Hum. Reprod. Advance Access originally published online on April 20, 2007
Human Reproduction 2007 22(7):1816-1823; doi:10.1093/humrep/dem075
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Highly purified FSH is as efficacious as recombinant FSH for ovulation induction in women with WHO Group II anovulatory infertility: a randomized controlled non-inferiority trial
1 Leeds General Infirmary, Department of Obstetrics and Gynaecology, Clarendon Wing, Leeds General Infirmary, Belmont Grove, Leeds LS2 9NS, UK 2 Center for Reproductive Medicine of the Vrije Universiteit Brussel (VUB), Brussels, Belgium 3 Rigshospitalet, Fertility Clinic, Copenhagen, Denmark 4 Ferring Pharmaceuticals A/S, Obstetrics and Gynaecology, Clinical Research and Development, Copenhagen, Denmark
5 Correspondence address. Tel: +44-113-392-2728; Fax: +44-113-392-2446; E-mail: adam.balen{at}leedsth.nhs.uk
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Abstract |
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BACKGROUND: The objective of this study was to demonstrate non-inferiority of a highly purified urinary follicle stimulating hormone (HP-FSH) preparation compared with a recombinant (rFSH) preparation with respect to ovulation rate (primary end-point).
METHODS: This was a randomized, open-label, assessor-blind, multinational study. Women with anovulatory infertility WHO Group II and resistant to clomiphene citrate were randomized (computer-generated list) to stimulation with HP-FSH (n = 73) or rFSH (n = 78) using a low-dose step-up protocol. The non-inferiority limit was prespecified at –20%.
RESULTS: The ovulation rate was 85.2% (51/62) with HP-FSH and 90.9% (60/66) with rFSH (per-protocol population), and non-inferiority was demonstrated [95% confidence interval: –16.9; 5.6]. No differences were noted between groups in number of follicles 
12 mm, 15 mm or 18 mm, mono-follicular development, pregnancy rates, endometrial thickness, number of ovarian stimulation syndrome cases or frequency of injection site reactions/pain. The singleton live birth rate was 15% in both groups (11/73 with HP-FSH and 12/78 with rFSH).
CONCLUSIONS: This urinary HP-FSH preparation is non-inferior compared with a rFSH preparation with respect to ovulation rate in anovulatory WHO Group II women failing to ovulate or conceive on clomiphene citrate.
Key words: highly purified FSH/ovulation induction/polycystic ovary syndrome/recombinant FSH
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Introduction |
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The goal of ovulation induction for World Health Organization (WHO) Group II anovulatory women is to achieve mono-ovulation. Ovarian stimulation with follicle stimulating hormone (FSH) preparations in low-dose step-up protocols has been shown to be successful in producing mono-follicular development in more than half of the women undergoing therapy. These low-dose step-up protocols minimize the risk of multiple follicular development and the associated risks of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy (Homburg and Howles, 1999
). Comparative studies among FSH preparations in low-dose step-up protocols have shown similar ovulation and pregnancy rates with the use of the different preparations (Bayram et al., 2001) in clomiphene citrate resistant women (no or varying definitions of resistance in the different studies), although some have reported a difference between preparations in the rate of mono-follicular development (Yarali et al., 1999) or treatment efficiency (Coelingh Bennink et al., 1998).
Potential clinical differences among FSH preparations have been attributed to their different isoform profiles. FSH preparations have substantial variations in size and structure of the carbohydrate chains, with different numbers of antennae (from two to five) and various levels of sialylation and sulfation (Green and Baenziger, 1988a,b; Gervais et al., 2003). These variations in structure and type of sugar residues within the glycoprotein may cause markedly different in vivo biological activity, most likely due to differences in receptor binding ability and metabolic clearance (Wide, 1986; Wide and Hobson, 1986; Galway et al., 1990; Bishop et al., 1995; Burgon et al., 1996; Timossi et al., 2000; Barrios-De-Tomasi et al., 2002; Gervais et al., 2003). The degree of sialylation is often discussed in terms of acidic (i.e. more sialic acid molecules) versus less acidic (i.e. less sialic acidic molecules) FSH isoforms.
FSH preparations have primarily been classified by the manufacturing method rather than by their actual differences in isoform composition. The introduction of recombinant technology has resulted in FSH preparations with a high proportion of less acidic isoforms compared with the human derived urinary preparations available previously, such as urofollitropin Metrodin HP (Lambert et al., 1995; Horsman et al., 2000). Using advanced and optimized chromatographic techniques, urinary human FSH can currently be manufactured with a defined isoform profile, in addition to achieving a high batch-to-batch consistency and purity (Wolfenson et al., 2005). A urinary highly purified FSH (HP-FSH) preparation (BRAVELLE, Ferring Pharmaceuticals A/S, Copenhagen, Denmark) claimed to contain a high proportion of less acidic isoforms (Wolfenson et al., 2005) has been shown to provide similar efficacy as recombinant follitropin 
in down-regulated women undergoing controlled ovarian stimulation for assisted reproductive technologies (Dickey et al., 2002, 2003) and ovulation induction (Feigenbaum et al., 2001). No studies had compared this HP-FSH preparation versus follitropin 
nor had it been investigated in non-down-regulated women undergoing ovulation induction.
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Materials and Methods |
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Study population
Anovulatory WHO Group II women, who had failed to ovulate or conceive on clomiphene citrate, were recruited at 22 fertility centers (12 in Belgium, 7 in Denmark and 3 in the UK). The inclusion criteria were (i) women with good physical and mental health, aged between 18 and 39 years who failed to ovulate with clomiphene citrate doses of at least 100 mg/day for at least 5 days or failed to conceive after three cycles of ovulation induction with clomiphene citrate (ii) WHO Group II infertility with chronic anovulation (amenorrhea or oligomenorrhea, or anovulatory cycles based on progesterone levels in women with cycle lengths of 21–35 days) (iii) infertility for
1 year before randomization (iv) BMI 19–35 kg/m2 at the time of randomization (v) at least one patent tube documented within 3 years prior to screening (vi) normal pelvis documented by a transvaginal ultrasound with respect to uterus, Fallopian tubes and ovaries within 3 months prior to screening (vii) early follicular phase serum FSH levels 1–12 IU/l and levels of prolactin and total testosterone not suggestive of hyperprolactinemia or androgen-secreting tumors (viii) a male partner with semen analysis showing acceptable values for intrauterine insemination (IUI), or semen from a donor and (ix) signed informed consent form, prior to screening. The exclusion criteria included (i) a history of 12 unsuccessful ovulation induction cycles (ii) persistent ovarian cysts (15 mm) for >1 cycle or ovarian endometrioma on ultrasound (iii) any significant systemic disease, endocrine or metabolic abnormalities (pituitary, thyroid, adrenal, pancreas, liver or kidney) (iv) use of any non-registered investigational drug during the 3 months before screening or previous participation in the study and any concomitant medication that would interfere with the evaluation of the study medication (non-study hormonal therapy, except thyroid medication, anti-psychotics, anxiolytics, hypnotics, sedatives and need for continuous use of prostaglandin inhibitors) (v) treatment with clomiphene citrate, metformin, gonadotrophins or GnRH analogues within 1 month prior to randomization (vi) pregnancy, lactation or contraindication to pregnancy (vii) current or past (last 12 months) abuse of alcohol or drugs (viii) a history of chemotherapy (except for gestational conditions) or radiotherapy (ix) undiagnosed vaginal bleeding (x) tumors of the ovary, breast, adrenal gland, pituitary or hypothalamus; malformation of sexual organs incompatible with pregnancy and (xi) hypersensitivity to any trial product.
Study design
This was a randomized, open-label, assessor-blind, parallel-group, multicenter, multinational study comparing HP-FSH (BRAVELLE; Ferring Pharmaceuticals A/S) and recombinant (rFSH) (follitropin , GONAL-F; Serono, Geneva, Switzerland) with respect to ovulation rates using a low-dose step-up protocol. It was designed as a non-inferiority study and the control group was a preparation with established efficacy in anovulatory women undergoing ovulation induction. The study was carried out in accordance with the Declaration of Helsinki on good clinical practice and ethical committee approval was obtained in all participating centers. The study was conducted from November 2002 to October 2003 and delivery follow-up was completed in 2004. Eligible subjects were randomized 1:1 to HP-FSH or rFSH at the time of starting stimulation, based on a computer-generated randomization list prepared by an independent statistician. The block size was four, but this was concealed during the study. All investigators and sponsor study staff were blinded to treatment allocation throughout the study, and the treatment code was not unblinded for any subject during the study. Gonadotrophin distribution was handled by study nurses.
Stimulation treatment was started 2–5 days after a spontaneous or progesterone-induced menstrual bleed. HP-FSH was provided as a vial with powder and a vial with solvent for reconstitution, and rFSH was provided as an ampoule with powder and an ampoule with solvent for reconstitution. All volumes injected were 1 ml irrespective of FSH dose. Identical needles and syringes were provided for all subjects (needle 26G x 1/2'' Terumo and 2 ml syringe Becton Dickinson S.A.). The starting dose of HP-FSH or rFSH was 75 IU daily, which was maintained for 7 days. After the first 7 days, the gonadotrophin dose was either maintained or increased by 37.5 IU increments according to individual response. Subjects were maintained on any specific dose level for at least 7 days. The maximum allowed daily dose was 225 IU and subjects were treated with gonadotrophin for a maximum of 6 weeks. Compliance was assessed by self-reported diaries of gonadotrophin use. Gonadotrophin stimulation was maintained until at least one of the following criteria for human chorionic gonadotrophin (hCG) administration were met: one follicle with a diameter of 17 mm or two to three follicles with a diameter of 15 mm. Subjects were not given hCG in either of the following situations: no follicular response after 6 weeks of gonadotrophin treatment, 4 follicles with diameters of 15 mm or serum estradiol (E2) levels >2000 pg/ml. Subjects who reached the hCG criteria received a single s.c. or i.m. injection of hCG (PROFASI, Serono) at a dose of 5000 IU to trigger ovulation. Subjects given hCG were recommended sexual intercourse or were planned for IUI according to the standards at the investigational site; luteal support was prohibited. At least one blood sample was taken during the mid-luteal phase (6–9 days after hCG administration) and analysed for progesterone by a central laboratory. A quantitative pregnancy test (serum -hCG) was taken 12–16 days after hCG administration. In case of pregnancy, a transvaginal ultrasound was performed 7 ± 2 weeks and 12 ± 2 weeks after hCG administration to confirm clinical and ongoing pregnancy, respectively. All pregnancies were followed up to delivery.
Study end-points
The primary objective of the study was to demonstrate non-inferiority of HP-FSH compared with rFSH with respect to ovulation rate after one cycle of gonadotrophin treatment. Ovulation was defined as a mid-luteal serum progesterone concentration of 25 nmol/l ( 7.9 ng/ml), as used in other studies (Coelingh Bennink et al., 1998; Hugues et al., 2005). In case of a progesterone value suggestive of ovulation but below 25 nmol/l, it was possible for the clinic to collect a new sample (still in the mid-luteal phase); a progesterone concentration of this second sample 25 nmol/l documented ovulation. Measurement of mid-luteal progesterone was performed by a central laboratory using competitive immunoassay using direct chemiluminometric technology with a sensitivity of 0.48 nmol/l (Quest Diagnostics Limited, Heston, UK). The protocol also allowed that subjects with a clinical pregnancy documented via transvaginal ultrasound would be counted as subjects with ovulation in the absence of a mid-luteal progesterone sample; this was the case for one subject in the HP-FSH group. Patients who had discontinued from the study prior to the ovulation visit (n = 10) were defaulted to a negative response (ovulation = ‘no') in the statistical analysis.
Other clinical parameters evaluated were clinical pregnancy rate (transvaginal ultrasound showing at least one intrauterine gestation sac with fetal heart beat 7 ± 2 weeks after hCG administration), ongoing pregnancy rate (transvaginal ultrasound showing at least one viable fetus 12 ± 2 weeks after hCG administration), live birth rate, singleton live birth rate, number of follicles according to size, number of subjects with mono-follicular (one follicle 17 mm and no follicles of 15–16 mm) and bi-/multifollicular (2 follicles 15 mm) development, endometrial thickness at the time of hCG administration and efficiency in terms of total gonadotrophin dose administered and duration of gonadotrophin treatment. The major safety end-points were the incidence of OHSS [categorized as mild, moderate or severe according to Golan's classification (Golan et al., 1989)], multiple pregnancies and the number of cancellations due to risk of hyper-response. In addition, the local tolerability (injection site reactions in terms of redness, pain, itching, swelling and bruising) was assessed by the subject in a diary 1 and 24 h after administration throughout the stimulation phase.
Statistical analysis
The sample size calculation was based on comparison of two binomial proportions with a two-sided significance level of 0.05 and a power of 80%. The overall expected ovulation rate was 80%, and the non-inferiority limit for the absolute difference between treatments (HP-FSH–rFSH) was prespecified at –20%. This limit was used in a previous clinical trial with ovulation rate as the primary endpoint (The International Recombinant Human Chorionic Gonadotropin Study Group, 2001). A 20% reduction in ovulation rate would be expected to translate to a decrease in live birth rate of 5%, which would be considered to be a clinically relevant difference between treatments. On the basis of these conditions, 126 women (63 per group) were needed for the study. The estimate of the difference in ovulation rate between treatment groups with corresponding two-sided 95% confidence interval (CI) was calculated using the SAS procedure GENMOD using a binomial distribution with the identity link function. Subjects with no information on ovulation were defaulted to a negative response. The analyses on ovulation rate were made on both the per-protocol (PP) and intention-to-treat basis (ITT; all randomized subjects), with the PP analysis specified as the primary. Secondary end-points were analysed in the same way as the primary end-point for binary data, and for continuous data two-sample t-test and Wilcoxon test were used to compare treatment groups. The secondary end-points are presented for the ITT analysis set. The ITT population for analysis of efficacy end-points included subjects according to planned randomization, whereas the safety population included subjects according to the actual treatment received (Fig. 1). No adjustment for multiplicity was performed, as there was only one primary end-point, and all other end-points were considered secondary. The main analysis of efficacy and safety end-points was unadjusted.
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Results |
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In total, 186 subjects were screened and 151 were randomized: 73 to HP-FSH and 78 to rFSH (Fig. 1). Of the randomized subjects, 69 (94.5%) in the HP-FSH group and 72 (92.3%) in the rFSH group completed the study. The remaining subjects were withdrawn due to adverse events (HP-FSH 1/73; vaginal bleeding), non-compliance (rFSH 1/78), excessive response (HP-FSH 1/73; rFSH 4/78), personal reasons (HP-FSH 1/73) and other (HP-FSH 1/73; rFSH 1/78). Subject demographics, baseline characteristics and infertility history (Table 1) were not statistically significant different between the two treatment groups with the exception of menstrual cycle status. Oligomenorrhea or amenorrhea was more frequent in the HP-FSH group (79.5%) than in the rFSH group (62.8%; Table 1). Among the women included in the study, 33.8% had failed to ovulate with at least 100 mg of clomiphene citrate for at least 5 days. The endocrine profile at the time of starting stimulation (including luteinizing hormone [LH], FSH, LH/FSH ratio, E2, progesterone, prolactin, androstenedione, total testosterone, sex hormone binding globulin, glucose and insulin) was comparable among subjects in the two groups (Table 2), with a non-clinically relevant difference in androstenedione being the only statistically significant difference between groups.
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A total of 127 subjects (61/73 [84%] in the HP-FSH group and 66/78 [85%] in the rFSH group) were included in the PP population. The major reasons for protocol violation were incorrect dose adjustment and hCG administered despite hCG criteria not being met or being exceeded (Fig. 1). With regard to the primary end-point, the ovulation rate for the PP population was 85.2% (52/61) in the HP-FSH group and 90.9% (60/66) in the rFSH group (difference –5.7%; 95% CI [–16.9; 5.6]), demonstrating non-inferiority of HP-FSH compared with rFSH with respect to ovulation induction. Non-inferiority was supported by the results of the ITT (all randomized) analysis where the ovulation rate was 80.8% (59/73) in the HP-FSH group and 88.5% (69/78) in the rFSH group (difference –7.6%; 95% CI [–19.1; 3.8]). The sensitivity of the main analysis of ovulation rate was investigated when adjusting for age and BMI, and the results were consistent and similar to the unadjusted analysis (data not shown).
Follicular development was analysed according to follicle diameter. The results are displayed in Table 3. There was no significant difference between HP-FSH and rFSH in the mean number of follicles that on the day of hCG administration were 12 mm, 15 mm or 18 mm. The distribution of subjects with one, two or three follicles 15 mm or 18 mm was comparable between treatment groups. The distribution of subjects with mono-follicular development did not differ significantly between the HP-FSH and rFSH groups; 40/73 (54.8%) versus 40/78 (51.3%). Bi-/multifollicular development was observed for 27/73 (37.0%) and 32/78 (41.0%) in the HP-FSH and rFSH groups, respectively. Inadequate follicular development occurred in 6/73 (8.2%) and 6/78 (7.7%) of the subjects in the HP-FSH and rFSH groups, respectively. The rate of excessive response leading to cancellation of the cycle was 1/73 (1.4%) with HP-FSH and 4/78 (5.1%) with rFSH.
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Among the subjects who received hCG, IUI was performed for 61% (42/69) in the HP-FSH group and 69% (48/70) in the rFSH group. The positive
-hCG, clinical and ongoing pregnancy rates and live birth rates were comparable for HP-FSH and rFSH treatment (Table 3). The multiple pregnancy rates were 15.4% (2/13) in the HP-FSH group and 25.0% (4/16) in the rFSH group. The singleton live birth rate was 15.1% (11/13) and 15.4% (12/16) in the HP-FSH and rFSH groups, respectively. E2 levels (mean ± standard deviation [SD]) at the end of the stimulation prior to hCG administration were similar in the HP-FSH group and the rFSH group (1480 ± 1571 and 1518 ± 1001 pmol/l, respectively). There were no significant differences between treatment groups in endometrial thickness at the day of hCG administration. All except one ongoing pregnancy occurred in subjects with an endometrial thickness 7 mm on the day of hCG administration. As there was an imbalance in distribution of subjects in each treatment group with respect to menstrual history, duration of FSH treatment and total FSH dose administered are presented by menstrual history in Table 3. The clinical safety data are summarised in Table 4. The frequency of subjects with adverse events was similar in the two treatment groups (39.7% for both; 29/73 versus 31/78) as well as the adverse event profile, with the most frequently reported adverse events being headache, pelvic pain, vaginal bleeding and nausea. The percentage of subjects experiencing mild, moderate or severe adverse events was similar in both groups. Two subjects experienced OHSS during the study, one in each treatment group; both were mild OHSS occurring in subjects where hCG was administered despite the cancellation criterion being met. Early pregnancy loss was documented for three subjects in both treatment groups corresponding to 4.1% (3/73) in the HP-FSH group and 3.8% (3/78) in the rFSH group. Neonatal intensive care admission was required for 15.4% (2/13) of the ongoing pregnancies in the HP-FSH compared with 37.5% (6/16) in the rFSH group: three neonates in the HP-FSH group and eight in the rFSH group. The admissions were primarily due to prematurity in twins.
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Both treatments were associated with good local tolerability (Table 4). The majority of subjects administered FSH themselves (57/73 [78.1%] and 55/78 [70.5%] in the HP-FSH and rFSH groups, respectively). Bruising at the injection site was the most frequently reported local reaction in both groups (31/73 [42.4%] in the HP-FSH group and 29/78 [37.2%] in the rFSH group). None of the subjects treated with HP-FSH reported moderate or severe early (1 h) or late (24 h) local reactions for redness, pain, itching or swelling.
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Discussion |
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This randomized, assessor-blind, multicenter, multinational study demonstrates that the urinary HP-FSH preparation tested is non-inferior to a rFSH preparation in anovulatory WHO Group II women who failed to ovulate or conceive with clomiphene citrate. No statistically significant or clinically relevant differences were found between the two treatment groups for any of the clinical end-points. Comparable follicular development and E2 levels were obtained during stimulation with HP-FSH and rFSH follitropin
, supporting the concept that the main pharmacodynamic properties of these compounds are very similar. Data from other studies comparing this HP-FSH preparation and rFSH follitropin in anovulatory or ovulatory down-regulated women suggest that there are no differences in follicular development (Feigenbaum et al., 2001; Dickey et al., 2002, 2003). The percentage of subjects with mono- or bi-/multifollicular development was similar between the two treatment groups, with the majority of subjects in both groups achieving mono-follicular development (51.3–54.8%). While this figure is in line with previous reports (Yarali and Zeyneloglu, 2004), further consideration should be given to how to improve ovulation induction protocols to increase mono-follicular development without compromising efficacy. Maintenance of the starting dose for 14 days rather than 7 days may result in a higher rate of mono-follicular development, but the pregnancy rate per cycle tends to decrease and the duration of treatment will increase in a proportion of patients (Homburg and Howles, 1999). Endometrial thickness was comparable between the two groups, as would be expected when comparing preparations with only FSH activity.
The clinical and ongoing pregnancy rates and live birth rates are satisfactory considering the type of population and the use of a low-dose step-up protocol with strict criterion for cancellation if >3 follicles of 15 mm or greater were seen. There are limited data on ongoing pregnancy rates or live birth rates per cycle in this type of population with a low-dose step-up protocol, as some of the comparative studies between rFSH and urinary FSH preparations did not report these rates (Coelingh Bennink et al., 1998; Yarali et al., 1999). However, clinical pregnancy rates per cycle of 17% (Homburg and Howles, 1999; Yarali and Zeyneloglu, 2004) have been reported with the use of low-dose step-up protocols and this figure is comparable to the 17.8–21.8% reported in the present study. Independently of the treatment received, approximately one in every six women initiating treatment in this study (15.2%) achieved a singleton live birth.
Efficiency of treatment parameters was analysed according to menstrual status, as this feature is expected to have an impact on the threshold dose (et al., 2002), and as there was an imbalance between treatment groups in the distribution of subjects according to menstrual cycle status. The results diverged in different directions depending on menstrual cycle characteristics at study entry, with a tendency toward more gonadotrophin consumption and longer treatment with the rFSH preparation compared with the HP-FSH preparation in amenorrheic subjects, but higher efficiency of rFSH versus HP-FSH in women with oligomenorrhea and anovulatory cycles of 21–35 days. This apparent discrepancy is considered likely to be related to the few subjects in each subgroup. In the context of factors with potential influence on treatment efficiency, the inclusion of subjects with BMI up to 35 kg/m2 also deserves to be addressed. We have previously shown that increasing BMI in patients undergoing ovulation induction therapy is associated with significantly greater gonadotrophin consumption (Balen et al., 2006). Ovulation rate and pregnancy rate were however not affected by BMI within the 19–35 kg/m2 range (Balen et al., 2006). In the present trial, the treatment groups were balanced with respect to BMI at baseline.
The heterogeneity of the urinary FSH preparations and possibly also of the rFSH preparations should be kept in mind when evaluating the studies comparing urinary FSH preparations versus rFSH. It can be argued that grouping of studies based only on the manufacturing process may no longer be appropriate from a methodological point of view, as isoform compositions are claimed to differ between preparations (Wolfenson et al., 2005). In addition to the data from the current study versus follitropin , this specific urinary HP-FSH preparation has been shown to have comparable clinical efficacy and no difference in treatment efficiency compared with follitropin (Feigenbaum et al., 2001; Dickey et al., 2002, 2003).
No relevant differences in the frequency or profile of adverse events were noted between the two groups. Despite the effort to minimize the risk of OHSS and reduce the risk of multiple pregnancies with the use of a low-dose step-up protocol with adequate monitoring of follicular response and a strict criterion for cancellation based on follicle number/size, the incidence of OHSS was 1.4 and 1.3% with the HP-FSH and rFSH preparations, respectively, and the frequency of multiple pregnancies ranged from 15.4 to 25.0%. The two OHSS cases, however, were mild and occurred in subjects in whom >3 follicles of 15 mm or greater were observed and where the cycles therefore should have been cancelled. Strict adherence to the cancellation policy should have a major impact on preventing OHSS in these populations. It should, however, be noted that the two subjects with OHSS became pregnant and this will need to be taken into consideration when evaluating the risks and benefits associated with therapy. The multiple pregnancy rate is in line with the 24% reported with low-dose step-up protocols in which the starting dose is kept for 7 days rather than 14 days (Homburg and Howles, 1999). However, efforts should be made to reduce the multiple pregnancy rates in ovulation induction to below 5%. Multiple pregnancies accounted for 2/13 pregnancies with HP-FSH and 4/16 pregnancies with rFSH. Although the absolute numbers in both groups are small, it can be speculated that the more multiple pregnancies in the rFSH group are related to the follicular development. No statistically significant differences were noted between HP-FSH and rFSH with respect to follicular development, but there was a tendency toward more large follicles and a higher percentage of bi/multi-follicular development (2 follicles 15 mm on the day of hCG) in the rFSH group. Among the six patients with multiple pregnancies, both patients in the HP-FSH group and three of four patients in the rFSH group had bi-/multi-follicular development.
Subcutaneous administration of this HP-FSH preparation with a high proportion of less acidic isoforms has been shown to give less pain and fewer dermatological reactions than follitropin in women undergoing controlled ovarian stimulation (Dickey et al., 2002, 2003). In the present study, local tolerability was specifically investigated by the subjects' self-assessment of any early (1 h) or late (24 h) local reactions and suggested good local tolerability for both preparations. In contrast to other studies (Dickey et al., 2002, 2003), no statistically significant differences were noted in this comparative study versus follitropin which could be attributed to the lower daily doses in ovulation induction or to potential differences between follitropin and in terms of local tolerability.
In summary, the results of this study confirm the non-inferiority of this HP-FSH preparation compared with a rFSH preparation with respect to ovulation rates in anovulatory WHO Group II women failing to ovulate or conceive on clomiphene citrate. Comparable pharmacodynamic, clinical and safety profiles are obtained with the use of these preparations in ovulation induction when following a low-dose step-up protocol.
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Acknowledgements |
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The authors would like to thank Per Sørensen M.Sc., Biometrics, Ferring Pharmaceuticals A/S, for conduct of the statistical analyses. The study was sponsored by Ferring Pharmaceuticals A/S, Copenhagen, Denmark. We would like to thank all participating centers. Belgium: AZ-VUB, Brussels; Virga Jesse Ziekenhuis, Hasselt; AZ Groeninge, Kortrijk; CHR Citadelle, Liège; Hôpital Erasme, Brussels; ZOL Campus St. Jan, Genk; Centre Hospitalier Notre Dame, Charleroi; AZ St. Lucas, Gent; Private Practice, Aalter; AZ Jan Portaels Campus Zuid, Vilvoorde; UZ Gasthuisberg, Leuven; Universitair Ziekenhuis, Gent. Denmark: Copenhagen University Hospital; Brædstrup Hospital; Randers Hospital; Skive Hospital; Holbæk Hospital; Herlev Hospital; Odense University Hospital. UK: Leeds Hospital; Birmingham Women's Hospital; St. Michael's Hospital, Bristol. These data were presented at the 20th Annual ESHRE Meeting, Berlin, Germany, 2004.
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References |
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Submitted on September 29, 2006; resubmitted on February 15, 2007; accepted on February 28, 2007.
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