Premature LH Research Articles

Dose-finding study of daily GnRH antagonist for the prevention of premature LH surges in IVF/ICSI patients: optimal changes in LH and progesterone for clinical pregnancy

An optimal range of LH concentrations for achieving pregnancy has not been established. The aim of this study was to investigate the effect of various LH levels induced by different GnRH antagonist doses on IVF outcome. This was a prospective, single centre study including 144 IVF patients, stimulated with recombinant FSH from cycle day 2, and co-treated with daily GnRH antagonist (antide/Iturelix) (2 mg/2 ml, 1 mg/ml, 0.5 mg/ml, 0.5 mg/0.5 ml or 0.25 mg/ml) from cycle day 7 onwards. Serum samples were taken three times daily. Clinical pregnancies were only observed within a particular range of change in LH levels. The upper and lower thresholds for the mean LH area under the curve (AUC), adjusted for the baseline LH level before the antagonist was started (LH AUC(-S6); S6=stimulation day 6) were -2.2 and 12.4 (IU/l) respectively (a negative value=below baseline levels). There were no clinical pregnancies outside these threshold values. Similar results were found for progesterone, the threshold levels of progesterone AUC(-S6) were 3.98 and -1.21 ng/ml. Moreover, there were no pregnancies with progesterone levels >0.26 ng/ml/follicle on the day of hCG. Excessive or insufficient suppression of LH and progesterone levels during GnRH antagonist administration and high progesterone/follicle on hCG day seems to be associated with impaired clinical pregnancy rates.

LH suppression following different low doses of the GnRH antagonist ganirelix in polycystic ovary syndrome

Elevated LH concentration is a common feature in polycystic ovary syndrome (PCOS). This study was designed to establish whether elevated LH levels in PCOS might be suppressed to normal range values by the administration of different low doses of GnRH antagonist, which subsequently might reverse the anovulatory status of these patients. Twenty-four PCOS patients with elevated endogenous LH concentrations were randomized into 3 different dose groups, receiving either 0.125 mg (Group A), 0.250 mg (Group B) or 0.500 mg (Group C) ganirelix sc daily for 7 subsequent days. During the first day of treatment, LH and FSH levels were assessed at 20 min intervals, during 8 h. Thereafter LH, FSH, androgens, estradiol (E2) and inhibins were assessed daily and frequent ultrasound scans were performed for 7 days to record follicle development. Repeated GnRH antagonist administration induced a significant suppression of LH (and to a lesser extent of FSH) serum levels, which was comparable between the different doses. Six hours after ganirelix administration, endogenous LH was suppressed by 49, 69 and 75%, and endogenous FSH was suppressed by 23, 19 and 25%, respectively. The decrease in serum LH and FSH levels was transient and lasted for 12 h, after which serum levels returned to baseline levels at 24 h after drug administration. Androgen levels were not significantly suppressed using this regimen. E2 levels decreased significantly (p < 0.001) and suppression was most pronounced in Group C. Spontaneous follicle development or ovulations were not recorded during the course of treatment. In conclusion, the present study demonstrates that the GnRH antagonist ganirelix is capable of normalising elevated LH levels in PCOS patients, in doses similar to the ones previously shown to prevent a premature LH rise during ovarian hyperstimulation for in vitro fertilization (IVF). In addition, the transient suppression of elevated endogenous LH levels per se does not re-establish normal follicle development in PCOS. However, follicle development may be insufficiently supported by the accompanied subtle suppression of endogenous FSH. Similarly, a transient decline in E2 levels does not effectively restore normal pituitary ovarian feedback. Moreover, these results support the contention of a limited role of LH in the pathogenesis of PCOS.

Use of antagonists in ovarian stimulation protocols

Gonadotrophin-releasing hormone (GnRH) antagonists have been introduced in IVF to prevent premature LH surge. They bind competitively to pituitary receptors and prevent endogenous GnRH from exerting any stimulus on pituitary cells, avoiding the initial 'flare-up' effect and decreasing gonadotrophin secretion within a few hours. Pituitary reserve and gonadotrophin synthesis are not affected; therefore, the recovery of pituitary function is rapid. Two different regimes have been described. The multiple-dose protocol involves the administration of 0.25 mg cetrorelix (or ganirelix) daily from day 6–7 of stimulation, or when the leading follicle is 14–15 mm, until human chorionic gonadotrophin (HCG) administration. The single-dose protocol involves the single administration of 3 mg cetrorelix on day 7–8 of stimulation. Both antagonists with either regimen seem to be equally effective in the prevention of the LH surge. Compared with a long luteal agonist protocol, the treatment is shorter and requires a smaller amount of gonadotrophins. Pregnancy rate seems to be lower, but a decrease in the incidence of severe ovarian hyperstimulation syndrome (OHSS) is reported by several studies. A promising aspect of antagonists may be the possibility of making treatment less aggressive. Finally, in antagonist cycles, ovulation triggering is possible by GnRH agonists, avoiding the deleterious effect of HCG and thus preventing OHSS.

Recombinant gonadotrophin-based, ovarian hyperstimulation syndrome-free stimulation of the high responder: suggested protocol for further research

Ovarian stimulation of the high responder remains controversial. The narrow margin between a too low gonadotrophin dose (and abnormal oestradiol rise) and excessive stimulation (risk of OHSS) is a challenging situation. This study describes an OHSS-free protocol, based on the use of recombinant gonadotrophins for stimulation and gonadotrophin-releasing hormone (GnRH) antagonist to prevent premature LH surge. In six patients with a previous history of excessive response, stimulation was started on day 3 of cycle with recombinant FSH. When follicular diameter reached 13−14 mm, a daily injection of GnRH antagonist was added, together with a daily dose of 75 IU of recombinant LH. When the leading follicles reached 17 mm in diameter, ovulation was triggered with a single dose of 0.2 mg triptorelin. Luteal support with vaginal oestradiol and progesterone was started on the day of oocyte retrieval. None of the patients developed clinically significant OHSS. Mean maximal oestradiol concentration was 23,209 pmol/l, and mean number of embryos obtained per patient was 20.5. Fresh embryo transfer resulted in one ongoing pregnancy and two chemical pregnancies. Thaw cycles have resulted so far in two additional ongoing pregnancies. This protocol removes the risk of OHSS and has a good clinical outcome, and therefore merits further research.

Optimizing GnRH antagonist administration: meta-analysis of fixed versus flexible protocol

A meta-analysis was conducted to investigate whether flexible gonadotrophin-releasing hormone (GnRH) antagonist administration according to follicular size would be more beneficial than starting on a fixed day. Only randomized controlled trials were included after a comprehensive search strategy. The data were combined for meta-analysis with RevMan software. Eleven trials were identified, but only four randomized controlled trials met the inclusion criteria. There was no statistically significant difference in pregnancy rate per woman randomized, although there was a trend towards a higher pregnancy rate with the fixed protocol, especially with delayed administration beyond day 8 [odds ratio (OR) 0.7, 95% confidence interval (CI) 0.45−1.1]. There was no premature LH surge in any participant in either protocol. However, there was a statistically significant reduction both in number of antagonist ampoules (OR −1.2 95%, CI −1.26 to −1.15) and amount of gonadotrophin (OR 95.5 IU, 95% CI 74.8−116.1) used in the flexible protocol. In conclusion, there was no statistically significant difference in pregnancy rate between flexible and fixed protocols. There was a statistically significant reduction in the amount of recombinant FSH with the flexible protocol.

New protocol for commencing the GnRH antagonist in assisted conception treatment cycles: elimination of the premature LH surge with similar pregnancy rates

GnRH antagonists have been used with increasing frequency in assisted reproduction treatments over the past few years and have been associated with quicker and more profound LH suppression and shorter treatment cycles than conventional GnRH agonists. Usually, these are commenced on day 6 of FSH stimulation without allowing for patient variation in response to treatment. The study was aimed at individualising this protocol to the patients' ovarian response. The control group included 215 treatment cycles where the GnRH antagonist was commenced on day 6 of FSH stimulation. A new individualised protocol was formulated, applied to practice and 172 treatment cycles following that were analysed. The study group had no premature LH surges (LH > 10 iu x mL(-1)) compared to the control group who had a rate of 4.1%. There was also a higher fertilisation and clinical pregnancy rate in the study group (P = 0.06). It is concluded that the new individualised GnRH antagonist protocol eliminates premature LH surges in assisted conception treatment cycles and may improve clinical pregnancy rates compared to the conventional protocol of "day 6 commencement".

Effective prevention of premature LH surges by the GnRH antagonist ganirelix acetate during controlled stimulation for intra-uterine insemination (IUI)

To establish the efficacy of ganirelix acetate to prevent premature LH rises and luteinization in women undergoing controlled ovarian stimulation for IUI. A multi-center, double-blind, placebo-controlled, randomized trial. Women were between 18 and 39 years of age; had regular menstrual cycles and were treated for unexplained infertility or mild male factor. After screening and inclusion in the trial, 104 patients were randomized to the ganirelix group and 100 patients were randomized to the placebo group. Stimulation was started on cycle day 2 or 3 and the starting dose of recFSH (Follistim®/Puregon® Pen) was decided by the investigator. Treatment with ganirelix (ganirelix acetate, NV Organon, 0.25 mg/day) or placebo was started as soon as one or more follicles ≥ 14 mm were seen on ultrasound. Ovulation for IUI was induced when at least one follicle ≥ 18 mm was observed, but only when no more than 3 follicles ≥ 14 mm were present. A premature LH rise was defined as an LH rise ≥ 10 IU/L during ganirelix/ placebo treatment. The difference in incidence between the two treatment groups was tested using an exact method for the risk difference. Treatment characteristics between the ganirelix group (N=103) and the placebo group (N=100) were comparable with a median recFSH stimulation of 8 days and a median recFSH dose of 538 IU and 584 IU, respectively. Of the subjects who started stimulation, IUI was cancelled for 10 women (9.7%) in the ganirelix group and in 14 women (14.0%) in the placebo group. The median duration of ganirelix treatment was 3 days. Prior to the administration of investigational drug, one subject in the ganirelix group and 6 subjects in the placebo group had a premature LH rise. During ganirelix treatment, 3 subjects (2.9%) had a premature LH rise, none of them with concomitant P rises (≥ 1 ng/mL). During placebo treatment, 22 subjects (22%) had a premature LH rise, and 13 out of those 22 subjects had concomitant rises of P. Three of these 13 subjects with premature luteinization spontaneous ovulated. None of subjects with premature LH and concomitant P rises became pregnant. The observed difference in frequencies of premature LH rises was significantly lower in the ganirelix group than in the placebo group for the Intent-To-Treat analysis and Per-Protocol analysis. In the ganirelix group 13 ongoing pregnancies and in the placebo group 12 ongoing pregnancies were established. In each group two set of twins were reported, other established pregancies were singletons. Treatment with daily 0.25 mg ganirelix acetate effectively prevented premature LH rises, premature luteinization and spontaneous ovulation in subjects undergoing controlled ovarian stimulation for IUI.

Prospective, randomized, controlled, multicenter clinical trial comparing cetrorelix acetate (CET) and ganirelix acetate (GAN) in a flexible protocol for the prevention of premature leutinizing hormone (LH) surge in ART − interim results

This study evaluates the comparative safety and non-inferiority of single dose cetrorelix acetate 3 mg to daily ganirelix acetate 0.25 mg in the inhibition of premature LH surge (LH <10 IU/L on day of human chorionic gonadotropin[hCG]) in women undergoing cycle programmed ovarian stimulation prior to ART. Phase IV, randomized (1:1), open-label, multicenter study in premenopausal infertile women between the ages of 18 and 39 years. Interim analysis of data from the first 90 patients treated (half of planned enrollment). Oral contraceptive pill (OCP) dosing began at menses onset. Follitropin alfa multi-dose (r-hFSH) 225 IU therapy began 5 days after last OCP and could be adjusted (75–450 IU) starting on stimulation day 6. A single dose of CET 3 mg sc or daily doses of GAN 0.25 mg sc were administered when the lead follicle reached =14 mm. Human menopausal gonadotropin (hMG) 75 IU was administered daily starting the day of antagonist administration. If hCG administration criteria were not met 4 days after receiving CET 3 mg, daily CET 0.25 mg was started. Lyophilized recombinant-hCG 250 mcg sc was administered when the patient had at least 1 follicle =18 mm, at least 2 other follicles =16 mm, an acceptable serum estradiol level, and no criterion for discontinuation. IVF or ICSI was performed, and vaginal micronized progesterone 8% administered for luteal phase support. To examine differences in treatment effects for continuous variables analysis of variance models for the ranked data were used. Most women in the CET group (71.1%) received only a single CET 3 mg dose. Of those few patients requiring supplemental CET 0.25 mg, 85% needed only 1 additional dose. Pregnancies (beta-hCG >10 IU/L, clinical pregnancy not available) were reported in 53 of 90 patients (59%), with no statistically significant difference between treatment groups. No difference in mild or moderate OHSS was seen between groups; 1 severe case occurred in the GAN group resulting in hospitalization. Median (min, max); mean ± standard deviation; NS: not significant Both GnRH antagonists delivered comparable results in preventing LH surges when used in an OCP programmed, flexible protocol. A single sc injection of CET 3 mg resulted in fewer injections compared to the GAN protocol.

Optimizing GnRH antagonist administration: A meta-analaysis of fixed vs flexible protocol

The most commonly used method for administration of the antagonist is on a daily dose of 0.25 mg starting on a fixed day (day 6 of gonadotrophin stimulation). As there are individual variations in patient response to ovarian stimulation, then a starting GnRH antagonist according to follicular size (flexible protocol) could be of value. The aim is to investigate whether flexible GnRH antagonist administration according to follicular size would be more beneficial than starting it in a fixed day. Meta-analysis of randomized controlled trials A comprehensive search strategy was applied including searching Cochrane Menstrual Disorders and Subfertility Review Group specialized register, MEDLINE and EMBASE databases, Hand searching the reference lists of included studies, review and relevant textbooks and abstracts of major international meetings. Only randomised controlled trials in which subfertile couples undergoing ovulation induction using GnRH antagonist as part of an assisted reproductive cycle were included. The data combined for meta-analysis with RevMan software (using the Mantel-Haenszel method). Outcomes: Primary outcomes included pregnancy rate (per woman or per couple) and incidence of premature LH surge. Secondary outcomes included number of oocytes retrieved, amount of antagonist ampoules used, amount of gonadotrophins needed Seven trials were identified (Ludwig et al, 2001, Mansour et al, 2002, Othman et al, 2003, Klipesten et al, 2003, Mochtaret al, 2003 and Escudero et al, 2004.) Only three RCT met out inclusion criteria (Ludwig et al, 2001, Mochtar et al, 2003 and Escudero et al, 2004) enrolling 373 participants. There was no statistically significant difference in pregnancy rate per woman randomized O.R 0.7 (95% CI 0.45–1.1). There was no premature LH surge in any participants in both protocols. However, there was statistically significant reduction both in number of antagonist ampoules and amount of gonadotrophins used in the flexible protocol (O.R -1.2 95% CI -1.26–-1.15). There was a trend to an increase in the number of oocytes retrieved with the flexible protocol (OR 1.28 95% CI 0.9–1.6). The flexible protocol yields similar pregnancy rate as the fixed protocol but is more cost effective. However, further studies with large sample size and adequate power are needed.

The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest.

This review exposes the follicular abnormalities responsible for anovulation in polycystic ovary syndrome (PCOS). The putative pathophysiological explanations involve the principal intra- and extra-ovarian regulators which intervene during normal folliculogenesis to control the initial recruitment and growth and then the cyclic recruitment. We propose the hypothesis that the follicular problem in PCOS is 2-fold, but with the two abnormalities being linked. First, the intra-ovarian hyperandrogenism may promote early follicular growth, leading to a 2-5 mm follicle excess. Second, the ensuing excessive number of selectable follicles would inhibit the selection process, presumably through follicle-follicle interaction involving granulosa cell (GC) products such as the anti-Müllerian hormone (AMH). These factors would induce a reversible refractoriness to the FSH-induced differentiation of GC. This explanation challenges but does not exclude other hypotheses about the follicular arrest, such as the premature LH action on the GC of selectable follicles. Hyperinsulinism or insulin resistance would act as a second hit, worsening the follicular arrest either through amplification of the intra-ovarian hyperandrogenism or through dysregulation of the GC. The loss of cyclic rhythm would prevent the inter-cycle elevation of FSH, thus perpetuating the impairment of the ovulation process.

207OVARIAN STIMULATION, TRANSVAGINAL, ULTRASOUND-GUIDED OOCYTE RETRIEVAL, ICSI AND BLASTOCYST PRODUCTION IN SEQUENTIAL MEDIA IN THE WESTERN LOWLAND GORILLA (GORILLA GORILLA GORILLA)

Two young (ages: 15 and 16 yr;; studbook # 947 and # 939, respectively) parous female gorillas were initially primed with daily oral monophasic estrogen/progesterone treatment (Ovcon 35: Bristol-Myers Squibb Co., Princeton, NJ, USA) for 3 mo to synchronize their menstrual cycles. After withdrawing treatment, urine was tested daily for occult blood (Hemastix;; Baxter Healthcare Corp., Deerfield, IL, USA). On days 3–10 following the onset of menses (Day 1), ovarian activity was stimulated with 225 IU human FSH im (Repronex;; Ferring Pharmaceuticals, New South Wales, Australia). Then on Days 6–8 this treatment was combined with 25mg GnRH antagonist im (Antagon;; Organon, West Orange, NJ, USA) to prevent premature endogenous LH release. Final oocyte maturation was stimulated 36h after the last FSH/GnRH treatment with 10,000IU hCG im (Profasi;; Serono Lab., Hingham/Rockland, MA, USA) and oocyte retrieval was performed 36h post-hCG administration in sternal recumbency (knee-chest) using a 3–6mHz probe, 17-ga needles and 87mmHg (VMAR-5000 Regulated Vacuum Pump;; Cook Veterinary Products). Both gorillas displayed a thickened endometrium, and approximately 6 (# 947) to 10 (# 939) maturing follicles (10–15mm) were detected in each animal. In female # 947, one oocyte was collected but peritoneal fluid and pathology (hydrosalpinx) were also diagnosed and the right ovary showed no follicular development. A total of 3 oocytes were recovered in highly viscous follicular fluid containing massive amounts of cumulus cells. They were transported in a HEPES-buffered transport medium in a portable incubator (CryoLogic, Mulgrave, Victoria, Australia) at 37°C by airline immediately from Brownsville to Dallas, TX, USA, and within 6-h post-retrieval were fertilized by ICSI using cryopreserved sperm collected by rectal probe electrostimulation (age: est. 40yr ; studbook # 268). The fertilized oocytes were cultured in Gardner’s Sequential Medium at 37°C in 6% CO2 all three cleaved and developed to blastocysts by 115h post-ICSI. One high-quality expanding blastocyst was transported back to Brownsville, TX, and transferred transcervically into the oocyte donor (studbook # 939), and two fair-quality blastocysts were transported overnight to Omaha, NE, and transferred into a synchronized gorilla recipient (age: 29yr; studbook # 543/91). Weekly urine samples from the two embryo transfer recipients are being tested for pregnancy diagnosis using OvuQuick test strips (Quidel, San Diego, CA, USA). Acknowledgments: This research was supported in part by the Morris Animal Foundation (Ruth Morris Keesling Animal Health Study).

Comparative efficacy and safety of cetrorelix with or without mid-cycle recombinant LH and leuprolide acetate for inhibition of premature LH surges in assisted reproduction

An open label, randomized, multi-centre study was performed to compare cetrorelix and leuprolide acetate for prevention of premature LH surge and to assess whether patients treated with cetrorelix benefit from addition of recombinant human (r-h)LH. Normo-ovulatory women ( n = 74) undergoing ovarian stimulation prior to intracytoplasmic sperm injection were treated with leuprolide acetate ( n = 25) before ovarian stimulation with recombinant human FSH (r-hFSH) or with cetrorelix 3 mg on stimulation day 7 (with ( n = 25) or without ( n = 24) r-hLH 150 IU on days 7–10). The main outcome measures were the number of metaphase II (MII) oocytes retrieved; secondary efficacy end-points; adverse events (AE) and other safety measures. There were no significant differences between groups for MII oocytes retrieved, duration of stimulation, total r-hFSH dose and pregnancy rates. The group treated with cetrorelix alone had a significantly lower concentration of oestradiol per follicle compared with the other groups. The majority of AE were mild to moderate in severity. Cetrorelix and leuprolide acetate appear to have comparable efficacy and safety, although cetrorelix has the advantage of typically requiring only one injection.

Increasing the dose of human menopausal gonadotrophins on day of GnRH antagonist administration: randomized controlled trial

A significantly lower pregnancy rate following the gonadotrophin-releasing hormone (GnRH) antagonist protocol as compared with the long GnRH agonist protocol has been reported. The objective of this study was to investigate whether increasing the dose of gonadotrophins on the day of antagonist administration would increase the pregnancy rate. This study is an open labelled, randomized controlled trial and allocation was done using sealed envelopes. One hundred and fifty-one subfertile couples undergoing IVF/intracytoplasmic sperm injection (ICSI) cycles were included in the study. Ovarian stimulation was started on day 3 of the cycle, using 150–300 IU human menopausal gonadotrophin (HMG)/day. From day 8 onward, daily vaginal ultrasound and daily urinary LH estimation were performed. If a premature LH rise was detected, the cycle was cancelled. The antagonist (0.25 mg daily) was started when the leading follicle reached 15 mm in mean diameter and LH testing in urine was negative up to and including the day of human chorionic gonadotrophin (HCG) injection. Patients were randomized on the day of starting the antagonist into two groups: group A, 72 patients with no increase in HMG dose, and group B, 79 patients in whom the dose of HMG was increased by 75 IU on the day of antagonist administration, and continued till the day of HCG administration. The results showed no statistically significant difference between the groups regarding number of oocytes retrieved, embryos obtained, implantation rate, clinical pregnancy rate and multiple pregnancy rate. It was concluded that there is no clinical evidence for increasing the dose of HMG on the day of antagonist administration.

Réhabilitation du protocole clomiphène–gonadotrophines en FIV par l’utilisation d’un antagoniste du GnRH

Objective. – To assess the ability of GnRH antagonists to prevent LH surges during superovulation for IVF in classical stimulation protocols with clomiphene and gonadotropins. Patients and methods. – Fifty-eight patients were treated with clomiphene (100 mg daily for 5 days starting on cycle day 2) and gonadotropins (225 UI HMG on cycle days 5, 7 and 9), with monitoring starting on cycle day 10. Cetrorelix, 0.25 mg, was administered daily when dominant follicle diameter reached 18 mm and/or plasma estradiol levels 800 pg/ml. Results. – No premature LH surge was observed during the 48 stimulation cycles completed. The pregnancy rate was 20.8% per punction and 25.6% per transfer, and there was no clinical ovarian hyperstimulation syndrome in these series. Conclusions. – Cetrorelix, 0.25 mg, optimizes the classical stimulation with clomiphene and gonadotropins by preventing LH surges; the so-completed protocol yields acceptable pregnancy rates with lower hormone quantities and reduced risks of ovarian hyperstimulation, and becomes a convenient choice when “softer” treatments for IVF are considered.

Progesterone antagonists and progesterone receptor modulators: an overview

Since the original description of the structure of the antiprogestin, mifepristone, was published, numerous related compounds have been synthesized which may function as progesterone antagonists (PAs) or progesterone receptor modulators (PRMs). The latter are mixed agonists–antagonists. Both PAs and PRMs have therapeutic applications in female health care. Mifepristone is predominantly a PA and displays only minimum agonist activity in certain systems. Together with a prostaglandin, mifepristone can terminate pregnancies of less than 9 weeks duration, and it may also be used at later gestational ages. Mifepristone causes expulsion of the uterine contents following intrauterine fetal death. A mifepristone–prostaglandin combination has been shown to be very effective treatment in women with menses delay of 11 days or less. Many PAs and PRMs display antiproliferative effects in the endometrium. Serum estradiol levels however remain in the early to mid-follicular phase range. For this reason, they have application in the treatment of endometriosis and myoma without being associated with bone loss and hypoestrogenism. PRMs may also find application in the treatment of dysfunctional bleeding as well as an adjunct to estrogens in hormone replacement therapy in postmenopausal women. Many PAs have contraceptive potential by suppressing follicular development and blocking the LH surge. Low doses may also be potential contraceptives by retarding endometrial maturation without affecting ovulation or inducing bleeding. Mifepristone is an excellent agent for use as an emergency “postcoital” contraceptive. PAs may also be useful in IVF programs to prevent a premature LH surge and to delay the emergence of the implantation window. In addition to their use in women’s health care, mifepristone and several other PAs are potent antiglucocorticoid agents and may be used to treat ACTH-independent Cushing’s syndrome. They may also be used in the treatment of tumors containing steroid receptors and in other situations which require suppression of the ACTH-cortisol axis.

Comparison of GnRH antagonist cycles with and without oral contraceptive pill pretreatment in poor responders

Objective: One of the most difficult challenges in the practice of assisted reproductive technologies is the management of poor responders. Previous studies examining the use of oral contraceptive pills (OCPs) with in vitro fertilization (IVF) cycles have reported positive benefits: a decrease in time needed for suppression, decrease in the amount of gonadotropins needed for stimulation, elimination of premature LH surges, and possible improvement in pregnancy rates. However, these studies examining the effects of OCPs have all been performed with GnRH agonists using either a long or flare protocol. In the present study, we seek to compare IVF outcomes in poor responders undergoing GnRH antagonist cycles with and without the use of oral contraceptive pills before ovarian stimulation. Design: Retrospective study of patients undergoing IVF August 2001–August 2002. Materials and Methods: We evaluated records from 194 cycles in which GnRH antagonists were used in patients identified as poor responders. Medical charts were evaluated for patient characteristics, cycle types, as well as pregnancy outcomes. Use of OCP pretreatment was based on scheduling availability or patient preference. Results: During the study period, 138 patients underwent 194 antagonist cycles, both with oral contraceptive pills (n=146) and without oral contraceptive pills (n=48). The two groups did not differ in age, gravity, parity, day 3 FSH, number of previous cycles or cause of infertility. Patients that used oral contraceptive pills required more total ampules of gonadotropins (5888 v. 4410 IU, p=0.009). The two groups of patients did not differ in number of follicles produced, oocytes retrieved or number of embryos. The pregnancy rate did not differ between the two groups. Tabled 1 Conclusion: In this patient population of poor responders, pregnancy outcomes were the same whether or not OCP pretreatment was used. Since there is no difference in pregnancy outcome, the use of OCP pretreatment may be determined by the need for scheduling flexibility. However, patients that use OCPs may require a significantly higher dose of gonadotropins for ovarian stimulation.

Comparison of daily ganirelix administration to a long protocol agonist for controlled ovarian hyperstimulation in oocyte donors: The results of a prospective randomized controlled trial

Objective: GnRH antagonists have demonstrated their effectiveness in ART by suppressing the endogenous LH surge. Some studies have suggested a trend toward lower implantation and pregnancy rates, albeit without achieving statistical significance. Researchers have postulated that there may be the potential for blockage of ovarian, endometrial, and embryonic GnRH receptors. This study compares the use of GnRH antagonists with mid-luteal depot GnRH agonists in donor oocyte cycles. Design: Prospective randomized controlled clinical trial. Materials and Methods: 29 oocyte donors were randomized to two groups. Group A had 17 donors that received 3.75 mg depot leuprolide acetate in the mid-luteal phase. Group B had 12 donors that received ganirelix 0.25 mg daily, starting when at least 2 follicles reached 12–14 mm diameter. All donors received OCPs the month prior to stimulation. All donors were started on 3–5 amps of rFSH, and 1 amp of hMG if their baseline LH were <0.5 mIU/mL. An additional amp of hMG was given daily upon starting ganirelix. HCG 10,000 U IM was given when at least two follicles reached 18–20 mm diameter. Each donor donated oocytes to 2–3 recipients. Recipients received 1.875 mg depot leuprolide acetate in the late luteal phase prior to endometrial preparation. Oral estradiol 6 mg/d and estradiol patch 0.1 mg/d were given until transfer. Progesterone in oil was given IM starting 3 days before transfer. ICSI was done on all mature oocytes. All transfers were done 3 days after ICSI. Results: Group A had 17 donors and 36 recipients. Group B had 12 donors and 26 recipients. Donor age, recipient age, and donor BMI were similar in both groups. There were no premature LH surges and no cancellations in either group. Peak E2, LH, and P4 levels were similar in both groups. The number of oocytes retrieved, mature oocytes, fertilized oocytes, embryos transferred, implantation rates, and clinical pregnancy rates were not statistically different between groups. (Table 1) Tabled 1 Conclusion: The GnRH antagonist ganirelix can achieve similar clinical efficacy compared to a long protocol with a depot GnRH agonist in donor oocyte cycles, suggesting no effect on embryo quality. Dissociating the GnRH antagonist from the recipient endometrium may account for the lack of a trend toward lower implantation and pregnancy rates in this study.

High dose Follicle Stimulating Hormone (FSH) and Human Menopausal Gonadotropin (HMG) combined with a single dose of Cetrorelix: can it normalize the response of the poor responder?

Objective: Numerous protocols have been proposed for poor responders undergoing IVF. Several investigators have suggested the use of GnRH antagonists in this patient population. While previous studies have confirmed the efficacy of a single dose of the gonadotropin-releasing hormone (GnRH) antagonist, Cetrorelix, in preventing premature LH surges, the few available data have not shown any benefits with regard to pregnancy rates. The purpose of this study was to compare IVF outcomes in low responders using single dose Cetrorelix with patients using a GnRH agonist long protocol.

High dose of rec-LH overcomes the deleterious effect of high dose GnRH antagonist on embryonic implantation

High dose of rec-LH overcomes the deleterious effect of high dose GnRH antagonist on embryonic implantation

Actions of GnRH antagonists on IGF-II, IGF-binding protein-2 and pregnancy-associated plasma protein-A in human granulosa-lutein cells.

Recently, GnRH antagonists (GnRHants) have been introduced for the prevention of premature LH surges during controlled ovarian hyperstimulation (COH). Here we investigated whether the GnRHants cetrorelix and ganirelix exert effects on the human ovarian IGF system. Since controversy exists on the action of GnRH agonists in the human ovary, we also tested the effect of triptorelin on IGF-II, IGF-binding protein-2 (IGFBP-2) and pregnancy-associated plasma protein-A (PAPP-A) in cultured human granulosa-lutein cells. In vitro cell culture study in a research laboratory of a university hospital. Cells were obtained from patients treated with different protocols of COH. In addition to gonadotropins they received triptorelin or cetrorelix. Cells were treated with triptorelin, cetrorelix or ganirelix, 1 nmol/l each, for 48 h. IGF-II, IGFBP-2 and PAPP-A were measured by RIA and enzyme immunoassay respectively. GnRHants and triptorelin did not affect IGF-II, IGFBP-2 or PAPP-A. We conclude that GnRHants do not exert any significant effects on the IGF system of granulosa-lutein cells and therefore their introduction into protocols of COH is unlikely to impair ovarian function.