Recombinant hCG Research Articles

Endometrial, subendometrial, and ovarian stromal blood flow in patients treated with two different doses of recombinant human chorionic gonadotropin

The effects of two different doses of recombinant hCG on blood flow to the uterus and ovary on the day of oocyte retrieval were studied by three-dimensional Doppler ultrasonography in 60 women during IVF treatment. There were no differences in all the indices of endometrial, subendometrial, and ovarian stromal blood flow in women who had received 250 microg or 500 microg of recombinant hCG for final oocyte maturation.

Vascular endothelial growth factor response to exogenous chorionic gonadotropic hormone in the luteal phase of women with a history of severe ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome (OHSS) is a severe complication of ovarian stimulation. No reliable test exists to predict the syndrome. The objective of the present prospective observational study was to examine vascular endothelial growth factor (VEGF) secretion after human chorionic gonadotropin (hCG) administration in the luteal phase of a spontaneous cycle of women with a history of severe OHSS. Five women with a history of severe OHSS were administered 250 mug recombinant hCG intravenously on day 21 of a spontaneous menstrual cycle. Plasma samples were collected at regular intervals from 15 min before hCG to 6 h thereafter and the free VEGF plasma concentrations were determined. Plasma levels of free VEGF remained at the lower detection limit of the assay throughout the observational period. Women with previous severe OHSS do not show a significant short-time response of VEGF secretion upon hCG administration. No evidence was found to support the notion that women inclined to develop a severe form of the syndrome after ovarian stimulation could possibly be identified by the VEGF short-time secretory response to exogenous hCG in the luteal phase of a spontaneous cycle.

Age-matched comparison of recombinant and urinary HCG for final follicular maturation

This age-matched retrospective analysis compared the clinical outcomes of recombinant human chorionic gonadotrophin (rHCG) and urinary HCG (uHCG) in patients undergoing fresh, nondonor IVF cycles. The patients underwent ovarian stimulation by standard gonadotrophin-releasing hormone (GnRH) agonist down-regulation or a GnRH antagonist protocol using recombinant FSH (rFSH) alone or in combination with human menopausal gonadotrophin. When two or more follicles had attained a mean diameter of 20 mm, follicular triggering was achieved with either Ovidrel® (rHCG) 250 μg SC or uHCG 10,000 IU IM. Patients receiving rHCG were considered subjects, and they were age-matched in a 1:2 ratio to patients receiving uHCG, who were designated as controls. The main outcome measures were number of oocytes retrieved, number of mature oocytes obtained, number of oocytes fertilized and clinical pregnancy rates. A total of 273 subjects were age-matched and compared with 546 controls. Recombinant HCG had a minimal effect on the number of oocytes retrieved (13.4 versus 13.2), mature oocytes (10.5 versus 10.3) and oocytes fertilized (8.2 versus 7.8) compared with uHCG. Pregnancy (46.0 versus 45.2%) and clinical pregnancy rates (38.1 versus 36.8%) were similar for rHCG and uHCG. Recombinant HCG was as effective as uHCG for final follicular maturation in IVF cycles.

Impact of a GnRH Antagonist (Ganirelix®) on the Outcome of Controlled Ovarian Hyperstimulation (COH) in PCOS Patients: A Prospective and Randomized Study

Impact of a GnRH Antagonist (Ganirelix®) on the Outcome of Controlled Ovarian Hyperstimulation (COH) in PCOS Patients: A Prospective and Randomized Study

A Comparison of Recombinant Follicule Stimulating Hormone (REC FSH) To Combination REC FSH Plus Human Menopausal Gonadotropin (HMG) in Gonadotropin Releasing Hormone (GNRH) Antagonist in Vitro Fertilization (IVF) Cycles

To evaluate the clinical outcomes of adding LH, as hMG, in GnRH antagonist protocols in younger versus older patients. Retrospective analysis comparing all patients undergoing assisted reproduction treated during 2001 through 2003 with GnRH antagonist protocols in a large group practice with a single IVF laboratory. A total of more than 1300 fresh, nondonor IVF cycles were available for analysis. These included a broad spectrum of patients presenting for assisted reproductive technologies. Protocols using a GnRH antagonist (Cextrorelix®, Serono, Inc., Rockland, MA or Ganarelix®, Organon, West Orange, NJ), were employed along with the administration of rec FSH (Follitropin-α, Serono or Follitropin-β, Organon) or rec FSH supplemented with hMG (Pergonal®, Serono or Repronex®, Ferring, Suffren, NY) in a large cohort of younger (<35 years old) versus older (≥35 years old) patients. Final follicular maturation was achieved with either urinary (10,000 IU im) or recombinant hCG (250 ug sc Ovidrel®, Serono) when 2 or more lead follicles had a minimum mean diameter of 20 mm. Oocyte retrieval was performed 35 hours after hCG injection. Standard laboratory protocols were followed, including intracytoplasmic sperm injection, assisted hatching for cleavage embryos, and extended culture for blastocyst transfer, as clinically appropriate. Ultrasound guided embryo transfer was performed and all patients received luteal progesterone support. Serum hCG levels were measured 15 days after retrieval, and a clinical pregnancy was defined as the presence of a gestational sac on ultrasound. The main outcome measures were oocytes retrieved and pregnancy rates for patients treated with rec FSH alone versus rec FSH plus hMG. Data were analyzed by multiple linear or logistic regression depending on type. A p<0.05 was considered statistically significant. As expected, fertility declined with age as assessed by multiple response variables (p < 0.0001). Patients treated with rec FSH alone had significantly more oocytes retrieved (+2.1, see Figure), mature oocytes (+2.2), oocytes fertilized (+1.9), embryos that cleaved (+1.5) and 6-cell embryos at day 3 of culture (+0.5) compared to patients treated with rec FSH+hMG. Rec FSH treatment yielded more oocytes, better embryo development and tended to increase pregnancy rates compared to treatment with rec FSH in combination with hMG. Although both FSH and LH are obligatory for follicular development in humans, exogenous hMG does not appear to be required or beneficial in most IVF patients given GnRH antagonists to block endogenous LH surges.

Comparison of Blastocyst Formation Between Standard and Clomiphene Citrate (CC) Stimulated In Vitro Fertilization (IVF) Cycles

Many studies have shown that single blastocyst transfer can achieve pregnancy rates comparable to that of multiple embryo transfer. Nonetheless controlled ovarian hyperstimulation (COS) with daily injection of gonadotropins designed to produce large numbers of eggs is the most commonly employed protocol in human IVF. The aim of current study is to determine whether a less expensive, minimal stimulation IVF protocol using clomiphene citrate (CC) in combination with a small addition of human menopausal gonadotropin (hMG), yielding only a modest number of eggs, will produce blastocysts with success rates similar to standard protocols which are designed to yield many eggs. Prospective and randomized. Patients enrolling for IVF were randomized into two groups. Both groups received one cycle of oral contraceptives (OCP’s) before commencement of IVF stimulation. Group 1, clomiphene citrate protocol (CC-IVF): daily clomiphene citrate 50 mg was initiated orally on day 3 after OCP’s until gonadotropin releasing hormone agonist (GnRHa) nasal spray (Synarel) was administered. hMG 150 IU subcutaneous(SQ) every 48 hours was begun on day 8. Group 2, microdose GnRHa (Lupron) flare protocol (Lupron-IVF): Lupron 25 mcg SQ was begun on cycle day 3 after OCP’s followed by daily recombinant follicle stimulating hormone (rFSH) 150-225 IU plus human menopausal gonadotropin (hMG) 75-150 IU SQ on day 5 after OCP’s. Final oocyte maturation was triggered by GnRHa nasal spray (Synarel) in the CC-IVF protocol, and by 250 mcg recombinant hCG in the Lupron-IVF protocol. Follicular development was monitored by transvaginal ultrasound as well as plasma estradiol and LH levels. All monitoring and oocyte retrievals were performed by the same physician and all IVF procedures were performed by the same embryology team within the same period of the time. Statistical analysis was performed using t-test and chi square analysis. As displayed in the table dramatically less gonadotropin was used in the CC-IVF cycles than the Lupron-IVF cycles. While the average numbers of oocytes obtained and subsequent number of blastocysts were higher in Lupron-IVF cycles, the blastocyst formation rate was similar between the CC-IVF cycles and the Leupron-IVF cycles. Tabled 1 The minimal stimulation protocol with clomiphene citrate and hMG produces fewer oocytes as compared with a standard protocol using daily injection of rFSH, hMG and GnRHa. However, the oocytes obtained from the minimal stimulation protocol have similar potential to generate blastocysts. Minimal stimulation simplifies IVF procedures, and reduces the incidence of hyperstimulation syndrome. Single blastocyst transfer with minimal ovarian stimulation will also reduce the risk of multiple pregnancy and its complications.

Urinary Human Chorionic Gonadotropin (hCG), Intramuscular or Subcutaneously Administered, Yields higher hCG Serum and Follicular Levels Than Recombinant hCG in Egg Donors

Benefits of easy and improved local tolerance of subcutaneous recombinant HCG (rhCG) administration has been widely reported. To evaluate and compare the efficacy and safety of 250 microg of recombinant hCG with 10,000 UI of urinary hCG (uhCG) in egg donors administered subcutaneously or intramuscularly. Prospective, randomized, double blind clinical trial. Sixty egg donors from November 2003 to June 2004 who underwent a controlled ovarian hyperstimulation (COH) in our clinic were included. Using a random number table, egg donors were randomized into one of three treatment arms. COH was followed by 10,000 IU uhCG injection, given intramuscularly (i.m.) (n=20) or subcutaneously (s.c.) (n=20), or 250 microg rhCG by s.c route (n=20). Only egg donors with body mass index below 32 and between 18 to 35 years old were accepted. There were no statistically significant differences in age or body mass index (BMI) among donors receiving uhCG or rhCG sc-im. Mean days of stimulation, total dose of gonadotrophins were similar in all groups. Mean number of oocytes retrieved per treatment group were similar as well as mean numbers of metaphase II oocytes retrieved. There were no differences between mean numbers of zygotes obtained in both groups. No patients with no oocytes retrieved were found. Implantation rate and pregnancy rate were similar in recipients. Serum oestradiol and progesterone levels were similar in all groups on day of oocyte retrieval and 5 days after hCG injection, as well as progesterone levels in follicular fluid. Statistically significant differences were found in hCG serum and follicular fluid levels between groups (* p < 0.01). No adverse events were registered by any patient receiving hCG by either injection method. Tabled 1 Recombinant and urinary hCG subcutaneously administered are effective and well tolerated in the induction of final follicular maturation and luteinization in egg donors. This investigation suggests that clinical use of uhCG by sc. is suitable for egg donors and could enhance the fulfilment. In addition, lower hCG serum and follicular levels were obtained with rhCG group and that could be considered in high responders with increased risk of ovarian hyperstimulation syndrome.

Triggering Ovulation by GnRH Agonist Leuprolide Acetate Does Not Adversely Affect the Number and Quality of the Oocytes as Compared to Recombinant hCG in Oocyte Donation Cycles

Triggering Ovulation by GnRH Agonist Leuprolide Acetate Does Not Adversely Affect the Number and Quality of the Oocytes as Compared to Recombinant hCG in Oocyte Donation Cycles

Follicular Fluid Profile After Stimulation With Highly Purified Menotropin and Recombinant FSH in IVF Cycles

To investigate the hormonal milieu in the follicles of women stimulated with highly purified menotropin or recombinant FSH while undergoing IVF treatment. Analysis of a large, randomized, open-label, assessor-blind, multicenter, multinational trial (MERIT) comparing two gonadotropin preparations in IVF cycles with the long GnRH agonist protocol. 731 ovulatory women with tubal factor, mild male factor, endometriosis stage I/II or unexplained infertility were downregulated with triptorelin 0.1 mg SC daily from the mid-luteal phase and randomised to either HP-hMG (MENOPUR, Ferring Pharmaceuticals) (n=363) or recombinant FSH (GONAL-F, Serono) (n=368). The starting dose was 225 IU SC for the first five days and thereafter dose adjustments of 75 IU were allowed not more frequently than every four days. Recombinant hCG 250 μg SC was administered when 3 or more follicles of 17 mm or greater were observed. Follicular fluid from at least one follicle of 17 mm or more was collected for 676 women (HP-hMG: 335, recombinant FSH: 341) and analysed centrally for FSH, LH, hCG, estradiol, progesterone, androstenedione, total testosterone, SHBG, insulin, inhibin A, inhibin B, VEGF and IGF-1. For each parameter, the treatment difference with 95% confidence interval and p-value was estimated based on a linear model of the ln-transformed data including treatment and age strata as the explanatory variables. The levels of FSH, LH, hCG and estradiol detected in the follicular fluid were significantly (p<0.0001) higher among women stimulated with HP-hMG compared to those exposed to recombinant FSH. Follicular levels of progesterone were significantly (p<0.0001) higher in the recombinant FSH group than in the HP-hMG group. Androstenedione and total testosterone were significantly (p<0.0001) higher with HP-hMG compared to recombinant FSH, while SHBG did not differ significantly, leading to significantly (p<0.0001) higher FAI levels in the HP-hMG group. The ratios of androstenedione / estradiol, total testosterone / estradiol and progesterone / estradiol were all significantly (p<0.0001) higher in the follicular fluid from women in the recombinant FSH group compared to the HP-hMG group. The follicular levels of insulin were not significantly different between the two groups. Concerning the inhibins, inhibin A was significantly (p<0.01) higher in the recombinant FSH group while inhibin B was significantly (p<0.001) higher in the HP-hMG group. The inhibin A / inhibin B ratio was significantly (p<0.0001) higher in the recombinant FSH group. The follicular level of VEGF was significantly (p<0.001) higher among women stimulated with recombinant FSH. The IGF-1 levels detected in the follicular fluid were not significantly different between treatment groups. Major differences in the follicular fluid endocrine profile exist between women stimulated with HP-hMG and those stimulated with recombinant FSH. The follicular micro-environment associated with gonadotropins containing LH-activity is more estrogenic than androgenic or progestogenic compared to that associated with preparations without LH activity. These distinct profiles may be of relevance for interpreting differences on embryo quality parameters.

Prediction of Ongoing Pregnancy in an IVF Cycle Based on Clinical, Sonographic and Endocrine Parameters at Baseline

To identify those baseline variables prior to stimulation that independently predict ongoing pregnancy in women undergoing IVF treatment. Analysis of a large, randomized, open-label, assessor-blind, multicenter, multinational trial (MERIT) comparing two gonadotropin preparations in IVF cycles with the long GnRH agonist protocol. Ongoing pregnancy data were collected from 731 ovulatory women with tubal factor, mild male factor, endometriosis stage I/II or unexplained infertility. Polycystic ovarian syndrome and poor response in previous cycles were exclusion criteria. All were downregulated with triptorelin 0.1 mg SC daily from the mid-luteal phase and randomised to either HP-hMG (MENOPUR, Ferring Pharmaceuticals) (n=363) or recombinant FSH (GONAL-F, Serono) (n=368). The starting dose was 225 IU SC for the first five days and thereafter dose adjustments of 75 IU were allowed not more frequently than every four days. Recombinant hCG 250 μg SC was administered when 3 or more follicles of 17 mm or greater were observed. Transfer of 1-2 embryos of pre-defined minimum quality criteria was done on Day 3. Ongoing pregnancy was defined as at least one viable fetus 10-11 weeks after embryo transfer. An analysis was made on the association between ongoing pregnancy and demographic (age, BMI, duration of menstrual cycle), infertility history (duration, previous treatments, previous pregnancies, cause of infertility), sonographic (antral follicles, ovarian volume, endometrial thickness) and endocrine (LH, FSH, progesterone, androstenedione, total testosterone, SHBG, FAI) data after downregulation, immediately before start of stimulation (day 1). The predictive value of each variable was summarised as an odds ratio (OR) of ongoing pregnancy with 95% confidence interval (CI). Significance testing was based on the Wald test. All variables with an indication of influence (regarded as a p-value < 0.1) in a univariate analysis were included in the multivariate analysis. The multivariate model was reduced stepwise and variables with p< 0.1 were kept in the final model. All results relate to the multivariate analysis. In the analysis of demographics and infertility history, age as well as primary cause and duration of infertility were significant predictors of ongoing pregnancy. Among the assessments made on day 1, endometrial thickness, serum total testosterone and duration of GnRH agonist before start of stimulation were significant predictors. Taking all variables before starting stimulation into account, age (p<0.05), primary cause of infertility (p<0.05), total testosterone (p<0.05) and endometrial thickness (p=0.07) were significant independent predictors. Women ≤ 29 and 30-34 years had increased chance of ongoing pregnancy compared to women 35-37 years of age, with an odds ratio of 2.71 (95% CI: 1.46-5.32) and 2.40 (95% CI: 1.33-4.62), respectively. Mild male or tubal factor resulted in decreased chance of ongoing pregnancy with an odds ratio of 0.40 (95% CI: 0.20-0.75) and 0.59 (95% CI: 0.40-0.88), respectively, compared to unexplained infertility. The odds were 0.54 (95% CI: 0.31-0.91) for total testosterone and 0.87 (95% CI: 0.73-1.01) for endometrial thickness. Age below 35 years, unexplained infertility and low total testosterone prior to starting stimulation are favorable prognostic factors for ongoing pregnancy in IVF cycles.

Early Cleavage Improves Ongoing Pregnancy Rate When Transferring Non-Top Quality Embryos in IVF Cycles

To evaluate the development potential of embryos with early cleavage into top quality embryos and the impact of early cleavage on ongoing pregnancy rates in women undergoing IVF treatment. Analysis of a large, randomized, open-label, assessor-blind, multicenter, multinational trial (MERIT) comparing two gonadotropin preparations in IVF cycles with the long GnRH agonist protocol. Embryo quality and ongoing pregnancy data were collected from 731 ovulatory women with tubal factor, mild male factor, endometriosis stage I/II or unexplained infertility. All were downregulated with triptorelin 0.1 mg SC daily from the mid-luteal phase and randomised to either HP-hMG (MENOPUR, Ferring Pharmaceuticals) (n=363) or recombinant FSH (GONAL-F, Serono) (n=368). The starting dose was 225 IU SC for the first five days and thereafter dose adjustments of 75 IU were allowed not more frequently than every four days. Recombinant hCG 250 μg SC was administered when 3 or more follicles of 17 mm or greater were observed. A total of 7535 oocytes were obtained. Embryo quality was evaluated at 28h, 44h and 68h (±1h) after standard IVF insemination locally at site and subsequently centrally by three independent embryologists based on digital images. All embryologists were blinded to treatment allocation and each others results. A top quality embryo was pre-defined as having 4-5 cells on Day 2, ≥ 7 cells of equal size and ≤ 20% fragmentation on Day 3 and no multinucleation. Transfer of 1-2 embryos of pre-defined quality criteria (minimum: ≥ 4 cells with no cleavage arrest and ≤ 20% fragmentation) was done on Day 3. Ongoing pregnancy was defined as at least one viable fetus 10-11 weeks after embryo transfer. The analysis was based on the central evaluation of embryos and included embryos for which individual outcome was determined, meaning all women with 0% or 100% ongoing implantation rate after single or double embryo transfer. A total of 1123 embryos were 2-cells at 28h based on the central evaluation. Embryos with 2-cells at 28h had a significantly (p<0.001) higher chance of developing into a top quality embryo (32%) compared to those embryos that were not 2-cells at 28h (5%). The ongoing pregnancy rate for women with transfer of top quality embryos was 39% with early cleaved embryos (2-cell at 28h) and 40% with not early cleaved embryos. Concerning non-top quality embryos, the ongoing pregnancy rate was 35% for women with transfer of early cleaved embryos which was significantly (p<0.05) higher than the 19% observed for embryos with no early cleavage. Among single embryo transfers, the ongoing pregnancy rate/implantation rate was 17% for embryos that were 1-cell at 28h compared to 36% for 2-cell embryos (p<0.05). For women with double-embryo transfer, the ongoing pregnancy rate was 36% when both embryos transferred were 2-cells at 28h and 29% when both embryos were 1-cells. Embryos that reach the 2-cells stage at 28h after insemination have a significantly higher chance of developing into top quality embryos. Information on early cleavage will not increase pregnancy rates when transferring top quality embryos on Day 3, but will dramatically increase the pregnancy rates if the embryo transferred is of non-top quality.

Prediction of Ongoing Pregnancy in an IVF Cycle Based on Embryo Quality Parameters

To identify those embryo quality parameters that independently predict ongoing pregnancy in women undergoing IVF treatment. Analysis of a large, randomized, open-label, assessor-blind, multicenter, multinational trial (MERIT) comparing two gonadotropin preparations in IVF cycles with the long GnRH agonist protocol. Embryo quality and ongoing pregnancy data were collected from 731 ovulatory women with tubal factor, mild male factor, endometriosis stage I/II or unexplained infertility. All were downregulated with triptorelin 0.1 mg SC daily from the mid-luteal phase and randomised to either HP-hMG (MENOPUR, Ferring Pharmaceuticals) (n=363) or recombinant FSH (GONAL-F, Serono) (n=368) with a starting dose of 225 IU SC for the first five days. Recombinant hCG 250 μg SC was administered when 3 or more follicles of 17 mm or greater were observed. Embryo quality was evaluated at 28h, 44h and 68h (±1h) after standard IVF insemination locally at site and subsequently centrally by three independent embryologists based on digital images. All embryologists were blinded to treatment allocation and each others results. Transfer of 1-2 embryos of pre-defined quality criteria (minimum: ≥ 4 cells with no cleavage arrest and ≤ 20% fragmentation) was done on Day 3. Ongoing pregnancy was defined as at least one viable fetus 10-11 weeks after embryo transfer. The predictive value of cell number, blastomere uniformity, degree of fragmentation, localisation of fragments, cytoplasmic appearance and multinucleation on ongoing pregnancy was investigated. The analysis included embryos for which individual outcome was determined, meaning all women with 0% or 100% ongoing implantation rate after single or double embryo transfer.The influence of each variable was summarised as an odds ratio with 95% confidence interval (CI). Significance testing was based on the Wald test. All variables with an indication of influence (regarded as a p-value < 0.1) in a univariate analysis were included in the multivariate analysis. The multivariate model was reduced stepwise and variables with p< 0.1 were kept in the final model. All results relate to the multivariate analysis. The final model revealed three significant (p< 0.05) independent predictors of ongoing pregnancy: cell number and blastomere uniformity at 44h and cell number at 68h. Embryos with < 4 cells at 44h had an odds ratio of ongoing pregnancy of 0.73 (95% CI: 0.64-0.83) compared to embryos at the 4-5 cell stage. Embryos with > 5 cells at 44h also had a reduced odds ratio compared to 4-5 cells, but not significant. Embryos with equally sized blastomeres at 44h had an odds ratio of ongoing pregnancy of 1.13 (95% CI: 1.02-1.25) relative to those with unequally sized blastomeres. At 68h, embryos with < 7 cells and embryos with > 8 cells had reduced odds of ongoing pregnancy compared to embryos with 7-8 cells. The odds ratio was 0.82 (95% CI: 0.72-0.93) for embryos with < 7 cells and 0.77 (0.64-0.92) for embryos with > 8 cells relative to embryos with 7-8 cells at 68h. Transfer of embryos that had 4-5 cells of equal size at 44h and 7-8 cells at 68h resulted in an ongoing pregnancy rate of 25%, while transfer of embryos that did not fulfil any of these criteria yielded a rate of 2%. Cell number at 44h and 68h as well as blastomere uniformity at 44h are independent predictors of ongoing pregnancy when transferring embryos on Day 3.

In Vivo Infusion of Interleukin-1β and Chorionic Gonadotropin Induces Endometrial Changes that Mimic Early Pregnancy Events in the Baboon

Both human chorionic gonadotropin (hCG) and IL-1beta induce changes in the endometrium that are associated with the establishment of pregnancy. We investigated the synergistic effect of these two embryonic signals on endometrial function using a baboon model of simulated pregnancy. Recombinant hCG (30 IU/d) was infused between d 6 and 10 post ovulation (PO) to mimic blastocyst transit. On the expected day of implantation (d 10 PO), IL-1beta (12 ng/d) or IL-1 receptor antagonist (IL-1Ra; 12 ng/d) was infused for an additional 5 d. Endometria were harvested on d 15 PO. Both hCG and hCG plus IL-1beta induced marked differences in the distribution of alpha-smooth muscle actin, proliferation marker Ki67, decidualization marker IGF-binding protein-1, and cyclooxygenase-1. The most marked effect of IL-1beta was the induction of IGF-binding protein-1 protein in stromal cells close to the apical surface, whereas cyclooxygenase-1 was down-regulated in the glandular epithelium. Protein arrays of uterine flushings showed significant suppression of death receptors, Fas and TNF receptor 1, in the hCG- with or without IL-1beta-treated groups, suggesting an inhibition of apoptosis. Additionally, cytotoxic T lymphocyte antigen-4, matrix metalloproteinase-3, and IL-4 were suppressed in treated animals compared with controls. However, no differences were observed in cytokine profile between hCG-treated and hCG- plus IL-1beta-treated baboons. This study confirms that in preparation for pregnancy, the primate endometrium undergoes both morphological and functional changes, which are modulated by hCG and IL-1beta, that lead to the inhibition of apoptosis and the development of an immunotolerant environment. These changes suggest that infusion of IL-1beta at the time of implantation into the nonpregnant baboon treated with hCG synergizes with hCG and mimics the early endometrial events associated with the presence of an embryo.

A Prospective, Randomized, Double-Blind Study to Compare Two Doses of Recombinant Human Chorionic Gonadotropin in Inducing Final Oocyte Maturity and the Hormonal Profile during the Luteal Phase

Different doses of human chorionic gonadotropin (hCG) have been used in various in vitro fertilization (IVF) treatment protocols to achieve final oocyte maturation. There is as yet no agreement on the optimum dose required. The objective of this study was to compare the effectiveness of 250 and 500 microg recombinant hCG (r-hCG), which represented the lower and upper limits of the dose range, in inducing final oocyte maturation during IVF and intracytoplasmic sperm injection cycles. This was a prospective, randomized, double-blind study. This study was performed at an IVF clinic in a teaching hospital. Sixty patients with an indication for intracytoplasmic sperm injection were studied. The treatment dose used was 250 or 500 microg r-hCG. The percentage of metaphase II oocytes retrieved per patient, as an indicator of oocyte maturation, and the hormone profiles of the treatment cycle starting from the day of hCG up to hCG+10 d were the main outcome measures. The percentage of metaphase II oocytes was similar in the two groups (89.3% vs. 86.0%; P = 0.326) despite higher serum and follicular fluid hCG levels on hCG+2 and hCG+4 d, as was the follicular fluid to serum hCG ratio in the 500-microg r-hCG group. Serum estradiol and progesterone levels were comparable initially, but became significantly higher in the 500-microg r-hCG group on hCG+10 d. The two doses of r-hCG were equally effective in inducing final oocyte maturation. It remains unclear whether the higher midluteal estradiol and progesterone levels in the 500-microg r-hCG group confer any benefit.

Recombinant luteinizing hormone supplementation to recombinant follicle-stimulating hormone induced ovarian hyperstimulation in the GnRH-antagonist multiple-dose protocol

Suppression of endogenous LH production by mid-follicular phase GnRH-antagonist administration in controlled ovarian hyperstimulation protocol using recombinant (rec) FSH preparations void of LH activity may potentially affect ovarian response and the outcome of IVF treatment. The present study prospectively assessed the effect of using a combination of recFSH and recLH on ovarian stimulation parameters and treatment outcome in a fixed GnRH-antagonist multiple dose protocol. 127 infertile patients with an indication for IVF or ICSI were recruited and randomized (using sealed envelopes) to receive a starting dose of either 150 IU recFSH (follitropin alpha) or 150 IU recFSH plus 75 IU recLH (lutropin alpha) for ovarian hyperstimulation. GnRH-antagonist (Cetrorelix) 0.25 mg was administered daily from stimulation day 6 onwards up to and including the day of the administration of recombinant HCG (chorion gonadotropin alpha). Gonadotropin dose adjustments were allowed from stimulation day 6 onwards, HCG was administered as soon as three follicles > or =18 mm were present. The primary outcome parameter was treatment duration until administration of HCG. Exogenous LH did not shorten the time necessary to reach ovulation induction criteria. Serum estradiol (E(2)) and LH levels were significantly higher on the day of HCG administration in the recLH-supplemented group (1924.7 +/- 1256.4 vs 1488.3 +/- 824.0 pg/ml, P < 0.03), and 2.1 +/- 1.4 vs 1.4 +/- 1.5 IU/l, P < 0.01, respectively). Except for higher E(2) and LH levels on the day of HCG administration, no positive trend in favour of additional LH was found as defined by treatment outcome parameters.

Recombinant versus urinary gonadotrophins for triggering ovulation in assisted conception

The objective of this systematic review was to assess the safety and efficacy of subcutaneous recombinant (r) HCG and high-dose rLH compared with intramuscular urinary (u) uHCG for inducing final oocyte maturation and triggering ovulation. We searched the Cochrane Menstrual Disorders and Subfertility Group trials register (August 27, 2003), the Cochrane Central Register of Controlled Trials (CENTRAL on The Cochrane Library, issue 4, 2003), MEDLINE (1966 to February 2004) and EMBASE (1980 to February 2004). Searches were not limited by language. The bibliographies of included and excluded trials and abstracts of major meetings were searched for additional trials. Authors and pharmaceutical companies were contacted for missing and unpublished data. Only truly randomized controlled trials (RCTs) were included. Assessment of inclusion/exclusion, quality assessment and data extraction were performed independently by at least two reviewers. Seven RCTs were identified, four comparing rHCG and uHCG and three comparing rhLH and uHCG. There was no statistically significant difference between rHCG and uHCG regarding the ongoing pregnancy/live birth rate [odds ratio (OR) 0.98; 95% confidence interval (CI) 0.69-1.39], clinical pregnancy rate, miscarriage rate or incidence of ovarian hyperstimulation syndrome (OHSS). There was no statistically significant difference between rhLH and uHCG regarding the ongoing pregnancy/live birth rate (OR 0.94; 95% CI 0.50-1.76), pregnancy rate, miscarriage rate or incidence of OHSS. rHCG was associated with a reduction in the incidence of local site reactions (OR 0.47; 95% CI 0.32-0.70). According to these data, there is no evidence of a difference in clinical outcomes between urinary and recombinant gonadotrophins used for induction of final follicular maturation. Additional factors should be considered when choosing gonadotrophin type, including safety, cost and drug availability.

Comparison between urinary and recombinant hCG during ovulation induction in IUI cycles: A prospective randomized clinical trial

Urinary and recombinant hCG have been studied and shown to have similar effects in the final stages of follicular maturation in IVF cycles. The objective of this study was to compare the effects of recombinant hCG to those of urinary hCG in IUI cycles for non-tubal infertility.

Preliminary experience comparing the efficiency of inhibitors of aromatase (Letrozole™) and clomiphene citrate (Serophene™) in controlled ovarian stimulation (COH) in a prospective clinical trial

To compare the efficacy of Letrozole and Serophene as adjuvants to gonadotropins in COH cycles combined with intrauterine insemination (IUI) therapy. Prospective cohort study in a tertiary teaching center. Twenty-eight patients undergoing IUI therapy received from day 3 to day 7 of the cycle either letrozole 2.5 mg/day (n=12) or Serophene 100 mg/day (n=16). All patients received 75 IU of recombinant follicle stimulating hormone (rFSH) starting on day 7 on stimulation until the day of hCG administration. Ovulation was triggered with recombinant hCG (250 mcg) when the leading follicle(s) reached 18 mm in diameter. A single IUI was performed 36 hours thereafter using a soft-pass insemination catheter (Cook™, Indiana, USA) in a 500 μL volume following wash/centrifugation in isolate medium. Only patients with over a 1-year unexplained infertility were included. Tubal patency was confirmed with hysterosalpingography and pelvis normality ascertained by laparoscopy. Couples with abnormal semen parameters were excluded from the study. There were no differences in demographic characteristics between groups. A very significantly lower peak serum estradiol level was observed in the group receiving letrozole + rFSH compared with Serophene + rFSH (914 ± 187 vs 1207 ± 309 pg/mL, respectively, P< 0.007). There was no differences in number of follicles (range of 1–5) There was no difference in endometrial thickness at the time of hCG administration among groups. The clinical pregnancy rate was similar between groups (23.2% vs 22.1% respectively). Inhibitors of aromatase appear to constitute a good alternative to clomiphene citrate in patients with unexplained infertility undergoing gonadotropin-stimulated COH cycles combined with IUI therapy.

Is recombinant hCG as efficient as urinary hCG in a routine use in an IVF/ICSI program ?

Is recombinant hCG as efficient as urinary hCG in a routine use in an IVF/ICSI program ?

Comparison between two protocols of ovarian stimulation using a depot formulation of GnRH-agonist and a fixed-dose regimen of recombinant FSH: A prospective randomized study

This study aims to compare 150 IU and 200 IU of recombinant FSH in a fixed-dose regimen in women undergoing assisted reproductive technology (ART) cycles, employing the long protocol of pituitary down-regulation with a depot formulation of GnRH agonist. Prospective and randomized study in a tertiary care institutional hospital. We studied 76 normo-ovulatory women with age less than 35 years old, undergoing ART cycles. After pituitary suppression with a single intramuscular administration of a GnRH agonist (Lupron® 3.75, Abbott, Brazil), patients were randomized to groups A and B. In group A (n = 40), ovarian stimulation was performed with a fixed dose of 150 IU of recombinant FSH (r-FSH, Puregon®, Organon, Brazil). In group B (n = 36), ovarian stimulation was performed with a fixed dose of 200 IU of r-FSH (Puregon® Organon, Brazil). In both groups, the fixed dose was maintained until hCG administration. When at least three follicles > 17 mm had developed, ovulation was triggered with 10,000 IU of hCG (Profasi®, Serono, Brazil) or 250 μg of recombinant hCG (Ovidrel® Serono, Brazil). Follicular aspiration was carried out 35–36 hours later. The cancellation rates, the total dose of r-FSH administered, the number of mature oocytes retrieved, fertilization rate and pregnancy rate determined by fetal heart, were evaluated in the two groups. For the statistical analysis, chi square test and Student’s t test were utilized when appropriate. Both treatment groups were comparable in demographic and infertility characteristics. In group A, 1 cycle was cancelled (2.5%) and in group B, 3 cycles were cancelled (8%). The cancellation rates were not statistically different in both groups (P > 0.05). The number of oocytes retrieved was similar in groups A and B. In group A, 225 oocytes were retrieved (mean: 7.03 per cycle) and in group B, 233 oocytes were collected (mean: 7.06 per cycle). The percentage of mature oocytes retrieved (91% in group A versus 87.1% in group B), the fertilization rate (69% in group A versus 74% in group B) and pregnancy rate per transfer (25.0% in group A versus 26.6% in group B), were not statistically different in both groups (P > 0.05). The mean dose of r-FSH administered was significantly higher in group B (1,620 ± 215 IU in group A versus 2,078 ± 275 in group B; P < 0.05). Our results show that a daily fixed dose of 150 IU r-FSH is as efficient as 200 IU in ART cycles, and is associated with lower gonadotropin dose and cost. We conclude that the dose of 150 IU r-FSH is more cost-effective and may be the dose of choice for ovarian stimulation in a fixed-dose regimen in normo-ovulatory women with age less than 35 years.