Arch Gynecol Obstet DOI 10.1007/s00404-013-3057-8

GYNECOLOGIC ENDOCRINOLOGY AND REPRODUCTIVE MEDICINE

Assessment of ovarian stromal blood flow after metformin treatment in women with polycystic ovary syndrome Ahmed K. Makled • Mohamed El Sherbiny Rania Elkabarity



Received: 23 July 2013 / Accepted: 9 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013

Abstract Purpose To authenticate the effect of metformin treatment on ovarian stromal blood flow in women with polycystic ovary syndrome (PCOS) using 3-dimensional (3D) power Doppler. Methods The current case–control study was conducted at Ain Shams University Maternity Hospital. A total of 60 women diagnosed to have PCOS were included as group 1. Another 40 fertile women who were recruited from outpatient clinic for contraception without PCOS with regular menstrual cycles were included as control group (group 2). All women underwent 3D power Doppler evaluations of ovarian stroma. Anthropometric, hormonal and biochemical criteria were also measured. All women in group 1 received metformin hydrochloride 500 mg tablets, which were started in a step-up maneuver every 5 days, from one to three tablets per day. The same parameters were also measured after the 3 months duration of treatment. Results A total of 100 women were finally analyzed. At the start of the study, there were no statistically significant differences between group 1 and group 2 and regarding age

and body mass index, but the waist/hip ratio and Ferriman– Gallwey scoring were statistically different between the 2 groups. The mean ovarian volume and stromal volume were significantly larger in group 1. 3D power Doppler indices [the vascularization index (VI), the flow index (FI) and the (VFI) vascularization-flow index] were much higher in group 1 than in group 2 (1.38 ± 0.76 vs. 4.69 ± 1.37, P \ 0.05, 26.59 ± 2.26 vs. 32.66 ± 4.37, P \ 0.05, and 0.76 ± 0.39 vs. 1.54 ± 0.69, P \ 0.05, respectively). After 3 months of using metformin in normal weight PCO women, there was a statistically significant improvement in group 1 regarding, hirsutism, most of hormonal measurements. Also 3 months metformin treatment significantly reduce VI, FI and VFI (4.69 ± 1.37 vs. 2.95 ± 1.52, P \ 0.05, 32.66 ± 4.37 vs. 29.48 ± 4.98, P \ 0.05 and 1.54 ± 0.69 vs. 1.21 ± 0.7 P \ 0.05, respectively). Using Receiver operator characteristic, there was no cut-off value of VI, FI or VFI to detect ovulation in women of PCOS. Conclusions Metformin seems to have a beneficial effect in normal weight PCO women via correcting ovarian stromal blood flow and hormonal profiles.

All authors have contributed significantly and are responsible about the content of this manuscript.

Keywords Metformin  Ovarian stromal blood flow  Polycystic ovary syndrome  3D power Doppler

A. K. Makled (&) Department of Obstetrics and Gynecology, Faculty of Medicine, Ain Shams University, Abbasia, Cairo, Egypt e-mail: [email protected] M. El Sherbiny Ultrasound and fetal care unit, Ain-Shams University, Cairo, Egypt R. Elkabarity Department of clinical pathology, Faculty of Medicine, Ain-Shams University, Cairo, Egypt

Abbreviations CI Confidence interval 3D 3-dimensional ASRM American Society for Reproductive Medicine BMI Body mass index ESHRE European Society for Human Reproductive and Embryology ICC Intraclass correlation coefficient FI Flow index

123

Arch Gynecol Obstet

FSH HCG HDL HOMA LDL LH PCOS PRF QUICKI ROC SD STIC TG TVUS VFI VI WHR

Follicle-stimulating hormone Human chorionic gonadotropin High density lipoprotein Homeostatic model assessment Low density lipoprotein Luteinizing hormone Polycystic ovary syndrome Pulse repetition frequency Quantitative insulin sensitivity check indexes Receiver operator characteristic Standard deviation Spatiotemporal image correlation Triglycerides Transvaginal ultrasound Vascularization-flow index Vascularization index Waist-to-hip ratio

Introduction The Polycystic ovary syndrome (PCOS) is a heterogeneous disorder, whose principal features include androgen excess, insulin resistance, ovulatory dysfunction, and/or polycystic ovaries, and is recognized as one of the most common endocrine/metabolic disorders of women [1]. PCOS accounts for 10–15 % of female infertility and about 80 % of anovular infertility, in particular [2]. Currently, there is increasing evidence that insulin sensitizers are particularly effective in inducing ovulation in patients with PCOS [3]. Metformin, a biguanide, is the most widely used drug for the treatment of type 2 diabetes worldwide. Its primary action is to inhibit hepatic glucose production, but it also increases the sensitivity of peripheral tissues to insulin. The increase in insulin sensitivity, which contributes to the efficacy of metformin in the treatment of diabetes, has also been shown in non-diabetic women with the PCOS [4]. In women with PCOS, long-term treatment with metformin may increase ovulation, improve menstrual cyclicity, and reduce serum androgen levels [5]; the use of metformin may also improve hirsutism [6]. Ovarian stromal blood flow dysfunction has been authenticated by different ways in women with PCOS. Insulin action and nitric oxide production may authenticate the link between endothelial dysfunction and insulin resistance. The mechanism of this resistance may be due to post-binding defect in insulin receptor-mediated intracellular signaling ideology [7]. Defective endothelial vasomotor function in PCO women resulting in anatomical and functional vessel changes which can be detected by Doppler US and can be improved by metformin treatment [8, 9]. 3-dimensional (3D) power Doppler ultrasound is a beneficial non-invasive method to authenticate the vascularization of the ovarian stroma in

123

women with PCO [10]. 3D Doppler ultrasound is progressively used in authenticating ovarian stromal blood flow and has displayed lower impedance to flow in ovarian stromal vessels in PCOS women [11]. The aim of the current work was to authenticate the effect of metformin treatment on ovarian stromal blood flow in women with PCOS using 3D power Doppler.

Patients and methods This case–control study was conducted at Ain Shams University Maternity Hospital during the period from September 2012 to June 2013 after being approved by the ethical and research committee of council of Obstetrics and Gynecology Department, Ain Shams University. The study purpose and procedures were explained to all enrolled women and a written informed consent was obtained from each participant. The included women were divided into 2 groups: group 1 (cases) 60 women who were recruited from patients attending infertility outpatient clinic with a diagnosis of PCOS and group 2 (controls) 40 fertile women who were recruited from outpatient clinic for contraception without PCOS with regular menstrual cycles. PCOS was diagnosed according to criteria stated by European Society of Human Reproduction and Embryology (ESHRE) and American Society of Reproductive Medicine (ASRM) by at least 2 out of 3 of the following: menstrual disturbance (amenorrhea or oligomenorrhea), clinical and/or biochemical sign of hyperandrogenism and/or typical ultrasonographic finding of PCO (with one ovary being sufficient for diagnosis), defined as the presence of 12 or more follicles measuring 2–9 mm in diameter or ovarian volume over 10 ml [12]. Women with hyperandrogenism for causes other than PCOS (e.g., congenital adrenal hyperplasia, presence of androgen secreting tumors or Cushing syndrome), diabetic women, women receiving any drugs which affect carbohydrate metabolism within 3 months before the study, women with hyperprolactinemia or thyroid disorders, were excluded. None of the included women received medical treatment for induction of ovulation for the preceding 3 months. Before starting treatment, venous blood samples were taken from all women on day 3 of spontaneous menses or withdrawal bleeding after 5-day treatment of oral norethisterone 10 mg daily, after fasting for 8 h. The serum was divided into two samples. The first sample was sent immediately for checking fasting blood glucose. The other sample was stored at -20 °C till the time of assay of all samples for serum insulin and free testosterone, luteinizing hormone (LH), follicular stimulating hormone (FSH) using immulite 2000 chemiluminescent immunometric assay apparatus (Immulite, Diagnostic Products Corp., Los Angeles, CA, USA). Mid-

Arch Gynecol Obstet

luteal progesterone was assayed using immulite 2000 chemiluminescent immunometric assay apparatus (Immulite, Diagnostic Products Corp., Los Angeles, CA, USA). Lipid profile [triglycerides (TG), Low density lipoprotein (LDL) and high density lipoprotein (HDL)] was assayed using synchron autoanalyser (Beckman instrument incorporation, California, USA). Blood samples were taken at the end of the treatment period for re-checking serum levels of previously measured parameters. Anthropometric measurements were assessed before and three months after treatment, these included, body mass index (BMI) waist-tohip ratio (WHR). BMI was calculated through the formula  BMI ¼ weight ½kilograms=height2 ½m2  . WHR was defined as the ratio between the smallest circumference of torso (between the 12th rib and iliac crest) and circumference of the hip (which is the maximal extension of the buttocks) [13]. Homeostatic model assessment (HOMA) and the quantitative insulin sensitivity check indexes (QUICKI) were used for assessment of insulin resistance. HOMA was calculated as: ½fasting plasma glucoseðmmol/lÞ  fasting plasma insulin ðIU/mlÞ=22:50. QUICKI was calculated as: 1=½logðINSULIN; lIU/mlÞ  logðGLUCOSE; mg/dlÞ. Mid-luteal serum progesterone was also measured. Assessment of hirsutism was done by Ferriman–Gallwey (FG) score C8 indicated hirsutism [7]. All women had Transvaginal ultrasound (TVUS) using transvaginal 3D power Doppler VolusonÒ E6 systems (Voluson Expert, General Electric Medical Systems, Milwaukee, WI), with a 4–9 MHz curved transducer. The examinations were done during the early follicular phase (days 4–7). All TVUS examinations were done by a single senior observer who was blind to allocation. Total follicular volume, total ovarian volume, stromal volume, the vascularization index (VI), the flow index (FI) and the (VFI) vascularization-flow index were measured as previously described by Battaglia et al. By subtracting the total follicular volume from the total ovarian volume we calculated the stromal volume [11]. All patients were examined under the same conditions. For every woman the power Doppler setting was standardized as follows: gain, 4.20; frequency, mid; Quality, high; wall motion filter, low 2; pulse repetition frequency (PRF), 1.30 kHz; gray map, 6; balance, 205; threshold, 30; ensemble, 23. The sampling volume angle was set to 50. All women in group 1 received metformin hydrochloride 500 mg tablets (GlucophageÒ, Bristol-Myers Squibb, New York, USA) that was started in a step-up maneuver every 5 days, from one to three tablets per day. This dose was guarded as tolerated throughout the 3 months of the study. TVUS was also performed every other day starting from day 9 of the first spontaneous or induced cycle following the 3 months treatment period. TVUS was performed; good response was achieved when at least one

mature follicle becomes C18 mm in diameter. When the optimal follicle size was reached, human chorionic gonadotropin (HCG) [10,000 IU] (ChoriomonÒ, [5,000 IU] IBSA, Switzerland) was given intramuscularly. Women were reassessed by TVS, 48 h after administration of HCG for ovulation signs (free fluid in the pouch of Douglas and/or transformation of the mature follicle into corpus luteum) [14]. Quantitative bhCG was done 2 weeks later to confirm chemical pregnancy. TVS was performed 4 weeks after positive bhCG to confirm the presence of intrauterine pregnancy. The women were advised not to take any other drugs or do any modifications in their life style (i.e., losing weight, herbal products etc.). Sample size justification The sample size was determined to produce study power of 80 % and the statistical significance is set to 95 %, based on the ovarian stromal VI differences between PCOS women and controls reported by Pan et al. [15] (3.99 % ± 2.38 vs. 1.44 % ± 1.20). Statistical analysis The statistical analysis was performed using the SPSS software (19.0 version, SPSS Inc., Chicago, IL, USA). The description of quantitative (numerical) variables was performed in the form of mean ± standard deviation (SD). The description of qualitative (categorical) data was performed in the form of number of cases and percentage. The analysis of numerical variables was performed using independent Student’s t test or paired t test in the same group. The Pearson correlation coefficient test was used to rank variables against each other either positively or inversely. The mean differences of the differences between measurements of the same observer were used as indicators of intraobserver repeatability. A best intraobserver repeatability was achieved when the mean of the differences was very close to 0. The Intraclass correlation coefficient (ICC) and 95 % confidence interval (CI) were used as expressions of reliability. They vary from 0 to 1, which indicates the maximum reliability. Values greater than 0.70 are usually accepted as good correlation coefficients [16]. Receiver–operating characteristics (ROC) curves were done for the 3 indices (VI, FI and VFI) and we tried to define a cut-off value to predict improvement in ovarian function by 3D Doppler indices. Results A total 100 women were finally analyzed. Comparison between group 2 and group 1 at the start of the study

123

Arch Gynecol Obstet Table 1 Comparison between group 2 and group 1 at the start of the study regarding demographic, anthropometric, laboratory and radiological data

Group 2 (n = 40) Age (years)

25.26 ± 2.22 30.71 ± 4.42

31.2 ± 4.75

0.549

0.62 ± 0.13

0.76 ± 0.17

\0.05*

2.20 ± 1.5

8.51 ± 3.4

\0.05*

104.18 ± 20.67

\0.05*

46.23 ± 10.52

40.47 ± 13.82

\0.05*

145.71 ± 14.74

192.63 ± 27.51

\0.05*

Day 3 Luteinizing hormone (LH) mIU/ml

6.86 ± 1.8

10.68 ± 2.68

\0.05*

High density lipoprotein HDL (mg/dl) Triglycerides (mg/dl) Day 3 follicular stimulating hormone (FSH) mIU/ml

9.53 ± 2

8.72 ± 2.52

0.088

LH/FSH ratio (day 3)

0.74 ± 0.24

1.26 ± 0.27

\0.05*

Free testosterone, ng/ml Fasting blood glucose mg/dl

0.66 ± 0.2 72.1 ± 6.61

0.96 ± 0.26 106.18 ± 27

\0.05* \0.05*

Fasting insulin uU/ml

3.83 ± 0.93

9.28 ± 2.03

\0.05*

Homeostatic model assessment (HOMA)

0.66 ± 0.21

2.42 ± 1

\0.05*

Quantitative insulin sensitivity check indexes (QUICKI)

0.41 ± 0.02

0.33 ± 0.02

\0.05*

10 ± 1.82

1.45 ± 1.75

\0.05*

Mean ovarian volume (ml3)

4.30 ± 1.15

8.84 ± 1.67

\0.05*

Mean stromal ovarian volume (ml3)

3.52 ± 1.058

6.62 ± 1.6

\0.05*

Progesterone (day 21)

 

Analysis using independent t test * Significant

Table 2 Comparison between women of group 1 before and after 3 months of metformin treatment regarding demographic, anthropometric, laboratory and radiological data

Body mass index (BMI) (kg/m2) The waist: hip ratio

High density lipoprotein (HDL) (mg/dl) Day 3 Luteinizing hormone (LH) (mIU/ml) LH/FSH (follicular stimulating hormone ratio) (day 3)

1.54 ± 0.69

\0.05*

After metformin treatment

P-value 

31.28 ± 4.75

30.27 ± 4.35

0.231

0.76 ± 0.17

0.74 ± 0.17

0.456

8.51 ± 3.4

8.01 ± 3.4

\0.05* S

104.18 ± 20.67

96.22 ± 2.59

\0.05* S

40.47 ± 13.82

42.64 ± 10.19

\0.05* S

192.63 ± 27.51

180.86 ± 27.9*

\0.05* S

10.68 ± 2.69

8.56 ± 2.9

\0.05*

1.26 ± 0.27

0.93 ± 0.36

\0.05*

Free testosterone, ng/ml

0.96 ± 0.26

0.79 ± 0.24

\0.05*

1.45 ± 1.75

4.89 ± 3.97

\0.05*

106.19 ± 27.03

78.22 ± 19.29

\0.05*

9.28 ± 2.03

7.97 ± 2.27

\0.05*

Fasting blood glucose (mg/dl)

123

0.76 ± 0.39

Progesterone (day 21) Fasting insulin (uU/ml)

Analysis using Paired T test

\0.05* \0.05*

Before metformin treatment

Triglycerides (mg/dl)

* Significant

4.69 ± 1.37 32.66 ± 4.37

Mean ovarian vascularization-flow index (VFI) (0–100)

Ferriman–Gallwey scoring

 

1.38 ± 0.76 26.59 ± 2.26

Mean ovarian vascularization index (VI) % Mean ovarian flow index (FI) (0–100)

Low density lipoprotein (LDL) (mg/dl)

Data are presented as mean ± standard deviation

0.58

68.69 ± 12.35

Ferriman–Gallwey scoring Low density lipoprotein (LDL) (mg/dl)

25.46 ± 2.1

P-value 

BMI (kg/m2) The waist: hip ratio

Data are presented as mean ± standard deviation

Group 1 (n = 60)

Homeostatic model assessment (HOMA)

2.41 ± 1

1.53 ± 0.79

\0.05*

Quantitative insulin sensitivity check indexes (QUICKI)

0.34 ± 0.02

0.36 ± 0.02

\0.05*

Mean ovarian volume (ml3)

8.84 ± 1.67

7.56 ± 1.48

\0.05*

Mean stromal ovarian volume (ml3)

6.62 ± 1.6

5.32 ± 1.46

\0.05*

Mean ovarian vascularization index (VI) %

4.69 ± 1.37

2.95 ± 1.52

\0.05*

32.66 ± 4.37 1.54 ± 0.69

29.48 ± 4.98 1.21 ± 0.7

\0.05* \0.05*

Mean ovarian flow index (FI) (0–100) Mean ovarian vascularization-flow index (VFI) (0–100)

Arch Gynecol Obstet Table 3 Correlations between 3 dimensional power Doppler indices and some variables in group 1 after metformin treatment HOMA Mean ovarian vascularization index (VI) %

r P-value

Mean ovarian flow index (FI) (0–100)

r P-value

Mean ovarian vascularization-flow index (VFI) (0–100)

r P-value

QUICKI

BMI (kg/m2)

The waist: hip ratio

0.364

-0.421

0.394

0.502

\0.05*

\0.05*

\0.05*

\0.05*

0.375

-0.427

0.463

0.647

\0.05*

\0.05*

\0.05*

\0.05*

0.473

-0.486

0.217

0.356

\0.05*

\0.05*

0.102

\0.05*

Analysis using Pearson correlation HOMA Homeostatic model assessment, QUICKI Quantitative insulin sensitivity check indexes, BMI Body mass index * Significant

regarding demographic, anthropometric, laboratory and radiological data are shown in Table 1. Effects of 3 months of treatment with metformin in group 1 on demographic, anthropometric, laboratory and radiological data are shown in Table 2. The ICC with 95 % CI for 3D power Doppler indices (VI, FI and VFI) and ovarian volume were 0.95 (95 % CI 0.86–0.97), 0.95 (95 % CI 0.86–0.94), 0.96 (95 % CI 0.88–0.96), and 0.98 (95 % CI 0.96–0.98) respectively. The current study showed a statistically significant correlations between 3D power Doppler indices of ovarian stroma and HOMA, WHR and BMI (except VFI and BMI where the correlation was not statistically significant). There was a negative correlation between QUIKI and all 3D Doppler indices (Table 3). On comparing women with normal weight [BMI \ 30 (kg/ m2) and Obese women [BMI C 30 (kg/m2)] after metformin in group 1, we found that there was a statistically significant difference in fasting blood glucose. Although fasting insulin difference was not statistically significant, but the HOMA and QUIKI were significantly better in normal weight women. Ovarian stromal 3D power Doppler indices were better in normal weight women except mean ovarian VFI, which was lower in normal weight women, but it did not reach a statistically significant difference (Table 4). Although we detected ovulation in 12 cases after using Metformin for 3 months in women of group 1. Yet, pregnancy was not achieved in any case. We did ROC curve analysis to get a cut-off value to detect ovulation in PCO cases after using metformin for 3 months; nevertheless, there was no cut-off value of VI, FI or VFI to detect ovulation in our study (Fig. 1). Figure 2 shows ovarian volume by 3D power Doppler before treatment. Figure 3 shows ovarian vasculatures by 3D power Doppler after treatment. Figure 4 shows VI, FI and VFI of ovarian stroma by 3D power Doppler before treatment. Figure 5 shows VI, FI and VFI of ovarian stroma by 3D power Doppler after treatment.

Discussion To the best of our knowledge, the current study is the largest study authenticating the effect of metformin treatment on ovarian stromal blood flow using 3D power Doppler ultrasound. The current study demonstrated that 3D power Doppler indices of the ovarian stroma were significantly higher in women with PCOS, this agrees with other investigators [17]. In our study, the 3D sonographic parameters were significantly correlated with free testosterone as well as the Ferriman–Gallwey score. In addition, hypertrophy of the stroma was correlated with increased stromal blood flow. These findings may be explained by a

Table 4 Comparison between normal weight and obese women with PCOS (in group 1) after 3 months of metformin treatment

Fasting blood glucose (mg/dl) Fasting insulin (uU/ml)

BMI \ 30 (kg/m2) n = 31

BMI C 30 (kg/m2) n = 29

72.13 ± 6.57

84.31 ± 25.24 \0.05*

7.44 ± 1.97

Pvalue 

8.50 ± 2.46

0.077

HOMA

1.23 ± 0.47

1.83 ± 0.95

\0.05*

QUIKI

0.37 ± 0.02

0.36 ± 0.02

\0.05*

Mean ovarian vascularization index (VI) %

2.48 ± 0.89

3.46 ± 1.87

\0.05*

28 ± 4.38

31 ± 5.21

\0.05*

1.30 ± 0.88

0.373

Mean ovarian flow index (FI) (0-100) Mean ovarian vascularization-flow index (VFI)

1.13 ± 0.5

BMI Body mass index, PCOS Polycystic ovary syndrome, HOMA Homeostatic model assessment, QUICKI Quantitative insulin sensitivity check indexes   Analysis using independent T test * Significant

123

Arch Gynecol Obstet

Fig. 1 ROC curve analysis to get a cut off value to detect ovulation in PCO cases after using metformin for 3 months. FI Flow index, ROC Receiver operator characteristic, VI Vascularization index, VFI vascularization-flow index

Fig. 2 Ovarian volume by 3D power Doppler before treatment with metformin

123

mechanism of neovascularization or activation of vasoactive factors that in turn may affect androgen synthesis within the ovary [7]. Our results confirmed that the previous studies concluded that patients with PCOS have an increased stromal volume and vascularity as evident by 3D Doppler indices of ovarian stromal vasculature. Moreover, Stromal vascularity is significantly higher in patients with PCOS who are hirsute [18]. In group 1, the Doppler indices (VI, FI and VFI) were improved in PCO women with normal BMI after metformin treatment. This agrees with a previous study which concluded that Pre-treatment with metformin prior to intracytoplasmic sperm injection in women with PCOS does not enhance clinical outcome. Nevertheless, among normal weight PCOS women, pregnancy rates were improved in women pre-treated with metformin [19]. The better response in normal weight PCO women to metformin is authenticated by the hypothesis that, in obese but not normal weight women, microvascular and metabolic insulin sensitivity are decreased, independent of PCOS. Therefore, obese PCOS women in particular may be at increased risk of metabolic and cardiovascular diseases [20]. Nevertheless, the results of our study were in contrast to those of other investigators who concluded that those patients with PCOS have an increased stromal volume and vascularity as evident by 3D Doppler indices of ovarian stromal vasculature who are of normal weight [18]. A recent study in UK showed that low-dose therapeutic

Arch Gynecol Obstet Fig. 3 Ovarian vasculatures by 3D power Doppler after treatment with metformin

Fig. 4 VI, FI and VFI of ovarian stroma by 3D power Doppler before treatment with metformin

regimen with rosiglitazone and Metformin (500 mg twice daily), has commensurate useful impacts on metabolic, hormonal and morphological criteria of PCOS, but no manifest effect on vascular parameters in a population. The previous study did not use 3D Doppler, also the differences from our study may be attributed to the lower dose of

Metformin and the smaller sample size they used [21]. This beneficial effect of metformin in improving the ovarian stromal blood flow did not reflect on ovulation rate in 12 out of 60 (20 %) and no pregnancy occurred. This may be attributed to the use of metformin only without concomitant use of ovulation induction drugs. In the current study,

123

Arch Gynecol Obstet Fig. 5 VI, FI and VFI of ovarian stroma by 3D power Doppler after treatment with metformin

the power Doppler settings were standardized for all women. Regarding the issue of standardization, the hope will go some way towards standardizing machine settings when evaluating 3D power Doppler indices. However, even with such standardization, several feebleness of the 3D power Doppler technique will remain. For example, there are differences in the approach in which tissues and organs are evaluated [22]. Also, the effect of attenuation should not be ignored, and can be avoided by normalizing the intensity of signals during 2D assessment [23, 24]. Another manner to compensate for the effect of attenuation and machine settings would be to settle indices that relate maximum, average and minimum VI, FI and VFI noticed during a cardiac cycle. However, this is only applicable if the 3D power Doppler dataset is captured using spatiotemporal image correlation (STIC). Without standardization of all these issues, it is anticipated that investigators will continue to obtain divergent results when assessing the same end-point using 3D power Doppler [22, 25]. While it is impractical to expect a consensus on all these parameters in a short period of time, investigator believes that standardized machine settings would be a large step in the appropriate direction [22]. The strength of the current study is that it is the largest study authenticating the effect of metformin treatment on ovarian stromal blood flow using 3D power Doppler ultrasound. The limitations of the current study included the non-inclusion of another control group with PCOS, without treatment with metformin, but this may be due to

123

ethical point of view. Another limitation was the absence of ovulation induction drugs, so as to increase the ovulation rate and pregnancy rate, but we did not add these drugs so as to assign the change in ovarian stromal blood flow to metformin only and also some investigators considered that metformin was one of ovulation induction drugs [5]. Lastly, another limitation is the failure of the ROC curves to make a definitive cut-off value of VI, FI or VFI to detect ovulation in women with PCOS. Conclusion Metformin seems to have a beneficial effect in normal weight PCO women via correcting ovarian stromal blood flow and hormonal profiles. Conflict of interest The authors do not have any conflicts of interest. All authors have substantially contributed to the concept and design, acquisition of data, analysis and interpretation of data, drafting the article and critical revision, and final approval of the version to be published. The authors funded the research.

References 1. Azziz R (2007) Definition, diagnosis and epidemiology of polycystic ovary syndrome, Chap. 1. In: Azziz R (eds) The Polycystic Ovary syndrome; Current Concepts in Pathogenesis and Clinical Care, 1st edn. Springer, Berlin, pp 1–16 2. Balen A (2007) Strategies for ovulation induction in the management of anovulatory polycystic ovary syndrome, Chap 7. In:

Arch Gynecol Obstet

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

Azziz R (eds) The Polycystic Ovary syndrome; Current Concepts in Pathogenesis and Clinical Care, 1st edn. Springer, Berlin, pp 99–116 Rizk A, Bedaiwy M, Al-Inany H (2005) N-acetyl-cysteine is a novel adjuvant to clomiphene citrate in clomiphene citrate– resistant patients with polycystic ovary syndrome. Fertil Steril 83:367–370 Nestler JE, Stovall D, Akhter N, Iuorno MJ, Jakubowicz MJ (2002) Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome. Fertil Steril 77:209–215 Harborne L, Fleming R, Lyall H, Norman J, Sattar N (2003) Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome. Lancet 361:1894–1901 Harborne L, Fleming R, Lyall H, Sattar N, Norman J (2003) Metformin or antiandrogen in the treatment of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab 88(9): 4116–4123 Ozcimen EE, Uckuyu A, Ciftci FC, Zeyneloglu HB (2009) The effect of metformin treatment on ovarian stromal blood flow in women with polycystic ovary syndrome. Arch Gynecol Obstet 280(2):263–269 Alexandraki K, Protogerou AD, Papaioannou TG, Piperi C, Mastorakos G, Lekakis J et al (2006) Early microvascular and macrovascular dysfunction is not accompanied by structural arterial injury in polycystic ovary syndrome. Hormones (Athens) 5(2):126–136 Diamanti-Kandarakis E, Alexandraki K, Protogerou A, Piperi C, Papamichael C, Aessopos A et al (2005) Metformin administration improves endothelial function in women with polycystic ovary syndrome. Eur J Endocrinol 152(5):749–756 Alcazar JL, Kudla MJ (2012) Ovarian stromal vessels assessed by spatiotemporal image correlation–high definition flow in women with polycystic ovary syndrome: a case–control study. Ultrasound Obstet Gynecol 40:470–475 Battaglia C, Battaglia B, Morotti E, Paradisi R, Zanetti I, Meriggiola MC et al (2012) Two- and three-dimensional sonographic and color Doppler techniques for diagnosis of polycystic ovary syndrome. The stromal/ovarian volume ratio as a new diagnostic criterion. J Ultrasound Med 31(7):1015–1024 Rotterdam ESHRE/ASRM–sponsored PCOS Consensus Workshop Group (2004) Revised 2003 Consensus on Diagnostic Criteria and Long-Term Healthy Risks related to Polycystic Ovary Syndrome. Fertil Steril 81:19–25 Elnashar A, Fahmy M, Mansour A, Ibrahim K (2007) N-acetyl cysteine versus metformin in treatment of clomiphene citrate– resistant polycystic ovary syndrome: a prospective randomized controlled study. Fertil Steril 88(2):406–409 Martins WP, Vieira CVR, Teixeira DM, Barbosa MAP, Dassunc¸a˜o LA, Nastri CO (2013) Ultrasound for monitoring controlled ovarian stimulation: a systematic review and meta-

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

analysis of randomized controlled trials. Ultrasound Obstet Gynecol. doi:10.1002/uog.12566 Pan HA, Wu MH, Cheng YC, Li CH, Chang FM (2002) Quantification of Doppler signal in polycystic ovary syndrome using three-dimensional power Doppler ultrasonography: a possible new marker for diagnosis. Hum Reprod 17:201–206 Merce´ LT, Go´mez B, Engels V, Bau S, Bajo JM (2005) Intraobserver and interobserver reproducibility of ovarian volume, antral follicle count, and vascularity indices obtained with transvaginal 3-dimensional ultrasonography, power Doppler angiography, and the virtual organ computer-aided analysis imaging program. J Ultrasound Med 24(9):1279–1287 El Behery MM, Diab AE, Mowafy H, Ebrahiem MA, Shehata AE (2011) Effect of laparoscopic ovarian drilling on vascular endothelial growth factor and ovarian stromal blood flow using 3-dimensional power Doppler. Intern J Gynecol Obstet 112: 119–121 Lam PO, Johnson IR, Raine-Fenning NJ (2007) Three-dimensional ultrasound features of the polycystic ovary and the effect of different phenotypic expressions of the parameters. Hum Reprod 22:3116–3123 Kjotrod SB, von During V, Carlsen SM (2004) Metformin treatment before IVF/ICSI in women with polycystic ovary syndrome; a prospective, randomized, double blind study. Hum Reprod 19:1315 Ketel IJ, Stehouwer CD, Serne´ EH, Korsen TJ, Hompes PG, Smulders YM et al (2008) Obese but not normal-weight women with polycystic ovary syndrome are characterized by metabolic and microvascular insulin resistance. J Clin Endocrinol Metab 93:3365–3372 Mohiyiddeen L, Watson AJ, Apostolopoulos NV, Berry R, Alexandraki KI, Jude EB (2013) Effects of low-dose metformin and rosiglitazone on biochemical, clinical, metabolic and biophysical outcomes in polycystic ovary syndrome. J Obstet Gynaecol 33:165–170 Martins WP, Nastri CO (2011) Reproducibility of 3D power Doppler placental vascular indices. Arch Gynecol Obstet 283: 403–404 Bugg GJ, Raine-Fenning NJ (2009) In vitro dual perfusion of human placental lobules as a flow phantom to investigate the relationship between fetoplacental flow and quantitative 3D power Doppler angiography. Placenta 30:130–135 Raine-Fenning NJ, Nordin NM, Ramnarine KV, Campbell BK, Clewes JS, Perkins A et al (2008) Determining the relationship between three-dimensional power Doppler data and true blood flow characteristics: an in vitro flow phantom experiment. Ultrasound Obstet Gynecol 32:540–550 Martins WP, Raine-Fenning NJ, Ferriani RA, Nastri CO (2010) The questionable value of VOCAL indices of perfusion. Ultrasound Obstet Gynecol 36:127–128

123

Assessment of ovarian stromal blood flow after metformin treatment in women with polycystic ovary syndrome.

To authenticate the effect of metformin treatment on ovarian stromal blood flow in women with polycystic ovary syndrome (PCOS) using 3-dimensional (3D...
579KB Sizes 0 Downloads 0 Views