Ultrasonographic patterns of polycystic ovaries: color Doppler and hormonal correlations

Transcription

1 Ultrasound Obstet Gynecol 1998;11: Ultrasonographic patterns of polycystic ovaries: color Doppler and hormonal correlations C. Battaglia, P. G. Artini, M. Salvatori, S. Giulini, F. Petraglia, N. Maxia and A. Volpe Department of Obstetrics and Gynecology, University of Modena, Italy Key words: POLYCYSTIC OVARIES, COLOR DOPPLER, HORMONES ABSTRACT Ultrasound has been used in the identification of two different morphological patterns of polycystic ovaries, namely a peripheral cystic pattern and a general cystic pattern. The aim of this study was to evaluate whether patients with the peripheral form of polycystic ovaries showed different ovarian and uterine blood flow from those with the general form, and to investigate whether there was a correlation between the forms and different hormonal parameters. Eighteen patients with the general form and 16 patients with the peripheral form of polycystic ovary underwent clinical, biochemical, gray-scale and color Doppler ultrasonographic evaluation. The parameters analyzed confirmed polycystic ovarian syndrome (PCOS) in all patients. Individual levels of plasma luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, androstenedione and estradiol did not differ between the groups. However, there was a significantly higher LH/FSH ratio and a greater stromal echodensity in the peripheral cystic group than in the general. Doppler ultrasonography demonstrated significantly lower pulsatility index values in the intraovarian arteries of the peripheral cystic group and a higher rate of visualization of these arteries than in the general. These findings suggest that, apart from the LH/FSH ratio, the different morphological types of polycystic ovary do not reflect differences in endocrine profile. The differences in blood flow demonstrated by Doppler assessment in each case, however, showed that PCOS does not predetermine a single intraovarian blood flow pattern. INTRODUCTION Polycystic ovarian syndrome (PCOS) is one of the most widely discussed and controversial areas in gynecological endocrinology. The etiology of the syndrome is uncertain because of the wide spectrum of disorders encompassed in the diagnosis 1 3. Minimal signs of hyperandrogenism in lean normally menstruating women, and obesity, severe hirsutism and oligo- or amenorrhea (as originally described by Stein and Leventhal 4 ) represent opposite poles of the clinical spectrum in this condition. Despite the vast amount of clinical, laboratory and experimental data that has been accumulated, the pathogenesis of PCOS remains a subject of speculation. Both an ovarian morphological anomaly (doubling of the cross-sectional area, doubling of the number of ripening and atretic follicles, a 5% increase in tunica thickness, a 33% increase of cortical and a five-fold increase of medullar stroma) 5 and abnormal hormone production (hyperandrogenism, inappropriate gonadotropin secretion, hyperinsulinism) 3 have been shown. The heterogeneity of the clinical and endocrine features is still a problem in the definition of PCOS Ultrasonographic examination is currently used for evaluating polycystic ovaries. The ultrasound criteria for diagnosis of PCOS have been defined by Adams and colleagues 13 as the presence of multiple cysts (> 1, 2 8 mm in diameter) arranged around an echogenic stroma. These parameters were shown to be strictly correlated with histopathological findings 14. Matsunaga and coworkers 15 identified two types of PCOS on the basis of ultrasonographic patterns: a peripheral cystic pattern and a general cystic pattern. In the former type, small cysts are located in the subcapsular region, whereas in the latter type, the small cysts occupy both the subcapsular and the stromal regions of the ovary. Nishigaki 16 recently demonstrated that plasma androstenedione levels are significantly higher in the patients with the general cystic pattern, suggesting that the ovarian ultrasonographic morphology may be associated with different endocrine abnormalities. Correspondence: Dr C. Battaglia, Department of Obstetrics and Gynecology, University of Modena, Via del Pozzo, 71, 411 Modena, Italy ORIGINAL PAPER 332 Received Revised Accepted

2 Transvaginal color Doppler facilitates the detection of small vessels in the utero-ovarian circulation and the measurement of impedance to flow in this vascular tree. We recently showed 17, and Zaidi and co-workers 18 and Aleem and co-workers 19 successively confirmed that, in patients with PCOS, significant changes occur within the intraovarian vessels. Furthermore, uterine artery resistance was shown to be increased in PCOS The aim of the present observational study was to evaluate whether patients with the general pattern and those with the peripheral pattern of polycystic ovaries show differences in their ovarian and uterine blood flow and whether there is a correlation between these patterns and specific hormonal parameters. PATIENTS AND METHODS The study protocol was approved by the local Ethics Review Committee. Women with PCOS (n = 34) (age range years) attending the Gynecological Endocrinology Clinic participated in the study after giving informed consent. PCOS was previously diagnosed on the basis of the following criteria: hirsutism, menstrual disturbances (oligoor amenorrhea), increased plasma circulating androgens, luteinizing hormone (LH)/follicle stimulating hormone (FSH) ratio of > 2.5 and typical ultrasonographic ovarian findings (> 1 small-sized follicles, ovarian volume > 8 ml, and increased ovarian stroma echogenicity). Patients were subdivided according to ultrasonographic findings into the group with a general cystic pattern (n = 18) and the group with a peripheral cystic pattern (n = 16) (Figure 1). Although in the general population the ratio of general/peripheral patterns is about 1 : 8, patients were selected to obtain roughly equal numbers in each group. All the patients had acne and/or seborrhea and hirsutism (Ferriman Gallwey score > 8). None had hypertension (systolic blood pressure > 14 mmhg and/or diastolic blood pressure > 9 mmhg), or was a heavy smoker or took regular intense exercise. Furthermore, they had not received hormonal therapy for at least 4 months before the study. Patients with ultrasound evidence of multifollicular (> 6 follicles) ovaries in which the follicles were > 4 mm in maximum diameter and distributed evenly throughout the ovary and in which there was no increase in stromal echodensity were not included in the study. Twenty-five (73%) patients were oligomenorrheic (cycle length > 35 days), and nine (27%) were amenorrheic (no vaginal bleeding for 6 months). The mean body mass index [BMI = weight (kg)/height 2 (m 2 )] was 23.8 ± 3.2 (range 21 31). Hirsutism was evaluated according to the Ferriman Gallwey method 2. The mean menarchal age was not significantly different between patients with the general cystic pattern (12.4 ± 1. years) and those with the peripheral cystic pattern (12. ±.7 years). Oligomenorrheic patients were studied in the early follicular phase (cycle days 3 5), whereas amenorrheic patients were studied at random. Gray-scale and color Doppler imaging and hormonal and biochemical assays were performed in all patients. Ultrasound and Doppler examination Ultrasonographic examination of the ovaries was performed with the use of a 6.5-MHz transvaginal transducer (Esaote AU 59 Asynchronous and AU 4 Idea; Esaote, Genoa, Italy): ovarian volume and the number, diameters and distribution of follicles were recorded 14. The volume a b Figure 1 (a) Peripheral cystic pattern. The small microcysts are aligned in the subcapsular region of the ovary. The ovarian stroma appears hyperechogenic (stromal score = 2). (b) General cystic pattern. Numerous small cysts occupy the entire ovarian parenchyma. The hyperechogenic stroma is less pronounced Ultrasound in Obstetrics and Gynecology 333

3 was calculated by the formula: V = π/6 D 1 D 2 D 3, where D 1 is the longitudinal diameter, D 2 the anteroposterior diameter and D 3 the transverse diameter of the ovary. The echogenicity of the ovarian stroma was scored as (normal), 1 (moderately increased) and 2 (markedly increased) 21,22. No significant differences between left and right ovaries were observed, and therefore the average value of both ovaries was used for statistical analysis. Doppler flow measurements of the uterine and intraovarian vessels were performed transvaginally with a 6.5-MHz color Doppler system (Esaote AU 59 Asynchronous and AU 4 Idea color Doppler). All the patients were in a semirecumbent position and were evaluated between 8. and 11. to exclude effects of circadian rhythmicity on uterine blood flow 23. Furthermore, they rested in a waiting room for at least 15 min before being scanned and completely voided the bladder in order to minimize external effects on pelvic blood flow 24. A 5-Hz filter was used to eliminate low-frequency signals originating from vessel wall movements. Color signals were sought in the stroma at the maximum distance from the surface of the ovary. The ovarian stroma was considered to be avascular if no blood vessels were demonstrated by color Doppler imaging. When several blood vessels were detected inside the ovarian stroma, only the one with the lowest downstream impedance was selected for Doppler measurements. Color flow images of the ascending branches of the uterine arteries were sampled laterally to the cervix in a longitudinal plane. The angle of insonation was always adjusted to obtain maximum color intensity. When good signals were obtained, blood flow velocity waveforms were recorded by placing the sample volume across the vessel and activating the pulsed Doppler mode. The pulsatility index (PI), defined as the difference between peak systolic and enddiastolic flow divided by the mean maximum flow velocity, was calculated for the ovarian stromal and uterine arteries. For each examination, the mean value of three consecutive waveforms was obtained. No significant differences between the PIs of the left and right uterine arteries were observed, and, therefore, the average value of both arteries was used. Similarly, the lowest PIs of the stromal arteries were not significantly different between the left and right ovaries and the mean value was used. The correlation between PI and heart rate was tested by using linear regression analysis. A weak and statistically non-significant inverse correlation was found. Therefore, in the results the PIs have not been corrected for heart rate. Ultrasound and color Doppler analyses were performed by a single examiner (C.B.) who was unaware of the hormonal status of the scanned patients. Hormonal assay and biochemical evaluation Peripheral blood was obtained from all patients between 8. and 11., after an overnight fast, on the same day that Doppler examination took place, and different hormonal parameters were analyzed. Blood samples were collected and centrifuged, and the plasma was separated and stored at 2, and subsequently assayed as previously reported 17,25. Plasma concentrations of LH, FSH, testosterone, androstenedione and estradiol were determined by radioimmunoassay (Radim, Pomezia, Italy). The LH/FSH concentration ratio was calculated. The levels of serum insulin and insulin-like growth factor I (IGF-I) were determined by a double-antibody radioimmunoassay (Amersham, Milan, Italy; and Immuno Nuclear Corp., Stillwater, USA, respectively). Plasma glucose level was determined by a method involving the use of glucoseoxidase. Statistical analysis Data are presented as mean ± standard deviation, unless otherwise indicated. Differences between groups were assessed with Student s t test and χ 2 test where necessary. The relationship between parameters was assessed by stepwise multiple linear regression. A probability of.5 was considered as statistically significant. RESULTS Clinical (Ferriman Gallwey score of > 8), hormonal (increased LH, LH/FSH ratio and androstenedione levels) and ultrasound findings (high number of small-sized follicles, augmented ovarian volume and increased echodensity of ovarian stroma) confirmed PCOS in all patients of both groups (Table 1). The levels of plasma LH, FSH, estradiol, androstenedione and testosterone did not differ between the groups, but the LH/FSH concentration ratio was significantly higher in the peripheral than the general cystic patients and was associated with a higher incidence of an ultrasonographic stromal score of 2 (Table 1). Plasma insulin, IGF-I and glucose levels showed no significant differences between the groups. In the group with the general cystic pattern, the mean age (22.6 ± 2.4 years) was significantly lower than in the group with the peripheral cystic pattern (25.4 ± 1.7 years; p <.5). Table 1 Clinical, hormonal, biochemical and ultrasonographic findings. The normal range is derived from normally ovulating patients at the Gynecological Endocrinology Clinic Body mass index (kg/m 2 ) Ferriman Gallwey score LH (IU/l) FSH (IU/l) LH/FSH ratio Estradiol (pmol/l) Testosterone (nmol/l) Androstenedione (nmol/l) Ovarian volume (ml) Small-sized follicles Stromal score (%) 1 2 *, p <.5; **, p <.1 General (n = 18) 22.6 ± ± ± ± ± ± ± ± ± Peripheral (n = 16) 24.4 ± ± ± 1.3 *3.58 ±.36* 66. ± ± ± ± ± ** 82** Normal range Ultrasound in Obstetrics and Gynecology

4 Table 2 Doppler findings. The normal range is derived from normally ovulating patients at the Gynecological Endocrinology Clinic On Doppler analysis, elevated resistance within the uterine arteries was observed in all patients and there were no significant differences between the groups. In the peripheral cystic patients, in comparison with the general cystic group, significantly lower PI values were observed in the ovarian stromal arteries (Table 2). In addition, in the general, the intraovarian vessels were not visualized in four patients (22%). In both groups the mean uterine artery PI values were inversely correlated with plasma estradiol (r =.3339; p <.5), and positively correlated with androstenedione levels (r =.4235; p <.1). Furthermore, ovarian stromal artery PIs were inversely correlated with the LH/FSH ratio (r =.3438; p <.5). DISCUSSION General (n = 18) Peripheral (n = 16) Normal range Uterine artery Pulsatility index 3.75 ± ± Ovarian stromal artery Pulsatility index Visualization (%) 1.42 ± ±.18** 1* NM NM, not measurable in patients without polycystic ovarian syndrome before the 5th day of the menstrual cycle; *, p <.5; **, p <.1 Since the advent of ultrasound scanning, an accurate estimation of the prevalence of polycystic ovaries in different study populations has been possible Furthermore, the use of transvaginal probes has shown that ultrasound findings correlate well with laparoscopic measurements and histological features, probably making it the most sensitive diagnostic index for PCOS in comparison with the clinical and endocrinological features 2,3. Moreover, as recently demonstrated, Doppler analysis can be a valuable additional tool for the diagnosis of PCOS In the present study, other than confirming the possible role of Doppler velocimetry in the diagnosis of PCOS, different Doppler patterns in the peripheral and general s of PCOS patients were observed. This finding adds a further possible confounding factor to the investigation of the syndrome. In all the women studied, elevated plasma androstenedione and LH levels and a high LH/FSH ratio were observed. At Doppler analysis, as previously observed 17, the mean uterine artery PI was shown to be positively correlated with androstenedione, and the ovarian stromal artery PI was inversely correlated with the LH/FSH ratio. However, patients with the peripheral cystic pattern showed a higher percentage of vessel visualization (1% vs. 78%) and significantly lower PI values in their intraovarian arteries than did patients with the general cystic pattern. These findings were associated with higher LH/FSH ratio values and a higher incidence of ultrasound score of 2 in stromal echodensity in the group with the peripheral pattern than in those with the general pattern. Hypersecretion of LH during the follicular phase of the menstrual cycle occurs in PCOS and is associated with hyperplasia of the ovarian theca and stromal cells. Increased vascularity has been demonstrated by color Doppler imaging and pulsed Doppler spectral analysis within the ovary Elevated LH levels may be responsible for increased stromal vascularization by influencing neoangiogenesis, catecholaminergic stimulation and leukocyte and cytokine activation Complex mechanisms may underlie the difference between the ultrasonographic features of the two groups. We speculated that, in the patients with the peripheral cystic pattern, the persistence of LH stimulation, as shown by the elevated LH/FSH ratio, may be associated with a worsening of vascular and stromal cell transformations. In contrast with Nishigaki 16 and Takahashi and colleagues 14, who reported that the general cystic pattern is associated with an ovarian steroidogenesis disorder whereas the peripheral cystic pattern is associated with abnormal gonadotropin secretion, our results suggest that the different ovarian morphologies do not necessarily reflect different endocrine patterns but may be considered an evolution of the same endocrinological alteration. Thus, the ovarian morphology may evolve from a normal multicystic to a polycystic peripheral pattern via a general cystic stage. From the above data it is possible to conclude that PCOS itself does not predetermine a single intraovarian blood flow pattern. 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