{"paper_id":"eb44990a-abd5-4675-af24-b1473efa4a7a","body_text":"Controlled ovarian hyperstimulation improves the cycle fecundity rate in part by increasing the number of follicles available for fertilization and correcting subtle, unpredictable ovulatory dysfunction. Intrauterine insemination (IUI) is an established treatment for infertility due to cervical factor, male factor, or with an unexplained etiology. Combined with IUI, ovulation induction (OI) is recommended for many causes of infertility in patients with patent fallopian tubes ( 1 ). The overall success rate of IUI is approximately 10-15% ( 2 , 3 ). Women with minor endometriosis or infertility due to unknown reasons may elect to undergo OI/ IUI to increase the pregnancy rate, but the risk of multiple gestations is also increased ( 3 ). To date, no ideal stimulation protocol that provides a high pregnancy rate and low rate of complications such as ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies has been identified ( 3 , 4 ).\nOI aims at the selection of a single follicle that will be able to reach the pre-ovulatory size and rupture. A recent retrospective cohort study indicated that induction of more than one follicle did not improve the ongoing pregnancy rate, but increased the risk of multiple pregnancies ( 3 ). Thus, it was suggested that in all IUI cycles for unexplained non-conception monofollicular growth should be sought to reduce the number of multiple pregnancies. Controlled OI with recombinant human follicle stimulating hormone (rFSH) has been shown to be predictive of ongoing pregnancy rate, and studies have attempted to determine the r-FSH threshold (i.e. r-FSH dose on the day when a follicle is <10 mm in diameter) on the basis of pre-treatment and screening characteristics ( 4 , 6 ). The Gonal-f  ® New Generation Pre-Filled Pen (Merck\nSerono, Germany) is a disposable, pre-filled drug delivery system intended for the subcutaneous injection of multiple and variable doses of a liquid formulation of r-FSH. It is indicated to induce the development of multiple follicles in patients participating in an assisted reproductive technology program ( 7 , 10 ). Though limited data is available, studies have also shown that r-FSH seems to be at least as effective as urinary FSH preparations ( 11 , 13 ) and exhibits a similar safety profile ( 11 ).\nBecause the induction of more than one follicle does not increase the pregnancy rate, but does increase the risk of multiple gestations, the r-FSH threshold that can result in monofollicular development should be identified. The purpose of this study was to evaluate the safety and efficacy of an r-FSH low-dose step-up regimen for OI/IUI.\n\nThis was a single center, prospective, observational study on the use of r-FSH ( Gonal-f  ®  in\nsubjects undergoing OI/IUI. All patients provided written informed consent for participation in the study, and the study was approved by the Research Ethics Committee of Far Eastern Memorial Hospital, New Taipei, Taiwan.\nThe inclusion criteria were women between 20 and 35 years of age, regular menstrual cycles of 25-35 days, the presence of both ovaries, normal uterine cavity and patent fallopian tubes as investigated by either ultrasound scan, hysteroscopy, or hysterosalpingography, normal baseline serum FSH level (<10 μg/dL), and male partner semen analysis considered adequate for IUI in accordance to the center’s standard practice (i.e. <1×10  7  sperm/mL after sperm\nwashing). The exclusion criteria included extrauterine pregnancy or abortion in the past 3 months, abnormal gynecologic bleeding of undetermined origin, history of OHSS, and known hypersensitivity to human rFSH preparations.\nThe objective of r-FSH therapy is to develop\na single mature Graafian follicle from which the\novum will be liberated after the administration\nof hCG. A starting dose of r-FSH 112.5 IU/day\nwas begun on the 3 rd  day following an induced\nor spontaneous menses. Transvaginal ultrasound\n(SSD-1700, Aloka Co., Japan) monitoring was\nperformed every 2 days beginning on the 7 th  day.\nIf on the 7 th  day, a follicle had not reached 11 mm\nin diameter, the dose was increased to 150 IU/day\n(+37.5). If ultrasound on the 9th day did not show\na follicle had reached 11 mm, the dose was again\nincreased by 37.5 IU (187.5 IU/day). The same increase\nwas made if on the 11th day, a follicle had\nnot reached 11 mm. The maximum dose administered\nwas 225 IU/day.\nWhen an optimal response was obtained (dominant\nfollicle ≥18 mm), a single subcutaneous injection of\nrecombinant-human chorionic gonadotropin (r-hCG,\n6500 IU, Ovidrel®, Merck Serono, Germany) was\nadministered 24 hours after the last r-FSH injection.\nSerum estradiol (E 2 ) was measured on the day of rhCG.\nIntrauterine insemination was then performed\n24 hours later. If an excessive ovarian response (i.e.\nE 2 >3500 μg/dL) occurred, treatment was stopped and\nr-hCG withheld. A new cycle was then initiated at a\nlower r-FSH dosage than that of the prior cycle, and\nthe cycle with the hyper-response was excluded from\nthe analysis. A maximum of three cycles (excluding\nthose in which a hyper-response occurred) were allowed\nin an individual patient.\nMonifollicular development was defined as only one follicle with a diameter ≥16 mm. Clinical pregnancy was defined as a pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs based on the definition proposed by the International Committee for Monitoring Assisted Reproductive Technology (ICMART) ( 14 ).\nThe primary endpoint was the clinical pregnancy rate. The secondary endpoints were multiple pregnancy rate and occurrence of OHSS. The Shapiro-Wilk test was implemented to test whether the distributions of continuous variables met the assumption of a bell shape. Normally distributed continuous data were presented as mean ± standard deviation (SD), while categorical data were presented as number (n) and percentage (%). Nonnormally distributed data were presented as median (range). Descriptive statistics were performed using Statistical Package for the Social Sciences (SPSS) version 15.0 (SPSS Inc., USA).\n\nBetween January 2010 and September 2010, 30\nconsecutive women were enrolled in the study. The\nstudy was conducted in the Department of Obstetrics\nand Gynecology, Far Eastern Memorial Hospital,\nNew Taipei, Taiwan. One patient with an abnormal\nbaseline serum FSH level was excluded in the follow-\nup visit. Twenty-eight women underwent only\none OI/IUI cycle. One woman failed to get pregnant\nat her first OI/IUI cycle, and then received her 2nd OI/\nIUI cycle. Thus, a total of 30 OI/IUI cycles were performed\nin this study and analyzed.\nBaseline data are shown in  table 1 . On the day of r-hCG, all 30 cycles had follicles at least 16 mm in diameter, the median E 2 level was 898.0 pg/mL, and the mean endometrial thickness was 12.0 mm. The average total r-FSH dose was 1030.0 IU, and the average daily r-FSH dose was 122.5 IU. The average r-FSH dose when the follicular diameter was <10 mm in diameter (i.e. threshold of r-FSH) was 131.3 IU. The average length of time from the first injection of r-FSH until the day of r-hCG injection was 8.0 days. Twelve cycles met the defined criteria for monofollicular development on the day of r-hCG administration ( Table 2 ).\nClinical pregnancy was observed in nine ( 30.0%, 95% confidence interval (CI)=12.6 to 47.4%) cycles, and a total of nine gestational sacs were found at follow-up. However, lack of fetal heart activity was found in two gestational sacs, thus the pregnancy rate in which a fetal heart beat was present was 23.3% (95% CI=7.3 to 39.4%). OHSS was observed in three (10.0%, 95% CI=0 to 21.4%) cycles and in all cases was grade I (mild: ascites with bilateral ovarian size less than 8 cm). In all patients, OHSS symptoms resolved within 1 week with conservative management.\nThere were two subjects with eight follicles ≥16 mm, and they had high estradiol levels, 3205 pg/ ml and 3493 pg/ml. These two subjects had a hyper-response, but did not get pregnant.\nBaseline patient data (n=29)\n*;There were four cases of male factor infertility. In these cases,\nthe sperm concentration after washing was >1×107/ml, which\nwas considered adequate for IUI.\na ; Mean ± standard deviation,  b ; Number (percentage),  c ; Median\n(range), BMI; Body mass index, IUI; Intrauterine insemination,\nFSH; Follicle stimulating hormone, r-FSH; Recombinant FSH and\n§;The 5 patients with tubal factor infertility had tubal obstruction\nand/or adhesions which were treated prior to participation\nin the study.\nClinical variables and outcomes of 30 cycles of ovulation induction and intrauterine insemination\nMonifollicular development was defined as only one follicle with a diameter ≥16 mm.\na ; Median (range),  b ; Mean ± standard deviation, c; Number (percentage; 95% confidence interval), E 2 ;\nEstradiol, OHSS; Ovarian hyperstimulation syndrome, hCG; Human chorionic gonadotropin and r-FSH;\nRecombinant follicle stimulation hormone.\n\nThe r-FSH low-dose step-up regimen described\nin this study was shown to be associated with a\ngood clinical pregnancy rate (30.0%), and no\nmultiple pregnancies were observed. In addition,\nthough OHSS occurred in 10% of the cycles, all\ncases were mild and resolved with conservative\nmanagement.\nr-FSH, which completely lacks LH activity and\nextraneous human protein, has numerous advantages\nover prior medications ( 8 ,  10 ,  11 ). The results\nfrom a recent randomized study suggests that\nthe use of r-FSH, as compared to urinary formulations,\nresults in an increased clinical pregnancy rate\n[25.9% with follitropin alpha, 13.8% with urinary\nFSH and 12.5% with hepatic 3-hydroxy-3-methylglutaryl\n(hMG)] in IUI cycles for unexplained infertility ( 2 ). Another study, however, found that\nhighly purified urinary FSH is as efficacious as r-\nFSH for ovulation induction in women with World\nHealth Organization (WHO) group II anovulatory\ninfertility ( 12 ) and provides a similar singleton\nlive birth rate (15.1% with urinary FSH group vs.\n15.4% with r-FSH), despite a difference in clinical\npregnancy rate (17.8% with urinary FSH group\nvs. 21.8% with r-FSH group). Based on the clinical\npregnancy rate data of the two aforementioned\nstudies, it seems that the use of r-FSH in our study\nis a reasonable choice for OI/IUI.\nAs with prior FSH formulations, an ideal protocol\nof r-FSH has yet to be determined. Our protocol\naimed for a monofollicular cycle and this\noccurred in 41.4% of the cases. It is always a challenge\nto determine the FSH threshold to achieve a monofollicular cycle. The lowest dose to develop\na follicle has to be determined and then the optimal\ndose for a monofollicular cycle is determined. In\nthis study, we set the endpoints as clinical pregnancy\nrate, multiple pregnancy rate, and OHSS\nrate rather using an endpoint of monofollicular\ncycles. With a starting dose of r-FSH of 112.5 IU,\na few women will be hyper-responsive. These patients\nmay do better with a lower dose (i.e. 75 IU\nof r-FSH), but a dose of 75 IU r-FSH might not\nreach the FSH threshold for most of the patients.\nThe two subjects with eight follicles ≥16 mm exhibited\na hyper-response, but did not get pregnant.\nThey may have other infertility problems which\nmay be addressed by  in vitro  fertilization (IVF).\nDespite the fact that no multiple pregnancies in our study, there were two subjects with a hyperresponse. Thus, we cannot neglect the possibility of multiple pregnancies while utilizing this regimen into clinical practice.\nDemirol and Gurgan ( 2 ) reported an OI protocol\nwith a daily dose of 75 IU r-FSH if the patient’s\nbody mass index (BMI) was <25 kg/m 2 , and 150\nIU if the patient’s BMI was ≥25 kg/m 2 . Balen et\nal. ( 12 ) treated patients with the starting dose of\n75 IU r-FSH daily for 7 days, and then an increase\nof 37.5 IU increments according to the individual\nresponse. Chung et al. ( 15 ) compared two different\nr-FSH doses (150 IU vs. 100 IU every other\nday) with 5 days of concomitant clomiphene citrate\n(100 mg/day) for OI/IUI, and found that the\nlow r-FSH dose (100 IU) resulted in a lower multiple\npregnancy rate (12.5%). However, the clinical\npregnancy rates reported by the authors (14.5% in\nthe 150 IU group and 20.4% in 100 IU group) were\nlower than the 30% found in our study. Though\nthe starting r-FSH dose (112.5 IU) in our study\nwas higher than that of Balen et al. ( 12 ) and equal\nto the average of Demirol and Gurgan ( 2 ), the\nnon-inferior clinical pregnancy rate in our study\n(30.0%) as compared to those (25.9%) and Balen\net al. (21.8%), lack of multiple pregnancies and\nlow OHSS rate suggests our protocol a viable\nchoice for OI/IUI ( 2 ,  12 ).\nThe primary limitations of this study are the small sample size and lack of control group. A randomized controlled study comparing the rFSH low-dose step-up regimen with spontaneous/ natural cycles would be beneficial. The low-dose regimen described may decrease the overall cost; however, a cost analysis was not part of the study design.\n\nThe r-FSH low-dose step-up regimen for OI/IUI is a practical method with a low rate of complications and low risk of multiple pregnancies for younger infertile women with good pre-treatment characteristics. Further clinical studies are required to define the optimal dose of r-FSH, and whether the same regimen can be applied in aged patients with a similar outcome.","source_license":"CC-BY-4.0","license_restricted":false}