leuprolide and iturelix

Follicular atresia in granulosa and theca cells occurs by apoptosis through weak hormonal stimulation. We have previously proposed an in vitro model to study this process by inducing apoptosis in BGC-1, a bovine granulosa cell line, and in primary cultures from ovaries with or without corpus luteum (CPGB+ and CPGB-, respectively), with different doses of gonadotropin releasing hormone (GnRH) analogs (leuprolide acetate (LA) as agonist and antide as antagonist). BGC-1 represent immature granulosa cells, whereas CPGB represent different degrees of luteinization. Our aim was to evaluate the intracellular pathways involved in the GnRH regulation of apoptosis in BGC-1. Treatment with LA 100nM but not with antide led to an increase in BAX over BCL-2 expression, showing antagonism of antide. All treatments inhibited phospholipase-D (PLD) activity compared to control, implying agonist behavior of antide. Progesterone in vitro production and 3β-hydroxysteroid dehydrogenase (3β-HSD) expression revealed different degrees of luteinization: BGC-1 were immature, whereas CPGB+ were less differentiated than CPGB-. We concluded that LA-induced apoptosis in BGC-1 occurs by activation of the mitochondrial pathway and by inhibition of PLD activity and that antide might work both as an antagonist of the intrinsic pathway and as an agonist of the extrinsic protection pathway by inhibiting PLD activity.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Cattle; Cell Differentiation; Cell Line; Cells, Cultured; Enzyme Activation; Female; Gene Expression Regulation, Developmental; Genes, bcl-2; Gonadotropin-Releasing Hormone; Granulosa Cells; Leuprolide; Mitochondria; Oligopeptides; Ovary; Phospholipase D; Signal Transduction

To elucidate the physiologic mechanism responsible for the supraphysiologic gonadotropin release from the pituitary induced by gonadotropin-releasing hormone (GnRH) agonist in female rats primed with GnRH antagonist.. Controlled experimental intervention.. Government research facility.. Forty 8-week-old Sprague-Dawley rats.. Forty oophorectomized rats were randomized into four treatment groups of 10: group A, control vehicles; group B, GnRH agonist (leuprolide acetate; 1.7 microg/kg twice a day) on day 4; group C, GnRH antagonist (Nal-Lys; 3 mg/kg each day) days 1 to 4; or group D, GnRH antagonist (Nal-Lys; 3 mg/kg each day) days 1 to 4 plus GnRH agonist (1.7 microg/kg twice a day) on day 4.. Immunohistochemical methods, Northern and in situ hybridization to quantitate pituitary follicle-stimulating hormone beta (FSH-beta), luteinizing hormone beta (LH-beta), and GnRH receptor (GnRH-R) messenger RNA (mRNA), and receptor protein levels in all treatment groups.. Treatment with GnRH antagonist was associated with increased storage of gonadotropin in the pituitary for FSH-beta and LH-beta, but mRNA levels were unchanged. The GnRH-R mRNA decreased after GnRH-agonist treatment but remained stable in the GnRH-antagonist treatment groups. Levels of GnRH-R were decreased after GnRH-antagonist treatment.. These data indicate that the in vivo mechanism responsible for the exaggerated release of gonadotropins in rats primed with GnRH antagonist and treated with GnRH agonist was an increase in releasable gonadotropin pools coupled with a reduction in GnRH-R, but receptor function was preserved.

Topics: Animals; Blotting, Northern; Female; Fertility Agents, Female; Follicle Stimulating Hormone, beta Subunit; Gonadotropin-Releasing Hormone; Gonadotropins, Pituitary; Hormone Antagonists; Immunohistochemistry; In Situ Hybridization; Leuprolide; Luteinizing Hormone, beta Subunit; Oligopeptides; Ovariectomy; Ovulation Induction; Pituitary Gland; Rats; Rats, Sprague-Dawley; Receptors, LHRH; RNA, Messenger

An adequate vascular supply is important to provide endocrine and paracrine signals during follicular development. We evaluated the direct in vivo effects of both the GnRH-agonist Leuprolide acetate (LA) and the GnRH-antagonist Antide (Ant) on the expression of VEGF-A and ANPT-1 and their receptors in ovarian follicles from prepubertal eCG-treated rats. We also examined whether the changes observed in apoptosis by GnRH-I analogs have an effect on the caspase cascade. LA significantly decreased the levels of VEGF-A, its receptor Flk-1, and ANPT-1 when compared to controls, while the co-injection of Ant interfered with this effect. No changes were observed in the levels of Tie-2 after treatment with these analogs. When we measured the follicular content of caspase-3 protein, we observed that LA significantly increased the level of the active form. The co-injection of Ant interfered with this effect and Ant alone significantly decreased caspase-3 cleavage. IHC analyses corroborated these data. Notably, while LA increased caspase-3 activity levels, Ant decreased them when compared to controls. In follicles obtained from LA-treated rats, cleavage of PARP (a substrate of caspase-3) from the intact 113-kDa protein showed a significant enhancement in an 85-kDa fragment. The co-injection of Ant interfered with this effect. Ant alone significantly decreased PARP cleavage as compared to controls. We conclude that the decrease in VEGF-A, its receptor Flk-1/KDR, and ANPT-1 produced by the administration of GnRH-I agonist is one of the mechanisms involved in ovarian cell apoptosis. This suggests an intraovarian role of an endogenous GnRH-like peptide in gonadotropin-induced follicular development.

Topics: Angiopoietin-1; Animals; Apoptosis; Caspase 3; Enzyme Activation; Female; Gonadotropin-Releasing Hormone; Injections, Subcutaneous; Leuprolide; Neovascularization, Physiologic; Oligopeptides; Ovarian Follicle; Ovary; Rats; Rats, Sprague-Dawley; Receptor, TIE-2; Structure-Activity Relationship; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Our purpose was to evaluate the effect of the GnRH agonist (GnRHa), leuprolide acetate (LA), and the GnRH antagonist (GnRHant), Antide, on apoptosis and expression of apoptosis-related proteins in endometrial epithelial cell (EEC) cultures from patients with endometriosis and controls (infertile women without endometriosis).. Biopsy specimens of eutopic endometrium were obtained from 22 patients with endometriosis and from 14 women that served as controls. Apoptosis was examined in EEC after incubation with LA and Antide. Bax, Bcl-2, Fas and FasL expression was evaluated after exposure to LA, Antide or a combination of both. The percentage of apoptotic cells (%ApC) was assessed by the acridine orange-ethidium bromide technique, and protein expression was evaluated by western blot and immunocytochemistry.. LA 100 and 1000 ng/ml increased the %ApC in EEC from patients with endometriosis (both P < 0.05) and controls (p < 0.05 and P < 0.01, respectively). Antide 10(-5) M increased the %ApC in EEC from patients with endometriosis and controls (P < 0.01). In EEC from women with endometriosis, Bax expression increased after treatment with LA, Antide and LA + Antide (P < 0.05, P < 0.001 and P < 0.001), whereas Bcl-2 expression decreased after exposure to LA and Antide (P < 0.001 and P < 0.01). FasL expression increased after LA, Antide and LA + Antide treatments (P < 0.01, P < 0.001 and P < 0.01). No significant changes were observed on Fas expression.. GnRH analogues enhanced apoptosis in EEC, and this was accompanied by an increase in expression of the pro-apoptotic proteins Bax and FasL and a decrease in expression of the anti-apoptotic protein Bcl-2.

Topics: Apoptosis; bcl-2-Associated X Protein; Cells, Cultured; Endometriosis; Endometrium; Epithelial Cells; Fas Ligand Protein; fas Receptor; Female; Gene Expression Regulation; Gonadotropin-Releasing Hormone; Humans; Immunohistochemistry; Infertility, Female; Leuprolide; Oligopeptides; Proto-Oncogene Proteins c-bcl-2

The GnRH agonist leuprolide acetate (LA) inhibited DNA synthesis in epidermal growth factor-stimulated human granulosa luteinized cell cultures. This effect was blocked by the prior addition of a GnRH antagonist antide (ANT), and this compound per se was able to produce a stimulatory effect of DNA synthesis on basal conditions. Leuprolide acetate produced an increase in the percentage of apoptotic cells, and when these two factors were co-incubated, ANT blocked the apoptotic effect produced by LA.

Topics: Apoptosis; Cell Proliferation; Female; Gonadotropin-Releasing Hormone; Granulosa Cells; Humans; Leuprolide; Oligopeptides

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.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Cytochromes c; Estrous Cycle; Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Leuprolide; Oligopeptides; Ovarian Follicle; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley

This study was performed to investigate the expression of embryo-derived gonadotropin-releasing hormone (GnRH) and its receptor, and to determine the role of GnRH in porcine preimplantation embryos. In Experiment 1, porcine blastocysts derived from in vitro fertilization (IVF) and cultured in North Carolina State University (NCSU)-23 medium were subjected to reverse transcription polymerase chain reaction (RT-PCR) amplification with specific primers for GnRH and its receptor. The results showed that GnRH and its receptor were expressed in porcine IVF blastocysts. In order to investigate the role of GnRH in embryo development, porcine IVF embryos were cultured in NCSU-23 supplemented with different concentrations (0, 0.1, 1, or 10 microM) of a GnRH agonist (leuprolide, Experiment 2) or GnRH antagonist (antide, Experiment 3). Supplementing the culture medium with 0.1 or 1 microM leuprolide increased the rate of blastocyst formation (28.5 or 27.6% versus 20.2%) and mean total cell number (129 versus 104) compared to the control group. In contrast, antide significantly decreased the rate of blastocyst formation [12.6% (0.1 microM), 10.2% (1.0 microM), or 8.9% (10.0 microM) versus 22.8% (control)] and total cell number [69 (1 microM) or 68 (10 microM) versus 104 (control)]. In Experiment 4, porcine IVF embryos were cultured in NCSU-23 medium containing 1 microM antide plus 1 microM leuprolide. The embryotrophic effect of GnRH agonist was reversed by co-supplementing with GnRH antagonist. In conclusion, the present study demonstrated that supplementing a culture medium with GnRH agonist can improve blastocyst formation and the quality of porcine IVF embryos, and that this action was mediated through GnRH receptors.

Topics: Animals; Blastocyst; Cells, Cultured; Culture Media; Embryonic Development; Fertilization in Vitro; Gene Expression; Gonadotropin-Releasing Hormone; Leuprolide; Oligopeptides; Receptors, LHRH; Reverse Transcriptase Polymerase Chain Reaction; Swine

To examine the effects of GnRH antagonists on preantral follicle survival in vivo and to investigate whether GnRH antagonist use during cyclophosphamide treatment would protect the ovary and preserve primordial follicle survival in a murine model.. Prospective basic research study.. Research laboratory in an academic medical center.. Adult C57Bl/6 mice (5 to 6 weeks old).. Mice received either a single injection of GnRH agonist (leuprolide acetate) on study day -10 or injections of the GnRH antagonist (antide or cetrorelix) on study days -3 and 0. Some animals also received the chemotherapeutic agent cyclophosphamide on day 0. All animals were killed by CO2 asphyxiation on day 7. To examine direct vs. indirect effects, some mice received GnRH antagonist under the bursa of one ovary, with the contralateral ovary receiving vehicle. Ovaries were fixed in Kahle's solution; 7-mum tissue sections were stained with Lillie's allochrome, and preantral follicles were counted on every fifth section.. Numbers of primordial, primary, and secondary follicles.. Systemic administration of both GnRH antagonists caused a significant destruction of primordial follicles compared with control mice. Similar results were obtained whether the antagonists were administered systemically or directly to the ovary. Gonadotropin-releasing hormone agonist had no effect on primordial follicle numbers by itself but reduced the follicular depletion caused by cyclophosphamide.. In contrast to the effects of GnRH agonists to reduce chemotherapeutic destruction of primordial follicles, GnRH antagonists do not protect the ovary from the damaging effects of cyclophosphamide. More importantly, GnRH antagonists alone deplete primordial follicles in this murine model, likely through a direct effect on the ovary. Whether these observations apply to other species requires further study.

Topics: Animals; Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Leuprolide; Mice; Mice, Inbred C57BL; Oligopeptides; Ovarian Follicle

The aim of the present study was to evaluate the effect of GnRH analogues on the in-vitro eutopic endometrial cell apoptosis and release of interleukin-1beta (IL-1beta) and vascular endothelial growth factor (VEGF).. Biopsy specimens of eutopic endometrium obtained from 16 women with untreated endometriosis and 14 controls were studied. Apoptosis, IL-1beta and VEGF release were evaluated in epithelial endometrial cell cultures after incubation with leuprolide acetate (LA) as GnRH agonist, antide as GnRH antagonist, and a combination of both. The percentage of apoptotic cells was evaluated by the acridine orange-ethidium bromide technique, and IL-1beta and VEGF concentrations were assessed by using commercial enzyme-linked immunosorbent assay (ELISA) kits.. We found that LA (100 ng/ml) enhanced apoptosis in endometrial cell cultures from endometriosis patients and controls and this effect was reversed by antide at 10(-7) mol/l. IL-1beta and VEGF release was downregulated by LA in cultures from controls and endometriosis patients. The addition of antide 10(-7) mol/l reversed this inhibition. Endometrial cultures treated with antide at 10(-7) mol/l did not show any significant effects compared with basal conditions.. GnRH agonists appear to have a direct effect in endometrial cells cultures, by enhancing the percentage of apoptotic cells and decreasing the release of pro-mitogenic cytokines such as IL-1beta and VEGF.

Topics: Apoptosis; Case-Control Studies; Cells, Cultured; Endometriosis; Endometrium; Female; Gonadotropin-Releasing Hormone; Humans; Interleukin-1; Leuprolide; Oligopeptides; Vascular Endothelial Growth Factor A

There is growing evidence that suggests a direct action of gonadotropin-releasing hormone agonist (GnRH-a) on endometrial growth. Consequently, our purpose was to evaluate the effect of GnRH-a on in vitro eutopic endometrial cell growth and apoptosis.. Prospective study.. Research institute and clinical fertility center.. Sixteen women with untreated endometriosis and 14 controls.. Biopsy specimens of eutopic endometrium were obtained from all subjects. Apoptosis and cell proliferation were examined in epithelial endometrial cell cultures after incubation with leuprolide acetate (LA), antide, and a combination of both.. The percentage of apoptotic cells was evaluated by the acridine orange-ethidium bromide technique; cell proliferation was assessed by (3)H-thymidine incorporation.. Leuprolide acetate (LA) (100 ng/mL) enhanced apoptosis in endometrial cultures from patients with endometriosis and controls, and this effect was reversed by antide 10(-7)M. Cell proliferation was down-regulated by LA at 1, 10, and 100 ng/mL in cultures from women without and with endometriosis. The addition of antide 10(-7)M reversed this inhibition.. GnRH-a appears to have a direct effect by enhancing the apoptotic index and decreasing the cell proliferation in endometrial cells.

Topics: Acridine Orange; Apoptosis; Biopsy; Cell Division; Endometriosis; Epithelial Cells; Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leuprolide; Oligopeptides; Prospective Studies; Thymidine; Transforming Growth Factor beta

Gonadotropin releasing hormone analogues (GnRHa) are often used to regress endometriosis implants and prevent premature luteinizing hormone surges in women undergoing controlled ovarian stimulation. In addition to GnRH central action, the expression of GnRH and receptors in the endometrium implies an autocrine/paracrine role for GnRH and an additional site of action for GnRHa. To further examine the direct action of GnRH (Leuprolide acetate) in the endometrium, we determined the effect of GnRH on endometrial stromal (ESC) and endometrial surface epithelial (HES) cells expression and activation of Smads (Smad3, -4 and -7), intracellular signals activated by transforming growth factor beta (TGF-beta), a key cytokine expressed in the endometrium. The results show that GnRH (0.1 microM) increased the expression of inhibitory Smad7 mRNA in HES with a limited effect on ESC, while moderately increasing the common Smad4 and Smad7 protein levels in these cells (P < 0.05). GnRH in a dose--(0.01 to 10 microM) and time--(5 to 30 min) dependent manner decreased the rate of Smad3 activation (phospho-Smad3, pSmad3), and altered Smad3 cellular distribution in both cell types. Pretreatment with Antide (GnRH antagonist) resulted in further suppression of Smad3 induced by GnRH, with Antide inhibition of pSmad3 in ESC. Furthermore, co-treatment of the cells with GnRH + TGF-beta, or pretreatment with TGF-beta type II receptor antisense to block TGF-beta autocrine/paracrine action, in part inhibited TGF-beta activated Smad3. In conclusion, the results indicate that GnRH acts directly on the endometrial cells altering the expression and activation of Smads, a mechanism that could lead to interruption of TGF-beta receptor signaling mediated through this pathway in the endometrium.

Topics: Adult; Cells, Cultured; Culture Media, Serum-Free; DNA-Binding Proteins; Dose-Response Relationship, Drug; Endometrium; Female; Gene Expression Regulation; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leuprolide; Oligodeoxyribonucleotides, Antisense; Oligopeptides; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; RNA, Messenger; Smad3 Protein; Smad4 Protein; Smad7 Protein; Stromal Cells; Trans-Activators; Transforming Growth Factor beta

The objective of this study was to elucidate the biological significance of GnRH and antiprogestins and antiestrogen in leiomyoma and their interactions with ovarian steroid 'add-back' therapy. Leiomyoma and myometrial smooth muscle cells (LSMC and MSMC) were isolated and exposed to GnRH agonist (leuprolide acetate, LA), 17beta-estradiol (E2), medroxyprogesterone acetate (MPA), GnRH antagonist (Antide), estrogen antagonist, ICI182780 (Fulvestrant) and progesterone antagonists RU486 (Mifepristone) and ZK98299 (Onapristone) and combinations thereof. The rate of DNA synthesis, cell proliferation and transforming growth factor-beta (TGF-beta) expression were then determined. In both cell types, we found that in a dose-dependent manner, LA inhibited, whereas E2, MPA and the combination of E2 + MPA stimulated, the rate of DNA synthesis in these cells. Antide reversed the inhibitory effect of LA, while LA partly inhibited the stimulatory effect of the steroids. In addition, RU486, ICI182780 and ZK98299 at 0.1 micro mol/l or higher doses inhibited the rate of DNA synthesis and partly reversed the effects of E2 and/or MPA. We also found that LSMC expressed elevated levels of TGF-beta1 compared with MSMC. In both cell types, the effects of LA, E2, MPA, RU, ZK and ICI and combinations thereof on TGF-beta1 production were reflective of their effects on DNA synthesis. In line with this, TGF-beta1 was found to stimulate DNA synthesis and the E2-, TGF-beta1- or E2 + TGF-beta1-induced DNA synthesis was found to be inhibited by TGF-beta1 neutralizing antibodies and/or LA. In conclusion, the results provide further evidence that GnRH agonist- and RU486-induced leiomyoma regression is mediated in part through an interactive mechanism that results in altered cell growth and suppression of TGF-beta production.

Topics: Estradiol; Estrogen Receptor Modulators; Female; Gonadotropin-Releasing Hormone; Gonanes; Humans; Leiomyoma; Leuprolide; Medroxyprogesterone Acetate; Mifepristone; Muscle Development; Myocytes, Smooth Muscle; Myometrium; Oligopeptides; Progestins; Steroids; Transforming Growth Factors

Fas ligand induces cell death by means of apoptosis in a variety of cell types when cross-linked with its natural receptor, Fas. GnRH receptor-bearing tumors undergo apoptosis in vivo and in vitro with GnRH agonists. To provide a potential association of the Fas system with the antiproliferative signaling process of GnRH receptor, we have evaluated the regulation of Fas ligand expression in GnRH receptor-positive tumors and cloned cell lines known to have substantial GnRH receptors. Surgically removed uterine endometrial carcinomas and ovarian carcinomas had been screened for GnRH receptor expression before analysis. Fas ligand protein was characterized by immunoblotting of membrane proteins with the specific antibody. Fas ligand messenger RNA was determined by RT-PCR using oligonucleotide primers synthesized according to the published Fas ligand sequence. Incubation with a GnRH analog (1 mumol/L) induced the expression of Fas ligand messenger RNA and immuno-reactive Fas ligand with a lag time of 48 h in cloned cell lines (endometrial carcinoma HHUA cells, and ovarian carcinoma SK-OV-3 and Caov-3 cells). There was no detectable Fas ligand expression within 24 h. The stimulatory effect of GnRH on Fas ligand protein expression revealed a dose dependency; a half-maximal effect occurred with 10 nmol/L GnRH analog (P < 0.01). The stimulated Fas ligand expression could be neutralized by displacement of GnRH from its receptor by GnRH antagonist antide. Cells isolated from GnRH receptor-bearing ovarian carcinomas and uterine endometrial carcinomas gave identical results to those obtained in cloned cell lines. These data demonstrate the functional coupling of stimulated Fas ligand expression to GnRH receptor activation. Increased Fas ligand level within the GnRH receptor-bearing tumors might promote apoptotic cell death through attack on intratumoral Fas-positive cells that could, at least in part, account for the antiproliferative action of the hormone.

Topics: Apoptosis; Buserelin; Endometrial Neoplasms; fas Receptor; Female; Gene Expression; Humans; Leuprolide; Oligopeptides; Ovarian Neoplasms; Polymerase Chain Reaction; Receptors, LHRH; RNA-Directed DNA Polymerase; RNA, Messenger; Tumor Cells, Cultured

Gonadotropin-releasing hormone (GnRH) has been found to be expressed within the ovary and to modulate cell differentiation in ovarian cells. In the present study we have analyzed the influence of GnRH on DNA synthesis in rat granulosa cells. Cells were obtained from immature DES-treated rats and cultured in defined medium (DMEM:F12) containing combinations of FSH, estradiol, and transforming growth factor-beta (TGF-beta), both in the presence and absence of GnRH. A GnRH analog, Leuprolide (GnRHa), caused a dose-dependent inhibition of 3H-thymidine incorporation in cells cultured in the presence of FSH (20 ng/ml) and TGF beta (2.5 ng/ml), at concentrations as low as 5 x 10(-11) M. Similarly, a complete inhibition of hormonally stimulated DNA synthesis were observed with another analog (Buserelin, ED50 = 1.58 +/- 0.22 x 10(-10) M) and native GnRH (ED50 = 1.4 +/- 0.3 x 10(-6) M). A competitive antagonist of GnRH (Antide) was used to neutralize the GnRH agonist effects. Antide 10(-8) M could prevent the inhibition elicited by 10(-7) M of Leuprolide. These results suggest that GnRH may play a role in the regulation of rat granulosa cell proliferation during follicular development.

Topics: Animals; Cell Division; Cells, Cultured; Diethylstilbestrol; DNA Replication; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Granulosa Cells; Hormone Antagonists; Leuprolide; Nucleic Acid Synthesis Inhibitors; Oligopeptides; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta

To evaluate the impact of chronic GnRH antagonist therapy on the extent of GnRH agonist-induced gonadotrope desensitization.. Prospective and controlled.. Primate Research Center.. Six reproductive age cycling female baboons (Papio cyanocephalus anubis).. The animals were divided into two groups. Group A received a total of 19 pulses of 0.83 microgram/kg leuprolide acetate (LA) on a 12-hour dosing schedule. Group B received Nal-Lys (3 mg/kg then 1 mg/kg every other day) for 1 week and then added an identical 19 pulses of LA while continuing Nal-Lys therapy.. Characterization of the gonadotropin response was done by collecting serum samples at -15, 0, 15, 30, 60, 90, 120, 240, and 480 minutes relative to the injection of the LA.. After equivalent baseline responses, the baboons pretreated with Na-Lys had an increased LH and FSH response to the administration of the LA. After a total of 19 pulses of the LA, the Nal-Lys-treated animals had an increased FSH response in comparison to the untreated controls. This indicates that the extent of gonadotrope desensitization was reduced in the presence of the GnRH antagonist.. The presence of GnRH antagonist reduces the extent of gonadotrope desensitization in response to the administration of repetitive pulses of GnRH agonist.

Topics: Animals; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Leuprolide; Luteinizing Hormone; Oligopeptides; Papio; Prospective Studies; Reference Values

Chronic GnRH antagonist therapy produces enhanced gonadotrope responsiveness to supraphysiologic stimuli despite the lack of any measurable suppression of gonadotropin levels. This indicates that GnRH antagonists fundamentally alter gonadotrope response mechanisms without inhibiting gonadotropin release. Beyond the physiologic implications, these data may eventually impact the development of clinical protocols. Benefits could include enhancements in the endogenous gonadotropin flare during controlled ovarian hyperstimulation cycles. Additionally, proposed contraceptive protocols where GnRH antagonists are used to produce the initial inhibition in gonadotropin release and are then followed by a GnRH-a (to avoid the gonadotropin flare) may in fact produce paradoxical results.

Topics: Animals; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Kinetics; Leuprolide; Luteinizing Hormone; Oligopeptides; Papio