Ori M. Avrech

Superovulation before IVF by recombinant versus urinary human FSH (combined with a long GnRH analog protocol): A comparative study

PurposeGonal-F (Serono, Aubonne, Switzerland) is a recombinant human follicle stimulating hormone (FSH) synthesized in vitroby cells into which genes encoding for FSH subunits have been inserted. This preparation exhibits physiochemical, immunological, and pharmacological properties that bear great similarity to those of native human FSH. It has a high specific activity and can be administered subcutaneously. To compare the efficacy and safety of Gonal-F with those of urinary human FSH (Metrodin; Serono) in achieving superovulation for IVF purposes in a prospective, randomized study.MethodsTwenty infertile patients (normo-ovulatory healthy women) were recruited for the study and allocated at random to the Gonal-F or Metrodin groups. The treatment protocol consisted of pituitary down regulation by GnRH analog (Buserelin; Hoechst, Frankfurt, Germany) employing the “long” protocol initiated at the midluteal phase (900 μg/day, intranasal administration). Gonal-F (SC) or Metrodin (IM) was injected daily (225 IU/day) starting on cycle day 3. Dose adjustment was performed, when necessary, from cycle day 7.ResultsOf the 20 cycles analyzed, none was canceled due to poor response. No cases of adverse effects (including local intolerance) or ovarian hyperstimulation syndrome were recorded in either group. They did not differ significantly in the following treatment-dependent variables: hormone profile, duration of FSH treatment, total FSH dose required to achieve follicular maturation, and the number of oocytes retrieved, fertilized, and replaced.ConclusionsThese preliminary data concur with previous studies in demonstrating that Gonal-F is as effective and safe as Metrodin (when given in combination with a “long” protocol of GnRH analog) in inducing controlled ovarian hyperstimulation for IVF purposes. Its mode of administration (SC instead of IM) offers an additional advantage over the urinary human FSH.

Gonadotropin stimulation following GnRH-a priming for poor responders in in vitro fertilization-embryo transfer programs

The effect of gonadotropin-releasing hormone agonist (GnRH-a) administration before gonadotropin super-ovulation on the stimulation characteristics of poor responder patients was assessed in an in vitro fertilization (IVF) program. Thirty consecutive patients who had exhibited low ovarian response (fewer than four retrieved oocytes) in at least two previous IVF cycles (control cycles, n = 60), were eligible for the study. GnRH-a (nafarelin) was administered daily for 7–10 days from the mid-luteal phase of the previous cycle until the first day of menstruation. Menotropin treatment was commenced on cycle day 3 (with no additional GnRH-a) (study cycles, n = 39). A significantly higher number of oocytes was retrieved (p < 0.0002) and a higher number of embryos transferred (p < 0.003) in the study cycles than in the control cycles. No cases of premature luteinizing hormone surge were recorded. Pregnancy rates per embryo transfer and per cycle were 10.4% and 7.7% for the study cycles and 2.8% and 1.6% for the control cycles, respectively. GnRH-a, administered prior to gonadotropin treatment, should be an additional option of ovulation induction protocol for poor responders in IVF programs.

Treatment variables in relation to oocyte maturation: lessons from a clinical micromanipulation-assisted in vitro fertilization program.

Objective: In an effort to understand the mechanism underlying the improved pregnancy rate observed in IVF cycles when gonadotropin-releasing hormone analogues (GnRH-a) are applied, we investigated a possible relationship between treatment variables and oocyte-nuclear maturity.Design: Nuclear maturity was retrospectively assessed in cumulus-free, denuded oocytes, obtained from women undergoing micromanipulation-assisted IVF treatment following controlled ovarian hyperstimulation with GnRH-a and menotropins.Setting: The setting was the infertility and IVF unit of a tertiary academic medical center.Participants: Two hundred twenty-one patients underwent 435 treatment cycles.Main Outcome Measure: This was the proportion of germinal vesicle-intact immature (GVII) oocytes.Results: One hundred fifty-four of the 3520 oocytes studied (4.4%) were in the GVII stage. These oocytes were found in 66 of the treatment cycles (15.2%) and in 54 of the patients (24.4%). Cycles in which GVII oocytes were detected did not differ from those in which all the aspirated oocytes were mature in the following respects: patient age, type and duration of infertility, controlled ovarian hyperstimulation protocol and time of ovum pickup. However, the GVII group was characterized by a significantly higher peak estradiol level, as well as a higher number of mature follicles visualized sonographically (diameter, >14 mm) and oocytes retrieved.Conclusions: Comparing the present findings with previously published data, it appears that the inclusion of GnRH-a in the stimulation regimen is associated with a lower proportion of immature oocytes. A higher occurrence of oocyte-nuclear immaturity is apparently associated with a significantly better ovarian response to stimulation. The high incidence of immature oocytes observed in patients with normospermic partners and low fertilization rates in previous cycles may suggest that the fertilization failure in some of these cases is due to oocyte, rather than sperm, dysfunction.

The initial flare-up induced by gonadotropin releasing hormone agonist may serve as a predictor of ovarian response in the current IVF-ET treatment cycle in normogonadotropic women aged 40-48 years.

AbstractObjective: Our purpose was to assess the potential role of the baseline hormone profile in combination with the initial pattern of response to gonadotropin releasing hormone (GnRH) analogue in predicting ovarian function and hence reproductive outcome in normogonadotropic patients aged 40 years or older undergoing IVF treatment. Patients and Methods: A retrospective analysis of 394 controlled ovarian hyperstimulation (COH) cycles that reached the stage of oocyte retrieval was conducted. The study included 163 normogonadotropic (serum FSH ≤15 IU/L) patients aged between 40 and 48 years who had regular menstrual cycles. Superovulation was achieved using menotropins in combination with GnRH analog (short protocol, beginning on menstrual day 2). The ovarian response was monitored on the third cycle day, the day following the first GnRH analogue administration. Results: Cycle distribution by patient age was 175 (44.4%), 122 (30.9%), and 97 (24.7%), while the patient distribution was 85 (52.2%), 48 (29.5%), and 30 (18.3%) for age groups 40–41, 42–43, and 44–48 years, respectively. The mean total dose of menotropins needed for optimal COH was 1787 IU (range, 600–6000 IU). This dose increased with age, while the yield of oocytes and embryos declined (P<0.05; ANOVA). A positive correlation was demonstrated between the E2 level on day 3 (GnRH analogue flare effect) and the outcome of the treatment cycle (number of oocytes and embryos). Using multiple stepwise regression analysis, it was demonstrated that the initial (day 3) serum E2 levels, combined with baseline FSH levels, patients age and body mass index enabled early prediction of the ovarian response in the current IVF-ET treatment cycle (oocytes=8.2−0.18×Age+0.17×BMI−0.12×FSH+0.0042×E2). Conclusions: Multiple-parameter analysis demonstrated that the use of the initial E2 response to GnRH analogue stimulation combined with basic clinical data may assist in the prediction of ovarian function and hence the reproductive outcome in normogonadotropic IVF patients aged 40 years or older. This may serve as a clinical tool for improving patient selection and treatment outcome in IVF-ET.

Inclusion of standard and low-dose gonadotropin releasing hormone-analog (short protocol) in controlled ovarian hyperstimulation regimens in normogonadotropic patients aged 40-48 years who are undergoing in vitro fertilization

We aimed to compare the efficiency of three controlled ovarian hyperstimulation protocols in achieving superovulation in normogonadotropic patients aged 40 years or more, who were undergoing in vitro fertilization (IVF) treatment. This was a prospective randomized clinical study, carried out in the Infertility and IVF Unit of an academic tertiary hospital. A total of 219 normogonadotropic patients (serum follicular stimulating hormone level < 15 mIU/ml) aged 40-48 years, with regular menstrual cycles, were randomly allocated to one of three short follicular protocols: menotropins only (group A), menotropins plus a mini-dose of gonadotropin releasing hormone (GnRH)-analog (600 μg/day) (group B), or menotropins plus a standard dose (900 μg/day) of a GnRH-analog (group C). Those cycles that reached the stage of oocyte retrieval (67, 70 and 71cycles, respectively) were analyzed. The mean daily dose of menotropins needed for ovarian stimulation was higher when GnRH-analog was used (groups B and C) (p < 0.02; ANOVA), although there was no significant difference in the time of human chorionic gonadotropin injection (average: cycle day 11). Peak estradiol levels (p < 0.02), number of oocytes retrieved (3.9, 5.4 and 5.5 oocytes/cycle, respectively, p < 0.02) and number of embryos transferred (1.6, 1.8 and 2.1 embryos/cycle, respectively, p < 0.05) were higher when GnRH-analog was included in the controlled ovarian hyperstimulation protocol. The IVF treatment resulted in 19 pregnancies (9.1% implantation rate), with a similar distribution among all three groups (11.9%, 8.6% and 7.0%). However, a higher miscarriage rate was noted in the menotropins-only group (67.5% vs. 33.3% and 40.0% of pregnancies). No differences were observed in any of the aforementioned variables between the mini-dose and standard dose GnRH-analog groups (groups B and C). In conclusion, controlled ovarian hyperstimulation before IVF treatment in normogonadotropic patients aged 40 years or more is more effective when a GnRH-analog (short protocol) is included in the treatment regimen. In this selected group of patients, reducing the daily dose of GnRH-analog does not improve the treatment results.

Is Diagnostic Testicular Fine Needle Aspiration Necessary in Azoospermic Men Before Sperm Aspiration/Extraction for Intracytoplasmic Sperm Injection Cycles?

AbstractPurpose: To determine whether diagnostic testicular fineneedle aspiration (TEFNA) sampling needs to be performedin azoospermic men prior to obtaining testicular sperm cellsfor IVF-ICSI procedures. Methods: Ten azoospermic patients underwent TEFNA in1993–1996. During 1997, all patients underwent testicularsperm aspiration (TESA) and/or testicular sperm extraction(TESE) to retrieve spermatozoa for IVF-ICSI cycles. Theresults of the two procedures performed in two separatehospitals were compared. Results: Diagnostic TEFNA revealed spermatozoa in fivepatients; identical results in four were found duringIVF-ICSI cycles. In three patients, only Sertoli cells were foundon TEFNA, in two of them TESA/TESE showed identicalresults, and in one, two spermatozoa were detected byCyto-SEM. In the remaining two patients, spermatids orspermatocytes were found on both procedures. Conclusions: There was a very good correlation betweenthe diagnostic and therapeutic procedures. We suggest thatin azoospermic patients, diagnostic TEFNA is valuable inorder to avoid unnecessary controlled ovarianhyperstimulation in the female partner for IVF. In patients in whomspermatozoa are detected, cryopreservation may beperformed for later IVF-ICSI cycles.

Serum P-selectin Level During Controlled Ovarian Hyperstimulation – a Preliminary Report

Objective:  To measure levels of serum P‐selectin in patients undergoing controlled ovarian hyperstimulation (COH) cycles and to determine their possible correlation to COH variables.