C.A. Benadiva

Withholding gonadotropin administration is an effective alternative for the prevention of ovarian hyperstimulation syndrome

OBJECTIVE To evaluate the outcomes of IVF and the incidence of ovarian hyperstimulation syndrome (OHSS) after discontinuing gonadotropin therapy in patients at risk of developing OHSS by delaying hCG administration until a drop in serum E2 levels was observed. DESIGN Retrospective study. SETTING IVF program at a university center. INTERVENTIONS Gonadotropin administration was withheld in 22 patients (group 1) when their serum E2 level was > or = 3,000 pg/mL (conversion factor to SI unit, 3.671). Patients continued GnRH analogue injections daily, and hCG was administered when serum E2 levels dropped to < or = 3,000 pg/mL. Outcomes were compared with 26 patients (group 2) in whom embryo transfer was canceled and all embryos cryopreserved for transfer during a subsequent unstimulated cycle. MAIN OUTCOME MEASURES Outcomes of IVF and incidence of OHSS were compared in both groups of patients. In group 1, follicular and hormonal parameters before and after the coasting interval were compared in pregnant versus nonpregnant patients. In addition, serum hormonal profiles were evaluated daily during the coasting period to determine the effects of gonadotropin withdrawal. RESULTS Although the mean number of oocytes retrieved was significantly higher in group 2, fertilization rates, miscarriage rates, delivery rates/stimulation cycle, and the incidence of OHSS did not differ significantly between the two groups. CONCLUSION Withholding gonadotropin administration is an effective alternative to prevent the development of severe OHSS in a high-risk population. Although the risk of cancellation cannot be completely eliminated, this strategy can provide a high pregnancy rate without the need to repeat multiple frozen-thawed cycles.

Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization

OBJECTIVE To determine the role of endometrial sampling for identification and treatment of chronic endometritis (CE) in patients undergoing IVF-ET who repeatedly failed to conceive despite the transfer of good-quality embryos. DESIGN Retrospective chart review. SETTING University-based tertiary fertility center. PATIENT(S) Thirty-three patients with recurrent implantation failure (RIF) who underwent endometrial sampling and subsequent ET were analyzed based on immunohistochemically confirmed CE: CE present on biopsy (group 1; n = 10) and CE absent on biopsy (group 2; n = 23). Patients with RIF undergoing IVF cycles during the same time period who did not have endometrial sampling were used as controls (group 3; n = 485). INTERVENTION(S) Endometrial sampling for CE and subsequent antibiotic treatment in affected patients followed by another IVF-ET cycle. RESULT(S) Chronic endometritis was identified in 30.3% of patients with RIF. Group 1 had lower implantation rates (11.5%) in the IVF cycle following treatment than did group 2 and group 3 (32.7% and 20.3%, respectively). Clinical pregnancy and ongoing pregnancy rates were similar across groups. CONCLUSION(S) Recurrent implantation failure warrants investigation of CE as a contributing factor. Women demonstrating CE on endometrial sampling have lower implantation rates in a subsequent IVF-ET cycle; however, there were no differences in subsequent clinical pregnancy or ongoing pregnancy rates after successful antibiotic treatment.

Cortisol levels in human follicular fluid

This study shows that cortisol levels in follicular fluids in stimulated cycles were correlated with oocyte maturity and in vitro fertilizability. The levels were significantly higher than the concentrations found in spontaneous cycles. Our findings suggest that the presence of cortisol in follicular fluid may play a role in follicular development and oocyte maturation.

Dual trigger of oocyte maturation with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin to optimize live birth rates in high responders

OBJECTIVE To compare live birth rates after dual trigger of oocyte maturation with GnRH agonist (GnRHa) and low-dose hCG versus GnRHa alone in high responders with peak E(2) <4,000 pg/mL at risk of ovarian hyperstimulation syndrome (OHSS). DESIGN Retrospective cohort study. SETTING University-based tertiary-care fertility center. PATIENT(S) Patients <40 years old with peak E(2) <4,000 pg/mL at risk of OHSS who underwent IVF/intracytoplasmic sperm injection with GnRH antagonist protocol and triggered with GnRHa alone or GnRHa plus 1,000 IU hCG (dual trigger) for oocyte maturation. INTERVENTION(S) GnRHa alone versus dual trigger. MAIN OUTCOME MEASURE(S) Live birth, implantation, and clinical pregnancy rates and OHSS. RESULT(S) The dual-trigger group had a significantly higher live birth rate (52.9% vs. 30.9%), implantation rate (41.9% vs. 22.1%), and clinical pregnancy rate (58.8% vs. 36.8%) compared with the GnRHa trigger group. One case of mild OHSS occurred in the dual-trigger group, and there were no cases of OHSS in the GnRHa trigger group. CONCLUSION(S) Dual trigger of oocyte maturation with GnRHa and low-dose hCG in high responders with peak E(2) <4,000 pg/mL improves the probability of conception and live birth without increasing the risk of significant OHSS.

GnRH agonist to induce oocyte maturation during IVF in patients at high risk of OHSS

The aim of this retrospective study was to evaluate the effectiveness of gonadotrophin-releasing hormone agonist (GnRHa) to trigger oocyte maturation in patients with polycystic ovarian syndrome (PCOS) or previous high response. The outcome of ovarian stimulation and IVF in patients using GnRHa to trigger oocyte maturation after co-treatment with GnRH antagonist (study group) was compared with patients using human chorionic gonadotrophin (HCG) to trigger oocyte maturation after a dual pituitary suppression protocol with oral contraceptive pill (OCP) and GnRHa overlap (control group). All patients received intramuscular progesterone for luteal support but patients in the study group received additional supplementation with oestradiol patches. The mean number of oocytes, proportion of mature oocytes and fertilization rate were similar between the study and control groups. Implantation rate (38.6% versus 45.1%), clinical pregnancy rate (69.6% versus 60.9%) and delivery rate (62.5% versus 56.5%) were similar in the study and control groups respectively. There was one case of moderate ovarian hyperstimulation syndrome (OHSS) in the control group and none in the study group. GnRHa is effective in triggering oocyte maturation in patients with PCOS or previous high response. Further randomized studies are required to evaluate its effectiveness in the prevention of OHSS in this group of patients.

Dose of human menopausal gonadotropin influences the outcome of an in vitro fertilization program

This study compares outcomes of in vitro fertilization (IVF) in two groups of 57 patients when either 2 (group 1) or 3 (group 2) ampules of human menopausal gonadotropin (hMG) were administered daily. Treatment began on day 3 of the cycle and was discontinued when at least 2 follicles attained diameters greater than or equal to 1.5 cm. Human chorionic gonadotropin (hCG) was given either 24 or 48 hours after the last dose of hMG. Although serum estradiol levels were lower in group 1, the average number of oocytes retrieved (3.2 versus 2.9), fertilized (1.9 versus 2.0), and cleaved (1.7 versus 1.8) per completed cycle did not differ between groups 1 and 2. Likewise, the number of oocytes that fertilized abnormally was similar in both groups (0.5 versus 0.3/cycle). However, the number of atretic oocytes (0.03 versus 0.5/cycle) and the percent of oocytes recovered from the cul-de-sac (0 versus 7.2%) were significantly (P less than 0.05) lower in group 1. In group 1, administration of hCG 48 hours after the last dose of hMG was associated with a higher number of cleaving embryos (2.1 versus 1.5/cycle) and a higher pregnancy rate (34.8 versus 14.7%; P less than 0.05) when compared with injection at 24 hours. In group 2, the interval between hMG and hCG did not influence these results. Together, the associations between fewer oocytes that were atretic or recovered from the cul-de-sac, and a trend toward a higher pregnancy rate, suggest that follicular recruitment with 2 ampules of hMG is more appropriate than 3 ampules in an IVF program.

Ovarian response of individuals to different doses of human menopausal gonadotropin

Hormonal profiles were compared in 14 ovulatory women who were treated with two different doses of gonadotropins in successive in vitro fertilization cycles. All patients suffered from mechanical causes of infertility. Serum estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and progesterone (P) were measured daily during the follicular phase. Women were arbitrarily classified as high responders (E2 greater than 1000 pg/ml on the day of human chorionic gonadotropin administration, n = 8) or as low responders (E2 less than 1000 pg/ml, n = 6), according to the peak E2 levels during the cycle when they received 3 ampules of human menopausal gonadotropin (hMG). When patients were treated with 3 ampules of hMG, serum FSH, LH, and P concentrations increased significantly during the follicular phase in high responders but remained unchanged in low responders. When these patients were treated with 2 ampules of hMG, the temporal profiles of the hormones were similar, but the magnitude of increases in serum levels of gonadotropins and sex steroids was significantly reduced in high responders. The authors conclude that temporal individuality of endocrine profiles cannot be altered by varying the dose of gonadotropin. Increases in hormone levels accompanying a high response to hMG can, however, be dampened by lowering the dose. In contrast, hormone concentrations are not influenced by changing the dose of hMG in low responders.

In vitro fertilization versus tubal surgery: is pelvic reconstructive surgery obsolete?

OBJECTIVE To compare the results of pelvic reconstructive surgery with cumulative success rates of IVF for couples with tubal factor infertility. DATA RESOURCES Outcomes of pelvic surgery were obtained from a review of articles from the literature identified by directed Medline searches. Cumulative pregnancy rates of 771 couples with tubal factor infertility treated at the Cornell IVF program between December 1989 and December 1992 were calculated by life-table analysis. RESULTS Overall delivery rate per transfer for patients with tubal factor was 28.9% (303 deliveries per 1,048 transfers) and did not appear to be affected significantly by the presence of a secondary diagnosis. A significant decline in pregnancy rates was observed with advancing age: age < 30 years, 48.4%; 30 to 34 years, 44%; 35 to 38 years, 28%; 39 to 40 years, 20%; 41 to 42 years, 9%; and > 42 years, 4.3%. Cumulative pregnancy rates for cycles 1 to 4 were 32%, 59%, 70%, and 77%, respectively, in patients with only tubal factor, and 28%, 55%, 62%, and 75% in patients with tubal combined with other associated infertility factors. CONCLUSIONS Our experience suggest that > 70% of women with tubal factor infertility will have a live birth within four cycles of treatment with IVF. These results compare favorably with the best outcomes after tubal reconstructive surgery. In older women, because of the rapid decline of fertility potential with advancing age, efforts should be directed toward the treatment method that provides the highest likelihood of success within the shortest time interval.

Superovulation with human menopausal gonadotropins is associated with endometrial gland-stroma dyssynchrony *

OBJECTIVE To investigate the prevalence of endometrial inadequacy in endometrial biopsies from women undergoing superovulation with hMG and to correlate these findings with the hormonal milieu. DESIGN Controlled, retrospective analysis. SETTING University-based, tertiary referral, outpatient infertility clinic. SUBJECTS Endometrial biopsies were performed during the late luteal phase in 89 women undergoing hMG superovulation combined with IUI. Results were compared with the initial biopsies obtained as part of their routine infertility evaluation. MAIN OUTCOME MEASURES Biopsies were dated by two different observers using standard dating criteria. Serum samples obtained during the midluteal phase were assayed in duplicate for E2 and P levels using commercially available RIAs. RESULTS Fifty-seven percent of the endometrial biopsies showed differences in the dating of the glandular epithelium that differed by > 2 days when compared with the stroma. In contrast, only 13% of endometrial biopsies obtained during a nonstimulated cycle showed gland-stroma dyssynchrony. When cycles associated with gland-stroma dyssynchrony were compared with cycles associated with coordinated development of the glands and stroma, no significant differences were observed in E2 level on the day of hCG administration, midluteal serum P, midluteal E2 level, or P:E2 ratios. CONCLUSIONS This study demonstrates that when endometrial biopsies are obtained during the late luteal phase in patients undergoing ovarian hyperstimulation there is a significant dyssynchrony in the maturation of the glandular epithelium and the stroma. This may reflect the degree of responsiveness of an individual womans endometrium rather than a result of the hormonal milieu.

New algorithm for OHSS prevention

Ovarian hyperstimulation syndrome (OHSS) still remains a life-threatening complication of in vitro fertilization treatment (IVF), keeping patients and especially those, who previously experienced OHSS, from attempting infertility treatment and childbearing. The recent implementation of four new modalities: the GnRH antagonist protocol, GnRH agonist (GnRHa) triggering of ovulation, blastocyst transfer and embryo/oocyte vitrification, renders feasible the elimination of OHSS in connection with ovarian hyperstimulation for IVF treatment. The proposed current algorithm is based on the number of follicles developed after ovarian stimulation, setting a cut-off level at the development of 18 or more follicles. Further, fulfilling this criterion, the algorithm is based on four decision-making points: the final day of patient work-up, the day of triggering final oocyte maturation, day-1 post oocyte pick-up (OPU) and day-5 post OPU.If the physician decides to administer hCG for final oocyte maturation regardless the type of analogue used, he has the option on day-1 to either freeze all embryos or to proceed to day-5. On this day, based on the clinical condition of the patient, a decision should be made to either transfer a single blastocyst or to vitrify all blastocysts available. However, this strategy will not guarantee an OHSS free luteal phase especially if a pregnancy occurs. If the physician decides to trigger ovulation with GnRHa, feasible only with the antagonist protocol, embryos can be cultured until day-5. On this day a transfer can be performed with no risk of OHSS and spare blastocysts may be vitrified. Alternatively, on day-1 or day-2 post OPU, all embryos could be frozen.Hopefully, in a near future, GnRHa triggering and vitrification of oocytes will become everyday practice. Only the combined use of a GnRH antagonist protocol with GnRHa triggering and subsequent single blastocyst transfer or embryo/oocyte freezing will completely abolish the risk of OHSS after ovarian hyperstimulation.