http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, Early Online: 1–5 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2014.995617
ORIGINAL ARTICLE
Comprasion of ovarian stromal blood flow measured by color Doppler ultrasonography in polycystic ovary syndrome patients and healthy women with ultrasonographic evidence of polycystic Ozhan Ozdemir1, Mustafa Erkan Sari1, Dilek Kalkan1, Esra Meltem Koc2, Seyda Ozdemir3, and Cemal Resat Atalay1
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Department of Obstetrics and Gynecology, Ankara Numune Education and Research Hospital, Ankara, Turkey, 2Department of Family Medicine, Mamak Public Healthcare Centers, Ankara, Turkey, and 3Department of Clinical Biochemistry, Diskapi Yildirim Beyazit Education and Research Hospital, Ankara, Turkey Abstract
Keywords
Objective: To compare ovarian stromal artery blood flows measured by Doppler ultrasonography of polycystic ovary syndrome (PCOS) patients and healthy women with polycystic ovarian image in ultrasonography. Methods: Forty-two patients diagnosed with PCOS according to the criteria of 2003 Rotterdam Concencus Conferance on PCOS and 38 healthy volunteers with polycystic ovarian image in ultrasonography were included in the study. Ovarian volumes and ovarian stromal artery blood flows were measured by 3-dimensional (3-D) ultrasonography and Doppler ultrasonography in all patients. Results: In patients with PCOS, ovarian stromal artery pulsatility index (PI) and resistivity index (RI) were found significantly different from healthy women with polycystic ovarian image in ultrasonography (p50.05). 3-D ovarian volumes were found significantly higher in patients with PCOS (p50.05), and a negative correlation was also obtained between ovarian volumes and ovarian stromal artery resistivity indices. Conclusion: Ovarian stromal artery Doppler examination could have an importance to explain the pathophysiology of PCOS, but there are few publications in the literature about PCOS and the details of ovarian stromal artery Doppler parameters in patients with polycystic ovarian image only. We conclude that Doppler ultrasonography findings of PCOS patients might be helpful in understanding the clinical follow-up and etiology of the disease.
Ovarian stromal artery Doppler, ovarian volume, polycystic ovary syndrome
Introduction Polycystic over syndrome (PCOS) was first described by Stein and Leventhal in 1935. It is a common endocrinologic disorder which affects 5–10% of fertile women [1]. This sydrome is characterized by hyperandrogenism, chronic anovulation and menstrual disorders, and may also comprise comorbidities such as hyperinsulinism, insulin resistance, early onset type II diabetes, dyslipidemia, cardiovascular diseases and infertility [2]. Despite there are lots of ongoing researches on prevelance, laboratory findings and clinical symptoms of PCOS, its etiology is still not well understood due to the clinical and biochemical variety of the disease. Hence, it appears to be one of the most controversial issues in reproductive endocrinology. Polycystic ovary syndrome was broadly discussed in the annual meeting of ‘‘European Society of Human Reproduction and Embryology’’ (ESHRE) in 2003. The consensus reported that
Address for correspondence: Dr Ozhan Ozdemir, Department of Obstetrics and Gynecology, Ankara Numune Education and Research Hospital, Ankara 06010, Turkey. Tel: +905052255078. E-mail: [email protected]
History Received 8 July 2014 Revised 15 November 2014 Accepted 3 December 2014 Published online 29 December 2014
PCOS is an ovarian dysfunction syndrome, and hyperandrogenism and polycystic ovarian apperance are its major signs [3]. Most of the researchers admit that patterns of blood flow is directly associated with the morphology and function of the relevant organ. Most of the researches showed that there is a significant increase in the numbers of intraovarian stromal artery and peak systolic blood flow velocities in women with PCOS compared to healthy women with normal ovarian morphologies [4–7]. Although the Doppler analysis of ovarian circulation is not included in the Rotterdam Diagnosis Criteria, detection of changes in intrastromal ovarian blood flow patterns makes us think that ovarian stromal Doppler evaluation might be helpful in understanding the pathophysiology of this syndrome. Clinical importance of the polycystic appearance of the ovaries still remains uncertain. Thirty-three percent of women with PCOS have the sonographic appearance of polycystic ovaries, however this appearance alone is not enough for the diagnosis. Besides, 18–25% of healthy fertile women have similar polycystic appearance [8]. Detection of the discrepancies between women with PCOS and women with polycystic appearance only will contribute to the understanding of the pathophysiology of PCOS. Herein, we compared the association between ovarian stromal arterial blood flows and ovarian volumes in these two groups.
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Materials and methods This study was undertaken in Ankara Numune Training and Research Hospital with the approval of the local ethics committee. Forty-two patients who applied to our clinic with PCOS diagnosis according to the 2003 Rotterdam Consensus Conference on PCOS (ESHRE-ASRM) criteria, and 38 healthy volunteers with similar demographic features and regular menstrual periods who have polycystic appearances in ultrasonography but do not fulfill other ESHRE-ASRM criteria were included in this study. Exclusion criteria for the patients were as follows: systemic diseases such as diabetes or hypertension, active liver diseases, history of using steroids or sex hormones in the last 6 months, alcoholics, pregnancy, and nursing. In this previously stated conference, PCOS was defined as a syndrome occuring out of an ovarian dysfunction, and diagnosed by the exclusion of prolactinoma, androgen secreting tumors and congenital adrenal hyperplasia besides consisting of two or more of the following conditions: oligoovulation or anovulation, clinical, biochemical signs of hyperandrogenism, or sonographic polycystic appearance of at least one of the ovaries. Sonographic polycystic appearance is defined as follows: twelve or more follicles of 2–9 mm diameter in a single ovary and/or increased ovarian volume (410 cm3) [3]. Demographic features of the patients together with their weights (in kilograms – kg), heights (in meters-m), and body mass indices (BMI) (kg/m2) were recorded. Ferriman–Gallwey scoring system was used for the diagnosis and determination of the severity of hirsutism, and a total score of 8 was accepted as hirsutism. Hormonal and sonographic evaluations were performed in the early follicular phase (2–5th days) of the spontaneous menstrual cycles in all patients. Ultrasound evaluation Ultrasonographic evaluations were performed with a 6.5 MHz transducer which has a color Doppler capability (Samsung, Medison SONOACE X8; 3DC2-6 4D Convex Probe, South Korea). The numbers and distributions of the antral follicles (2– 9 mm) in both ovaries and the ovarian volumes were recorded. The 3-D volume was generated by automatic rotation of the mechanical transducer by 360 . All patients were studied between 8:00 a.m. and 11:00 a.m. to exclude the effects of the circadian rhythmicity on ovarian blood flows. Furthermore, participants rested in a waiting room for at least 15 minutes before being scanned and completely emptied their bladder in order to minimize the external effects on blood flow. For ovarian stromal blood vessel measurements, color signals were sought in the ovarian stroma at a maximum distance from the surface of the ovary. Blood vessels located close to the wall of a follicle were not measured. In case of several blood vessels detected inside the ovarian stroma, the vessel with the lowest downstream impedance only was selected for Doppler measurements [4]. Resistance index (RI) and pulsatility index (PI) were electronically calculated using the following formula: PI ¼ (S D)/mean, RI ¼ (S D)/S, where S is the peak shifted Doppler frequency, D is the minimum Doppler shifted frequency and ‘‘mean’’ is the mean maximum Doppler shifted frequency over the cardiac cycle. The lowest PIs and RIs of the stromal arteries were not significantly different between the left and right ovaries with the mean values used. Only one single examiner performed the sonographic and Doppler studies in all women to avoid interobserver variations. Moreover, this examiner was blinded to clinical data and hormonal status of all women to avoid biases. Hormonal evaluation Blood samples were collected from each patient on the same day as Doppler flow analysis between 8:00 a.m. and 10:00 a.m., and
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the following hormones were assayed: luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), estradiol (E2), total testosterone (tT), free testosterone (fT), insulin, 17a-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone sulfate (DHEAS). All hormones except 17-OHP were measured on the same day using a COBAS E601 analyzer (Roche Diagnostics, Indianapolis, IN) by electrochemiluminescent (ECLIA) technique. Blood levels of fT were determined by Radio Immune Assay (RIA) using Immunotech (Marseille, France). 17-OHP level was determined by using another RIA kit (MP Biomedicals, Santa Ana, CA). Insulin resistance, defined by the Homeostasis Model Assessment – Insulin Resistance Index (HOMA-IR), was calculated by fasting insulin (mU/L) multiplied by fasting glucose (mmol/L), and divided by 22.5. Statistical analysis All data were analyzed using the Statistical Package for the Social Sciences for Windows version 17.0 (SPSS, Chicago, IL). Data are presented as mean ± standard deviation. Statistical analysis included Student’s t-test and Pearson’s test for normally distributed continuous data and the Mann–Whitney U-test for non-normally distributed data. Correlation analysis between parameters was performed, calculating Pearson’s or Spearman’s coefficient as appropriate. Statistical significance was defined as p50.05.
Results The characteristics of the PCOS patients and the polycystic ovaries (PCO) only patients are shown in Table 1. The mean ages of the women in the PCOS and PCO only groups were similar. In women with PCOS, tT, fT, 17-OHP, DHEAS, LH, and the LH/FSH ratio were significantly higher, and these patients also had higher BMIs (p50.05). On the other hand, Levels of FSH, prolactin and E2 were comparable between the two groups (p40.05). Ferriman–Gallwey hirsutism scores, insulin resistance Table 1. Clinical, biochemical, hormonal, and pelvic Doppler sonographic parameters of women with PCOS and women with PCO only groupa. PCOS (n ¼ 40)
PCO only (n ¼ 40)
Age (years) 22.3 ± 5.1 22.7 ± 5.9 BMI (kg/m2) 24.4 ± 3.1 22.5 ± 3.5 FSH (mIU/L) 6.6 ± 3.2 6.9 ± 3.6 LH (mIU/L) 12.5 ± 4.2 6.0 ± 2.1 E2 (pg/mL) 54.3 ± 19.7 52.1 ± 19.6 LH/FSH 1.89 ± 1.07 1.12 ± 0.70 Total testosterone (ng/mL) 0.47 ± 0.14 0.25 ± 0.10 Free testosterone (pg/mL) 2.73 ± 1.05 1.82 ± 0.64 17-OHP (ng/mL) 1.18 ± 0.63 0.82 ± 0.54 DHEAS (lg/dL) 322.63 ± 112.09 242.13 ± 83.31 Prolactin 23.34 ± 3.15 22.27 ± 2.93 Hirsutism score 11.12 ± 4.18 5.97 ± 2.01 HOMA-IR 3.03 ± 0.75 2.38 ± 0.27 Ovarian volume (cm3) 11.43 ± 4.79 4.86 ± 2.40 OARI 0.48 ± 0.05 0.82 ± 0.11 OAPI 0.89 ± 0.07 1.30 ± 0.27
p Values NS 0.027* NS 0.006* NS 0.001* 0.001* 0.001* 0.001* 0.001* NS 0.001* 0.001* 0.002* 0.001* 0.001*
PCOS: Polycystic Ovary Syndrome, PCO: Polycystic Ovaries, NS: Not Significant, BMI: Body Mass Index, FSH: Follicle Stimulating Hormone, LH: Luteinizing Hormone, E2: Estradiol, 17-OHP: 17Hydroxyprogesterone, DHEAS: Dehydroepiandrosterone Sulfate, HOMA-IR: Homeostasis Model Assessment of Insulin Resistance, OAPI: Ovarian Stromal Artery Pulsatility Index, OARI: Ovarian Stromal Artery Resistance Index. a Values are given as mean ± SD. *p50.05.
Stromal blood flow in PCOS
DOI: 10.3109/09513590.2014.995617
Table 2. Correlation of ovarian stromal artery pulsatility and resistance indices with clinical, hormonal, and biochemical characteristics of women with PCOS and women with PCO only group. Ovarian stromal arter PI
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Ovarian volume (cm3) Hirsutism score LH (mIU/L) Free testosterone (pg/mL) Total testosterone (ng/mL) LH/FSH ratio DHEAS (lg/dL) BMI (kg/m2) HOMA-IR
Ovarian stromal arter RI
PCOS r
PCO only r
PCOS r
PCO only r
0.541* 0.301* 0.246* 0.541* 0.074* 0.527* 0.350* 0.120 0.267*
0.057 0.043 0.034 0.132 0.002 0.039 0.164 0.020 0.033
0.471* 0.295* 0.313* 0.476* 0.067* 0.491* 0.361* 0.214 0.030*
0.033 0.024 0.041 0.155 0.006 0.089 0.022 0.032 0.041
PCOS: Polycystic Ovary Syndrome, PCO: Polycystic Ovaries, PI: Pulsatility Index, RI: Resistance Index, LH: Luteinizing Hormone, DHEAS: Dehydroepiandrosterone Sulfate, BMI: Body Mass Index, r: Pearson correlation coefficient, HOMA-IR: Homeostasis Model Assessment of Insulin Resistance. *p50.05.
scores and mean ovarian volume were significantly higher in PCOS women compared to the PCO only group (p50.05). However, we observed that ovarian stromal artery RIs and PIs were found significantly lower in patients with PCOS (p50.05). Among the PCO only group, there was no significant correlation between ovarian artery PI ovarian artery RI, ovarian volume and any of the other parameters (Table 2). In contrast, among women with PCOS, ovarian stromal artery PI and RI were inversely correlated with LH, fT, tT, and DHEAS levels, LH/FSH ratio, Ferriman–Gallwey hirsutism scores, ovarian volumes and HOMA-IR scores.
Discussion Polycystic ovary syndrome is one of the most common endocrinologic disorders among fertile woman, and its etiology is still not well understood [1]. Eighteen to twenty-five percent of healthy fertile women have the appearance of PCOs, however its importance still remains uncertain [8]. It is still controversial whether normal ovulatory women with the sonographic appearance of PCOs but without any other PCOS symptoms are subgroups of PCOS or normal variants only [9]. In our study, BMI, LH/FSH ratio, blood testosteron level, insulin resistancy, ovarian volume and hirsutism scores of women with PCOS were found to be significantly higher than women with the appearance of PCO only. Elevation of LH and LH/FSH ratios, which is related with the hyperplasia of ovarian techa and stromal cell, is one of the most important pathophysiologic features of PCOS [10]. Elevated LH levels may also lead to an increase in stromal vascularisation by affecting neoangiogenesis, cathecholaminergic stimulation, and the activation of leukocytes and cytokines [11]. Similar with many other studies in the literature, our study states that ovarian stromal arterial PI and RI values are lower in women with PCOS than women with the appearance of PCOs only. The lower PI and RI values are possible indicators of the increased number and dilatation of ovarian stromal vessels in PCOS [12]. We also found a negative correlation between ovarian stromal artery PI, RI and LH/FSH ratios which, in addition, correlates with the association of LH levels with the increase in stromal vascularity. Ovarian techal and stromal cell hyperplasia which occurs due to elevated levels of LH also leads to an increase in ovarian volumes [10]. In our study, we
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showed that ovarian volumes are higher in women with PCOS than women with the appearance of PCOs only, besides a negative correlation with ovarian stroma artery PI and RI values. Experimental studies have shown that insulin and Insulin-like Growth Factor (IGF) stimulate the angiogenesis and vasodilatation in the ovarian tissue. The exact mechanism of this effect could not have been explained yet, but vascular smooth muscle relaxation, endothelial activation and IGF receptor stimulation may be possible theories [13]. In our study, we found that insulin resistancy is higher in women with PCOS than women with the appearance of PCOs only, and there was also a negative correlation between insulin resistancy and the increase in ovarian stromal vascularity. Former studies have shown that blood IGF levels are significantly increased in PCOS. There are also studies which reported negative correlations between blood IGF levels and ovarian stromal artery PI values [13]. Insulin-like Growth Factor 1 has an important role in steroidogenesis and follicular development, and it is also thought to be associated with the follicular development disorders in PCOS [14]. Increased levels of serum androgens in PCOS, particularly DHEAS, have vasoconstructive effects, and there are studies showing that this can cause increased resistance against uterine blood flow [15]. On the other hand, high levels of local androgens in PCOS cause an increase in ovarian stromal vascularity [16]. We also found a negative correlation between stromal artery PIs, RIs, DHEAS and levels of testosteron in PCOS favoring former data. Androgens can also affect the ovarian perfusion indirectly via insulin resistancy. Obesity is common in patients with PCOS, and 50% of them have truncal obesity [17]. In our study, we found that pateints with PCOS have significantly higher BMIs compared to the women with the appearance of PCOs only however, we could not find any relation between BMI and stromal arterial RI, PI values. There is inconsistency about the relationship between obesity and stromal arterial blood flow in the literature, and some of them insist on the indirect effect via insulin resistancy [18]. Many studies have shown that modified Ferriman–Gallwey score which is used as an indicator of hyperandrogenism is found to be higher in PCOS compared to normal population [19]. Yet, another study showed that modified Ferriman–Gallwey score is found to be higher in patients with PCOS compared to the women with the appearance of PCOs only [12]. In our study, we found that modified Ferriman–Gallwey scores are higher in women with PCOS compared to the women with the appearance of PCOs only, besides a negative correlation is found with these scores and stromal artery PI and RI values. The risk of overian hyperstimulation syndrome is higher in infertile women with PCOS compared to the infertile women with normal ovarian functions. Although the underlying mechanism has not been clearly understood, increased ovarian stromal blood flow velocity and decreased resistancy in women with PCOS is thought to be responsible from increased sensitivity to the gonadotrophin therapy [13]. Although many studies concerning ovarian stromal blood flow in PCOS have been published in the recent 20 years, there is not an accepted conclusion present yet. Although different results have been reported in these studies, most of them concluded with ovarian blood flow increase. Twelve PCOS patients were compared to with infertile patients with normal ovalutory cycles in the case control study of Zaidi et al. in which 2-D technology was used, and it was stated that the mean values of ovarian stromal peak systolic velocity are increased despite no difference in PI values [5]. Women with PCOS were compared to a control group in the case control study of Battaglia et al., and it was stated that RI values were found to be lower in PCOS [10]. In the study of
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Aleem et al., women with were compared to healthy, normally ovulating women using 2-D technology, and it was stated that stromal vascularity was significantly increased in PCOS [6]. A similar study performed by Dolz et al. in which 3-D technology was used, reported that ovarian vascularity was increased in 65 women with PCOS compared to 25 women in the control group [20]. Subfertile patients accompanying with PCOS were compared to patients who have regular menstrual cycles and normal ovarian morphologies by Pan et al. by using 3-D technology, and they concluded that ovarian volume and vascularity increased in PCOS [7]. Women with PCOS were compared to normal ovulatory infertile patients in the prospective observational case control study of Lam et al., and it was stated that ovarian stromal vascularity was significantly higher in PCOS [21]. Women with PCOS were compared to healthy women with the appearance of PCOs in a case control study of Bostancı et al., reporting that ovarian stromal artery PI and RI values were significantly lower in PCOS [11]. This finding correlates well with our study. Women with PCOS were compared to healthy women in a case control study performed by Jarvelle et al. using 3-D technology, and no difference was found in ovarian vascularities between the two groups unlike our study and many others in the literature. But this finding must be evaluated carefully because of the small sampling size [22]. Similarly, infertile women with PCOS were compared to fertile women in a study performed by Ng et al. using 3-D technology, and no difference was found between groups regarding ovarian blood flow. Although anovulation and the appearance of PCOs were present in the patients of this study, clinicial and laboratory findings of hyperandrogenism were disregarded [23]. Women with PCOS were compared to ovulatory infertile patients in a prospective observational cohort study performed by Younis et al. in which 3D technology was used, and it was stated that there was no difference between groups regarding stromal blood flow [24]. It should be noted that other factors could have contributed to the controversy in the literature regarding stromal ovarian flow in women with PCOS. Study design and setting, PCOS criteria used, fertile or nonfertile controls, as well as 2-D or 3-D Doppler technology used, could have also played a role in this controversy among the different studies. Blood levels of vascular endothelial growth factor (VEGF) are higher in women with PCOS compared to women with normal functioning ovaries, and it is thought that the increase in ovarian stromal blood flow is based on the overexpression of VEGF [25]. Vascular endothelial growth factor not only has a role in angiogenesis, but also causes stromal growth in the connective tissue by increasing microvascular permeability in theca cells which, in addition, leads to an increase in IGF-1 synthesis. Ovarian androgen production also increases related to these changes [26]. Positive correlation was found between serum VEGF and LH levels, testosteron levels, and ovarian Doppler blood flow velocities [25]. High levels of VEGF in PCOS can partially explain the vascularization of ovarian stroma, and this hypothesis is supported by the strong immunohistochemical staining of VEGF in the ovarian stroma of women with PCOS [27]. Increased expression of VEGF in PCOS is caused by increased LH stimulus, and increase in the expression of VEGF mRNA parallel to LH levels is also observed. It is thought that LH levels play an important role in the regulation of vascular permeability which is organized by VEGF in theca cell layer [28].
Conclusions Ovarian stromal artery Doppler examination may have an important role in the explanation of the pathophysiologyof PCOS; however, there are only a few studies regarding the details
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of the parameters of ovarian stromal artery Doppler examination in PCOS and women with the appearance of PCOs. We think that Doppler examination of ovarian stromal blood flow may be useful in understanding the etiology and clinical features of PCOS.
Declaration of interest The authors do not have a conflict of interest.
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21. Lam P, Johnson I, Raine-Fenning N. Three-dimensional ultrasound features of the polycystic ovary and the effect of different phenotypic expressions on these parameters. Hum Reprod 2007;22:3116–23. 22. Jarvela IY, Mason HD, Sladkevicius P, et al. Characterization of normal and polycystic ovaries using three-dimensional power Doppler ultrasonography. J Assist Reprod Genet 2002;19:582–90. 23. Ng EH, Chan CC, Yeung WS, Ho PC. Comparison of ovarian stromal blood flow between fertile women with normal ovaries and infertile women with polycystic ovary syndrome. Hum Reprod 2005; 20:1881–6. 24. Younis JS, Jadaon JE, Haddad S, et al. Prospective evaluation of basal stromal Doppler studies in women with good ovarian reserve and infertility undergoing in vitro fertilization-embryo transfer treatment: patients with polycystic ovary syndrome versus ovulatory patients. Fertil Steril 2011;95:1754–8.
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25. El Behery MM, Diab AE, Mowafy H, et al. Effect of laparoscopic ovarian drilling on vascular endothelial growth factor and ovarian stromal blood flow using 3-dimensional power Doppler. Int J Gynaecol Obstet 2011;112:119–21. 26. Elmashad AI. Impact of laparoscopic ovarian drilling on antiMu¨llerian hormone levels and ovarian stromal blood flow using three-dimensional power Doppler in women with anovulatory polycystic ovary syndrome. Fertil Steril 2011;95:2342–6. 27. Abd EL, Aal DM, Mohamed SA, et al. Vascular endothelial growth factor and insulin-like growth factor-1 in polycystic ovary syndrome and their relation to ovarian blood flow. Eur J Obstet Gynecol Reprod Biol 2005;118:219–24. 28. Pirwany I, Tulandi T. Laparoscopic treatment of polycystic ovaries: is it time to relinquish the procedure? Fertil Steril 2003; 80:241–51.
ORIGINAL ARTICLE
Comprasion of ovarian stromal blood flow measured by color Doppler ultrasonography in polycystic ovary syndrome patients and healthy women with ultrasonographic evidence of polycystic Ozhan Ozdemir1, Mustafa Erkan Sari1, Dilek Kalkan1, Esra Meltem Koc2, Seyda Ozdemir3, and Cemal Resat Atalay1
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1
Department of Obstetrics and Gynecology, Ankara Numune Education and Research Hospital, Ankara, Turkey, 2Department of Family Medicine, Mamak Public Healthcare Centers, Ankara, Turkey, and 3Department of Clinical Biochemistry, Diskapi Yildirim Beyazit Education and Research Hospital, Ankara, Turkey Abstract
Keywords
Objective: To compare ovarian stromal artery blood flows measured by Doppler ultrasonography of polycystic ovary syndrome (PCOS) patients and healthy women with polycystic ovarian image in ultrasonography. Methods: Forty-two patients diagnosed with PCOS according to the criteria of 2003 Rotterdam Concencus Conferance on PCOS and 38 healthy volunteers with polycystic ovarian image in ultrasonography were included in the study. Ovarian volumes and ovarian stromal artery blood flows were measured by 3-dimensional (3-D) ultrasonography and Doppler ultrasonography in all patients. Results: In patients with PCOS, ovarian stromal artery pulsatility index (PI) and resistivity index (RI) were found significantly different from healthy women with polycystic ovarian image in ultrasonography (p50.05). 3-D ovarian volumes were found significantly higher in patients with PCOS (p50.05), and a negative correlation was also obtained between ovarian volumes and ovarian stromal artery resistivity indices. Conclusion: Ovarian stromal artery Doppler examination could have an importance to explain the pathophysiology of PCOS, but there are few publications in the literature about PCOS and the details of ovarian stromal artery Doppler parameters in patients with polycystic ovarian image only. We conclude that Doppler ultrasonography findings of PCOS patients might be helpful in understanding the clinical follow-up and etiology of the disease.
Ovarian stromal artery Doppler, ovarian volume, polycystic ovary syndrome
Introduction Polycystic over syndrome (PCOS) was first described by Stein and Leventhal in 1935. It is a common endocrinologic disorder which affects 5–10% of fertile women [1]. This sydrome is characterized by hyperandrogenism, chronic anovulation and menstrual disorders, and may also comprise comorbidities such as hyperinsulinism, insulin resistance, early onset type II diabetes, dyslipidemia, cardiovascular diseases and infertility [2]. Despite there are lots of ongoing researches on prevelance, laboratory findings and clinical symptoms of PCOS, its etiology is still not well understood due to the clinical and biochemical variety of the disease. Hence, it appears to be one of the most controversial issues in reproductive endocrinology. Polycystic ovary syndrome was broadly discussed in the annual meeting of ‘‘European Society of Human Reproduction and Embryology’’ (ESHRE) in 2003. The consensus reported that
Address for correspondence: Dr Ozhan Ozdemir, Department of Obstetrics and Gynecology, Ankara Numune Education and Research Hospital, Ankara 06010, Turkey. Tel: +905052255078. E-mail: [email protected]
History Received 8 July 2014 Revised 15 November 2014 Accepted 3 December 2014 Published online 29 December 2014
PCOS is an ovarian dysfunction syndrome, and hyperandrogenism and polycystic ovarian apperance are its major signs [3]. Most of the researchers admit that patterns of blood flow is directly associated with the morphology and function of the relevant organ. Most of the researches showed that there is a significant increase in the numbers of intraovarian stromal artery and peak systolic blood flow velocities in women with PCOS compared to healthy women with normal ovarian morphologies [4–7]. Although the Doppler analysis of ovarian circulation is not included in the Rotterdam Diagnosis Criteria, detection of changes in intrastromal ovarian blood flow patterns makes us think that ovarian stromal Doppler evaluation might be helpful in understanding the pathophysiology of this syndrome. Clinical importance of the polycystic appearance of the ovaries still remains uncertain. Thirty-three percent of women with PCOS have the sonographic appearance of polycystic ovaries, however this appearance alone is not enough for the diagnosis. Besides, 18–25% of healthy fertile women have similar polycystic appearance [8]. Detection of the discrepancies between women with PCOS and women with polycystic appearance only will contribute to the understanding of the pathophysiology of PCOS. Herein, we compared the association between ovarian stromal arterial blood flows and ovarian volumes in these two groups.
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O. Ozdemir et al.
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Materials and methods This study was undertaken in Ankara Numune Training and Research Hospital with the approval of the local ethics committee. Forty-two patients who applied to our clinic with PCOS diagnosis according to the 2003 Rotterdam Consensus Conference on PCOS (ESHRE-ASRM) criteria, and 38 healthy volunteers with similar demographic features and regular menstrual periods who have polycystic appearances in ultrasonography but do not fulfill other ESHRE-ASRM criteria were included in this study. Exclusion criteria for the patients were as follows: systemic diseases such as diabetes or hypertension, active liver diseases, history of using steroids or sex hormones in the last 6 months, alcoholics, pregnancy, and nursing. In this previously stated conference, PCOS was defined as a syndrome occuring out of an ovarian dysfunction, and diagnosed by the exclusion of prolactinoma, androgen secreting tumors and congenital adrenal hyperplasia besides consisting of two or more of the following conditions: oligoovulation or anovulation, clinical, biochemical signs of hyperandrogenism, or sonographic polycystic appearance of at least one of the ovaries. Sonographic polycystic appearance is defined as follows: twelve or more follicles of 2–9 mm diameter in a single ovary and/or increased ovarian volume (410 cm3) [3]. Demographic features of the patients together with their weights (in kilograms – kg), heights (in meters-m), and body mass indices (BMI) (kg/m2) were recorded. Ferriman–Gallwey scoring system was used for the diagnosis and determination of the severity of hirsutism, and a total score of 8 was accepted as hirsutism. Hormonal and sonographic evaluations were performed in the early follicular phase (2–5th days) of the spontaneous menstrual cycles in all patients. Ultrasound evaluation Ultrasonographic evaluations were performed with a 6.5 MHz transducer which has a color Doppler capability (Samsung, Medison SONOACE X8; 3DC2-6 4D Convex Probe, South Korea). The numbers and distributions of the antral follicles (2– 9 mm) in both ovaries and the ovarian volumes were recorded. The 3-D volume was generated by automatic rotation of the mechanical transducer by 360 . All patients were studied between 8:00 a.m. and 11:00 a.m. to exclude the effects of the circadian rhythmicity on ovarian blood flows. Furthermore, participants rested in a waiting room for at least 15 minutes before being scanned and completely emptied their bladder in order to minimize the external effects on blood flow. For ovarian stromal blood vessel measurements, color signals were sought in the ovarian stroma at a maximum distance from the surface of the ovary. Blood vessels located close to the wall of a follicle were not measured. In case of several blood vessels detected inside the ovarian stroma, the vessel with the lowest downstream impedance only was selected for Doppler measurements [4]. Resistance index (RI) and pulsatility index (PI) were electronically calculated using the following formula: PI ¼ (S D)/mean, RI ¼ (S D)/S, where S is the peak shifted Doppler frequency, D is the minimum Doppler shifted frequency and ‘‘mean’’ is the mean maximum Doppler shifted frequency over the cardiac cycle. The lowest PIs and RIs of the stromal arteries were not significantly different between the left and right ovaries with the mean values used. Only one single examiner performed the sonographic and Doppler studies in all women to avoid interobserver variations. Moreover, this examiner was blinded to clinical data and hormonal status of all women to avoid biases. Hormonal evaluation Blood samples were collected from each patient on the same day as Doppler flow analysis between 8:00 a.m. and 10:00 a.m., and
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the following hormones were assayed: luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), estradiol (E2), total testosterone (tT), free testosterone (fT), insulin, 17a-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone sulfate (DHEAS). All hormones except 17-OHP were measured on the same day using a COBAS E601 analyzer (Roche Diagnostics, Indianapolis, IN) by electrochemiluminescent (ECLIA) technique. Blood levels of fT were determined by Radio Immune Assay (RIA) using Immunotech (Marseille, France). 17-OHP level was determined by using another RIA kit (MP Biomedicals, Santa Ana, CA). Insulin resistance, defined by the Homeostasis Model Assessment – Insulin Resistance Index (HOMA-IR), was calculated by fasting insulin (mU/L) multiplied by fasting glucose (mmol/L), and divided by 22.5. Statistical analysis All data were analyzed using the Statistical Package for the Social Sciences for Windows version 17.0 (SPSS, Chicago, IL). Data are presented as mean ± standard deviation. Statistical analysis included Student’s t-test and Pearson’s test for normally distributed continuous data and the Mann–Whitney U-test for non-normally distributed data. Correlation analysis between parameters was performed, calculating Pearson’s or Spearman’s coefficient as appropriate. Statistical significance was defined as p50.05.
Results The characteristics of the PCOS patients and the polycystic ovaries (PCO) only patients are shown in Table 1. The mean ages of the women in the PCOS and PCO only groups were similar. In women with PCOS, tT, fT, 17-OHP, DHEAS, LH, and the LH/FSH ratio were significantly higher, and these patients also had higher BMIs (p50.05). On the other hand, Levels of FSH, prolactin and E2 were comparable between the two groups (p40.05). Ferriman–Gallwey hirsutism scores, insulin resistance Table 1. Clinical, biochemical, hormonal, and pelvic Doppler sonographic parameters of women with PCOS and women with PCO only groupa. PCOS (n ¼ 40)
PCO only (n ¼ 40)
Age (years) 22.3 ± 5.1 22.7 ± 5.9 BMI (kg/m2) 24.4 ± 3.1 22.5 ± 3.5 FSH (mIU/L) 6.6 ± 3.2 6.9 ± 3.6 LH (mIU/L) 12.5 ± 4.2 6.0 ± 2.1 E2 (pg/mL) 54.3 ± 19.7 52.1 ± 19.6 LH/FSH 1.89 ± 1.07 1.12 ± 0.70 Total testosterone (ng/mL) 0.47 ± 0.14 0.25 ± 0.10 Free testosterone (pg/mL) 2.73 ± 1.05 1.82 ± 0.64 17-OHP (ng/mL) 1.18 ± 0.63 0.82 ± 0.54 DHEAS (lg/dL) 322.63 ± 112.09 242.13 ± 83.31 Prolactin 23.34 ± 3.15 22.27 ± 2.93 Hirsutism score 11.12 ± 4.18 5.97 ± 2.01 HOMA-IR 3.03 ± 0.75 2.38 ± 0.27 Ovarian volume (cm3) 11.43 ± 4.79 4.86 ± 2.40 OARI 0.48 ± 0.05 0.82 ± 0.11 OAPI 0.89 ± 0.07 1.30 ± 0.27
p Values NS 0.027* NS 0.006* NS 0.001* 0.001* 0.001* 0.001* 0.001* NS 0.001* 0.001* 0.002* 0.001* 0.001*
PCOS: Polycystic Ovary Syndrome, PCO: Polycystic Ovaries, NS: Not Significant, BMI: Body Mass Index, FSH: Follicle Stimulating Hormone, LH: Luteinizing Hormone, E2: Estradiol, 17-OHP: 17Hydroxyprogesterone, DHEAS: Dehydroepiandrosterone Sulfate, HOMA-IR: Homeostasis Model Assessment of Insulin Resistance, OAPI: Ovarian Stromal Artery Pulsatility Index, OARI: Ovarian Stromal Artery Resistance Index. a Values are given as mean ± SD. *p50.05.
Stromal blood flow in PCOS
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Table 2. Correlation of ovarian stromal artery pulsatility and resistance indices with clinical, hormonal, and biochemical characteristics of women with PCOS and women with PCO only group. Ovarian stromal arter PI
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Ovarian volume (cm3) Hirsutism score LH (mIU/L) Free testosterone (pg/mL) Total testosterone (ng/mL) LH/FSH ratio DHEAS (lg/dL) BMI (kg/m2) HOMA-IR
Ovarian stromal arter RI
PCOS r
PCO only r
PCOS r
PCO only r
0.541* 0.301* 0.246* 0.541* 0.074* 0.527* 0.350* 0.120 0.267*
0.057 0.043 0.034 0.132 0.002 0.039 0.164 0.020 0.033
0.471* 0.295* 0.313* 0.476* 0.067* 0.491* 0.361* 0.214 0.030*
0.033 0.024 0.041 0.155 0.006 0.089 0.022 0.032 0.041
PCOS: Polycystic Ovary Syndrome, PCO: Polycystic Ovaries, PI: Pulsatility Index, RI: Resistance Index, LH: Luteinizing Hormone, DHEAS: Dehydroepiandrosterone Sulfate, BMI: Body Mass Index, r: Pearson correlation coefficient, HOMA-IR: Homeostasis Model Assessment of Insulin Resistance. *p50.05.
scores and mean ovarian volume were significantly higher in PCOS women compared to the PCO only group (p50.05). However, we observed that ovarian stromal artery RIs and PIs were found significantly lower in patients with PCOS (p50.05). Among the PCO only group, there was no significant correlation between ovarian artery PI ovarian artery RI, ovarian volume and any of the other parameters (Table 2). In contrast, among women with PCOS, ovarian stromal artery PI and RI were inversely correlated with LH, fT, tT, and DHEAS levels, LH/FSH ratio, Ferriman–Gallwey hirsutism scores, ovarian volumes and HOMA-IR scores.
Discussion Polycystic ovary syndrome is one of the most common endocrinologic disorders among fertile woman, and its etiology is still not well understood [1]. Eighteen to twenty-five percent of healthy fertile women have the appearance of PCOs, however its importance still remains uncertain [8]. It is still controversial whether normal ovulatory women with the sonographic appearance of PCOs but without any other PCOS symptoms are subgroups of PCOS or normal variants only [9]. In our study, BMI, LH/FSH ratio, blood testosteron level, insulin resistancy, ovarian volume and hirsutism scores of women with PCOS were found to be significantly higher than women with the appearance of PCO only. Elevation of LH and LH/FSH ratios, which is related with the hyperplasia of ovarian techa and stromal cell, is one of the most important pathophysiologic features of PCOS [10]. Elevated LH levels may also lead to an increase in stromal vascularisation by affecting neoangiogenesis, cathecholaminergic stimulation, and the activation of leukocytes and cytokines [11]. Similar with many other studies in the literature, our study states that ovarian stromal arterial PI and RI values are lower in women with PCOS than women with the appearance of PCOs only. The lower PI and RI values are possible indicators of the increased number and dilatation of ovarian stromal vessels in PCOS [12]. We also found a negative correlation between ovarian stromal artery PI, RI and LH/FSH ratios which, in addition, correlates with the association of LH levels with the increase in stromal vascularity. Ovarian techal and stromal cell hyperplasia which occurs due to elevated levels of LH also leads to an increase in ovarian volumes [10]. In our study, we
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showed that ovarian volumes are higher in women with PCOS than women with the appearance of PCOs only, besides a negative correlation with ovarian stroma artery PI and RI values. Experimental studies have shown that insulin and Insulin-like Growth Factor (IGF) stimulate the angiogenesis and vasodilatation in the ovarian tissue. The exact mechanism of this effect could not have been explained yet, but vascular smooth muscle relaxation, endothelial activation and IGF receptor stimulation may be possible theories [13]. In our study, we found that insulin resistancy is higher in women with PCOS than women with the appearance of PCOs only, and there was also a negative correlation between insulin resistancy and the increase in ovarian stromal vascularity. Former studies have shown that blood IGF levels are significantly increased in PCOS. There are also studies which reported negative correlations between blood IGF levels and ovarian stromal artery PI values [13]. Insulin-like Growth Factor 1 has an important role in steroidogenesis and follicular development, and it is also thought to be associated with the follicular development disorders in PCOS [14]. Increased levels of serum androgens in PCOS, particularly DHEAS, have vasoconstructive effects, and there are studies showing that this can cause increased resistance against uterine blood flow [15]. On the other hand, high levels of local androgens in PCOS cause an increase in ovarian stromal vascularity [16]. We also found a negative correlation between stromal artery PIs, RIs, DHEAS and levels of testosteron in PCOS favoring former data. Androgens can also affect the ovarian perfusion indirectly via insulin resistancy. Obesity is common in patients with PCOS, and 50% of them have truncal obesity [17]. In our study, we found that pateints with PCOS have significantly higher BMIs compared to the women with the appearance of PCOs only however, we could not find any relation between BMI and stromal arterial RI, PI values. There is inconsistency about the relationship between obesity and stromal arterial blood flow in the literature, and some of them insist on the indirect effect via insulin resistancy [18]. Many studies have shown that modified Ferriman–Gallwey score which is used as an indicator of hyperandrogenism is found to be higher in PCOS compared to normal population [19]. Yet, another study showed that modified Ferriman–Gallwey score is found to be higher in patients with PCOS compared to the women with the appearance of PCOs only [12]. In our study, we found that modified Ferriman–Gallwey scores are higher in women with PCOS compared to the women with the appearance of PCOs only, besides a negative correlation is found with these scores and stromal artery PI and RI values. The risk of overian hyperstimulation syndrome is higher in infertile women with PCOS compared to the infertile women with normal ovarian functions. Although the underlying mechanism has not been clearly understood, increased ovarian stromal blood flow velocity and decreased resistancy in women with PCOS is thought to be responsible from increased sensitivity to the gonadotrophin therapy [13]. Although many studies concerning ovarian stromal blood flow in PCOS have been published in the recent 20 years, there is not an accepted conclusion present yet. Although different results have been reported in these studies, most of them concluded with ovarian blood flow increase. Twelve PCOS patients were compared to with infertile patients with normal ovalutory cycles in the case control study of Zaidi et al. in which 2-D technology was used, and it was stated that the mean values of ovarian stromal peak systolic velocity are increased despite no difference in PI values [5]. Women with PCOS were compared to a control group in the case control study of Battaglia et al., and it was stated that RI values were found to be lower in PCOS [10]. In the study of
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Aleem et al., women with were compared to healthy, normally ovulating women using 2-D technology, and it was stated that stromal vascularity was significantly increased in PCOS [6]. A similar study performed by Dolz et al. in which 3-D technology was used, reported that ovarian vascularity was increased in 65 women with PCOS compared to 25 women in the control group [20]. Subfertile patients accompanying with PCOS were compared to patients who have regular menstrual cycles and normal ovarian morphologies by Pan et al. by using 3-D technology, and they concluded that ovarian volume and vascularity increased in PCOS [7]. Women with PCOS were compared to normal ovulatory infertile patients in the prospective observational case control study of Lam et al., and it was stated that ovarian stromal vascularity was significantly higher in PCOS [21]. Women with PCOS were compared to healthy women with the appearance of PCOs in a case control study of Bostancı et al., reporting that ovarian stromal artery PI and RI values were significantly lower in PCOS [11]. This finding correlates well with our study. Women with PCOS were compared to healthy women in a case control study performed by Jarvelle et al. using 3-D technology, and no difference was found in ovarian vascularities between the two groups unlike our study and many others in the literature. But this finding must be evaluated carefully because of the small sampling size [22]. Similarly, infertile women with PCOS were compared to fertile women in a study performed by Ng et al. using 3-D technology, and no difference was found between groups regarding ovarian blood flow. Although anovulation and the appearance of PCOs were present in the patients of this study, clinicial and laboratory findings of hyperandrogenism were disregarded [23]. Women with PCOS were compared to ovulatory infertile patients in a prospective observational cohort study performed by Younis et al. in which 3D technology was used, and it was stated that there was no difference between groups regarding stromal blood flow [24]. It should be noted that other factors could have contributed to the controversy in the literature regarding stromal ovarian flow in women with PCOS. Study design and setting, PCOS criteria used, fertile or nonfertile controls, as well as 2-D or 3-D Doppler technology used, could have also played a role in this controversy among the different studies. Blood levels of vascular endothelial growth factor (VEGF) are higher in women with PCOS compared to women with normal functioning ovaries, and it is thought that the increase in ovarian stromal blood flow is based on the overexpression of VEGF [25]. Vascular endothelial growth factor not only has a role in angiogenesis, but also causes stromal growth in the connective tissue by increasing microvascular permeability in theca cells which, in addition, leads to an increase in IGF-1 synthesis. Ovarian androgen production also increases related to these changes [26]. Positive correlation was found between serum VEGF and LH levels, testosteron levels, and ovarian Doppler blood flow velocities [25]. High levels of VEGF in PCOS can partially explain the vascularization of ovarian stroma, and this hypothesis is supported by the strong immunohistochemical staining of VEGF in the ovarian stroma of women with PCOS [27]. Increased expression of VEGF in PCOS is caused by increased LH stimulus, and increase in the expression of VEGF mRNA parallel to LH levels is also observed. It is thought that LH levels play an important role in the regulation of vascular permeability which is organized by VEGF in theca cell layer [28].
Conclusions Ovarian stromal artery Doppler examination may have an important role in the explanation of the pathophysiologyof PCOS; however, there are only a few studies regarding the details
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of the parameters of ovarian stromal artery Doppler examination in PCOS and women with the appearance of PCOs. We think that Doppler examination of ovarian stromal blood flow may be useful in understanding the etiology and clinical features of PCOS.
Declaration of interest The authors do not have a conflict of interest.
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