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Gynecological Endocrinology
ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: http://www.tandfonline.com/loi/igye20
Improved cycle outcomes after laparoscopic
ovarian diathermy in hyper-responder patients
with previous ART failure
Recai Pabuccu, Emre Goksan Pabuccu, Asli Yarci Gursoy, Gamze Sinem
Caglar, Muserref Banu Yilmaz & Ozlem Ozdegirmenci
To cite this article: Recai Pabuccu, Emre Goksan Pabuccu, Asli Yarci Gursoy, Gamze Sinem Caglar, Muserref Banu Yilmaz & Ozlem Ozdegirmenci (2014) Improved cycle outcomes after laparoscopic ovarian diathermy in hyper-responder patients with previous ART failure, Gynecological Endocrinology, 30:12, 881-884, DOI: 10.3109/09513590.2014.943729
To link to this article: https://doi.org/10.3109/09513590.2014.943729
Published online: 31 Jul 2014.
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ISSN: 0951-3590 (print), 1473-0766 (electronic)
Gynecol Endocrinol, 2014; 30(12): 881–884
!2014 Informa UK Ltd. DOI: 10.3109/09513590.2014.943729
ANTI MULLERIAN HORMONE
Improved cycle outcomes after laparoscopic ovarian diathermy in
hyper-responder patients with previous ART failure
Recai Pabuccu1,2, Emre Goksan Pabuccu1, Asli Yarci Gursoy1, Gamze Sinem Caglar1, Muserref Banu Yilmaz1, and Ozlem Ozdegirmenci3
1
Department of Obstetrics and Gynaecology, Faculty of Medicine, Ufuk University, Ankara, Turkey,2Centrum Clinic Women Health and IVF Center, Ankara, Turkey, and3Zekai Tahir Burak Women Healthcare, Education and Research Hospital, Ankara, Turkey
Abstract
Excessive response to ovarian stimulation is common among hyper-responder patients undergoing assisted reproductive technology (ART). Cycle cancellations and severe ovarian hyperstimulation syndrome (OHSS) are all detrimental consequences observed within this cohort and several approaches have been proposed to enhance outcomes. The current study is designed to evaluate whether laparoscopic ovarian diathermy (LOD) improves ART outcomes and pregnancy rates by reducing Anti-mullerian hormone (AMH) levels in a group of patients who had a history of recurrent ART failure and high response. A total of 40 hyper-responder patients with history of previous ART failure were included. Group I consisted of 22 patients that underwent LOD prior to ART. Group II consisted of 18 patients that underwent only ART. Cycle outcomes of groups were compared. Following LOD, significant reduction in AMH levels were detected in group I (4.75 ng/mL to 2.25 ng/mL). Clinical pregnancies were similar among groups (40% versus 27.8% p¼ 0.65). There was no cycle cancellation in Group I, whereas there were three cycle cancellations observed due to OHSS in Group II. Our results indicate that LOD might offer enhanced fertility outcomes and may reduce the likelihood of cycle cancellations in hyper-responders with previous ART failures.
Keywords
Assisted reproductive technology, folliculogenesis, ovary History
Received 28 June 2014 Revised 30 June 2014 Accepted 8 July 2014 Published online 31 July 2014
Introduction
Excessive response to ovarian stimulation is a common problem in assisted reproduction technology (ART) cycles and is more frequently observed in patients that are defined as hyper-responders. This group tends to be more sensitive to exogenous gonadotropins due to large number of recruitable follicles and they are more likely to have cancelled cycles (up to 8%) due to excessive response [1]. Another detrimental result observed within this cohort is ovarian hyperstimulation syndrome (OHSS) [2]. Predicting excessive response is considerably important prior to ovarian stimulation and anti-Mu¨llerian hor-mone (AMH) has been considered as a promising marker to predict OHSS and excessive response in ART cycles [3].
AMH has also been proposed to play an important role in human folliculogenesis by altering the sensitivity of follicles to circulating FSH [4,5]. It has been suggested that a change in the serum concentration of AMH with laparoscopic ovarian dia-thermy (LOD) facilitates resumption of intra-ovarian processes of follicle selection and progression to dominance and ovulation [6]. Hence, the technique has been found effective to maintain ovulation.
In order to reduce cycle cancellations and to improve outcomes, LOD has been suggested as an effective method
prior to ART [7–9]. Nevertheless, the data in literature evaluating the prognostic value of LOD on success rates of ART is very limited for hyper-responder population. The current study is designed to evaluate whether LOD improves ART outcomes and pregnancy rates by reducing AMH levels in a group of selected patients who had a history of recurrent IVF failure and high response.
Materials and methods Patient selection
After reviewing medical records of 2660 ART cycles in a single center between January 2011 and January 2013, a total of 40 hyper-responder patients with a history of at least three failed gonadotropin-IUI cycles followed by two failed ART cycles were available for analyses. Hyper-response was defined as a history of15 oocytes retrieved following a standard controlled ovarian stimulation (COH) protocol [10,11]. Medical histories of previous ART cycles of the subjects included in the study revealed either cycle cancellation due to OHSS risk or failed cycles after embryo transfer. Exclusion criteria were AMH levels 54 ng/mL, age 438 or 518 years, and preimplantation genetic diagnosis (PGD) or testicular sperm extraction (TESE) cycles.
Before starting a new ART cycle, according to our treatment policy, all hyper-responder subjects that fulfil the selection criteria were offered to undergo LOD procedure in order to improve the ART outcomes. A total of 22 (55%) subjects accepted the procedure and three months following LOD, ART cycle was Address for correspondence: Emre Goksan Pabuccu M.D., Ufuk
University, Faculty of Medicine, Department of Obstetrics and Gynaecology, Ankara, Turkey. E-mail: pabuccu@hotmail.com
initiated (Group I). In Group I, two cases conceived spontan-eously within three months after LOD and were excluded from the study. The remaining 18 (45%) subjects refused ovarian diathermy procedure and started a new ART cycle (Group II).
Blood samples for AMH analyses were obtained from all participants before any intervention. In Group I AMH analyses were repeated three months after LOD before initiation of a new ART cycle. AMH concentrations were analyzed by commercially available ELISA kit (Diagnostic System Laboratories, Beckman Couter, Webster, NY). The intra- and inter-assay coefficients of variation for AMH were 4.6% and 8%, respectively.
LOD procedure
LOD procedure was carried out laparoscopically by monopolar needle (Karl Storz, ND, Germany). Four punctures were made on the antimesenteric side of each ovary at a power setting of 40 W, applied for 5 s at each point; totally applying 800 J at each ovary. The same surgeon performed all LOD procedures.
Controlled ovarian hyperstimulation
One ART cycle of each patient was included in the study. Ovarian stimulation was carried out with recombinant FSH (Gonal-F, Merck Serono, Istanbul, Turkey) beginning from the second day of the menstrual cycle with maximal starting dose of 150 IU/daily and fix GnRH antagonist (Cetrotide, Merck Serono, Istanbul, Turkey) was introduced (0.25 mcg/day) on the sixth day to all subjects. Transvaginal ultrasound–directed oocyte retrieval was performed 35 h after recombinant hCG (Ovitrelle, Merck Serono, Istanbul, Turkey). GnRH-a was administered for the final oocyte maturation in the presence of high serum estradiol levels (4500 pg/mL) and/or high number of follicles (415) measuring 12 mm during the late follicular phase of the ovarian stimulation cycle. Embryo transfer was performed 3 or 5 days after oocyte retrieval. For luteal support, all patients received 8% progesterone gel/daily (Crinone, Merck Serono, Istanbul, Turkey) and 2 mg (p.o.) estradiol hemihydrate three times a day, starting with the evening after oocyte retrieval and continuing until a negative pregnancy test or a viable fetus was documented by transvaginal ultrasonography. Subjects that received GnRH-a for the final oocyte maturation also received single bolus of 1500 IU hCG on the OPU day. A biochemical pregnancy was defined as b-hCG concentration 4 10 IU/L on the twelfth day after transfer. A clinical pregnancy was defined as presence of an intrauterine gestational sac with a heartbeat 3 weeks after a positive hCG test.
For the data analysis SPSS for Windows, version 11.5 was used (SPSS Inc., Chicago, IL). Whether the distributions of continuous and metric discrete variables were normally or not was determined by the Kolmogorov–Smirnov test. Continuous and metric discrete variables were shown as mean ± SD (95% CI) or median (min–max), where applicable. While mean differences between groups were compared by Student’s t test, otherwise, the Mann–Whitney U test was applied for comparisons of median values. Nominal data was analyzed by Pearson’s Chi-square or Fisher’s exact test. A p value50.05 was considered statistically significant.
Results
The baseline characteristics of Group I and II (age, body mass index, basal FSH, LH, fasting plasma glucose, fasting insulin, basal antral follicle count) are given in Table 1. None of the above parameters differed significantly between the groups (p50.05). Initial median AMH levels in Group I were significantly lower than Group II (4.75 ng/mL versus 5.65 ng/mL, respectively,
p¼ 0.033). Difference between initial (4.75 ng/mL) and post-drilling (2.2 ng/mL) AMH levels of subjects in Group I was also found to be significant (p50.001). Although it did not achieve statistical significance, there were relatively higher clinical pregnancy rates in Group I (40% versus 27.8%, p¼ 0.652). Due to the low number of cases, statistical analyses of OHSS were not feasible; there were only one mild OHSS in Group I (5%) and three (16.6%) in Group II (Table 2).
Discussion
The current study demonstrates that LOD prior to ART cycle seems to increase pregnancy rates in hyper-responders with AMH levels 4 ng/mL and with previous multiple ART failures. The exact mechanism of action is still unclear; however, thermal destruction of early antral follicles that are producing excess amount of AMH is standing at the forefront of theories. Reduction of AMH levels may contribute to follicle sensitivity to circulating FSH and may promote both initial and cyclic recruitments by enhancing follicular microenvironment. Improved follicular microenvironment contributes to better follicle cohort responsive Table 2. Cycle outcomes of the groups.
Group I (IVF/ICSI following LOD) (n¼ 20) Group II (Only IVF/ICSI) (n¼ 18) p Value Total gonadotropin consumption (IU) 1800.6 ± 977.2 1719.7 ± 589.1 0.762 Peak estradiol (pg/mL) 3088 ± 1033 3439 ± 1090 0.400 No of retrieved oocytes (MII) 12.1 ± 4.5 15.4 ± 5.0 0.036*
No of mature oocytes 9.5 ± 4.6 11.6 ± 3.8 0.135
No of 2PN 7.7 ± 4.0 7.1 ± 3.5 0.634
Fertilization rate (%) 77.4 ± 24.7 62.0 ± 21.8 0.050* Total duration (days) 11 [10–14] 9.5 [8–14] 0.035*
No of transferred embryo 1 [1–2] 1 [1–2] 0.553
No of good quality embryos 1 [0–2] 1 [0–2] 0.553
Implantation rate (%) 37.5 ± 45.5 25.0 ± 42.9 0.426
OHSS 1(5%) 3 (%16.6) 0.170
Clinical pregnancy rate (%) 8 (%40) 5 (%27.8) 0.652 *p value50.05.
LOD: laparoscopic ovarian drilling; AMH: antimu¨llerian hormone; FSH: follicle stimulating hormone; LH: luteinizing hormone; OHSS: ovarian hyperstimulation syndrome.
Table 1. Demographic characteristics of study groups. Group I (IVF/ICSI following LOD) (n¼ 20) Group II (Only IVF/ICSI) (n¼ 18) p Value Age (years) 28.8 ± 5.0 29.1 ± 4.9 0.875
Body mass index 26.3 ± 4.0 25.9 ± 4.1 0.783
AMH (ng/mL) 4.75 [4–7.6] 5.65 [4.2–10.5] 0.033*
Post drilling AMH (ng/mL) 2.20 [1.3–3.8] NA 50.001*
FSH (IU/L) 4.7 ± 1.8 4.7 ± 1.8 0.920
LH (mIU/mL) 8 [3.2–19.9] 7.1 [3.3–24.6] 0.264
Antral follicle count 14.2 ± 2.37 15.2 ± 3.47 0.267 fasting plasma glucose (ng/dL) 83.4 ± 5.8 85.4 ± 7.7 0.347 Fasting insuline (IU/mL) 10.1 ± 2.8 9.8 ± 3.8 0.839
Homa-IR value 2.1 ± 0.5 2.1 ± 0.8 0.935
*p value50.05.
LOD: laparoscopic ovarian drilling; AMH: antimu¨llerian hormone; FSH: follicle stimulating hormone; LH: luteinizing hormone; OHSS: ovarian hyperstimulation syndrome.
to COH and may result in higher fertilization and pregnancy rates while lowering the risk of severe OHSS.
Studies evaluating predictors of LOD success have already focused on many parameters including body mass index, androgen levels, LH levels and age [12–15]. In a previous study, pre-treatment AMH levels were found to be the most important predictors of ovulation rather than BMI, age, testoster-one and ovarian volume [6]. Similarly, El-Mashad et al. proposed AMH and ovarian stromal three-dimensional power Doppler study as useful tools in evaluating the outcome of LOD in anovulatory PCOS patients [16]. The data of Amer et al. clearly showed a significant (25%) reduction in plasma AMH levels following LOD with a monopolar cautery applying 600 J per ovary [6]. In our study design, only cases with AMH levels 4 ng/mL were asked to undergo a LOD procedure and the total amount of energy applied was within the recommended effective range which is 600-1200 Joule [17–19]. The pre and post-operative mean AMH levels in our study were 4.75 ng/mL (4.0–11.0 ng/mL) and 2.2 ng/mL (1.3–4.5 ng/mL) respectively, with a mean of 53% reduction in AMH levels. The total amount of energy applied in our study was 800 J per ovary. The significant reduction in AMH levels may explain favorable results in our study. When performing LOD, it is crucial not to exceed the proper amount of energy.
To date, very few authors evaluated the efficacy of LOD on IVF outcomes in high-responders [9,20,21]. Tozer et al. reported that, LOD procedure before IVF is associated with higher ongoing pregnancy rates (29% versus 10%) [20]. Similarly Colacurci et al. reported significantly increased ongoing preg-nancy rates in IVF cycles following LOD (28.6% versus 7.3%) [9]. In a small number of patients, Ferraretti reported 58% clinical pregnancy rate subsequent to transvaginal ovarian drilling in patients with 2 IVF failure [22]. In the prospective study of Rimmington et al., higher rate of pregnancies per cycle was reported in the group with prior LOD compared with controls (32% versus 36%) [8]. We reported 40% clinical pregnancy rate subsequent to LOD compared with 27.8% in the group with no intervention. Although the difference is not statistically signifi-cant, trend towards higher clinical pregnancies in Group I is noteworthy.
Less cycle cancellations and reduced OHSS rates in ART cycles subsequent to LOD seems as other advantages of the procedure. Rimmington et al. reported four OHSS cases in control group compared with only one in the LOD arm. Moreover, there were no cancelled cycles due to excessive response in the group with prior LOD. Authors suggested that patients with previous OHSS history or cycle cancellation benefited from LOD along with favorable pregnancies and low OHSS rates [8]. Likewise, Feraretti et al. reported no cancelled cycles subsequent to LOD compared with high cancellation rate in historical matches [22]. In the present study, four subjects in Group II received GnRH-a for the final oocyte maturation and no OHSS was observed within them. On the other hand, three cases that received hCG for the final oocyte maturation developed OHSS and embryo transfer procedure was abandoned in the same group. In all cancelled cycles, serum estradiol levels were54500 pg/mL during late follicular phase. In Group I, neither GnRH-a for the final oocyte maturation nor cycle cancellation was required due to excessive response. Only one mild OHSS case was detected that which did not require any intervention.
Cycles following LOD obviously result with lower peak estradiol levels and lower numbers of retrieved oocytes compared to standard ovarian stimulation cycles. Thermal destruction of ovarian tissue result with decreased numbers of recruitable follicles and patients require higher doses of gonadotropins. In our study, Group I required relatively higher doses, however
the difference was not significant. Additionally, we observed higher numbers of fertilized oocytes and fertilization rate despite significantly lower numbers of retrieved oocytes in Group I. The outcomes were similar to previous studies [20,22]. It seems that LOD may decrease the number of recruitable follicles by reducing circulating AMH and enhancing follicu-lar sensitivity to FSH, which might lead to better oocyte quality. Higher clinical pregnancies in Group I further support this idea.
Despite a small study group and retrospective study design, our data is unique for evaluating a specific group of patients that will mostly benefit from LOD. Although, a larger number of patients were required for optimum interpretation of statistical analysis, our results indicate that LOD might offer enhanced fertility outcomes in hyper-responders with previous ART failures. The mechanism of action for the restoration of ovulation and fertility is not exactly known. However reduced likelihood of cycle cancellations due to excessive response and higher ongoing pregnancies in the subsequent ART cycle are the consequences of the technique. In this context, LOD stands as a considerable and discussable option for hyper-responder patients prior to further ART attempt. Uniform patient selection criteria and best AMH cut-offs that mostly benefit from the procedure are definitely needed to be conclusive.
Declaration of interest
Authors report no declaration of interest.
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