Oral Contraceptive Pretreatment Research Articles

Oral Contraceptive (OC) Pre-treatment Does not Influence Oocyte Yield in Poor Responders Undergoing Gonadotropin Releasing Hormone (GnRH) Antagonist Cycles for In Vitro Fertilization (IVF)

Concern exists over the potential suppressive effects of OC’s in poor responders undergoing controlled ovarian stimulation for IVF±ICSI. However, studies examining outcomes of OC pre-treatment are limited, particularly in GnRH antagonist cycles. The aim of this study is to ascertain the impact of OC pre-treatment in poor responders undergoing GnRH antagonist IVF cycles.

Ganirelix acetate use in normal- and poor-prognosis patients and the impact of estradiol patterns

To evaluate cycle outcomes in patients with either poor or normal prognosis undergoing IVF treatment with a GnRH antagonist (ganirelix acetate) for LH suppression. Nonrandomized, noncontrolled, retrospective review. 204 patients, aged 23-41 years, undergoing IVF. Patients completed 225 consecutive cycles of IVF with a GnRH antagonist (Antagon; Organon, Roseland, NJ) for LH surge prevention. Sixty cycles were conducted in patients with a known poor prognosis, whereas 165 were conducted in patients with a normal IVF prognosis. Pregnancy rate (PR), for the series as a whole and according to prognosis, and serum E2 patterns. The PR per initiated cycle for the series as a whole was 33.3%. The pregnancy rate was 42.1% per ET for the entire series, with a cycle cancellation rate of 21%. When evaluated by prognosis, the poor-prognosis patients had PRs of 8.3% per attempt and 15% per transfer, whereas the normal-prognosis patients had PRs of 40% per attempt and 45% per transfer. Pregnancy rate did not vary by E2 pattern (drop, plateau, or rise). Oral contraceptive pretreatment was noted to be associated with high cancellation rates in the group of known poor responders, whereas for the group as a whole, cycle outcome was unaffected by the use of oral contraceptives. Use of GnRH antagonists in patients with an a priori poor IVF prognosis results in predictably poor outcomes. Patients without factors predicting poor outcome have acceptable PRs. The pattern of E2 rise immediately after initiation of GnRH antagonists does not predict cycle outcome. Oral contraceptives can be successfully used to schedule antagonist-based IVF cycles but might increase the risk of cycle cancellation in some patient populations.

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

To compare the effects of oral contraceptive (OC) pill pretreatment in recombinant FSH/GnRH-antagonist versus recombinant FSH/GnRH-agonist stimulation in in vitro fertilization (IVF) patients, and to evaluate optimization of retrieval day. Prospective, randomized, multicenter study. Private practice and university centers. Eighty patients undergoing IVF who met the appropriate inclusion criteria. Four study centers recruited 80 patients. The OC regimen began on cycle days 2 to 4 and was discontinued on a Sunday after 14 to 28 days. The recombinant FSH regimen was begun on the following Friday. The GnRH-agonist group was treated with a long protocol; the GnRH-antagonist was initiated when the lead follicle reached 12 to 14 mm. When two follicles had reached 16 to 18 mm, hCG was administered. The primary outcome measures were the number of cumulus-oocyte complexes, day of the week for oocyte retrieval, and total dose and days of stimulation of recombinant FSH. Secondary efficacy variables included pregnancy and implantation rate; serum E(2) levels on stimulation day 1; serum E(2), P, and LH levels on the day of hCG administration; follicle size on day 6 and day of hCG administration; the total days of GnRH-analogue treatment; total days on OC; total days from end of OC to oocyte retrieval; and the cycle cancellation rate. Patient outcomes were similar for the days of stimulation, total dose of gonadotropin used, two-pronuclei embryos, pregnancy (44.4% GnRH-antagonist vs. 45.0% GnRH-agonist, P=.86) and implantation rates (22.2% GnRH-antagonist vs. 26.4% GnRH-agonist, P=.71). Oral contraceptive cycle scheduling resulted in 78% and 90% of retrievals performed Monday through Friday for GnRH-antagonist and GnRH-agonist. A one day delay in OC discontinuation and recombinant FSH start would result in over 90% of oocyte retrievals occurring Monday through Friday in both groups. The OC pretreatment in recombinant FSH/GnRH-antagonist protocols provides a patient-friendly regimen and can be optimized for weekday retrievals. No difference was seen in number of 2PN embryos, cryopreserved embryos, embryos transferred, implantation and pregnancy rates between the two stimulation protocols.

Ovarian suppression with oral contraceptive pills prior to ART: can you get too much of a “good” thing?

Objective: Women undergoing ART are frequently placed on oral contraceptive pills (OCP) for pre-cycle ovarian suppression and to assist in patient scheduling. In our military hospital-based ART program, patients are enrolled world-wide into quarterly cycles. This often necessitates a long duration of oral contraceptive ART pre-cycle suppression (> 42 days). The objective of this study is to compare the effect of prolonged oral contraceptive pre-treatment on ART cycle outcome. Design: Retrospective Cohort Analysis. Materials and Methods: Women undergoing their first ART cycle from January 2002 to September 2002 were included for analysis. All were pre-treated with 35 microgram monophasic oral contraceptive pills. Ovarian hyperstimulation was with 40 microgram GnRH-agonist flare gonadotropin protocols (Leondires et al., 1999). All infertility diagnoses, ART cycle types, and stimulation protocols were considered. Cycle cancellation and clinical pregnancy rates (CPR) per cycle start and embryo transfer were then compared between ART cycles in which OCP pre-ART cycle pretreatment was ≤ 42 and > 42 days. Statistical significance was determined by χ2, with a p < 0.05 considered significant. Results: 327 ART cycles met criteria for inclusion in the analysis. OCP pre-treatment of ≤ 42 days (mean 31.1) occurred in 166 cycles. OCP pre-treatment of > 42 days (mean 64.6) occurred in 161 cycles. Patient age and basal FSH were not significantly different in both groups. The cycle cancellation rate was 9.6% in women treated ≤ 42 days vs. 25.5% in women treated > 42 days (p < 0.05). The CPR per cycle start was 40.4% in women treated ≤ 42 days vs. 34.8% in women treated > 42 days. CPR per transfer was 44.7% in women treated ≤ 42 days vs. 46.7% in women treated > 42 days. Cancellations in both groups were restricted to poor ovarian response. The significant differences are noted in Table 1. Tabled 1 Conclusion: Prolonged oral contraceptive pill use for pre-cycle ovarian suppression increases the cancellation rate in ART, presumably by decreasing ovarian response. In patients who achieve embryo transfer, however, pregnancy rates are not affected.

Oral contraceptive pretreatment for scheduling in IVF patients treated with either rFSH/GnRH Antagonist or rFSH/GnRH agonist

Objectives: (1) To compare the clinical effects of oral contraceptive pill (OCP) pretreatment for cycle scheduling in rFSH/GnRH antagonist (ANT) vs. rFSH/GnRH agonist (AG) stimulation in IVF patients, and (2) to evaluate optimization of retrieval day with OCP. Design: Prospective, randomized. Material and Methods: Four study centers equally recruited 80 patients with inclusion criteria: age≤ 38, d3 FSH ≤ 10, basal antral follicle > 5, 19<BMI <32, 26< cycle day (CD) <34, and ≤1 previous ART cycle. All subjects began OCP (Desogen®, Organon USA, Roseland, NJ) on CD 2–4 and discontinued on a Sunday after 14–28 d of treatment. Evening dosing of rFSH (Follistim®, Organon USA) at 300 IU/day began on the Friday (5th day post OCP) following OCP discontinuation. Dose adjustments of 75–150 IU rFSH were allowed. In AG group, GnRH agonist (Lupron®, TAP, Chicago, IL) had a 5 day overlap with OCP at 0.5 mg/d and decreased to 0.25 mg/d with rFSH start. In ANT group (Antagon(tm), Organon USA), an evening dose of 250 μg/d ANT was initiated when lead follicle had a mean diameter of 12–14 mm. HCG was administered when 2 or more follicles reach ≥16–18 mm. ET occurred on d2, 3 or 5. According to individual clinic protocols, luteal support was provided. Serum β-hCG and ultrasound confirmed clinical pregnancy. Results: Of 80 patients, 39 were randomized to ANT and 41 in AG; 36 in ANT and 40 in AG to embryo transfer. Cancellations were: ANT- 2 poor response, 1 personal reason; AG- 1 no fertilization. There were no differences in patient age, BMI, day 3 FSH and OCP duration between ANT and AG. The mean (±SE, range) number of days of rFSH in ANT (9.1 + 0.3, 6–12) and AG (9.0 + 0.2, 6–12) was not different. The dose of gonadotropin utilized was similar between ANT and AG (2706 + 146 vs 2724 + 118, respectively). Patient outcomes were similar in the number of oocytes retrieved, number of embryos, ongoing pregnancy rate and implantation rate. OCP cycle scheduling resulted in 89% and 95% of retrievals performed on five days of week for ANT and AG, respectively. Conclusions: OCP pretreatment in rFSH/ANT protocols for IVF provides a patient-friendly regimen with fewer injections and can be optimized for weekday retrievals. There was no difference in number of oocytes retrieved, 2 PN embryos, embryos transferred, implantation and pregnancy rates between the two stimulation protocols. To optimize scheduling for weekday retrievals, OCP pretreatment should be discontinued on Monday (vs. Sunday) and rFSH should be initiated on Saturday (vs. Friday). Supported by: an unrestricted educational grant from Organon Pharmaceuticals Inc.

Antagonists in poor-responder patients

Objective To review treatment options for poor-responding patients who are undergoing infertility treatment. Design Review article and case studies. Results A comprehensive determination of potential ovarian response for the poor-responding patient is important in the individualization of treatment options for these patients. Treatment options include both the microdose flare leuprolide acetate and GnRH antagonist stimulation protocols. For GnRH antagonist stimulation protocols, individualization of treatment includes use of oral contraceptive pretreatment and alterations in duration of gonadotropin stimulation and start day of antagonist administration. Conclusions For poor-responding patients, the benefits of using GnRH antagonists for the suppression of premature LH surges plus the determination that stimulation protocols that include GnRH antagonists are at least as good as the microdose flare and provide better cycle outcomes than the long luteal leuprolide acetate down-regulation protocols have the potential to bring changes to the existing protocols for ovarian stimulation.

Pregnancy rates are maintained in poor responders with a simple GnRH antagonist protocol compared to microdose GnRH agonist flare

Objective: The microdose GnRH agonist flare stimulation protocol is widely adopted by in vitro fertilization (IVF) centers for poor responders. However, oral contraceptive (OCP) pretreatment in these cycles could delay or reduce the response in some patients, and compromise the prognosis. When GnRH antagonists were introduced, we speculated that some low responders could benefit from starting gonadotropin stimulation at the beginning of a spontaneous cycle without OCP pretreatment, to avoid the delayed suppression that may occur with OCP. In this study, we compared IVF outcomes in low responders treated with a simple GnRH antagonist stimulation versus a traditional microdose GnRH agonist flare stimulation.

A pilot study to assess oral contraceptive (OC) pretreatment in women undergoing controlled ovarian hyperstimulation (COH) in ganirelix acetate cycles

Objective: To assess the feasibility and impact of pretreatment with OCs for scheduling women undergoing COH in GnRH antagonist cycles. Design: This was a multicenter, open-label pilot trial of healthy female partners of infertile couples. Materials/Methods: Subjects were females of infertile couples for whom COH and in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI) were indicated. The subjects were ≥18 and ≤35 years of age with normal menstrual cycles. Their body mass index had to be less than 29 kg/m2 with a weight limit of >50 kg and <90 kg. Subjects took OCs (Desogen®) once daily for 14 to 21 days beginning on day 1 to 3 of the menstrual cycle. Recombinant follicle stimulating hormone (rFSH, Follistim) at a starting dose of 225 IU was administered subcutaneously once daily beginning on the fourth day after discontinuation of the OC. Ganirelix acetate (250 g/day) was started on day 6 of rFSH treatment or when the lead follicle reached a mean diameter of 12 mm. Human chorionic gonadotropin (hCG) was administered on the first day that 3 follicles with a diameter of greater than 17 mm were observed by ultrasonography. Results: The study is ongoing and to date 77 patients have been enrolled, 69 have been treated with the OC, 61 have received hCG, 59 have undergone oocyte retrieval, and 58 have had embryo transfer. An average of 2.2 embryos was transferred per patient. Of the subjects who have had oocyte retrieval, the mean number of oocytes retrieved (± standard deviation [SD]) was 16.5 ± 8.5. The mean total rFSH dose was 2458 IU and the mean duration of stimulation was 9 days. The mean number of good-quality embryos (Grades I and II) achieved was 8.5 ± 4.9. Of those patients completed to date who received embryo transfer, the implantation rate was 26% and the pregnancy rate (positive fetal heartbeat at 5 to 6 weeks) was 37%. Conclusions: The preliminary results of this study indicate that OCs can be successfully used to schedule patients prior to COH in ganirelix cycles. Supported by: Supported by Organon Inc, West Orange, New Jersey.

Daily low dose recombinant hCG and recombinant FSH: a novel stimulation protocol for IVF

Objective: Stimulation protocols often utilize oral contraceptive pre-treatment prior to initiation of GnRH agonists or antagonists to facilitate scheduling of the IVF cycle. In some cases, this leads to profound suppression of endogenous gonadotropins. Prior investigation has demonstrated that initiation of FSH prior to resolution of this suppression is associated with delayed follicular growth and increased consumption of gonadotropins. It has been proposed that LH deficiency is responsible for this delayed response. Many IVF programs currently employ ’mixed’ stimulation protocols using HMG together with FSH preparations in attempt to overcome this problem. Despite this approach, some patients may continue to have a suboptimal response. This is likely due to the short half-life of the LH component of hMG preparations. Recombinant HCG has recently become available. This drug may serve as a source of LH activity with a significantly longer half life and duration of action than the LH component of HMG. This study was undertaken to evaluate the potential benefit of using a daily low dose of recombinant hCG as an adjunct to recombinant FSH treatment for ovulation induction in IVF patients.

A comparative trial of metformin and oral contraceptive pretreatment in patients with polycystic ovary syndrome undergoing ICSI for severe male factor infertility.

Objective: The aim of our study was to evaluate the effect of metformin and oral contraceptive (OC) pretreatment in patients with polycystic ovaries (PCO) and high body mass index (BMI) undergoing assisted reproductive techniques.

Oral contraceptive pre-treatment for IVF cycles employing recombinant FSH and a GnRH antagonist.

Objective: Recent reports have demonstrated that GnRH antagonists can be successfully used in conjunction with rFSH for IVF. In these investigations, gonadotropin stimulation was initiated following the onset of a spontaneous menses. Many IVF centers may be reluctant to employ these protocols secondary to cycle scheduling concerns. Difficulties in predicting cycle start dates leads to difficulty predicting the range of dates on which the egg retrieval and embryo transfer may be performed. Previous studies have touted the use of oral contraceptives for pretreatment in GnRH agonist/gonadotropin protocols as a means to facilitate IVF cycle scheduling. The purpose of this study is to evaluate the effect of oral contraceptive pretreatment in IVF cycles using a recFSH and a GnRH antagonist.

Pulsatile luteinising hormone releasing hormone for ovulation induction in subfertility associated with polycystic ovary syndrome.

In normal menstrual cycles, gonadotrophin releasing hormone (GnRH) secretion is pulsatile, with intervals of 60-120 minutes in the follicular phase. Treatment with pulsatile GnRH infusion by the intra-venous or subcutaneous route using a portable pump has been used successfully in patients with hypogonadotrophic hypogonadism. Assuming that the results would be similar in polycystic ovary syndrome (PCOS), pulsatile GnRH has been used to induce ovulation in patients with PCOS. But, although ovulation and pregnancy has been achieved, the use of pulsatile GnRH in PCOS patients is controversial. To assess the effectiveness of pulsatile GnRH administration in women with clomiphene-resistant polycystic ovary syndrome (PCOS), in terms of ovulation induction, pregnancy, miscarriage, multiple pregnancy and ovarian hyperstimulation syndrome (OHSS). The search strategy of the Menstrual Disorders and Subfertility review group was used to identify all relevant trials. Please see Review Group details. All relevant published RCTs were selected. Non-randomised controlled trials were eligible for inclusion if treatment consisted of GnRH administration versus another treatment to induce ovulation in subfertile women with PCOS. A computerised MEDLINE and EMBASE search was used to identify randomised and non randomised controlled trials. The reference lists of all studies found were checked for relevant articles. One RCT (Bringer 1985a) and one abstract (Coelingh 1983) were identified this way. Relevant data were extracted independently by two reviewers (NB, MW). Validity was assessed in terms of method of randomization, completeness of follow-up, presence or absence of cross-over and co-intervention. All trials were screened and analysed for predetermined quality criteria. 2X2 tables were generated for all the relevant outcomes. Odds ratios were generated using the Peto modified Mantel-Haenszel technique. Three RCTs and one non-randomised comparative trial were identified comparing four different treatments: GnRH versus HMG, GnRH following GnRHa pre-treatment versus no pre-treatment, GnRH and FSH versus FSH, and GnRH following GnRHa pre-treatment versus GnRH following oral contraceptive pre-treatment. This means that there was only one trial in any one comparison. In the first two studies, data of pre- and post-cross-over were not described separately. Therefore, these results could not be included in the MetaView analysis. The odds ratio for ovulation rate was 16 (95 % CI: 1.1-239) in the study comparing GnRH and FSH with FSH. When GnRH after GnRHa pre-treatment was compared with GnRH after oral contraceptive pre-treatment, an odds ratio of 7.5 (95 % CI: 1.2-46) was obtained. All trials were small and of too short duration to show any significance in pregnancy results. Per study only one to four pregnancies occurred. Multiple pregnancies were not seen. OHSS was seen only in the patients stimulated with HMG. The four trials describing four different comparisons with a short follow up (1 to 3 cycles) were too small to either prove or discard the value of pulsatile GnRH treatment in patients with polycystic ovary syndrome.

Short-term gonadotropin suppression with oral contraceptives benefits poor responders prior to controlled ovarian hyperstimulation.

A comparative study of four treatment regimens for women with a history of poor response to controlled ovarian hyperstimulation (COH) during attempts at in vitro fertilization (IVF) and embryo transfer suggested the feasibility of pretreatment with oral contraceptives (OCs). The 60 women enrolled in the study exhibited one or more of the following in an initial stimulated IVF cycle: three or fewer dominant follicles recruited serum estradiol levels of 300 pg/ml or below and/or a spontaneous luteinizing hormone (LH) surge prior to oocyte retrieval. Study subjects were assigned to one of four protocols: Group I--OCs for 3 weeks followed by COH; Group II--luteal phase leuprolide acetate with subsequent COH; Group III--short-flare Lupron with subsequent COH; and Group IV--COH alone. COH consisted of 150 IU/day of pure follicle-stimulating hormone (pFSH) and 150 IU/day of human menopausal gonadotropin (hMG). The mean age of women in each group ranged from 36.0 to 38.8 years. There were no significant differences among groups in terms of number of days of stimulation total ampoules of hMG and pFSH required peak serum estradiol and progesterone number of oocytes retrieved and fertilized and embryos transferred. However the pregnancy rate was significantly higher (p < 0.05) in Group I (9/30 30%) than in Group II (2/32 6%) Group III (0/11 0%) and Group IV (0/10 0%). The good outcome associated with OC pretreatment may reflect production or alterations of local ovarian growth factors and/or changes in endometrial expression. Administration of exogenous estrogen may be particularly beneficial for perimenopausal women in their forties with ovarian follicular depletion.

Gonadotropin suppression with oral contraceptives before in vitro fertilization

One hundred eighty-one stimulation cycles in which gonadotropin suppression with oral contraceptives (OCs) preceded induction of follicle stimulation (study group) and 113 stimulation cycles without pituitary suppression (control group) were compared. The mean length of ovarian suppression was 35.3 +/- 0.9 days. No spontaneous luteinizing hormone (LH) surges occurred when the use of OC preceded ovarian hyperstimulation, whereas in the control group the incidence of LH surges was 19.5%. The mean amount of human menopausal gonadotropin required was significantly lower in the study group than in the control group (8.9 +/- 0.4 and 10.9 +/- 0.4 ampules, respectively). Significantly more follicles greater than or equal to 1.5 cm in diameter were seen on the day before oocyte retrieval and significantly more oocytes were retrieved per attempt in the group with OC pretreatment. Our data clearly demonstrate that OCs are useful in vitro fertilization stimulation protocols to facilitate scheduling of cycles and to prevent spontaneous LH surges.