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Hum. Reprod. Advance Access originally published online on April 21, 2006
Human Reproduction 2006 21(8):2121-2125; doi:10.1093/humrep/del121
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.For Permissions, please email: journals.permissions@oxfordjournals.org

A prospective trial comparing oocyte donor ovarian response and recipient pregnancy rates between suppression with gonadotrophin-releasing hormone agonist (GnRHa) alone and dual suppression with a contraceptive vaginal ring and GnRH

F. Martínez1,3, M. Boada1, B. Coroleu1, E. Clua1, N. Parera1, I. Rodríguez2 and P.N. Barri1

1 Servicio de Medicina de la Reproducción and 2 Unidad de Bioestadística, Departamento de Obstetricia y Ginecología, Institut Universitari Dexeus, Barcelona, Spain

3 To whom correspondence should be addressed at: Servicio de Medicina de la Reproducción, Institut Universitari Dexeus, P Bonanova, 67, 08017 Barcelona, Spain. E-mail: pacmar{at}dexeus.com


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: Contraceptive treatment before gonadotrophin-releasing hormone agonist administration presents advantages in women with a tendency to hyper-response and simplifies donor–recipient treatment synchronization. This study compares response to gonadotrophin stimulation under hypophyseal suppression in oocyte donors with or without vaginal contraceptive pretreatment. METHODS: One hundred and ninety oocyte donors were recruited in a single centre and prospectively assigned to one of two treatment groups, according to the day of the week menstruation initiated: Group VC–, no prior vaginal contraceptive and Group VC+, prior vaginal contraceptive. RESULTS: VC+ patients presented a significantly higher cancellation rate, lower plasma estradiol levels and fewer follicles >12 mm on the day of hCG, versus the VC– group. Number of oocytes recovered was significantly lower in the VC+ group. All the cases of severe ovarian hyperstimulation syndrome (SOHSS) were in the VC– group. Pregnancy rates by embryo transfer to synchronic recipients were similar between VC+ and VC– (59.5 versus 57.9%, respectively). CONCLUSIONS: Vaginal contraceptive pretreatment resulted in a higher ovarian suppression, whereas SOHSS rate was lower than in donors who did not receive pretreatment. There were no differences in pregnancy rates between the two groups of synchronic oocyte recipients.

Key words: oocyte donor/ovarian response/dual suppression/GnRHa/contraceptive vaginal ring


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
In the setting of IVF, the use of hypophyseal suppression with gonadotrophin-releasing hormone agonist analogues (GnRHa) before stimulation with gonadotrophins has shown an increase in the number of oocytes obtained, higher fertilization rates, better embryo quality and higher pregnancy rates (Hughes et al., 1992Go). One excellent method for achieving hypophyseal suppression is administration of a single i.m. injection of a depot GnRH preparation (Orvieto et al., 2002Go). It has been suggested that treatment with a contraceptive preparation before GnRH administration will improve the outcomes of IVF in women with a tendency to hyper-respond, including those with polycystic ovarian syndrome (Damario et al., 1997Go). Moreover, prior contraceptive administration decreases the period of time required to reach hypophyseal suppression (exposure time to GnRH is shorter and suppression is less intense); hence, gonadotrophin requirements and the period of ovarian stimulation are reduced (Biljan et al., 1998aGo). In addition, the risk of cyst formation is lower, and hypophyseal suppression with GnRH is guaranteed. It has been reported that the need to confirm suppression by plasma determinations or sonographic control is eliminated when gonadotrophin treatment is started at least 14 days after the administration of GnRH (Biljan et al., 1998aGo).

Oocyte donors are women with a normal-to-high potential response to gonadotrophin stimulation under GnRH suppression. Prior treatment with a combined contraceptive can improve this response and provide a higher margin of synchronization with the recipient. Moreover, it can facilitate adaptation of the requirements of treatment monitoring to those of flexibility among the team of professionals involved (Barnat et al., 2005Go). The combined hormone-releasing vaginal ring (NuvaRing®, Organon, Barcelona, Spain) is an effective contraceptive method with excellent control of the cycle; it is convenient, well tolerated and highly acceptable to users (Dieben et al., 2002Go).

The aim of the present study is to compare the response to gonadotrophin stimulation under hypophyseal suppression in oocyte donors with or without prior combined hormone treatment by vaginal route. The primary outcome measures are the total number of oocytes recovered, number of days of gonadotrophin stimulation and total dose required. Secondary outcome measures include the cancellation rate because of hyper-response or poor response, the occurrence rate of severe ovarian hyperstimulation syndrome (SOHSS) and the clinical pregnancy rate following embryo transfer in synchronic recipients.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Acknowledgements
 References
 
A total of 190 women from a single centre who met the clinical and legal requisites for oocyte donation were recruited for the study. In the 2 months before treatment, all the donors had undergone a general and gynaecological examination with cytology, baseline plasma FSH and estradiol determinations, gynaecological sonography with assessment of antral follicle count, a detailed history-taking to rule out personal and family risk background, and karyotype and molecular study of cystic fibrosis mutations. Candidates with a sonographic diagnosis of polycystic ovaries were excluded (Rotterdam ESHRE/ASRM-Sponsored PCOS and consensus workshop Group, 2004Go). All the donors were aged less than 35 years and had baseline FSH levels of <10 mIU/ml, BMI <30, no history of hereditary disease and normal results in all the examinations performed.

All the women included in the study met the requirements of current Spanish legislation for oocyte donors (Ley 35/1988 and 45/2003), including the previous examinations and signed informed consent, and all accepted use of the vaginal contraceptive. The study was approved by the Ethics Committee of Institut Universitari Dexeus. This report was elaborated according to the CONSORT statement (Moher et al., 2001Go).

The 190 donors were prospectively assigned by the donor-oocyte coordinator to one of the two treatment groups, according to the day of the week when menstruation initiated: Group VC–, no prior vaginal contraceptive, donors whose first day of menstruation occurred on Monday, Tuesday or Wednesday and Group VC+, prior vaginal contraceptive, donors whose first day of menstruation occurred on Thursday to Sunday (Figure 1) (Vlaisavljevic et al., 2003Go).


Figure 1
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  		Figure 1. Schematic representation of the two treatment protocols. Group VC–: gonadotrophin-releasing hormone agonist (GnRHa) suppression alone; Group VC+: vaginal contraceptive + GnRH dual suppression. The vaginal contraceptive ring was inserted on cycle days 3–5, continued for 15–25 days and discontinued on a Sunday. GnRH i.m. injection was administered on cycle day 20–23. hMG stimulation began on Thursday or Friday.

 
Treatment
The vaginal contraceptive used (NuvaRing®) was a transparent ring, 54 mm in diameter by 4 mm thick. Each ring contained 2.7 mg of ethinyl estradiol and 11.7 mg of etonogestrel, which are released at a rate of 15 µg of ethinyl estradiol and 120 µg of etonogestrel per day. In the setting of the present study, the ring was inserted in the vagina after the third or fourth day of menstruation and left in place for 18–24 days.

Hypophyseal suppression was attained by intramuscular injection of 3.75 mg of leuprorelin acetate (Ginecrin Depot®, Abbott Laboratories S.A., Madrid, Spain) on days 20–22 of the preceding cycle. In the group treated with a vaginal ring, the injection was administered at 15–18 days after placement of the ring.

At 14–16 days after GnRH injection, stimulation was started with three ampoules of a fixed dose of human menopausal gonadotrophin (hMG; Lepori®, Madrid, Spain) daily for 5 days and a varying dose according to the individual response starting from the sixth day up to the day of hCG administration.

Monitoring began on the sixth day of stimulation, with plasma estradiol determinations and transvaginal sonography every 2 or 3 days, depending on individual response. Administration of 10 000 U of hCG (hCG Lepori®) was indicated as soon as >3 follicles having a diameter of >20 mm were observed; oocyte retrieval by follicle puncture was scheduled 36 h later. Puncture was performed on an outpatient basis under propofol sedation. At the time of discharge, patients were provided with specific instructions on life activities in the following days, a telephone contact for any eventuality, and the possibility to consult at the clinic if complications developed, including symptoms of ovarian hyperstimulation (Figure 1).

All donors underwent a sonographic study and follow-up visit 10–14 days after follicle puncture to confirm their well-being and to reinstate the contraceptive method when applicable.

Stimulation cycles were cancelled when the donor presented a response of less than six follicles >12 mm after 9 days of gonadotrophin stimulation, when there was a high risk of hyperstimulation or when there was an adverse reaction to the medication. An attempt was made to guarantee that each recipient would receive at least six mature oocytes.

The oocyte recipients, primed with 6 mg of estradiol valerate per day (Progynova®, 1 mg, Schering España S.A., Madrid, Spain) for a minimum of 14 days, were synchronized to additionally begin vaginal micronized progesterone treatment at 600 mg per day (Utrogestan® 200 mg, Seid, Madrid, Spain) on the day of oocyte recovery. Recipients with ovarian function were inhibited with depot GnRH. After oocyte recovery, standard IVF and/or ICSI procedures and laboratory techniques were followed, depending on the quality of the semen of the recipient’s partner (Coroleu et al., 2000Go). Replacement treatment was maintained until the results of plasma beta-hCG determination were obtained, 12 days after embryo transfer. If results were negative, treatment was discontinued. If results were positive, clinical confirmation of pregnancy was undertaken using ultrasound. For the purposes of the study, only clinical pregnancies with sonographic evidence of embryo cardiac activity were counted. When pregnancy was confirmed, hormone treatment was maintained until the eleventh week of gestation.

For cases in which the recipient or her partner could not come to the centre at the time of oocyte donation, insemination of the donated oocytes with previously cryopreserved semen was offered (asynchronic cycles, not analysed in this study). The resulting embryos were frozen and, after adequate preparation of the recipient endometrium, transfer was scheduled in an asynchronic cycle.

Sample size
To detect a between-treatment difference of four retrieved oocytes, and assuming an overall standard deviation (SD) of 7.5 oocytes in a bilateral comparison with an alpha error of 0.05, a sample size of 59 patients per treatment arm was required to reach 80% statistical power (Machin et al., 1997Go).

Statistical analysis
Quantitative variables were compared with parametric tests (Student’s t or analysis of variance) or non-parametric tests (Mann–Whitney U or Kruskal–Wallis), depending on whether the conditions required for each of the tests were met. Categorical variables were compared with the chi-square test or Fisher’s exact test, where appropriate. All statistical analyses were done with SPSS, version 12.0. All tests were bilateral and significance was set at a P-value of 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Acknowledgements
 References
 
Between 1 March and 31 October 2004, a total of 190 donors were enrolled in the study: VC– group, n = 89, and VC+ group, n = 101. Donor mean age was 26.9 ± 4.4 years, and BMI was 22.8 ± 3.2. General characteristics are summarized in Table I. Nine donors did not return for the GnRH injection, six in the VC– group and three in the VC+ group. All the donors who received the analogue (n = 181) initiated gonadotrophin stimulation (Figure 2). Nine donors were cancelled because of a poor response (one in the VC– group and eight in the VC+ group). Cancellation was significantly higher in the VC+ group (1.7 versus 9.2%, P < 0.05). Only the 172 donors who underwent follicle puncture were included in the analysis of treatment duration, gonadotrophin dose, estradiol levels on the day of hCG administration and oocytes retrieved. VC-pretreated patients presented significantly lower plasma estradiol levels and significantly fewer follicles >12 mm in diameter on the day the pre-ovulatory hCG dose was administered, and required a larger, although non-significant, total dose of gonadotrophins versus the non-pretreated group. Hence, the number of oocytes recovered was significantly lower in the VC+ group. All the cases of SOHSS requiring hospitalization (1–2 days) were in the VC– group (Table II).


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  		Table I. Donor characteristics

 

Figure 2
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  		Figure 2. Flowchart of patient status throughout the study. Donors were randomized to the vaginal contraceptive + GnRHa (VC+) or GnRHa only (VC–) groups according to the weekday menstruation started. aOne donor was cancelled because of poor response. bEight donors were cancelled because of poor response; OPU = oocyte pickup.

 

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  		Table II. Donor response, cancellation rate and severe ovarian hyperstimulation syndrome (SOHSS) rate

 
A total of 2526 oocytes were retrieved and assigned to 176 recipients. Oocyte donations were performed in a synchronized cycle among 150 recipients, with embryo transfer 2 days after follicle puncture. The remaining oocyte donations were performed in an asynchronic cycle. At the time of writing, embryo transfer to all the recipients of oocytes from these donations has not as yet been completed.

On the basis of consensus in our oocyte donation programme, we always attempt to transfer two embryos. The pregnancy rates by embryo transfer were similar between VC+ and VC– (59.5 versus 57.9%, respectively). Characteristics of the recipients and results of the donation cycle are summarized in Table III.


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  		Table III. Recipient and oocyte data

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Acknowledgements
 References
 
Donors of oocytes are usually young women with an excellent ovarian reserve. In many cases, the baseline ultrasound shows multifollicular ovaries, and the donors’ response to stimulation treatment tends to be high. In 1997, in a retrospective IVF study (Damario et al., 1997Go), a protocol for double suppression with GnRH and oral contraceptive was described for stimulation treatment in patients with polycystic ovarian syndrome or a history of hyper-response. According to the authors, this method provided several advantages: a reduction in the time required to reach hypophyseal suppression, scheduled initiation of the cycle and elimination of the need for hypophysectomy control. Moreover, the rates of fertilization, implantation and clinical pregnancy were higher with this method.

In a retrospective case-control study in 31 patients, other authors showed that pretreatment with oral contraceptives before hypophyseal suppression with GnRH decreased the formation of cysts without affecting later follicular recruitment and pregnancy rates (Biljan et al., 1998aGo). These findings were subsequently confirmed by the same group in a prospective randomized study in 83 patients (Biljan et al., 1998bGo). Furthermore, several authors have affirmed that pretreatment with oral contraceptives eliminates the need for hormonal or sonographic monitoring to confirm that hypophyseal suppression is attained if gonadotrophin treatment is started at least 14 days after initiation of GnRH administration. This approach clearly simplifies the treatment and monitoring required, which is particularly advantageous for oocyte donors.

The present study assesses the effect of pretreatment with a vaginal contraceptive prior to hypophyseal suppression on the response to gonadotrophin stimulation in oocyte donors. One of the main limitations is the method of treatment allocation by day of the week, instead of a true randomization. The purpose of this was to schedule treatment in a way that oocyte pick up would be performed during weekdays while trying to avoid a subjective assignment and other bias.

We found that that vaginal contraceptive pretreatment provided greater hypophyseal suppression, which resulted in higher gonadotrophin requirements, more cancellations because of low response and a smaller number of retrieved oocytes. In addition, the rate of SOHSS was significantly lower.

Various authors have indicated that oral contraceptives have a potent suppressor effect, which compromises the response to gonadotrophin stimulation (Benadiva et al., 1988Go), lengthens the duration of stimulation and is associated with increased cancellations (Maschiach et al., 1988Go). These findings suggest that profound hypophyseal suppression is produced in patients receiving combined hormonal contraception, which is still evident during the following cycle of ovulation induction. Nevertheless, other authors have observed a beneficial effect of contraceptive use (Lindheim et al., 1996Go) in cycles without analogues, particularly in women with a history of poor response. In the present study, gonadotrophin stimulation was started in the VC+ group 5 days after discontinuing the contraceptive, considered to be the latency phase necessary to reestablish endogenous FSH levels in cycles without analogues (Kemeter and Feichtinger, 1989Go; Gonen et al., 1990Go). We do not know whether an interval of 7 days would have been more favourable for stimulation, as has been suggested, although in the present study, recovery of endogenous gonadotrophin levels could not be expected as a GnRH analogue was administered concomitantly.

In our VC+ group, the dose of gonadotrophin stimulation, levels of plasma estradiol on the day of hCG and number of oocytes recovered were similar to the reported findings of Barnat et al. (2005)Go in a group of IVF patients with normal response, treated with oral contraceptives, GnRH and recombinant FSH.

Donors who did not receive the contraceptive presented a response similar to that of normally responding individuals treated with the standard long protocol (Coroleu et al., 2000Go), although the SOHSS rate was higher. This higher rate may be related to the dose of gonadotrophins used, the young age of the donors, the BMI or the good ovarian reserve. As SOHSS should be avoided in general, but particularly among oocyte donors, we have adopted a more moderate stimulation regimen after analysing the results of this study.

It is noteworthy that there were no differences in the number of oocytes inseminated or fertilized, or in the number of embryos attained, even though the number of oocytes proceeding from the VC– donors was significantly higher than those from the VC+ group. In keeping with Barnat et al. (2005)Go, our results support the suggestion that only the most competent oocytes become fertilized and continue normal development.

When the synchronic cycles of embryo transfer were compared, the pregnancy rate between those receiving oocytes from donors pretreated with vaginal contraceptive and those receiving oocytes from donors without pretreatment was identical. That is, prior vaginal contraceptive use did not have an effect on the pregnancy rate.

The objective of contraceptive pretreatment was to simplify donor treatment. However, the result was a higher degree of suppression, which led to cancellation of more cycles and higher gonadotrophin requirements. On the basis of this outcome, our group has decided not to continue this treatment approach. It is possible, however, that the protocol would be suitable for individuals with polycystic ovarian syndrome, as was initially suggested (Damario et al., 1997Go). It should be pointed out that the combined hormonal contraceptive preparation was administered by vaginal route in the present study, and this fact may have had an impact on the response. Our overall results do not differ from the reported response of IVF patients treated with oral contraceptive, daily analogue administration and stimulation with high doses of recombinant FSH (Barnat et al., 2005Go). It would be interesting to prospectively compare the two contraceptive administration routes, oral or vaginal, to determine the influence on stimulation.

The ovarian hyperstimulation rate observed and the elevated number of oocytes retrieved in our group receiving GnRH alone is a cause for concern, even though none of the donors presented a clinical or sonographic diagnosis of polycystic ovarian syndrome. To reduce the risk, we have reduced the standard initial dose of three ampoules of hMG per day to two ampoules per day.

In summary, results are presented of a prospective, comparative study assessing the effect of pretreatment with a vaginal contraceptive before hypophyseal suppression on the response to gonadotrophin stimulation in oocyte donors. Vaginal contraceptive pretreatment resulted in a higher cancellation rate because of poor response and greater, non-significant, gonadotrophin requirements, whereas the SOHSS rate was lower than in donors who did not receive pretreatment. There were no differences in the pregnancy rates between the two groups of synchronic oocyte recipients.


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
This work has been done under the auspicies of the "Cátedra de Investigación en Obstetricia I Ginecología" of Department of Obstetrics and gynaecology, Institut Universitari Dexeus, Universitat Autonoma de Barcelona.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Barnat LI, Chantilis SJ, Hurst B, Dickey RP. (2005) 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. Fertil Steril 83:321–330.[CrossRef][Web of Science][Medline]

Benadiva CA, Tureck R, Ben-Rafael Z, Mastroianni L, Blasco L, Flickinger GL. (1988) Ovarian response to human menopausal gonadotropin following suppression with oral contraceptives. Fertil Steril 50:516–520.[Web of Science][Medline]

Biljan MM, Mahutte NG, Dean N, Hemmings R, Bissonnette F, Tan SL. (1998a) Pretreatment with an Oral Contraceptive Is Effective in Reducing the Incidence of Functional Ovarian Cyst Formation During Pituitary Suppression by Gonadotropin-Releasing Hormone Analogue. J Assist Reprod Genet 15:599–604.[CrossRef][Web of Science][Medline]

Biljan MM, Mahutte NG, Dean N, Hemmings R, Bissonnette F, Tan SL. (1998b) Effects of pretreatment with an oral contraceptive on the time required to achieve pituitary suppression with gonadotropin-releasing hormone analogues and on subsequent implantation and pregnancy rates. Fertil Steril 70:1063–1069.[CrossRef][Web of Science][Medline]

Coroleu B, Carreras O, Veiga A, Martell A, Martinez F, Belil I, Hereter L, Barri PN. (2000) Embryo transfer under ultrasound guidance improves pregnancy rates after in-vitro fertilization. Hum Reprod 15:616–620.[Abstract/Free Full Text]

Damario MA, Barmat L, Liu H-C, Davis OK, Rosenwaks Z. (1997) Dual suppression with oral contraceptives and gonadotropin releasing-hormone agonists improves in-vitro fertilization outcome in high responder patients. Hum Reprod 12:2359–2365.[Abstract/Free Full Text]

Dieben TOM, Roumen FJME, Apter D. (2002) Efficacy, Cycle Control, and User Acceptability of A Novel Combined Contraceptive Vaginal Ring. Obstet &Gyaecol 100:585–593.

Gonen Y, Jacobson W, Casper RF. (1990) Gonadotropin suppression with oral contraceptives before in vitro fertilization. Fertil Steril 53:282–287.[Web of Science][Medline]

Hughes EG, Fedorkow DM, Daya S, Sagle MA, Van de Koppel P, Collins JA. (1992) The routine use of gonadotropin-releasing hormone agonists prior to in vitro fertilization and embryo transfer: a meta-analysis of randomized controlled trials. Fertil Steril 58:888–896.[Web of Science][Medline]

Kemeter P and Feichtinger W. (1989) Experience with a new fixed-stimulation protocol without hormone determinations for programmed oocyte retrieval for in-vitro fertilization. Hum Reprod 4:Suppl., 53–58.[Medline]

Lindheim S, Barad DH, Witt B, Diktoff E, Sauer MV. (1996) Short-term gonadotropin suppression with oral contraceptives benefits poor responders prior to controlled ovarian hyperstimulation. J Assist Reprod Genet 13:745–747.[CrossRef][Web of Science][Medline]

Machin D, Campbell M, Fayers P, Pinol A. (1997) Simple Size for Clinical Studies. 2nd edn (Blackwell Science, London, England).

Maschiach S, Dor J, Goldenberg M, Shalev J, Blankstein J, Rudak E, Shoam Z, Finelt Z, Nebel L, Golman B. (1988) Protocols for induction of ovulation. The concept of programmed cycle. Ann N Y Acad Sci 541:37–42.[Web of Science][Medline]

Moher D, Schultz KF, Altman DG. (2001) The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. Lancet 357:1191–1194.[CrossRef][Web of Science][Medline]

Orvieto R, Kerner R, Krissi H, Ashkenazi J, Ben Rafael Z, Bar-Hava I. (2002) Comparison of leuprolide acetate and triptorelin in assisted reproductive technology cycles: a prospective, randomized study. Fertil Steril 78:1268–1271.[CrossRef][Web of Science][Medline]

Rotterdam ESHRE/ASRM-Sponsored PCOS and consensus workshop Group. (2003) consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 81:19–25 Revised.[Web of Science]

Vlaisavljevic V, Reljic M, Lovrec VG, Kovacic B. (2003) Comparative effectiveness using flexible single-dose GnRH antagonists (Cetrorelix) and single-dose long GnRH agonist(Goserelin) protocol for IVF cycles- a prospective, randomized study. RBMOnline 7:301–308.

Submitted on January 17, 2006; resubmitted on March 22, 2006; accepted on March 23, 2006.


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