| | Amenorrhea and resumption of menstruation after uterine artery embolization for fibroidsReceived 9 June 2008; received in revised form 7 July 2008; accepted 24 July 2008. published online 03 September 2008. Abstract ObjectivesTo determine whether women will experience permanent amenorrhea following uterine artery embolization for fibroids, and whether rates of onset differ in the long term according to age at the time of the procedure. ResultsThe likelihood of incurring permanent amenorrhea was significantly higher in group C. The cumulative rates in groups A, B, and C were 0%, 1.4%, and 19.7% at 3 years and 0%, 11.2%, and 40.4% at 6 years. ConclusionThe rates of onset of permanent amenorrhea changed over time and differed according to age at the time of the procedure, with little likelihood of permanent amenorrhea at 6 years for women younger than 40 years at the time of the procedure. 1. Introduction  Uterine artery embolization has gained popularity as an alternative to major surgery for symptomatic fibroids [1], [2], [3], [4], [5], [6], [7], [8]. This minimally invasive treatment can provide durable symptom control, apparently with few serious complications in most patients, although premature ovarian failure has been reported as one possible complication [9], [10]. It is not known, however, whether adverse events related to the procedure may develop in the long term. In its 2004 guidelines for the improvement of uterine artery embolization, the Society of Interventional Radiology defined premature ovarian failure as the presence of amenorrhea, elevated follicle-stimulating hormone levels, and menopausal symptoms. It also estimated the rates of transient amenorrhea to range from 5% to 10%, and those of permanent amenorrhea to range from 0% to 3% in women younger than 45 years and from 7% to 14% in women older than 45 years [11]. These estimates were based on reports published in the short and medium term (range, several months to 2 years following embolization) [1], [2], [3], [4]. To our knowledge, there have been few publications on rates of onset of permanent amenorrhea in the long term (up to 5 years following embolization) and their association with age at the time of the procedure [7], [8]. Both patients and physicians need to know whether uterine artery embolization may be associated with early permanent amenorrhea. The purpose of this study was to determine whether the rates of onset of permanent amenorrhea change over time and whether they differ according to age at the time of uterine artery embolization for symptomatic fibroids. 2. Patients and methods This retrospective study used a prospectively acquired database concerning 211 consecutive women who underwent uterine artery embolization for symptomatic uterine fibroids at our hospital over 77 months, from December 1997 to May 2004. All data were collected in June 2007. The procedure had been performed between 3 and 4 years previously in 37 patients, between 4 and 5 years previously in 49 patients, between 5 and 6 previously in 62 patients, between 6 and 7 years previously in 36 patients, between 7 and 8 years previously in 23 patients, and more than 8 years previously in 4 patients. All women were Asian, premenopausal, and their mean ±SD age was 42.8±4.1 years (range, 31–53 years). Twenty-four women (11%) had previously undergone myomectomy, 73 (35%) had received gonadotropin-releasing hormone agonists, and 10 (5%) had taken birth control pills. Of the 211 patients, 183 had no interest in a future pregnancy at the time of embolization. In principle, we did not perform the procedure in women who desired a future pregnancy because the data on fertility after embolization were insufficient. Nevertheless, we performed it in 28 of these women because they absolutely refused to undergo major surgery or because, in the opinion of their gynecologists, there was no treatment option for them other than hysterectomy or a difficult myomectomy. None of the patients were amenorrheic before the procedure although 4 (1.9%) were experiencing menopausal symptoms such as hot flashes, night sweats, mood swings, and/or vaginal dryness. These 4 patients were older than 45 years (range, 47–53 years). All women gave oral and written informed consent. The institutional ethics committee approved the study. The axial and sagittal views of the pelvis obtained by magnetic resistance imaging for each patient before the procedure were prospectively reviewed by experienced radiologists. The mean±SD volume of the largest tumor was 323±327 mL (range, 4–1972 mL), the mean uterine volume was 903±531 mL (range, 151–2790 mL), and the mean number of fibroids 1 cm or larger was 6.1±5.7 (range, 1–32). Uterine artery embolization was performed by the unilateral femoral approach using local anesthesia, as previously described [8]. A microcatheter was used in all but 4 patients. The embolic agent consisted of gelatin sponge particles of approximately 500 to 1000 μm, which the operator snipped from gelatin sponge sheets (Yamanouchi, Tokyo, Japan) using a scalpel and small scissors. The angiographic endpoint was complete or near stasis in the ascending uterine artery. We routinely invited the patients for followed-up visits 1 week, 4 months, and 1 year after the procedure. After 1 year, if the patients experienced fibroid- or embolization-related problems, they were followed up as necessary. We also instructed the patients to inform us of any adverse reaction that may occur. We inquired about menstrual status, menopausal symptoms, and such conditions as menorrhagia, pain during menstruation, and bulk-related symptoms before the embolization. After the embolization, at 4 months, 1 year, and then annually, the women answered in writing a serial questionnaire inquiring whether they had been menstruating; and if they had been amenorrheic, inquiring for how long, and how many consecutive cycles they had missed since they answered the previous questionnaire. It also inquired whether they had undergone any additional gynecologic interventions such as hysterectomy, myomectomy, hysteroscopic treatment, dilation and curettage, angiography, or embolization since they answered the previous questionnaire. If a patient responded affirmatively, we did not send her any more questionnaires because the treatment could affect the onset of amenorrhea. However, the patient's menstrual status at that time was considered to be that indicated on the previous questionnaire. The patients were defined as lost to follow-up when a questionnaire remained unanswered. We considered these patients to be censored at this point, and their responses to the previous questionnaire were considered to indicate their status at the time they were censored. The patients who underwent hormonal treatment after embolization were censored for the same reason, and their responses to the previous questionnaire were considered to indicate their status at the time they were censored. We divided the women into 3 groups according to their age at the time of embolization. Group A consisted of women of younger than 40 years, group B of women between 40 and 44 years, and group C of women aged of 45 years or older. An absence of menstruation after embolization was evidenced from answers to the serial questionnaire and routine or unanticipated hospital visits. Permanent amenorrhea was defined as amenorrhea occurring after the embolization, with menstruation not resuming for 12 or more months. Age at onset of permanent amenorrhea was assessed for each group. The cumulative rates of onset of permanent amenorrhea were then assessed for each group, and compared among the groups using the Kaplan-Meier product limit method on the basis of the answers to the questionnaire or unanticipated hospital visits. The log-rank test was used for the statistical evaluation of each group. P<0.05 was considered significant. 3. Results Table 1 shows baseline characteristics for each group. Bilateral uterine artery embolization was successfully performed in 208 (99%) of the 211 patients. Catheterization of the access uterine artery failed in 2 patients, and the remaining patient had no contralateral uterine artery. No embolization of the ovarian artery was performed. | | |  | Characteristic | Group A(n=39) | Group B(n=98) | Group C(n=74) | |
|---|
| Patient age, y | 36.6±2.2 | 42.0±1.4 | 47.1±2.1 | | | No. of patients with a previous fibroid surgery | 8 (21) | 9 (9) | 7 (9) | | | Volume of dominant fibroid, mL | 361±454 | 327±302 | 299±276 | | | No. of fibroids | 7.2±6.8 | 5.7±5.4 | 6.2±5.5 | | | Uterine volume, mL | 983±689 | 872±464 | 902±523 | | | Menorrhagia | 33 (85) | 79 (81) | 63 (85) | | | Pain during menstruation | 13 (33) | 26 (27) | 20 (27) | | | Bulk-related symptoms | 27 (69) | 76 (78) | 61 (82) | | | Follow-up duration, mo | 45.3±23.6 | 44.6±23.3 | 44.0±21.4 | | | No. of patients lost to follow-up | 9 (23) | 32 (33) | 23 (31) | | | No. of patients who had additional treatment | 8 (21) | 7 (7) | 4 (5) | | | | |
The mean follow-up time was 44.5 months (range, 0.5–84 months); 64 (30.3%) of the 211 original patients were lost to follow-up, 24 at 1 year, 18 at 2 years, 6 at 3 years, 11 at 4 years, and 5 at 5 years. Moreover, 23 patients underwent the following additional gynecologic interventions: 10 of whom hysterectomy (n=10), myomectomy (n=3), hysteroscopic treatment (n=9), and dilatation and curettage (n=1), and another 2 patients underwent hormonal treatment after embolization. In groups A, B, and C, respectively, the cumulative rates of onset of permanent amenorrhea were 0%, 0%, and 4.1% at 1 year; 0%, 1.4%, and 19.7% at 3 years; 0%, 1.4%, and 25.5% at 4 years; 0%, 3.1%, and 25.5% at 5 years; and 0%, 11.2%, and 40.4% at 6 years (Fig. 1). The rates of onset of permanent amenorrhea were significantly lower in groups A and B than in group C (P=0.002 and P=0.001, respectively), and the difference between groups A and B was not significant (P=0.09). In group B, 6 (9%) of 66 patients who completed the follow-up experienced permanent amenorrhea whereas 60 (91%) did not. In group C, 15 (29%) of 51 patients who completed the follow-up developed permanent amenorrhea whereas 36 (71%) did not. Table 2 shows age at onset of permanent amenorrhea in each group. | | | | | Group A | Group B | Group C | |
|---|
| Mean age, y | NA | 47.5±1.5 | 49.9±2.4 | | | Range, y | NA | 45–49 | 46–54 | | | | |
4. Discussion In this study, the cumulative rates of onset of permanent amenorrhea increased over time for women aged 40 years or older at the time of the embolization (groups B and C), but there was no onset of permanent amenorrhea after up to 6 years of follow-up in women who were younger than 40 years at the time of the procedure (group A). These results suggest that the cumulative rates of onset of permanent amenorrhea change over time for women who undergo uterine artery embolization for symptomatic fibroids, and that these rates differ in the long term according to age at the time the procedure. We feel that these results can contribute to predicting the possibility of the onset of permanent amenorrhea in the long term in women undergoing embolization—a useful information for patients who must provide informed consent to the procedure and its follow-up. We calculated the cumulative rates of onset of permanent amenorrhea after embolization using the Kaplan-Meier product limit method rather than crude rates because we accounted for the patients lost to follow-up, for those who underwent further gynecologic intervention after embolization, for the duration of follow-up for each patient, and for the distribution of amenorrhea onset over time [8], [12]. Although 64 (30.3%) of the 211 original patients were lost to follow-up, we believe the Kaplan-Meier product limit method to be suitable to measure cumulative rates of onset of permanent amenorrhea after embolization over time and compare them among groups. Spies et al. [7] reported 42 of 181 women experienced permanent amenorrheas 5 years after embolization with polyvinyl alcohol particles, for a crude rate of amenorrhea of 23%. The mean age at the time of embolization was 46.0 years and the mean age at first report of amenorrhea was 50.0 years. These results are likely to be similar to the results of the present study, in which the cumulative rates of onset of permanent amenorrhea were 25.5% at 5 years in women 45 years or older at the time of embolization (mean age, 47.1 years), and the mean age at permanent amenorrhea onset in this group was 49.9 years. On the basis of hormone levels, ovarian volume, and antral follicular number after embolization, Tropeano et al. [13] concluded that the procedure had no short-term effect (up to 12 months) on ovarian reserve in women younger than 40 years. We did not assess hormone level and anatomical changes in ovaries over time in the present study, but our results might have corroborated those of Tropeano et al. [13] because we documented no onset of permanent amenorrhea, which would have indicated ovarian failure, up to 6 years after embolization. Although there are reports that permanent amenorrhea can occur in women younger than 40 years [4], [5], [6], [7], it did not occur in any woman in that age group in our study. In a study by Chrisman et al. [10] that included laboratory assessments, ovarian failure occurred in 9 (43%) of 21 women 45 years or older, but in none of 45 younger women, during a follow-up ranging from 12 to 77 weeks (mean, 21 weeks). We did not perform laboratory assessments in the present study, but women 45 years or older had significantly higher rates of onset of permanent amenorrhea, which is a sign of ovarian failure, than younger women. The mean age at menopause has been estimated at 51 years in the general population [14]. In the present study, the mean age at onset of permanent amenorrhea was 47.5 years in group B and 49.9 years in group C. These values, however, only concerned the women who experienced permanent amenorrhea, not the entire groups, and therefore cannot be compared with the value for a general population. Therefore, larger detailed studies allowing for a much longer follow-up time after embolization are required to determine the actual mean age at permanent amenorrhea onset in different age groups. We divided patients into 3 groups on the basis of age at baseline. Forty years was chosen for the first threshold because it was reported that ovarian follicle loss begins to increase after the age of 30 years, and that 40 years corresponds to a border between normal and decreased ovarian capacity [13], [15], [16], [17]. The next threshold, 45 years, was chosen because it was reported that women aged 45 years or older had a higher incidence of increased levels of follicle stimulating hormone and ovarian failure than younger women after embolization [10], [11]. There are several limitations to our study. First, permanent amenorrhea onset after embolization was determined on the basis of a serial questionnaire in the course of a long-term follow-up. However, we did not assess menopausal symptoms and had no available laboratory data such as serum levels of follicle-stimulating hormone, luteinizing hormone, and estradiol, and therefore had no proof of ovarian failure or menopause; besides, we did not assess ovarian volume and antral follicle number before or after the procedure, and therefore could not determine the effect of embolization on ovarian reserve. Second, we only investigated whether menstruation was present or absent after embolization, but not changes in cycle length, duration of flow, and menstrual blood loss over time. Third, we used gelatin sponge particles as the embolic agent. Although our results seemed similar to those of other authors, who mostly use nonspherical polyvinyl alcohol particles [7], it is possible that other embolic agents (eg, tris-acryl gelatin microspheres or spherical polyvinyl alcohol) were used in some of the other studies, and produced different outcomes. Fourth, permanent amenorrhea occurs by virtue of aging and/or by the influence of embolization. Therefore, in this study designed with a long-term follow-up, we could not determine whether each onset of permanent amenorrhea after embolization was caused by aging, by the influence of embolization, or by both. We conclude that the rates of onset of permanent amenorrhea change over time after embolization, and that they differ by age at the time of embolization. Moreover, we suggest that there is little likelihood of permanent amenorrhea onset, at least up to 6 years after the procedure, in women younger than 40 years at baseline. References [1]. 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Department of Radiology, Saiseikai Shiga Hospital, Ritto, Shiga, Japan  Corresponding author. Department of Radiology, Saiseikai Shiga Hospital, Ohashi 2-4-1, Ritto-city, Shiga, 520-3046, Japan. Tel.: +81 775 521221; fax: +81 775 53 8259.
PII: S0020-7292(08)00337-8 doi:10.1016/j.ijgo.2008.07.010 © 2008 Elsevier Inc. All rights reserved. | |
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