Effect Of GnRH Analogue Research Articles

Alteration of gonadotropin-releasing hormone receptor expression with the progression of prostate cancer in the Dunning rat adenocarcinoma sublines

Inhibitory effects of GnRH analogues on tumour growth in vitro suggests that such direct effects may be of importance also in vivo. However, the role of GnRH receptors (GnRH-R) in prostate tumour progression is largely unknown. The aim was therefore to investigate the variation of GnRH-R expression with prostate tumour progression using Dunning rat adenocarcinoma sublines representing different prostate tumour grades. GnRH-R levels were quantified in the rat dorsolateral (DLP) and Dunning sublines (PAP, AT-1, AT-2, AT-3, MatLyLu) using competitive RT–PCR and Western blot. The results showed that all Dunning sublines had significantly elevated GnRH-R mRNA expression levels compared with DLP. Comparison of GnRH-R mRNA levels between different tumour grades revealed no difference in mRNA expression. However, the anaplastic and highly metastatic AT-3 and MatLyLu tumours displayed a tendency for lower GnRH-R mRNA values than the non-metastatic tumour sublines. Our data demonstrate the expression of GnRH-R in normal rat DLP and in different Dunning sublines. However, GnRH-R seems not to be involved in tumour progression.

Preoperative administration of GnRH-a plus tibolone to premenopausal women with uterine fibroids: evaluation of the clinical response, the immunohistochemical expression of PDGF, bFGF and VEGF and the vascular pattern

Aim of the study is to compare the effects of preoperative therapy with tibolone plus gonadotropin-releasing hormone analogue (GnRH-a) in premenopausal women with those of GnRH-a alone on clinical response, uterine volume, immunohistochemical expression of platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and vascular features of myomas. Seventy women with symptomatic uterine fibromatosis were treated for four months with leuprorelin acetate alone or plus tibolone. Untreated patients were submitted to uterine surgery directly. Uterine volume, hematological data, BMD, myoma-related symptoms and hot flushes were evaluated at the admission and before surgery. Immunohistochemical expression of PDGF, bFGF and VEGF, vascular changes and CD105 expression, as a marker of angiogenesis, were evaluated in myomas obtained after surgery. Uterine volume and myoma-related symptoms reduced and hematological variables increased in treated patients. BMD decreased in patients treated with GnRH-a alone. Hot flushes were less in GnRH-a plus tibolone group than in GnRH-a group. Immunohistochemical expression of PDGF, bFGF and VEGF, vascularization and angiogenesis reduced in treated patients in comparison with untreated ones. In conclusion, the administration of tibolone plus GnRH-a before uterine surgery does not change the clinical and immunohistochemical effects of GnRH-a alone.

Gonadotropin-Releasing Hormone Antagonist Antide Inhibits Apoptosis of Preovulatory Follicle Cells in Rat Ovary1

Analogs of GnRH, including agonists (GnRH-a) and antagonists (GnRH-ant), have been widely used to inhibit gonadotropin pituitary release. Aside from the effect of GnRH analogs on the pituitary-gonadal axis, studies have shown that GnRH has extrapituitary effects, particularly on rat and human ovaries. In the present study, we evaluated the direct in vivo effects of the GnRH-a, leuprolide acetate (LA), or the GnRH-ant, Antide (Ant), either singly or together, on ovarian follicular development in prepubertal eCG-treated rats. LA significantly decreased ovarian weight, whereas Ant increased ovarian weight compared with controls; however, coinjection of both compounds had no effect. In addition, LA increased the number of preantral follicles (PFs) and atretic follicles, and decreased the number of early antral follicles (EAFs) and preovulatory follicles (POFs). Coinjection of Ant interfered with this LA effect. Ant alone increased the number of POFs compared with that of controls. Analysis of apoptosis has shown that LA increases the percentage of apoptotic cells in PFs, EAFs, and POFs; however, Ant prevented this effect. In addition, Ant alone decreased the percentage of apoptotic cells in EAFs and POFs. Data have shown that Ant per se inhibited BAX translocation from cytosol to mitochondria and retained cytochrome C in the mitochondria, whereas LA induced cytochrome C release. We conclude that Ant inhibits apoptosis in preovulatory follicles through a decrease of BAX translocation to mitochondria, suggesting that GnRH may act as a physiological intraovarian modulator factor that is able to interfere with follicular development through an increase in apoptotic events mediated by an imbalance among the BCL-2 family members.

Effect of Gonadotropin-Releasing Hormone Analogs on Bcl-2 and Bax expression in endometrial cultures from patients with endometriosis

Effect of Gonadotropin-Releasing Hormone Analogs on Bcl-2 and Bax expression in endometrial cultures from patients with endometriosis

Gonadotropin-releasing hormone induces apoptosis of prostate cancer cells: role of c-Jun NH2-terminal kinase, protein kinase B, and extracellular signal-regulated kinase pathways.

A standard therapy used today for prostate cancer is androgen ablation by gonadotropin-releasing hormone analogs (GnRH-a). Although most patients respond to androgen ablation as an initial systemic therapy, nearly all cases will develop androgen resistance, the management of which is still a major challenge. Here, we report that GnRH-a can directly induce apoptosis of the androgen-independent prostate cancer-derived DU145 and PC3 cell lines. Using specific inhibitors, we found that the apoptotic effect of GnRH-a is mediated by c-Jun NH2-terminal kinase (JNK) and inhibited by the phosphatidylinositol 3'-kinase (PI3K)-protein kinase B (PKB) pathway. Indeed, in DU145 cells, GnRH-a activates the JNK cascade in a c-Src- and MLK3-dependent manner but does not involve protein kinase C and epidermal growth factor receptor. Concomitantly, GnRH-a reduces the activity of the PI3K-PKB pathway, which results in the dephosphorylation of PKB mainly in the nucleus. The reduction of PKB activity releases PKB-induced inhibition of MLK3 and thus further stimulates JNK activity and accelerates the apoptotic effect of GnRH-a. Interestingly, extracellular signal-regulated kinase is also activated by GnRH-a, and this occurs via a pathway that involves matrix metalloproteinases and epidermal growth factor receptor, but its activation does not affect JNK activation and the GnRH-a-induced apoptosis. Our results support a potential use of GnRH-a for the treatment of advanced prostate cancer and suggest that the outcome of this treatment can be amplified by using PI3K-PKB inhibitors.

Expression of gonadotropin-releasing hormone receptor and effect of gonadotropin-releasing hormone analogue on proliferation of cultured gastric smooth muscle cells of rats.

To investigate the expression of gonadotropin-releasing hormone (GnRH) receptor and the effects of GnRH analog (alarelin) on proliferation of cultured gastric smooth muscle cells (GSMC) of rats. Immunohistochemical ABC methods and in situ hybridization methods were used to dectect protein and mRNA expression of GnRH receptor in GSMC, respectively. Techniques of cell culture, OD value of MTT test, measure of (3)H-TdR incorporation, average fluorescent values of proliferating cell nuclear antigen (PCNA) and flow cytometric DNA analysis were used in the experiment. The cultured GSMC of rats showed immunoreactivity for GnRH receptor; positive staining was located in cytoplasm. GnRH receptor mRNA hybridized signals were also detected in cytoplasm. When alarelin (10(-9), 10(-7), 10(-5) mol/L) was administered into the medium and incubated for 24 h, OD value of MTT, (3)H-TdR incorporation and average fluorescent values of PCNA all decreased significantly as compared with the control group (P<0.05). The maximum inhibitory effect on cell proliferation was achieved a concentration of 10(-5) mol/L and it acted in a dose-dependent manner. Flow cytometric DNA analysis revealed that alarelin could significantly enhance ratio of G(1) phase and decrease ratio of S phase of GSMC of rats (P<0.05). The maximum inhibitory effect on ratio of S phase was at the concentration of 10(-5) mol/L and also acted in a dose-dependent manner. Our data suggest that GnRH receptor can be expressed by GSMC of rats. GnRH analogue can directly inhibit proliferation and DNA synthesis of rat GSMC through GnRH receptors.

The effect of GnRH analogs on urinary incontinence after ablation of the ovaries in dogs

After removal of the ovaries approximately 20% of dogs develop urinary incontinence. Removal of the gonads results in estrogen deficiency and chronic elevation in the production and secretion of FSH and LH. The gonadotrophins may directly or indirectly, adversely affect the sphincter function of the urethra. Estrogen replacement therapy and treatment with sympathomimetics, such as ephedrine or phenylpropanolamine (PPA), are effective only in some of the affected dogs, and many of these subsequently become nonresponsive. Since the role of the elevated gonadotrophins has not been elucidated, we used depot preparations of GnRH analogues to down-regulate gonadotrophins once or twice in 13 ovariectomized (ovx), incontinent dogs, which were either refractory to α-adrenergics ( n=11) or in which α-adrenergics were contraindicated ( n=2). Dogs were treated with leuprolide, deslorelin, buserelin or triptorelin. In 7 dogs treatments with GnRH analogues alone ( n=11) resulted in continence for 50–738 days (mean 247). In all dogs except one, where GnRH treatments did not resolve the incontinence completely, additional treatment with phenylpropanolamine was successful. With additional treatment of phenylpropanolamine complete continence was restored for 21–367 days (mean 159). All treatments caused long-term reduction of circulating FSH and LH concentrations to very low or undetectable levels. No adverse effects of treatments were observed.

GnRH Analogues, Transvaginal Ultrasound-Guided Drainage and Intracystic Injection of Recombinant Interleukin-2 in the Treatment of Endometriosis

We performed a double-blind, randomised controlled trial to evaluate the results of ultrasound-guided aspiration of endometriomas under the effect of GnRH analogues and a possible additional beneficial effect by leaving 600,000 IU of recombinant interleukin-2 (rIL-2) in the cysts. Twenty-four women with endometriosis-related symptoms, increased values of CA-125 and transvaginal ultrasonography showing endometriomas >3 cm who were initially sent to us for laparotomy and conservative surgery for endometriosis were included. Main outcome measures were severity of symptoms, size and percentage of echographical reduction of endometriomas and CA-125 levels after 2 menses post-GnRH analogues. Secondary outcome measures were the time until recurrence of abnormal parameters and the need for surgery after treatment. We found moderate clinical results after treatment with drainage plus GnRH analogues and significantly improved results in women having received rIL-2 intracystically. There were no side effects. Two out of 3 previously infertile patients became pregnant after therapy. Though the rates of recurrence of endometriomas ≧3 cm were similar in both groups, the period until recurrence was significantly greater when rIL-2 was used, and the rates of recurrence of symptoms and increased CA-125 values were also significantly lower in patients who received rIL-2. Surgery was finally performed on 10 patients (4 with and 6 without previous rIL-2 treatment) during follow-up (30 ± 12.7 months). These findings led to the conclusion that transvaginal ultrasound-guided puncture and aspiration of endometriomas under endometrial suppressive therapy with GnRH analogues have some value for endometriosis treatment, improving the clinical manifestations and avoiding some surgical therapies, and that rIL-2 left in the cyst increases these beneficial effects significantly.

Effects of gonadotropin-releasing hormone analog on milt production enhancement in starry flounder Platichthys stellatus

: The treatment of exogenous gonadotropin or gonadotropin-releasing hormone analog (GnRHa) is able to solve some problems that are caused by small milt volume or viscous milt in artificial insemination of flatfish species. However, the mechanism of the action of the exogenous hormones on milt production has not been well understood. Therefore, experiments were carried out to study the effects of GnRHa on the milt production and characteristics of seminal plasma in starry flounder Platichthys stellatus. Males were implanted with GnRHa pellets at three different dosages (50, 100 or 200 μg/kg body weight) during their natural spawning season. Milt volume and sperm production increased in a dose-dependent manner after GnRHa pellet treatments. Spermatocrit and sperm concentration were significantly lower in GnRHa treated groups than in the control group. The sperm motility index was high from day 4 to day 49 in all experimental groups including the control group, and it declined after day 49 in all groups except the 200 μg treated group in which it remained high until day 85. During the experimental period, osmolality, K+ and total protein tended to be higher in the control group than in the GnRHa treated groups. The results suggested that GnRHa treatment increased the milt volume and sperm production ability in starry flounder. The increase of milt volume was twice as rapid as the increase of sperm production. No significant differences in physicochemical composition of blood plasma and seminal plasma were found according to GnRHa dosages, but there were significant differences between GnRHa treated groups and the control group.

Effect of gonadotropin-releasing hormone analogs on the apoptosis and release of IL-1 and VEGF in endometrial cultures from patients with endometriosis

Objective: To evaluate the effect of the treatment with GnRH analogs (agonist = ag and antagonist = ant) on the apoptosis and interleukin-1 (IL-1) and vascular endothelial growth factor (VEGF) release by cultures of epithelial cells from eutopic endometrial tissue of patients with endometriosis (EDT). Design: Prospective study. Materials/Methods: For cultures of epithelial endometrial cells (EEC), we have employed biopsies obtained in proliferative phase by laparoscopy from 16 untreated patients with EDT and 14 controls (without EDT). Purification and culture of EEC were done according to the technique described by Bongso et al. (Hum. Reprod. 1988;3:705–713). Cultures were treated with Leuprolide acetate (LA) 100 ng/ml as GnRHag, or Antide (A) 10 -7 M as GnRHant or both, LA+A. Percentages of apoptotic cells (ApC) were measured using the acridine orange - ethidium bromide technique and levels of IL-1 and VEGF in culture supernatants were measured using ELISA commercial kits. Comparisons among groups were performed by Kruskal-Wallis nonparametric ANOVA test, and Dunn’s multiple comparison test. Results: Treatment with LA enhanced values of ApC in cultures from EDT patients ( 23.9 +/− 8.0% to 41.7 +/− 9.6%, p <0.01) and from controls (18.2 +/− 6.3% to 42.5 +/− 14.7%, p <0.05). Simultaneously LA treated cultures showed significantly decreased levels of IL-1 and VEGF. Values of IL-1 obtained in EDT patients were 223.0 +/− 56.0 pg/ml in basal conditions vs 83.6 +/− 16.3 pg/ml in LA treated cultures, p <0.05, and values obtained in controls were 201.5 +/− 58.6 pg/ml vs. 98.1 +/− 54.8 pg/ml in basal and LA treated cultures respectively (p <0.03). VEGF levels were 283.64 +/− 83.9 pg/ml vs 134.4 +/− 37.3 pg/ml in basal and LA treated ECC cultures from EDT patients respectively (p <0.04), and in controls VEGF values were 201.5 +/− 58.6 pg/ml in basal conditions vs 96.1 +/− 54.8 pg/ml in LA treated cultures (p <0.03). Cultures of ECC from patients and controls treated with GnRHant did not show any significant differences compared to basal conditions. Also, the addition of A to cultures of ECC pre-treated with LA, reverted the increased apoptosis and the drop in IL-1 and VEGF levels. We found no difference in any of the parameters studied between cell cultures from EDT patients and controls. Conclusions: GnRHag has local effects, by enhancing the percentage of ApC and decreasing the release of pro-mitogenic cytokines as IL-1 and VEGF in endometrial cells. GnRHant alone did not produce any significant effect but reverted the changes caused by treatment with GnRHag. Supported by: Agencia de Promocion Cientifica y Tecnologica de la Republica Argentina.

Immunotropic effects of gonadotropin-releasing hormone analog under conditions of emotional painful stress.

Surfagon, a synthetic analog of gonadotropin-releasing hormone injected before emotional painful stress dose-dependently changed the number of antibody-producing cells in rats and phagocytic and functional activities of neutrophils in mice. In castrated animals this peptide increased all studied parameters. This suggests that sex steroids are not involved in the realization of these effects.

A meta-analysis of studies of the effect of GnRH 11-14 days after insemination on pregnancy rates in cattle

AbstractThe aim of the study was to conduct a meta-analysis of published data on the effect of GnRH analogues given between 11 and 14 days after first insemination, on pregnancy rates of cattle, to ascertain if a consolidated estimate of treatment response could be determined. The results of 18 studies from 13 published papers were analysed. Odds ratios calculated for each study were found to be heterogeneous, i.e. there was significant variation in treatment response among studies, between 0 and 22% improvement in pregnancy rate. Logistic regression analysis showed that five variables affected the outcome of the model, viz., herd type (beef or dairy), age of animal (cow or heifer), oestrus synchronisation and method and time of pregnancy diagnosis. However when all variables were included only 6/13 of the publications could be analysed (2,541 /10,833 animals).

Effect of gonadotropin-releasing hormone analogue (GnRHa) and pimozide on plasma levels of sex steroids and ovarian development in sea bass ( Dicentrarchus labrax L.)

To synchronise and advance spawning, European sea bass females in late vitellogenesis were treated with two i.p. injections of GnRH analogue alone (5 and 20 μg/kg BW) given 12 h apart, or combined with pimozide (PIM) (10 mg/kg BW) either in the first or second injection. Saline-injected and untreated females were used as controls. Administration of GnRHa alone or combined with PIM accelerated the final oocyte maturation (FOM) and induced spawning. However, 48 h after the second injection the size of oocytes and the percentage of oocytes in GVBD stage were lower in the PIM-treated females. The number of eggs spawned was highest in the group that received GnRHa alone and lowest in the group that received PIM in the second injection. Plasma levels of 17β-oestradiol (E2) increased sharply at 12 h after the first injection of GnRHa alone or combined with PIM, decreasing after a second injection of GnRHa alone. However, the plasma E2 decreases was much slower in females that received the PIM in the first injection. Females that received PIM in the second injection still showed elevated plasma E2 during a longer period. Plasma testosterone (T) increase was parallel to the plasma E2 decrease and peaked earlier in the group that received GnRHa alone in both injections. Low and nonsignificant changes of 17α,20β-dihydroxy-4-pregen-3-one (17,20β-P) were observed in plasma during the time that the animals were sampled. The results demonstrate that the use of PIM does not improve the GnRHa treatment and the use of GnRHa alone during the last stages of vitellogenesis is enough to induce FOM in the European sea bass.

Early maturity in the male striped bass, Morone saxatilis: follicle-stimulating hormone and luteinizing hormone gene expression and their regulation by gonadotropin-releasing hormone analogue and testosterone.

Striped bass are seasonal breeding fish, spawning once a year during the spring. All 3-yr-old males are sexually mature; however, 60-64% of the fish mature earlier as 1- or 2-yr-old animals. The endocrine basis underlying early maturity in 2-yr-old males was studied at the molecular level by monitoring changes in pituitary beta FSH and beta LH mRNA levels by ribonuclease protection assay, and correlating these changes to stages of testicular development. In maturing males, the mRNA levels of beta FSH were elevated during early spermatogenesis, whereas beta LH mRNA levels peaked during spermiation. The appearance of spermatozoa in the testis was associated with a decrease in beta FSH mRNA and a rise in beta LH mRNA abundance. Immature males had lower levels of beta LH mRNA than maturing males, but there were no differences in beta FSH mRNA levels between immature and maturing males. The regulation of gonadotropin gene expression in 2-yr-old males was studied by the chronic administration of GnRH analogue (GnRHa) and testosterone (T), with or without pimozide (P) supplementation. In immature males, the combination of T and GnRHa stimulated a three- to fivefold increase in beta FSH and beta LH mRNA levels, but the same treatment had no effect on gonadotropin gene expression in maturing males. In addition, the coadministration of P to immature males suppressed the stimulatory effect of GnRHa and T on beta FSH and beta LH mRNA levels, suggesting that dopamine may have a novel role in regulating gonadotropin gene expression.

A meta-analysis of studies of the effect of GnRH 11–14 days after insemination on pregnancy rates in cattle

A number of studies have used GnRH between 11 and 14 days after insemination to improve pregnancy rates in cows, however published results have not been consistent. We wished to investigate whether a consolidated estimate of the response could be quantified. Therefore we conducted a meta-analysis of the available data, 19 studies from 14 published papers, on the effect of GnRH analogs on pregnancy rate when given between Days 11 and 14 after first insemination. Odds ratios (the relative probability of pregnancy between treated and control cows) were compared for each study and found to vary significantly among studies, ranging from 0 to 22%. We showed by logistic regression analysis that response to GnRH treatment varied with cow type (beef or dairy), age (cow or heifer), estrus synchronization (synchronized or natural), pregnancy diagnosis (method and time) and effect of individual study. When all these variables were included only 6 of 14 publications could be analyzed, representing 2,541 instead of 10,945 cows. In this limited subgroup of data, a significant improvement in pregnancy rate was detected among treated cattle (odds ratio = 1.33; P<0.01).

Effects of Gonadotropin-Releasing Hormone Analog on Expression of Genes Encoding the Growth Hormone/Prolactin/Somatolactin Family and a Pituitary-Specific Transcription Factor in the Pituitaries of Prespawning Sockeye Salmon

Gonadotropin-releasing hormone (GnRH) is a possible secretagogue of growth hormone (GH) and somatolactin (SL) in teleosts. Effects of GnRH on the levels of pituitary mRNAs encoding GH, prolactin (PRL), and SL were therefore examined in prespawning sockeye salmon (Oncorhynchus nerka). A capsule of GnRH analog (GnRHa) was implanted into the dorsal muscle of maturing sockeye salmon for 3 weeks. The levels of hormonal mRNAs were then determined by a quantitative dot blot analysis using single-stranded sense DNA of the same sequence of mRNA as the standard. Further, we analyzed effects of GnRHa on expression of the genes encoding pituitary-specific transcription factor (Pit-1/GHF-1). Relative levels of Pit-1/GHF-1 mRNAs were estimated by Northern blot analysis, which showed specific 2- and 3-kb bands of mRNAs. GnRHa significantly increased the level of SL mRNA in the males, but not in the females, compared to the control fish. It did not induce significant increases in the levels of GH and PRL mRNAs in both the males and the females. The levels of Pit-1/GHF-1 mRNAs in the control males tended to be higher than those in the initial controls, so that GnRHa might not be effective in enhancing expression of Pit-1/GHF-1 gene, except for the level of 3-kb Pit-1/GHF-1 mRNA in the females treated with 150 μg GnRHa. The pattern of changes in the levels of Pit-1/GHF-1 mRNAs were similar to those of GH and PRL mRNAs in both the males and the females and to that of SL mRNA in the females. These results indicate that, in prespawning sockeye salmon, GnRH can stimulate SL gene expression, but probably not through the Pit-1/GHF-1-dependent system.

Gonadotropin-releasing hormone analog repairs reduced endometrial cell apoptosis in endometriosis in vitro

Objective: Impaired sensitivity of endometrial tissue to spontaneous apoptosis in women with endometriosis contributes to the abnormal implantation and growth of endometrium at ectopic sites. Our purpose was to examine the effect of gonadotropin-releasing hormone analog, widely used in the treatment of endometriosis, on the reduced rate of endometrial apoptosis in endometriosis. Study Design: Paired ectopic and eutopic endometrial tissue specimens were obtained from 13 patients with endometriosis, and control samples were taken from 8 patients with uterine myoma. Apoptotic cell death was assessed biochemically and morphologically with an enzyme-linked immunoassay and Hoechst No. 33342 staining of deoxyribonucleic acid fragment, respectively. Results: Spontaneous apoptosis was significantly lower in ectopic and eutopic endometrial tissue from patients with endometriosis (0.22 ± 0.082 in absorbance) than in endometrial tissue from control subjects (0.52 ± 0.483)( P < 0.001). Incubation with a gonadotropin-releasing hormone analog (1 μmol/L) increased the apoptotic rate of endometrial cells from patients with endometriosis to 0.56 ± 0.501 ( P < .001). The effect of this gonadotropin-releasing hormone revealed a dose dependency; a half-maximal effect occurred with 10 nmol/L; however, the control endometrium was not affected. Conclusion: Exposure to gonadotropin-releasing hormone results in changes of the sensitivity of endometriotic endometrium to spontaneous apoptosis; these changes in sensitivity may, in turn, release endometrial cells from resistance to apoptosis and result in reduced survival and growth. This phenomenon could, at least in part, account for the therapeutic action of gonadotropin-releasing hormone analog on endometriosis. (Am J Obstet Gynecol 2000;182:1142-6.)

Antiproliferative effects and insulin-like growth factor-I expression in Balb-C 3T3 fibroblasts after treatment with somatostatin and gonadotropin-releasing hormone analogs

The present study was aimed to compare antiproliferative effects of somatostatin (SS) and gonadotropin-releasing hormone analogs (GnRHa) on a fibroblast cell line. Proliferation index, cell count, viability of the cells and insulin-like growth factor-I (IGF-I) immunoreactivity were determined after treatment with either SS (100 microM/ml), GnRHa (35 nM/ml) or SS and GnRHa of Balb-C 3T3 mouse fibroblasts. It was found that the proliferation index, cell count, viability and IGF-I immunoreactivity were not affected by GnRHa treatment as compared with no treatment (p > 0.05). Application of SS to the fibroblasts resulted in a significant reduction in proliferation index, cell count, and IGF-I immunoreactivity as compared with GnRHa treatment and no treatment, but it had no effect on cell viability. The labelling index in SS-treated cells was significantly reduced as compared with combined treatment with SS and GnRHa. In conclusion, a direct effect of GnRHa on fibroblast cells in culture could not be demonstrated. SS had direct inhibitory effects on cell proliferation possibly via inhibition of IGF-I effects without affecting cell viability.

Atypical Endometrial Hyperplasia Treatment with Progestogens and Gonadotropin-Releasing Hormone Analogues: Long-Term Follow-up

Objective.The aim of this study was to assess the long-term effect of gonadotropin-releasing hormone analogues (GnRH-a) in combination with high-dose progestogens in the treatment of atypical endometrial hyperplasia in selected surgical high-risk patients and in women desiring reproductive potential. We hypothesized that this therapy is effective for most couples.Methods.In the Department of Gynecology of a university hospital, a conservative treatment was offered to a series of 22 patients with atypical endometrial hyperplasia who had a surgical or anesthetic risk history or wished to preserve their fertility potential. After informed consent, they were treated with 500 mg norethisterone acetate weekly for 3 months and 3.75 mg Triptorelin depot every month for 6 months. Three patients failed to complete the study, so the group finally consisted of 19 subjects. They were prospectively followed for 5 years by hysteroscopy and multiple selected biopsies every 6 months.Results.At a 5-year follow-up, regression was noted in 16 patients (84.2%), persistence in 1 (5.1%), recurrence in 1 (5.1%), and progression in 1 (5.1%).Conclusion.Consistent with our hypothesis, combined treatment with progestogens and GnRH-a is an effective alternative in selected patients with atypical endometrial hyperplasia.

Gonadotropin-Releasing Hormone Analog and Sex Steroids Shorten Homing Duration of Sockeye Salmon in Lake Shikotsu

Abstract Gonadotropin-releasing hormone analog (GnRHa), testosterone (T) or 17α, 20β-dihydroxy-4-pregnen-3-one (DHP) was implanted in lacustrine sockeye salmon (Oncorhynchus nerka) to examine their effects on homing behavior prior to spawning. Maturing adult fish in Lake Shikotsu were captured by a set net adjacent to their natal hatchery in September and October, 1997. They were tagged, implanted with hormones and released at the center of lake. More than 70% of released fish returned to the hatchery. In September, GnRHa-implanted fish returned significantly earlier than the controls regardless of sexes. DHP also shortened homing duration in the females but not in the males. T tended to reduce homing duration in the males, however it did not have any significant effect in the females. In October, fish in all groups quickly returned within a few days after the release. Hence, the shortening effect of GnRHa on homing duration was not seen. The October fish may be already well primed by endogenous hormones....