Long-term effects of uterine fibroid embolization on ovarian reserve: a prospective cohort study

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1 Long-term effects of uterine fibroid embolization on ovarian reserve: a prospective cohort study Giovanna Tropeano, M.D., a Carmine Di Stasi, M.D., b Sonia Amoroso, M.D., a Maria Rosaria Gualano, M.D., c Lorenzo Bonomo, M.D., b and Giovanni Scambia, M.D. a a Department of Obstetrics and Gynecology, b Department of Radiology, and c Epidemiology and Biostatistics Unit, Institute of Hygiene, Universita Cattolica del Sacro Cuore, Rome, Italy Objective: To determine whether uterine fibroid embolization may advance ovarian follicular depletion in reproductive-aged women with apparently normal baseline ovarian function. Design: Prospective cohort study. Setting: University tertiary care center. Participant(s): Thirty-six patients aged 26 to 39 years with fibroids, regular menstrual cycles, and day 3 serum FSH levels <10 miu/ml and 36 matched control women. Intervention(s): Day 3 serum FSH and E 2 levels and ultrasound-based antral follicle count and ovarian volume were determined before (baseline) and at 12, 24, 36, 48, and 60 months after embolization and compared with those of the control group. Menstrual status was determined annually on the basis of prospectively recorded menstrual calendars. Main Outcome Measure(s): Longitudinal changes in hormone levels, ultrasound measures, and bleeding patterns. Result(s): Although the FSH and E 2 levels increased significantly and the antral follicle count and ovarian volume values declined significantly over time within the groups, no significant differences were found between the groups. The cycle remained regular in all but two women (one in the embolization group and one in the control group), who started having cycle irregularity after 24 months and 36 months follow-up, respectively. Conclusion(s): This long-term follow-up study suggests that fibroid embolization does not lead to an accelerated decline in ovarian reserve in younger patients. (Fertil Steril Ò 2010;94: Ó2010 by American Society for Reproductive Medicine.) Key Words: Uterine fibroid embolization, ovarian reserve In recent years, uterine artery embolization has emerged as a safe, effective, and durable alternative to hysterectomy and myomectomy for treating symptomatic uterine fibroids (1 8). However, transient or permanent ovarian failure has been described after uterine artery embolization in up to 5% of women (9 11). Most of these cases have been in patients over the age of 45 years, but there have been anecdotal reports of ovarian dysfunction in younger women (5 7, 12, 13). The most likely cause is believed to be nontarget ovarian embolization via the utero-ovarian collaterals (14), causing hypoxic ovarian damage and loss of ovarian follicles (13, 15 17). It remains unknown, however, whether this is a sporadic event or whether there might be a generalized effect of uterine artery embolization on ovarian function that is more likely to be apparent in perimenopausal women, who have an already diminished follicle reserve. For younger patients with a full follicle complement the likelihood of immediate alterations in menstrual cyclicity and hormone levels would be less, but relative damage from uterine artery embolization might compromise subsequent ovarian function and even cause ovarian failure at an earlier age than would otherwise occur (17, 18). Received September 23, 2009; revised November 30, 2009; accepted December 1, 2009; published online January 13, G.T. has nothing to disclose. C.D.S. has nothing to disclose. S.A. has nothing to disclose. M.R.G. has nothing to disclose. L.B. has nothing to disclose. G.S. has nothing to disclose. Reprint requests: Giovanna Tropeano, M.D., Department of Obstetrics and Gynecology, Universita Cattolica del Sacro Cuore, Largo Gemelli 8, Rome, Italy (FAX: ; giovanna. tropeano@rm.unicatt.it). So far, however, data concerning the ovarian impact of uterine artery embolization are limited and inconsistent (13, 16, 18 21). In particular, because for most of the reported cases of ovarian dysfunction in younger patients, no detailed information on baseline ovarian function was given (2, 6, 12), a causal connection with the procedure remains uncertain. Previously, in a prospective study of regularly cycling patients younger than 40 years who underwent uterine artery embolization, we found no change in ovarian reserve, as assessed by cycle day 3 (basal) serum FSH and E 2 levels and ultrasound-based ovarian volume and antral follicle count, up to 12 months after treatment (22). It could be argued, however, that in such women it might take more than 12 months for subtle damage to become identifiable on conventional ovarian reserve parameters. This previous study was the beginning of a continuing longitudinal study concerning ovarian function after uterine artery embolization. This present study was designed to determine whether uterine artery embolization may advance ovarian follicular depletion and even the time of ovarian failure in younger patients with apparently normal baseline ovarian function. To this end, we performed a 5-year follow-up comparative study using a matched cohort design in which hormonal (basal serum FSH and E 2 levels), ultrasound (antral follicle count and ovarian volume), and clinical markers (menstrual cycle length) were used concurrently to evaluate the ovarian impact of uterine artery embolization. MATERIALS AND METHODS Between December 2000 and December 2003, 36 white women with symptomatic fibroids were recruited consecutively among patients presenting for 2296 Fertility and Sterility â Vol. 94, No. 6, November /$36.00 Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert

2 uterine artery embolization at our institution. Details of our uterine artery embolization protocol have been provided earlier (22, 23). In brief, patients were considered suitable for treatment if they had symptoms sufficiently severe to warrant hysterectomy or myomectomy and wished to avoid surgery. Because of the uncertain effects of uterine artery embolization on fertility, our protocol excluded women desiring future pregnancy unless hysterectomy was their only remaining option. Inclusion criteria for this study were [1] age <40 years, [2] regular (21 35 days) menstrual cycles, [3] normal ovarian reserve, as indicated by basal FSH levels <10 IU/L and E 2 levels <75 pg/ml, [4] no history of ovarian surgery or ovarian abnormalities, [5] no history of infertility, ovulatory dysfunction, or other endocrine disorders, [6] no hormonal therapy in the 3 months preceding the enrollment, and [7] no history of smoking. All patients underwent uterine artery embolization within 10 days of menstruation. All procedures were performed by one interventional radiologist in a standardized fashion. Polyvinyl alcohol particles (Contour; Boston Scientific/Target Therapeutics, Fremont, CA) sized 355 to 500 mm were used in all cases. Only if an anastomosis with the ovarian artery was observed, 500- to 700-mm polyvinyl alcohol particles were used to prevent migration of particles into the ovarian artery. The embolization endpoint was occlusion of the perifibroid plexus, with sluggish flow remaining in the main uterine artery. No ovarian arteries were embolized. Postprocedural care and follow-up protocol have been described previously (22). As a control group, 36 healthy volunteers meeting the aforementioned inclusion criteria were recruited over the same period from our family planning clinic and matched by race, age (1 year), body mass index (BMI) (1 kg/ m 2 ), and parity (1 with matched pair; no previous miscarriage) to women undergoing uterine artery embolization. The study was approved by the local Institutional Review Board, and written informed consent was obtained from all participants. Ovarian Reserve Testing On day 3 of the cycle preceding uterine artery embolization and on day 3 of the cycle occurring 12, 24, 36, 48, and 60 months after uterine artery embolization, patients underwent blood sampling for hormone measurements and transvaginal ultrasound examination. Similarly, control women underwent blood sampling and transvaginal ultrasound examination on day 3 of a spontaneous cycle occurring within 60 days of recruitment and then at the same intervals as patients having uterine artery embolization throughout the study period. Height and weight were measured for BMI calculation at these time points. Furthermore, at each assessment, study participants were provided menstrual calendars and asked to record the menstrual dates over the next 12 months. Cycle irregularity was defined as any change in cycle length R7 days from the subject s personal baseline that occurred for at least two cycles over 12 months (24). Follow-up evaluation was discontinued if a woman in a matched pair became pregnant, began using any type of hormone therapy, underwent uterine or ovarian surgery, or was lost to follow-up. Blood samples for hormone measurements were centrifuged and frozen in aliquots at 20 C until assayed. Assays were performed by the local laboratory using commercially available immunoassay kits (22). The sensitivity of the FSH assay (Advia-Centaur; Bayer Diagnostics, Tarrytown, NY) was 0.3 IU/L, and the E 2 assay (Elecsys; Roche Diagnostics, Indianapolis, IN) was 5 pg/ml. The interassay and intra-assay coefficients of variation were 1.7% and 2.4% and 3.1% and 3.8%, respectively. All ultrasound examinations were performed by one examiner with Esaote Technos equipment (Esaote, Genova, Italy) using a 5.0- to 9.0-MHz transvaginal probe. Round or oval echo-free structures in each ovary were regarded as follicles, and all follicles up to 5 mm were counted. The volume of each ovary was calculated by measuring the three perpendicular diameters and applying the prolate ellipsoid formula (25). Volumes and follicle numbers of both ovaries were added for the total ovarian volume and antral follicle count. Statistical Analysis Data were analyzed with SPSS 12.0 for Windows (SPSS, Inc., Chicago, IL) and presented as mean (SD). Plots were constructed for mean FSH, E 2, antral follicle count, ovarian volume, and cycle length values using all available data at baseline and at each follow-up interval. Longitudinal differences between groups were evaluated with repeated-measures ANOVA. The results of Pillai s test were considered. Within-group comparisons were performed at all time points compared with baseline with use of the paired Student s t-test. P values <.05 were considered statistically significant. RESULTS All patients had technically successful bilateral uterine artery embolization. All resumed menses on average 21.0 days (range, days) after embolization. Over the study period, 6 women (two women in the uterine artery embolization group and four control women) became pregnant, 6 women (three per group) began using hormonal contraception, 1 woman who had uterine artery embolization underwent myomectomy for symptom recurrence, and 3 controls were lost to followup. Therefore, of the 36 pairs of women initially recruited, 36 were studied at baseline and at 12 months, 29 were studied at 24 months, 23 were studied at 36 months, and 20 were studied at 48 and 60 months. As expected by matching, at baseline there were no differences between groups in mean age, BMI, parity, cycle length, hormone levels, or ultrasound measures (Table 1). Similarly, at 60 months follow-up, there were no differences between groups in TABLE 1 Baseline characteristics of women undergoing uterine artery embolization and control women. Characteristic a Women undergoing uterine artery embolization (n [ 36) Control women (n [ 36) Age (y) Parity (No.) BMI (kg/m 2 ) Menstrual cycle length (d) FSH (IU/L) E 2 (pg/ml) Antral follicle count (No.) Ovarian volume (cm 3 ) Note: Values are expressed as means SD. a No significant differences for any parameter between women having uterine artery embolization and control women. Fertility and Sterility â 2297

3 age (uterine artery embolization, years; controls, years, P¼.66) or BMI (uterine artery embolization, kg/m 2 ; controls, kg/m 2, P¼.37). Figure 1 displays mean FSH and E 2 levels over time for each group. Longitudinal changes in FSH did not differ between groups (ANOVA, P¼.19), even though a significant FSH increase from baseline to the 60-month assessment occurred within both groups (uterine artery embolization, from IU/L to IU/L; controls, from IU/L to IU/L, P<.001). Within-group analysis revealed no substantial change from baseline until the 12-month control (uterine artery embolization, from IU/L to IU/L, P¼.23; controls, from IU/L to IU/L, P¼.52). Subsequently, there was progressive FSH increase, which reached statistical significance at 36 months in both uterine artery embolization (P¼.02) and control (P<.001) groups. In the uterine artery embolization group, there were three women whose FSH level increased to >10 IU/L over time. Of these, one was aged 38 years and the others were aged 39 years at baseline. The increase was observed first at 36 months in one patient and at 48 months in the other two patients. Levels of FSH >10 IU/L also were observed at 48 months in two control women, who were both 39 years old at baseline. Longitudinal changes in mean E 2 did not differ between groups (ANOVA, P¼.92). There was progressive increase in E 2, which reached statistical significance at 60 months in uterine artery embolization (from pg/ml to pg/ml, P¼.011) and at 48 months in control women (from pg/ml to pg/ml, P¼.041). Longitudinal changes in mean antral follicle count and ovarian volume (Fig. 2) did not differ between groups (antral follicle count: P¼.75, and ovarian volume: P¼.098 at Pillai s test). Within-group analysis showed a decline in antral follicle count and ovarian volume over time, which reached statistical significance at 60 months in both women having uterine artery embolization (antral follicle count, from to , P¼.008; ovarian volume, from cm 3 to cm 3, P¼.004) and control women (antral follicle count, from to , P<.001; ovarian volume, from cm 3 to cm 3, P¼.003). Table 2 summarizes longitudinal changes in cycle length. Although both groups showed progressive cycle lengthening, there was no difference between groups (ANOVA, P¼.49). The cycle remained regular in all but two women (one who had uterine artery embolization and one control woman) who started having cycle irregularity after the 24-month and the 36-month follow-up, respectively. These two women were aged 38 and 39 years, respectively, at baseline. No woman had amenorrhea or menopausal symptoms (i.e., vasomotor symptoms, night sweats, or vaginal dryness) throughout the study. FIGURE 1 Mean ( SD) values of basal serum FSH and E 2 before (baseline) and at 12, 24, 36, 48, and 60 months after uterine artery embolization in patients (open bars) and paired control women (closed bars). The numbers below the graph represent the pairs of women who were studied at each time point. FIGURE 2 Mean ( SD) values of antral follicle count (AFC) and ovarian volume (OV) before (baseline) and at 12, 24, 36, 48, and 60 months after uterine artery embolization in patients (open bars) and paired control women (closed bars). The numbers below the graph represent the pairs of women who were studied at each time point Tropeano et al. Ovarian reserve after uterine fibroid embolization Vol. 94, No. 6, November 2010

4 TABLE 2 Menstrual cycle length at baseline and at 12, 24, 36, 48, and 60 months follow-up in women who underwent uterine artery embolization and paired control women. Cycle length a Women undergoing uterine artery embolization Control women Baseline (n ¼ 36) mo (n ¼ 36) mo (n ¼ 29) mo (n ¼ 23) mo (n ¼ 20) mo (n ¼ 20) Note: The numbers in parentheses represent the pairs of women who were evaluated at each time point. Values are expressed as mean SD. a No significant differences at any time point between women having uterine artery embolization and control women. DISCUSSION Because uterine artery embolization is gaining widespread acceptance as a viable treatment option for fibroids, understanding its effects on subsequent ovarian function becomes increasingly relevant. In this study we performed a long-term evaluation of ovarian function after uterine artery embolization in a longitudinal prospective comparison cohort. To assess the impact of uterine artery embolization, we serially measured before and up to 5 years after treatment a combination of hormonal and ultrasound parameters that currently are used as prognostic indicators of ovarian reserve in infertile women (26 29) and determined longitudinal changes in cycle length, which is a known marker of reproductive aging (24, 30). The rationale for this approach was that, because there is no single tool currently available to assess ovarian reserve fully (31, 32), the combined use of more markers could improve the ability to identify even subtle damage induced by uterine artery embolization. We used matched pairs of women with strict inclusion criteria to avoid confounding factors potentially correlated with functional ovarian status. We focused on women aged <40 years because the rate of follicular depletion with age (ovarian aging) is known to accelerate markedly in the late 30s (33, 34), and 40 years of age seems to best dichotomize premenopausal women with normal and diminished ovarian capacity (35 37). Additionally, to minimize potential bias due to the known interindividual variability in the rate of ovarian aging (36 38), we only included regularly menstruating women who had normal basal FSH and E 2 levels. The hypothesis that our study set out to explore that uterine artery embolization may hasten ovarian failure led us to predict that, compared with controls, women having uterine artery embolization will show different patterns of longitudinal changes in ovarian reserve markers and will be more likely to enter menopausal transition (cycle irregularity) or become menopausal within a 5-year period. Our data do not support the hypothesis. First, we found no remarkable changes in any ovarian reserve marker up to 12 months after uterine artery embolization, which confirms our previous observations and those from other series with short-term followup (range, 3 6 months) (16, 19 21). Second, the changes in ovarian reserve markers observed after 12 months were similar for cases and controls, which indicated their lack of biologic relationship with uterine artery embolization. Finally, during the study period patients having uterine artery embolization did not appear to be more likely than controls to have cycle irregularity or other symptoms (e.g., hot flashes) suggestive of entry into the menopausal transition (30). Because it seems unlikely that even subtle damage from uterine artery embolization would not alter ovarian reserve test results and/or cycle characteristics within several years, our findings strongly suggest that uterine artery embolization did not affect ovarian reserve adversely in our study population. To our knowledge, this is the first study to report prospective data on the long-term ovarian impact of uterine artery embolization on younger patients and compare them with appropriate matched-paired control women. Our results are in contrast to those of a published randomized trial comparing uterine artery embolization and hysterectomy (18). In this study, both treatments were found to affect ovarian reserve, as measured by FSH and antim ullerian hormone levels before and up to 2 years after treatment (18). The discrepancy between these findings and ours could be accounted for to some extent by differences in population demographics. Although the age range of the patients in that trial was not given, the reported mean age (44.6 years for patients having uterine artery embolization and 45.4 years for patients having a hysterectomy) implies that the population was substantially older than that we studied (18). Because the data were not stratified by age, the impact of this factor on the observed changes in hormone levels remains unknown. The reliability of data from that trial also is hampered by a number of study design limitations, including the lack of detailed data on baseline ovarian function, the inability to obtain serum samples strictly on cycle day 3 to obtain a standardized measure of ovarian reserve, and the lack of a control group for the occurrence of ovarian aging with time (18). With regard to bleeding patterns after uterine artery embolization, our data are consistent with those from a recent retrospective study of 211 patients by Katsumori et al. (39). These authors found that the rate of onset of permanent amenorrhea increased over time for women aged R40 years at the time of embolization, but there was no onset of permanent amenorrhea after up to 6 years follow-up in women <40 years old at the time of uterine artery embolization (39). There are two potential limitations of this study. First, given the relative infrequency that uterine artery embolization is performed in younger women, the sample size was relatively small, which could be a source of a type II error in our analysis. Second, although cases and controls were accurately matched for factors known to influence ovarian status (i.e., age, race, parity, BMI, smoking status), one can never be certain that they were similar in all respects. In conclusion, this long-term follow-up study failed to show an accelerated decline in ovarian reserve after uterine artery embolization for fibroids in young women with apparently normal baseline Fertility and Sterility â 2299

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