Effect of Total Abdominal Hysterectomy on Ovarian Blood Supply in Women of Reproductive Age

Article Effect of Total Abdominal Hysterectomy on Ovarian Blood Supply in Women of Reproductive Age Eliana Aguiar Petri Nahás, MD, Anaglória Pontes, MD, Jorge Nahas-Neto, MD, Vera Therezinha Medeiros Borges, MD, Rogério Dias, MD, Paulo Traiman, MD Objective. The purpose of this study was to evaluate the effect of total abdominal hysterectomy on ovarian blood supply using transvaginal color Doppler ultrasonography in women of reproductive age. Methods. This prospective study included 61 women aged 40 years or younger who were divided into 2 groups: group 1, comprising 31 patients who underwent total abdominal hysterectomy (TAH); and group 2, comprising 30 women with no abnormalities. Inclusion criteria included normal ovarian function at baseline, with basal follicle-stimulating hormone levels of less than 15 mui/ml, normal body weight, no tobacco use, and no history of laparotomy or ovarian disease. Ovarian arterial blood supply by determination of the pulsatility index (PI) on Doppler analysis and ovarian volume on transvaginal ultrasonography were assessed at baseline and at 6 and 12 postoperative months. The Student t test, profile analysis, and Friedman and Mann-Whitney tests were used in the statistical analysis of data. Results. Statistical analysis of baseline data revealed that both groups were homogeneous. At months 6 and 12, greater ovarian volumes and lower PI values were observed in patients who underwent TAH (P <.05). By the end of the study, in 8 of the 31 patients who underwent TAH (25.5%), benign ovarian cysts were observed. In the control group, all the parameters studied remained unchanged. Conclusions. The reduced PI values observed on Doppler ultrasonography suggested a decrease in the resistance flow in the ovarian arteries in women of reproductive age who underwent TAH. Key words: Doppler velocimetry; hysterectomy; ovarian arteries; ultrasonography. Abbreviations BMI, body mass index; PI, pulsatility index; RI, resistive index; TAH, total abdominal hysterectomy Received April 23, 2004, from the Department of Gynecology and Obstetrics, Botucatu Medical School, São Paulo State University, São Paulo, Brazil. Revision requested June 10, 2004. Revised manuscript accepted for publication October 6, 2004. Address correspondence and reprint requests to Eliana Aguiar Petri Nahás, MD, Department of Gynecology and Obstetrics, Botucatu Medical School, São Paulo State University, Rubião Júnior, Botucatu, São Paulo, Brazil 18618-970. E-mail: epetri@fmb.unesp.br The issue of whether ovaries should be preserved or removed is still controversial for the gynecologist who performs total abdominal hysterectomy (TAH). 1 3 The mean age of the women who undergo this kind of surgery is 45 years, and in 68% of cases, age ranges from 35 to 50 years. 3 According to Laughlin et al, 4 prophylactic oophorectomy with TAH deprives a large number of women of the beneficial effects of endogenous sexual steroids, and the consequences of lower ovarian androgen levels at menopause are unknown. Hysterectomy reduces the risk of ovarian cancer. This may be explained by reduced exposition to vaginal carcinogens, changes in the ovarian blood supply, and detection of unknown ovarian disease during surgery. 5,6 2005 by the American Institute of Ultrasound in Medicine J Ultrasound Med 2005; 24:169 174 0278-4297/04/$3.50

Effect of Total Abdominal Hysterectomy on Ovarian Blood Supply The surgical stress brought about by TAH may affect the ovarian blood supply and thereby may alter ovarian function. 7 The blood supplied to the tubes and ovaries derives from the uterine and ovarian arteries. The ovarian artery, originating from the aorta, is present in the infundibulopelvic ligament and divided into 3 branches. The lateral branch of the ovary and the uterine artery branch, the medial ovarian branch that runs along the ovarian-uterine ligament in the mesovarium, anastomose to form the ovarian arcade. Such distribution, however, shows anatomic variations. 8 With the use of the xenon Xe 133 radioisotope to measure ovarian blood supply immediately after TAH, Janson and Jansson 9 reported that the surgery reduced ovarian clearance by 50% to 90%, suggesting an acute diminution in ovarian perfusion derived from the ligation of the adnexal branches of the uterine arteries. This procedure would increase intraovarian pressure, damage ovarian microcirculation, and lead to ovarian failure. 10,11 Over the last decade, Doppler ultrasonography has become an established technique in the investigation of the uterofetoplacental circulation and ovarian hemodynamics during the menstrual cycle. The variations in pelvic arterial flow velocity detected on Doppler ultrasonography are associated with hormonal and angiogenic factors. During ovulation, the resistance of the ovarian vessels decreases under the influence of sexual steroids and blood flow to the ovaries is increased. 12 15 Kurjak and Kupesic 15 measured ovarian flow velocity in normally cycling women and in women at menopause. They reported that Doppler signals of diastolic ovarian arterial blood flow gradually decrease to absence in women more than 5 years after menopause. 15 The measurement of flow velocity is based on the Doppler effect described by Christian Doppler. The color observed on Doppler ultrasonography corresponds to the velocity and turbulence of blood inside a vessel. Several indices are used in the analysis and variation in flow velocity, such as pulsatility index (PI) and resistive index (RI), which yield both reliable and comparable data on the circulatory event. 16 Every pelvic vessel has its own wave pattern. In the ovarian artery, flow velocity is low, and resistance varies with the cycle phase. 12,16 The PI is probably the most accurate parameter to describe changes in pulsatility and peripheral resistance and is inversely proportional to flow. 17 Dogan et al 18 assessed ovary perfusion by Doppler ultrasonography before and 6 months after TAH in 43 women younger than 45 years and found no statistically significant differences in the RI values observed before after surgery or in the control group. They concluded that ovarian supply remained unchanged 6 months after TAH. 18 To date, little is known about the flow velocity pattern in ovarian arteries after TAH. Therefore, the purpose of this study was to perform a Doppler analysis of the ovarian blood supply in women at reproductive age who underwent TAH. Materials and Methods This prospective, longitudinal, case-control study included 61 women 40 years or younger who were allocated into 2 groups: group 1, consisting of 31 patients who had TAH for benign diseases of the uterus; and group 2, consisting of 30 healthy women (control). All subjects showed regular menstrual cycles and normal ovarian function (luteal progesterone >5 ng/ml) and had no history of surgery or tubal ligation. None of them had received any kind of medication that could affect the results within the preceding 6 months. Exclusion criteria included smoking and obesity (body mass index [BMI] 30 kg/m 2 ). In all cases, baseline follicle-stimulating hormone levels were less than 15 miu/ml on at least 2 occasions. Informed consent was obtained from all patients, and the study was approved by the Research Ethics Committee of Botucatu Medical School. Initially, a complete medical history was taken; physical and gynecologic examinations were performed; and oncotic evaluations and transvaginal ultrasonography were conducted for each patient. Data included information on age, menarche, menstrual cycle, parity, weight, height, and BMI. The follow-up duration was 12 months. Ovarian volume was measured by transvaginal ultrasonography, and Doppler ultrasonography was used to assess the ovarian flow velocity waveform by measuring the PI at baseline and 6 and 12 months after hysterectomy. All examinations were conducted during the follicular phase of the menstrual cycle by the same investigator, in the afternoon. In hysterectomized women and the control group, the follicular phase was determined by the absence of 170 J Ultrasound Med 2005; 24:169 174

Petri Nahás et al both a dominant follicle and corpus luteum. The mean examination length was 20 minutes. Transvaginal ultrasonography was performed with a Sonochrome system (GE Healthcare, Milwaukee, WI) with an endovaginal 7.5-MHz probe for morphologic imaging of the uterus and ovaries and color Doppler ultrasonography. Baseline measures included transverse (T), anteroposterior (AP), and longitudinal (L) diameters of the uterus and ovaries and volume (V), which was estimated using the formula V (cubic centimeters) = T (centimeters) AP (centimeters) L (centimeters) 0.52. Left and right ovarian artery flow in the pelvic infundibulum was visualized with the color Doppler technique, and the typical velocity spectrum of this vessel was determined. Blood flow impedance was expressed as the PI. The PI values were calculated electronically according to the formula PI = S D/mean, where S was the peak systolic velocity; D was the minimum diastolic velocity; and mean was the mean flow velocity. Aiming at accurate data collection, at least 5 similar flow velocity waves of satisfactory quality were obtained. In the statistical analysis, the Student t test was used to compare baseline clinical and ultrasonographic parameters. The PI, which showed normal distribution, was assessed by profile analysis followed by the Tukey method of multiple comparisons (data expressed as mean ± SD). Ovarian volume values, which showed abnormal distribution, were assessed by Friedman and Mann-Whitney tests, and the results were expressed as median, minimum, and maximum values. The significance level was set at 5%, and data were calculated with SAS version 6.3 software (SAS Institute Inc, Cary, NC). Results Baseline clinical and ultrasonographic characteristics of the patients who underwent TAH and those of the control group were statistically compared and are shown in Table 1. The groups were homogeneous regarding age, menarche, parity, menstrual cycle interval, and BMI. In relation to ultrasonographic measures, only uterine volume differed between groups. The patients in the hysterectomy group showed preoperative values significantly higher than those of the control group (Table 1). Pulsatility index values were significantly reduced at months 6 and 12 in both ovaries of the women who had TAH and the control group (Figures 1 and 2). At month 6, ovarian vessels could not be found for PI measurement in 4 (6.4%) of 62 ovaries in the hysterectomized women and in 4 (6.7%) of 60 ovaries in the control group. At month 12, the same occurred in 2 (3.2%) of 62 ovaries of the patients who underwent TAH and in 3 (5.0%) of 60 ovaries in the control group. In the patients who underwent TAH, ultrasonography revealed that right and left median ovarian volumes significantly increased at months 6 and 12 compared with the control group (Figures 3 and 4). At month 6, 13 (41.9%) of 31 patients who underwent TAH had functional ovarian cysts that were 27 to 324 cm 3 in volume and more frequent on the left side (9 of 13). However, at month 12, in 10 (76.9%) of these 13 cases, these cysts were no longer observed. Conversely, over this period, 5 new cases arose, with volumes ranging from 36.5 to 82 cm 3. Therefore, at month 12, 8 (25.5%) of the 31 patients still had cysts of benign aspect. In the control group, ovaries were observed to be normal throughout follow-up (Figures 3 and 4). One of the patients, whose ovarian volume was 324 cm 3 at month 6, reported a painful and tumorous left iliac fossa during a gynecologic examination at month 12. Ultrasonography revealed a 421-cm 3 cyst in the left adnexal region. Tests results for the tumor markers can- Table 1. Comparison Between the Baseline Clinical and Ultrasonographic Characteristics in Women of Reproductive Age Who Underwent TAH (n = 31) and Those of the Control Group (n = 30) TAH Control Variable (Group 1) (Group 2) P* Age, y 37.61 ± 2.60 36.66 ± 2.93.18 Age at menarche, y 12.84 ± 1.57 12.70 ± 1.46.72 Parity (No. of children) 2.22 ± 1.38 1.83 ± 1.82.20 Menstrual interval, d 28.35 ± 1.85 28.43 ± 2.09.87 BMI, kg/m 2 25.64 ± 3.16 24.79 ± 2.78.38 Right ovary volume, cm 3 6.04 ± 2.42 6.95 ± 2.13.13 Left ovary volume, cm 3 6.38 ± 2.94 6.83 ± 2.46.52 Right Doppler PI 2.61 ± 0.58 2.93 ± 0.84.15 Left Doppler PI 2.86 ± 0.64 3.00 ± 0.82.20 Uterus volume, cm 3 309.0 ± 243.64 92.23 ± 5.86.001 Values are mean ± SD. *P <.05 is significant (Student t test). Group 1 > group 2. J Ultrasound Med 2005; 24:169 174 171

Effect of Total Abdominal Hysterectomy on Ovarian Blood Supply Figure 1. Comparison between PI values for the right ovarian artery in women of reproductive age who underwent TAH (n = 31) and those of the control group (n=30). Data are expressed as mean values ± SD. cer antigen 125, reactive C Protein, and carcinoembryonic antigen were negative. Exploratory laparotomy was conducted, and a retention cyst was found on the left side, whereas histopathologic examination revealed a tube with peritubal fibrosis and a left ovary with cystic follicles, a corpus luteum, and a corpus albicans. Preoperative conditions included hypermenorrhea (77.42%), secondary dysmenorrhea (54.84%), pelvic pain (19.35%), polymenorrhea (12.9%), and increased abdominal volume (9.68%). Most patients reported more than 1 symptom. The mean hospitalization length ± SD was 5.68 ± 1.62 days. Histopathologic findings included 21 cases of leiomyomas (67.74%), 5 cases of adenomyosis (16.14%), 3 cases of diffuse uterine hypertrophy (9.67%), and 2 cases of a normal uterus (6.45%). Discussion Figure 2. Comparison between PI values for the left ovarian artery in women of reproductive age who underwent TAH (n = 31) and those of the control group (n = 30). Data are expressed as mean values ± SD. Figure 3. Comparison between volumes of the right ovary in women of reproductive age who underwent TAH (n = 31) and those of the control group (n = 30). Data are expressed as a box plot. Horizontal lines represent the median; squares represent 25th and 75th percentiles; and error bars represent 10th and 90th percentiles. The effects of TAH on ovarian function remain controversial. Some studies indicate that the prevalence of ovarian failure is higher in women who undergo TAH, 7,11,19 whereas others report no decrease in ovarian function. 10,20 The advance of menopause age after hysterectomy has been hypothesized to correlate with a rise in the follicular atresia rate. The uterus would inhibit follicle depletion, and its surgical removal at reproductive age would accelerate follicular loss, suggesting a paracrine effect of the uterus, endometrium, or both on ovarian function. 21 The other hypothesis, the increased prevalence of ovarian failure after hysterectomy, would result from the stretching of the vessels within the pelvic infundibulum, followed by thrombosis and a reduction in ovarian blood supply. 10,11,20 To investigate such hypotheses, this study aimed at assessing ovarian blood supply before and after surgery by Doppler ultrasonography of the ovarian arteries at the follicular phase of the menstrual cycle because flow is reduced and similar in both ovaries during this period. However, immediately before ovulation and over the initial luteal phase, perfusion is greater in the dominant ovary, and both PI values and vascular impedance are reduced. 12,13 The comparison of baseline PI values between groups revealed similarity. However, in the patients who underwent hysterectomy, mean PI values were significantly reduced in both left and right ovarian arteries at months 6 and 12, sug- 172 J Ultrasound Med 2005; 24:169 174

Petri Nahás et al gesting an increase in ovarian blood perfusion in comparison with the control group. This finding is not consistent with the hypothesis of reduced ovarian blood supply after TAH. To date, there is a shortage of studies on ovarian perfusion after hysterectomy as assessed by Doppler ultrasonography. In the only study available to our knowledge, the authors did not show any significant change in the RI of ovarian supply 6 months after surgery. 18 In this study, the mean baseline ovarian volume was 6.5 cm 3, in agreement with the literature. 22 Pavlik et al, 22 studying ovarian volume by transvaginal ultrasonography in 58,673 women aged 25 to 91 years, found that the upper limit of normal ovarian volume was 20 cm 3 for premenopausal women and 10 cm 3 for postmenopausal women. The mean volume was 6.1 cm 3 in women aged 30 to 39 years. These authors observed a significant reduction in ovarian volume with each decade. 22 In our investigation, a significant increase in ovarian volume was observed 6 and 12 months after TAH. Flow elevation, as shown by the reduction in the PI, is likely to reflect the larger size of the ovaries after the surgery. In the control group, ovaries remained unchanged throughout the study. In this investigation, 8 (25.5%) of 31 patients showed functional cysts on ultrasonography after 12 months of follow-up. Only 1 patient (3.2%) underwent exploratory laparotomy, which revealed adhesions and inclusion cysts. Residual ovary syndrome, which includes persistent pelvic mass, pain, and dyspareunia, has been reported by women who underwent TAH (prevalence range, 1% 3%) and reflects a possible ovarian dysfunction secondary to adhesions and perioophoritis, which interfere with the follicular development. 23 A sure diagnosis cannot be established unless postoophorectomy symptoms are resolved. The most common histopathologic findings are functional cysts of unknown physiopathologic nature, in more than 50% of cases. 1,24 These cysts frequently appear within the first postoperative year and, in most cases, are spontaneously resolved, as shown in this study. However, 5% to 8% of hysterectomized patients require subsequent surgeries for benign ovarian diseases. 3 Menon et al 25 reported that ovarian cysts were detected at ultrasonography in 18 (30%) of 60 cases, more frequently within the first year after surgery, with oophorectomy occurring in 5% of these cases. Figure 4. Comparison between volumes of the left ovary in women of reproductive age who underwent TAH (n = 31) and those of the control group (n = 30). Data are expressed as a box plot. Horizontal lines represent the median; squares represent the 25th and 75th percentiles; and error bars represent the 10th and 90th percentiles. Zalel et al, 26 in a prospective study, performed follow-up ultrasonographic examinations in 73 hysterectomized women at a mean age of 44.5 years over 4 years. They found ovarian cysts in 37 women (50.7%), from whom 4 were submitted to exploratory laparotomy. The most common histopathologic findings were paraovarian cysts (2 cases), cystoadenoma, and hydrosalpinx with periovarian adhesions. 26 Pete and Bõsze 27 observed cysts in 6 (9.2%) of 65 patients who underwent TAH, and 3 (4.6%) of 65 who underwent additional surgery within 3 years. On the basis of the results presented here, a reduction in the PI was verified, reflecting a decrease in the resistance flow in the ovarian arteries after hysterectomy, suggesting a possible increase in ovarian blood supply. This finding is not consistent with the assumption that a reduced blood supply is the only causative agent of ovarian failure after hysterectomy in women of reproductive age who undergo TAH. References 1. Dekel A, Efrat Z, Orvieto R, et al. The residual ovary syndrome: a 20-year experience. Eur J Obstet Gynecol Reprod Biol 1996; 68:159 164. 2. Fong YF, Lim FK, Arulkumaran S. Prophylactic oophorectomy: a continuing controversy. Obstet Gynecol Surv 1998; 53:493 499. J Ultrasound Med 2005; 24:169 174 173

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