Abstract
BACKGROUND:
Fibrocystic changes (FCC) is the most common benign breast disease. The main pathophysiologic mechanism of FCC, excessive cell proliferation in response to monthly estrogen and progesterone changes. Regarding to antiproliferative of metformin, the aim of this study is the evaluation of the effect of metformin on FCC in women who were referred to gynecology clinics of Arak
METHODS:
This study is a double blind placebo control randomized clinical trial. At the first among women who were referred to gynecology of Arak, 186 women with FCC between 18-40 years were selected. The women were randomly classified into three groups. The first group took metformin and the second group as placebo group took vitamin E and the third group did not take any drug during six months. All groups were compared in clinical symptoms based on visual analogue scale (VAS) and the sonographic data also were recorded and compared. Data analysis was performed by unilateral variance, student t and Chi-square.
RESULTS:
The three groups were not different in aspect of mean of the cysts number, cyst size, tenderness and discharge from breast before the intervention, but after the intervention, there was a significant decrease in metformin group (p value < 0.001) based on variance analysis test. There was not a meaningful difference of pain and the location of cysts between the groups after the intervention.
CONCLUSIONS:
The present study showed that metformin is effective in treatment of FCC and decreasing of clinical symptoms and imaging items.
Keywords
Introduction
Fibrocystic changes of breast (FCC) is the most common benign disease of breast in women. These changes usually occur in fertility period between 20 and 50 years old. Although there are the other names of the disease including fibrocystic disease, Cooper disease, Mazoplazia and Reclus but the name of FCC is preferred at present, because these changes are seen in 50% as clinical and in 90% as histological in women [1].
However, the pathogenesis of the disease is not clearly defined, but it seems that hormonal imbalance especially estrogen dominancy against progesterone play a key role in development of the disease.
FCC is include both cysts (micro and macro) and solid lesions as adenosis, epithelial hyperplasia with and without atypia, apocrine metaplasia, radical scars and papilloma [1].
There have been challenges if FCC converts to cancerous changes or not for so long. Some cysts seem as solid lesion by sonography [2]. So, there are not unique sonographic criteria for FCC. Because of this, FCC is diagnosed based on history and physical examination [3]. Cyclic mastalgia is one of the most common symptoms of FCC. On the other hand, one of the reasons of breast pain is FCC that present as cyclic mastalgia and FCC is responsible for breast pain in 75% [4]. There are several treatment options including danazol, tamoxiphen and hormonal treatments for FCC [5]. Vitamin E is well known for treatment of FCC. Khanna showed that vitamin E reduced breast pain in 41% in comparison to danazol 72.1% [6]. Parsaee concluded that taking daily vitamin E for two months in FCC patients improved breast pain [7], however Rosolowich concluded that vitamin E was ineffective on breast pain [8]. There have been tried some other treatments such as fish oil, bromocriptine, buserelin and oral contraceptive [9]. So, there is not the unique treatment for the disease.
Metformin belongs to biguanids and the most common drug used for type two diabetes and metabolic syndrome [10]. Obesity and its association with hyperinsulinemia and glucose intolerance and type two diabetes increase the risk of breast disease including breast cancer [11].
Metformin reduce hyperinsulinemia and insulin resistance through reducing adenosine mono phosphate kinase (AMPK) that has a key role in cell energy and hemostasis [12]. The activation of this pathway lead to decreasing of cell proliferation. In fact, metformin has ant proliferative properties [10]. Metformin strongly inhibits dose dependently prostate cell proliferation [13]. In addition, metformin could reduce colon and breast cell proliferation. Oral and parenteral taking of metformin in rats inhibited 55% and 35% tumor growth respectively [14]. Phonix showed that metformin suppressed significantly, estrogen positive receptor breast cells proliferation, but it had a minimal effect on negative estrogen receptor breast cells [15].
Regarding to basic pathophysiology of FCC that is extra proliferation of breast cells in response to monthly changes of estrogen and progesterone and also because of anti proliferative effects of metformin, we aimed to evaluate the effects of metformin on FCC breast changes.
Method
This is a placebo control double blind randomized clinical trial. Among women who were referred to gynecology clinic, 186 women with FCC between 18 and 40 years old, with cyclic breast disease and breast pain for at least one week during every monthly mense, for six months were selected. Randomization assignment was conducted using computer-generated random numbers as blindness by a trained midwife at clinic.
The inclusion criteria were the persistence of breast endocrine structures and breast FCC or breast mass and having imaging and clinical criteria of FCC. Malignancy ruled out by core biopsy, open biopsy or FNA (fine needle aspiration biopsy) and also by cytology examination of breast discharge. Mamography and sonography were performed for all patients.
This research was done in accordance with the Declaration of Helsinki and informed consent was received from all subjects.
All patients were taken history and clinical exam during luteal phase. The breast pain, tenderness and the amount of breast discharge score based on VAS (Visual Analogue Scale) were recorded. Also the number and the size of cysts based on sonography were recorded. Then the participants were classified into three groups and were treated and after six months were re-examined and imaging was also repeated (Table 1).
The first interventional group took metformin 500 mg twice a day, the second interventional group took vitamin E 400 mg daily and the third group as the control group didn’t receive any treatment during six months. Questionnaire was filled out for all participants based on clinical history and physical examination. The patients with malignancy, diabetes, taking any drugs, kidney or heart or pulmonary diseases and also who had drug intolerance were excluded.
Data analysis was performed by SPSS version 16. Frequency percent and charts and mean of variables were used to describe the data (Table 2). One-way variance analysis, student t test, pried t test and Chi-square were used to compare the variables between the groups. P value less than 0.05% was considered significant.
Results
The mean age of participants in metformin, vitamin E and control groups was 30.4 ± 3.91, 30 ± 3.17 and 30.2 ± 2.93 years respectively that based on variance analysis there was not a significant difference between the three groups (p > 0.05) (Table 1). Based on analysis variance, the mean of the number of cysts, cyst size, tenderness and breast pain at the basal had no significant difference between the groups, but they had a significant difference between the groups at the end of the study (p < 0.05). The frequency of cyst location at the basal was not different between the groups, but at the end of the study, in situation when there were unilateral in metformin, vitamin E and control groups was 25(37.3%), 13(19.4%) and 29(43.3%) and when the cysts were bilateral, was 21(22.3%), 42(44.7%) and 31(33%) respectively that showed there is a meaningful difference between the groups after the intervention (p < 0.5) (Table 2).
Discussion
Based on the results, metformin in comparison to vitamin E that is a routine treatment for FCC is more effective on the number and the size of cysts and clinical symptoms such as breast pain and tenderness.
FCC is the most common benign breast disease that seems to be related to the hormonal changes in women. FCC causes symptoms such as breast pain and tenderness [1]. Yet, there is not any effective treatment for FCC to improve all symptoms of the disease. So, the patients usually are not satisfied with the present treatments and it is needed to develop newer treatments [5].
Metformin is the first step drug for diabetes and has antitumoral properties. Several studies have shown that among whom take metformin, the risk of cancer and also the mortality rate of cancer has been reduced [10]. Also, metformin intake has been associated with the better response to chemotherapy [16]. The effects of metformin on breast cancerous cells are induced in two ways; direct and indirect. Indirect effects of metformin that are insulin dependent and are on both cells and whole organism include; decreasing of serum insulin level, reduced IGF-1 and mTOR() suppression [17].
Regarding to mitogenic and anti apoptosis effects of insulin, metformin through insulin decreasing induce anti cancer effects, especially in cancers such as breast and colon cancers that are strongly associated to obesity and hyperinsulinemia [11]. In addition, cancers such as breast cancer present high levels of insulin receptors and high serum insulin levels that are associated to the risk of breast cancer relapse and mortality. So, metformin decreases the stimulatory effects of insulin on breast cancerous cells [18].
Direct effects of metformin are due to the activation of AMPK (Activated Protein Kinase) through mitochondrial breating suppression. This protein kinase has a key role in homeostasis and metabolism and it is sensitive to increasing intracellular AMP to ATP ratio [19]. AMP acts as an energy sensor and cause the phosphorilation of effectors that stimulate ATP producing signals and suppress ATP consuming pathways [12].
Metformin also cause AMPK activation through TH
Gandinisara through a metaanalysis of 71 studies in 1966 to 2013 on 65540 cases of cancers found that metformin reduced the incidence of cancer to 31% and the mortality risk of cancer to 34 % [22].
Ting yang through a metaanalysis in 2015 on 838333 case showed that metformin didn’t reduce the incidence of cancer but reduced the mortality rate of cancer [23].
Dowling evaluated the effect of metformin 500 mg twice a day for 18 days and conclude that the anticancer effects of metformin in short time is due to indirect effects of metformin [24].
Insulin by binding to insulin receptor induces mitogenic and antiapoptosis effects in breast cancer and high serum insulin level is associated with the increased risk of cancer and worse prognosis [11]. Metformin intake cause weight loss and reduce BMI, FBG, HOMA-IR (Homeostatic Model Assessment-insulin Resistance), cell proliferation and its marker Ki-67, and increase cell apoptosis and its marker TUNEL (Terminal deoxynucleatidyl transferase (TdT) dUTP Nick End Labeling) and it also reduce insulin receptors in tumor cells [25].
Hadad showed that metformin 500 mg daily for one week and then 1 g for second week reduced significantly cancer biomarker of Ki-67 [26]. However, all studies don’t confirm these effects. For example, Kanlinsykevin conclude that metformin intake had no effect on proliferative markers in breast cancer but it caused weight loss and reduced serum insulin level [27]. As above mentioned this is the first study that evaluates the effects of metformin on FCC. Regarding to proliferative changes as one of the pathogenic mechanisms of FCC, metformin probably with its anti proliferative and anti inflammatory effects lead to reduced the number and the size of the cysts and clinical symptoms.
Conclusion
The present study showed that metformin is effective to reliefe the clinical symptoms and imaging items of FCC. Although more high quality researches are needed in different ethnic populations to confirm these results.
The authors declare that there is no conflict of interest regarding the publication of this article.