Loss of ovarian reserve after uterine artery embolization: a randomized comparison with hysterectomy
1 Department of Gynaecology, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands 2 Department of Radiology, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands 3 Department of Gynaecology, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands 4 Department of Internal Medicine, Erasmus Medical Centre, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands 5 Department of Public Health Epidemiology, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
6 Correspondence address. Tel: +31-20-5663740; Fax: +31-20-5669119; E-mail: w.j.k.hehenkamp{at}amc.nl
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Abstract |
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BACKGROUND: Ovarian failure as a complication of uterine artery embolization (UAE) for symptomatic uterine fibroids has raised concerns about this new treatment modality.
METHODS: We investigated the occurrence of ovarian reserve reduction in a randomized trial comparing UAE and hysterectomy by measuring follicle stimulating hormone (FSH) and anti-Mullerian hormone (AMH). A total of 177 pre-menopausal women with menorrhagia due to uterine fibroids were included (UAE: n = 88; hysterectomy: n = 89). FSH and AMH were measured at baseline and at several time-points during the 24 months follow-up period. Follow-up AMH levels were also compared to the expected decrease due to ovarian ageing during the observational period.
RESULTS: FSH increased significantly compared to baseline in both groups after 24 months follow-up (within group analysis: UAE: + 12.1; P = 0.001; hysterectomy: + 16.3; P < 0.0001). No differences in FSH values between the groups were found (P = 0.32). At 24 months after treatment the number of patients with FSH levels > 40 IU/l was 14/80 in the UAE group and 17/73 in the hysterectomy group (relative risk = 0.75; P = 0.37). AMH was measured in 63 patients (UAE: n = 30; hysterectomy: n = 33). After treatment AMH levels remained significantly decreased during the entire follow-up period only in the UAE group compared to the expected AMH decrease due to ageing. No differences were observed between the groups.
CONCLUSIONS: This study shows that both UAE and hysterectomy affect ovarian reserve. This results in older women becoming menopausal after the intervention. Therefore, the application of UAE in women who still wish to conceive should only be considered after appropriate counselling.
Key words: anti-Müllerian hormone/hysterectomy/menopause/uterine artery embolization/ovarian reserve
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Introduction |
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Since its introduction in 1995 uterine artery embolization (UAE) has become increasingly popular for the treatment of fibroid-related menorrhagia (Ravina et al., 1995
). UAE has been proposed by some enthusiasts to replace hysterectomy altogether as a final solution for fibroid disease in selected patients. Safety and efficacy have been evaluated in several large case-series (McLucas et al., 2001; Spies et al., 2001; Walker and Pelage, 2002; Pron et al., 2003), but well designed randomized trials are lacking. Therefore, we initiated the randomized EMMY (EMbolization versus hysterectoMY) trial. Some short-term and long-term results of the EMMY trial have been published earlier (Hehenkamp et al., 2005, 2006a; Volkers et al., 2006a, 2006b).
Reduction of ovarian reserve after hysterectomy leading to (early) menopause has been described (Siddle et al., 1987; Kaiser et al., 1989; Derksen et al., 1998; Cooper and Thorp, 1999; Nahas et al., 2003; Chan et al., 2005). Since early menopause is associated with an increased risk for osteoporosis and cardiovascular disease (Kritz-Silverstein and Barrett-Connor, 1993; van der Schouw et al., 1996; Hu et al., 1999), UAE might provide a benefit. However, also after UAE the onset of menopause has been described (Chrisman et al., 2000; Stringer et al., 2000; Messina et al., 2002; Tulandi et al., 2002). The true incidence of persistent ovarian failure after UAE is unknown but has been estimated to be < 2% (Goodwin et al., 1999). No randomized controlled trials have focused on this subject. Permanent ovarian failure can be demonstrated by increased FSH and LH levels, increased menopausal symptoms and decreased estradiol (E2) levels, which all occur typically after the onset of menopause (Speroff and Fritz, 2005).
To test the extent of ovarian reserve reduction (i.e. loss of oocytes) FSH, LH, E2 and menopausal symptoms are of no use, since they only change or occurs after the actual onset of the menopausal transition (Soules et al., 2001; Speroff and Fritz, 2005). Ovarian reserve reduction can better be tested by measuring anti-Müllerian-hormone (AMH). AMH in women reaches its highest level after puberty (Hudson et al., 1990) and gradually decrease over time in normo-ovulatory women (de Vet et al., 2002). Furthermore AMH is cycle independent (Cook et al., 2000; Hehenkamp et al., 2006b). AMH has been acknowledged as being a reliable marker of ovarian reserve, especially in relation to the quantity of remaining follicles in the ovaries (van Rooij et al., 2002, 2004). To the best of our knowledge, relative damage to the ovaries has not been tested after both hysterectomy and UAE.
This report focuses on the occurrence of ovarian reserve reduction after UAE in comparison to hysterectomy as determined by clinical (i.e. menopausal symptoms) and hormonal markers (i.e. FSH, LH, E2 and AMH).
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Materials and Methods |
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Study design
The EMMY study is a multi-centre, randomized controlled trial, conducted in the Netherlands. A detailed description of the study has been provided earlier (Hehenkamp et al., 2005
) and will be discussed here only briefly. Patients were included when their predominant complaint was menorrhagia, they had uterine fibroids and were to be scheduled for hysterectomy. Patients who desired future pregnancy were excluded. After written informed consent had been obtained, computer-based randomization was carried out, assigning patients 1:1 to either UAE or hysterectomy.
The study was approved by the Central Committee Involving Human Subjects (www.ccmo.nl) and by the local ethics committees of all participating hospitals.
Procedures
Uterine artery embolization
UAE was performed by an interventional radiologist. For UAE, polyvinyl alcohol particles (PVA, Contour, Boston Scientific, Beek, The Netherlands) with a size of 355–500 µm were used. Only if an anastomosis with the ovarian artery was observed particles with a size of 500–700 µm were used to prevent migration of particles into the ovarian artery. PVA was injected into each uterine artery until there was no parenchyma filling of the fibroids anymore (target embolization) or until the main uterine artery was blocked and there was stasis of contrast (selective embolization). No embolization of ovarian arteries was carried out, because of the assumed high risk for ovarian damage. In case of extensive collaterals of the uterine artery to the cervix and vaginal wall, the procedure was stopped.
Hysterectomy
The type of hysterectomy and the route of access were left at the discretion of the attending gynaecologist. We did not establish consensus guidelines for concomitant adnexal surgery. If adnexa were removed, note was made.
Endpoints of the study
To assess the impact of both treatments on the menopausal transition FSH, LH and E2 were measured in both groups at baseline and at 6 weeks and 6, 12 and 24 months follow-up. Also menopausal symptoms were assessed at these time points, with an additional questionnaire at 18 months follow-up.
Impact of treatments on ovarian reserve was tested by measuring AMH at baseline and 1 day, 6 weeks and 6, 12 and 24 months after treatment. AMH was measured in a subset of patients for logistic reasons. These patients were recruited in the four hospitals (Academic Medical Centre, Amsterdam; Onze Lieve Vrouwe Gasthuis, Amsterdam; Universitary Medical Centre, Utrecht and Rijnstate hospital, Arnhem) that were expected to contribute the largest number of patients to the trial and that could reliably store the samples before collecting them for analysis in a central laboratory.
Comparisons were made between the groups at all time points and within the groups compared to baseline.
Blood sampling and laboratory assays
Blood samples were preferably taken on the 3 day of the menstrual cycle.
All blood samples were assayed for levels of FSH (Abbott, Bager, DPC and Roche), LH (Bayer, DPC and Rochc) and E2 (Abbott, Bager, DPC and Roche) using each hospital laboratory's own assay. Blood samples taken for measurement of AMH were allowed to clot, centrifuged, serum collected, frozen at – 20°C within 3 h and stored until assayed in a central laboratory. The samples were assayed in a number of consecutive assays during a short period after all samples had been collected (Laboratory for Internal Medicine, Erasmus Medical Centre) using an enzyme-immunometric assay (DSL Webster, TX, USA). Inter- and intra-assay coefficients of variation were below 5% at the level of 3 µg/l, and below 11% at the level of 13 µg/l. The detection limit of the assay was 0.026 µg/l. Repeated freezing and thawing of the samples or storage at 37°C for 1 h did not significantly affect results. A comparison of this assay with the ultrasensitive version of the assay method provided by Immunotech-Coulter (Marseilles, France) in 82 samples with AMH concentrations between 0 and 15 µg/l yielded a correlation coefficient of 0.85. The formula of the regression line was AMH (DSL) = 0.495 x AMH(ic) – 0.03. In order to keep results comparable with earlier published data, we multiplied all results by a factor 2.0 (van Rooij et al., 2002, 2004, 2005).
Questionnaires on menopausal transition status (Table 1)
Standardized questionnaires (Table 1) were used to measure menopausal symptoms: the Kupperman score (Kupperman et al., 1953), the Kupperman score as modified by Wiklund et al. (1992) and a score developed by Oldenhave et al. (1993) yielding 3D: vasomotor complaints, atypical symptoms and vaginal dryness.
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This resulted in scores ranging from 0–51 (original and modified Kupperman), 0–6 (vasomotor symptoms Oldenhave) and 0–63 (atypical symptoms Oldenhave). The Oldenhave vaginal dryness score reflects the weight of the individual score yielding a score ranging from 0 to 3. For all instruments higher scores represented more menopausal symptoms.
At the outpatient clinic visits (6 weeks and 6/12/24 months after treatment), UAE patients were asked if and when menstrual periods had resumed.
Statistical analysis
Outcomes were analysed according to the intention to treat principle unless stated otherwise. A P-value < 0.05 was considered statistically significant. Plots were constructed for average values of FSH, LH, E2, AMH and menopausal scores, using all available data at baseline, 6 weeks and at 6 months intervals after treatment (until 24 months). Missing values for laboratory results were not imputed. Both, within group and between group analysis was performed for all outcome parameters. For parametric data a Student's t-test was performed, while for non-parametric data a Mann–Whitney-U or a Wilcoxon test was used. Change from baseline was calculated for all visits after treatment. Differences between the groups were calculated by analysing change from baseline at 6 weeks and 6, 12 and 24 months. Longitudinal differences between groups were evaluated with repeated measurements analyses for all longitudinally available data (i.e. both for hormones and menopausal questionnaires).
FSH values were categorized for each outpatient visit (<10, 10–20, 20–30, 30–40 and > 40 IU/l). Logistic regression analysis was performed to assess the risk of the occurrence of menopause. Since menopausal status cannot be determined by absence of menstrual flow in hysterectomy patients, we used FSH levels in excess of 40 IU/l at 24 months follow-up to assess menopause (Speroff and Fritz, 2005). The normal mid-follicular FSH peak does not reach these levels, and therefore this threshold value was assumed to indicate persistent ovarian arrest. The following co-variables were included in the logistic regression, whenever univariate analysis revealed P-values < 0.1: intended treatment (UAE/hysterectomy), age at baseline (>/<45 years), ethnicity (Caucasian, black or other), body mass index (continuous), uterus volume (continuous), parity (parous/non-parous), smoking (yes/no), comorbidity (yes/no) and previous surgical treatment (yes/no). This analysis was repeated for both groups (UAE/hysterectomy) separately as well. In the hysterectomy group the following variables were added: type of hysterectomy (abdominal/not abdominal) and duration of hysterectomy (continuous); in the UAE group the following variables were added: unilateral selective UAE (yes/no), bilateral selective UAE (yes/no), number of required vials of PVA (continuous), presence of anastomozing vessels between uterine and ovarian arteries as detected at angiography, either unilateral (yes/no) or bilateral (yes/no) and secondary hysterectomy after UAE (yes/no).
The natural decrease of AMH was calculated according to an earlier report (van Rooij et al., 2005). Follow-up values of AMH measurements were compared to both baseline AMH values and the expected calculated AMH values. For AMH, a per-protocol analysis was performed to assess the exact impact of UAE on ovarian reserve: whenever a secondary hysterectomy was performed in the UAE group the subsequent AMH values were excluded from further analysis.
Subtle ovarian reserve reduction was explored by performing linear regression analysis with the change of AMH level (24 months AMH level minus baseline AMH level) as the dependent variable, with the same co-variables and the same procedure as the logistic regression analysis described above. For the questionnaires, the average individual score was used when only one question was missing. In case of > 1 question missing or when only the question on ‘hot flushes’ was missing, the whole score was excluded from analysis.
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Patients
Between March 2002 and February 2004, 177 patients (out of 349 eligible patients) agreed to participate in the study. A total of 88 patients were randomized to the UAE group and 89 patients to the hysterectomy group. In the UAE group, 81 patients underwent the allocated procedure compared to 75 in the hysterectomy group (Fig. 1). Baseline characteristics did not differ between both groups (Table 2). At randomization, two patients had a unilateral oophorectomy previously (both > 10 years ago). Their baseline FSH values were 6.0 and 8.5 IU/l. They were both randomized to the UAE group. In the UAE group, the procedure failed bilaterally in four cases. These patients subsequently had a hysterectomy, but were followed up in the UAE group (in the intention to treat analysis). In the follow-up period of 24 months, 15 additional patients had a secondary hysterectomy after UAE due to clinical failure (Volkers et al., 2006a
).
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UAE patients resumed having menstrual periods on average 24.4 days (SD: 24.4; median: 24; range: 0–172 days) after the procedure. Two patients did not have menstrual periods anymore after undergoing UAE.
Hormonal parameters
Figure 2 displays mean values (with 95% confidence intervals (CI)) of FSH, LH and E2 over time for each treatment. Pretreatment FSH measurements were not available for 3/75 hysterectomy patients. After treatment, FSH values increased in both groups, peaked at 6 weeks, decreased until 6 months and then increased again slowly until 24 months. FSH levels after treatment were consistently higher after hysterectomy than after UAE, but the repeated measurement analysis revealed no significant differences between the groups (FSH: P = 0.41; LH: P = 0.16; E2: P = 0.12). Table 3 lists average differences between baseline values for each group and estimates at 6 weeks and 6, 12, 24 months after treatment. In general, FSH increased significantly over time within the groups compared to baseline values (except for 6 months in the UAE group). LH increased significantly at all times within both groups. Average E2 levels increased significantly, except for 6 weeks after treatment in the UAE group. Table 4 lists number of patients by FSH levels, time and treatment group. No differences between the two groups were observed. FSH levels > 40 U/l at 24 months follow-up were observed in 14/80 (17.5%) UAE patients compared to 17/73 (23.3%) hysterectomy patients (relative risk = 0.75; 95% CI: 0.40–1.41; P = 0.37). Hormonal replacement therapy was used at 24 months follow-up by five women (three in UAE group and two in hysterectomy group).
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Multivariate logistic regression analysis on FSH > /< 40 IU/l revealed only age > 45 years at baseline (odds ratio: 4.46; 95% CI: 1.79–11.14; P = 0.001) to be significantly associated with FSH levels > 40 IU/l after treatment. Treatment allocation (UAE/hysterectomy) was not associated with this outcome (P = 0.38). Separate analyses per treatment group revealed no treatment-related variables to be predictive of ovarian failure (i.e. FSH > 40 IU/l).
Analysis of AMH was based on 63 included patients (30 UAE versus 33 hysterectomy) of whom pretreatment serum was available. The mean age of these 63 patients was not significantly different between the groups (UAE: 45.0; hysterectomy: 45.2; P = 0.84). The same applies to mean baseline FSH (UAE: 7.7 IU/l; hysterectomy: 7.9 IU/l; P = 0.95). None of the patients in either group had had a uni- or bilateral oophorectomy previously or during hysterectomy. In the UAE group 6 women (20%) had a secondary hysterectomy between 12 and 24 months follow-up. Only AMH values after the secondary hysterectomy were excluded from further analysis. Figure 3 displays means (with SE) of AMH values over time, together with the natural decrease of AMH as expected for the age-range of our patients. Follow-up samples were available for 61/63 (97%) patients (at 6 months), 60/63 (95%) patients (at 12 months) and 53/63 (84%) patients (at 24 months). In hysterectomy patients, mean AMH values decreased until 6 weeks after treatment. Between 6 weeks and 12 months the mean AMH values recovered to the expected (normal) values and remained that way until 24 months follow-up. Mean AMH values of UAE patients decreased initially with a slight recovery between 6 weeks and 6 months, but remained significantly under the expected value range until 24 months follow-up. Repeated measurements analysis revealed no differences between the groups.
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Table 3 displays mean change scores for AMH levels compared to baseline (except for the measurement 1 day after the procedure, which was only used for plotting purposes). AMH levels in the UAE group decreased significantly at all time points, both compared to baseline and compared to expected levels. In the hysterectomy group the change from baseline was only significant at 6 and 24 months (P = 0.010 and P = 0.027, respectively), while none of the observed values were significantly lower than the expected decrease. In the between group analysis, there was only a significant difference at 6 weeks (P = 0.005).
Univariate analysis on decrement of AMH 24 months after treatment revealed no variables to be predictive (all: P > 0.10). As demonstrated in Table 3 as well, treatment allocation was not associated with the outcome (P = 0.27).
Menopausal parameters
Baseline menopausal scores were not available for 11/81 (13.6%) UAE and 9/75 (12.0%) hysterectomy patients. Response rates to the follow-up questionnaire were 155/156 (99%, 6 weeks), 151/156 (97%, 6 months), 151/156 (97%, 12 months), 150/156 (96%, 18 months) and 154/156 (99%, 24 months), respectively.
In Fig. 4, the mean menopausal scores (95% CI) of both treatments are plotted over time for the Kupperman, Wiklund and Oldenhave (vasomotor, vaginal dryness and atypical symptoms) scores. Repeated measurement analysis revealed no differences between the groups (Kupperman: P = 0.65; Wiklund: P = 0.83; Oldenhave vasomotor: P = 0.63; Oldenhave vaginal dryness: 0.63 and Oldenhave atypical symptoms: P = 0.63). The baseline scores did not differ significantly between groups.
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Average differences with baseline values for each group at 6 weeks and 6, 12 and 24 months follow-up are listed in Table 3. Only the Oldenhave atypical symptoms at 12 months after treatment were significantly different between both groups.
Within group analysis revealed several significant changes compared to baseline (indicated by ‘*’ in Table 3). The Kupperman and Wiklund scores decreased the most, with significant changes in the short term. The Oldenhave vasomotor score was significantly increased in both groups at 24 months follow-up. Vaginal dryness was only significantly increased at 18 months follow-up in the hysterectomy group and atypical symptoms decreased significantly in both groups at all occasions.
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Discussion |
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The effect of UAE on the ovaries in comparison to hysterectomy has not been established earlier. Ovarian function after hysterectomy has been investigated extensively. Some studies have shown that hysterectomy affects the age at which the onset of menopause occurs (Siddle et al., 1987
) and that hysterectomy may increase the incidence of menopausal symptoms (Riedel et al., 1986; Menon et al., 1987; Oldenhave et al., 1993; Hartmann et al., 1995; Stadberg et al., 2000). Also, FSH and/or LH levels have been shown to increase significantly after hysterectomy (Kaiser et al., 1989; Derksen et al., 1998; Cooper and Thorp, 1999; Nahas et al., 2003; Chan et al., 2005) although others did not confirm these findings (Stone et al., 1975; Chalmers et al., 2002).
In contrast, the present knowledge on the effect upon ovarian function after UAE is limited, and derives mainly from case reports and small series. Permanent loss of ovarian function after UAE resulting in menopause has been reported in several studies (Chrisman et al., 2000; Stringer et al., 2000; Messina et al., 2002; Tulandi et al., 2002). This complication seems to occur mainly in women > 45 years of age (Chrisman et al., 2000; Spies et al., 2001). Transient ovarian failure has also been described (Amato and Roberts, 2001; Hascalik et al., 2004) but other studies did not show any untoward effects on ovarian function from UAE (Ahmad et al., 2002; Salomon et al., 2003; Descargues et al., 2004; Healey et al., 2004; Tropeano et al., 2004). Ovarian damage is thought to occur after UAE because of passage of embolization particles through anastomotic vessels between uterine and ovarian arteries, causing hypoxic ovarian damage and tissue loss (Tulandi et al., 2001). Indeed, it has been confirmed that embolization particles can be found at histopathologic examination of ovarian tissue after UAE (Payne et al., 2002). Furthermore, loss of ovarian perfusion, as demonstrated by sonographic assessment, directly after treatment in a substantial number of patients has been observed (Ryu et al., 2001).
In our study, very few differences in effect on ovarian reserve were found between UAE and hysterectomy: both treatments cause damage to the ovaries, as substantiated by a significant rise in FSH and LH serum levels. The drop in AMH levels immediately after treatment represents the loss of ovarian tissue, probably as a result of vascular compromise with ensuing ischaemia, either by inadvertent embolization of ovarian vasculature in UAE, or by compromising ovarian bloodflow by ligating anastomozing vessels during hysterectomy. Results of indicators of ovarian reserve tests tend to partially recover after both treatments, supporting earlier observations that ovarian failure may be transient (Amato and Roberts, 2001; Hascalik et al., 2004). After the (partial) recovery of ovarian function, the decrement is only significant after UAE when compared to the expected decrement due to ageing, thereby indicating that UAE might be even more harmful to ovarian reserve status than hysterectomy.
Multivariate regression analysis revealed that higher age (>45 years of age) predicted the occurrence of elevated, post-menopausal FSH values. This indicates that women with low ovarian reserve (older women and women with higher FSH values at baseline) are prone to develop a menopausal state. However, the decrease in AMH in the first 24 months, which was not correlated with age, indicates that every woman experiences loss of ovarian reserve. For older women with less ovarian reserve, this means that menopause is more likely to occur. For younger women, however, relative damage occurs, which does not result in menopause, but which might impair ovarian reserve and may affect future prospects of becoming pregnant. Although this damage may be missed altogether by low-sensitivity diagnostic tests, such as FSH measurements and by assessment of clinical signs and symptoms, analysis of AMH patterns, however, reveal its presence.
Reduction of ovarian reserve is of special importance when UAE is used in the treatment of women desiring future fertility, which is now still being discouraged (Tulandi et al., 2001; ACOG Committee Opinion 2004; Andrews et al., 2004; Hascalik et al., 2004). The impact on future fertility was not the scope of our trial, which excluded women with a desire for future pregnancy. Although UAE has been advocated by some to be used in women who do wish to conceive, our results discourage this view.
Our patients had no alternative other than hysterectomy, since other treatment options (i.e. medical therapy, endometrium ablation or myomectomy) were not possible or had already provided insufficient clinical results. Therefore, ovarian damage could not be avoided. With the proper indication, UAE might provide a suitable alternative for hysterectomy, since no differences in impact on ovarian reserve between the treatments were found. For patients with less severe fibroid-related complaints or patients with the desire for future fertility, one should keep in mind that ovarian damage may occur when UAE is undertaken, and might be avoided with other treatment choices.
In contrast to a rise in average FSH levels, no significant increase in menopausal symptoms was observed, except for the Oldenhave vasomotor symptoms. This is probably consistent with the absence of low E2 levels as found in the present study. In contrast, E2 levels increased, probably as a result of hyper-stimulation of the ovaries by elevated FSH values as found in our study (Speroff and Fritz, 2005).
A limitation of our study was the inability to obtain serum samples strictly at the 3 day of the menstrual cycle to obtain a standardized parameter for ovarian reserve (Scott et al., 1989). This standardization was sometimes impossible because of permanent vaginal blood loss prior to the intervention, absence of menstrual bleeding in post-hysterectomy patients or irregular menstrual cycles. Therefore average FSH values might be higher by inclusion of mid-cycle samples. However, FSH values normally do not reach the threshold level we used as indicator of menopause (i.e. > 40 IU/l, Speroff and Fritz, 2005).
Furthermore, we did not have a control group for the occurrence of ovarian ageing over time. However, AMH values in both groups dropped dramatically immediately after treatment in comparison to the normal (expected) decrease of AMH for our patients' age group (Fig. 3). This indicates instant ovarian damage that may have been caused by demise of the follicle cohort responsible for the AMH levels. The mechanism of (partial) recovery of the AMH levels thereafter may be attributed to restoration of the follicle cohort from the primordial follicle pool. However, since AMH levels do not reach the expected level over time for the UAE group, it may be suggested that the primordial pool has also suffered irreparable damage in this group.
Furthermore, our study population was relatively old compared to the population of women who have a desire for future pregnancy. The occurrence of a significant and permanent drop in AMH levels in the UAE group might be different in a younger age group, i.e. the age group of particular interest when desire for future fertility is at stake. We encourage future studies to address these matters.
In conclusion, both UAE and hysterectomy affect ovarian reserve. No differences between treatments on ovarian function were observed, however. Especially when future pregnancy is desired, UAE should only be offered after appropriate counselling.
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Acknowledgements |
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We would like to thank all participating patients, EMMY-trial group members, nurses and other contributors who made the trial possible. We thank M. Nuberg, H. van Welsum and M. Cornet for their administrative efforts. The EMMY-trial participants and hospitals: J. Reekers, W. Ankum, M. Burger, G. Bonsel, Erwin Birnie, W. Hehenkamp and N. Volkers (Academic Medical Center, Amsterdam); S. de Blok and C. de Vries (Onze Lieve Vrouwe Gasthuis, Amsterdam); T. Salemans and G. Veldhuyzen van Zanten (Atrium Medical Centre, Heerlen); D. Tinga and T. Prins (Groningen University Hospital, Groningen); P. Sleyvers and M. Rutten (Bosch Medical Centre, Den Bosch); M. Smeets and N. Aarts (Bronovo Hospital, The Hague); P. van der Moer and D. Vroegindeweij (Medical Centre Rijnmond-Zuid, Rotterdam); F. Boekkooi and L. Lampmann (St. Elisabeth Hospital, Tilburg); G. Kleiverda, (Flevo Hospital, Almere); R. Dik and J. Marsman (Gooi-Noord Hospital, Laren); C. de Nooijer, I. Hendriks and G. Guit (Kennemer Gasthuis, Haarlem); H. Ottervanger and H. van Overhagen, (Leyenburg Hospital, The Hague); A. Thurkow (St. Lucas/Andreas Hospital, Amsterdam); P. Donderwinkel and C. Holt (Martini Hospital, Groningen); A. Adriaanse and J. Wallis, (Medical Center Alkmaar, Alkmaar); J. Hirdes, J. Schutte and W. de Rhoter (Medical Center Leeuwarden, Leeuwarden); P. Paaymans and R. Schepers-Bok (Hospital Midden-Twente, Hengelo); G. van Doorn, J. Krabbe and A. Huisman, (Medisch Spectrum Twente, Enschede); M. Hermans and R. Dallinga (Reinier de Graaf Gasthuis, Delft); F. Reijnders and J. Spithoven, (Slingeland Hospital, Doetichem); W. de Jager and P. Veekmans, (St. Jans Gasthuis, Weert); P. van der Heijden, M. Veereschild and J. van den Hout, (Twenteborg Hospital, Almelo); I. van Seumeren, A. Heinz, R. Lo and W. Mali (University Hospital Utrecht, Utrecht); J. Lind and Th. de Rooy (Westeinde Hospital, The Hague); M. Bulstra and F. Sanders (Diakonessenhuis Utrecht, Utrecht); J. Doornbos (De Heel Hospital, Zaandam); P. Dijkhuizen and M. van Kints (Rijnstate Hospital, Arnhem) and Ph. Engelen and R. Heijboer (Slotervaart Hospital, Amsterdam).
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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ACOG Committee Opinion. Uterine artery embolization. Obstet Gynecol (2004) 103:403–404.[Medline]
Ahmad A, Qadan L, Hassan N, Najarian K. Uterine artery embolization treatment of uterine fibroids: effect on ovarian function in younger women. J Vasc Interv Radiol (2002) 13:1017–1020.[Web of Science][Medline]
Amato P, Roberts AC. Transient ovarian failure: a complication of uterine artery embolization. Fertil Steril (2001) 75:438–439.[CrossRef][Web of Science][Medline]
Andrews RT, Spies JB, Sacks D, Worthington-Kirsch RL, Niedzwiecki GA, Marx MV, Hovsepian DM, Miller DL, Siskin GP, Raabe RD, et al. Patient care and uterine artery embolization for leiomyomata. J Vasc Interv Radiol (2004) 15:115–120.[Web of Science][Medline]
Chalmers C, Lindsay M, Usher D, Warner P, Evans D, Ferguson M. Hysterectomy and ovarian function: levels of follicle stimulating hormone and incidence of menopausal symptoms are not affected by hysterectomy in women under age 45 years. Climacteric (2002) 5:366–373.[Web of Science][Medline]
Chan CC, Ng EH, Ho PC. Ovarian changes after abdominal hysterectomy for benign conditions. J Soc Gynecol Investig (2005) 12:54–57.[Web of Science]
Chrisman HB, Saker MB, Ryu RK, Nemcek AA Jr, Gerbie MV, Milad MP, Smith SJ, Sewall LE, Omary RA, Vogelzang RL. The impact of uterine fibroid embolization on resumption of menses and ovarian function. J Vasc Interv Radiol (2000) 11:699–703.[Web of Science][Medline]
Cook CL, Siow Y, Taylor S, Fallat ME. Serum mullerian-inhibiting substance levels during normal menstrual cycles. Fertil Steril (2000) 73:859–861.[CrossRef][Web of Science][Medline]
Cooper GS, Thorp JM Jr. FSH levels in relation to hysterectomy and to unilateral oophorectomy. Obstet Gynecol (1999) 94:969–972.[CrossRef][Web of Science][Medline]
de Vet A, Laven JS, de Jong FH, Themmen AP, Fauser BC. Antimullerian hormone serum levels: a putative marker for ovarian aging. Fertil Steril (2002) 77:357–362.[CrossRef][Web of Science][Medline]
Derksen JG, Brolmann HA, Wiegerinck MA, Vader HL, Heintz AP. The effect of hysterectomy and endometrial ablation on follicle stimulating hormone (FSH) levels up to 1 year after surgery. Maturitas (1998) 29:133–138.[CrossRef][Web of Science][Medline]
Descargues G, Mauger TF, Douvrin F, Clavier E, Lemoine JP, Marpeau L. Menses, fertility and pregnancy after arterial embolization for the control of postpartum haemorrhage. Hum Reprod (2004) 19:339–343.
Goodwin SC, McLucas B, Lee M, Chen G, Perrella R, Vedantham S, Muir S, Lai A, Sayre JW, DeLeon M. Uterine artery embolization for the treatment of uterine leiomyomata midterm results. J Vasc Interv Radiol (1999) 10:1159–1165.[Web of Science][Medline]
Hartmann BW, Kirchengast S, Albrecht A, Metka M, Huber JC. Hysterectomy increases the symptomatology of postmenopausal syndrome. Gynecol Endocrinol (1995) 9:247–252.[Web of Science][Medline]
Hascalik S, Celik O, Sarac K, Hascalik M. Transient ovarian failure: a rare complication of uterine fibroid embolization. Acta Obstet Gynecol Scand (2004) 83:682–685.[CrossRef][Web of Science][Medline]
Healey S, Buzaglo K, Seti L, Valenti D, Tulandi T. Ovarian function after uterine artery embolization and hysterectomy. J Am Assoc Gynecol Laparosc (2004) 11:348–352.[CrossRef][Web of Science][Medline]
Hehenkamp WJ, Volkers NA, Birnie E, Reekers JA, Ankum WM. Pain and return to daily activities after uterine artery embolization and hysterectomy in the treatment of symptomatic uterine fibroids: results from the randomized EMMY trial. Cardiovasc Intervent Radiol (2006a) 29:179–187.[CrossRef][Web of Science][Medline]
Hehenkamp WJ, Looman CW, Themmen AP, de Jong FH, te Velde ER, Broekmans FJ. Anti-Mullerian hormone levels is in the spontaneous menstrual cycle do not show substantial fluctuation. J Clin Endocrinol Metab (2006b) 91:4057–4063.
Hehenkamp WJ, Volkers NA, Donderwinkel PF, De Blok S, Birnie E, Ankum WM, Reekers JA. Uterine artery embolization versus hysterectomy in the treatment of symptomatic uterine fibroids (EMMY trial): peri- and postprocedural results from a randomized controlled trial. Am J Obstet Gynecol (2005) 193:1618–1629.[CrossRef][Web of Science][Medline]
Hu FB, Grodstein F, Hennekens CH, Colditz GA, Johnson M, Manson JE, Rosner B, Stampfer MJ. Age at natural menopause and risk of cardiovascular disease. Arch Intern Med (1999) 159:1061–1066.
Hudson PL, Dougas I, Donahoe PK, Cate RL, Epstein J, Pepinsky RB, MacLaughlin DT. An immunoassay to detect human Mullerian inhibiting substance in males and females during normal development. J Clin Endocrinol Metab (1990) 70:16–22.
Kaiser R, Kusche M, Wurz H. Hormone levels in women after hysterectomy. Arch Gynecol Obstet (1989) 244:169–173.[CrossRef][Web of Science][Medline]
Kritz-Silverstein D, Barrett-Connor E. Early menopause, number of reproductive years, and bone mineral density in postmenopausal women. Am J Public Health. 83:983–988.
Kupperman HS, Blatt MH, Wiesbader H, Filler W. Comparative clinical evaluation of estrogenic preparations by the menopausal and amenorrheal indices. J Clin Endocrinol Metab (1953) 13:688–703.
McLucas B, Adler L, Perrella R. Uterine fibroid embolization: nonsurgical treatment for symptomatic fibroids. J Am Coll Surg (2001) 192:95–105.[CrossRef][Web of Science][Medline]
Menon RK, Okonofua FE, Agnew JE, Thomas M, Bell J, O'Brien PM, Dandona P. Endocrine and metabolic effects of simple hysterectomy. Int J Gynaecol Obstet (1987) 25:459–463.[CrossRef][Medline]
Messina ML, Bozzini N, Halbe HW, Pinotti JA. Uterine artery embolization for the treatment of uterine leiomyomata. Int J Gynaecol Obstet (2002) 79:11–16.[CrossRef][Medline]
Nahas E, Pontes A, Traiman P, Nahas-Neto J, Dalben I, De Luca L. Inhibin B and ovarian function after total abdominal hysterectomy in women of reproductive age. Gynecol Endocrinol (2003) 17:125–131.[Web of Science][Medline]
Oldenhave A, Jaszmann LJ, Everaerd WT, Haspels AA. Hysterectomized women with ovarian conservation report more severe climacteric complaints than do normal climacteric women of similar age. Am J Obstet Gynecol (1993b) 168:765–771.[Web of Science][Medline]
Payne JF, Robboy SJ, Haney AF. Embolic microspheres within ovarian arterial vasculature after uterine artery embolization. Obstet Gynecol (2002) 100:883–886.[CrossRef][Web of Science][Medline]
Pron G, Cohen M, Soucie J, Garvin G, Vanderburgh L, Bell S. The Ontario uterine fibroid embolization trial. Part 1. Baseline patient characteristics, fibroid burden, and impact on life. Fertil Steril (2003) 79:112–119.[CrossRef][Web of Science][Medline]
Ravina JH, Herbreteau D, Ciraru-Vigneron N, Bouret JM, Houdart E, Aymard A, Merland JJ. Arterial embolisation to treat uterine myomata. Lancet (1995) 346:671–672.[CrossRef][Web of Science][Medline]
Riedel HH, Lehmann-Willenbrock E, Semm K. Ovarian failure phenomena after hysterectomy. J Reprod Med (1986) 31:597–600.[Web of Science][Medline]
Ryu RK, Chrisman HB, Omary RA, Miljkovic S, Nemcek AA Jr, Saker MB, Resnick S, Carr J, Vogelzang RL. The vascular impact of uterine artery embolization: prospective sonographic assessment of ovarian arterial circulation. J Vasc Interv Radiol (2001) 12:1071–1074.[Web of Science][Medline]
Salomon LJ, De Tayrac R, Castaigne-Meary V, Audibert F, Musset D, Ciorascu R, Frydman R, Fernandez H. Fertility and pregnancy outcome following pelvic arterial embolization for severe post-partum haemorrhage. A cohort study. Hum Reprod (2003) 18:849–852.
Scott RT, Toner JP, Muasher SJ, Oehninger S, Robinson S, Rosenwaks Z. Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertil Steril (1989) 51:651–654.[Web of Science][Medline]
Siddle N, Sarrel P, Whitehead M. The effect of hysterectomy on the age at ovarian failure: identification of a subgroup of women with premature loss of ovarian function and literature review. Fertil Steril (1987) 47:94–100.[Web of Science][Medline]
Soules MR, Sherman S, Parrott E, Rebar R, Santoro N, Utian W, Woods N. Executive summary: stages of reproductive aging workshop (STRAW). Fertil Steril (2001) 76:874–878.[CrossRef][Medline]
Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility (2005) 7th edn. Wilkins: Philadelphia: Lippincott Williams &.
Spies JB, Ascher SA, Roth AR, Kim J, Levy EB, Gomez-Jorge J. Uterine artery embolization for leiomyomata. Obstet Gynecol (2001) 98:29–34.[CrossRef][Web of Science][Medline]
Spies JB, Roth AR, Gonsalves SM, Murphy-Skrzyniarz KM. Ovarian function after uterine artery embolization for leiomyomata: assessment with use of serum follicle stimulating hormone assay. J Vasc Interv Radiol (2001) 12:437–442.[Web of Science][Medline]
Stadberg E, Mattsson LA, Milsom I. Factors associated with climacteric symptoms and the use of hormone replacement therapy. Acta Obstet Gynecol Scand (2000) 79:286–292.[CrossRef][Web of Science][Medline]
Stone SC, Dickey RP, Mickal A. The acute effect of hysterectomy on ovarian function. Am J Obstet Gynecol (1975) 121:193–197.[Web of Science][Medline]
Stringer NH, Grant T, Park J, Oldham L. Ovarian failure after uterine artery embolization for treatment of myomas. J Am Assoc Gynecol Laparosc (2000) 7:395–400.[CrossRef][Web of Science][Medline]
Tropeano G, Di Stasi C, Litwicka K, Romano D, Draisci G, Mancuso S. Uterine artery embolization for fibroids does not have adverse effects on ovarian reserve in regularly cycling women younger than 40 years. Fertil Steril (2004) 81:1055–1061.[CrossRef][Web of Science][Medline]
Tulandi T, Sammour A, Valenti D, Child TJ, Seti L, Tan SL. Ovarian reserve after uterine artery embolization for leiomyomata. Fertil Steril (2002) 78:197–198.[CrossRef][Web of Science][Medline]
Tulandi T, Sammour A, Valenti D, Stein L. Images in endoscopy: uterine artery embolization and utero-ovarian collateral. J Am Assoc Gynecol Laparosc (2001) 8:474.[CrossRef][Web of Science][Medline]
van der Schouw YT, van der GY, Steyerberg EW, Eijkemans JC, Banga JD. Age at menopause as a risk factor for cardiovascular mortality. Lancet (1996) 347:714–718.[CrossRef][Web of Science][Medline]
van Rooij IA, Broekmans FJ, Scheffer GJ, Looman CW, Habbema JD, de Jong FH, Fauser BJ, Themmen AP, te Velde ER. Serum antimullerian hormone levels best reflect the reproductive decline with age in normal women with proven fertility: a longitudinal study. Fertil Steril (2005) 83:979–987.[CrossRef][Web of Science][Medline]
van Rooij IA, Broekmans FJ, te Velde ER, Fauser BC, Bancsi LF, de Jong FH, Themmen AP. Serum anti-Mullerian hormone levels: a novel measure of ovarian reserve. Hum Reprod (2002) 17:3065–3071.
van Rooij IA, Tonkelaar I, Broekmans FJ, Looman CW, Scheffer GJ, de Jong FH, Themmen AP, te Velde ER. Anti-Mullerian hormone is a promising predictor for the occurrence of the menopausal transition. Menopause (2004) 11:601–606.[CrossRef][Medline]
Volkers NA, Hehenkamp WJ, Birnie E, Ankum WM, Reekers JA. Uterine artery embolization versus hysterectomy in the treatment of symptomatic uterine fibroids: two-years' outcome from the randomized EMMY trial. In: Am J Obstet Gynecol (2006a) in press.
Volkers NA, Hehenkamp WJ, Birnie E, de Vries C, Holt C, Ankum WM, Reekers JA. Uterine artery embolization in the treatment of symptomatic uterine fibroid tumors (EMMY trial): periprocedural results and complications. J Vasc Interv Radiol (2006bl) 17:471–480.[CrossRef][Web of Science][Medline]
Walker WJ, Pelage JP. Uterine artery embolisation for symptomatic fibroids: clinical results in 400 women with imaging follow up. BJOG (2002) 109:1262–1272.[Web of Science][Medline]
Wiklund I, Holst J, Karlberg J, Mattsson LA, Samsioe G, Sandin K, Uvebrant M, von Schoultz SB. A new methodological approach to the evaluation of quality of life in postmenopausal women. Maturitas (1992) 14:211–224.[CrossRef][Web of Science][Medline]
Submitted on December 20, 2006; resubmitted on March 21, 2007; accepted on April 2, 2007.
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