inline - Vol 9. No 5. 2004 494-499 Reprodiuiive BioMedicine Online: www.rhmimUne.comlAitkiel 1452 on web 25 August 21X)4

Article

Ovulation induction with urinary FSH orrecombinant FSH in polycystic ovary syndromepatients: a prospective randomized analysis ofcost-effectiveness

Sandra Gerli received his medical degree fram the University of Perugia, Italy in 1984. In1988 he completed his Residency in obstetrics and gynaecology in Perugia and took up aResearch Fellowship in gynaecological endocrinology and infertility at the University ofIrvine, California, USA. Since 1990 he has been working at the Department ofGynecological, Obstetrical and Pediatric Sciences, University of Perugia as an AssistantProfessor. Dr Gerli has been the coordinator of several research projects, and a guestspeaker at 39 national and international congresses. He is the author and co-author of 188publications in national and international journals and books. His research interests includeinfertility, gynaecological endocrinology, endoscopy and perinatal medicine.

Dr Sandro Gerli

Sandro Ger l i ' \ Maria Luisa Casini-, Vittorio Unfer\ Loredana Costabile', Marcella Mignosa"*, Gian Carlo Di Renzo"*'Centre of Reproductive and Perinatal Medicine, Department of Gynecological, Obstetrical and Pediatric Sciences,University of Perugia, ItalyDepartment of Human Physiology and Pharmacology 'Vittorio Erspamer', University 'La Sapienza', Rome, Italy

-'A.G.UN.CO. Obstetrics and Gynaecology Centre, Roma, Italy"•Department of Gynecological, Obstetrical and Pediatric Sciences, University of Perugia, Perugia, Italy•^Correspondence: e-mail: gerber@unipg.it

AbstractThe aim of this prospective, randomized trial was to compare the clinical results and the cost-effectiveness of urinary FSH(uFSH) and recombinant FSH (rFSH) in ovarian stimukition for intrauterine insemination (IUI) cycles in polycystic ovarysyndrome (PCOS) patients. One-hundred and seventy PCOS infertile patients undergoing IUI were enrolled, and protocolsof ovarian stimulation with uFSH or rFSH were randomly assigned. The total number of cycles performed was 379 {182and 197. respectively). The main outcome measures were the number of mature foUicles.thedaysof stimulation, the numberof ampoules and IU used per cycle, the biochemical/clinical pregnancy rates, the number of multiple pregnancies and thecost-effectiveness. No statistically significant differences were found in the follicular development, length of stimulation.pregnancy rates, delivery rates and multiple pregnancies between the two groups. In the uFSH group, the cost per cycleremained significantly lower (€218.51 ± 88.69 versus €312.22 ± 118.12; P < 0.0001). even though a significantly highernumber of IU of gonadotrophins were used (809.3 ± 271.9 versus 589.1 ± 244.7; P < 0.0001). The cost-effectiveness (i.e.within a group, the total cost of all cycles divided by no. of clinical pregnancies) was 1729.08 in the uFSH group and3075.37 in the rFSH group. In conclusion. uFSH and rFSH demonstrated the same effectiveness in ovarian stimulation inIUI cycles in PCOS patients. The urinary preparation is more cost-effective due to the difference of its cost per IU.

Keywords: cost-ejfectiveness. intraulerine inscminalioii. ovarian Mimutaliou. FCOS. rccoinbinun! I'SH. urinary FSH

IntroductionPolycystic ovary syndrome (PCOS) is considered to be one ofthe most common endocrinopathies in women of thereproductive age (Diamanti-Kandarakis c/c//.. 1999). Moreover,it is al.so the most common cause of anovulatory infenility(Carmina and Lobo. 1999). The main treatments of infertility inPCOS patients are performed by ovarian stimulation with FSH.a reduction in insulin concentration and a decrease in LH levels.

These are considered to be the main points of the thera|.x.'utictreatment (Seibel e! uL. iy84;Jakubowic/ and Nestler. 1997;Dale el al.. 1998; Homburg. 1998; Nestier el al.. 1998:Diamanti-Kandarkiscfu/.. 1999; Yarali and Zeynclogki. 2(X)4).Clomiphene citrate is often used as first-Iinc treatment in PCOS(Sovino('r(i/..2002). In case clomiphene citrate treatment is notsuccessful it is generally preceded by direct FSH stimulation(Homburg. 2003). In order to avoid the occurrence of ovarianhyperstimutation syndrome (OHSS) and multiple pregnancies.

Arlicic - Ovulation induction with urinarj or recombinant FSH in PCOS - S Gerli el al.

FSH stimulation is performed with a low-dose protocol (YaraliandZeyneloglu.2(X)4).

IVF and intrauterine insemination (IUI) require ovarianstimulation to increase the number of mature oocytes (Guzickeial.. 1998;Tempteton and Morris, 1998). Human menopausalgonadotrophin (HMG) has been used for ovarian siimulation.Unfortunately. HMG has a low specific activity and containssignificant amounts of LH. LH was thought to lead to pooroocyte quality, reduced fertilization rates, lower embryonicviability and early pregnancy loss (Stanger and Yovich. 1985).The development and use of other urine-derived FSHpreparations UiFSH) containing smaller quantities o\ LHresulted in higher pregnancy rates compared with the use ofHMG in IVF cycles (Daya ('/(//.. 1995).

The development ol' a new medicinal product containinghuman recetnibinant FSH (rFSH) was thought to representihc ultimate solution for ovulation induction, given thatrFSH is completely free from LH. Although thispresumption was appealing, clinical results in IVF from theuse of rFSH were not outstanding. Moreover, some recenttrials have shown that the addition of exogenous LH tod{>wnregulated rFSH-stimulated cycles. improvedimplantation rate (Gordon el at.. 2001). shortened treatmentduration, reduced menotropin consumption and may havi.'decreased the occurrence of side-effects (Filicori el (//..2001). However, there are many important factors tomention in favour of rFSH preparations. These factorsinclude the absence of any other human contaminant proteinand the fact that the production is independent t>f urinecollection, ensuring a constant FSH supply and guaranteeinga batch-to-batch consistency.

Aside from the previously mentioned benefits, the productionof rFSH has higher medical costs. In fact many trials have beencarried out in order to analyse the efficacy and the cost-effectiveness o\' rFSH in comparison to urinary preparations.Large-scale clinical trials and meta-analysis studies have beenperformed in order to show the difference between rFSH anduFSH in IVF cycles. (Daya and Gunby ci al.. 1999; Hoomans(•/ al.. 1999; Agrawal el al., 2(K)0; AMnany el al.. 2003).Moreover, evidence of clinical effectiveness alone is not asufficient indication to justify the use of a medical product.Therefore, the analysis of relative eost-elTectiveness oftreatments is becoming increasingly important. The effortsundertaken to create cost-effectiveness models failed to revealwhich preparation was associated with a better pregnancy rateand lower costs in IVF cycles. However, it is also important tomention that some studies reported better results whenrecombinant products were used (Daya el al., 2001; Sykes vial..2(

Apart from the fact that lUl is a well-known cost-effectivetreatment for infertility, no studies have been publishedconcerning a cost-effectiveness evaluation of rFSH versusuFSH in IUI cycles in PCOS patients. A study has alreadybeen conducted by the current authors to evaluate the cosl-effectiveness of rFSH in comparison to uFSH in IUI cyclesin normal inlertile patients (Gerli el al.. 2004). As far as weknow, this is the first trial conducted with the purpose ofdetermining which preparation (between urinary andrecombinant FSH) is more cost-effective in IUI cycles in

women suffering from PCOS.

Materials and methods

Patients

PCOS women with a history of at least two years of infertilitywere recruited in the authors' centres. According to Azzi/(2004). diagnostic criteria for PCOS evaluations are: clinicaland/or biochemical hyperandrogenism. chronic anovulationand exclusion of related disorders. A diagnostic screening wasperformed including gynaecological and ultrasoundexamination, semen analysis, hormonal assessment andhysterosalpingogram. Semen parameters were analysedaccording to World Health Organization (WHO) criteria(WHO. 1992). The cycles were assessed as ovulatory cycles ifserum progesterone concentrations in mid-luteal phase wereadequate. Patients with suspected lubaric occlusion duringultrasound examination or hysterosalpingogram underwentlaparoscopic examination. Patients who did not present tubalfactor, male factor and hypergonadotrophism were previouslytreated with clomiphene citrate, according to the protocolsused in the treatment centres. Those who became clotniphenecitrate-resistant or those who did not remain pregnant (within12 months for patients under 30 years or 6 months for patientsover 30 years) were placed in the IUI protocol study.

The study was approved by the local ethics committee.Moreover, all patients signed an informed consent to theprocedure following the enrolment.

Study design

A total of 170 patients were assigned to two groups, accordingto a randomization table. The characteristics of the two groupsare shown in Table 1. Group A (/( = 82) was treated withuFSH; Group B (/i = 88) was treated with rFSH. Protocols ofovarian stimulation were created according to well-knownguidelines (Royal College of Obstetricians andGynaecologists. 1999). The recombinant preparation(Purcgon: Organon, the Netherlands) was injectedsubcutaneously (s.c.) beginning on day 2 of the cycle with adosage of 50 !U/day. The urinary product (Fostimon, IBSAFarmaceutici Italia) was administered s.c. beginning on thesecond day of the cycle with 75 lU/day. Ovarian response wasassessed on day 6 or 7 of the cycle, and the dosage wasadjusted according to the patient's response. If the ovarianresponse was excessive, the cycle was cancelled. In the case ofa single dominant follicle development (poor responder), thepatients were warned of the possibility of having a lowerlikelihood of pregnancy. They were also advised that the riskof multiple pregnancy was extremely low. However, somepatients decided to interrupt the cycle. The patients at risk ofhyperstimulation syndrome (more than five follicles il7mm)were cancelled (excessive responders). In the statistical dataall cancelled cycles for excessive response or for patient'sdecision in the case of development of a single follicle wereincluded.

No plasma horinone concentrations were evaluated since theseparameters are not necessary in IUI treatment. Therefore theseanalyses were not included in the treatment protwol. Allpatients were given lO.OOO IU o\' human chorionic

Article - Ovukition induction with urinary or recombinant FSH in PCOS - 5 Gcrti ci at.

Table I. Demographic characteristics of patients.

Group A iuFSH) Group B (rFSH)

Number of patientsAge (years) (mean * SD)Body mass index (kg/m-) (mean ± SD)Duration of infertility (years) (mean ± SD)

N<i siaiisijfiil d I He re I ices •\'ctc loiind hclwcon yroups, iliiis

8228.6 ± 2.723.1 ±2d2.2 ± 1.4

29d ±2.423.7 ± 2.02.3 ± 1.3

gonadotrophin (HCG) (Profasi HP; Scrono Pharmaceuticals)i.m. when the largest follicle reached a diameter olat least ISmm. A single IlJI was pertbmied 32-4() h alter Ihe injection ofHCG. No luteai support treatment was given to ihe patienis.

A pregnancy test was given if menstrualion did not (X-cur withintwo weeks oC insemination.

End-points

Main outcome measures were: number of follicles >l 7 mm, daysof stimulation, number of ampK>iiies and IU used pcv cycle,biochemical and clinical pregnancy rates, costs per cycle, andcost-effectiveness. The multiple pregnancies obtained,spontaneou.s abortions, cases of OHSS and cancelled cycles werecounted.

Clinical results

A biochemical pregnancy was defined as a small and transientincrease in fi-HCG concentrations. A clinical pregnancy wasdetennined by the visualization of an cmbr>'o with eardiacactivity at 6-7 weeks of pregnancy.

Spontaneous abortion was classified as the loss of the pregnancybetween the tlfth and twelfth week ot" gestation.

Cost analysis

The cost of a single ampoule of uFSH and rFSH was examinedduring the study according to the Italian Formulary(L'Infomiatore Farmaceutico, 2001) (€20.11 and €26.45,respectively). The cost per cycle was calculated by multiplyingthe cost of a single IU with the mean number of IU used percycle.

The cost-effectiveness was calculated by multiplying the cosi percycle by the total number of cycles perfonned in each group, thendividing the result for the number of clinical pregnanciesobtained in the group during the trial.

Statistical methods

Given ihat almost all variables in the analysis of the data showeda nun-normal distribution (in Ihe Shapiro-Wilk test and normalpr()bability plots), the non parametric Mann-Whitney U test was

used to analyse the continuous variables and Fisher's exact testand the / " test were used for categorical variables.

The significance level was set at P < 0.05. The results weredescribed in terms of mean ± standard deviation (SD) andconfidence intervals (CI). in order to facilitate comparisonof the data with those of the literature. AN data analyseswere carried out with SPSS release 10.1.1 for Windows(SPSS Inc., Chicago. USA. 1999).

ResultsA total of 379 cycles (in 1 70 patients) were included in thestudy. Before beginning the stimulation protocol, twopatients in Group A and three palients in Group B requestedto be withdrawn from one of the cycles for personal reasons.Therefore these five cycles were not considered. Bothgroups (182 and 197 cycles respectively in the uFSH groupand the rFSH group) were comparable in demographiccharacteristics and duration of infertility (Table 1).

Clinical results did not reveal significant differencesbetween the two groups (see Table 2). Twenty-nine cycleswere cancelled: 13 in the uFSH group (11 due to the risk ofhyperstimulation and 2 for poor response) and 16 in therFSH group (15 for risk of hyperstimulation and I for poorresponse). Follicular development was comparable in thetwo groups. No statistically significant differences werefound in the number of gonadotrophin ampoulesadministered and in the days of stimulation. In the rFSHgroup, there was a tendency to have a longer stimulationperiod and additionally a higher number of FSH ampouleswere used. A slightly higher (not significant) pregnancy rate(12.6% versus 11.2%) was obtained with the use o\' rFSH.No differences were found in the number of spontaneousabortions between the two groups (13.0% in group A and15.0% in group B). and the number of multiple pregnancies(1.6% in group A and \ .59t in group B). No OHSS wererecorded.

'I'he data related to costs are shown in Table 3. Asignificantly higher number {P < 0.0001) of IU of FSH wereused in the uFSH group (809.3 ± 27 1.9; 95'7< CI 721.1-930.5versus 5H9.I ± 244.7: 95% CI 544.7-675.8). with asignificantly lower cost iP < 0.0001) per cycle (€218.51 ±

Article - Ovulation induction with urinarj or rccombiniint FSH in PCOS - S Gerli a al.

Table 2. Clinicai results.

Group A (iiFSH) Group B IrFSHi

Follicles >I7 mm (mean ± SD)Days of stimulation (mean ± SD)Number of ampoules per cycle (mean ± SD)Biochemical pregnancy rate (9()Cliiiical pregnancy rate {%)Spontaneous abortion (%)Multiple pregnancies (%)Cancelled cycles (%)

2.3 ± 1.510.2 + 2.11! .3 ± 4.22/182(1.1)22/197(11.2)3/23(13.0)3/182(1.6)13/182(7.1)

2.4 ± 1.79.K ± 1.910,8 ±4.93/197(1.3)23/182(12.6)3/20(15.0)3/197(1.5)16/197(8.1)

No staLJsticiil diI Vs were found between groups, thus f-valuc urc IKII

Table 3. Cost-effectiveness analysis.

Cost per ampoule (€)Cost per IU (€)Mumbcr of IU per cycle(mean ± SD)

Cost per cycle (€)

Cost of all cycles (€)Cost-effectiveness (€)''

GroiipMiiFSH)

20.110.27809.3 ±271.9^'(721.1-930.5)218.51 ±88.69'̂ ^(152.6-270.4)39 768.821 729.08

Group B (rFSH)

26.450.53589.1 ± 244.7''(544.7-675.8t312.22 ± 118.12 '̂(215.3-375.8)61 507.343 075.37

Dijfercnce'

6.340.26-220.2

93.71

21 738.521346.28

Viilucs ari.- means iir mciiris ± SD (in parenthesis 95*3 Cl).

\ F S H - J F S H .

CalLtiliilcd by dividiii!; ilic Iiiul cost iif al! iho cjule pfrlormcd in iht; s;ri>up by Lhe nuniher i

prejiniinuies obuiinod in the same group.

^> < IKKXH luKSH ^roup versus rhSil group).

88.69; 95VrCl 152.6-270.4 versus € 3 12.22 ± 118.12:95%CI 215.3-375.8). Tbe cost-effectiveness was €1729.08 inthe uFSH group and €3075.37 in the rFSH group.

DiscussionDuring the last decade Ibe production of recombinant FSH hasbeen considered to be a turning point in endtXTine research,parlicuhirly in the field of human reproduction. Urinarypreparations of gonadotrophins have been progressively replacedby the new biotechnological products which complelely lack ofany LH activity and other human protein. These compoundscontaminate the urinary preparations. However, it must bestressed that the highly purified FSH has proved to be a safe andefficient preparation in ovarian stimulation (Gerli el al.. 1999).

Having more puritieJ and scientifically advanced productsavailable on the niiirkct docs not necessarily mean that betlerresults can be achieved in terms of efficacy. For this reason,several studies have been carried out to determine whether rFSHwas able lo improve IVF outcomes compared with thoseobtained using urinary products.

The higher medical costs of the recombinant products motivatedmany researchers to cany out numerous trials in order to explorethe efficacy and the relative cost-effectiveness of altemalivetreatments in IVF cycles (Ola ei al., 2tK)l: Silverberg el ai.2(X)2). The efforts undertaken to pcribrm meta-analysis and tocreate cost-effectiveness models failed to reveal whichpreparation was associated wiih a better pregnancy rate and withlower costs in IVF cycles. However, it is important toacknowledge thai recombinant products showed a tendency togive better results (Daya et al.. 2001: Ola el al.. 2001).

Intrauicrinc insemination has been considered as ihe first-linetreatment in patients aged under 37 years, with a short durationof inlertility and no severe male factor or tubal factor. Severalstudies have been performed to assess the efficacy and analysethe cost-L'ffcctivcncss of the treatment. Results havedemonstrated that although IVF tended to be more effective ona per-cycte basis than IUI. ihe latter had a higher cumulativepregnancy rate at the end of the programmed treatment cyclesin idiopathic subfertility and male subfertility. because of thelower drop-out rate (Goverde ct al.. 2000). Moreover a meta-analysis showed that ovarian stimulation with gonadotrophinsin IUI cycles has a better probability of conception than IUIalone (Hughes. 1997).

Article - OvulatJon induction with urinary' or recombinant I-Sfl in PCOS - .S' Gcrti ei at.

This is the first trial that analyses clinical results and CDst-effcclivcness of ditlcrcnt FSH preparations used in lUI cyclesin PCOS patienis. In this study ihc pregnancy rates weresimilar In the two groups of patients, whieh led to the decisionto analy.se the cost-benefit in each group.

This study could bc easily criticised since different numbers ofiU of FSH were used according to the different types of hSH(50 for rFSH and 75 for uFSH). The recombinant preparationwas administered in lower concentration for two reasons: asupposedly higher efficacy and bioactivity of the product (Out('/ (//.. lyy?), and the drug availability in llaly (50 and 100 IUper ampoule). On the other hand administration of a singlevial of 50 lU was preferred instead of running the risk ofhyperstimulation syndrome and a higher multiple pregnancyrate.

Two outcome measures have been considered as reliablemarkers of drug bioaetivity: the number of mature follicles andthe cancellation rate, the latter being the expression of anexcessive or a poor response. Similar results in tenns uf thesetwo parameters were obtained in both groups (means of 2.3 ±1.5 and 2.4 ± 1.7 mature follicles for Groups A and Brespectively). This indicates that the pharmacologicalstimulation of the ovaries was similar and comparable in btithstudy groups. There were no differences in ihe efficiency of thetreatments, since there were similar biochemical and clinicalpregnancy rates in the two groups.

The number of stimulation days and the number of ampoulesused were not statistically different. On the contrary, the meannumber of IU administered to the patients, as shown in Table3, were significantly higher in the uFSH group. As previouslymentioned, this group received a higher daily dosage of FSH.Although such dala should allow us to come to the conclusionthat a higher cost per cycle (and per pregnancy) is connectedlo the use of uFSH, it is counterbalanced by the lower per IUprice of uFSH in comparison lo the recombinani formulation.

Silverberg and colleagues (Silverberg c! tit.. 2002) receiUlycompared Ihe co.st-effeetiveness of rFSH and uFSH in IVFcycles. They concluded that the economic effectivenes.s of adrug depends less on its costs and rather more on the clinicaloutcomes associated with its use. The results of the presentstudy are strictly in contrast with this statement: a highlysignificant difference was found in favour of the urinaryproduct, which is mainly due to the lower eost of this product.The possibility cannot he excluded that the conclusion reachedby Silverberg may be applied to IVF cycles but may not bevalid for ovulation induction in lUI cycles.

It must also be remembered that aside from pregnancy ordelivery rates, the main outcome measures of the studiesperfonned in IVF cycles were the number of growing follicles.the number of oocytes retrieved and the number of embryosobtained. The higher the values were, the belter the efficacy ofthe drug was. In ovulation induction for lUl cycles where nopituitary down-regulation protocols are used, the goal of thestimulation is different. The aim is to obtain no fewer than twoand no more than four mature oocytes. A stronger stimulationcould either result in a multiple pregnaney or at worst, inhyperstimulation (Farhi ei at.. 1996). Therefore, the differentresults obtained in the analysis of the cost-effectiveness of the

Iwo FSH compounds is explained by the diverse perspective inthe evaluation of Ihe outcomes of ovarian stimulation, logetherwilh the diverse methodology in obtaiTiing these results.

Numerous studies concerning the potential improvement ofIVF outcomes using rFSH versus uFSH have been published,whereas few data comparing ihe urinary and recombinantproducts in ovulalion induction are available (Yarali ct al.,1999: Gleichcrand Karande. 2000).

Yarali and colleagues (Yarali <v (//.. I999| prospeetivelycompared ihe efficacy and safely of recombinani and urinaryproducts for ovulation induction in palienls wilh clorniphenecitrate-resistant. normogonadotrophic. and chronicanovuiation. The main outcome measures of this study wereihe cumulative ovulation and pregnancy rates, the total amountof gonadotrophin used throughout the stimulation andfollicular development. No differences were found betweenthe two treatment groups (Yarali ci at... 1999). In contrast, alarge cohorl sludy in unselected patients revealed a possibledetrimental effecl of the FSH preparation compared withpreparations containing HMG (Gleicher and Karande. 2000).

Taking into account clinical outcome measures, it is difficull loachieve statistically significant results due to the limitednumber of cycles analysed and the low value of pregnancyrates. These are considered to be the only two clinicallyrelevant parameters in ovulation induction or IUI cycles.Hence it is extremely important to assess the cost of eachpregnancy obtained with both treatment options. Inconsequence it is important to suggest the use of the more cost-effective drug. In this study it has been demonstrated that thecost per cycle and the cost per pregnancy were 4491 and 36%respectively higher when the reeombinant products were used.Additionally ihc total amount of IUI used in the rFSH groupwas lower in comparison to the uFSH one (2l.2Vc less than inthe uFSH group).

The results of this study have demonstrated that the use of amore expensive reeombinani produci does nol seem cost-effective in protocols of ovulation induction in lUl cycles inPCOS patients.

Acknowledgments

We wcnrld like to ihank Dr Su/etle Paolella for her Englishlanguage editing support.

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Received 7 .Inly 2004; rcfcrecd 19 July 2004; uciepied 42004.