GYNAECOLOGY
Laparoscopic Myomectomy Versus Uterine Artery Embolization: Long-Term Impact on Markers of Ovarian Reserve Rebecca Arthur, MD, MSc, FRCSC,1,3 John Kachura, MD, FRCPC,2,4 Grace Liu, MD, MSc, FRCSC, FaCOG,1,5 Crystal Chan, MD, MSc, FRCSC,1,3 Heather Shapiro, MD, FRCSC1,3 Department of Obstetrics and Gynaecology, University of Toronto, Toronto ON
1
Department of Medical Imaging, University of Toronto, Toronto ON
2
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, Toronto ON
3
Division of Vascular and Interventional Radiology, Department of Medical Imaging, Mount Sinai Hospital, Toronto ON
4
Department of Obstetrics and Gynaecology, Sunnybrook Health Sciences Centre, Toronto ON
5
Abstract Objective: To compare the relative long-term effects on ovarian reserve of treating fibroids in reproductive-aged women with uterine artery embolization (UAE) versus laparoscopic myomectomy (LM), using sensitive measures including antral follicle count (AFC) and serum anti-Müllerian hormone (AMH). Methods: We undertook a retrospective cohort pilot study to evaluate the utility and feasibility of carrying out a larger prospective trial. Thirteen women were evaluated in this study, including eight in the UAE group and five in the LM group. They were identified from a larger group of 125 women who had undergone LM and 200 women who had undergone UAE at a participating institution at least 12 months previously; of these, 32 who had UAE and 27 who had LM were of reproductive age and eligible to participate. Participants had an assessment of ovarian reserve including measurements of serum AMH, estradiol, and FSH, and ultrasound assessment of AFC and ovarian volume. Results: Median serum AMH levels were significantly lower in women who had undergone UAE at least 12 months previously than in women who had undergone LM (0.78 ng/mL [range 0.67 to 1.28] vs. 2.17 ng/mL [range 1.17 to 2.38], P = 0.01). Median AFC per ovary was also significantly lower in women who had UAE than in those who had LM (3.5 [range 2 to 7] vs. 7 [range 6 to 11], P = 0.03). Median levels of FSH and E2 and of ovarian volume were not significantly different between the two groups.
Key Words: Uterine artery embolization, laparoscopic myomectomy, fibroid, myoma, ovarian reserve, AMH, antral follicle count Competing Interests: None declared. Received on September 14, 2013 Accepted on November 15, 2013
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Conclusion: Reproductive-aged women who have undergone treatment of fibroids with UAE may have lower ovarian reserve over the long term (> 12 months) than women with fibroids treated with LM. This could have an adverse impact on future response to fertility treatment and/or fecundity. This finding may inform the choice of minimally invasive treatment for fibroids in reproductiveaged women who have not completed childbearing. It suggests that further study in this area is warranted before the application of UAE is expanded to young reproductive-aged women.
Résumé Objectif : Comparer, chez des femmes en âge de procréer, la prise en charge de fibromes par embolisation de l’artère utérine (EAU) à leur prise en charge au moyen d’une myomectomie par laparoscopie (ML), pour ce qui est des effets relatifs à long terme sur la réserve ovarienne (déterminés au moyen de mesures sensibles, dont la numération des follicules antraux [NFA] et le taux sérique d’hormone antimüllérienne [HAM]). Méthodes : Nous avons mené une étude de cohorte rétrospective pilote afin d’évaluer l’utilité et la faisabilité de mener un essai prospectif de plus grande envergure. Treize femmes ont été évaluées dans le cadre de cette étude (huit dans le groupe EAU et cinq dans le groupe ML). Elles ont été identifiées à partir d’un groupe plus étendu comprenant 125 femmes qui avaient subi une ML et 200 femmes qui avaient subi une EAU au sein d’un établissement participant au moins 12 mois au préalable; de ces femmes, 32 de celles qui avaient subi une EAU et 27 de celles qui avaient subi une ML étaient en âge de procréer et admissibles à l’étude. Les participantes ont été soumises à une évaluation de leur réserve ovarienne (mesures des taux sériques d’HAM, d’estradiol et de FSH, et évaluation échographique de la NFA et du volume ovarien). Résultats : Les taux sériques médians d’HAM étaient considérablement moins élevés chez les femmes qui avaient subi une EAU au moins 12 mois au préalable que chez les femmes
Laparoscopic Myomectomy Versus Uterine Artery Embolization: Long-Term Impact on Markers of Ovarian Reserve
qui avaient subi une ML (0,78 ng/ml [plage : 0,67 - 1,28] vs 2,17 ng/ml [plage : 1,17 - 2,38], P = 0,01). La NFA médiane par ovaire était également considérablement moins élevée chez les femmes qui avaient subi une EAU que chez celles qui avaient subi une ML (3,5 [plage : 2 - 7] vs 7 [plage : 6 - 11], P = 0,03). Le volume ovarien et les taux médians de FSH et d’E2 n’étaient pas considérablement différents d’un groupe à l’autre. Conclusion : Les femmes en âge de procréer qui ont fait l’objet d’une EAU visant la prise en charge de leurs fibromes pourraient présenter, à long terme (> 12 mois), une réserve ovarienne moins élevée que celle des femmes ayant vu leurs fibromes être pris en charge au moyen d’une ML, ce qui pourrait exercer un effet indésirable sur la fertilité et/ou sur la réaction à de futurs traitements de procréation assistée. Cette constatation pourrait éclairer la décision quant au recours à un traitement à effraction minimale pour assurer la prise en charge des fibromes chez les femmes en âge de procréer qui souhaitent encore connaître une ou des grossesses. Elle laisse également entendre que la tenue d’autres études dans ce domaine s’avère justifiée avant que le recours à l’EAU ne soit élargi aux jeunes femmes en âge de procréer.
J Obstet Gynaecol Can 2014;36(3):240–247
INTRODUCTION
U
terine fibroids affect 50% to 80% of reproductiveaged women1 and can lead to significant morbidity including menorrhagia, infertility, and mass-effect symptoms. In reproductive-aged women wishing to retain fertility, symptomatic fibroids have traditionally been excised through abdominal myomectomy. The abdominal incision required for this surgery, however, leads to a significant hospital stay and recovery period.2 This has led to the development of less invasive alternatives. One such approach is laparoscopic myomectomy.2 By avoiding a laparotomy incision, this approach allows for a short recovery period.3 In addition to a shorter hospital stay and recovery period, decreased blood loss and decreased postoperative adhesions in comparison to abdominal myomectomy have been shown in case series.4 Uterine artery embolization is another less invasive approach for the treatment of uterine fibroids. It is a safe and effective treatment in which a catheter inserted through the common femoral artery is used to deliver
ABBREVIATIONS AFC
antral follicle count
AMH
anti-Müllerian hormone
E2
estradiol-17β
FSH
follicle stimulating hormone
LM
laparoscopic myomectomy
UAE
uterine artery embolization
particles to obstruct blood supply through the uterine artery, resulting in ischemia and regression of fibroids.5,6 Although UAE is less invasive than surgical treatments and also results in a shorter recovery period,7,8 it is generally only recommended in reproductive-aged women who do not want to preserve fertility.7,9 However, numerous case studies have described pregnancies with reassuring outcomes occurring after UAE. This has led to increasing acceptance of performing UAE in reproductive-aged women, perhaps even in women for whom childbearing is not complete.6,10,11 When contemplating the best course of treatment for uterine fibroids in reproductive-aged women, it is important to consider the potential impact of each of the procedures on ovarian reserve, because ovarian dysfunction can lead to accelerated onset of menopause and diminished fertility. UAE may adversely affect the ovaries because of the anatomy of the pelvic blood vessels and the collateral blood supply of the uterus.12 It is also possible that LM could affect ovarian function via inadvertent interruption of the ovarian blood supply or through direct ovarian injury. The term “ovarian reserve” refers to the number and quality of remaining oocytes in the ovaries and reflects remaining reproductive capacity. When ovarian reserve is decreased in reproductive-aged women, it can lead to a diminished response to ovarian stimulation with fertility treatments and potentially to decreased fecundity.13 Ovarian reserve cannot be directly measured but can be estimated with hormone assays and ultrasound measurements. The most common traditional measures include assays of serum follicle stimulating hormone and estradiol-17β and ultrasound measurement of ovarian volume, performed on the third day of menstruation.14–16 However, these measurements are often affected only in cases of severe compromise.13,17 More sensitive measurements include day three antral follicle counts using transvaginal ultrasound and serum anti-Müllerian hormone levels, both of which are more closely correlated with ovarian follicle number and responsiveness to fertility treatment than the more traditional parameters.13,17,18 To begin to address the impact of various approaches to treatment for fibroids on ovarian reserve, we performed a retrospective cohort pilot study to compare the relative long-term effect on ovarian reserve of treating fibroids in reproductive-aged women with uterine artery embolization or with laparoscopic myomectomy. To our knowledge, this is the first study to compare these approaches directly using sensitive measures, including both AFC and AMH, to evaluate ovarian reserve following either procedure in women of reproductive age. MARCH JOGC MARS 2014 l 241
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METHODS
We conducted this retrospective cohort pilot study to evaluate the utility and feasibility of carrying out a larger scale prospective trial. It was conducted at two universityaffiliated hospitals in the department of obstetrics and gynaecology at one site and of interventional radiology at the other. Markers of ovarian reserve (serum FSH, serum E2, serum AMH, ovarian volume, and AFC) were assessed and compared between reproductive-aged women who had previously undergone either UAE or LM for the treatment of fibroids at least 12 months previously. Eligible women were between 20 and 43 years of age at the time of the study and had undergone either LM or UAE at one of the study institutions at least 12 months before the study date. Potential participants were contacted initially by mail and then by follow-up telephone call. Subjects were excluded if they had undergone any additional intervention to treat their fibroids, either before or after the UAE or LM procedure of interest. They were also excluded if they had ever had any ovarian surgery. All study subjects gave informed consent for their participation. Study participants were asked to undergo a one-time assessment of ovarian reserve involving ultrasound and blood parameters in the early follicular phase of their menstrual cycle. They were also asked to complete a questionnaire to confirm personal characteristics and inclusion/exclusion criteria information. All serum measurements were performed in one laboratory using the same assays performed in a single run. AMH levels were measured via ELISA with the Gen II assay (Beckman Coulter Canada, Mississauga ON). The detection limit was 0.14 ng/mL. FSH and E2 were measured using electrochemiluminescence immunoassays (Roche Diagnostics, Laval QC). The minimum detection range for E2 was 18.4 pmol/L and for FSH was 0.100 IU/L. Ultrasound was performed by experienced ultrasonographers who were blinded to the study group. AFC was defined as the total number of visible follicles in each ovary measuring between 2 and 10 mm. Ovarian volume was calculated using the prolate ellipsoid formula (L × H × W × 0.523) after measuring each ovary in three dimensions. AFC and ovarian volume were assessed in each ovary to account for possible differential impacts on each ovary from uterine artery catheterization/occlusion on the ipsilateral side and to minimize possible masking of any such effect by the contralateral side. In cases in which an ovary could not be visualized, the result was recorded 242 l MARCH JOGC MARS 2014
as “non-visible.” If cysts were noted, the dimensions were measured, the volumes were calculated, and cyst characteristics were described. Uterine Artery Embolization Technique
Procedures were performed in a similar fashion by one of three experienced interventional radiologists at a single institution. Patients received antibiotic prophylaxis and medication for pain control during the procedure. A 4 French vascular sheath was inserted into the right common femoral artery using aseptic Seldinger technique19 and local anaesthesia and was advanced in retrograde fashion. A 4 French C2 Glidecath and a .035 angled Glidewire (Terumo Medical Corp., Somerset NJ) were used to select the left common and internal iliac arteries. The left uterine artery was embolized at its proximal ascending segment beyond the cervicovaginal branch to near-complete occlusion using Cook polyvinyl alcohol foam particles of 300 to 500 μm (Cook Medical Inc., Bloomington IN). A Waltman loop20 was then formed over the aortic bifurcation and removed after the right common and internal iliac arteries were selected. The right uterine artery was selected to its proximal ascending segment and embolized in the same fashion. Patients were admitted to hospital overnight following the procedure for pain control using a morphine patient-controlled analgesia pump. Laparoscopic Myomectomy Technique
All laparoscopic myomectomy procedures were performed by a single experienced surgeon at one institution. Fibroid mapping via transvaginal ultrasound and sonohysterogram was performed preoperatively to document fibroid size and location and to exclude any submucosal fibroids. Patients did not receive preoperative treatment with GnRH agonists. A vasopressin solution was injected into the serosa and myometrium overlying the fibroid to decrease bleeding. A horizontal incision was performed with sparing use of unipolar cautery through the serosa and myometrium to the level of the fibroid. Fibroids were enucleated along the cleavage plane with great care to avoid the endometrial cavity and to avoid manipulation of the cornua or fallopian tubes. The myometrial defect was closed with interrupted sutures in layers via laparoscopic suturing. The excised fibroids were removed with an electrical morcellator. The serosa was closed with a continuous baseball stitch, and a barrier agent of oxidized regenerated cellulose was placed on the uterine incisions. Patients were admitted to hospital for monitoring overnight and were discharged on the next day. A chart review was performed to gather information about the outcomes of LM and UAE procedures. The UAE procedure was considered to be successful if it resulted in complete bilateral peripheral uterine artery occlusion at the
Laparoscopic Myomectomy Versus Uterine Artery Embolization: Long-Term Impact on Markers of Ovarian Reserve
end of the procedure. The LM procedure was considered successful if all fibroids of 2 cm diameter or larger were removed completely. Complications were defined as severe pain not reacting to standard pain control, blood loss requiring transfusion, groin hematoma, injury to abdominal organs other than uterus, conversion to laparotomy, large vessel injury, reoperation for hemoperitoneum, prolonged hospitalization (> 1 night), readmission to hospital, and infection. The primary endpoints of the study were differences between the two groups in median AMH and median antral follicle count. The secondary endpoints included differences in median serum levels of FSH and E2 and median ovarian volume. These parameters were measured for each participant on a single day in the early follicular phase (menstrual cycle day 2, 3, or 4). A Mann-Whitney U test was used to compare the two groups with respect to AMH, AFC, FSH, E2, and ovarian volume data, as well as participant characteristics. This test was chosen because of the small sample size of the study, as it does not assume a normal distribution of data and corrects for variance. To minimize the impact of any outliers in this small sample, the endpoint data are reported as medians ± standard error. Patient characteristics are reported as means ± standard deviation. Differences were considered to be statistically significant if P 0.05). All patients in both groups had procedures that were technically successful. They were all admitted to hospital overnight according to the routine at the involved institutions and were discharged the next morning. With regard to complications, one patient in the LM group had blood loss requiring a transfusion; in the UAE group, one patient had pain that did not react to standard pain control during the procedure and required additional medications. Median AMH levels were significantly lower in women whose fibroids were treated with UAE than in those who had LM (0.78 ng/mL [range 0.67 to 1.28] vs. 2.17 ng/mL [range 1.17 to 2.38], P = 0.01). Median AFC per ovary was also significantly lower in women treated with UAE than in those who had LM (3.5 [range 2 to 7] vs. 7 [range 6 to 11], P = 0.03). Median levels of FSH and E2 and of ovarian volume were not significantly different between the two groups (Table 2). DISCUSSION
In this study, we found that both AMH levels and AFC were significantly lower in reproductive-aged women whose fibroids had been treated more than 12 months previously with UAE than in women who had had their fibroids removed via LM. This finding suggests that ovarian reserve may be significantly lower in the long term following fibroid treatment with UAE than following treatment via LM, and that this should be considered when determining treatments for reproductive-aged women. That differences were seen only in AMH levels and AFC and were not detected with less sensitive markers of ovarian reserve (serum FSH, serum E2, or ovarian volume) likely reflects inherent limitations of these more traditional markers. The reliability of FSH levels as a marker of ovarian reserve is known to be limited because of a widely variable sensitivity, particularly when levels are in the normal range.13,17,18 Similarly, basal E2 levels and ovarian volume demonstrate significant variability and cannot reliably distinguish between abnormal and normal ovarian reserve.13,21,22 By contrast, AMH levels and antral follicle MARCH JOGC MARS 2014 l 243
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Table 1. Baseline characteristics of study participants LM (n = 5)
UAE (n = 8)
P
Age, years, mean (SD)
39.4 (4.2)
40.9 (1.9)
NS
BMI, kg/m2, mean (SD)
27.7 (4.9)
29.3 (6.8)
NS
Black
2
2
Caucasian
2
2
Other
1
4
Race, n
Number of fibroids, median (range)
2.2 (1 to 7)
2.5 (2 to 8)
NS
Diameter largest fibroid, cm, median (range)
9.0 (6 to 10)
6.7 (2.8 to 13.5)
NS
Abnormal bleeding
80
100
Mass effect symptoms
60
88
Pain
40
63
Urinary symptoms
80
50
Fibroid symptoms before procedure, % of group
Table 2. Comparison of ovarian reserve markers in women treated with laparoscopic myomectomy versus uterine artery embolization > 12 months previously
AMH, ng/mL AFC, per ovary
LM (n = 5)
UAE (n = 8)
P
2.17 (1.17 to 2.38)
0.78 (0.67 to 1.28)
0.01
7 (6 to 11)
3.5 (2 to 7)
0.03
FSH, IU/L
5.4 (4.7 to 7.5)
7.6 (5.8 to 9.35)
NS
Estradiol, pmoL/L
184 (91 to 187)
182 (137 to 213)
NS
5.78 (3.1 to 14.9)
5.6 (2.8 to 6.5)
NS
Ovarian volume, cm
3
All data were compared with Mann-Whitney U test and are presented as median (range).
counts are promising newer measures that, when reduced, have moderate to high specificity as screening tests for a poor ovarian follicular response to stimulation.13,23–25 While increases in FSH levels have been observed in older women following UAE,6,26–28 previous studies that also included younger women have not shown short-term differences in FSH levels. Spies et al. found that FSH levels increased by more than two standard deviations from baseline in women older than 45 years, but they found no significant difference in women under 42 years of age.26 Mara prospectively compared the effects of UAE with those of myomectomy in young women with a mean age of 32 years, and found no significant difference between the two groups in the number of women with elevated serum FSH six months after treatment.29 Similarly, Tropeano et al. found no change in serum FSH levels or AFC after 244 l MARCH JOGC MARS 2014
UAE in women with a mean age of 35 years.30 This may have been due to the shorter duration of follow-up ( 40 IU/L following UAE is no higher than in women following hysterectomy. These studies, however, screened for postmenopausal levels of FSH and not for more subtle changes in ovarian reserve. Indeed, a large randomized prospective study by Hehenkamp et al. evaluating the impact of both hysterectomy and UAE on the ovarian reserve of older women suggests both procedures adversely affect the ovaries.35 This study compared measures of ovarian reserve, including both FSH and AMH levels, with baseline levels after either hysterectomy or UAE, and compared these between the two treatment groups. The authors found that both procedures led to ovarian damage, reflected by a sudden decline from baseline in AMH levels immediately after treatment that was not correlated with age. While there was some recovery in both groups after six weeks, the AMH levels remained below expected in the UAE group throughout the 24-month follow-up period. Unlike the decline in AMH, elevations of FSH > 40 IU/L post-procedure were found to be associated with age > 45 years irrespective of treatment. Hehenkamp et al. suggested that both treatments led to a loss of ovarian reserve that could be detected with AMH evaluation regardless of age but that significant elevations in FSH > 40 IU/L occurred primarily in older women > 45 years of age irrespective of treatment.
It makes biologic sense that both hysterectomy and UAE could adversely affect ovarian reserve. Hysterectomy necessarily interrupts the utero-ovarian ligament and anastomosing vessels, and has been shown to advance the age of menopause by four years compared with women who do not undergo hysterectomy.36 With respect to UAE, ovarian reserve is at risk via collateral blood supply to the ovaries. Immediately following the procedure, a loss of ovarian perfusion has been demonstrated on ultrasound.37 Moreover, histopathologic assessment has demonstrated the presence of embolization particles in ovarian tissue.38,39 While LM theoretically could also impair ovarian reserve via inadvertent disruption of ovarian blood supply or direct damage, studies thus far using sensitive measures have not shown an adverse effect. Cela et al. prospectively evaluated ovarian reserve following LM in young women six months after the procedure.40 Compared with baseline measures, there was no significant change in AFC or AMH levels following LM. Similarly, a pilot study by Browne et al. comparing response to IVF treatment before and after abdominal myomectomy found no difference in total gonadotropin dose required or number of oocytes retrieved, suggesting that ovarian reserve was not affected.41 Our findings suggest that UAE may adversely affect ovarian reserve in younger reproductive-aged women over the long term but that this difference may not be detectable using traditional measures such as serum FSH. It may also be that the subtle changes in ovarian reserve that occur in younger women may become apparent in the longer term as women approach the end of their reproductive years. It is not clear, however, what clinical impact such differences in ovarian reserve would have. Although diminished ovarian reserve correlates with ovarian follicle numbers and responsiveness to fertility treatment, the reported normal ranges vary and are mostly derived from an infertility population, making inferences about natural fertility difficult.13 It may be that the difference in ovarian reserve may be of practical importance only for those who already have a diminished reserve pre-procedure or for women planning to undergo fertility treatment. With respect to ovarian reserve and response to fertility treatment, the American Society for Reproductive Medicine’s 2012 committee opinion on testing and interpreting measures of ovarian reserve stated that a cut-off value for serum AMH of 12 months) compared to women treated with LM. A relative decrease in ovarian reserve could adversely affect the future response to fertility treatments and/or fecundity. This finding may inform the selection of a minimally invasive treatment for fibroids in reproductive-aged women who have not completed childbearing. It suggests that further study in this area is warranted before the application of UAE is expanded to young reproductive-aged women. REFERENCES 1. Cramer SF. The frequency of uterine leiomyomas. Am J Clin Pathol 1990;94(4 Suppl 1):435–8. 2. Goodwin SC, Bradley LD, Lipman JC, Stewart EA, Nosher JL, Sterling KM, et al. Uterine artery embolization versus myomectomy: a multicenter comparative study. Fertil Steril 2006;85(1):14–21.
7. Tropeano G, Amoroso S, Scambia G. Non-surgical management of uterine fibroids. Hum Reprod Update 2008;14(3):259–74. 8. Gupta JK. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev 2012;5. May 16;5:CD005073. doi:10.1002/14651858.CD005073. pub3. Review. PMID: 22592701. 9. American College of Obstetricians and Gynacologists. ACOG practice bulletin. Alternatives to hysterectomy in the management of leiomyomas. Obstet Gynecol 2008;112(2 Pt 1):387–400. 10. Walker WJ, McDowell SJ. Pregnancy after uterine artery embolization for leiomyomata: a series of 56 completed pregnancies. Am J Obstet Gynecol 2006;195(5):1266–71. 11. Ravina JH, Vigneron NC, Aymard A, Le Dref O, Merland JJ. Pregnancy after embolization of uterine myoma: report of 12 cases. Fertil Steril 2000;73(6):1241–3. 12. Ouyang Z, Liu P, Yu Y, Chen C, Song X, Liang B, et al. Role of ovarian artery-to-uterine artery anastomoses in uterine artery embolization: initial anatomic and radiologic studies. Surg Radiol Anat 2012;34(8):737–41. 13. Practice Committee of the American Society for Reproductive medicine. Testing and interpreting measures of ovarian reserve: a committee opinion. Fertil Steril 2012;98(6):1407–15. 14. Ranieri DM, Quinn F, Makhlouf A, Khadum I, Ghutmi W, McGarrigle H, et al. Simultaneous evaluation of basal follicle-stimulating hormone and 17β-estradiol response to gonadotropin-releasing hormone analogue stimulation: an improved predictor of ovarian reserve. Fertil Steril 1998;70(2):227–33. 15. Pavlik EJ, DePriest PD, Gallion HH, Ueland FR, Reedy MB, Kryscio RJ, et al. Ovarian volume related to age. Gynecol Oncol 2000;77(3):410–2. 16. Bancsi LF, Broekmans FJ, Mol BW, Habbema JD, te Velde ER. Performance of basal follicle-stimulating hormone in the prediction of poor ovarian response and failure to become pregnant after in vitro fertilization: a meta-analysis. Fertil Steril 2003;79(5):1091–100. 17. Riggs RM, Duran EH, Baker MW, Kimble TD, Hobeika E, Yin L, et al. Assessment of ovarian reserve with anti-müllerian hormone: a comparison of the predictive value of anti-müllerian hormone, follicle-stimulating hormone, inhibin B, and age. Am J Obstet Gynecol 2008;199(2):202.e1, 202.e8. 18. Fanchin R, Schonäuer LM, Righini C, Guibourdenche J, Frydman R, Taieb J. Serum anti-müllerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3. Hum Reprod 2003;18(2):323–7. 19. Seldinger SI. Catheter replacement of the needle in percutaneous arteriography; a new technique. Acta Radiologica 1953;39(5):368–76. 20. Waltman AC, Courey WR, Athanasoulis C, Baum S. Technique for left gastric artery catheterization. Radiology 1973;109:732-4.
3. Agdi M, Tulandi T. Endoscopic management of uterine fibroids. Best Pract Res Clin Obstet Gynaecol 2008;22(4):707–16.
21. McIlveen M, Skull JD, Ledger WL. Evaluation of the utility of multiple endocrine and ultrasound measures of ovarian reserve in the prediction of cycle cancellation in a high-risk IVF population. Hum Reprod 2007;22(3):778–85.
4. Alessandri F, Lijoi D, Mistrangelo E, Ferrero S, Ragni N. Randomized study of laparoscopic versus minilaparotomic myomectomy for uterine myomas. J Minim Invasive Gynecol 2006;13(2):92–7.
22. Phophong P, Ranieri DM, Khadum I, Meo F, Serhal P. Basal 17β-estradiol did not correlate with ovarian response and in vitro fertilization treatment outcome. Fertil Steril 2000;74(6):1133–6.
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23. Fiçicioglu C, Kutlu T, Baglam E, Bakacak Z. Early follicular antimüllerian hormone as an indicator of ovarian reserve. Fertil Steril 2006;85(3):592–6. 24. Muttukrishna S, McGarrigle H, Wakim R, Khadum I, Ranieri D, Serhal P. Antral follicle count, anti-mullerian hormone and inhibin B: predictors of ovarian response in assisted reproductive technology? BJOG 2005;112(10):1384–90. 25. Gnoth C, Schuring AN, Friol K, Tigges J, Mallmann P, Godehardt E. Relevance of anti-mullerian hormone measurement in a routine IVF program. Hum Reprod 2008;23(6):1359–65. 26. 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(4):437–42. 27. Ahmad A, Qadan L, Hassan N, Najarian K. Uterine artery embolization for treatment of uterine fibroids: Effect on ovarian function in younger women. J Vasc Interv Radiol 2002;13(10):1017–20. 28. Tulandi T, Sammour A, Valenti D, Child TJ, Seti L, Tan SL. Ovarian reserve after uterine artery embolization for leiomyomata. Fertil Steril 2002;78(1):197–8. 29. Mara MM. Midterm clinical and first reproductive results of a randomized controlled trial comparing uterine fibroid embolization and myomectomy. Cardiovasc Intervent Radiol 2008;31(1):73–85. 30. 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(4):1055–61. 31. McLucas B, Danzer H, Wambach C, Lee C. Ovarian reserve following uterine artery embolization in women of reproductive age: a preliminary report. Minim Invasive Ther Allied Technol 2013;22(1):45–9. 32. Seifer DB, Baker VL, Leader B. Age-specific serum anti-müllerian hormone values for 17,120 women presenting to fertility centers within the United States. Fertil Steril 2011;95(2):747–50.
33. van der Kooij SM, Hehenkamp WJK, Volkers NA, Birnie E, Ankum WM, Reekers JA. Uterine artery embolization vs hysterectomy in the treatment of symptomatic uterine fibroids: 5-year outcome from the randomized EMMY trial. Am J Obstet Gynecol 2010;203(2):105.e1,105.e13. 34. Moss J, Cooper K, Khaund A, Murray L, Murray G, Wu O, et al. Randomised comparison of uterine artery embolisation (UAE) with surgical treatment in patients with symptomatic uterine fibroids (REST trial): 5-year results. BJOG 2011;118(8):936–44. 35. Hehenkamp WJK, Volkers NA, Broekmans FJM, de Jong FH, Themmen APN, Birnie E, et al. Loss of ovarian reserve after uterine artery embolization: a randomized comparison with hysterectomy. Hum Reprod 2007;22(7):1996–2005. 36. Farquhar CM, Sadler L, Harvey SA, Stewart AW. The association of hysterectomy and menopause: a prospective cohort study. BJOG 2005;112(7):956–62. 37. Ryu RK, Chrisman HB, Omary RA, Miljkovic S, Nemcek AA, Saker MB, et al. The vascular impact of uterine artery embolization: prospective sonographic assessment of ovarian arterial circulation. J Vasc Interv Radiol 2001;12(9):1071–4. 38. Garcia L, Isaacson K. Utero-ovarian vessel after uterine artery embolization. J Minim Invasive Gynecol 2012;19(1):12. 39. Payne JF, Robboy SJ, Haney AF. Embolic microspheres within ovarian arterial vasculature after uterine artery embolization. Obstet Gynecol 2002;100(5):883–6. 40. Cela V, Freschi L, Simi G, Tana R, Russo N, Artini PG, et al. Fertility and endocrine outcome after robot-assisted laparoscopic myomectomy (RALM). Gynecol Endocrinol 2013;29(1):79–82. 41. Browne H, McCarthy-Keith D, Stegmann B, Spies J, Armstrong A. Ovarian response in women undergoing ovarian stimulation after myomectomy. Fertil Steril 2008;90(5):2004.e19, 2004.e21. 42. Kwee J, Schats R, McDonnell J, Themmen A, de Jong F, Lambalk C. Evaluation of anti-müllerian hormone as a test for the prediction of ovarian reserve. Fertil Steril 2008;90(3):737–43.
MARCH JOGC MARS 2014 l 247
Laparoscopic Myomectomy Versus Uterine Artery Embolization: Long-Term Impact on Markers of Ovarian Reserve Rebecca Arthur, MD, MSc, FRCSC,1,3 John Kachura, MD, FRCPC,2,4 Grace Liu, MD, MSc, FRCSC, FaCOG,1,5 Crystal Chan, MD, MSc, FRCSC,1,3 Heather Shapiro, MD, FRCSC1,3 Department of Obstetrics and Gynaecology, University of Toronto, Toronto ON
1
Department of Medical Imaging, University of Toronto, Toronto ON
2
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, Toronto ON
3
Division of Vascular and Interventional Radiology, Department of Medical Imaging, Mount Sinai Hospital, Toronto ON
4
Department of Obstetrics and Gynaecology, Sunnybrook Health Sciences Centre, Toronto ON
5
Abstract Objective: To compare the relative long-term effects on ovarian reserve of treating fibroids in reproductive-aged women with uterine artery embolization (UAE) versus laparoscopic myomectomy (LM), using sensitive measures including antral follicle count (AFC) and serum anti-Müllerian hormone (AMH). Methods: We undertook a retrospective cohort pilot study to evaluate the utility and feasibility of carrying out a larger prospective trial. Thirteen women were evaluated in this study, including eight in the UAE group and five in the LM group. They were identified from a larger group of 125 women who had undergone LM and 200 women who had undergone UAE at a participating institution at least 12 months previously; of these, 32 who had UAE and 27 who had LM were of reproductive age and eligible to participate. Participants had an assessment of ovarian reserve including measurements of serum AMH, estradiol, and FSH, and ultrasound assessment of AFC and ovarian volume. Results: Median serum AMH levels were significantly lower in women who had undergone UAE at least 12 months previously than in women who had undergone LM (0.78 ng/mL [range 0.67 to 1.28] vs. 2.17 ng/mL [range 1.17 to 2.38], P = 0.01). Median AFC per ovary was also significantly lower in women who had UAE than in those who had LM (3.5 [range 2 to 7] vs. 7 [range 6 to 11], P = 0.03). Median levels of FSH and E2 and of ovarian volume were not significantly different between the two groups.
Key Words: Uterine artery embolization, laparoscopic myomectomy, fibroid, myoma, ovarian reserve, AMH, antral follicle count Competing Interests: None declared. Received on September 14, 2013 Accepted on November 15, 2013
240 l MARCH JOGC MARS 2014
Conclusion: Reproductive-aged women who have undergone treatment of fibroids with UAE may have lower ovarian reserve over the long term (> 12 months) than women with fibroids treated with LM. This could have an adverse impact on future response to fertility treatment and/or fecundity. This finding may inform the choice of minimally invasive treatment for fibroids in reproductiveaged women who have not completed childbearing. It suggests that further study in this area is warranted before the application of UAE is expanded to young reproductive-aged women.
Résumé Objectif : Comparer, chez des femmes en âge de procréer, la prise en charge de fibromes par embolisation de l’artère utérine (EAU) à leur prise en charge au moyen d’une myomectomie par laparoscopie (ML), pour ce qui est des effets relatifs à long terme sur la réserve ovarienne (déterminés au moyen de mesures sensibles, dont la numération des follicules antraux [NFA] et le taux sérique d’hormone antimüllérienne [HAM]). Méthodes : Nous avons mené une étude de cohorte rétrospective pilote afin d’évaluer l’utilité et la faisabilité de mener un essai prospectif de plus grande envergure. Treize femmes ont été évaluées dans le cadre de cette étude (huit dans le groupe EAU et cinq dans le groupe ML). Elles ont été identifiées à partir d’un groupe plus étendu comprenant 125 femmes qui avaient subi une ML et 200 femmes qui avaient subi une EAU au sein d’un établissement participant au moins 12 mois au préalable; de ces femmes, 32 de celles qui avaient subi une EAU et 27 de celles qui avaient subi une ML étaient en âge de procréer et admissibles à l’étude. Les participantes ont été soumises à une évaluation de leur réserve ovarienne (mesures des taux sériques d’HAM, d’estradiol et de FSH, et évaluation échographique de la NFA et du volume ovarien). Résultats : Les taux sériques médians d’HAM étaient considérablement moins élevés chez les femmes qui avaient subi une EAU au moins 12 mois au préalable que chez les femmes
Laparoscopic Myomectomy Versus Uterine Artery Embolization: Long-Term Impact on Markers of Ovarian Reserve
qui avaient subi une ML (0,78 ng/ml [plage : 0,67 - 1,28] vs 2,17 ng/ml [plage : 1,17 - 2,38], P = 0,01). La NFA médiane par ovaire était également considérablement moins élevée chez les femmes qui avaient subi une EAU que chez celles qui avaient subi une ML (3,5 [plage : 2 - 7] vs 7 [plage : 6 - 11], P = 0,03). Le volume ovarien et les taux médians de FSH et d’E2 n’étaient pas considérablement différents d’un groupe à l’autre. Conclusion : Les femmes en âge de procréer qui ont fait l’objet d’une EAU visant la prise en charge de leurs fibromes pourraient présenter, à long terme (> 12 mois), une réserve ovarienne moins élevée que celle des femmes ayant vu leurs fibromes être pris en charge au moyen d’une ML, ce qui pourrait exercer un effet indésirable sur la fertilité et/ou sur la réaction à de futurs traitements de procréation assistée. Cette constatation pourrait éclairer la décision quant au recours à un traitement à effraction minimale pour assurer la prise en charge des fibromes chez les femmes en âge de procréer qui souhaitent encore connaître une ou des grossesses. Elle laisse également entendre que la tenue d’autres études dans ce domaine s’avère justifiée avant que le recours à l’EAU ne soit élargi aux jeunes femmes en âge de procréer.
J Obstet Gynaecol Can 2014;36(3):240–247
INTRODUCTION
U
terine fibroids affect 50% to 80% of reproductiveaged women1 and can lead to significant morbidity including menorrhagia, infertility, and mass-effect symptoms. In reproductive-aged women wishing to retain fertility, symptomatic fibroids have traditionally been excised through abdominal myomectomy. The abdominal incision required for this surgery, however, leads to a significant hospital stay and recovery period.2 This has led to the development of less invasive alternatives. One such approach is laparoscopic myomectomy.2 By avoiding a laparotomy incision, this approach allows for a short recovery period.3 In addition to a shorter hospital stay and recovery period, decreased blood loss and decreased postoperative adhesions in comparison to abdominal myomectomy have been shown in case series.4 Uterine artery embolization is another less invasive approach for the treatment of uterine fibroids. It is a safe and effective treatment in which a catheter inserted through the common femoral artery is used to deliver
ABBREVIATIONS AFC
antral follicle count
AMH
anti-Müllerian hormone
E2
estradiol-17β
FSH
follicle stimulating hormone
LM
laparoscopic myomectomy
UAE
uterine artery embolization
particles to obstruct blood supply through the uterine artery, resulting in ischemia and regression of fibroids.5,6 Although UAE is less invasive than surgical treatments and also results in a shorter recovery period,7,8 it is generally only recommended in reproductive-aged women who do not want to preserve fertility.7,9 However, numerous case studies have described pregnancies with reassuring outcomes occurring after UAE. This has led to increasing acceptance of performing UAE in reproductive-aged women, perhaps even in women for whom childbearing is not complete.6,10,11 When contemplating the best course of treatment for uterine fibroids in reproductive-aged women, it is important to consider the potential impact of each of the procedures on ovarian reserve, because ovarian dysfunction can lead to accelerated onset of menopause and diminished fertility. UAE may adversely affect the ovaries because of the anatomy of the pelvic blood vessels and the collateral blood supply of the uterus.12 It is also possible that LM could affect ovarian function via inadvertent interruption of the ovarian blood supply or through direct ovarian injury. The term “ovarian reserve” refers to the number and quality of remaining oocytes in the ovaries and reflects remaining reproductive capacity. When ovarian reserve is decreased in reproductive-aged women, it can lead to a diminished response to ovarian stimulation with fertility treatments and potentially to decreased fecundity.13 Ovarian reserve cannot be directly measured but can be estimated with hormone assays and ultrasound measurements. The most common traditional measures include assays of serum follicle stimulating hormone and estradiol-17β and ultrasound measurement of ovarian volume, performed on the third day of menstruation.14–16 However, these measurements are often affected only in cases of severe compromise.13,17 More sensitive measurements include day three antral follicle counts using transvaginal ultrasound and serum anti-Müllerian hormone levels, both of which are more closely correlated with ovarian follicle number and responsiveness to fertility treatment than the more traditional parameters.13,17,18 To begin to address the impact of various approaches to treatment for fibroids on ovarian reserve, we performed a retrospective cohort pilot study to compare the relative long-term effect on ovarian reserve of treating fibroids in reproductive-aged women with uterine artery embolization or with laparoscopic myomectomy. To our knowledge, this is the first study to compare these approaches directly using sensitive measures, including both AFC and AMH, to evaluate ovarian reserve following either procedure in women of reproductive age. MARCH JOGC MARS 2014 l 241
Gynaecology
METHODS
We conducted this retrospective cohort pilot study to evaluate the utility and feasibility of carrying out a larger scale prospective trial. It was conducted at two universityaffiliated hospitals in the department of obstetrics and gynaecology at one site and of interventional radiology at the other. Markers of ovarian reserve (serum FSH, serum E2, serum AMH, ovarian volume, and AFC) were assessed and compared between reproductive-aged women who had previously undergone either UAE or LM for the treatment of fibroids at least 12 months previously. Eligible women were between 20 and 43 years of age at the time of the study and had undergone either LM or UAE at one of the study institutions at least 12 months before the study date. Potential participants were contacted initially by mail and then by follow-up telephone call. Subjects were excluded if they had undergone any additional intervention to treat their fibroids, either before or after the UAE or LM procedure of interest. They were also excluded if they had ever had any ovarian surgery. All study subjects gave informed consent for their participation. Study participants were asked to undergo a one-time assessment of ovarian reserve involving ultrasound and blood parameters in the early follicular phase of their menstrual cycle. They were also asked to complete a questionnaire to confirm personal characteristics and inclusion/exclusion criteria information. All serum measurements were performed in one laboratory using the same assays performed in a single run. AMH levels were measured via ELISA with the Gen II assay (Beckman Coulter Canada, Mississauga ON). The detection limit was 0.14 ng/mL. FSH and E2 were measured using electrochemiluminescence immunoassays (Roche Diagnostics, Laval QC). The minimum detection range for E2 was 18.4 pmol/L and for FSH was 0.100 IU/L. Ultrasound was performed by experienced ultrasonographers who were blinded to the study group. AFC was defined as the total number of visible follicles in each ovary measuring between 2 and 10 mm. Ovarian volume was calculated using the prolate ellipsoid formula (L × H × W × 0.523) after measuring each ovary in three dimensions. AFC and ovarian volume were assessed in each ovary to account for possible differential impacts on each ovary from uterine artery catheterization/occlusion on the ipsilateral side and to minimize possible masking of any such effect by the contralateral side. In cases in which an ovary could not be visualized, the result was recorded 242 l MARCH JOGC MARS 2014
as “non-visible.” If cysts were noted, the dimensions were measured, the volumes were calculated, and cyst characteristics were described. Uterine Artery Embolization Technique
Procedures were performed in a similar fashion by one of three experienced interventional radiologists at a single institution. Patients received antibiotic prophylaxis and medication for pain control during the procedure. A 4 French vascular sheath was inserted into the right common femoral artery using aseptic Seldinger technique19 and local anaesthesia and was advanced in retrograde fashion. A 4 French C2 Glidecath and a .035 angled Glidewire (Terumo Medical Corp., Somerset NJ) were used to select the left common and internal iliac arteries. The left uterine artery was embolized at its proximal ascending segment beyond the cervicovaginal branch to near-complete occlusion using Cook polyvinyl alcohol foam particles of 300 to 500 μm (Cook Medical Inc., Bloomington IN). A Waltman loop20 was then formed over the aortic bifurcation and removed after the right common and internal iliac arteries were selected. The right uterine artery was selected to its proximal ascending segment and embolized in the same fashion. Patients were admitted to hospital overnight following the procedure for pain control using a morphine patient-controlled analgesia pump. Laparoscopic Myomectomy Technique
All laparoscopic myomectomy procedures were performed by a single experienced surgeon at one institution. Fibroid mapping via transvaginal ultrasound and sonohysterogram was performed preoperatively to document fibroid size and location and to exclude any submucosal fibroids. Patients did not receive preoperative treatment with GnRH agonists. A vasopressin solution was injected into the serosa and myometrium overlying the fibroid to decrease bleeding. A horizontal incision was performed with sparing use of unipolar cautery through the serosa and myometrium to the level of the fibroid. Fibroids were enucleated along the cleavage plane with great care to avoid the endometrial cavity and to avoid manipulation of the cornua or fallopian tubes. The myometrial defect was closed with interrupted sutures in layers via laparoscopic suturing. The excised fibroids were removed with an electrical morcellator. The serosa was closed with a continuous baseball stitch, and a barrier agent of oxidized regenerated cellulose was placed on the uterine incisions. Patients were admitted to hospital for monitoring overnight and were discharged on the next day. A chart review was performed to gather information about the outcomes of LM and UAE procedures. The UAE procedure was considered to be successful if it resulted in complete bilateral peripheral uterine artery occlusion at the
Laparoscopic Myomectomy Versus Uterine Artery Embolization: Long-Term Impact on Markers of Ovarian Reserve
end of the procedure. The LM procedure was considered successful if all fibroids of 2 cm diameter or larger were removed completely. Complications were defined as severe pain not reacting to standard pain control, blood loss requiring transfusion, groin hematoma, injury to abdominal organs other than uterus, conversion to laparotomy, large vessel injury, reoperation for hemoperitoneum, prolonged hospitalization (> 1 night), readmission to hospital, and infection. The primary endpoints of the study were differences between the two groups in median AMH and median antral follicle count. The secondary endpoints included differences in median serum levels of FSH and E2 and median ovarian volume. These parameters were measured for each participant on a single day in the early follicular phase (menstrual cycle day 2, 3, or 4). A Mann-Whitney U test was used to compare the two groups with respect to AMH, AFC, FSH, E2, and ovarian volume data, as well as participant characteristics. This test was chosen because of the small sample size of the study, as it does not assume a normal distribution of data and corrects for variance. To minimize the impact of any outliers in this small sample, the endpoint data are reported as medians ± standard error. Patient characteristics are reported as means ± standard deviation. Differences were considered to be statistically significant if P 0.05). All patients in both groups had procedures that were technically successful. They were all admitted to hospital overnight according to the routine at the involved institutions and were discharged the next morning. With regard to complications, one patient in the LM group had blood loss requiring a transfusion; in the UAE group, one patient had pain that did not react to standard pain control during the procedure and required additional medications. Median AMH levels were significantly lower in women whose fibroids were treated with UAE than in those who had LM (0.78 ng/mL [range 0.67 to 1.28] vs. 2.17 ng/mL [range 1.17 to 2.38], P = 0.01). Median AFC per ovary was also significantly lower in women treated with UAE than in those who had LM (3.5 [range 2 to 7] vs. 7 [range 6 to 11], P = 0.03). Median levels of FSH and E2 and of ovarian volume were not significantly different between the two groups (Table 2). DISCUSSION
In this study, we found that both AMH levels and AFC were significantly lower in reproductive-aged women whose fibroids had been treated more than 12 months previously with UAE than in women who had had their fibroids removed via LM. This finding suggests that ovarian reserve may be significantly lower in the long term following fibroid treatment with UAE than following treatment via LM, and that this should be considered when determining treatments for reproductive-aged women. That differences were seen only in AMH levels and AFC and were not detected with less sensitive markers of ovarian reserve (serum FSH, serum E2, or ovarian volume) likely reflects inherent limitations of these more traditional markers. The reliability of FSH levels as a marker of ovarian reserve is known to be limited because of a widely variable sensitivity, particularly when levels are in the normal range.13,17,18 Similarly, basal E2 levels and ovarian volume demonstrate significant variability and cannot reliably distinguish between abnormal and normal ovarian reserve.13,21,22 By contrast, AMH levels and antral follicle MARCH JOGC MARS 2014 l 243
Gynaecology
Table 1. Baseline characteristics of study participants LM (n = 5)
UAE (n = 8)
P
Age, years, mean (SD)
39.4 (4.2)
40.9 (1.9)
NS
BMI, kg/m2, mean (SD)
27.7 (4.9)
29.3 (6.8)
NS
Black
2
2
Caucasian
2
2
Other
1
4
Race, n
Number of fibroids, median (range)
2.2 (1 to 7)
2.5 (2 to 8)
NS
Diameter largest fibroid, cm, median (range)
9.0 (6 to 10)
6.7 (2.8 to 13.5)
NS
Abnormal bleeding
80
100
Mass effect symptoms
60
88
Pain
40
63
Urinary symptoms
80
50
Fibroid symptoms before procedure, % of group
Table 2. Comparison of ovarian reserve markers in women treated with laparoscopic myomectomy versus uterine artery embolization > 12 months previously
AMH, ng/mL AFC, per ovary
LM (n = 5)
UAE (n = 8)
P
2.17 (1.17 to 2.38)
0.78 (0.67 to 1.28)
0.01
7 (6 to 11)
3.5 (2 to 7)
0.03
FSH, IU/L
5.4 (4.7 to 7.5)
7.6 (5.8 to 9.35)
NS
Estradiol, pmoL/L
184 (91 to 187)
182 (137 to 213)
NS
5.78 (3.1 to 14.9)
5.6 (2.8 to 6.5)
NS
Ovarian volume, cm
3
All data were compared with Mann-Whitney U test and are presented as median (range).
counts are promising newer measures that, when reduced, have moderate to high specificity as screening tests for a poor ovarian follicular response to stimulation.13,23–25 While increases in FSH levels have been observed in older women following UAE,6,26–28 previous studies that also included younger women have not shown short-term differences in FSH levels. Spies et al. found that FSH levels increased by more than two standard deviations from baseline in women older than 45 years, but they found no significant difference in women under 42 years of age.26 Mara prospectively compared the effects of UAE with those of myomectomy in young women with a mean age of 32 years, and found no significant difference between the two groups in the number of women with elevated serum FSH six months after treatment.29 Similarly, Tropeano et al. found no change in serum FSH levels or AFC after 244 l MARCH JOGC MARS 2014
UAE in women with a mean age of 35 years.30 This may have been due to the shorter duration of follow-up ( 40 IU/L following UAE is no higher than in women following hysterectomy. These studies, however, screened for postmenopausal levels of FSH and not for more subtle changes in ovarian reserve. Indeed, a large randomized prospective study by Hehenkamp et al. evaluating the impact of both hysterectomy and UAE on the ovarian reserve of older women suggests both procedures adversely affect the ovaries.35 This study compared measures of ovarian reserve, including both FSH and AMH levels, with baseline levels after either hysterectomy or UAE, and compared these between the two treatment groups. The authors found that both procedures led to ovarian damage, reflected by a sudden decline from baseline in AMH levels immediately after treatment that was not correlated with age. While there was some recovery in both groups after six weeks, the AMH levels remained below expected in the UAE group throughout the 24-month follow-up period. Unlike the decline in AMH, elevations of FSH > 40 IU/L post-procedure were found to be associated with age > 45 years irrespective of treatment. Hehenkamp et al. suggested that both treatments led to a loss of ovarian reserve that could be detected with AMH evaluation regardless of age but that significant elevations in FSH > 40 IU/L occurred primarily in older women > 45 years of age irrespective of treatment.
It makes biologic sense that both hysterectomy and UAE could adversely affect ovarian reserve. Hysterectomy necessarily interrupts the utero-ovarian ligament and anastomosing vessels, and has been shown to advance the age of menopause by four years compared with women who do not undergo hysterectomy.36 With respect to UAE, ovarian reserve is at risk via collateral blood supply to the ovaries. Immediately following the procedure, a loss of ovarian perfusion has been demonstrated on ultrasound.37 Moreover, histopathologic assessment has demonstrated the presence of embolization particles in ovarian tissue.38,39 While LM theoretically could also impair ovarian reserve via inadvertent disruption of ovarian blood supply or direct damage, studies thus far using sensitive measures have not shown an adverse effect. Cela et al. prospectively evaluated ovarian reserve following LM in young women six months after the procedure.40 Compared with baseline measures, there was no significant change in AFC or AMH levels following LM. Similarly, a pilot study by Browne et al. comparing response to IVF treatment before and after abdominal myomectomy found no difference in total gonadotropin dose required or number of oocytes retrieved, suggesting that ovarian reserve was not affected.41 Our findings suggest that UAE may adversely affect ovarian reserve in younger reproductive-aged women over the long term but that this difference may not be detectable using traditional measures such as serum FSH. It may also be that the subtle changes in ovarian reserve that occur in younger women may become apparent in the longer term as women approach the end of their reproductive years. It is not clear, however, what clinical impact such differences in ovarian reserve would have. Although diminished ovarian reserve correlates with ovarian follicle numbers and responsiveness to fertility treatment, the reported normal ranges vary and are mostly derived from an infertility population, making inferences about natural fertility difficult.13 It may be that the difference in ovarian reserve may be of practical importance only for those who already have a diminished reserve pre-procedure or for women planning to undergo fertility treatment. With respect to ovarian reserve and response to fertility treatment, the American Society for Reproductive Medicine’s 2012 committee opinion on testing and interpreting measures of ovarian reserve stated that a cut-off value for serum AMH of 12 months) compared to women treated with LM. A relative decrease in ovarian reserve could adversely affect the future response to fertility treatments and/or fecundity. This finding may inform the selection of a minimally invasive treatment for fibroids in reproductive-aged women who have not completed childbearing. It suggests that further study in this area is warranted before the application of UAE is expanded to young reproductive-aged women. REFERENCES 1. Cramer SF. The frequency of uterine leiomyomas. Am J Clin Pathol 1990;94(4 Suppl 1):435–8. 2. Goodwin SC, Bradley LD, Lipman JC, Stewart EA, Nosher JL, Sterling KM, et al. Uterine artery embolization versus myomectomy: a multicenter comparative study. Fertil Steril 2006;85(1):14–21.
7. Tropeano G, Amoroso S, Scambia G. Non-surgical management of uterine fibroids. Hum Reprod Update 2008;14(3):259–74. 8. Gupta JK. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev 2012;5. May 16;5:CD005073. doi:10.1002/14651858.CD005073. pub3. Review. PMID: 22592701. 9. American College of Obstetricians and Gynacologists. ACOG practice bulletin. Alternatives to hysterectomy in the management of leiomyomas. Obstet Gynecol 2008;112(2 Pt 1):387–400. 10. Walker WJ, McDowell SJ. Pregnancy after uterine artery embolization for leiomyomata: a series of 56 completed pregnancies. Am J Obstet Gynecol 2006;195(5):1266–71. 11. Ravina JH, Vigneron NC, Aymard A, Le Dref O, Merland JJ. Pregnancy after embolization of uterine myoma: report of 12 cases. Fertil Steril 2000;73(6):1241–3. 12. Ouyang Z, Liu P, Yu Y, Chen C, Song X, Liang B, et al. Role of ovarian artery-to-uterine artery anastomoses in uterine artery embolization: initial anatomic and radiologic studies. Surg Radiol Anat 2012;34(8):737–41. 13. Practice Committee of the American Society for Reproductive medicine. Testing and interpreting measures of ovarian reserve: a committee opinion. Fertil Steril 2012;98(6):1407–15. 14. Ranieri DM, Quinn F, Makhlouf A, Khadum I, Ghutmi W, McGarrigle H, et al. Simultaneous evaluation of basal follicle-stimulating hormone and 17β-estradiol response to gonadotropin-releasing hormone analogue stimulation: an improved predictor of ovarian reserve. Fertil Steril 1998;70(2):227–33. 15. Pavlik EJ, DePriest PD, Gallion HH, Ueland FR, Reedy MB, Kryscio RJ, et al. Ovarian volume related to age. Gynecol Oncol 2000;77(3):410–2. 16. Bancsi LF, Broekmans FJ, Mol BW, Habbema JD, te Velde ER. Performance of basal follicle-stimulating hormone in the prediction of poor ovarian response and failure to become pregnant after in vitro fertilization: a meta-analysis. Fertil Steril 2003;79(5):1091–100. 17. Riggs RM, Duran EH, Baker MW, Kimble TD, Hobeika E, Yin L, et al. Assessment of ovarian reserve with anti-müllerian hormone: a comparison of the predictive value of anti-müllerian hormone, follicle-stimulating hormone, inhibin B, and age. Am J Obstet Gynecol 2008;199(2):202.e1, 202.e8. 18. Fanchin R, Schonäuer LM, Righini C, Guibourdenche J, Frydman R, Taieb J. Serum anti-müllerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3. Hum Reprod 2003;18(2):323–7. 19. Seldinger SI. Catheter replacement of the needle in percutaneous arteriography; a new technique. Acta Radiologica 1953;39(5):368–76. 20. Waltman AC, Courey WR, Athanasoulis C, Baum S. Technique for left gastric artery catheterization. Radiology 1973;109:732-4.
3. Agdi M, Tulandi T. Endoscopic management of uterine fibroids. Best Pract Res Clin Obstet Gynaecol 2008;22(4):707–16.
21. McIlveen M, Skull JD, Ledger WL. Evaluation of the utility of multiple endocrine and ultrasound measures of ovarian reserve in the prediction of cycle cancellation in a high-risk IVF population. Hum Reprod 2007;22(3):778–85.
4. Alessandri F, Lijoi D, Mistrangelo E, Ferrero S, Ragni N. Randomized study of laparoscopic versus minilaparotomic myomectomy for uterine myomas. J Minim Invasive Gynecol 2006;13(2):92–7.
22. Phophong P, Ranieri DM, Khadum I, Meo F, Serhal P. Basal 17β-estradiol did not correlate with ovarian response and in vitro fertilization treatment outcome. Fertil Steril 2000;74(6):1133–6.
246 l MARCH JOGC MARS 2014
Laparoscopic Myomectomy Versus Uterine Artery Embolization: Long-Term Impact on Markers of Ovarian Reserve
23. Fiçicioglu C, Kutlu T, Baglam E, Bakacak Z. Early follicular antimüllerian hormone as an indicator of ovarian reserve. Fertil Steril 2006;85(3):592–6. 24. Muttukrishna S, McGarrigle H, Wakim R, Khadum I, Ranieri D, Serhal P. Antral follicle count, anti-mullerian hormone and inhibin B: predictors of ovarian response in assisted reproductive technology? BJOG 2005;112(10):1384–90. 25. Gnoth C, Schuring AN, Friol K, Tigges J, Mallmann P, Godehardt E. Relevance of anti-mullerian hormone measurement in a routine IVF program. Hum Reprod 2008;23(6):1359–65. 26. 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(4):437–42. 27. Ahmad A, Qadan L, Hassan N, Najarian K. Uterine artery embolization for treatment of uterine fibroids: Effect on ovarian function in younger women. J Vasc Interv Radiol 2002;13(10):1017–20. 28. Tulandi T, Sammour A, Valenti D, Child TJ, Seti L, Tan SL. Ovarian reserve after uterine artery embolization for leiomyomata. Fertil Steril 2002;78(1):197–8. 29. Mara MM. Midterm clinical and first reproductive results of a randomized controlled trial comparing uterine fibroid embolization and myomectomy. Cardiovasc Intervent Radiol 2008;31(1):73–85. 30. 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(4):1055–61. 31. McLucas B, Danzer H, Wambach C, Lee C. Ovarian reserve following uterine artery embolization in women of reproductive age: a preliminary report. Minim Invasive Ther Allied Technol 2013;22(1):45–9. 32. Seifer DB, Baker VL, Leader B. Age-specific serum anti-müllerian hormone values for 17,120 women presenting to fertility centers within the United States. Fertil Steril 2011;95(2):747–50.
33. van der Kooij SM, Hehenkamp WJK, Volkers NA, Birnie E, Ankum WM, Reekers JA. Uterine artery embolization vs hysterectomy in the treatment of symptomatic uterine fibroids: 5-year outcome from the randomized EMMY trial. Am J Obstet Gynecol 2010;203(2):105.e1,105.e13. 34. Moss J, Cooper K, Khaund A, Murray L, Murray G, Wu O, et al. Randomised comparison of uterine artery embolisation (UAE) with surgical treatment in patients with symptomatic uterine fibroids (REST trial): 5-year results. BJOG 2011;118(8):936–44. 35. Hehenkamp WJK, Volkers NA, Broekmans FJM, de Jong FH, Themmen APN, Birnie E, et al. Loss of ovarian reserve after uterine artery embolization: a randomized comparison with hysterectomy. Hum Reprod 2007;22(7):1996–2005. 36. Farquhar CM, Sadler L, Harvey SA, Stewart AW. The association of hysterectomy and menopause: a prospective cohort study. BJOG 2005;112(7):956–62. 37. Ryu RK, Chrisman HB, Omary RA, Miljkovic S, Nemcek AA, Saker MB, et al. The vascular impact of uterine artery embolization: prospective sonographic assessment of ovarian arterial circulation. J Vasc Interv Radiol 2001;12(9):1071–4. 38. Garcia L, Isaacson K. Utero-ovarian vessel after uterine artery embolization. J Minim Invasive Gynecol 2012;19(1):12. 39. Payne JF, Robboy SJ, Haney AF. Embolic microspheres within ovarian arterial vasculature after uterine artery embolization. Obstet Gynecol 2002;100(5):883–6. 40. Cela V, Freschi L, Simi G, Tana R, Russo N, Artini PG, et al. Fertility and endocrine outcome after robot-assisted laparoscopic myomectomy (RALM). Gynecol Endocrinol 2013;29(1):79–82. 41. Browne H, McCarthy-Keith D, Stegmann B, Spies J, Armstrong A. Ovarian response in women undergoing ovarian stimulation after myomectomy. Fertil Steril 2008;90(5):2004.e19, 2004.e21. 42. Kwee J, Schats R, McDonnell J, Themmen A, de Jong F, Lambalk C. Evaluation of anti-müllerian hormone as a test for the prediction of ovarian reserve. Fertil Steril 2008;90(3):737–43.
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