Ovarian stimulation by clomiphene citrate and hMG in combination with cetrorelix acetate for ICSI cycles

BACKGROUND: The introduction of GnRH antagonists such as cetrorelix acetate has made possible the simplification of ovarian stimulation. However, the most effective protocol for their administration has not yet been clearly defined. METHODS: Forty women with male-factor infertility undergoing 40 ICSI cycles were included in the study. Clomiphene citrate at 100 mg a day was given from cycle day 3 through day 7. hMG at 150 IU was given on cycle days 4, 6 and 8, and was adjusted from day 9 according to the follicular and hormone responses. Cetrorelix acetate at 2.5 mg was administered when the leading follicle reached 14 mm. The remaining 0.5 mg was divided into two 0.25 mg injections for possible later use. Serum FSH, LH, estradiol and progesterone levels were measured daily from the day of cetrorelix acetate injection until hCG was given. RESULTS: Serum LH level was suppressed effectively for 4 days. Four patients (10%) needed one or two additional injections of 0.25 mg cetrorelix acetate. No premature LH surge was detected in any of the women treated. Sixteen women became pregnant (40%), of which 14 pregnancies (35%) were ongoing at the time of writing. CONCLUSIONS: This study demonstrates that this new protocol is feasible for couples with male-factor infertility undergoing ICSI.     

Ovarian stimulation with HMG: results of a prospective randomized phase III European study comparing the luteinizing hormone-releasing hormone (LHRH)-antagonist cetrorelix and the LHRH-agonist buserelin. European Cetrorelix Study Group

In this prospective and randomized study, 188 patients received the luteinizing hormone-releasing hormone (LHRH) antagonist cetrorelix, and 85 patients the LHRH agonist buserelin to prevent endogenous luteinizing hormone (LH) surges during ovarian stimulation in in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. Ultimately, 181 patients (96.3%) in the cetrorelix group, and 77 (90.6%) in the buserelin group, reached the day of the human chorionic gonadotrophin (HCG) injection. The mean number of human menopausal gonadotrophin (HMG) ampoules administered and the mean number of stimulation days with HMG were significantly less in the cetrorelix group than in the buserelin group (P < 0.01). A rise in LH and progesterone concentrations was observed in three of the 188 patients (1.6%) who received cetrorelix. On the day of the HCG administration, more follicles of a small diameter (11-14 mm) were observed in the buserelin group than in the cetrorelix group (P = 0. 02) and the mean serum oestradiol concentration was significantly higher in patients who received buserelin than in those who received cetrorelix (P < 0.01). Similar results were observed in fertilization, cleavage and pregnancy rates in the two groups. In conclusion, the use of the LHRH antagonists might be considered more advantageous because of the short-term application needed to inhibit gonadotrophin secretion, so allowing a reduction in the treatment time in a clinically significant manner.     

Comparison of agonistic flare-up-protocol and antagonistic multiple dose protocol in ovarian stimulation of poor responders: results of a prospective randomized trial

The management of poor responders in IVF has always been a big problem. The ideal approach has yet to be formulated. In this study we aim to compare two alternative stimulation protocols. A total of 48 poor responder patients described from previous cycles were included and grouped into two: group I consisted of 24 patients in 24 cycles in which leuprolide acetate (40 microg s.c. per day) was initiated on cycle day 2 followed by exogenous gonadotrophins on cycle day 3; group II consisted of 24 patients in 24 cycles in which ovarian stimulation included gonadotrophin-releasing hormone (GnRH) antagonist (cetrorelix, 0.25 mg daily during late follicular phase) administration. While only the oestradiol concentrations on the day of HCG were lower in group II compared with group I, the clinical pregnancy and implantation rates among groups did not show any significance. The impact of these two regimens in ovarian stimulation of poor responders seem to be same and to establish these results further randomized studies with larger sample sizes are required.     

Use of cetrorelix in combination with clomiphene citrate and gonadotrophins: a suitable approach to 'friendly IVF'?

BACKGROUND: With the recently introduced GnRH antagonists, soft stimulation protocols on the basis of clomiphene pretreatment should be possible as the pituitary remains fully sensitive at the beginning of the cycle. METHODS: A prospective trial was carried out on 107 patients undergoing IVF treatment using the multiple dose GnRH antagonist protocol (cetrorelix), clomiphene citrate, and either HMG (n = 54) or recombinant FSH (rFSH) (n = 53). Different stimulation protocols were used to find the most appropriate one for clinical application. RESULTS: Both treatment groups, HMG and rFSH, yielded comparable results concerning gonadotrophin dose, stimulation days and pregnancy rate. A mean number of 6.34 +/- 4.4 metaphase II oocytes was retrieved and a mean number of 2.45 +/- 0.65 embryos was transferred. However, the overall rate of premature LH surges was 21.5% (defined as measurement of LH >10 IU/l and progesterone >1 ng/ml) which is unacceptable for clinical practice. CONCLUSIONS: Increasing the daily cetrorelix dose from 0.25 to 0.5 mg might decrease the number of premature LH surges. Soft stimulation protocols with clomiphene should be used cautiously.     

Ovarian stimulation by concomitant administration of cetrorelix acetate and HMG following Diane-35 pre-treatment for patients with polycystic ovary syndrome: a prospective randomized study

BACKGROUND: Patients with polycystic ovary syndrome (PCOS) may need a longer period of pituitary downregulation to suppress the elevated serum LH and androgen levels effectively during IVF treatment using the GnRH agonist long protocol. We proposed a stimulation protocol incorporating Diane-35 and GnRH antagonist (Diane/cetrorelix protocol) and compared it with the GnRH agonist long protocol for PCOS patients. METHODS: Part I of the study was an observational pilot study to evaluate the hormonal change as a result of the Diane/cetrorelix protocol (n = 26). Part II of the study was a prospective randomized study comparing the Diane/cetrorelix protocol (n = 25) and the GnRH agonist long protocol (n = 24). In the Diane/cetrorelix protocol, patients were pre-treated with three cycles of Diane-35, followed by 0.25 mg of cetrorelix on cycle day 3. From day 4, cetrorelix and gonadotrophin were administered concomitantly until the day of HCG injection. RESULTS: Serum LH, estradiol and testosterone levels were suppressed comparably in both protocols at the start of gonadotrophin administration. Serum LH was suppressed at constant levels without a premature LH surge in the Diane/cetrorelix protocol. The clinical results for both protocols were comparable, with significantly fewer days of injection, lower amounts of gonadotrophin used and lower estradiol levels on the day of HCG injection following the Diane/cetrorelix protocol. Furthermore, there was no significant difference in clinical pregnancy outcome between the two stimulation protocols. CONCLUSIONS: The Diane/cetrorelix protocol has a similar pregnancy outcome to the GnRH agonist long protocol for women with PCOS undergoing IVF treatment.     

Tailoring the GnRH antagonist cetrorelix acetate to individual patients' needs in ovarian stimulation for IVF: results of a prospective,randomized study

INTRODUCTION: This study was performed to evaluate whether a tailored approach to the administration of the GnRH antagonist cetrorelix acetate according to follicular size leads to a reduction in the amount of Cetrotide vials used and/or an increased number of monitoring visits. METHODS: Sixty patients were prospectively randomized (using sealed envelopes) to receive either the fixed multiple dose antagonist protocol starting on day 6 of stimulation (group 1), or an individualized protocol with the time of antagonist start according to follicle size (14 mm, group 2), or an individualized single dose protocol (group 3). Recombinant human (rh)FSH was used. The primary endpoints were the number of Cetrotide vials and number of monitoring visits. Statistical power for the parameter Cetrotide vials was 80%. RESULTS: Patients in group 1 needed significantly more Cetrotide vials (6.81 +/- 1.61) than patients of group 2 (4.59 +/- 1.65; P < 0.01). The number of monitoring visits was similar between the three groups. Surprisingly, the number of retrieved oocytes was significantly higher in the individualized groups as compared with group 1. Despite a significantly lower total amount of rhFSH used, estradiol levels were significantly higher in group 2 as compared with group 1. CONCLUSION: Tailoring of GnRH antagonist protocols leads to an optimization of ovarian stimulation with more oocytes retrieved despite less rhFSH used, and the same number of monitoring visits.     

An unusual steroid-producing ovarian tumour: case report

The rapid onset of virilization in a post-menopausal woman is usually the result of androgen secretion from a tumour of adrenal or ovarian origin. Androgen secreting neoplasms of the ovary are rare and usually show autonomous secretion. Rarely, these may be driven by the high levels of gonadotrophins seen in the post-menopausal state. We describe the case of a 67-year-old woman with high serum testosterone and estradiol in association with the high gonadotrophin levels usually associated with the post-menopausal state. All hormonal parameters showed a significant suppression over 12 h with administration of the GnRH antagonist, cetrorelix. This observation implies that excess hormone synthesis was of ovarian origin and was gonadotrophin driven. Localization of the tumour was not possible by conventional ultrasound or computerized tomography scanning, but was achieved by venous sampling. Complete cure was achieved by total abdominal hysterectomy and bilateral salpingo-oophorectomy, with restoration of the endocrine profile to that expected for a post-menopausal woman. Rapidly acting GnRH antagonists, such as cetrorelix, offer a safe and useful diagnostic and therapeutic option in the management of ovarian steroid-secreting tumours, which show gonadotrophin dependency.     

Subtle progesterone rise in the single-dose gonadotropin-releasing hormone antagonist (cetrorelix) stimulation protocol in patients undergoing in vitro fertilization or intracytoplasmic sperm injection cycles

A subtle rise in serum progesterone during the late follicular phase in patients undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycles is a frequent event that can decrease implantation and pregnancy rates in controlled ovarian hyperstimulation (COH) protocols that use a gonadotropin-releasing hormone (GnRH) antagonist. The aim of the present study was to evaluate the prevalence and effect of the subtle progesterone rise during COH with single-dose GnRH antagonist in combination with clomiphene citrate (CC) and human menopausal gonadotropins (hMG) in IVF or ICSI cycles. Ninety-five women undergoing COH with CC, hMG and a single 2.5 mg dose of the GnRH antagonist, cetrorelix, were enrolled in the study. Patients were grouped according to serum progesterone level on the day of human chorionic gonadotropin (hCG) administration (P < 1.2 ng/ml or P ≥ 1.2 ng/ml). The incidence of a subtle progesterone rise was 54.7% (52/95). The group with P ≥ 1.2 ng/ml had significantly higher serum levels of luteinizing hormone (p = 0.002) and estradiol (p < 0.001) on the day of hCG injection than the group with P < 1.2 ng/ml, and more oocytes were retrieved (p = 0.001). However, there was no significant difference in fertilization, clinical pregnancy or implantation rate between the two groups. In conclusion, a subtle progesterone rise during the late follicular phase is common but not associated with pregnancy outcome.     

Therapeutic potential of GnRH antagonists in the treatment of precocious puberty

Pituitary-gonadal axis activation depends upon pulsatile hypothalamic gonadotropin-releasing hormone (GnRH) secretion. This phenomenon has led to clinical use of GnRH agonists in the treatment of central precocious puberty. GnRH analogues contain substitutions of the native decapeptide. Depending upon the substitutions, the analogues have GnRH agonistic or antagonistic properties. The pharmacokinetics of GnRH agonists, the established treatment of precocious puberty, includes an initial ‘flare-up’ of the pituitary-gonadal axis, followed by a reduced luteinising hormone secretion by desensitisation of pituitary GnRH receptors. Antagonistic GnRH analogues act by competitive binding to the pituitary GnRH receptors, thereby preventing the action of endogenous GnRH – theoretically offering a more direct and dose-dependent treatment alternative. The antagonist available today in Germany is a concomitant in assisted reproduction with only 1 – 3 days duration. However, long-acting depot preparations of other GnRH antagonists are in primate-testing phase. Our animal tests indicate strong potential for the development and testing of long-acting depot preparations of GnRH antagonists in treating precocious puberty.