Use Of GnRH Antagonists Research Articles

Combined treatment of high and very high risk prostate cancer: results of neoadjuvant treatment

Purpose of the study. Assessment of safety and short‑term effectiveness of high and very high‑risk prostate cancer neoadjuvant chemo‑ hormonal treatment without distant metastases.Patients and methods. Combined hormone chemo‑ radiation treatment of 33 patients with prostate cancer of high and very high risk of progression without distant metastases was performed. Metastases to regional lymph nodes were found in 9 patients according to the examination data (MRI, MSCT), no metastases were detected in 24 patients. All patients underwent combined chemohormonal therapy in the amount of 4 courses of docetaxel intravenously at a dose of 75 mg/m2 every 3 weeks as the first stage of treatment. in combination with androgen deprivation therapy with agonists or antagonists of GnRH before performing radical radiation therapy (combined or remote). All patients underwent neoadjuvant hormone therapy: 16 patients – with the use of GnRH antagonists (Degarelix), 17 – with the use of GnRH agonists (Gozerelin/Leuprorelin/Triptorelin). The toxicity of the presented treatment regimen and its immediate effectiveness – the effect on the level of prostate‑s pecific antigen (PSA), prostate volume, and the quality of urination – were evaluated.Results. Treatment regimen was highly effective concerning PSA decrease (from initial median level 79,67 ng/ml to 1,45 ng/ml after neoadjuvant treatment), all subjects responded well, no non‑responders observed. Median prostate volume decreased from 44 cm3 to 25 cm3 after treatment, which guaranteed availability and safety of further radical radiation treatment. Urinary function was restored in all subject with initial urinary retention.Conclusion. Neoadjuvant chemo‑h ormonal treatment was highly effective in PSA level, prostate volume decrease and functional results improvement which secured further radical radiation treatment in one of its types. Toxicity was acceptable, adverse events did not exceed grade II in most cases and did not lead to treatment discontinuation in any cases, while quality of life remained high enough.

Stimulation techniques and protocols for poor responders in IVF cycles, future prospective methods and techniques, precaution programs.

Purpose: To identify trends regarding approaches, currently used by IVF centers in Greece, in order to treat poor responders. Methods: A retrospective evaluation utilizing the results of a web-based survey was performed. Results: Responses from 36 IVF centers via a web-based survey in Greece was conducted to elucidate optimal treatment strategies of poor responders. IVF specialized Doctors of units with a median of 300 IVF cycles per year were asked to anonymously fill in a set of questions on this complex topic. Results were analyzed, treatment strategies or combinations of protocols or adjuvant therapies used were compared. Also compared number of oocytes retrieved, as well as fertility and pregnancy rates among various IVF centers, based on their responses. A total of 36 centers participated in our survey, (from total 59 IVF centers) forming a web-based questionnaire. Due to responses on question if they observe an increase in the prevalence of poor responders ranging from: 1 - 3 % (8.6%, n=3), 4 - 9% ,(11.1% ,n=4), mainly 20% (47.21% ,n=17), but also greater than 20% (33.3% ,n=12) in total of cases treated in Greek IVF centers. Also, the most common age group of poor responders is 40-50 years of age according to 80%(n=29) of respondents. (Table 1). The review of international medical literature compared with answers received to our questionnaire suggests that no ideal treatment stimulation protocol exist. The following protocols have been described and compared:1).Long protocol with Agonist (25.%,n=9)2).Short protocol with Antagonist (52.8%,n=19)3).Short protocol with Agonist (19.4%,n=7)4).Stimulation only with Gonadotropins (5.6%,n=2)5).Natural Cycle (66.7%,n=24)6).Flare-up protocol (13.9%,n=5)7).Duo-Stim Protocol (11.1%9,n=4)8).Delayed start protocol (11.% ,n=4)9).Protocol with cofifollitropine (13.9%,n=5)10). Clomiphene Citrate Protocol with or without Gonadotropins (41.7%, n=15)11). Clomiphene Citrate Protocol with or without Aromatase inhibitors (19.4%, n=7)12).Letrozole with or without recombinant FSH GnRH Antagonist Use (2.8%, n=1)13). Letrozole with Clomiphene Citrate plus FSH & LH (2.8%, n=1)14). Letrozole with FSH & LH plus GnRH antagonist (2.8%, n=1)15).Protocol with Antagonists in combination with Letrozole(27.8%,n=10) . (Table 2). We also represent results regarding the use of adjuvant treatment modalities to further improve results of stimulation cycles such as: a)Oestrogens(52.2%,n=12),b)Growth Hormone (4.3%,n=1),c)Testosterone (8.7%,n=2),d)Co-enzyme Q10 (56.5%,n=13),e)DHEA (78.3%,n=18). (Table 3). All available therapeutic strategies used and according to international literature and in accordance with data derived from Greek IVF centers, oocyte harvesting ranges at low levels, around 2 to 4 oocytes (88.6% ,n=3), 0-1 (8.6%,n=3), 5-8 (11.4%,n=4) and none of the IVF specialists collected more than 8 oocytes. Oocyte quality is also compromised, in (54.3%, n=19) only one oocyte of A quality was harvested, while 2 and 0, 3 or 4 oocytes of A quality were collected in (49.2%,n=15)and(5.7%,n=2).(Table 4.) , according with data fully verifying the term poor responders. Moreover, we observed that abortion rates are increased >20% (41.2%, n=14), 10-20% (29.4%,n=10), 5-10% (11.8%,n=4) and 1-5% (17.6%,n=6) )(Table 5), as well as pregnancy rates are affected 5-10% (29.4%,n=10) and 10-20% (29.4%,n=10) )(Table 6), while percentages of live pregnancies over 20% is observed in (17,6%,n=6) and under 6% in (23.5%,n=8)(Table 7). Conclusion: All responses from the IVF specialists demonstrate the difficulty of treating this heterogenic group of subfebrile women. The egg donation is the treatment with increased success rate in comparison with different used treatments with agonists , antagonists cc, natural cycle, adjuvant treatments , the success rates of treatment in poor responders in IVF stimulation fluctuates from 7 to 24%. Prognosis is further improved if IVF specialist proposes and proceeds timely to the proper individualized therapeutic strategy.

Factors influencing the number of mature oocytes and cryopreservable blastocysts in hyperresponder patients triggered with a GnRH analog.

This study aimed to investigate which patient and cycle characteristics may affect the number of mature oocytes and cryopreservable blastocysts in the GnRH analog trigger cases. This was a retrospective cohort study of 2749 GnRHa trigger cycles in patients at risk of OHSS, including a group of PGT patients, between 2011 and 2020 at Istanbul Memorial Hospital, ART and Reproductive Genetics Center. Patient and cycle characteristics were evaluated using the Generalized Linear Mixed Model (GLMM). The number of mature oocytes and the number of cryopreservable blastocysts were evaluated. A one-unit increase in female age, daily gonadotropin dose, E2 level on day 2, and LH level on trigger day significantly decreased the number of mature oocytes retrieved (p < 0.001) and the number of cryopreservable blastocysts as p < 0.001, p < 0.001, p < 0.001, and p = 0.003, respectively. The duration of GnRH antagonist use also decreased the number of mature oocytes retrieved (p < 0.001) but not the number of cryopreservable blastocysts. The GLMM used in our study showed that a one-unit increase in female age, daily gonadotropin dose, E2 level on day 2, and LH level on trigger day significantly decreased the number of mature oocytes retrieved and the number of cryopreservable blastocysts.

Hormonal parameters and embryological outcomes of in vitro fertilisation/intra cytoplasmic sperm injection cycles in women using dydrogesterone for the prevention of premature luteinizing hormone surge during ovarian stimulation

Aim. To evaluate the hormonal parameters and embryological outcomes of an ovarian stimulation protocol using dydrogesterone to prevent the premature LH surge in IVF/ICSI programmes.&#x0D; Materials and methods. A prospective study randomised, including 79 women with normal ovarian reserve undergoing ovarian stimulation for IVF/ICSI with recombinant FSH (rFSH) from Day 2 or 3 of the menstrual cycle. To prevent the premature LH surge, participants in Group 1 (n=38) received oral dydrogesterone 20 mg/day from the start of ovarian stimulation until the day of ovulation trigger administration. Participants in Group 2 (n=41) received a GnRH antagonist. We evaluated the starting and total dose of gonadotropins, duration of stimulation, serum levels of LH, oestradiol and progesterone on Day 1 and 6 of stimulation and the day of trigger administration, number of retrieved and mature oocytes, fertilization rate, and the number of blastocysts and cryopreserved embryos.&#x0D; Results. There were no significant differences in most hormonal parameters, characteristics of the ovarian stimulation and embryological outcomes between the two groups. Serum levels of progesterone in the dydrogesterone arm were higher than in the GnRH antagonist arm (2.3 nmol/l [2.03.4] vs 1.5 [1.02.4] nmol/l; p=0.026), but without any impact on the embryological outcomes.&#x0D; Conclusion. Prevention of premature LH surge in ovarian stimulation cycles using oral dydrogesterone may represent a convenient alternative to the conventional use of GnRH antagonists, reducing the number of required injections and potentially increasing the convenience in patients who are not planning a fresh embryo transfer.

Therapeutic effects of an oral gonadotropin‐releasing hormone receptor antagonist, relugolix, on preventing premature ovulation in mild ovarian stimulation for IVF

PurposeCan relugolix, a novel oral gonadotropin‐releasing hormone receptor (GnRH) antagonist, function as an alternative ovulation inhibitor to GnRH antagonist injections?MethodsThis single‐center, cross‐sectional retrospective study compared premature ovulation rates and clinical outcomes in IVF treatment after mild ovarian stimulation with 40 mg of relugolix (relugolix group) or 0.25‐mg injections of ganirelix acetate or cetrorelix acetate (injection group) between March 2019 and January 2020. Of 247 infertile women (256 IVF cycles) aged ≤42 years, 223 women (230 cycles) were evaluated. In the relugolix and injection groups, we compared 104 and 85 cycles after GnRH antagonist use before the LH surge (LH levels <10 mIU/ml) and 22 and 19 cycles during the LH surge (LH levels ≥10 mIU/ml), respectively.ResultsBefore the LH surge, the ovulation rates in the two groups were very low (p = 0.838), however; during the LH surge, the cycles using relugolix had a high ovulation rate of 40.9% compared with no ovulation in the injection group (p = 0.002). There were no significant differences in embryo culture findings and pregnancy outcomes between the two groups.ConclusionsAlthough relugolix had a high ovulation suppressive effect, when the LH surge occurred, its effect was insufficient.

The Effect of Luteinising Hormone Suppression in In Vitro Fertilisation Antagonist Cycles.

Use of GnRH antagonists in IVF stimulation protocols shortens controlled ovarian hyperstimulation (COH) and reduces the risk of ovarian hyperstimulation syndrome (OHSS). However, profound reduction in LH levels has been associated with use of GnRH antagonists. This study aims to determine if LH suppression during GnRH antagonist cycles results in poorer IVF outcomes. This was a prospective pilot longitudinal study where serum LH levels were measured on day 2/3 of the menstrual cycle before COH, 1/2 days following institution of GnRH antagonist and at the day of ovulation trigger. A threshold of LH <0.5 IU/L was used to define profound LH suppression. Data on IVF outcomes was collected. Logistic regression analysis was used to investigate risk factors associated with LH suppression following GnRH antagonist IVF treatment. Ninety-one eligible women were recruited. Women underwent a standard antagonist cycle with Puregon 200u and Ganirelix. No participant had LH <0.5 IU/L prior to GnRH antagonist treatment, and 27 participants (29.7%) had significant LH suppression at either time point. Predictors of profound LH suppression following GnRH antagonist treatment identified (P < 0.20) were age (OR = 0.80, P = 0.013), no previous ovulation induction (OR = 0.26, P = 0.033) and previous GnRH antagonist IVF cycle (OR = 4.32, P = 0.125). Numbers of oocytes, embryos and ongoing pregnancy rates at 12 weeks gestation in patients with and without LH suppression did not differ significantly. We found associations between clinical characteristics and risk of profound LH suppression in women undergoing GnRH antagonist IVF cycles, but no significant differences in IVF and pregnancy outcomes between women with and without significant LH suppression.

Comparing the Implications of IVF-Induced Pregnancy by Two Regimens with a Flexible Dose of GnRH Antagonist and a Half Fixed Dose of GnRH Antagonist

Introduction: In an IVF cycle after ovulation stimulation, the goal is to prevent LH surge and wasting follicles. The use of GnRH antagonists to achieve this goal has been considered by infertility specialists in recent years. Two fixed or flexible drug regimens have been tested. The aim of this study was to compare the implications of induced pregnancy by two regimens with a flexible dose of GnRH antagonist and a half fixed dose of GnRH antagonist that was evaluated for the first time. Materials and Methods: This randomized double-blinded controlled trial was conducted on 140 patients referring to the infertility department of Shariati Hospital between June 2017 and June 2018 who were candidates for IVF. Patients who were candidates for cyclic therapy with GnRH antagonists were randomly assigned (with a randomized table of numbers) to either the fixed dose group with a half dose of the GnRH antagonist (Group A, n = 70) or the flexible GnRH antagonist dose (Group B, n = 70). Results: There was also difference in the numbers of IVF or IUI cycles across the two groups. The mean degree of the sperm motility and sperm morphology percentages were similar in the spouses of women in the two groups. With regard to the outcome of IVF, no difference was revealed in the mean number of mature follicles, number of retrieved oocytes, and number of transferred embryos (Table 3). The successful clinical pregnancy rate in the groups A and B was 20.0% and 18.6% respectively with no difference (p = 0.830). The successful clinical pregnancy rate in the groups A and B was 20.0% and 18.6% respectively with no difference (p = 0.830). Based on the multivariable logistic regression analysis, the fixed dose regimen with half dose of GnRH antagonist or GnRH flexible dose antagonist dose did not affect the IVF success. The final determinants of the success of IVF were the percentage of sperm morphology (OR = 1.237, P = 0.015) and BMI of the patients (OR = 0.836, P = 0.019). Conclusion: Both GnRH antagonist regimens with flexible doses and the GnRH antagonist with a half fixed dose have similar effects on the outcome of IVF. Among the factors predicting the success rate of IVF, the role of reducing the morphology of sperm and obesity is very prominent.

Desogestrel versus antagonist injections for LH suppression in oocyte donation cycles: a crossover study

To study whether ovarian response to corifollitropin among oocyte donors (OD) is different when oral desogestrel (DSG) is used to block the luteinizing hormone (LH) surge when compared to GnRH-antagonist use. This is a retrospective, cohort study at a private, university-based, IVF center including 35 OD. Patients underwent two stimulation cycles under corifollitropin alfa (CFT), one under an antagonist and another under DSG, between February 2015 and May 2017. In antagonist cycles, daily ganirelix was administered since a leading follicle reached 14 mm. In the DSG cycles, daily oral DSG was prescribed. The main outcome measure was oocytes retrieved. Compared to antagonist cycles, cycles under DSG received fewer injections (10.3 ± 2.8 vs. 5.0 ± 2.1, p < .001), nominally lower total supplementary gonadotropin dose (497.4 ± 338.9I U vs. 442.9 ± 332.8 IU, p=.45) with a lower total cost of medication (1018.6 ± 191.0€ vs. 813.8 ± 145.9€, p<.001). There were no differences in the total number of retrieved oocytes between groups (17.4 ± 7.5 vs. 18.6 ± 8.9, p=.34). In the corresponding oocyte recipients, clinical pregnancy rate was similar between groups: 52.0% vs. 58.6%, respectively (p=.78). ODs’ stimulation’s response under DSG is similar when compared to (17.4 ± 7.5 vs. 18.6 ± 8.9, p=.34) but associated with less injections and lower medication costs. The main advantage of this strategy is its simplicity, an aspect of utmost importance in the management of ODs.

Addition of oestradiol to progesterone for luteal phase support in GnRh antagonist IVF/ICSI cycles

Objective: Studies have found conflicting results with respect to the use of progesterone alone or oestrogen and progesterone as luteal phase support for in vitro fertilisation (IVF)/ICSI cycles involving use of GnRh antagonist. The purpose of the study is to determine the effect of luteal phase supplementation with oestradiol and progesterone versus progesterone alone in women undergoing IVF/ICSI-Embryo transfer (ET) in relation to the pregnancy rate. Design: This was a retrospective observational study spanning 1 year conducted at Medicover Fertility, New Delhi. A sample size of 150 women was taken. Materials and Methods: All women underwent controlled ovarian stimulation by gonadotropin and GnRh antagonist protocol. Oocyte retrieval was performed after 34 to 36 hours of hCG trigger and embryos were transferred 3 days after oocyte retrieval. According to luteal phase support protocol, two groups were made: study group (oestrogen plus progesterone, n = 75) and control group (progesterone alone, n = 75). Results: The study and control group did not differ for age, religion, duration of infertility, cause and type of infertility. Out of 75 women in the study group, 31 women conceived, the pregnancy rate being 41%. In the control group, 27 out of 75 women conceived, the pregnancy rate being 36%. Thus, the pregnancy rate was observationally higher in the study group, but the difference was not statistically significant (P value = 0.50). Conclusion: Giving oestradiol supplementation along with progesterone in the luteal phase did not improve pregnancy rates significantly. Further, more studies are required to see hormonal profile of oestradiol and progesterone levels during luteal phase and its correlation with pregnancy rate.

Progesterone rise after agonist trigger inprogesterone-primed stimulated cycles differs from antagonist cycles

Progesterone-primed (PP) stimulated cycles are a safe and effective alternative to antagonist cycles for controlling the endogenous LH rise in any clinical situation in which endometrium receptiveness is not an issue, i.e. oocyte donors (OD). Some concern may exist regarding the quality of the endocrine response to the final oocyte maturation trigger when performed with a GnRH agonist bolus. The objective is to describe the endocrine response to GnRH agonist trigger in antagonist (ANT) versus PP stimulated cycles in OD. Retrospective OD underwent ovarian stimulation with gonadotropins at a private, university-based infertility clinic between Jan’17-Mar’18. Serum estradiol evaluation and ultrasound scans were performed for monitoring response. Endogenous LH peak was controlled with either daily injections of GnRH antagonist starting when leading follicle diameter ≥14 mm (ANT) or with daily oral 75mcg desogestrel (PP) from stimulation day 1 until trigger. When >3 follicles >18 mm were observed, patients were triggered with 0.2 mg of triptorelin and oocyte retrieval was performed 36 hours later. Serum LH and P were measured at trigger and the following day (trigger+1). Considering only recipients undergoing a fresh cycle and single embryo transfer, laboratory and clinical outcomes were analyzed. Wilcoxon Mann-Whitney test was used. A total of 404 OD cycles were included. There were no differences in mean age, AMH between groups. After agonist trigger, significantly lower serum P were observed in PP compared to ANT groups both at trigger and the following day. No differences were observed in serum LH levels. The average number of MIIs, fertilization rates and total number of usable embryos were also similar. OD treated with gonadotropins displayed significantly lower P before and after agonist trigger when oral desogestrel was used for the control of endogenous LH compared to the use of GnRH antagonist. It is hypothesized that differential endogenous LH inhibition during stimulation with a GnRH antagonist or PP could be associated to the different outcomes.Tabled 1Estradiol, progesterone and LH values on Triggering day and day after trigger, and cycle outcomesPP Group (n=207)ANT group (n=197)p-valueEstradiol at trigger (pg/ml)1939.1±1235.52065.3±1325.10.483Days of stimulation10.0±2.610.5±2.00.048Follicles at trigger19.7±6.119.9±7.00.984P4 at trigger0.9±0.71.5±1.2<0.001P4 at trigger+110.8±6.013.4±7.90.002LH at trigger0.9±0.90.7±0.70.146LH at trigger+130.2±22.134.3±24.70.071MII oocytes14.2±7.415.4±7.90.129Recipient Fresh cyclesn=106n=89Total Number of usable embryos5.1±2.25.1±2.20.925Clinical Pregnancy Rate72.6% (77/106)53.9% (48/89)0.007 Open table in a new tab

Lower rate of early pregnancy loss in patients experiencing early-onset low LH in GnRH antagonist cycles supplemented with menotropin.

The role of LH during controlled ovarian stimulation (COS) in the general population remains contentious. There is no consensus on the indications for LH supplementation during COS. The purpose of this study is to determine whether menotropin supplement is associated with decreases in early pregnancy loss rates in patients exhibiting low endogenous LH during COS. This is a single-center, retrospective cohort from a university-affiliated hospital. Patients were enrolled from the in-vitro fertilization center from January, 2011 to December, 2014. Patients who experienced a LH level≦0.8mIU/mL during stimulation were identified, and patients that received menotropin supplementation were compared to those without menotropin supplementation. Outcome variables, including the number of oocytes retrieved, embryos obtained, implantation rates, pregnancy rates and early pregnancy loss rates, were compared. Patients that experienced low LH during GnRH antagonist protocol and were supplemented with menotropin were associated with lower early pregnancy loss when compared with patients without menotropin supplementation (26.7% vs. 11.5%, p=0.045). More specifically, in patients who exhibited early-onset low LH, before the use of GnRH antagonists, menotropin supplementation was associated with significantly lower early pregnancy loss compared with non-supplemented patients (3.3% vs. 29.0%, OR: 0.08, p=0.012). Beneficial effects persisted after adjusting for confounders (aOR: 0.103, 95% CI: 0.011-0.933). Menotropin supplementation is associated with decreased early pregnancy loss in patient who exhibited low LH during GnRH antagonist cycles. This effect is especially prominent in patients who experience low LH before the start of GnRH antagonists.

Luteal phase stimulation is associated with lower peak estradiol levels and less GNRH antagonist use while yielding the same outcomes as conventional follicular phase stimulation

Elevated levels of estradiol are associated with an increase in the incidence of ovarian hyperstimulation syndrome (OHSS) in women undergoing IVF treatment. GnRH antagonists are frequently used in conventional antagonist protocols to prevent a premature luteinizing hormone (LH) surge, though they are known to be invasive and costly. We hypothesize that an alternative protocol initiating stimulation in the luteal phase, wherein progesterone may serve as a natural inhibitor of the LH surge, in combination with an aromatase inhibitor, may be a comparable protocol for women undergoing IVF who are at risk for OHSS. Additional benefits to using this protocol include fewer medication costs to the patient and decreased chance of cycle cancellation due to OHSS. The purpose of this study was to compare peak estradiol levels, duration of GnRH antagonist use, and oocyte yield in a luteal phase stimulation compared to a conventional follicular phase stimulation protocol. This was a retrospective study in a private IVF program examining 56 patients treated with either a standard follicular phase stimulation or luteal phase stimulation between January and October 2017. We included all women with ovulatory cycles, age < 39, BMI < 30 kg/m2, and CD3 FSH < 9. Luteal phase protocol consisted of daily 250 IU Follistim, 5 IU microdose hcg and 5mg daily letrozole initiated after spontaneous ovulation or inducing with 200mg vaginal progesterone twice daily. GnRH antagonist (ganirelix acetate or cetrorelix acetate) was initiated when leading follicle size >15mm or when E2 levels were > 200 pg/mL. Baseline characteristics were collected for all patients and the primary outcomes measured were oocyte yield, duration of GnRH antagonist use, and peak E2 levels. Baseline characteristics were similar between both protocol groups. Peak estradiol levels were 647 and 4669 pg/mL in luteal and conventional stimulations, respectively (p <0.01). GnRH antagonist was administered for 3.3 days in luteal protocols compared to 5.4 days in a conventional protocol, while the total number of stimulation days were similar (11.3 vs 10.1, p = 0.29). The average oocyte yield between antagonist and luteal stimulations was not significantly different (12.9 vs 13.6, p=0.72) (Table 1). No cases of premature luteinization, ovulation, or OHSS were observed in either group.Tabled 1Table 1ParameterStimulation ProtocolP-valueAntagonist(n=29)Luteal(n=27)Maternal age (range)34.4 (25-39)33.7 (26-39)0.43CD 3 FSH6.96.00.44BMI22.522.30.82Stim duration (d)10.111.3<0.01*GnRH antagonist duration (d)5.43.2<0.01*Stim day at time of GnRHa start5.79.1<0.01*Peak E2 (pg/ml)4669.9656.3<0.01*# oocytes retrieved13.612.70.60*p<0.05 Open table in a new tab *p<0.05 Luteal phase stimulation with use of letrozole is associated with significantly lower peak estradiol level while producing similar competent oocytes compared to conventional follicular phase stimulation. This protocol may be preferred for women at higher risk of developing OHSS or for women with endometriosis. In addition, progesterone exposure during the luteal phase can be used to prevent premature luteinization, therefore requiring fewer GnRH antagonist injections and reducing cost.

Research development of a new GnRH antagonist (Elagolix) for the treatment of endometriosis: a review of the literature.

Limitated studies have reported the efficacy of GnRH antagonist on endometriosis symptoms. The aim of our study was to review all available trials to investigate the medical treatment of endometriosis with only GnRH antagonists, with special attention to pharmacodynamic activity, safety, and efficacy. Pub Med and Sciencedirect database were searched using terms of "endometriosis treatment", "GnRH antagonist", and "Elagolix". The search was limited to clinical studies published in English. Title and abstract were screened to identify relevant articles. Five studies covering use of GnRH antagonist were found. A phase 1 study evaluated the safety, pharmacokinetics, and inhibitory effects on gonadotropins and estradiol of single dose and 7 day elagolix administration to healthy premenopausal women; two phase II studies evaluated efficacy in patient with endometriosis. Moreover, there are two Phase III clinical trials just completed. GnRH antagonists may have the advantage of oral administration and lower incidence of adverse events. Currently, only Phase II studies have been published demonstrating promising results in terms of efficacy, safety, and tolerability. From the results of the phase III studies, elagolix may become a valuable addition to the armamentarium of pharmacological agents to treat endometriosis-related pain.

Clinical Value of Basal Serum Progesterone Prior to Initiate Ovarian Hyper-Stimulation with GnRH Antagonists: A Retrospective Cohort Study

Background: The routine assessment of day 3 serum progesterone prior to initiation of ovarian hyper-stimulation with the use of GnRH antagonists is under debate. In this study, we evaluated the clinical utility of this policy. Methods: Retrospective cohort study of women undergoing in vitro fertilization (IVF) with the use of GnRH antagonists aimed at determining the frequency of cases with progesterone levels exceeding the recommended threshold of 1,660 pg/ml and at evaluating whether this assessment may be predictive of pregnancy. Results: Serum progesterone exceeded the recommended threshold in one case (0.3%, 95% CI 0.01-1.5). The median (interquartile range) basal progesterone in women who did (n = 95) and did not (n = 217) become pregnant were 351 (234-476) and 380 (237-531) pg/ml, respectively (p = 0.28). The 90th percentile of the basal progesterone distribution in women who became pregnant was 660 pg/ml. Cases with serum progesterone exceeding this threshold in successful and unsuccessful cycles were 10 (10%) and 30 (14%), respectively (p = 0.47). The capacity of basal progesterone to predict pregnancy was evaluated using receiver operating characteristic curve (area under the curve = 0.54, 95% CI 0.47-0.61, p = 0.28). No graphically evident threshold emerged. Conclusion: Routine day 3 serum progesterone assessment in IVF cycles with the use of GnRH antagonists is not justified. Further evidence is warranted prior to claiming its systematic use.

Age, independent from ovarian reserve status, is the main prognostic factor in natural cycle in vitro fertilization

To analyze natural cycle IVF (NC-IVF) results according to patient age, ovarian reserve status following the Bologna criteria, cause of infertility, and modification of the cycle with the use of GnRH antagonist. Retrospective cohort study. Tertiary-care university hospital. Nine hundred forty-seven natural cycles carried out in 320 patients. Analysis of 947 NC-IVF outcomes performed in one single center between January 2010 and December2014. Pregnancy rates per cycle started, per ET, and per patient, as well as ongoing pregnancy rate at a minimum of 12weeks of gestation. Among the three age groups analyzed (≤35years, 36-39years, and ≥40years), pregnancy rates per cycle were significantly lower in the older group of patients (11.4% vs. 11.6% vs. 5.9%). In addition, miscarriage rate (7.7% vs. 34.4% vs. 50%) and ongoing pregnancy rate (10.6% vs. 7.6%vs. 3.0%) were negatively affected by patient age. However, no differences were observed according to patient ovarian reserve status, cause of infertility, or modification of the cycle with GnRH antagonist. The multivariate logistic regression confirmed that patient age was the only variable that could predict pregnancy in NC-IVF cycles (odds ratio, 0.93; 95% confidence interval, 0.88-0.98). NC-IVF is a feasible and "patient-friendly" option to be offered to young patients, independent of their ovarian reserve status.

Effects of gonadotropin-releasing hormone agonist and antagonist on ovarian activity in a mouse model for polycystic ovary

PCOS is a major cause of anovulatory infertility in women in their reproductive age. However, its etiology and pathophysiology remain uncertain. The immature mice chronically injected with DHEA, termed as PCO-mice, develop numerous large cystic follicles, high circulating androgen and anovulation similar to PCOS in women. Although PCO-mice show decreased ovarian GnRH I-receptor in immunoblot but show increased immunostaining for GnRH I-receptor in oocytes of cystic follicles. PCO-mice show reduced ovarian LH receptor expression, circulating estradiol and progesterone level compared to normal mice injected with vehicle only. The treatment with low dose of GnRH-Agonist in PCO-mice restores ovarian LH receptor expression to the level of normal mice and promote ovulation and formation of functional corpus luteum. GnRH-Antagonist although cause ovulation in PCO-mice but does not restore LH receptor expression to the level of normal mice, and they show low circulating progesterone and hypertrophied vacuolated corpus luteum. Our study suggests that GnRH-agonist restores ovulation in PCO-mice and produces biphasic and beneficial effect over the use of GnRH-Antagonist.

Evaluation of Role of GnRH Antagonist in Intrauterine Insemination (IUI) Cycles with Mild Ovarian Hyperstimulation (MOH): A Prospective Randomised Study.

To evaluate the role of GnRH antagonist in prevention of premature LH surge and increasing pregnancy rates in IUI cycle with mild ovarian hyperstimulation (MOH). Prospective parallel, randomised controlled study. Couples diagnosed with unexplained, male factor subfertility and with one or both tubes patent were randomised to receive either a GnRH antagonist (study group) or no intervention (control group). All women were treated with clomiphene citrate (D3-D7) followed by HMG. A GnRH antagonist was added when one or more follicles of 16mm diameter or more were visualised in the study group. When at least one follicle reached a size of ≥18mm, ovulation was induced by hCG injection. A single IUI was performed 36h later. The primary outcome was premature LH surge and pregnancy rate. The secondary outcomes were the amount of gonadotropins used, duration of use of GnRH antagonist and incidence and severity of OHSS. A total of seventy patients attending the infertility clinic in the outpatient department of Obstetrics and Gynecology, of a tertiary care centre, were recruited in the study which was carried out from August 2011 to March 2013. The study group included 34 women and 36 in the control arm. The incidence of premature LH surge was significantly lower in the antagonist group as compared to the control group 2.9 vs. 13.9%, with a p value of <0.001. The clinical pregnancy rates were similar in both the groups 8.8 vs. 11.1%, p value being 1.000. The amount of gonadotropins used in GnRH antagonist group was lower than in control group but not statistically significant. Duration of GnRH antagonist was 1.85±0.61days in the study group. The delayed administration of GnRH antagonists in MOH with IUI cycles when follicle size is ≥16mm is beneficial in terms of preventing the occurrence of premature LH surge but with no improvement in pregnancy rates.

Abstract 596: Androgen Deprivation Therapy--Induced Weight Gain and Atherosclerosis in Prostate Cancer: Differences Between Orchiectomy, GnRH Agonist and Antagonist

Cardiovascular disease (CVD) is one of the most common causes of mortality in prostate cancer patients. In prostate cancer treatment androgen deprivation therapy (ADT) is associated with weight gain and development of the metabolic syndrome. However, different modes of ADT can achieve castration. A post-hoc analysis of phase III trials suggests that GnRH antagonists are associated with less cardiac events in men with pre-existing CVD during the first year of ADT. We investigated the effects of bilateral orchiectomy, GnRH agonists and GnRH antagonists on the development of CVD in a mouse model. We hypothesize that GnRH antagonists will associate with reduced adiposity and development of atherosclerosis compared to GnRH analogues and orchiectomy. We used LDL receptor knockout mice (n=12/group) as models for CVD to investigate and compare the effects of orchiectomy, sham surgery, sham surgery plus GnRH antagonist (degarelix) and sham surgery plus GnRH agonist (leuprolide). Longitudinal weight gain (4 months), visceral fat accumulation (CT measurements), fasting blood glucose, glucose tolerance, serum triglycerides, and testosterone levels were studied along with characteristics of aortic atherosclerotic plaques. Leuprolide-treated mice gained significantly more weight and visceral fat compared to mice treated with degarelix. Significantly lower levels of serum triglycerides and better response to glucose loading were recorded in mice treated with degarelix. The atherosclerotic plaque area in the aortic sinus in leuprolide-treated and orchiectomized mice was significantly larger than in control mice, but not significantly different from control in degarelix-treated mice. The necrotic plaque area with degarelix was significantly smaller compared to leuprolide-treated and orchiectomized mice. In a preclinical mouse model, the use of GnRH antagonists attenuates weight gain and development of atherosclerosis.

MP24-11 GNRH ANTAGONISTS ASSOCIATE WITH LESS WEIGHT GAIN AND MILDER CHARACTERISTICS OF THE METABOLIC SYNDROME AND ATHEROSCLEROSIS COMPARED TO SURGICAL CASTRATION AND GNRH ANALOGUES IN PRE-CLINICAL ANIMAL MODEL

You have accessJournal of UrologyProstate Cancer: Basic Research I1 Apr 2014MP24-11 GNRH ANTAGONISTS ASSOCIATE WITH LESS WEIGHT GAIN AND MILDER CHARACTERISTICS OF THE METABOLIC SYNDROME AND ATHEROSCLEROSIS COMPARED TO SURGICAL CASTRATION AND GNRH ANALOGUES IN PRE-CLINICAL ANIMAL MODEL Wilhelmina CM. Duivenvoorden, Sarah Hopmans, Geoff Werstuck, and Pinthus Jehonathan Wilhelmina CM. DuivenvoordenWilhelmina CM. Duivenvoorden More articles by this author , Sarah HopmansSarah Hopmans More articles by this author , Geoff WerstuckGeoff Werstuck More articles by this author , and Pinthus JehonathanPinthus Jehonathan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.292AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Androgen deprivation therapy (ADT) is associated with weight gain, development of the metabolic syndrome (MS) and eventually cardiovascular (CVS) morbidity and mortality. While different modes of ADT can achieve castration, they affect serum FSH levels differently. Motivated by the observation that the incidence of adiposity, MS and CVD accompanies the incremental increase in serum FSH levels in menopause, we hypothesize that GnRH antagonists which maximally inhibit FSH levels will associate with reduced adiposity and development of MS and CVD compared to GnRH analogues and orchiectomy. METHODS In vivo, we used LDL receptor knockout mice on normal and high fat diet (n=12/group) as models for MS to investigate and compare the effects of orchiectomy, sham surgery, sham surgery plus GnRH antagonist (degarelix) and sham surgery plus GnRH agonist (enantone). Longitudinal weight gain (4 months), visceral fat accumulation (CT measurements), fasting blood glucose, glucose tolerance, serum triglycerides, FSH, LH and testosterone levels were studied along with characteristics of aortic atherosclerotic plaques. RESULTS Expectedly, the lowest and highest serum FSH levels were recorded in mice treated with degarelix vs. orchiectomy and significantly lower levels of FSH and LH in mice treated with degarelix vs. enantone were observed. Enantone-treated mice gained significantly more weight and visceral fat compared to mice treated with degarelix. Significantly lower levels of serum triglycerides and better response to glucose loading were recorded in mice treated with degarelix. Preliminary analysis of the atherosclerotic aortic plaques reveals that the plaque area in enantone-treated and orchiectomized mice was significantly larger than in control mice (p=0.019 and 0.018, respectively), but that this was not the case in degarelix-treated mice, where the plaque area was not significantly different from control. CONCLUSIONS In a preclinical mouse model, the use of GnRH antagonists as ADT attenuates weight gain and development of the MS and atherosclerosis. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e263 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Wilhelmina CM. Duivenvoorden More articles by this author Sarah Hopmans More articles by this author Geoff Werstuck More articles by this author Pinthus Jehonathan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

A prospective randomised controlled study comparing a low-cost antagonist protocol using oral ovulation inducing agents in IVF-ICSI cycles with a standard agonist long protocol

The objective of this prospective randomised controlled study was to compare the cost-effectiveness of a low cost antagonist protocol using oral ovulation inducing agents (Clomiphine Citrate or Aromatase Inhibitors) with a standard long GnRH agonist protocol in IVF-ICSI cycles. IVF-ICSI cycles at our centre from 2006 to 2012 were prospectivly studied for gonadotropin usage and cost effectiveness. The patients in the study underwent a long GnRH-Agonist or an Antagonist protocol after randomisation using a computer generated list. The antagonist protocol patients were given only oral ovulogens (Clomiphine Citrate or Aromatase Inhibitors) for the first five days of cycle, followed by gonadotropins. A total of 346 IVF-ICSI cycles were prospectivly studied in patients less than 40 years of age. All patients received low-dose oral contraceptive pills in the preceding cycle. They were randomised into two groups using a computer generated list. The agonist group underwent the standard long GnRH analogue protocol. The antagonist group received oral ovulation inducing agents (Clomiphene Citrate / Aromatase Inhibitor) for the first five days of cycle followed by gonadotropins and 0.25mg antagonist (Cetrorelix) injection daily till the day of hCG, using a flexible antagonist start approach. There was a significant difference in the gonadotropin usage between the two groups. As a result, the cost of the oral ovulation inducing agents (Clomiphene Citrate / Aromatase Inhibitor) - gonadotropin - antagonist cycle was significantly lower than the long GnRH agonist - gonadotropin protocol. Though the mean number of oocytes retrieved was higher in the long protocol group, yet the clinical pregnancy rate per transfer was similar in both the groups. Use of GnRH antagonist in combination with oral ovulation inducing agents offers the advantage of an economical method of stimulation in IVF-ICSI cycles, as compared to the agonist protocol, with a similar pregnancy rate.