leuprolide and cetrorelix

Topics: Animals; Antineoplastic Agents; Female; Genital Neoplasms, Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leuprolide; Receptors, LHRH; Triptorelin Pamoate

To compare the IVF outcomes of letrozole/antagonist and microdose GnRH agonist flare up protocols in poor ovarian responders undergoing intracytoplasmic sperm injection.. A randomized controlled trial was performed in patients with one or more previous failed IVF cycles in which four or less oocytes were retrieved when the gonadotrophin starting dose was at least 300 IU/day. Sixty patients were randomized by computer-generated list to receive either letrozole/antagonist (mild stimulation) n = 30 or GnRH-a protocol (microdose flare) n = 30.. Both groups were similar with respect to background and hormonal characteristics (age, duration of infertility, BMI, FSH, LH and E2). The clinical pregnancy rate per cycle was similar in both groups (13.3 vs. 16.6%; OR = 0.769; 95% CI = 0.185, 3.198). The doses of used gonadotropins and the number of stimulation days were significantly lower in the letrozole/antagonist protocol. The peak E2 level on the day of hCG, the endometrial thickness, the retrieved oocytes, the number of fertilized oocytes, the number of transferred embryos and the cancellation rate were statistically similar in both groups.. The letrozole/antagonist protocol is a cost-effective and patient-friendly protocol that may be used in poor ovarian responders for IVF/ICSI.

Topics: Adult; Aromatase Inhibitors; Drug Resistance; Egypt; Estradiol; Female; Fertility Agents, Female; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Infertility, Female; Letrozole; Leuprolide; Menotropins; Nitriles; Ovary; Ovulation Induction; Pregnancy; Pregnancy Rate; Sperm Injections, Intracytoplasmic; Triazoles

The selection of developmentally competent human gametes may increase the efficiency of assisted reproduction. Spermatozoa and oocytes are usually assessed according to morphological criteria. Oocyte morphology can be affected by the age, genetic characteristics, and factors related to controlled ovarian stimulation. However, there is a lack of evidence in the literature concerning the effect of gonadotropin-releasing hormone (GnRH) analogues, either agonists or antagonists, on oocyte morphology. The aim of this randomized study was to investigate whether the prevalence of oocyte dysmorphism is influenced by the type of pituitary suppression used in ovarian stimulation.. A total of 64 patients in the first intracytoplasmic sperm injection (ICSI) cycle were prospectively randomized to receive treatment with either a GnRH agonist with a long-term protocol (n: 32) or a GnRH antagonist with a multi-dose protocol (n: 32). Before being subjected to ICSI, the oocytes at metaphase II from both groups were morphologically analyzed under an inverted light microscope at 400x magnification. The oocytes were classified as follows: normal or with cytoplasmic dysmorphism, extracytoplasmic dysmorphism, or both. The number of dysmorphic oocytes per total number of oocytes was analyzed.. Out of a total of 681 oocytes, 189 (27.8%) were morphologically normal, 220 (32.3%) showed cytoplasmic dysmorphism, 124 (18.2%) showed extracytoplasmic alterations, and 148 (21.7%) exhibited both types of dysmorphism. No significant difference in oocyte dysmorphism was observed between the agonist- and antagonist-treated groups (P>0.05). Analysis for each dysmorphism revealed that the most common conditions were alterations in polar body shape (31.3%) and the presence of diffuse cytoplasmic granulations (22.8%), refractile bodies (18.5%) and central cytoplasmic granulations (13.6%). There was no significant difference among individual oocyte dysmorphisms in the agonist- and antagonist-treated groups (P>0.05).. Our randomized data indicate that in terms of the quality of oocyte morphology, there is no difference between the antagonist multi-dose protocol and the long-term agonist protocol. If a GnRH analogue used for pituitary suppression in IVF cycles influences the prevalence of oocyte dysmorphisms, there does not appear to be a difference between the use of an agonist as opposed to an antagonist.

Topics: Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leuprolide; Oocytes; Ovulation Induction; Receptors, Gonadotropin; Sperm Injections, Intracytoplasmic

To compare the level of apoptosis and DNA fragmentation in the human granulosa cell (GC) layer exposed to an agonist or antagonist of GnRH in intracytoplasmic sperm injection (ICSI) cycles supplemented with recombinant LH (rLH).. Patients without ovulatory dysfunction, aged ≤37 years and in their first ICSI cycle were prospectively randomised to receive either a long GnRH agonist protocol or a multi-dose antagonist protocol. In both groups, recombinant FSH supplemented with rLH was used for ovarian stimulation, and the GCs were collected during oocyte denudation. The GCs were then analysed for DNA fragmentation by TUNEL assay and for apoptosis using the annexin-V assay. The outcomes were given as the percentage of GCs with DNA fragmentation and apoptosis out of the total number of GCs analysed. Comparison of the agonist versus the antagonist group was performed using the Mann-Whitney test.. DNA fragmentation: 32 patients were included in either the GnRH agonist group (n=16) or the antagonist group (n=16). The percentage of GCs with positive DNA fragmentation did not differ significantly (P=0.76) between the agonist group (15.5 ± 9.4%) and the antagonist group (18.8 ± 13.3%). Apoptosis: 28 patients were included in either the GnRH agonist group (n=14) or the antagonist group (n=14). The percentage of GCs positive for apoptosis did not differ significantly (P=0.78) between the agonist group (34.6 ± 14.7%) and the antagonist group (36.5 ± 22%).. The results suggest that therapy with either an agonist or antagonist of GnRH is associated with comparable levels of DNA fragmentation and apoptosis in granulosa cells in ICSI cycles supplemented with rLH.

Topics: Adult; Apoptosis; Cell Separation; DNA Fragmentation; Family Characteristics; Female; Gonadotropin-Releasing Hormone; Granulosa Cells; Hormone Antagonists; Humans; Infertility; Leuprolide; Luteinizing Hormone; Male; Oocyte Retrieval; Ovulation Induction; Recombinant Proteins; Sperm Injections, Intracytoplasmic

In a pilot study, implantation and pregnancy rates per transfer were favorable in recipients of donated eggs treated with a single dose of cetrorelix acetate 3 mg compared with recipients of donated eggs treated with the long protocol (42.3% vs. 30.5%, and 71.0% vs. 46.7%, respectively; NS). The stimulation protocol based on gonadotropins and a single dose of cetrorelix acetate 3 mg is adequate in terms of safety and comfort of donors and the likelihood of pregnancy among recipients, although these favorable results require confirmation in future studies.

Topics: Adult; Delayed-Action Preparations; Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Gonadotropins; Hormone Antagonists; Humans; Leuprolide; Oocyte Donation; Ovulation Induction; Pilot Projects; Pituitary Gland; Pituitary Hormones; Pregnancy; Pregnancy Rate; Tissue Donors; Young Adult

To compare the effectiveness of leuprorelin and cetrorelix, when used as preoperative endometrial thinning agents prior to transcervical resection of endometrium (TCRE).. A prospective, double-blind randomised controlled trial.. Gynaecological department of a UK district general hospital.. A total of 106 premenopausal women with dysfunctional uterine bleeding, undergoing TCRE.. Women were equally randomised to 3.75 mg of leuprorelin acetate (3-4 weeks) or 3 mg cetrorelix (4-7 days) prior to TCRE. About 1 ml saline was given as placebo in both arms.. Amenorrhoea rate at 6 months, endometrial thickness using transvaginal ultrasound on the day of operation.. A total of 100 women completed the trial with no loss to follow up. Amenorrhoea rate at 6 months after surgery was high in both groups (80% cetrorelix and 84% leuprorelin) with no statistical significance. All endometrial outcome measures including endometrial thickness on ultrasound, histology and operative appearance were more favourable in leuprorelin group as compared with cetrorelix (P values 0.013, <0.001 and 0.003 respectively). More women in leuprorelin group had hot flushes as compared with cetrorelix (15/50 versus 6/50; P = 0.047). No significant differences were seen in other outcome measures.. In dosages used, leuprorelin produced more consistent thinning of the endometrium as compared with cetrorelix, although this did not make any significant difference to operative or menstrual outcomes. The endometrial thinning effect with cetrorelix does appear to be more favourable than that seen at postmenstrual phase in other studies. The optimum (possibly higher) dosage of cetrorelix for this purpose has not yet been established.

Topics: Adult; Double-Blind Method; Endometrium; Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leiomyoma; Leuprolide; Menorrhagia; Menstruation; Patient Satisfaction; Postmenopause; Preoperative Care; Prospective Studies; Treatment Outcome; Uterine Neoplasms

To investigate the efficacy of gonadotropin releasing hormone antagonist (GnRH) in poor responders undergoing in vitro fertilization.. Ninety-six patients with poor ovarian response in previous treatment cycles were prospectively randomized into two groups. Forty-four patients were stimulated with GnRH antagonist multidose protocol and 45 patients received a standard long agonist protocol. Ovarian response was evaluated by transvaginal ultrasound and hormonal parameters. Cycle characteristics and treatment outcomes were statistically compared between groups.. There was significantly reduced duration of stimulation and consumption of gonadotrophins in the antagonist group when compared to the agonist group. The estradiol concentrations on the day of human chorionic gonadotropin (hCG) injection, the number of oocytes retrieved, and the number of embryos transferred were similar for both groups. In the antagonist group, eight (18.1%) ongoing pregnancies were achieved and in the agonist group, ten (22.2%) clinical pregnancies were achieved but the difference was not statistically significant.. The present study was not powered to detect clinically relevant differences between two protocols in outcomes such as pregnancy rate, with confidence.

Topics: Adult; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fertility Agents, Female; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leuprolide; Ovulation Induction; Pregnancy; Pregnancy Outcome

Both gonadotropin-releasing hormone (GnRH) analogs and antagonists have been used for pituitary desensitization during controlled ovarian hyperstimulation (COH). We aimed to determine the minimum effective daily dose of GnRH antagonist in women undergoing COH. We also compared the efficiency of a GnRH antagonist and a GnRH agonist.. Women undergoing in vitro fertilization/intracytoplasmic sperm injection and embryo transfer were divided into five groups: (1) cetrorelix 0.25 mg ( n = 86); (2) cetrorelix 0.2 mg ( n = 28); (3) cetrorelix 0.15 mg ( n = 30); (4) leuprolide acetate (LA) 0.5 mg/day ( n = 58); (5) single half-dose LA depot 1.88 mg ( n = 49). Cetrorelix was administered daily from menstrual day 8 until the day of human chorionic gonadotropin administration. LA or LA depot was started on day 21 of the previous menstrual cycle.. We observed lower gonadotropin (Gn) dosages, estradiol (E2) levels and reduced risk of ovarian hyperstimulation syndrome (OHSS) in the GnRH antagonist groups. A higher risk of luteinizing hormone (LH) surge was noted in cetrorelix 0.2 and 0.15 mg groups. Gn dosages (IU)/E2 levels (pg/mL) in each group were: (1) 1,949.4/1,191.1; (2) 1,869.6/1,010.8; (3) 1,856.7/1,023.6; (4) 2,184.5/1,323.6; and (5) 2,103.5/1,313.5, respectively. LH/OHSS risks were: (1) 3.5%/5.8%; (2) 7.1%/3.6%; (3) 13.3%/3.3%; (4) 3.4%/8.6%; and (5) 2%/8.2%, respectively. Number of oocytes/embryos/grade I, II embryos were: (1) 9.4/7.9/5.8; (2) 7.5/4.2/3.6; (3) 6.3/4.1/3.1; (4) 12.3/8.9/6.6; and (5) 11.8/8.4/6.1, respectively. There was no significant difference in terms of clinical outcomes between groups 1, 4 and 5, except for higher abortion rates (AR) in group 1. Pregnancy rate (PR)/implantation rate (IR) ratios in groups 1, 4, and 5 were statistically higher than those in groups 2 and 3. Chemical PR/IR/AR were: (1) 30.2%/5.9%/7%; (2) 21.4%/5.1%/7.1%; (3) 16.7%/4.1%/10%; (4) 32.8%/5.5%/8.6%; and (5) 30.6%/5.7%/8.2%, respectively.. The lowest effective dosage of cetrorelix for pituitary desensitization during COH luteolysis is 0.25 mg, resulting in a comparable PR but a higher AR when compared with GnRH agonist.

Topics: Adult; Chorionic Gonadotropin; Dose-Response Relationship, Drug; Drug Administration Schedule; Estradiol; Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Ovarian Hyperstimulation Syndrome; Ovulation Induction; Pregnancy; Pregnancy Rate; Sperm Injections, Intracytoplasmic

The aim of the present study was to investigate the effect of gonadotropin-releasing hormone (GnRH) antagonists (GnRH-ant) on follicular fluid (FF) insulin-like growth factor-I (IGF-I) and FF vascular endothelial growth factor (VEGF) levels. Sixty women undergoing assisted reproduction were randomized and assigned to two different GnRH analog regimens: GnRH agonist (GnRH-a) and GnRH-ant. FF VEGF and FF IGF-I concentrations were significantly increased in the patients treated with GnRH-ant (p < 0.001). In the same patients we observed a statistically significant reduction in serum luteinizing hormone (LH) and estradiol (E2) levels (p < 0.001 and p < 0.05, respectively), FF E2 and FF androstenedione levels (p < 0.05 and p < 0.001, respectively), as well as a reduction in the number of pregnancies although this was not statistically significant. In the GnRH-ant group, FF VEGF levels were positively correlated with FF IGF-I levels, and both were negatively correlated with serum LH levels. The increase in FF IGF-I and FF VEGF levels in women treated with GnRH-ant could be explained by a deleterious follicular environment in response to profound suppression of LH and E2 levels.

Topics: Adult; Androstenedione; Chorionic Gonadotropin; Estradiol; Female; Follicular Fluid; Gonadotropin-Releasing Hormone; Humans; Infertility; Insulin-Like Growth Factor I; Leuprolide; Luteinizing Hormone; Ovulation Induction; Pregnancy; Vascular Endothelial Growth Factor A

To compare the outcome of using gonadotropin-releasing hormone (GnRH) antagonists versus agonists in women with polycystic ovary disease (PCOD) who underwent controlled ovarian hyperstimulation (COH) for assisted reproductive techniques (ART).. A total of 129 patients with PCOD were randomly allocated to undergo COH with a GnRH antagonist (59 patients) and GnRH agonist (leuprolide acetate) (70 patients) to prevent a premature luteinizing hormone (LH) surge. Assisted fertilization following oocyte retrieval and embryo transfer was performed.. None of the cycles were cancelled due to a premature LH surge. There was no significant difference between the antagonist and agonist arms in the number of gonadotropin ampules consumed per cycle. However, in the antagonist arm a shorter duration of ovarian stimulation was recorded as compared to the agonist arm. Although similar numbers of oocytes was retrieved from both groups of patients, the quality of the oocytes, as measured by metaphase 2/total oocyte ratio, was lower in the antagonist arm as compared to the agonist arm. Pregnancy rates were 57.6% and 58.5% in the antagonist and agonist arms, respectively (p > 0.05). Implantation rates were not different (34.0% and 34.6%, respectively). The frequency of ovarian hyperstimulation syndrome also did not differ between the treatment groups (5% and 7.1%, respectively).. The size of our study, on a specific subgroup of patients, does not allow a reliable conclusion regarding ART outcomefollowing the use of a GnRH antagonist versus agonist. Nevertheless, the protocol with the antagonist gave results that were as good as those of the protocol with the agonist in this PCOD patient population.

Topics: Adult; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fertilization in Vitro; Follow-Up Studies; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Infertility, Female; Leuprolide; Ovulation Induction; Pilot Projects; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Rate; Probability; Prospective Studies; Risk Assessment; Statistics, Nonparametric

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.

Topics: Adolescent; Adult; Drug Therapy, Combination; Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Infertility, Female; Leuprolide; Luteinizing Hormone; Ovulation Induction; Pregnancy; Pregnancy Rate; Reproductive Techniques, Assisted

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.

Topics: Adult; Chorionic Gonadotropin; Embryo Implantation; Estradiol; Female; Fertilization in Vitro; Follicle Stimulating Hormone; Follicular Phase; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Menotropins; Middle Aged; Ovulation Induction; Pregnancy; Prospective Studies

Peptide therapeutics showcase number of advantages compared to the traditional small molecule drugs, e,g. they usually have higher affinity to target and lower toxicity profiles. Endogenous peptides are mostly cleared from the body through renal clearance or proteolytic hydrolysis. As a part of drug discovery, metabolite identification is an important part in their development to identify metabolic hot spots and to further improve their stability. As the catabolism of the peptides and peptide-like drugs is often considered to be extrahepatic, the use of in vitro systems derived from these organs might be beneficial. In this study, multiple extrahepatic metabolic systems were evaluated for the applicability for peptide metabolism studies. Three peptide drugs (leuprorelin, cetrorelix, cyclosporin) were incubated in kidney and intestinal S9 fraction ( ± NADPH), fresh plasma (anticoagulants EDTA and heparin separately), and plated proximal tubule cells. Additionally, leuprorelin was also incubated with human kidney microsomes and cytosol to further investigate the NADPH-dependent metabolism detected in kidney S9 fraction. Both substrate disappearance and metabolite formation were monitored, using UPLC/HR-MS analysis of the collected samples.Overall, the largest number of metabolites was formed in the incubation with kidney S9 fraction, followed by intestinal S9, while incubations with proximal tubule cells produced lower number of metabolites All investigated peptides were stable in plasma and only a few metabolites were detected, likely because the studied peptide drugs have been optimized to be stable in plasma. Leuprorelin showed NADPH-dependent metabolite formation in kidney S9 fraction, while the metabolism of cetrorelix was more NADPH independent. As expected, formation of cytochrome P450 (CYP) catalyzed metabolism of cyclosporine was not observed with the employed extrahepatic systems. The NADPH-dependent metabolism of leuprorelin was detected also in the incubation with kidney cytosol, but not with kidney microsomes, and was thus not caused by CYPs or FMOs, but with cytosolic NADPH-dependent drug metabolizing enzymes. These enzymes could, in principle, activate the amide bond via reductive or oxidative metabolism outside the amide bond. The identity of the involved drug metabolizing enzymes in this process is still unknown.

Topics: Amides; Cyclosporine; Cytochrome P-450 Enzyme System; Gonadotropin-Releasing Hormone; Humans; Kidney; Leuprolide; Microsomes, Liver; NADP

The number of approved peptide therapeutics has increased significantly in recent years. Peptide therapeutics have many advances over small molecule drugs, such as higher affinity to target and lower toxicity profiles. Although peptide-like drugs are mainly metabolized/catabolized in the body for smaller peptides and amino acids, metabolite identification still has an essential part of in their development, especially if their structure contains modified amino acids, and also to identify the metabolic soft spots enabling modification to more stable sequence. The use of human derived in vitro systems is an important tool when investigating metabolism of peptide drugs, and comparison of results by various hepatic systems was investigated here. Peptides were incubated in several different in vitro human liver-derived subcellular and cellular incubation systems, i.e. liver S9 fraction, suspended cryo-preserved human primary hepatocytes and plated Upcyte hepatocytes. Samples were collected at different time points and analysed by UPLC/HR-MS-method developed for the purpose. Both substrate disappearance and metabolite formation were monitored, and the systems were compared. S9 fraction formed the highest number of metabolites for leuprorelin and cetrorelix, while for desmopressin and cyclosporin, primary hepatocytes and liver S9 produced similar metabolite profiles. Interestingly, not only cyclosporin, but also leuprorelin and cetrorelix showed metabolites whose formation was CYP (NADPH) dependent in liver S9. For leuprorelin and cetrorelix, the metabolites that showed NADPH dependency with liver S9, were not detected with hepatocytes, even though for leuprorelin these reactions played a major role in liver S9. The hydrolytic metabolic reactions were very similar between liver S9 and hepatocytes, i.e. the metabolite profiles in hepatocytes matched better with liver S9 profiles without NADPH, which may be caused by cell uptake rate limitation with hepatocytes, or then hydrolytic processes are more stressed in peptide metabolism with hepatocytes, in comparison to CYP-mediated processes.

Topics: Cyclosporine; Deamino Arginine Vasopressin; Gonadotropin-Releasing Hormone; Hepatocytes; Humans; Leuprolide; Liver; Microsomes, Liver

Gonadotropin-releasing hormone (GnRH) modulators are widely used in numerous reproductive conditions including infertility. Several clinical studies showed mixed results regarding the efficacy of GnRH modulators in patients with polycystic ovary syndrome (PCOS). Along with this, few preclinical studies focus on the effect of GnRH modulators in PCOS-induced animals. Therefore, the present study was designed to study the effect of leuprolide and cetrorelix on hormonal, metabolic, and menstrual dysfunction PCOS rats. Prepubertal female rats were divided into four groups: Group I received a normal pellet diet and Groups II, III, and IV received 40% high-fat diet for 105 days. Similarly, adult female rats were divided into four groups: Group I received 1% carboxymethylcellulose (CMC) and Groups II, III, and IV received letrozole (1 mg/kg, per oral [p.o.] in 1% CMC) for 21 days. Thereafter, leuprolide (2.5 µg/rat, s.c.) and cetrorelix (10 µg/kg, subcutaneous [s.c.]) treatment were given to Group III and Group IV animals, respectively, for 21 days. Oral glucose tolerance test, lipid profile, fasting glucose, insulin, estrus cycle, hormonal profile, ovary weight, ovarian histopathological changes, and LHR and FSHR expressions were measured. Treatment with leuprolide and cetrorelix did not improve glucose intolerance, insulin level, insulin sensitivity indices, sex hormone levels, lipid profile, and estrus cycle. Only testosterone level, total cholesterol level, and follicular development were improved. Therefore, it was concluded that both leuprolide and cetrorelix showed improvement in follicular development, which could be helpful for improving fertility in PCOS.

Topics: Animals; Blood Glucose; Disease Models, Animal; Drug Evaluation, Preclinical; Estrous Cycle; Female; Gonadotropin-Releasing Hormone; Insulin; Leuprolide; Lipids; Ovary; Polycystic Ovary Syndrome; Rats; Rats, Sprague-Dawley

We retrospectively compared neonatal sex after antagonist- versus long-stimulation protocols followed by fresh in vitro fertilization (IVF) or fresh intracytoplasmic sperm injection (ICSI) with either protocol. We reviewed data for 762 IVF/ICSI cycles in 2015, including 23 IVF procedures. We summarized sex outcomes in the entire cohort, and for the additional subgroups: embryo transfer day and number of embryos transferred, and number of oocytes recovered and maternal age. Among 169 live births for all protocols combined, 50.9% of babies were male, and we saw no difference between the antagonist versus long-stimulation groups (52.3% vs 48.3% male babies, respectively; P = .740). Our results also showed no significant difference in sex proportion when comparing IVF versus ICSI, although a higher proportion of babies were male with the antagonist-ICSI protocol. Differences between the additional subgroups were also neither clinically nor statistically significant.

Topics: Adult; Chorionic Gonadotropin; Embryo Transfer; Female; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Humans; Infant, Newborn; Leuprolide; Male; Maternal Age; Menotropins; Oocytes; Retrospective Studies; Saudi Arabia; Sex Ratio; Socioeconomic Factors; Sperm Injections, Intracytoplasmic

Recent studies have suggested that GnRH agonists (GnRHags) protect ovarian function following chemotherapy. Here, we study the effect of a combination of GnRH antagonist (GnRHan) and GnRHag for gonadal protection from gonadotoxic chemotherapy in adolescent female rats. Cycling Sprague Dawley rats were treated at adolescent age. Thirty female rats were randomized to 5 treatment groups (n = 6/group): (1) placebo, (2) cyclophosphamide (CPA) alone, (3) GnRHan followed by GnRHag with placebo, (4) GnRHan followed by GnRHag with CPA, and (5) GnRHag with CPA. The main outcome measure was live birth rate (LBR), and secondary measures included rat weight, ovarian volume, and follicles. Group 2 had decreased LBR compared to all other groups. Group 4 and 5 had LBR similar to placebo. There was no difference in the ovarian volume. The CPA-alone group had decreased number of antral follicles compared to control. These studies demonstrate that the combination of GnRHan and GnRHag and GnRHag alone preserved fertility in female adolescent rats following gonadotoxic chemotherapy treatment. The addition of a GnRHan to a GnRHag does not confer a greater protective effect.

Topics: Animals; Antineoplastic Agents, Alkylating; Cyclophosphamide; Female; Fertility Agents, Female; Fertility Preservation; Gonadotropin-Releasing Hormone; Hormone Antagonists; Leuprolide; Models, Animal; Ovary; Rats; Rats, Sprague-Dawley

To determine the effect of GnRH analogues (GnRH-a) leuprolide acetate (LA) and cetrorelix acetate on gonadal hormone-regulated expression of extracellular matrix in uterine leiomyoma three-dimensional (3D) cultures.. Laboratory study.. University research laboratory.. Women undergoing hysterectomy for symptomatic leiomyomas.. The 3D cell cultures, protein analysis, Western blot, immunohistochemistry.. Expression of extracellular matrix proteins, collagen 1, fibronectin, and versican in leiomyoma cells 3D cultures exposed to E2, P, LA, cetrorelix acetate, and combinations for 24- and 72-hour time points.. The 3D leiomyoma cultures exposed to E2 for 24 hours demonstrated an increased expression of collagen-1 and fibronectin, which was maintained for up to 72 hours, a time point at which versican was up-regulated significantly. Although P up-regulated collagen-1 protein (1.29 ± 0.04) within 24 hours of exposure, significant increase in all extracellular matrix (ECM) proteins was observed when the gonadal hormones were used concomitantly. Significant decrease in the amount of ECM proteins was observed on use of GnRH-a, LA and cetrorelix, with 24-hour exposure. Both the compounds also significantly decreased ECM protein concentration despite the presence of E2 or both gonadal hormones.. This study demonstrates that GnRH-a directly affect the gonadal hormone-regulated collagen-1, fibronectin, and versican production in their presence. These findings suggest that localized therapy with GnRH-a may inhibit leiomyoma growth even in the presence of endogenous gonadal hormone exposure, thereby providing a mechanism to eliminate the hypoestrogenic side effects associated with GnRH-a therapy.

Topics: Antineoplastic Agents, Hormonal; Cell Culture Techniques; Cell Line, Tumor; Collagen Type I; Estradiol; Extracellular Matrix; Female; Fibronectins; Gonadotropin-Releasing Hormone; Humans; Leiomyoma; Leuprolide; Medroxyprogesterone Acetate; Time Factors; Uterine Neoplasms; Versicans

The aim of the presented study is to investigate the impact of progesterone change in the late follicular phase on the pregnancy rates of both agonist and antagonist protocols in normoresponders.. A total of 201 normoresponder patients, who underwent embryo transfer were consecutively selected. 118 patients were stimulated using a long luteal GnRH agonist protocol and 83 using a flexible antagonist protocol. The level of change in late follicular phase progesterone was calculated according to the progesterone levels on the hCG day and pre-hCG day (1 or 2 days prior to hCG day) measurement.. Clinical pregnancy rates were comparable between long luteal and antagonist group (35.6 and 41%, respectively). The incidence of progesterone elevation on the hCG day was 11% in long luteal and 18% in antagonist group (p = 0.16). In pregnant cycles, p levels both on the hCG day and pre-hCG day measurement were significantly higher in antagonist than agonist cycles (p = 0.029, p = 0.038, respectively). The change of p level was statistically significant in non-pregnant cycles both for the agonist (-0.17 ± 0.07; 95% CI: -0.29 to -0.37) and antagonist groups (-0.18 ± 0.07; 95%CI: -0.31 to -0.04).. Late follicular phase progesterone levels were stable during the cycles of pregnant patients irrespective of the protocols and were shown to be higher in pregnant patients in antagonist cycles when compared to agonist cycles.

Topics: Adult; Case-Control Studies; Embryo Transfer; Estradiol; Female; Follicle Stimulating Hormone; Follicular Phase; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leuprolide; Luteinizing Hormone; Ovulation Induction; Pregnancy; Pregnancy Rate; Progesterone; Sperm Injections, Intracytoplasmic

A total of 413 consecutive infertile patients (572 cycles) with a body mass index (BMI) of ≥ 25 kg/m(2) were enrolled into the study. The luteal-long GnRH agonist group (Group I) constituted 211 patients (300 cycles) and the flexible-multidose GnRH antagonist group (Group II) constituted 202 patients (272 cycles). The duration of stimulation (d) (10.1 ± 2.5 vs. 9.2 ± 2.0; p < 0.01); the total dose of gonadotrophin used (IU) (3,099.4 ± 2,885.0 vs. 2,684.0 ± 1,046.4; p < 0.05) and the E2 level on the day of hCG (pg/ml) (2,375.8 ± 1,554.6 vs. 1,905.6 ± 1,598.8; p < 0.01) were significantly lower in Group II when compared with Group I. However, the ongoing pregnancy per embryo transfer (37.0% vs. 25.7%; p < 0.05) and the implantation rate (25.7% vs. 15.6%; p < 0.01) were significantly lower in Group II when compared with Group I. In conclusion, we noted that the luteal-long GnRH agonist protocol produced higher implantation rates and higher clinical-ongoing pregnancy rates in overweight and obese patients when compared with the flexible-multidose GnRH antagonist protocol.

Topics: Adult; Clinical Protocols; Contraceptives, Oral, Hormonal; Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Infertility; Leuprolide; Luteal Phase; Obesity; Overweight; Pregnancy; Pregnancy Rate; Reproductive Techniques, Assisted; Retrospective Studies; Time Factors

To find out if GnRH agonist (GnRHa) and GnRH antagonist (GnRHant) offer ovarian protection from cyclophosphamide (Cyc) and if AMH expression is affected.. This experimental study was conducted in Baskent University Animal research laboratory and 66 virgin Wistar albino rats were assigned to six groups. The control group received intraperitoneal saline injection. The GnRHa group had a single dose of leuprolide acetate (1 mg/kg) 28 days prior to saline injection. The GnRHant group had a single dose of cetrorelix acetate (0.1 mg/kg) 1 h prior to saline injection. The Cyc group had a single intraperitoneal dose of Cyc (75 mg/kg). The GnRHa+Cyc group had a single dose of leuprolide acetate (1 mg/kg) 28 days prior to Cyc (75 mg/kg). The GnRHant+Cyc group had single dose of cetrorelix acetate (0.1 mg/kg) 1 h prior to Cyc (75 mg/kg). At day 35, the animals were euthanized, and their ovaries were removed. Primordial follicles were counted and AMH expression was determined. The Kruskal-Wallis, χ(2), or Fisher's exact test was used where appropriate. p < 0.05 was considered statistically significant.. PMF count was reduced in GnRHant (p < 0.01) and Cyc (p < 0.01) groups. Cyc, GnRHa+Cyc and GnRHant+Cyc groups had similar numbers of PMF. AMH expression was reduced in Cyc, GnRHa+Cyc and GnRHant+Cyc groups (p < 0.01).. Neither GnRHa nor GnRHant can offer protection against Cyc-induced damage. GnRHant itself reduces the number of primordial follicles.

Topics: Animals; Cyclophosphamide; Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Leuprolide; Ovarian Follicle; Ovary; Rats; Rats, Wistar

GnRH agonist (GnRH-a) triggering is associated with a reduced risk of ovarian hyperstimulation syndrome (OHSS) compared with human chorionic gonadotropin (hCG) in assisted reproduction technology cycles. We have shown that ovarian pigment epithelium derived factor (PEDF), a potent antiangiogenic factor, counteracts vascular endothelial growth factor (VEGF) expression and that OHSS is correlated with hCG-induced impaired PEDF to VEGF ratio.. The objective of the study was to explore whether GnRH-a triggering could directly modulate PEDF/VEGF balance in granulosa cells.. The design of the study was a mouse model and cultured granulosa cells.. Changes in PEDF and VEGF were measured by quantitative PCR and Western blot analysis. OHSS symptoms were recorded by changes in body weight and in peritoneal vascular leakage, quantified by the modified Miles vascular permeability assay.. GnRH-a stimulation significantly increased PEDF and decreased VEGF mRNA and protein levels both in rat granulosa cell line and human primary granulosa cells in vitro. GnRH-a and hCG triggering inversely modulated PEDF mRNA and protein level in human granulosa cells in vivo. In the GnRH-a triggering mouse model, we showed similar increase in PEDF to VEGF ratio as in the in vitro results. OHSS-predisposed mice did not develop OHSS parameters after GnRH-a triggering, opposed to hCG-triggered mice. Finally, GnRH-a triggering of OHSS-predisposed mice significantly increased ovarian PEDF to VEGF ratio compared with hCG-triggered mice and control mice.. GnRH-a triggering induces a direct effect on PEDF/VEGF balance in granulosa cells inversely to hCG. Our results suggest a novel elucidation to the GnRH-a triggering-mediated risk reduction of OHSS and may clarify the pros and cons of this triggering method.

Topics: Adult; Animals; Cell Line; Cells, Cultured; Chorionic Gonadotropin; Eye Proteins; Female; Fertility Agents, Female; Gene Expression Regulation, Developmental; Gonadotropin-Releasing Hormone; Granulosa Cells; Humans; Leuprolide; Mice, Inbred ICR; Nerve Growth Factors; Ovarian Hyperstimulation Syndrome; Ovulation Induction; Rats; Receptors, LHRH; Serpins; Signal Transduction; Vascular Endothelial Growth Factor A; Young Adult

This article describes the rational design, synthesis and pharmacological properties of amide-linked cyclic analogues of Luteinizing Hormone-Releasing Hormone (LHRH) with substitutions at positions 1 (Pro), 6 (D-Leu/D-Trp), 9 (Aze) and 10 (BABA/Acp). These LHRH analogues fulfil the conformational requirements that are known in the literature (bend in the 5-8 segment) to be essential for receptor recognition and activation. Although, they are characterised by an overall low binding affinity to the LHRH-I receptor, the cyclic analogues that were studied and especially the cyclo(1-10)[Pro(1), D-Leu(6), BABA(10)] LHRH, exhibit a profoundly enhanced in vitro and in vivo stability and improved pharmacokinetics in comparison with their linear counterpart and leuprolide. Upon receptor binding, cyclo(1-10)[Pro(1), D-Leu(6), BABA(10)] LHRH causes testosterone release in C57/B16 mice (in vivo efficacy) that is comparable to that of leuprolide. Testosterone release is an acutely dose dependent effect that is blocked by the LHRH-I receptor antagonist, cetrorelix. The pharmacokinetic advantages and efficacy of cyclo(1-10)[Pro(1), D-Leu(6), BABA(10)] LHRH render this analogue a promising platform for future rational drug design studies towards the development of non-peptide LHRH mimetics.

Topics: Amides; Animals; Cells, Cultured; Drug Design; Gonadotropin-Releasing Hormone; HEK293 Cells; Humans; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Protein Stability; Receptors, LHRH

To determine the direct effect that GnRH analogues leuprolide acetate and cetrorelix acetate have on extracellular matrix in human leiomyoma and patient-matched myometrial cells.. Laboratory study.. University hospital.. None.. Cell culture, proliferation studies, and messenger RNA and protein analysis.. Expression of GnRHR1, COL1A1, fibronectin, and versican variant V0 in treated leiomyoma cells and patient-matched myometrial cells.. Leiomyoma cells were treated with GnRH analogues for 6, 24, and 120 hours. Leuprolide treatment for 6 hours resulted in an increase in expression of GnRHR1 (4.02 ± 0.12-fold), COL1A1 (6.41 ± 0.29-fold), fibronectin (9.69 ± 0.18-fold), and versican variant V0 (7.58 ± 0.43-fold). Leiomyoma cells treated with cetrorelix for 6 hours showed a decreased expression of GnRHR1 (0.5 ± 0.15-fold), COL1A1 (3.79 ± 0.7-fold), fibronectin (0.92 ± 0.09-fold), and versican variant V0 (0.14 ± 0.07-fold). Leuprolide treatment of leiomyoma cells at high concentrations (10(-5) M) did not result in an increase in protein production. Cetrorelix treatment of leiomyoma cells for 6 hours showed an increase in fibronectin protein production (3.14 ± 0.09-fold). Protein production of leiomyoma cells treated with cetrorelix for 120 hours demonstrated a decrease in GnRHR1 (0.51 ± 0.07-fold), COL1A1 (0.35 ± 0.07-fold), fibronectin (1.94 ± 0.08-fold), and versican variant V0 (0.77 ± 0.19-fold).. Our findings demonstrate that GnRH analogue treatment directly regulated COL1A1, fibronectin, and matrix proteoglycan production. The reduction in versican variant V0 gene expression caused by cetrorelix treatment, and its association with the osmotic regulation of leiomyomas, presents a new and innovative approach to therapy for this disease.

Topics: Antineoplastic Agents, Hormonal; Cell Proliferation; Collagen Type I; Collagen Type I, alpha 1 Chain; Dose-Response Relationship, Drug; Extracellular Matrix Proteins; Female; Fibronectins; Gene Expression Regulation, Neoplastic; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leiomyoma; Leuprolide; Receptors, LHRH; RNA, Messenger; Time Factors; Tumor Cells, Cultured; Uterine Neoplasms; Versicans

To describe our experience with random-start IVF with the use of GnRH agonist for final oocyte maturation, to reduce the risk of ovarian hyperstimulation syndrome.. Case series.. University-based center for reproductive endocrinology and infertility.. Patients with a new diagnosis of cancer who presented with a narrow time frame for IVF before initiating cancer therapy.. Random-start GnRH antagonist cycles with GnRH agonist trigger for final oocyte maturation.. Number of oocytes retrieved, fertilization rate, rates of ovarian hyperstimulation syndrome.. Cycles were started in the late follicular or luteal phase, and the duration of controlled ovarian hyperstimulation ranged between 8-13 days. A total of 14-40 oocytes were retrieved and 5-20 embryos cryopreserved for each patient.. Random-start IVF is a reasonable option for fertility preservation in those cancer patients for whom the treatment window may be narrow. In addition, the use of a GnRH agonist for final oocyte maturation may decrease the potential risk of ovarian hyperstimulation syndrome.

Topics: Adult; Female; Fertility; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Random Allocation; Young Adult

To investigate the effects of GnRH antagonist (GnRH-ant) and agonist (GnRH-a) in the prevention of postoperative pelvic adhesions by a visual scoring system and immunohistochemical methods in a rat uterine horn model.. Controlled experimental animal study.. Animal laboratory at an academic research environment.. Twenty-one Wistar albino rats.. Rats were randomized into three groups. One week before the operation the rats received either GnRH-ant or GnRH-a or saline solution; they then underwent surgical laparotomy, and both uterine horns were traumatized by a scalpel. Three weeks later, all rats were sacrificed and extension and severity of the adhesions in each group were scored by a visual scoring system. Adhesion tissues were evaluated immunohistochemically for vitronectin and u-PAR.. Scores of extend and severity of adhesions and staining of vitronectin and u-PAR.. The extent of adhesion scores were 1.85 ± 0.86, 0.78 ± 1.05, and 0.42 ± 0.64, and the severity of adhesion scores were 1.71 ± 0.91, 0.57 ± 0.85, 0.50 ± 0.75 for control, GnRH-ant, and GnRH-a groups, respectively. The extent and severity of adhesions were significantly lower in both GnRH-ant and GnRH-a groups when compared with the control group. Adhesion extent scores in the GnRH-a group were lower than in the GnRH-ant group, but this difference was not significant. vitronectin and u-PAR staining were significantly greater in both the GnRH-ant and GnRH-a groups than in the control group.. GnRH-ant as well as GnRH-a reduced postoperative adhesion formation in a rat model. This finding was supported immunohistochemically by vitronectin and u-PAR staining.

Topics: Animals; Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Immunohistochemistry; Leuprolide; Postoperative Complications; Rats; Rats, Wistar; Receptors, Urokinase Plasminogen Activator; Severity of Illness Index; Time Factors; Tissue Adhesions; Uterine Diseases; Uterus; Vitronectin

The present retrospective and controlled comparative study was designed to evaluate the pregnancy rate achieved using a modified, fixed, multiple-dose 0.125mg gonadotropin-releasing hormone (GnRH) antagonist protocol with the long GnRH agonist protocol as the control group.. One hundred and twenty unselected women between 30 and 40 years of age, in their first cycle of IVF/ICSI, with a baseline follicle-stimulating hormone (FSH) <10 IU and an antral follicle count >3 were assigned into two groups: (1) the study group received 0.125mg of cetrorelix daily starting on Day 6 of stimulation; and (2) the control group received leuprolide daily starting in the mid-luteal phase of the preceding cycle. Both groups were given a flexible dose of recombinant FSH for stimulation. An ongoing pregnancy rate of more than 12 weeks was the primary outcome measure of the study.. Primary and secondary outcomes were comparable in both groups. A shorter duration of stimulation, a lower dosage of recombinant FSH consumption and a thinner endometrium on the day of human chorionic gonadotropin administration were all observed in the GnRH antagonist group.. A dosage of 0.125mg GnRH antagonist protocol was effective for these unselected patients during IVF/ET.

Topics: Adult; Drug Administration Schedule; Embryo Transfer; Female; Fertility Agents, Female; Fertilization in Vitro; Follicle Stimulating Hormone, Human; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Infertility; Leuprolide; Ovulation Induction; Pregnancy; Pregnancy Rate; Retrospective Studies; Sperm Injections, Intracytoplasmic

To compare pregnancy rates following the transfer of thawed frozen embryos according to the type of GnRH antagonist or agonist used during controlled ovarian hyperstimulation (COH).. Retrospective review of frozen embryo transfers according to whether a GnRH agonist or antagonist was used. Furthermore to determine if a specific antagonist/agonist resulted in higher pregnancy rates than the other.. The pregnancy rates in two different age categories were similar whether the COH regimen used the GnRH agonist leuprolide acetate or the GnRH antagonist cetrorelix. However, lower pregnancy rates were found with the GnRH antagonist ganirelix.. These data reached similar conclusions as was found comparing these three agents in fresh embryo transfer.

Topics: Adult; Embryo Transfer; Endometrium; Female; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Ovulation Induction; Pregnancy; Pregnancy Outcome; Retrospective Studies

To compare leuprolide acetate to hCG as the trigger for final oocyte maturation in oocyte donor cycles.. Retrospective review.. Academic IVF donor program.. Thirty-two healthy oocyte donors aged 21-33 years with adequate ovarian reserve.. Donors were down-regulated with cetrorelix and received either leuprolide acetate (n = 12) or hCG (n = 20) for final oocyte maturation.. Embryo number, embryo quality, fertilization, implantation, clinical pregnancy, and ovarian hyperstimulation syndrome rates.. The numbers of total oocytes (23 vs. 15), mature (metaphase II) oocytes (22 vs. 13), embryos (15 vs. 10), and cryopreserved embryos (12 vs. 6) per treatment cycle were significantly greater in the leuprolide arm than in the hCG arm. Fertilization rates (73% vs. 78%), implantation rates (30% vs. 29%), and clinical pregnancy rates (40% vs. 50%) were not statistically different between the arms. There were no cases of ovarian hyperstimulation syndrome.. Leuprolide acetate-triggered oocyte donor cycles yielded similar fertilization, implantation, and clinical pregnancy rates to hCG-triggered cycles.

Topics: Adult; Chorionic Gonadotropin; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Intercellular Signaling Peptides and Proteins; Leuprolide; Oocyte Donation; Oocytes; Ovarian Follicle; Ovulation Induction; Pregnancy; Retrospective Studies; Young Adult

To investigate the effects of a gonadotropin-releasing hormone antagonist (GnRH-ANT) on the expression of anti-Müllerian Hormone (AMH) and aromatase (via the exon CYP19IIa promoter), in cultured human granulosa cells (hGCs) and the human granulosa cell line (HGL5).. Primary cell cultures of hGCs and culture of HGL5 cells.. Academic center.. Women undergoing IVF because of male factor, tubal infertility, or donor eggs.. hGCs and HGL5 cells were treated with a GnRH-ANT (1 nM and 1 μM) alone or in combination with cAMP (1 mM). Media was collected and stored at -80°C until assayed.. mRNA levels of CYP19 IIa, AMH, steroidogenic factor 1 (SF-1) and liver receptor homologue-1 (LRH-1) were determined by quantitative polymerase chain reaction. ELISA was used to determined estradiol (E(2)) levels in the culture media. Pooled results from triplicate experiments were analyzed using one-way analysis of variance with Student-Newman-Keuls multiple-comparison methods.. The GnRH-ANT decreased the expressions of CYP19 IIa, AMH, SF-1, and LRH-1. cAMP induced aromatase and AMH expression. Cotreatment with cAMP and GnRH-ANT caused a dose-dependent suppression of AMH and CYP19 IIa mRNA. A GnRH agonist (GnRH-A) increased the mRNA expressions of CYP 19 IIa and AMH. The GnRH-ANT decreased E(2) production in cultured hGCs.. GnRH-ANTs, in addition to their central suppressive effects on the pituitary, may have a direct effect on ovarian granulosa cells with inhibition of aromatase and AMH expression. Furthermore, the inhibitory effect could be mediated via suppression of SF-1 and LRH-1, and may play a role in estrogen-mediated ovarian folliculogenesis.

Topics: Adult; Anti-Mullerian Hormone; Aromatase; Cell Line; Cells, Cultured; Cyclic AMP; Dose-Response Relationship, Drug; Estradiol; Female; Gonadotropin-Releasing Hormone; Granulosa Cells; Humans; Leuprolide; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Steroidogenic Factor 1

This study evaluated women with a high body mass index (BMI) (>40 kg/m(2)) and low BMI (<18 kg/m(2)) undergoing assisted reproduction treatment and determined whether the type of gonadotrophin-releasing hormone (GnRH) analogue used has an impact on cycle parameters and outcome. The study analysed 65 women with high BMI and 118 with low BMI. In the former group, polycystic ovarian syndrome was significantly more prevalent in the agonist long protocol (ALP) group (P=0.01) and gonadotrophin consumption was lower, peak oestradiol concentrations and total number of oocytes retrieved were higher in the ALP group compared with the antagonist (ANT) group. Implantation rate (IR), pregnancy rate (PR) per embryo transfer and early pregnancy loss rate (EPLR) were similar in both stimulation groups, with overall rates of 21.6%, 55.4% and 44.4%, respectively. In women with low BMI, peak oestradiol concentrations, total oocytes retrieved, mature oocytes and transferred embryos were higher in the ALP group compared with ANT group. IR, PR/embryo transfer and EPLR were similar in both groups, with overall rates of 24.3%, 52.5% and 16.1%, respectively. In all patients, no difference was found between ALP and ANT protocols concerning treatment outcome. Contrary to the reasonable EPLR observed in women with low BMI, the high rate found in women with high BMI is remarkable.

Topics: Abortion, Spontaneous; Adult; Body Mass Index; Embryo Implantation; Embryo Transfer; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Ovulation Induction; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Rate; Retrospective Studies

To determine if controlled ovarian hyperstimulation (COH) regimens using the gonadotropin releasing hormone (GnRH) agonist leuprolide acetate result in higher pregnancy and implantation rates than COH regimens using the GnRH antagonists cetrorelix or ganirelix following fresh and frozen embryo transfer.. Retrospective analysis was performed evaluating the pregnancy rates with the first fresh and first frozen embryo transfer cycles according to which protocol was used. A haphazard decision was made on which protocol to use. Women were required to be < 40 years of age and have had > or = 5 eggs retrieved.. Significantly lower implantation rates were seen with ganirelix compared to leuprolide acetate or cetrorelix.. These data should hopefully encourage interest in a prospective study to determine if conclusions about the inferiority of ganirelix are not merely fortuitous.

Topics: Adult; Cryopreservation; Embryo Transfer; Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Pregnancy; Pregnancy Rate; Retrospective Studies

In the present study, we aimed to compare the effects of cetrorelix and leuprolide on endometriosis.. This randomized, placebo-controlled, single-blind, experimental study was performed on 45 Wistar adult female rats in the Experimental Surgery Laboratory at Ondokuz Mayis University. After the peritoneal implantation of endometrial tissue, rats were randomized to three equal intervention groups: (i) control group, (ii) leuprolide group, and (iii) cetrorelix group. Six weeks later, following implant volume measurements (volume-1) by performing a second laparotomy, saline (0.1 cc/rat) was administered subcutaneously to the control group once a week, leuprolide (0.075 mg/kg) subcutaneously to the leuprolide group twice at 4-week intervals and cetrorelix (0.001 mg/rat/day) subcutaneously to the cetrorelix group for 8 weeks. At the end of the treatment, by performing a third laparotomy, implant volumes were remeasured (volume-2) and implants were totally excised for histopathological examination. The volume-1 and volume-2 values within the groups, and stromal and glandular tissue scores between the groups were compared.. In both the leuprolide group and the cetrorelix group, volume-2 as compared to volume-1 had significantly reduced (P < 0.01, P < 0.01 respectively), while there was no significant volume change in the control group (P > 0.05). In this group, when compared with the control group, glandular and stromal tissues had significantly lessened (P < 0.01, P < 0.01 respectively).. Leuprolide and cetrorelix were found to have similar efficacy in the regression of both the size and the histological structure of experimental endometriotic implants.

Topics: Animals; Antineoplastic Agents, Hormonal; Endometriosis; Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Laparotomy; Leuprolide; Random Allocation; Rats; Rats, Wistar; Single-Blind Method

HOXA10 is an essential regulator of endometrial receptivity. To determine the effect of GnRH antagonists on endometrial receptivity, we assessed endometrial HOXA10 expression in GnRH antagonist, GnRH agonist, and natural cycles.. Prospective case-control study.. University academic medical center.. Nineteen subjects were included: 12 subjects underwent controlled ovarian hyperstimulation with recombinant FSH and used either a GnRH antagonist or a GnRH agonist; seven control subjects underwent natural cycles.. Pipelle endometrial biopsies were obtained 11 days after hCG administration or spontaneous LH surge in untreated cycles, respectively. Immunohistochemistry was used to assess HOXA10 protein expression in endometrial glands and stroma.. Endometrial HOXA10 protein expression.. HOXA10 expression was significantly decreased in endometrial stromal cells in GnRH antagonist-treated cycles compared with GnRH agonist-treated cycles or natural cycle control subjects. There was no significant difference in glandular cell HOXA10 expression among the three groups.. Use of GnRH antagonists may be associated with impaired HOXA10 expression in endometrial stromal cells and thus may affect endometrial receptivity.

Topics: Adult; Biopsy; Case-Control Studies; Endometrium; Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Homeobox A10 Proteins; Homeodomain Proteins; Hormone Antagonists; Humans; Leuprolide; Ovulation Induction; Prospective Studies; RNA, Messenger; Stromal Cells

Prostate cancer (PCa) growth initially depends on circulating androgens. Gonadotropin-releasing hormone (GnRH) agonists are currently used for the treatment of PCa. However, after an initial responsiveness to hormonal deprivation, PCa progresses and metastasizes. Recently, also GnRH antagonists have been used for clinical trials in patients with PCa and the results seem promising. The components of the plasminogen activator (PA) system (urokinase-type PA, uPA; PA inhibitors, PAI-1/2; uPA receptor, uPAR) have been implicated in the local degradation of the extracellular matrix (ECM) and PCa progression. The aim of this study was to test the possible effects of the treatment with an agonist (Leuprolide, GnRH-A) and an antagonist (Cetrorelix, GnRH-ANT) of GnRH on the expression and activity of uPA and PAI-1 in the conditioned media of DU145 and PC3, two PCa androgen-independent cell lines. The involvement of the PA system in the control of cellular migration was also investigated. The results obtained in DU145 and PC3 cells show that both GnRH-A and GnRH-ANT: i) inhibit cell proliferation; ii) significantly decrease the enzymatic activity and the secretion of uPA; iii) significantly increase the protein levels of PAI-1; iv) induce a significant decrease of the migratory and invasion PCa capabilities. This study suggests that GnRH analogues exhibit not only an antiproliferative effect, but also an anti-metastatic action exerted through the inhibition of the activity of PA system and might provide a rational basis for the development of clinical strategies for those tumours that progress towards an androgen-independent condition characterized by a higher metastatic potential.

Topics: Antineoplastic Agents, Hormonal; Blotting, Western; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leuprolide; Male; Neoplasm Invasiveness; Plasminogen Activators; Prostatic Neoplasms

In order to compare the mechanism for the down regulation of the mRNA expression of pituitary receptors induced by GnRH antagonist (GnRHant) to that by GnRH agonist (GnRHa), we examined the effects of GnRHant (Cetrorelix, 333 mug/kg/day), GnRHa (leuprolide depot, 333 microg/kg), and GnRHant combined with GnRHa on LH response to exogenous GnRH, pituitary LH content, LH beta subunit mRNA, and GnRH receptor (GnRH-R) mRNA levels at 2, 5, 24, 72 hours, and 7 days after the treatment in ovariectomized rats. GnRHant significantly decreased serum LH, the LH response of the pituitary to exogenous GnRH, and the pituitary LH content compared to the control treatment, though GnRHa significantly increased serum LH. GnRHant with GnRHa significantly diminished the GnRHa-induced flare-up phenomenon. GnRHant significantly decreased LH beta mRNA and GnRH-R mRNA levels, but the magnitude of the decrease in these mRNA levels by GnRHant was significantly less than those by GnRHa until 72 hours following treatment. Prolonged treatment of GnRHant caused a marked inhibition of LH beta mRNA and GnRH-R mRNA expression, similar to that caused by GnRHa. Combination treatment with GnRHa and GnRHant was demonstrated to decrease LH beta mRNA and GnRH-R mRNA levels as much as GnRHa alone and GnRHant alone over 7 days of the treatment. The present study showed differences between GnRHant and GnRHa treatment in the reduction of GnRH-R mRNA levels up to 72 hours after the treatment, and indicated that the suppression of GnRH-R mRNA by GnRHant was the maximal by GnRHa 7 days after the treatment because more profound suppression was not observed upon additional treatment with GnRHa. The findings in the present study support the hypothesis that the mechanism by which GnRHant leads to down-regulation of the mRNA expression of pituitary receptors is similar to that of GnRHa.

Topics: Animals; Delayed-Action Preparations; Down-Regulation; Drug Synergism; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hormone Antagonists; Leuprolide; Luteinizing Hormone; Luteinizing Hormone, beta Subunit; Pituitary Gland; Rats; Rats, Sprague-Dawley; Receptors, LHRH; RNA, Messenger

GnRH analogs have antiproliferative and/or apoptotic effects on prostate cancer cells. Also, neurotrophin receptors TrkA and p75 have been reported in normal prostate suggesting a role in the gland growth control. In prostate cancer, TrkA receptors seem to be overexpressed and p75 receptors show a decreased expression. These changes in neurotrophin receptors may be related with unbalanced growth in malignant cells. In the present study we investigate the effects of GnRH analogs (leuprolide and cetrorelix) on the expression of TrkA and p75 neurotrophin receptors in primary cultures of human prostate cancer cells.. Tissue was obtained from radical prostatectomies due to prostate adenocarcinoma. Cells were isolated after sequential enzyme digestion and cultured in defined media. Nerve growth factor (NGF) receptors in untreated cultures were estimated by immunofluorescence. Cultures were treated with leuprolide (agonist) or cetrorelix (antagonist) and expression of TrkA and p75 receptors were evaluated by semi quantitative RT-PCR (polymerase chain reaction) and western blot. Cell proliferation was estimated by MTT method and apoptosis through COMET assay.. Both leuprolide and cetrorelix induced a significant increase in p75 receptor gene and protein expression at a concentration that induce apoptosis and decrease proliferation. TrkA receptors showed no changes in presence of GnRH analogs.. GnRH analogs, leuprolide, and cetrorelix, change the ratio between neurotrophin receptors TrkA and p75 by increasing gene and protein expression of p75 receptor. Considering that TrkA receptor is related with proliferation and p75 with apoptosis, we suggest that our findings may explain, in part, the effect of GnRH analogs on prostate cancer growth.

Topics: Adenocarcinoma; Antineoplastic Agents, Hormonal; Apoptosis; Blotting, Western; Cell Proliferation; Comet Assay; Epithelial Cells; Formazans; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms; Receptor, Nerve Growth Factor; Receptor, trkA; Receptors, Nerve Growth Factor; Reverse Transcriptase Polymerase Chain Reaction; Tetrazolium Salts

To compare embryo implantation in Wistar rats submitted to ovarian stimulation using recombinant FSH (rFSH) with cetrorelix acetate or leuprolide acetate.. Experimental study.. Faculty of medicine animal facility.. Fifty-six female Wistar rats with normal estrus cycles and 30 male.. Ovarian stimulation and laparotomy (by the day 13 of gestation).. Embryo implantation.. The female rats were subdivided into four groups: group 1, medicated with rFSH, hCG, and cetrorelix acetate; group 2, medicated with rFSH, hCG, and leuprolide acetate; group 3, medicated with rFSH and hCG; and group 4, in which only saline solution was administered. The female rats were mated with fertile male rats on the day of hCG administration with copulation confirmed through cytologic vaginal analysis. The females were killed on the 13th day of gestation. After laparotomy, comparison and identification was done regarding the numbers of corpora lutea and embryo implantations and gestation rates. Group 1 presented lower numbers of corpora lutea and embryo implantations in comparison to the other groups (P<.05). A difference was not found in the gestation rates between the groups.. The number of embryo implantations in Wistar rats medicated with rFSH and cetrorelix acetate is lower than that of rats medicated with rFSH and leuprolide acetate.

Topics: Animals; Embryo Implantation; Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Gonadotropins; Hormone Antagonists; Leuprolide; Male; Ovulation Induction; Pregnancy; Rats; Rats, Wistar

GnRH agonists and antagonists are utilized for avoiding premature ovulation in assisted reproductive cycles, (ART) this retrospective study was designed to compare both treatments in controlled ovarian hyperstimulation (HOC) in oocyte donors.. Between Jan99 and Mar03, 141 oocyte donors underwent ART receiving either 0.25 mg daily of a GnRH antagonist (Cetrorelix) from day 6 of stimulation (51 patients) or a long protocol with a GnRH agonist (Leuprolide acetate) (90 patients.) FSHr alone or with HMG or LHr were employed for ovarian stimulation. hCG (Profasi, Serono) was administrated when more than three follicles above 18 mm in diameter were observed, oocyte retrieval was performed 34 hours later. Embryo transfer was performed 3-5 days later.. Both groups were homogeneus for age (p=0.142), day 3 FSH (p=0.115), type and total dose of gonadotrophins utilized. There were no significant differences in follicles number (p=0.522), oestradiol levels on the day of hCG (p=0.310) and fertilization rates (p=0.177) The mean number of oocytes retrieved and metaphase II oocytes was significantly lower in GnRH agonist group, (12 vs. 13.9, p=0.05 and 8.6 vs 11; p=0.007) There was no statistical differences in pregnancy and implantation rates between agonist and antagonist groups (52.2% vs 60.8%, 15.1% vs 18.3%; p=0.327 and 0.652).. The high number of metaphase oocytes and the high pregnancy rate observed in the oocyte donors provide evidence that GnRH antagonist does not impair ovarian response, embryo quality or pregnany rates. In oocyte donors cycles the GnRH antagonist is a valid alternative to GnRH agonist, providing the benefit of more flexibility in patient's scheduling.

Topics: Adult; Embryo Implantation; Estradiol; Female; Fertility Agents, Female; Fertilization; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Infertility; Leuprolide; Oocyte Donation; Ovarian Hyperstimulation Syndrome; Ovulation Induction; Pregnancy; Retrospective Studies; Treatment Outcome

Luteinizing hormone-releasing hormone (LHRH) antagonists work by directly inhibiting LHRH without any initial stimulation of the LHRH receptor. The physiologic response is a direct and rapid decrease in luteinizing hormone, follicle-stimulating hormone, and testosterone without any flare. Although there has been extensive basic-science work on these medications, practical shortcomings have limited clinical studies in prostate cancer. Many of these compounds induce significant histamine-mediated side effects, and until recently, no depot form existed. In 2 recent phase-3 studies comparing abarelix depot with leuprolide and with leuprolide plus bicalutamide, abarelix lowered serum testosterone more quickly. None of the 89 patients on leuprolide alone were castrate on day 8 as opposed to 72% of the 180 patients randomized to abarelix (P <0.001). Similarly, none of the combination group were castrate by day 8, whereas 68% of the abarelix patients were castrate (P <0.001). In addition, 82% of the patients treated with leuprolide and 86% of those given leuprolide/bicalutamide had testosterone surge, whereas none of the abarelix patients did (P <0.001 for both studies). Both phase 2 and phase 3 data show abarelix to be well tolerated. In conclusion, LHRH antagonists offer the physiologic response of orchiectomy without surgery. These medications are well tolerated and a depot form now exists. The expansion of indications for androgen deprivation, such as downsizing or intermittent therapy, could provide many opportunities for their use. Despite these encouraging advances, however, their routine use for advanced prostate cancer may depend on demonstration of a survival advantage in avoiding flare.

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Disease-Free Survival; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leuprolide; Male; Oligopeptides; Orchiectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Testosterone; Therapeutics; Treatment Outcome

In order to investigate whether gonadotrophin-releasing hormone (GnRH) antagonists exert a significant effect on steroid secretion in vivo compared with GnRH agonists, concentrations of sex steroid hormones (oestradiol, progesterone and testosterone) were studied in follicular fluid from women undergoing ovarian stimulation and treated with either GnRH agonist or antagonist. In addition, the correlation between follicular fluid steroid hormone concentrations and variables of follicular and oocyte development was evaluated.. Microparticle enzyme immunoassay and radioimmunoassays were used.. The mean (SEM) follicular fluid oestradiol concentration was significantly lower in patients treated with GnRH antagonist than in those treated with GnRH agonist (542.0 +/- 76.9 versus 873.0 +/- 105.1 pg/ml, P = 0.02), which correlates with the mean serum oestradiol concentrations found in these two groups. No significant differences were found between groups in follicular fluid progesterone concentrations. Women undergoing GnRH antagonist treatment showed similar concentrations of follicular fluid testosterone compared with GnRH agonist-treated women (14.8 +/- 1.1 versus 13.3 +/- 2.7 ng/ml). The oestradiol:testosterone ratio was markedly reduced in women treated with GnRH antagonist (49.1 +/- 2.3 versus 60.1 +/- 4.4, P = 0.04). In contrast, no differences were found either in the progesterone:testosterone ratio, or in the oestradiol:progesterone ratio.. GnRH antagonist therapy in women undergoing ovarian stimulation had a significant effect on ovarian follicular steroidogenesis.

Topics: Adult; Chorionic Gonadotropin; Estradiol; Female; Fertilization in Vitro; Follicle Stimulating Hormone; Follicular Fluid; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone; Humans; Immunoenzyme Techniques; Leuprolide; Ovary; Ovulation Induction; Progesterone; Radioimmunoassay; Recombinant Proteins; Sperm Injections, Intracytoplasmic; Testosterone

We studied the effects of luteinising hormone-releasing hormone (LHRH) agonist leuproreline (1 microM for 96 h) and LHRH antagonist cetrorelix on the cell growth of primary cultures from nine human endometrial cancers using the sulphorhodamine colorimetric test. Histological examinations and reverse transcription and polymerase chain reaction amplification (RT-PCR) for LHRH receptors were also performed. The endometrial cancers examined had a medium to high degree of proliferative activity and a low degree of apoptotic power; furthermore, they expressed the LHRH receptor RNA variably, detectable in 71% of cases. The addition of leuproreline or cetrorelix to cell cultures inhibited growth in a statistically significant way compared to untreated control cells; nevertheless, the percentage of cell growth inhibition obtained was very variable. These data suggest that LHRH analogues can exert differential inhibitory effects on the growth of endometrial cancer, which seems to be independent of the expression of specific LHRH receptors.

Topics: Aged; Cell Division; Endometrial Neoplasms; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Middle Aged; Postmenopause; Receptors, LHRH; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured