformin. J Endocrinol Diabetes Obes 4(2): 1089.

*Corresponding authorDaniela Angerame Yela, Departamento de Tocoginecologia, Faculdade de Ciências Médicas Universidade Estadual de Campinas - UNICAMP Rua Alexander Fleming, 101, Cidade Universitária CEP 13083-881 - Campinas, SP, Brazil, Tel: +55-19-3521-9306; Fax: +55-19-3521-9306; Email:

Submitted: 24 June 2016

Accepted: 27 July 2016

Published: 27 July 2016

ISSN: 2333-6692

Copyright© 2016 Yela et al.

OPEN ACCESS

Keywords•Polycystic ovary syndrome•Metformin•Body mass index•Homeostasis model assessment for insulin resistance•Metabolic parameters

Research Article

Evaluation of Metabolic Parameters in Women with Polycystic Ovary Syndrome after Treatment with MetforminDaniela Angerame Yela1*, Gabriel Gustavo Crispim Marquez2, and Cristina Laguna Benetti-Pinto1

1Department of Obstetrics and Gynecology, University of Campinas (UNICAMP), Brazil2School of Medical Sciences, University of Campinas (UNICAMP), Brazil

Abstract

Objective: To evaluate the influence of metformin therapy on metabolic parameters in women with polycystic ovary syndrome (PCOS).

Methods: A retrospective study evaluating medical charts of 62 women of reproductive age diagnosed with POS according to the Rotterdam criteria, which were given metformin. Age, parity, clinical and metabolic parameters (triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol, fasting serum glucose, fasting insulin, homeostasis model assessment for insulin resistance (HOMA - IR), weight, body mass index (BMI), arterial blood pressure) were evaluated before and 6 months after metformin use.

Results: The mean patient age was 28.69 ± 8.52 years, 70.97% were nulliparous women, and 67.74% were obese. Six months after metformin use, there was a significant improvement in the HOMA - IR index (initial HOMA - IR: 4.48 ± 2.95; final HOMA - IR index: 3.70 ± 2.70; p 0.006). No significant improvement in lipid profile and serum glucose and insulin levels were observed (initial and final values for total cholesterol were respectively: 188.79 ± 43.36 mg/dl and 182.84 ± 36.49 mg/dl p = 0.14, for LDL cholesterol 112.59 ± 37.54 mg/dl and 107.68 ± 33.53 mg/dl p = 0.27, for triglycerides 164.27 ± 89.52 mg/dl and 155.05 ± 77.37 mg/dl p = 0.30, for serum glucose 98.20 ± 38.80 mg/dl and 95.51 ± 36.47 mg/dl p = 0.35 and for insulin 18.73 ± 13.05 µUI/mL and 16.65 ± 12.42 µUI/mL p = 0.10). Blood pressure levels and HDL cholesterol remained stable (p = 0.61 and 0.85, respectively). No reduction in BMI was observed with the use of metformin (P = 0.21).

Conclusion: Metformin reduced insulin resistance in PCOS. However, it had no influence on metabolic parameters.

INTRODUCTIONPolycystic ovary syndrome (PCOS) is an endocrine and

metabolic dysfunction in the hypothalamic – pituitary -ovarian axis which affects around 3-8% of women of reproductive age [1].

The consensus of Rotterdam was developed in 1990 and ratified in 2003. It defined that the diagnosis of PCOS requires at least two of the following 3 criteria: oligoamenorrhea or amenorrhea, clinical and/or biochemical evidence of hyperandrogenism and presence of polycystic ovaries on ultrasound, excluding other potential causes (thyroid dysfunction, congenital adrenal hyperplasia, Cushing’s syndrome, androgen - secreting tumors, hyperprolactinemia) [1-3]. These women have clinical and reproductive manifestations (oligoamenorrhea or amenorrhea, hirsutism, acne, infertility and pregnancy - related

complications), metabolic manifestations (insulin resistance, glucose intolerance, diabetes mellitus, obesity, metabolic syndrome) and cardiovascular disease. Furthermore, other less obvious manifestations of the disorder may include impairment in quality of life, low self -esteem, depression and anxiety [4,5].

When PCOS is associated with obesity, the treatment of choice is lifestyle modification, weight loss and physical activity to promote a higher permeability to insulin, reducing the risk of diabetes and cardiovascular disease. Drug options are glitazones, derivatives of tiazolidinediones, which decrease insulin resistance. However, these drugs may cause a slight weight gain and are contraindicated in patients with hepatic disease or chronic cardiac disease. Finally, metformin, a biguanide, is the most commonly used drug in the treatment of metabolic syndrome [6].

CentralBringing Excellence in Open Access

Yela et al. (2016)Email:

J Endocrinol Diabetes Obes 4(2): 1089 (2016) 2/3

In a systematic review, some studies showed that metformin reduced obesity and insulin resistance. However, there was no improvement in lipid profile, in contrast to other studies that have described inverse results [7]. Therefore, the lack of a more conclusive and consensual response concerning the effectiveness of treatment with metformin indicates the need for further studies, in view of the incidence of PCOS and severity of the effects of the metabolic syndrome. Therefore, the aim of this study was to evaluate alterations in metabolic parameters in women with PCOS after six months of metformin use.

MATERIALS AND METHODSA retrospective study was carried out to evaluate metabolic

parameters in women with polycystic ovary syndrome after six months of treatment with metformin, including 62 women managed at the Endocrine Gynecologic Outpatient Facility of the Department of Obstetrics and Gynecology of the Women’s Healthcare Center (CAISM) of the University of Campinas (UNICAMP).

Cases were gathered from 2013 until sample size was obtained. Sample size was based on the mean difference between BMI at the beginning of metformin use and six months after metformin use in women with polycystic ovary syndrome. In 2011, Maciel et al., observed that women with polycystic ovary had a BMI of 30.9 ± 7.0 before starting metformin therapy. Six months after initiating drug use, the BMI of these women was 30.0 ± 6.9. From that study, sample size was calculated according to the methodology demonstrated by Hulley et al., using the t-test for dependent samples, considering a 5% significance level and 90% power of test [8,9]. Therefore, the study included 62 patients diagnosed with PCOS according to the Rotterdam criteria. These women had been using metformin for at least 6 months.

Metformin was indicated only in women diagnosed with PCOS who had insulin resistance established by the HOMA - IR. Fasting glucose (mg/dl) is multiplied by fasting insulin (µUI/mL) and divided by 22.5 to calculate the homeostasis model assessment for insulin resistance (HOMA - IR). According to this index, insulin resistance occurs at values above 2.71 [10].

Metformin was initiated at a daily dose of 500 mg during a main meal, followed by a weekly increase in dose of 500 mg, if necessary (maximum dose of 2500-2550 mg/day, divided into three doses during meals).

A chart dedicated to this research study was used. It contained information on age, parity, marital status, color, school education and clinical and metabolic parameters (triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol, fasting glucose, fasting insulin, HOMA - IR, weight, BMI, arterial blood pressure).

This study was approved by the Research Ethics Committee of the institution under number 711386/2014.

For statistical analysis, the frequencies, means and standard deviation of the variables were calculated. To evaluate the action of metformin on metabolic parameters after six months of use, the paired t-test was employed. A level of significance of p ˂ 0.05 was adopted. For the performance of these procedures, SAS version 9.2 software was used.

RESULTS AND DISCUSSIONThe mean patient age was 28.69 ± 8.52 years, 70.97% were

nulliparous women and 67.74% were obese (Table 1).

Before and after treatment, 52 (83.87%) women had insulin resistance. There was a significant improvement in the HOMA - IR index (initial HOMA - IR: 4.48 ± 2.95; final HOMA - IR: 3.70 ± 2.70; p ˂ 0.006). Before treatment, 32 (51.61%) women had triglyceride levels above 150mg/dl and after treatment, 30 (48.38%) women had these levels of triglycerides. Regarding HDL cholesterol before treatment, 40 (64.61%) women had levels lower than 50 mg/dl. After treatment, 35 (56.45%) women had HDL cholesterol levels below 50 mg/dl.

Despite improvement in lipid profile and serum glucose and insulin values, the reduction was not significant (initial total cholesterol: 188.79 ± 43.36 mg/dl and final total cholesterol: 182.84 ± 36.49 mg/dl p = 0.14, initial LDL cholesterol: 112.59 ± 37.54 and final LDL levels: 107.68 ± 33.53 p = 0.27, initial triglyceride levels: 164.27 ± 89.52 mg/dl and final triglyceride levels: 155.05 ± 77.37 mg/dl p = 0.30, initial serum glucose levels: 98.20 ± 38.80 mg/dl and final serum glucose levels 95.51 ± 36.47 mg/dl p = 0.35 and initial insulin: 18.73 ± 13.0 µUI/mL and final insulin: 16.65 ± 12.42 µUI/mL p = 0.10). Blood pressure levels, BMI and HDL cholesterol remained stable (p = 0.61 and 0.85, respectively) (Table 2).

Hyperinsulinemia is an important parameter used to decide whether therapy with metformin should be initiated in women with PCOS to prevent potential diabetes mellitus [11]. In our study, all women had insulin resistance measured by the HOMA - IR method.

We observed a significant improvement in the HOMA - IR index. Although there was a significant reduction of HOMA - IR index this was not enough to make the index of levels within the normal range which could be observed if the follow - up time that women were longer. Lipid profile and serum glucose and insulin values showed an insignificant improvement. Blood pressure levels, BMI and HDL remained stable.

Literature presents results similar to ours with significant improvement of HOMA - IR index and without change in parameters metabolic equipped with metformin use of 6 months [8,12]. In contrast, other studies demonstrated that there was an improvement in metabolic parameters. Studies showed that the use of metformin in women with PCOS promoted weight reduction, improvement in BMI, increased HDL cholesterol and decreased arterial blood pressure [13-16].

Table 1: Characteristics of women with with PCOS (n = 62).

Women characteristics Mean ± SD or n (%)

Age (years) 28.69 ± 8.52

BMI (kg/m2) 36.77 ± 6.79

Menarche 11.73 ± 1.68

No pregnancy(0) 44(70.97)

Pregnancy (≥1) 18(29.03)

None diseases 11(17.74)

Arterial hypertension 5(0.08 )

Diabetes Mellitus 3( 0.04)

Obesity 42(67.74)

Others diseases 1(0.01)

SD = standard deviation, BMI = body mass index

CentralBringing Excellence in Open Access

Yela et al. (2016)Email:

J Endocrinol Diabetes Obes 4(2): 1089 (2016) 3/3

There were also studies showing results similar to ours. A systematic review of some studies showed that metformin could lead to a reduction in obesity, insulin resistance without any improvement in lipid profile, while other studies demonstrated inverse results [7]. Another study including 137 women with PCOS showed a significant improvement in weight loss, BMI, HOMA - IR, cholesterol and triglycerides [17].

In a meta - analysis by Salpeter et al., women with PCOS demonstrated a decrease in BMI, a mean decline in fasting serum glucose levels and improvement in the HOMA - IR. There was a decrease in fasting insulin levels, although it was not a significant decline. Furthermore, HDL cholesterol increased while triglycerides decreased [18]. Although these studies there is still doubt about the effect of metformin on metabolic parameters in women with PCOS.

The limitation of our study was its retrospective nature, which can frequently exclude women, due to insufficient data contained in patient medical charts. Another limitation may be the time of observation of women with PCOS in metformin therapy.

CONCLUSIONIn conclusion, metformin is a good medication for the

control of metabolic parameters in patients with polycystic ovary syndrome. Treatment with metformin may also decrease cardiovascular risk and dyslipidemia.

REFERENCES1. Wei W, Zhao H, Wang A, Sui M, Liang K, Deng H, et al. A clinical study on

the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. Eur J Endocrinology. 2012; 166: 99-105.

2. Chang J, Azziz R, Legro R, Lobo R. The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Revised 2003 consensus

on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Fertil Steril. 2004; 81: 19-25.

3. Escobar-Morreale HF, Carmina E, Dewailly D, Gambineri A, Kelestimur F, Moghetti P, et al. Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update. 2012; 18: 146-170.

4. Thomson RL, Buckey JD, Lim SS, Noakes M, Clifton PM, Norman RJ, et al. Lifestyle management improves quality of life and depression in over weight and obese women with polycystic ovary syndrome. Fertil Steril. 2010; 94: 1812-1816.

5. Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol. 2011; 7: 219-231.

6. Urbanetz AA, Piazza MJ, Gruetzmacher C, Oliveira MT, Carvalho NS. Síndrome dos ovários policísticos: aspectos atuais das abordagens terapêuticas. Femina. 2009; 37: 255-260.

7. Aire WMY, Fonseca AM, Bagmoli VR, Fassolas G, Baracat EC. Síndrome do ovário policístico e metiformina: revisão baseada em evidencias. Femina. 2009; 37: 585-602.

8. Maciel GA, Hayashida SA, da Costa LC, Marcondes JA, da Fonseca AM, Soares JM Jr, et al. Influence of LH and high-density lipoprotein cholesterol (HDL-C) on metformin response in women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2011; 157: 180-184.

9. Hulley SB, Cummings SR, Browner WR, Grady D, Hearst N, Newman TB. Delineando a Pesquisa Cínica. 3a ed. São Paulo: Artmed S A, 2008.

10. Geloneze B, Repetto EM, Geloneze SR, Tambascia MA, Ermetice MN. The threshold value for insulin resistance (HOMAIR) in an admixtured population. IR in the Brazilian Metabolic Syndrome Study. Diabetes Res Clin Prac. 2006; 72: 219-220.

11. Mathur R, Alexander CJ, Yano J, Trivax B, Azziz R. Use of metformin in polycystic ovary syndrome. Am J Obstet Gynecol. 2008; 199: 596-609.

12. Singh S, Akhtar N, Ahmad J. Plasma adiponectin levels in women with polycystic ovary syndrome: impact of metformin treatment in a case-control study. Diabetes Metab Syndr. 2012; 6: 207-211.

13. Trolle B, Flyvbjerg A, Kesmodel U, Lauszus FF. Efficacy of metformin in obese and non-obese women with polycystic ovary syndrome: a randomized, double-blinded, placebo-controlled cross-over trial. Hum Reprod. 2007; 22: 2967-2973.

14. Cheang KI, Huszar JM, Best AM, Sharma S, Essah PA, Nestler JE. Long-term effect of metformin on metabolic parameters in the polycystic ovary syndrome. Diab Vasc Dis Res. 2009; 6: 110-119.

15. Heutling D, Schulz H, Nickel I, Kleinstein J, Kaltwasser P, Westphal S, et al. Asymmetrical Dimethylarginine, Inflammatory and Metabolic Parameters in Women with Polycystic Ovary Syndrome before and after Metformin Treatment. J Clinic Endocrinol Metaboli. 2008; 93: 82-90.

16. Fulghesu AM, Romualdi D, Di Florio C, Sanna S, Tagliaferri V, Gambineri A, et al. Is there a dose-response relationship of metformin treatment in patients with polycystic ovary syndrome? Results from a multicentric study. Hum Reprod. 2012; 27: 3057-3066.

17. Velija-Ašimi Z. Evaluation of endocrine changes in women with the polycystic ovary syndrome during metformin treatment. Bosn J Basic Med Sci. 2013; 13: 180-185.

18. Salpeter SR, Buckley NS, Kahn JA, Salpeter EE. Meta-analysis: metformin treatment in persons at risk for diabetes mellitus. Am J Med. 2008; 121; 149-157.

Table 2: Evaluation of metabolic parameters after 6 months of metiformin therapy (n = 62).

Variables Mean ± SDinitial

Mean ± SDfinal P*

Total Cholesterol(mg/dl) 188.79 ± 43.36 182.84 ± 36.49 0.141

LDL(mg/dl) 112.59 ± 37.54 107.68 ± 33.53 0.272

HDL(mg/dl) 47.50 ± 15.42 47.79 ± 11.46 0.859Triglycerides(mg/

dl) 164.27 ± 89.52 155.05 ± 77.37 0.302

Glycemia(mg/dl) 98.20 ± 38.80 95.51 ± 36.46 0.351

Insulin (µUI/mL) 18.73 ± 13.05 16.65 ± 12.42 0.109

Homa-IR 4.48 ± 2.95 3.70 ± 2.77 0.006

BMI(kg/m2) 36.77 ± 6.79 36.32 ± 7.16 0.219Systolic pressure

(mmHg) 120.16 ± 13.24 123.06 ± 14.44 0.097

Diastolic pressure(mmHg) 76.11 ± 9.80 77.08 ± 17.49 0.615

SD = standard deviation, LDL = Low Density Lipoproteins, HDL = High Density Lipoproteins, Homa-IR= homeostasis model assessment for insulin resistance, BMI = body mass index. *paired t-test

Yela DA, Crispim Marquez GG, Benetti-Pinto CL (2016) Evaluation of Metabolic Parameters in Women with Polycystic Ovary Syndrome after Treatment with Met-formin. J Endocrinol Diabetes Obes 4(2): 1089.

Cite this article