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Importance of a 5- versus 7-day pill-free interval in a GnRH antagonist protocol using corifollitropin alfa: a prospective cohort study in oocyte donors
1 The first two authors should be considered as joint first authors.
Alicia Pérez-Calvo
Footnotes
1 The first two authors should be considered as joint first authors.
Affiliations
Servicio de Medicina de la Reproducción, Department of Obstetrics, Gynaecology and Reproduction, Hospital Universitario Dexeus, Calle Sabino Arana, 5-19 - Planta 1, 08028 Barcelona, Spain
1 The first two authors should be considered as joint first authors.
Affiliations
Servicio de Medicina de la Reproducción, Department of Obstetrics, Gynaecology and Reproduction, Hospital Universitario Dexeus, Calle Sabino Arana, 5-19 - Planta 1, 08028 Barcelona, Spain
Servicio de Medicina de la Reproducción, Department of Obstetrics, Gynaecology and Reproduction, Hospital Universitario Dexeus, Calle Sabino Arana, 5-19 - Planta 1, 08028 Barcelona, Spain
Servicio de Medicina de la Reproducción, Department of Obstetrics, Gynaecology and Reproduction, Hospital Universitario Dexeus, Calle Sabino Arana, 5-19 - Planta 1, 08028 Barcelona, Spain
Servicio de Medicina de la Reproducción, Department of Obstetrics, Gynaecology and Reproduction, Hospital Universitario Dexeus, Calle Sabino Arana, 5-19 - Planta 1, 08028 Barcelona, Spain
Servicio de Medicina de la Reproducción, Department of Obstetrics, Gynaecology and Reproduction, Hospital Universitario Dexeus, Calle Sabino Arana, 5-19 - Planta 1, 08028 Barcelona, Spain
In this prospective cohort study, oocyte donors were recruited prospectively and assigned to receive corifollitropin alfa: 5 days after pill discontinuation (group D5; 42 donors), or 7 days after pill discontinuation (group D7; 50 donors) in a gonadotrophin-releasing hormone antagonist protocol. Fixed additional daily doses of 200 IU recombinent FSH (rFSH) were started after 7 days of corifollitropinalfa, until triggering. No significant differences in basal characteristics were observed between both groups. In group D5, mean (SD) total additional rFSH dose was 659 (452) IU; in group D7, total rFSH dose was 459 (356) IU (P = 0.022). Duration of stimulation was significantly longer in group D5 compared with group D7 (P = 0.002). No differences were found in total number of oocytes obtained. Total number of injections was significantly lower in group D7 compared with group D5 (9.8 [3.2] versus 11.9 [3.9], respectively; P = 0.004). Total cost of medication used for donor treatment was significantly higher in group D5 than in group D7 (P = 0.015). After more than 22 days of pill-taking, extending the pill-free interval to 7 days significantly reduces the total dose of gonadotrophins, duration of stimulation, total cost of medication and total number of injections.
), its use and effectiveness has expanded notably. The indications for undergoing an oocyte donation cycle have increased, as has the efficiency of this technique (
The design of optimal ovarian stimulation protocols is important for all patients undergoing an assisted reproduction technique, although it is particularly desirable for oocyte donors, for whom the utmost safety, efficiency and convenience should be guaranteed and risks minimized.
Current treatment regimens usually consist of administration of daily injections of exogenous gonadotrophins and gonadotrophin-releasing hormone (GnRH) analogues, generally self-administered, which can last up to 2 weeks. To simplify ovarian stimulation protocols, corifollitropin alfa was introduced, enabling the first seven daily injections of any FSH preparation to be replaced (
A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol.
). This relatively new compound is usually administered on day 2 or 3 of the menstrual cycle, with the advantage of being more patient friendly, as less injections cause less distress to the patient, help to improve treatment compliance and prevent errors during the administration of gonadotrophins (
Advances in recombinant DNA technology: corifollitropin alfa, a hybrid molecule with sustained follicle-stimulating activity and reduced injection frequency.
As in patients undergoing IVF and intracytoplasmic sperm injection (ICSI), the use of the GnRH antagonist protocol in oocyte donors reduces treatment duration and total consumption of gonadotrophins; GnRH antagonists are better tolerated and easier to manage compared with GnRH agonists (
). Moreover, final oocyte maturation can be induced with a GnRH agonist bolus, thus preventing the risk of the ovarian hyperstimulation syndrome (OHSS) (
Early ovarian hyperstimulation syndrome is completely prevented by gonadotropin releasing-hormone agonist triggering in high-risk oocyte donor cycles: a prospective, luteal-phase follow-up study.
). Because of its effectiveness and safety potential, the GnRH antagonist protocol combined with GnRH agonist triggering has been advocated as the treatment of first choice for oocyte donors (
Early ovarian hyperstimulation syndrome is completely prevented by gonadotropin releasing-hormone agonist triggering in high-risk oocyte donor cycles: a prospective, luteal-phase follow-up study.
Donors are often prescribed a pre-treatment with oral contraceptive pills (OCP) before ovarian stimulation with gonadotrophins to facilitate appointment-making and treatment scheduling. Scheduling donor stimulation is important to reduce weekend oocyte retrievals and to distribute the workload throughout the week, therefore reducing the amount of unplanned work. Adequate scheduling facilitates synchronization with the recipients in the event of fresh donation, according to patients' or physicians' preferences.
Nevertheless, there is an ongoing debate about the pros and cons of OCP pre-treatment, especially the outcomes of GnRH antagonist cycles in patients undergoing ovarian stimulation for IVF (
), and the effect of OCP use on the total dose of gonadotrophins consumed, the duration of the stimulation and the clinical pregnancy rate. Even when given for a short period of time and even if ovarian stimulation is started after a wash-out period, OCP pre-treatment might negatively affect endometrial receptivity and IVF outcome (
). The possible effect in oocyte donation cycles is probably negligable, as the oocyte quality is not hindered in case of pretreatment with OCP in IVF cycles (
No studies addressing this issue in a donor population have been published, to our knowledge. Combined hormonal contraception inhibits the hypothalamic–pituitary axis causing a decrease in FSH and LH, leading to the suppression of follicular activity and ovulation. Current OCPs result in a decrease in pituitary gonadotrophin secretion, particularly during the pill-free interval (PFI) (
Effects of oral contraceptive, synthetic progestogen or natural estrogen pre-treatments on the hormonal profile and the antral follicle cohort before GnRH antagonist protocol.
An endocrine wash-out period of 5 days had been suggested to start ovarian stimulation. A shorter interval between the last OCP and gonadotrophin stimulation would result in a poorer and slower response owing to a strong early suppression, with higher gonadotrophin consumption (
A randomized prospective trial comparing gonadotropin-releasing hormone (GnRH) antagonist/recombinant follicle-stimulating hormone (rFSH) versus GnRH-agonist/rFSH in women pretreated with oral contraceptives before in vitro fertilization.
Cetrorelix in an oral contraceptive-pretreated stimulation cycle compared with buserelin in IVF/ICSI patients treated with r-hFSH: a randomized, multicentre, phase IIIb study.
). Increasing the wash-out period to more than 5 days has also resulted in higher gonadotrophin consumption compared with women who had not been pre-treated with OCP (
A randomized prospective trial comparing gonadotropin-releasing hormone (GnRH) antagonist/recombinant follicle-stimulating hormone (rFSH) versus GnRH-agonist/rFSH in women pretreated with oral contraceptives before in vitro fertilization.
Cetrorelix in an oral contraceptive-pretreated stimulation cycle compared with buserelin in IVF/ICSI patients treated with r-hFSH: a randomized, multicentre, phase IIIb study.
). These studies were carried out using daily injections of gonadotrophins for ovarian stimulation in patients undergoing IVF–ICSI.
A later beginning of ovarian stimulation with recombinant FSH (rFSH) in the follicular phase in patients undergoing IVF results in a reduction in total gonadotrophin consumption (
Follicular phase endocrine characteristics during ovarian stimulation and GnRH antagonist cotreatment for IVF: RCT comparing recFSH initiated on cycle day 2 or 5.
A randomized comparison of two ovarian stimulation protocols with gonadotropin-releasing hormone (GnRH) antagonist cotreatment for in vitro fertilization commencing recombinant follicle-stimulating hormone on cycle day 2 or 5 with the standard long GnRH agonist protocol.
). Moreover, a randomized clinical trial in which ovarian stimulation with corifollitropin alfa was initiated on day 4 instead of day 2 of the cycle, resulted in a significant reduction of the additional consumption of rFSH (
The aim of the present study was to evaluate whether the administration of corifollitropin alfa 7 days after discontinuation of the OCP instead of 5 days resulted in a decrease in the total consumption of gonadotrophins in a GnRH antagonist protocol for oocyte donors.
Material and methods
Study design
This prospective cohort study included oocyte donor patients from the Oocyte Donation Programme at the Hospital UniversitarioDexeus of Barcelona, and was conducted between February 2015 and May 2016. The study was approved by the Ethical Committee of the Dexeus University Hospital on 27 November 2014 (reference number CPMP/ICH/135/95) and the Department of Health of the Government of Catalonia on 25 February 2015 (reference number 03365/2789/2015), and was registered in clinicaltrials.gov (NCT02490150).
Eligibility criteria
The women included in the study were healthy oocyte donor patients aged between 18 and 35 years, with regular menstrual cycles (i.e. between 26 and 35 days), and body mass index between 18 and 28 kg /m2 without any relevant personal or family history. The patients had a normal karyotype and a negative screening for sexually transmitted diseases. The patients agreed to participate in the study and signed an informed consent.
The exclusion criteria included oocyte donors with an antral follicle count over 20, hypersensitivity to the active substance or to any of its excipients, abnormal vaginal bleeding of unknown cause, presence of ovarian cysts or enlarged ovaries, history of ovarian hyperstimulation syndrome (OHSS), a previous ovarian stimulation cycle with more than 30 follicles of 11 mm or wider (as recommended by the Elonva® Summary of Product Characteristics).
Ovarian stimulation protocol
The donor patients were recruited prospectively and assigned to one of the two treatment groups: ‘group D5’ included oocyte donors, who started ovarian stimulation with corifollitropin alfa 5 days after OCP discontinuation, whereas in ‘group D7’, the oocyte donors started 7 days after OCP discontinuation. The GnRH antagonist protocol was prescribed in both groups (Figure 1).
Figure 1Ovarian stimulation protocol. In group D5, corifollitropin alfa was administered 5 days after discontinuing the oral contraceptive pill. In group D7, corifollitropin alfa was administered 7 days after discontinuing the oral contraceptive pill. The GnRH antagonist protocol was prescribed in both groups. OCP, oral contraceptive pill; rFSH, recombinant FSH.
Taking into account the Summary of Product Characteristics, corifollitropin alfa can be administered in the early follicular phase (second to fourth day of bleeding). Treatment assignment was carried out by the coordinating nurse to equally distribute the workload throughout a 7-day working schedule. Donors were consecutively assigned to take the last OCP on a Wednesday and to have the corifollitropin alfa administered at the clinic on the following Monday (Group D5) or Wednesday (Group D7). All donors were pre-treated with combined oral contraceptives for 17–23 days (ethinylestradiol 30 µg and levonorgestrel 150 µg; Ovoplex®, Wyeth Farma, Spain). A total of 42 oocyte donors were assigned to group D5 and 50 oocyte donors were assigned to group D7.
Corifollitropin alfa (Elonva®, MSD, Spain) was used for ovarian stimulation. Administration of the GnRH antagonist ganirelix (Orgalutran®, MSD, Spain) was initiated on stimulation day 6 in both treatment arms at a daily dose of 0.25 mg to prevent a premature LH surge. Suppression with the GnRH antagonist was continued until the day of final oocyte maturation. Endocrine monitoring (with serum oestradiol evaluation) and ultrasound scan were carried out on day 6 of stimulation and repeated every second day thereafter until trigger, depending on the patients' response. The administration of fixed daily doses of 200 IU rFSH (Puregon®, MSD, Spain) was initiated after the seventh day of corifollitropin alfa (if needed), until the criteria of triggering final oocyte maturation (i.e. ≥3 follicles of ≥18 mm) were met. Cycles were cancelled if less than six follicles measuring more than 12 mm in diameter were observed on the day 8 of of stimulation.
A GnRH agonist (triptorelin [Decapeptyl®, Ipsen Pharma, Spain], 0.2 mg) bolus was used to induce final oocyte maturation. Oocyte retrieval was carried out 36 h later. The recruited mature oocytes were either vitrified or donated to the corresponding recipient for a fresh cycle (
How does vitrification affect oocyte viability in oocyte donation cycles? A prospective study to compare outcomes achieved with fresh versus vitrified sibling oocytes.
The primary end-point of the study was total gonadotrophin consumption. Secondary end-points included the cycle characteristics: duration of stimulation, serum oestradiol levels, number of oocytes retrieved and cancellation rate.
Power calculation
Power calculation assumed mean rFSH consumption of the reference group to be 463 units (
), the mean of the experimental group to be 246 units and the standard deviation of both groups to be 300 units, to reach 80% power in a Student's t-test for two independent samples, with a significance level set at 5%; it was necessary to include 31 donors in the control group (group D5) and 31 donors in the experimental group (group D7), totalling 62 donors in the study. Estimating a anexpected percentage of dropouts is 10%, it would be necessary to recruit at least 70 donors in the study.
Statistical analysis
Continuous variables were described by mean and standard deviation. To compare means between groups, the t-test or Wilcoxon Mann–Whitney test were used according to normality assumptions. IBM® SPSS® Statistics v22.0 software was used for statistical analyses. P < 0.05 was considered statistically significant.
Results
A total of 92 oocyte donors were included, 42 in group D5 and 50 in group D7, with a mean age of 26.0 (SD 4.6) years and plasma anti-Müllerian hormone (AMH) levels of 3.0 (SD 1.6) ng/ml; antral follicle count 17 (SD 3) and body weight 59.2 (SD 8.5) kg. Baseline characteristics by treatment group are shown in Table 1. No significant differences in these characteristics were observed between both groups. The mean duration of OCP intake before pill-free interval was 22.3 days (SD 8.0) in group D5 and 22.1 days (SD 6.9) in group D7.
The mean duration of stimulation was 9.8 days (SD 1.7), with a total additional dose of daily gonadotrophins of 550 IU (SD 413). A mean of 14.1 oocytes (SD 7.5) were obtained. The cycle characteristics by treatment group are presented in Table 2. None of the cycles were cancelled. The patients in group D7 needed a significantly lower total dose of gonadotropins (P = 0.022) and fewer days of stimulation (P = 0.002). No differences were found in the total number of oocytes obtained. The total number of injections (corifollitropin alfa injection, GnRH antagonist, daily rFSH, GnRH agonist trigger) was significantly lower in group D7 compared with group D5, namely 9.8 [SD 3.2] and 11.9 [SD 3.9] injections, respectively; (P = 0.004). No additional administration of rFSH was needed in 9 nine donors (three from group D5 and 6 from group D7), as the triggering criteria on day 8 of stimulation was reached. Plasma oestradiol levels on day 6 of corifollitropin alfa injection were significantly higher in group D7 compared with group D5 (P = 0.001).
Table 2Characteristics of the response to stimulation.
The same differences persisted when the analysis took into account the duration of OCP intake before pill-free interval (data not shown). The total number of days of OCP intake before the interval did not affect the outcomes. The total cost of medication used for donor treatment (including total consumption of contraceptive pills, gonadotrophins, GnRH antagonist injections and GnRH agonist bolus) was calculated for both treatment groups. Total cost of medication used for donor treatment was significantly higher in group D5 (€1124.6 [SD 237.7]) than in group D7 (€1009.8 [SD 204.6]); P = 0.015.
Discussion
This is the first study to assess the use of corifollitropin alfa given after pre-treatment with oral contraceptives with two different pill-free intervals prior to the administration of corifollitropin alfa in oocyte donors using a GnRH antagonist protocol. It clearly demonstrates that increasing the pill-free interval from 5 to 7 days significantly reduces the duration of ovarian stimulation, total gonadotropin consumption and the number of injections without affecting the total number of oocytes obtained.
In our trial, after a single injection of corifollitropin alfa, the criteria for final oocyte maturation were met in 7.14% of the patients in Group D5 compared with 12% of the patients in Group D7, obviating the need for any additional rFSH injections. IVF patients prefer fewer injections in the stimulation treatment as long as the results are the same (
evaluated the degree of donor satisfaction after stimulation with corifollitropin alfa. The results of the study did not show significant differences in the clinical parameters or in clinical pregnancy rates (
). Donors treated with corifollitropin alfa who had been treated with daily rFSH in an earlier oocyte donation cycle expressed a preference for corifollitropin alfa. In our study, a wider interval, together with the administration of corifollitropin alfa, reduced the total number of injections, presumably an attractive aspect for the donor.
The reduction in the number of injections (2.14), total dose of gonadotrophins used (200 IU), and the duration of stimulation (1 day) also translated into a significant reduction in the total cost of medication, namely €115, according to the Spanish market. In the study by
, the reduction in cost of medication was only apparent in gonadotrophin consumption, but not in GnRH antagonists used, when the initiation of stimulation was initiated on day 4 of the cycle (
In patients undergoing an IVF or ICSI treatment, an interval of at least 5 days between the last pill and the beginning of stimulation has been recommended so that the capacity to respond to the exogenous stimulus of gonadotropins is not affected (
Effects of oral contraceptive, synthetic progestogen or natural estrogen pre-treatments on the hormonal profile and the antral follicle cohort before GnRH antagonist protocol.
). Coinciding with these authors, our study demonstrates the importance of PFI and the administration of corifollitropin alfa for donor stimulation and hypothalamic-pituitary axis recovery, because fewer days of stimulation (9.3 [1.6] versus 10.3 [1.6] days) and a lower total additional dose of daily gonadotrophins (459 [356] versus 659 [452] IU) were needed in group D7 compared with group D5. Our results do not concur with the authors who found that increasing the wash-out period by more than 5 days also resulted in higher gonadotrophin consumption compared with women who had not been pre-treated with OCP, as mentioned in the Introduction (
A randomized prospective trial comparing gonadotropin-releasing hormone (GnRH) antagonist/recombinant follicle-stimulating hormone (rFSH) versus GnRH-agonist/rFSH in women pretreated with oral contraceptives before in vitro fertilization.
Cetrorelix in an oral contraceptive-pretreated stimulation cycle compared with buserelin in IVF/ICSI patients treated with r-hFSH: a randomized, multicentre, phase IIIb study.
Interestingly, the duration of OCP intake before the PFI did not affect the cycle outcomes. The degree of pituitary–ovarian recovery that emerges during the PFI has been related to the ethinylestradiol dose of the OCP (
). In this study, an OCP with ethinylestradiol 30 µg and levonorgestrel 150 µg was used.
The lower requirements of gonadotrophins in group D7 could also be related to the duration of pill taking (22.1 days [SD 6.9] in Group D7 and 22.3 days [SD 8.0] in group D5), longer than the standard 14–20 days interval. This may have led to a more profound pituitary suppression and, thus, the longer pill free interval may have been beneficial. It should be stressed, however, that long OCP intake (i.e. for several months) should be avoided, as suboptimal response after GnRH agonist can occur in these patients, because of pituitary suppression (
A significantly higher serum oestradiol level was observed in group D7 on day 6 of ovarian stimulation. One could speculate that this is probably the reflection of the lower degree of hypothalamic–pituitary endogenous suppression owing to the longer pill-free interval (
Effects of oral contraceptive, synthetic progestogen or natural estrogen pre-treatments on the hormonal profile and the antral follicle cohort before GnRH antagonist protocol.
). After OCP pre-treatment and a PFI of 4 days, an increase in the length of stimulation and higher LH requirement was observed in suppressed (serum FSH and LH ≤1.2 mIU/ml) IVF patients over the age of 35 years (
Does the degree of hypothalamic-pituitary-ovarian recovery after oral contraceptive pills affect outcomes of IVF/ICSI cycles receiving GnRH-antagonist adjuvant therapy in women over 35 years of age?.
). The donor population in our study was younger than 35 years. No supplementary LH was used and FSH plasma levels were not measured. No differences were found in the number of oocytes retrieved between both treatment groups, although this study was not designed to show or refute such difference.
There has been a concern about higher OHSS risk after delayed administration of corifollitropin (
). In a recent meta-analysis, seven randomized clinical trials were examined, including 2138 patients who were given corifollitropin alfa and 1788 women who were given daily rFSH in ovarian stimulation protocols in IVF (
). The investigators concluded that corifollitropin alfa was as effective as rFSH in live birth and clinical pregnancy rates. The greater number of oocytes retrieved shows the higher effectiveness of this new long-acting FSH, but they also warned about the possible increased risk of OHSS in high-responders. To avoid this complication, a GnRH agonist bolus should be used, which was applied in all patients included in our trial. Additionally, donors with an antral follicle count over 20, or a prior history of OHSS, were excluded from the study. No cases of OHSS were reported in our study.
The non-randomized design is certainly a limitation, because any bias cannot be ruled out. According to Spanish legislation, randomized trials require significant financial support, that we could not raise. The population of oocyte donors is homogenous owing to the strict eligibility criteria. We did not analyse pregnancy rates in the corresponding recipients because it was not the initial aim of the study, and also because many of the oocytes are still vitrified. Another limitation is the absence of the endocrine profile at the end of the stimulation, because no information can be provided on the progesterone level, which is of major importance when applying this new approach in patients undergoing fresh embryo transfer for some (
Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles.
In conclusion, adequate scheduling of ovarian stimulation cycles remains crucially important, especially in oocyte donor patients. When using oral contraceptives for more than 22 days before ovarian stimulation with corifollitropin alfa, extending the pill-free interval to 7 days reduces the consumption of gonadotrophins, the duration of stimulation, and therefore the total cost of the treatment and the total number of injections. Before this strategy could be generally recommended, however, it should be evaluated in patients undergoing an IVF–ICSI treatment.
Acknowledgement
This work was carried out under the auspices of the Càtedrad' Investigació en Obstetrícia I Ginecologia of the Department of Obstetrics and Gynecology, Hospital Universitari Quirón Dexeus, Universitat Autònoma de Barcelona. We would like to thank Monica Reig for her assistance in writing.
References
Baerwald A.R.
Olatunbosun O.A.
Pierson R.A.
Ovarian follicular development is initiated during the hormone-free interval of oral contraceptive use.
A randomized prospective trial comparing gonadotropin-releasing hormone (GnRH) antagonist/recombinant follicle-stimulating hormone (rFSH) versus GnRH-agonist/rFSH in women pretreated with oral contraceptives before in vitro fertilization.
Follicular phase endocrine characteristics during ovarian stimulation and GnRH antagonist cotreatment for IVF: RCT comparing recFSH initiated on cycle day 2 or 5.
Early ovarian hyperstimulation syndrome is completely prevented by gonadotropin releasing-hormone agonist triggering in high-risk oocyte donor cycles: a prospective, luteal-phase follow-up study.
Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles.
Effects of oral contraceptive, synthetic progestogen or natural estrogen pre-treatments on the hormonal profile and the antral follicle cohort before GnRH antagonist protocol.
A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol.
Advances in recombinant DNA technology: corifollitropin alfa, a hybrid molecule with sustained follicle-stimulating activity and reduced injection frequency.
A randomized comparison of two ovarian stimulation protocols with gonadotropin-releasing hormone (GnRH) antagonist cotreatment for in vitro fertilization commencing recombinant follicle-stimulating hormone on cycle day 2 or 5 with the standard long GnRH agonist protocol.
Cetrorelix in an oral contraceptive-pretreated stimulation cycle compared with buserelin in IVF/ICSI patients treated with r-hFSH: a randomized, multicentre, phase IIIb study.
Does the degree of hypothalamic-pituitary-ovarian recovery after oral contraceptive pills affect outcomes of IVF/ICSI cycles receiving GnRH-antagonist adjuvant therapy in women over 35 years of age?.
How does vitrification affect oocyte viability in oocyte donation cycles? A prospective study to compare outcomes achieved with fresh versus vitrified sibling oocytes.
Dr Perez has been a specialist in obstetrics and gynaecology since 2009, and obtained a Masters degree in Reproduction in 2009. She has been working at The Hospital Universitari Quiron-Dexeus since 2009. Her main interest is in Human Reproduction and Lower Genital Tract Disease. She has presented a number of oral and poster communications at national and international congresses of gynaecology and infertility. Her currently research interest is simplification of stimulation protocols for oocyte donors.
Key message
Extending the pill-free interval to 7 days significantly reduces the total dose of gonadotrophins, duration of stimulation, total cost of medication and total number of injections in oocyte donors treated with oral contraceptives for over 22 days.
Article info
Publication history
Published online: July 14, 2017
Accepted:
June 27,
2017
Received in revised form:
June 23,
2017
Received:
January 19,
2017
Declaration: The authors report no financial or commercial conflicts of interest. Medical Writing assistance was funded by Merck Sharp & Dohme of Spain.
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