trelstar and Genital-Neoplasms--Female

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

Studies on the natural history of endometriosis have demonstrated that the majority of endometriosis implants tend to progress, a finding that indicates eradication of the lesions by medical and/or surgical approaches. Infertility and dysmenorrhea are other indications for medical therapy in this disease. In recent prospective and controlled studies, progestin (at high doses), gestrinone and GnRH agonist analogues have been equally effective as regards elimination of endometriosis and relief of endometriosis-associated symptoms, compared to danazol, a standard treatment in endometriosis. These four classes of drugs differ, however, in their adverse effects and as regards compliance. Danazol is a steroid with androgenic and anabolic effects and it adversely affects lipid metabolism. Gestrinone and 17-OH progestins are weaker, and GnRH agonist analogues and some progestins neutral in these respects. GnRH agonist analogues induce a hypo-estrogenic state with associated climacteric symptoms and mineral loss from the bones. The clinical value of combinations of GnRH analogue and steroid(s), used to prevent these side-effects, is so far unclear. Laparoscopic microsurgery has revolutionized the treatment of endometriosis lesions. Hence, hormone treatment as a supplement to microsurgical approaches may become a dominant form of medical therapy in endometriosis. The definitive value of pre- or post-operative hormonal treatment in this disease should, however, be tested in controlled trials. Such studies have proved antiprostaglandins to be useful in the treatment of dysmenorrhea secondary to endometriosis. Because each of the four drugs was ineffective in the treatment of infertility associated with endometriosis it is a waste of time to expose patients desiring pregnancy to long-term hormonal therapy. Ovarian hyperstimulation with IVF and other methods of assisted fertilisation are promising alternatives, but their definitive value is so far unproven in this disease. Conclusively, the significance of medical therapy in endometriosis is only partly resolved, and therefore, many therapeutic problems await prospective randomised trials and new innovations.

Topics: Combined Modality Therapy; Danazol; Delayed-Action Preparations; Dysmenorrhea; Endometriosis; Female; Genital Neoplasms, Female; Gonadotropin-Releasing Hormone; Humans; Infertility, Female; Laparoscopy; Progestins; Prospective Studies; Prostaglandin Antagonists; Randomized Controlled Trials as Topic; Triptorelin Pamoate

The majority of ovarian, endometrial, and breast cancers express gonadotropin-releasing hormone (GnRH) receptors. Apart from reproductive organs (ovaries, fallopian tubes, and uterus) that are normally removed during surgical therapy of ovarian or endometrial cancer, pituitary gonadotrophs also express GnRH receptors. The signal transduction pathway in tumor cells is basically different from the classic GnRH receptor signal transduction, which is known to operate in the pituitary gonadotrophs and can therefore be considered tumor specific. Other organs and hematopoetic stem cells do not express GnRH receptors. We have recently shown specific activation of nucleus factor kappaB in ovarian, endometrial, and breast cancers after treatment with GnRH agonists. Based on this tumor-specific signaling pathway and the distribution pattern of GnRH receptors, we have developed and successfully tested a gene therapy concept by using a GnRH analogue as an inducer for the transcription of a therapeutic gene in cell culture and in nude mice.

Topics: Animals; Antineoplastic Agents, Hormonal; Antiviral Agents; Cell Line, Tumor; Female; Ganciclovir; Genetic Therapy; Genital Neoplasms, Female; Humans; Mice; NF-kappa B; Plasmids; Prodrugs; Receptors, LHRH; Signal Transduction; Thymidine Kinase; Transcription Factors; Triptorelin Pamoate

The majority of human endometrial (>80%), ovarian (>80%) and breast (>50%) cancers express GnRH receptors. Their spontaneous and epidermal growth-factor-induced proliferation is dose- and time-dependently reduced by treatment with GnRH and its agonists. In this study, we demonstrate that the GnRH agonist triptorelin inhibits estradiol (E2)-induced cancer cell proliferation.. The proliferation of quiescent estrogen receptor alpha (ER alpha)-/ER beta-positive, but not of ER alpha-negative/ER beta-positive endometrial, ovarian and breast cancer cell lines, was significantly stimulated (P<0.001) (ANOVA) after treatment with E2 (10(-8) M). This effect was time- and dose-dependently antagonized by simultaneous treatment with triptorelin. The inhibitory effect was maximal at 10(-5) M concentration of triptorelin (P<0.001). In addition, we could show that, in ER alpha-/ER beta-positive cell lines, E2 induces activation of serum response element (SRE) and expression of the immediate early-response gene c-fos. These effects were blocked by triptorelin (P<0.001). E2-induced activation of estrogen-response element (ERE) was not affected by triptorelin.. The transcriptional activation of SRE by E2 is due to ER alpha activation of the mitogen-activated protein kinase (MAPK) pathway. This pathway is impeded by GnRH, resulting in a reduction of E2-induced SRE activation and, in consequence, a reduction of E2-induced c-fos expression. This causes downregulation of E2-induced cancer cell proliferation.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Division; Cell Line, Tumor; Dose-Response Relationship, Drug; Endometrial Neoplasms; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Female; Gene Expression; Genes, fos; Genital Neoplasms, Female; Gonadotropin-Releasing Hormone; Humans; Ovarian Neoplasms; Proto-Oncogene Proteins c-fos; Response Elements; Serum Response Element; Triptorelin Pamoate

Spontaneous and epidermal growth-factor-induced proliferation of human gynecological cancer cell lines is dose- and time-dependently reduced by treatment with the luteinizing hormone-releasing hormone (LHRH) agonist triptorelin and antagonist Cetrorelix. This antiproliferative activity is probably directly mediated through the LHRH receptors expressed by the tumor cells interacting with growth-factor-dependent mitogenic signal transduction. We have examined whether epidermal growth-factor (EGF)-induced expression of the early response gene c-fos is reduced by LHRH analogs.. Human endometrial (Ishikawa, Hec-1A), ovarian (EFO-21, EFO-27, SK-OV-3), and breast cancer cell lines (MCF-7) were rendered quiescent by incubation (72 h) in the absence of fetal calf serum and phenol red. This was followed by a 15-min incubation in the absence or presence of the LHRH agonist triptorelin (100 nM) or the antagonist Cetrorelix (100 nM) before the cells were stimulated for 10 min with EGF (100 nM). C-fos mRNA expression was determined by semi-quantitative RT-PCR using a synthetic DNA fragment as internal standard. C-Fos protein synthesis was determined by SDS-PAGE and semi-quantitative Western blotting.. In cells derived from endometrial and ovarian cancer, maximal c-fos mRNA expression (seven- to ninefold over basal level) was obtained 30 min after EGF stimulation. In the breast cancer cell line MCF-7 this effect was obtained 60 min after EGF treatment. In all of the lines expressing LHRH receptor, EGF-induced c-fos mRNA expression as well as c-Fos protein synthesis was dose-dependently reduced by treatment with LHRH agonists and antagonists. At 100 nM concentrations of the LHRH analogs, c-fos expression was reduced to baseline levels. No effect of LHRH analogs on EGF-induced c-fos expression was observed in the ovarian cancer cell line SK-OV-3, which does not express the LHRH receptor.. These results suggest that the binding of LHRH agonists and antagonists to their receptors inhibits the mitogenic signal transduction pathway of the EGF receptor in endometrial, ovarian, and breast cancer cell lines. The coupling of both signal transduction systems mediates the antiproliferative effect of LHRH analogs.

Topics: Antineoplastic Agents, Hormonal; Down-Regulation; Epidermal Growth Factor; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Genes, fos; Genital Neoplasms, Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Luteolytic Agents; Proto-Oncogene Proteins c-fos; Receptors, LHRH; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Triptorelin Pamoate; Tumor Cells, Cultured

The increasing use of analogs of Gn-RH during treatment of some benign gynaecological diseases, has induced the authors to investigate the principal collateral effects, fixing one's attention on the loss of bony mass.. This perspective research has considered 38 patients selected for two diseases "endometriosis" and "uterine fibromyomatosis". The therapy has been effected with triptorelin intramuscularly in a dose of 3.75 mg every 28 days for six months, in all six phials.. After a half-yearly cycle of therapy, the loss of bony mass was valued about 3% medium.. In the light of other studies too, it was decided to confirm the necessity of associating other medicines able to prevent the side effects caused by their analogs of Gn-RH.

Topics: Adult; Bone Density; Endometriosis; Female; Fibroma; Genital Diseases, Female; Genital Neoplasms, Female; Growth Hormone-Releasing Hormone; Humans; Leiomyoma; Middle Aged; Osteoporosis; Triptorelin Pamoate; Uterine Neoplasms