GnRH Antagonist Treatment Research Articles

FSH Induced in Vitro Growth of Small Antral Follicles are not Impacted by GnRH Agonist or Antagonist Treatment in Mice

FSH Induced in Vitro Growth of Small Antral Follicles are not Impacted by GnRH Agonist or Antagonist Treatment in Mice

Donor spermatogenesis in de novo formed seminiferous tubules from transplanted testicular cells in rhesus monkey testis.

Can transplanted primate testicular cells form seminiferous tubules de novo, supporting complete spermatogenesis? Cryopreserved testicular cells from a prepubertal monkey can reorganize in an adult monkey recipient testis forming de novo seminiferous tubular cords supporting complete spermatogenesis. De novo morphogenesis of testicular tissue using aggregated cells from non-primate species grafted either subcutaneously or in the testis can support spermatogenesis. Two postpubertal rhesus monkeys (Macaca mulatta) were given testicular irradiation. One monkey was given GnRH-antagonist treatment from 8 to 16 weeks after irradiation, while the other received sham injections. At 16 weeks, cryopreserved testicular cells from two different prepubertal monkeys [43 × 106 viable (Trypan-blue excluding) cells in 260 μl, and 80 × 106 viable cells in 400 μl] were transplanted via ultrasound-guided injections to one of the rete testis in each recipient, and immune suppression was given. The contralateral testis was sham transplanted. Testes were analyzed 9 months after transplantation. Spermatogenic recovery was assessed by testicular volume, weight, histology and immunofluorescence. Microsatellite genotyping of regions of testicular sections obtained by LCM determined whether the cells were derived from the host or transplanted cells. Transplanted testis of the GnRH-antagonist-treated recipient, but not the sham-treated recipient, contained numerous irregularly shaped seminiferous tubular cords, 89% of which had differentiating germ cells, including sperm in a few of them. The percentages of donor genotype in different regions of this testis were as follows: normal tubule, 0%; inflammatory, 0%; abnormal tubule region, 67%; whole interior of abnormal tubules, >99%; adluminal region of the abnormal tubules, 92%. Thus, these abnormal tubules, including the enclosed germ cells, were derived de novo from the donor testicular cells. Not applicable. The de novo tubules were observed in only one out of the two monkeys transplanted with prepubertal donor testicular cells. These findings may represent a promising strategy for restoration of fertility in male childhood cancer survivors. The approach could be particularly useful in those exposed to therapeutic agents that are detrimental to the normal development of the tubule somatic cells affecting the ability of the endogenous tubules to support spermatogenesis, even from transplanted spermatogonial stem cells. This work was supported by research grants P01 HD075795 from Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD/NIH) to K.E.O and Cancer Center Support Grant P30 CA016672 from NCI/NIH to The University of Texas MD Anderson Cancer Center. The authors declare that they have no competing interests.

Stimulation with recombinant FSH acutely and significantly increases inhibin B and estradiol in women after GnRH antagonist treatment: a model to study FSH regulation of ovarian function

Obesity is associated with decreased pituitary output of LH and FSH, inadequate folliculogenesis, and reduced ovarian steroid and peptide hormone production. It remains unclear whether the underlying pathophysiology is related to abnormal hypothalamic-pituitary dynamics, abnormal ovarian environment, or both. The persistent deficit in FSH secretion, despite the lack of restraint and normal pituitary FSH reserve, remains unexplained. FSH pulsatility is challenging to evaluate, given its long half-life and low signal-to-noise ratio, and current analytic methods fail to adequately characterize the hormone secretion dynamics of FSH and its feedback. We hypothesized that both Inhibin B and Estradiol (E2) levels will be acutely increased following exogenous, pulsatile recombinant (r) FSH administration, after a GnRH antagonist blockade. This will establish a model to study ovarian, FSH-stimulated E2 and inhibin secretion, independent of the pituitary, to determine mechanisms underlying the FSH/ovarian dysregulation in obesity. A pilot, cohort study of 9 normal-weight, cycling women at the University of Colorado School of Medicine. Participants (mean age 26.3 ± 4.9 years; BMI 22.2 ± 1.3 kg/m2) underwent frequent blood sampling (q10 min) during a 26-hour overnight study visit. Following an initial baseline10-hour collection to assess unstimulated LH and FSH secretion, Cetrotide (EMD Serono) was administered subcutaneously twice: 3 mg at hour 10 and 0.25mg at hour 16. Frequent blood sampling resumed (hours 16-26) and rFSH (Gonal-F; 30 IU) was given intravenously every hour. LH, FSH and E2 were measured by immunoassays (Centaur XP, Siemens). Functional sensitivity is 0.1 mIU/mL and the intra- and inter-assay coefficients of variation were 3.8 and 4.1%, respectively. Inhibin B was analyzed by ELISA (Beckman Coulter). Functional sensitivity is 10 pg/mL and the intra- and inter-assay coefficients of variation were 1.8 and 4.9%, respectively. Statistical significance was determined by paired t test. Normal LH & FSH pulsatility was confirmed for the 10-hour baseline frequent sampling period for all subjects. Administration of Cetrotide reliably suppressed endogenous LH and FSH secretion. Repeated boluses of rFSH mimicked endogenous FSH pulses and significantly increased FSH levels over the course of the infusion (p<0.001). Starting from 6 hours post rFSH administration (after 180 IU) we observed a significant increase in both inhibin B (60%) and E2 (80%) production (p=0.01 and p<0.01 respectively). We herein report that exogenous FSH, administered in a pulsatile fashion after GnRH blockade, induced significant, acute increases in both E2 and Inhibin B, in normal weight women. This experimental paradigm can be used to investigate FSH feedback mechanisms in obesity or other environmental insults impacting ovarian function.

EFFECTS OF GONADOTROPIN-RELEASING HORMONE ANTAGONIST DEGARELIX ON MUSTH AND SERUM TESTOSTERONE CONCENTRATIONS IN ASIAN ELEPHANTS ( ELEPHAS MAXIMUS).

Two male Asian elephants (bulls 1 and 2) in musth were subcutaneously injected with a long-acting gonadotropin-releasing hormone (GnRH) antagonist, degarelix acetate (240 μg/kg; total dose of 960 mg). Musth behavior (MB) and temporal gland secretions (TGS) were monitored and serum testosterone concentrations were determined. In bull 1, MB and TGS ceased on day 1 and reappeared 5.5 mo after the treatment (day 0). During the subsequent musth cycle, MB and TGS ceased on day 1 and did not appear for 4 mo. In bull 2, MB and TGS ceased at day 7 after the treatment. Musth behavior and TGS recurred on Day 11 and continued for 1 wk, then disappeared for 8 mo. Serum testosterone concentrations decreased ( P < 0.05) in all occasions from day 0 (29.8 ± 15.8 ng/ml; mean ± SEM) to day 1 (2.2 ± 1.1 ng/ml), suggesting a sudden drop in circulating testosterone in musth elephants after the GnRH-antagonist treatment.

Added value today of hormonal measurements in ovarian stimulation in gonadotropin-releasing hormone antagonist treatment cycle.

Traditional approach of ovarian stimulation monitoring for in-vitro fertilization involves transvaginal sonography and serum estradiol measurements. Accumulating evidence has shown that hormonal evaluations during ovarian stimulation allow individual cycle optimization, moving away from only predicting the risk of ovarian hyperstimulation syndrome, but in addition assessing the impact of ovarian stimulation on endometrial receptivity, quality of oocytes, and subsequently embryos. The purpose of this review is to discuss the relevance and added value of hormonal monitoring during ovarian stimulation in gonadotropin-releasing hormone antagonist cycles where most of the advances have occurred. Basal hormonal status, particularly estradiol, progesterone, and luteinizing hormone are instrumental in prediction of the patients with poor prognosis. Estradiol levels on the day of trigger are less sensitive in predicting ovarian hyperstimulation syndrome then the number of follicles more than 11 mm in diameter. Progesterone elevation on the day of trigger is associated with lower pregnancy rates. The gold standard treatment for progesterone elevation is to adopt a freeze-all strategy when the threshold of 1.50 ng/ml is exceeded. The effect of progesterone elevation on embryo quality remains to be confirmed by more trials. Endocrine monitoring during ovarian stimulation allows fine-tuning of the physiology of the stimulated cycle and thereby increases the chances of successful treatment outcome.

Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood.

Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and corresponds with a high degree of comorbidities and economic burden. How PCOS is passed on from one generation to the next is not clear, but it may be a developmental condition. Most women with PCOS exhibit higher levels of circulating luteinizing hormone, suggestive of heightened gonadotropin-releasing hormone (GnRH) release, and Anti-Müllerian Hormone (AMH) as compared to healthy women. Excess AMH in utero may affect the development of the female fetus. However, as AMH levels drop during pregnancy in women with normal fertility it was unclear if their levels were also elevated in pregnant women with PCOS. Here, we measured AMH in a cohort of pregnant women with PCOS and control women and found that AMH is significantly more elevated in the former group versus the latter. To determine if the elevation of AMH during pregnancy in women with PCOS is a bystander effect or a driver of the condition in the offspring, we modelled our clinical findings by treating pregnant mice with AMH and followed the neuroendocrine phenotype of their female progeny postnatally. This treatment resulted in maternal neuroendocrine-driven testosterone excess and diminished placental metabolism of testosterone to estradiol, resulting in a masculinization of the exposed female fetus and a PCOS-like reproductive and neuroendocrine phenotype in adulthood. We found that the affected females had persistently hyperactivated GnRH neurons and that GnRH antagonist treatment in the adult female offspring restored their neuroendocrine phenotype to a normal state. These findings highlight a critical role for excess prenatal AMH exposure and subsequent aberrant GnRH receptor signaling in the neuroendocrine dysfunctions of PCOS, while offering a new potential therapeutic avenue to treat the condition during adulthood.

Pregnancy outcome in delayed start antagonist versus microdose flare GnRH agonist protocol in poor responders undergoing IVF/ICSI: An RCT

Over the years, many article on different aspects of pathogenesis and management of poor ovarian responders have been published but there is no clear guideline for treating themyet. This study was designated to compare the effectiveness of a delayed start protocol with gonadotropin-releasing hormone (GnRH) antagonist and microdose flare-up GnRH agonist protocol in poor ovarian responders. This randomized clinical trial consisted of 100 poor ovarian responder women in assisted reproductive technologies cycles. They were divided randomly in delayed-start antagonist protocol (with estrogen priming followed by early follicular-phase GnRH antagonist treatment for 7 days before ovarian stimulation) and microdose flare-up GnRH agonist protocol. The main outcome was clinical pregnancy rate and second outcome was the number of retrieved oocytes, mature oocytes, 2PN number, fertilization rate, and implantation rate. Fertilization rate, clinical pregnancy rate, and ongoing pregnancy rates were not significantly different between the two studied protocols. Number of retrieved oocytes (5.10±3.41 vs. 3.08±2.51) with p=0.002, mature oocytes (4.32±2.69 vs. 2.34±1.80) with p=0.003, number of 2PN (3.94±1.80 vs. 2.20±1.01) with p=0.001 and implantation rate (19.40% vs. 10.30%) with p=0.022 were significantly higher in delayed antagonist group. The delayed-start protocol can improve ovarian response in poor responders by stimulating and synchronizing follicle development.

Gonadotropin Releasing Hormone Agonists or Antagonists for Preimplantation Genetic Diagnosis (PGD)? A Prospective Randomised Trial.

The use of GnRH analogue medication is essential in reproductive medicine to avoid premature ovulation by pituitary suppression for the duration of ovarian stimulation by gonadotrophins. The type of pituitary suppression by either GnRH agonist analogues versus GnRH antagonist analogues may result in different embryological hence clinical results. Preimplantation genetic diagnosis is a subtype of IVF in which embryos are created for genetic diagnosis of hereditary disorders in order to avoid genetically affected children. Embryological quality hence ovarian stimulation in preimplantation genetic diagnosis is crucial as genetic selection will reduce the number of available embryos to a fraction of the total. The aim of this study was to assess the efficiency of GnRH antagonist versus GnRH agonist treatment for pituitary suppression in ovarian stimulation for PGD, by proxy of number and quality of embryos at cleavage stage available for biopsy. We conducted a prospective randomised controlled trial comparing pituitary suppression by GnRH antagonist versus GnRH agonist in ovarian stimulation for PGD. The primary outcome measure was the number of embryos of sufficient quality for biopsy at cleavage stage. Secondary outcome parameters were the number of blastocysts available of top quality, and clinical pregnancy rate. There was no difference in number of oocytes retrieved, embryos at cleavage stage available for biopsy or embryo quality. The clinical pregnancy rate was higher in the GnRH agonist group; however the sample size was insufficient to allow conclusions. The use of GnRH agonist versus antagonist treatment does not result in differences in a number of oocytes, embryos or embryo quality in ovarian stimulation for preimplantation genetic diagnosis.

A gonadotropin-releasing hormone antagonist reduces serum adrenal androgen levels in prostate cancer patients

BackgroundAdrenal androgens play an important role in the development of castration-resistant prostate cancer therapeutics. The effect of gonadotropin-releasing hormone (GnRH) antagonists on adrenal androgens has not been studied sufficiently. We measured testicular and adrenal androgen levels in patients treated with a GnRH antagonist.MethodsThis study included 47 patients with histologically proven prostate cancer. All of the patients were treated with the GnRH antagonist degarelix. The mean patient age was 73.6 years. Pre-treatment blood samples were collected from all of the patients, and post-treatment samples were taken at 1, 3, 6, and 12 months after starting treatment. Testosterone (T), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), 17β-estradiol (E2), and androstenedione (A-dione) were measured by liquid chromatography-mass spectrometry. Dehydroepiandrosterone-sulfate (DHEA-S), luteinizing hormone, and follicle-stimulating hormone levels were measured by electro-chemiluminescence immunoassays.ResultsA significant reduction in T level (97.3% reduction) was observed in the patients 1 month after initiating treatment. In addition, levels of DHT, E2, DHEA-S, and A-dione decreased 1 month after initiating treatment (93.3, 84.9, 16.8, and 35.9% reduction, respectively). T, DHT, E2, DHEA-S, and A-dione levels remained significantly suppressed (97.1, 94.6, 85.3, 23.9, and 40.5% reduction, respectively) 12 months after initiating treatment. A significant decrease in DHEA level (15.4% reduction) was observed 12 months after initiating treatment.ConclusionsSerum adrenal androgen levels decreased significantly in patients treated with a GnRH antagonist. Thus, long-term GnRH antagonist treatment may reduce serum adrenal androgen levels.

Pregnancy outcome of “delayed start” GnRH antagonist protocol versus GnRH antagonist protocol in poor responders: A clinical trial study

Background:Management of poor-responding patients is still major challenge in assisted reproductive techniques (ART). Delayed-start GnRH antagonist protocol is recommended to these patients, but little is known in this regards.Objective:The goal of this study was assessment of delayed-start GnRH antagonist protocol in poor responders, and in vitro fertilization (IVF) outcomes.Materials and Methods:This randomized clinical trial included sixty infertile women with Bologna criteria for ovarian poor responders who were candidate for IVF. In case group (n=30), delayed-start GnRH antagonist protocol administered estrogen priming followed by early follicular-phase GnRH antagonist treatment for 7 days before ovarian stimulation with gonadotropin. Control group (n=30) treated with estrogen priming antagonist protocol. Finally, endometrial thickness, the rates of oocytes maturation, , embryo formation, and pregnancy were compared between two groups. Results:Rates of implantation, chemical, clinical, and ongoing pregnancy in delayed-start cycles were higher although was not statistically significant. Endometrial thickness was significantly higher in case group. There were no statistically significant differences in the rates of oocyte maturation, embryo formation, and IVF outcomes between two groups.Conclusion:There is no significant difference between delayed-start GnRH antagonist protocol versus GnRH antagonist protocol.

The effect of rLH supplementation to the GnRH-antagonist protocol on endocrine dynamics in the advanced reproductive age.

To explore serum endocrine dynamics, specifically LH levels, following rLH supplementation to rFSH following GnRH-antagonist treatment in the advance reproductive age. Women were prospectively and similarly treated employing rFSH and the flexible GnRH-antagonist protocol, while rLH was supplemented only to the study group. Serum FSH, LH, E2, and P were evaluated throughout the follicular phase. Three strategies were a priori planned to examine endocrine dynamics among women enrolled. While serum LH drop were similar before GnRH-antagonist stimulation, it dropped more times in the control group compared to the study group. Among women receiving rFSH only, serum LH levels dropped ≤2, ≤1 and ≤0.5mIU/mL in 71.4, 46.4, and 28.6% of cases, while this occurred only in 38.7% (P = 0.01), 6.5% (P = 0.0004) and 3.2% (P = 0.007) of women receiving combined rFSH and rLH treatment, respectively. The same trend was found when serum LH dropped in at least two occasions following the GnRH-antagonist administration. Conversely, serum LH diagrams throughout the follicular phase did not differ between the two groups. Furthermore, individual area under the curve values of LH, E2, and P was similar between the two groups following GnRH-antagonist initiation. Different strategies to explore LH dynamics following the GnRH-antagonist administration have resulted in diverse results, implying the need for a consensus definition of LH threshold for adequate folliculogenesis and steroidogenesis. Such action would pave the way for understanding which groups of patients may benefit from rLH supplementation.

Comparison of GnRH antagonist and agonist mini-dose long protocols in infertile cases undergoing controlled ovarian hyperstimulation

The purpose of the present study was to determine if there is a difference between multi-dose gonadotropin releasing hormone (GnRH) antagonist protocol and long GnRH agonist protocol. This retrospective study compared the data pertaining to patients chosen as per predetermined acceptance criteria, 113 of whom were administered multi-dose antagonist protocol for controlled ovarian hyperstimulation (COH) while 133 were administered long agonist protocol for COH at Suleymaniye Teaching Hospital of Obstetrics and Gynecology. While cancellation rate was found to be significantly higher in antagonist group (17.7% vs 11.28%), the number of follicles > 14 mm and > 16 mm, E2 level, and the number of retrieved oocytes on the day of hCG trigger were significantly lower in the same group. However, there was no difference between fertilization rates and embryonic development rates. The pregnancy rates per transfer and per cycle were found to be 40.9% and 31.7%, respectively; in the antagonist group they were lower, though not significantly, when compared to agonist group (44.1% and 39.1%, respectively). Ongoing pregnancy rates were found to be similar between the groups. GnRH antagonist treatment protocol has a level of efficacy similar to agonist treatment protocol in terms of pregnancy results for all groups.

A short course of metformin does not reduce OHSS in a GnRH antagonist cycle for women with PCOS undergoing IVF: a randomised placebo-controlled trial.

Does 'metformin' reduce the incidence of ovarian hyperstimulation syndrome (OHSS) for women with polycystic ovary syndrome (PCOS) undergoing a GnRH antagonist assisted conception treatment cycle? A short course of metformin does not reduce the incidence of OHSS for women with PCOS undergoing a GnRH antagonist treatment cycle. Metformin does reduce the incidence of OHSS in a GnRH-agonist treatment cycle. A randomised placebo-controlled trial (RCT) using metformin or placebo. Randomisation was blinded to both patient and investigator, using a random permuted blocks method with a 50:50 allocation ratio. The study was completed over 5 years (2009-2014) with 153 randomised patients. A sample size calculation based on the incidence of OHSS was completed prospectively suggesting a minimum of 146 recruits was required for the trial with a power of 80% and a type 1 error of 0.05. All patients met the Rotterdam criteria for PCOS and were treated with a standard GnRH antagonist IVF/ICSI treatment cycle in a tertiary infertility clinic. The study medication was started prior to stimulation and continued to oocyte retrieval. Of the 153 patients, 77 received metformin and 76 placebo. There was no reduction in the incidence of moderate-severe OHSS (Placebo (PLA) 12.2%, metformin (MET)=16%, 95% CI -0.08-0.16, P =0.66). There was no difference in total gonadotrophin dose (PLA = 1200, MET=1200, 95% CI -118.67-118.67, P =0.75), oocytes retrieved (PLA = 15, MET = 14, 95% CI -2.37-4.37, P =0.66) or fertilisation rate (PLA=60.7%, MET=53.3%, 95% CI -0.96-14.94, P =0.07). However, using metformin resulted in a reduced clinical pregnancy rate (CPR) per cycle started (PLA=48.7%, MET=28.6%, 95% CI 0.04-0.35, P =0.02) and live birth rate (PLA = 51.6%, MET = 27.6%, 95% CI 0.05-0.40, P =0.02). Furthermore, when ethnicity was taken into account there was a significant reduction in pregnancy outcome for the South Asian population irrespective of metformin or placebo use (CPR per cycle started, White Caucasian=44.4%, South Asian=19.4%; 95% CI 0.06-0.39, P =0.01). This study was only undertaken on an infertility population with PCOS with a limited duration of study medication use. This is the first adequately powered RCT to assess the impact of metformin on OHSS in a high-risk group (women with PCOS) undergoing a GnRH antagonist cycle. It does not support the empirical prescribing of metformin as an adjunct to a GnRH antagonist treatment cycle. None. EudraCT number 2009-010952-81. 21 September 2009. 30 October 2009.

Effects of long-acting GnRH antagonist, degarelix acetate, on plasma insulin-like peptide 3, testosterone and luteinizing hormone concentrations, and scrotal circumference in male goats

We recently reported that plasma insulin-like peptide 3 (INSL3) concentrations increased soon after endogenous and exogenous stimulations of LH in male goats and bulls. However, the effects of LH suppression on INSL3 secretion are unknown in domestic animals. Here, we examined the effects of a long-acting GnRH antagonist (degarelix acetate; 4 mg/kg) on the secretions of plasma INSL3 and testosterone in two phases, an immediate and a long-term phase in male goats (n = 6; aged, 13–16 months). During the immediate phase, blood was taken at 15-minute intervals for 8 hours on Days −5, 0, and 3. The GnRH antagonist was administered after 2-hour sampling of Day 0. Moreover, a daily blood sample was taken from Day 0 to Day 7, followed by twice a week until 9 weeks and finally at week 10. The scrotal circumference was recorded before treatment and continued biweekly until week 10. Concentrations of LH, INSL3, and testosterone in plasma were determined by EIA and the pulsatile nature of secretion analyzed using pulse XP software. The mean concentrations, pulse frequency (per hour), and pulse amplitude (peak-nadir) of plasma LH and testosterone reduced from pretreatment to posttreatment Day 0 and Day 3 (P < 0.05). A decline in mean concentrations, pulse frequency, and pulse amplitude of INSL3 was exhibited on posttreatment Day 3 compared with pretreatment (P < 0.01). During long-term sampling, a decline (P < 0.01) in plasma testosterone and INSL3 concentrations was observed 1 day after treatment and remained lower until 8.5 weeks after treatment, and thereafter returned to pretreatment levels. A reduction in scrotal circumference was recorded 4 weeks after treatment and remained lower until 10 weeks after treatment (P < 0.05). In conclusion, the acute regulation of INSL3 by LH was confirmed by reduction of plasma INSL3 levels within 3 days after GnRH antagonist treatment in male goats. Although the onset of suppression of testosterone was more rapid than that of INSL3, the low levels persisted for 8.5 weeks for both hormones, and subsequently the concentrations returned to pretreatment levels. A significant reduction in testicular size was also observed. The quick, long-lasting, and transient suppression of testosterone and INSL3 after a single injection implies a potential application of this antagonist in reversible long-term chemical castration in male goats.

GnRH antagonist administration to postpone a weekend intrauterine insemination: a large cohort study from a public center.

BackgroundIn Spanish public hospital Reproduction Units it is very problematic to perform programmed intrauterine insemination (IUI) on weekends, if indicated. Small previous pilot studies suggest that using a GnRH antagonist to avoid an LH weekend surge would allow to perform IUI on the following Monday, not impairing the expected pregnancy rate.MethodsBetween 1st January 2007 and 31st December 2015, 4.782 intrauterine inseminations were performed at Valladolid University Clinic, Spain, corresponding to 1.650 women. Of them, 911, corresponding to 695 women, should ideally have been performed during the weekend. If it happened that a member of the Reproduction Unit was on duty during that particular weekend, the standard protocol was not interrupted, and the IUI performed as planned (control group, 685 IUIs). If the former was not the case, the weekend gap was bridged by administering 0.25 mg GnRH antagonist (GnRHa). Ovulation was induced by means of 250 ug recombinant HCG (rHCG) 36 h prior to IUI on the following Monday (study group, 226 IUIs).ResultsThere were no differences in the clinical pregnancy rate (13.7 cc vs. 16.2 %, p = 0.371) or in the ongoing pregnancy rate between groups (11.9 % vs. 14.9 %, p = 0.271). The multiple pregnancy rate was also comparable in both groups (14.7 % vs. 18.5 %, p = 0.77).ConclusionsWomen with a planned IUI which cannot be performed at the ideal date can be offered postponement for two days with the support of GnRHa treatment, with results that are not inferior to those expected applying the regular protocol.

Effect of FSH supplementation on the GnRH antagonist suppressed growth of PC-3 cell xenografts in nude mice.

e630 Background: One of the fundamental differences between GnRH agonist and antagonist treatment is the permanent suppression of FSH by antagonist, while a rebound in FSH secretion has been documented upon agonist treatments. To assess the potential beneficial effects of permanent FSH suppression in the hormone ablation treatment of prostate cancer we studied the effect of the GnRH antagonist degarelix in the absence and presence of FSH supplementation on the growth of PC-3 human prostate cancer cell xenografts in nude mice. Methods: Intact (n = 20) and gonadectomized (n = 20) nude male mice were inoculated with 2 x 106PC-3 cells. Half of each group received degarelix treatment at 10 mg/kg body weight s.c. In a second experiment (n = 10/group), degarelix treatment was supplemented with recombinant human FSH at10 IU/kg/day using i.p. ALZET osmotic minipumps. Tumor growth in both experiments was monitored for 4 weeks by external inspection and caliper measurement, after which the mice were sacrificed. Results: The first experiment demonstrated that degarelix treatment significantly reduced tumor growth by 33% and 35%, respectively, in intact and gonadectomized mice as compared to non-treated controls (p&lt;0.0001 for each). In the second experiment, FSH reversed the inhibitory effect of degarelix in intact mice. Conclusions: These results demonstrated that the suppression of PC-3 xenograft growth by GnRH antagonist treatment was completely inhibited by concomitant FSH treatment. The findings prove experimentally the principle that combined FSH and LH suppression by GnRH antagonist could offer an advantage over the isolated LH suppression by GnRH agonist upon prostate cancer treatment. [Table: see text]

Does the addition of growth hormone to the in vitro fertilization/intracytoplasmic sperm injection antagonist protocol improve outcomes in poor responders? A randomized, controlled trial

To evaluate the effectiveness of the addition of growth hormone (GH) to the antagonist protocol in IVF/intracytoplasmic sperm injection cycles in poor responders. Parallel randomized, controlled, open-label trial. University hospital. A total of 141 patients (GH, n = 68; gonadotropins only, n = 73) were enrolled. Twenty-five patients had their cycles cancelled. Analysis was performed per cycle start as well as per ET. Patients received the antagonist protocol with or without GH supplementation. Mean number of cumulus complexes, metaphase II oocytes retrieved and fertilized, chemical and clinical pregnancy rates, early miscarriage rate, ongoing pregnancy and live birth rates. The addition of GH significantly lowered duration of hMG treatment, duration of GnRH antagonist treatment, and dose of gonadotropin. It significantly increased mean E2 levels on the day of hCG administration, number of collected oocytes (7.58 ± 1.40 vs. 4.90 ± 1.78 [mean ± SD]), number of metaphase II oocytes (4.53 ± 1.29 vs. 2.53 ± 1.18), number of fertilized oocytes (4.04 ± 0.96 vs. 2.42 ± 1.03), and number of transferred embryos (2.89 ± 0.45 vs. 2.03 ± 0.81). There was no significant difference in the clinical pregnancy rate per cycle (22.1% vs. 15.1%) or live birth rate per cycle (14.7% vs. 10.9%). Growth hormone as an adjuvant treatment in IVF/intracytoplasmic sperm injection cycles for poor responders should be cautiously used with the antagonist protocol, because there is still no identified impact on pregnancy outcomes. However, evaluation of the clinical pregnancy and live birth rates in our data was limited by low statistical power. ClinicalTrials.gov Identifier: NCT02195947.

Ultrastructural analysis of granulosa cells of IVF patients

Objective: To compare the percentage and ultrastructure of normal and abnormal granulosa cells and their effect on fertilization and pregnancy rate between gonadotropin releasing hormone (GnRH) agonist and antagonist treatment. Materials and Methods: In this study, granulosa cells obtained from 22 women undergoing in vitro fertilization (IVF) treatment due to unexplained infertility with either with GnRH agonist (n=11) or GnRH antagonist (n=11) were evaluated by light and electron microscopy. Results: GnRH agonist and antagonist therapy was found to have no effect in terms of abnormal granulosa cell percentage (0.0679 &#x00B1; 0.08977 vs 0.0481 &#x00B1; 0.05164; p > 0.05), fertilization [85 (45-90) vs 75 (64-93)] and pregnancy rate (37% vs 46%). Light microscopic observations showed similar features of normal cells of agonist and antagonist-treated cells. Ultrastructural evaluation also revealed that there was no difference between cells of two treatment groups. Conclusion: Both GnRH agonist and antagonist treatment for ovarian stimulation may have similar effects on granulosa cells at the morphological and ultrastructural level, as well as on fertilization and pregnancy rates.

Pretreatment with oral contraceptive pills to identify poor responders that may benefit from rLH supplementation during GnRH-antagonist treatment for IVF: A pilot perspective study proposal.

Controlled ovarian stimulation, using a gonadotrophin-releasing hormone (GnRH) antagonist protocol, is a potential treatment option for women with a low response to other fertility treatments as it appears to be at least as effective as GnRH agonists (long protocol). However, previous studies have indicated that the administration of GnRH antagonist may cause an excessive reduction in endogenous luteinizing hormone (LH) levels. The use of recombinant LH (rLH) supplementation during ovarian stimulation is controversial. The present article proposes a future study focused on women aged ≥40 years old, with the aim of identifying patients who are poor responders to GnRH-antagonist treatment that may benefit from rLH supplementation. We hypothesize that patients with suppressed hypothalamic-pituitary-axis activity may benefit from rLH supplementation, as GnRH-antagonist administration has the potential to induce a marked reduction in LH levels in such patients compared with that in patients that exhibit a regular recovery following the administration of oral contraceptive pills (OCPs). Furthermore, patients with hyper-responsive hypothalamic-pituitary-axis activity may be affected by ‘low-gonadotropin-responsiveness’, similar to that observed in patients with any mutation in the follicle-stimulating hormone (FSH) receptor, who are known to benefit from rLH supplementation. The proposed pilot study would include 120 women who are predicted to be poor responders to GnRH-antagonist treatment. All subjects will be allocated at random (using 2:1 computerized randomization) into two study groups: Group A (OCP-treated) and group B (control). For all patients, the serum values of FSH, LH and 17β estradiol (E2) will be detected on day 3 of the menstrual cycle preceding OCP treatment (baseline) and at day 4 following OCP treatment. The Δ-variation from baseline levels for all markers, the FSH/LH ratio and the E2/FSH ratio will be determined. Δ-variation from the baseline of the FSH and LH values will be used to further categorize group A patients into subgroups A1–4, based on respective quartile numbers (Q1–4). Patients admitted to each of the four subgroups A1–4, based on their FSH quartile, will be selected at random to receive rLH supplementation (ratio, 1:1) during ovarian stimulation. If the resulting data are able to identify women that may benefit from rLH supplementation during ovarian stimulation, a large part of inconclusive evidence regarding rLH supplementation will be clarified. If patients supplemented with rLH (according to abnormal recovery of hypothalamic-pituitary-axis activity after OCP treatment) exhibit an improved ovarian response during in vitro fertilization (IVF) and subsequent pregnancy rate, the pre-IVF OCP test could be adopted as a useful tool for improving the success rate of assisted reproductive technologies in poorly-responding patients.

Antimüllerian hormone: prediction of cumulative live birth in gonadotropin-releasing hormone antagonist treatment for in vitro fertilization

To assess the accuracy of antimüllerian hormone (AMH) in predicting cumulative live birth rate (CLBR) within 1 year after treatment initiation in GnRH antagonist treatment cycles for in vitro fertilization (IVF). Observational (retrospective) substudy as part of an ongoing prospective cohort study. University medical center. A total of 487 patients scheduled for IVF/intracytoplasmic sperm injection (ICSI). Patients starting their first IVF/ICSI cycle with 150 or 225 IU recombinant FSH and GnRH antagonist cotreatment were included. Serum samples collected before the first IVF treatment were used to determine AMH. Treatment data after treatment initiation for a maximum of 1 year were recorded. Prediction of CLBR with the use of AMH. The model for predicting CLBR within 1 year included age at first treatment, AMH, type of infertility, and previous assisted reproductive technology treatment leading to live birth. The accuracy in discriminating between women who did or did not achieve a live birth was only 59%. AMH had intermediate added value in the prediction of CLBR as demonstrated by the net reclassification improvement (total 29.8). A nomogram based on age and AMH was developed by which a subgroup of patients could be identified with the poorest pregnancy prospects. The predictive accuracy of AMH for 1-year CLBR in GnRH antagonist treatment cycles was limited and did not yield much additional value on top of age. Withholding treatment based on predictors such as age and AMH, or a combination, remains problematic. www.clinicaltrials.gov, NCT02309073.