Comparison of follitropin β administered by a pen device with follitropin β administered by a conventional syringe in patients undergoing IVF-ET

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1 ORIGINAL ARTICLE pissn eissn Clin Exp Reprod Med 2011;38(1):37-41 Comprison of follitropin β dministered by pen device with follitropin β dministered by conventionl syringe in ptients undergoing IVF-ET Hyuk-Je Kng 1, Chung-Hoon Kim 1, Jun-Woo Ahn 1, Hyng-Ah Lee 2, Sung-Hoon Kim 1, Hee-Dong Che 1, Byung-Moon Kng 1 1 Division of Reproductive Endocrinology nd Infertility, Deprtment of Obstetrics nd Gynecology, Asn Medicl Center, University of Ulsn College of Medicine, Seoul; 2 Deprtment of Obstetrics nd Gynecology, Kngwon Ntionl University Hospitl, Kngwon Ntionl University School of Medicine, Chuncheon, Kore Objective: To compre the effectiveness nd convenience of pen device for the self-dministrtion of follitropin β with conventionl syringe delivering follitropin β solution in ptients undergoing IVF-ET. Methods: GnRH gonist long protocol ws used for controlled ovrin stimultion (COS) in ll subjects. A totl of 100 ptients were rndomized into the pen device group or the conventionl syringe group on the first dy of COS. Locl tolernce rections were ssessed within 5 minutes, t 1 hour nd t 3 hours fter ech injection. On the dy of hcg injection, ptients were sked to rte their overll pin nd convenience experienced with self-injection on visul nlogue scle (VAS). Results: There were no differences in ptients chrcteristics between the two groups. The durtion of COS ws significntly shorter in the pen device group thn in the conventionl syringe group. Ptients included in the pen device group needed significntly smller mount of follitropin β. However, no differences between the two groups were found in IVF results nd pregnncy outcome. The incidence of locl pin within 5 minutes, t 1 hour nd t 3 hours fter the injection ws significntly lower in the pen device group. VAS scores indicted tht injections using the pen device were significntly less pinful nd more convenient. Conclusion: The pen device for self-dministrtion of follitropin β is less pinful, sfer nd more convenient for the ptients, nd cn be more effective becuse of the shorter durtion nd smller dose of follitropin β when compred with the conventionl syringe. Keywords: Ovultion Induction; In Vitro Fertiliztion; Injections, Subcutneous; Follicle Stimulting Hormone, Bet Subunit; Humn Introduction Urinry FSH hd been replced by recombinnt humn FSH (rhfsh) Received: Sep 5, 2010 Revised: Oct 27, 2010 Accepted: Nov 11, 2010 Corresponding uthor: Chung-Hoon Kim Division of Reproductive Endocrinology nd Infertility, Deprtment of Obstetrics nd Gynecology, Asn Medicl Center, University of Ulsn College of Medicine, Pungnp-dong, Songp-gu, Seoul , Kore Tel: Fx: E-mil: chnkim@mc.seoul.kr * Presented t 61th Annul Meeting of Americn Society of Reproductive Medicine in Montrel, Cnd. *This work ws supported by the Orgnon grnt This is n Open Access rticle distributed under the terms of the Cretive Commons Attribution Non-Commercil License ( which permits unrestricted non-commercil use, distribution, nd reproduction in ny medium, provided the originl work is properly cited. becuse rhfsh hs lower risk of immunogenicity nd infection thn tht of the urinry products. Recombinnt products re highly pure ( > 99%), nd indeed, no ntibodies to FSH hve been detected in serum smples from ptients who hve injected rhfsh. Therefore, the use of this recombinnt product hs resulted in more efficient nd predictble ovultion induction or controlled ovrin stimultion (COS). Additionlly, rhfsh hs been shown to be suitble for subcutneous (SC) dministrtion nd SC injections llow for esy self-dministrtion by ptients [1,2]. RhFSH ws first vilble s freeze-dried lyophilized powder, which hd to be dissolved in wter for injection before dministrtion. Recently, rhfsh hs been mde vilble s premixed redy-to-use solution nd this product hs been considered more ptient friend- Copyright THE KOREAN SOCIETY FOR REPRODUCTIVE MEDICINE 37

2 Clin Exp Reprod Med 2011;38(1):37-41 ly. A subsequent dvnce in ptient-friendly regimens is the development of rhfsh solution, which is stored in crtridge form for dministrtion with pen device. This multiple-use pen device for SC self-dministrtion of rhfsh, which is pproved under the brnd nme Puregon Pen hs been vilble in Europe since This pen injector is n dpted insulin pen, which hs been shown to be better ccepted by dibetes ptients in comprison with conventionl syringes, s it provides for n esier, sfer, more ccurte nd more discrete insulin injection [3]. This study ws performed to compre the effectiveness nd convenience of pen device for the self-dministrtion of rhfsh (follitropin β) with conventionl syringe delivering rhfsh solution in ptients undergoing COS for IVF-ET. Methods This study ws prospective, rndomized, single center, group comprtive study. A totl of 100 infertile Koren women who were scheduled for IVF-ET with or without ICSI were enrolled in this study nd they were divided into the pen device group or the conventionl syringe group by computer-generted rndomiztion list using rndom numbers on the first dy of COS. The ptients were yers of ge t the time of screening, nd hd norml ovultory cycles (24-35 dys in length), hd body mss index (BMI) between 18 nd 29 kg/m², nd were willing to self-inject rhfsh. Ptients who hd history of current endocrine bnormlities, such s polycystic ovry syndrome, hyperprolctinemi, nd previous history of IVF-ET in which less thn three oocytes were retrieved were excluded in this study. Ptients who hd ny bnormlities tht would interfere with dequte stimultion, previous hospitliztion due to severe ovrin hyperstimultion syndrome (OHSS), history of previous (within 12 months) or current buse of lcohol or drugs were lso excluded from this study. All ptients received the sme COS regimen, GnRH gonist lutel long protocol using triptorelin cette (Decpeptyl; Ferring, Mlmo, Sweden). After n bsence of ovrin ctivity ws confirmed by trnsvginl ultrsound nd/or serum estrdiol levels fter the dministrtion of triptorelin cette for t lest 2 weeks, ovrin stimultion with rhfsh ws crried out in both groups, strting with 200 or 250 IU follitropin β. On the first dy of ovrin stimultion, ll subjects were rndomized to self-dminister rhfsh using pen device (Puregon Pen; Orgnon, Oss, Netherlnd) equipped with needle sized 29 G 13 mm or conventionl syringe equipped with needle sized 25 G 16 mm by computer generted rndomiztion list using rndom numbers. On the first dy of ovrin stimultion, ptients were instructed how to self-inject subcutneously into the bdominl wll round the umbilicus with pen device or conventionl syringe nd supervised in order to ensure correct self-injection. After stimultion dy 5, the dose of follitropin β ws djusted ccording to the individul ovrin response monitored by trnsvginl ultrsound exmintions. When one leding follicle reched 18 mm in dimeter or 2 or more follicles reched 17 mm, oocyte mturtion ws triggered with 10,000 IU of hcg (Pregnyl; Orgnon) dministered s single intrmusculr injection. Trnsvginl ultrsound-guided oocyte retrievl ws performed 36 hours fter hcg dministrtion. Embryos were trnsferred 3 dys fter oocyte retrievl. Lutel support ws provided by dministering 90 mg of vginl progesterone gel (Crinone gel 8%; Serono SA, Genev, Switzerlnd) once dily from the dy of oocyte retrievl. Serum β-hcg levels were mesured 11 or 12 dys fter embryo trnsfer. Pregnncies were confirmed by rising serum β-hcg concentrtions nd trnsvginl ultrsonogrphic evidence of gesttionl sc. If pregnncy ws dignosed, vginl progesterone dministrtion ws continued for nother 5 to 7 weeks. Clinicl pregnncy ws defined s the presence of gesttionl sc by ultrsonogrphy, while the miscrrige rte per clinicl pregnncy ws defined s the proportion of ptients who filed to continue development before reching 20 weeks of gesttion mong ll clinicl pregnncies. 1. Locl tolernce nd convenience ssessment After every injection of follitropin β, the severity of locl tolernce symptoms ws ssessed by the ptients themselves nd recorded in locl tolernce diry book, within 5 minutes, t 1 hour nd t 3 hours fter injection. Locl tolernce items scored were pin, redness, itching, bruising nd swelling. The severity of symptoms ws scored s none, mild, moderte, or severe. The incidence of ech locl tolernce item ws compred between the pen device group nd the conventionl syringe group. Incidence indictes the percentge of subjects with mild, moderte or severe locl tolernce symptoms for ech item t ech ssessment. Additionlly, on the dy of hcg dministrtion, ptients were sked to rte their overll pin nd convenience experienced with this self-injection method on visul nlogue scle (VAS). The VAS rnged from 0 (severe pin, not convenient) to 10 (no pin, very convenient). 2. Sttisticl nlysis The men vlue ws expressed s the men ± stndrd devition (SD). A Student s t-test ws used to compre the men vlues. The chi-squre test nd Fisher s exct test were used for the comprison of frctions. Sttisticl significnce ws defined s p <0.05. All nlyses were performed using SPSS ver (SPSS Inc., Chicgo, IL, USA). 38

3 HJ Kng et l. Pen device vs. conventionl syringe for follitropin β Tble 1. Ptients chrcteristics Results Pen Syringe p-vlue No. of ptients Ptients ge (yr) 33.2± ±3.5 NS Husbnds ge (yr) 37.8± ±5.9 NS Infertility durtion (yr) 3.4± ±1.9 NS Ptients with primry infertility 16 (32.0) 18 (36.0) NS BMI (kg/m²) 25.6± ±2.4 NS Endocrine profile Bsl FSH (miu/ml) 6.2± ±1.3 NS Bsl LH (miu/ml) 5.4± ±1.6 NS T (ng/ml) 0.3± ±0.1 NS Free T (pg/ml) 0.5± ±0.2 NS SHBG (nmol/l) 52.4± ±13.3 NS Estrdiol (pg/ml) 29.8± ±9.6 NS Prolctin (ng/ml) 13.4± ±3.5 NS Indictions Tubl/peritonel fctor 22 (44.0) 21 (42.0) NS Mle fctor 16 (32.0) 18 (36.0) NS Unexplined 12 (24.0) 11 (22.0) NS Vlues re presented s men±sd or number (%). NS, not significnt; BMI, body mss index; FSH, follicle stimulting hormone; LH, luteinizing; T, testosterone; SHBG, sex hormone binding globulin. There were no differences in the ge of ptients nd spouses, BMI, infertility durtion, the rte of the ptients with primry infertility, bsl endocrine profile nd indictions for IVF/ICSI between the two groups (Tble 1). The durtion of COS with rhfsh ws significntly shorter in the pen device group thn in the conventionl syringe group (p < 0.05). Ptients included in the pen device group needed significntly less rhfsh, with 2,091.0 ± IU compred with 2,248.0±405.0 IU in the conventionl syringe group (p<0.05). However, no differences were found between the two groups in the numbers of oocytes retrieved, mture oocytes, fertilized oocytes, grde I/ II embryos, frozen embryos nd trnsferred embryos. Also, there were no differences between the two groups in the clinicl pregnncy rte, implnttion rte, miscrrige rte, multiple pregnncy rte nd the incidence of severe OHSS (Tble 2). The incidence of locl pin within 5 minutes fter injection ws significntly lower in the pen device group (p < 0.05). The incidence of locl redness within 5 minutes fter injection ws lso significntly lower in the pen device group (p<0.05). The incidence of locl pin t 1 hour nd 3 hours fter injection were significntly lower in the pen device group (p< 0.05, p<0.05) (Figure 1). The men overll pin score ssessed by VAS ws significntly higher in the pen device group thn in the conventionl syringe group (9.3±0.9 vs. 8.6±1.4; p<0.01), Tble 2. Comprison of controlled ovrin stimultion results nd IVF outcome nd the convenience score ws lso significntly higher in the pen device group (9.4 ± 0.7 vs. 8.0 ± 1.6; p<0.001). Discussion Pen Syringe p-vlue No. of cycles No. of ICSI cycle 15 (30.0) 16 (32.0) NS Durtion of COS (dy) 8.7± ±1.3 p<0.05 Totl dose of rhfsh (IU) 2,091.0± ,248.0±405.0 p<0.05 No. of oocytes retrieved 9.8± ±2.7 NS No. of MII oocytes 8.9± ±2.8 NS No. of fertilized oocytes 8.8± ±2.8 NS No. of grde I, II oocytes 3.2± ±1.3 NS No. of frozen embryos 1.7± ±1.1 NS No. of embryo trnsferred 2.9± ±0.3 NS Clinicl pregnncy rte 17/50 (34.0) 18/50 (36.0) NS Implnttion rte 19/145 (13.1) 20/150 (13.3) NS Miscrrige rte 4/17 (23.5) 4/18 (22.2) NS Multiple pregnncy rte 2/17 (11.8) 2/18 (11.1) NS Incidence of severe OHSS 1/50 (2) 2/50 (4) NS Vlues re presented s number (%) or men±sd. ICSI, intrcytoplsmic sperm injection; NS, not significnt; COS, controlled ovrin stimultion; rhfsh, recombinnt humn follicle stimulting hormone; MII, metphse II; OHSS, ovrin hyperstimultion syndrome. The introduction of pen device for the dministrtion of recombinnt insulin in the tretment of dibetes resulted in significnt improvements for ptients in terms of locl discomfort, ccurte dosing nd convenience to the ptients [4-6]. The development of the pen device mde it possible for ptients to self-inject mediction, reduce the number of visits to the clinic nd dminister ccurte doses of drugs. A similr pen device for the injection of gondotropin ws deemed necessry for the convenience nd effectiveness of the ptients. A study by Voortmn et l. [7] demonstrted tht injections of similr mounts of follitropin β using either dissolved cke with conventionl syringe or redy-for-use solution with pen device were bio-equivlent, fter correction for injection losses by weighing the mount injected with norml syringe. A difference of pproximtely 18% ws found between serum FSH concentrtions obtined using the two formultions, which ws cused by differences between the nticipted volume nd the ctul volume injected with the norml syringe [7]. Another study showed tht follitropin β dministered with pen device is not only well tolerted but lso more efficcious with respect to ovrin stimultion outcome when compred with the conventionl syringe [8]. In our study, the number of dministr- 39

4 Clin Exp Reprod Med 2011;38(1):37-41 (%) Pen device group Syringe group 5 min = within 5 min fter injection 1 hr = t 1 hr fter injection 3 hr = t 3 hr fter injection p<0.05, others not significnt min 1 hr 3 hr 5 min 1 hr 3 hr 5 min 1 hr 3 hr 5 min 1 hr 3 hr 5 min 1 hr 3 hr Pin Redness Itching Bruising Swelling Figure 1. Locl tolernce rection. tion dys nd mount of follitropin β required for COS were significntly reduced in the pen device group over those in the conventionl syringe group. These results suggest tht the difference between the nticipted volume nd the ctul volume injected ws higher in the conventionl syringe group nd tht n dministrtion of rhfsh by pen device reduced injection losses. A previous study showed tht injection pin is experienced less frequently when follitropin β is dministered by pen device thn when follitropin α is dministered with conventionl syringe [9]. In this study, the reson the locl pin t the injection site ws lower in the pen device group my hve been tht the pen device ws equipped with finer nd shorter needle nd injected smller volume of rhfsh [9]. In our study, ptients lso experienced locl pin less frequently fter injection when they used the pen device for injections. Overll pin ssessed by VAS ws lso significntly lower in the pen device group thn in the syringe group. None of the ptients withdrew from our study becuse of the pin or other side effects. In ddition, the incidence of severe OHSS ws comprble between the two groups. Therefore, the pen device delivering rhfsh is judged to be t lest s sfe s the conventionl syringe. Moreover, the present study demonstrted tht the pen device is more convenient nd esy to hndle, when compred with the conventionl syringe. The pen device delivering follitropin β permits ccurte titrtion of rhfsh doses in increments of 25 IU. Individulized tretment for COS ws therefore possible t the miniml effective dose. In conclusion, the pen device for self-dministrtion of follitropin β is sfe, less pinful nd more convenient for ptients undergoing COS, nd cn be more effective becuse of the shorter durtion nd smller dose of follitropin β, when compred with conventionl syringe. A reduction of pinful injections nd the tretment period, nd the convenient dministrtion of rhfsh cn mke IVF tretment esier nd more ptient-friendly. Conflict of interest No potentil conflict of interest relevnt to this rticle ws reported. References 1. Howles CM, Loumye E, Giroud D, Luyet G. Multiple folliculr development nd ovrin steroidogenesis following subcutneous dministrtion of highly purified urinry FSH preprtion in pituitry desensitized women undergoing IVF: multicentre Europen phse III study. Hum Reprod 1994;9: Wiklnd M, Borg J, Hmberger L, Svlnder P. Simplifiction of IVF: miniml monitoring nd the use of subcutneous highly purified FSH dministrtion for ovultion induction. Hum Reprod 1994;9: Kdiri A, Chribi A, Mroun F, Abbou MR, el Guermi N, Wdjinny A, et l. Comprison of NovoPen 3 nd syringes/vils in the cceptnce of insulin therpy in NIDDM ptients with secondry filure to orl hypoglycemic gents. Dibetes Res Clin Prct 1998;41: Bohnnon NJ. Insulin delivery using pen devices. Simple-to-use tools my help young nd old like. Postgrd Med 1999;106: Robertson KE, Glzer NB, Cmpbell RK. The ltest developments in insulin injection devices. Dibetes Educ 2000;26: Bohnnon NJ, Ohnnesin JP, Burdn AL, Holcombe JH, Zgr A. Ptient nd physicin stisfction with the Humulin/Humlog Pen, new 3.0-mL prefilled pen device for insulin delivery. Clin Ther 2000;22:

5 HJ Kng et l. Pen device vs. conventionl syringe for follitropin β 7. Voortmn G, vn de Post J, Schoemker RC, vn Gerven JM. Bioequivlence of subcutneous injections of recombinnt humn follicle stimulting hormone (Puregon(R)) by Pen-injector nd syringe. Hum Reprod 1999;14: Rm Rju GA, Surynryn K, Jy Prksh G, Murli Krishn K. Comprison of follitropin-bet dministered by pen device with conventionl syringe in n ART progrmme: retrospective study. J Clin Phrm Ther 2008;33: Crenmehr E, Bontje PM, Hoomns E, Voortmn G, Mnnerts BM. Follitropin-bet dministered by pen device hs superior locl tolernce compred with follitropin-lph dministered by conventionl syringe. Reprod Biomed Online 2001;3: