Human Reproduction Vol.18, No.7 pp.

14321437, 2003

DOI: 10.1093/humrep/deg244

Ovarian stromal blood ow changes after laparoscopic ovarian cauterization in women with polycystic ovary syndrome
Mohammad Ebrahim Parsanezhad1,4, Mohammad Hadi Bagheri1, Saeed Alborzi2 and Ernst Heinrich Schmidt3
Department of Obstetrics and Gynecology, School of Medicine and 2Department of Radiology, Medical School, Shiraz University ttingen of Medical Sciences, Shiraz, Iran and 3Department of Obstetrics and Gynecology, evang. Diakonie teaching hospital, Go University, Bremen, Germany
4 1

To whom correspondence should be addressed at: PO Box 713451657, Shiraz, Iran. E.mail: parsame@sums.ac.ir
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BACKGROUND: Women with PCOS have signicant differences in intra-ovarian and uterine artery haemodynamics. The aims of this study were to compare the ovarian stromal blood ow before and after laparoscopic ovarian diathermy, and to evaluate the value of these parameters in predicting the outcome of treatment in women with polycystic ovaries. METHODS: Colour Doppler blood ow within the ovarian stroma was recorded and serum concentrations of FSH, LH and testosterone were measured in 52 women with polycystic ovaries before and after laparoscopic ovarian diathermy. Ovulation was evaluated by folliculometry and progesterone assay in the rst menstrual cycle after operation. RESULTS: Six to 10 weeks after the diathermy, serum concentrations of LH and testosterone decreased signicantly (P = 0.001). The mean T SD peak systolic velocity decreased from 14.04 T 6.28 to 12.49 T 6.32 cm/s (P = 0.001), pulsatility index increased from 0.98 T 0.36 to 1.78 T 0.72 (P = 0.001), and resistance index increased from 0.55 T 0.16 to 0.71 T 19 (P = 0.001). A total of 73% of the women ovulated. There were signicant negative correlations between pulsatility index and LH (r = 0.43, P = 0.001), pulsatility index and testosterone (r = 0.40, P = 0.003) and pulsatility index and LH/FSH ratio (r = 0.53, P = 0.001). CONCLUSIONS: Laparoscopic ovarian diathermy in women with polycystic ovary syndrome may result in a decrease in ovarian stromal blood ow velocity. There was a signicant correlation between hormonal and ovarian stromal blood-ow changes. Changes in the Doppler parameters were signicantly higher in women who ovulated. The measurement of ovarian stromal blood ow by colour Doppler may be of value in predicting the outcome of treatment.
Key words: blood ow/cauterization/Doppler haemodynamics/polycystic ovary

Introduction Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility accounting for >70% of cases (Speroff et al., 1999; Kelestimur et al., 2000). This is a topic more likely to generate greater controversy about aetiology or pathogenesis than any other disease in gynaecological endocrinology (Speroff et al., 1999). Recently, there has been much interest regarding the potential role of transvaginal colour and pulsed Doppler ultrasound in assessing the ovarian and uterine blood ow of PCOS (Dolz et al., 1999). Most investigators would agree that the blood ow and the vascular pattern of an organ are directly related to the organ's morphology and function (Collins et al., 1991). Women with PCOS have signicant differences in intra-ovarian and uterine artery haemodynamics compared with women with normal ovaries (Battaglia et al., 1995; Aleem and Predanic, 1996; Zaidi et al., 1998; Vralacnik-Bokal and Meden-Vrtovec, 1998). 1432

The ovarian stromal blood ow differences are likely to be due to a primary disorder within the polycystic ovary, or vice-versa (Zaidi et al., 1995). These women have an increased ovarian stromal blood ow velocity in the early follicular phase of the normal menstrual cycle (Zaidi et al., 1995; Battaglia et al., 1997). This increase in ovarian stromal blood ow velocity has also been observed after pituitary suppression and after controlled superovulation in women undergoing IVF treatment (Engmann et al., 1999a). Zaidi et al. (1995) have shown a positive independent relationship between ovarian stromal blood ow velocity in the early follicular phase and subsequent ovarian follicular response, even in women with normal ovaries. In this study, patients with peak systolic velocity, (PSV) >10 cm/s had a better ovarian response and a higher clinical pregnancy rate than those with diminished ovarian stromal blood ow (PSV <10 cm/s). A variety of surgical options for the treatment of PCOS have been applied in women
European Society of Human Reproduction and Embryology

Ovarian stromal blood ow changes

Figure 1. Pattern of hormonal and Doppler parameter changes in women with PCOS undergoing ovarian diathermy. * = Signicant differences of each variable (comparison of before and 610 weeks after operation) (P < 0.05).

with PCOS who are clomiphene citrate (CC) resistant. Laparoscopic ovarian diathermy (LOD) represents an effective treatment for patients and possesses numerous advantages over gonadotrophin therapy (Cohen, 1996). Although a mechanism explaining the benecial effects of LOD on PCOS has not yet been demonstrated (Al-Took, 1999), one possible explanation is that LOD reduces androgen production, which inhibits normal follicular development (Tulandi et al., 1997). The ovarian stromal blood ow abnormalities in PCOS have been previously described (Battaglia et al., 1995; Aleem et al., 1996; Zaidi et al., 1998; Vralacnik-Bokal and Meden-Vrtovec, 1998), the possible effects of medical induction of ovulation on ovarian blood ow (Agrawal, 1998; Zaidi et al., 1998; Zaidi, 2000), effects of LOD on ovarian steroidogenesis (Greenblatt and Casper, 1987; Cohen, 1996; Felemban et al., 2000) and on ovarian stromal echogenecity (Al-Took et al., 1999) in CC-resistant PCOS have been also described. The inuence of LOD on the ovarian stromal blood ow has not as yet been studied. Evaluation of ovarian stromal blood ow before and after LOD may be considered a way to study the effects of this therapeutic intervention, or the mechanism by which the ovary may respond. The aims of this study were (i) to compare the ovarian stromal blood ow before and after LOD and (ii) to evaluate the value of these parameters in predicting the outcome of treatment. Materials and methods
From December 1996 to April 2002, 79 women with PCOS were studied in the Infertility and Reproductive Endocrinology Division, Department of Obstetrics and Gynecology, Shiraz University of

Medical Sciences, Shiraz, Iran, the Department of Obstetrics and ttingen Gynecology evang. Diakonie Teaching Hospital, Go University, Bremen, Germany and the Department of Radiology, Shiraz University of Medical Sciences, Shiraz, Iran. Patients' ages were 1932 years. Clinical evidence of hyperandrogenism was noted in all patients. Serum levels of LH, FSH and testosterone were measured in the early follicular phase (days 24 of the spontaneous or induced menstrual cycle) using the radioimmunoassay technique (RIA). Baseline transvaginal colour Doppler ultrasound scanning was performed on days 24 of the cycle to assess ovarian stromal blood ow. Criteria for inclusion were the following: infertility secondary to anovulation, as indicated by amenorrhoea or oligomenorrhoea, elevated serum LH levels, normal or low FSH levels, elevated LH/ FSH ratio, clinical evidence of androgen excess (acne, hirsutism), elevated serum levels of testosterone and ultrasound ndings of enlarged ovaries with multiple small cysts scattered around the periphery and highly echogenic stroma, and previously documented anovulation by transvaginal ultrasound follicular monitoring while taking clomiphene citrate (CC) in doses of b150 mg. Hysterosalpingography, post-coital test and semen analysis were normal in all subjects. The Ethics Review Committee for Human Research at our university approved the study. Informed consent was obtained from each individual. Laparoscopic ovarian diathermy was performed using the two-puncture technique. We used an optic that had an operative channel. The laparoscope was introduced through a sub-umbilical incision and grasping forceps were introduced suprapubically to stabilize the ovary by grasping the ovarian ligament. After assessment of the pelvic structures and tubal patency, an insulated needle connected to a unipolar electrocautery unit was inserted through the operative channel of the optic. Eight to 10 cautery points 34 mm in diameter were created in each ovary with a current of 4 mA applied through the laparoscopic-insulated needle. Hormonal assay and blood ow assessment were performed 2 days after the operation and repeated 610 weeks thereafter (in the early follicular phase of the rst post-operative menstruation). Folliculometry was performed on days 1517 and serum progesterone concentration was measured on days 1921 (mid-luteal phase) of the same cycle. This cycle was monitored to assess hormonal prole, ovarian stromal Doppler parameters and nally to detect ovulation. Ovulation was considered when the mean diameter of the leading follicle was b15 mm and serum progesterone level b5 ng/ml. A single radiologist performed all Doppler sonographies. Pulsatility index (PI), resistance index (RI), and peak systolic velocity (PSV) were measured in each scan. A colour Doppler ultrasound machine (Aloka Model SSD-1700) with a 5 MHz transvaginal transducer was used. Stromal blood ow of both ovaries was evaluated by colour and power Doppler ultrasonography. By means of colour and power Doppler ow imaging, colour signals were searched in the ovarian stroma away from the ovarian surface or near the wall of a follicle. By placing the colour Doppler gate over the ovarian stroma, areas of maximum colour intensity, representing the greatest Doppler frequency shifts, could be visualized, then selected for pulsed Doppler examination. Peak systolic blood ow velocity wave-forms were thus detected, and optimal ow velocity wave-forms were selected for analysis after angle correction. Then PI and RI were calculated in each selected Doppler wave. Both right and left ovaries were observed and analysed in each patient, revealing no statistical signicance in Doppler parameters of ovarian stromal arteries. Therefore, the mean value for all ovarian blood ow parameters was calculated and used in the statistical analysis. The intra-ovarian blood ow of each ovary was assessed by studying blood vessels in the ovarian stroma (small arteries in the ovarian stroma not close to the surface of the ovary or near the wall of a follicle).

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M.E.Parsanezhad et al. Table I. Pre-operative and post-operative serum hormone concentrations, Doppler blood ow velocity and 95% condence intervals of the differences in women with PCOS undergoing ovarian diathermy. Values are mean T SD FSH (mIU/ml) Before operation 610 weeks after operation 95% CI (Upper) 95% CI (Lower) P-value *= Signicant P-value. Table II. Correlation between hormonal and Doppler parameter changes after operation in women with PCOS undergoing ovarian diathermy Doppler parameters Hormonal prole D-FSH D-LH D-LH/FSH D-T D-PSV P-value 0.37 0.20 0.06* 0.13 r D-PI P-value 0.14 0.001 0.000 0.003 r 0.43 0.53 0.40 D-RI P-value 0.24 0.054* 0.001 0.04 r 0.43 0.30 6.42 T 1.85 7.55 T 1.98 0.40 1.84 0.003* LH (mIU/ml) 16.86 T 4.53 11.7 T 4.82 6.64 3.65 0.001* LH/FSH 2.67 T 0.55 1.59 T 0.65 1.32 0.82 0.001* T (ng/ml) 1.18 T 0.32 0.72 T 0.28 0.58 0.34 0.001* PSV (cm/s) 14.04 T 6.82 12.49 T 6.32 2.05 1.04 0.001* PI 0.98 T 0.36 1.78 T 0.72 0.63 0.98 0.001* RI 0.55 T 0.16 0.71 T 0.19 0.11 0.21 0.001*

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r = Correlation coefcient. D = Differences between values before and 610 weeks after operation. *Borderline signicance.

Statistical methods The relationship between ovarian stromal blood ow indices and hormonal changes after LOD was examined by the Pearson correlation test. Paired t-test was used to compare mean values. In order to determine the correlation between Doppler indices and hormonal changes including ovulation, we used t-test and Pearson correlation test. The data were rst tested for normality using the KolmogrovSmirnov test. P < 0.05 was considered statistically signicant.

Results A total of 79 women was recruited but 27 cases were excluded from the analysis because they had not completed the measurements. Therefore, 52 patients were used for the nal analysis. Data analysis showed a fall in the serum concentrations of LH, testosterone and LH/FSH ratio starting on day 2 after LOD. Hormonal prole and Doppler parameters, before, 2 days and 610 weeks after the operation are shown in Figure 1. LH decreased from 16.86 T 4.53 pre-operatively to 11.7 T 4.82 mIU/ml (610 weeks after operation) (P = 0.001). Mean T SD serum concentrations of testosterone before and 610 weeks after the operation were 1.18 T 0.32 and 0.72 T 0.28 ng/ ml respectively (P = 0.001). When compared with preoperation levels, serum concentration of FSH increased from 6.24 T 1.85 before operation to 7.55 T 1.98 mIU/ml 610 weeks after operation (P = 0.03). The mean T SD of PI and RI (610 weeks after operation) were signicantly higher than those in pre-operation values (P = 0.001), and that of PSV was signicantly lower (P = 0.001). LH/FSH ratio decreased from 2.67 T 0.55 before LOD to 1.59 T 0.65, 610 weeks thereafter. Changes in serum hormonal concentrations and Doppler blood ow velocity and 95% condence interval of the differences, before and 610 weeks after LOD are shown in Table I. We found signicant negative correlations between LH and PI (r = 1434

Figure 2. Mean hormonal and Doppler parameter changes in PCOS women undergoing ovarian diathermy who ovulated after operation. * = Signicant differences of each variable (comparison of before and 610 weeks after operation) (P < 0.05).

0.43, P = 0.001), testosterone and PI (r = 0.40, P = 0.003), testosterone and RI (r = 0.30, P = 0.043), LH/FSH ratio and PI (r = 0.53, P < 0.001) and RI (r = 0.43, P = 0.001). Correlations between hormonal and Doppler parameter changes are shown in Table II. Of all the women, 73.1% ovulated as indicated by mid-luteal serum progesterone levels (b5 ng/ml) and leading follicular diameter (b15 mm). After adjustment, PI increased signicantly in women who ovulated after LOD (P = 0.001). Although statistically insignicant, in the adjusted analyses, an

Ovarian stromal blood ow changes

Figure 3. Mean hormonal and Doppler parameter changes in PCOS women undergoing ovarian diathermy who did not ovulate after operation. * = Signicant differences of each variable (comparison of before and 610 weeks after operation) (P < 0.05).

increase in RI was observed in women that ovulated after operation (Figure 2). In post-operation analyses, the changes in Doppler indices in women who did not ovulate were not signicant when compared with their pre-operation values (Figure 3). All variables (PSV, PI, RI, LH, FSH, testosterone, age, progesterone, follicular size) had normal distribution. Discussion The results of this study demonstrate that ovarian stromal blood ow velocity declined after LOD in women with PCOS. Hormonal alteration that occurred after LOD in our patients was consistent with previous reports (Naether, 1993; Liguri et al., 1996). The ovulation and pregnancy rate after LOD varied from 2080% (Greenblatt and Casper, 1993; Tiitinen et al., 1993; Donesky and Adashi, 1995). Our study had been designed to evaluate the Doppler parameters of ovarian stroma and hormonal prole including ovulation before and after LOD. Thus long-term follow-up and pregnancy rate were not considered. Colour Doppler ultrasound permits accurate noninvasive assessment of blood ow to the reproductive organs. It has been used for the assessment of uterine and ovarian blood ow in normal cycles (Sladkevicius et al., 1993; Zaidi, 2000), PCOS (Ajossa et al., 2001; Zaidi et al., 1995; 1998; Zaidi, 2000), and after IVF attempts (Faver et al., 1993; Balakier and Stronell et al., 1994). The vascular changes observed during the entire folliculogenesis process seem to play an important role in ovulation (Campbell et al., 1993; Sladkevicius et al., 1993; Balakier et al., 1994; Dolz et al., 1999). Regarding this point, some reports now exist in the literature arguing that ovulation in humans depends on changes in blood ow to the follicle and that the main blood supply to the Graaan follicle is directed predominantly to a wreath of blood vessels that lie

along the inner border of theca interna (Macchiarelli et al., 1995). Our study is the rst study in the literature to report a signicant correlation between some Doppler indices and hormonal changes including ovulation after ovarian diathermy (Table II). In this study, we have demonstrated a dramatic fall in ovarian blood ow in parallel with LH and testosterone level, and LH/FSH ratio 610 weeks after surgery (Table I). We were also able to show that PI signicantly decreased in women who ovulated after ovarian diathermy. Although statistically not signicant, in the adjusted analyses, RI increased (P > 0.05) when measured 610 weeks after operation in subjects that ovulated after the operation but PSV showed no change. The pathophysiology of abnormal ovarian blood ow in PCOS is not clearly understood. One possible explanation is that serum estradiol (E2) might have a role as the moderator of uterine and ovarian vascularity (Steer et al., 1990; de Ziegler et al., 1991; Zaidi, 2000). Greenblatt and Casper (1987) showed a fall in E2 level starting the rst day after LOD, reaching the minimum level by day 4 after operation and beginning to rise thereafter. Thus the hypothesis of any correlation between serum E2 levels and ovarian blood ow changes remains elusive. On the other hand, a signicant decrease in vascular impedance to blood ow in the ovarian artery (Deutinger et al., 1989), and in vessels around the follicles, in correlation with an increase in the number of follicles and serum E2 concentration (Weiner et al., 1993), was observed after ovarian stimulation with gonadotrophins. As we demonstrated, ovarian blood ow decreased starting on day 2 following the operation and remained low for at least 2 months. Considering these observations and the data reported by Schurz et al. (1993), it seems that some factors other than E2 could be the cause of increased ovarian stromal vascularity in PCOS. Dolz et al. (1999) suggested that different mechanisms may be responsible for the haemodynamic anomalies that are uniformly observed in patients who do not undergo the type of luteal conversion occurring in normally cycling women. They suggested that the abnormal haemodynamic patterns may be due to an abnormal timing of LH-dependent prostaglandin release. Bourne and co-workers (1991) described a direct correlation between LH levels, prostaglandin activity and blood ow changes in the ovary. An alteration in the nely tuned timing for release of specic prostaglandins is likely to interfere with ovulation in humans. Engmann et al. (1999b) showed that ovarian stromal artery blood ow velocity declines after short term (23 weeks) treatment with GnRH agonist and increases signicantly on the day of hCG administration. The decline in ovarian artery blood ow velocity after GnRH agonist therapy is unlikely to be due to a hypoestrogenic effect. There is evidence that GnRH agonist therapy has a direct inhibitory effect on granulosa and luteal cell function and may play an important role in processes such as follicular atresia and luteal regression (Sharpe et al., 1982); therefore the ovaries are quiescent after GnRH agonist therapy. Primordial or smaller preantral follicles do not have any special vascular supply of their own and derive their blood supply from stromal blood vessels (Findaly, 1986). Subsequent growth of primary follicles leads to development of a vascular network with increased 1435

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M.E.Parsanezhad et al.

follicular blood ow. Thus the stromal blood ow velocity in an inactive or quiescent ovary may reect the baseline blood ow perfusion. Laparoscopic ovarian diathermy may result in the reduction in the number of small and intermediate follicles that usually seen in PCOS, it has the same effect on ovarian stromal tissue (Naether, 1993; Liguri et al., 1996). Regarding these effects and the above-mentioned mechanism by which ovarian stromal blood ow declined after GnRH agonist therapy (Findaly, 1986), we can hypothesize that the decline in ovarian stromal blood ow velocity could be the result of the direct electrical and/or thermal effects of LOD. Considering the increased ovarian stromal blood ow velocity in PCOS (Battaglia et al., 1995; Zaidi et al., 1995) and its possible effects on ovarian steroidogenesis, there might be a possible benecial effect of diminished ovarian stromal blood ow velocity on ovarian steroidogenesis in PCOS. Our data shed no light on these possibilities since we did not measure E2 or prostaglandins and no data regarding the direct effect of diminished ovarian stromal blood ow on ovarian steroidogenesis is available. In this study, we reported our preliminary ndings regarding the effects of LOD on ovarian stromal blood ow. The results show that Doppler indices of ovarian stromal blood ow signicantly changed after LOD and these changes are signicantly correlated with hormonal changes and subsequent ovulation. Our results provide a potential new avenue for evaluation of ovarian stromal blood ow changes after LOD. These data also suggest that the measurement of ovarian stromal blood ow by colour Doppler may be of value in predicting the prognosis of PCOS related problems after LOD. However, we believe that further research on a larger sample size is needed to determine whether an interaction occurs between LOD, ovarian stromal blood ow and ovarian steroidogenesis. Acknowledgements
We wish to thank Miss Marzieh Dehbozorgian for her help with statistical analyses.

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