Is ovarian reserve diminished after laparoscopic ovarian drilling?

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1 Gynecological Endocrinology, March2009;25(3): OVARY Is ovarian reserve diminished after laparoscopic ovarian drilling? MURAT API Haseki Education and Research Hospital, Istanbul, Turkey (Received 7 September 2008; revised 28 October 2008; accepted 28 October 2008) Gynecol Endocrinol Downloaded from informahealthcare.com by Yeditepe Univ. on 05/13/15 Abstract Background. Surgical therapy with laparoscopic ovarian drilling (LOD) may avoid or reduce the need for gonadotrophins or may facilitate their use. However, the procedure, though effective, can be traumatic on the ovaries, which may cause postoperative adhesions and/or diminished ovarian reserve (DOR). Objective. To review the available literature, whether the LOD is harmful on the ovarian reserve markers. Search strategy. A literature search was conducted using the keywords LOD, laparoscopic ovarian diathermy, PCOS, ovarian reserve, premature ovarian failure (POF). TheMEDLINEandEMBASEdatabasesandtheCochraneDatabaseofSystematic Reviews were searched. Selection criteria. All trials, case reports and letters to the editor in the PubMed database were included. Data collection and analysis. Along with the long-term clinical follow-up research articles, four that were specifically identifying the ovarian reserve tests were included in this review. Among these, three of them compared before and after LOD values, and one of them compared ovarian reserve markers among different groups of subjects; those with LOD, those with PCOS without LOD and those with normal ovulatory controls. Results. There were statistically significant differences between Day 3 FSH, inhibin B levels, ovarian volume and antral follicle count before and after LOD in some of the reports. Although the after LOD values were found to be lower than the before LOD values by means of ovarian reserve markers, the after values stayed higher than normal when compared with normal women without PCOS. Conclusion. Although the available data in the literature is limited, there was no concrete evidence of a DOR or POF associated with LOD in women with PCOS. Most of the changes in the ovarian reserve markers observed after LOD could be interpreted as normalisation of ovarian function rather than a reduction of ovarian reserve. LOD, if applied properly, normalises the exaggerated ovarian morphologic and endocrinologic properties. Keywords: Laparoscopic ovarian drilling, diminished ovarian reserve, polyscystic ovarian syndrome Introduction Polycystic ovary syndrome (PCOS) is a very common reproductive disorder, affecting approximately 5 10% of women in their child bearing years [1]. Although the primary defect in PCOS is unclear, the treatment aims to restore ovulatory cycles so that pregnancy can be achieved. The main goal of treatment of anovulatory infertility is the induction of mono-ovulatory cycles [2 4]. The use of gonadotrophins for the ovulation induction in anovulatory PCOS women has been extensively studied, showing ahighsuccessrate[5].however,duringgonadotrophin administration, there is a need for an experienced physician and careful sonographic and biochemical monitoring to avoid or reduce the risk of ovarian hyperstimulation and multiple pregnancies. Since the risk for these complications is particularly higher in PCOS patients, several treatments have been proposed to induce mono-ovulation in these women before gonadotrophin use [6]. Ovarian wedge resection had been the first established treatment for anovulatory PCOS patients but was largely abandoned due to the risk of post-surgical adhesions and the introduction of medical ovulation induction [7 9]. Surgical therapy with laparoscopic ovarian drilling (LOD) may avoid or reduce the need for gonadotrophins or may facilitate their use. The procedure can be performed with less trauma and fewer postoperative adhesions [10,11]. Several studies have claimed that ovarian drilling is followed, at least temporarily, by a high rate of spontaneous Correspondence: Murat Api, Haseki Education and Research Hospital, Istanbul, Turkey. muratapi@hotmail.com ISSN print/issn online ª 2009 Informa Healthcare USA, Inc. DOI: /

2 160 M. Api ovulation and conception, and/or that subsequent medical ovulation induction becomes easier [12]. Because the procedure targets the partial destruction of the ovaries in women with PCOS, the increased risk of premature ovarian failure (POF) is an ongoing concern in the LOD. In this review, available medical literature was evaluated to shed light on this complex issue. Methodology of this review To address the possible adverse effect of LOD on the ovarian function, there is a need to perform a properly designed long-term, prospective, randomised controlled study. Although there has been no such study conducted to solve this unanswered question, some articles in medical journals have addressed this issue. Therefore, a literature search was conducted using the following Keywords: LOD, laparoscopic ovarian diathermy, PCOS, ovarian reserve and POF. TheMEDLINEandEMBASEdatabases and the Cochrane Database of Systematic Reviews were searched. All trials, case reports and letters to the editor in the PubMed database were also included. POF and DOR: definition and evaluation POF is diagnosed when sex steroid deficiency, elevated gonadotrophins, and amenorrhoea are found in women less than two standard deviations below the mean age estimated for the reference population [13]. There are a variety of causes of POF: chromosomal and genetic abnormalities, autoimmune disease, viral infections and iatrogenic therapy (e.g. pelvic surgery, chemotherapy, radiotherapy). Diminished ovarian reserve (DOR) results from ovarian follicle depletion or dysfunction. The determination of both the quantity and quality of the follicular pool may allow the prediction of women who may under-respond or over-respond to controlled ovarian hyperstimulation protocols in assisted reproductive technology programs. Ovarian reserve markers: inhibin-b, anti-mullerian hormone, antral follicle count, Day-3 FSH, ovarian volume The currently used tests of ovarian reserve are not well established and have significant limitations. In addition, the applicability of these markers in PCOS is questionable. Nevertheless, there are several markers have been defined to measure the ovarian reserve to predict the future ovarian response. In an ART population, the women, who were found to have decreased serum inhibin-b levels (545 pg/ml) on cycle Day 3, have demonstrated a poorer response to ovulation induction and were less likely to conceive than women who had higher inhibin-b levels [14]. In a case control study, women who showed clinical outcomes consistent with declining ovarian reserve had decreased Day 3 serum inhibin-b levels despite having low FSH concentrations [15]. Anti-Mullerian hormone (AMH) or Mullerianinhibiting substance is produced constitutively from birth until menopause in women. Because it is produced solely by the functional granulosa cells of preantral follicles, it has plausibility as a marker of ovarian reserve. Higher early follicular phase serum AMH levels were found to be associated with a greater number of retrieved oocytes in IVF [16 18]. With the decrease in the number of the antral follicles with age, AMH production appears to become diminished, and it invariably will become undetectable at and after menopause [19 21]. The serum AMH was almost comparable with the antral follicle count (AFC) but was superior to basal FSH and inhibin-b levels in receiver operating characteristic curve analysis. The improved cycle-to-cycle consistency of AMH when compared with other markers of ovarian follicular status is in keeping with its peculiar production by follicles at several developmental stages and further supports its role as a cost-effective, reliable marker of ovarian fertility potential [21]. The AFC showed the highest discriminating potential for predicting poor ovarian response among the ovarian reserve markers tested. The AFC defined as the number of follicles smaller than 10 mm in diameter detected by transvaginal ultrasound in early follicular phase was shown to be a predictor of the number of oocytes retrieved and the cancellation rates in IVF [22]. The ovarian volume has been reported to be another predictor of ovarian response to COH [23]. In different trials, the total ovarian volume, the volume of the smallest ovary and the mean ovarian volume, measured by transvaginal ultrasound, have been reported to correlate with the response to COH. Women with a mean ovarian volume less than 3 cm 3 had higher cancellation rates. The ability of the test to predict pregnancy was poor [24 26]. The required amount of energy used by LOD The amount of energy applied during the procedure seems to be crucial both for the treatment effect and preservation of the ovarian reserve. The calculation of the amount of thermal energy used in LOD depends on the number of punctures, power setting and duration of each puncture. The amount of energy (J) ¼ power (W) 6 duration (s) 6 number of punctures. The clinical response to LOD seems to be dosedependent, with an increase in the frequency of

3 ovulation and conception with an increasing dose of thermal energy up to 600 J/ovary [27]. When this formula is applied to the data in the studies by several authors, applied energies vary between 640 and 16,000 J, i.e. Gjonnaess [28] has used 250 W for 3 s in each puncture and performed more than five punctures in each ovary ( ¼ J); Armar et al. [29] have used 640 J (40 W 6 4s6 4 ¼ 640 J) and Dabirashrafi [30] has used 16,000 J (eight holes W 6 5s¼ 16,000 J) and reported severe ovarian atrophy. The long term safety of ovarian surgery for PCOS has been confirmed in several previous studies. There is no documentation that LOD has caused acute ovarian failure [31 36]. The only case of ovarian failure reported in the literature resulted from the use of excessive energy (16,000 J) compared with the usual dose of J [30]. The long-term effects of LOD on the ovarian function There is considerable controversy as to how long the beneficial effects of LOD last. The long-term follow-up study by Dahlgren et al. [35] showed that menopause occurred later in PCOS women who underwent ovarian wedge resection compared with non-pcos women. In a follow-up study to investigate the long-term effects of LOD, 116 anovulatory women with PCOS who underwent LOD between 1991 and 1999 were evaluated [36]. The hospital records were reviewed, and most patients attended for a transvaginal ultrasound scan and blood sampling to measure the serum concentrations of LH, FSH, testosterone, androstenedione and sex hormone-binding globulin. The LH:FSH ratio, mean serum concentrations of LH and testosterone and free androgen index decreased significantly after LOD and remained low during the medium- and long-term follow-up periods. The mean ovarian volume decreased significantly from 11 ml before LOD to 8.5 ml at medium-term and remained low (8.4 ml) at longterm follow-up. They concluded that the beneficial endocrinological and morphological effects of LOD appear to be sustained for up to 9 years in most patients with PCOS. The amount of damage inflicted by LOD is much less compared with that by wedge resection. Amer et al. [36] reported no single case of POF during this long follow-up period. In a recent research by Mohiuddin et al. [34], the long-term effects of LOD in a group of women who had participated in a randomised controlled trial 6 10 years earlier was surveyed. It was revealed that 29 of the 33 women who had completed their postal questionnaire had had undergone LOD. The mean FSH level of these women was found to be 5.7 IU/l (SD 3.7) ranging from 50.1 to 18.4 IU/l. The number of periods per year were said to be increased from 3.5 at study entry to 7.8 in the follow-up period in women not on the oral contraceptive. They reported that after undergoing laparoscopic ovarian diathermy, 79% (23 of 29) of the women delivered live infants, and over the follow-up period, 35 babies were delivered. Further fertility treatment was needed by 14 of 29 women who underwent LOD [34]. Since the mean FSH levels did not display an increment, it is suggested that LOD is not a procedure that leads to DOR. Ovarian reserve markers after LOD Ovarian reserve after LOD 161 On extensive research of the literature, four studies have been found which have addressed the ovarian reserve markers related to LOD. Three of the four studies are longitudinal in design and the forth is cross-sectional. The details of these four studies have been presented in Table I and additional characteristics of the studies are as follows: In the first trial, Kandil and Selim [37] have conducted an observational study to assess the ovarian reserve after three different methods for induction of ovulation in 60 women who were between 30 years and 40 years of age and had PCOS. Participants have been divided equally into three groups allocated to clomiphene citrate or ovarian drilling either unilateral or bilateral [37]. Ovarian reserve testing has been performed before and 3 months after the treatment methods. The mean basal serum inhibin B levels showed a significant decrease after bilateral drilling compared with the predrilling level ( vs pg/ml; p ¼ 0.031). The AFCs and summed ovarian volume showed a significant decrease after bilateral drilling ( vs ; p ¼ and vs /mm 3 ; p ¼ 0.001). They have concluded that DOR might occur after bilateral ovarian drilling but not after clomiphene citrate induction of ovulation or unilateral drilling. However, physiological serum inhibin B levels in women with good ovarian reserve are known to be greater than 45 pg/ml [14]. Although Kandil and Selim [37] have shown that the inhibin B levels were significantly decreased after the bilateral LOD, the levels still remained higher than the normal values. Furthermore, the other parameter of ovarian reserve which was the mean AFCs after bilateral laparoscopic drilling (15 follicles) seems to be higher than the normal population values. Kandil and Selim [37] have also concluded that the ovarian volume was statistically significantly decreased. However, the difference between the pre- and post-procedure volumes (1 ml) did not make any clinical implication and the volume after the procedure (10.3 ml on the average) still remained in the range of the normal women at their reproductive age [24 26].

4 162 M. Api Gynecol Endocrinol Downloaded from informahealthcare.com by Yeditepe Univ. on 05/13/15 Table I. Four studies demonstrated in the table addressing the effect of laparoscopic ovarian drilling (LOD) on the ovarian reserve markers. Number of PCOS medically treated PCOS bilateral LOD Normal Authors participants Ovarian reserve PCOS ovulatory [reference] in studies markers Before After p a Before After p b patients controls p c Kandil and Selim [37] Medically treated (n ¼ 20); LOD (n ¼ 20) Day 3 FSH CCCT Day 3 Inhibin B AFC Ovarian volume Lockwood et al. [38] LOD (n ¼ 8); PCOS (n ¼ 10); Control (n ¼ 5) Day 5 Inhibin B Mean FSH NS Mean LH Amer et al. [39] PCOS with LOD (n ¼ 50) Inhibin B NS Inhibin B non-obese NS Inhibin B obese NS LH FSH Weerakiet et al. [40] LOD (n ¼ 21); PCOS (n ¼ 21); Control (n ¼ 21) Day 3 AMH NS d Day 3 Inhibin B 0.82(0 91) NS d 5.16(0 185) 0(0 68.9) NS Ovarian volume NS d Day 3 FSH 6.9( ) ( ) 7.1(4.3 19) AFC 19(8 17) (10 72) 13(5 28) All values are means + SD, only means or median (range) where available. Inhibin B values are in pg/ml, FSH and LH values are in miu/ml, ovarian volumes represent summed volume of both ovaries (cm 3 ). NS, not significant; CCCT, clomiphene citrate challenge test FSH results; AFC, antral follicle count; AMH, Anti-Mullerian hormone (ng/ml). Statistically significant p values are shown with bold figures. a p values for comparison before and after medical treatment. b p values for comparison before and after LOD. c p values for comparison between PCOS without LOD and normal ovulatory controls. d p values for comparison between PCOS with LOD and PCOS without LOD.

5 The second article by Lockwood et al. [38] investigated the possible role of inhibin B in the pathology of PCOS. Serum inhibin B levels have been measured in 10 women with PCOS on cycle Day 5 of a spontaneous or progestrogen-provoked bleed and compared with the levels on cycle Day 5 of 10 women with regular ovulatory cycles [38]. The mean serum inhibin B levels in the PCOS patients were significantly higher than those in normal controls, (248 (+ 43.4) pg/ml vs. 126 (+ 18.6) pg/ ml; p ). In this study by Lockwood et al. [38], 10 women with clomiphene resistant PCOS and 5 normal controls have consented to undergo serial blood sampling on cycle Day 5. Their mean serum inhibin B levels have fallen to the upper limit of the normal range ( pg/ml), and the pulsatility has been recognised to be initiated. It is said that the inhibin B pulses are possibly being generated directly by the ovary in response to the pulses of GnRH in the peripheral circulation, or indirectly in response to FSH pulses arising in the pituitary. They have reported that the function of inhibin B pulses in the mid-follicular phase of the normal cycle remains to be elucidated, but the absence of the normal pulsatile pattern in women with PCOS, in conjunction with high basal levels of inhibin B arising from the multiple small follicles characteristic of the PCOS ovary, appears to reinforce the development of a large cohort of small, developmentally arrested, and ultimately atretic follicles in these patients. They have proposed that initiation of normal inhibin B pulsatility by LOD in patients with polycystic ovaries appears to correlate with the post-operative onset of ovulatory cycles. This study supports that the lower inhibin B levels after LOD in women with PCOS are not translated to be harmful, rather it may restore the deteriorated ovarian function. In the third report addressing the ovarian reserve by Amer et al. revealed that the pre-operative median plasma concentration of inhibin B was 110 pg/ml (range, pg/ml) and no statistically significant change of inhibin B after LOD was observed in the overall group of women with PCOS or in the subgroup of non-obese PCOS women with higher pre-operative inhibin B. They concluded that the lack of any change of inhibin B after LOD makes it unlikely that this hormone has any role to play in the mechanism of action of LOD [39]. Although the previous two reports revealed that inhibin B values were significantly decreased after LOD, it has not been confirmed in the third trial with a larger study population, where the median inhibin B values still remained above the normal population reference levels (Figure 1). The fourth trial addressing the effects of LOD on the ovarian reserve was conducted in a crosssectional design by Weerakiet et al. [40] and they Ovarian reserve after LOD 163 Figure 1. Inhibin B levels before and after laparoscopic ovarian drilling (LOD) in polycystic ovarian syndrome. p values on each consecutive bars represent significance of mean inhibin B values (shown on each bar) in each studies. n values under the names of the authors of each study represent the number of subjects whose inhibin B levels available before and after LOD. Horizontal reference line at 45 pg/ml is the normal lowest level of inhibin B. studied the ovarian reserve in women with PCOS, who underwent LOD. The women with PCOS undergoing LOD were enrolled in the study (the LOD group). Their Day 3 serum AMH, inhibin B, FSH levels, AFC and summed ovarian volume have been compared with those of PCOS women, who did not undergo LOD (the PCOS group, n ¼ 21) and those of normal ovulatory women (the control group, n ¼ 21). AMH levels have been found to be lower in the LOD group ( ng/ml) than in those of the PCOS ( ng/ml) group, where the difference was not statistically significant. On the other hand, AMH levels have been found to be statistically significantly lower in normal ovulatory control group ( ng/ml) than in PCOS group without LOD. Although the AMH levels of the LOD group were found to be lower than the PCOS group without LOD (p ¼ NS) and higher than normal ovulatory control subjects (p ¼ 0.058), the differences were not statically significant. The mean Day 3 serum FSH levels were significantly higher and AFC was significantly lower in the LOD group than those in the PCOS group. AMH levels, AFC and summed ovarian volume were significantly higher, but the mean FSH was significantly lower, in the PCOS group compared with those in the control group. There were no significant differences in the inhibin B levels between groups. The authors have shown that the ovarian reserve was diminished in the LOD-applied PCOS patients when compared with PCOS women who did not undergo a LOD procedure. Both the PCOS women who underwent LOD and those who did not have demonstrated significantly greater ovarian reserve than the age-matched controls having normal ovulatory menstruation [40].

6 164 M. Api Ovarian overactivity theory in PCOS According to the above-mentioned studies, there seems to be a higher ovarian reserve in the PCOS patients when compared with that in the normal ovulatory controls. This higher ovarian reserve might be the responsible pathophysiological background of the high ovarian activity leading to anovulation and other endocrinological disturbances in PCOS. This proposed mechanism of exaggerated ovarian activity can be reduced to the physiological level by a surgical procedure, namely LOD, but sometimes the reduction created by surgery may remain insufficient; therefore, the ovarian hyperfunction still stays at supra-physiologic state [27,41,42]. In addition to the afore-mentioned studies evaluating the short-term effects of LOD on ovarian function, the follow-up studies have demonstrated that the long-term results of LOD were favourable and the theory of ovarian hyperfunction in PCOS has been supported [31 36]. Opponents have argued against these results since most of the pathophysiologic explanations of PCOS were genetic in origin and it was impossible for a metabolic disturbance with a genetic background to be treated by surgery. However, the hypothesis of ovarian overactivity in patients with PCOS is surmised to be similar to the metabolic disturbances in hyperthyroidism. When the thyroid hyperfunction can not be controlled by medical therapies, the surgical alternative namely partial thyroidectomy is performed From this point of view, ovarian hyperfunction could also be restored by surgical destruction of some part of the functional ovarian tissue. If we go back to 1935, Stein and Leventhal [43] incidentally figured out the effectiveness of wedge resection of the ovaries on seven patients (two of them became pregnant), although their main intention was to diagnose the pathology in those hirsute, amenorrhoeic, infertile women rather than to treat them, but this good faith error resulted as the standard of therapy for PCOS until the clomiphene was popularised in early seventies [7]. Some other novel medical alternatives namely, insulin sensitisers, aromatase inhibitors and gonadotrophins have helped for the reproductive problem of women with PCOS. However, a considerable number of women with PCOS do not respond or hyper-respond to these medications and suffer from their unwanted complications. Therefore, in case of medical therapy failure, surgery still remains to be an effective alternative on a hyperfunctioning endocrine organ, namely the polycystic ovaries. Conclusion Based on the limited evidence presented in this review, LOD, when applied properly, does not seem to compromise the ovarian reserve in PCOS women. Data on the long term effects of LOD are reassuring and have not shown an indication of POF or early menopause. Proclamation of its adverse effect as DOR, which is not more than a theoretical concern and not supported by the evidence-based medicine or the practice in this area, is too early until the properly conducted trials reach the final conclusion. The scarce data available in the literature seems to suggest that the exaggerated ovarian function might be the underlying pathophysiology of anovulatory infertility in PCOS. From this point of view, it would not be wrong to assume that reducing the functional ovarian tissue by means of an operative approach namely LOD restores the metabolic disturbances and starts ovulatory cycles. 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