Basal serum pituitary hormone levels and outcome of in vitro fertilization utilizing a flare nasal gonadotropin releasing hormone agonist and fixed low-dose follicle-stimulating hormone/human menopausal gonadotropin regimen

Day 2 serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are prognostic indicators in treatment with in vitro fertilization (IVF) and FSH is especially useful in predicting the ovarian response to superovulation.     

Comparison of the efficacy and safety of a new recombinant human follicle-stimulating hormone (DA-3801) with follitropin-alpha (Gonal-F) in women undergoing controlled ovarian hyperstimulation for assisted reproductive technology

AIM: To compare the efficacy and safety of a new recombinant human follicle-stimulating hormone (FSH; DA-3801) with follitropin-alpha (Gonal-F) in women undergoing controlled ovarian hyperstimulation (COH) for assisted reproductive technology (ART). METHODS: This was a phase III, multicenter, randomized, non-inferiority study. A total of 97 women were randomized to receive COH using DA-3801 (DA-3801 group, n = 49) or Gonal-F (Gonal-F group, n = 48). All subjects underwent COH using a gonadotropin-releasing hormone (GnRH) antagonist protocol. The primary efficacy endpoint was the number of oocytes retrieved, and the secondary efficacy endpoints included the total dose of FSH, the duration of stimulation, the serum estradiol levels on the day of human chorionic gonadotropin (hCG) administration, and the fertilization, implantation and pregnancy rates. Safety was evaluated using pre- and post-treatment laboratory tests and all adverse events were recorded. RESULTS: The number of oocytes retrieved was 13.0 +/- 6.2 (DA-3801) versus 10.6 +/- 6.7 (Gonal-F) in the intention-to-treat (ITT) population, and 12.7 +/- 6.4 (DA-3801) versus 11.0 +/- 7.1 (Gonal-F) in the per-protocol (PP) population. The non-inferiority of DA-3801 was demonstrated with differences of 2.3 +/- 6.5 (95% confidence interval [CI] = 0.13, infinity) and 1.7 +/- 6.7 (95% CI = -0.74, infinity), respectively, in the ITT and PP populations. The total dose of FSH used (1789.8 +/- 465.5 vs 2055.6 +/- 646.7 pg/mL, P = 0.027) and duration of stimulation (8.3 +/- 1.4 vs 9.1 +/- 1.9 days, P = 0.036) in the ITT population were significantly lower in the DA-3801 group. Other secondary efficacy endpoints, including pregnancy and implantation rates and the incidence and severity of adverse events, were comparable between the two groups. CONCLUSIONS: The results of this study demonstrate that DA-3801 is not inferior to follitropin-alpha in terms of its efficacy and safety in women undergoing COH for ART.     

Comparison of controlled ovarian stimulation with human menopausal gonadotropin or recombinant follicle-stimulating hormone

OBJECTIVE: To carefully examine the features of controlled ovarian stimulation performed with recombinant FSH-alpha or hMG. DESIGN: Controlled, prospective, randomized comparison of fixed gonadotropin regimens. SETTING: Academic research institution. PATIENT(S): Fifty infertile patients who were candidates for IUI. INTERVENTION(S): Patients were randomized to receive a fixed regimen of recombinant FSH-alpha (150 IU/day, 25 patients) or hMG (150 IU/day, 25 patients), after GnRH-agonist suppression (long regimen). MAIN OUTCOME MEASURES: Daily measurements of serum LH, immunoreactive FSH, hCG, E(2), P, and T. Transvaginal pelvic ultrasound every 2 days. Pregnancy and abortion rates. Cost of medications.Two recombinant FSH-alpha-treated patients did not respond. Despite matched daily FSH dose, duration of treatment (hMG 10.8 +/- 0.4 vs. recombinant FSH-alpha 12.4 +/- 0.5 days), gonadotropin dose (21.7 +/- 0.8 vs. 25.3 +/- 1.3 ampoules), gonadotropin cost (288 +/- 10 vs. 1,299 +/- 66 /cycle), serum P levels, and small preovulatory follicle number were significantly lower, and LH, hCG, immunoreactive FSH levels, and larger follicles on day 8 were significantly higher in hMG-treated patients. The pregnancy, abortion, and twin pregnancy rates did not differ. CONCLUSION: The hMG administration was associated with: [1]. increased serum LH activity and immunoreactive FSH levels during treatment; [2]. reduced signs of premature luteinization; [3]. differential modulation of folliculogenesis; [4]. lower treatment duration, gonadotropin dose, and cost; and [5]. clinical outcome comparable to recombinant FSH-alpha.     

Luteal estradiol administration strengthens the relationship between day 3 follicle-stimulating hormone and inhibin B levels and ovarian follicular status

OBJECTIVE: To investigate whether the prevention of early follicular growth by luteal E(2) administration improves the relationship between day 3 hormone measurements and the ovarian follicular status. DESIGN: Prospective, cohort study. SETTING: Assisted reproductive technology unit in Clamart, France. PATIENT(S): One hundred sixty-two infertile women. INTERVENTION(S): Participants received oral 17beta-E(2), 4 mg/day, from day 20 to the next cycle day 1 (n = 81) or served as controls (n = 81). Serum E(2), inhibin B, and FSH were measured during the 3 days after E(2) discontinuation (FD1, FD2, and FD3) in E(2)-treated women and on cycle day 3 (CD3) in controls. Early antral follicles were counted at ultrasound scans on FD3 and CD3. MAIN OUTCOME MEASURE(S): Hormonal-follicular correlations on FD3 and CD3. RESULT(S): As expected, after E(2) withdrawal, inhibin B and FSH increased from FD1 to FD3 whereas E(2) decreased. Correlations between FSH and inhibin B and follicular counts were stronger on FD3 than on CD3. CONCLUSION(S): Luteal E(2) administration notably strengthens the relationship between serum FSH and inhibin B levels and the number of antral follicles on day 3. This approach may represent an alternative test of ovarian follicular status.     

Effect of ovarian stimulation with recombinant follicle-stimulating hormone,gonadotropin releasing hormone antagonists,and human chorionic gonadotropin on endometrial maturation on the day of oocyte pick-up

OBJECTIVE: To assess the effect of ovarian stimulation with recombinant FSH, GnRH antagonists, and hCG on endometrial maturation on the day of oocyte pick-up. DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENT(S): Fifty-five women undergoing controlled ovarian hyperstimulation for IVF/intracytoplasmic sperm injection (ICSI). INTERVENTION(S): [1] Ovarian stimulation with recombinant FSH, starting on day 2 of the cycle and GnRH antagonist, starting after a median of 6 days of recombinant FSH stimulation (range, 5-12 days); [2] hCG administration for ovulation induction; and [3] aspirational biopsy of endometrium at oocyte pick-up. MAIN OUTCOME MEASURE(S): Endometrial histology at oocyte pick-up by Noyes criteria. RESULT(S): Advancement of endometrial maturation (2.5 +/- 0.1 days) as compared to the expected chronological date was observed in all antagonist cycles at oocyte retrieval. Endometrial advancement at oocyte pick-up increased in line with values of LH at initiation of stimulation and the duration of recombinant FSH treatment before the antagonist was started. CONCLUSION(S): The higher the values of LH at initiation of stimulation and the longer the duration of recombinant FSH treatment before the antagonist is started, the more advanced the endometrial maturation at oocyte pick-up.     

Recombinant follicle-stimulating hormone versus human menopausal gonadotropin in the late follicular phase during ovarian hyperstimulation for in vitro fertilization

OBJECTIVE: To study the effect of exogenous LH in the late follicular phase on ongoing pregnancies and at the different stages of IVF-ET (stimulation, fertilization, and implantation) in patients with low endogenous LH. DESIGN: Retrospective cohort study with modeling of the different phases of IVF-ET. SETTING: IVF center of the teaching hospital in Bordeaux, France. PATIENT(S): Women undergoing IVF and ICSI treatment. INTERVENTION(S): One group received recombinant FSH alone (FSH group) and the other received recombinant FSH and hMG in the late follicular phase (i.e., when the largest follicle reached 14 mm) (FSH/hMG group). MAIN OUTCOME MEASURE(S): Ongoing pregnancy, number of oocytes, and number of embryos.RESULT(S): The FSH/hMG group had a higher probability of having at least one oocyte (odds ratio [OR] = 2.75 [1.11-6.80]), of having at least one embryo after oocyte retrieval (OR = 2.84 [1.33-6.07]), and of ongoing pregnancy after ET (OR = 2.04 [0.83-5.01]), and globally had a higher probability of ongoing pregnancy (OR = 2.83 [1.19-6.71]). CONCLUSION(S): In ovarian hyperstimulation for IVF-ET, LH supplementation in the late follicular phase of women with low endogenous LH is beneficial for ongoing pregnancy by increasing the rate of success of all stages of the treatment.     

Substituting human chorionic gonadotropin by gonadotropin-releasing hormone agonist to trigger final follicular maturation,during controlled ovarian hyperstimulation,results in less systemic inflammation

Background.?To investigate the degree of systemic inflammation, as reflected by serum C-reactive protein (CRP) levels, associated with controlled ovarian hyperstimulation (COH) with human chorionic gonadotropin (hCG) or gonadotropin-releasing hormone (GnRH) agonist for the induction of final follicular maturation.

Design.?Prospective, observational study.

Setting.?An in vitro fertilization (IVF) unit of an academic medical center.

Patients.?Twenty-four women undergoing COH and IVF with the flexible GnRH antagonist protocol were prospectively assigned to receive hCG or GnRH agonist for the induction of final follicular maturation.

Methods.?Blood was drawn three times during COH for measurement of sex-steroid and CRP levels: the day on which adequate suppression was obtained (Day-0); the day of or prior to administration of hCG (Day-hCG); and (3) the day of ovum pick-up (Day-OPU). Levels were compared among the three time points in the two groups.

Results.?No between-group differences were observed in terms of patient age, gonadotropin dosage, duration of stimulation or number of oocytes retrieved. Serum CRP levels were significantly higher on Day-OPU than on Day-hCG and Day-0, but the difference was significant only in the hCG group (p<0.03 for both). The percentage change in CRP levels after hCG administration (Day-OPU vs. Day-hCG) (96%) was higher than that after GnRH administration (23%).

Conclusion.?Administration of GnRH agonist in patients undergoing COH for IVF yields a lesser degree of systemic inflammation, as reflected by CRP levels, than hCG.     

The clinical efficacy and efficiency of a 100-IU starting dose of recombinant follicle stimulating hormone (Puregon) in Korean women undergoing in vitro fertilization and embryo transfer

AIM: A prospective, non-comparative study was conducted to evaluate the efficacy and efficiency of a starting dose of 100 IU recombinant follicle stimulating hormone (rhFSH, Puregon) in women undergoing ovarian stimulation prior to in vitro fertilization (IVF). METHODS: A total of 40 women were down-regulated with gonadotropin releasing hormone agonist (long protocol), then treated with a fixed dose of 100 IU rhFSH for the first 4 days, and the dose of gonadotropin administration was adjusted according to patient's response thereafter. A maximum number of 3 embryos were transferred in 32 patients. RESULTS: Nine patients were treated with intracytoplasmic sperm injection, and 24 with conventional IVF. The duration of stimulation was 10.8 +/- 1.8 days, serum estradiol concentration on human chorionic gonadotropin day was 1693.0 +/- 1651.2 pg/mL, and 1480 +/- 450 IU rhFSH was used. A mean number of 8.4 +/- 5.7 oocytes were retrieved, 4.9 +/- 4.3 embryos obtained, 2.4 +/- 0.9 embryos transferred, and 3.5 +/- 3.2 embryos cryopreserved. The proportion of mature oocytes was 71.6%, and the fertilization rate was 86.4%. Clinical pregnancy was achieved in 8 patients (25.0%), and all of these pregnancies are ongoing or delivered. There were 3 cases of twin gestations (37.5%). The implantation rate was 13.1% (11/84). There was one case of moderate ovarian hyperstimulation syndrome, however, the patient recovered within 7 days without any complications. CONCLUSION: The starting dose of 100 IU rhFSH has a good safety profile, and is adequate in controlled ovarian hyperstimulation for IVF with a small amount of gonadotropin administered.     

Studies on the effects of initial injection doses of follicle stimulating hormone on the pregnancy and the ovarian hyperstimulation syndrome incidence in polycystic ovarian syndrome patients

Background:  Patients with polycystic ovarian syndrome (PCOS) are often resistant to clomiphene citrate, which causes the need for subsequent gonadotropin treatment. However, careful administration is required because of the potential side-effects, that is, ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy.
Methods:  Forty-three cycles in 22 patients with PCOS were enrolled in this study. Ovarian stimulation was initiated on day 7 of the menstrual cycle with 150 IU/day of follicle stimulating hormone (FSH; 150 IU course), 100 IU/day (100 IU course), and 75 IU/day (75 IU course), successively. If follicles over 12 mm in diameter did not develop after 1 week, the dose was increased. In each treatment course, the number of developed follicles, the serum estradiol level before ovulation, total FSH dosage and duration of administration, the incidence of OHSS, and pregnancy rate were examined.
Results and Conclusion:  The largest number of developed follicles and the highest serum estradiol level were found in the 150 IU course. In contrast, the total FSH dosage and duration of administration were highest and longest in the 75 IU course. The incidence of OHSS and pregnancy rate were highest in the 150 IU course and in the 75 IU course, respectively. The present study indicates that 100 IU or 75 IU of FSH is recommended as an initial injection dose for PCOS patients. (Reprod Med Biol 2003; 2 : 63–67)     

Hormone profiles under ovarian stimulation with human menopausal gonadotropin (hMG) and concomitant administration of the gonadotropin releasing hormone (GnRH)-antagonist Cetrorelix at different dosages

Purpose: The premature LH surge in ART programs seems to be avoided by daily administration of the GnRH-antagonist Cetrorelix during the midcycle phase in controlled ovarian hyperstimulation with hMG. The dosage necessary for sufficient suppression of the pituitary gland is not yet defined. Methods: To elucidate this question three daily dosages (3, 1, 0.5 mg) were administered and the hormone profiles obtained as well as the number of oocytes retrieved, the fertilization rate, and the consumption of HMG were compared. Results: No premature LH surge could be observed at any of the three dosages administered. Both gonadotropins were deeply suppressed. The fertilization rates of the oocytes obtained were 45.3% in the 3-mg group, 53.1% in the 1-mg group, and 67.7% in the 0.5-mg group. The average uses of hMG ampoules were 30 in the 3-mg group, 27 in the 1-mg group, and 26 in the 0.5-mg group. Conclusions: Cetrolix, 0.5 mg/day, administered during the midcycle phase of controlled ovarian hyperstimulation with hMG is enough to prevent completely the premature LH surge. Perhaps even lower dosages would be sufficient. Regarding fertilization rates and use of hMG, the lower dosage seems to be the most favorable.Presented in part at the IXth World Congress on In Vitro Fertilization and Alternate Assisted Reproduction, April 3–7, 1995, Vienna, Austria.     

Effect of urinary versus recombinant follicle-stimulating hormone on platelet function and other hemostatic variables in controlled ovarian hyperstimulation

OBJECTIVE: To determine the effect of urinary versus recombinant FSH on platelet function and hemostatic variables in women undergoing controlled ovarian hyperstimulation cycles. DESIGN: Randomized clinical study. SETTING: Major university-based infertility and in vitro fertilization unit and hemostasis laboratory. PATIENT(S): Ten healthy women (in vitro study), and 24 women undergoing routine controlled ovarian hyperstimulation cycles (in vivo study), randomly assigned to receive either urinary (u-FSH) or recombinant gonadotropin (r-FSH). INTERVENTION(S): In vitro study: effect of preincubation of plasma with u-FSH or r-FSH, in the presence or absence of estradiol, on platelet function and coagulation parameters. In vivo study: Changes in platelet function and coagulation parameters after treatment with u-FSH or r-FSH during controlled ovarian hyperstimulation cycles. MAIN OUTCOME MEASURE(S): Platelet aggregation and ATP release, activated protein C resistance ratio, free protein S. RESULT(S): In vitro study: Platelet aggregation and ATP release were significantly inhibited by u-FSH relative to r-FSH in both the presence and absence of estradiol (P=.047). In vivo study: Platelet function was significantly inhibited after treatment with u-FSH (P=.05) but not with r-FSH. In both studies, small changes of minor clinical significance were noted in activated protein C resistance and free protein S levels. CONCLUSION(S): The different platelet response to u-FSH and r-FSH may have clinical implications in selected patients, especially those at risk of thromboembolic complications, in decisions regarding the appropriate medication for controlled ovarian hyperstimulation cycles.     

Clinical outcomes of assisted reproductive technology treatment by using a self‐injection of recombinant human chorionic gonadotropin as the final maturation trigger

Purpose

To evaluate the efficacy and safety of self‐injections of the prefilled recombinant human chorionic gonadotropin (r‐hCG) in a syringe in assisted reproductive technology (ART) treatment for the maturation trigger (MT), as compared to self‐injections of conventional hCG and intranasal administration of gonadotropin‐releasing hormone agonist (GnRH‐a).

Methods

Between January and April, 2017, 396 patients who underwent oocyte retrieval were recruited. Of these, 396 patients were classified into three groups, according to the types of MT: (1) the urinary human chorionic gonadotropin (u‐hCG) group that consisted of patients who had a self‐injection of u‐hCG (n = 127); (2) the GnRH‐a group that received nasal administration of GnRH‐a (n = 159); and (3) the r‐hCG group that had a self‐injection of r‐hCG (n = 110). Several ART outcomes were evaluated.

Results

The mature oocyte retrieval rate was not different between the u‐hCG, r‐hCG, and GnRH‐a groups and the fertilization and cleavage rates were similar between the three groups. The clinical pregnancy rates did not significantly differ between the GnRH‐a group and the u‐hCG group; however, it was significantly lower in the GnRH‐a group, compared to the r‐hCG group. No difference was observed in the incidence of moderate or more severe ovarian hyperstimulation syndrome among the three groups.

Conclusion

The self‐injection of the prefilled r‐hCG is a favorable MT for ART patients.     

Reducing the dose of human chorionic gonadotropin in high responders does not affect the outcomes of in vitro fertilization

OBJECTIVE: The lowest effective hCG dose in high responders during IVF-embryo transfer (ET) has not been established. This study was performed to confirm that a dose of 3,300 IU is sufficient to provide adequate oocyte maturation and fertilization. DESIGN: Retrospective review of IVF clinical data. SETTING: Infertility center at a tertiary care university. PATIENT(S): Ninety-four IVF cycles were analyzed from high responders based on peak E(2) levels. Demographics were compared including age, diagnosis, and stimulation protocol. INTERVENTION(S): On the day of hCG administration, if E(2) levels were >/=2,500 but <4,000 pg/mL, patients received 5,000 IU (group A). For levels between 4,000 pg/mL and 5,500 IU pg/mL, they received 3,300 IU (group B). MAIN OUTCOME MEASURE(S): Number of oocytes retrieved, proportion of mature oocytes, fertilization rates, chemical and clinical pregnancy rates (PR). The incidence and severity of ovarian hyperstimulation syndrome (OHSS) was also analyzed. RESULT(S): Mean ages were 35.4 +/- 0.7 and 33.2 +/- 0.7 for groups A and B, respectively. Peak E(2) levels differed significantly (2,907 +/- 76 vs. 4,260 +/- 129 pg/mL), as well as the mean number of eggs retrieved (15.9 +/- 0.9 vs. 20.3 +/- 1.2). Proportion of mature eggs (81.6% vs. 81.9%), fertilization rate (70.5% vs. 68.7%), chemical PR (58.7% vs. 58.7%), and clinical PR (50.0% vs. 43.5%) were similar. There was no difference in the incidence of mild, moderate, or severe OHSS. CONCLUSION(S): A reduced hCG dose of 3,300 IU results in a similar proportion of mature eggs, similar fertilization rates, and similar PRs compared to 5,000 IU. Reducing the dose of hCG does not eliminate the risk of OHSS in a high-risk group.