TECHNIQUES AND INSTRUMENTATION

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1 TECHNIQUES AND INSTRUMENTATION FERTILITY AND STERILITY VOL. 76, NO. 4, OCTOBER 2001 Copyright 2001 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. Transvaginal ovarian drilling: a new surgical treatment for improving the clinical outcome of assisted reproductive technologies in patients with polycystic ovary syndrome Anna P. Ferraretti, Ph.D., Luca Gianaroli, M.D., Maria C. Magli, B.Sc., Elisabetta Iammarrone, M.D., Elisabetta Feliciani, M.D., and Daniela Fortini, B.Sc. Reproductive Medicine Unit, Società Italiana per gli Studi sulla Medicina della Riproduzione srl, Bologna, Italy Objective: To evaluate the efficacy of transvaginal ovarian drilling (TVOD) in patients with polycystic ovary syndrome (PCOS) who were undergoing IVF treatment. Design: Pilot study. Setting: Reproductive medicine unit. Patient(s): Eleven patients with PCOS undergoing treatment with assisted reproductive technology (ART). Intervention(s): Selection criterion for TVOD was repeated poor performance in 2 previous IVF cycles. Main Outcome Measure(s): Controlled ovarian hyperstimulation parameters, number of eggs collected, fertilization rate, embryo cleavage rate, implantation rate, pregnancy rate compared with the cycles before TVOD. Result(s): In the cycle after TVOD, a significantly higher dosage of FSH was used ( IU vs IU) to collect a higher number of oocytes in the presence of similar E 2 values at the day of hcg administration. This resulted in significantly higher fertilization and cleavage rates (27% vs. 66% and 54% vs. 72%, respectively). The pregnancy and the implantation rates after TVOD were similar to those for normovulatory patients undergoing IVF for tubal factor infertility during the study period. Conclusion(s): Our data suggest that the TVOD is effective in improving IVF results in difficult to treat patients with PCOS, and it is less invasive and less expensive when compared with laparoscopic ovarian diathermy. (Fertil Steril 2001;76: by American Society for Reproductive Medicine.) Key Words: Ovarian drilling, PCOS, IVF treatment, pregnancy rate, implantation rate Received December 22, 2000; revised and accepted April 23, Reprint requests: Anna P. Ferraretti, Ph.D., Società Italiana per gli Studi sulla Medicina della Riproduzione srl, Via Mazzini, 12, 40137, Bologna, Italy (FAX: ; sismer@sismer.it) /01/$20.00 PII S (01) Polycystic ovary syndrome (PCOS) that is associated with infertility can be a difficult therapeutic problem. It is clear that the first approach taken for women with PCOS should be the administration of antiestrogen therapy, but while clomiphene citrate (CC) is successful in inducing ovulation in more than 80% of the treated women, the cumulative pregnancy rate after 6 months of therapy is only 40% (1). The therapeutic option for patients with PCOS who fail to conceive with CC is gonadotropin therapy. Gonadotropin treatment in these patients offers a cumulative pregnancy rate of 70% after 4 6 cycles (2) but is associated with an increased risk of developing severe ovarian hyperstimulation syndrome (OHSS) and an increased rate of multiple pregnancy (3). Over the past 10 years, IVF-ET has been offered to the patients with PCOS who failed to conceive after repeated ovulation induction and, of course, to patients with PCOS with other infertility factors. Patients with PCOS undergoing treatment with assisted reproductive technology (ART) show a different performance compared with normovulatory infertile patients (4). Patients with PCOS respond differently to controlled ovarian hyperstimulation compared with women with normal ovaries, and they are more likely to have canceled cycles because of 812

2 the high risk of OHSS (5) or because of a lack of E 2 increase, despite the growth of several small follicles (6). In addition, the general consensus from published studies is that patients with PCOS yield a greater number of oocytes per retrieval but have a lower proportion of fertilized eggs and a lower percentage of morphologically normal embryos compared with women with tubal infertility (7). However, when normal cleaving embryos are available for transfer, the pregnancy rate and the live-birth rates are comparable to those for other infertile couples (8, 9). An intrinsic egg factor seems to be responsible for the limited performance of infertility treatments in some patients with PCOS, but when this ovarian factor is overcome, the implantation rate of the developed embryos seems to be similar to normovulatory women undergoing ART. Nevertheless, a subgroup of patients with PCOS repeatedly produce poor results in IVF treatment and require special care (10). Since laparoscopic ovarian diathermy (LOD) has replaced ovarian wedge resection, this surgical treatment has been offered to CC-resistant patients with PCOS even to increase the spontaneous ovulation rate and to decrease complications from gonadotropin treatment in simple ovulation induction or in ART cycles. In addition, a significantly better ongoing pregnancy rate after the IVF-ET procedure in women pretreated by means of LOD has been reported (11). In this study, we tested the efficiency of a new surgical approach, which consists of transvaginal ovarian drilling (TVOD) in difficult to treat patients with PCOS undergoing IVF. MATERIALS AND METHODS Between January 1998 and December 1999, 11 patients with PCOS, aged years, were selected for the study out of 823 patients undergoing treatment with ART. They had a duration of infertility of years. PCOS diagnosis was based on the typical ultrasound (US) patterns as described by Adams (12), anovulation or oligomenorrhoea with LH/FSH ratio higher than 3 (mean values: LH, miu/ml; FSH, miu/ml), and testosterone levels 0.6 ng/ml (mean value, ng/ml). The body mass index was kg/m 2, and late onset congenital hyperplasia was excluded. The selection criterion was repeated poor performance in at least 2 previous IVF cycles using GnRH agonist down-regulation protocols (13). The patients were asked to undergo TVOD before entering a new treatment cycle with the aim of improving IVF outcome. They were informed that this procedure was a new technique, the efficiency of which has not yet been demonstrated, although LOD, performed with the same aim, has already been demonstrated to be efficient. The specific consent form was approved by our Institutional Review Board. TVOD was performed under anesthesia with Propofol (Diprivan; Zeneca, Basiglio, Milan, Italy) using a 17-gauge, 35-cm long needle (K-OPS-1235-Cook IVF, Brisbane, Australia), connected to a continue vacuum pressure (Craft pump; Rocket Medical, Watford, UK). Each ovary was repeatedly punctured from different angles, and all the small follicles visible by US were aspirated and scraped. Patients were discharged after 2 3 hours and followed up with by US, hematocrit, and hemoglobin concentration the next morning. After TVOD, all patients were asked to enter a new IVF cycle as soon as possible. In this cycle, they were stimulated using conventional controlled ovarian hyperstimulation (COH) protocols and monitoring parameters as in the previous unsuccessful IVF cycles performed before TVOD. In each patient, the starting exogenous FSH dosage was the same as that used in the cycles performed before TVOD. Insemination technique, oocyte and embryo culture conditions, and transfer procedure were similar in all cycles before and after TVOD according to the description in Gianaroli et al. (14). During the TVOD procedure, the aspirated material was observed in the IVF laboratory with the aim of recovering immature oocytes to use for our research protocol for in vitro maturation if an informed consent was previously obtained from the couple. RESULTS Before TVOD, the patients underwent 23 cycles. Twelve cycles were canceled for different reasons: ovarian response with high risk of developing OHSS (circulating E 2 levels 1,000 pg/ml [conversion factor to SI units, 3.671] on cycle day 7; 3 cycles), poor response (less than three preovulatory follicles; 2 cycles), or lack of follicular growth 12 mm and/or lack of E 2 increase 100 pg/ml despite an increased daily FSH dosage of up to 450 IU/d (7 cycles). In the remaining 11 cycles that reached egg retrieval because of adequate response, 10.3 oocytes/cycle were collected after using a mean number of ampoules of FSH. The fertilization rate was 27% and the embryo cleavage rate 54%. Only 5 cycles yielded embryos available for transfer, but no embryo implantation was observed. The 11 patients underwent TVOD without any complication. The surgical procedure lasted 35 6 minutes; no bleeding during or after the puncture was observed; no abdominal/pelvic pain and no temperature rise was reported after patient discharge. Figure 1 shows the US appearance of the ovaries before surgical procedure and on the next day. The typical US imaging (several small echoless areas between 2 and 5 mm, mainly distributed in the subcapsular region) changed after TVOD into a more homogeneous feature. Eighty-five nonatresic immature oocytes collected during the procedure from the first five patients were entered into a research study, the results of which have been already published (15). FERTILITY & STERILITY 813

FIGURE 1 Appearance of the ovaries by ultrasound before transvaginal ovarian drilling (A) and 24 hours later (B). Patients began a new IVF cycle 2 6 months after TVOD.

3 FIGURE 1 Appearance of the ovaries by ultrasound before transvaginal ovarian drilling (A) and 24 hours later (B). Patients began a new IVF cycle 2 6 months after TVOD. In these cycles, all patients reached the egg retrieval stage and a mean number of oocytes were collected. The fertilization rate was 66%. In one cycle, all the zygotes were cryopreserved because of OHSS risk (16) and the patient underwent two thawed transfer cycles. Out of 12 transfers, seven (58%) clinical pregnancies occurred: six regular and ongoing to term and one spontaneously aborted at 11 weeks. One case of severe OHSS requiring hospitalization occurred in one pregnant patient. She was treated according to our previously published protocol (17), and the pregnancy continued to term. Up to date, eight healthy babies have been born. Table 1 compares the cycles performed after TVOD with the 23 cycles performed for the same 11 patients before TVOD. After TVOD, a significantly higher dosage of FSH was required by patients to develop adequate follicular growth and a higher number of oocytes were collected, but similar E 2 levels occurred on the day of hcg administration. The fertilization and cleavage rates were significantly higher after TVOD, and normal cleaving embryos were available 814 Ferraretti et al. Transvaginal ovarian drilling Vol. 76, No. 4, October 2001

4 TABLE 1 In vitro fertilization results in 11 patients with polycystic ovary syndrome before and after transvaginal ovarian drilling (TVOD). Variable Before TVOD After TVOD No. of stimulated cycles No. of canceled cycles 12 0 No. of egg retrievals No. of FSH ampoules a b 17 E 2 at hcg (pg/ml) a 3, , No. of follicles 16 mm at the day of hcg administration No. of eggs a Fertilization rate, % b Embryo cleavage rate, % b No. of transferred cycles (%) 5 (22) 12 (100) Embryos/ET a No. of surplus embryos cryopreserved 0 13 No. of clinical pregnancies (%) 0 7 (58) Implantation rate, % 26 Full-term pregnancy rate, % 50 a Values are mean SD. b P.05. for transfer in all cycles. The pregnancy and the implantation rates in these difficult to treat patients with PCOS after TVOD was similar to normovulatory patients undergoing IVF for tubal factor infertilty during the study period (Table 2). DISCUSSION Invasive surgical treatment for PCOS to restore physiological function has been demonstrated to be effective since TABLE 2 In vitro fertilization results in normovulatory infertile patients, aged years, treated during the study period (January 1998 December 1999). Variable Value No. of stimulated cycles 511 No. of canceled cycles 54 No. of egg retrievals 457 No. of FSH ampoules a E 2 at hcg (pg/ml) a 2,102 1,039 No. of eggs a Fertilization rate, % 73 Embryo cleavage rate, % 75 No. of transferred cycles 328 b No. of clinical pregnancies (%) 134 (41) Implantation rate, % 27 Full-term pregnancy rate, % 37 a Values are mean SD. b In 109 cycles, all the zygotes were cryopreserved for OHSS risk (18). This approach was the preferred therapy until the early 1970s, when it was demonstrated that it is associated with a high incidence of postoperative pelvic adhesions that may lead to subsequent mechanical infertility (19). The development of operative laparoscopy permitted the introduction of a minimally invasive procedure for surgical treatment of patients with PCOS. The first publication concerning pregnancies after laparoscopic ovarian biopsy with cauterization dates back to 1972 (20). Since early 1980, the LOD approach for PCOS CCresistant patients was described by several investigators using unipolar current, mechanical scissors, or laser technique. The experiences of the different investigators have been recently collected into a complete review (11). The results reported after LOD show small differences according to the technique used, and the global percentage of ovulatory cycles was 78.1%, with a spontaneous pregnancy rate of 49.4%. In addition, some investigators showed that LOD pretreatment improves the results in patients with PCOS undergoing treatment with ART (low cancellation rate, higher implantation rate, lower miscarriage rate) (21, 22). The precise mechanism through which surgical therapy improves the ovarian function in patients with PCOS has not yet been defined. It has been postulated that ovarian trauma may impair local androgen synthesis with associate reduction of intraovarian androgen levels and a diminished androgen inhibitory effect on follicular maturation (23). Decreased androgen levels may result in lowered peripheral conversion of androgen to estrogen and hence in a decreased positive feedback on LH secretion (24). It is likely that other factors, such as inhibin and other unknown local ovarian substances, may also be involved (25). The removal of these inhibitor factors through the drainage of ovarian microcysts or the destruction of ovarian tissue can permit the recruitment of a new cohort of follicles either spontaneously or under exogenous FSH stimulation. In this study, we showed that even the new TVOD technique can act at the ovarian levels to improve the subsequent follicular maturation and therefore the oocyte competence under COH for IVF. The 11 patients with PCOS selected by repeated poor performance and/or poor oocyte quality in ART cycles showed a significantly better performance when pretreated by means of TVOD: no cycle cancellation and significantly higher fertilization and cleavage rates, which suggest a better intrafollicular oocyte maturation. After TVOD, the ovarian response of the studied patients to exogenous gonadotropins, the implantation rates, and the pregnancy rates were similar to equally aged normovulatory women undergoing ART because of tubal factor or male factor infertility. The requirement of higher doses of FSH to develop an equal number of preovulatory follicles after TVOD suggests a modified ovarian responsiveness to FSH, more similar to normovulatory patients. However, TVOD did not completely prevent the occurrence of OHSS. FERTILITY & STERILITY 815

5 Compared with LOD, TVOD seems to have the same efficacy, at least in improving IVF results in difficult to treat patients with PCOS, with the advantages of being less invasive and less expensive. In addition, TVOD leads to the aspiration of all small follicles present in the deeper ovarian structure visible by US and may reduce the risk of adhesion formation that can result from LOD (26, 27). The number of cases reported is too small to draw any conclusions, but the excellent results observed after TVOD in a particular group of difficult to treat patients with PCOS encourage the routine use of this procedure in patients with PCOS undergoing treatment with ART. If the results are confirmed in a larger group of patients, this simple surgical approach can even be evaluated for restoring spontaneous ovulatory cycles, as suggested by Mio et al. in 1991 (28). References 1. European Society of Human Reproduction and Embriology (ESHRE). Female infertility: treatment options for complicated cases. Hum Reprod 1997;12: Tadokoro N, Vollenhoven B, Clark S, Baker G, Kovacs G, Burger H, et al. Cumulative pregnancy rates in couples with anovulatory infertility compared with unexplained infertility in an ovulation induction program. Fertil Steril 1997;9: Hamilton-Fairley D, Franks S. Common problems in induction of ovulation. Clin Obstet Gynaecol 1990;4: Balen A. In-vitro fertilization and the patient with polycystic ovaries. In: Kovacs GT, ed., Polycystic ovary syndrome. Cambridge: Cambridge University Press, 2000: Smith J, Camus M, Devroeye P, Evard P. Incidence of severe ovarian hyperstimulation syndrome after gonadotropin releasing hormone agonist/hmg superovulation for in-vitro fertilization. Hum Reprod 1991; 6: Owen EJ, West CA, Mason BA, Jacobs HS. Cotreatment with growth hormone for poor responders in IVF-ET. Fertil Steril 1991;56: Dor J, Shulman A, Levran D, Feldberg D, Ashkenazi D, Ben-Rafael Z. The treatment of patients with polycystic ovary syndrome by in-vitro fertilisation: a comparison of results with those patients with tubal infertility. Hum Reprod 1990;5: MacDougall JM, Tan SL, Balen AH, Jacobs HS. A controlled study comparing patients with and without polycystic ovaries undergoing in vitro-fertilisation and the ovarian hyperstimulation syndrome. Hum Reprod 1993;8: Homburg R, Berkowitz D, Levy T, Feldberg D, Ashkenazi D, Ben- Rafael Z. In-vitro fertilization and embryo transfer for the treatment of infertility associated with polycystic ovary syndrome. Fertil Steril 1993; 60: Kodama H, Fukuda J, Karube H, Matsui T, Shimizu Y, Tanaka T. High incidence of embryo transfer cancellations in patients with polycystic ovarian syndrome. Fertil Steril 1995;10: Cohen J. Laparoscopic surgical treatment of infertility related to polycystic ovary syndrome. In: Kovacs GT, ed., Polycystic ovary syndrome. Cambridge: Cambridge University Press, 2000; Adams J, Franks S, Polson DW. Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotropin-releasing hormone. Lancet 1985; Ferraretti AP, Magli C, Feliciani E, Montanaro N, Gianaroli L. Relationship of timing of agonist administration in the cycle phase to the ovarian response to gonadotropins in the long down-regulation protocols for assisted reproductive technologies. Fertil Steril 1996;65: Gianaroli L, Fiorentino A, Magli CM, Ferraretti AP, Montanaro N. Prolonged sperm-oocyte exposure and high sperm concentration affect embryo viability and pregnancy rate. Hum Reprod 1996b;11: Anderiesz C, Ferraretti AP, Magli C, Fiorentino A, Fortini D, Gianaroli L, et al. Effect of recombinant human gonadotropin on human, bovine and murine oocyte meiosis, fertilization and embryonic development in vitro. Hum Reprod 2000;15: Ferraretti AP, Gianaroli L, Magli C, Fortini D, Selman HA, Feliciani E. Elective cryopreservation of all pronucleate embryos in women at risk of ovarian hyperstimulation syndrome: efficiency and safety. Hum Reprod 1999;14: Ferraretti AP, Gianaroli L, Diotallevi L, Trounson AO. Dopamine treatment for severe ovarian hyperstimulation syndrome. Hum Reprod 1992;7: Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935;29: Dahlgren E, Johansson S, Lindstedt G, Knutsson F, Odèn A, Olof JP, et al. Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long-term follow-up focusing on natural history and circulating hormone. Fertil Steril 1992a;57: Cohen J, Audebert A, De Brux J, Giorgi H. Biopsie ovarienne et survenue d une grossesse. Nouvelle Presse Medicale 1972;1: Gurgan T, Yarali H, Urban B. Laparoscopic treatment of PCO disease. Hum Reprod 1994;9: Tulandi T, Saleh A, Morris D, Jacobs HS, Payne NN, Tan SL. Effects of laparoscopic ovarian drilling on serum vascular endothelial growth factor and on insulin responses to the oral glucose tolerance in women with polycystic ovary syndrome. Fertil Steril 2000;74: Greenblatt E, Casper RF. Endocrine changes after laparoscopic ovarian cautery in polycystic ovarian syndrome. Am J Obstet Gynecol 1987; 42: Sumioki H, Utsunomiya T. Ovarian drilling. In: Kempers R, Cohen J, Haney AF, Yongers JB, eds., Fertility and reproduction medicine. New York: Elsevier Science 1998: Tropeano G, Liberale I, Vuolo IP, Barini A, Caroli G, Carfagna P, et al. Effects of ovary suppression by a long-acting GnRH-agonist on circulating GH, insulin-like growth factor I and insulin levels in women with polycystic ovary syndrome. J Endocrinol Invest 1997;20: Dabirashrati H, Mohamad K, Behjatnia Y, Moghadami-Tabrizi N. Adhesion formation after ovarian electrocauterization on patients with PCO syndrome. Fertil Steril 1991;55: Naether OGJ, Fischer R. Adhesion formation after laparoscopic electrocoagulation of the ovarian surface in polycystic ovary patients. Fertil Steril 1993;60: Mio Y, Toda T, Tanikawa, Terado H, Harada T, Terakawa N. Transvaginal ultrasound guided follicular aspiration in the management of anovulatory infertility associated with polycystic ovaries. Fertil Steril 1991;56: Ferraretti et al. Transvaginal ovarian drilling Vol. 76, No. 4, October 2001

In Vitro Fertilization in Clomiphene-Resistant Women with Polycystic Ovary Syndrome

Original Article Effect of Laparoscopic Ovarian Drilling on Outcomes of In Vitro Fertilization in Clomiphene-Resistant Women with Polycystic Ovary Syndrome Maryam Eftekhar, M.D. 1, Razieh Deghani Firoozabadi,