Use Of Cetrorelix Research Articles

Effect of the gonadotropin-releasing hormone antagonist cetrorelix on the prevention of chemotherapy-induced ovarian damage in women with hematological malignancy

Gonadotropin-releasing hormone (GnRH) agonists are the most commonly used pharmaceutical treatment for ovarian protection during chemotherapy [1,2]. A recent study showed that a combination of GnRH agonists and antagonists induced a long-lasting suppression of gonadotropins but did not completely prevent flare-up of follicle stimulating hormone [3]. The aim of the present study was to evaluate the use of cetrorelix, a GnRH antagonist, for prevention of ovarian damage during chemotherapy in patients with a hematologic malignancy, such as Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and acute leukemia (AL). The study included 24 women (mean age at diagnosis, 23.3± 6.4 years) who had been diagnosed with a hematologic malignancy (15 HL, 4 NHL, and 5 AL). All patients received chemotherapy with various cytotoxic agents, including cyclophosphamide, and 3 mg of cetrorelix subcutaneously every second day. Data were compared retrospectively with 31 women (mean age, 26.4±6.2 years) who had been diagnosed with a hematologic cancer (18 HL, 12 NHL, and 3 AL) and received the same chemotherapy, but without cetrorelix. The study was approved by the Institutional Review Board. Pb0.05 was considered significant at statistical analysis. Among the 23 evaluable women (1 died) who received cetrorelix, the incidence of secondary amenorrhea 6 months after cessation of treatment was significantly lower compared with the women who did not receive cetrorelix (4.3% vs 27.3%, P=0.036; Table 1). No significant differences were observed between the 2 groups in the mean serum levels of follicle-stimulating hormone, estradiol, and anti-Mullerian hormone after completion of chemotherapy (P>0.05; Table 1), suggesting a degree of ovarian damage despite cetrorelix administration.

Failure of the GnRH antagonist ganirelix to block the positive feedback effect of exogenous estrogen in normal women

This study investigated whether the GnRH antagonist ganirelix is able to block the positive-feedback effect of E2 in normal women. Ganirelix was unable to block the positive-feedback effect, suggesting that the clinical efficacy of GnRH antagonists in IVF cycles is determined by the hyperstimulation process.

GnRH antagonist, cetrorelix, for pituitary suppression in modern, patient-friendly assisted reproductive technology

Background: Gonadotropin-releasing hormone (GnRH) analogues are used routinely to prevent a premature luteinizing hormone (LH) surge in women undergoing assisted reproductive technology (ART) treatments. In contrast to GnRH agonists, antagonists produce rapid and reversible suppression of LH with no initial flare effect. Objective: To review the role of cetrorelix, the first GnRH antagonist approved for the prevention of premature LH surges during controlled ovarian stimulation in modern ART. Method: A review of published literature on cetrorelix. Results: Both multiple- and single-dose cetrorelix protocols were shown to be at least as effective as long GnRH agonist regimens for pituitary suppression in Phase II/III clinical trials. Furthermore, cetrorelix co-treatment resulted in similar live birth rates but a shorter duration of gonadotropin stimulation, a lower total gonadotropin dose requirement and lower incidence of ovarian hyperstimulation syndrome compared with long agonist regimens. A single-dose cetrorelix protocol further decreased the number of injections required. Preliminary studies have also produced promising data on the use of cetrorelix in modified ART protocols, such as frozen embryo transfer and donor oocyte recipient cycles. Conclusion: Cetrorelix offers a potential therapeutic alternative to GnRH agonists during controlled ovarian stimulation and has become an integral part of modern, patient-friendly reproductive medicine.

Cetrorelix in the treatment of female infertility and endometriosis

The use of cetrorelix within ovarian-stimulation protocols demonstrates several advantages compared with gonadotropin-releasing hormone (GnRH) agonist-containing protocols, which include, for example, significantly less time for analogue treatment and a reduction in the amount of gonadotropins needed. Furthermore, fewer side effects can be expected. There is no difference regarding endometrium quality and hormone profiles, and the results of assisted reproduction cycles are comparable. Cetrorelix also seems to be useful in the treatment of endometriosis which, in most cases, is an estrogen-dependent disease. Furthermore, fewer side effects occur with this agent (e.g., postmenopausal symptoms) and no estradiol add-back is needed. In the future, new nonpeptic GnRH antagonists are expected to be available for oral administration. Although they are still under investigation, these agents have the potential to improve patients’ comfort and compliance.

P-795: Effectiveness of using hMG-low dose hCG-GnRH antagonist protocol with unsuccessful hMG-GnRH antagonist protocol cases (full term pregnancies had not resulted) in-vitro fertilization (IVF) cycles

GnRH antagonist does not create flare-up effects such as are seen with GnRH agonist, and secretion of gonadotropin is immediately controllable. However, a decrease in the number or quality of oocytes extracted occurs as a result of the strong effects of GnRH antagonist in some cases. The purpose of our study was to consider what kind of results can be obtained by using hCG at 50 units from the day of GnRH antagonist use in cases that had not previously reached full term pregnancy using the hMG-GnRH antagonist protocol. Retrospective evaluation using the patient’s previous IVF stimulation attempts as a historical control. The subjects were 14 cases on whom IVF was carried out (28 cycles: 14 cycles with oral contraceptive pill-hMG-GnRH antagonist protocol and 14 cycles with oral contraceptive pill-hMG-low dose hCG-GnRH antagonist protocol). All the cases had been unsuccessful even though the antagonist protocol not using low dose hCG had been carried out (full term pregnancies had not resulted). Regarding the ovulation induction method, an oral contraceptive pill was used from day 3 of menstruation in the cycle prior to extracting the eggs. Ovarian stimulation was started from day 4 after completion of a course of oral contraceptive pills. In both antagonist protocols the type of ovulation induction drug was changed depending on the LH level just before beginning ovarian stimulation. When serum LH was more than 1.5mIU/ml, pure urinary FSH or recombinant FSH was used, and when serum LH was less than 1.5mIU/ml hMG (Humegon, Organon, Osaka) was used. Daily hypodermic injections of Cetrorelix 0.25 mg/day were started from the time the leading follicle reached 14 mm. The treatment regime was changed to hMG (Pergogreen:in a ratio of FSH and LH at one to one) from the day Cetrorelix was started. Urinary hCG at 50 units was used together with hMG from the day that use of Cetrorelix was started in the low dose hCG protocol. When the average diameter of the leading follicle reached 20 mm, the type of ovulation induction drug was changed to hCG at 10000 units. No statistical difference was noted between the two groups for the amount of hMG (no low dose hCG group 2680.4±1039.5 vs low dose hCG group 3235.7±1171.5). However, the mean number of oocytes retrieved was significantly higher in the low dose hCG group (no low dose hCG group 9.7±3.7 vs low dose hCG group 14.6±6.3, p<0.05). The fertilization rate was significantly higher in the low dose hCG group (no low dose hCG group 57.1% vs low dose hCG group 69.6%, p<0.05). The blastomere number on the day 3 was significantly higher in the low dose hCG group (no low dose hCG group 6.0±2.4 vs low dose hCG group 7.0±2.2, p<0.05). Moreover, the blastocyst formation rate was significantly higher in the low dose hCG group (no low dose hCG group 37.5% vs low dose hCG group 63.0%, p<0.05). No statistical difference was noted between the two groups for the clinical pregnancy rate (FHM) per ET (no low dose hCG group 7.7% vs low dose hCG group 33.3%). The results of this study suggest that increases in the number of oocytes extracted, the fertilization rate, the average number of day 3 blastomeres, and blastocyst formation rates can all be increased by using low dose hCG to control the overly strong effectiveness of GnRH antagonist in cases that had not reached full term pregnancy using the GnRH antagonist protocol.

Use of gonadotropin-releasing hormone antagonists to overcome the drawbacks of intrauterine insemination on weekends

To assess the usefulness of the GnRH antagonist cetrorelix to prevent LH surge and to avoid intrauterine insemination at weekends when a gynecologist on duty is not available and the ultrasound scan on Friday showed > 1 and < 3 follicles > or = 17 mm in diameter. Open-label, randomized, prospective study. Reproductive medicine unit in an acute care teaching hospital in Barcelona, Spain. Infertile patients undergoing controlled ovarian hyperstimulation (COH) and IUI. Treatment with recombinant FSH was started on day 3. In women assigned to the control group (n = 32), recombinant FSH was continued up to the day of hCG administration. In patients assigned to the GnRH antagonist group (n = 35), half of the dose of recombinant FSH was given for 2 more days in addition to cetrorelix (0.25 mg SC) until the day of hCG administration. Recombinant FSH doses, E(2) level on the day of hCG administration, number and diameter of follicles, endometrial thickness, and number of pregnancies. Only a case of premature ovulation occurred in the cetrorelix group. There were no significant differences between the study groups in the total mean number of follicles, follicles > 10 mm and < 17 mm, and follicles > or = 17 mm. The mean concentration of E2 on the day of hCG administration and the endometrial thickness were significantly higher in the cetrorelix group. Eleven pregnancies were achieved, 7 (20%) in the cetrorelix group (4 singleton, 3 twins) and 4 (12.5%) in controls (4 singleton). No case of ovarian hyperstimulation syndrome (OHSS) occurred. The use of cetrorelix to avoid IUI at weekends when the ultrasound scan on Friday shows > 1 and < 3 follicles > or = 17 mm is a useful alternative for medical centers in which a gynecologist on call is not available.

Luteinizing hormone-releasing hormone antagonist Cetrorelix regulates the expression of Gαs and Gαi protein subunits and adenylate cyclase activity in rat ovary, breast and pituitary

The mechanisms by which luteinizing hormone-releasing hormone (LH-RH) antagonists act on extra-pituitary tissues are poorly understood. In view of extensive use of Cetrorelix in gynecology and oncology, we investigated its effects on signal transduction pathways of G-protein coupled receptors and adenylate cyclase which are involved in a huge array of cellular events including normal and pathological cell proliferation. Thirty days after a single i.m. injection of 3 mg Cetrorelix pamoate depot to female rats, normal or ovariectomized, we evaluated the effects of this chronic treatment on the expression of alphas and alphai G-protein subunits in the ovary, breast and pituitary, as well as the adenylate cyclase response in vitro to LH-RH, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP). Varied patterns of response to Cetrorelix, depending on the gland and estrogenic status were observed. Western blot analysis showed a modest decrease of alphas and a modest increase of alphai G-protein subunit levels in ovary, a marked increase of alphas and alphai levels in breast, and a lack of effect on alphas/alphai levels in pituitary. In the ovary, adenylate cyclase activity was not changed by in vitro addition of LH-RH, but the responses to VIP and PACAP increased after Cetrorelix treatment. In the breast, chronic administration of the LH-RH antagonist decreased the adenylate cyclase response to PACAP, which returned to normal after ovariectomy. In the pituitary, Cetrorelix abolished the stimulatory effect of VIP upon adenylate cyclase activity. Thus, the LH-RH antagonist Cetrorelix exerted selective modifications at different steps of the G-protein coupled receptors/adenylate cyclase system of signal transduction in the rat ovary, breast and pituitary.

Safety aspects of gonadotrophin-releasing hormone antagonists in ovarian stimulation procedures: ovarian hyperstimulation syndrome and health of children born

The safety of ovarian stimulation procedures or the procedure of assisted reproduction in general can be estimated by various parameters. Two of the most important are the health of children born after the procedure and the incidence of ovarian hyperstimulation syndrome (OHSS). The latter is important because it is the most severe, potentially life-threatening complication of any stimulation procedure. The use of gonadotrophin-releasing hormone (GnRH) antagonists in ovarian stimulation protocols has had no impact on the health of children born. This was proven in 227 children born after the use of cetrorelix and in 73 children born after the use of ganirelix. To analyse the incidence of OHSS and the impact of GnRH antagonists on clinical pregnancy rates compared with the long protocol, a meta-analysis was done. This showed a reduction of OHSS with the use of cetrorelix. Furthermore, when compared with the long protocol, clinical and ongoing pregnancy rates were not significantly reduced with the use of cetrorelix. Taken together, the use of GnRH antagonists are safe with regard to children's health. The incidence of OHSS does not increase with ganirelix, and a reduction can be expected with cetrorelix.

Outcome of cryopreserved pronuclear oocytes obtained after ovarian stimulation with either HMG or recFSH and the GnRH-antagonist cetrorelix

The present retrospective study evaluated the outcome of frozen–thaw cycles with oocytes obtained either during a multiple dose protocol of cetrorelix, or after the use of a gonadotrophin-releasing hormone (GnRH) agonist. A total of 101 subfertile couples were included. These couples had a total of 222 transfers of frozen–thawed pronuclear oocytes after IVF/intracytoplasmic sperm injection (ICSI) treatment. According to the stimulation protocol during various cycles, four groups were established: cetrorelix/recombinant FSH (recFSH) (69 cycles), cetrorelix/human menopausal gonadotrophin (HMG) (10 cycles), GnRH-agonist/recFSH (71 cycles) and GnRH-agonist/HMG (72 cycles). The transfer cycles were mildly stimulated with transdermal oestradiol. No statistically significant difference was seen among the four groups regarding post-thaw survival rate, cumulative embryo score, implantation rate and pregnancies. Frozen–thawed pronuclear oocytes obtained with the use of cetrorelix give satisfactory implantation and pregnancy rates, similar to those obtained with a GnRH-agonist. These results do not depend on the gonadotrophins (HMG or recFSH) used in the collecting cycle.

Health of 227 children born after controlled ovarian stimulation for in vitro fertilization using the luteinizing hormone–releasing hormone antagonist cetrorelix

Objective: To summarize data from completed phase II and III clinical trials on children born after controlled ovarian stimulation using the luteinizing hormone–releasing hormone antagonist cetrorelix. Design: All children born after ovarian stimulation in patients treated for infertility who were in prospective studies until March 23, 1999. Setting: Academic research center. Patient(s): Children born after IVF or IVF plus ICSI. Intervention(s): Controlled ovarian stimulation with cetrorelix in a multiple-dose or single/dual-dose protocol. Main Outcome Measure(s): Outcome of pregnancy and, in deliveries, the date of birth, number and sex of children born, birth weight, body length, and abnormalities were recorded. At approximately 1 year of age and 2 years of age, body weight and length and abnormalities in physical and mental development were recorded. Result(s): Two hundred nine and 18 children were born after fresh and frozen embryo transfers, respectively. Of the pregnancies, 76.2% (179 of 234) resulted in live birth and ectopic pregnancy occurred in 3.4% (8 of 231); one heterotopic pregnancy and four induced abortions were recorded. The malformation rate among all live births, stillbirths, and aborted fetuses was 3.1%. Conclusion(s): Use of cetrorelix in controlled ovarian stimulation does not harm the subsequently born children.

Comparison of cryopreservation outcome with human pronuclear stage oocytes obtained by the GnRH antagonist, Cetrorelix, and GnRH agonists

This retrospective study was performed to examine the implantation and pregnancy rates of frozen–thawed pronuclear stage oocytes obtained with the use of a GnRH antagonist, Cetrorelix (Cetrotide ® ASTA-Medica, Frankfurt/M, Germany) used in a multidose protocol with hMG, and to compare these results with those obtained after a conventional long GnRH analogue protocol (Decapeptyl-Depot, Ferring, Kiel, Germany). The study population consisted of 31 infertile couples with frozen–thawed pronuclear stage oocytes after ICSI treatment using the GnRH antagonist Cetrorelix (Cetrorelix ®) and 31 infertile couples with frozen–thawed pronuclear stage oocytes after ICSI treatment using the long GnRH analogue protocol. Patients underwent ICSI after down regulation with a GnRH agonist (Decapeptyl) and stimulation with hMG, or a GnRH antagonist (Cetrorelix) and hMG. The supernumerary pronuclear stage oocytes were cryopreserved and transferred in a later mildly stimulated cycle. The implantation and pregnancy rates for frozen–thawed pronuclear stage oocytes derived from the GnRH antagonist compared with the GnRH agonist were 3.26% versus 3.73% ( P=1.0000) and 8.33% versus 10.25% ( P=1.0000), respectively. To our knowledge we report here the first pregnancies obtained by the transfer of cryopreserved pronuclear stage embryos generated from ICSI using a GnRH antagonist in the collecting cycle. The use of Cetrorelix in a multiple dose protocol in combination with hMG does not demonstrate a negative effect on viability, implantation potential or pregnancy outcome as compared to 2PN conceptuses obtained from a long GnRH agonist-hMG protocol.

GnRH antagonist in single-dose applications.

Previous studies on ovarian stimulation have confirmed the efficacy of a single dose of the gonadotrophin-releasing hormone (GnRH) antagonist, Cetrorelix, in preventing premature LH surges. The single-dose protocol is easy to use and assures patient compliance. When compared with the long protocol using a depot administration of the GnRH agonist, triptorelin, the IVF results in patients treated with Cetrorelix showed a shorter treatment duration, reduced amount of human menopausal gonadotrophin (HMG) required and a lower occurrence of ovarian hyperstimulation syndrome (OHSS). The pregnancy rates did not differ significantly between the two treatments. The use of Cetrorelix in natural cycles associated with gonadotrophins reduced the rate of premature LH surges and, therefore, the cancellation rate. The stimulation was minimal and the preliminary pregnancy rates were satisfactory. If a larger study confirms the results of the natural cycle with HMG support, the single-dose administration of GnRH antagonist could represent an interesting first-choice IVF treatment in selected indications. The tolerance of Cetrorelix was excellent in all patients, with only mild and transitory reactions at the injection site. New GnRH antagonists are already available for clinical use in some countries, and they will certainly change ovarian stimulation protocols. If the pregnancy rates are confirmed, the main advantages of these new compounds are the reduction in side-effects and complications of the stimulation protocol; a clear benefit to the patients.

Treatment of uterine leiomyomas with luteinizing hormone-releasing hormone antagonist Cetrorelix

The efficacy of the luteinizing hormone-releasing hormone antagonist Cetrorelix (SB-75) in the medical management of uterine leiomyomas (fibromas) was evaluated. Cetrorelix was administered to 18 pre-menopausal women with myomas with a mean age of 33.3 years, who had been candidates for hysterectomy. The initial dose of Cetrorelix was 5 mg twice daily s.c. for the first 2 days and thereafter 0.8 mg was given twice daily s.c. for at least 3 months. The mean duration of the treatment was 4.4 months. Before the therapy with Cetrorelix, the mean uterine volume, measured by ultrasonography, was 395.4 +/- 69.2 ml (range 89-1166). Sixteen patients showed a progressive reduction in uterine volume from 410.4 +/- 77.1 to a mean of 230.8 +/- 52.6 ml at 3 months. All patients became amenorrhoeic and had hot flushes. After treatment with Cetrorelix, a surgical myomectomy was performed in 12 women. One of the patients subjected to myomectomy after therapy with Cetrorelix became pregnant. These patients have been followed for up to 25 months and only in one case has the uterine volume increased after therapy. Three patients had good responses to therapy with Cetrorelix and it was decided to follow them only by observation. One patient became pregnant 2 months later. In the other patient, the uterine volume remained unchanged for the duration of the follow-up of 2 years and the third patient showed an increase after 21 months. In three patients, it was necessary to perform total hysterectomy. In 14 patients, serum concentrations of luteinizing hormone, follicle stimulating hormone and oestradiol decreased after the administration of the first dose of Cetrorelix and continued at subnormal values throughout therapy. In 15 patients who were not subjected to total hysterectomy, menstrual function returned at 1 month after cessation of treatment. Overall results support the use of Cetrorelix for the management of uterine leiomyomas.