Controlled Ovarian Hyperstimulation Protocol Research Articles

Ultrashort gonadotropin-releasing hormone agonist combined with flexible multidose gonadotropin-releasing hormone antagonist for poor responders in in vitro fertilization/embryo transfer programs

To evaluate the appropriate controlled ovarian hyperstimulation (COH) protocol in poor responders, we compared the stimulation characteristics of 21 cycles, which included the ultrashort gonadotropin-releasing hormone (GnRH) agonist combined with the flexible multidose GnRH antagonist, to the patients' previous failed in vitro fertilization attempts. The use of an ultrashort GnRH-agonist/GnRH-antagonist COH protocol resulted in a statistically significantly greater number of follicles larger than 14 mm on the day of hCG administration, a higher number of oocytes retrieved and embryos transferred, and a reasonable clinical pregnancy rate (14.3%).

Estradiol production during controlled ovarian hyperstimulation correlates with treatment outcome in women undergoing in vitro fertilization–embryo transfer

To study the value of E(2) production during controlled ovarian hyperstimulation (COH) in predicting IVF-ET outcome. Historical cohort. Academic infertility center. A cohort of 270 patients who completed 324 consecutive IVF-ET treatment cycles. None. Area under the curve for E(2) levels (AUC-E(2)) from the first day of COH until the day of hCG administration was calculated and cycles grouped into low, average, and high AUC-E(2) groups. Clinical pregnancy rates per cycle were compared among the three groups, and correlations with AUC-E(2) values were calculated for all patients and after sub-grouping according to age, COH protocol and infertility diagnosis. Cycles with low and high AUC-E(2) values had significantly lower pregnancy rates particularly in patients 35 years or older. There was a positive correlation between AUC-E(2) and pregnancy rates up to a certain AUC-E(2) level above which a negative correlation was found. The turning point between positive and negative correlations occurred at a significantly lower AUC-E(2) level in patients 35 years or older. Estradiol production during COH correlates with IVF-ET outcome. Women >35 years of age seem more vulnerable to high E(2) levels.

The in vitro maturation (IVM) of human oocytes for in vitro fertilization (IVF): is it time yet to switch to IVM-IVF?

The recent study by Li et al. observed that human oocytes from patients with polycystic ovary syndrome (PCOS) matured in vitro exhibited a higher proportion of abnormal spindle structures and disturbed chromosomal configurations compared with in vivo-matured oocytes from a control group of PCOS patients. This article discusses the obstacles that must be overcome and factors that must be monitored when attempting to optimize conditions for the in vitro maturation of human oocytes, with particular attention to the strengths and weaknesses of the study by Li et al.

Oocyte maturity and preimplantation development in relation to follicle diameter in gonadotropin-releasing hormone agonist or antagonist treatments

To analyze the distribution of oocytes nuclear maturational stages and intracytoplasmic sperm injection (ICSI) outcome in relation to follicular size, after controlled ovarian hyperstimulation (COH), using gonadotropin-releasing hormone (GnRH) antagonist or agonist protocols. Prospective comparative study. Fertility unit in an academic hospital. Normo-ovulatory patients with unexplained, male and/or tubal factor infertility undergoing ICSI treatment. Oocytes were retrieved from small (7-12 mm) and large follicles (>12 mm). Oocyte nuclear maturation stage, fertilization and pre-implantation embryonic development of the mature ova evaluated. Distribution of oocyte maturation stages from small follicles did not differ between the two COH protocols. From large follicles, a statistically significantly higher percentage of immature oocytes was retrieved after antagonist compared with agonist treatment (16 vs 11%, respectively). No statistically significant differences existed regarding ICSI outcome of mature ova within the same follicle diameter range between COH protocols. Inseminated ova from small follicles presented a significantly higher number of embryos with delayed development on day 3 after ICSI. A greater heterogeneity of maturity was found in the population of oocyte stages that were present after the antagonist protocol. Matured oocytes retrieved from small follicles generated embryos of lower developmental potential than oocytes derived from larger follicles.

The influence of urinary versus recombinant gonadotropin on serum P-selectin levels in vivo

Objective. To determine the levels of serum P-selectin in patients undergoing controlled ovarian hyperstimulation (COH) cycles with urinary (uGn) versus recombinant gonadotropins (rGn) and their possible correlation with COH variables.Methods. This study was carried out in a large university-based infertility and in vitro fertilization unit. A total of 14 consecutive patients underwent our routine COH protocol for unexplained infertility with either uGn or rGn. Blood was drawn three times during the COH cycle: on day 2 or 3 of the menstrual cycle and before gonadotropin treatment (day-0); on the day of or prior to human chorionic gonadotropin (hCG) administration (day-hCG); and on the day of ovulation (day-OVU). Levels of sex steroids and serum P-selectin were compared among the three time points between the uGn and rGn subgroups. P-selectin was measured with a commercial quantitative sandwich immunoassay technique.Results. In both Gn subgroups, there was a non-significant increase in P-selectin level between day-hCG and day-0. In the rGN subgroup, no significant difference was observed in P-selectin levels between day-OVU and day-hCG. In the uGn subgroup, P-selectin levels were significantly lower in day-OVU as compared to day-hCG (p < 0.04) and day-0 (p < 0.04). No differences were noted between the uGn and rGn subgroups in patient age, number of gonadotropin ampules used or estradiol and progesterone levels during the COH cycle or P-selectin on day-0 or day-hCG. However, on day-OVU, P-selectin levels were significantly lower in the uGn than the rGn subroups (p < 0.01).Conclusion. The increase in serum P-selectin level during COH until the peak of estradiol level was significantly attenuated after hCG administration in patients pretreated with uGn, but not rGN. It would therefore be prudent in patients at risk of developing thromboembolism undergoing COH to use uGN rather than rGN in order to attenuate platelet activation.

GnRH Agonist Versus GnRH Antagonist During Controlled Ovarian Hyperstimulation (COH): Is There an Effect on Oocyte Maturity and Aneuploidy?

Background: With the advent of GnRH antagonists, another option has become available to the Reproductive Endocrinologist in the individualization of COH protocols for each patient. The divergent mechanisms used to obtain the ultimate goal of preventing the premature LH surge by GnRH-agonist and GnRH-antagonist has implications on the resulting oocyte. This would have particular importance in patients 35 years and older, a population known to have limited numbers of available mature oocytes and at higher risk for aneuploidy.

Estradiol production during controlled ovarian hyperstimulation correlates with the risk of pregnancy loss in pregnancies achieved after IVF-ET

Several factors have been suggested to explain for the poor outcome of pregnancies achieved after in vitro fertilization (IVF-ET) compared to spontaneous pregnancies. These include maternal age, exposure of the gametes and embryos to in-vitro conditions as well as the infertility factor itself. Controlled ovarian hyperstimulation (COH) with the inevitably associated supraphysiologic estradiol (E2) levels, is believed to explain at least in part for the poor obstetric outcome after IVF-ET. The objective of this study was to study the value of E2levels attained during COH in correlating the risk for pregnancy loss after IVF-ET. Retrospective analysis of 236 consecutive pregnancies achieved after IVF-ET. E2production during COH has been calculated as area under the curve for E2levels (AUC-E2) from the first day of COH until the day of hCG administration. Correlation between E2 production and rate of pregnancy loss has been calculated for all pregnancies and after controlling for age, COH protocol, and infertility diagnosis. Correlations have been calculated for total AUC-E2and for AUC-E2per administered FSH (AUC-E2/FSH) and AUC-E2 per follicle (AUC-E2/Follicle), separately and after combining AUC-E2/FSH and AUC-E2/Follicle (combined formula calculated as AUC-E2/FSH over AUC-E2/Follicle). Pregnancy cycles have been divided into low, average and high groups according to E2 production (AUC-E2, AUC-E2/FSH, AUC-E2/Follicle and combined formula values). Rates of pregnancy loss have been compared among the three groups for all patients and after controlling for age, stimulation protocol and infertility factor. Both low and high AUC-E2values were associated with higher pregnancy loss. The group of average AUC-E2 has been associated with lowest risk for pregnancy loss. This was true for all pregnancy cycles combined together and after controlling for age, COH protocol and infertility diagnosis. AUC-E2/Follicle positively correlated with pregnancy loss while AUC-E2/FSH had a negative correlation. The combined formula had the strongest negative correlation with pregnancy loss. Estradiol production during COH correlates with the risk for pregnancy loss. Low E2 production may reflect reduced ovarian reserve with anticipated poor quality oocytes and higher pregnancy loss, while high E2 levels seem to be associated with higher pregnancy loss potentially due to possible deleterious effects on the endometrium, developing oocyte/embryo or other possible targets. Optimizing COH protocols to achieve optimum E2 levels may reduce pregnancy loss after IVF-ET.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Comparison of GnRH agonist and antagonist protocols for controlled ovarian hyperstimulation (COH) in poor response IVF patients

The cancellation rate in IVF cycles, due to poor response to COH, is reported to be up to 30%. Various COH protocols have been tried in poor responders, but no clear cut data exists to determine which protocols are the most appropriate. We compared two protocols for COH in poor responders with the objective of improving their stimulation and live birth rate.

Impact of controlled ovarian hyperstimulation on endometrial gene expression profiles during the window of implantation

Gene expression profiling of human endometrial receptivity has recently started and demonstrated that endometrial receptivity is an active process involving hundreds of up-/down-regulated genes. In the present work, we have investigated the impact of controlled ovarian hyperstimulation (COH) on endometrial gene expression in human endometrial receptivity. Endometrial samples were collected from ovum donors at days LH+2 (n=5) and LH+7 (n=5) as determined by urinary LH surge during a single natural cycle. Also, endometrial samples were obtained from the same patient at day LH+7 (n=5) of the natural cycle and at day hCG+7 (n=5) of the next cycle during COH used for IVF treatment. Genomic analysis of endometrial samples was performed using microarray technology. The protocol for ovarian stimulation consisted of a long protocol with leuprolide acetate with FSH/HP, hMG and hCG. Leuprolide acetate and gonadotropin injections were discontinued the day of hCG administration, and progesterone supplementation was not administered. Samples were hybridized onto the GeneChip HG_U133A (Affymetrix) encompassing more than 22,000 human DNA fragments, and the results were validated by RT-PCR and quantitative RT-PCR . Our study demonstrates that the gene expression in the COH hCG+7 samples is deregulated as compared to the natural cycle at LH+7. No luteal support was administered during COH for ovum donation, in order to get a clear comparison between natural and COH cycles. Genes regulated during the window of implantation in the natural cycle are more comparable with the LH+2 than with the LH+7 patterns in the COH cycle. This suggests a delay in the gene expression regulation that is required for the formation of a receptive endometrium in COH cycles. This remarkable finding justifies furthers research to identify COH protocols with minimal impact on endometrial development. Our study demonstrates that the gene expression in the COH hCG+7 samples is deregulated as compared to the natural cycle at LH+7. No luteal support was administered during COH for ovum donation, in order to get a clear comparison between natural and COH cycles. Genes regulated during the window of implantation in the natural cycle are more comparable with the LH+2 than with the LH+7 patterns in the COH cycle. This suggests a delay in the gene expression regulation that is required for the formation of a receptive endometrium in COH cycles. This remarkable finding justifies furthers research to identify COH protocols with minimal impact on endometrial development.

Novel long-acting human follicle stimulating hormone (FSH) analogue requires fewer injections than standard recombinant FSH during non-human primate ovarian hyperstimulation

Current recombinant gonadotropin preparations are administered as daily injections due to their relatively short half-life. Decreasing the frequency of administration would facilitate therapy and be more tolerable for the patient. We have developed a single chain recombinant human FSH (rhFSH) analogue with four additional N-linked glycosylation sites (rhFSH-N4) which in the murine model, has a prolonged half-life and greater in vivo bioactivity than commercially available rhFSH. In a previously reported controlled ovarian hyperstimulation (COH) trial in the baboon, 75 IU of rhFSH-N4 was shown to have a prolonged half-life of 48 hours, but failed to induce adequate follicular growth. The objective of this study was to induce folliculogenesis in the baboon using a single high-dose injection of rhFSH-N4 and to compare its effectiveness to daily rhFSH. Experimental study. COH was initiated in a multiparous, regularly cycling female baboon by administering a single 200 IU injection of rhFSH-N4 subcutaneously (SC) on the second day of her menstrual cycle. Concurrently, a second female baboon began daily SC injections of 75IU rhFSH also on day 2 of her menstrual cycle. Both baboons were monitored daily with serum estradiol (E2), luteinizing hormone (LH) and FSH levels. Pelvic ultrasound was performed under anesthesia (ketamine/xylazine) every other day throughout the cycle to monitor number and size of follicles. Once E2 levels plateaued in the baboon receiving rhFSH-N4, daily SC injections of 75 IU rhFSH were begun to maintain follicular growth during the COH cycle. Once E2 levels had peaked in both baboons, daily progesterone levels were added to detect spontaneous ovulation. Gonadotropin stimulation was terminated on cycle day 12, when no further increases in E2 levels or follicular growth could be detected. After a single high-dose injection of rhFSH-N4, serum FSH levels rose rapidly to a peak level of 17.9 mIU/mL, and gradually declined to a level of 7.2 mIU/mL by cycle day 7, at which point daily injections of 75 IU rhFSH were initiated (Fig. 1.) Estradiol levels mimicked the FSH levels, in that a single injection of rhFSH-N4 maintained elevated estradiol levels for six days before requiring additional daily rhFSH (Fig. 2.) Multiple follicular growth (4–7 follicles of >5mm diameter) was documented by ultrasound on cycle day 8 for both baboons. Neither baboon demonstrated an endogenous LH surge during the stimulation protocol, indicating the need for hCG to induce ovulation in future COH cycles. The use of a 200 IU loading dose of a novel, long-acting hFSH analogue, rhFSH-N4, in baboons as part of a modified human ovarian stimulation protocol was successful in recruitment of multiple follicles while requiring significantly fewer injections than commercially available rhFSH. Decreasing the number of daily injections is particularly advantageous for baboon COH protocols as it minimizes the amount of daily stress on the animal. Ultimately, use of a long-acting hFSH analogue could reduce the number of daily injections required of women undergoing ovarian hyperstimulation during in-vitro fertilization cycles.

Serum P-selectin level during controlled ovarian hyperstimulation--a preliminary report.

To measure levels of serum P-selectin in patients undergoing controlled ovarian hyperstimulation (COH) cycles and to determine their possible correlation to COH variables. Large university-based infertility and in vitro fertilization unit. Fourteen consecutive patients undergoing our routine COH protocol for unexplained infertility. Blood was drawn three times during the COH cycle: (1) day 2 or 3 of the menstrual cycle, before gonadotropin treatment (Day-0); (2) day of or prior to human chorionic gonadotropin (hCG) administration (Day-hCG); and (3) day of ovulation (Day-OVU). Serum levels of sex steroids and P-selectin were compared among the three time points. P-selectin was measured with a commercial quantitative sandwich immunoassay technique. To reduce interpatient variability, the percent difference between the Day-0 (non-stimulated, basal) level and the Day-hCG and Day-OVU levels was calculated. P-selectin level on Day-hCG was significantly higher than on Day-0 (P < 0.05) and non-significantly higher than on Day-OVU (P < 0.12). No significant correlations were observed between serum P-selectin and patient age, amount of gonadotropins used, or estradiol or progesterone level. The increase in serum P-selectin level during COH until peak estradiol suggests that COH may potentiate a state of platelet activation which is substantially attenuated after hCG administration.

Effect of controlled ovarian hyperstimulation in IVF on endometrial gene expression profiles

Controlled ovarian hyperstimulation (COH) used in IVF produces lower implantation rates per embryo transferred compared to natural cycles utilized in ovum donation, suggesting a suboptimal endometrial development. Endometrial receptivity has recently been investigated in natural menstrual cycles with the aid of microarray technology. The aim of this study is to investigate the impact of COH using urinary gonadotrophins with a long protocol with GnRH agonists without progesterone supplementation (similar to the natural cycle) on endometrial gene expression profiles during the window of implantation by comparing the profiles at day hCG + 7 of COH versus LH + 7 of a previous natural cycle in the same women. For this purpose we have used microarray technology by Affymetrix (GeneChip HG_U133A), which allows more than 22,000 genes to be tested simultaneously. Results were validated by semi-quantitative PCR and quantitative PCR experiments. We found that more than 200 genes showed a differential expression of more than 3-fold when COH and normal cycles were compared at hCG + 7 versus LH + 7. We simultaneously re-analysed the LH + 2 versus LH + 7 endometrial gene expression profiles in previous natural cycles in the same subject using this specific GeneChip, the results obtained were consistent with our own published results. This is the first time that gene expression profiles of the endometrium during COH are reported. The large degree of gene expression disturbance is surprising and highlights the need for further efforts to optimize COH protocols.

Use of a novel long-acting human follicle-stimulating hormone analogue containing four extra n-linked carbohydrates in the ovarian hyperstimulation of a female baboon

Objective: A single chain human follicle-stimulating hormone (FSH) analogue with four additional N-linked glycosylation sites (rhFSH-N4) has recently been shown to prolong elimination half-life (T1/2) and increase biopotency as compared to commercially available recombinant human FSH (rhFSH) in the murine model. Longer-acting gonadotropins may improve patient compliance and comfort by requiring fewer injections in women undergoing controlled ovarian hyperstimulation (COH) protocols for in vitro fertilization (IVF). Superovulation with rhFSH given daily and collection of oocytes via aspiration has been examined in the baboon. Use of rhFSH-N4 in baboons for the purpose of COH and collection of multiple oocytes via uterine lavage, as well as T1/2 determination of the analogue, were examined. Design: Experimental study. Materials and Methods: A multiparous, regularly cycling female baboon was chosen to undergo COH using experimental rhFSH-N4. Ovarian stimulation was initiated on day 1 of the menstrual cycle with a subcutaneous (SC) injection of rhFSH-N4 (75 IU). A 2nd dose of the rhFSH-N4 (75 IU) was given on day 5 when serum estradiol (E2) levels had plateaued. A GnRH antagonist (250μg SC) was given daily starting on day 6 until the day of hCG administration. Serum E2, FSH, and progesterone levels were measured daily. Pelvic ultrasound was performed under anesthesia (ketamine/xylazine) every other day to monitor number and size of follicles until hCG was given. Recombinant hCG (250μg SC) was given when majority of follicles were >5mm in diameter. 7 days post-ovulation, uterus was lavaged under anesthesia with 10ml of warm, sterile, isotonic, culture medium using a 27-g double-barreled cannula through the cervical canal to collect unfertilized oocytes. Results: Serum E2 levels started to rise on day 3 and plateaued after 5 days, requiring a 2nd dose of rhFSH-N4 to be given. Serum E2 peaked and plateaued by day 6–9 of stimulation. Follicular development was not observed until day 8–9. Majority of the follicles (n=7) increased to >5mm in diameter on day 10 when hCG was given. No oocytes were collected via uterine lavage 7 days post-ovulation. Serum FSH levels increased after each dose of rhFSH-N4, and its T1/2 was 48 hours. Serum progesterone levels followed a pattern consistent with ovulation after administration of hCG. Conclusions: Prolonged T1/2 of rhFSH-N4 in a primate species was confirmed. Use of rhFSH-N4 in baboons as part of a modified human COH protocol is successful in inducing follicular development as evident by increased E2 production and growing follicular size, while requiring fewer injections as compared to commercially available rhFSH. However, no oocytes were collected via uterine lavage. Protocol needs to be modified to account for the delayed tubal transport that may accompany hyperstimulation. Tubal lavage, although more invasive, may be considered to increase yield of oocyte collection if inadequate results persist despite delaying the time of uterine lavage. Once the problem of oocyte collection is cleared, the protocol can be modified to allow animals to be bred during the COH cycle with the goal of collecting multiple embryos to isolate baboon embryonic stem (ES) cells, which may provide an in vitro model of ES cell differentiation similar to human ES cells. Ultimately, use of a long-acting hFSH analogue for COH in women undergoing IVF may be beneficial by requiring fewer injections, thereby increasing comfort and compliance.

Recombinant FSH and pregnancy-associated plasma protein

Objectives: To evaluate the effect of rec-FSH on the ovarian follicular environment in controlled ovarian hyperstimulation (COH) cycle, we compared the expression of the markers that have been reported to reflect the follicle health. Study design: A total of 31 women (<35 years) with normal ovarian function were allocated to three different COH protocols (urinary FSH (u-FSH)+hMG, rec-FSH only, or u-FSH only). E 2, P4, leptin and IGF-I levels in serum or follicular fluid (FF) were measured with radioimmunoassay; cyclin D2, EGF receptor (EGF-R), and inhibin-α mRNA levels in luteinized granulosa cells were measured with RT-PCR; and IGFBP-4 and PAPP-A levels in FF were measured with Western blot analysis. Results: There were no significant differences in serum E 2, P4 and leptin levels and follicular leptin and IGF-I levels. Cyclin D2, EGF-R, and inhibin-α mRNA expression in luteinized granulosa cells were not different among three groups. However, follicular IGFBP-4 and PAPP-A levels in rec-FSH group were significantly higher than other groups ( P<0.05). Conclusions: The use of rec-FSH increases the expression of follicular PAPP-A reflecting IGFBP-4 proteolytic activity and it may influence positively the follicular environment.

In COH/IUI, Intermediate Follicles Are Better Predictors of Multiple Pregnancies Than Mature Follicles

Objective: Multiple pregnancies are the paramount complication of controlled ovarian hyperstimulation (COH), representing >25% of all pregnancies. In COH/IUI cycles, decision of cycle cancellation due to high risk of multiple pregnancy is commonly based on the number of mature follicles (≥16 mm) (Valbuena et al, 1996). Yet, for some authors no relationship exists between mature follicular count and multiple pregnancy rates (Dodson et al, 1988; Goldemberg et al, 1994) and intermediate follicular cohort (12–15 mm) has been shown to yield healthy oocytes (Nagai et al, 1997). Hence, to improve our capability for identify cycles at high risk of multiple pregnancies, we studied the relationships between intermediate and mature follicular cohorts and the number of gestational sacs obtained in COH cycles with IUI. Design: Retrospective study on relationships between the number intermediate and mature follicles and gestational sacs. Materials and Methods: We studied 252 consecutive conception COH/IUI cycles, leading to 187 single pregnancies (74%), 48 twin pregnancies (19%), and 17 triple pregnancies (7%) undertaken in 225 women, aged 19–40, between 1994 and 1999. COH protocols included clomiphene citrate + hMG (n=52), hMG (n=84), and GnRH-a + FSH (n=116). Follicular growth was monitored by serial serum E2 and follicular ultrasounds. hCG was administered when at least 1 follicle reached 16 mm in diameter. Conception cycles were sorted into 2 groups according to follicular sizes on the day of hCG administration: intermediate cohort (12–15 mm; n=721 follicles) and mature cohort (16–20 mm; n=591 follicles). Relationships were assessed by simple regression calculation. Results: The intermediate cohort correlated negatively with patients’ ages (r=−0.17; P<0.005), whereas mature cohort failed to correlate with age. Both follicular cohorts were strongly correlated with serum E2 levels on the day of hCG administration. (0.32; P<0.0001 and 0.38; P<0.0001), but the intermediate cohort showed a stronger correlation with the number of gestational sacs than the mature cohort (r=0.19; P<0.002 vs. r=0.14; P<0.04, respectively). Type of protocol did not influence intermediate or mature follicular count. Conclusion: 1. The observation that, in COH, intermediate follicular cohort is correlated with the number of gestational sacs confirms that 12–15 mm follicles can ovulate healthy oocytes. This leads us to revise our usual criteria of follicular maturation. 2. The positive correlation between intermediate follicular cohort and patients’ ages may be a reflection of the high responsiveness to COH and adequate ovarian reserve of young patients. 3. Intermediate follicular count is a better predictor of multiple pregnancies than the number of mature follicles and should be taken into account in the decision of cycle cancellation.

New approaches to ovarian stimulation.

Suppression of endogenous hormone production by gonadotrophin-releasing hormone (GnRH) agonists followed by controlled ovarian hyperstimulation (COH) with human gonadotrophins, especially the so-called 'long protocol' has developed from second-line into first-line therapy. Due to this attitude premature luteinization can be safely avoided, enhancing therapeutic efficacy. Recombinant preparations of human follicle stimulating hormone (FSH) have been proven to be effective within COH according to the long protocol. The high purity of these compounds may have clinical advantages. GnRH antagonists could be successfully introduced in COH protocols. Also, daily injections in the midcycle phase according to the 'Lübeck protocol', as single or only dual administrations around day 9 seem to abolish any premature LH rises. Due to their different pharmacological mode of action, based on a classic competitive receptor blockage GnRH antagonists avoid any flare-up period and allow ovarian stimulation to start within the spontaneous cycle. Pregnancy rates are comparable to those after long protocol stimulation. Combination of softer stimulation regimes like clomiphene citrate and low dose HMG with midcycle administration of GnRH antagonists may be the way to a cheap, safe and efficient ovarian stimulation. It seems to be high time for modest forms of ovarian stimulation, lowering burden and risk for our patients.

The Performance of Subcutaneously Injected Fertinex When Used as the Sole Gonadotropin for In Vitro Fertilization Stimulation

Objective: To assess the performance of Fertinex (urofollitropin; Serono Laboratories, Norwell, MA) in stimulating the development of multiple follicles and initiating subsequent pregnancy in patients undergoing controlled ovarian hyperstimulation (COH) for IVF. Design: Prospective observational study. Setting: Private assisted reproductive technology (ART) center. Patient(s): Ninety-three women who underwent an IVF cycle of COH in which Fertinex was used as the sole gonadotropin. Intervention(s): The COH protocol included Fertinex with leuprolide acetate down-regulation in the late luteal phase or the early follicular phase. Embryo transfer was performed after 3 days of culture. Main Outcome Measure(s): Stimulation parameters, embryologic data, and pregnancy rates (PRs). Result(s): Ninety-three patients underwent 97 cycles of COH, with a cancellation rate of 13.4%. The clinical PR was 42% per initiation, 49% per retrieval, and 51% per transfer. Shorter stimulation periods, lower estradiol levels either per follicle punctured or per oocyte retrieved, and slower embryo development were observed. Patients responded to Fertinex in three distinct stimulation patterns: escalating response with a peak estradiol level of ≤3,000 pg/mL, escalating response with a peak estradiol level of >3,000 pg/mL, or escalating response characterized by a drop in the estradiol level or a plateau before hCG administration. All three responses had similar PRs. Conclusion(s): Fertinex can be used successfully as the sole gonadotropin for COH in ART without compromising high PRs. Traditional estradiol response curves or cancellation criteria may not apply when Fertinex is used as the sole gonadotropin for COH in ART.

Poor fertilization may be related to oocyte or zona pellucida recognition defects specific to certain hyperstimulation regimens and limited to some males but not others: a case report

To determine if the controlled ovarian hyperstimulation (COH) regimen may cause sperm to appear subfertile only to improve considerably by changing the COH protocol. Case report with retrospective review of previous fertilization rates according to COH protocol used. Fertilization and pregnancy rates (PRs) after IVF-ET. Known fertile donor sperm failed to fertilize any of 11 oocytes compared with 14 of 18 for processed retrograde ejaculate using the same oocyte pool. Retrospective analysis of other cycles for different female patients but same donor found 16.6% fertilization rate whenever luteal phase leuprolide acetate (LA)-hMG regimen was used compared with 70.6% with short-flare regimen. Some COH regimens may cause oocyte or zona pellucida changes that create recognition defects for some sperm but not others. Interestingly, the sperm with the binding defect with the luteal phase LA-hMG COH protocol exhibited good fertilization rates with oocytes prepared with the short-flare protocol and demonstrated high in vivo PRs after IUI.

Angiotensin-converting enzyme inhibition reverses luteal phase steroid production in oocyte donors

To determine whether angiotensin-converting enzyme (ACE) inhibition would affect ovarian steroid synthesis in the oocyte donors undergoing controlled ovarian hyperstimulation (COH). The IVF program of the University of Southern California. Prospective matched clinical trial. Twelve oocyte donors were studied in 28 hyperstimulation cycles. Donors underwent a standard COH protocol. Follicle aspiration was performed 34 hours after administration of hCG. After the procedure, seven donors were administered the ACE inhibitor, captopril, 6.25 mg orally twice daily for 4 days. The remaining patients served as controls. Serum E2, P, plasma prorenin, active renin, and angiotensin II (Ang II). Angiotensin II increased after aspiration in both groups but was significantly lower in those receiving captopril. Peak P in the captopril group was significantly lower than controls (81.8 +/- 27.8 versus 208.5 +/- 23.9 ng/mL [conversion factor to SI unit, 3.180]). Peak E2 was significantly higher (2,222.4 +/- 875.3 versus 425.6 +/- 490.4 pg/mL [conversion factor to SI unit, 3.671]). Active renin and Ang II correlated with P. In stimulated cycles, inhibition of Ang II production appears to raise serum E2 and lower P levels. Angiotensin II, therefore, may have a role in the regulation of ovarian steroid synthesis.