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Polycystic ovary syndrome. A therapeutic challenge
Bayram, N.
Publication date
2004
Link to publication
Citation for published version (APA):
Bayram, N. (2004). Polycystic ovary syndrome. A therapeutic challenge.
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C H A P T E RR 2
Recombinantt FSH in alternative doses
orr versus urinary g o n a d o t r o p i n s for
ovulationn induction in subfertility associated
hh polycystic ovary syndrome
NerimanNeriman Bayram, Madelon van Wely, Fulco van der Veen
Abstract t Background d
Overr the last four decades, various urinary FSH (uFSH) products of different purity have beenn developed. In 1988 recombinant FSH (rFSH ) was prepared by transfecting Chinese hamsterr ovary cell lines with both FSH subunit genes. It is unknown which of these FSH preparationss to prefer, regarding effectiveness and safety. Essential in ovulation induction withh gonadotrophins is the time during which the serum FSH is above the threshold at whichh recruitment of follicles occurs. Extending this time carries the risk of multiple folliclee development and multiple pregnancies. Because of this, various dose regimens havee been developed to minimize these complications.
Objectives s
Too compare in women with clomiphene-resistant polycystic ovary syndrome (PCOS) the effectivenesss and safety of 1) rFSH with uFSH and 2) various dose regimens of rFSH.
Searchh strategy
Wee searched the Cochrane Menstrual Disorders and Subferrility Group trials register (searchedd 1st May 2004), PubMed, MEDLINE, Web of Science (all searched 1985 to Mayy 1 2004), and reference lists of articles. We also contacted manufacturers and researcherss in the field.
Selectionn criteria
Alll relevant published RCT's were selected. Randomised controlled trials were eligible for inclusionn if treatment consisted of recombinant FSH versus urinary FSH or recombinant FSHH in different dose regimens, to induce ovulation in women with clomiphene citrate resistantt PCOS.
D a t aa collection & analysis
Thee main outcome measure was ongoing pregnancy/live birth per woman. Secondary outcomess were ovulation, pregnancy, miscarriage, multiple pregnancy and ovarian hyperstimulationn syndrome (OHSS). Relevant data were extracted independently by two reviewerss (NB, MW). Odds ratios were generated using the Peto modified Mantel-Haenszell technique. The main outcome measure was ongoing pregnancy/live birth per woman.. Secondary outcomes were ovulation, pregnancy, miscarriage, multiple pregnancy andd ovarian hyperstimulation syndrome (OHSS). Relevant data were extracted independentlyy by two reviewers (NB, MW). Odds ratios were generated using the Peto modifiedd Mantel-Haenszel technique.
Mainn results
Threee randomised trials comparing rFSH versus uFSH were identified. Only one trial providedd data on the primary outcome, ongoing pregnancy, while all three studies providedd data on the secondary outcomes. No difference was found in ongoing pregnancy ratee (OR 1.10, 95% CI 0.51 to 2.35). There was no difference in clinical pregnancy rate (ORR 0.95, 95% CI 0.64 to 1.41), nor between any of the other secondary outcomes. Fourr small trials with different dose regimens were identified. As each of the four included trialss compared different regimens, no trial results could be combined. None of the trials
presentedd data on ongoing pregnancy/live birth. In the first trial that compared chronic loww dose step up regimen versus conventional regimen no statistically significant differencess were found for clinical pregnancy rate (OR 1.62, 95% CI, 0.64 to 4.07), nor inn the other secondary pregnancy outcomes. However, significantly fewer follicles >10 mmm diameter (WMD -3.30, 95% CI -5.34 to -1.26) were found in the group treated with thee chronic low dose step up regimen. The second trial compared two starting doses in a chronicc low dose step up regimen. The clinical pregnancy rate was comparable in both stimulationn regimens (OR 0.79, 95% CI 0.12 to 4.96). The third trial compared a chronicc low dose step up regimen with modified step down regimen. No difference in clinicall pregnancy rate could be proven (OR 1.90, 95% CI 0.18 to 19.97).
Thee fourth trial compared a chronic low dose step up regimen with a step down regimen revealedd also no statistically significant differences in clinical pregnancy rate (OR 1.41, 95%% CI 0.57 to 3.46). Similarly no difference could be proven in any of the other pregnancyy outcomes. However, significantly more monofollicular development (OR 4.24,, 95% CI 2.27 to 7.92) and less multifollicular development (OR 0.13, 95% CI 0.06 too 0.29) was observed in the chronic low dose step up group.
Reviewers'' conclusions
Att this moment there is not sufficient evidence to determine whether rFSH or uFSH is preferablee for ovulation induction in women with clomiphene citrate resistant PCOS. No differencee could be proven between the four different dose regimens. However, the conventionall regimen is known to be plagued by OHSS and multiple pregnancies and usagee should therefore be discouraged.
Background d
Polycysticc ovary syndrome (PCOS) is the most common cause of female anovulatory infertility.. To induce ovulation, clomiphene citrate (CC) is the first line of treatment. However,, about 20% of patients are CC resistant i.e. they do not ovulate after a maximumm dose of clomiphene citrate (100-200 mg) (Imani et al., 1998). Since 1958, thesee patients are treated with follicle stimulating hormone (FSH), originally extracted fromm pituitary glands (Gemzell et al., 1958) and later extracted from post-menopausal urinee (Lunenfeld et ah, I960).
Overr the last four decades, various urinary FSH products have been developed. Menotropinn (human menopausal gonadotrophins (hMG), available since the early 1960s, containss FSH, LH and large quantities of potentially allergenic urinary proteins. Urofollitropinn (FSH), available since the mid 1980s, is devoid of LH, but is still contaminatedd with urinary proteins. Highly purified urofollitropin (FSH-HP), available sincee the mid 1990s contains very small amounts of urinary proteins. Lack of urinary proteinss diminishes adverse reactions such as local allergy or hypersensitivity (Bififoni et al.,, 1994; Albano et al., 1996) whereas the absence of LH has no negative influence on folliculogenesiss of PCOS patients (van Weissenbruch et al., 1993; Hayden et al., 1999). Too obtain higher purity, complete absence of LH, high specific bioactivity, absolute source control,, independence of urine collection and batch to batch consistency, recombinant FSHH (rFSH ) was synthesized in 1988. This was realised by transfecting Chinese hamster ovaryy cell lines with both FSH subunit genes (Keene et al., 1989; Howies et al., 1996). Att present, two preparations of rFSH are available. The first one, marketed in 1995, is follitropinn alpha (Gonal F®), soon followed by follitropin beta (Puregon®). Both preparationss are similar to pituitary and urinary FSH, although they show minor differencess in the structure of the carbohydrate side chains and contain more basic and lesss acidic isohormones than the natural hormones (Hard et al., 1990, de Leeuw et al., 1996,, Andersen, 2004 in press).
Ovulationn induction with FSH bears the risk of multiple follicle development and multiplee pregnancies (Nugent et al., 2004). To reduce these complications, various dose regimenss have been developed (Brown 1978; Hamilton-Fairley et al., 1991, van Santbrink etal.,, 1995).
Att present, the most frequently used dose regimens are the chronic low dose step up and stepp down regimens. In a previous review the effectiveness of urinary FSH was compared withh hMG in patients with PCOS (Nugent et al., 2004). In this review we compare the effectivenesss and safety of rFSH with urinary gonadotrophins and the effectiveness and safetyy of various regimens using rFSH.
Objectives s
11 To determine the safety and effectiveness of recombinant FSH compared with urinary gonadotrophinss used for ovulation induction in women with clomiphene citrate resistant PCOS. .
22 To determine the safety and effectiveness of various dose regimens of recombinant FSH usedd for ovulation induction in women with clomiphene citrate resistant PCOS.
Criteriaa for considering studies for this review Typess of studies
AA trial was eligible for inclusion if it dealt with the use of a recombinant FSH versus urinaryy gonadotrophins or recombinant FSH in various dose regimens, and if primary outcomess of ovulation rate and pregnancy rate were specified. The participants were allocatedd by a randomisation procedure.
Typess of participants
Womenn with clomiphene citrate resistant PCOS undergoing ovulation induction. Clinicall and endocrinological characteristics, infertility work-up, age, duration of infertilityy and previous treatment(s) if available were specified in the trial characteristics table. .
Typess of interventions
1)) Recombinant FSH versus Urinary FSH
2)) Recombinant FSH versus Human menopausal gonadotrophin (HMG) 3)) Recombinant FSH versus Recombinant FSH (various dose regimens)
Typess of outcome measures
Primaryy Outcome:
Ongoingg pregnancy or live birth rate per woman
Secondaryy Outcomes:
Clinicall pregnancy rate (per woman)
Ovulationn rate (per woman, if available, otherwise per cycle)
Incidencee of ovarian hyperstimulation syndrome (OHSS) (per woman) Incidencee of multiple pregnancy (per woman)
Miscarriagee rate (per woman)
Incidencee of multifollicular growth (per woman) Totall gonadotrophin dose
Totall duration of stimulation
Oestradioll levels on day hCG administration
Numberr of follicles on the day of hCG administration
Searchh strategy for identification of studies
Thiss review has drawn on the search strategy developed for the Cochrane menstrual Disorderss and Subfertility Group as a whole.
1.. The following electronic databases were searched: -- MEDLINE (1966-April 2004)
-- EMBASE (1988-April 2004)
-- Cochrane Controlled Clinical Trials Register (CCTR) Thee following keywords were used;
ovulationn induction, gonadotropins, recombinant FSH and FSH.
2.. Handsearching of the references mentioned in the obtained studies was performed
3.. Serono Benelux BV and NV Organon, the manufacturers of follitropin alpha (Gonal F®) andd follitropin beta (Puregon®) respectively, were asked for ongoing studies and unpublishedd data.
Methodss of the review
Selectionn of studies & quality assessment
Dataa from included trials was processed as described in the Cochrane Handbook (Clarke andd Oxman, 2003). All selected studies were assessed and evaluated for methodological qualityy and appropriateness for inclusion without consideration of their results.
Trialss were screened and analysed for the following quality criteria and methodological details:: method and timing of randomisation; number of patients randomised and analysed;; whether they were single or multicenter studies; parallel or cross-over design; blindingg of treatment; the use of sequential analysis or factorial design; the presence of a powerr calculation; duration of follow-up; whether pregnancy was a measured outcome and,, if so, how this was diagnosed; how pregnancy results were presented (particularly whetherr cumulative conception curves with the use of life table analysis were employed); andd the source of any funding.
Relevantt trials were screened independently by two authors (NB and MW). Differences off opinion were registered and resolved by consensus with the senior author (FV). Iff crossover studies were identified, data were included in the review from the pre-crossoverr period where possible. If pre-crossover data could not be extracted, the results off pre- and post-crossover study periods were given descriptively. The data were extracted intoo two-by-rwo tables and checked for accuracy by N. Bayram and M. van Wely. If necessary,, additional data was requested from the authors. For dichotomous data, odds ratioss with 95% confidence intervals were calculated for each individual trial using the Petoo modification of the Mantel-Haenszel method (Peto, 1987). For continuous data the weightedd mean was calculated. When median and range were given instead of mean and SD,, the mean was estimated by logarithmic transformation of the minimum and maximumm values and the SD was imputed from the overall SD of other studies. In the absencee of heterogeneity of treatment effect among trials, which was tested using the Breslow-Dayy chi-square test, the data were pooled. For pooled dichotomous data an overalll combined OR with 95% CI's was calculated using the Peto method and for continuouss data a weighted mean difference (WMD) with 95% CI was calculated using thee inverse variance method. Negative values in W M D indicate a benefit of "treatment group"" over controls.
D e s c r i p t i o nn o f s t u d i e s
Pleasee see Appendix I for details of the study methods and participants of the seven trials includedd in the analysis.
Typess of studies
RecombinantRecombinant FSH versus urinary FSH
Threee trials were identified meeting the inclusion criteria (Loumaye et al., 1996; Coelingh Benninkk et al., 1998; Yarali et al., 1999). All trials compared ovulation induction with rFSHH versus uFSH in clomiphene citrate resistant patients. The study of Loumaye 1996 wass described in a review on human gonadotrophins produced by recombinant DNA technology.. By personal communication additional data on this trial was obtained and all thesee data was incorporated in this review. In total 451 women were included in the trials comparingg rFSH with uFSH.
RecombinantRecombinant FSH versus HMG
Noo trials could be identified comparing rFSH with hMG.
RecombinantRecombinant FSH versus recombinant FSH - various dose regimens
Fourr trials were identified meeting the inclusion criteria (Hedon et al., 1998; Balasch et al.,, 2000; Balasch et al., 2001; Christin-Maitre et al., 2003). Trials comparing various dose regimenss using urinary FSH were excluded as these are evaluated in another systematic revieww (Nugent et al., 2004). In total 237 women were included in the trials.
TypesTypes of participants
Polycysticc ovary syndrome was defined as a combination of at least two of three criteria; clinicall features (oligo/amenorrhoea, chronic anovulation), endocrinological abnormalitiess (hyperandrogenism and/or high LH/FSH ratio) and polycystic ovaries diagnosedd with ultrasonography. Chronic anovulation was mainly defined by cycle length off >35 days or amenorrhea. The participants were all clomiphene citrate-resistant, anovulatoryy women. Clomiphene citrate resistancy was defined as failure to ovulate or failuree to conceive if ovulation occured after various numbers of cycles. The maximum dosee of clomiphene citrate differed in the trials. In one trial no definitions on PCOS or clomiphenee citrate resistance were given (Loumaye et al., 1996).
TypesTypes of intervention
Threee trials compared recombinant FSH with urinary FSH using the chronic low dose stepp up regimen. Loumaye et al., 1996 and Yarali et al., 1999 compared Gonal-F with Metrodinn and Coelingh Bennink 98 compared Puregon with Metrodin. Loumaye 1996 didd not describe cancellation criteria. The cycles were cancelled by Coelingh Bennink et al.,, 1998 if more than three follicles of & 15 mm were present or if there was no follicular responss after 42 days of treatment. Yarali et al., 1999 cancelled cycles if more than 44 follicles a 15 mm were present or if there was no follicular response after 35 days off treatment.
Fourr trials compared various dose regimens of recombinant FSH. Hedon et al., 1998 comparedd a chronic low dose step up versus conventional step up protocol (Gonal-F) after
onee cyle. Injection of hCG was withheld if four or more follicles >14 mm were present. Twoo trials used a crossover design. The first trial compared two starting doses in a chronic loww dose step up protocol (Gonal-F and Puregon) (Balasch et al., 2000) and the second triall compared a chronic low dose step up regimen with modified step down regimen (Gonal-F)) (Balasch et al., 2001). No cancellation criteria were described in the first trial. Inn the second trial ovulation was triggered by one subcutaneous injection of 5000 IU hCGG when no more than three follicles with a mean diameter of 16 mm were present. Thee last trial compared a chronic low dose step up regimen with the step down regimen (Puregon)) (Christin-Maitre et al., 2003). Patients were treated for three consecutive cyles. H C GG administration was withheld if four or more follicles > 16 mm in diameter were presentt and/or if the serum oestradiol level was >1000 pg/ml. In addition ovarian stimulationn was cancelled in the absence of follicular development after 21 days of stimulationn or in case of cyst development.
TypesTypes of outcome measures
Pregnancyy rate, ovulation rate, miscarriage rate, multiple pregnancy rate, ovarian hyperstimulationn syndrome rate, total FSH dose, duration of stimulation, cancellation rate,, single follicle development, number of follicles >10 mm on day of HCG administration,, oestradiol concentration on day of HCG were reported. In the trials comparingg different regimens no definitions of any of the outcome parameters was given. Inn the trials comparing rFSH with uFSH definitions of ovulation and clinical pregnancy weree given. In one trial only a definition of ongoing pregnancy was given (Coelingh Benninkk et al., 1998).
Methodologicall quality of included studies
Alll seven trials included were randomised clinical trials. Three studies were single center studiess (Yarali et al., 1999; Balasch et al., 2000; Balasch et al., 2001) and the other four studiess were multicenter studies (Loumaye et al., 1996; Coelingh Bennink et al., 1998; Hedonn et al., 1998; Christin-Maitre et al., 2003). Two studies used a randomisation list thatt corresponded with patient drug codes (Coelingh Bennink et al., 1998; Yarali et al.,
1999),, two studies used sealed envelopes (Loumaye et al., 1996; Christin-Maitre et al., 2003),, one study used computerized allocation stratified by center (Hedon et al., 1998) andd for two studies the method of randomisation is unknown (Balasch et al., 2000; Balaschh et al., 2001). Only one study performed a power calculation (Loumaye et al., 1996).. An intention-to-treat analysis was performed in one trial only (Coelingh Bennink ett al., 1998). This trial also was assessor-blind, whereas the other six were open-label. Doublee blinding should have been possible for the three trials comparing rFSH with uFSH,, but this was not done as rFSH was supplied in vials and uFSH in ampoules. Withdrawalss after randomisation were mentioned in all trials. In the three trials comparingg rFSH with uFSH women were treated for a maximum of three cycles. For thesee trials no information was present on losses to follow-up after the first cycle. Only threee trials gave information on duration and timing of the trial (Coelingh Bennink et al., 1998;; Hedon et al., 1998; Yarali et al., 1999). Of the trials comparing different dose regimens,, two were crossover trials (Balasch et al., 2000; Balasch et al., 2001).
Thee sample size of the studies ranged between 22 to 222 women and the follow up was shortt (1 to 3 cycles).
Results s
RecombinantRecombinant FSH versus urinary FSH
(Loumaye(Loumaye et al., 1996; Coelingh Bennink et al., 1998; Yarali et al., 1999)
Dataa per woman could be extracted for all outcome measures except for ovulation rate whichh is reported per cycle. There was no evidence of statistical heterogeneity. The primaryy outcome i.e. live birth rate per woman was not reported in any of the trials (Loumayee et al., 1996; Coelingh Bennink et al., 1998; Yarali et al., 1999). Only one trial (Coelinghh Bennink et al., 1998) provided data on ongoing pregnancy, while all three studiess provided data on the secondary outcomes. No difference was found in ongoing pregnancyy rate (OR 1.10, 95% CI 0.51 to 2.35). After pooling the data, the clinical pregnancyy rate was not statistically significant different (OR 0.95, 95% CI, 0.64 to 1.41). Ovulationn rate per cycle was available in all studies but because of absence of the exact numberr of cycles in the study by Loumaye et al., 1996 only the data from Coelingh Benninkk et al., 1998 and Yarali et al., 1999 could be pooled with an overall OR 1.19 (95%% CI, 0.78 to 1.80).
Thee miscarriage rate per woman was comparable in all studies with an overall OR 1.22, (95%% CI 0.60 to 2.46). Ovarian hyperstimulation syndrome ocurred in 0.9% in both groupss (Loumaye et al., 1996) and in 7.6% in the rFSH group versus 4,5% in the uFSH groupp (Coelingh Bennink et al., 1998). No cases of OHSS occurred in the study of Yarali ett al., 1999. Overall, the pooled OR was not statistically significant different (OR 1.55, 95%% CI 0.50 to 4.84).
Loumayee et al., 1996 found 3 % versus 7% multiple pregnancies for rFSH and uFSH respectively.. From this study data on the order of multiple pregnancies could not be retraced.. In the other two studies one twin and one triplet pregnancy (2%) versus one twinn pregnancy (1.5%) (Coelingh Bennink et al., 1998) and no multiple pregnancies (0%)) versus three twin pregnancies (8.5%) (Yarali et al., 1999) were found in the rFSH groupp and the uFSH group respectively. There was no difference in multiple pregnancy inn the rFSH group compared with uFSH in these trials (OR 0.44, 95% CI 0.16 to 1.19). Continuouss outcome measures like total FSH dose, duration of stimulation, oestradiol (E2)) level and number of follicles of various diameters on the day of hCG administration weree only reported by Coelingh Bennink et al., 1998 and Yarali et al., 1999. Total FSH dosee and duration of stimulation and E2 level did not differ significantly between rFSH andd uFSH with a W M D of-216, 95% CI -733 to 312, -2.6, 95% CI -5.6 to 0.3 and 67, 95%% CI -67 to 200 for rFSH and uFSH respectively.
Ass various diameters for number of follicles were used, these data could not be pooled. Coelinghh Bennink et al., 1998 reported three different groups of follicle diameter after one,, two and three consecutive cycles. In the first group mean number (SD) of follicles a l 22 mm and in the second group number of follicles a l 5 mm and in the third group numberr of follicles ^18 mm were described. Only in the group of follicles &12 mm after thee first cycle a statistically significant difference was found: (WMD 1.00, 95% CI 0.17 too 1.83) between the rFSH and uFSH group.
Yaralii et al., 1999 reported two different groups of follicle diameter after one cycle. In the firstt group mean number of follicles of 10-14mm and in the second group number of follicless > 14 mm were described. Only in the second group a statistically significant differencee was found: (WMD 1.10, 95% CI 0.39 to 1.81) between rFSH and uFSH group.
RecombinantRecombinant FSH versus recombinant FSH - various dose regimens
Ass each of the four included trials compared various dose regimens, no trial results could bee combined. Analyses are therefore presented separately for each comparison.
1.. Chronic low dose step up regimen versus conventional step up regimen (Hedon et al., 1998) Thee primary outcome i.e. live birth rate or ongoing pregnancy was not reported. No statisticallyy significant difference in clinical pregnancy rate was found: 14 of 53 women (26%)) versus 9 of 50 women (18%) (OR 1.62, 95% CI, 0.64 to 4.07). Ovulation rate perr woman was similar comparing the regimens during one cycle. Thirty of 53 women (( 57%) and 29 of 50 women (58%) ovulated respectively (OR 0.95, 95% CI, 0.43 to 2.06).. Miscarriage rates per woman were 1.9% and 2% respectively (OR 0.62, 95% CI 0.033 to 11.34). OHSS ocurred in one patient in each rFSH treatment group. There was noo difference in multiple pregnancy rate per woman. Two twins (4%) in the chronic low dosee step up regimen and two twins (4%) in the conventional regimen were observed (OR 0.94,, 95% CI 0.13 to 6.89).
Continuouss outcome measures like total FSH dose, duration of stimulation, oestradiol (E2)) level and number of follicles of different measures on the day of hCG gift were also reported.. The results of mean (SD) total FSH dose used and the mean (SD) duration of stimulationn did not differ significantly with a W M D of-45 (95% CI -346 to 255) and
1.55 (95% CI -0.87 to 3.87) respectively. Mean E2 {SD) concentration after one cycle was significantlyy lower in the chronic low dose regimen, 504 (477) pg/ml compared with the conventionall regimen 989 (740) pg/ml (WMD -485, 95% CI -743 to -227).
TwoTwo different groups of follicle diameter after one cycle were reported. In the first group meann number (SD) of follicles >10 mm and in the second group mean number (SD) of follicless a l 6 were described. Only in the group of follicles >10 mm was a statistically significantt difference found (WMD -3.30, 95% CI -5.34 to -1.26) in favour of the chronicc low dose.
2.. Two starting doses (37.5 IU versus 50 IU) in a chronic low dose step up regimen (Balaschh et al., 2000)
Thee primary outcome i.e. live birth rate or ongoing pregnancy was not reported. No statisticallyy significant difference in clinical pregnancy rate per woman were found: three off 12 women (25%) versus three of 10 women (30%) respectively (OR 0.79, 95% CI 0.122 to 4.96). All 22 participating women ovulated in the first cycle in both groups. No dataa was reported for the outcomes miscarriage, OHSS or multiple pregnancy. As no data fromm the pre-crossover period could be obtained on the continuous outcome measures likee mean total FSH dose, mean duration of stimulation, mean oestradiol (E2) level and meann number of follicles of different measures on the day of hCG administration, these parameterss were not included in the MetaView analysis.
3.. Chronic low dose step up regimen versus modified step down regimen (Balasch et al., 2001) )
Thee primary outcome i.e. live birth rate or ongoing pregnancy was not reported. No statisticallyy significant difference in clinical pregnancy rate per woman was found: two of 155 women (13%) and one of 14 women (7%) (OR 1.90, 95% CI 0.18 to 19.97). All 29
participatingg women ovulated after the first cycle. No data was reported for the outcomes miscarriagee and multiple pregnancy. No cases of OHSS occurred. As no data from the pre-crossoverr period could be obtained on the continuous outcome measures like mean totall FSH dose, mean duration of stimulation, mean oestradiol (E2) level and mean numberr of follicles of different measures on the day of hCG administration, these parameterss were not included in the MetaView analysis.
4.. Chronic low dose step up regimen versus step down regimen (Christin-Makre et al., 2003) )
Thee primary outcome i.e. live birth rate or ongoing pregnancy was not reported. No statisticallyy significant difference in clinical pregnancy rate per woman were found: 17 of 444 women (38.6%) and 12 of 39 (31%) (OR 1.41, 95% CI 0.57 to 3.46). Ovulation rate perr cycle was significantly different (OR 2.24, 95% CI, 1.18 to 4.27). It is unclear how thee miscarriages were calculated, but no differences were found; 12.5% versus 16.7%. Threee cases of moderate OHSS were reported but it is not clear in which treatment group. Twoo twin pregnancies (4,5% per woman) in the step up protocol and two twin and one triplett pregnancy (8% per woman) in the step down protocol were observed (OR 0.58, 95%% CI 0.10 to 3.50).
Continuouss outcome measures like total FSH dose, duration of stimulation, oestradiol (E2)) level and number of follicles of different measures on the day of hCG gift were also reported.. The mean (SD) total FSH dose used was not statistically different (WMD -16, 95%% CI -241 to 209). A significant difference was found for mean duration of stimulationn (OR 5.50, 95% CI 3.217.79) and E2 levels on day of hCG gift (WMD -395,, 95% CI-770 to-19).
InIn this study the rate of monofollicular (1 follicle >l6mm), bifollicular (2 follicles >16mm)) and multifollicular (at least 3 follicles >16mm) development was described. Noo difference was observed in bifollicular development (OR 0.59, 95% CI 0.26 to 1.30), whereass a significant difference was found in monofollicular (OR 4.24, 95% CI 2.27 to 7.92)) and multifollicular development (OR 0.13, 95% CI 0.06 to 0.29).
Discussion n
Ovulationn induction involves the use of medication or surgery to stimulate development off a mature follicle in the ovary of women who have chronic anovulation and infertility. Att this moment recombinant FSH and urinary FSH are commonly used for this purpose. Thee main difference between these two types of gonadotrophins is the presence or urinary proteinn contaminants in uFSH.
Yet,, impurity affects safety only if it should be demonstrated that any of the potential contaminantss adversely affect either the patients' health or treatment outcome. The urinaryy preparations of human gonadotrophins have been widely used for 40 years and noo infections have been associated with their injection, even in the past when the urinary extractss were rather impure (Balen, 2002, Gleicher et al., 2003). In spite of this, urinary FSHH is more immunogenetic leading to local and allergic reactions (Biffoni et al., 1998, Battagliaa et al., 2000).
Recombinantt FSH is more basic and resembles Metrodin more closely than Metrodin HP, whichh is more acidic (Lambert et al., 1995). Therefore the bio-potency of FSH increases inn the order highly purified urofollitropin (Metrodin HP), urofollitropin (Metrodin) and rFSHH (Lambert et al., 1995). Loumaye et al., 1996 and Yarali et al., 1999 compared Gonal-FF with Metrodin and Coelingh Bennink et al., 1998 compared Puregon with Metrodinn in a chronic low dose step up regimen. Several parameters are commonly used ass indicators for the biopotency of FSH: number of follicles >12 mm, E2 level on the day off H C G administration, total dose of FSH required to induce follicular development and thee duration of stimulation.
Indeed,, (Coelingh Bennink et al., 1998) found significantly more follicles in the range of 12-14mmm in the rFSH group, although this was not found for follicles larger than 15 mm. Furthermore,, rFSH required a significantly shorter treatment period to induce ovulation inn the first cycle. There was no proof of a difference in mean E2 level and total dose requiredd between rFSH and uFSH. Yarali et al., 1999 also studied the indicators for bioactivityy mentioned above. This trial however found no difference in number of follicles inn the range of 10-14 mm in the rFSH group. No differences were observed in E2 level, totall FSH dose and treatment period required to induce ovulation. More importantly, resultss from the pooled data showed no difference in ovulation rate per cycle (OR 1.19, 9 5 %% CI 0.78 to 1.80), clinical pregnancy rate per woman (OR 0.95, 95% CI 0.64 to 1.41),, multiple pregnancy rate per woman (OR 0.44, 95% CI 0.16 to 1.21), miscarriage ratee per woman (OR 1.26, 95% CI 0.59 to 2.70) and OHSS per woman (OR 1.55, 95% CII 0.50 to 4.84).
Apartt from the gonadotrophin used, the stimulation regimen is of importance in ovulationn induction. The conventional regimen used to be the standard stimulation protocoll but has now been abandoned. It is well known that the use of the conventional regimenn results in high rates of multiple pregnancies (33%) and ovarian hyperstimulation syndromee (up to 14%) (Homburg, 2003; Yarali, 2004). These complications are due to thee supraphysiological doses of FSH that are administered in the conventional regimen. Thee chronic low dose step up has been introduced to prevent the development of multiple follicles,, multiple pregnancies and OHSS as seen in conventional step up regimens. Basic thinkingg behind the chronic low dose step up regimen is the "threshold theory", that statess that FSH recruits and maintains one follicle only if it does not exceed a certain level (Brownn 1978). The principle of the chronic low dose step up regimen is to employ a low startingg dose for 14 days and then to use small incremental dose rises (usually half an ampoule)) when necessary, at intervals of not less than 7 days, until follicular development iss initiated (Seibel et al., 1984; Hamikon-Fairley et al., 1991). In the one trial that comparedd the chronic low dose step up with the conventional step up regimen no differencess were found in effectiveness which may be due to the small size of this study (Hedonn et al., 1998). Although a difference in OHSS and multiple pregnancies was not foundd there were significantly fewer follicles >10 mm diameter (WMD 3.30, 95% CI -5.344 to -1.26) in the group treated with the chronic low dose step up regimen.
AA possible criticism of the chronic low dose step up regimen is that, unlike the events of thee normal ovulatory cycle in which decreasing FSH concentrations are seen throughout thee follicular phase, FSH levels may be elevated during the follicular phase (Dale et al., 1993).. In order to mimic more closely the events of the normal ovulatory cyle the step downn regimen has been introduced with a starting dose of 150 IU and decreasing the dose byy 0.5 ampoules when a follicle of 10 mm develops and by the same amount every 3 days
iff follicular growth continues (Fauser et al., 1993). A key issue of the step down regimen iss to estimate the FSH threshold of follicular development in order to determine the FSH startingg dose. Therefore a "dose-finding" low-dose step up regimen is first offered for these patientss followed by the step down regimen. A comparison of the step down regimen with thee chronic low dose step-up regimen in a small randomised controlled trial with uFSH demonstratedd a higher monofollicular growth rate of cycles in the step down regimen (88%)) compared with step up regimen (56%) (van Santbrink and Fauser 1997). In the stepp down-group, duration of treatment and gonadotrophin requirement were significantlyy reduced. However, the study by Christin-Maitre et al., 2003 with a larger samplee size, comparing the chronic low dose step up regimen versus the step down regimenn with rFSH, demonstrated superiority of the step up regimen with regard to the ratess of monofollicular development (OR 4.24, 95% CI 2.27 to 7.92), ovulation (OR 2.24,, 95% CI, 1.18 to 4.27) and multifollicular development (OR 0.13, 95% CI 0.06 to 0.29).. Although the mean duration of stimulation was significantly longer (OR 5.50, 95%% CI 3.21-7.79) in the step up regimen, no significant difference was found in the totall dose of FSH used (WMD -16, 95% CI -241 to 209).
Inn the chronic low dose step up regimen a starting dose of no higher than 75 IU is used. InIn theory, risk of multifollicular development and multiple pregnancies can be prevented whenn an even lower starting dose is used. From the largest cohort study of the chronic low dosee step up regimen (White et al., 1996) it was possible to compare the results of a startingg dose of 75 IU with that of 52.5 IU, with an incremental dose rise of 37.5IU or 22.5IUU respectively. No significant differences between the two groups were found but pregnancyy rate per patient, monofollicular growth rate and miscarriage rate were all in favourr of the lower starting dose. Although having a very small sample size with a crossoverr design similar clinical pregnancy rates and ovulation rates were observed in the randomizedd controlled trial comparing 37.5 IU with 50 IU (Balasch et al., 2000). InIn summary, there is as yet insufficient evidence to conclude that rFSH is more effective thann uFSH. Therefore, it is questionable whether its high costs should be traded off its purity,, independence of urine collection, absolute source control and batch to batch consistency.. No difference could be proven between the four different dose regimens. However,, the conventional regimen is known to be plagued by OHSS and multiple pregnanciess and its usage should therefore be discouraged.
Reviewers'' conclusions Implicationss for practice
Thee newly developed recombinant gonadotroph ins have clear advantages, particularly availability,, batch to batch consistency and self-administration. Based on the differences inn terminal sialic acid residues, which confer different charge patterns to the gonadotropin preparations,, differences in biological activity are expected. The role of biological activity inn ovulation induction still has to be resolved. However, at this moment this does not have clearr clinical consequence as both rFSH and uFSH are equally effective for ovulation inductionn in women with PCOS. Furthermore, attention should be given to the costs involvedd in these treatments. The higher costs associated with the rFSH can present a problem,, particulary in a society with decreasing health resources.
regimenn should be preferred to the now outdated conventional regimen.
Implicationss for research
Moree randomised controlled trials with sufficient power are necessary to estimate the differencee of rFSH and uFSH, if one exists. The theoretical advantage of a "dose finding" stepp up cycle preceding the step down cycle has to be determined in a randomized controlledd trial. Evaluations of the outcomes should relate to effectiveness, as well as to adversee effects and cost-effectiveness. There is also a need to report all relevant outcomes, includingg life birth, multiple follicular development, OHSS, multiple pregnancy and miscarriagee rates. Parallel rather than crossover design and an intention to treat analysis shouldd be used. The need for large numbers means that such trials would be best organisedd on a multicentre basis.
References s
Referencess to included studies
Balaschh J, Fabregues F, Creus M, Casamitjana R, Puerto B, Vanrell JA. (2000) Recombinant human follicle-stimulatingg hormone for ovulation induction in polycystic ovary syndrome: a prospective, randomized trial off two starting doses in a chronic low-dose step-up protocol. J. Ass. Reprod. Gen. 17, 561-565.
Balaschh J, Fabregues F, Creus M, Puerto B, Penarrubia J, Vanrell J A. (2001) Follicular development and hormonee concentrations following recombinant FSH administration for anovulation associated with polycysticc ovarian syndrome: prospective, randomized comparison between low-dose step-up and modified step-downn regimens. Hum. Reprod. 16, 652-656.
Christin-Maitree S, Hugues JN, on behalf of the Recombinant FSH study Group. (2003) A comparative randomizedd multicentric study comparing the step-up versus step-down protocol in polycystic ovary syndrome.. Hum. Reprod. 18, 1626-1631.
Coelinghh Bennink HJT, Fauser BCJM, Out HJ. (1998) Recombinant follicle-stimulating hormone (FSH; Puregon)) is more efficient than urinary FSH (Metrodin) in women with clomiphene citrare-resistant, normogonadotropic,, chronic anovulation: a prospective, multicenter, assessor-blind, randomized, clinical trial.. Fertil. Steril. 69, 19-25.
Hedonn B, Hugues JN, Emperaire JC, Chabaud JJ, Barbereau D, Boujenah A, Howies CM, Truong F. (1998) AA comparative prospective study of a chronic low dose versus a conventional ovulation stimulation regimen usingg recombinant human follicle stimulating hormone in anovulatory infertile women. Hum. Reprod. 13, 2688-2692. .
Loumayee E, Martineau I, Piazzi A, O'Dea L, Ince S, Howies C, Decosterd G, Van Loon K, Galazka A. (1996) Clinicall assessment of human gonadotrophins produced by recombinant DNA technology. Hum. Reprod.
Yaralii H, Bukulmez O, Gurgan T. (1999) Urinary follicle-stimulating hormone (FSH) versus recombinant FSHH in clomiphene citrate-resistant, normogonadotropic, chronic anovulation: a prospective randomized study.. Fertil. Steril. 72, 276-281.
Referencess to excluded studies
Attiaa AM, Hamza HS, Soliman EM. (2003) Effectiveness and cost-effectiveness of urinary FSH versus recombinantt FSH in clomiphene citrate-resistant anovulatory infertile patients: Opposing the policy of abandoningg the use of urinary FSH. Middle East Fertility Society Journal, 8.
Fulghesuu AM, Apa R, Belosi C, Ciampelli M, Selvaggi L Jr, Cucinelli F, Caruso A, Mancuso S, Lanzone. (2001)) A Recombinant versus urinary follicle-stimulating hormone in the low-dose regimen in anovulatory patientss with polycystic ovary syndrome: a safer and more effective treatment Horm. Res. 55, 224-228. Szilagyii A, Bartfai G, Manfai A, Koloszar S, Pal A, Szabo I. (2004) Low-dose ovulation induction with urinary gonadotropinss or recombinant follicle stimulating hormone in patients with polycystic ovary syndrome. Gynecoll Endocrinol 18, 17-22.
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vann Weissenbruch MM, Schoemaker HC, Drexhage HA, Schoemaker J. (1993) Pharmacodynamics of humann menopausal gonadotrophin (HMG) and follicle stimulating hormone (FSH). The importance of the FSHH concentration in initiating follicular growth in polycystic ovary-like disease. Hum. Reprod. 8, 813-821.
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Characteristicss of excluded studies
Attiaa et al., 2003: Not truly randomised and the starting dose differed between groups, i.e. 50 IE in the rFSH groupp and 75IE in the uFSH group.
Fulghesuu et al., 2001: Non-randomized controlled trial.
Szilagyy et al., 2004: Participating patients were treated with clomiphene citrate and gonadotrophins before randomization. .
