Low-dose hCG Research Articles

A combination of GnRH agonist and low dose hCG for triggering ovulation in oocytes donors is associated with smaller ovarian size and lower estradiol levels following oocyte retrieval

To compare the effect of triggering ovulation with HCG, GnRh analog(GnRh-a) or a combination of GnRh-a and low-dose HCG on cycle outcome and ovarian size and estrodiol(E2) levels post-retrieval in oocyte donors(DE)

Effect of low dose hCG support on GnRH-agonist triggered IVF/ICSI cycles

To assess the reproductive outcome (pregnancy rate and OHSS rate) in high responders after triggering final oocyte maturation with a combination of GnRH-agonist and hCG (500 to 1,000 IU) as compared with those triggered with GnRH-agonist alone and those treated with long protocol. Controlled interventional study. In high responders, three groups of ovulation induction cycles were allocated as below: (30 cycles for each group) 1. GnRH-antagonist protocol, triggered with a combination of GnRH-agonist and hCG (500 to 1,000 IU, depending on the peak Estradiol level) for final oocyte maturation 2. GnRH-antagonist protocol, triggered with GnRH-agonist alone for final oocyte maturation. 3. Long protocol (triggered with 10,000 IU hCG for final oocyte maturation) The clinical pregnancy rate and the rate of ovarian hyperstimulation syndrome (OHSS) were compared among the three groups. No significant differences were seen regarding positive hCG/ET rate, clinical pregnancy rate, and rate of early pregnancy loss between group 1 (GnRH-agonist and hCG dual trigger) and group 3 (long protocol). A tendency of lower pregnancy rate was noted in group 2 (GnRH-agonist trigger alone). There was no OHSS in group 1 (GnRH-agonist and hCG dual trigger) and group 2 (GnRH-agonist trigger alone). For higher responders, dual trigger with a combination of GnRH-agonist and hCG is safe considering the complication of OHSS, and as effective as conventional long protocol regarding the pregnancy outcome.

Dual trigger of oocyte maturation with gonadotropin releasing hormone agonist (GnRHa) and low dose human chorionic gonadotropin (hCG) to optimize conception rates in high responders

Induction of oocyte maturation with GnRHa is effective in prevention of ovarian hyperstimulation syndrome (OHSS). However, our recent data have shown a lower probability of conception in patients triggered with GnRHa whose peak estradiol (E2) is <4000 pg/mL. We evaluated pregnancy rates after dual GnRHa and low dose hCG trigger in high responders with peak E2<4000 pg/mL.

Low-dose human chorionic gonadotropin may improve in vitro fertilization cycle outcomes in patients with low luteinizing hormone levels after gonadotropin-releasing hormone antagonist administration

To evaluate the effect of low levels of endogenous luteinizing hormone (LH) and low-dose human chorionic gonadotropin (hCG) supplementation on in vitro fertilization (IVF) cycle outcomes in a gonadotropin-releasing hormone (GnRH) antagonist protocol. Retrospective study. Military medical center. General in vitro fertilization/embryo transfer (IVF-ET) population. Addition of low-dose urinary hCG to IVF stimulations using a recombinant follicle-stimulating hormone (FSH) and GnRH antagonist protocol. Implantation and live-birth rates. As part of a larger cohort of 239 patients, 42 patients with LH levels ≤ 0.5 mIU/mL were evaluated. In the larger cohort, there were no differences in implantation and pregnancy rates between the recombinant FSH only (n = 113) and the recombinant FSH with low-dose hCG supplementation (n = 126) groups. In the FSH-only group, patients with LH levels ≤ 0.5 mIU/mL had decreased implantation rates (19% vs. 42%) and live-birth rates (25% vs. 54%) as compared with patients with LH levels >0.5 mIU/mL. Low LH patients in the recombinant FSH with low-dose urinary hCG group had statistically significantly higher implantation rates (54% vs. 19%) and live-birth rates (64% vs. 25%) as compared with patients with similar low LH levels in the recombinant FSH-only group. Endogenous LH levels ≤ 0.5 mIU/mL after GnRH antagonist treatment are associated with statistically significantly lower implantation and pregnancy rates in recombinant FSH-only cycles. The addition of low-dose urinary hCG results in improved implantation and live-birth rates in patients with low LH levels.

Comparison of “triggers” using leuprolide acetate alone or in combination with low-dose human chorionic gonadotropin

This retrospective study of fresh autologous blastocyst transfers in high responders compared ongoing pregnancy rates in cycles that followed trigger with GnRH agonist (GnRHa) alone with standard luteal support, GnRHa alone with enhanced luteal support, or GnRHa with concomitant low-dose hCG (dual trigger). Ongoing pregnancy rates were significantly increased with the dual trigger or with enhanced luteal support, whereas the incidence of clinically significant ovarian hyperstimulation syndrome was 0.0% in the groups receiving only GnRHa and 0.5% (1 of 182) in patients receiving GnRHa with concomitant low-dose hCG.

The effect of low dose human chorionic gonadotropin on follicular response and oocyte maturation in PCOS patients undergoing IVF cycles: a randomized clinical trial of efficacy and safety

To compare the efficacy of two regimens of low dose human chorionic gonadotropin (hCG) on follicular response and oocyte maturation in women with polycystic ovarian syndrome (PCOS). Ninety women with PCOS who underwent assisted reproduction were eligible for this controlled, prospective, randomized study. Our trial was performed at Royan Institute Reproductive Research Center over a 24-month period. Ovarian stimulation in all groups was initiated with recombinant FSH, 150 IU daily. The dose and duration of FSH treatment were adjusted by monitoring follicular development with ultrasound and estradiol levels. Patients were randomized using a block randomization technique which assigned them to three groups: group A (control group) continued r-FSH until oocyte retrieval. In group B, r-FSH was reduced to 75 IU once the lead follicle reached 14 mm in mean diameter and low dose hCG (100 IU/day) was initiated. In group C, r-FSH was discontinued and low dose hCG (200 IU/day) was begun when the lead follicle reached 14 mm in mean diameter. The main outcome measure was follicular response and oocyte maturation. As compared to the FSH only group, groups which were given low dose hCG had lower gonadotropin consumption and fewer immature oocytes than the control group. No women in the low dose hCG groups developed severe ovarian hyper-stimulation syndrome. Fertilization, implantation and pregnancy rates were similar in the three groups. A combination of FSH and low dose hCG improved oocyte maturity and preserved outcomes with improved safety and lowered cost.

Ovarian Hyperstimulation Syndrome Prevention Strategies: Reducing the Human Chorionic Gonadotropin Trigger Dose

This article reviews the biological plausibility and evidence for the use of a low triggering dose of human chorionic gonadotropin (hCG) in the prevention of ovarian hyperstimulation syndrome (OHSS). A systematic search of the literature revealed very little published data for or against the use of low-dose hCG in the prevention of OHSS after assisted reproductive technology. We have had success at avoiding OHSS as a result of gentle stimulation and low-dose sliding scale hCG trigger based on estradiol (E₂) levels. We therefore present the biological plausibility for such an approach by reviewing the relationship between OHSS, vascular endothelial growth factor, and hCG; the physiology of hCG; the relationship between risk of OHSS and E₂ at trigger; and the physiology of alternative methods of triggering such as recombinant luteinizing hormone and gonadotropin-releasing hormone agonist. We also present the results of a quasi-experimental before and after study of the sliding scale protocol for hCG trigger dose in in vitro fertilization with or without intracytoplasmic sperm injection cycles.

A prospective randomized study comparing clomiphene citrate supplemented with recombinant FSH or low-dose hCG in ovarian stimulation for intruterine insemination

OBJECTIVE: The aim of this trial is to compare the outcomes of ovarian stimulation for intrauterine insemination (IUI) with clomiphene citrate (CC) supplemented with either recombinant FSH or low-dose hCG.

Cyclooxygenase-2 network as predictive molecular marker for clinical pregnancy in in vitro fertilization

The gene expression of human endometrium on the day of oocyte retrieval of pregnant and nonpregnant patients in a stimulated IVF cycle was compared in two independent groups with different GnRH-antagonist ovarian stimulation protocols. The present data suggest that increased gene expression of cyclooxygenase-2, together with the expression of other molecules in the cyclooxygenase-2 network, on the day of oocyte retrieval in GnRH-antagonist cycles coincides with a lower probability of achieving a clinical pregnancy in this cycle.

Gene expression profile in the endometrium on the day of oocyte retrieval after ovarian stimulation with low-dose hCG in the follicular phase

The past decade has seen growing interest in ovarian stimulation protocols with GnRH antagonists in an effort to reduce the incidence of potential complications, such as cyst formation and ovarian hyperstimulation syndrome, and thus improve the clinical experience for patients. Current assisted reproductive technique programmes also increasingly utilize milder protocols for ovarian stimulation. In a recently published randomized controlled trial, we showed that low-dose hCG can be utilized clinically to replace recombinant FSH (rFSH) during the late follicular phase in a GnRH antagonist protocol. This regimen leads to a significant reduction in rFSH consumption, while the ICSI outcome, in terms of oocyte yield and ongoing pregnancy rate, remains comparable with the control regimen of rFSH plus a GnRH antagonist. In the present study, the influence of the administration of low-dose hCG on the endometrium was assessed. A comparison was made between two protocols for ovarian stimulation with GnRH antagonists, namely the classical protocol with rFSH and the protocol with low-dose hCG in the late follicular phase. We analysed the morphological pattern and gene expression profile of human endometrium on the day of oocyte retrieval. No morphological differences were observed and only a minimal set of 65 differentially expressed probe sets between the treatment groups were identified, enabling a similar efficacy to support implantation.

Low-dose human chorionic gonadotropin versus estradiol/progesterone luteal phase support in gonadotropin-releasing hormone agonist–triggered assisted reproductive technique cycles: understanding a new approach

It remains unclear how GnRH agonist (GnRHa) triggering affects the luteal phase, so we investigated the luteal phase after GnRHa triggering, supported with conventional E(2)/P with or without low-dose hCG. E(2)/P support, compared with low-dose hCG, induced a shorter luteal phase (11.2 ± 1.1 vs. 15.0 ± 1.6 days) and fewer subjective complaints (0 vs. 42%), whereas hCG caused more free fluid accumulation and enlarged ovaries than E(2)/P alone. Steroids and low-dose hCG differentially affected corpus luteum function, ovarian size, free fluid accumulation, and patient comfort.

Progesterone rise on the day of HCG administration (premature luteinization) in IVF: An overdue update

Premature luteinization (PL) refers to a rise in serum progesterone (P) levels on the day of hCG administration. Most studies used an absolute P level on the day of hCG administration as an indicator of PL, and the cutoff level differed from 0.8 to 2 ng/mL. Some authors defined PL as a P/E2 ratio of >1. There is a marked variation in the incidence (13% to 71%), of PL due to discrepancies in definition, population characteristics and/or treatment protocols. The pathogenesis of PL in COH is still poorly understood. Several hypotheses may be considered to explain this phenomenon: elevation of follicular LH levels, serum accumulation of HCG from HMG, increased LH receptor sensitivity of the granulosa cells to FSH, or poor ovarian response with increased LH sensitivity. The consequences of this premature elevation of serum P on IVF outcome remain controversial. Attempts to prevent COH include: use of Low-dose hCG alone in the late COH stages, flexible antagonist protocol, use of mifepristone, aspiration of a single leading follicle, hCG administration when the levels of serum P exceeded 1.0 ng/mL.

Early hCG addition to rFSH for ovarian stimulation in IVF provides better results and the cDNA copies of the hCG receptor may be an indicator of successful stimulation

A simple, safe and cost-effective treatment protocol in ovarian stimulation is of great importance in IVF practice, especially in the case of previous unsuccessful attempts. hCG has been used as a substitute of LH because of the degree of homology between the two hormones. The main aim of this prospective randomized study was to determine, for the first time, whether low dose hCG added to rFSH for ovarian stimulation could produce better results compared to the addition of rLH in women entering IVF-ET, especially in those women that had previous IVF failures. An additional aim was to find an indicator that would allow us to follow-up ovarian stimulation and, possibly, modify it in order to achieve a better IVF outcome; and that indicator may be the cDNA copies of the LH/hCG receptor. Group A patients (n = 58) were administered hCG and Group B rLH (n = 56) in addition to rFSH in the first days of ovarian stimulation. The number of follicles and oocytes and, most importantly, implantation and pregnancy rates were shown to be statistically significantly higher in the hCG group. This study has also determined, for the first time to our best knowledge, m-RNA for LH/hCG receptors in the lymphocytes of peripheral blood 40 h before ovum pick-up. cDNA levels of the hCG receptor after ovarian stimulation were significantly higher among women receiving hCG compared to those receiving LH. In addition, higher levels were encountered among women with pregnancy compared to those without, although this was not statistically significant due to the small number of pregnancies. It seems that hCG permits a highly effective and more stable occupancy of rLH/hCG receptors and gives more follicles and more oocytes. The determination of cDNA copies could be, in the future, a marker during ovulation induction protocols and of course a predictor for the outcome of ART in the special subgroup of patients with previous failures.

Can 200 IU of hCG replace recombinant FSH in the late follicular phase in a GnRH-antagonist cycle? A pilot study

GnRH-antagonist protocols shorten the treatment period and reduce inconvenience for IVF patients. This randomised controlled trial (RCT) further explored whether low-dose hCG can be used clinically to replace recombinant FSH (rFSH) during the late follicular phase in a GnRH-antagonist protocol. Seventy ICSI patients undergoing controlled ovarian stimulation (COS) in a GnRH-antagonist protocol was randomized into two groups. The control group received a standard treatment with rFSH (Puregon) plus a GnRH-antagonist, daily from Day 6 of stimulation. In the study group, rFSH was discontinued when six follicles >or=12 mm were observed and estradiol levels were >600 ng/l; rFSH was subsequently replaced by low-dose hCG (200 IU/l daily). Mean values (SD) for dose and duration of rFSH treatment in the control versus low-dose hCG group were 1617 (280) versus 1273 (260) IU rFSH [between-group difference -344, 95% confidence interval (CI) -483 to -205; P < 0.001], and 8.2 (1.6) versus 6.4 (1.3) days (-1.8, -2.6 to -1.1; P < 0.001), respectively. The mean number of metaphase II oocytes of 10.1 versus 8.9 (between-group difference -1.2, 95% CI -3.9 to 1.5) and the ongoing pregnancy rates of 10/35 (29%) versus 13/35 (37%) (between-group difference 8.6%; 95% CI -13.0 to 29.1%; P = 0.45) for control versus hCG, respectively, did not differ. In this pilot trial, substitution of rFSH by low-dose hCG in the final days of COS leads to a reduction of FSH consumption whereas ICSI outcome, in terms of oocyte yield and ongoing pregnancy rate, remains comparable to the traditional regimen (ClinicalTrials.gov, trial number: NCT00750100).

Poor progression of day 3 embryos to blastocyst stage of development may be related to a paternal origin of anueploidy. A case report

OBJECTIVE: Male factor infertility has been shown to significantly reduce blastocyst production and the question remains whether this effect is caused by the paternal genome or other oocyte or laboratory factors. DESIGN: Case report. MATERIALS AND METHODS: A 40.5 - year old patient underwent 24 chromosome microarray-based aneuploidy screening. Thirty one oocytes were retrieved following ovarian stimulation using a down regulation protocol with Follistim and low dose hCG. The oocytes were denuded of cumulus cells with hyaluronidase 2 hours after retrieval followed by the insemination by ICSI of 26 metaphase II oocytes 4 hours later. Twenty two oocytes fertilized normally. 21 of these pronuclear embryos exhibited normal cleavage 24 hours later. On day 3 of growth; 4 embryos arrested, 4 embryos developed to the 4 cell stage and 13 embryos to the 8 cell stage. All cleaving embryos were placed into extended culture and assessed at day 5 of development for possible trophectoderm biopsy and analysis of biopsy tissue by mPGD. If these embryos were deemed normal after mPGD analysis, the normal embryos would then be cryopreserved and replaced in a subsequent frozen embryo transfer cycle. All other arrested embryos were processed as whole embryos for mPGD analysis. RESULTS: On day 5 of development, only two embryos had progressed to become morphologically normal expanded blasotcysts. They were cryopreserved for future attempts at conception after trophectoderm biopsy. The remaining 19 whole embryos were processed for mPGD analysis including 13 embryos that failed to develop in extended culture and 6 embryos that arrested at the morula stage of development. Of the 21 embryos evaluated by mPGD, 19 embryos were determined to be aneuploid including the two cryopreserved blastocyst embryos. Five of the arrested embryos were diagnosed as normal. Thirteen embryos were fingerprinted (11 arrested embryos and 2 frozen embryos). 100% of the errors from the arrested embryos were paternal in origin. 100% of the errors in the cryopreserved embryos which had normal morphologic development were maternal in origin. CONCLUSIONS: These data demonstrate that the male contribution to aneuploidy may be significant in some cases. The issue of differential impact of male and female chromosomal errors on embryonic development, particularly between day 3 and 5, deserves further systematic evaluation.

Different ovarian stimulation protocols for women with diminished ovarian reserve

To review the available treatments for women with significantly diminished ovarian reserve and assess the efficacy of different ovarian stimulation protocols. Literature research performed among studies that have been published in the Pubmed, in the Scopus Search Machine and in Cohrane database of systematic reviews. A lack of clear, uniform definition of the poor responders and a lack of large-scale randomized studies make data interpretation very difficult for precise conclusions. Optimistic data have been presented by the use of high doses of gonadotropins, flare up Gn RH-a protocol (standard or microdose), stop protocols, luteal onset of Gn RH-a and the short protocol. Natural cycle or a modified natural cycle seems to be an appropriate strategy. Low dose hCG in the first days of ovarian stimulation has promising results. Molecular biology tools (mutations, single nucleotide polymorphisms (SNPs)) have been also considered to assist the management of this group of patients. The ideal stimulation for these patients with diminished ovarian reserve remains a great challenge for the clinician, within the limits of our pharmaceutical quiver.

Does leutinizing hormone activity in the form of low-dose hCG or hmg produce better outcomes for GnRH antagonist art cycles stimulated with rFSH?

The objective of the study is to determine if the addition of LH activity in the form of low-dose hCG or HMG to controlled ovarian hyperstimulation with exogenous rFSH offers any advantage over stimulation with rFSH alone in woman with a normal prognosis.

Recombinant follicle-stimulating hormone (rFSH) supplemented with low-dose human chorionic gonadotropin compared with rFSH alone for ovarian stimulation for in vitro fertilization

Low-dose hCG supplementation was administered at the start of ovarian stimulation, concomitantly with recombinant FSH (rFSH) in GnRH antagonist cycles, and these were compared with GnRH-a cycles that used rFSH alone. The low-dose hCG group had similar implantation and pregnancy rates but had significantly reduced rFSH requirements, allowing for an average cost savings of $600 per cycle.

P-795: Effectiveness of using hMG-low dose hCG-GnRH antagonist protocol with unsuccessful hMG-GnRH antagonist protocol cases (full term pregnancies had not resulted) in-vitro fertilization (IVF) cycles

GnRH antagonist does not create flare-up effects such as are seen with GnRH agonist, and secretion of gonadotropin is immediately controllable. However, a decrease in the number or quality of oocytes extracted occurs as a result of the strong effects of GnRH antagonist in some cases. The purpose of our study was to consider what kind of results can be obtained by using hCG at 50 units from the day of GnRH antagonist use in cases that had not previously reached full term pregnancy using the hMG-GnRH antagonist protocol. Retrospective evaluation using the patient’s previous IVF stimulation attempts as a historical control. The subjects were 14 cases on whom IVF was carried out (28 cycles: 14 cycles with oral contraceptive pill-hMG-GnRH antagonist protocol and 14 cycles with oral contraceptive pill-hMG-low dose hCG-GnRH antagonist protocol). All the cases had been unsuccessful even though the antagonist protocol not using low dose hCG had been carried out (full term pregnancies had not resulted). Regarding the ovulation induction method, an oral contraceptive pill was used from day 3 of menstruation in the cycle prior to extracting the eggs. Ovarian stimulation was started from day 4 after completion of a course of oral contraceptive pills. In both antagonist protocols the type of ovulation induction drug was changed depending on the LH level just before beginning ovarian stimulation. When serum LH was more than 1.5mIU/ml, pure urinary FSH or recombinant FSH was used, and when serum LH was less than 1.5mIU/ml hMG (Humegon, Organon, Osaka) was used. Daily hypodermic injections of Cetrorelix 0.25 mg/day were started from the time the leading follicle reached 14 mm. The treatment regime was changed to hMG (Pergogreen:in a ratio of FSH and LH at one to one) from the day Cetrorelix was started. Urinary hCG at 50 units was used together with hMG from the day that use of Cetrorelix was started in the low dose hCG protocol. When the average diameter of the leading follicle reached 20 mm, the type of ovulation induction drug was changed to hCG at 10000 units. No statistical difference was noted between the two groups for the amount of hMG (no low dose hCG group 2680.4±1039.5 vs low dose hCG group 3235.7±1171.5). However, the mean number of oocytes retrieved was significantly higher in the low dose hCG group (no low dose hCG group 9.7±3.7 vs low dose hCG group 14.6±6.3, p<0.05). The fertilization rate was significantly higher in the low dose hCG group (no low dose hCG group 57.1% vs low dose hCG group 69.6%, p<0.05). The blastomere number on the day 3 was significantly higher in the low dose hCG group (no low dose hCG group 6.0±2.4 vs low dose hCG group 7.0±2.2, p<0.05). Moreover, the blastocyst formation rate was significantly higher in the low dose hCG group (no low dose hCG group 37.5% vs low dose hCG group 63.0%, p<0.05). No statistical difference was noted between the two groups for the clinical pregnancy rate (FHM) per ET (no low dose hCG group 7.7% vs low dose hCG group 33.3%). The results of this study suggest that increases in the number of oocytes extracted, the fertilization rate, the average number of day 3 blastomeres, and blastocyst formation rates can all be increased by using low dose hCG to control the overly strong effectiveness of GnRH antagonist in cases that had not reached full term pregnancy using the GnRH antagonist protocol.

P-745: Equivalence of human menopausal gonadotrophin (HMG) and dilute human chorionic gonadotropin (hCG) for luteinizing hormone (LH) activity in ovarian stimulation for in vitro fertilization

Although the role of LH is controversial, evidence suggests that downregulation protocols for controlled ovarian stimulation in IVF may benefit from a source of LH activity for adequate folliculogenesis. The best method to provide LH activity is unknown. In this study we compared ovarian stimulation outcomes for IVF cycles utilizing LH activity from hMG versus low dose hCG. Retrospective analysis. Records of IVF cycles using a stimulation protocol of FSH plus either HMG or dilute hCG were reviewed. Use of either HMG or low dose hCG varied among physicians within a large ART center according to physician preferences. Analysis was restricted to cycles using a long Lupron downregulation protocol to limit patient and treatment heterogeneity. Patient age, baseline FSH, E2 at trigger, stimulation length, oocyte number, mature oocyte number, cleaving embryo number, day 3 cell number and fragmentation, and number of embryos per transfer were compared between HMG and dilute hCG cycles by t-test. The percentages of cancelled retrievals and transfers, the percentage of transfers performed at the blastocyst stage, and clinical pregnancy rates were compared by chi-square analysis. A total of 474 cycles were identified for analysis (HMG n = 356, dilute hCG n = 118). Mean age (33.8 versus 34.5 years, p = 0.070) and baseline FSH (6.9 versus 7.2 IU/L, p = 0.15) were similar between the HMG and dilute hCG groups. Rates of cycle cancellation (9.6% versus 11.9%, p = 0.48) and transfer cancellation (2.5% versus 2.9%, p = 0.82) were similar between the two groups. A similar proportion of transfers were conducted at the blastocyst stage between the two groups (49.4% versus 51.5%). The two groups did not differ in E2 at trigger, stimulation length, numbers of oocytes or embryos, embryo cell numbers or fragmentation on day 3, or numbers of embryos transferred (Table). Clinical pregnancy rates were very similar between the two groups (49.7% versus 48.3%, p = 0.79).Tabled 1 Both protocols using either hMG or low dose hCG as the source of LH activity provided similar IVF cycle outcomes. Individual practitioners may prefer one source over another and may desire flexibility in selecting these different protocols based on clinical experience, patient preference, cost, or convenience.