cetrorelix and Body-Weight

To determine the minimal effective daily dose of gonadotropin-releasing hormone (GnRH) antagonist in lower-weight Asian women undergoing controlled ovarian hyperstimulation (COH).. A prospective randomized controlled trial of GnRH antagonist was performed. A total of 58 women with body weight of 40-50 kg accepted COH and transvaginal embryo transfer. Patients were divided into two groups: Group 1 patients (n = 28) were given a fixed cetrorelix dose of 0.2 mg/day; Group 2 patients (n = 30) were given a fixed cetrorelix dose of 0.15 mg/day. Cetrorelix was administered from menstrual day 8 until the day of human chorionic gonadotropin (hCG) administration. Serum luteinizing hormone (LH) and estradiol (E2) concentration were measured on the day of hCG administration. Gonadotropin dosages, LH and E2 concentrations, retrieved oocyte and embryo numbers, ovarian hyperstimulation syndrome (OHSS), embryo quality, and the rates of fertilization, implantation and pregnancy in both groups were compared.. The clinical pregnancy/implantation rates in Group 1 were higher than those in Group 2 (28.6%/10.4% vs. 20%/4.1%). The numbers of oocytes retrieved/Grade I-II embryos were higher in Group 1 than Group 2 (10.5/7.8 vs. 8.3/3.9). A lower percentage of LH surge and higher E2 levels on the day of hCG administration were observed in Group 1 compared to Group 2 (5.9%/1,610.8 pg/mL vs. 26.7%/1,023.6 pg/mL). There were no statistical differences between the two groups when comparing gonadotropin dosage and OHSS.. The lowest effective dosage of cetrorelix is 0.2 mg in COH and pituitary downregulation for lower-weight Asian women.

Topics: Adult; Asian People; Body Weight; Embryo Implantation; Estradiol; Female; Fertilization in Vitro; Follicle Stimulating Hormone, Human; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Luteinizing Hormone; Ovulation; Ovulation Induction; Pregnancy; Prospective Studies; Treatment Outcome

Although histopathology is considered the gold standard for assessing testicular toxicity in the nonclinical setting, identification of noninvasive biomarkers for testicular injury are desirable to improve safety monitoring capabilities for clinical trials. Inhibin B has been investigated as a noninvasive biomarker for testicular toxicity. This study investigates the correlation of Inhibin B in Wistar Han rats with the onset and reversibility of testicular histopathology from classical testicular toxicants carbendazim, cetrorelix acetate (CTX), and 1,2-dibromo-3-chloropropane (DBCP). The dose regimen included Interim (day 8), Drug (day 29), and nondosing Recovery (day 58) Phases. Inhibin B was not effective at predicting the onset of carbendazim- or CTX-mediated testicular pathology in rats. Inhibin B was reduced by DBCP administration at the end of the Drug Phase only, acting as a leading indicator of the onset of testicular toxicity before the onset of germ cell depletion. However, since Inhibin B was only decreased at the end of the Dosing Phase and not at the Recovery Phase, when the onset of testicular pathology occurred, it is unclear if monitoring Inhibin B would provide sufficient advanced warning for the onset of testicular pathology. Furthermore, follicle stimulating hormone was decreased following CTX and DBCP administration in the Interim Phase and CTX in the Drug Phase. Inhibin B has limited predictive capacity as a leading testicular biomarker in rats.

Topics: Animals; Benzimidazoles; Biomarkers; Body Weight; Carbamates; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Inhibins; Luteinizing Hormone; Male; Organ Size; Propane; Rats; Rats, Wistar; Survival Analysis; Testis

Long-term treatment with gonadoliberin analogs is used to block the hypothalamic-pituitary-gonadal axis. The use of these agents is generally considered to be safe; however, some observations suggest the possibility of adverse effects.. We investigated whether a 3-months administration of a low dose (6 µg/kg b.w.) of dalarelin - a new agonist, and cetrorelix - a known antagonist of GnRH to female rats causes morphological changes in pituitary gland, ovaries, uterus and liver (HE and VG staining); effects on pituitary, hepatic and blood enzyme activities (histochemical and kinetic methods, respectively), and on the blood lipid profile (colorimetric methods); and to what extent these changes are reversible.. Applying analogs effectively inhibited ovulation, affected the uterine endometrium and changed histological appearance of the liver (e.g., steatosis). They altered activities of marker enzymes of cellular respiration, gluconeogenesis and intracellular digestion in the liver and, partially in the pituitary gland, caused undesirable changes in the activities of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and creatine kinase, and a concentration of cholesterol HDL fraction and triglycerides in the blood. Both morphological and enzymatic effects were more evident after antagonist administration; changes in the blood lipid profile were more evident after agonist administration. In both analogs histological and enzymatic changes persisted a relatively long time after the discontinuation of the treatment.. The low dose of dalarelin and cetrorelix is sufficient to cause limited damage of hepatic cells and may modify the function of pituitary, ovaries, uterus and liver as well as other organs, even after discontinuation of the treatment.

Topics: Animals; Body Weight; Densitometry; Dose-Response Relationship, Drug; Enzymes; Female; Gonadotropin-Releasing Hormone; Immunohistochemistry; Liver; Organ Size; Organ Specificity; Ovary; Pituitary Gland; Rats; Rats, Sprague-Dawley; Time Factors; Uterus

The question of whether adjustment to body weight is necessary in in-vitro fertilization (IVF) cycles using GnRH antagonists is currently under discussion. Therefore, a data analysis of five prospective studies using either the single- or the multiple-dose antagonist protocol with cetrorelix (Cetrotide) was performed. The influence of stimulation procedure, gonadotrophins and body weight on pregnancy rate was evaluated in a linear logit model. The effect of the stimulation procedure and body weight on the cumulus-oocyte complex (COC) and follicle number was explored in an ANOVA model. Cetrorelix plasma concentrations were tested for any correlation with body weight. Baseline and outcome parameters in different body weight groups (<50 kg, 50-59 kg, 60-69 kg, 70-79 kg, > or =80 kg) were assessed for human menopausal gonadotrophin and recombinant human FSH stimulation separately. Cetrorelix plasma concentrations were correlated with body weight, but no influence of the type of stimulation or body weight on pregnancy rate was found. Body weight did not influence cetrorelix plasma concentrations. In contrast, body weight significantly influenced the number of retrieved COC as well as the number of follicles on the day of human chorionic gonadotrophin administration. Body weight does not influence the outcome of treatment in cetrorelix cycles.

Topics: Body Weight; Cell Count; Female; Fertilization in Vitro; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Linear Models; Menotropins; Oocytes; Osmolar Concentration; Ovarian Follicle; Ovulation Induction; Pregnancy; Pregnancy Rate; Retrospective Studies; Tissue and Organ Harvesting; Treatment Outcome

Although the gonadotropic control of the spermatogenic process is well established, the endocrine regulation of the timing and kinetics of germ cell development has received little attention. We found previously that the administration of a GnRH antagonist (ANT) over a period of 25 days could retard spermatid development and slightly prolong cycle length in intact adult cynomolgus monkeys (Macaca fascicularis). The aim of the present study was to investigate the effects of extended exposure to ANT on the duration of the cycle of the seminiferous epithelium in the monkey. Additionally, the duration of spermatogenesis was studied in the ANT-exposed rat model. In experiment 1, monkeys were given either saline or ANT (n=6/group) and on day 30 all animals received a single injection of 5-bromodeoxyuridine (BrdU) to label S-phase germ cells. Testicular biopsies were taken on days 39, 43, 47 and 51 (end of treatment) for BrdU localization and flow cytometric analysis. ANT treatment suppressed hormone levels, reduced testis size by >70% and severely impaired germ cell production. Despite these alterations, cycle duration remained unchanged at all time-points compared with controls (10.12+/-0.15 days vs 10.16+/- 0.44 days). In experiment 2, adult male Sprague-Dawley rats (n=15/group) received either vehicle (VEH) or ANT for 14 days and received BrdU injection on day 2. Cycle duration was found to be shorter in the ANT-treated group (12.45+/-0.09 days) than in the control group (12.75+/-0.08, P<0.05). As spermatogenic cycle length in this control group was longer than that of our historical controls (range: 12.37-12.53 days), experiment 2 was repeated (n=10/group). In experiment 3, cycle duration was 12.51+/-0.02 for VEH and 12.46+/-0.05 for the ANT-treated group (P>0.05) in both species. We concluded that the duration of the cycle of the seminiferous epithelium in monkeys and rats is independent of gonadotropins but is rather regulated by the spermatogenic tissue itself.

Topics: Animals; Body Weight; Bromodeoxyuridine; Gonadotropin-Releasing Hormone; Gonadotropins; Hormone Antagonists; Macaca fascicularis; Male; Organ Size; Rats; Rats, Sprague-Dawley; Seminiferous Epithelium; Spermatogenesis; Testis; Testosterone

The aim of this study was to test the antagonist of LH-RH (Cetrorelix), agonist [D-Trp6]LH-RH (triptorelin) and new bombesin antagonists RC-3940-II and RC-3950-II for their effect on the growth of an androgen-independent prostate cancer cell line, DU-145, xenografted into nude mice. Xenografts were grown in male nude mice, and after 4 weeks, the animals were treated either with saline (control) or with one of the analogues. One group of mice was given a combination of Cetrorelix and RC-3950-II. Treatment was given for 4 weeks. Tumour and body weights, and tumour volumes were measured. At sacrifice, tumours were dissected for histological examination and receptor studies. Serum was collected for measurement of hormone levels. The final tumour volume in control animals injected with saline was 577 +/- 155 mm3 and that of animals treated with Cetrorelix only 121.4 +/- 45 mm3 (P < 0.01). Bombesin antagonists RC-3940-II and RC-3950-II also significantly reduced DU-145 tumour volume in nude mice to 84.9 +/- 19.9 and 96.8 +/- 28 mm3, respectively. Agonist [D-Trp6]LH-RH did not significantly inhibit tumour growth. Serum levels of LH were decreased to 0.08 +/- 0.02 ng/ml (P < 0.05) in the Cetrorelix treated group as compared to 1.02 +/- 0.1 ng/ml for the controls, and testosterone levels were reduced to castration levels (0.01 +/- 0.01 ng/ml). Specific receptors for EGF and LH-RH in DU-145 tumours were significantly downregulated after treatment with Cetrorelix, RC-3940-II and RC-3950-II. Although LH-RH could be a local regulator of growth of prostate cancer, the fall in LH-RH receptors is not fully understood and the inhibitory effects of Cetrorelix and bombesin antagonists on DU-145 tumour growth might be attributed at least in part to a downregulation of EHF receptors. Since Cetrorelix and bombesin antagonists inhibit growth of androgen-independent DU-145 prostate cancers, these compounds could be considered for the therapy of advanced prostate cancer in men, especially after relapse.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Bombesin; ErbB Receptors; Gastrins; Genitalia, Male; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Male; Mice; Mice, Nude; Peptide Fragments; Prostatic Neoplasms; Receptors, Bombesin; Receptors, LHRH; Testosterone; Transplantation, Heterologous; Tumor Cells, Cultured

We investigated the effects of our synthetic bombesin/gastrin-releasing peptide (GRP) antagonists and somatostatin analogue RC-160 on the growth of human small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (non-SCLC) lines in nude mice. Athymic nude mice bearing xenografts of the SCLC NCl-H69 line or non-SCLC NCl-H157 line were treated for 5 and 4 weeks, respectively, with somatostatin analogue RC-160 or various bombesin/GRP antagonists. RC-160, administered s.c. peritumorally at a dose of 100 micrograms per animal per day, inhibited the growth of H69 SCLC xenografts as shown by more than 70% reduction in tumour volumes and weights, as compared with the control group. Bombesin/GRP antagonists, RC-3440, RC-3095 and RC-3950-II, given s.c. peritumorally at a dose of 20 micrograms per animal per day, also inhibited the growth of H69 SCLC tumours. RC-3950-II had the greatest inhibitory effect and decreased tumour volume and weights by more than 80%. The growth of H-157 non-SCLC xenografts was significantly reduced by treatment with RC-160, but not with bombesin/GRP antagonist RC-3095. In mice bearing either tumour model, administration of RC-160 significantly decreased serum growth hormone and gastrin levels. Specific high-affinity receptors for bombesin and somatostatin were found on membranes of SCLC H69 tumours, but not on non-SCLC H157 tumours. Receptor analyses demonstrated high-affinity binding sites for epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) on the membranes of H69 and H157 tumours. EGF receptors were down-regulated on H69 tumours after treatment with RC-160 and bombesin/GRP antagonists. The concentration of binding sites for EGF and IGF-I on the H157 tumours was decreased after treatment with RC-160, but bombesin/GRP antagonist RC-3095 had no effect. These results demonstrate that bombesin/GRP antagonists inhibit the growth of H-69 SCLC, but not of H-157 non-SCLC xenografts in nude mice, whereas somatostatin analogue RC-160 is effective in both tumour models. This raises the possibility that these peptide analogues could be used selectively in the treatment of various subclasses of lung cancer.

Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Binding Sites; Body Weight; Bombesin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cell Division; Gastrin-Releasing Peptide; Gastrins; Gonadotropin-Releasing Hormone; Growth Hormone; Humans; Lung Neoplasms; Male; Mice; Mice, Nude; Molecular Sequence Data; Neoplasm Transplantation; Peptide Fragments; Peptides; Receptors, Somatotropin; Somatostatin; Substrate Specificity; Transplantation, Heterologous

Female BDF1 mice inoculated with MXT (3.2) estrogen independent mouse mammary carcinoma were treated for three weeks with microcapsules of the luteinizing hormone-releasing hormone (LH-RH) agonist [D-Trp6]LH-RH, the antagonist SB-75, the somatostatin analog RC-160, or combinations. The lack of estrogen dependence of the tumor was proved by bilateral surgical ovariectomy, which had no effect. In two experiments, treatment with 25 micrograms/day doses of each analog alone resulted in a significant inhibition of tumor growth as shown by a 40-53% inhibition of tumor volumes, 38-43% decrease in tumor weights, and histological signs of tumor regression. However, the combination of SB-75 or [D-Trp6]LH-RH with somatostatin analog RC-160 caused greater reduction of tumor volume (68 and 61%) or tumor weights (59 and 56%), than single analogs, and histologically the occurrence of apoptosis and decrease in AgNOR numbers was more pronounced in the groups receiving combination therapy. Specific binding sites for [D-Trp6]LH-RH, EGF, and IGF-I were demonstrated in the tumor membranes. The binding capacity of LH-RH receptors was decreased by treatment with the analogs, the greatest down-regulation being caused by combination therapy. A significant decrease in EGF binding capacity was observed after treatment with the LH-RH analogs, alone or especially in combination with somatostatin analog RC-160. The combination of these analogs also caused a reduction in IGF-I receptors. The finding that LH-RH agonists and antagonists and somatostatin analogs inhibit the growth of estrogen independent mammary tumors, and that combinations are more effective than single analogs, might be of practical importance in human breast cancer therapy.

Topics: Amino Acid Sequence; Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Drug Compounding; Drug Screening Assays, Antitumor; Drug Synergism; Female; Gonadotropin-Releasing Hormone; Mammary Neoplasms, Experimental; Mice; Molecular Sequence Data; Neoplasm Proteins; Receptors, Cell Surface; Somatostatin; Triptorelin Pamoate

Inhibitory effects of the sustained delivery systems (microcapsules and microgranules) of a potent antagonist of luteinizing hormone-releasing hormone N-Ac-[3-(2-naphthyl)-D-alanine1, 4-chloro-D-phenylalanine2, 3-(3-pyridyl)-D-alanine3, D-citrulline6, D-alanine10]LH-RH (SB-75) on the growth of experimental prostate cancers were investigated. In the first experiment, three doses of a microcapsule preparation releasing 23.8, 47.6, and 71.4 micrograms of antagonist SB-75 per day were compared with microcapsules of agonist [D-Trp6]LH-RH liberating 25 micrograms/day in rats bearing Dunning R3327H transplantable prostate carcinoma. During 8 weeks of treatment, tumor growth was decreased by [D-Trp6]LH-RH and all three doses of SB-75 as compared to untreated controls. The highest dose of SB-75 (71.4 micrograms/day) caused a greater inhibition of prostate cancer growth than [D-Trp6]LH-RH as based on measurement of tumor volume and percentage change in tumor volume. Doses of 23.8 and 47.6 micrograms of SB-75 per day induced a partial and submaximal decrease, respectively, in tumor weight and volume. Tumor doubling time was the longest (50 days) with the high dose of SB-75 vs. 15 days for controls. The body weights were unchanged. The weights of testes, seminal vesicles, and ventral prostate were greatly reduced in all three groups that received SB-75, and testosterone levels were decreased to nondetectable values in the case of the two higher doses of SB-75. LH levels were also diminished. Similar results were obtained in the second experiment, in which the animals were treated for a period of 8 weeks with microgranules of SB-75. Therapy with microgranules of SB-75 significantly decreased tumor growth as measured by the final tumor volume, the percentage change from the initial tumor volume, and the reduction in tumor weight. The results indicate that antagonist SB-75, released from sustained delivery systems, can produce a state of chemical castration and effectively inhibit the growth of experimental prostate cancers. The efficacy of the antagonist SB-75 in inhibiting androgen-dependent Dunning prostatic carcinoma and the absence of side effects suggest its possible usefulness for the treatment of hormone-sensitive tumors.

Topics: Adenocarcinoma; Animals; Body Weight; Capsules; Delayed-Action Preparations; Dose-Response Relationship, Drug; Gonadotropin-Releasing Hormone; Male; Organ Size; Prostatic Neoplasms; Rats; Rats, Inbred Strains

Female BDF1 mice bearing MXT mammary adenocarcinomas were treated for 3 weeks with the luteinizing hormone-releasing hormone (LH-RH) antagonist [Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10]-LH-RH (SB-75), with the agonist D-Trp6-LH-RH, with tamoxifen (5 micrograms per animal per day subcutaneously), with the combination of D-Trp6-LH-RH and tamoxifen, or by surgical ovariectomy. SB-75 and D-Trp6-LH-RH were administered in the form of microcapsules releasing 25 micrograms/day. The reduction in tumor weights after treatment with SB-75, D-Trp6-LH-RH, D-Trp6-LH-RH plus tamoxifen, or ovariectomy was 84%, 64%, 33%, and 67%, respectively. Tamoxifen alone was ineffective. Histologically, the regressive changes in the treated tumors were characteristic of apoptosis (programmed cell death). In view of its potency and its immediate inhibitory effect, the LH-RH antagonist SB-75 should be considered as a possible new hormonal agent for the treatment of breast cancer.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Body Weight; ErbB Receptors; Female; Gonadotropin-Releasing Hormone; Insulin-Like Growth Factor I; Luteinizing Hormone; Mammary Neoplasms, Experimental; Mice; Receptors, Cell Surface; Receptors, LH; Receptors, Somatomedin