trelstar and Disease-Models--Animal

Topics: Age Factors; Carcinoma; Clinical Trials as Topic; Disease Models, Animal; Female; Follicle Stimulating Hormone; Gonadotropins; Goserelin; Humans; Leuprolide; Luteinizing Hormone; Menopause; Middle Aged; Ovarian Neoplasms; Receptors, LHRH; Remission Induction; Risk Factors; Survival Rate; Treatment Outcome; Triptorelin Pamoate

To determine the effect of dopamine agonists in a surgically induced endometriosis model on rats.. In this prospective randomized experimental study, surgical induction of endometriosis was performed by autotransplantation technique on 52 adult female Wistar-Albino rats. Endometriosis formation was confirmed by a second-look laparotomy (n:48) 1 month later. Four study groups were randomly generated according to their treatment regimens: group 1 (leuprolide acetate, n = 12), group 2 (bromocriptine, n = 12), group 3 (cabergoline, n = 12) and group 4 (control, n = 12). Endometriotic implants were excised for histopathological examination after treatment at the setting of laparotomy. The mean surface areas and histopathological glandular tissue (GT) and stromal tissue (ST) scores of endometriotic implants were studied and compared among groups.. After 30 days of treatment, the mean surface area of the endometriotic implants of leuprolide acetate, bromocriptine and cabergoline groups was significantly decreased. The regression of endometriotic foci size in comparison to control was highest in group 1, followed by group 2, then group 3. In the histopathological evaluation both the ST and GT scores of group 1, 2 and 3 were significantly decreased in comparison to controls without a statistically significant difference between the groups.. Dopamine agonists are as effective as GnRH agonists in the regression of experimental endometriotic implants in rats. Further trials are needed to elucidate the pathways affected by dopamine agonists.

Topics: Adult; Animals; Antineoplastic Agents; Bromocriptine; Cabergoline; Disease Models, Animal; Dopamine Agonists; Endometriosis; Endometrium; Ergolines; Female; Gonadotropin-Releasing Hormone; Humans; Laparotomy; Leuprolide; Prospective Studies; Random Allocation; Rats; Rats, Wistar; Triptorelin Pamoate

To present a rat model of subcutaneous endometriosis for the study of pathophysiology and the effects of drugs.. Fifty three-month-old female Wistar rats (Rattus norvergicus) were distributed into one control group and four treatment groups: estradiol (2.5; 5; 10 mg/kg s.c.), medroxyprogesterone acetate (0.5; 2; 5 mg/kg s.c.), triptorelin pamoate (0.18; 0.56 mg/kg s.c.) and acetylsalicylic acid (3 mg/kg per os). The animals were autoimplanted subcutaneously with 4x4-mm uterine fragments to induce endometriosis. The endometriomas were measured on days 1, 7, 14 and 21. The relative dry and wet weights of the endometrioma were used to evaluate response to the drug. Endometrial-like tissue was confirmed by histology. The greatest weight gain was observed on day 14 (relative wet weight: 29.1 ± 6.7 mg%, relative dry weight: 5.3 ± 0.9 mg %). Treatments were administered between day 5 and day 14.. The relative wet weight of the hemiuterus in the 10 mg/kg estradiol group differed significantly from control and the other two estradiol groups (p=0.0001). In the medroxyprogesterone acetate group the weight decreased significantly but this decrease was not dose-dependent. Weight reduction was also significant in the triptorelin pamoate and the acetylsalicylic acid groups.. The model of subcutaneous endometriosis is reproducible, low-cost and easy to perform, and suitable for the study of pathophysiology and the effects of drugs.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Hormonal; Aspirin; Connective Tissue Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Endometriosis; Estradiol; Estrogens; Female; Medroxyprogesterone Acetate; Rats, Wistar; Reproducibility of Results; Subcutaneous Tissue; Time Factors; Triptorelin Pamoate

To study antitumor activity of triptorelin - agonist of gonadotropin-releasing hormone and exemestane - inhibitor of aromatase in monotherapy and in combination with cisplatin on the model of receptor-positive for estrogens and progesterone malignant ascites transplantable ovarian tumor (TOT), to assess therapeutic pathomorphosis and level of VEGF expression in tumor cells using diffe-rent combinations of cytostatics and hormonal drugs.. 72 female Wistar rats, which underwent intraperitoneal transplantation of ascitic TOT, by 5·10(6) cells per animal, have been involved in the study. Rats were divided into 8 groups, 9 rats in each group. Histological study with assessment of therapeutic pathomorphosis in TOT and immunohistochemical study has been carried out. Survival of animals in the studied groups has been evaluated.. Among animals treated in regimen of monotherapy, the most pronounced antiangiogenic activity in TOT has been observed on application of hormonal drugs (triptorelin - 39.4 ± 1.9 and exemestane - 33.9 ± 1.4%; р = 0.003), the highest grade of treatment pathomorphosis in TOT has been observed at treatment with cisplatin (11.7%; р = 0.001). Combination of triptorelin and exemestane has amplified antiangiogenic activity in TOT (12.2 ± 0.9%; р = 0.001), but has not significantly changed rates of pathomorphosis (22.1 ± 0.4%; р=0.005) and survival of animals (32.2%; р = 0.007) as compared with the same rates in rats treated with hormonal drugs in monotherapy. Significant correlation between VEGF expression and pathomorphosis has been established (relative part of viable tumor tissue (RPVTT)) in TOT (r = 0.712; р = 0.001), as well as between RPVTT and life-span of animals (r = -0.320; р = 0.007). However, lack of correlation between VEGF expression in cells of TOT and survival of rats has been determined (r = -0.194; р = 0.11). Combination of cytostatic agent with triptorelin or exemestane has demonstrated significantly high rates of therapeutic pathomorphosis (10.1 ± 0.1% and 16.2 ± 0.3%, respectively) and antiangiogenic activity in TOT (21.4 ± 1.4% and 15.0 ± 1.3%, respectively) as well as the highest survival of animals (100.0%, increase of life-span (ILS) = 231.9% and 85.7%, ILS = 205.8%, respectively) as compared with the same one in rats treated in regimen of monotherapy with cisplatin, triptorelin, exemestane or by combination of hormonal drugs. Among animals treated by combination of cytostatic drug with triptorelin, two were cured, and among rats, which received cisplatin and exemestane, one animal was cured.. Triptorelin and exemestane increase antitumor activity of cisplatin in respect to the malignant ascitic TOT and significantly increase survival of animals, especially when triptorelin and cisplatin are used in combination.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Androstadienes; Animals; Antineoplastic Agents; Apoptosis; Aromatase Inhibitors; Ascites; Cell Proliferation; Cisplatin; Disease Models, Animal; Drug Synergism; Female; Gonadotropin-Releasing Hormone; Immunoenzyme Techniques; Ovarian Neoplasms; Rats; Rats, Wistar; Triptorelin Pamoate; Tumor Cells, Cultured

In the male, metabolic syndrome (MetS) is associated to an increased risk of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). A recently established rabbit model of high fat diet (HFD)-induced MetS showed hypogonadism and the presence of prostate gland alterations, including inflammation, hypoxia and fibrosis. The present study investigated whether HFD-induced MetS might also alter bladder structure and function. Testosterone and the farnesoid X receptor (FXR) agonist INT-747, were evaluated for possible effects on HFD bladder. MetS rabbits develop bladder alterations, including fibrosis (reduced muscle/fiber ratio), hypoxia [2-fold increase as compared to regular diet (RD) group], low-grade inflammation (increased leukocyte infiltration and inflammatory markers) and RhoA/ROCK hyperactivity. Bladder strips from HFD rabbits, pre-contracted with carbachol, showed an overactive response to the selective ROCK inhibitor Y-27632. All these HFD-induced bladder alterations were partially blunted by testosterone and almost completely reverted by INT-747. Both treatments prevented some MetS features (glucose intolerance and visceral fat increase), thus suggesting that their effects on bladder could be ascribed to an improvement of the metabolic and/or hypogonadal state. However, a pathogenetic role for hypogonadism has been ruled out as GnRH analog-induced hypogonadal rabbits, fed a regular diet, did not show any detectable bladder alterations. In addition, INT-747 did not revert the MetS-induced hypogonadal state. FXR mRNA was highly expressed in rabbit bladder and positively associated with visceral fat increase. A direct effect of INT-747 on bladder smooth muscle was further suggested by inhibition of RhoA/ROCK-mediated activity by in vitro experiments on isolated cells. In conclusion, HFD-related MetS features are associated to bladder derangements, which are ameliorated by testosterone or INT-747 administration. INT-747 showed the most marked effects in counteracting MetS-related RhoA/ROCK overactivity, thus opening novel therapeutic opportunities for this drug.

Topics: Androgens; Animals; Blood Glucose; Cell Movement; Chenodeoxycholic Acid; Cholesterol; Diet, High-Fat; Disease Models, Animal; Hypogonadism; Male; Metabolic Syndrome; Muscle Contraction; Myocytes, Smooth Muscle; Prostate; Rabbits; Receptors, Androgen; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Testosterone; Triglycerides; Triptorelin Pamoate; Urinary Bladder

The synergistic effect of the co-morbidities that comprise metabolic syndrome (MetS) is increasingly being recognised as an important contributor in the pathology of a broad spectrum of seemingly disparate conditions. However, in terms of male reproductive function, beyond erectile dysfunction, little is known about the influence of this cohort (collectively or separately) on spermatogenesis and sperm quality. The aims of this study were to assess the reproductive tract of a MetS animal model for detrimental changes, to determine whether a group of compounds (advanced glycation end products and their receptor) known to cause cell dysfunction and DNA damage was present and assess whether hypogonadotropic hypogonadism was the main contributing factor for the changes seen. Animals fed a high-fat diet were found to have significantly increased cholesterol, triglycerides, blood glucose, mean arterial pressure and visceral fat levels. Although serum testosterone was decreased, no changes were seen in either testicular or epididymal histology. Immunolocalisation of N(ε)-carboxymethyl-lysine and the receptor for advanced glycation end products was found in the testes, epididymides and sperm of the two treated groups of animals; however, ELISA did not show any difference in protein levels. Similarly, assessment of sperm nuclear DNA (nDNA) fragmentation by acridine orange test did not find significant differences in nDNA integrity. We conclude that the minimal effect on spermatogenesis and sperm quality seen in our model is probably due to the moderate increase of blood glucose rather than the hypogonadism.

Topics: Animals; Dietary Fats; Disease Models, Animal; DNA Fragmentation; Epididymis; Glycation End Products, Advanced; Gonadotropin-Releasing Hormone; Hyperglycemia; Hypogonadism; Lysine; Male; Metabolic Syndrome; Rabbits; Random Allocation; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Semen Analysis; Spermatogenesis; Spermatozoa; Testis; Triptorelin Pamoate

Central precocious puberty is commonly treated by gonadotropin releasing hormone (GnRH) agonists. To compare modes of action and effectiveness of GnRH analogues and assess treatment combinations of agonistic (triptorelin) and antagonistic (cetrorelix acetate) GnRH analogues with established treatment, we used prepubertal 31-d-old ovariectomized female rats. Strongest inhibition of LH and FSH occurred after 2-d treatment with antagonist alone (LH 0.08 +/- 0.02 versus 3.2 +/- 0.56 ng/mL in controls; FSH 10.8 +/- 2.8 versus 44.2 +/- 5.0 ng/mL in controls, p < 0.001). Combined agonist/antagonist was second most effective of the treatments (after 5 d treatment, LH 0.52 +/- 0.15 versus 4.9 +/- 1.1 ng/mL in controls; p < 0.01). Pituitary gonadotropin subunit LHbeta mRNA levels were inhibited in all groups except controls, but pituitary GnRH receptor mRNA was stimulated by agonist yet unaffected by combined analogues. Explanted ovaries were incubated with either analogue, both 10-6 M. After 4 h, GnRH receptor mRNA levels were significantly reduced by antagonist but not agonist. To verify puberty-inhibiting effects of GnRH analogues, we used 26-d-old female rats with androgen-induced precocious puberty after injecting subcutaneously single 300 microg danazol on postnatal d 5. Single application of cetrorelix depot (cetrorelix embonate) reduced serum estradiol levels and pituitary LHbeta expression; GnRH receptor mRNA levels were down-regulated in the pituitary and ovary (p < 0.05). In androgen-induced precocious puberty model, single injection of antagonist effectively arrests premature hormonal activation and down-regulates pituitary and ovarian GnRH receptors. We conclude that GnRH analogue combination and especially antagonist alone treatment most directly suppress gonadotropin levels. This implies that early treatment gonadotropin flare-up associated with agonist treatment is avoidable.

Topics: Androgens; Animals; Danazol; Disease Models, Animal; Estrogen Antagonists; Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Hypothalamus; Luteolytic Agents; Ovariectomy; Ovary; Pituitary Gland; Puberty, Precocious; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Receptors, LHRH; Triptorelin Pamoate; Uterus

The purpose of this study was to determine the effects of long-term combined sexual hormone replacement therapy on the biomechanical properties of the small artery wall in castrated female rats.. 30 non-pregnant mature female Sprague-Dawley rats were pharmacologically ovariectomized with 750 microg/kg triptorelin im. every 4th week. Ten of them received combined hormone replacement in form of 15 mg/kg medroxyprogesterone acetate (MPA) im. every 2 weeks and 450 microg/kg estradiol propionate im. once a week. Ten castrated animals received MPA only. Ten control, castrated animals were given the vehicles of these steroids. Ten other animals were kept parallelly, receiving the vehicles of all drugs (control animals). After 12 weeks of treatment cylindrical segments of the saphenous artery were isolated and cannulated at both ends and subjected to in vitro microarteriographic test. Pressure diameter curves, in the range of 0-200 mmHg, were recorded from segments in normal Krebs-Ringer (nKR) solution, in contraction with norepinephrine (1.6 x 10(-5) M), and then in relaxation with papaverine (2.8 x 10(-5) M). Biomechanical parameters were calculated based on the pressure diameter curves.. Combined hormone replacement therapy significantly increased the passive diameter of small arteries, as compared to those from ovariectomized animals without hormone replacement. MPA monotherapy did not alter the vessel diameter, the inner radii at 100 mmHg intraluminal pressure were, 300+/-9 microm in the control castrated, 340+/-7 microm in the estradiol + MPA replaced and 306+/-8 microm in the MPA treated groups (P < 0.05 between the control castrated and the combined treatment groups). The vascular reactivity to norepinephrine or papaverine was not changed significantly either by combined hormone replacement or by MPA monotherapy when compared with ovariectomized controls. No significant alterations were found in wall thickness and distensibility.. These results suggest that chronic medroxyprogesterone pretreatment does not influence the geometric, elastic and contractile properties of small arteries in castrated female rats. The combination of MPA + estradiol increased the morphological lumen: the morphological vasodilatation induced by estrogen, described earlier, was not affected by the addition of this progestin to the regimen.

Topics: Animals; Arteries; Biomechanical Phenomena; Disease Models, Animal; Estradiol; Female; Hormone Replacement Therapy; Luteolytic Agents; Medroxyprogesterone Acetate; Ovariectomy; Postmenopause; Rats; Rats, Sprague-Dawley; Triptorelin Pamoate; Vascular Resistance

To investigate the influence of tamoxifen, danazol and triptorelin (a GnRH agonist) on estrogen and progesterone receptors of rat endometrium, 44 castrated Sprague-Dawley rats were divided into four equal groups, and each group received either no treatment or one of the agents. After administration of the agents, estrogen and progesterone receptor levels, detected by immunohistochemical methods, were compared with the controls. Estrogen and progesterone receptors were significantly higher in the tamoxifen group than the controls (p<0.05), but this was not noticed in the triptorelin group (p>0.05). Receptor levels were higher in the danazol group than the controls, but it was significant only in the estrogen receptors. Among the 3 groups, receptor levels were higher than in the control group. There was not any correlation among the estrogen and progesterone receptor levels in all groups. Steroid receptor manipulations can be used in the treatment of gynecologic cancer, but further investigations are needed.

Topics: Animals; Danazol; Disease Models, Animal; Estrogen Antagonists; Female; Luteolytic Agents; Ovariectomy; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen; Triptorelin Pamoate; Uterus

The purpose of our study was to characterize the time-dependent effect of gonadotropin-releasing hormone analog (GnRH-a) therapy on endometriosis explant using the rat model. Endometriosis was induced in 60 mature female rats. One group of treated animals as well as controls were killed at 2, 4, 6 and 8 weeks of treatment at which time the explant was evaluated. Explant volume was significantly reduced in all treatment groups, an effect that was more significant in animals treated for greater than or equal to 4 weeks compared with those treated for only 2 weeks. We conclude that GnRH-a treatment caused gradual regression of endometrial explant that was effectively complete by 4 weeks of treatment. We further conclude that this experimental model may be useful in the evaluation of other modes of endometriosis therapy.

Topics: Analysis of Variance; Animals; Delayed-Action Preparations; Disease Models, Animal; Endometriosis; Female; Gonadotropin-Releasing Hormone; Organ Culture Techniques; Ovariectomy; Rats; Rats, Inbred Strains; Reference Values; Time Factors; Triptorelin Pamoate; Uterus

The combination of hormonal treatment based on a long-acting delivery system for the agonist [6-D-tryptophan]luteinizing hormone-releasing hormone ([D-Trp6]-LH-RH) with the chemotherapeutic agent Novantrone (mitoxantrone dihydrochloride) was studied in the Dunning R3327H rat prostate cancer model. Microcapsules of [D-Trp6]-LH-RH formulated from poly(DL-lactide-co-glycolide) and calculated to release a controlled dose of 25 micrograms/day were injected intramuscularly once a month. Novantrone (0.25 mg/kg) was injected intravenously once every 3 weeks. Three separate experiments were carried out. When the therapy was started 45 days after transplantation and continued for 70 days, tumor volume in the presence of the microcapsules (966 +/- 219 mm3) or Novantrone (3606 +/- 785 mm3) given alone was significantly decreased compared to controls (14,476 +/- 3045 mm3). However, the combination of microcapsules and Novantrone caused a greater inhibition of tumor growth (189 +/- 31 mm3) than the single agents. Similar effects were seen when the percent increase in tumor volume was examined. Tumor volume increased 10,527 +/- 1803% for the control group. The inhibition of growth caused by the [D-Trp6]LH-RH microcapsules alone (672 +/- 153% increase in volume) was again greater than that caused by Novantrone alone (2722 +/- 421% increase). The combination of the two agents was again the most effective, resulting in an increase in tumor volume of only 105 +/- 29%. Control tumors weighed 30.0 +/- 6.5 g. Tumor weights were much less in the groups treated with either microcapsules (3.28 +/- 0.69 g) or Novantrone (19.53 +/- 3.3 g) alone. The lowest tumor weights after 70 days of treatment were obtained in the group that received the combination of [D-Trp6]LH-RH microcapsules and Novantrone (1.02 +/- 0.2 g). Testes and ventral prostate weights were significantly diminished by the administration of microcapsules of [D-Trp6]LH-RH alone or in combination with Novantrone. In both of these groups, luteinizing hormone and prolactin levels were reduced and serum testosterone was suppressed to undetectable levels. Similar results were obtained in two other experiments in which the duration of treatment was 60 or 105 days. These results suggest that the overall response could reflect the inhibition of proliferation of hormone-independent cancer cells by Novantrone in addition to the suppressive effect of [D-Trp6]LH-RH on the growth of androgen-dependent tumor cells. The administratio

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Capsules; Delayed-Action Preparations; Disease Models, Animal; Gonadotropin-Releasing Hormone; Male; Mitoxantrone; Prostatic Neoplasms; Rats; Rats, Inbred Strains; Triptorelin Pamoate