|Year : 2019 | Volume
| Issue : 4 | Page : 1371-1375
Effect of metformin treatment on ovarian stromal blood flow in women with polycystic ovary syndrome
Mehany M Abd EL-Sattar1, Osama A EL-Kelany1, Alaa EL-Din F EL-Halaby1, Hussein M A Esmaeel2
1 Department of Obstetrics and Gynecology, Faculty of Medicine, Menoufia University, Menoufia Governate, Egypt
2 Resident of Obstetrics and Gynecology Resident at Tala General Hospital, Tala, Menoufia Governate, Egypt
|Date of Submission||25-Sep-2018|
|Date of Decision||17-Nov-2018|
|Date of Acceptance||25-Nov-2018|
|Date of Web Publication||31-Dec-2019|
Hussein M A Esmaeel
Shebin El-Khom City, Menoufia Governorate
Source of Support: None, Conflict of Interest: None
The aim was to study the effect of metformin treatment on ovarian stromal blood flow in women with polycystic ovary syndrome (PCOS).
PCOS is an endocrine disorder that affects mostly women of reproductive age. Metformin has positive biochemical effects in PCOS patients' therapy.
Patients and methods
A case–control study was conducted on 98 women who were divided into: group I which included 49 infertile women with PCOS and group II which included 49 fertile women without PCOS. All patients attended the Obstetrics and Gynecology Outpatient Clinic at Menoufia University Hospitals and Tala General Hospital, Egypt, from April to November 2017. Detailed history, clinical examination, routine baseline investigations, and Doppler flow were done.
There was a statistically significant difference between the studied groups regarding weight, BMI, follicle-stimulating hormone, and Doppler post-treatment resistance and pulsatility indices (left, right). There was a statistically highly significant difference (P ≤ 0.001) regarding Doppler posttreatment resistance and pulsatility indices (left, right) before and after metformin treatment. Also, a nonsignificant correlation was recorded between Doppler resistance and pulsatility indices (left, right) and age, weight, BMI, follicle-stimulating hormone (mIU/ml), and luteinizing hormone (mIU/ml) in the patients group after metformin treatment.
Metformin has a beneficial effect in women with PCOS via correcting the ovarian stromal blood flow and hormonal profile. Ovarian stromal Doppler markers such as the resistance index and pulsatility index can help us to follow up the therapy of PCOS patients.
Keywords: color Doppler, metformin, ovarian artery, polycystic ovary, pulsatility index
|How to cite this article:|
Abd EL-Sattar MM, EL-Kelany OA, EL-Halaby ADF, Esmaeel HM. Effect of metformin treatment on ovarian stromal blood flow in women with polycystic ovary syndrome. Menoufia Med J 2019;32:1371-5
|How to cite this URL:|
Abd EL-Sattar MM, EL-Kelany OA, EL-Halaby ADF, Esmaeel HM. Effect of metformin treatment on ovarian stromal blood flow in women with polycystic ovary syndrome. Menoufia Med J [serial online] 2019 [cited 2020 Feb 16];32:1371-5. Available from: http://www.mmj.eg.net/text.asp?2019/32/4/1371/274253
| Introduction|| |
Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects mostly women of reproductive age. This syndrome is characterized by oligomenorrhea, hyperandrogenemia, and infertility. PCOS is diagnosed by the presence of two of the following three diagnostic criteria: oligomenorrhea and/or anovulation, clinical and/or biochemical features of hyperandrogenism, and the presence of polycystic ovary morphology according to Sirmans and Pate . It is known that there is an association between PCOS and increased insulin resistance. Peripheral target tissue resistance, decreased hepatic clearance, or increased pancreatic sensitivity are the mechanisms determining the state of insulin resistance . There are some pharmacological agents that reduce insulin levels and improve insulin sensitivity; metformin is one of them. Metformin acts by inhibiting gluconeogenesis in the liver, stimulating peripheral uptake of glucose, and thus improving insulin resistance . Endothelial dysfunction has been investigated by different methods in women with PCOS. Insulin resistance may be linked to endothelial dysfunction by several mechanisms including insulin action and nitric oxide production. Metformin improves endothelial function by the alteration in insulin resistance . Metformin also improves hyperandrogenism and thus its vasoconstrictive effect on vascular tissues . Women with PCOS also show differences in intraovarian and uterine artery hemodynamics compared with women with normal ovaries. Ovarian stromal blood flow can be assessed by color Doppler and power Doppler ultrasound. Increased ovarian stromal blood flow has been a new parameter to diagnose polycystic ovaries in the ultrasound . Ovarian stromal Doppler of pulsatility index (PI) and resistance index (RI) for both ovaries are found significantly lower in PCOS patients than in women with normal ovaries . Owing to the positive biochemical effects of metformin therapy in PCOS patients, it may also reduce ovarian stromal blood flow which is higher in PCOS patients than in women with normal ovaries. So, this study aims to monitor the effect of metformin treatment on ovarian stromal blood flow in women with PCOS.
| Patients and Methods|| |
A case–control study was conducted on 98 women who were divided into two groups. Group I (patients) consisted of 49 women complaining of infertility and diagnosed with PCOS and group II (control) consisted of 49 fertile women without PCOS. All patients attended the Obstetrics and Gynecology Outpatient Clinic at Menoufia University Hospitals and Tala General Hospital, Egypt, during the period from April to November 2017.
All the participants have signed a written informed consent with explaining the aim of the study before the study initiation. Approval was obtained from the ethics committee of the Faculty of Medicine, Menoufia University.
Sampling methods: The sample size was calculated using the computer sample block randomization type. During the preselection visit, exclusion and inclusion criteria were applied with a recording of full medical history, findings on abdominal and local examination and on ultrasonography examination along with the results of the investigations.
Subjects included in the study were divided into two groups as follows:
- Group I (patients): included 49 women complaining of infertility and diagnosed with PCOS. All the women in this group were given metformin hydrochloride (850 mg) (Cidophage Retard 850 mg tablet) twice daily for 3 months. However, neither diet nor exercise was recommended for these 3 months
- Group II (control): included 49 fertile women without PCOS. Contrary to the women in group I, the women in group II were not given any drug during the 3-month period.
Women complaining of infertility and diagnosed with PCOS.
History of ovarian surgery, treatment with oral contraceptives, antiandrogen, or any other medicine that could affect carbohydrate metabolism or hormonal values. All other etiologic factors of hirsutism and oligo/anovulation including: hyperprolactinemia, hypogonadotropic hypogonadism, thyroid disorder, congenital adrenal hyperplasia, androgen-secreting tumors, Cushing's syndrome, type 2 diabetes mellitus, chronic hypertension, pregnant, smokers, or alcohol consumption.
All the participating women who fulfill the eligibility criteria were subjected to: history taking including special habits, menstrual history especially last menstrual history, medical disorders, past obstetric history; physical examination including general condition, weight, height, BMI, blood pressure, temperature, pulse; hormonal assays including luteinizing hormone (LH) and follicle-stimulating hormone (FSH); and finally a complete Doppler flow assessment of the ovarian stromal blood flow.
PCOS was diagnosed according to the criteria of the Rotterdam ESHRE-ASRM-sponsored PCOS Consensus Workshop Group when two of the three following criteria are met: oligomenorrhea (<6 menstrual periods in the preceding year), anovulation, clinical, and/or biochemical signs of hyperandrogenism, presence of greater than or equal to 12 follicles in each ovary measuring 2–9 mm in diameter and/or increased ovarian volume (>10 ml).
Blood samples were collected from all participants after a 12 h overnight fast. The sample was stored at −20°C till the time of assay of all samples for serum LH and FSH using IMMULITE 2000 chemiluminescent immunometric assay apparatus (IMMULITE; Diagnostic Products Corp., Los Angeles, California, USA). After that, transvaginal ultrasound with pulsed and color Doppler were performed on all the participants with a 6.5 MHz microconvex transvaginal probe (Logiq P5; General Electric Co., Fairfield, Connecticut, USA). Prior to the examination, the bladder was emptied completely to prevent the negative effect of compression on ovarian blood flow. First, the uterus and the two ovaries were evaluated and then color and pulsed Doppler were performed on both ovaries by the same gynecologist. In pulsed Doppler mode, the high-pass filter was set at 50 Hz and the axial length of the sample was set to 2.5 mm. In color Doppler mode, vascularization of the perifollicular vessel was visualized. The blood circulation was studied in each ovary by examining the perifollicular vessels in the ovarian stroma far from the surface of the ovary and located near the wall of a follicle. Pulsed Doppler was measured after applying color Doppler. By placing the color Doppler, areas of maximum color intensity and the greatest Doppler frequency shifts could be visualized and then selected for pulsed Doppler. When that occurred, we evaluated the pulsed Doppler of the ovary more than once and optimal flow velocity wave forms were detected. In the pulsed Doppler analysis, RI and PI were automatically calculated by the machine. Both right and left ovaries were observed and analyzed in each patient using these Doppler parameters. After a 3-month time, transvaginal ultrasound and color and pulsed Doppler were performed for both ovaries again in the patients' group. Finally, the same Doppler parameters were analyzed in each patient.
Analysis of data was done by DELL computer using the statistical package for the social sciences (SPSS), Version 22 (SPSS Inc., Chicago, Illinois, USA) as follows: Description of quantitative variables as mean, SD, or median and range as appropriate. Student's t-test was used to collectively indicate the presence of any significant difference between the two groups for a normally distributed quantitative variable. Paired t-test was used to compare the same groups as regards quantitative variables (mean ± SD). Pearson's correlation analysis was used to show the strength and direction of association between two quantitative variables. P value less than 0.05 was considered a significant difference and P value greater than 0.05 was considered a nonsignificant difference, while P value less than 0.001 was considered a highly significant difference.
| Results|| |
The mean age of the studied patients was 27.45 ± 2.65, and 28.27 ± 2.66 years in the control group. There was a statistically nonsignificant difference (P > 0.5) between the two studied groups (patients and control) regarding their age (year) and height (cm). On the other hand, there was a statistically significant difference (P < 0.05) between the two studied groups regarding their weight (kg) and BMI (kg/m 2) [Table 1].
Additionally, there was a statistical highly significant difference (P < 0.001) between the two studied groups regarding FSH, LH, and Doppler resistance and pulsatility indices (left, right). All of them were significantly higher in the control group than in the patients group except for LH which was higher in the patients group than in the control group [Table 2].
|Table 2: Pretreatment follicle-stimulating hormone, luteinizing hormone, Doppler resistance, and pulsatility indices (left, right)|
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Furthermore, there was a statistically highly significant difference (P ≤ 0.001) regarding Doppler resistance and pulsatility indices (left, right) before and after metformin treatment. Resistance and pulsatility indices (left, right) were significantly higher after metformin treatment than before treatment [Table 3].
|Table 3: Doppler indices of the patients group before and after metformin treatment|
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Also, there was a nonsignificant correlation (P > 0.05) between Doppler resistance and pulsatility indices (left, right) and age, weight, BMI, FSH (mIU/ml), and LH (mIU/ml) in the patient group after metformin treatment [Table 4].
|Table 4: Correlation coefficients between Doppler indices and some variables in the patient group after metformin treatment|
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| Discussion|| |
In the current study, there was a statistically highly significant difference between the two studied groups regarding FSH, LH, and Doppler posttreatment resistance and pulsatility indices (left, right). All of them were significantly higher in the control group than in the patient group except for LH which was higher in the patient group than in the control group. In the same line, a case–control study was conducted by Makled et al.  on 60 women who were diagnosed to have PCOS and included as group 1 and 40 fertile women who were recruited from the outpatient clinic for contraception without PCOS with regular menstrual cycles and included as the control group (group 2). They found that there were statistically significant differences between groups 1 and 2 regarding LH and LH/FSH ratio (day 3). But the follicle-FSH was not significantly different (P = 0.088) among groups 1 and 2. In addition, Rautio et al.  found that BMI, W/H ratio, LH, E2, and LH/FSH ratio were lower after metformin treatment. This is due to the improving effect of metformin on insulin resistance and lipid profile. In recent years, there have been reports about the Doppler imaging of ovarian stroma in PCOS patients. Although Zaidi et al.  reported greater ovarian stromal peak systolic velocity in PCOS patients, Aleem and Predanic  reported no difference between normal and PCOS patients they found lower PI and RI in PCOS patients. Using three-dimensional (3D) ultrasound, Pan et al.  demonstrated a higher ovarian stromal blood flow in PCOS women. Jarvela et al.  reported a similar blood flow between PCOS and women with normal ovaries. As shown, there are conflicting results in the literature with respect to ovarian stromal blood flow. The reason for the increased ovarian stromal blood flow in PCOS patients before metformin treatment may be explained by elevated LH levels, which can cause increased stromal vascularization by influencing neoangiogenesis. Tonic hypersecretion of LH in PCOS may be responsible for increased ovarian stromal vascularization through few different mechanisms involving neoangiogenesis and catecholaminergic stimulation (β_ 1 and β_ 2 adrenergic stimulation), which induce vasodilatation and leukocyte cytokine activation . Furthermore, Lobo et al.  found that the serum LH levels and LH/FSH ratio showed a significant decrease compared with the variable effects observed earlier, while, Pedernera et al.  found that there was no statistically significant difference between the studied groups regarding FSH and LH after 6 months of treatment with metformin.
Furthermore, there were statistical highly significant differences regarding Doppler posttreatment resistance and pulsatility indices (left, right) before and after metformin treatment. Doppler post-treatment resistance and pulsatility indices (left, right) were significantly higher after metformin treatment than before treatment. These results agreed with the studies of Zaidi et al.  and Aleem and Predanic  who reported a significant difference between normal and PCOS patients, but they found lower PI and RI in PCOS patients, while Palomba et al.  compared the effects of metformin and clomiphene citrate on ovarian vascularity in patients with PCOS and they reported that the patients with PCOS who ovulated with metformin treatment and healthy women were similar in the ovarian blood flow. However, in PCOS patients PI and RI values were higher after metformin treatment. Also, Findlay  reported that after metformin treatment, PI and RI of ovarian Doppler parameters were higher than the values before therapy. The normal values of ovarian stromal blood flow are not known but lower ovarian stromal blood flow after metformin treatment may be regarded as a positive result. By comparing the right and left ovaries regarding pulsed Doppler parameters, no difference was observed in PI and RI. This is due to the existence of the similar metabolic effects in both ovaries before and after metformin treatment. This result enabled us to use any of the two ovaries for the calculation of Doppler parameters in PCOS patients. Also, there was nonsignificant correlation (P > 0.05) between Doppler resistance and pulsatility indices (left, right) and age, weight, BMI, FSH (mIU/ml), and LH (mIU/ml) in the patient group after metformin treatment. Our results are supported by the study of Stridsklev et al.  who found that there was a nonsignificant correlation between the lowest and mean PI with age and BMI in metformin and placebo groups. In contrast to our study, Makled et al.  found that there was a significant correlation between mean ovarian flow index (FI) and BMI (P < 0.05). Also, our Doppler findings agreed with Carmina and Lobo  who also found that increased ovarian stromal blood flow was a characteristic feature of women with PCOS (reduced PI and RI). However, they found no correlation between increased ovarian volume and blood flow by 2D Doppler. BMI, W/H ratio, LH, LH/FSH ratio, and E2 values were significantly lower in the after-treatment group and the area under curve for insulin (AUC insulin) was higher in the before-treatment group than in the after-treatment group.
| Conclusion|| |
Metformin has a beneficial effect in women with PCOS via correcting the ovarian stromal blood flow and hormonal profile. Ovarian stromal Doppler markers such as RI and PI can help us to follow up the therapy of PCOS patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clini Epidemiol 2014; 6
Amato MC, Vesco R, Vigneri E, Ciresi A, Giordano C. Hyperinsulinism and polycystic ovary syndrome (PCOS): role of insulin clearance. J Endocrinol Investig 2015; 38
Pernicova I, Korbonits M. Metformin mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol 2014; 10
Kocer D, Bayram F, Diri H. The effects of metformin on endothelial dysfunction, lipid metabolism and oxidative stress in women with polycystic ovary syndrome. Gynecol Endocrinol 2014; 30
Hurliman A, Brown K, Maille J, Mandala N, Casson M, Osol G, et al
. Hyperandrogenism and insulin resistance, not changes in body weight, mediate the development of endothelial dysfunction in a female rat model of polycystic ovary syndrome (PCOS). Endocrinology 2015; 156
De Leo V, Musacchio MC, Cappelli V, Massaro MG, Morgante G, Petraglia F. Genetic, hormonal and metabolic aspects of PCOS: an update. Reprod Biol Endocrinol 2016; 14
Ozdemir O, Sari ME, Kalkan D, Koc EM, Ozdemir S, Atalay CR. Comparison of ovarian stromal blood flow measured by color Doppler ultrasonography in polycystic ovary syndrome patients and healthy women with ultrasonographic evidence of polycystic. Gynecol Endocrinol 2015; 31
Makled A, Sherbiny M, Elkabarity R. Assessment of ovarian stromal blood flow after metformin treatment in women with polycystic ovary syndrome. Arch Gynecol Obstet 2014; 289
Rautio K, Tapanainen JS, Ruokonen A, Morin-Papunen LC. Effects of metformin and ethinyl estradiol-cyproterone acetate on lipid levels in obese and non-obese women with polycystic ovary syndrome. Eur J Endocrinol 2005; 152
Zaidi J, Campbell S, Pittrof R. Ovarian stromal blood flow in women with polycystic ovaries a possible new marker for diagnosis? Hum Reprod 1995; 10
Aleem FA, Predanic M. Transvaginal color Doppler determination of the ovarian and uterine blood flow characteristics in polycystic ovary disease. Fertil Steril 1996; 65
Pan HA, Wu MH, Cheng YC, Li CH, Chang FM. Quantification of Doppler signal in polycystic ovary syndrome using three-dimensional power Doppler ultrasonography: a possible new marker for diagnosis. Hum Reprod 2002; 17
Jarvela IY, Mason HD, Sladkevieius P. Characterization of normal and polycystic ovaries using three-dimensional power Doppler ultrasonography. J Assist Reprod Genet 2002; 19
Findlay JK. Angiogenesis in reproductive tissues. J Endocrinol 1986; 111
Lobo RA, Shoupe D, Serafini P, Brinton D, Horton R. The effects of two doses of spironolactone on serum androgens and anagen hair in hirsute women. Fertil Steril 2008; 43
Pedernera E, Solis L, Peralta I, Velázquez PN. Proliferative and steroidogenic effects of follicle stimulating hormone during chick embryo gonadal development. Gen Comp Endocrinol 1999; 116
Palomba S, Russo T, Orio F. Uterine effects of metformin administration in anovulatory women with polycystic ovary syndrome. Hum Reprod 2006; 21
Stridsklev S, Carlsen S, Salvesen Q, Clemens I, Vanky E. Mid-pregnancy Doppler Ultrasound of the Uterine Artery in metformin- Versus Placebo-Treated PCOS Women: A Randomized Trial. J Clin Endocrinol Metab 2014; 99
Carmina E, Lobo RA. Polycystic ovary syndrome (PCOS): arguably the most common endocrinopathy is associated with significant morbidity in women. J Clin Endocrinol Metab 1999; 84
[Table 1], [Table 2], [Table 3], [Table 4]