Effects of gonadotropin-releasing hormone antagonists on the expression of vascular endothelial growth factor and its receptors in a rat model of ovarian hyperstimulation syndrome

Background Ovarian hyperstimulation syndrome （OHSS） is one of the most life-threatening complications of assisted reproduction treatments. Gonadotropin-releasing hormone antagonists （GnRHanta） are thought to be effective in preventing this complication, and some clinical trials have found lower incidences of OHSS in patients treated with GnRHanta. Our aim was to investigate the effects of GnRHanta on vascular permeability and the expression of vascular endothelial growth factor （VEGF） and its receptors in a rat model of OHSS. Methods An immature early OHSS rat model was established. Three ovarian stimulation protocols were used： pregnant mare serum gonadotropin/human chorionic gonadotropin （hCG） alone, with a GnRHanta, or with a gonadotropin-releasing hormone agonists （GnRHa）. Blood and tissue samples were collected at 48 hours after hCG administration. Vascular permeability was evaluated by measuring the Evans-Blue content of extravasated peritoneal fluids. The expression of VEGF and its receptors, including fit-1 and KDR, were detected by reverse transcriptase-polymerase chain reaction and Western blotting. Results Treatment with both a GnRHanta and a GnRHa resulted in significant reductions in serum estradiol and peritoneal vascular permeability, as well as decreased ovarian expression of VEGF and its two receptors. However, GnRHanta treatment caused a greater reduction in serum estradiol concentrations, and in VEGF receptor mRNA expression than GnRHa. There were no significant reductions in the expression of VEGF or its receptors in extra-ovarian tissues, including the liver, lungs and peritoneum. Conclusion Our results reveal that GnRHanta are more potent than GnRHa in preventing early OHSS through down-regulation of the expression of VEGF and its receptors in hyperstimulated ovaries.

Effect of Dual Trigger In Vitro Fertilization and Intracytoplasmic Sperm Injection During the Gonadotropin-releasing Hormone-Antagonist Cycle on Final Oocyte Maturation and Cumulative Live Birth Rate in Women with Diminished Ovarian Reserve

Objective It is well known that a dual trigger treatment can improve clinical outcomes of in vitro fertilization(IVF)in high or normal ovarian responders.However,it is not clear whether dual triggering also benefits patients with diminished ovarian reserve(DOR).The aim of this study was to investigate whether a dual trigger treatment of gonadotropin-releasing hormone(GnRH)agonist combined with human chorionic gonadotropin(hCG)for final follicular maturation improves the cumulative live birth rate(CLBR)during the GnRH-antagonist cycle in patients with DOR.Methods This retrospective study included patients with DOR who received a GnRH-antagonist protocol during IVF and intracytoplasmic sperm injection(IVF-ICSI)cycles at Peking University People’s Hospital from January 1,2017 through December 31,2017.Oocyte maturation was triggered by GnRH combined with hCG(n=110)or hCG alone(n=71).Embryos were transferred on the third day after oocyte retrieval or during a subsequent freeze-thaw cycle.Patients were followed up for 3 years.Results The dual trigger treatment did not affect CLBR,which is an overall determinant of the success rate of assisted reproductive technology(ART).Women in the dual trigger group had significantly higher rates of fertilization than those in the hCG group(90.1%vs.83.9%,P=0.040).Conclusion Dual trigger with GnRH agonist and hCG did not improve CLBR in patients with DOR,but did slightly improve fertilization rate,oocyte count,and embryo quality.

Targeted-cryosurgical ablation of the prostate with androgen deprivation therapy:quality of life in high-risk prostate cancer patients

Aim： To present preliminary results on health-related quality of life （QoL）, prostate-associated symptoms and therapeutic effects of targeted-cryosurgical ablation of the prostate （TCSAP） with androgen deprivation therapy （ADT） in high-risk prostate cancer （PCa） patients. Methods： Thirty-four men with high-risk PCa features underwent TCSAP, and ADT was added to improve the treatment outcomes. High-risk parameters were defined as either prostate-specific antigen （PSA） ≥ 10ng/mL, or Gleason score 〉 8, or both. The Genito-Urinary Group of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 （EORTC QLQ-C30） with prostate-cancer-specific module （QLQ-PR25） was used for evaluating morbidities and PSA levels were recorded every 3 months. PSA failure was defined as the inability to reach a nadir of 0.4 ng/mL or less. Results： Although it was not statistically significant, the global health status scores increased after TCSAP with ADT. The scores for five functional scales also became higher after treatment. The most prominent symptom after treatment was sexual dysfunction, followed by treatment-related and irritative voiding symptoms. Conclusion： TCSAP with ADT appears to be minimally invasive with high QoL except for sexual dysfunction. Long-term follow-up of PSA data and survival is necessary before any conclusions can be made on the efficacy of this promising new therapeutic modality in the treatment of PCa.

Hormone naive prostate cancer： predicting and maximizing response intervals

Hormone naive advanced prostate cancer is subdivided into two disease states： biochemical recurrence and traditional M 1 （metastatic） prostate cancer and characterized by no prior hormonal therapy or androgen deprivation therapy （ADT）. In biochemical recurrence/ prostate-specific antigen （PSA） recurrence, men should be risk-stratified based on their PSA doubling time, the Gleason score and the timing of the recurrence. In general, only men who are at high risk should be considered for early/immediate ADT although this is best done using shared decision with the patient. The type of ADT to be used in biochemical recurrence ranging from oral-only peripheral blockade （peripheral androgen deprivation） to complete hormonal therapy （combined androgen blockade [CAB]） remains in debate owing to lack of randomized controlled trials （RCT）. However, there is good RCT support for use of intermittent hormonal therapy （IHT）. There is also limited research on biomarker response （PSA and testosterone decline） to predict prognosis. On the other hand, in the setting of M1 hormone naive prostate cancer, there are many more RCT＇s to inform our decisions. CAB and gonadotrophin-releasing hormone antagonists perhaps provide a slight efficacy advantage while IHT may be slightly inferior with minimal M1 disease. The PSA nadir at 7 months after starting ADT is a powerful prognostic tool for M1 patients. There is growing recognition that serum testosterone （T） control while on ADT is linked to the development of castrate-resistant prostate cancer. Especially for a M 1 patient, maintaining a serum T below 20-30 ng d1-1 prolongs the response to ADT. Novel oral agents （abiraterone and enzalutamide） may soon find use in hormone naive disease and may alter the treatment landscape. Despite over 75 years of experience with ADT, many questions remain, and the field continues to evolve.

Comparison of Vaginal Gel and Intramuscular Progesterone for In vitro Fertilization and Embryo Transfer with Gonadotropin-Releasing Hormone Antagonist Protocol

Background： Luteal support is a key to patients undergoing in vitro fertilization and embryo transfer （IVF-ET） with gonadotropin-releasing hormone （GnRH）-antagonist protocol. This study aimed to compare the effect between vaginal progesterone （VP） and intramuscular progesterone （IMP） with GnRH-antagonist protocol alter IVF-ET. Methods： A total of 1760 patients （18 years ≤ age ≤35 years） undergoing IVF-ET with GnRH-antagonist protocol were studied retrospectively between September 2014 and August 2015 in Peking University Third Hospital. In the patients, 1341 patients received VP （VP group） and 419 patients received IMP （IMP group） as luteal support. We compared clinical outcomes between these two groups. The primary objective of the study was the live birth rate. Measurement data between the two groups were conducted using independent samples t-test. The variables in line with non-normal distribution were expressed as median （p25 and p75） and were compared using nonparametric Mann. Whitney U-test. Results： Live birth rate in VP group was 38.55%, significantly higher than that in the IMP group, which was 30.79% （x^2 = 8.287, P= 0.004）. The clinical intrauterine pregnancy rate and implantation rate in VP group were also significantly higher than those in the IMP group （clinical intrauterine pregnancy rate 47.35% vs. 41.29%, x^2= 4.727, P = 0.030： implantation rate 30.99% vs. 25.26%, x^2=14.546, P 〈 0.001）. Any statistically significant differences in ectopic pregnancy and abortion rates between two groups were not observed. Conclusion： Luteal support with VP had better clinical outcomes for young women undergoing IVF-ET with GnRH-antagonist protocol.

The effect of serum luteinizing hormone on trigger day with a GnRH antagonist protocol in IVF/ICSI treatment

Objective:To investigate the effect of serum luteinizing hormone(LH)on trigger day with a Gonadotrophinreleasing hormone(GnRH)antagonist protocol in patients receiving in vitro fertilization/intracytoplasmic sperm injection(IVF/ICSI)treatment for pregnancy outcomes.Methods:We retrospectively reviewed the medical documents of patients receiving IVF/ICSI with fresh embryo transfers from the Reproductive Medicine Center of Peking University People's Hospital between January 2016 and December 2018.730 patients were included and divided into three groups by their serum LH level determined on trigger day.All patients were categorized into Group A,Group B,and Group C based on LH concentrations<1.0 IU/L,1.0–5.0 IU/L,and from 5.0 to 10.0 IU/L on trigger day during the cycle,respectively.Comparisons were made between the three groups.Results:There was a significant difference in implantation rates between Group A and Group C(24.8%versus 40.1%,respectively,P<0.05).The clinical pregnancy rates(39.3%versus 54.3%,respectively,P=0.078)and live birth rate(LBR)(32.1%versus 46.5%,respectively,P=0.116),though the differences were not significant.Multivariate logistic regression analysis showed that the OR of Group C for clinical pregnancy(OR=1.849,P=0.040)and for LBR(OR=1.915,P=0.034)were significant using Group A as the base level.Conclusions:Our study has demonstrated that patients with higher serum LH levels(5.0–10.0 IU/L)on trigger day in the GnRH antagonist protocol may confer better clinical outcomes than those with lower LH levels(<1.0 IU/L).

Effects of Luteinizing Hormone Supplementation on Ovarian Response and Assisted Reproductive Technology Outcomes in Antagonist In vitro Fertilization/Intracytoplasmic Sperm Injection Cycles: A Meta-analysis

Objective:The study objective was to investigate the effects of luteinizing hormone(LH)supplementation on ovarian response and assisted reproductive technology(ART)outcomes in in vitro fertilization/intracytoplasmic sperm injection cycles with a gonadotropin(Gn)-releasing hormone antagonist protocol.Methods:This is a meta-analysis,and nine published randomized controlled trials(1,685 patients)were included.Continuous data were extracted in the form of mean±standard deviation and population size,whereas dichotomous data were extracted in the form of odds ratio.Results:The total amount of follicle-stimulating hormone(FSH)used,the duration of stimulation(DOS),the number of eggs in MII stage,the total number of formed embryos,the clinical pregnancy rate,and live birth rates were similar between groups,but the estrogen level on the day of human chorionic Gn(hCG)administration was slightly higher in the LH supplementation group.On subgroup analysis,it was reported that the addition of LH could significantly increase estrogen levels on the day of hCG administration in patients older than 35 years,and LH supplementation starting on the day of FSH administration may slightly extend the DOS.Moreover,regardless of the timing of LH supplementation,an increase in estrogen levels was found on the day of hCG administration.Conclusions:LH supplementation of an antagonist protocol increases estrogen levels on the day of hCG administration,but does not increase the number of mature oocytes retrieved,and also fails to improve ART outcomes.

Different Pretreatments before Application of GnRH Antagonist Protocol in Controlled Ovarian Hyperstimulation

Objective To analyze the clinical features and outcome of patients who used different pretreatments before application of gonadotropin-releasing hormone antagonist protocol during in vitro fertilization - embryo transfer （IVF-ET） cycles, and to explore how effective to use the antagonist protocol. Methods A retrospective analysis was performed. All the ET cycles were divided into three groups, group A （n=125） used short acting GnRH agonist before GnRH antagonist treatment, group B （n=113） used short-acting oral contraceptives before GnRH antagonist treatment, group C （n=81） was untreated before GnRH antagonist treatment. All the patients had no tubal fluid, endometrial polyps and no anatomical abnormalities of the uterus, from April 2010 to December 2010. The patient＇s age, dose and duration of gonadotropin （Gn） treatment, the serum LH and E2 levels on the day of hCG injection, the number of oocytes retrieved, the rates of good-quality embryos, the clinical pregnancy rates were compared. At the same time, 261 GnRH agonist long protocol cycles （group D） were selected at the same period as further comparison. Results The patients in group C （32.9 ~ 4.8 years） were significantly older than those in groups A and B （31.6 ___＋3.7 years, 31.2 ___%4.1 years）（P 〈0.05）. The dose and the duration of Gn in group C were significantly lower than those in groups A and B. The serum LH level on the day of hCG injection in group A and group B was significantly lower than that in group C （P 〈0.05）, especially in group A. The endometrium was the thinnest in group B. There were no significant differences in the fertilization rates and the good-quality embryosrates among them. The clinical pregnancy rate of group B decreased significantly compared with groups A and C （P〈0. 05）. The clinical pregnancy rate of group C was the highest among them. There was no significant difference of clinical pregnancy rates between group C and group D （37% vs 40.2%,P〉0.05）. However, the dose （19.8 ±6.6 ampoule vs 26.4 ±8.1 ampoule） and the duration （9.0± 1.6 d vs 11.6±2.5 d） of Gn treatment in group C were decreased significantly than those in group D, P〈0.05. Conclusion The short acting GnRH agonist used before GnRH antagonist treatment during IVF-ET cycles failed to improve the pregnancy rates, the use of short-acting oral contraceptives before GnRH antagonist treatment makes the pregnancy rates decrease significantly, but untreated before GnRH antagonist protocol can get a better clinical outcome compared with agonist long protocol Untreated GnRH anagonist protocol is the best GnRH anagonist protocol.