cetrorelix and Leiomyoma

Topics: Clinical Trials as Topic; Female; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leiomyoma; Receptors, LHRH; Regional Blood Flow; Uterus

While GnRH agonists have become well-established tools for preoperative treatment of uterine fibroids or postoperative treatment in endometriosis for 3-6 months, GnRH antagonists seem to offer important advantages due to their specific pharmacological mode of action. Avoiding any flare-up effect, it seems to be possible to reduce treatment time to about only 2-4 weeks in the case of fibroids to obtain a clinically relevant reduction in size. Furthermore, due to the classic competitive receptor blockade induced by GnRH antagonists, it is feasible to preserve residual oestradiol secretion for a period of 8 weeks in patients with endometriosis. Endometriosis patients undergoing this treatment reported a symptom-free period, with no signs of mood changes, hot flushes, loss of libido, vaginal dryness or other symptoms. Serum oestradiol oscillated around a mean level of 50 pg/ml during therapy. Sequential administration of the GnRH antagonist cetrorelix (Cetrotide), in a 3 mg dosage once weekly over 8 weeks in the case of endometriosis or administration every 4th day for a time span of 2-4 weeks for fibroids, creates a new opportunity for medical treatment. Although 3 mg of cetrorelix acetate obviously acts as an intermediate depot preparation, results obtained so far are very preliminary.

Topics: Endometriosis; Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leiomyoma; Neoplasms; Uterine Neoplasms

Topics: Animals; Disease Models, Animal; Endometrial Neoplasms; Endometriosis; Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leiomyoma; Luteinizing Hormone; Male; Ovarian Neoplasms; Receptors, LHRH; Testosterone; Uterine Neoplasms

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

A depot preparation of the LHRH-antagonist Cetrorelix was used for the preoperative treatment of 20 premenopausal women with symptomatic uterine fibroids to undergo surgery. In an open, prospective and randomised study, 60 mg of this depot preparation were administered i.m. at the second day of cycle. Patients were randomised for a second dosage of 60 mg or 30 mg to be injected on day 21 or day 28 of treatment according to the degree of estradiols' suppression (< 50 pg/mL). The operation was carried out after six or eight weeks of treatment according to the timing of second dosages administration. Weekly transvaginal sonography as well as MRI before and after Cetrorelix treatment were performed for fibroids volume assessment; 16 patients showed satisfactory suppression of gonadotrophins and sexual steroids. No flare up effect was to be observed. In this group of patients the maximum reduction in fibroids size was of 33.5% at the end of treatment. After 14 days of treatment the reduction was of 31.3%. Within the group of good responders (reduction of fibroids size > 20%) the volume of the biggest fibroid after 14 days of treatment was of 56.7% of the initial assessment. Although MRI showed minor mean shrinkage rates of only 25.4% of the initial volume, these differences in comparison to transvaginal sonography were not statistically significant. The avoidance of any flare up phenomenon by the LHRH-antagonist may explain this fast reduction in size. The basic advantages of this treatment modality are the reduction of treatment time with a fast restoration of the ovarian function. The rate of poor responders may be reduced by improving the galenic preparation.

Topics: Adult; Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leiomyoma; Middle Aged; Premenopause; Preoperative Care; Uterine Neoplasms

A depot preparation of the third-generation gonadotrophin-releasing hormone (GnRH) antagonist Cetrorelix (SB-75) was used for preoperative treatment in twenty premenopausal patients with symptomatic uterine fibroids who were to undergo surgery. In a prospective, open, randomized setting 60 mg of Cetrorelix pamoate salt was administered i.m. on cycle day 2. Patients were randomized for a second dose of 30 or 60 mg of Cetrorelix depot, which was administered according to the degree of oestradiol suppression (<50 pg/ml) on treatment day 21 or 28. Surgery was done after 6 or 8 weeks of treatment, depending on second dosage administration. Weekly transvaginal sonography (TVS) and magnetic resonance imaging (MRI) before and after treatment was performed, for fibroid volume assessment. Sixteen patients showed satisfactory suppression of gonadotrophins and sex steroid secretion, avoiding any initial flare-up effect. In these patients a mean shrinkage rate of largest fibroid volume of 33.5% at the end of treatment could be observed according to TVS, while the mean shrinkage rate obtained after 14 days of treatment was 31.3%. In good responders (shrinkage >20%) largest fibroid volume at day 14 was approximately 56.7% of basic assessment. Although MRI showed minor mean shrinkage rates of only 25.4% of the initial volume, these differences in comparison to TVS assessment were not statistically significant. The avoidance of any initial flare-up in gonadotrophin secretion may explain this extremely fast reduction in fibroid size. The advantages of GnRH antagonist treatment in this indication consist in the short treatment time with a fast restoration of the ovarian function. The rate of poor responders may be reduced by using an improved slow release preparation.

Topics: Adult; Chemistry, Pharmaceutical; Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leiomyoma; Middle Aged; Treatment Outcome; Uterine Neoplasms

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

Topics: Adult; Female; Follicular Phase; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Hysterectomy; Leiomyoma; Luteal Phase; Middle Aged; Pregnancy; Ultrasonography; Uterine Hemorrhage; Uterine Neoplasms; Uterus

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

We investigated the potential of gonadotropin-releasing hormone (GnRH) agonists and GnRH antagonists to inhibit cell proliferation in endometriotic and endometrial stromal cells.. Twenty patients with ovarian endometriomas and 18 patients with uterine fibromas were recruited. Endometriotic and endometrial stromal cells were obtained from the ovarian chocolate cyst linings and the eutopic endometria of premenopausal women with uterine fibromas, respectively.. GnRH agonist or antagonist treatment attenuated tumor necrosis factor (TNF)-α-induced cell proliferation in the endometrial stromal cells, whereas endometriotic stromal cells did not respond to treatment. The endometriotic stromal cells exhibited a decreased expression of the type I GnRH receptor compared with the endometrial stromal cells. GnRH agonists or antagonists did not repress TNF-α-induced IL-8 production in endometriotic stromal cells.. GnRH agonists and antagonists have similar effects in slowing the growth of endometrial stromal cells. Endometriotic stromal cells resist the antiproliferative effect of GnRH agonists and antagonists.

Topics: Adult; Blotting, Western; Buserelin; Cell Proliferation; Endometriosis; Endometrium; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression; Gonadotropin-Releasing Hormone; Humans; Interleukin-8; Leiomyoma; Ovarian Diseases; Premenopause; Receptors, LHRH; Stromal Cells; Tumor Necrosis Factor-alpha; Uterine Neoplasms

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

The objective of this study was to elucidate the effects of GnRH antagonist Cetrorelix on proliferation and apoptosis in human leiomyoma cells cultured in vitro. Isolated leiomyoma cells were subcultured in phenol red-free DMEM supplemented with 10% fetal bovine serum for 120 h and then stepped down to serum-free conditions in the presence or absence of graded concentrations of Cetrorelix (10(-5) to 10(-8) mol/liter) for 6 d. Cultured leiomyoma cells were used for semiquantitative RT-PCR, immunocytochemistry, Western blot analysis, and terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling assay. RT-PCR analysis revealed the presence of mRNAs encoding for GnRH receptor and epidermal growth factor (EGF) in cultured leiomyoma cells. The number of viable cultured leiomyoma cells was significantly (P < 0.01) decreased by treatment with Cetrorelix compared with untreated control cultures. Immunocytochemical examination demonstrated that treatment with Cetrorelix attenuated the expression of proliferating cell nuclear antigen (PCNA) and EGF in cultured leiomyoma cells. Western blot analysis revealed that treatment with 10(-5) mol/liter Cetrorelix significantly (P < 0.01) decreased PCNA expression. In addition, treatment with 10(-5) mol/liter Cetrorelix remarkably increased the terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling-positive rate and poly(ADP-ribose) polymerase expression at 24 h of treatment compared with untreated control cultures (P < 0.01). Furthermore, treatment with 10(-5) mol/liter Cetrorelix decreased immunoreactive EGF protein and EGF mRNA expression in cultured leiomyoma cells at 4 d of treatment. GnRH antagonist Cetrorelix may directly inhibit leiomyoma cell growth by down-regulating proliferation in association with a decrease in EGF mRNA expression and by up-regulating apoptosis in those cells.

Topics: Adult; Apoptosis; Base Sequence; Cell Survival; DNA Primers; Epidermal Growth Factor; Female; Gene Expression Regulation, Neoplastic; Gonadotropin-Releasing Hormone; Humans; Leiomyoma; Poly(ADP-ribose) Polymerases; Premenopause; Proliferating Cell Nuclear Antigen; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured; Uterine Neoplasms

This report suggests the possibility that a gonadotropin-releasing hormone (GnRH) antagonist initiates apoptosis not only by causing a sex hormone deficit by inhibiting GnRH secretion in the pituitary gland, but also by acting directly on leiomyoma cells promoting apoptosis.

Topics: Adult; Apoptosis; Female; Gonadotropin-Releasing Hormone; Humans; Leiomyoma; Tumor Cells, Cultured; Uterus