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

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Effect of GnRH agonist alone or combined with different low-dose hCG on cumulative live birth rate for high responders in GnRH antagonist cycles: a retrospective study.

BACKGROUND: There is insufficient evidence regarding the impact of dual trigger on oocyte maturity and reproductive outcomes in high responders. Thus, we aimed to explore the effect of gonadotropin-releasing hormone agonist (GnRHa) trigger alone or combined with different low-dose human chorionic gonadotropin (hCG) regimens on rates of oocyte maturation and cumulative live birth in high responders who underwent a freeze-all strategy in GnRH antagonist cycles. METHODS: A total of 1343 cycles were divided into three groups according to different trigger protocols: group A received GnRHa 0.2 mg (n = 577), group B received GnRHa 0.2 mg and hCG 1000 IU (n = 403), and group C received GnRHa 0.2 mg and hCG 2000 IU (n = 363). RESULTS: There were no significant differences in age, body mass index, and rates of oocyte maturation, fertilization, available embryo, and top-quality embryo among the groups. However, the incidence of moderate to severe ovarian hyperstimulation syndrome (OHSS) was significantly different among the three groups (0% in group A, 1.49% in group B, and 1.38% in group C). For the first frozen embryo transfer (FET) cycle, there were no significant differences in the number of transferred embryos and rates of implantation, clinical pregnancy, live birth, and early miscarriage among the three groups. Additionally, the cumulative ongoing pregnancy rate and cumulative live birth rate were not significantly different among the three groups. Similarly, there were no significant differences in gestational age, birth weight, birth height, and the proportion of low birth weight among subgroups stratified by singleton or twin. CONCLUSIONS: GnRHa trigger combined with low-dose hCG (1000 IU or 2000 IU) did not improve oocyte maturity and embryo quality and was still associated with an increased risk of moderate to severe OHSS. Therefore, for high responders treated with the freeze-all strategy, the single GnRHa trigger is recommended for final oocyte maturation, which can prevent the occurrence of moderate to severe OHSS and obtain satisfactory pregnancy and neonatal outcomes in subsequent FET cycles.

Ovarian Hyperstimulation Syndrome after GnRH Agonist Triggering and Freeze-All Protocol? Never Not, Hardly Ever: A Systematic Review of Case Reports.

INTRODUCTION: Ovarian hyperstimulation syndrome (OHSS) is a severe complication associated with controlled ovarian stimulation (COS). GnRH agonist (GnRH-a) triggering is considered an efficient strategy to prevent OHSS in the high-risk patient. METHODS: We performed a review of 11 cases of early and severe OHSS following GnRH-a triggering and freeze-all protocol. Electronic databases were searched from inception of each database until October 2021, to identify case reports and case series that reported OHSS after GnRH-a triggering and freeze-all approach describing patient demographics, COS protocol, and patient outcomes. RESULTS: From the literature review, it is possible to suggest that (1) following GnRH-a triggering, the risk of early and severe OHSS is not totally cancelled; (2) despite it is not possible to predict the event, polycystic ovary syndrome is the most common risk factor; (3) the use of GnRH antagonist starting from the day of PU may represent a valid strategy for preventing OHSS in women with high-risk profile; (4) following the unexpected onset of OHSS, measuring serum levels of human chorionic gonadotropin (hCG) is helpful to exclude an inadvertent exogenous administration or a pregnancy. CONCLUSION: The statement that OHSS risk is eliminated when GnRH-a triggering, a freeze-all strategy, and no hCG in the luteal phase may generate the idea that this event cannot occur. Although rare, these cases have been observed in a relatively short period of time.

How frequent is severe ovarian hyperstimulation syndrome after GnRH agonist triggering in high-risk women? A systematic review and meta-analysis.

The aim of the present systematic review and meta-analysis was to assess the incidence of severe ovarian hyperstimulation syndrome (OHSS) after triggering of final oocyte maturation with gonadotrophin releasing hormone agonist (GnRHa) in high-risk women. The pooled incidence of severe OHSS in high-risk women who did not receive any form of luteal phase support was 0% (95% CI 0.0 to 0.0, I2 = 0%, random-effects model, 14 data sets, 983 women). The pooled incidence of severe OHSS in high-risk women in whom HCG was added to standard luteal phase support was 1% (95% CI 0.0 to 2.0, I2 = 27.02%, random-effects model, 10 data sets, 707 women). The incidence of severe OHSS in high-risk women triggered by a combination of GnRHa and HCG (dual triggering), who received standard luteal phase support, was 1% (95% CI 0.0 to 3.0, one study, 182 women). The incidence of severe OHSS in high-risk women, is not eliminated when HCG is administered either concomitantly with GnRHa (dual triggering), during the luteal phase after GnRHa triggering, or both. On the contrary, it is eliminated when no luteal support is administered.

The effectiveness and safety of in vitro maturation of oocytes versus in vitro fertilization in women with a high antral follicle count.

STUDY QUESTION: What is the effectiveness and safety of IVM compared with IVF for the treatment of women with high antral follicle count (AFC)? SUMMARY ANSWER: In women with high AFC undergoing assisted reproductive technique (ART), IVM is an effective alternative compared with IVF, while it eliminates the risk of ovarian hyperstimulation syndrome (OHSS). WHAT IS KNOWN ALREADY: IVM is postulated to be an alternative to conventional IVF to avoid OHSS. It has particular potential in women with high AFC who are known to be at increased risk of OHSS. To date, IVM and IVF have only been compared in small cohort studies. STUDY DESIGN, SIZE AND DURATION: We performed a retrospective cohort study including 919 women, of whom 608 underwent IVM and 311 IVF. The treatments were conducted at IVFMD, My Duc Hospital, Ho Chi Minh, Vietnam, from July 2015 to December 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied infertile women aged 18-38 years with an indication for ART and with an AFC ≥24. Women received either IVM or IVF treatment depending on patient's or physician's preference. In IVM cycles, women received 3 days of FSH 100 IU/day followed by hCG 10 000 IU. In IVF cycles, women underwent a gonadotropin-releasing hormone antagonist protocol and were triggered with hCG 6500 IU. Outcome measures were live birth rate (LBR) after first embryo transfer and cumulative LBR after one complete cycle, defined as the chance of having live birth after all fresh and frozen transfers of embryos derived from one IVM/IVF cycle. We also report on clinical pregnancy, miscarriage, multiple pregnancy and OHSS. MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics including age and BMI were comparable between groups. In the IVM group (608 started cycles), there were 511 fresh and 167 frozen transfers. In the IVF group (311 started cycles), there were 209 fresh and 185 frozen transfers. The number of mature oocytes, embryos, good embryos and frozen embryos was significantly lower in the IVM compared with the IVF group. LBRs after the first transfer were 222/608 (36.5%) versus 127/311 (40.8%) (adjusted odds ratio [OR], 0.74; 95% confidence interval [CI], 0.42-1.30). Cumulative LBRs after one completed cycle were 239/608 (39.3%) versus 155/311 (49.8%) (adjusted OR, 0.52; 95% CI, 0.30-0.89). OHSS did not occur in the IVM group versus 11/311 (3.5%) in the IVF group. LIMITATIONS AND REASONS FOR CAUTION: Our study is limited by its non-randomized design. Randomized clinical trials are required to precisely compare the outcomes after IVM versus IVF. WIDER IMPLICATIONS OF THE FINDINGS: In infertile women with a high AFC, IVM is a feasible alternative to standard IVF that markedly reduces OHSS and is potentially more patient friendly and cost effective. STUDY FUNDING/COMPETING INTEREST(S): No external funding was sought to support this work. B.W.M. is supported by a National Health Medical Research Council Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck and Guerbet. All other authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: NA.

The effect of clomiphene citrate and human chorionic gonadotropin on the expression of CatSper1, CatSper2, LHCGR, and SF1 genes, as well as the structural changes in testicular tissue of adult rats.

The purpose of this study was to investigate the effect of clomiphene citrate and human chorionic gonadotropin (HCG) on the structural changes, as well as the evaluation of the expression of cation channel sperm-associated protein 1 (CatSper1), cation channel sperm-associated protein 2 (CatSper2), luteinizing hormone/choriogonadotropin receptor (LHCGR), and steroidogenic factor 1 (SF1) genes in testicular tissue of rats. All rats divided into five groups as follows; G1 as the control group that received normal saline, G2 received olive oil, G3 received 100 IU/kg HCG, G4 received 5 mg/kg clomiphene citrate, and G5 received 5 mg/kg clomiphene citrate and 100 IU/kg HCG. At the end of the experiment period, Day 56, blood samples were taken and the serum was isolated. Then, histomorphometric analysis, hormonal assess, and real-time polymerase chain reaction to measure the expression of CatSper1, CatSper2, LHCGR, and SF1 genes were performed. The results showed that the concentrations of testosterone, follicle-stimulating hormone, and luteinizing hormone were decreased in the G4 group, whereas these parameters were increased in the G3 group. A comparison of the sperm quality indicated a significant reduction in the quality of sperm cells in the G4 group compared with other groups. The quality of sperm was significantly enhanced in the G3 and G5 groups in comparison with the G1 group. Also, our findings demonstrated that the expression of CatSper1, CatSper2, LHCGR, and SF1 genes were significantly elevated in the G3 group when compared with other experimental groups. According to the obtained results, it seems that clomiphene citrate reduces the process of spermatogenesis and the detrimental impacts of this compound would be neutralized by the administration of HCG.

Risk of ovarian torsion is reduced in GnRH agonist triggered freeze-all cycles: a retrospective cohort study.

Ovarian torsion (OT) in IVF is rare, however, the consequences are significant, which include ovariotomy. In the present study, it was aimed for the first time to compare the incidence of OT between hCG triggered cycles with ICSI and fresh transfer and GnRH-agonist triggered cycles with the ICSI-freeze-all and frozen embryo transfer (FET). In total, 15,577 ICSI cycles performed between 2001 and 2016 were categorised into two groups (Group 1, n: 9978): cycles with controlled ovarian stimulation (COS) and hCG-triggered (Group 2, n: 5599) and COS, with GnRH-agonist only triggered and freeze-all. Thirteen patients (0.13%) were diagnosed with OT and corrected by laparoscopy (12) and laparotomy (1) in Group 1. One patient (0.018%) was diagnosed with OT and corrected by laparotomy in Group 2 (Group 1 vs. Group 2, p = .049). The incidence of severe ovarian hyperstimulation syndrome (OHSS) was 2.4% in Group 1 and 0.05% in Group 2 (p < .001). The use of freeze-all with GnRH agonist trigger in ART significantly reduced the incidence of OT and concomitantly OHSS, with no effect on the reproductive outcome. Impact Statement What is already known on this subject? Adnexal ovarian torsion (OT) is a well-known gynaecological event that constitutes a surgical emergency. Assisted reproduction technologies (ART) may result in ovarian conditions that predispose patients to ovarian hyperstimulation syndrome (OHSS) and torsion. What the results of this study add? The combined use of GnRH agonist trigger for final oocyte maturation after OS with freeze-all and frozen embryo transfer (FET) significantly reduces the incidence of OT, as well as OHSS. What the implications are of these findings for clinical practice and/or further research? The treatment strategy of GnRH agonist trigger with freeze-all significantly reduces the risks of adverse complications.

The effect of acupuncture on anti-mullerian hormone and assisted reproduction outcome in Polycystic Ovary Syndrome patients undergoing in vitro fertilization.

OBJECTIVES: To evaluate the effect of acupuncture at follicular phase of menstrual cycle on anti-mullerian hormone levels in patients with polycystic ovary syndrome undergoing in-vitro fertilisation and to see its impact on assisted reproduction outcome. METHODS: The prospective, randomised, controlled trial was conducted from March 2011 to July 2012 at the Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. In the center, the patients randomly chose odd or pair number, the patients with odd numbers classified as an interventional group and the patients with paired numbers as non-interventional group. Infertile polycystic ovary syndrome patients aged 20-40 years were enrolled from the hospital's Assisted Reproduction Centre from March 2011 to July 2012. The patients were randomised into two groups, with one receiving follicular phase acupuncture for 30-40 minutes according to the principles of traditional Chinese medicine, and the other group not getting subjected to acupuncture. Serum and follicular anti-mullerian hormone concentration were determined. RESULTS: Of the 102 patients, 33(32.4%) were in the intervention group, while 69(67.6%) were in the control group. There was no significant effect of acupuncture on serum and follicular fluid anti-mullerian hormone levels in the intervention group compared to the control group (p>0.05). Serum progesterone and estradiol levels on the day of giving human chorionic gonadotrophin, as well as serum progesterone and estradiol levels on the day of oocytes pick-up were significantly lower in the intervention group (p<0.05). Number of embryos transferred, clinical and ongoing pregnancy rates were significantly higher in the intervention group (p<0.05) with a significant decrease of ovarian hyper-stimulation syndrome rate in the intervention group (p<0.05). CONCLUSIONS: Follicular phase acupuncture was found to have a positive effect for polycystic ovary syndrome patients undergoing in-vitro fertilisation, but it had no effect on anti mullerian hormone concentrations.

Day two post retrieval 1500 IUI hCG bolus, progesterone-free luteal support post GnRH agonist trigger - a proof of concept study.

Small dose of hCG (1500 IU) on the day of oocyte retrieval, followed by daily progesterone administration, is currently the preferred way to secure adequate luteal support following GnRH agonist trigger. In the current proof-of-concept study, we explored the possibility that a bolus of 1500 IU hCG, given two days after oocyte retrieval, may be sufficient to sustain adequate luteal support without additional progesterone treatment. From February 2015 to August 2016, we obtained 44 pregnancies following GnRHa trigger followed by day 2 hCG (1500 IU) support only (study group). Data from these 44 cycles were compared with the latest 44 pregnancies obtained following hCG (6500 IU) trigger followed by conventional progesterone luteal documented (control group). Mean progesterone levels (14 days postoocyte retrieval) in the study and control groups were 197 nmol/l and 173 nmol/l, respectively (NS). Mean E2 levels (14 days post oocyte retrieval) in the study group was 6937 pmol/l, significantly higher (p < .001) than in the control group (3.276 pmol/l). We conclude that bolus of 1500 IU hCG, administered 2 days after retrieval, can provide excellent support, without the need to further supplement with progesterone.

A randomized controlled trial comparing the efficacy and safety of two HMG preparations gaining their LH bioactivity from different HCG sources.

In this prospective, controlled, randomized, multicentre, non-inferiority study, efficacy and safety of two HMG preparations (Menopur®- Ferring and Meriofert®- IBSA Institut Biochimique SA) for ovarian stimulation were compared (270 women undergoing IVF aged between 18 and 39 years; BMI 30 kg/m2 or less; less than three prior completed assisted reproduction technique cycles). A standard long down-regulation with gonadotrophin-releasing hormone agonist protocol, with HCG triggering was used; primary end-point was total number of oocytes retrieved; attention was paid toovarian hyperstimulation syndrome (OHSS). No statistically significant differences between the treatment groups were reported for most of the clinically significant end-points, including embryo quality, fertilization rate, implantation rate, ongoing pregnancy rate and live birth rate. Total number of oocytes retrieved was higher in the new HMG group compared with the reference (11.6 ± 6.6 and 9.7 ± 5.9, respectively, with a 95% CI of the difference equal +0.43 to +3.43). Increased number of oocytes was obtained through a shorter stimulation, but HMG units per oocyte retrieved were equivalent. The safety profile of the products for frequency of ovarian hyperstimulation syndrome was the same. This study showed that the new HMG preparation is a viable alternative for conducting ovarian stimulation in IVF cycles.

Risk of endometrial cancer in women treated with ovary-stimulating drugs for subfertility.

BACKGROUND: Medical treatment for subfertility principally involves the use of ovary-stimulating agents, including selective oestrogen receptor modulators (SERMs), such as clomiphene citrate, gonadotropins, gonadotropin-releasing hormone (GnRH) agonists and antagonists, as well as human chorionic gonadotropin. Ovary-stimulating drugs may act directly or indirectly upon the endometrium (lining of the womb). Nulliparity and some causes of subfertility are recognized as risk factors for endometrial cancer. OBJECTIVES: To evaluate the association between the use of ovary-stimulating drugs for the treatment of subfertility and the risk of endometrial cancer. SEARCH METHODS: A search was performed in CENTRAL, MEDLINE (Ovid) and Embase (Ovid) databases up to July 2016, using a predefined search algorithm. A search in OpenGrey, ProQuest, ClinicalTrials.gov, ZETOC and reports of major conferences was also performed. We did not impose language and publication status restrictions. SELECTION CRITERIA: Cohort and case-control studies reporting on the association between endometrial cancer and exposure to ovary-stimulating drugs for subfertility in adult women were deemed eligible. DATA COLLECTION AND ANALYSIS: Study characteristics and findings were extracted by review authors independently working in pairs. Inconsistency between studies was quantified by estimating I2. Random-effects (RE) models were used to calculate pooled effect estimates. Separate analyses were performed, comparing treated subfertile women versus general population and/or unexposed subfertile women, to address the superimposition of subfertility as an independent risk factor for endometrial cancer. MAIN RESULTS: Nineteen studies were eligible for inclusion (1,937,880 participants). Overall, the quality of evidence was very low, due to serious risk of bias and indirectness (non-randomised studies (NRS), which was reflected on the GRADE assessment.Six eligible studies, including subfertile women, without a general population control group, found that exposure to any ovary-stimulating drug was not associated with an increased risk of endometrial cancer (RR 0.96, 95% CI 0.67 to 1.37; 156,774 participants; very low quality evidence). Fifteen eligible studies, using a general population as the control group, found an increased risk after exposure to any ovary-stimulating drug (RR 1.75, 95% CI 1.18 to 2.61; 1,762,829 participants; very low quality evidence).Five eligible studies, confined to subfertile women (92,849 participants), reported on exposure to clomiphene citrate; the pooled studies indicated a positive association ( RR 1.32; 95% CI 1.01 to 1.71; 88,618 participants; very low quality evidence), although only at high dosage (RR 1.69, 95% CI 1.07 to 2.68; two studies; 12,073 participants) and at a high number of cycles (RR 1.69, 95% CI 1.16 to 2.47; three studies; 13,757 participants). Four studies found an increased risk of endometrial cancer in subfertile women who required clomiphene citrate compared to a general population control group (RR 1.87, 95% CI 1.00 to 3.48; four studies, 19,614 participants; very low quality evidence). These data do not tell us whether the association is due to the underlying conditions requiring clomiphene or the treatment itself.Using unexposed subfertile women as controls, exposure to gonadotropins was associated with an increased risk of endometrial cancer (RR 1.55, 95% CI 1.03 to 2.34; four studies; 17,769 participants; very low quality evidence). The respective analysis of two studies (1595 participants) versus the general population found no difference in risk (RR 2.12, 95% CI 0.79 to 5.64: very low quality evidence).Exposure to a combination of clomiphene citrate and gonadotropins, compared to unexposed subfertile women, produced no difference in risk of endometrial cancer (RR 1.18, 95% CI 0.57 to 2.44; two studies; 6345 participants; very low quality evidence). However, when compared to the general population, an increased risk was found , suggesting that the key factor might be subfertility, rather than treatment (RR 2.99, 95% CI 1.53 to 5.86; three studies; 7789 participants; very low quality evidence). AUTHORS' CONCLUSIONS: The synthesis of the currently available evidence does not allow us to draw robust conclusions, due to the very low quality of evidence. It seems that exposure to clomiphene citrate as an ovary-stimulating drug in subfertile women is associated with increased risk of endometrial cancer, especially at doses greater than 2000 mg and high (more than 7) number of cycles. This may largely be due to underlying risk factors in women who need treatment with clomiphene citrate, such as polycystic ovary syndrome, rather than exposure to the drug itself. The evidence regarding exposure to gonadotropins was inconclusive.

Severe ovarian hyperstimulation syndrome after combined GnRH-agonist and low-dose human chorionic gonadotropin trigger in a patient with a single kidney.

Ovarian hyperstimulation syndrome (OHSS) following gonadotropin-releasing hormone agonist (GnRH-a) trigger is rare. Here, we report a case of severe OHSS after combined GnRH-a and low-dose human chorionic gonadotropin (hCG) trigger in a patient with a single kidney. The patient is a 32-year-old women with a two-year history of infertility. The patient's history was significant for a single kidney, that is, she had donated a kidney to a family member three years ago. The patient underwent controlled ovarian stimulation (COS) for in vitro fertilization (IVF) and received a combined 2 mg GnRH-a and 1500 IU hCG ovulatory trigger. Estradiol (E2) levels on the day of and after the trigger were 3800 pg/mL and 4001 pg/mL, respectively. Four days after the trigger, the patient began experiencing nausea, abdominal distention and dyspnea, and her blood testing revealed hemoconcentration (hemoglobin: 16.9 g/dL; hematocrit: 51.0%) and an elevated creatinine level (1.16 mg/dL). Fresh embryo transfer was deferred. The patient was admitted to the hospital for fluid monitoring and prophylactic anticoagulation. Following inpatient management, her hemoglobin, hematocrit and creatinine levels normalized. The current report highlights that the systemic effects of OHSS can be accentuated in patients with preexisting renal disease or a single kidney.

Elevated progesterone and its impact on birth weight after fresh embryo transfers.

PURPOSE: The purpose of the study was to examine the association between serum progesterone levels on the day of hCG administration and birth weight among singleton live births after fresh embryo transfer. METHODS: This study was conducted as a retrospective cohort database analysis on patients who underwent IVF treatment cycles from January 2004 to April 2012. The study was performed at a University affiliated private infertility practice. All cycles that had achieved a singleton live birth after fresh embryo transfer and for which progesterone was measured on the day of hCG administration were examined. Generalized linear models were used to calculate mean birth weight and z-scores. RESULTS: We analyzed 817 fresh IVF embryo transfers in which birth weight, gestational age, and progesterone (ng/mL) level on day of hCG administration were documented. While there was a decrease in birth weight as progesterone quartile [≤0.54; >0.54 to ≤0.81; >0.81 to ≤1.17; >1.17 ng/mL] increased, the difference in mean birth weights among the four quartiles was not statistically significant (p = 0.11) after adjusting for maternal age and peak estradiol levels. When dichotomizing based on a serum progesterone considered clinically elevated, cycles with progesterone >2.0 ng/mL had a significantly lower mean singleton birth weight (2860 g (95% CI 2642 g, 3079 g)) compared to cycles with progesterone ≤2.0 ng/mL (3167 g (95% CI 3122 g, 3211 g) p = 0.007)) after adjusting for maternal age and estradiol. CONCLUSION: We demonstrated that caution should be exercised when performing fresh embryo transfers with elevated progesterone levels and in particular with levels (>2.0 ng/mL) as this may lead to lower birth weight.

Ovarian hyperstimulation syndrome following GnRH agonist trigger-think ectopic.

PURPOSE: This study aims to report a case of ovarian hyperstimulation syndrome (OHSS) following GnRH agonist trigger for final follicular maturation. METHODS: This study is a retrospective chart review. RESULTS: We report the first case of OHSS following GnRH agonist trigger for final follicular maturation and freeze-all, masking extrauterine pregnancy (EUP). The present case report elucidates the feasibility of stimulating and recruiting ovarian follicles yielding mature oocytes during early pregnancy and the ability of GnRH agonist to trigger final follicular maturation during pregnancy, in the presence of high progesterone and hCG levels. CONCLUSIONS: Since OHSS almost always develops after hCG administration or in early pregnancy, its occurrence following GnRH agonist trigger should alert physician to search for either an inadvertent administration of exogenous hCG, or the endogenous secretion of hCG by pregnancy, e.g. EUP, or as part of a paraneoplastic syndrome.

Human Chorionic Gonadotropin Has Anti-Inflammatory Effects at the Maternal-Fetal Interface and Prevents Endotoxin-Induced Preterm Birth, but Causes Dystocia and Fetal Compromise in Mice.

Human chorionic gonadotropin (hCG) is implicated in the maintenance of uterine quiescence by down-regulating myometrial gap junctions during pregnancy, and it was considered as a strategy to prevent preterm birth after the occurrence of preterm labor. However, the effect of hCG on innate and adaptive immune cells implicated in parturition is poorly understood. Herein, we investigated the immune effects of hCG at the maternal-fetal interface during late gestation, and whether this hormone can safely prevent endotoxin-induced preterm birth. Using immunophenotyping, we demonstrated that hCG has immune effects at the maternal-fetal interface (decidual tissues) by: 1) increasing the proportion of regulatory T cells; 2) reducing the proportion of macrophages and neutrophils; 3) inducing an M1 → M2 macrophage polarization; and 4) increasing the proportion of T helper 17 cells. Next, ELISAs were used to determine whether the local immune changes were associated with systemic concentrations of progesterone, estradiol, and/or cytokines (IFNgamma, IL1beta, IL2, IL4, IL5, IL6, IL10, IL12p70, KC/GRO, and TNFalpha). Plasma concentrations of IL1beta, but not progesterone, estradiol, or any other cytokine, were increased following hCG administration. Pretreatment with hCG prevented endotoxin-induced preterm birth by 44%, proving the effectiveness of this hormone as an anti-inflammatory agent. However, hCG administration alone caused dystocia and fetal compromise, as proven by Doppler ultrasound. These results provide insight into the mechanisms whereby hCG induces an anti-inflammatory microenvironment at the maternal-fetal interface during late gestation, and demonstrate its effectiveness in preventing preterm labor/birth. However, the deleterious effects of this hormone on mothers and fetuses warrant caution.

The Effectiveness of hCG and LHRH in Boys with Cryptorchidism: A Meta-Analysis of Randomized Controlled Trials.

To systematically review the efficacy of hCG and LHRH on testicular descent in boys with cryptorchidism, comprehensive search was performed to identify randomized controlled trials (RCTs) in PubMed, EMBASE, the Cochrane Library, Wanfang Database, and China National Knowledge Infrastructure (CNKI) up to March 2014. Outcomes included testicular complete descent rate (TCDR) and cure rate of patients. Study quality was evaluated using the Jadad scale. Meta-analysis was performed using Review Manager software. Finally, 13 studies were included. hCG and LHRH increased TCDR comparing with control group. The success rate of hCG and LHRH was 24 and 19%, respectively. Further, hCG and LHRH had significant effect on bilateral cryptorchidism, but not on unilateral cryptorchidism. All side effects were transitory and not severe, but if they have long-term harms were not clear. hCG and LHRH can effectively increase TCDR and there was no significant difference between them. However, the hormones cannot be recommended for everyone because of their low success rates and potential long-term harms. Further studies are needed to determine the efficacy of hormonal treatment for subtypes of cryptorchidism.

Late-onset hypogonadism: the advantages of treatment with human chorionic gonadotropin rather than testosterone.

The traditional pharmacological treatment of patients with late onset hypogonadism (LOH) is represented by different formulations of testosterone (T) or alternatively by the extractive human chorionic gonadotropin (HCG). The hormone replacement treatment (HRT) is associated with the potential increase of hematocrit, serum concentrations of prostate-specific antigen (PSA) and prostate volume. Moreover, the gynecomastia represent a condition frequently associated with HRT. Recent evidences showed the role of leydig cells in the 25-hydroxylation of vitamin D and the elevated frequency of hypovitaminosis D among LOH patients. Finally, another important aspect of LOH is represented by the frequency of secondary infertility due to age or to traditional HRT. This study evaluated 40 LOH patients treated for 6 months with extractive HCG (n = 10 patients) and three different formulations of T: transdermal (n = 10 patients), undecaonate (n = 10 patients) and enantate (n = 10 patients). Hormonal, anthropometric, metabolic and sperm parameters were evaluated and compared. Moreover, the main safety parameters and the results of the main questionnaires were evaluated. After treatment, HCG group showed serum concentrations of 25-OH-vitamin D significantly higher (p < 0.05) and serum concentrations of oestrogens significantly lower (p < 0.05) compared with other groups. Moreover, they showed a mean value of hematocrit, PSA and prostate volume significantly lower (p < 0.05) compared with other groups. Finally, all the groups treated with T showed a significant reduction (p < 0.05) of sperm density and of percentage of spermatozoa with progressive motility compared with HCG group.

Decreased expression of aquaporin 2 is associated with impaired endometrial receptivity in controlled ovarian stimulation.

Recently, there has been evidence of decreased implantation rates with in vitro fertilisation and embryo transfer due to controlled ovarian stimulation (COS). The aim of this study was to investigate the effect of COS on embryo implantation and the role of aquaporin 2 (AQP2). We recruited eight patients who underwent COS and 40 matched controls. Endometrial samples were collected on Day 4~8 after injection of human chorionic gonadotrophin in the COS group and in the mid-secretory phase in the control group. Human endometrial morphological changes after COS were examined and expression of AQP2, leukaemia inhibitory factor (LIF) and integrin B3 (ITGB3) were determined by quantitative polymerase chain reaction, western blotting and immunohistochemistry in human endometrium and Ishikawa cells. Attachment rates were obtained using the embryo attachment test. The results showed that endometrial epithelial cells from the COS group were disrupted and lacked pinopodes. Messenger RNA and protein levels of AQP2, LIF and ITGB3 decreased in endometrial samples from the COS group. Knockdown of AQP2 resulted in reduced expression of LIF and ITGB3 and reduced embryo attachment rates. In conclusion, impaired endometrial receptivity in patients who underwent COS is correlated with a decreased expression of AQP2.

Human chorionic gonadotrophin priming for fertility treatment with in vitro maturation.

BACKGROUND: In vitro maturation (IVM) is a fertility treatment that involves the transvaginal retrieval of immature oocytes, and their subsequent maturation and fertilisation. Although the live birth rate is lower than conventional in vitro fertilisation (IVF) with ovarian stimulation, it is a useful treatment, as it avoids the risk of ovarian hyperstimulation syndrome (OHSS). Women with polycystic ovaries (PCO) or polycystic ovarian syndrome (PCOS) are at an increased risk of OHSS. Thus, IVM may be a more useful treatment in this patient group.Strategies to maximise the maturation rates of the immature oocytes are important. This review focuses on the administration of human chorionic gonadotrophin (hCG) prior to immature oocyte retrieval. OBJECTIVES: To determine the effectiveness and safety of hCG priming in subfertile women who are undergoing IVM treatment in the context of assisted reproduction. SEARCH METHODS: We searched the following electronic databases up to 29 August 2016: Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL. We also searched the trial registries ClinicalTrials.gov and WHO ICTPR to identify ongoing and registered trials. We sought recently published papers not yet indexed in the major databases, and reviewed the reference lists of reviews and retrieved studies as sources of potentially relevant studies. There were no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared hCG priming with placebo or no priming in women undergoing IVM. We also included RCTs that compared different doses of hCG, or the timing of oocyte retrieval. The primary outcomes were live birth rate and miscarriage rate per woman randomised. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, and with a third author, assessed risk of bias and extracted data. We contacted the original authors where data were missing. For dichotomous outcomes, we used the Mantel-Haenszel method to calculate odds ratios (OR). For continuous outcomes, we calculated the mean differences (MD) between treatment groups. We assessed statistical heterogeneity using the I² statistic. We assessed the overall quality of the evidence using GRADE methods. MAIN RESULTS: We included four studies, with a total of 522 women, in the review. One of these studies did not report outcomes per woman randomised, and so was not included in formal analysis. Three studies investigated 10,000 units hCG priming compared to no priming. One study investigated 20,000 units hCG compared to 10,000 units hCG priming. Three studies only included women with PCOS (N = 122), while this was an exclusion criteria in the fourth study (N = 400).We rated all four studies as having an unclear risk of bias in more than one of the seven domains assessed. The quality of the evidence was low, the main limitations being lack of blinding and imprecision.When 10,000 units hCG priming was compared to no priming, we found no evidence of a difference in the live birth rates per woman randomised (OR 0.65, 95% confidence intervals (CI) 0.24 to 1.74; one RCT; N = 82; low quality evidence); miscarriage rate (OR 0.60, 95% CI 0.21 to 1.72; two RCTs; N = 282; I² statistic = 21%; low quality evidence), or clinical pregnancy rate (OR 0.52, 95% CI 0.26 to 1.03; two RCTs, N = 282, I² statistic = 0%, low quality evidence). Though inconclusive, our findings suggested that hCG may be associated with a reduction in clinical pregnancy rates; 22% of women who received no priming achieved pregnancy, while between 7% and 23% of women who received hCG priming did so.The study comparing 20,000 units hCG with 10,000 units hCG did not report sufficient data to enable us to calculate odds ratios.No studies reported on adverse events (other than miscarriage) or drug reactions. AUTHORS' CONCLUSIONS: This review found no conclusive evidence that hCG priming had an effect on live birth, pregnancy, or miscarriage rates in IVM. There was low quality evidence that suggested that hCG priming may reduce clinical pregnancy rates, however, these findings were limited by the small number of data included. As no data were available on adverse events (other than miscarriage) or on drug reactions, we could not adequately assess the safety of hCG priming. We need further evidence from well-designed RCTs before we can come to definitive conclusions about the role of hCG priming, and the optimal dose and timing.