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Middle East Fertility Society Journal Vol. 10, No. 3, 2005 © Copyright Middle East Fertility Society

The effects of different releasing hormone analogues in IVF cycles

Cem Fiçicioğlu, M.D., Ph.D., Assoc.Prof. Seval Taşdemir, M.D. Tayfun Kutlu, M.D. Leyla Altuntaş, M.D.

Zeynep Kamil Women and Children's Hospital, Reproductive Medicine-Infertility & IVF unit, Istanbul.

ABSTRACT

Objective: To compare , Leuprolide and sodium in women undergoing controlled ovarian hyperstimulation for in vitro fertilization cycles. Settings: Zeynep Kamil Women and Children's Hospital Reproductive Endocrinology - Infertility - IVF Center. Material and Methods: Sixty patients were haphazardly distributed for each GnRH-a group. GnRH-a was administrated, starting on the 21st day of menstrual cycles for the long protocol: Triptorelin (Decapeptyl, 0.1 mg) as 0.1 mg/day SC, leuprolide (Lucrine, 5 mg flacon) as 0.5 mg/day SC and nafarelin (Synarel, 2 mg/mi ) as 200 micrograms to each nostril with a daily total dosage of 800 micrograms. The responses from each group were compared on the basis of duration of stimulation, total dosage of gonadotropin, E2 values on day 5, the down regulation duration, cyst formation, E2 values on the 1st day of stimulation and HCG, values and endometrial thickness on the HCG day, the number oocytes picked up, fertilization rates, the number of transferred embryos, and implantation ratios. Results: Evaluating Triptorelin (T), Leuprolide (LA) and Nafarelin (NA) groups respectively, E2 values on the 1st day of menstrual cycles, measured to confirm the down regulation for each GnRH-a, were 24.67 pg/ml, 21.23 pg/ml, 29.62 pg/ml (p<0.05); the total gonadotropin usage (ampoules) were 47.15 ± 12.97, 39.45 ± 13.97, 36.72 ± 13.14 (p<0.05); the number of retrieved oocytes were 9,89 ± 5,98, 10,50 ± 3,69 and 9,19 ± 5,31 (p>0,05); the fertilization rates were 89%, 100% and 100% (p>0.05). The implantation and pregnancy rates, the two major parameters of the study were 5% and 15% in T, 16.5% and 40% in LA, 14.8% and 38.8% in NA groups respectively (p>0,05). Conclusions: Even though the success rates in Triptorelin group were somewhat lower, the results of every GnRH-a group were statistically similar; but to reach the same outcome we had to use more in this former group. Cost-effectivity analysis of the three GnRH-a makes Leuprolide and Nafarelin better choices than Triptorelin. However, we must state that our study has two major limitations to give a concrete conclusion, namely the study was not randomized and the number of patients was very small. Key words: Assisted reproductive techniques, GnRH-a, controlled ovarian hyperstimulation, Triptorelin, Nafarelin, Leuprolide acetate.

Gonadotropin releasing hormone (GnRH) before oocyte retrieval (1) Induction of follicle are used extensively as adjuncts to ovarian development and ovulation in patients with stimulation protocols in Assisted Reproductive anovulatory cycles are secondary usage. Technologies (ART). The analogues are used to Different GnRH analogues with different modulate and control endogenous gonadotropin biological effectiveness, different plasma half life output, their major role is to prevent LH surge and different ways of administration have been developed by modifying the 6th and 10th position Correspondence: Doç. Dr. Cem Fiçicioğlu Bağdat cad. No: 272 amino acids. These changes make the analogue D: 10 Ankara apt. Caddebostan, Istanbul. Tel: 0216 411 53 27, more potent and long lasting. Therefore, there may Fax: 0216 369 59 92, e-mail: [email protected] be significant differences between the clinical

212 Fiçicioğlu et al. Different LHRH- analogues in IVF MEFSJ effects of these specific GnRH agonists. administered to each nostril twice a day, with a Leuprolide has a half life of 90 minutes whereas total dosage of 800 micrograms per day; the last nafarelin's half life is 3-4 hours, triptorelin's half group received 0.1 mg of life is 4,2 hours. Leuprolide is 50-80 times, triptorelin (Decapeptyl, 0.1 mg s.c. injection; Er- nafarelin 200 times, triptorelin 36-144 times more Kim) once a day. On the 2nd day of menstruation powerful than the natural GnRH (2,3). Leuprolide during the analogue application procedure, and triptorelin are administered as sc injection, gonadotropin treatment, highly purified nafarelin as intranasal treatment. Both ways have urofollitrophin (Metrodin HP, 75 IU amp; Serono) absorption effects, which look like the depot effect. with doses between 150-225 IU, was initiated in However, the swallowing and the loss of patients who were assumed to have adequate by proteolysis in intranasal treatment do not occur suppression with E 2 levels less than 50 pg/ml, LH in sc injection. levels less than 5 IU/L, progesterone levels less Our objective is to compare the effects of three than 1 ng/ml and endometrial thickness below 4 different GnRH-a, i.e. Triptorelin, Leuprolide mm. The same day, GnRH analogue dose was acetate and Nafarelin sodium and their ways of halved to lower the gonadotropin requirement and administration in, in vitro fertilization cycles. was given until oocyte pick-up. Cysts bigger than 2 centimeters detected by USG were aspirated in the presence of TV-USG. MATERIALS AND METHODS On 5th day of induction, dosage was increased (step-up protocol) in patients whose 9 60 IVF/ICSI patients were haphazardly mm-sized follicles were less than 3 and E2 levels distributed, in equal numbers, for the 3 GnRH were below 100 pg/ml. On the other hand, step- analogue program groups in our study. After down protocol was administered in patients whose physical and gynecologic examinations, basal follicles were bigger than 11-12 mm and E2 levels hormonal analyses were made for each patient on were above 400 pg/ml. the basis of their blood FSH, LH, and E2 levels Gonadotropin treatment was continued as "step- through immunoenzymatic methods on the 3rd day up" or "step-down" on the basis of USG follow-up of menstruation. Endometrial thickness results and hormonal levels. Treatment cycle was measurements were performed by transvaginal cancelled if developing follicles were less than 3 or ultrasonography. Spermiogram, E2 levels could not reach 300 pg/ml. hysterosalpinography, serologic tests, cervical 10000 IU hCG (Pregnyl 5000 IU, Organon) culture, blood type and CBC were carried out for was injected intramuscularly when at least 3 each couple. Any information about their previous follicles bigger than 18 mm were detected through treatment modalities was recorded. TV_USG and E2 levels were above 150-200 pg/ml Patients who were previously diagnosed with per follicle bigger than 14 mm. 34-36 hours after Polycystic Ovary Syndrome and over 38 years old, the HCG injection follicular aspiration procedure whose FSH levels were above 10 IU/L, in whom was carried out. Controlled Ovarian Hyperstimulation were Mature oocytes were decomposed from the previously tried twice, and for whom TESA or follicular fluid and were placed into IVF-G1 and TESE were planned, were not included in this G-2 culture media. Purification procedure of study. cumulus cells was completed 4-6 hours after The long protocol was applied to each patient, oocyte harvesting followed by microinjection. starting on the 21st day of the . Evaluation of the fertilization was made 16-18 Three different GnRH analogues were used in each hours after microinjection and cells with 2 group. Leuprolide (Lucrin, 5 mg/ml, flacon, pronuclei were separated. Embryos were injections; Abbott) was administered as daily 0.5 transferred in the 48 or 72 hours, using embryo mg subcutaneous injections in one group; in transfer catheter (Wallace 1816 N). another group, 200 micrograms of nafarelin Patients were monitored by serum quantitative (Synarel, 2mg/ml nasal spray; Ali Raif) was hCG levels 12-14 days after embryo transfer.

Vol. 10, No. 3, 2005 Fiçicioğlu et al. Different LHRH- analogues in IVF 213 14

12

10

8 % 6

4

2

0 Male Tubal Unexplained

Triptoreline Leuprolide Nafareline

Figure 1. The causes of infertility in the study groups

Ultrasonographic determination of a gestational Kruskall Wallis Variance Analysis, Student T Test, sac was recognized as a clinical pregnancy. Mann Whitney U Test. Chi-square and Fischer Implantation rate was calculated by dividing the exact tests were used in the comparison of number of gestational sac (single, double, triple) to qualitative data. Results were evaluated with 95% the number of embryos transferred in patients who confidence interval, and the significance at p<0.05 became pregnant. levels. Natural micronised progesterone (Utrogestan, micronised progesterone 100 mg soft capsules, Lab. Besins-Isvesco, Paris) was applied 3x2 RESULTS vaginally until 12th week of gestation as the supply. Sixty subjects, who were accepted into the ART In each group, duration of stimulation, total program, were involved in our study. Each groups dosage of gonadotropin, E2 level on day 5 of the (Triptorelin group (T), Leuprolide group (LA), cycle, duration between the first day of GnRH-a Nafarelin group (NA)) had 20 subjects. The and the first day of menstruation, cyst formation infertility causes of these three groups were ''male during the treatment period, E2 levels at the factor'' for 10, 14 and 11 cases, ''tubal factor'' for 4, beginning of the induction date and on hCG day, 3 and 7 cases, ''unexplained infertility'' for 4, 3 and progesterone level and endometrial thickness on 2 cases respectively. The 2 cases of endometriosis hCG day, number of oocytes retrieved, number of were in the Triptorelin group. The distribution of mature oocytes, rate of fertilization, number of infertility causes between groups was similar embryo transferred, rate of pregnancy and rate of (p>0.05). (Figure 1) implantation were compared. Two patients in the NA group were excluded To evaluate the data, SSPS for Windows 10.0 because of inadequate E2 suppression. COH was program was utilized for statistical evaluation. cancelled in 6 cases out of the remaining 58 Following methods were used in the comparison of because of insufficient ovarian response (2 in each quantitative data: Oneway Anova, Tukey Hsd, group). Embryo transfer could not be completed due

214 Fiçicioğlu et al. Different LHRH- analogues in IVF MEFSJ Table 1. Treatment results in each groups

Triptorelin Leuprolide Nafarelin p

Number of cycles 20 20 18 Stimulation duration (day) 10.10 ± 1.30 9.20 ± 1.70 9.00 ± 1.18 p > 0.05 Gonadotropin dosage (ampoules) 47.15 ± 12.97 39.45 ± 13.97 36.72 ± 13.14 P< 0.05 Day 5,E2(pg/ml) 228.8 ± 160.63 210.67 ± 211.83 228.57 ± 176.53 p > 0.05 Interval between beginning of GNRH-a and 1st day of stimulation 7.10 ± 2.42 8.40 ± 3.15 9.40 ± 2.56 p > 0.05 Cyst formation on GnRHa usage 4 (%20) 1 (%5) 2 (%10.0) p > 0.05 E2 value on the day first day of stimulation (pg/ml) 24.67 ± 5.91 21.23 ± 2.41 29.62 ± 15.7 p < 0.05 E2 (pg/ml) on the day HCG 2090.4±1335.7 2117.9 ± 1236.9 1851.3 ± 1405.9 p > 0.05 Endometrial line on the day HCG (mm) 10.36 ± 2.09 11.17 ± 2.31 10.00 ± 1.74 p > 0.05

to cessation of cellular division in one patient of 24.67 pg/ml in T group, 21.23 pg/ml in LA group Leuprolide group. and 29.62 pg/ml in NA group. The difference was There was no difference of age between the 3 statistically significant, but not clinically (p<0.05). groups; the mean age being respectively 30.55 + There was no statistically significant difference 3.22 (26-38) in the T group, 30.50 ( 28.52 (23-37) between the three groups in terms of the E2 levels in the LA group and 29.94 ( 4.80 (23-38) in the on day 5 of the cycle, stimulation duration, E2 NA group. The basal levels of FSH were also levels on the HCG day and the endometrial similar: 6.5 ( 3.9 mIU/ml in the T group, 6.6 ( 3.7 thickness on the HCG day (Table 1). mIU/ml in the LA group and 6.8 ( 3.9 mIU/ml in The mean number of the gonadotropin the NA group. ampoules that were used during induction was the Effects of menstrual cycle suppressions on highest in T group being 47.15. This was a these three GnRH analogues and the results of the statistically significant difference (Table 1). stimulation have been compared on the basis of 22 However, the gonadotropin usage in LA and the parameters. The period between the first day of the NA groups was similar. GnRH application and the first day of There was no statistically significant difference menstruation was 7.1 days in T group, 8.4 days in between the number of retrieved, mature, fertilized LA group and 9.4 days in NA group. This oocytes and transferred embryos in any groups difference was not significant (p>0,05). But the (p>0,05). (Table 2) period was observed to be the longest in the NA Implantation and pregnancy rates, the two and the shortest in the T group. major parameters of the study were 5% and 15% in Cyst formation occurred in 7 patients during T, 16.5% and 40% in LA, 14.8% and 38.8% in NA GnRH treatment: 4 in the T, 1 in the LA and 2 in groups respectively. Although the Triptorelin the NA group. But no significant difference was group rates were lower than two other groups, this found (p>0.05). These cysts were aspirated by TV- difference was not statistically significant (p>0,05) USG. (Table 3). The mean E2 levels to confirm the adequate suppression on the first day of menstruation were

Table 2. Number of oocytes picked up and fertilization rate according to the groups.

Triptorelin Leuprolide Nafarelin p

Number of retrieved oocytes 9.89 ± 5.98 10.50±3.69 9.19 ± 5.31 p > 0.05 Mature oocytes (%) 75.15± 26.9 73.70±19.23 85.01±15.33 p > 0.05 Fertilized oocytes (%) 46.37±27.03 55.88±19.57 57.80±20.35 p > 0.05 Number of transferred embryos 3.36±1.180 3.44 ± 1.61 3.68 ± 1.30 p > 0.05

Vol. 10, No. 3, 2005 Fiçicioğlu et al. Different LHRH- analogues in IVF 215 Table 3. Pregnancy rates in the groups (%, Per stimulation cycle) .

Triptorelin Leuprolide Nafarelin p

Implantation rates 5.0% 16.5% 14.8% p > 0.05 Pregnancy rates 15.0% 40% 38.8% p > 0.05 Biochemical pregnancy 5% 5% 11.1% p > 0.05 Clinical pregnancy rates 10.0% 35.0% 27.7% p > 0.05 Cycle Cancellation rates 10.0% 10.0% 11.1% p > 0.05

DISCUSSION pregnancy and implantation ratios were in favor of LA, and the mature and fertilized oocyte ratios In ART procedures, GnRH analogues can were in favor of NA. In T group, clinical successfully be used in controlled ovarian pregnancy and implantation ratios were the lowest. hyperstimulation to prevent LH peak and to Tanos et al. compared nafarelin (3x200mcg/day provide better follicular growth and maturation. nasal spray) and triptorelin (0.5 mg/day sc.) in a In initial studies on GnRH analogues, it was prospective study that consisted of ovulation determined that cycle cancellations were induction of 40 patients with normal ovulatory dramatically reduced and rate of were functions and bilateral tubal obstruction (7). clearly increased. Preventing the LH peak, high Triptorelin was administered to 20 patients who quality oocytes were retrieved and pregnancy rates took nafarelin in the first cycle and the other 20 increased. However, total gonadotropin dose patients who took triptorelin in the first cycle were increased also (2). Yet the expense of increased given nafarelin. In this manner, every patient was dosage is compensated by the decrease in cycle provided to be a control for herself. Both agonists cancellation, which results in the rise of the were found to be effective in suppression, while in pregnancy ratios (2,3). triptorelin cycles pituitary and ovarian suppression In recent studies, the effect of premature was more clearly exhibited. This study showed that luteinization on cyclic consequences is under triptorelin cycles implicate less E2 levels and more discussion (1, 4, 5, 6). In addition, it is a fact that gonadotropin usage. Nafarelin was found to be ovarian hyperstimulation may cause excessive economical because of fewer gonadotropin luteinization even with low LH levels (6). In the ampoules used, shorter duration of stimulation and study of Dantas, premature LH peak was not the short period between the first day of GnRH-a observed and premature luteinization did not seem interval and OPU day. In our study, we found to have a major effect on pregnancies determined exactly the same result in point of view of by the embryonic quality and endometrial gonadotropin usage; there was no statistically development since pregnancy ratios were 17% in significant difference in terms of the total both study groups (1). gonadotropin dosages between the LA and NA Corson et al. in a prospective, randomized, groups whereas in T group high total dosages were double blind study, used leuprolide (0.5 mg/day sc) required. The ovarian suppression was the least in in 22 patients and nafarelin (3x200 mcg/day nasal NA group, indicating that not all what is spray) in 17 patients in the IVF long protocol. statistically significant should be clinically According to this study, nafarelin as a nasal spray significant. used for pituitary suppression in COH can be an Martin et al. (8) in a retrospective analysis of alternative to leuprolide sc injection with a few or 226 patients and Franco et al. (9) in another study no quantitative and qualitative differences in terms with 238 patients who used nafarelin and of the HMG dosage used, E2 levels, the amount leuprolide for the IVF cycle, found no statistically and quality of the collected oocytes and significant difference between the two groups in fertilization ratio (2). Even though the difference in terms of the maximum E2 level, the gonadotropin our study was not statistically significant, clinical ampoules used, the amount of collected oocytes,

216 Fiçicioğlu et al. Different LHRH- analogues in IVF MEFSJ ratio of mature and fertilized oocytes, pregnancy and the need for gonadotropin ampoules was less miscarriages, implantation rates and cycle in nafarelin treatment group. Consequently, the cancellation. But take home baby ratio in the study effectiveness of nafarelin was identical in of Martin was 34% in NA and 20% in LA groups comparison to the other GnRH agonists. As our respectively (p<0.05). Martin et al. explained the study results are parallel, Nafarelin seems to be analogues' effect on birth rates with the influence more advantageous and comfortable because of the on oocyte quality. decrease in the number of gonadotropin ampoules In the study of Parinaud et al. (10) which and the way of administration. compared leuprolide, Triptorelin and , it It is well known that pregnancy ratios are was considered that the analogues' effect on oocyte higher in cycles with analogue use (14). Elgendy quality and implantation rates was not only due to and Simon et al suggest reducing the dosage of their impact on the but also due to GnRH-a, as we did, after pituitary suppression at their impact on the ovaries. However, none of the beginning of stimulation in order to lower these hypotheses have yet been tested. There is no gonadotropin usage (15, 16). This has no adverse significant difference among the pregnancy ratios effect on ovarian response and clinical results. in different stimulation cycles. As a conclusion, Finally, GnRH-a should be chosen on the basis with this study, Parinaud et al. assumed that in the of the criteria of cost, patient's comfort, availability higher responder group whose ovarian reserves of the drug, clinical effectiveness and good results. were good, buserelin can be recommended while in It is apparent that studies have different the poor responder group with low ovarian conclusions, but in general LA and NA exhibited reserves triptorelin usage may be appropriate. more successful results than T. We must claim that Loh et al. (11) in a randomized study which our study has two major limitations to give a included the pituitary suppression time, total HMG concrete conclusion and is not fully powered to dosage, the number of retrieved and also frozen answer the question raised: the study was not embryos and clinical pregnancy ratios (for each randomized and the number of patients was very cycle in LA group 21.4%, in NA group 16.3%), small. However we found out that even though the did not determined any statistically significant success rates in Triptorelin group were somewhat difference between LA and NA groups. In our lower, the results of every group were statistically study, clinical pregnancy ratios per stimulated similar; but to reach the same outcome we had to cycle were 35% in LA group and 27.7% in NA use more gonadotropins in this former group. We group. Loh et al. concluded that intranasal think that triptorelin achieves more suppression in nafarelin might be an alternative to and effective as short terms than leuprolide and nafarelin and much as Leuprolide for pituitary suppression. requires more gonadotropin ampoules for Yuzpe et al. (12) compared nafarelin (400 and stimulation. Cost-effectivity analysis of the three 600 mcg/day) and leuprolide (0.5 mg/day) by a GnRH-a makes Leuprolide and Nafarelin better retrospective study of IVF. 12 days after usage of choices than Triptorelin. Clinical effectiveness, GnRH analogue sufficient suppression ratios were patient comfort and its ease of use are the major 82%, 87%, and 65% respectively. Pregnancy ratios advantages of Nafarelin. Leuprolide, in the other on each embryo transfer were 13/60 (22%), 19/63 hand, emerges as a safe and easy handling (30%) and 18/103 (18%) respectively. Pregnancy alternative with a shorter half-life and higher ratio in our study for each transfer was better than success rates and has the advantages of sc injection Yuzpe study and higher in LA group than the NA . group (41% and 31.2% in order). In T group, this rate was 17.6%. Wong et al. (13) formulated a meta-analysis REFERENCES with 1024 patients, 597 of them using nafarelin, 348 buserelin, 14 triptorelin and 55 leuprolide. 1. Dantas ZN, Vicino M, Balmaceda JP, Asch RH, Stone Pregnancy ratios at every embryo transfer were SC. Comparison between nafarelin and leuprolide acetate for in vitro fertilization: preliminary clinical study. Fertil observed to be equal. The stimulation was shorter Steril .1994; 61(4): 705-708

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