A prospective randomized clinical trial comparing an individual dose of recombinant FSH based on predictive factors versus a ‘standard’ dose of 150 IU/day in ‘standard’ patients undergoing IVF/ICSI treatment

B. Popovic-Todorovic1,3, A. Loft1, H.Ejdrup Bredkjæer2, S. Bangsbøll1, I.K. Nielsen2 and A.Nyboe Andersen1

1 The Fertility Clinic 4071, Rigshospitalet, Copenhagen and 2 The Fertility Clinic, Hvidovre Hospital, Hvidovre, Denmark

3 To whom correspondence should be addressed at: The Fertility Clinic 4071, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark. e-mail: drbiba{at}yahoo.com


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: The study aim was to compare the use of individual rFSH doses between 100 and 250 IU/day (calculated using the rFSH dose normogram) with a standard dose of rFSH of 150 IU/day. METHODS: This prospective randomized dual-centre clinical trial included 267 first IVF/ICSI cycles using the long agonist protocol in ‘standard’ patients. Following down-regulation, 262 patients were randomized using computer-generated lists using ‘clusters of 10’ into the individual dose (study) group (n = 131) or the standard dose (control) group (n = 131). RESULTS: In the study group, 101 patients (77.1%) had an appropriate response (defined as 5–14 oocytes), compared with 86 (65.6%) in the control group (P < 0.05). Fewer than five oocytes were retrieved in two patients (1.5%) in the study group, compared with 14 patients (10.7%) in the control group (P < 0.05). By comparison, >14 oocytes were retrieved from 27 patients (20.6%) in the study group and from 26 (19.8%) control patients (P = NS). Eighty-six per cent of the individual dose patients did not require any dose adjustment on day 8, compared with 45% of the standard dose patients (P < 0.01). The ongoing pregnancy rate per initiated cycle was 36.6% in the study group and 24.4% in the control group (P < 0.01). One patient (0.8%) in the study group, and four patients (3.1%) in the control group, were hospitalized due to ovarian hyperstimulation syndrome. CONCLUSIONS: An individual dose regimen in a well-defined ‘standard’ patient population increased the proportion of appropriate ovarian responses and decreased the need for dose adjustments during controlled ovarian stimulation. A higher ongoing pregnancy rate was observed in the individual dose group.

Key words: individual rFSH dose normogram/IVF/ICSI patients/ovarian response/standard patients


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Assisted reproduction techniques with IVF generally involve controlled ovarian hyperstimulation (COH), most frequently with GnRH agonist down-regulation in the long protocol. Following the introduction of recombinant FSH preparations (rFSH), a number of clinical trials have been carried out in order to define the optimal rFSH starting dose (Devroey et al., 1998Go; Out et al., 1999Go; 2000; 2001; The Latin-American Puregon IVF Study Group, 2001Go). In the clinical studies, the dose regimens for standard patients range from 100 to 250 IU/day, but there is no real consensus on the optimal starting rFSH dose.

A ‘standard patient’ is usually defined as a patient aged less than 40 years, with a regular menstrual cycle and a normal basal FSH. In Scandinavia, such patients are commonly treated with 150 IU/day rFSH. This dose is used in order to achieve a compromise between giving a dose that is high enough to ensure development of a reasonable number of mature follicles, whilst minimizing the risk of ovarian hyperstimulation syndrome (OHSS). The problem in administering a standardized dose (whether 100, 150, 200, 225 or 250 IU/day) is that the treatment results in a very wide variability in the number of mature follicles and oocytes.

The main clinical decision to be made is administration of an optimal rFSH dose during the first week of the first treatment cycle. The rFSH dose after day 8 of stimulation may be guided by the assessment of the response during the first week and in subsequent cycles when, knowing the ovarian response, the dosage is far easier.

The clinical concern is how—and to what extent—is it possible to avoid the inappropriate response by individualizing the rFSH dose. Inappropriate responses may be due to inherent biological mechanisms in relation to differences in the number of recruitable follicles, follicle sensitivity to rFSH, and rFSH pharmacodynamics. On the other hand, the response might also be due to factors that could be predicted and at least partly controlled by altering the dose of rFSH.

A prospective study of predictive factors from the present authors’ clinic (Popovic-Todorovic et al., 2003Go) confirmed and extended earlier findings (Lass et al., 1997Go; Seifer et al., 1997Go; Tomas et al., 1997Go; Chang et al., 1998Go; El Nemr et al., 1998Go; Engmann et al., 1999Go; Lass and Brinsden, 1999Go; Syrop et al., 1999Go; Tinkanen et al., 1999Go; Ng et al., 2000Go; Bancsi et al., 2002Go; Kupesic and Kurjak, 2002Go) by showing that, using a multiple regression analysis, only the total number of antral follicles, total Doppler score and smoking status predicted the number of aspirated oocytes in patients treated with 150 IU/day rFSH. In order to implement the available knowledge on these predictive factors into clinical practice, the suggestion was made for an rFSH dosage normogram consisting of the total number of antral follicles on days 2–5, total Doppler score on days 2–5, total ovarian volume on days 2–5, age, and smoking status (Table I). The purpose of the normogram was to develop a clinical tool to prescribe an optimal dose of rFSH that would yield to an appropriate number of oocytes, arbitrarily defined between 5 and 14. The hypothesis is that, by using an individual rFSH dose regimen, a more uniform oocyte distribution can be achieved than by giving a standard dose of 150 IU/day to all patients.


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Table I. rFSH dosage normogram
 
The aim of the present randomized prospective study was to compare the use of a standard dose of rFSH of 150 IU/day with an individual dose between 100 and 250 IU/day, calculated on the basis of the rFSH dose normogram.

The study had two main end-points: (i) to test whether the rFSH dosage normogram predicted the ovarian response; and (ii) to test whether use of the normogram for patients provided clinical benefits in relation to a more appropriate ovarian response.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This was a prospective randomized dual-centre study conducted at the fertility clinics of the Rigshospitalet and Hvidovre hospitals. A total of 267 patients was included between January 2002 and January 2003. The inclusion criteria were: first IVF/ICSI treatment cycle; normal basal serum FSH level (with current assays, up to 12.5 IU/l); presence of both ovaries; regular spontaneous menstrual cycle (21–35 days); maximum age 39 years at the onset of treatment; and no evidence of endocrine disorders. Exclusion criteria were the presence of ovarian cysts and inaccessible ovaries.

Upon the onset of menstrual bleeding in a spontaneous cycle preceding GnRH-analogue treatment, patients telephoned the clinic whereupon they were asked to participate in the clinical trial. All patients were seen between days 2 and 5 of the cycle, at which time their informed consent was obtained. Ovarian ultrasonography was performed using a Panther 2002 ADI (B-K Medical, Gentofte, Denmark) with a 6.5 MHz transvaginal probe (thermal index 1). The exposure time and acoustic output were kept at the lowest levels. The number of antral follicles (<5 mm and <10 mm) was counted. The maximum longitudinal (D1), anteroposterior (D2) and transverse (D3) diameters of each ovary were measured, and the ovarian volume was calculated (D1xD2xD3x0.523). Ovarian stromal blood flow was evaluated using power Doppler, and a semi-quantitative score was allocated to each ovary according to the number and area of the power Doppler signals (Popovic-Todorovic et al., 2003Go). Score 1 (poor flow) was given in the presence of only a few and scanty signals, suggesting a poor vascularization. Score 3 (good flow) was given in the presence of several pronounced Power Doppler signals. A score of 2 (moderate flow) was allocated to those ovaries with intermediary findings. The total Doppler score (the sum of scores for each ovary) was analysed as a predictive factor the values being 2, 3, 4, 5 and 6.

All patients were treated with the long protocol using nafarelin (Synarela®; Pharmacia, Denmark) 200 µg administered intranasally three times daily during down-regulation, beginning on day 21 of the cycle, and with 200 µg twice daily from day 1 of rFSH stimulation until the day of hCG treatment. The duration of down-regulation was at least 14 days.

Upon confirmation of pituitary desensitization (i.e. no ovarian cysts, endometrial thickness <5 mm), the number of antral follicles was counted (<5 mm and <10 mm), ovarian volume measured, and a power Doppler score was again allocated for each ovary. On the first day of stimulation, patients were randomized via computer-generated lists using ‘clusters of 10’. Randomization was carried out after the ultrasound examination, when the patient was considered ready to start stimulation. The randomization system was open, but handled independently of the clinicians treating the patients. The study group (n = 131) received an individual starting dose of 100–250 IU/day rFSH (Puregon Pen®; Organon, Denmark), while the control group (n = 131) were allocated to the standard starting dose of 150 IU/day rFSH (Puregon Pen®). The dose was maintained during the first 8 days of stimulation.

The ovarian response was assessed on day 8 of stimulation: the number of follicles >11, >13, >15 and >17 mm was noted, and the ovarian volume measured. Dose adjustments were allowed after day 8 of stimulation. The dose was increased if the leading follicles were <10–11 mm and in case of asynchrony (i.e. more than 4 mm difference between the leading follicle and the next pool). The rFSH dose was reduced if a risk of developing an excessive number of follicles (>20) was acknowledged. The same procedures were repeated on the day of/prior to the administration of hCG (10 000 IU; Profasi®; Serono, Denmark) with the addition of blood samples for measurement of estradiol, FSH and LH.

Aspiration was offered to all patients who had at least one follicle >17 mm on the day of/prior to hCG, for the purposes of the study. Aspiration was performed at 36 h after hCG administration. The numbers of follicles aspirated and oocytes retrieved were recorded during aspiration. Standard IVF and ICSI procedures were used, and the embryos were transferred on day 2. Four-cell embryos with <20% fragmentation were considered to be good quality embryos. All patients were treated with vaginal progesterone (Progestan®; Organon) 200 mg three times daily from the day of embryo transfer until hCG evaluation 14 days later. No further progesterone supplementation was administered.

Patients were asked to score any associated pain and discomfort at 1 week after aspiration by using a visual analogue scale (VAS). The VAS (which provides an objective measure of pain) allowed patients to grade their perceived intensity of pain on a line between 0 and 100 mm.

The actual investigation protocol was approved by the Scientific Ethical Committee for Copenhagen Municipality.

The hormone assays were carried out as described previously (Popovic-Todorovic et al., 2003Go).

Sample size considerations and statistical analysis
Having arbitrarily defined appropriate responses as the retrieval of 5–14 oocytes, the last 2442 cycles at the Fertility Clinic, Rigshospitalet were analysed. This cohort comprised 30% of patients with inappropriate responses (i.e. <=4 or >=15 oocytes retrieved); hence, 70% of the patients were believed to develop an adequate response. The assumption made was that the individual rFSH dosage would reduce the incidence of inappropriate responses by 50% (i.e. from 30% to 15%). In other words, the incidence of appropriate response would be 85%.

Sample size calculation showed that with 125 patients in each treatment group, a 15% increase in the incidence of an appropriate response could be detected between the study and the control group with a power of 80% using a two-sided chi-square test and a significance threshold of 5%.

The t-test and chi-square test were used as appropriate.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 282 patients was assessed for eligibility. Among these patients, eight refused to participate (via telephone), while after clinical examination seven patients did not meet the inclusion criteria. Following the inclusion of 267 patients, five dropped out prior to randomization (four for personal reasons; one patient became spontaneously pregnant) (Figure 1). A total of 262 patients was randomized at the Fertility clinics at the Rigshospitalet (n = 190) and Hvidovre (n = 72) hospitals.



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Figure 1. Flow diagram of a dual-centre trial comparing the use of an individual dose of recombinant FSH based on predictive factors versus a ‘standard’ dose of 150 IU/day in ‘standard’ patients undergoing IVF/ICSI treatment.

 
The study (individual dose) group and the control (standard dose) group were comparable with regard to demographic traits: age; body mass index; cycle length; causes of infertility; and treatment mode (Table II). The main cause of infertility in both groups was male factor (57.3 and 60.3% in the study and control groups respectively. Likewise, there was no difference in the proportion of smokers in the two groups (30.5 and 33.6% respectively).


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Table II. Patient demographics and infertility characteristics
 
Data relating to the follicular response to rFSH, dose alterations, hormone determinations, duration of stimulation and doses of rFSH administered are listed in Table III. Although the average number of follicles >10 mm on day 8 of stimulation was similar (6.61 in the study group versus 6.24 in the control group), the range was wider in the control group (0–33 versus 0–18). Eight patients (6.1%) in the control group had >18 follicles which were >10 mm on day 8 of stimulation. Significantly fewer patients (P < 0.01; chi-square test) had a dose alteration on day 8 in the study group than in the control group. Some 66% of the individual dose patients did not undergo any dose change on day 8, compared with 46% of the standard dose patients.


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Table III. Stimulation characteristics
 
The mean dose increment was 64 IU/day in the study group (range 10–125) versus 94 IU/day in the controls (range 33–193). Among those patients who had a lower dose after day 8 of stimulation, the mean decrement was 22 (range 10–40) IU/day in the study group compared with 43 (range 8–75) IU/day in the control group. The difference between the two groups was significant (P < 0.0001; Mann–Whitney test).

The two groups were alike with respect to mean size and mean total number of follicles on the day of/before hCG administration, and also in terms of serum levels of FSH, LH and estradiol. The duration of stimulation was similar in the two groups.

In the study group, 130 patients (99.2%) underwent aspiration (Table IV), with one cancellation caused by a lack of response to stimulation. Among the control patients, aspiration was performed in 126 (96.2%), the five cancellations being due to a lack of response (n = 2; 1.5%) or a risk of OHSS (n = 3; 2.3%).


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Table IV. Treatment outcome
 
In the individual dose group, 114 patients (87.0%) underwent embryo transfer; the 16 (12.2%) cancellations were due either to no fertilization or cleavage (n = 9), spermatozoa not available for ICSI (n = 3), low quality embryos (n = 3), or ‘other reasons’ (n = 1). In the control dose group, a total of 115 patients (87.8%) underwent embryo transfer; the 11 (8.4%) cancellations were due to either no fertilization or cleavage (n = 7), poor quality embryos (n = 3), or ‘other reasons’ (n = 1). In both groups the ‘other reasons’ for transfer cancellation were the personal wish of the patients, who did not want transfer of donor sperm-fertilized embryos; rather, the embryos were cryopreserved.

Oocyte distribution in the two groups, including those patients who did not undergo oocyte retrieval, is shown in Figure 2. In the individual dose group, 101 patients (77.1%) had an appropriate ovarian response (5–14 oocytes) compared with 86 patients (65.6%) in the control dose group. Two women (1.5%) in the study group had fewer than five oocytes retrieved, compared with 14 women (10.7%) in the control group (P = 0.002). An excessive response occurred in 27 (20.6%) of the individual dose patients, but this was not significantly different from that in the standard dose patients (n = 26; 19.8%). The overall differences in the number of oocytes between the two groups was significant (P = 0.006; chi-square test).



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Figure 2. Oocyte distribution in the individual and standard dose group. Patients who had aspiration cancelled are also included. In the individual dose group, 101 patients (77.1%) had an appropriate ovarian response (5–14 oocytes) compared with 86 (65.6%) in the standard dose group. Two women (1.5%) in the study group had <5 oocytes retrieved versus 14 (10.7%) in the control group (P = 0.002). There was no statistically significant difference among the number of patients with excessive response (>14 oocytes) in the two groups: 27 (20.6%) of the individual dose patients versus 26 (19.8%) of the standard dose patients.

 
The mean number of aspirated follicles (15.4 versus 14.3) and retrieved oocytes (11.3 versus 10.1) was similar in the study and control groups respectively (P = 0.054; not significant).

Among the individual dose patients, 42 (36.8%) had a single embryo transfer (SET), 72 (62.3%) had a dual embryo transfer, and none had three embryos replaced. In the SET subgroup, 24 women (57.1%) had embryos cryopreserved (average 6.2 embryos), whereas in the dual transfer group 30 women (41.7%) had embryos cryopreserved (average four embryos).

Among the control group, 28 patients (24.3%) had SET, 86 (74.8%) had two embryos replaced, and only one patient (0.9%) had a triple embryo transfer. Fourteen women (50%) in the SET subgroup had embryos cryopreserved (average 5.8). Among those women who had two embryos transferred, 38 (44.2%) had embryos cryopreserved (average 4.6).

Elective SET was chosen by 23 patients (20.2%) in the study group, and by 14 (12.2%) in the standard dose group.

The clinical pregnancy rate per initiated cycle was 45% in the study group and 35.9% in the control group. Significantly more women had an ongoing pregnancy per initiated cycle in the study group (36.6%) than in the control group (24.4%) (P = 0.03). One individual dose group patient (0.8%) and four (3.1%) standard dose group patients were hospitalized due to OHSS.

The starting dose was divided arbitrarily according to the rFSH dosage normogram into three categories: 100–125 IU/day (‘high-responder’); >125–175 IU/day (‘normo-responder’); and >175–250 IU/day (‘low-responder’). In order to answer the question of whether the model could predict ovarian response, the mean number of oocytes was plotted against the different starting dose categories in the study and control groups (Figure 3). In the latter case, it was the normogram-derived starting dose categories which were analysed. The mean oocyte numbers were significantly different between the two patient groups for the dose categories in the presumed ‘high’ and ‘low’ responders: 15.3 (control group) versus 12.7 (study group) and 6.6 (control group) versus 9.9 (study group) (P < 0.001). In contrast, oocyte numbers were similar in the predicted ‘normo-responder’ group 11.2 (control group) versus 11.7 (study group).



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Figure 3. Mean numbers of oocytes in relation to the arbitrarily defined starting rFSH dose categories, both in patients with individual and standard doses. The three categories were 100–125 IU/day (‘high responder’); >125–175 IU/day (‘normo responder’); and >175–250 IU/day (‘low responder’). In the individual dose group the starting rFSH doses were predicted doses, whilst in the control group the starting rFSH dose was 150 IU/day in all patients, irrespective of the predicted dose. The mean number of oocytes differed significantly among the 100–125 and >175–250 IU/day dose categories (P < 0.001) between the study and the control groups.

 
Finally, an examination of the VAS scores showed that the two groups suffered similar levels of pain and discomfort (Figure 4). In the study group, 120 patients (91.6%) returned the VAS form, as did 122 (93.1%) in the controls. The mean VAS scale values for the two groups were 3.1 and 3.2 respectively.



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Figure 4. Visual analogue scale (VAS) of pain and discomfort; distribution of VAS values between the two groups. Mean values were 3.1 and 3.2 in the individual and standard dose groups respectively. Median values were 3.0 and 2.5.

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This is the first prospective randomized study to investigate the use of individual rFSH dosage based on a prediction model constructed as a normogram, with the main end-point being the effect on the distribution of retrieved oocytes. The results showed that an individual dosage regimen in a well-defined first IVF/ICSI cycle ‘standard’ patient population increased the proportion of appropriate ovarian responses, and decreased the incidence of dose alterations during the course of COH. A higher ongoing pregnancy rate per initiated cycle was observed in the individual dosage group.

Several studies have been conducted to compare different rFSH starting doses, including 100 versus 200 IU (Out et al., 1999Go; 2001) and 150 versus 250 IU (Out et al., 1999Go; The Latin-American Puregon IVF Study Group, 2001Go). These studies were conducted in well-defined populations of ‘standard’ patients, although the inclusion criteria were not restricted to first treatment cycles. The number of retrieved oocytes was the common primary end point in all studies. The results showed that the administration of a higher dose led to the retrieval of more oocytes and similar pregnancy rates, but the increased dose did not compensate for the age-related decline in ovarian function. However, in all studies the range of retrieved oocytes was wide, from 1 to 35.

Upon fresh embryo transfer there is a steady increase of pregnancy rates in patients with rising number of oocytes, but this increase eventually levels off (De Vries et al., 1999Go; Sharma et al., 2002Go). However, the side effects and risks continue to increase. This concept is illustrated graphically in Figure 5, which shows the relationship between oocyte numbers, benefits (pregnancies) and risks. From an ideal point of view, the patients should be in the high benefit–low risk window. How can the number of patients in this window be optimized?



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Figure 5. Distribution of oocytes, benefits and risks—the present and the ideal situation.

 
The present authors’ main hypothesis was that use of the normogram to determine individual doses would result in a narrower distribution of ovarian responses. This would imply that fewer patients would develop inadequate or excessive numbers of oocytes.

The present results show that by using the individual starting dose, a narrower distribution of ovarian responses was obtained. The incidence of patients with inadequate responses was reduced (1.5% for individual doses versus 10.7% for standard doses; P < 0.05), and more patients had between 5 and 14 oocytes retrieved (101 versus 86 respectively in the two groups; P < 0.05). However, the number of patients with an excessive response remained similar between the two groups (20.6 and 19.8% respectively).

The rFSH dosage normogram used in the present study was based on the predictive factors of ovarian response (Popovic-Todorovic et al., 2003Go). Indeed, the categorization of patients according to the predicted ovarian responsiveness closely related to the observed number of oocytes, confirming this prediction model. Also, when using the normogram to determine the starting rFSH dose, the mean number of oocytes retrieved for the ‘high’ and ‘low’ responder dose categories differed significantly between the two groups (P < 0.001). In practice, this means that the present model identified the patients in the standard dose group who should have had starting doses from 100–125 IU/day as being potential ‘high responders’, and indeed the average number of oocytes was 15.3 (Figure 3). The model also identified patients presumed to be ‘low responders’ and who should have received >175–250 IU/day as the starting dose. These patients indeed had a lower average number of oocytes (i.e. 6.6). It is known from clinical experience that the majority of patients respond well to the standard starting dose of 150 IU/day, and the patients for which the present model suggested a dose of ~150 IU/day (i.e. from >125–175 IU/day) had an average number of 11.2 oocytes retrieved. In the individual dose group, when starting doses were administered according to the dosage normogram, the differences among the three dose categories levelled off, the mean number of oocytes retrieved being 12.7 (100–125 IU/day), 11.7 (>125–175 IU/day) and 9.9 (>175–250 IU/day).

The present authors’ hypothesis was that the use of the individual dosage regimen would decrease the proportion of inappropriate responses by 50% (i.e. from 30% to 15%). When examining the results, that proportion decreased from 34.4 to 22.9%—that is, by 30% (P < 0.05). Although the proportion of inappropriate responses was significantly decreased, the goal of 50% was not reached due to the fact that the number of patients with >14 oocytes at retrieval remained similar. The study design that allowed the change of dose after day 8 of stimulation might explain this finding. Limitations in the present ability to account fully for the biology of the ovarian response might also account for the similar number of high responders, but it may also be due to the limitations of the dosage normogram itself.

On further examination of the stimulation, fewer patients had dose alterations in the individual dose group, and the mean dose increments and decrements after day 8 of stimulation were smaller. This substantiates the ability of the dosage normogram to predict an optimal individual starting dose. On the other hand, blinding was not carried out on day 8 dose adjustments as they can never be instituted under strict criteria, and the proportion of patients who needed dose adjustments might be a potential source of bias.

Although the present clinical trial was not designed to compare pregnancy rates, the ongoing pregnancy rate per initiated cycle was significantly higher in the individual dose group. This might be a coincidence, as a similar number of initiated cycles ended in embryo transfer. The difference can neither be explained by the differences in patients who had elective SET, nor by the total number of embryos or by the number of cryopreserved embryos.

To the best of the present authors’ knowledge, this is the first clinical trial conducted in ‘standard’ patients which investigates the use of individual starting rFSH doses based on a number of predictive factors. Although no specific studies have been conducted as such, the clinical practice of administering higher rFSH dose according to age has been reported. The cut-off value for age is usually 35 years; that is, patients aged <35 years are given 150 IU/day, whilst those aged >35 years are started on a higher rFSH dose (usually 225–300 IU/day). In one study investigating predictive factors (Kupesic and Kurjak, 2002Go), patients were given 150–300 IU/day depending on their age, although the age cut-off values were not stated.

In another report (Harrison et al., 2001Go), patients were randomized to two groups of rFSH starting doses (150 versus 200 IU/day and 300 versus 400 IU/day) according to their basal FSH level in order to individualize the rFSH starting dose, but only one predictive factor was addressed. Herein, an attempt has been made to use a more individual approach, first by determining the predictive factors in a well-defined population of ‘standard’ patients and creating an rFSH dosage normogram (Popovic-Todorovic et al., 2003Go), which has subsequently been clinically tested in the present study.

In conclusion, the individual starting dosage regimen results in a more optimal number of oocytes being retrieved. The present dosage normogram is a construction which is based not only on scientifically documented variables, but also on clinical assumptions. It is a bedside tool which is both easy and fast to use. It is fair to say that a number of suggestions for similar normograms could be made, but the data obtained from this prospective randomized trial justifies the tailor-made starting dose approach from the first treatment cycle in a well-defined group of ‘standard’ patients.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Bancsi, L.F., Broekmans, F.J., Eijkemans, M.J., de Jong, F.H., Habbema, J.D. and te Velde, E.R. (2002) Predictors of poor ovarian response in in vitro fertilization: a prospective study comparing basal markers of ovarian reserve. Fertil. Steril., 77, 328–336.[CrossRef][ISI][Medline]

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DeVries, M.J., De Sutter, P. and Dhont, M. (1999) Prognostic factors in patients continuing in vitro fertilization or intracytoplasmic sperm injection treatment and dropouts. Fertil. Steril., 72, 674–678.[CrossRef][ISI][Medline]

Devroey, P., Tournaye, H., Van Steirteghem, A., Hendrix, P. and Out, H.J. (1998) The use of a 100 IU starting dose of recombinant follicle stimulating hormone (Puregon) in in-vitro fertilization. Hum. Reprod., 13, 565–566.[Free Full Text]

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Lass, A., Skull, J., McVeigh, E., Margara, R. and Winston, R.M. (1997) Measurement of ovarian volume by transvaginal sonography before ovulation induction with human menopausal gonadotrophin for in-vitro fertilization can predict poor response. Hum. Reprod., 12, 294–297.[Abstract]

Ng, E.H., Tang, O.S. and Ho, P.C. (2000) The significance of the number of antral follicles prior to stimulation in predicting ovarian responses in an IVF programme. Hum. Reprod., 15, 1937–1942.[Abstract/Free Full Text]

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Submitted on June 19, 2003; accepted on August 6, 2003.