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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 3  |  Page : 153-158

Therapeutic effect of metformin on patients with polycystic ovary syndrome with normal insulin sensitivity: A retrospective study


1 Department of Health Management, Renji Hospital, Shanghai Jiao Tong University, Shanghai 200127, China
2 Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200090, China
3 Department of Gynecology, Obstetrics and Gynecology Hospital; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai 200090, China

Date of Submission08-May-2019
Date of Web Publication27-Sep-2019

Correspondence Address:
Ying-Li Shi
Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200090
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.268160

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  Abstract 


Objective: This study aimed at elucidating the therapeutic effectiveness of metformin in polycystic ovary syndrome (PCOS) patients with normal clinical indices of insulin sensitivity.
Methods: This study was a retrospective cohort study. Based on their homeostasis model of assessment of insulin resistance (HOMA-IR) results, PCOS patients (n = 113) were allocated to either the IR Group (IR, HOMA-IR >2.69) or the non-IR Group (NIR, HOMA-IR ≤2.69). Metformin was administered to all patients, and their medical history, menstrual status, and endocrine and metabolic characteristics were obtained before and after treatment. The one-way analysis of variance was used to determine the differences between the IR and NIR groups. The paired t-test was used to determine the differences between pre- and posttreatment results.
Results: Analyses of baseline characteristics showed that the incidence of IR and glycolipid metabolism is higher within elder PCOS patients. Metformin improved menstrual cycle and ovulation rate in NIR patients, similar to those in IR patients. In the NIR group, metformin decreased luteinizing hormone (LH) levels, free androgen index (FAI) levels, body mass index, and waist circumference, but had no obvious effect on glucose, insulin, and lipid profiles. Whereas in the IR group, metformin not only decreased LH and FAI levels, but also improved glycolipid metabolism.
Conclusions: The effect of metformin on PCOS patients with normal insulin sensitivity index suggests that the mechanism of menstrual improvement may not be related to IR. In addition, metformin can improve glycolipid metabolism. Therefore, metformin is suitable for long-term treatment of PCOS and should be more widely used.

Keywords: Endocrine Characteristics; Glycolipid Metabolism; Insulin Resistance; Metformin; Polycystic Ovary Syndrome


How to cite this article:
Liu WW, Li DH, Luo XZ, Tang LL, Shi YL. Therapeutic effect of metformin on patients with polycystic ovary syndrome with normal insulin sensitivity: A retrospective study. Reprod Dev Med 2019;3:153-8

How to cite this URL:
Liu WW, Li DH, Luo XZ, Tang LL, Shi YL. Therapeutic effect of metformin on patients with polycystic ovary syndrome with normal insulin sensitivity: A retrospective study. Reprod Dev Med [serial online] 2019 [cited 2019 Oct 17];3:153-8. Available from: http://www.repdevmed.org/text.asp?2019/3/3/153/268160




  Introduction Top


Polycystic ovary syndrome (PCOS) is a heterogeneous condition characterized mainly by hyperandrogenism, chronic anovulation, and infertility[1] and affects 5.6% of women of reproductive age in China.[2] Its onset is usually at the beginning of menarche. The presence of the combination of metabolic syndrome and PCOS in adolescents was reported to be nearly 3-fold higher than the presence of metabolic syndrome without PCOS in adolescents.[3] Aging results in increased visceral fat deposition, and higher insulin resistance (IR) and glycolipid metabolism, which may be responsible for the increased prevalence of metabolic syndrome in the US, increasing from 6.7% in the 20s to 43.5% in the 60s.[4] The main cause of metabolic disorder is hyperinsulinemia and IR,[5] while PCOS is significantly associated with increased coronary heart disease (CHD) risk [6] and hypertension.[7],[8] Women with PCOS (>40%) usually develop impaired glucose tolerance (IGT) or type 2 diabetes.[9] Lifestyle changes, including exercise and a low-fat, low-carbohydrate diet, can reduce weight and improve IR.

At present, there are four principles of PCOS treatment, including reducing androgen levels, regulating menstruation, improving IR, and promoting pregnancy. Lifestyle changes as first-line treatment [10] are associated with low adherence and sustainability,[11] due to the combined effects of high insulin and androgen levels. Although oral contraceptives can effectively improve the menstrual cycle, protect the endometrium, and reduce the androgen levels, they have no effect on IR and other metabolic syndrome defects, and their long-term application contributes to glucose intolerance, abnormal lipid profiles, and cardiovascular disease.[12],[13]

Metformin, a second-generation biguanide, is mainly used as an oral antihyperglycemic agent for treating type II diabetes mellitus and commonly used to improve PCOS-induced IR. It has been shown to improve PCOS-induced reproductive and metabolic defects.[14],[15] Many guidelines restrict its administration to PCOS patients with abnormal glucose metabolism.[10],[16],[17],[18] However, a recent study elucidated a strong correlation between metformin administration and increased ovulation rate in PCOS patients without abnormal glucose metabolism.[19] Notwithstanding, the mechanisms of its effects in PCOS are not fully elucidated. If metformin truly induces ovulation and improves metabolism, then it should be more widely used in women with PCOS. This study aimed at evaluating whether metformin has a similar effect on PCOS patients with or without IR.


  Methods Top


Study population

This study included 113 women who attended the PCOS Department in the reproductive endocrinology clinic of Obstetrics and Gynecology Hospital, Fudan University, from November 2015 to April 2018. To be included, they must be a current PCOS patient and not have been administered hormones or glycometabolism-regulating medication for 6 months. Patients with other hyperandrogenemia -causing diseases were excluded.

The Rotterdam criteria were used for PCOS diagnosis, which characterizes PCOS according to the following three key features: (1) oligo- or anovulation clinically manifested in menstrual cycle disturbance (the main condition); (2) clinical and/or biochemical signs of hyperandrogenism; and (3) the presence of polycystic ovaries in an ultrasound without other endocrine disorders. Two of these key features must be present before PCOS is diagnosed.

Patients were treated with metformin (1.5 g/d) from Shanghai Shiguibao in Shanghai, China, for 3 months.

Study methods

Classification of subgroups

HOMA-IR is a model of the relationship between glucose and insulin, which can be used to predict fasting steady-state glucose and insulin concentrations. The product of fasting glucose and fasting insulin is an index of hepatic IR, calculated as follows:

HOMA-IR = (FINS × FPG)/22.5

Where, FINS – fasting insulin (mU/L) and FPG – fasting plasma glucose (mmol/L).

Being the most practical value for clinical diagnoses of IR, HOMA-IR is not sufficiently predictive of the euglycemic clamp measures of insulin action, leading to no global consensus regarding the optimal indications for metformin. Age-, ethnicity-, and gender-specific differences in HOMA-IR levels reportedly exist, with women over 50 years having higher levels.[20] In this study, we used the 75% HOMA-IR cutoff value of 2.69,[21] widely used in PCOS research.[22],[23] Patients were allocated to either the IR group (if HOMA-IR was equal to or below 2.69) or the non-IR (NIR) group (if HOMA-IR was above 2.69) based on their HOMA-IR levels.

Research procedure

All characteristics were determined before and 3 months after metformin treatment. Physical examinations, including height, weight, and waist circumference, were performed by a doctor, according to the standard protocol. B-scan ultrasonography was used to find out whether the patient was in the early follicular phase and then blood was drawn. If the blood was not in the early follicular phase, blood was drawn again within 5 days of menstruation to check the related hormones. Oral glucose tolerance (OGTT) and insulin release tests were performed. Glucose levels were measured using a hexokinase enzymatic reference method. Insulin levels were measured using a radioimmunoassay kit (Coat A Count Insulin) from Diagnostic Product Corp. (Los Angeles, CA, USA). The endocrine characteristics included follicle-stimulating hormone, luteinizing hormone (LH), total testosterone (TT), sex hormone-binding globulin (SHBG), estradiol (E2), progesterone (P), prolactin, dehydroepiandrosterone (DHEA-S), 17-hydroxyprogesterone (17a-OHP), and cortisol levels. The metabolic characteristics included total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein cholesterol (HDL), apolipoprotein A (APO-A), APO-B, free fatty acid (FFA), and lipoprotein A levels.

Indicators

  1. Improved menstrual cycle: shorter menstrual cycle and natural menstruation
  2. Ovulation: the patients' basal body temperature presented as a typical double phase
  3. Insulin area under the curve = 0.25 × fast insulin + 0.5 × insulin 30 min + 0.75 × insulin 60 min + insulin 120 min + 0.5 × insulin 180 min
  4. Body mass index (BMI) = weight (kg)/height 2 (m 2)
  5. Free androgen index (FAI) = TT (nmol/L) × 100/SHBG (nmol/L).


Statistical analyses

Statistical analyses were performed using the SPSS v22.0 software (SPSS Inc., Chicago, IL, USA). The Chi-square test was used to analyze differences in ovulation rate and improved menstrual cycle rate between the IR and NIR groups. One-way analysis of variance was used to analyze the differences in continuous variables (all parameters excluding ovulation rate and improved menstrual cycle rate) between the IR and NIR groups, and a paired t-test was used to analyze the differences between the pre- and post-treatment results.


  Results Top


Baseline characteristics

Baseline characteristics are displayed in [Table 1]. Patients in the IR group were elder than those in the NIR group, indicating that the disorder of glucose metabolism is aggravating with age in PCOS patients. BMI and waist circumference values were higher in the IR group than in the NIR group. The endocrine and metabolic characteristics of patients in the IR group were worse than those in the NIR group, indicating that endocrine health was closely related to metabolism. There were no differences in the TT and DHEA-S levels between the IR and NIR groups. However, SHBG levels significantly decreased in the IR group, leading to significant increase in FAI levels. This suggests that androgen activity increased in the IR group, which may have increased metabolic side effects [Table 1].
Table 1: Baseline characteristics of women with PCOS

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Effects of metformin on menstrual cycle and ovulation

Seven patients lacked information on the efficacy of metformin in the menstrual cycle. Three months after metformin treatment, the menstrual cycle of 89 patients improved, and in 66 patients, ovulation was induced. In the IR group, metformin treatment resulted in menstrual cycle improvement and ovulation stimulation (mostly in the 1st month of treatment) in 83.0% (39/47) and 63.8% (30/47) of the patients, respectively. In the NIR group, metformin treatment resulted in menstrual cycle improvement and ovulation stimulation in 84.7% (50/59) and 61.0% (36/59) of the patients, respectively. There were no statistically significant differences in the improved menstrual cycle (P = 0.178) and ovulation rates (P = 0.216) between the IR and NIR groups [Figure 1], suggesting that metformin's therapeutic effect was not correlated with IR.
Figure 1: Effects of metformin on menstrual cycle and ovulation.

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Effects of metformin on endocrine characteristics

In the IR group, LH and TT levels significantly decreased, whereas SHBG levels increased, leading to decreased FAI levels [Table 2]. LH and FAI levels also significantly decreased in the NIR group, but SHBG levels increased, although not statistically significant.
Table 2: Endocrine characteristics of women with PCOS at baseline and after 3 months of treatment with metformin

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Effects of metformin on glucose metabolism

The effect of metformin on glucose metabolism was determined using the OGTT and insulin release tests. Normally, the concentration of insulin peaks 30–60 min postglucose (75 g) administration. The peak concentration should be <5 times that before administration of glucose and should be reduced to normal level after 180 min.[16]

In the IR group, metformin reduced glucose levels in each phase, especially at 0 and 180 min (P < 0.05). However, it had no significant (P ≥ 0.05) effects on the plasma glucose levels of each phase in the NIR group [Figure 2], indicating metformin has no effect on the plasma glucose levels of patients with normal glucose metabolism.
Figure 2: Glucose release curve before and after metformin treatment.

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Metformin inhibited insulin secretion in the IR group, with significant difference at 0, 60, 120, and 180 min (P < 0.05). However, it had no effect in the NIR group (P ≥ 0.05) [Figure 3].
Figure 3: Insulin release curve before and after metformin treatment.

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Effects of metformin on lipid metabolism

BMI and FAI are risk factors for metabolic syndrome and IR in women with PCOS,[17],[18] which positively correlates with HOMA-IR. The 3-month administration of metformin resulted in remarkably declined waist circumferences and BMIs in both the IR and NIR groups.

FFA, TG, TC, LDL, and APO-B are risk factors for cardiovascular disease, whereas HDL and APO-A can be regulated to prevent cardiovascular diseases. Metformin administration significantly decreased plasma TC and TG levels and increased APO-A levels in the IR group; however, it had no significant effect in the NIR group [Table 3]. These results indicate that abnormal lipid metabolism was positively correlated with HOMA-IR, and metformin can significantly improve the metabolism of lipids in PCOS patients, which in a long run decreases the risk of CHD.
Table 3: Metformin characteristics of women with PCOS at baseline and after 3 months treatment with metformin

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  Discussion Top


Although metformin has been proven efficacious in PCOS patients, it is not universally indicated for these patients. The American Society for Reproductive Medicine recommends the use of metformin in women with PCOS and IGT who do not respond adequately to calorie restriction and lifestyle changes.[16] The American Endocrine Society recommends its use in women with a combination of PCOS, type 2 diabetes mellitus, or IGT and failed lifestyle modification treatment.[17] It has also been shown that metformin is efficacious only in a specific subgroup of women with PCOS with IR, menstrual disturbance, ovulation rates, and consecutive infertility problems.[18] These guidelines restrict its use to only a minority of PCOS patients. However, strong evidence exists on metformin's ability to increase the ovulation rate and ameliorate the metabolic defects in women with PCOS.[24]

This study aimed at elucidating the efficacy of metformin in PCOS patients with normal clinical indices of insulin sensitivity. We found that 3-month metformin treatment significantly improved ovulation and menstrual cycle rates in both IR and NIR groups, suggesting that the efficacy of metformin treatment was not related to clinical indicators of IR. Metformin was also found to reduce LH and FAI levels in both groups, suggestive of the mechanisms of its effects on menstruation and ovulation. At the hypothalamic level, metformin acts via the AMPK pathway, essential for modulating the secretion of LH.[25] In addition, metformin inhibited the secretion of insulin in the IR group, but had no effect on that of the NIR group, which may result from its direct effect on ovarian steroidogenesis in PCOS patients without IR, independent of its effects on insulin sensitivity.[1]

The focus of treatments for PCOS may switch from targeting early age reproductive disorders to targeting long-term metabolic and cardiovascular disorders.[6],[16],[26] The clinical features of PCOS are heterogeneous among races; 60%–70% of PCOS patients in America have hirsutism, while those in Eastern-Asia have milder hairy.[27] In China, hyperandrogenism is very common and the prevalence of metabolic disorders is extremely high.[24] The clinical heterogeneity of PCOS indicates the need for personalized treatment. In the present study, we found that PCOS patients with IR were elder. In addition, glucose and lipid metabolism were more impaired in the IR than the NIR group, indicating that IR and glycolipid metabolism disorders worsen with age. It is, therefore, essential to consider long-term health when selecting a treatment option. For instance, early control of IR is vital for the prevention of long-term complications. In addition, metformin to some extent improved the glucose and lipid metabolisms of PCOS patients in the IR group. However, due to the short period of metformin administration and young ages of patients in the NIR group, the effect of metformin on their glycolipid metabolism remained unclear.

This study has several advantages and limitations. One of its advantages is that the sample size is much larger than that of similar studies.[17],[28] Moreover, the results are relatively more reliable because all patients were recruited by the same doctor (using the same standards) and all blood samples were tested at the same hospital. The limitation of this study is that the vast majority of the patients are infertile, eager to conceive in the short term, which limits our long-term observation of the efficacy. Compared with half a year observation in other studies, the duration of metformin treatment in this study is only 3 months, which limits our long-term observation of metformin on reproductive endocrine and glycolipid metabolism. As the study is still under way, more results will be published in the future.

In conclusion, this study confirmed that metformin could improve the menstrual cycle and ovulation rate of PCOS patients regardless of IR. It also improves glycolipid metabolism. Metformin should be the first choice for the treatment of PCOS because this disease is often accompanied by cardiovascular and cerebrovascular metabolic diseases. However, this conclusion needs to be confirmed by long-term, double-blind, placebo-controlled studies.

Acknowledgment

The authors thank all the patients included in this study. The authors are thankful to Priscilla Funsina, Maternal and Child Health, School of Public Health, Fudan University, Shanghai, China, for assistance in modifying the English writing.

Financial support and sponsorship

This study was funded by the Natural Science Foundation of Shanghai (No. 19ZR1406700).

Conflicts of interest

There are no conflicts of interest.


  Reproductive and Developmental Medicine Top


The 2nd Meeting of the 1st Editorial Board

The 2nd meeting of the 1st editorial board for Reproductive and Developmental Medicine (hereafter referred to as RDM) was held on June 16, 2019 in the Obstetrics and Gynecology Hospital of Fudan University. A total of 24 members of the editorial board attended the meeting. Cong-jian Xu (President of the Obstetrics and Gynecology Hospital of Fudan University), Yuan-chun Li (Director of the Shanghai Institute of Planned Parenthood Research), and Bing Liu (Vice President of the Chinese Medical Association Publishing House) addressed the meeting respectively. Da-jin Li (Associate Editor-in-Chief, Director of the RDM editorial office) introduced the work of the 1st editorial board and new editorial board members, reviewed the achievements of RDM since its establishment and proposed the plan for the next two years. The editorial board members fully recognized the achievements of RDM, provided feasible comments and suggestions. Prof. Cong-jian Xu summarized the meeting and expressed his heartfelt appreciation for the contributions made from all the editorial board members and affirmed his resolution to upgrade the journal to a higher level.





 
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