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Can ovarian stromal blood flow predict the response to stimulation in polycystic ovary syndrome patients undergoing infertility treatment
Address for correspondence: Dr Ruchika Sood, KJIVF and Laparoscopy Centre, 23-24 Gagan Vihar, Delhi 110051, India. E-mail: info.kjivf@gmail.com
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Abstract
Aim:
To find out the difference in ovarian stromal blood flow in polycystic ovary syndrome (PCOS) and non-PCOS infertile patient and role of ovarian stromal blood flow as predictor of follicular response.
Design:
Prospective study.
Setting:
KJIVF and Laparoscopy Centre, Delhi.
Materials and methods:
Total 120 patients were recruited and divided into two equal groups. PCOS and non-PCOS infertile women of less than 35 years of age undergoing intrauterine insemination and in vitro fertilization (IVF) were included. Baseline and poststimulation two-dimensional transvaginal ultrasound with color and power Doppler was performed. Blood flow velocity waveforms with optimal flow were selected for measurement of systolic/diastolic ratio, peak systolic velocity (PSV), pulsatility index, and resistive index.
Intervention:
Color Doppler for ovarian stromal blood flow.
Statistical analysis:
Statistical testing was performed with the statistical package for the social science system version SPSS 17.0.
Results:
(a) Day 2/3 ovarian stromal PSV was significantly higher in PCOS women when compared with non-PCOS. (b) Positive correlation between ovarian stromal PSV and follicular response in patients with both PCOS and non-PCOS.
Conclusion:
Stromal vascularity in PCOS can be used as an additional criterion for the diagnosis of PCOS and ovarian stromal blood flow can be used as predictor of follicular response in IVF cycles especially in patients with PCOS.
Keywords
NON-PCOS
ovarian stromal blood flow
PCOS
INTRODUCTION
Polycystic ovary syndrome (PCOS) is the commonest anovulatory disorder in infertility practice. Anovulation is the cause of infertility in 30% of the cases, and 90% of anovulation cases are actually caused by PCOS.[1]
In addition, patients with PCOS are more prone to develop ovarian hyperstimulation syndrome (OHSS) and Doppler may help in predicting OHSS.
Other than variety of paracrine and endocrine factors,[2] adequate blood supply plays an important role for normal ovarian function.[3] Ovarian stromal microvasculature has been assessed with the use of both color and power Doppler in normal as well as polycystic ovaries.[4] Some authors have found significantly higher vascularity among PCOS,[5,6,7] whereas others did not.[8,9] In addition, it can be used as a predictor of follicular response as described by few studies[10,11,12,13] but with no definite consensus.
Therefore, we conducted this study to gain insight into the ovarian stromal blood flow in infertile women with PCOS when compared with women with non-PCOS with normal ovarian reserve. In addition, our goal was to evaluate the association of Doppler indices to the follicular response to gonadotropin stimulation in controlled ovarian stimulation and to predict the response to stimulation during intrauterine insemination (IUI)/in vitro fertilization (IVF) cycles.
SUBJECTS AND METHODS
This was a prospective controlled study conducted at our center for a period of 6 months from November 2020 to April 2021.
Study population
All patients with infertility with PCOS and non-PCOS women attending the assisted reproductive technology (ART) center and meeting the inclusion criteria were selected.
Inclusion criteria:
Patients with PCOS undergoing IUI or IVF cycles in study group
Normal ovarian reserve patients undergoing IUI or IVF cycles in controlled group.
Age less than 35 years.
Exclusion criteria:
Patient with thin endometrium less than 7 mm
Abnormal morphology
High resistance flow and absent subendometrial blood flow on Doppler
Immunologic factors such as antiphospholipid syndrome
Endometriosis and other pelvic pathology
History of investigation report suggestive of Koch.
Deranged thyroid and prolactin levels.
Sample size
The total sample size was set as 120 [60 per group calculated from an effect size of 0.8, power of 80%, and of 0.05, where the standard deviation (SD) of two groups was 2.5].
Our sample size was based on Doppler measurement between patients with normal ovaries and those with polycystic ovaries. A previous study[13] using a similar protocol indicated that patient with polycystic ovaries had a higher mean ovarian stromal peak systolic velocity (PSV) than patients with normal ovaries.
The formula for calculating sample size is as follows:
where Zα/2 is the critical value of normal distribution at α/2 (e.g., for a confidence level of 95%, a is 0.05, and the critical value is 1.96), Zβ is the critical value of the normal distribution at β (e.g., for a power of 80%, bβ is 0.2), and M1 and M2 are the expected sample mean of the two groups. s1 and s2 are the expected sample SD of the two groups.
The patients were divided into two groups.
Study group: Infertility patients with PCOS as defined by Rotterdam criteria.[14]
Control group: Non-PCOS infertility patients.
Rotterdam criteria: The presence of two from the following three diagnostic criteria:
oligo- and/or anovulation,
clinical and/or biochemical features of hyperandrogenism, and
the presence of polycystic ovary morphology.
To make a diagnosis of polycystic ovaries, either 12 or more follicles measuring 2 to 9 mm in diameter or increased ovarian volume (10 cm3) should be present on scanning. Written informed consent was taken from all the selected women in a language understood by them. All patients underwent transvaginal sonography on day 2 or day 3 of the menstrual cycles as routinely performed at our center. Single examiner performed the ultrasound and Doppler studies in all women to avoid interobserver variation. In addition, basal endocrine hormonal profiles were assessed as routinely performed at our center. After complete evaluation, patient underwent superovulation in IUI and controlled ovarian hyperstimulation in IVF cycles depending on the patient’s age and previous response. Monitoring of follicular growth was carried out with serial ultrasound scans and the dose was adjusted according to the follicular response as routinely performed. In addition, all selected patients underwent repeat Doppler studies after gonadotropin stimulation on the day of human chorionic gonadotropin (HCG) administration. When three or more leading follicles at least 18 mm in diameter in IVF cycles and one leading follicle more than 18 mm in IUI cycles as measured by ultrasound, 5000 IU of HCG was administered.
Ovarian Doppler studies
Color and power Doppler ultrasound was performed to record of variance from Doppler flow with the use of two dimensional (2D) endovaginal probe of 5 to 9 MHz frequency. The areas of maximum color intensity represent the greatest Doppler frequency shifts for pulse Doppler examination. Blood flow velocity waveforms with optimal flow were selected for measurement of systolic/diastolic (S/D) ratio, PSV, pulsatility index (PI), and resistive index (RI). A recording was taken as satisfactory when there were at least three equally intense waveforms in a row. For each woman, the average of each index in stimulated ovary was calculated and used for statistical analysis.
Statistical analysis
Statistical testing was performed with the statistical package for the social science system version SPSS 17.0 (IBM). Continuous variables were presented as mean ± SD or median (interquartile range) for non-normally distributed data. Categorical variables were expressed as frequencies and percentages. The comparison of normally distributed continuous variables between the groups was performed using Student t test. Nominal categorical data between the groups were compared using Chi-squared test for Fisher exact test as appropriate. Non-normal distribution continuous variables were compared using Mann–Whitney U test. For all statistical tests, P < 0.05 was taken to indicate a significant difference.
Ethical clearance: Ethical clearance was taken from ethical committee.
Financial statement: Cost of Doppler was borne by our center.
RESULTS
In this study, a total of 120 subjects were recruited and divided into two equal groups: patients with PCOS and patients with non-PCOS with normal reserve.
Table 1 summarizes the basic characteristics of patients such as age, duration of infertility, etc., which were similar. No patients had severe obesity even in PCOS group. Equal number of patients underwent both the procedures, that is, IUI and IVF in both groups. Average number of follicles formed and the protocol used for superovulation/COH and mean dose of gonadotropin used were also similar in both of the groups. However, mean duration of gonadotropin stimulation was statistically significantly less in PCOS group than in non-PCOS group in patients undergoing IUI or IVF. Higher LH/FSH ratio and anti mullerian hormone (AMH) levels as high as 9 ng/mL were observed in PCOS group and the values were higher in patients with OHSS. Hormonal profile was normal in non-PCOS group.
There were no significant differences in the baseline ovarian Doppler indices between right and left ovaries and so the mean value was calculated for each patient and used for further analysis. Baseline and Doppler parameters after stimulation by HCG included PSV (cm/second), S/D ratio, RI, and PI.
Mean value of baseline PSV was significantly higher for PCOS group than non-PCOS group in Table 2. However, no significant difference in two groups poststimulation was found.
Patients with hyperresponse in PCOS group had statistically significantly increased PSV and decreased S/D ratio in comparison with normal response in baseline scan. Low S/D ratio is suggestive of low resistance flow in ovaries which was found in patients with hyperresponse [Table 3], even though there was no difference in RI or PI. However, there was no significant difference in Doppler parameters between PCOS and non-PCOS group in poststimulation.
Table 4 summarizes strong uphill correlation between PSV and follicular response at baseline in IVF subjects in both the groups. In addition, the correlation was found to be moderate uphill in IUI in both groups, whereas baseline RI showed mild downhill correlation with follicular response in IVF subjects. S/D and PI did not show any correlation in baseline in both groups.
The PSV was found to be significantly higher in subjects with body mass index (BMI) ≤ 25 at baseline than in subjects with BMI > 25 [Table 5], whereas baseline S/D ratio and PI were found to be significantly lower in subjects with BMI ≤ 25. However, no such significance was reached in poststimulation phase [Table 5].
Similarly, in PCOS group, patients with BMI ≤ 25 were found to be associated with higher baseline PSV values than patients with PCOS with BMI > 25 [Table 6].
Non-PCOS subjects with lower BMI showed significantly higher baseline PSV, whereas S/D ratio as well as RI was significantly lower [Table 7].
Table 8 compares changes in Doppler parameter on stimulation. PSV was found to be significantly increased and S/D ratio, RI, and PI were found to be significantly decreased poststimulation in total population as well as in PCOS and non-PCOS groups.
DISCUSSION
Monitoring of stimulated cycles is performed primarily by 2D ultrasound. Most scans are carried out in gray scale. Additionally, color and power Doppler has been observed as prognostic tool. With newer machines having better resolution, power pulse Doppler, virtual organ computer-aided analysis imaging program may further simplify monitoring.
This study was aimed to compare the ovarian stromal vascularity among PCOS and normal reserve non-PCOS group and to assess the role of ovarian stromal blood flow in predicting ovarian follicular response in patients undergoing ovarian stimulation.
When we recorded and compared baseline ovarian Doppler parameters, significantly higher baseline PSV was found among PCOS women when compared with non-PCOS women. Panchal and Nagori[15] also suggested stromal PSV of 5-10 cm/second in normal ovaries with normal reserve and response. They also stated that if ovarian stromal PSV is >10 cm/second, then ovaries are prone to hyperstimulation. In our study, six patients from PCOS group undergoing IVF had hyperresponse and were found to have statistically significantly increased mean PSV and decreased S/D ratio in comparison with patients with normal response in PCOS group. No difference was found between RI and PI in these patients. No patient in IUI group had hyperresponse because of strict protocol and monitoring.
Pan et al. in their study compared and quantified three-dimensional power Doppler parameters in patients with PCOS to patients with non-PCOS.[16] They found significantly increased ovarian stromal vascular flow index (VFI) 2.1 ± 1.32 than 0.80 ± 0.97, flow index (FI) 50.26 ± 3.02 than 44.44 ± 5.42, vascularization index (VI) 3.99 ±2.38 than 1.44 ± 1.20, and ovarian volume 12.9 ± 4.27 than 6.10 ± 3.14 in PCOS group than in non-PCOS group.
Considering the fact that adequate blood flow is necessary for follicular development and polycystic ovaries are highly sensitive to gonadotropin treatment, it can be inferenced that inherent higher ovarian stromal vascularity may be responsible, for the exaggerated response to ovarian stimulation in patients with PCOS.[17] Engmann et al.[18] also demonstrated significantly higher ovarian stromal PSV among PCOS women on baseline in early follicular phase, on the HCG administration day, and even after pituitary downregulation. Additionally, LH in patients with PCOS varied from 2.1 IU/L to 6.2 IU/L with mean value of 2.6 IU/L, whereas in patients with non–PCOS, it was normal.
We found no significant difference in PI, RI, and S/D ratios between two groups which was in accordance with the study by Younis et al.[13] Younesi et al.[19] also found no significant difference in RI. But in contrast, Ozkan et al.[20] reported significantly lower PI, RI, and S/D ratios in PCOS group than in normal patients in bilateral ovarian arteries.
In our study, we found that there was significant difference between baseline and poststimulation Doppler parameters. We found that PSV was increased, whereas S/D ratio, RI, and PI were decreased significantly. Pinkas et al.[21] also documented decrease in RI and PI on prestimulation and on HCG day.
In the present study, positive correlation was detected between baseline ovarian stromal PSV and follicular response among both the groups similar to previous studies. Zaidi et al.[10] demonstrated that mean ovarian PSV was significantly correlated with the ovarian follicular response, after adjusting for the confounding factors. In poor response, group mean ovarian stromal PSV was significantly lower when compared with PCOS women. We could not compare this with poor response group because none of our patient has shown poor response on stimulation. Engmann et al.[18] also suggested association between ovarian stromal blood flow PSV and the number of oocytes retrieved.
On the other hand, Ng et al.[9] demonstrated that ovarian stromal blood flow indices have no role in predicting the ovarian follicular response. They also observed that normal weight BMI PCOS women were found to have significantly higher total ovarian VI/FI/VFI than overweight PCOS women. So they concluded that normal weight PCOS women had significantly higher vascularization indices when compared with overweight PCOS. Similarly, we also noted that PSV was found to be significantly higher in the subjects with BMI ≤ 25 at both baseline and poststimulation in both the groups, whereas S/D ratio and PI were found to be significantly lower in these patients. However, in PCOS group, all patients had BMI varying between 25 and 27 and in non-PCOS group, the BMI varied between 25 and 25.6. Hence, only minimal deranged BMI patients were recruited. Similar to our study, Arora et al.[22] positively correlated the predictive value of ovarian stromal blood flow with follicular response. Our results also showed that ovarian stromal blood flow helps in predicting clinical pregnancy in non-PCOS women with normal ovarian reserve undergoing IVF cycle. Baseline PSV was found to be significantly higher among pregnant women in this group; however, it was not significant in PCOS group or in total patients. It may be an incidental finding and requires more data for any consensus. In one previous study which has showed the role of stromal blood flow for prediction of pregnancy, stromal ovarian PSV was found to be significantly higher in the conception PCOS group when compared with the non-conception group.[18] However Younis et al.[13] concluded that ovarian stromal blood flow has no role in predicting IVF outcome. More studies are needed before reaching a definite conclusion on this issue.
Strength of the study:
Prospective study
Similar baseline characteristics of both the groups such as age and mean duration of infertility.
Monitoring by 2D power Doppler ultrasound which is the mainstay of patient’s monitoring in almost all centers.
Ultrasounds performed by a single operator that limits the interobserver bias.
Limitations of the study:
Small sample size.
No poor responders/anovulation during study period.
CONCLUSION
Baseline ovarian stromal PSV was found to be significantly higher for PCOS group (11.46 ± 2.4) compared to normal reserve non-PCOS group. Higher PSV suggests higher ovarian stromal vascularity in PCOS which could be used as an additional criterion for diagnosis of PCOS.
No significant difference was found between RI, PI, and S/D between two groups.
Baseline PSV in patients with hyperresponse in PCOS group was higher (14.21 ± 1.67) and S/D ratio was lower (2.52 ± 0.56) compared to normal response group.
Baseline PSV was found to be significantly higher in subjects with BMI ≤ 25, whereas S/D ratio and PI were found to be significantly lower when compared with subjects with BMI ≥ 25 but it could not be correlated with any difference in ovarian follicular response between these groups.
Strong positive correlation was detected between baseline PSV and ovarian follicular response after gonadotropin stimulation in IVF subjects among both the groups, hence could be used as a predictor for predicting follicular response in IVF cycles.
More studies with wider sample size are needed before reaching to any definite conclusion.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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