'GnRH agonist trigger: looking for the coin under the lamp post?'.
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Chorionic Gonadotropin↗
Biomedical subjects
S Kol
Publications and source records attributed to S Kol.
Ovarian interleukin-1-induced gene expression: privileged genes threshold theory.
Interleukin (IL)-1, an established mediator of inflammation, is also a mediator of ovulation (a cyclic inflammatory-like process). We have shown that IL-1 beta induces the in vitro expression of genes believed to play important role in ovulation (IL-1 beta itself, its receptors, IL-1 beta receptor antagonist, glucose transporters 1 and 3, secretory and cytosolic phospholipase A(2), prostaglandin endoperoxide synthase 1 and 2). These experiments suggest that the target genes are turned on over a relatively narrow IL-1 beta dose range. Moreover, IL-1 induces gene expression in what appears to be a hierarchical manner. We hypothesize that IL-1 induces a host of ovulation-associated genes, in a manner that is not only dose-dependent, but also obeys a certain hierarchical order, serving as 'check gates' in securing successful ovulation.
Female↗
Should we explore OHSS full clinical scope?...
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Chorionic Gonadotropin↗
[How to prevent completely ovarian hyperstimulation with GnRH-based stimulation protocols].
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Chorionic Gonadotropin↗
Ovarian stimulation in in vitro fertilization with or without the "long" gonadotropin-releasing hormone agonist protocol: effect on cycle duration and outcome.
OBJECTIVE: To study the correlation between stimulation duration of IVF cycles, with and without GnRH agonist (GnRH-a), and cycle outcome. DESIGN: Retrospective analysis of data. SETTING: University-affiliated IVF clinic. PATIENT(S): 998 IVF cycles in which long GnRH-a protocol was used, and 155 cycles with hMG only. INTERVENTION(S): IVF cycles. MAIN OUTCOME MEASURE(S): Cycle outcome in number of oocytes and embryos, and pregnancy rate. RESULT(S): The mean stimulation duration (+/-SD) was 9.6+/-1.7 and 6.7+/-1.0 for the GnRH-a and the hMG-only cycles, respectively (P<0.01). In the GnRH-a group, no statistically significant correlation between cycle duration and pregnancy rate was found. Interestingly, the patients treated for 9 days had the highest number of oocytes retrieved and the highest pregnancy rate. Stimulation duration was not affected by age in either protocol. GnRH-a cycles yielded a significantly higher number of oocytes and embryos compared to cycles without GnRH-a. The pregnancy rate was similar in both groups. CONCLUSION(S): Stimulation duration in the long GnRH-a protocol group was significantly longer than in the hMG-only group. Stimulation duration was not affected by age. No statistically significant correlation was found between stimulation duration and cycle outcome in the long protocol group.
Adult↗
The low responder female IVF patient with hypogonadotropic hypogonadism: do not give up!
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Adult↗
Severe OHSS: yes, there is a strategy to prevent it!
Effective measures to prevent ovarian hyperstimulation syndrome (OHSS) remain controversial. It became almost 'common knowledge' that there is no strategy that may completely prevent OHSS. Extensive clinical experience (albeit not derived from prospective randomized studies) clearly documents the ability of a single administration of gonadotrophin-releasing hormone (GnRH) agonist to effectively trigger ovulation, while completely eliminating any threat of clinically significant OHSS. This strategy cannot be used if the pituitary is down-regulated (as is the case in most assisted reproductive cycles today), however, the newly-introduced GnRH antagonists open new opportunities for implementing this strategy, since the pituitary preserves its responsiveness to GnRH agonists. Combining GnRH antagonist-based ovarian stimulation (particularly in 'high responders'), with GnRH agonist-driven ovulation triggering will make severe OHSS a disease of the past in assisted reproduction.
Female↗
Embryo implantation and GnRH antagonists: GnRH antagonists in ART: lower embryo implantation?
Recently, concerns have been raised regarding possible adverse effects of gonadotrophin-releasing hormone (GnRH) antagonists on extra-pituitary reproductive cells and organs, i.e. ovarian cells, oocyte, embryo, endometrium. These concerns are based on numerous in-vitro studies suggesting decreased biosynthesis of growth factors caused by local action of GnRH antagonists. Clinically, it has been shown that the use of high doses (< or =1 mg daily) of GnRH antagonists is associated with low implantation rates in IVF. Although such direct adverse effect of GnRH antagonists cannot be ruled out at this time, so far clinical experience points to profound LH suppression as the major caveat associated with the use of high doses of GnRH antagonists. Very low LH concentrations are associated with aberrant concentrations of oestradiol during ovarian stimulation, which may in turn adversely effect implantation potential. The clinical data available thus far on the use of GnRH antagonists originate from protocols designed for clinical studies. It is predicted that as more clinical experience is gained, and with protocol modifications to suit individual patient response, GnRH antagonists will be comparable with the agonists in terms of cycle outcome.
Embryo Implantation↗
Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report: short communication.
A new treatment option for patients undergoing ovarian stimulation is the gonadotrophin-releasing hormone (GnRH) antagonist protocol, with the possibility to trigger a mid-cycle LH surge using a single bolus of GnRH agonist, reducing the risk of developing ovarian hyperstimulation syndrome (OHSS) in high responders and the chance of cycle cancellation. This report describes the use of 0.2 mg triptorelin (Decapeptyl) to trigger ovulation in eight patients who underwent controlled ovarian hyperstimulation with recombinant FSH (rFSH, Puregon) and concomitant treatment with the GnRH antagonist ganirelix (Orgalutran) for the prevention of premature LH surges. All patients were considered to have an increased risk for developing OHSS (at least 20 follicles > or =11 mm and/or serum oestradiol at least 3000 pg/ml). On the day of triggering the LH surge, the mean number of follicles > or =11 mm was 25.1 +/- 4.5 and the median serum oestradiol concentration was 3675 (range 2980-7670) pg/ml. After GnRH agonist injection, endogenous serum LH and FSH surges were observed with median peak values of 219 and 19 IU/l respectively, measured 4 h after injection. The mean number of oocytes obtained was 23.4 +/- 15.4, of which 83% were mature (metaphase II). None of the patients developed any signs or symptoms of OHSS. So far, four clinical pregnancies have been achieved from the embryos obtained during these cycles, including the first birth following this approach. It is concluded that GnRH agonist effectively triggers an endogenous LH surge for final oocyte maturation after ganirelix treatment in stimulated cycles. Our preliminary results suggest that this regimen may prove effective in triggering ovulation and could be said to prevent OHSS in high responders. The efficacy and safety of such new treatment regimen needs to be established in comparative randomized studies.
Adult↗
Non-steroidal anti-inflammatory drugs (NSAIDs) block the late, prostanoid-dependent/ceramide-independent component of ovarian IL-1 action: implications for the ovulatory process.
The therapeutic efficacy and antiovulatory properties of non-steroidal anti-inflammatory drugs (NSAIDs) is attributed to their ability to suppress prostaglandin endoperoxide synthase (PGS) activity. Given the likely role of interleukin (IL)-1 in the inflammatory (and probably the ovulatory) process, we set out to evaluate whether the antiovulatory property of NSAIDs is attributable, in part, to the inhibition of ovarian IL-1 action. Whole ovarian dispersates from immature rats were cultured under serum-free conditions in the absence or presence of the indicated agents. At the conclusion of the culture period, total RNA was extracted and probed for transcripts corresponding to PGS-1, PGS-2, IL-1beta, IL-1 receptor antagonist (IL-1RA) or type I IL-1 receptor (IL-1R) by a solution hybridization/ribonuclease protection assay. Treatment with indomethacin was without significant effect on the early (1 h) response to IL-1beta; however, it led to complete and highly significant dose-dependent blockade of the late (48 h) response to IL-1beta as assessed in terms of PGS-2 transcripts, proteins and activity. The addition of PGE2 to cells augmented the ability of IL-1beta to upregulate PGS-2 transcripts. Moreover, the addition of PGE2 to indomethacin-treated cells all but reversed the ability of indomethacin to suppress the IL-1beta effect at both the PGS-2 transcript and protein levels. The upregulation by IL-1 of IL-1beta, IL-1R and IL-1RA transcripts was similarly inhibited by indomethacin. Taken together, these observations suggest that the anti-ovulatory property of NSAIDs may be due, in part, to blockade of the late, prostanoid-dependent component of ovarian IL-1 action.
Animals↗
The rat intraovarian interleukin (IL)-1 system: cellular localization, cyclic variation and hormonal regulation of IL-1beta and of the type I and type II IL-1 receptors.
An increasing body of evidence supports the possibility that intraovarian interleukin (IL)-1 plays an intermediary role in the periovulatory cascade. To gain further insight into the intraovarian IL-1 hypothesis, we studied the cellular localization cyclic variation and hormonal regulation of IL-1beta, as well as of the type I and type II IL-1 receptors (IL-1R) in immature rats. In situ hybridization localized IL-1beta and type I IL-1R transcripts to the granulosa cell compartment, the innermost layers of the theca interna and to the oocyte of the untreated immature ovary. Molecular probing of whole ovarian material in the course of a simulated estrous cycle revealed a progressive preovulatory increase in IL-1beta and type I IL-1R transcripts to an in vivo peak at the time of ovulation (3.0- and 2.5-fold increases over untreated controls; P < 0.05). Comparable efforts to localize and probe for type II IL-IR transcripts failed to elicit a detectable signal. The basal in vitro expression pattern of IL-1beta and type II IL-1R transcripts by whole ovarian dispersates revealed an early (4 h) spontaneous increase to a peak (2.1- and 5.8-fold increases over time 0: P < 0.05) followed by a gradual decline to a 48 h nadir. Treatment of whole ovarian dispersates with the IL-1 receptor antagonist (IL-1RA) or with IL-1beta failed to alter the initial (4 h) burst of IL-1beta or of type II IL-1R expression thereby suggesting IL-1-independence. Treatment with hCG proved equally ineffective. However, longer-term treatment of whole ovarian dispersates with IL-1beta produced a significant secondary increase (5.9-fold over time 0; P < 0.05) in IL-1beta (but not type II IL-1R) transcripts by 48 h. This IL-1 effect was completely blocked by co-treatment with IL-1RA thereby suggesting mediation via a specific IL-1 receptor. Qualitatively comparable but quantitatively reduced results obtained for isolated granulosa cells. The basal in vitro expression pattern of type I IL-1R transcripts by whole ovarian dispersates revealed a progressive spontaneous increase (3.1-fold increase overall) over the 48 h culture. Treatment with IL-1beta produced a significant (P < 0.05) increase (5-fold) in type I IL-1R transcripts by 48 h, an effect which was completely blocked by co-treatment with IL-1RA. Taken together, these observations: (1) localize IL-1beta and its type I receptor to granulosa cells, the innermost layers of the theca interna and to the oocyte; (2) confirm their periovulatory in vivo expression pattern; (3) document their expression by untreated cultured whole ovarian dispersates; and (4) demonstrate their in vitro responsiveness to receptor-mediated/IL-1-driven autocrine amplification. The type II IL-1R was undetectable in vivo, its in vitro expression pattern proving IL-1- and hCG-independent. The periovulatory expression pattern of IL-1beta and its receptor (type I) is compatible with the notion that the intraovarian IL-1 system may play an intermediary role in the ovulatory process.
Animals↗
Expression and hormonal regulation of rat ovarian interleukin-1beta converting enzyme, a putative apoptotic marker: endocrine- and paracrine-dependence.
It is the purpose of this paper to assess the expression, cellular localization, and hormonal regulation of rat ovarian interleukin (IL)-1beta converting enzyme (ICE), a putative apoptotic marker. In agreement with previous observations ICE transcripts were noted in relatively increased abundance in the thymus, lung, spleen and small intestine. Although ICE transcripts were barely expressed in the untreated, immature rat ovary, they were apparent throughout a simulated estrous cycle. The in vivo expression of ovarian ICE rose gradually from 6 h after ovulation triggering to a peak (1.74-fold increase versus control, P < 0.05) 24 h after human chorionic gonadotropin administration, a marked and significant decrease to baseline being noted 24 h later. To examine the effect of in vitro culture on ovarian ICE gene expression, whole ovarian dispersates from immature rats were cultured without treatment for 72 h. ICE gene expression significantly (P < 0.01) increased to a maximum 24 h post plating (2.55-fold increase as compared with time zero). Treatment with IL-1beta was associated with a small but statistically insignificant increase in ovarian ICE gene expression. Similarly, provision of IL-RA resulted in a modest, albeit statistically insignificant, decrease in ovarian ICE gene expression. Treatment with GnRH (but not FSH, LH or PMSG) significantly (P < 0.05) increased ovarian ICE gene expression (41.5% increase versus control). Treatment with dexamethasone (but not diethylstilbestrol, R5020 or R1881) produced a significant (P < 0.05) 42.3% decrease in ovarian ICE gene expression as compared with untreated controls. Treatment with TNF alpha (but not ET-1, TGF alpha, TGF beta, IGF-I or bFGF) produced a significant (P < 0.01) 2.5-fold increase in ovarian ICE gene expression as compared with untreated controls. Taken together, our present findings: (1) reaffirm the ovarian expression of the ICE gene, (2) document a periovulatory increase in ovarian ICE gene expression, (3) show the inhibitory effect of glucocorticoids in this regard, and (4) establish TNF alpha as an upregulator. Taken together, these findings suggest a role for ovarian ICE either in the context of apoptosis/atresia or in the context of the ovulatory process.
Animals↗
A prospective randomized study comparing intramuscular with intravaginal natural progesterone in programmed thaw cycles.
A simple programmed thaw cycle is described, during which the endometrium is prepared with oral oestradiol, followed by a natural progesterone source. This method involves minimal blood tests and uses inexpensive medications. Originally, an i.m. progesterone-in-oil preparation was used. Although highly successful in achieving high serum progesterone concentrations, the daily injections of the oily compound were found to be problematic from the patients' perspective. To examine the possibility of replacing the injectable progesterone with a vaginal preparation we conducted a prospective randomized study of 1 year's duration, during which time 170 and 184 thawing cycles were done with injectable and vaginal progesterone respectively. Although the progesterone blood concentrations obtained with the injectable preparation were more than twice those obtained with the vaginal progesterone, the clinical pregnancy rates (defined as percentage thawing cycles with gestational sac(s)/embryo transfer as demonstrated on ultrasound, 4 weeks after embryo transfer) were similar for both groups (15.9 and 16.8% respectively). Implantation and abortion rates were also comparable. These results agree with previous reports of higher uterine progesterone concentrations after the vaginal application. We conclude that the combination of oral oestradiol and vaginal progesterone is an effective, simple and inexpensive approach for programmed thaw cycles.
Administration, Intravaginal↗
Early transvaginal embryo aspiration: a safer method for selective reduction in high order multiple gestations.
Assisted reproduction technologies and ovulation induction for treatment of infertility continue to cause high order multiple gestations. Increased perinatal morbidity and mortality, as well as maternal morbidity, may complicate these pregnancies. Selective fetal reduction, an acceptable therapeutic approach in these cases, is usually performed at or after the ninth week of gestation, with KCl injected in the vicinity of the fetal heart, and is associated with a total pregnancy loss rate of 11.7%. We report our experience with 90 women who underwent early (mean 7.5 weeks gestation, range 7. 0-8.0 weeks) transvaginal selective embryo aspiration. The mean number of viable embryos before and after reduction was 3.5 and 2.1 respectively. Six (6.7%) pregnancies were lost before 24 gestational weeks. One miscarriage occurred at the tenth gestational week. The other five pregnancies were aborted at 17.3-21.6 weeks gestation. Additional interventions were performed in three of these pregnancies: genetic amniocentesis in two cases and cervical suture in one case. In the subset of 39 patients with>/=4 embryos, only one (2.6%) pregnancy loss was recorded. This loss rate is significantly lower (P < 0.05) than the 15.3% loss rate in patients with >/=4 fetuses calculated from other work. Four (4.4%) other pregnancies were complicated by premature delivery (25-28 weeks gestation). Mean gestational age of delivered pregnancies in our series was 35.7 weeks. In conclusion, early transvaginal embryo aspiration is a simple and relatively safe method for multiple pregnancy reduction. The overall pregnancy loss rate associated with early embryo aspiration is similar to that of procedures performed at later gestational age, but is significantly lower when the initial number of embryos is four or greater.
Evaluation Studies as Topic↗
High doses of gonadotrophin-releasing hormone antagonist in in-vitro fertilization cycles do not adversely affect the outcome of subsequent freeze-thaw cycles.
The clinical application of gonadotrophin-releasing hormone (GnRH) antagonists instead of GnRH agonists, to prevent spontaneous premature luteinizing hormone surge during ovarian stimulation for assisted reproduction treatment has been advocated. A recent, double-blind, dose-finding study, including six dosages of the GnRH antagonist ganirelix, in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (FSH), has indicated that high doses of GnRH antagonist (1 or 2 mg once daily) are associated with a low implantation rate. This follow-up study reports on the pregnancy rate after replacement of cryopreserved embryos obtained in stimulation cycles of the above-mentioned trial. Ovarian stimulation was initiated on day 2 of the cycle, with daily injections of 150 IU recombinant FSH. Ganirelix (0.0625, 0.125, 0.25, 0.5, 1.0 or 2.0 mg) was administered once daily from stimulation day 6 onwards, up to and including the day of human chorionic gonadotrophin. Retrieved oocytes were fertilized by in-vitro fertilization (IVF) or intracytoplasmic sperm injection and a maximum of three fresh embryos was transferred. Excess embryos were frozen, and subsequently used in either natural or programmed cycles. Until June 1998, 11 ongoing pregnancies (12-16 weeks after embryo transfer) were achieved from 46 cycles in which embryos had been first frozen (23.9% per transfer). Six of these 11 patients had been treated with a high dose of ganirelix (1.0 or 2.0 mg) during the IVF cycles in which the embryos were obtained. In conclusion, our data suggest that high dosages of ganirelix do not adversely affect the potential of embryos to establish clinical pregnancy in freeze-thaw cycles.
Adult↗
Ovarian interleukin-1 receptor antagonist in rats: gene expression, cellular localization, cyclic variation, and hormonal regulation of a potential determinant of interleukin-1 action.
It is hypothesized that the intraovarian interleukin (IL)-1 system plays a prominent role in the regulation of follicular development and ovulation. A central component of the intraovarian IL-1 system is the IL-1 receptor antagonist (IL-1RA), a protein acting as a pure IL-1 receptor antagonist and one for which intracellular (icIL-1RA) and secretory (sIL-1RA) varieties have been described. It was the objective of this study to explore rat ovarian IL-1RA gene expression, to establish the identity and relative abundance of its alternative transcripts, to study its cellular localization, to determine its cyclic variation, and to assess its hormonal regulation. Protected IL-1RA cDNA fragments corresponding to either sIL-1RA or icIL-1RA were barely detectable in untreated whole ovarian tissue of immature rat origin. However, sIL-1RA transcripts reached a maximal value (3.3-fold increase over untreated control values; p < 0.05) 12 h after hCG administration (time of projected ovulation). In situ hybridization localized IL-1RA to mural, antral, and cumulus granulosa cells. Modestly intense staining was also apparent in oocytes. The basal pattern of sIL-1RA expression by cultured whole ovarian dispersates was characterized by a spontaneous increase to a peak value at 4 h. The early (4 h) sIL-1RA burst proved IL-1-, nitric oxide-, and protein biosynthesis-independent. However, treatment with IL-1beta led to a secondary sIL-1RA peak at 48 h, an effect that was substantially reversed by IL-1RA. This stimulatory effect of IL-1beta on IL-1RA expression proved relatively specific, and nitric oxide independent, but contingent upon de novo protein biosynthesis. The in vitro expression of icIL-1RA was barely detectable. Taken together, these in vivo and in vitro observations 1) document the rat ovary as a site of IL-1RA (sIL-1RA > cIL-1RA) expression, 2) localize the relevant transcripts to the granulosa cell, 3) disclose peak expression at the time of ovulation, and 4) establish IL-1 dependence.
Animals↗
Rat ovarian interleukin-1alpha: interleukin-1-dependent in vitro expression.
Evidence exists supporting the possibility that intraovarian interleukin-1 (IL-1) may play an intermediary role in the periovulatory cascade. Although the existence of a mammalian intraovarian IL-1 system has been convincingly demonstrated, most efforts have focused on the possibility that the mammalian ovary is a site of IL-1b production, reception, and action. The objective of this study was to explore the possibility of ovarian IL-1a expression, characterize its pattern of expression by cultured ovarian cells, and study its hormonal regulation. The basal in vitro expression of IL-1a by cultured whole ovarian dispersates from immature rats increased spontaneously, reaching a peak (sixfold increase over untreated controls) at 4 h. Treatment with an IL-1 receptor antagonist (IL-1RA), human chorionic gonadorropin, or IL-1b failed to attenuate the initial 4-h burst of IL-1a expression. By contrast, treatment of whole ovarian dispersates with IL-1b for 48 h resulted in significant upregulation of IL-1a transcripts (60-fold increase). This IL-1b effect was completely blocked by cotreatment with IL-1RA, thereby suggesting mediation via a specific IL-1 receptor. The IL-1b effect proved to be protein biosynthesis and eicosanoid dependent, nitric oxide independent, and relatively specific in that it was not reproduced by a select series of other granulosa cell agonists.
Animals↗
Transforming growth factor-beta1 is a potent inhibitor of interleukin-1beta action in whole ovarian dispersates.
Transforming growth factor beta1 (TGFbeta1) acts as an inhibitor of the actions of interleukin-1beta (IL-1beta) in various organ systems. In order better to understand the inter|P-actions between these polypeptides in the ovary, we evaluated the effect of TGFbeta1 co-treatment on various IL-1beta-mediated actions in cultures of whole ovarian dispersates. Treatment with IL-1beta enhanced media accumulation of nitrites (4.8-fold), prostaglandin E2 (PGE2, 3. 9-fold) and lactate (2.0-fold), and enhanced glucose consumption (2. 1-fold). Treatment with TGFbeta1 alone did not significantly affect any of these parameters. However, the addition of TGFbeta1 inhibited IL-1beta-stimulated nitrite (100%), PGE2 (44%) and lactate (78%) accumulation and inhibited IL-1beta-stimulated glucose consumption (74%) in a dose-dependent manner. The addition of TGFbeta1 also suppressed the steady-state levels of IL-1beta-stimulated IL-1beta, type I IL-1 receptor and IL-1 receptor antagonist transcripts (98, 67 and 83% inhibition respectively). These data suggest that TGFbeta1 is capable of inhibiting several IL-1beta-stimulated endpoints. Since IL-1 has been identified as a possible proinflammatory mediator of ovulation and TGFbeta has been implicated as a promotor of fibrosis and healing, we speculate that IL-1 and TGFbeta might play antagonistic roles in the normal ovulatory sequence.
Animals↗