{"paper_id":"68082095-4390-4b9a-8501-c648ca9cece0","body_text":"Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2012 Jun; 156(2):159–163.\n159\nThe efficacy of conversion from IUI to IVF-ET in infertility patients \nwith hyper-response to ovulation induction: A retrospective study\nYiping Zhonga#, Jin Lib#, Ying Yinga, Haitao Wua, Canquan Zhoua, Yanwen Xua, Qiong Wanga, Jie Lia, Xiaoting Shena\nBackground. The aim of the study was to determine the efficacy of in vitro fertilization and embryo transfer (IVF-ET) \nin patients with hyper-response to ovulation induction for intrauterine insemination (IUI).  \nMethods. Patients with polycystic ovary syndrome (PCOS) who were initially treated with IUI in our centre between Jan \n2007 and Oct 2010 were retrospectively analyzed. The ovarian hyper-stimulation syndrome (OHSS) found in 50 patients \nwas then treated with IVF-ET following informed consent.  \nResults. The fresh transfer had 42 cycles and a total of 87 embryos were transferred. Urine pregnancy tests were posi-\ntive in 15 patients and fetal heart beat was detected in 12 patients by transvaginal ultrasound, from which 3 patients \nhad two fetuses, 2 patients had three fetuses, and 7 patients had a single fetus. The overall clinical pregnancy rate was \n28.5% (12/42) for the fresh embryo transfer. A total of 21 cycles of frozen embryo transfer with up to 55 embryos were \nconducted for patients who were not pregnant at the end of fresh embryo transfer cycles or who did not receive fresh \nembryo transfer in the first place. Urine pregnancy tests were positive in 10 patients and fetal heart beat was detected \nin 8 patients. The clinical pregnancy rate was 38.1% (8/21) for frozen embryo transfer. \nConclusion. We conclude that IVF-ET is an effective method for patients with hyper-response to ovulation induction \nin IUI.\nKey words: polycystic ovary syndrome, in vitro fertilization and embryo transfer, ovulation induction, intrauterine \ninsemination\nReceived: September 9, 2011; Accepted with revision: April 12, 2012; Available online: June 1, 2012\nhttp://dx.doi.org/10.5507/bp.2012.044\naReproductive Medicine Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, 510080\nbGuangdong No.2 Provincial People's Hospital, Guangzhou, China, 510000\n#Authors contributed equally to the work\nCorresponding author: Canquan Zhou, e-mail: zhoucanquan@hotmail.com \nINTRODUCTION \nWith the advance of assisted reproductive technology, \na combination of ovulation induction with intrauterine \ninsemination (IUI) has achieved great success in the treat-\nment of infertility. However, the pregnancy rate remains \nstill unstable and depends on the condition of each indi-\nvidual case. To select the appropriate time window for \nIUI, the common way is to utilize the natural cycle or \novulation induction and monitor the follicle phase. Cycle-\nstimulated or non-cycle-stimulated IUI is considered as \nthe first-line treatment for infertility caused by common \netiological factors, including asthenozoospermia, semen \nliquefaction, sexual dysfunction, abnormal secretion of \nthe female cervical mucus, and immunological complica-\ntions\n1,2. In addition, many retrospective and prospective \nstudies have confirmed that using gonadotropin (Gn) to \nstimulate ovary and increase the number of follicles can \nachieve a better fertilization and implantation rate, thus \nultimately improving the pregnancy rate\n3. \nAlthough this approach generally increases the clinical \npregnancy rate, a subset of hyper-responsive patients reports \nmultiple follicle development and over-stimulation of the \novary, resulting in an increased risk of multiple pregnancy, \npreterm birth, miscarriage, and obstetric complications. \nFor these patients, successful pregnancy depends on careful \ncontrol of the cycles, adjustment of the Gn dose, cancella-\ntion of the cycle or use of in vitro fertilization and embryo \ntransfer (IVF-ET). The level of estradiol (E2) and the num-\nber of follicles determine whether the cycles need to be can-\ncelled or IVF-ET should be performed. Fortunately, with \nthe development and application of gonadotropin-releasing \nhormone analogues (GnRH-a), the conversion from IUI to \nIVF-ET becomes more feasible. Furthermore, cycle cancel-\nlation is frustrating for both the patients and physicians, and \nposes huge burdens, both psychologically and financially, \non the patients and their families. The conversion from IUI \nto IVF-ET can largely avoid this problem.\nInterestingly, to date, few studies have investigated the \nefficacy of the conversion from IUI to IVF-ET. In this \npresent study, we directly addressed this and reported the \nefficacy of IVF-ET in patients who suffered from hyper-\nresponse to ovulation induction for IUI.\nMATERIALS AND METHODS\nSubjects\nAll the subjects in this study were chosen from pa-\ntients admitted to the Center for Reproductive Medicine \n\nBiomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2012 Jun; 156(2):159–163.\n160\nTable 1. Basic clinical information of the subjects.\nConversion \nfrom IUI to \nIVF-ET\nAge\n(yr)\nduration of \ninfertility (yr)\nBMI\n(kg2/cm)\nBasic FSH\n(IU/L)\nLH\n(IU/L)\nPRL\n(ng/mL)\nE2\n(pg/mL)\nT\n(ng/mL)\n30.90±4.02 4.82±3.16 20.46±1.97 4.82±1.50 6.31±5.29 19.89±9.66 40.40±21.87 0.82±0.50\nat the First Affiliated Hospital of Sun Yat-sen University \nbetween Jan 2007 and Oct 2010. The study was approved \nby the ethics committee of Sun Yat-sen University and \nwritten consent was obtained from all subjects. Patients \nwith liver and kidney disorders, acute or chronic infec-\ntious diseases and reproductive tract inflammation were \nexcluded. All subjects had polycystic ovary syndrome \n(PCOS). Oviduct liquid passing test, hysterosalpingog-\nraphy and/or laparoscopy examinations confirmed that \nat least one side of the oviduct was clear. All patients \nreceived IUI with informed consent. Among these pa-\ntients, 50 cases displayed hyper-response of the ovary to \nthe ovulation induction drugs and were switched to IVF-\nET treatment with further informed consent. Infertility \nwas caused by ovulation failure, cervical factors, immu-\nnological factors, mild endometriosis, male factors (such \nas asthenozoospermia and semen liquefaction), and other \nunexplained infertility.\nConversion from IUI to IVF-ET\nA total of 50 patients had 50 cycles. Starting 3-5 \ndays after the menstrual cycle, the basic evaluation was \nconducted by ultrasound examination. If the size of the \npoly-cysts was smaller than 10 mm, medication was ini-\ntiated with commonly prescribed Gn, such as human \nmenopausal gonadotropin (HMG) or follicle-stimulating \nhormone (FSH), at the dose of 75-150 IU. After constant \nmedication for 4-6 days, transvaginal B-ultrasound exami-\nnation was performed to monitor the development of fol-\nlicles and the dose of the drugs was adjusted accordingly. \nBased on our clinical experience and previous literature, \nhyper-response to Gn was operationally defined as the \noccurrence of more than 4 follicles with a diameter larger \nthan 14 mm or the level of E2 higher than 1500 pg/mL \n(ref.\n4). Once hyper-response was found, we consulted with \nthe patients and decided whether the cycle needed to be \ncancelled or IVF-ET needed to be performed. Most of \nthe patients consented to switch to IVF-ET. If more than \n3 follicles had a diameter larger than 17 mm or more \nthan 2 follicles had a diameter larger than 18 mm, or the \nurine luteinizing hormone (LH) test was positive, human \nchorionic conadotropin (HCG) was injected intramuscu-\nlarly at a dose of 5,000-10,000 IU. Approximately 35-36 h \nafter the HCG injection, vaginal ultrasound-guided oocyte \nretrieval was performed by the puncture of ovary. Three \ndays after the oocyte retrieval, embryo transfer was con-\nducted. Luteal support was accomplished by intramuscu-\nlar injection of progesterone at a dose of 40 mg per day, \nor intramuscular injection of 2000 IU HCG every three \ndays for a total of 4 days, or utilization of progesterone \nvaginally. Fourteen days after the embryo transfer, a morn-\ning urine pregnancy test was performed. If the pregnancy \ntest turned out to be positive, the medication was con-\ntinued. The occurrence of the embryo sac by ultrasound \nexamination 3 weeks later indicated clinical pregnancy. If \nthe embryo sac examination was negative, the medication \nwas terminated.\nSemen collection and processing\nAccording to World Health Organization standard \nprocedures, semen samples from the patients’ couples \nwere collected after 3-7 days of sex abstinence using the \nmasturbation sperm retrieval method. Semen samples \nwere delivered to the laboratory within 30 min. After gra-\ndient centrifugation and upstream processing, the sperm \nconcentration was adjusted to 1×10\n6/mL. The volume of \nthe semen for fertilization was 0.2-0.5 mL. Regular testing \nwas performed on the semen samples before and after \nwashing.\nStatistical analysis\nThe data were expressed as mean ± standard devia-\ntion (SD). The statistical analysis was performed using \nMicrosoft Excel software.\nRESULTS\nBasic clinical information of the subjects\nThe average age of the subjects was 30.90 ± 4.02 yr, \nranging from 23 to 42 yr. Of the patients, 33 had primary \ninfertility and 17 had secondary infertility. The average \nduration of infertility was 4.82 ± 3.16 yr, ranging from 1 \nto 15 yr. The average body mass index (BMI) was 20.46 \n± 1.97, ranging from 16.80 to 27.34. The average level \nof basic FSH was 4.82 ± 1.50 IU/L, ranging from 0.5 \nto 7.28 IU/L. The average level of LH was 6.31 ± 5.29 \nIU/L, ranging from 0.7 to 26.43 IU/L. The average level \nof prolactin (PRL) was 19.89 ± 9.66 ng/mL, ranging from \n4.3 to 45.74 ng/mL. The average level of E2 was 40.40 ± \n21.87 pg/mL, ranging from 10 to 98 pg/mL. The average \nlevel of testosterone (T) was 0.82 ± 0.50 ng/mL, ranging \nfrom 0.07 to 2.75 ng/mL (Table 1). \nCycle parameters of the patients\nThe total dose of Gn used was 1339.2 5 ±826.74 IU, \nranging from 450 to 2200 IU. The average number of fol-\nlicles larger than 14 mm was 8.24 ± 2.98, ranging from 4 \n\nBiomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2012 Jun; 156(2):159–163.\n161\nTable 2. Cycle parameters of the patients.\nConversion \nfrom IUI to \nIVF-ET\nGn total dose Number of \nfollicles>=14mm\nThickness of \nthe endome-\ntrium (mm)\nOvum\nnumber\nNumber of \nfertilized \novum\nNumber of \nnormal embryo-\ngenesis\nNumber of \navailable \nembryos\n1339.25±826.74 8.24±2.98 10.85±2.43 14.37±7.76 7.65±5.03 7.44±4.92 5.29±4.20\nTable 3. Clinical efficacy of conversion from IUI to IVF-ET.\nGroup\nCycles\nEmbryos \ntransferred\nClinical \npregnancy \nrate\nBiochemical \npregnancy\nSpontaneous \nabortion\nOviductal \npregnancy\nSingle fetus\nTwo fetuses\nThree fetuses\nFresh transfer 42 87 (12/42) 28.5% 0 21732\nFrozen transfer 21 55 (8/21) 38.1% 1 10521\nto 22. Ovum was collected from 49 patients with an aver-\nage number of 14.37 ± 7.76, ranging from 2 to 35. Ovum \nwas not collected from 1 patient. Ovum was fertilized in \n49 patients. The average number of fertilized ovum was \n7.65 ± 5.03, ranging from 1 to 20. The average number of \nnormal embryogenesis was 7.44 ± 4.92, ranging from 1 to \n20. The average number of available embryos was 5.29 ± \n4.20, ranging from 1 to 18. The average thickness of the \nendometrium was 10.85 ± 2.43 mm, ranging from 6 to \n19mm when HCG was injected (Table 2). \nClinical efficacy of conversion from IUI to IVF-ET\nFresh embryo transfer was cancelled in 6 cases to \nprevent the occurrence of ovarian hyper-stimulation syn-\ndrome (OHSS). The fresh transfer had 42 cycles and a \ntotal of 87 embryos were transferred. Urine pregnancy test \nshowed positive in 15 patients and fetal heart beat was de-\ntected in 12 patients by transvaginal ultrasound, of which \n3 patients had two fetuses, 2 patients had three fetuses, \nand 7 patients had single fetus. In the remaining 3 cases, \nextrauterine pregnancy occurred in 1 patient and no fetal \nheart beat was detected in 2 patients. The overall clinical \npregnancy rate of IVF-ET was 28.5% (12/42). Among \nthe 6 patients who did not receive fresh embryo transfer, \n1 patient to date has not undergone embryo transfer yet. \nIn another case, after thawing, the frozen embryo was \ncompleted lyzed and thus no transfer was performed. A \ntotal of 21 cycles of frozen embryo transfer with up to \n55 embryos were conducted for the patients who were \nnot pregnant at the end of fresh embryo transfer cycles \nor who did not receive fresh embryo transfer in the first \nplace. Urine pregnancy test was positive in 10 patients and \nfetal heart beat was detected in 8 patients by transvaginal \nultrasound, of which 2 patients had two fetuses, 1 patient \nhad three fetuses, and 5 patients had single fetus. For the \nremaining 2 cases, no fetal heart beat was detected in 1 \npatient and biochemical pregnancy occurred in 1 patient. \nThe clinical pregnancy rate was 38.1% (8/21) (Table 3). \nDISCUSSION\nIn our hospital, the cycle pregnancy rate of patients \nreceiving IUI treatment fluctuates between 8% and 15%. \nThe fresh cycle pregnancy rate is 28.5% and the frozen \ncycle pregnancy rate is 38.1%, which are slightly lower \nthan those reported (57% and 48%, respectively) (ref.\n4,5). \nA randomized, case-control study reveals that in infertility \npatients caused by male factors or mild endometriosis, \nthe live birth rate of artificial insemination for patients \nwith mild ovarian hyper-stimulation is higher than that for \npatients without any condition\n6. A recent comprehensive \nanalysis of patients with unexplained infertility shows that \nthe pregnancy rate of artificial insemination with moni-\ntored ovulation cycles is 4%. In comparison, the natural \npregnancy rate guided by mild hyper-stimulation of cycles \nis 8%. Moreover, the pregnancy rate of artificial insemina-\ntion combined with mild hyper-stimulation of cycles can \nreach 18% (ref.\n7).  \nIn this study, all 50 patients who converted from IUI \nto IVF were hyper-responders. Based on the Rotterdam \ncriteria, all patients were diagnosed as PCOS, which was \nconsidered an indication of potential hyper-responder. \nFor these patients, the traditional effective treatment ap-\nproach for infertility, the IUI combined with ovulation in-\nduction, has profound disadvantages including high rates \nof cycle cancellation and multiple fetal implantations\n8. \nPrevious studies have showed that the rate of multiple \nfetal implantations is 7.5-29% (ref.\n9) in patients receiving \nIUI and ovarian stimulation10.\nMost previous studies which compared the pregnancy \nrate between the IVF group and the conversion from IUI \nto IVF group reported that the clinical pregnancy rate \nwas similar between the two groups. However, the im-\nplantation rate in the conversion from IUI to IVF group \nwas much higher than that in the regular IVF group\n4. A \nrelated finding is that the E2 level in the conversion from \nIUI to IVF group was significantly lower than that in the \n\nBiomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2012 Jun; 156(2):159–163.\n162\nregular IVF group. High levels of E2 may increase uterine \ncontraction and thus adversely affect the IVF implanta-\ntion rate. However, some other studies report opposite \nfindings\n11.\nThe application of Gn for ovulation cycle stimula-\ntion and IUI treatment has the following characteristics. \nFirstly, Gn improves the quality of the eggs and sperms \nduring the therapeutic cycle, which increases the probabil-\nity of pregnancy\n12. Secondly, administration of HMG can \ncorrect a variety of abnormalities caused by critical luteal \ndysfunction, including low LH peak, abnormal LH secre-\ntion, abnormal follicular development, low levels of E2 \nsecretion cycle, luteinized unruptured follicle syndrome, \nand ovarian incompetence. Thirdly, recombinant Gn can \nameliorate the low levels of FSH in patients with PCOS. \nFourthly, direct injection of treated sperms into the uter-\nine cavity provides a reasonable therapy for the treatment \nof infertility caused by oligospermia, asthenospermia and \ncervical factors. Finally, application of Gn can achieve a \nremarkable pregnancy rate of 23% for patients with unex-\nplained infertility. To sum up, it is a simple, effective, and \neconomic method\n13. \nIf such complications happen in IUI medical centers \nwith IVF capabilities, the patients should be offered IVF \ntreatment as an alternative. For IUI medical centers with-\nout IVF faciltiies, the patients should be transferred to \nother hospitals where IVF is routinely performed. \nConversion to IVF can reduce the occurrence of \ncomplications and potential risks that the patients may \nexperience. More importantly, larger numbers of ova \nand embryos can be obtained after conversion to IVF \nand this increases the pregnancy rate. Compared to con-\ntrolled ovarian hyperstimulation (COH) followed by IVF, \nthe conversion from IUI to IVF uses lower doses of Gn. \nFor this reason,  patients can have better endometrial re-\nceptivity, the implantation rate can be increased, and the \ncost can be lowed\n14. When there are more than 4 follicles \nlarger than 14 mm on the day HCG was injected; multiple \nfollicles can develop\n15. In the present study, the average \nnumber of follicles obtained from 49 patients was 14.37, \nwhich is consistent with previous findings. These results \nsuggest that IVF treatment should be considered when \nthere are more than 4 dominant follicles larger than 14 \nmm on the day HCG is injected. \nThe selection of appropriate ovulation stimulation \nprogram and handling of multiple follicle development \nshould be considered with extreme caution for the treat-\nment of infertility patients with hyper-responses. PCOS \npatients have the potential for hyper response to ovulation \nstimulation. Therefore, cancellation of the cycle or conver-\nsion to IVF should be well-prepared ahead of ovulation \nstimulation. For example, electrocardiogram, chest X-ray \nand other IVF-related examinations should be performed \nin advance. However, there is relatively insufficient sup-\nport to conduct the tube baby test (body check). Cycle \ncancellation can prevent the occurrence of OHSS, but it \nalso poses huge burdens on the patients, both psychologi-\ncally and financially. In medical centers with the ability \nto perform IVF, most patients with hyper-response to \novulation stimulation prefer conversion to IVF to cycle \ncancellation. \nOne study has reported that a combination of follicle \nrupture and IUI can be used in patients with multiple fol-\nlicle development during the process of ovulation stimula-\ntion\n16. On the one hand, this can increase the possibility \nfor pregnancy. On the other hand, rupture of the follicles \nand controlling the number of the implanted embryos \ncan reduce the likelihood of multiple pregnancy and over-\nstimulation of the ovary. Multiple pregnancy rates can \nalso be reduced by aspiration of supplementary follicles \nfollowed by IUI (ref.\n15). In the present study, we also man-\naged to aspirate some of the ova using ultrasound-guided \nfollicle aspiration. The aspirated ovum was used for IFV \nand the formed embryo was frozen. The remaining 1 or \n2 mature follicles were used for IUI treatment or directed \nnatural pregnancy. This strategy worked well for the most \nof our patients.  \nApplication of an antagonist is also feasible during \nthe process of ovarian stimulation and IUI treatment. \nHowever, this reduces the clinical pregnancy rate, possibly \ndue to its impact on the endometrial receptivity. Rather \nthan pure antagonist treatment, mild stimulation of the \novary can be achieved by personalized therapeutic pro-\ngram. For example, during the first ovulation stimulation, \nclomiphene or letrozole may be individually administered; \nwhereas in the later stage, Gn can be used for ovulation \nstimulation. Finally, for those patients with high BMI, \nappropriate pretreatment should be conducted before in \nvitro reproductive techniques are used. For example, im-\nprovements of living habits and increasing the physical \nactivity can be beneficial for losing weight.\nIn summary, our results demonstrate that conver-\nsion to IVF-ET is an efficient method for patients with \nhyper-responses to ovulation induction during regular IUI \nstimulation cycle. In addition, it has a relatively high preg-\nnancy rate. However, the choice of in vitro reproductive \ntechnique varies in each case. For example, single embryo \ntransfer may be considered to avoid multiple pregnancies \nfor those patients with relatively good conditions\n5. The \nlimitation of this study is small number of subjects and \nlack of a control group in which the hyper-responsive pa-\ntients remain on IUI treatment. We believe that prospec-\ntive, multi-site, randomized, and case-control studies are \nurgently need to determine the feasibility and effective-\nness of conversion to IVF in hyper-responsive patients \nwith unknown causes or male factors infertility.\nACKNOWLEDGEMENT\nThe work was supported by science and technology \nprojects of Guangdong Province (2009B030801155) and \nresearch projects for the members of the Guangdong \npopulation and family planning committee (2010243).\n\nBiomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2012 Jun; 156(2):159–163.\n163\nCONFLICT OF INTEREST STATEMENT\nAuthor’s conflict of interest diclosure:  The authors \nstated that there are no conflicts of interest regarding the \npublication of this article.\nREFERENCES\n 1. Karande VC, Korn A, Morris R, Rao R, Balin M, Rinehart J, Dohn K, \nGleicher N. 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